DD284005A5 - PROCESS FOR THE PREPARATION OF BENZAZEPINE AND BENZOTHIAZEPINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of benzazepine and benzothiazepine derivatives of general formula I and pharmaceutically acceptable salts thereof, wherein X represents one of the groups CH 2 or S; which is characterized by reacting a compound of general formula II in a solvent with a base and subsequently the compound thus obtained with a compound of the formula or a protected form thereof, wherein L is a leaving group such as a halogen or tosyloxy group, and optionally the product obtained is converted into a pharmaceutically acceptable salt. The above compounds are used in medicines with vasodilator effect. Formulas I, II {method; manufacture; Benzazepine derivatives; Benzothiazepine derivatives; pharmaceutically; salts; Base; protected form; Leaving group; tosyloxy; Drug; gefaeszerweiternd}

Description

Process for the preparation of benzazepine and benzothiazepine derivatives

Field of application of the invention ;

The application of the invention is in the field of drugs with vasodilator effect.

Characteristic of the known state of the art

Some starting materials for the preparation of the benzazepine and benzothiazepine derivatives of the invention are described in U.S. Patents 4,752,645, 4,748,239, 3,562,257 and 4,694,002.

Aim of the invention;

The aim of the invention is to provide new drugs with vasodilator effect.

Explanation of the essence of the invention;

The invention has for its object to provide new drugs with vasodilator effect, which are distinguished by their particular pharmaceutical activity compared to conventional compounds.

The invention relates to a process for the preparation of benzazepine and benzothiazepine derivatives of the general formula I.

and pharmaceutically acceptable salts thereof, wherein X represents one of the groups -CH ₂ - or -5-; R _{1 represents} one of the radicals -CH or -O-Y ₃ ; if X is the group -CH ₂ -ReSt, the radical R ₂

Sa) _n ,

CH-Y _C IN

H-CH

CH-Y, CH ₂ J _n , CH

.CH ₂ -CH ₂ Y ₅ -CH

< ^CH 2> n CH "

Y,

NY ₆ Y ₇

(CH ₂ J _n ,

CH- (CH,) ₇ Y _l4 , I ^ i ^ CH N-CH ₂

^Υ 6

15 (CH ₂ J _n ,

N "" NY ₆

(CH ₂ )

cder (CH ₂ J _n ,

N-Y

when X is the group -S-, R _{2 is} the balance

means;

(CH ₂ J _n , CH-CH

CH-CH I

^Y 6 ^Y 7

I fa:

CH-I

CH ₂ -CH ₂

CH ₂ - (CH ₂ J _n

^Y 6 ^Y 7 (CH ₂ J _n , CH

Y ₅ -CH

CtL

64 0 05

CH-Y, CH- (C

N-CH ₂ ^Y 6

CH

₁₄ ,

(CH ₂

N '

NY ₆ (CH ₂ )

or

means; R ₃ and R ₄ each independently represent a hydrogen or halogen atom, an alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy,

It

-O-C-NY ₈ Y ₉ , fluoro-substituted alkoxy, fluoro-substituted alkyl, (cycloalkyl) alkoxy, -NO ₂ -,

0 -NY ₁₀ Y ₁₁ -, -S (O) _m alkyl, -S (O) _n , aryl, -SY ₁₂ - or

Mean -OCY ₁₃ radical; η and η 'are independently 0, 1, 2 or 3

to have;

m is 0, 1 or 2;

Yi and Y ₂ each independently represent a hydrogen atom or an alkyl radical, or Y _{1 represents} a water atom and Y _{2 represents} an alkenyl, alkynyl, aryl, heteroaryl or cycloalkyl radical, or Y ₁ and Y ₂ together with the carbon atom they are bonded, a cycloalkyl radical;

Y _{3 represents} a hydrogen atom, an alkyl, alkanoyi, alkenyl, arylcarbonyl, heteroarylcarbonyl or

2fi

O is C-NY ₈ Y ₉ radical;

Each of Y ₄ and Y ₅ independently represents a hydrogen atom or an alkyl, aryl or arylalkyl group, and in the case of having both of these groups, they are not both a hydrogen atom or both when attached to the same carbon atom, none of which is a hydrogen atom ;

Each of Y ₆ and Y ₇ independently represents a hydrogen atom, an alkyl, cycloalkyl or arylalkyl radical or Y ₆ and Y ₇ together with the nitrogen atom to which they are attached represent an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl ligand;

Each of Y ₈ and Y ₉ independently represents a hydrogen atom, an alkyl, aryl or heteroaryl group or Y ₈ and Y ₉ together with the nitrogen atom to which they are attached represent a pyrrolidinyl, piperidinyl or morphilinyl group;

Y _{1 0} and Y ₁ · | each independently a hydrogen atom, an alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl or

C is -C-NY ₈ Y ₉ radical;

Y _{12 represents} a hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino radical;

Y _{13 represents} an alkyl, alkoxy or aryloxy radical. ; and

284

Y _{14 represents} a hydroxy, alkoxy, aryloxy or arylalkoxy radical;

which is characterized in that a compound of general formula II

(II) I / -N T \

R ₃

in a solvent with a base and then the compound thus obtained with a compound of the formula

R ₃ -L

or a protected form thereof, wherein L is a leaving group such as a halogen or tosyloxy group, and optionally converting the resulting product into a pharmaceutically acceptable salt.

In the following, the definitions of various terms used to describe the benzazepines obtainable according to the invention are further defined. These definitions apply to the entire description (unless otherwise limited in specific cases) either individually or as part of a larger group.

284 OO5

The terms "alkyl" and "alkoxy" refer to linear and branched radicals. These radicals preferably have 1 to 10 carbon atoms. The term "alkenyl" refers to linear and branched radicals. The radicals preferably have 2 to 10 carbon atoms.

The term "aryl" refers to phenyl and substituted phenyl. Examples of substituted phenyl radicals are radicals which are 1-, 2- or 3-fold by amino - (- NH ₂ ), alkylamino, dialkylamino, nitro / halogen, hydroxyl, trifluoromethyl, alkyl (1- 4 carbon atoms), alkoxy (1-4 carbon atoms), alkanoyloxy, carbonyl or carboxyl radicals.

The term "heteroaryl" refers to aromatic heterocyclic radicals having at least one heteroatom in the ring. Preference is given to pyridinyl, pyrrolyl, Iir.idazolyl, furyl, thienyl, oxazolyl or thiazolyl radicals.

The term "cycloalkyl" refers to radicals having from 3 to 7 carbon atoms.

The term "halogen" means fluorine, chlorine, bromine and iodine.

The terms "fluoro-substituted alkyl" and "fluoro-substituted alkoxy" refer to the above-described alkyl and alkoxy radicals in which one or more hydrogen atoms are replaced by fluorine atoms. Examples are the trifluoromethyl, 2,2,2-trifluoropropyl, pentafluoroethyl, Flnormethoy.y or difluoromethoxy.

The compounds of the formula I form acid addition salts with inorganic and organic acids, These salts

28 4 O O

are often valuable for isolating the products from the reaction mixture, forming the salt in a medium in which it is insoluble. The free base can then be neutralized by l.eutralization, e.g. with a base such as sodium hydroxide. Any other salts can then be prepared from the free base and corresponding inorganic or organic acids. Examples include hydrohalides, especially hydrochlorides and Hydrobrom4.de, sulfates, nitrates, phosphates, boranes, acetates, tartrates, maleates, citrates, succinates, benzoates, ascorbates, - salicylates, Methansuifonate, benzenesulfonates and toluenesulfonates.

The carbon atoms in the 3 and 4 positions of the benzazepine nucleus and the carbon atoms: "n of the 2 and 3 positions of the benzothiazepine nucleus of the compound of formula I are asymmetric. The compounds of formula I can therefore exist in enantiomeric and diastereomeric forms and as racemic mixtures thereof. All of these forms are within the scope of the invention. It is believed that the compounds of formula I which have the cis configuration are the most effective. These compounds are therefore preferred.

The compounds of formula I and the pharmaceutically acceptable salts thereof are valuable cardiovascular and cardiovascular agents. They function as the calcium-Zuaciiq blocking, vasodilating agents and are particularly useful for lowering blood pressure. By administering a preparation containing one (or more in combination) of the compounds of the invention, we reduce the blood pressure of a hypertonic mammal (e.g., a human). Daily doses of about 0.1 to 100 mg / kg of body weight per day, and preferably about 1 to 50 mg / kg per day per day are useful for lowering blood pressure and may be divided into single doses or 2 to 4

- 9 -

Day doses are administered. The preparations are preferably administered orally, although parenteral routes of administration, such as subcutaneous, intramuscular or intravenous administration, may also be used.

As a result of the Caicium access blocking effect of the compounds of formula I and their pharmaceutically acceptable salts, these compounds in addition to their suitability as antihypertensive agents are also valuable drugs against arrhythmia, heart attacks, Muskeif liinmern, asthma, blood deficiency, · to increase the ratio of HDL cholesterol to the total serum cholesterol in the blood and to curb myocardial infarction.

Also, the compounds of the invention are useful in the treatment of heart failure by congestion and peripheral vascular disease (eg, Raynaud's disease), thrombosis and atherosclerosis, in the treatment of cardiac hypertrophy (eg, hypertrophic cardiomyopathy), and in pulmonary hypertension as an adjunct in cardiac restorative solutions for cardiopulmonary bypass surgery and as an adjunct in thrombolytic therapy.

It is also believed that the compounds of this invention are useful in both the treatment of vascular disorders of the central nervous system, e.g. as an agent against stroke and migraine and in the treatment of bloodlessness in the brain and in subarachnoid hemorrhage, as well as in the treatment of behavioral disorders of the central. Nervous system, e.g. in the treatment of mental disorders such as depression, mania, anxiety and schizophrenia or in epilepsy or to

- ίο - 2 8 4 0 0

Support of cognitive ability, can be used.

Furthermore, it can be assumed that the compounds of the invention as diuretics, in the treatment of painful menstruations, ringing and other auditory and vestibular diseases, to alleviate various types of edema, to reverse adriamycin resistance, to control cell growth and Treatment of glaucoma, renal failure, liver damage (eg, cirrhosis of the liver), various endocrine hypersecretory states (eg, diabetes, spinal cord paraganglioma), drug-induced prolonged motor functions, allergies, nutritional disorders in muscle and cancer.

The compounds prepared according to the invention may also be used in combination with a β-adrenergic agent, an active compound, a diuretic, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide or benzthiazide, as well as ethacrynic acid, tricrynafen , Chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds, an inhibitor of angiotensin converting enzyme such as captopril, zofenopril, fosinopril, enalapril, delapril, pentopril, quinapril, ramipril, lisinopril and salts of such compounds or thrombolytic agents such as tissue plasminogen activator (GPA), recombinant GPA, streptokinase, urokinase, prourokinase and anisylated plasminogen streptokinase activator complex (APSAC, Eminase, Beecham Laboratories). If such combination

- 11 -

$ 28,400

Products are formulated in fixed doses, they are used in the compounds of the invention in the dose range described above and the other drugs in their approved dose range.

The compounds of formula I may be indicated for use as antihypertensive agents in the form of compositions such as e.g. Tablets, capsules or elixirs for oral administration or as sterile solutions or suspensions for parenteral administration. The compounds of the formula I can also be administered via a dermal patch or by means of a nasal inhalation solution. About 10 to 500 mg of the compound of formula I are mixed with a physiologically acceptable mediator, excipient, excipient, preservative, stabilizer, flavor, etc., into a unit dosage form as is common in pharmaceutical practice. The amount of the active ingredient in these compositions or formulations is selected to provide a suitable dosage amount in the above range.

The compounds of the formula I can be prepared from the corresponding compounds of the formula II

II

being represented. The preparation of the racemic and non-racemic forms of the compounds of the formula II

- 12 -

with X = CH ₂ is for compounds with R ₁ = -CH

is described in U.S. Patent 4, o2,645, for compounds with R = OY ₃ and Y ₃ = H is described in U.S. Patent 4,748,239. Compounds of formula II wherein X = S and R ₁ = OY ₃ are prepared according to US Patent 3,562,257. Compounds of

Ϊ-

Formula II with X = S and R ₁ f -CH are determined according to

Y ₂ U.S. Patent 4,694,002. Compounds of the formula II where R ₁ = OY ₃ and Y ₃ H can be obtained by alkylation or acylation by means of gc common techniques from the corresponding compounds of the formula II where R ₁ = OH.

The compounds of formula II wherein R ₁ = OH can in their non-racemic form by reacting the racemic compound of formula II with R ₁ = OH with a non-racemic acid or amino acid

Z ₁ ^ CO ₂ H, in which Z and Z _{1 are} different, using conventional Azylxerungsmethoden such as carbodiimide with a catalyst such as dimethylaminopyridine, a mixture of diastereomeric compounds II

O with R ₁ = _o

to be obtained. This mixture of diastereomers can be separated by one of ordinary skill in the art by chromatographic methods or crystallization. The non-racemic compounds of formula II where R ₁ = OH are obtained from the purified diastereomers by hydrolysis with a base such as sodium hydroxide or sodium methoxide.

- 13 -

Treatment of the compound of formula II with a base (e.g., sodium hydride or cesium carbonate) in an inert solvent (e.g., dimethylformamide or dimethyl sulfoxide), followed by reaction with the compound of the formula

III R ₂ -L,

where L represents a leaving group such as a halogen or a tosyloxy group gives the corresponding product of formula I. '

Optionally, a compound of formula I can also be prepared by reacting a compound of formula II with one of formula III under phase transfer conditions in a mixture of water and dichloromethane or toluene in the presence of a suitable base (eg, barium hydroxide or sodium hydroxide) and a catalyst (eg, benzyltrimethylammonium chloride or Tetra-n-butylammonium hydrogen sulfate).

Alternatively, the products of formula I with R ₁ = OH can be alkylated or acylated by known methods to obtain products of formula I with R ₁ = OY ₃ and Y ₃ = | = H.

A further preparation process for compounds of the formula I where R ₂ =

^{2 Υ} 7 \ / ^Y 6

comprises the treatment of a compound of formula II with an alkali metal hydride (e.g., sodium hydride) in one

r 14 -

28 4 o

inert solvent (e.g., dimethylformamide or dimethylsulfoxide), followed by reaction with a compound of the formula

IV

) _n , -CH-C = N

and gives the corresponding compound of formula V

CH-Y ₄

C = N

Reduction of the compound of formula V by e.g. Catalytic hydrogenation (e.g., rhodium on alumina) yields the corresponding product of Formula I of Formula VI

VI

^(CH ^ n '

CH-Y ₄

CH ₂

NH ₂

Reductive amination of a compound of formula VI with a suitable aldehyde or ketone and a chemical

- 15 -

8 4 0

Reducing agent (e.g., sodium cyanoborohydride) yields the corresponding product of Formula I of Formula VII

VIl

CH-Y

CH,

i.

^Y 6 ^Y 7

in which at least one of the Y ₆ and Y ₇ radicals is not a hydrogen atom.

Optionally, compounds of the formula I where R ₂ =

CH-Y ₄ CH-Y ₅

^Y 6 ^Y 7

(CH _? ) _N , CH ₂ -CH,

CH-CH ₂

(CH ₂ J _n , CH-Y ₄ CH-CH

^€ ^ 2

CH

or

(CH ₂ ) _n ,

Y _C -CH ⁵ \

N'Y,

by treating a compound of formula II with an alkali metal hydride (e.g., sodium hydride) in an inert organic solvent (e.g., dimethylformamide

- 16 -

or dimethyl sulfoxide), followed by reaction with a suitable compound of the formula

R _n

(CH ₂ ) _n , Y ₄ -CH-CY ₅ , CH ₂

(CHg) _n ,

Y ₄ -CH-C-CH II

CH-CH,

CH ₂ -C CH ₂

CH-CH,

^(CH 2> n

being represented.

The resulting compound of formula IX

can be reacted with ozone in an inert solvent (e.g., a halogenated hydrocarbon) followed by reduction (e.g., using a chemical reducing agent such as dimethyl sulfide) to yield the corresponding compound of Formula X.

R

- 17 -

with R _b

CH-CH

^H 2

, η · '< ^CH ₂ > _n . Y ₄ -CH-CY ₅ , Y ₄ -CH-C-Cl

O - <- - <- - - O (CHa) _n ,

n ¹

ii O

or Υ _ς -C-CH-CH, - (CH,) _Λ -CH ⁵ Ii 2 2'n

^(CH 2> n

A compound of the formula X can be reacted with a suitable amine of the formula

XI

HNY ₆ Y ₇

in the presence of a reducing agent (e.g., hydrogen using a catalyst such as palladium on charcoal or a chemical reducing agent such as sodium cyanoborohydride) to give the corresponding product of formula I.

It is also possible to use an intermediate level of Forr.el X

λ -CH-C-Υ_ or

CH-CH

(CH) by reacting the compound

- 18 -

el · formula II with a compound of the formula

XIIa

(CH ₂ ) _n , -C-

^Y 4- ^CIJ -S- ^Y 5

XIIb

to obtain.

Compounds of the formula I where R ₂ =

(CH ₂ )

NY ₆ (CH ₂ )

can be prepared by reacting a compound of formula II with an alkylating agent such as chloroacetonitrile to give a compound of formula I wherein R ₂ = -CH ₂ CN. The resulting compound of formula I with R ₂ = -CH ₂ CN can be reacted with an alcohol such as ethanol in the presence of a catalyst such as hydrochloric acid or sodium oxoethoxide to give a compound of formula I with R ₂ = -CH ₂ C = NH. Treatment of this Ver-OEt

Bonding with a diamine of the formula H ₂ N-CH ₂ (CH ₂ ) _n NHY ₆ gives compounds of the formula I with

(CH ₂ )

R, =

NY ₆ (CH ₂ )

Preferred compounds of this invention are those in which R _{3 is} attached to the 6- or 7-position of the benzazepine nucleus

19 -

$ 2840

or bound to the Ue 8 or 9 position of the benzothiazepine nucleus and a. Represents halogen, a trifluoromethyl or methoxy group, and fy is attached to the phenyl ring in the 4-position and is an alkoxy radical. Especially preferred are compounds with R ₃ as e * λθ 6-trifluoromethyl or 7-methoxy group on benzazepine nucleus or as an 8-methoxy group on benzothiazepine nucleus and with R ₄ as methoxy group.

AusführungsbGispiele

example 1

[1 (trans), 3,4] -l- [2- (dimethylamino) -cyclohexyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) ^ Hl-benzazepin monohydrochloride.

To a suspension of 0.3 g of sodium hydride (6.3 mmol of a 50% oil dispersion) in 20 ml of dry dimethylformamide is added 2.0 g of (ice) -1,4,4,5-tetrahydro-4- (4-methoxyphenyl ) -3-methyl-.beta.-trifluoromethyl) -2H-1-benzazepin-2-one (5.73 mmol) as a solid in one. The lye is stirred for 45 minutes and then a solution of 1.59 g (6.3 mmol) of (trans) -1-iodo-β- (dimethylamino) cyclohexane in 12 ml of dry dimethylformamide over a period of 15 minutes Minutes dropped. The solution is stirred at room temperature for 20 minutes and then heated to 75 ^° C. for 70 minutes. An additional 0.15 g of sodium hydride and 0.8 g of (trans) -1-iodo-2- (dimethylarino) cyclohexane are added and the temperature is maintained for a further 30 minutes. The solution is cooled and the dimethylformamide removed in vacuo. The residue is treated with water, the aqueous solution is extracted twice with ethyl acetate and the combined organic phases

- 20 -

washed with saturated brine, dried (magnesium sulfate) to give 3.15 g of a semi-solid.

Chromatography on silica gel with 1% triethylamine / 2% methanol / dichloromethane gives 0.74 g of the free base 3 of the title compound as a white foamy solid. The free base is dissolved in ether and mine. Hydrogen chloride saturated ether added, giving a white precipitate. The solution is concentrated and washed twice with ether to remove the excess hydrogen chloride. The remaining white solid is recrystallized from isopropanol / isopropyl ether to give 0.68 g of the title compound; Mp> 250 ° C.

Analysis calc. For C ₂₇ H ₃₄ ClF ₃ N ₂ O ₂ -LSH ₂ O:

C, 62.51; H 6,77; N 5.40; Cl 6,83; F .10.99 Gef .: C 62.59; H, 6.84; N 5.30; Cl 6.70; F 10.99.

Example 2

(Ice) -1- [2- (Dimethylamino) -propyl] -1,3,4,5-tetrahydro-4 · (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine-2 -on-monohydrochloride, isomer A

A stirred solution of 3.0 g (8.69 mmol) of (cis) -1,3,4,5-tetrahydro-4- (4-me-hoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H- l-Benzazepin-2-one in 9 ml of 2-butanone vd.rd with 1.7 g (10.75 mmol) of N, N, N'-methyl-2-chloro-1- (ethyl) -ethylamine, followed by 3.0 g (2 _f 17 mmol) of powdered potassium carbonate are treated and heated to reflux After about 2 days of heating is still

- ²¹ -

2 8 4 0 0

a significant amount of (ic) - ¹ , 3,4,5-tetrahydro-4- (4-methoxyphenyl) -S-methyl-ö- (trifluoromethyl) -2H-1-benzazepin-2-one is present. Another 1.2 g of N, N-dimethyl-2-chloro-1- (methyl) -ethylamine and 2.2 g of potassium carbonate are added and heating continued for one day. After cooling, the solids are filtered off, washed with .2-butanone, and the combined filtrates are concentrated. The residue is shaken with 90 ml of ethyl acetate and 30 ml of water, the phases are separated, and the ethyl acetate phase is washed with 30 ml each of water and saturated brine, dried (magnesium sulfate) and concentrated. The residue is taken up in ether, the concentration is repeated, the residue is dried by pumping to give 3.86 g of a solid. After two recrystallizations from I3opropylether to obtain 1.05 g of a solid; Mp 154-157 ° C (sublimation point 152 ⁰ C). TLC: major product, R _f = 0.51, by-product: R _f = 0.42 (90:10 dichloromethane / methanol); Main product: R _f = 0.27, by-product: R _f = 0.17 (30:70 acetone / hexane).

The material described above is chromatographed over 40 g silica gel using 30:70 acetone / hexane to give 0.6 g of the single isomer as a colorless solid: mp. 159-161 ⁰ C.

Analysis calculated for C ₂₄ H ₂₉ F ₃ N ₂ O _2.:

C 66.34; H 6.73; N 6,45 Found: C 66,5Ü; H 7.02; N 6,32

The residue of the second recrystallization from isopropyl ether and fractions of the chromatography described above, which are rich in the isomer A, are combined, chromatographed, yielding another 0.36 g of the identical material.

- 22 -

The two batches are combined (together 0.92 g), suspended in 25 ml of dry methanol, treated with 0.45 ml of 5N ethanolic hydrogen chloride and the solvent removed. The syrupy residue is triturated under ether, concentrated and dried by pumping. This procedure is repeated to give 0.92 g of the colorless, non-hygroscopic title hydrochloride salt; . Mp 101-104 ⁰ C (foaming), d: .ntern at 88 ° C. TLC: R _f = 0.40 (40:60 acetone / hexane); R _f = 0.25 (8: 1: 1 dichloromethane / methanol / acetic acid).

Analysis for C ₂₄ H ₂₉ F ₃ N ₂ O ₂ .HCl-0.5 H ₂ O:

C 60.05; H, 6.51; N, 5.84; Cl, 7.39, found: C, 59.93; H 6,87; N 6.04; Cl 7,14.

Example 3

(Ice) -1- [2- (Dimethylamino) -propyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1 benzazepine-2-one monohydrochloride, isomer B

The isopropyl ether mother liquor of the crystallization of the free base of isomer A in Example 2 is concentrated, and the residue is dried in an oil pump vacuum to give 2.4 g of a waxy residue. TLC (40:60 acetone / hexane) of this material shows a 40:60 mixture of isomer A and isomer B.

The mixture is chromatographed on silica gel with 40:60 acetone / hexane to give 0.49 g of the base of isomer B as a waxy solid. TLC: R _f = 0.19 (40:60 acetone / hexane). Di ^ solution of the base (0.48 g) in methanol is treated with 0.24 ml of 5 N ethanolic hydrogen chloride and the solvent is stripped off. The residue is triturated under ether, concentrated and pumped through

- 23 -

28 4 O O $

dried. This process is repeated to give 0.50 g of a colorless, slightly hygroscopic hydrochloride salt; . Mp 83-86 ° C (foaming), sintering at 76 ⁰ C. TLC: R, = 0.22 (40:60 acetone / hexane). Analysis for C ₂₄ H ₂₉ F ₃ N ₂ O ₂ -HCl-O ^ H ₂ O:

C 60.05; H, 6.51; N, 5.84; Cl, 7.39, found: C, 60.30; H 7,00; N 5.62; Cl 7,17.

Example 4

(Cis) -l- (2-Amino-l-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-l-benzazepin 2-one monohydrochloride, isomer B

A) (ice) -1,3,4, S-tetrahydro-4- (4-methoxyphenyl) -α, 3-dimethyl-2-oxo-6- (trifluoromethyl) -1H-1-benzazepine-1-acetonitrile, faster running isomer

To a suspension of 0.22 g of sodium hydride (5.37 mmol of a 60% oil dispersion) in 15 ml of dry dimethylformamide is added 1.50 g (4.29 mmol) of (ice) -3-methyl-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-1-benzazepin-2-one. The solution is stirred at room temperature for 15 minutes, cooled to ⁰ ° C. and 0.42 ml (5.37 mmol) of 2-chloropropionitrile added neat. The solution is stirred at 0 ^° C. for 10 minutes, warmed to room temperature for 15 minutes and heated to 45 ^° C. for 90 minutes. An additional 50 mg of sodium hydride and 0.15 ml of 2-chloropropionitrile are added and the solution is stirred at 45 ° C for 20 minutes. The reaction is quenched with 1 M ammonium chloride and the dimethylformamide is removed under high vacuum with gentle heating. The residue is partitioned between ether and 1 M ammonium

- 24 -

chloride, and the organic phase washed with saturated brine, dried (magnesium sulfate), concentrated to give a brown foamy solid which is combined with the crude product of a similar 1.68 mmol batch. The crude product consists of two diastereomers of the product, termed the faster-running isomer (FMI; R _f = 0.74, 50% ethyl acetate / hexane) and the slower-moving isomer (SMI; R _f = 0.66; 50% ethyl acetate / hexane). The solid is chromatographed on silica gel (60% ether / hexane) to give 0.90 g of the pure FMI as a white solid. Chromatography also provides 0.34 g of approximately pure SMI which is dissolved in hot hexane with 5% isopropyl ether and gives, on cooling, 0.29 g of pure SMI in the form of hexagonal prisms; Mp. 166-168 ⁰ C. chromatography of the mixed fractions gives 0.44 g of pure vreitere FMI (together 1.34 g) and 0.31 g of pure SMI (together 0.60 g).

B) (Eis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-one benzazepin-2-one monohydrochloride, isomer B

A solution of 0.87 g of (ice) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -α, 3-dimethyl-2-oxo-6- (trifluoromethyl) -1H-1-benzazepine 1-acetonitrile, faster-moving isomer (2.16 mmol) and 0.87 g of 5% rhodium on alumina in 125 mL of methanol / ammonia (1: 1) is bubbled under a hydrogen pressure of 352 kPa (50 psi) for 25 hours hydrogenated. The solution is filtered through celite, the celite washed twice with methanol, and the combined filtrates concentrated. The semi-solid residue is taken up in dichloromethane, through

- 25 -

4 Q O $

Celite filtered, concentrated and yielded 0.89 g of a white foamy solid. To a solution of 0.34 g of this material in ether is added hydrogen chloride saturated ether. The solution becoming milky is concentrated, the residue is taken up in methanol and concentrated again. This residue is taken up again in 1 ml of methanol, 20 ml of ether are added followed by 20 ml of hexane, and the solution is cooled. The white solid is filtered, dried, yielding 0.30 g of the title compound as a white solid; Mp 157-162 ° C (foaming). Analysis calc. For C ₂₂ H ₂₆ ClF ₃ N ₂ O ₂ .0.21 H ₂ O:

C 59.15; H 5.96; N 6.27; Cl 7,93; F 12,76; found: C 59.15; H 6,10; N 6.04; Cl, 7.84; F 12,78.

Example 5

(Ice) -1- [2- (dimethylamino) -1-methylethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -1H-benzazepine ^ -on-monohydrochloride, isomer B

A solution of 0.62 g of (cis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl ) Hl-benzazepine-monohydrochloride, isomer B (1.52 mmol, see Example 4), and 1.3 ml of 37% aqueous formaldehyde in 10 ml of acetonitrile is poured all at once with stirring into 0.31 g of solid sodium cyanoborohydride , then added 0.16 ml of acetic acid. The solution is stirred at room temperature for 2 hours, an additional 0.16 ml of acetic acid is added and the solution is stirred for 30 minutes. Ether and 5% potassium carbonate in water are added, the mixture is distributed, the organic phase is washed with saturated brine, dried (magnesium sulfate),

- 26 -

284 O OS

concentrated and gives 0.84 g of a thick oil. Chromatography on silica gel with 2% methanol / 1% triethylamine / dichloromethane gives 0.30 g of the pure free base of the title compound. This material is dissolved in ether, hydrogen chloride-saturated ether added, the white suspension is concentrated and the residue is dissolved twice in methanol and concentrated. Hot isopropyl ether is added to the glassy solid, then hot methanol is added dropwise until the solid dissolves. The solution is filtered, hot isopropyl ether added to a constant turbidity, and the solution is cooled. The waxy precipitate is filtered, dried in vacuo to give 220 mg of the title compound as a white solid; Mp> 220 ° C.

Analysis calculated for C ₂₄ H ₃₀ ClF ₃ N ₂ O ₂ -O ^ OH ₂ O.:

C, 59.84; H 6,53; N 5.81; Cl 7:36; F 11,83; found: C 59.84; H 6,52; N 5.76; Cl 7,27; F 11,93.

Example 6

(Cis) -1- [2- (dimethylamino) -1-methylethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-l- benzazepin-2-one monohydrochloride, isomer A

A) (Eis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-O- (trifluoromethyl) -2H-1-one benzazepin-2-one

A solution of 0.60 g (ice) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -α, 3 = dimethyl-2-oxo-6- (trifluoromethyl) -1H-1-benzazepine -l-acetonitrile, slower running isomer (1.49 mmol) and 0.49 g of 5% rhodium on alumina in 125 ml of methanol /

- 27 -

Ammonia (1: 1) is hydrogenated under a hydrogen pressure of 352 kPa (50 psi) for 20 hours. The solution is filtered through celite, the celite washed twice with methanol, and the combined filtrates concentrated. The semi-solid residue is taken up in dichloromethane, filtered through celite, concentrated to give 0.56 g of the title compound as a white foamy solid.

B) (ice) -1- [2- (dimethylamino) -1-methylethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl-1) -3-methyl-6- (trifluoromethyl) - ^ Hl-benzazepin monohydrochloride

A solution of 0.56 g of crude (cis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-O- (trifluoromethyl) - 2H-1-benzazepin-2-one (1.38 mmol) in 10 mL acetonitrile containing 1.2 mL of 37% aqueous formaldehyde is poured onto 0.28 g solid sodium cyanoborohydride (4.44 mmol) with stirring, then added 0.145 ml of acetic acid. The solution is stirred for 2 hours, added another 0.145 ml of acetic acid and stirred again for minutes. The reaction mixture is partitioned between ether and 10% aqueous potassium carbonate solution, the organic phases are washed with concentrated brine, dried (magnesium sulfate), concentrated to give 0.70 g of oil. This material is flash chromatographed on silica gel (1% methanol / 0.5% triethylamine / dichloromethane) to give 0.32 g of the pure free base of the title compound as a foamy solid. This material is dissolved in ether, hydrogen chloride is added to saturated ether to give a white precipitate. The ether is stripped off, the solid dissolved in methanol, and the solution concentrated. The solid gets back in

- 28 -

Dissolved methanol and the solution filtered through Celite and concentrated. The solid is dissolved in 2 ml of warm methanol, hot isopropyl ether is added until turbidity persists, the solution is cooled, and the solid is separated by filtration. There are obtained 0.27 g of the title compound as a white crystalline solid; Mp> 220 ° C.

Analysis calculated for C ₂₄ H ₃₀ ClF ₃ N ₂ O ₂ -HCl.:

C 61.20; H 6,42; N -5.95; Cl, 7.53; F 12,10; Found: C 61.15; H 6,52; N 5.88; Cl, 7.71; F 11,78.

Example 7

[2 (R) - [1 (R [*]), 3a, 4a)] - 3- (acetyloxy) -l, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - [(l -methyl-2-pyrrolidinyl) -methyl] -6- (trifluoromethyl) -1H-benzazepine-monohydrochloride

A) (R) - (-) - N- (t-Butoxycarbonyl) -2-pyrrolidinemethanol

To a solution of (R) - (-) - 2-pyrrolidinemethanol (5.0 g, 50 nunol) in dry Di.chlormethan (125 ml) at 0 ⁰ C a solution of di-t-butyl dicarbonate (13 g; 59.5 mmol) in 50 ml of dichloromethane was added dropwise over a period of 15 minutes. It immediately creates a carbon dioxide gas evolution. The cooling bath is removed and the mixture is stirred at room temperature for a further 6 hours. The reaction mixture is then concentrated under reduced pressure and the title compound is obtained in the form of a slightly yellow viscous oil (13 g). The crude product is used in the next reaction without further purification.

- 29 -

$ 28,400

B) (R) - (-) - N -methyl-2-pyrolidinylmethanol

Lithium aluminum hydride (7.6 g, 200 mmol) is added in small portions to dry tetrahydrofuran (200 mL) at 0 to 5 ^° C. Then a solution of R - (-) - N- (t -)) utoxycarbonyl) -2-pyrrolidinolethanol (13 g crude, 50 mmol) in dry tetrahydrofuran (100 ml) is added dropwise with vigorous stirring over a period of 45 minutes , After 30 minutes at 0 ⁰ C, the reaction mixture is heated to reflux for 16 hours. The reaction mixture is then cooled to ⁰ ° C. and the excess hydride is destroyed by slow addition of saturated aqueous sodium sulfate solution. The addition is continued until all inorganic salts precipitate in the form of a white granule. The mixture is diluted with ethyl acetate (500 ml), dried (magnesium sulfate), filtered, concentrated to give the title compound as a colorless oil (5.7 g). The crude product is used without further purification in the next reaction.

C) (R) -2- (Chloromethyl) -1-methylpyrrolidine hydrochloride

To a solution of (R) - (-) - N-methyl-2-pyrrolidinethanol (2.0 g, 17.4 mmol) in chloroform (18 mL) at ⁰ ° C is added thionyl chloride (0.74 g; 1 mmol) was added dropwise. The reaction mixture is refluxed for 2 hours then cooled to room temperature and concentrated under reduced pressure The residue is recrystallized from acetone / ether to give the title compound as a pale yellow solid (1.14 g).

- 30 -

D) [3 (R) - [I (R *) , 3a, Aa] ] - 1 - [(1-Methyl-2-pyrrolidinyl) -niethyl] -3- (hydroxy) -1,3,4,5 tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -1H-benzazepin-2-one

Sodium hydride (0.19 g, 8.1 mmol) is added to a solution of (3 (R) -cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine. Add 2-one (1.05 g, 3.0 mmol) in dry dimethylformamide (30 mL). The mixture is stirred at room temperature for one hour, then CR) -2- (chloromethyl) -l-methylpyrrolidine hydrochloride (0.78 g, 4.5 mmol) is added and the mixture is heated at 80 ^° C. for one hour , The reaction mixture is cooled, quenched with saturated aqueous potassium bicarbonate, and extracted with ethyl acetate three times. The combined extracts are washed with 10% aqueous lithium chloride, dried (magnesium sulfate) and concentrated. The crude yellow liquid is extracted on silica gel with 1 to 3% methanol in dichloromethane to give the title compound as a viscous liquid (0.24 g).

E) [3 (R) - [l (R [*]), 3a, 4a]] - 3- (acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- [ (l-methyl-2-pyrrolidinyl) methyl] -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

A solution of [3 (R) - [1 (R *), 3α, 4α]] - 1 - [(1-methyl-2-pyrrolidinyl) methyl] -3- (hydroxy) -1,3,4, 5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.24 g, 0.54 mmol), acetic anhydride (0.27 g, 2.68 mmol ) and 4-dimethylaminopyridine (0.07 g, 1.07 mmol) in

- 31 -

28 4 O O

dry dichloroethane (6 ml) is stirred at room temperature for 60 hours. The reaction mixture is then adsorbed on silica gel (60-200 mesh), poured onto a silica gel column, eluted with 1 to 3% methanol in dichloromethane to give the free base of the title compound. The viscous oil is dissolved in ether and treated with a saturated, ethereal hydrogen chloride solution. The white precipitate is recrystallized from toluene / hexane: Lert to give the title compound as a white solid (0.23g); Mp. ^ L-58 * 162 ° C. [a] _D = + 126.8 ° (c = l, 0, methanol).

Analysis Calc. For C ₂₆ H ₃₀ F ₃ ClN ₂ O ₄ · l, _0H? 0:

C 57.31; H 5.92; N 5:14; F, 10.46; Cl 6:51; Found: C 57.63; H 5.68; N, 5.23; F 10,21. Cl, 6.34;

Example 8

[3 (R) - [I (S *), 3a, 4a]] - 3- (acetyloxy) -1- [ 2- (dimethylamino) -3-phenylpropyl)] - 1,3,4,5-tetrahydro- 4- (4-methoxyphenyl) 6- (trifluoromethyl) -1H-benzazepine-monohydrochloride

A) (S) -2- (Dimethylamino) -3-phenyl-1-propanol

To a solution of (S) -2-amino-3-phenyl-1-propanol (6.0 g, 4.0 mmol) and 37% aqueous formaldehyde (20 ml) in acetonitrile (200 ml) is added sodium cyanoborohydride with stirring (4.0 g, 64 mmol) in small portions. The mixture is stirred for 30 minutes, then added dropwise to the solution of glacial acetic acid until neutral pH paper reacts. The mixture is stirred at room temperature for 2 hours, occasionally adding to a

- 32 -

neutral pH is added dropwise. The reaction mixture is then concentrated and the residual oil is diluted with 2N potassium hydroxide (250 ml). It is extracted three times with ethyl acetate, the combined extracts washed with 1 N potassium hydroxide and extracted three times with 1 N aqueous hydrochloric acid. The acid extracts are combined, neutralized with solid potassium hydroxide and extracted three times with ethyl acetate. The extracts are combined, dried (magnesium sulfate), concentrated to give the di & titled compound as a viscous oil (6.48 g).

B) (S) -1-Chloro-2- (dimethylamino) -3-phenylprope.nhydrochloride

To (S) -2- (dimethylamine) -3-phenyl-1-propanol (3 _f 0g, 16.7mmol) in chloroform (20ml) at ⁰ ° C is added thionyl chloride (5.97g, 50.2%) mmol). The reaction mixture is refluxed for two hours and then evaporated to dryness under reduced pressure. The residue is recrystallized from acetone / ether to give the title compound as an off-white solid (2.38 g, mp 167.5-168.5 ⁰ C.).

C) [3 (R) - [1 (S [*]), 3a, 4a]] - 1- [2- (dimethyland.no) -3-phenylpropyl] -3- (hydroxy) -1,3, 4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

Sodium dihydric acid (0.22 g, 9.0 mmol) is added to a solution of (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (m.p. 1.05 g, 3.0 mmol) in dry dimethylformamide (30 ml). The mixture becomes a room temperature

Stirred, then (S) -l-chloro-2- (dimethylamino) -3-phenylpropane hydrochloride (0.89 g, 4.5 nunol) was added, and the mixture heated to 85 ⁰ C for 2 hours. The reaction mixture is cooled, quenched with water and extracted three times with ethyl acetate. The combined extracts are washed three times with 10% aqueous lithium chloride and once with brine and dried (magnesium sulfate). After concentration, the crude product is chromatographed on a silica gel column with 10 to 30% ethyl acetate in hexane to give the title compound as a white foam (1.16 g).

D) [3 (R) - [1 (S [*]], 3a, 4a]) - 3- (acetyloxy) -1- [2- (dimethylamino) -3-phenylpropyl] -1,3,4,5 tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

A solution of [3 (R) - [1 (S *), 3α, 4α]] - 1- [2- (dimethylamino) -3-phenylpropyl] -3- (hydroxy) -1,3,4,5- tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.16 g, 2.26 mmol), acetic anhydride (1.16 g, 11.32 mmol). and 4-dimethylaminopyridine (0.55 g, 4.53 mmol) in dry dichloromethane (25 ml) is stirred at room temperature for 16 hours. The reaction mixture is adsorbed on silica gel (60-200 mesh), poured onto a silica gel column, eluted with 5-25% ethyl acetate in hexane to give the free base of the title compound as a white foam. The free base is dissolved in ether, an excess of ethereal hydrogen chloride solution is added to give the title compound as a white solid (0.96 g); Mp. 144-147 ⁰ C. [Ot] ₀ = + 52.40 ° (c = l, 0, methanol).

- 34 -

Analysis for C ₃₁ H ₃₄ CIF ₃ N ₂ O ₄ -O ^ oH ₂ O:

C 61.56; H 5.92; N, 4.63; Cl, 5.86; F 9,42; found: C 61.60; H 6,00; N 4.59; Cl, 5.93; F 9,23.

Example 9

[3 (R) - [I (R *), 3a, 4a]] -3- (acetoxy) -1- [2- (dimethylamino) -3-phenylpropyl] -1,3,4,5-tetrahydro-4 - (4-methoxyphenyl) 6- (trifluoromethyl) -1H-benzaraepin-1-monohydrochloride

A) (R) - (+) - 2- (Dimethylamino) -3-phenyl-1-propanol

To a solution of (R) - (+) - ^ - propanol (6g, 40 mmol) and 37% aqueous formaldehyde (20 ml) in acetonitrile (200 ml) is added sodium cyanoborohydride (4.0 g, 64 mmol) in small portions. The mixture is stirred for 30 minutes, then glacial acetic acid is added dropwise until the solution is neutral to pH paper. The mixture is stirred at Raur.temperatur for 2 hours, occasionally dropwise added to obtain the neutral pH of acetic acid. The reaction mixture is then concentrated and the residual oil is diluted with 2N potassium hydroxide solution (250 ml). It is extracted three times with ethyl acetate, the combined extracts are washed with a 1N potassium hydroxide solution and extracted with a 1N hydrochloric acid solution three times. The acid extracts are combined, neutralized with solid potassium hydroxide and extracted three times with ethyl acetate. The extracts are combined, dried (magnesium sulfate), concentrated to give the title compound as a viscous oil (6.23 g).

B) (R) -1-Chloro - (dimethylamine) -3-phenylpropane hydrochloride

To (R) - (+) - 2 - (dimethylamino) -3-phenyl-1-propanol (3.0 g, 16.7 mmol) in chloroform (20 mL) at ⁰ ° C is added thionyl chloride (6.0 g; 50.2 mmol) was added dropwise. The reaction mixture is heated under reflux for 2 hours, then concentrated to dryness under reduced pressure. The residue is recrystallized from acetone / ether to give the -title compound as an off-white solid (2.27 g; mp 170 to 171.5 ⁰ C.).

C) [3 (R) - [l (R [*]), 3a, 4or]] - 1- [2- (dimethylamino) -3-phenylpropyl] -3- (hydroxy) -1,3,4,5 tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

Sodium hydride (0.13 g, 5.4 mmol) is added to a solution of (3 (R) -cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (0.70 g, 2.0 mmol) in dry dimethylformamide (20 mL). The mixture is stirred at room temperature for one hour, then (R) -1-chloro-2- (dimethylamino) -3-phenylpropane hydrochloride (0.60 g, 3.0 mmol) is added, and the buffer is 2.5 Hours to 8O ⁰ C heated. The reaction mixture is cooled, quenched with water and extracted three times with ethyl acetate. The combined extracts are washed three times with 10% aqueous lithium chloride and once with brine, filtered, dried (magnesium sulfate) and concentrated. The crude product is passed through a silica gel column with 20 to 50% ethyl acetate in hexane

- 36 -

to give the title compound as a white foam (0.60 g).

D) [3 (R) -tl (R *) _f 3a, 4a] T- [acetyloxy) -1- [2- (dimethylamino) -3-phenylpropyl] -1,3,4, S-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

A solution of [3 (R) - [I (R *), 3a, 4a]] - 1- [2- (dimethylamino) -3-phenylpropyl] -3- (hydroxy) -1,3,4,5- tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.0 g, 1.95 mmol), acetic anhydride (1.0 g, 9.8 mmol), and 4-dimethylaminopyridine (0.48 g, 3.90 mmol) in dry dichloromethane (20 ml) is stirred for hours at room temperature A. The reaction mixture is adsorbed onto silica gel (60-200 mesh), poured onto a silica gel column, eluted with 5-25% ethyl acetate in hexane to give the free base as a white foam. The free base is dissolved in ether, an excess of ethereal hydrogen chloride solution added to give the title compound as a white solid (0.61 g); Mp 146-15O ⁰ C. [a] ₀ = + 137.3 ° (c = l, 0, methanol).

Analysis calc. For C ₃ , H _{3 4} ClF ₃ N ₂ O ₄ · 0.56 · H ₂ O:

C 61.93; H 5.89; N, 4.66; Cl 5.90; F, 9.48; found: C, 62.02; H 6.21; N, 4.67; Cl 5.83; F 9,33.

Example 10

(3 (R) -cis) -1- [2- (dimethylamino) -2-methylpropyl] -1,3,4,5-tetrahydro-2-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) ^ hl-benzazepin monohydrochloride

- 37

The following illustration is carried out under argon as protective gas. A stirred solution of (3 (R) -is) -3-hydroxy-4- (4-methoxy-phenyl) -6- (trifluoromethyl) -2H-benzazepin-2-one (2.5 g, 7 , 12 mmol) in 75 ml of dimethylformamide is treated with 0.3 g (7.5 mmol) of 60% sodium hydride and stirred for an additional hour. To this solution is added a dried toluene solution of 1-chloro-2- (dimethylamino) -2-methylpropane (formed from 3.75 g (21.8 mmol) of the hydrochloride salt by reaction with potassium carbonate in toluene) and the mixture is stirred in an oil bath at 71 to 78 ° - & - 1> 25 hours heated. After cooling, most of the dimethylformamide is removed using a rotary evaporator at 0.2 mm Hg and the residue is shaken with 125 ml of ethyl acetate and 50 ml of water. The phases are separated and the organic phase is washed with water (twice 50 ml) and saturated brine (25 ml), dried (magnesium sulfate) and concentrated. The solid residue is suspended in ether, concentrated again, and the solid is dried by pumping; Weight 3.33 g. This is combined with 0.64 g of a product from an earlier batch, dissolved in ether, filtered and concentrated. The solid residue (3.94 g) is shaken with 60 ml of ethyl acetate and 40 ml of water containing 17 ml of 1 N hydrochloric acid. The phases are separated and the organic phase extracted with 40 ml of water. The combined aqueous phases are washed with ether (the wash is discarded), added to 40 ml of ethyl acetate, 19 ml of 1N sodium hydroxide added, and the mixture is shaken and separated. The aqueous phase is extracted with ethyl acotate (twice 30 ml), the combined ethyl acetate phases washed with brine (20 ml), dried (magnesium sulfate) at one pressure

- 38 -

concentrated to 0.2 mm Hg and gives 3.66 g of solid. Subsequent crystallization from 25 ml of hot isopropanol gives a colorless substance (free base of the title compound) weighing 2.36 g; Mp 157-159 ⁰ C (sintering at 155 ⁰ C).

Analysis Calc. For C ₂₄ H ₂₉ F ₃ N ₂ O ₃

C 63.98; H 6,49; N 6,22; F, 12.65; Found: C 64.17; H 6,53; N 6.08; F 12,93.

The base (2.34 g) in 50 ml Etfcy-lacetat is treated with 1.2 ml of 5 N ethanolic hydrogen chloride, and the solvent removed to a pressure of 0.2 mm Hg. The almost solid residue is triturated under ethyl ether and the concentration is repeated, which, after drying by pumping, gives 2.67 g of the title compound as a colorless solid; Mp. 90-93 ⁰ C (foaming), sintering at 82 ⁰ C

[a] ₀ = + 114 ° (c = l, 0, methanol).

Analysis Calc. For C ₂₄ H ₂₉ F ₃ N ₂ O ₃ · 0.5H ₂ 0

C 58.12; H 6,30; N 5.64; Cl 7,15; Found: C 58.06; H 6,53; N 5.37; Cl 7,00;

Example 11

(3 (R) cis) -1- [2- (Dimethylamine) - - phenylethyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer A

A toluene solution of N, N-dimethyl-2-chloro-2-phenylethylamine is prepared by dispensing 3.59 g of the hydrosodium salt (16.3 mmol) between 15 mL of toluene and 100 mL of aqueous sodium bicarbonate. The aqueous phases are washed with a further 10 ml of toluene,

" ³⁹ " 284 0 0

and the combined organic phases dried (magnesium sulfate) and filtered. To a stirred suspension of 0.75 g of sodium hydride (15.6 mmol of a 50% oil dispersion) in 30 ml of dry dimethylformamide is added 5.0 g of (3 (R) -cis) -3-hydroxy-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (14.2 mmol) as a solid throughout. The solution is stirred for one hour at room temperature, heated to 7O ⁰ C and the toluene solution of N, N-dimethyl-2-chloro-2-phenylethylamine is added dropwise over a period of 2 hours. A solution of 1 g of the above-described hydrochloride salt (4.5 mmol) and 0.51 g of potassium t-butoxide (4.5 mmol) is stirred in 5 ml of dimethylformamide for 2 minutes and added to the alkylation reaction. The resulting solution was stirred at 7O ⁰ C for an additional 2.25 hours and quenched with aqueous sodium bicarbonate. The solvents are removed under high vacuum and with gentle heating. The residue is partitioned between ethyl acetate and aqueous sodium bicarbonate, the organic phase is washed with brine, dried (magnesium sulfate), filtered and concentrated to a light yellow, foamy, gummy substance. The crude product is dissolved in 25 ml of ether, seeded with (3 (R) -is) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, cooled and after filtration gives 0.25 g of (3 (R) -cis) -2-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one. Concentration of the mother liquor yields 7.23 g of a foamy solid which is extracted on silica gel (2% methanol / 0.5% triethylamine / dichloromethane) and 1.90 g of pure FMI (faster running isomer) in the form of a light yellow foamy solid results. A solution of 0.41 g of pure FMI is dissolved in ether and treated with hydrogen chloride saturated ether. The white solid is filtered, washed twice with ether,

- ⁴⁰ - 2 3 4 U κ s

dried in air to give 0.41 g of white solid. This material is dissolved in 2 ml of isopropanol / 6 ml of isopropyl ether with heating, and the solution is filtered off from a small amount of insoluble material. The filtrate is treated with hexane and the resulting white solid is separated by filtration, dried to give 0/39 g of the title compound; Mp 136-142 ⁰ C

[a] _D = + 146.2 ° (c = 1, methanol).

Analysis calculated for C ₂₈ H _{3 0} (MIF ₃ N ₂ -G ₃ · 0.52 mol H ₂ O.

C 61.77; H 5.75; N 5:14; Cl, 6.51; F, 10.47; found: C 61.77; H 6.02; N 5.26; Cl 6,46; F 10,63.

Example 12

(3 (R) cis) -1- [2- (Dimethylamine) -1-phenylethyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) ^ Hl-benzazepine ^ -one monohydrochloride, isomer B

From the chromatography of (3 (R) -is) -1- [2- (dimethylamino) -1-phenylethyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer A, no fractions are obtained with pure SMI (slower running isomer). Fractions containing SMI contaminated with FMI and (3 (R) -is) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one) are collected, concentrated and yielded 3.40 g of crude SMI. This material is again chromatographed over silica gel (2% methanol / 0.5% triethylamine / dichloromethane) to give 0.81 g SMI containing traces of FMI and significant amounts of (3 (R) -is) -3-hydroxy-4-. (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one. This fabric is on 6 plates

" ⁴¹ " 23 4 0 05

for preparative thin layer chromatography (5% methanol / dichloromethane), the major band cut out, extracted twice with 5% methanol / 1% triethylamine / dichloromethane, the combined extracts concentrated to give 0.41 g of the pure free base of the title compound. This material is dissolved in ether, filtered through Celite to remove turbidity, and hydrogen chloride is added to saturated ethers. The resulting white solid is filtered, washed twice with ether, dried in air to give 0.42 g of the title compound, a white solid; Mp. 165-171 ⁰ C. [a] _D = + 221.8 ° (c-1, methanol).

Analysis calculated for C ₂₈ H ₃₀ N ₂ O ₃ ClF ₃ -O ^ g H ₂ O.

C, 61.84; H 5.74; N 5.15; Cl, 6.51; F, 10.48; found: C, 61.84; H 5.81; N 5.07; Cl 6,12; F 10,18.

Example 13

[3 (R) - [1 (S *), 3a, 4a]] - 3- (acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethy. 1) -6- (trifluoromethyl) -1H-benzazepine-1-monohydrochloride

A) N- (Benzyloxycarbonyl) -2-pyrrolidinemethanol Powdered anhydrous potassium carbonate (41 g, 297 mmol) is added with stirring to a solution of (S) -2-pyrrolidinemethanol (6 g, 59.32 mmol) in acetone. (120 ml). The mixture is cooled to ⁰ ° C. and benzyl chloroformate (16.94 ml, 118 _f 6 mmol) is added dropwise. After 40 minutes, dilute the reaction mixture with ethyl acetate and water. The organic phase is separated off; the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried / concentrated (magnesium sulphate) and concentrated. The crude oil

- 42 - λ _Λ

ZS 4 ο O 5

is chromatographed on silica gel with 25% ethyl acetate in hexane to give the title compound (12.22 g) as a pale yellow oil.

B) (S) -1- (Benzyloxycarbonyl) -2- (bromomethyl) -pyrrolidine

Triphenylphosphine (4.46 g, 17 mmol) and carbon tetrabromide (5.64 g, 17 mmol) are added to a solution of N- (benzyloxyparbonyl) -2-pyrrolidinemethanol (2 g, 8.5 mmol) in ether (100 mL). given. The mixture is stirred at room temperature for 19 hours, cooled, and the precipitated solids are filtered off. The remaining solids are washed with hexane. The filtrate is concentrated and purified by chromatography on a silica gel column with 10 to 20% ethyl acetate in hexane. The title compound (2.11 g) is obtained in the form of a colorless oil.

C) [3 (R) - [I (S *), 3a, 4a]] - 1 - [(benzyloxycarbonyl-2-pyrrolidinyl) -methyl] -3-hydroxy-1,3,4,5-tetrahydro-4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

(3 (R) -is) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.8 g, 2.3 mmol) becomes Suspension of sodium hydride (0.066 g, 2.7 mmol) in dimethylformamide (23 ml). After one hour at room temperature, add (S) -1- (benzyloxycarbonyl) -2- (bromomethyl) -pyrrolidine (0.97 g, 3.4 mmol). The reaction mixture is heated for 2.5 hours at 65 ⁰ C, and then further amounts of sodium hydride (0.028 g, 1.14 mmol) and (S) -1- (benzyloxycarbonyl) -2- (bromomethyl) -pyrrole (0, 33 g, 1.14 mmol).

- 43 -

After a further hour at 65 ⁰ C, the mixture is cooled, diluted with water and extracted three times with ethyl acetate. The ethyl acetate extracts are combined, washed with 10% aqueous lithium chloride, dried (magnesium sulfate) and concentrated. The reverse residue is chromatographed over a silica gel column with 20-40% ethyl acetate in hexane to give the title compound (0.8 g).

D) [3 (R) - [1 (S *), 3a, 4a]] - 3-Aetoxy-1 - [(1-benzyloxycarbonyl-2-pyrrolidinyl) -methyl] -1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

N, N-dimethylaminopyridine (0.45 g, 3.7 mmol) is added to a solution of [3 (R) - [1 (S *), 3a, 4a]] - 1 - [(benzyloxycarbonyl-2-pyrrolidinyl) - methyl] -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.14g, 1.85mmol and acetic anhydride (0.87 mL, 9.24 mmol) in dichloromethane (20 mL). The mixture is stirred at room temperature for 4 days, adsorbed on silica gel (60 mesh) and flash chromatographed on a silica gel column with 10 to 40% ethyl acetate in hexane. The title compound (0.68 g) is obtained in the form of a viscous oil.

E) [3 (R) - [l (S *), 3a, 4a]] - 3- (acetoxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (2- pyrrolidinyl-methyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

44 -

Ammonium formate (0.23 g, 3.64 mmol) is added as a whole to a suspension of 10% palladium on charcoal (0.05 g) and [3 (R) - [1 (S *), 3α, 4α] j- 3-acetoxy-1 - [(benzyloxycarbonyl-2-pyrrolidinyl) methyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2- on (0.48 g, 0.73 mmol) in methanol (10 mL). The mixture is heated at reflux for 30 minutes, then cooled and filtered through celite. The remaining solids are washed with ethyl acetate. The filtrate is concentrated and a white foam is obtained, which is dissolved in ether and treated with an excess of ethereal hydrogen chloride solution. The solution is concentrated and crystallized from toluene / hexane to give the title compound (0.325 g) as an off-white solid; M.p. 217-219 ⁰ C. [a] _D = + 78.8 ° (c = 1, 0, methanol).

Analysis calc'd for C ₂ H _{2 7} F ₃ N ₂ O _4. HCl-O, 29 H ₂ O;

C, .566; H 5.37; N 5.42; Cl 6,86; F 11.02; Found: C 58.37; H, 5.57; N, 5.54; Cl 7.05; F 10.58.

Example 14

[3 (R) - [I (S *), 3a, 4a]] - 3- (acetoxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - [(l-methyl 2-pyrrolidinyl) -methyl] -6- (trifluoromethyl) -1H-benzazepine ^ -one monohydrochloride

A) (S) - (+) - N- (t-Butyloxycarbonyl) -2-pyrrolidine-methanol

To a solution of (S) - (+) - 2-pyrrolidinemethanol (10g, 100mmol) in dry dichloromethane (250ml) is added at 0 to 5 ^° C over a period of

- 45 -

A solution of di-t-butyl dicarbonate (26 g, 119 mmol) in 100 ml of dichloromethane was added dropwise for 30 minutes. After 6 hours at room temperature, the reaction mixture is concentrated to give the title compound (23.5 g) as a viscous oil.

B) (S) - (+) - N -methyl-2-pyrrolidinemethanol

A solution of (S) - (+,) - N- (t-butyloxycarbonyl) -2-pyrrolidinemethanol (17.5 g crude product, 87 mmol) in dry tetrahydrofuran (100 ml) at 0 to 5 ⁰ C of a suspension of Lithium aluminum hydride (11.4 g, 300 mmol) was added dropwise. The mixture is heated at reflux for 16 hours. It is then cooled in an ice-water bath, and excess hydride is destroyed by dropwise addition of a saturated sodium sulfate solution. The mixture is diluted with ethyl acetate and filtered through anhydrous magnesium sulfate. The remaining solid is washed thoroughly with ethyl acetate. The combined filtrates are concentrated under reduced pressure to give a yellow oil which is distilled to give the title compound; Bp. 97 ° C / 50 mm Hg.

C) (S) -2- (Chloromethyl) -1-methylpyrrolidine Thionyl chloride (3.28 ml, 45 mmol) is added to a solution of (S) - (+) - N-methyl-2-pyrrolidinemethanol (1.73 g 15 mmol) in chloroform (15 ml) at 0 to 5 ⁰ C added dropwise. The mixture is heated at reflux for 2 hours and then concentrated. The crude residue is crystallized from acetone / ether to give the title compound (1.48 g) as the hydrochloride salt.

- 46 - 28 4 0

D) [3 (R) - [1 (S *), 3a, 4a]] - 1 - [(1-methyl-2-pyrrolidinyl) -methyl] -3-hydroxy-1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

(3 (R) -is) -3-hydroxy-4 ~ (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.7 g, 2 mmol) becomes a suspension of Add sodium hydride (0.13 g, 5.4 mmol) in dimethylformamide (20 mL). The mixture is stirred at room temperature for one hour, cooled to ⁰ ° C., and the hydrochloride salt of (S) -2- (chloromethyl) -1-methylpyrrolidine (0.52 g, 3 mmol) is added Sodium hydride (0.012 g, 0.5 mmol) was added, the mixture was stirred for a further 3 hours and then diluted with water, extracted with ethyl acetate, and the ethyl acetate extract was washed with 10% aqueous lithium chloride, dried ( The crude residue is chromatographed on silica gel with 2 to 5% methanol in dichloromethane to give the title compound (0.65 g) as a white foam.

E) [3 (R) - [l (S *), 3a, 4a]] - 3- (acetoxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - [(1 -methyl-2-pyrrolidinyl) methyl] -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

N, N-dimethylaminopyridine (0.41 g, 3.34 mmol) is added to a solution of [3 (R) - [I (S *), 3a, 4a]] - l - [(1-methyl-2-) pyrrolidinyl) methyl] -3-hydroxy-l, 3,4,5-

- 47 -

tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.75 g, 1.67 mmol) and acetic anhydride (0.79 mL, 8.4 mmol) in Dichloromethane (18 ml). The mixture is stirred at room temperature for 24 hours. It is absorbed on coarse silica gel and flash chromatographed on a silica gel column with 2 to 3% methanol in dichloromethane., To give the title compound ils free base. The free base is dissolved in ether and then treated with an excess of ethereal hydrogen chloride solution. Another 20 ml of ether are added, the precipitated salts are decanted and dried at 7O ⁰ C in vacuo. The title compound (0.536 g) is obtained in the form of a white solid; Mp. 151-154 ⁰ C. [oc] _D = + 80.0 ° (c = l, 0, methanol).

Analysis calculated for C ₂₆ H ₂₉ F ₃ N ₂ CvHCl-O ^ _H2O.

C 58.00; H 5.85; N 5.20; Cl, 6.59; F 10.59; Found: C 57,74; H 5.56; N 4.93; Cl 7.01; F 10,16.

Example 15

r3 (R) - [l (R *), 3a, 4cr]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6- (trifluoromethyl) Ⓒ Hl-benzazepine-monohydrochloride

A) (R) -N- (benzyloxycarbonyl) -2-pyrrolidine-methanol

Benzyl chloroformate (6 mL, 39.5 mmol) is dissolved at ⁰ ° C. in a suspension of powdered anhydrous potassium carbonate (13.7 g, 99 mmol) and (R) -2-pyrrolidinemethanol (2 g, 19.8 mmol) in acetone (100 ml) was added dropwise. After 1 hour, dilute the reaction mixture with water and ethyl acetate. The

- 48 - 2 β 4 OO 5

organic phase is separated; the aqueous phase is extracted twice with ethyl acetate. The combined organic extracts are dried (magnesium sulfate), filtered and concentrated. The crude oil is chromatographed on a silica gel column with 20 to 60% ethyl acetate in hexane to give the title compound (4.57 g).

B) (R) -1- (Benzyloxycarbonyi) -2- (bromomethyl ) -pyrrolidine

A solution of (R) -N- (benzyloxycarbonyl) -2-pyrrolidinemethanol (4.55 g, 19.3 mmol), triphenylphosphine (10.2 g, 30.7 mmol) and carbon tetrabromide (12.8 g, 38, 7 mmol) in ether (200 ml) is stirred at room temperature overnight. The reaction mixture is diluted with hexane and filtered. Concentrate the filtrates and chromatograph the residue on a silica gel column with 5-10% ethyl acetate in hexane. The title compound (3.59 g) is obtained in the form of a colorless solid.

C) [3 (R) - [I (R *), 3a, 4a]] - 1 - [(1-Benzyloxycarbonyl-2-pyrrolidinyl) -methyl] -3-hydroxy-1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

(3 (R) -cis) -3-Hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (2.46 g, 7 mmol) is added to a suspension of sodium hydride (0.25 g, 10.5 mmol) in dimethylformamide (70 mL). The mixture is stirred at room temperature for 1 h and (R) -1- (benzyloxycarbonyl) -2- (bromomethyl) -pyrrolidine (3 g, 10.5 mmol) is added. The reaction mixture 4 hours at 8O ⁰ C

- 49 -

2θ 4 O O 5

and added more methanol (0.08 g, 3.5 mmol). For more ? Hours at 8O ⁰ C, the mixture is cooled ur '' - quenched with water. It is then extracted three times with ethyl acetate. The combined extracts are washed with a 10% aqueous solution of lithium chloride, dried (magnesium sulfate) and concentrated. The residue is chromatographed over a silica gel column using 1% methanol in dichloromethane to give the title compound (4.32 g) contaminated with unreacted (3 (R) -cis) -3-hydroxy-4- (4-methoxyphenyl) - 6- (trifluotmethyl) -2H-l-benzazepin-2-one.

D) [3 (R) - [I (R *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinyl) methyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

Ammonium formate (1/8 g, 28.3 mmol) is dispersed in total as a suspension of 10% palladium on charcoal (1 g) and [3 (R) - [1 (R *), 3α, 4α]] - l [(1-benzyloxycarbonyl-2- (pyrrolidinyl) methyl] -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6-trifluoromethyl) -2H-l-benzazepin-2- on (3.5 g, 5.66 mmol) in methanol (60 mL). The mixture is heated at reflux for 1.5 hours, cooled and filtered through celite. The remaining solid is washed with chloroform. The combined filtrates are concentrated and the residue is chromatographed on a silica gel column with 3 to 10% methanol in dichloromethane to give the free base of the title compound. The free bases are dissolved in ether and treated with an excess of ethereal hydrogen chloride solution. Concentrate under reduced pressure and finally in

- 50 -

284 o 05

Vacuum gives the title compound (0.21 g) as a white solid; Mp. 147-151 ⁰ C. [Ot] ₀ = + 108.5 ° (c «l, 0, methanol).

Analysis calculated for C ₂₃ H ₂₅ F ₃ N ₂ O ₃ · HCl-H ₂ O.

C 56.50; H 5.77; N 5.73; Cl 7.25; F, 11.66; found: C 56.76; H 5.74; N 5.50; Cl 7,12; F 11.36

Example 16

[3 (R) - [I (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6 - (trifluoromethyl) - ^ H-benzazepine - ^ - on monohydrochloride

A) [3 (R) - [I (S *), 3a, 4a]] - 1 - [(1-benzyloxycarbonyl-2-pyrrolidinyl) -methyl)] - 3-hydroxy-1, 3,4,5- tetrahydro-4- (4-methoxyphenyl) -6- ('. rifluoromethyl) -2H-1-benzazepin-2-one

(3 (R) -cis) -3-Hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.41 g, 4 mmol) is added to a suspension of sodium hydride (0.19 g, 4.8 mmol) in dimethylformamide (40 mL). After one hour, (S) -I- (benzyloxycarbonyl) -2- (bromomethyl) pyrrolidine (1.7 g; 6 mmol) was added and the mixture heated for 1.5 hours at 8O ⁰ C. Additional sodium hydride (0.05 g, 2 mmol) and (3 (R) -CX) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0 , 75 g, 2 mmol) is added. The reaction mixture is heated for a further 2 hours, cooled and quenched by the addition of water. It is then extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with 10% aqueous

- 51 -

Washed lithium chloride, dried (magnesium sulfate) and concentrated. The crude residue is chromatographed on a silica gel column with 30 to 50% ethyl acetate in hexane to give the title compound (1.12 g) as a white foam.

B) [3 (R) - [I (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinyl) methyl) -6- (trifluoromethyl) -1H-benzazepine-1-monohydrochloride ^ - -

Ammonium formate (0.57 g, 9.1 mmol) is added to a suspension of 10% palladium on charcoal (0.34 g) and [3 (R) - [1 (S *), 3α, 4α]] - l- (1-benzyloxycarbonyl-2-pyrrolidinyl) methyl] -3-hydroxy-l, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one (1.12 g, 1.82 mmol) in methanol (40 mL). The mixture is heated at reflux for 30 minutes, cooled and filtered through anhydrous magnesium sulfate. The remaining solid is washed with ethyl acetate. The combined filtrates are concentrated and then chromatographed on a silica gel column with 2 to 5% methanol in ethyl acetate followed by 10% methanol in dichloromethane to give the title compound free base (0.72 g). The free base is dissolved in ethyl acetate and treated with an excess of an ethereal solution of hydrogen chloride, concentrated in vacuo at 7O ⁰ C and dried to give the title compound (0.64 g); Mp 159-163 ⁰ C

[a] ₀ = + 71.3 ° (c = l, 0, methanol).

- 52 -

284OO

Analysis calc. For C ₂₃ H _{2 5} F ₃ N ₂ O ₃ .HCl-0.5 H ₂ O;

C 57.56; H 5.67; N, 5.84; Cl 7,39; F 11,88; Found: C 57.34; H 5.84; N 5.62; Cl 7,31; F 12,17.

Example 17

(3 (R) -CXS) -3- (acetoxy) -1- [2- (dimethylamino) -2-methylpropyl] -1, 3, 4, 5-tetrahydro-'4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

A stirred solution of 1.9 g (3.9 mmol) of (3R-cis) -1- [2- (dimethylanu.no) -2-methylpropyl] -1,3,4,5-tetrahydro-3-hydroxy -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride (see Example 10) in 50 ml of acetic anhydride is heated in an oil bath to a temperature of 110 to 124 ⁰ C (bath temperature ) heated. The acetylation is relatively slow and about 4.25 hours of heating is needed until the starting material can no longer be detected by TLC. In a side reaction, a by-product with a high R _f gradually forms during heating. After cooling, the bulk of the acetic anhydride is removed using a rotary evaporator at 0.2 mm Hg and the remaining oil (3, g) is taken up in 10 ml of ethyl acetate. As no crystallization occurs, the ethyl acetate is stripped off and the oil is triturated in ether to give a solid. The bulk of the ether is decanted and the material is triturated in fresh ether and cooled overnight.

The colorless solid, which becomes gelatinous, is filtered under argon, washed with ether (hygroscopic) and dried in vacuo. Free of solvents, the solid is no longer hygroscopic and long

- 53 -

can be exposed to the atmosphere; Weight 1.23 g; . Mp 88-91 ⁰ C (bubbles); Sintering at 81 ^° C.

[ot] _D = + 104 ° (c = l, 0, methanol).

Analysis calculated fo. C ₂₆ H ₃₁ N ₂ O ₄ -HCl-H ₂ O;

C 57.09; H 6,26; N 5.12; Cl 6,48; Found: C 57.46; H 6,46; N, 4.84; Cl 6,33.

Example 18

(3 (R) cis) -l- [l - [(dimethylamine) methyl] propyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- ( trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer B

A) (3 (R) -is) -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

To a stirred solution of 10 g of (3 (R) -is) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (28.5 mmol). and 4.85 g of imidazole (71.2 mmol) in 10 ml of dry dimethylformamide are added at 35 ^° C. 5.10 g of t-butyldimethylsilyl chloride. The solution is stirred at 35 ⁰ C overnight, cooled to room temperature and distributed to ether and water. The organic phase is washed with water and brine, dried (magnesium sulfate), concentrated to give 14.2 g of the title compound as an amorphous solid; Mp. 114-116 ⁰ C.

B) (3 (R) -cis) -3- (t -butyldimethylsiloxy) -1- [1- (cyano) -propyl] -4- (4-methoxyphenyl). -6- (trifluoromethyl) -2H-1-benzazepin-2-one

To a stirred solution of 0.54 g of sodium hydride (11.2 mmol of a 50% oil dispersion) in 10 ml of dry dimethylformamide are added 4 g of (3 (R) -is) -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (8.6 mmol) was added as a solid as a whole. The solution is stirred for 30 minutes, 1.33 g of 2-chlorobutyronitrile (12 _r 9 mmol) are added undiluted, and the solution is heated to 75 ⁰ C for one hour. A further 0.15 g of sodium hydride and 0.3 g of 2-chlorobutyronitrile are added, heated und'die solution for 45 minutes at 75 ⁰ C. The solution is quenched with 1 M ammonium chloride and dimethylformamide is removed in vacuo with gentle heating. The residue is partitioned between ether and 1 M ammonium chloride, the organic phase is washed with water and saturated brine, dried (magnesium sulfate), concentrated to give 4.68 g of a brown gum. Thin layer chromatography (50% ether / hexane) reveals a 3: 2 mixture of diastereomers of the product: the faster isomer (R _f = 0.63) and the slower isomer (R _f = 0.56). Flash chromatography on silica gel (30% ether / hexane) gives 1.10 g of the title compound, the faster-moving isomer, as a white solid; Mp. 54-57 ⁰ C.

C) (3 (R) -is) -1- [1 - [(Amino) -methyl) -propyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxypbenyl) -6- (trifluoromethyl) -2H-I benzazepine-2-one

A solution of 1.10 g of (3 (R) -cis) -3- (t-butyldimethylsiloxy) -1- [1- (cyano) -propyl] -4- (4-methoxyphenyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one (2.06 mmol) and 0.27 g rhodium on alumina in

-55- 2 RA nr \

100 ml of ammonia-saturated methanol is hydrogenated at 352 kPa (50 psi) for 6 hours. An additional 0.10 g of rhodium on alumina is added, the solution again saturated with ammonia and hydrogenated at 352 kPa (50 psi) for an additional 2 hours. The solution is filtered through celite, the celite is rinsed twice with methanol, the combined filtrates are concentrated to give 1.17 g of a foamy solid. Flash chromatography on silica gel (2% methanol / 0.5% triethylamine / dichloromethane) gives 0.70 g of the title compound as a gum.

D) (3 (R) -is) -1- [1 - [(dimethylamino) -methyl] -propyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H -l-benzazepin-2-one

To 0.26 g of solid sodium cyanoborohydride (4.2 mmol) at ⁰ ° C. in portions with stirring is added a solution of 0.70 g of (3 (R) -cis) -1- [1- (amino) -methyl] -propyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin ~ 2-one (1.30 mmol) and 1.2 ml of 37% aqueous Formaldehyde in 10 ml of acetonitrile followed by 0.14 ml of pure acetic acid. The ice-bath is removed, the solution stirred for 2 hours, an additional 0.05 ml of acetic acid added, and the solution stirred for a further 30 minutes. The solution is partitioned between ether and 10% aqueous potassium carbonate, the ether phase is washed with brine, dried (magnesium sulfate), concentrated to give 0.91 g of a thick oil. Flash chromatography on silica gel (1% methanol / 0.2% triethylamine / dichloromethane) gives 0.49 g of the title compound as a clear gum.

- 56 -

2 8 ^ 005

E) (3 (R) -cis) -1- [1- [(dimethylamino) -methyl] -propyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer B

A solution of 0.49 g of (3 (R) -cis) -l- [1- (dimethyl-mino) -methyl] -propyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.87 mmol) in 10 ml of dry dimethylformamide was added 0.55 g of tetrabutylaluminum fluoride trihydrate (1.74 mmol) in whole as a solid. The solution is stirred for 20 minutes, partitioned between ether and water, the organic phase washed with brine, dried (magnesium sulfate), concentrated to give 0.49 g of a semi-solid. Preparative thin layer chromatography (3 plates, 5% methanol / dichloromethane) gives 0.35 g of the free base of the title compound as a white, crystalline solid. The free base is suspended in ether, ethyl acetate added to give a clear solution followed by hydrogen chloride saturated ether. The resulting white solid is quickly separated by filtration, washed with ether, dried in vacuo to give 0.24 g of the title compound as a white solid; Mp. 144-148 ⁰ C. [Ct] ₀ = + 89.60 ° (c = l, methanol).

Analysis calculated for C ₂₄ H ₃₀ ClF ₃ N ₂ O _{3 2} O -IfOeH.

C 56f96; H 6,38; N 5.45; F 11.11; Cl 7,24; Found: C 56.96; H 6.40; N, 5.54; F 11,26; Cl 7,00.

- 57 -

² 840O ₅

Example 19

(3 (R) -cis) -l- [l - [(Dimethylamino) methyl] propyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- ( trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer A.

A) (3 (R) -is) -3- (t-butyldimethylsiloxy) -1- [1- (cyano) -propyl] -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine -2-one

By chromatography of the nitrile mixture described for (3 (R) -cis) -1- (1- (dimethylamino) -methyl] -propyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4- methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride (see Example 18), no pure slower moving isomer (SMI) can be obtained SMI-containing fractions are collected, concentrated and yielded 1.91 g This material is flash chromatographed over silica gel (25% ether / hexane) to give 1.21 g of the almost pure SMI of the title compound as a white solid.

B) (3 (R) -cis) -1- [1- (amino) -methyl] -propyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1 benzazepine-2-one

A solution of 1.21 g of (3 (R) -cis) -3- (t-butyldimethylsiloxy) -1- [1- (cyano) -propyl] -4- (4-methoxyphenyl) -6- (trifluoromethyl) - 2H-1-Benzazepin-2-one (2.27 mmol) and 0.30 g of 5% rhodium on alumina in 75 mL of ammonia-saturated methanol is hydrogenated at 50 psi for 5 hours. The solution is filtered through Celite and the combined filtrates are concentrated. There are 1.36 g

< ν

the raw title compound in the form of a clear rubbery substance.

C) (3 (R) -is) -1- [1- (dimethylamino) -methyl] -propyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H- l-benzazepin-2-one

To 0.46 g of solid sodium cyanoborohydride (7.26 mmol) at ⁰ ° C. in portions and with stirring is added a solution of 1.36 g of (3 (R) -cis) -1- [1- (amino) -methyl ] -propyl] -3- (t -butyldimethylsioxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (2.27 mmol) and 2.1 ml of 37% pure aqueous formaldehyde in 20 ml of acetonitrile, followed by 0.3 ml of pure acetic acid. The ice-bath is removed, the solution stirred for 2 hours, an additional 0.15 ml of acetic acid added, and the solution stirred for 2 hours. The solution is partitioned between ether and 10% aqueous potassium carbonate, the ether phase washed with 10% aqueous potassium carbonate and saturated brine, dried (magnesium sulfate), concentrated to give 1.31 g of a clear gum. Flash chromatography on silica gel (1% methanol / 0.5% triethylamine / dichloromethane) gives 1.02 g of a white foamy solid containing the crude title compound. This material is chromatographed on six preparative thin-layer plates (25% ethyl acetate / hexane), the band excised with R _f = 0.52 and extracted with 5% methanol / dichloromethane. The extract is filtered, the filtrate concentrated to give 0.44 g of the title compound as a light brown gum.

- ⁵⁹ - On,

2S 4 ο Ο 5

D) (3 (R) -cis) -1- [1- (dimethylamino) -methyl] -propyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - ( trifluoromethyl) -4H1-benzazepine-monohydrochloride, isomer A.

To a solution of 0.44 g of (3 (R) -cis) -1- [1- (dimethylamino) methyl] propyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) Add -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.78 mmol) in 10 mL of dry dimethylformamide, 0.49 g of tetrabutylammonium fluoride trihydrate (1.56 mmol) as a whole The solution is stirred for 25 minutes, partitioned between ether and water, the organic phase washed with saturated brine, dried (magnesium sulfate), concentrated to give 0.45 g of a brown gum.Process thin layer chromatography (3 plates, 2% methanol / dichloromethane) 0.36 g of the free base of the title compound in the form of a white crystalline solid, the free base is dissolved in ether, the solution filtered through Celite and hydrogen chloride saturated ether added to the filtrate, the resulting white solid is collected by filtration, washed twice Ether washed, dried in vacuo and gives 0.35 g of T Itelverbindung in the form of a white solid; Mp 126-131 ⁰ C

[a] ₀ = + 106.8 (c = l, methanol).

Analysis calculated for C ₂₄ H ₃₀ ClF ₃ N ₂ O ₃ · 0.78 H ₂ O.

C 57.54; H 6,35; N 5.59; Cl 7.08; F 11.38; Found: C 57.54; H 6,39; N 5.64; Cl 6,96; F 11.09.

- 60 -

0 O ₅

Example 20

(3 (R) -cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- [1-methyl-2- (methylamino) ethyl] -6- ( trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer B

A) (3 (R) -is) -3- (t -butyldimethylsiloxy) -1- (1-cyanoethyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one '

To a stirred solvent of (3 (R) -cis-3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (4 g; 60 mmol, see Example 18) in dry dimethylformamide (40 ml) is added sodium hydride in the form of a 60% oil dispersion (380 mg, 9.50 mmol) The solution is stirred at room temperature for 30 minutes and undiluted 2-chloropropionitrile (0, 8.66 mmol) the solution is for one hour at 5O ⁰ C heated, further 0.02 g of sodium hydride and 0.07 ml of 2-chloropropionitrile was added and the reaction heated to 5O ⁰ C for 3 hours the solution, 68 ml.. The reaction mixture is cooled to room temperature, concentrated in vacuo to remove the dimethylformamide, and the brown residue is partitioned between ethyl acetate and water The organic phase is washed with water and saturated brine, dried (magnesium sulfate), concentrated, and the residue taken through a silica gel column 5% ethyl acetate / hexane are chromatographed 1.76 g of the faster isomer of the title compound and 1.0 g of the slower moving isomer.

- 61 -

284

B) (3 (R) -cis) -1- [1- (amino) methyl] ethyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1 benzazepine-2-one

A solution of (3 (R) -cis) -3- (t -butyldimethylsiloxy) -1- (1-cyanoethyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 on (0.8g, 1.5mmol) in methanol (100ml) is added gaseous ammonia at ⁰ ° C for 5 minutes, saturated and 5% rhodium on alumina (0.2g) added. The solution is hydrogenated at 45 psi * for 1> 5 hours, additional catalyst (100 mg) added, and the solution hydrogenated at 55 psi for an additional hour. The mixture is filtered through Celite, which is subsequently rinsed with methanol. The combined filtrates are concentrated to give 0.75 g of the title compound.

C) (3 (R) -cis) -1- [1- (trifluoroacetylamino) -methyl] -ethyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H -l-benzazepin-2-one

To a solution of (3 (R) -cis) -1- [1- (amino) -methyl] -ethyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) 2 H-1-benzazepin-2-one (0.76 g, 1.46 mmol) and pyridine (0.37 mL, 4.66 mmol) in dichloromethane (10 mL) is added a solution of trifluoroacetic anhydride (0.41 mL 2.91 mmol) in 5 ml of dichloromethane over a period of 2 minutes and the solution stirred at room temperature overnight. Additional pyridine (0.37 ml, 4.66 mmol) and trifluoroacetic anhydride (0.41 ml) in 5 ml of dichloromethane are added and the solution is stirred for 20 minutes. The solution is extracted with water and saturated brine, dried (magnesium sulfate),

$ 28,400

concentrated to give 0.77 g of the title compound in the form of a red oil.

D) (3 (R) -cis) -1- [1- ([trifluoroacetyl) methylamino) methyl] ethyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- ( trifluoromethyl) -2H-l-benzazepin-2-one

To a solution of (3 (R) -cis) -1- [1- (trifluoroacetylamino) methyl] ethyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-Benzazepin-2-one (570 mg, 0.94 mmol) in dry dimethylformamide (5 mL) is added sodium hydride as a 60% oil dispersion (44.9 mg, 1.12 mmol). The solution is stirred at room temperature for 30 minutes, methyl iodide (0.07 ml, 1.12 mmol) is added, and the solution is stirred at room temperature for a further 2 hours. The solution is partitioned between ethyl acetate and water, the organic phase washed with water and saturated brine, dried (magnesium sulfate), concentrated to give 450 mg of the title compound as a red oil.

E) (3 (R) -CiS) -I- [1- (methylamino) -methyl] -ethyl] -3-

(T-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6-trifluoromethyl) -2H-l-benzazepin-2-one

A mixture of (3 (R) -cis) -1- [1- ([trifluoroacetate) -methylamino) -methyl] -ethyl] -3- (t -butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (450mg, 0.72mmol) and sodium carbonate (0.5g, 4.72mmol) in methanol (20mL) is heated at reflux overnight. The reaction is cooled to room temperature and

- 63 -

2% IO O $

concentrated and the residue is distributed zv / dichloromethane dichlorine and water. The; organic phase is washed with water and saturated brine, dried (magnesium sulfate) and concentrated. The residue is chromatographed over three preparative silica gel plates with 5% methanol / dichloromethane. The bands of the product are excised and extracted with 5% methanol / dichloromethane / 0.5% triethylamine. The mixture is filtered through Celite, then rinsed with dichloromethane. The combined filtrates are concentrated and the residue gives 230 mg of the title compound as a yellow oil.

F) (3 (R) -CiS) -1,3,4,5-Tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- [1-methyl-2- (methylamino) ethyl] -6 - (trifluoromethyl) -1H-benzazepine ^ -one monohydrochloride, isomer B

To a solution of (3 (R) -cis) -1- [1- (methylamino) -methyl] -ethyl] -3- (t-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-Benzazepin-2-one (1.2 g, 2.24 mmol) in dry tetrahydrofuran (50 mL) is added tetrabutylammonium fluoride trihydrate (1.06 g, 3.36 mmol). The solution is stirred overnight, concentrated, and the residue is partitioned between dichloromethane and water. The organic phase is washed with water and brine, dried (magnesium sulfate), concentrated to give 0.8f. g of a yellow oil. The residue is chromatographed on four preparative silica gel plates with 10% methanol / dichloromethane. The bands of the product are cut out and with 15%

- 64 -

Methanol / dichloromethane / O, extracted 5% triethylamine. The compound is dissolved in ether and hydrogen chloride-saturated ether added. A white solid is formed, which is filtered, rinsed with ether and gives 320 mg of the pure title compound; Mp 178-18O ⁰ C. [a] _D = + 63.90 (c = 1, ethanol).

Analysis calc. For C ₂ H _{2 5} F ₃ N ₂ O ₃ HCl-O, 98 H ₂ O;

C 55.45; H 5.90; N 5.73; Cl 7,94; F, 11.61; Found: C 55.45; H 5.91; N "9, -8-8; -Cl 7.44; F 11.96.

Example 21

(Cis) -l- (2-aminophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

A) (Ice) -1- (2-Nitrophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine-2 on

To a solution of 125 mg of sodium hydride (3.15 mmol of a 60% oil dispersion) in 5 ml of dry dimethylformamide is added 1.0 g (2.86 mmol) of (cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl- (6-trifluoromethyl) -2H-1-benzazepin-2-one. The solution is stirred at room temperature for 35 minutes, and 0.32 ml (3.0 mmol) of 2-fluoronitrobenzo.l are added dropwise undiluted. The solution is stirred at room temperature for 105 minutes and heated to 45 ⁰ C for 40 minutes. The solvent is removed under high vacuum with gentle heating, and the residue partitioned between ether and 1 M ammonium chloride solution. The organic phase is washed twice with water

- 65 -

and once with saturated brine, dried (magnesium sulfate), concentrated to give a yellow foamy solid which is dissolved in 25 ml of ether. Addition of 175 ml of hexane and cooling overnight give 0.78 g of the title compound A (58%) as a yellow crystalline solid.

B) (cis) -1- (2-Aminopheny1) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine-2 on-monohydröchlorid

A solution of 0.73 g (1.55 mmol) of the title compound A and 146 mg of 10% palladium on charcoal in 50 ml of absolute ethanol is hydrogenated for 4.25 hours and filtered through Celite. The celite is washed twice with ethanol and the combined filtrates are concentrated. The residue is dissolved twice in CCl ₄ , concentrated, and gives 0.73 g of a white foamy solid whose ¹ H and ¹³ C NMR spectra show the almost pure free base of the product. The residue is dissolved in 50 nl of ether and filtered through celite to remove turbidity. After adding hydrogen chloride-saturated ether and allowing to stand for 30 minutes, the white precipitate is separated by filtration, washed twice with ether, dried in vacuo at 75 ^° C. for several days to give 0.58 g (79%) of the title compound in the form a white powdery solid; Mp. 165-17O ⁰ C.

Analysis calcd. For C ₂₅ H ₂₃ F ₃ N ₂ O ₂ .0.9 HCl-0.19 H ₂ O;

C 63.00; H 5:13; N 5.88; F 11,96; Cl 6,96; Found: C 63.00; H, 4.87; N 6.03; F 11,79; Cl 6,55.

- 66 - ο _Λ

28 4 0 0 $

Example 22

(3 (R) -cis / -l- [2- (dimethylamino) phenyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethy1) -2H -l-beni: azepin-2-one inonohydrochlorid

A) (3 (R) -cis) -1- (2-nitrophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-hydroxy-6- (trifluoromethy 1) - 2H-1-bijnzazepine-2-one '

To a solution of (3 (R) -cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -1H-benzazepin-2-one (2 g, 5.69 mmol) in In dry dimethylformamide (1 ml), sodium hydride is added to a 60% oil dispersion (230 mg, 5.59 mmol) and the solution is stirred at room temperature for one hour and added to a solution of 1-fluoro-2-one. The reaction is stirred overnight at room temperature, concentrated in vacuo to remove the dimethylformamide, and the residue is partitioned between ethyl acetate and 1N The organic phase is washed with water and saturated brine, dried (magnesium sulfate), concentrated to give a yellow O]. The oil is dissolved in warm ethyl acetate and the yellow solid which crystallizes from the solution is filtered off, washed with cold ethyl acetate to give 1.68 g (63%) of the title compound A.

B) (3 (R) -is) -1- (2-nitrophenyl) -1,3,4,5-tetrahydro-4-methoxyphenyl) -S-acetyloxy-ö- (trifluoromethyl) -1H-1-benzazepine 2-one

"" "2S4 0 05

To a stirred solution of the title compound A (1.68 g, 3.56 mmol) and 4-dimethylaminopyridine (50 mg) in tetrahydrofuran (50 ml) is added pyridine (0.32 ml, 3.92 mmol), followed by acetic anhydride ( 0.44 ml, 4.63 mmol), and the reaction is stirred at room temperature overnight. The solution is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3x50 ml). The combined organic phases are washed with water, 1 N sodium bicarbonate and saturated brine and dried (magnesium sulfate). The solvent is removed in vacuo to give 0.85 g (46%) of the title compound B as a yellow solid.

C) (3 (R) -cis) -1- (2-aminophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-acetyloxy-6- (trifluoromethyl) -2H-1 benzazepine-2-one

To a solution of the title compound B (0.85 g, 1.65 mmol) in 100 mL of acetonitrile is added 10% palladium on charcoal (0.2 g). The solution is hydrogenated at 352 kPa (50 psi) for 3 hours. The mixture is filtered through Celite, which is then rinsed with acetonitrile. The combined filtrates are concentrated to give 0.60 g (75%) of the title compound C.

D) (3 (R) -c is) -1- (2-dimethylaminophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -S-acetyloxy-ö- (trifluoromethyl) Ⓒ benzazepin monohydrochloride

A solution of the title compound C (120 mg, 0.25 mmol) and 37% formaldehyde (0.6 ml) in

- 68 -

Acetonitrile (5 ml) is added to solid sodium cyanoborohydride (62 mg, 0.98 mmol). The reaction is stirred at room temperature for ΰ minutes, followed by the addition of 0.1 ml of acetic acid. Another 0.1 ml of acetic acid is added after 2 hours. The solution is partitioned between ethyl acetate and aqueous potassium carbonate. The organic phase is washed with aqueous potassium carbonate, water and brine, dried (magnesium sulfate) and concentrated. The residue is dissolved in ether and hydrogen chloride-saturated ether added. The result is a white solid. It is found by ¹ H-NMR that the acetyl group is partially hydrolyzed.

(3 (R) -cis) -1- [2- (dimethylamino) -phenyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) ^ hl-benzazepin monohydrochloride

A mixture of the title compound D (420 mg, 0.79 mmol) and potassium carbonate (2 g) in methanol (30 ml) is refluxed under argon for 5 hours. The reaction is cooled to room temperature, concentrated in vacuo and the residue extracted with dichloromethane. The organic phase is washed with water and brine, dried (magnesium sulfate) and concentrated. The residue is chromatographed on four preparative silica gel plates with ethyl acetate / hexane (1: 1). The bands of the product are excised and extracted with dichloromethane. The solution is filtered through celite, which is subsequently rinsed with dichloromethane. The combined filtrates are concentrated. The yellow solid is dissolved in ether and hydrogen chloride-saturated ether added. The slightly yellow

- 69 -

Ϊ8400

The solid is filtered, rinsed with ether to give 302 mg (74%) of the pure title compound; Mp 217-22O ⁰ C [Ci] ₀ = + 243.4 ° (c = l, 3, ethanol).

Analysis calculated for C ₂₆ H ₅ F ₃ N ₂ 0 ₂ · HCl-0 72 H ₂ O.

C 60.07; H 5.31; N 5.38; Cl, 6.81; F, 10.96; Found: C 60.07; H 5,27; N 5.18; Cl 6,89; F 10.62.

Example 23 - - - -

(3 (R) -cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyridinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepine -2-one monohydrochloride

A stirred solution of 5.0 g (14.2 mmol) of (3 (R) -is) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one In 150 ml of butanone, 2.8 g (17.1 mmol) of 2-chloromethylpyridine hydrochloride and 5.0 g (36.2 mmol) of powdered potassium carbonate are added and the mixture is refluxed overnight. TLC (95: 5 dichloromethane / methanol) shows completion of the reaction. After combining with an earlier batch (0.5 g), the solids are filtered off, washed with butanone and most of the solvent is removed using a rotary evaporator. The residue is shaken with 150 ml of ethyl acetate and 50 ml of water, the phases are separated, the organic phase washed with water (50 ml), saturated brine (50 ml), dried (magnesium sulfate), the solvent to 0.2 mm Hg deducted and leads to 7.3 g of a slightly yellow foamy residue. After standing over the weekend, the residue described above is taken up in ether to remove slightly insoluble

oranges material filtered, concentrated and dried by pumping. It gives 6.9 g of a slightly yellowish friable foam. TLC: R _f = 0.65 (95: 5 dichloromethane / methanol).

The above-described base in 50 ml of methanol is treated with 3.5 ml of 5 N ethanolic hydrochloric acid and the solvent stripped to a pressure of 0.2 mm Hg. The semi-solid residue is triturated in ether and the concentration repeated, which after drying by pumping to 8.3 g of a light? yellow solid leads. Subsequent crystallization from 90 ml of hot isopropanol yields 6.95 g (93%) of colorless product: mp 184-186 ⁰ C (foaming);. Sublimation at 17O ⁰ C. [CC] ₀ = + 97.0 ° (c = l, 0, methanol).

Analysis calculated for C ₂₄ H ₂₁ N ₂ F ₃ O ₃ -HCl-O ^ SH ₂ O.

C 58.54; H, 4.81; N 5.69; Cl 7,20; Found: C 58.46; H 5.15; N 5.34; Cl 7,24.

Example 24

(3 (R) cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-piperidinylmethyl) -6- (trifluoromethyl) -2H-l-benzazepin -2-one monohydrochloride, isomer A

A solution of 3.00 g (6.09 mmol) of the title compound of Example 23 in 200 ml of ethanol is treated with 0.30 g of PtO ₂ and in a Parr apparatus under a hydrogen pressure of 352 kPa (50 psi) for 2 hours hydrogenated. Examination by TLC at this point reveals that the reduction of the pyridyl group is complete. The catalyst is filtered off under nitrogen and the solvent stripped to give a solid residue. This is dissolved in 30 ml of acetonitrile and with 330 ml of ether

- 71 -

2β4 ο ο 5

diluted to form a solid. This mixture is cooled overnight, filtered, yielding 1.29 g (43%) of isomer A; Mp 177-18O ⁰ C (sublimation 16O ⁰ C). The isomer A is dissolved in 20 ml of hot isopropanol, filtered through a filter aid (to remove the last traces of the catalyst), cooled overnight, and filtered. This gives 0.72 g of a nearly colorless solid; [a] _D = + 112 ° (c = l, 0 methanol). After recrystallization from 18 ml of hot isopropanol, the product weighs 0.63 g (21%); Mp 177-18O ⁰ C (sublimation 16O ⁰ C); [a] ₀ + 113 * (c = l, 0, methanol); R _f = 0.59 (80:20 dichloromethane / methanol).

Analysis calculated for C ₂₄ H ₂₇ F ₃ N ₂ O ₃ · HCl 0.25 H ₂ O.

C 58.89; H 5.87; N 5.72; Cl 7,24; Found: C 58.82; H 5.90; N 5.68; Cl 7,23.

(3 (R) -is) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-piper-1-ylmethyl) -6- (trifluoromethyl) -2H -l-benzazepin-2-one-iuonohydrochloride, isomer B

Concentration of the filtrate, obtained during the first crystallization of isomer A, gives 1.46 g of the crude isomer B. Conversion to the free base followed by chromatography over 35 g of silica gel with dichloromethane / methanol (15: 1) gives 0.48 g of the pure isomer. This material is dissolved in 5 ml of chloroform and treated with 0.22 ml of 5.1 N hydrochloric acid in 3 ml of chloroform. Removal of the solvent in vacuo gives a solid which is triturated with ether. There are 0.54 g of the product; Mp 130-140 ⁰ C. [Ot] ₀ = + 66.0 ° (c = l, 0 methanol)

" ⁷² " 2ö4 0 05

Analysis of C ₂₄ H ₂₇ F ₃ N ₂ O ₃ -HCl-I ^ SH ₂ O;

C, 56.80; H 6.05; N, 5.52; Cl 6,98; found: C 56.77; H 5.77; N 5.39; Cl 6,93.

Example 25

[3 (R) - [1 (R *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (S-piperidinyl) -6- (trifluoromethyl) 2H-1-benzazepin-2-one inonohydrochloride.

A) [3 (R) - [I (S *), 3α, 4α]] - [(benzyl-2-pyrrolidinyl) -methyl] -3-hydroxy-1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

and

B) [3 (R) - [I (R *), 3a, 4a]] - 1- (benzyl-3-piperidinyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4- methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

Sodium hydride (1.44 g, 59.9 mmol) is added with stirring to a solution of (d-cis) -3- (acetoxy) -1- [2- (dimethylamino) ethyl] -1,3,4,5 -tetrahydro-4 - [(4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride (10 g, 28.5 mmol) in dry dimethylformamide (250 mL). After one hour at room temperature, the mixture is cooled to ⁰ ° C. and (S) -l-benzyl-2- (chloromethyl) -pyrrolidine (7.36 g, 30 mmol) is added as a whole. The mixture is warmed to room temperature and stirred for 4 hours. It is diluted with saturated aqueous potassium bicarbonate solution and extracted three times with ethyl acetate. The combined organic extracts are washed with 10% aqueous lithium chloride, dried (magnesium sulfate), filtered and concentrated. The orange solid is dissolved in a minimum amount of 0.5 N hydrochloric acid and

- 73 - Oo,

? 84005

extracted with ether three times to give unreacted (dcis) -3- (acetoxy) -1- [2- (dimethylamino] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) - To remove 2H-1-benzazepin-2-one monohydrochloride, solid sodium chloride is added, and the aqueous phase is extracted three times with ethyl acetate The combined extracts are dried (magnesium sulfate), filtered, concentrated to give the crude title compounds A and B in the form The adducts of title compound A and B can not be separated at this point and are taken over in the next step without further purification.

C) [3 (R) - [I (S *), 3a, 4a]] - 1 - [(2-pyrrolidinyl) methyl] -3-hydroxy-1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

and

D) [3 (R) - [I (R *), 3a, 4a]] - 1- (3-piperidinyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

Ammonium formate (9.58 g, 151.9 mmol) is added to a suspension of 10% palladium on charcoal (3.7 g) and a mixture of the title compound A and B (18.5 g, 33 mmol) under argon in dry Methanol (350 ml). The mixture is refluxed for 5 hours, cooled and filtered through anhydrous magnesium sulfate. The remaining solids are washed well with methanol. The filtrate is concentrated, dissolved in a minimum amount of water and washed three times with ether. The aqueous phase is basified with potassium bicarbonate and thrice

- 74 -

extract with ethyl acetate. The combined extracts are washed with water, dried (magnesium sulfate), filtered and concentrated. A mixture of the title compound C and the title compound D (10.89 g, 76%) is obtained in the form of a slightly yellow foam. The isomers can not be separated and are taken over in the next step without further purification.

E) [3 (R) - [I (S *), 3a, 4a]] - 1 - [(benzyloxycarbonyl-2-pyrrolidinyl) -methyl] -3-hydroxy-1, 3,4,5-tetrahydro-4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l ~ benzazepin-2-one

and

[3 (R) - [I (R *), 3a, 4a]] - 1- (benzyloxycarbonyl-3-piperidinyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

To a mixture of the title compounds C and D (7.07 g, 16.3 mmol) in 1,4-dioxane (80 mL) and saturated aqueous potassium bicarbonate (30 mL) is added benzyl chloroformate (5.84 g, 32.5 mmol). The reaction mixture is immediately diluted with water and extracted three times with ethyl acetate. The combined extracts are washed with brine, dried (magnesium sulfate), filtered and concentrated. The crude yellow liquid is chromatographed over silica gel with 15 to 30% ethyl acetate in hexane to give the title compound E (7.89 g, 85%, R _f = 0.38 (silica gel, 50% ethyl acetate / hexane)) and the title compound F (0.87 g, 9.4 % ΐ R _f = 0.50 (silica gel, 50% ethyl acetate / hexane)).

- 75 -

28 4 O O

G) [3 (R) - [I (R *), 3α, 4α]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (3-piperidinyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one inonohydrochloride

To a solution of the title compound F (800 mg, 1.41 mmol) in ethyl acetate (25 mL) and trifluoroacetic acid (1 mL) was added, with stirring, palladium hydroxide on charcoal (160 mg). The reaction flask is equipped with a balloon filled with hydrogen; The reaction flask is evacuated three times under reduced pressure and filled with hydrogen. The mixture is then stirred at room temperature overnight, before the hydrogen is removed and magnesium sulfate (anhydrous) is added. The solids are separated by filtration and washed well with ethyl acetate. The filtrate is washed three times with aqueous potassium bicarbonate. The combined aqueous phases were extracted with ethyl acetate and the organic extracts were combined, dried (magnesium sulfate), filtered and concentrated. The crude residue is triturated in 20 ml of ether and the precipitated free amine is filtered and dried. A white solid (420 mg) is obtained, which is dissolved in 5 ml of dichloromethane, to which an ethereal hydrogen chloride solution (5 ml) is added. Concentrate the solution under reduced pressure and finally in vacuo to give the title compound (450 mg, 68%) as a white solid; Mp. 183-188 ⁰ C. [Q] ₀ = + 102.6 (c = l, methanol).

- 76 -

Analysis calculated for C ₂₃ H ₂₅ F ₃ N ₂ O ₃ -HCl-H ₂ O. C 56.51; H 5.77; N 5.73; Cl 7.25;

Found: C 56.58; H 5.75; N, 5.53; Cl 7.02.

Example 26

[3 (R) - [1 (R *), 3a, 4a]] - 3- (acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (3-pipöridinyl) -6- (trifluoromethyl) - 1H-benzazepine-1-one-monohydrochloride

A) [3 (R) - [I (R *), 3a, 4a]] - 1- (benzyloxycarbonyl-3-piperidinyl) -3-acetyloxy-l, 3,4,5-tetrahydro-4- (4- methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

To a solution of the title compound F of Example (880 mg, 1.53 mmol) in ethyl acetate (20 mL) is added dropwise acyl chloride (700 μL) . The reaction mixture is heated to 7O ⁰ C for 24 hours, then it is cooled and excess acetyl chloride destroyed by the addition of methanol (2 ml). The mixture is diluted with ethyl acetate and washed three times with aqueous potassium bicarbonate. The combined aqueous phases are extracted once with ethyl acetate. The organic extracts are combined, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The result is Tite compound A (920 mg, 100%) in the form of a white foam.

- ^ΊΊ - 28 4

B) [3 (R) - [l (R *), 3ci _f 4a]] - 3- (Acetyioxy) -l, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (3- piperidinyl) -6- (t.rif luomethyl) -2H-1-benzazepine-2-one monohydrochloride

To a solution of the title compound A (920 mg, 1.53 mmol) in ethyl acetate (25 mL) and trifluoroacetic acid (1 mL), 200 mg of palladium hydroxide on activated carbon (Pearlman's catalyst) is added with stirring. The reaction flask is equipped with a Baiion-filled with hydrogen. The flask is evacuated three times under reduced pressure and filled with hydrogen from the balloon. Then it is stirred at room temperature overnight, then the balloon is removed. Anhydrous magnesium sulfate is added to the reaction mixture and filtered through a pad of magnesium sulfate. The solids are washed with ethyl acetate. The filtrates are washed three times with aqueous potassium bicarbonate. The combined aqueous phases are extracted twice with ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and concentrated. The brown oily residue (770 mg) is chromatographed on a silica gel column pre-treated with 1% triethylamine with 5% methanol in ethyl acetate to give the free amine (430 mg) as a white foam. The free amine is dissolved in dichloromethane and an excess of ethereal hydrogen chloride is added. The solution is concentrated under reduced pressure to give the title compound (420 mg, 65%) as a white solid; Mp 177-18O ⁰ C. [a] ₀ = + 107.9 ° (c = 1, methanol).

- 78 -

2840 Austrian

Analysis calcd. For C ₂₅ H ₂₇ F ₃ N ₂ O ₄ -HCl-O 1 H ₂ O;

C, 56.91; H 5.66; N, 5.31; Cl 6,72; F, 10.80; found: C, 56.84; H 5.67; N 5.38; Cl, 6.41; F 10,79.

Example 27

[3 {R) - [1 (S · '), 3a, 4a]] -6-chloro-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) rl- (2- pyrrolidinylmethyl) 2H-1-benzazepin-2-one

A) (S) -N-t-Butoxycarbonyl-2-pyrrolidinemethanol

(S) - (+) - 2-Pyrrolidinemethanol (15 g, 148.3 mmol) and di-t-butyl dicarbonate (40 g, 178 mmol) are stirred in dichloromethane (500 ml) at room temperature for 5 hours. The solvent is removed under reduced pressure and the crude product is reacted in the next step (B) without further purification.

B) (S) -N-t · Bu-oxycarbonyl-2 »(bromomethyl) -pyrrolidine

The title compound A (29, 148.3 mmol), triphenylphosphine (77.8 g, 297 mmol) and carbon tetrabromirri (99 g, 297 mmol) are stirred in ether (1000 mL) for 18 h at room temperature. The festival".! Precipitate is removed by filtration and the solid washed well with hexane. Concentration of the filtrate gives a yellow liquid which, after chromatography on a silica gel column with 0 to 5% ethyl acetate in hexane, gives the title compound B (17.49 g, 45%) as a colorless liquid.

- 79 -

C) [3 (R) - [I (S), 3α, 4α]] - 1 - [(t-Butoxycarbonyl) -2-pyrrolidinyl) -methyl] -3-hydroxy-1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

(Ice) -6-Chloro-4- (4-methoxyphenyl) -3-hydroxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (3.0 g, 9.44 mmol) is added to a suspension of sodium hydride (0.27 g, 11.33 mmol) in dimethylformamide (95 mL, stored over 4A molecular sieves) and stirred for <3 h. The title compound B (3.0 g, 11 , 33 mmol) is added, and the mixture is heated to 8O ⁰ C for 3 hours. Additional amounts of sodium hydride (0.11 g, 4.58 mmol) and title compound B (1.25 g, 4.72 mmol) are added. The reaction is heated for a further 2 hours at 80 °, cooled, quenched by the addition of water and extracted three times with ethyl acetate. The combined extracts are washed three times with 10% aqueous lithium chloride, dried (magnesium sulfate), and concentrated The crude yellow liquid is chromatographed on a silica gel column with 5 to 20% ethyl acetate in hexane to give the title compound C (0.65 g; 7%; [a] _D = + 135.2 ° (0 = 1.0, methanol)).

D) [3 (R) - [I (S *), 3a, 4a]] - 6-chloro-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- ( 2-pyrrolidinylmethyl) -2H-l-benzazepin-2-one

A solution of the title compound C (0.67 g, 1.34 mmol) and trifluoroacetic acid (1 mL, 13.1 mmol) is stirred in dichloromethane (10 mL) at room temperature for 6 hours. To make the reaction mixture alkaline, saturated aqueous potassium bicarbonate is added, which is then diluted with water

- 80 -

and extracted three times with ethyl acetate. The combined extracts are dried (magnesium sulfate), filtered, concentrated and give the crude product, which is chromatographed on preparative silica gel plates. This gives the title compound (0.28 g, 52 %) in the form of a pale yellow foam; Mp. 80-84 ⁰ C, [a] _D = + 148.0 ° (c = l, methanol).

Analysis calc'd for C ₂ H _{2 5} ClN ₂ O ₃ .42H ₂ O; C 64.70; H 6,38; N-6, -86-; Cl, 8.68;

found: C 64.96; H 6,34; N 6.60; Cl 8,78.

Example 28

[3 (R) -t1 (S *), 3a, 4a]] - 3- (acetyloxy) -6-chloro-l, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (2 -pyrrolidinylmethyl) -2H-l-benzazepin-2-one

A) [3 (R) - [I (S *), 3a, 4a]] - l - [(t-butoxycarbonyl-2-pyrrolid ^J .nyl) methyl] -3-acyetyloxy) -1, 3,4 , 5-tetrahydro-4 (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

N, N-Dimethylaminopyridine (0.35 g, 2.88 mmol) is added to a solution of the title compound C from Example 27 (0.72 g, 1.44 mmol) and acetic anhydride (0.68 mL, 7.2 mmol) in Dichloromethane (20 ml) was added. The mixture is stirred at room temperature for 18 hours, adsorbed on silica gel (60 to 200 mesh), chromatographed on a silica gel column with 10 to 20% ethyl acetate in hexane to give the title compound A (0.66 g, 85%) as a white foam ,

- 81 -

2S 4 O O

B) [3 (R) - [l (S *), 3a, 4a]] - 3- (acetyloxy) -6-chloro-l, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - (2-pyrrolidinylmethyl) -2H-l-benzazepin-2-one

A solution of the title compound A (0.65 g, 1.20 mmol) and trifluoroacetic acid (1.37 mL, 18.0 mmol) is stirred in dichloromethane (15 mL) at room temperature for 1.5 hours. To the reaction mixture is added saturated aqueous potassium hydrogen carbonate, followed by water, then extracted three times with ethyl acetate, dried (magnesium sulfate), filtered, concentrated to give the title compound (0.53 g, 100%) as a white foam; Mp. 74-78 ⁰ C. [a] _D = + 130.0 ° (c = l, methanol).

Analysis calculated for C ₂₄ H ₂₇ ClN ₂ O ₄ · 0.29H ₂ O. C, 64.33; 6:20; N 6.25; Cl, 7.91;

found: C, 64.61; H 6.09; N, 5.97; Cl 7.51.

Example 29

[3 (R) - [1 (2R *), 3α, 4α]] - 1- [2- (dimethylamino) -1-pheny1-propyl] -1,3,4,5-tetrahydro-3-hydroxy-4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A.

A) 1 (S), 2 (R) -2- (N, N-dimethylamino) -l-phenyl-1-propanol

To a suspension of 20 g of l (S), 2 (R) - (+) - norephedrine hydrochloride (106 mmol) in 50 mL of ether is added 21 g of 25% sodium methoxide in methanol (100 mmol). Another 50 ml of methanol are added and the solution is stirred for several minutes and filtered. The white precipitate is rinsed several times with ether, and the combined

- 82 -

Concentrated filtrates. This gives 16.6 g of the free base of l (S), 2 (R) - (+) - norephedrine in the form of a clear oil (100%). The free base is dissolved in 125 ml of acetonitrile and 37% aqueous formaldehyde (42 ml) added. With intermittent cooling through an ice bath, 10.5 g of sodium cyanoborohydride (167 mmol) are added in portions as a solid. Again with intermittent cooling, glacial acetic acid is added dropwise until the pH drops to 8. The solution is stirred at room temperature for 30 minutes and concentrated. The residue is extracted from 2 N sodium hydroxide solution three times with ether, the combined ether phases are washed with 0.5 N sodium hydroxide solution and extracted three times with 10% strength hydrochloric acid. The combined acid phases are neutralized with solid sodium hydroxide and extracted three times with ether. The combined ether layers are washed with saturated brine, dried (potassium carbonate), concentrated to give 15.6 g of the title compound A (82%) as a white crystalline solid.

B) l (R), 2 (R) -2- (N, N-dimethylamino) -l-phenyl-1-chloropropane

To a solution of the title compound A (15.2 g, 70.5 mmol) in dichloromethane (100 mL) is added dropwise thionyl chloride (20.6 mL, 282 mmol) in dichloromethane (100 mL) over a period of one hour. The addition of 200 ml of carbon tetrachloride and cooling to ⁰ ° C. does not give a solid product. Dichloromethane is distilled off and the remaining solution is cooled overnight, yielding a 1: 1 mixture of the 1 (R), 2 (R) and 1 (S), 2 (R) isomers of the title compound B as a pink

- 83 -

$ 28,400

Solid leads. It is obtained by filtration, followed by washing three times with hexane and drying in air. Recrystallization from 150 ml of acetone / 5 ml of methanol gives 0.98 g of the title compound B, isomer A in the form of light brown prisms

[a] ₀ = -110.9 (c = l, methanol).

C) [3 (R) - [I [2 (R *)], 3a, 4a]] * * 1- [2- (Dimethyland.no) -1-phenylpropyl] -3- (t -butyldimethylsiloxy) -1 , 3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin ~ 2-one, isomer A.

To a suspension of 93 mg of sodium hydride (1.93 mmol of a 50% oil dispersion) in 4 ml of dry dimethylformamide are added 0.75 g of 3-t-butyldimethylsilyl ether of (3 (R) -cis) -3-hydroxy-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.61 mmol). The solution is stirred for 10 minutes, heated to 7O ⁰ C and a solution of 0.87 g of the title compound B (3.22 mmol) and 0.36 g of potassium t-butoxide (3.22 mmol) in 2 ml of dry dimethylformamide added. The heating and stirring are continued for 70 minutes, an additional 45 mg of sodium hydride and 0.22 g of the title compound B are added, and the solution is heated for a further 90 minutes. The solution is quenched with aqueous potassium carbonate, dimethylformamide is removed under high vacuum with gentle heating, and the residue is partitioned between ether and aqueous potassium carbonate. The organic phase is washed with saturated brine, dried (magnesium sulfate), concentrated and gives 1.51 g of a light yellow oil. Flash chromatography on silica gel with 40% ethyl acetate / hexane gives 0.58 g of the title compound C as a white foamy

- 84 -

Solid, contaminated with about 20% of the imidate from the alkylation on the carbonyl oxygen of the amide.

D) [3 (R) - [1 [2 (Λ *)], 3a, 4a]] - 1- [2- (dimethylamino) -1-phenyl-propyl] -1,3,4,5-tetrahydro-3 -hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A.

To a solution of the crude title compound C (0.58 g; 1, 02 mmol) in dry tetrahydrofuran (25 mL) is added tetrabutylammonium fluoride trihydrate (0.68 g, 1.56 mmol) as a solid as a whole. The solution is stirred for 20 minutes and partitioned between ether and water. The aqueous phase is washed with ether, the combined organic phases are washed with saturated brine, dried (magnesium sulfate) and concentrated to give 0.51 g of a clear gum. This material is chromatographed over three preparative silica gel thin plates with 5% mathanol / dichloromethane. The band corresponding to R _f 0.48 (10% methanol / dichloromethane) is extracted with 10% methanol / dichloromethane / 0.5% triethylamine and the solution is filtered, concentrated to give 0.37 g of free base Title compound in the form of a white foamy solid. The free base is dissolved in ether, filtered through a pad of celite, and hydrogen chloride saturated ether added. The resulting white precipitate is collected by filtration, rinsed with ether, dried to give 205 mg of the title compound as a white, powdery solid; Mp> 220 ° C. [a] ₀ = + 180.0 (c = l, 0, methanol).

- 85 -

Analysis calculated for C ₂₉ H ₃₁ F ₃ N ₂ O ₃ -HCl-I ^ oH O _2.

C, 60.92; H 6.09; N 4,90; F 9,97; Cl 6,20; found: C, 60.92; H 6.05; N 4.74; F 9.76; Cl 6,11.

Example 30

[3 (R) - [l [2 (R *)] - 3a, 4a)] - 1- [2- (Dimethylamino) -1-phenylpropyl] -1, 3,4,5-tetrahydro-3-hydroxy -4- (4-metho-phenyl) -6- (trifluoromethyl) -H-benzazepine-monohydrochloride, isomer B - ** -

A) [3 (R) - [1 [2 (R *)] -3α, 4α]] -1- [2- (dimethylamino)) -1-phenylpropyl] -3- (t-butyldimethylsiloxy) -1,3 , 4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer B

To a suspension of 1.08 g of sodium hydride (22.6 mmol of a 50% oil dispersion) in dry dimethylformamide (10 ml) are added 3-t-butyldimethylsilyl ether of (3 (R) -is) -3-hydroxy-4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (3.5 g, 7.52 mmol). The solution is stirred for 30 minutes, a 1: 1 mixture of 1 (R), 2 (R) - and 1 (S), 2 (R) - (Ν, Ν-dimethylamino) -1-phenyl-1 chloropropane (3.05 g, 13 mmol, see Example 29) as a solid, and the solution is stirred and heated to 65 ^° C. for one hour. The solution is quenched with aqueous sodium bicarbonate, dimethylformamide is removed under high vacuum and gentle warming, and the residue is partitioned between ether and aqueous potassium carbonate. The organic phase is washed with saturated brine, dried (magnesium sulfate), concentrated and

- 86 -

gives 6.18 g of a thick brown oil. Flash chromatography on silica gel with 75% ether / hexane followed by 75% ethyl acetate / kexane gives 1.18 g of the crude title compound A (R _f = 0.41 in 50% ethyl acetate / hexane) contaminated with small amounts of the faster running one Isomers (Compound C from Example 29). Flash chromatography of this material on silica gel with 50% ethyl acetate / hexane gives 0.84 g of the title compound A (18%) as a yellow foamy solid.

B) [3 (R) -i1 [2 (R *)] - 3α, 4α]] - 1- [2- (dimethylamino) -1-phenylpropyl] -1,3,4,5-tetrahydro-3-hydroxy -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer B

To a solution of the crude title compound A (0.84 g, 1.34 mmol) in dry tetrahydrofuran (25 mL) is added tetrabutyl ammonium fluoride trihydrate (0.90 g, 2.86 mmol) as a solid as a whole. The solution is stirred for 30 minutes and partitioned between ether and water. The aqueous phase is washed with ether and the combined organic phases are washed with brine, dried (magnesium sulfate), concentrated to give 0.85 g of a clear gum. This material is chromatographed over 4 preparative trickle gel thin layer plates with 75% ethyl acetate / hexane. The corresponding the R _f value of 0.19 (75% ethyl acetate / hexane) band is extracted with 5% methanol / dichloromethane, the solution is filtered, eingeengi: to yield 0.50 g of the free base of the title compound as a white foamy solid. The free base is dissolved in ether, by a

- 87 -

Celite filtered, and hydrogen chloride saturated ether added. The resulting white precipitate is separated by filtration, rinsed with ether and dried. Upon standing, however, it appears hygroscopic. The solid is then dissolved in methanol, concentrated, suspended in hot isopropyl ether, and methanol is added dropwise until a clear solution is obtained. The solution is cooled and the resulting white solid was separated by filtration, dried to give 0 / 4r2 g of the title compound as a white powdery solid, mp. 191-192 ⁰ C.

= + 242.6 (c = l, 05, methanol).

Analysis calculated for C ₂₉ H _{3 1} F ₃ N ₂ O ₃ · HCl 0, 22H ₂ 0.

C, 62.98; H 5.91; N 5.06; Cl, 6.41; F 10,30; Found .; C, 62.98; H 5.79; N 5.04; Cl 6,21; F 10.58.

Example 31

[3 (R) -1 [2 (S *)], 3α, 4α]] - 1 - [(2- (dimethylamino) -1-phenylpropyl] -1,3,4,5-tetrahydro-3-hydroxy- 4- (4-methoxyphenyl) -6- (trifluoromethyl) -Hl-benzazepine-monohydrochloride, isomer B

A) l (R), 2 (S) -2- (N, N-dimethylamino) -l-phenyl-1-propano]

To a stirred solution of 1 (R), 2 (S) - (-) - norephedrir. (25 g, 0 _f 165 mol) and formaldehyde (50 ml of a 37% aqueous solution) in acetonitrile (150 ml) are added at ⁰ ° C 16.3 g of sodium cyanoborohydride (0.26 mol) in several portions. 35 ml of glacial acetic acid are added over a period of 20 minutes. The reaction will

- 88 - 2 ti 4 ο ο 5

Stirred at room temperature for one hour, concentrated to one third of the volume and neutralized to pH with 1 N sodium hydroxide solution. The solution is extracted with 3x100 ml of ether. The combined organic phases are washed with water and saturated brine, dried (magnesium sulfate) and concentrated. The compound is recrystallized from ethanol / water to give 7.01 g (24%) of the title compound A.

B) l (R), 2 (S) -2- (N, N-dimethylamino) -1-phenyl-1-chloropropane

To a stirred solution of the title compound A (2.19 g, 12.22 mmol) in chloroform (25 mL) is added a solution of thionyl chloride (8.89 mL, 122 mmol) in chloroform (15 mL) over a period of 5 minutes dropwise. The reaction is stirred for 15 minutes and concentrated. The dark residue is stirred with chloroform (2x100 ml) and triturated with 50% ether / hexane (3x100 ml). This gives 2.28 g (80%) of the title compound B as a yellow solid containing 15% of the 1S, 2S isomer.

C) [3 (R) - [1 [2 (S *)], 3or, 4or]] -1- [2- (dimethylanu.no) -1-phenylpropyl] -3- (t-butyldimethylsiloxy) -1, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer B

To a stirred solution of the compound of Part A of Example 18 (1.5 g, 3.22 mmol) in dry dimethylformamide (20 mL) is added sodium hydride in the form of a 60% oil dispersion (0.39 g, 9.67 mmol). given. The reaction is one hour under argon at room temperature for the title B compound (0.76 g; 3.22 mmol) is pur added and the reaction was stirred at 5O ⁰ C overnight. The

- 89 -

Solution is cooled to room temperature and concentrated. The residue is partitioned between water and dichloromethane. The organic phase is washed with water and brine, dried (magnesium sulfate) and concentrated. The residue is chromatographed on a silica gel column with 50% ether / hexane to give 1.18 g (56%) of the title compound C.

D) [3 (R) -1 [2 (S *)], 3α, 4α]] - 1 - [(2- (dimethylamino) -l-phenylpropyl] -1, 3,4, 5-tetrerhydro-3 hydroxy-4 - (4-n-ethoxyphenyl) -6- (trifluoromethyl) -2H-1-beri2: azepin-2-one monohydrochloride, isomer B

To a stirred solution of the title compound C (1.18 g, 1.78 mmol) in dry tetrahydrofuran (20 mL) is added tccra-n-butylammonium fluoride trihydrate (1.12 g, 3.56 mmol). The reaction is stirred for one hour at room temperature and then diluted with ether. The organic phase is washed with water and brine, dried (magnesium sulfate) and concentrated. The residue is chromatographed on a silica gel column with ether to give a solid which is dissolved in ether. Hydrogen chloride-saturated ether is added to give a white solid, which is filtered and rinsed with ether to give 470 mg of the pure title compound; Mp 148-151 ⁰ C

[a] _D = + 167.6 (c = 0.75, methanol).

Analysis calculated for C ₂₉ H ₃ F ₃ N ₂ O ₃ · HCl-1,87H ₂ O.

C 59.77; H 6,18; N, 4.80; Cl 6.08; F 9.78; Found: C 59.37; H 5.78; N 4,90; Cl, 6.51; F 9,84.

Example 32

[3 (R) - [1 [2 (S *)], 3α, 4α]] - 1- [2- (dimethylamino) -1-phenylpropyl] -1,3,4, o -tetrahydro-α-hydroxy ^ - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer A - ^. - -

A) l (S), 2 (S) -2- (N, N-dimethylamino) -l-phenyl-1-chloropropane

To a stirred solution of the compound of Part A of Example 31 (2.19 g, 12.22 mmol) in chloroform (25 mL) is added a solution of thionyl chloride (8.89 mL, 122 mmol) in chloroform (15 mL) dripped a period of 5 minutes. The reaction is stirred for one hour at room temperature and concentrated. The residue is stirred with chloroform (3 × 100 ml), triturated with 50% ether / hexane (4 × 100 ml) and gives a 1: 1 mixture of 1 (R), 2 (S) - and 1 (S), 2 (S. ) Isomers in the form of a yellow amorphous solid. Recrystallization from acetone gives 0.8 g of the pure title compound A.

B) [3 (R) - [l [2 (S *)], 3a, 4a]] - l - [(2- (dimethylamino) -1-phenylpropyl] -3- (t -butyldimethylsiloxy) -1, 3 , 4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A

A mixture of the title compound A (0.4 g, 1.72 mmol) of the compound of Part A from Example 18 (0.8 g, 1.42 mmol) and cesium carbonate (1.7 g, 5.16 mmol) in dry Dimethylformamide (10 ml)

- 91 -

is heated at 55 ⁰ C for 2 hours. The reaction is concentrated in vacuo and the residue triturated in water. The solid is separated and dissolved in ethyl acetate. The organic phase is dried (magnesium sulfate) and concentrated. The residue is chromatographed on a silica gel column with 50% ether / hexane to give 0.7 g of the pure title compound B.

C) [3 (R) - [I [2 (S *)], 3α, 4α]] -1- [2 - (dimethyland.no) -1-phenylpropyl] -1,3,4,5-th " Fcrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer A

To a stirred solution of the title compound B (0.7 g, 1.12 mmol) in dry tetrahydrofuran (20 mL) is added tetra-n-butylammonium fluoride trihydrate (0.35 g, 1.12 mmol). The reaction is stirred for 2 hours at room temperature and concentrated. The residue is partitioned between ethyl acetate and water. The organic phase is washed with water and brine, dried (magnesium sulfate) and concentrated. The residue is chromatographed over 4 preparative silica gel thin-layer plates with dichloromethane. The bands of the product are excised and extracted with 10% methanol / dichloromethane. The compound is dissolved in ether and hydrogen chloride-saturated ether added. The solution is concentrated, stirred with methanol to give 380 mg of the pure title compound as a white solid; Mp. 233-235 ⁰ C.

- 92 - 28 4

Analysis calculated for C ₂₉ H ₃₁ F ₃ N ₂ O ₃ -HCl-O ^ _H2O.

C 61.83; H 6.01; N 4,97; Cl 6,29; F 10,12; found: C 61.77; H 5.81; N 5.03; Cl, 6.54; F 10,00.

Example 33

[3 (R) - [I (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (3-pyrrolidinyl) -6 - (trifluoromethyl) -2H-

l-benzazepin-2-one monohydrochloride, fumaric acid salt (1: 1)

A) 3 (R) -1-Benzyl-3- (p-toluenesulfonyloxy) -pyrrolidine

A mixture of 3 (R) -1-benzyl-3-hydroxypyrrolidine (1 g, 5.6 mmol) and p-toluenesulfonyl chloride (1.6 g, 8.4 mmol) is stirred in pyridine (10 mL) for 4 hours. The reaction mixture is partitioned between a sodium bicarbonate solution and dichloromethane. The organic phase is washed with a sodium bicarbonate solution, followed by saturated brine. It is then dried (sodium sulfate), concentrated with low vacuum and finally concentrated on a high vacuum pump to remove the pyridine traces. The resulting yellow residue is flash chromatographed on a 5x25 cm silica gel column with 50% ethyl acetate / hexane. The pure fractions are concentrated to give 933 mg of the title compound A as a colorless oil.

B) [3 (R) - [I (S *), 3a, 4a]] - 1-benzyl-3-pyrrolidinyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A mixture of (3 (R) -cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

(911 mg, 2.60 mmol), the title compound A (900 mg, 2.72 mmol) and cesium carbonate (4.23 g, 13 mmol) in 26 mL of distilled methyl ethyl ketone are refluxed for 8 hours and stirred at room temperature for 18 hours , Add ethyl acetate (60 ml) and filter the suspension. The filtrate is concentrated and the residue is flash chromatographed on a 5x25 cm silica gel column according to the following elution scheme: 2 L 50% ethyl acetate / hexane, 1 L 66% ethyl acetate / hexane, 500 mL 1% methanol / ethyl acetate. The pure fractions are concentrated to give 1.24 g of a off-white solid. The solid is recrystallized from ethyl ether to give 935 mg (71%) of the title compound B as a white crystalline powder; Mp. 147-149 ⁰ C.

[3 (R) - [I (S *), 3a, 4a]] - l- (3-pyrrolidinyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-l-benzazepin-2-one

A mixture of the title compound B (865 mg, 1.7 mmol), ammonium formate (552 mg, 8.76 mmol) and 10% palladium on charcoal (150 mg) is refluxed in 25 ml of 75% methanol / acetic acid for 4 hours , At the same time, additional amounts of ammonium formate (220 mg, 3.5 mmol) and 10% palladium on charcoal (120 mg) are added, the mixture is refluxed for 30 minutes, then the catalyst is removed by filtration through Celite. The filter cake is washed well with methanol, and the filtrate concentrated in vacuo. The residue is partitioned between a sodium carbonate solution and ethyl acetate. The organic phase becomes more saturated

- 94 -

284 o 05

Brine, dried (sodium sulfate) and concentrated. The residue is passed through a 5x20 cm silica column pre-treated with 94% dichloromethane / 5% methanol / 1% triethylamine _; Flash chromatograph. The column is eluted first with 2 l of 5% methanol / dichloromethane, then with 2 l of 10% methanol / dichloromethane. The pure fractions are concentrated to give 60 mg (84%) of the title compound C as a colorless foam.

D) [3 (R) - [I (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (3-pyrrolidinyl) -6- (trifluoromethyl) -2H-1-benza2epin-2-one, fumaric acid salt (1: 1)

The title compound C (600 mg, 1.4 mmol) is dissolved in 5 ml of methanol and fumaric acid (166 mg, 1.43 mmol) is added as a hot methanolic solution. The solution is concentrated to dryness, the solid residue recrystallized from methanol / ethyl ether to give 650 mg (86%) of the title compound as a colorless crystalline solid; Mp 228-231 ⁰ C

[a] ₀ ²⁵ = + 57.8 ° (c = l, 0 acetic acid).

Analysis calc'd for C ₂ H _{2 3} F ₃ N ₂ O ₃ .C ₄ H ₄ O ₄ ;

C 58.20; H 5.07; N, 5.22; F, 10.62; Found: C 58.09; H, 4.81; N 5.27; F 10.45.

Example 34

[3 (R) - [1 (R *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (3-pyrrolidinyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1)

- 95 -

A) 3 (S) -1-Benzyl-3- (benzoyloxy) -pyrrolidine Diethyl azodicarboxylate (4.8 mL, 30 mmol) is added to a stirred solution of 3 (R) -l-benzyl-3-hydroxypyrrolidine (3.5 20 mmol), triphenylphosphine (7.86 g, 30 mmol) and benzoic acid (6.12 g, 50 mmol) in tetrahydrofuran (200 ml) were added dropwise at room temperature. After stirring for 1.5 hours, the tetrahydrofuran is removed in vacuo and the residue partitioned between 1 N hydrochloric acid and ethyl acetate. The ethyl acetate phase is again extracted with 1N hydrochloric acid, the combined acid phases are basified with solid sodium carbonate. The resulting basic phases are extracted with ethyl acetate. The ethyl acetate phase is washed with water and brine and dried (sodium sulfate). The organic phase is concentrated and the residue is briefly chromatographed over a 5x30 cm silica gel column with 25% ethyl acetate / hexane. The pure fractions are concentrated to give 3.30 g (59%) of the title compound A as a colorless oil.

B) 3 (S) -1-Benzyl-3-hydroxypyrrolidine

1N sodium hydroxide solution (25 ml, 25 mmol) is added to a solution of the title compound A (3.15 g, 11.2 mmol) in methanol (100 ml). The reaction mixture immediately turns cloudy and clears after 30 minutes. After stirring for a further 30 minutes, the methanol is removed in vacuo and the remaining aqueous mixture extracted with ethyl acetate. The organic phase is washed with water and saturated brine. After drying (sodium sulfate), the ethyl acetate is removed in vacuo to give

- 96 -

1.5 g (77%) of the title compound B in the form of a colorless oil.

C) 3 (S) -1-Benzyl-3- (p-toluenesulfonyloxy) -pyrrolidine

A mixture of the title compound B (1.45 g, 8.2 mmol) and p-toluenesulfonyl chloride (2.35 g, 12.3 mmol) is stirred in 16 ml of pyridine for 20 hours at room temperature. The reaction mixture is partitioned between ethyl ether and an aqueous sodium carbonate solution. The organic phase is washed with a sodium carbonate solution, water and saturated brine. After drying (sodium sulfate), the organic phase is first concentrated under a slight vacuum and finally under high vacuum to remove the pyridine traces. The residue is briefly chromatographed on a 5x25 cm silica gel column with 25% ethyl acetate / hexane, which concentrated pure fractions. This gives 2.31 g (85%) of the title compound C in the form of a slightly yellow oil.

D) [3 (R) - [I (R *), 3a, 4a]] - 1- (benzyl-3-pyrrolidinyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4- methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A mixture of the title compound C (2.2 g, 6.64 mmol), (3 (R) -is) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine 2-One (1.86 g, 5.31 mmol) and cesium carbonate (8.65 g, 26.5 mmol) are refluxed in 75 mL of methyl ethyl ketone for 18 hours. The reaction mixture is cooled, diluted with 150 ml of ethyl ether and filtered through Celite. The filtrates are concentrated and the residue is flashed on a 5x25 cm silica column with 75% ethyl acetate / hexane

- 97 -

Chromatograph. This leads only to a partial purification, so that the concentrated fractions (2.35 g, 88% raw material) are again chromatographed on a 5x25 cm silica gel column with 2.5% methanol / Oichlormethan. The pure fractions are concentrated to give 1.64 g (61%) of the title compound D as a white foam.

[3 (R) - [I (R *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (3 'pyrrolidinyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1)

A solution of the title compound D (1.58 g, 3.1 mmol) in 30 mL of glacial acetic acid is hydrogenated over 20% palladium (II) hydroxide on activated carbon for 3 hours at room temperature using a balloon-type flask. Then the catalyst is filtered off, and the filter cake washed with 15 ml of glacial acetic acid. The filtrates are diluted with 150 ml of water and the acidic mixture is basified with solid sodium carbonate. This mixture is extracted with ethyl acetate (150 ml). The organic phase is washed with saturated brine and dried (magnesium sulfate). After concentrating the filtrate, the residue is passed through a 5x25 cm silica column packed with 94% dichloromethane / 5% methanol / 1% triethylamine. The column is eluted as follows: 2 1 5% methanol / dichloromethane and 1 1 10% methanol / dichloromethane. The pure fractions are concentrated to a semi-solid residue which is dissolved in 5% methanol / dichloromethane and filtered through celite. The filtrates are concentrated to give 1.173 g (90%) of the free base as a white foam.

- 98 -

The free base (1.08 g, 2.57 mmol) is dissolved in methanol and fumaric acid (2.98 mg, 2.57 mmol) is added as a hot methanolic solution. The resulting solution is concentrated to a white foam that is recrystallized from hot isopropanol. Filtration and drying in vacuo give 925 mg (68%) of the title compound as a white crystalline solid; Mp. 214-216 ⁰ C. [a] _D ²⁵ = + 58.9 ° (c = 0.50, methanol).

Analysis Calc. For C ₂₂ H ₂₃ N ₂ F ₃ O ₃ -C ₄ H ₄ O ₄ -OjIC ₃ H ₈ O

(Isopropanol);

C, 58.22; H 5:17; N 5:16; F, 10.51; Found: C 58.07; H 5,11; N 5.26; F 10.44.

Example 35

This example corresponds to the title compound of Example 16, but shows an alternative method of preparing the title compound A of Example 16.

[3 (R) - [I (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6 - (trifluoromethyl) ^ H-benzazepin ^ -one monohydrochloride

A. (S) -1- (Benzyloxycarbonyl) -2 - [(4-methylphenyl-sulfonyloxy) -methyl] -pyrrolidine

To (S) -1- (benzyloxycarbonyl) -2-pyrrolidine-methanol (105.7 g, 449 mmol) in pyridine (400 mL) is added slowly at 0 ^° C p-toluenesulfonyl chloride (102.8 g, 539 mmol) , The reaction mixture is warmed to room temperature and stirred for a total of 20 hours. Half of the pyridine is removed under reduced pressure before mixing with

- 99 -

Water is diluted and extracted three times with ether. The combined extracts are extracted three times with dilute aqueous hydrochloric acid / aqueous copper sulfate, dried (magnesium sulfate), filtered, concentrated to give a crude, viscous liquid which is extracted three times with warm hexane. The dark-orange viscous liquid (147.7 g; 84%) solidifies at 5 ⁰ C slowly and gives the title compound A as a pale violet solid.

For example, [3 (R) - [I (S *), 3a, 4a]] - 1 - [(1-benzyloxycarbonyl-2-pyrrolidinyl) methyl] -3-hydroxy-i, 3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

(3R-CXS) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (25g; 71.2 mmol), cesium carbonate (34.8 g; 106.7 mmol) and the title A compound (34.6 g; 89.0 mmol) in dimethylformamide (200 ml) are heated to 5O ⁰ C. After 8 hours additional amounts of title compound A (2.8 g, 7.2 mmol) are added and stirring is continued for a further 12 hours. The reaction mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined extracts are washed three times with 10% aqueous lithium chloride, dried (magnesium sulfate), filtered and concentrated. The light yellow solid is triturated in ether (100 ml) for 30 minutes, then hexane (100 ml) added and stirred for a further 30 minutes. Filtration gives title compound 3 as a light yellow powder (34.5 g).

- 100 -

C. [3R- [I (S *), 3α, 4α]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6- (trifluoromethyl) -1H-benzazepine ^ -one monohydrochloride

The title compound B (35 g, 61.6 mmol), palladium hydroxide on charcoal (7 g) and acetyl chloride (35 mL) in absolute ethanol (700 mL) are charged into a Parr shaker and pressurized for 1 hour and 40 minutes shaken of 352 kPa (50 psi). After all of the hydrogen has evolved, anhydrous magnesium sulfate is added and the reaction mixture is filtered to remove the catalyst. The solids are washed well with absolute ethanol. The filtrate is concentrated and the residue is diluted with saturated aqueous potassium bicarbonate solution and extracted three times with ethyl acetate. The combined phases are dried (magnesium sulfate), filtered, concentrated to give a slightly yellow foam, which is dissolved in methanol (350 ml) and filtered. Fumaric acid (7.15 g, 61.6 mmol) is added and the reaction mixture heated on a steam bath until a homogeneous solution is formed. The solution is cooled and crystallized overnight.

- 101 -

284 0 0

The white crystalline solid is filtered and washed well with ethyl acetate to give the fumaric acid salt of the title compound (29.76 g, 88%). The fumaric acid salt is converted to the free base by washing with aqueous potassium bicarbonate solution and extracting with ether / ethyl acetate three times. An excess of ethereal hydrogen chloride is added to the free base dissolved in ether. The white precipitate is separated, dried and gives the title compound (21.6 g, 100% from the Ftimarat); Mp. 165-167 ⁰ C. [Ct] ₀ = + 75.3 ° (c = l, methanol).

Analysis Calc. For C ₂₃ H ₂₅ F ₃ N ₂ O ₃ -HCl-O ^ H ₂ O

C 57.07; H 5.72; N 5.79; Cl 7,32; F 11,78; Found: C 57.31; H 5.56; N, 5.55; Cl 7,42; F 12.03.

Example 36

[3R- [1 (S *), 3a, 4a]] - 3- (acetyloxy) -1,3,4,5-tetrahydro-7-methoxymethoxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl ) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1)

A. [3R- [1 (S *), 3a, 4a]] - 1 - [(N-Benzyloxycarbonyl-2-pyrrolidinyl) -methyl] -3-hydroxy-1,3,4,5-tetrahydro 4- ( 4-methoxyphenyl) -7- (methoxymethoxy) -2H-l-benzazepin-2-one

A suspension of cis -3-hydroxy-7-methoxymethoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one (1.5 g, 4.37 mmol), anhydrous cesium carbonate (2.84 g; 8.75 mmol) and the title compound A from Example 35 (2.55 g, 6.56 mmol) in dimethylformamide (50 ml) is heated to 58 ^° C. for 28 hours. The reaction mixture is cooled, diluted with water

- 102 -

and extracted three times with ethyl acetate. The organic extracts are combined, washed with 10% aqueous lithium chloride, dried (magnesium sulfate), filtered and concentrated to the crude product. A series of chromatography runs on silica gel columns are performed to isolate the desired (+) isomer of the title compound A. The first column is eluted with 20% ethyl acetate / dichloromethane to isolate the pure (±) -diastereomeres. The second column is eluted with 1 to 10% ether / dichloromethane to give the fast moving isomer of the title compound A (0.44 g; R _f = 0.64 (50% ether / dichloromethane), [a] _O = + 161.31 ° (c = l, 0, methanol)), the slower running isomer (0.08 g, R _f = 0.55 (50% ether / dichloromethane), [a] ₀ = -81.81 ° ( c = 1, 0, methanol)) and some mixed fractions (0.57 g). Final chromatography of the mixed fractions is performed with 4 to 10% ether / dichloromethane to give an additional amount of the faster isomer (0.33 g). The overall yield on the faster isomer is 0.77 g.

[3R- [I (S *), 3α, 4α]] - 1 - [(1-benzyloxycarbonyl-2-pyrrolidinyl) -methyl] -3- (acetyloxy) -1,3,4,5-tetrahydro- 4- (4-methoxyphenyl) -7- (methoxymethoxy) -2H-1-benzaze pin-2-one

The title compound A (0.70 g, 1.25 mmol), 4-dimethylaminopyridine (0.31 g, 2.5 mmol) and acetic anhydride (0.64 g, 6.24 mmol) is stirred at room temperature under argon for 14 hours , The reaction solution is adsorbed on silica gel (60 to 200 mesh) and passed over a silica gel column containing 20 to 40% ethyl acetate.

- 103 -

did / hexane chromatographed. The title compound B (0.74 g) is obtained in the form of a white foam.

C. [3R- [1 (S *), 3a, 4a]] - 3- (acetyloxy) -1,3,4,5-tetrahydro-7-methoxymethoxy-4- (4-methoxyphenyl) -1- (2 -pyrrolidinylmethyl) -2H-l-benzazepin-2-one _f fumaric acid salt (1: 1)

To a solution of the title compound B (0.64 g, 1.06 mmol) in ethyl acetate (10 mL) and trifluoroacetic acid (0.4 mL) was added under stirring palladium hydroxide on charcoal (130 mg). The reaction flask is equipped with a balloon filled with hydrogen. The reaction flask is evacuated under reduced pressure and filled with hydrogen. The mixture is then stirred vigorously at room temperature for 6 hours, then the hydrogen removed and anhydrous magnesium sulfate added. The solids are filtered off with suction and washed well with ethyl acetate. The filtrate is concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The organic phase is washed with aqueous potassium bicarbonate and distributed. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried (magnesium sulfate), filtered, concentrated to give the free amine as a pale orange foam (0.32 g). The free amine is dissolved in methanol (20 ml), fumaric acid (79.3 mg, 0.68 mmol) is added and stirred until a homogeneous solution is obtained. Concentration gives the title compound (0.41 g) as a pale yellow foam; Mp 126-13O ⁰ C [oc] _D = + 89.7 ° (c = 1, methanol).

- 104 -

Analysis Calc. For C ₂₆ H ₃₂ N ₂ O ₆ · C ₄ H ₄ O ₄ · 0.6 H ₂ O

C 60.50; H 6,30; N 4.71; found: C, 60.44; H 6,00; N 4,74.

Example 37

[3R- [1 (2S *, 4R *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-inethoxyphenyl) -1- [[4- (phenylmethoxy) -2-pyrro] idynyl] methyl] -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride - ^f * - -

A. (2S, 4R) -4-Hydroxy-1- (t-butoxycarbonyl) -2-pyrrolidinecarboxylic acid

A suspension of 20.0 g (0.152 mol) of trans-4-hydroxy-L-proline and 38.0 g (0.174 mol) of di-t-butyl dicarbonate in 250 ml of dioxane is gradually treated with 350 ml of 1 N sodium hydroxide solution, then stirred at room temperature for 24 hours. The mixture is concentrated in vacuo to approximately 200 ml, then diluted with 150 ml of water. After washing with ethyl acetate, the aqueous phase is acidified with 6 N hydrochloric acid, saturated with sodium chloride and extracted twice with ethyl acetate. The organic solution is washed with water and saturated brine, dried, concentrated and gives 30.9 g of the title compound A as a tan solid; Mp. 104-106 ⁰ C.

28 4 O O

- 105 -

Analysis calc. For C ₁₀ H ₁₇ NO ₅ :

C, 51.94; H 7.40; N 6.05; Found: C, 51.31; H, 7.65; N 5.67.

B. (2S, 4R) -4- (phenylmethoxy) -1- (t-butoxycarbonyl) -2-pyrrolidinecarboxylic acid

A solution of 7.04 g (30 nunol) of the title compound A unci 5.2 g (0.030 mol) Benzyloromid (benzyl chloride is used qenfauso) in 70 ml dimethylformamide in a dry ice bath of -78 ⁰ C with 0.38 g (9 The solution is washed with ethyl acetate and acidified to pH 2 with 6N hydrochloric acid, saturated with sodium chloride, and extracted twice with ethyl acetate to give 7 , 16 g of an oil Flash chromatography with ethyl acetate gives 4.44 g of the title compound B.

Analysis calc. For C ₁₇ H ₂ 3 NO ₅ :

C 63.53; H 7,21; N 4,35; Found: C 63.08; H 7:38; N 4.06.

C. (2S, 4R) -4- (phenylmethoxy) -1- (t-butoxycarbonyl) -2-pyrrolidinemethanol

A solution of 4.40 g (13 mmol) of the title compound B and 1.47 g (13 mmol) of ethyl chloroformate in 65 ml of tetrahydrofuran is added dropwise with a solution of 1.4 g (13 mmol) of triethylamine in 10 ml of THF. After stirring for one hour at room temperature, the mixture is filtered directly into a three-necked flask. To the stirred solution is then added dropwise a solution of 0.75 g (20 mmol) of sodium borohydride in 8 ml of water. After 1 hour, the solvent is removed, the residue is dissolved in ethyl acetate and washed with 1 N hydrochloric acid, water,

¹⁰⁶ - 2 8 4 0 0

1 N sodium hydroxide solution, water and saturated brine. The dried solution is concentrated to give 3.23 g of an oil. Flash chromatography with 33% ethyl acetate / hexane gives 2.76 g of the title compound C; [a] _D ²⁵ = -28.3 °; c = 1.86 (chloroform).

D. (2S, 4R) -4- (phenylmethoxy) -1- (t-butoxycarbonyl) -2- (bromomethyl) -pyrrolidine

A solution of 2.7 g (8.7 nuaol) of the title compound C, 5.8 g (17.4 mmol) of carbon tetrabromide and 4.5 g (17.4 mmol) of triphenylphosphine in 150 ml of ether is added at room temperature Night stirred. The ether is decanted and the remaining solids washed twice with hot hexane. Lie Hexane extracts are combined with the ether solution, the solvents are stripped to leave a semi-solid which is extracted twice with boiling hexane. The oily residue after stripping off the hexane is dissolved in ethyl acetate and treated with silica gel (60-200 mesh). The solvent is stripped off, the powder added to a column of the same silica gel and eluted with hexane to remove the excess carbon tetrabromide. Elution with 33% ethyl acetate / hexane gives 2.3 g of the desired title compound D. [a] _D ²⁵ = -37.9 °; c = 2.59 (chloroform).

E. [3R- [1 (2S * 4R *), 3α, 4α]] - 1 - [[1- (t-butoxycarbonyl) -4- (phenylmethoxy) -2-pyrrolidinyl] methyl] -3-hydroxy 1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A stirred solution of 0.93 g (2.6 mmol) (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoro-

- 107 -

methyl) -2H-1-benzazepin-2-one in dimethylformamide (10 mL) is replaced with 0.13 g of potassium hydride (3.3 mmol, 0.39 mL of 35% oil suspension) /. After one hour, a solution of the title compound D (1.23 g, 3.3 mmol) in dimethylformamide (2 ml) is added little by little to the reaction mixture, then heated for 18 hours (oil bath temperature 6O ⁰ C). The cooled mixture is diluted with ethyl acetate, washed twice with water and with saturated brine. The dried solvent is removed and 2.2 g of a semi-solid material are obtained. This crude product is dissolved in 5 ml of toluene, cooled for one hour, filtered to give 0.28 g of the starting material. Flash chromatography of the remaining solution over 4,000 ml of silica gel with 40% ethyl acetate / hexane gives 0.57 g of the title compound E as a glassy solid; [a] ₀ ²⁵ = + 116.9 °, c = l, 95 (chloroform).

F. [3R- [1 (2S *, 4R *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1 - [[4- ( phenylmethoxy) -2-pyrrolidinyl] methyl] -6- (trifluoromethyl) - H-1-benzazepin-2-one monohydrochloride

The title compound E (0.95 g, 1.48 mmol) is dissolved in 8 mL of dichloromethane containing 0.84 g (7.4 mmol) of trifluoroacetic acid. The solution is stirred overnight at room temperature. The solvent is removed. The residue is dissolved in toluene and the solvent is concentrated in vacuo to remove the excess acid. The residue, dissolved in ethyl acetate, is washed with 1 N sodium hydroxide solution, water and saturated brine. The solution is dried, concentrated and gives 0.51 g of the title compound as an oil. [a] ₀ ²⁵ = + 137.0 °, c = l, 0 (chloroform).

- 108 -

Analysis calc. For C ₃₀ H ₃₁ N ₂ F ₃ O,.

C 66.65; H 5.77; N 5.18;

found: C 65.13; H 5.69; N 5.04.

The substance described above is dissolved in 15 ml of ether and treated with one equivalent of ethereal hydrogen chloride. It forms 0.42 g of a colorless product; Mp 184-186 ⁰ C. [a] _D ²⁵ = + 50.4 °; c = 1, 15 (methanol).

Analysis calculated for C ₃₀ H ₃₁ F ₃ N ₂ O ₄ -HCl.:

C 60.55; H 5.93; N 4.70; Cl 5.95; Found: C 60, ^ 9; H 5.59; N 4,43; Cl 6,04.

Example 38

[3R- [1 (2S *, 4R *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-l - [(4-hydroxy-2-pyrrolidinyl) methyl] -4 - (4-methoxyphenyl) -6- (trifluoromethyl) -1H-benzazepine ^ -one monohydrochloride

To a suspension of the title compound of Example 37 (1.9 g, 3.5 mmol) in acetic acid (25 mL) is added 0.5 g of 10% palladium on charcoal and hydrogenated at atmospheric pressure for 24 hours. TLC (20% methanol / ethyl acetate) shows that about 60% has reacted. Another 0.2 g of catalyst is added and the reaction is continued for an additional 48 hours. The catalyst is filtered and washed with ethanol. The solution is concentrated in vacuo (4O ⁰ C), and the residue, dissolved in ethyl acetate, is washed with saturated sodium bicarbonate solution. This leads to the formation of a solid product, insoluble in any phase. 1.3 g of this material dissolved in 7 ml of hot

- 109 -

Ethanol, is filtered through Hyflo paper (# 50). The solvent is stripped off and the residue is treated with acetonitrile to give 0.77 g of a colorless solid; Mp. 212-214 ⁰ C. [a] _D ²⁵ = + 74.1 °, c = 0.72 (methanol).

The product described above is dissolved in 3 ml of methanol and treated with one equivalent of ethereal hydrogen chloride. The solvent is stripped off and the residue is treated with acetonitrile to give 0.61 g of a colorless solid; Mp. 214-216 ⁰ C. Analytically pure material is obtained by dissolving in hot methanol and gradual addition of acetonitrile, the methanol is removed by boiling. The cloudy suspension is cooled, filtered and gives 0.45 g of the colorless title compound; Mp. 217-218 ⁰ C. [α] ₀ ²⁵ = + 75.2 °, c = l, 0 (methanol).

Analysis for C ₂₃ H ₂₅ F ₃ N ₂ O ₄ -HCl-O ^ SH ₂ O:

C 55,21; H, 5.54; N 5.60; Cl 7.09; F 11.39; Found: C 55.24; H 5.50; N 5.62; Cl 7,29. F 11.37.

Example 39

[3R- [1 (2S *, 4S *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- [[4- (phenylmethoxy)] -2-pyrrole.ldinyl] methyl] -6- (trifluoromethyl) -1H-benzazepine ^ -one monohydrochloride

A. (2S, 4S) -4-Hydroxy-1- (t-butoxycarbonyl) -2-pyrrolidinecarboxylic acid

A solution of N-Boc-4-trans-hydroxy-L-proline (11.55 g, 0.05 mol) and triphenylphosphine (14.4 g, 0.055 mol) in dry THE '(450 mL) is added

- no - 2 8 4 0 0 §

Argon is added dropwise at 2O ⁰ C with a solution of diisopropyl azodicarboxylate in 50 ml of tetrahydrofuran over a period of 30 minutes, then stirred for a further hour (10.9 ml; 0.055 mol; 11.1 g). The reaction mixture is concentrated in vacuo to 100 ml, then treated with 100 ml. 1N sodium hydroxide solution. After stirring for 15 minutes, the tetrahydrofuran is removed and the remaining aqueous solution is washed with ethyl acetate, which is discarded. The aqueous phase is acidified to pH 1.5 with 6 N hydrochloric acid, saturated with sodium chloride and extracted twice with ethyl acetate. The organic fractions are washed with saturated brine, dried (magnesium sulfate) and concentrated in vacuo to give 13 g of a viscous oil. Trituration with hot isopropyl ether (IPE) and cooling gives 10.2 g of the title compound A; Mp 147-148.5 ^a C. [a] _D ²⁵ = -47.1 °, c = 0.92 (ethanol).

B. (2S, 4S) -4- (phenylmethoxy) -1- (t-butoxycarbonyl) -2-pyrrolidinecarboxylic acid

A solution of the title A compound (10.1 g; 43.8 mmol) and benzyl chloride (5.55 g, '3.8 mmol) in dry dimethylformamide (60 ml) is cooled under argon to -78 ⁰ C and sodium hydride (3 , 50 g, 87 mmol, 60% in an oil dispersion) was added throughout. The cooling bath is removed, the reaction mixture warmed to room temperature and stirred overnight. The mixture is poured onto ice and washed twice with ethyl acetate. The basic aqueous solution is acidified to pH 2.0 with 6N hydrochloric acid, saturated with sodium chloride and extracted twice with ethyl acetate. The organic fractions become more saturated

- Ill -

284O 05

Washed brine, combined, dried (magnesium sulfate), concentrated in vacuo to give 18.6 g of an oil. Flash chromatography over 1700 ml of LPS-1 silica gel and elution with 0.5% ethyl acetate / acetic acid gives 9.35 g of title compound B as a coarse solid. Recrystallization from isopropyl ether (IPE) gives 7.75 g of the title compound B; Mp HO-IIl ⁰ C. [a] _D ^s = -2Q, 8 ° _r c = 0.96 (, ethanol).

C. (2S, 4S) -4- (phenylmethoxy) * - 1- (t-butoxycarbonyl) -2-pyrrolidinomethane

A solution of the title B compound (7.75 g; 24 mmol) and ethyl chloroformate in 150 ml of dry tetrahydrofuran under argon at 15 to 2O ⁰ C dropwise with a solution of triethylamine (2.44 g; 24 mmol) in 10 ml of tetrahydrofuran over a period of 10 to 15 minutes. After stirring for 2 hours, the solids are filtered and washed with fresh tetrahydrofuran. The combined filtrates and washings are cooled and treated dropwise in a water bath at 15 ^° C. with a solution of sodium borohydride (1.36 g, 36 mmol) in 10 ml of water. After stirring for hours at room temperature, the volatiles are removed in vacuo and the residue, dissolved in ethyl acetate, is washed with 1N hydrochloric acid, water, 1N sodium hydroxide, water and brine. The dried (magnesium sulfate) organic fraction is concentrated in vacuo to give 7.2 g of the crude product. Flash chromatography on 1 LPS-1 silica gel with 4 l 30% ethyl acetate / hexane and 2 L 50% ethyl acetate / hexane gives 6.15 g of the title compound C as an oil. [a] _D ²⁵ = -18.5 °; c = 1, 5 (chloroform).

- 112 -

D. (2S, 4S) -4- (phenylmethoxy) -1- (t-butoxycarbonyl) -. 2- [ 4-methylphenylsulfonyloxy) -methylpyrrolidine

A solution of the title compound C (3.0 g, 9.6 mmol) in 15 mL of dry pyridine is treated with toluenesulfonyl chloride (2.05 g, 10.7 mmol) and stirred under argon at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1 N hydrochloric acid until the washing remains acidic (three to four times). Then it is washed with water, sodium bicarbonate solution and saturated brine. The dried (magnesium sulfate) organic fraction is concentrated in vacuo to give 4.55 g of an oil. Flash chromatography over 800 ml of LPS-1 silica gel with 20% ethyl acetate / hexane gives 3.9 g of the title compound D. [oc] _D ²⁵ = -8.01 °, c = 1.76 (chloroform).

E. [3R- [1 (2S *, 4S *), 3a, 4a]] - 1 - [[1- (t-butoxycarbonyl) -4- (phenylmethoxy) -2-pyrrolidinyl] methyl] -3-hydroxy -1,3,4,5-tetrahydro-4- (4-methoxyphrnyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A solution of (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benz-Hzepin-2-one (2.35 g, 6.7 mmol) and the title compound D (3.50 g; 7.6 mmol) in 25 ml of dry dimethylformamide under argon Cäsiuir- arbonat ^ (3.26 g; 10.05 mmo \.) was added, then heated overnight at 5O ⁰ C. The parent benzazepine remains, although tosylate is consumed. A further 0.4 g (0.8 mmol) of tosylate are added and the mixture stirred at 6O ⁰ C for 2 v / urther days. The Reaktjonsgemisch, diluted with ethyl acetate, is

- 113 -

264005

washed with water and brine, dried (magnesium sulfate), concentrated in vacuo to give 4.87 g of an oil. Flash chromatography over 1000 ml of LPS-1 silica gel with 17% toluene / ethyl acetate gives 3.36 g of the title compound E

[ot] _D ²⁵ = + 113.2 °; c = 0.84 (chloroform).

F. [3R- [1 (2S *, 4S *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hy-

droxy-4- (4-methoxyphenyl) -1 - [[4- (phenylmethoxy) -2-pyrrolidinyl] methyl] -6- (trifluoromethyl) -2H-I-benzazepin-2-one monohydrochloride

A solution of the title compound E (3.1 g, 4.84 mmol) in 10 mL of dichloromethane is decomposed under argon at room temperature with trifluoroacetic acid (7.5 mL, 0.1 mol) and heated at reflux for one hour. Volatiles are removed in vacuo and the residue, dissolved in ethyl acetate, washed with sodium bicarbonate solution, water and brine. The dried (magnesium sulfate) organic fraction is concentrated in vacuo to give 2.5 g of an oil. Flash chromatography over 800 ml of LPS-1 silica gel with 93% ethyl acetate / methanol gives 2.08 g of the title compound as an oil. [a] _D ²⁵ = + 141,1 °; c = 0.88 (chloroform).

The above-described free base (700 mg, 1.3 mmol) in 15 ml of acetonitrile is treated with an excess of ethereal hydrogen chloride. The volatiles are stripped off in vacuo, the residue triturated with isopropyl ether (IPE) to give 73 mg of the salt in the form of an off-white powder, mp 120-140 ° C (foaming). [Α] ₀ ²⁵ = + 78.6 °, c = 0.90 (methanol).

- 114 -

Analysis for C ₃₀ H ₃₁ F ₃ N ₂ O ₄ -HCl-O ^ H ₂ O:

C, 62.03; H 5.63; N, 4.82; F, 9.81; Cl 6,10; Found: C 61.93; H 5.77; N 4.92; F 9,79; Cl 6.01.

Example 40

[3R- [1 (2S *, 4S *), 3a, 4a]] - 1,3,3,5-tetrahydro-3-hydroxy-1- [(4-hydroxy-2-pyrrolidinyl) -methyl] -4 - (4-methoxyphenyl) -6 - (trifluoromethyl) - ^ H-benzetzepine ^ -one monohydrochloride

A solution of the title compound of Example 39 (1.25 g, 2.31 mmol) in 15 mL of methanol with 400 mg of 10% palladium on charcoal is treated with ammonium formate (730 mg, 11.6 mmol) and the mixture is left overnight heated to reflux temperature. TLC analysis shows that the reaction is incomplete. Additional 10% palladium on charcoal (200 mg) and ammonium formate (300 mg) are added and heating continued overnight. The catalyst is removed by filtration through colite and the solvent removed in vacuo. The residue, dissolved in ethyl acetate, is washed with 1 N sodium hydroxide solution, water and saturated brine. The dried (magnesium sulfate) organic solution is concentrated in vacuo to give 0.75 g of an oil. Flash chromatography over 200 ml of LPS-I silica gel (pretreated with dichloromethane / 1% triethylamine) with 95% dichloromethane / methanol gives 0.50 g of the title compound as a foam. . Mp 75-90 ⁰ C. [a] ₀ ²⁵ = + 148.9 °; c = 0.85 (chloroform).

The above-described free base (0.48 g, 1.06 mmol) in 10 mL of acetonitrile is excess

- 115 -? 8 4 O O 5

treated with ethereal hydrogen chloride, resulting in precipitation of the salt. The salt is separated, washed with acetonitrile and ether, dried in vacuo over P ₂ O ₅ at 100 ⁰ C to give 436 mg; . M.p. 252-255 ⁰ C. [a] _D ²⁵ = + 84.8 °; c = 0.56 (methanol).

Analysis for C ₂₃ H ₂₅ F ₃ N ₂ O ₄ -OjS H ₂ O:

C 56.73; H 5.38; N 5.75; Cl 7:28; F 11,71; Found: C 56.55; H, 5.26 ;, N, 5.70; Cl 7,48; F 11,74.

Example 41

[3R- [1 (3S *, 5S *), 3a, 4a]] -1,3,4,5'-tetrahydro-3-hydroxy-1- [5- (hydroxymethyl) -3-pyrrolidinyl] -4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1)

A. (2S, 4R) -4-Hydroxy-2-pyrrolidine-carboxylic acid methyl ester

Acetyl chloride (7.6 mL, 107 mmol) is added slowly to methanol (70 mL). The reaction is exothermic. (2S, 4R) -4-Hydroxy-2-pyrrolidinecarboxylic acid (10 g, 76.2 mmol) is added and the mixture is refluxed for 4 hours. During this time, another 3 ml of acetyl chloride in 30 ml of methanol are added. The mixture is refluxed for a further 3 hours. The reaction is cooled to room temperature and added to about 750 ml of diethyl ether. The resulting colorless crystals are filtered, dried, yielding 11.89 g of the title compound A.

- 116 -

28 4 O OS

B. (2S, 4R) -4-hydroxy-1- (phenylmethyl) -2-pyrrolidinecarboxylic acid methyl ester

A mixture of the title compound A (11.85 g, 65.2 mmol), triethylamine (18.55 mL, 130.04 mmol) and benzyl chloride (15 mL, 130.04 mmol) is refluxed in 60 mL of dichloromethane for 7 hours , The resulting suspension is partitioned between chloroform and 1N sodium hydroxide solution. The organic phase is washed with 1N sodium hydroxide followed by saturated brine. The organic phase is then dried (sodium sulfate) and concentrated. The crude residue is subjected to flash chromatography on a 12x35 cm silica gel column with the following elution certificate: 2 liters of dichloromethane, 4 liters of methanol / dichloromethane and 4 liters of methanol / dichloromethane. The pure fractions are concentrated to give 15.3 g of the title compound B as a colorless oil.

C. {2S, 4R) -4-Hydroxy-1- (phenylmethyl) -2-pyrrolidinemethanol

A suspension of lithium aluminum hydride (5 g, 126 mmol) in 250 ml of diethyl ether is cooled to ⁰ ° C. The title compound B (9.88 g, 42 mmol) is added dropwise as a solution in 150 ml of dimethyl ether. After stirring for ¹ hour at ⁰ ° C., the reaction mixture is carefully quenched by addition of 5 ml of water, 5 ml of 15% strength sodium hydroxide solution and 15 ml of water. After stirring for one hour at room temperature, the suspension is filtered through Celite and the filter cake is washed thoroughly with diethyl ether. The filtrate is concentrated together with toluene (2x100 ml). It arises

- 117 -

7.97 g of the title compound C in the form of a colorless oil.

D. (2S, 4R) -4-Hydroxy-1- (phenylmethyl) -2- (t-butyldiphenylsilyloxymethyl) -pyrrolidine

T-butylchlorodiphenylsilane (11.05 ml, 42.5 mmol) is added dropwise to a solution of the title compound C (7.97 g, 38.5 mmol) in 20 ml of pyridine at ⁰ ° C. After stirring for ¹ hour at ⁰ ° C., the reaction mixture is partitioned between ether and water. The organic phase is washed with water (2 × 50 ml), dried (magnesium sulfate) and concentrated. The crude residue is subjected to flash chromatography on a 2.5x40 cm silica gel column with dichloromethane (2 L) followed by 5% methanol / dichloromethane (2 L). The pure fractions are combined and the mixed fractions are again chromatographed on a 5x25 cm silica gel column with 2% methanol / dichloromethane. All pure fractions are concentrated to give 9.88 g of the title compound D.

E. (2S, 4R) -4 - [(4-Methylphenylsulfonyloxy) methyl] -1- (phenylmethyl) -2- (t-butyldiphenylsilyloxymethyl) pyrrolidone

p-Toluenesulfonyl chloride (3.10 g, 16.3 mmol) is added to a solution of the title compound D (4.56 g, 10.9 mmol) in 12 mL of pyridine at ⁰ ° C. After stirring for ¹ hour at ⁰ ° C. and 4 hours at room temperature, the reaction mixture is partitioned between a sodium bicarbonate solution and diethyl ether. The organic phase is dried (magnesium sulfate) and concentrated. DC shows that

- 118 -

2 ö 4 ο ο 5

considerable amounts of the title compound D remain unreacted. The residue is redissolved in pyridine (12 ml) and p-toluenesulfonyl chloride (2 g, 11 mmol) is added. The reaction mixture is stirred for an additional 18 hours. Work up described above gives a crude residue (5.8 g), which is subjected to flash chromatography on a 5x25 cm silica gel column with 80% hexane / ethyl acetate. The pure fraction is concentrated to give 4.442 g of the title compound E in the form of a slightly yellow oil

F. [3R- [1 (3S *, 5S *), 3a, 4a]] - 1- [5- (t -butyldiphenylsilyloxymethyl) -1- (phenylmethyl) -3-pyrrolidinyl] -3-hydroxy-1,3 , 4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A mixture of (3R-cis-l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.58 4.5 g), the title compound E (3.00 g, 5 mmol) and cesium carbonate (7.34 g, 22.5 mmol) is refluxed in distilled methyl ethyl ketone (45 ml) for 18 hours Add 50 mL of ether to the ambient temperature, filter the suspension through celite, wash the filter cake well with ether, and concentrate the filtrate to a dark orange oil, chromatograph on a 5x25 cm silica gel column with 15% ethyl acetate The pure fractions are concentrated to give 2.4 g of the title compound F as a colorless foam.

- 119 -

G. [3R-r1 (3S *, 5S *), 3α, 4α]] - 1- [5- (hydroxymethyl) -1- (phenylmethyl) -3-pyrrolidinyl] -3-hydroxy-l, 3,4, 5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-bi3nzazepin-2-one

A solution of tetrabutylammonium fluoride (2.90 g, 9.18 mmol) in 15 mL of tetrahydrofuran is added to a stirred solution of the title compound F (3.19 g / 4.17 mmol in 35 mL of tetrahydrofuran.) After two hours of stirring, the reaction mixture becomes diluted with diethyl ether (100 ml) and the diethyl ether phase is washed with water (50 ml) and saturated brine (50 ml) The organic phase is dried (magnesium sulfate) and concentrated The residue is subjected to flash chromatography over a 5x30 The pure fractions are combined, and the mixed fractions are again chromatographed over a 5 × 30 cm silica gel column according to the following elution scheme: 1 liter dichloromethane, 1 liter 1% methanol / dichloromethane, 1 ml methanol Dichloromethane, 500ml 3% methanol / dichloromethane and 500ml 5% methanol / dichloromethane The pure fractions from the run described above give 1.788g of the title Ver Bond G in the form of a white foam.

H. [3R- [1 (3S *, 5S *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-1- [5- (hydroxymethyl) -3-pyrrolidinyl] -4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1)

The title compound G (1.55 g, 2.87 mmol) is acidified over 20% palladium hydroxide on charcoal (175 mg) in ethylacetac (30 mL) for 24 hours

- 120 -

hydrogenated of a balloon apparatus. TLC at this time shows that substantial amounts of the starting material are unreacted. Additional 20% palladium hydroxide on charcoal (175 mg) is added and hydrogenation continued for an additional 48 hours. The reaction is still not saturated, so that the reaction mixture is filtered through celite and the filter cake is washed well with methanol (about 150 ml). The filtrate is concentrated to a dark residue, which is redissolved in methanol (30 ml, fresh flask). 20% palladium hydroxide on charcoal (370 mg) is added and the mixture is hydrogenated as described above for 8 hours. After this time, the reaction mixture is filtered and the filtrate is concentrated. The residue is chromatographed on a 5x25 cm silica gel column according to the following elution scheme: 2 1 94% dichloromethane / 5% methanol / 1% triethylamine, 1 1 89% dichloromethane / 10% methanol / 1% triethylamine. The pure fractions are concentrated to give a gray solid which is concentrated along with 50% toluene / methanol (50 ml) and 50% ethyl acetate / methanol (2 x 50 ml). This gives 1.04 g of the title compound. The free base (972 mg, 2.158 mmol) is dissolved in methanol and fumaric acid (250 mg, 2.158 mmol) is added as a hot methanolic solution. This solution is concentrated to a foam which is dissolved in a mixture of methanol, isopropanol and ethanol and filtered through Celite. The filtrate is concentrated to a yellow crystalline solid which is triturated with hot isopropanol to give 1.15 g of the title compound as a white crystalline solid; Mp. 212-214 ⁰ C (dec.) 168 ⁰ C (softening), 185 ⁰ C (darkening). TLC: R _f = 0.19;

- 121 -

264005

95% dichloromethane / 4% methanol / 1% ammonia (free base). [α] ₀ ²⁵ = + 66.8 (c = l, 0, methanol).

Analysis for C ₂₃ H ₂₅ F ₃ N ₂ O ₄ .C ₄ H ₄ O ₄ .0.5 C ₃ H ₈ O:

C 57.38; H, 5.58; F 9.55; N, 4.67; Found: C 57.33; H 5.59; F, 9.41; N 4,73.

Example 42 '

[3R- [1 (3R *, 5S *), 3a, 4a]] -1,3, * 75-tetrahydro-3-hydroxy-1- [5- (hydroxymethyl) -3-pyrrolidinyl] -4- (4 -methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1)

A. (2i>, 4S) -4 - (phenylcarbonyloxy) -1- (phenylmethyl) -2 (t-butyldiphenylsilyloxymethyl) -pyrrolidine

Diethyl azodicarboxylate (2.80 ml; 16.8 mmol) is added to a gerühi ^- th solution of the title D compound from Example 41 (5 g; 11.2 millimoles of), triphenylphosphine (4.41 g; 16.8 mmol) and benzoic acid ( 3.14 g, 28 mmol) in 110 ml of tetrahydrofuran was added dropwise at room temperature within 5 minutes. After two hours of stirring, the reaction mixture is partitioned between ethyl ether and saturated sodium carbonate solution. The organic phase is washed with saturated brine, dried (magnesium sulfate) and concentrated. The residue is subjected twice to flash chromatography over a 5x25 cm silica gel column with 5% ethyl acetate / He. The purest fractions are concentrated ai to give 3.97 g of the title compound A as a light yellow oil.

- 122 - 2 8 4 O U 5

B. (2S, 4i3) -4-hydroxy-1- (phenylmethyl) -2- (t-butyldiphenylsilyloxymethyl) -pyrrolidine

A mixture of Tite Compound A (3.95 g, 7.2 mmol), 1N sodium hydroxide solution (72 mL, 72 mmol), 72 mL of tetrahydrofuran and 72 mL of methanol is refluxed for one hour. The reaction mixture is partitioned between saturated brine and ethyl acetate. The ethyl acetate phase is washed with saturated brine, dried (magnesium sulfate) and concentrated. The residue is subjected to flash chromatography on a 5x20 cm silica gel column with 25% ethyl acetate / hexane. The pure fractions are concentrated unr ¹ gives 1.85 g of the title compound B in the form of a colorless oil.

C. (2S, 4S) -4 - [(4-methylphenylsulfonyloxy) -methyl] -l-

(Phenylmethyl) -2- (t-butyldiphenyl-silyloxymethyl) -pyrrolidin

A mixture of the title compound B (1.85 g, 4.15 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.25 mmol) in 5 mL of pyridine is stirred for 18 h at room temperature. The reaction gels are partitioned between saturated sodium carbonate solution and ethyl ether. The organic phase is washed with saturated brine, dried (magnesium sulfate) and concentrated. The residue is subjected to flash chromatography on a 5x25 cm silica gel column with 10% ethyl acetate / hexane. The pure fractions are concentrated to give 2.13 g of the title compound C as a colorless oil.

- 123 -

D. [3R- [1 (3R *, 5S *), 3α, 4α]] - 1- [5- (t -butyldip.'ienyl-silyloxymethyl) -1- (phenylmethyl) -3-pyrrolidinyl] -3- hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A mixture of the title compound C (2 g, 3.33 mmol), cesium carbonate (5.4 g, 16.7 mmol), (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- ( tr.if.luormethyl) -2H-1-benzazepin-2-one (1.2 g;, 3.33 mmol) and methyl ethyl ketone (30 ml) is refluxed for 20 hours. The reaction mixture is cooled to room temperature and 20 ml of ethyl ether are added. The resulting thick suspension is filtered through Celite and the filtrate is concentrated to dryness. The residue is subjected to flash chromatography on a 5x35 cm silica column with 20% ethyl acetate / hexane subjected. Concentration of the pure fractions gives 980 mg of the title compound D. Concentration of the mixed fractions gives 800 mg of impure material, which is again chromatographed on a 5x35 cm column according to the following elution scheme: 3 1 15% ethyl acetate / hexane and 1 liter 25% ethyl acetate / hexane , These pure fractions are combined with the pure fractions of the first run to give 1.45 g of the title compound D as a colorless oil.

E. [3R- [1 (3R *, 5S *), 3a, 4a]] - 1- [5- (hydroxymethyl) -1-

(Phenylmethyl) -3-pyrrolidinyl] -3-hydroxy-l, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

Add 1N solution of tetra-n-butylammonium fluoride (3.65 mL, 3.65 mmol) to a solution of the title compound D (1.395 g, 1.83 mmol) in 20 mL of tetrahydrofuran at room temperature. To

for 1 hour at room temperature, dilute the reaction mixture with 50 ml of diethyl ether and wash the resulting organic phase with water (50 ml). After washing with saturated brine and drying (magnesium sulfate), the filtrate is concentrated to a yellow foam, which is subjected to flash chromatography on a 5x30 cm silica gel column with 75% ethyl acetate / hexane. The pure fractions are concentrated to give 0.85 g of the title compound E as a white foam. '**

F. [3R- [1 (3R *, 5S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-1- [5- (hydroxymethyl) -3-pyriolidinyl] -4 - (4-methoxyphenyl) -6- (trifluoromethyl) -PH-1-benzazepin-2-one, fumaric acid salt (Isi)

A mixture of the title compound E (0.80 g, 1.48 mmol) and 20% palladium hydroxide on charcoal in 20 ml of acetic acid is hydrogenated by means of a balloon apparatus for 18 hours at room temperature. The catalyst is removed by filtration through Celite and the filter cake is washed with 20 ml of acetic acid. Removal of the acetic acid in vacuo results in an oil which is partitioned between saturated sodium carbonate solution and ethyl acetate. The organic phase is washed with saturated brine, dried (magnesium sulfate) and concentrated to a white foam. This foam is subjected to flash chromatography on a 5x20 ciu-Kieselgel. column according to the following Eluationsschema: 1 1 5% methanol / dichloromethane, 1 1 10% methanol / dichloromethane, 2 1 15% methanol / dichloromethane and 500 ml of 50% methanol / dichloromethane. The pure fractions are concentrated to give 595 mg

- 125 -

2 Γ 4 O O

(89%) of the free base of the title compound in the form of a white foam.

The free base (405 mg, 0.9 mmol) is dissolved in 3 mL of methanol and a solution of fumaric acid (104 mg, 0.9 mmol) in 2 mL of hot methanol is added. The resulting mixture is concentrated to a solid which was triturated with ether and 5O ⁰ C, 0.5 mm Hg is dried. This gives 532 mg of the title compound as a white powder; Mp 121-13O ⁰ C fZers-.). [a] _D ²⁵ = + 68.0 ° (c = 0.54, methanol).

Analysis for C ₂₈ H ₂₉ F ₃ N ₂ O ₈ · 1.41H ₂ O:

C 54.78; H 5.42; F, 9.63; N 4.73;

found: C 55,16; H 5,27; F 9,24; N 4,79.

Example 43

(3R-cis) -1 - [(4,5-dihydro-lH-imidazol-2-yl) methyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

A. 2-Chloromethyl-imidazoline hydrochloride

To a cooled solution of 2-chloromethyl-imidazoline hydrochloride salt (3 g, 19.4 mmol, presented in HeIv. Chim. Acta., 2J7, 1773 (1944)) in 5 mL of water is added about 75 mL of anhydrous ethyl ether. To this solution is added an excess of solid potassium carbonate, and the resulting mixture is stirred for 10 minutes. The ether phase is decanted and the remaining slurry four times with about 75 ml of anhydrous ethyl ether

washed. The ether phases are combined and dried (magnesium sulfate). After removal of the solvent in vacuo, 1.89 g of the title compound A remain in the form of a white foam; Mp. 63-64 ⁰ C.

For example, (3R-cis) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-l-bänzazepin-2-one

A solution of (3R-cisis * 3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (4.44 g, 12.6 mmol) and a 60% strength oil dispersion of sodium hydride (0.62 g; 15.5 mmol) in 70 ml of dry DMF (4 Å molecular sieves) is heated to 7O ⁰ C for 30 minutes Then 2-chloromethyl-imidazoline (1.08 g;. 9, 1 mmol) was added. The mixture is stirred at 7O ⁰ C for 16 hours. The Feaktionsgemisch is gewasc'ien twice with ice-water. The organic phases are combined, dried (magnesium sulfate), and evaporated to afford a yellow residue. The residue is dissolved in ethyl acetate and flash chromatography (800 ml silica gel pretreated with a methyl acetate / methanol / triethylamine solution (10: 1: 1)) Elution with ethyl acetate / methanol / triethylamine (10: 1: 0.1) gives 2 , 55 g of the title compound B. [a] _D ²⁵ = + 116.5 °, c = l, 07 (methanol).

C. (3R-cis) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-l-benzazepin-2-one monohydrochloride

A solution of title B compound (1.02 g, 23.5 mmol) in 30 mL of acetonitrile is added with a

Excess ethereal hydrogen chloride solution treated. The solvents are removed in vacuo, triturated with anhydrous diethyl ether to give the title compound (1.03 g). The title compound (0.96 g; 2.04 mmol) is recrystallized from dichloromethane and isopropanol to yield 0.86 g of the title compound: mp 128-13O ⁰ C.

[a] ₀ ²⁵ = + 90.6 °; c = 0.98 (methanol).

Analysis for C ₂₂ H ₂₂ F ₃ N ₃ O ₃ -HCl-1 H ₂ O:

C 53.77; H, 5.21; N, 8.557 Cl, 7.21; F 11.60; found: C 53.77; H 4.91; N 8,55. Cl 7,14; F 11.38.

Example 44

cis-1 [(4,5-dihydro-lH-imidazol-2-yl) methyl] -1,3,4,5-tetrahydro-3-hydroxy-7 "(methoxymethoxy) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1)

The title compound is prepared according to the procedure described in Example 43, but using cis-3-hydroxy-7-methoxymethoxy-4- (4-methoxyphenyl) -2H-1-benz-azepin-2-one in place of (3R- cis) -3-hydroxy-4- (4-methoxyphenyl -6- (trifluoromethyl) -2H-l-benzazepin-2-one used in step B of this example, mp 200-210 ⁰ C (dec.)..

Analysis calc. For C ₂ H ₃ H ₇ N ₃ O ₅ .C ₄ H ₄ O ₄ .0. 83 H ₂ O:

C 58,28; H 5.91; N 7.55; Found: C 58.46; H 5.73; N 7,37.

Example 45

(3R-cis) -1,3,4,5-Tetrahydro-3-hydroxy-1 - [(1H-imidazol-2-yl) -methyl] -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride

A. (3R-CXS) -1- [(1H-3-phenylmethyl-indazole-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-l-benzazepin-2-one

A solution of (3R-cis-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (2.02 g, 5.74 mmol). Phenylmethyl 2-chloromethylimidazole hydrochloride (1.67 g, 6.87 mmol), described in J. Am. Chem. Soc., 7.1, 383 (1949) and a 60% oil dispersion of sodium hydride (0.59 g; 14.8 mmol, 2.6 equivalents) is stirred overnight.

The reaction mixture is quenched with 1 N hydrochloric acid and then the pH is adjusted to about 11 with 50% sodium hydroxide solution. The reaction mixture is extracted twice with ethyl acetate. The organic phases are combined and washed twice with 50 ml of saturated sodium bicarbonate solution, followed by saturated brine (2x50 ml). The solvents are removed in vacuo leaving a reddish-brown oil. Flash chromatography over 800 ml of LPS-I silica gel with ethyl acetate / 5% methanol gives 1.11 g of the title compound A as a white foam. [a] _D ²⁵ = + 105.0 °; c = l, 01 (methanol).

B. (3R-cis) -1 - [(1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl ) -2H-l-benzazepin-2-one

A solution of the title compound A (1.09 g, 1.95 mmol) and 10% palladium on charcoal (0.24 g) in 5 mL of 95% alcohol is hydrogenated at atmospheric pressure overnight. The reaction mixture is filtered and the solvents removed in vacuo. The residue is taken up in ethyl acetate and washed with 1 ^ sodium hydroxide solution. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried (magnesium sulfate), concentrated in vacuo to give 0.666 g of the title compound B as a white foamy solid.

C. (SR-cis) -1-tetrahydro-S-hydroxy-11 (1H-imidazol-2-yl) -methyl] -4- (4-methoxyphenyl) -6- (trifluoromethyl) -1H-benzazepine - ^ - on monohydrochloride

A solution of the title compound B (0.52 g, 1.21 mmol) in acetonitrile is treated with an excess of ethereal hydrogen chloride. The volatiles are removed in vacuo and a white solid is formed. The solid is triturated with isopropyl ether and dried in vacuo over P ₂ O ₅ at 100 ⁰ C to give 0.45 g of the title compound; M.p. 188-191 ⁰ C. [a] _D ²⁵ = + 101.0 °; c = l, 02 (methanol).

- 130 -

Analysis for C ₂₂ H ₂₀ F ₃ N ₃ O ₃ -HCl-O ^ H ₂ O:

C 56.03; H 4.58; N, 8.91; Cl, 7.52; F 12.09; Found: C 56.20; H 4,35; N, 8, 92; Cl 7,15; F 11,71.

Example 46

[2S- [ 2a, 3a, 5 (R *)]] - 3- (acetyloxy) -2,3-dihydro-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1,5-benzothiazepine 4- (5H) -one monohydrochloride

A. S-I- (t-Butoxycarbonyl) -2 - [(4-methylphenyl) sulfonyl) -methyl] -pyrrolidine

To SI (t-butoxycarbonyl) -2-pyrrolidine-methanol (20.6 g, 102.4 mmol) in pyridine (100 mL) at room temperature under argon with stirring is added p-toluenesulfonyl chloride (23.4 g, 122.8 mmol). After 5 hours additional p-toluenesulfonyl chloride (9.8 g, 51.2 mmol) is added. After stirring for a total of 23 hours, the reaction mixture is diluted with ethyl acetate and washed three times with saturated aqueous copper sulfate solution. The organic phase is dried (magnesium sulfate), filtered and concentrated. The yellow liquid is chromatographed on a silica gel column with 10 to 30% ethyl acetate / hexane to give the title compound A (32.1 g) as a viscous colorless liquid.

For example, [2S- [2a, 3or, 5 (R *)]] - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (1- (t-butoxycarbonyl) -2-pyrrolidinyl ] methyl] -1,5-benzothiazepin-4- (5H) -one

(2S-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -l, 5-benzothiazepine-4- (5H) -one (3.56 g, 11.81 mmol);

- 131 -

Cesium carbonate (5.77 g; 17.72 mmol) and the title A compound (6.30 g; 17.72 nunol) in dimethylformamide (40 ml) v / ground to 5O ⁰ C heated. After 16 hours, cool the reaction mixture to room temperature, dilute with water and extract three times with ether. The combined extracts are washed three times with 10% aqueous lithium chloride, dried (magnesium sulfate), filtered and concentrated. The yellow foam is chromatographed on a silica gel column with 10 to 25% ethyl acetate / hexane to give the title compound B (4.51 g) as a yellow foam.

C. [2S- [2a, 3a, 5 (R *)]] - 2,3-dihydro-3- (acetyloxy) -2- (4-methoxyphenyl) -5- (1- (t-butoxycarbonyl) -2 -pyrrolidinyl] -methyl1-1,5-benzothiazepin-4- (5H) -one

The title compound B (1.0 g, 2.06 mmol), 4-dimethylaminopyridine (0.50 g, 4.13 mmol) and acetic anhydride (1.05 mL, 10.3 mmol) in dichloromethane (20 mL) were added Room temperature stirred under argon for 15 hours. The reaction solution is adsorbed on silica gel (60-200 mesh) and chromatographed on a silica gel column with 5 to 20% ethyl acetate / hexane. The title compound C (0.94 g) is obtained in the form of a white solid.

D. [2S- [2ot, 3a, 5 (R *)]] -3- (acetyloxy) -2,3-dihydro-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1,5- benzothiazepin-4 (5H) -one monohydrochloride

The title compound C (0.84 g, 1.60 mmol) in trifluoroacetic acid (50 mL) and dichloromethane (5 mL) is added under argon at room temperature for one hour

-132- P 8 4 O O C

touched. The reaction solution is concentrated under reduced pressure, then diluted with aqueous potassium hydrogencarbonate and extracted three times with ethyl acetate. The combined extracts are dried (magnesium sulfate), filtered and concentrated. The yellow foam is dissolved in ethyl acetate and an excess of ethereal hydrogen chloride added. Concentration, followed by trituration with ether (50 ml) gives the title compound (0.75 g) as a white foam; Mp 123-135 ⁰ C. [a] ₀ ²⁵ = + 66.06 °; (c = 1, methanol).

Analysis for C ₂₃ H ₂₆ N ₂ O ₄ S-HCl-O, 73 H ₂ O:

C 58.01; H 6.03; N 5.88; Cl 7,44; S 6,73; Found: C 58.00; H 6.06; N 5.89; Cl 7,18; S 6,48.

Example 47

[2S- [2a, 3a, 5 (R *)]] - 3- (acetyloxy) -2,3-dihydro-8-metnoxy-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1, 5-benzothiazepin-4- (5H) -one monohydrochloride

The title compound is prepared according to the procedure of Example 46, but cis-2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -8-methoxy-l, 5-benzothiazepine-4- (5H) -one instead of (2S-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4- (5H) -one used in Step B of this example; Mp 147-145 ° C, [a] _D ²⁵ = + 50.0 ° (c = 1, methanol).

- 133 -

Analysis for C ₂₄ H ₈ N ₂ O ₅ S-HCl-0.89 H ₂ O:

C, 56.63; H 6.09; N, 5.51; Cl 6, 97; S 6,30; found: C 56.72; H 5.94; N 5.42; Cl 7,15; S 6,30.

Example 48

[2S- [2a, 3a, 5 (R *)]] - 2, S-dihydro-S-hydroxy ^ - (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1,5-benzothiazepin-4- ( 5H) -one monohydrochloride

A. [2S- [2a, 3a, 5 (R *)]] - 2,3-dihydro-3-hydraxy-2- (4-methoxyphenyl) -5- (1- (benzyloxycarbonyl) -2-pyrrolidinyl] - methyl] -1,5-benzothiazepin-4- (5H) -one

(2S-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4- (5H) -one (1.25 g, 4.15 mmol), cesium carbonate ( 2.03 g, 6.22 mmol) and S-1-benzyloxycarbonyl) -2 - [(4-methylphenylsulfonyl-cyxy) -methyl] -pyrrolidine (2.02 g, 5.19 mmol) in dimethylformamide (20 mL) 5O ⁰ C heated. After 23 hours the reaction mixture is cooled to room temperature, diluted with water and extracted three times with ether. The combined extracts are washed three times with 10% aqueous lithium chloride, dried (magnesium sulfate), filtered and concentrated. The viscous yellow oil is chromatographed on a silica gel column with 15 to 30% ethyl acetate / hexane to give the title compound A (1.74 g) as a white solid.

- 134 -

_T 2S- [2oc, 3a, 5 (R *)]] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1,5-benzothiazepine 4- (5H) -one monohydrochloride

The title compound A (1.2 g, 2.31 mmol), 10% palladium on charcoal (1.2 g, 100% w / w), and ammonium formate (1.2 g, 19.0 After stirring for 5 hours, additional palladium on charcoal (0.6 g) is added and stirring continued for 19 hours, the reaction is cooled to room temperature, anhydrous magnesium sulfate is added, and the catalyst is filtered off The solids are washed well with methanol, the filtrate is concentrated and the residue is diluted with saturated aqueous potassium bicarbonate and extracted three times with ethyl acetate The combined extracts are dried (magnesium sulfate), filtered and concentrated to a pale yellow foam which is dissolved in dichloromethane Add excess ethereal hydrogen chloride and remove the volatiles under reduced pressure followed by trituration of the resulting solids with a 66% ether / dichloromethane mixture gives the ticel compound (0.35 g) as an amorphous white-n solid; Mp> 240 ° C (decomp.). [a] _D ²⁵ = + 91.0 °; (c = 1, methanol).

Analysis calculated for C _{2 1H 24} N ₂ O ₃ S-HCl-0.46 H ₂ O.:

C 58,26; H 6.06; N, 6,47; Cl 9.01; S 7,41; Found: C 58.45; H 5.76; N 6.28; Cl 9,35; S 7,41.

- 135 -

Example 49

[2S- [2α, 3α, 5 (R *)]] -2,3-dihydro-2- (4-m (vthoxyphenyl) -3- (2-methyl-1-oxopropoxy) -5- (2-pyrrolidinylmethyl ) -1,5-benzothiazepin-4- (5H) -one monohyc'rochlorid

A. [2S- [2a, 3a, 5 (R *)] 1-2,3-dihydro-3- (2-methyl-1-oxopropoxy) -2- (4-methoxyphenyl) -5- (1- (1) t-butoxycarbonyl) -2-pyrrolidinyl] methyl] -1,5-benzothiazepin-4- (5H) -one

A solution of [2S- [2a, 3a, 5 (K *)] ] -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (1- (t-butoxycarbonyl) -2- pyrrolidinyl] methyl] -1,5-benzothiazepine-4- (5H) -one (847 mg, 1.75 mmol), Ν, Ν-dimethylaminopyridine (427 mg, 3.5 mmol) and isobutyric anhydride (600 mL, 3 The reaction mixture is concentrated under reduced pressure and the residual oil chromatographed on a silica gel column with 10 to 20% ethyl acetate / hexane to give the title compound A (0.870 g ) in the form of a white foam.

[-2S- [2a, 3a, 5 (R *)]] -2,3-dihydro-2- (4-methoxyphenyl) -3- (2-methyl-1-oxopropoxy) -5- (2-) pyrrolidinylmethyl) -1,5-benzothiazepine-4- (5H) -one monohydrochloride

The title compound A (1.0 g, 1.84 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) is stirred for 15 minutes at room temperature. The reaction mixture is then concentrated under reduced pressure. concentrated, the resulting residue was dissolved in ethyl acetate and washed with saturated aqueous potassium bicarbonate. The aqueous phase is

- 136 - 28 A O O 5

extracted three times with ethyl acetate, and the combined organic phases are dried (magnesium sulfate), filtered and concentrated. The yellow solid is chromatographed on a silica gel column (pretreated with 1% triethylamine) with 7% methanol / dichloromethane. The free amine is dissolved in ether and converted to the hydrochloride salt by addition of an excess of ethereal hydrogen chloride Concentration provides a slightly yellow foam, which is triturated well with ether and filtered to give the title compound (0.70 g) Formed as a yellow solid, mp 197-199 ° C (dec.). [A] _D ²⁵ = + 34.86 ° (c = 1, methanol).

Analysis calc'd for C ₂ H ₃ O N ₂ O ₄ S-KCl-O, 3 H ₂ O: C, 60.47; H 6,42; N 5.64; Cl 7, -14; S 6:46;

gef. C 60.32; H 6,38; N 5.76; Cl, 6.80; S 6,55.

Example 50

12S- [2a, 3a, 5 (R *)] -2,3-dihydro-2- (4-methoxyphenyl) -3 - [[(methylamino) carbonyl] oxy] -5- (2-pyrrolidinylmethyl) -1, 5-benzothiazepine-4- (5H) -OR.-monohydrochloride

A. [2S- [2a, 3a, 5 (R *)]] - 2,3-dihydro-3 - [[(methylamino) -carbonyl] -oxy J-2- (4-methoxyphenyl) -5- (1 - (t-butoxycarbonyl) -2- pyrrolidinyl] methyl] -1,5-benzothiazepine ~4 (5H) -o: a

To a solution of [2S- [2a, Za, 5 (R *)]] - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (1- (t-butoxycarbonyl) - 2-pyrrolidinyl] -methyl] -1,5-benzothiazepine-4 · - (5H) -one (1.0 g, 2.06 μmol) in dry dichloro-toluene (15 ml) at ⁰ ° C with stirring triethylamine (116 mL, 0.82 mmol) and methyl isocyanate

- 137 - 2 ö 4 O O 5

(0.19 g, 3.30 min). The reaction mixture is warmed to room temperature. After 10 hours additional methyl isocyanate (0.19 g, 3.39 mmol) is added and stirring is continued for a further 5 hours. Water is added and the aqueous mixture extracted three times with ethyl acetate. The combined organic phasers are dried (magnesium sulfate), filtered and concentrated. The crude white foam is chromatographed on a silica gel column with 10 to 20% ethyl acetate / hexane to give the title compound (~0.89 g) as a white foam.

For example, [2S- [2a, 3a, 5 (R *)]] - 2,3-dihydro-2- (4-methoxyphenyl) -3 - [[(methylamino) carbonyl] oxy] -5- (2 -pyrrolidinylmethyl) -1,5-benzothiazepine-4- (5H) -one-nio-nium hydrochloride

The Titelverbittdung A (0.89 g; 1.64 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) is stirred for 30 minutes be \ room temperature. The reaction mixture is concentrated, the resulting residue is dissolved in ethyl acetate and washed with saturated aqueous potassium bicarbonate. The organic phase is separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried (magnesium sulfate), filtered and concentrated. The free base is dissolved in ether, adding a minimal amount of ethyl acetate to give a homogeneous solution. Excess ethereal hydrogen chloride is added and the volatiles removed under reduced pressure. The title compound (0.66 g) is obtained in the form of a pale yellow solid; . M.p. 170-177 ⁰ C. [a] _D ²⁵ = + 37.02 °; (c = 1, methanol).

- 138 -

Analysis calculated for C ₂₃ H ₂₇ N ₃ O ₄ S-HCl-H ₂ O:. C 55.70; H 6,10; N 8,47; Cl 7,15; S 6:46; gef. C 55.79; H 5.81; N, 8.49; Cl 7.03; S 6,50

Example 51

[3R- [1 (S *), 3a, 4a]] - 3- (Acetyldxy) -1,3,4,5-tetrahydro-7-methoxy-4- (4-methoxyphenyl) -1- (2-pyrrolidxnylmethyl ) -2H-l-benzazepin-2-on-monohydrochfiorid-

The title compound is prepared according to the procedure in Example 13 using cis-3-hydroxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one; Mp> 250 ° C; [Ot] ₀ ²⁵ = + 92.17 ° (c = l, methanol).

Analysis calc'd for C ₂ H ₃ O H ₂ O ₅ .HCl-0.2H ₂ O:

C, 62.74; H, 6.61; N 5.86; Cl 7,41, · gef. C, 62.88; H 6.70; N 6.04; Cl 7,26.

Example 52

[2S- (2a, 3a)] - 2,3-dihydro-5 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -3-hydroxy-2- (4-irethoxyphenyl ) -1,5-benzothiazepine-4- (5H) -one monohydrochloride

The title compound is prepared according to the procedure in Example 43 using (2S-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4- (5H) -one , The product is recrystallised from ethanol; Mp 252 ⁰ C (Zers.)

[a] _D = + 94.0 ° (C = I, 0, Mithanoi).

- 139 -

R _f = 0,? 8 (90% dichloromethane / 5% methanol / 5% acetic acid;

Analysis calc. For C ₂ O H ₂ , N ₃ O ₃ S-HCl-O, 7 H ₂ O.

C 55.53; H 5.45; N, 9.71; Cl 8,20; S 7,41; gef. C 55,38; H 5.64; N, 9.68; Cl 8,50; S 7.55.

Example 53 ·

[2S- (2α, 3α)] - 3- (acetyloxy) -2 ^ -dihydro-2- (4-methoxyphenyl) -5- (2-pyridinylmethyl) -1,5-benzothiazepin-4- (5H) -one -

monohydiochlorid

The title compound is prepared according to the procedure in Example 23 by heating of the title compound with acetic anhydride 3 hours lan-j at 110-115 ⁰ C. After recrystallization from acetonitrile, the colorless product melts at 200-202 ⁰ C (dec.).

[a] ₀ = + 137 ° (c = l, 0, methanol).

Analysis calculated for C ₂₄ H _{2 2} N ₂ O ₄ S-HCl-1, 5 H ₂ OC 57.88. H 5.26; N 5.63; Cl 7,12; S 6,44; gef. C, 58.09; H 5.20; N 5.62; Cl 7,48; S 6,52.

Example 54

(3R-C1S) -3- (acetyloxy) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-4- (4- methoxyphenyl) -6- (trifluoromethyl) -Hl-benzazepine-monohydrochloride

A. (3R-cis) -1- [(4,5-dihydro-1- (t-butoxycarbonyl) -imidazol-2-yl) -methyl] -β, 3,4,5-tetrahydro-3-hydroxy 4

- 140 -

(4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A solution of the title compound from Example 43 (3.83 g, 8.84 mmol) in 30 mL of dry dichloromethane is treated with t-BOC anhydride (2.77 g, 12.7 mmol, 1.4 equiv) and DMAP (0 , 11 g, 0.90 mmol). The solution is stirred overnight. The reaction mixture is concentrated to about 15 ml and subjected to flash chromatography on about 800 ml of LPS-I silica gel with 66% Hexarf / ethyl acetate. After removal of the solvents in vacuo, 1.51 g of the title compound A remain as a white solid foam; Mp. 114-116 ⁰ C.

(3R-cis) -3- (acetyloxy) -l - [(4,5-dihydro-1- (t-butoxycarbonyl) -imidazol-2-yl) -methyl] -l, 3,4,5-tetrahydro- 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A solution of the title compound A (1.50 g, 2.8 mmol) in 30 mL of dry dichloromethane is added with acetic anhydride (1.66 g, 16.2 mmol, 5.8 equivalents) and DMAP (0.68 g; 7 mmol, 2 equivalents). The solution is stirred overnight. The reaction mixture is adsorbed on about 30 ml of Celite and chromatographed over 350 ml of LPS-1 silica gel (1.5: 1: 0.1 hexane / ethyl acetate / methanol). After removal of the solvents in vacuo, 0.96 g of the title compound B remain as a white foam; Mp. 105-108 ⁰ C.

C. (3-R-cis) -3- (acetyloxy) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride

- 141 -

To a solution of the title compound B (0.87 g, 1.5 mmol) in 10 mL of dry dichloromethane is added 10 mL of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 2 hours. The solvents are removed in vacuo and the resulting oil taken up in ethyl acetate. The ethyl acetate phase is washed twice with saturated potassium carbonate solution, followed by saturated brine. The organic phase is dried (magnesium sulfate) and the solvents removed in vacuo. This gives 0.770 g of a white foam; . Mp 109-111 ⁰ C. A solution of the free base described above (0.740 g; 1.6 mmol) in ethyl acetate is treated with an excess of ethereal hydrogen chloride. The resulting solid is separated and washed four times with ethyl acetate. The solid is dissolved from the filter with acetonitrile and the solvents removed in vacuo. 0.42 g (51%) of the title compound are obtained in the form of a white solid; Mp 260-261 ⁰ C

[Ct] ₀ = + 84.6 °; c = 1, 11 (methanol).

Analysis Calc. For C ₂₄ H ₂₄ F ₃ N ₃ O ₄ · HCl 1.43 H ₂ O

C 53.72; H 5.04; N, 7.83; Cl, 10.62; F, 6.61; gef. C, 53.87; H 5:14; N, 7.68; Cl 10.70; F 6,79.

Example 55

(3R-C1S) -1 - [(4,5-dihydro-lH-imidazol-2-yl) methyl] -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4 -methoxyphenyl) -Hl-benzazepine-monohydrochloride

- 142 -

A. 2- [2- (5-Methoxy-2-nitrophenyl) -1- (4-methoxyphenyl) -ethyl] -propanedioic acid dimethyl ester

A stirred suspension of dimethyl p-methoxybenzylidene malonate (50 g, 0.20 mol) and a 60% oil dispersion of sodium hydride (8 g, 0.20 mol) in dry dimethylformamide (300 mL) is added dropwise with a solution of 3- Methyl 4-nitroanisole (17.25 g, 0.097 mol) was added in 150 ml of dry dimethylformamide over a period of one hour. The dark ReaktiOnsgemisch is stirred at room temperature for 10 hours, then quenched with glacial acetic acid. The slightly yellow solution is diluted with water and then extracted three times with ethyl acetate. The combined extracts are washed with 10% aqueous lithium chloride, dried (magnesium sulfate), filtered and concentrated. The residue is cooled in an ice-water bath for 2 hours, and the precipitated solid is filtered, washed with ethyl acetate, dried, to give 19.4 g of the title compound A as a yellow-white solid.

B. 2- [2- (2-Amino-5-methoxyphenyl) -1- (4-methoxyphenyl) -ethyl] -propanedioic acid dimethyl ester

A suspension of title compound A (19.4 g, 46.5 mmol) and 10% palladium on charcoal (2 g) in 300 mL of ethyl acetate is stirred under a hydrogen atmosphere overnight. The mixture is filtered through a pad of anhydrous magnesium sulfate and the remaining solids washed three times with ethyl acetate. The combined filtrates are concentrated under reduced pressure and

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17.85 g of the title compound B as a white solid.

C. 1,3,4, S -tetrahydro-V-methoxy-S- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

To a suspension of the title compound B (17.85 g, 42.8 mmol) in 200 ml of methanol is added a 25% solution of sodium methoxide in methanol (15 ml, 69.45 mmol). The mixture is refluxed for 3 hours. It is cooled to room temperature, cooled with an ice water bath and treated with glacial acetic acid. The mixture is diluted with water and extracted three times with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated sodium bicarbonate solution, water and brine, dried (magnesium sulfate), filtered and concentrated. The residue is triturated with 200 ml of ethyl acetate / ether (2: 1) and the white precipitate filtered, washed with ether, dried to give 14.73 g of the title compound C.

D. 1,3,4,5-Tetrahydro-3-hydroxy-7-methoxy-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

A solution of the title C compound (14.7 g; 41.4 mmol) in 200 ml of toluene and 200 ml of dry dimethylformamide is added dropwise at -78 ⁰ C and a 1.8 M solution of potassium tert-amylate in toluene (94 ml; 169.2 mmol). After 30 minutes, trimethyl phosphite (20.5 ml) is added and oxygen is passed continuously through the reaction mixture for 2 hours. The mixture is stirred at -78 ⁰ C for a further 4 hours and by adding 1 N hydrochloric acid (200 mL). The

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Cooling bath is removed and the mixture is diluted with water. The mixture is extracted three times with ethyl acetate. The ethyl acetate extracts are combined, washed with aqueous sodium methabisulfite and 10% aqueous lithium chloride, dried (magnesium sulfate), filtered and concentrated. The precipitated white solid is filtered, washed with ether and dried in vacuo. This gives 12.6 g of the title compound. The mother liquor is concentrated and chromatographed on a silica gel column with hexane, followed by 20% -70% ethyl acetate in hexane, to give an additional 1.5 g of the title compound D.

E. (Ice) -1,3,4,5-Tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

Anhydrous lithium iodide (19.21 g, 143.5 mmol) was added with stirring to a solution of the title compound D (13.64 g, 36.77 mmol) in 200 mL of pyridine and 2 mL of water. The mixture is heated under reflux for 7 hours, cooled, and distilled off the main part of the pyridine under reduced pressure. The dark residue is diluted with 250 ml of ethyl acetate and washed with an aqueous solution of sodium bisulfite. The aqueous phases are extracted once each with 200 ml of ethyl acetate. The ethyl acetate extracts are combined, washed three times with 1 N hydrochloric acid, dried (magnesium sulfate), filtered and concentrated. The residue is triturated with ethyl acetate and the precipitated solid is filtered, washed with ethyl acetate to give 7.96 g of the title alcohol containing a trace of the isomeric trans -alcohol. The mother liquor is concentrated and then over a silica gel column with 10 to 50%

- 145 -

Chromatograph ethyl acetate in hexane to give an additional 1.05 g of the title compound E.

F. [3R- (3a, 4a, 3S *)] - 3- (2-Benzyloxycarbonylamino-3-phenyl) -propionyl-1,3,4,5-tetrahydro-7-methoxy-4- (4-methoxyphenyl) -2H-l-benzazepin-2-one

To a suspension of Tizel compound E (7.24 g, 23.1 mmol) in 70 mL of tetrahydrofuran is added 2S-N-carbobenzyloxyaminophenylalanine (8.60 g, 28.88 mmol), followed by water-soluble carbodiimide (8.82 g 46.2 mmol). After one hour, Ν, Ν-dimethylaminopyridine (566 mg) is added and the homogeneous solution is stirred at room temperature for 1.5 hours. The Reakticnsgemisch 250 ml of ether are added and filtered. The filtrate is washed with 250 ml each of 1 N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried (magnesium sulfate), filtered and concentrated. The residue is chromatographed on a column of gravel with 50 to 75% ethyl acetate in hexane, followed by pure ethyl acetate to give 10.5 g of a white foam. The white foam is further chromatographed with 50% ethyl acetate / hexane to give 4.4 g of the diastereomeric (3S-cis) product and 4.6 g of the (3R-cis) title compound F.

G. (R-cis) -1,3,4,5-Tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

To a stirred suspension of title compound F (4.6 g, 7.73 mmol) in 85 mL of methanol is added a 25% solution of sodium nitrate in methanol (5.52 mL, 23.19 mmc.l). Within 5 to 10 minutes, all solids go into solution. After 30

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Minutes, the mixture is poured into 250 ml of 1 N aqueous acid and extracted three times with ethyl acetate. The ethyl acetate extracts are combined, dried (sodium sulfate), filtered and concentrated. The residue is triturated with 50% ethyl acetate / hetcan and the precipitated solid is filtered, dried in vacuo to give 1.73 g of the title compound. The mother liquor is concentrated and then chromatographed on a silica gel column with up to 75% ethyl acetate / hexane to give a further 350 mg of dent- titanium compound G as a white solid; . M.p. 171-173 ⁰ C. [Ot] ₀ = 187 ° (c = 0.55; methanol).

H. (3R-C1S) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) H-benzazepine-monohydrochloride

Sodium hydride (100 mg, 4.14 mmol) is added with stirring to a solution of the title compound G (1.08 g, 3.45 mmol) in 15 ml of dry dimethylformamide. Add 30 ml of 2-chloromethyl-imidazoline (490 mg, 4.14 mmol). The mixture is stirred at room temperature for 1.5 hours and then quenched with water. The mixture is extracted three times with ethyl acetate. The ethyl acetate extracts are combined and washed three times with 10% aqueous lithium chloride. The ethyl acetate extract is then washed with dilute hydrochloric acid and water. The aqueous extracts are combined, made alkaline with solid potassium bicarbonate and extracted five times with dichloromethane. The dichloromethane extracts are combined, dried (magnesium sulfate), filtered, concentrated to give 1.32 g of the free base of the title compound as a white solid. A solution of

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free base (1.8 g) in dichloromethane / ethyl acetate is added dropwise with an excess of ethereal hydrogen chloride and the precipitated white solid filtered, washed twice with ethyl acetate and twice with ether and dried in vacuo. Is obtained 1.64 g of the title compound? Mp = 183-188 ⁰ C. [a] _D = + 155.5 ° (c = l, 0, methanol).

Analysis Calc. For C ₂₂ H ₂₅ N ₃ O ₅ · HCl-0 62 _H? 0:

C 59.78; H 5, M ' _f N-9.51; Cl 8.02 gef. C 59.36; H 6,14; N 9.43; Cl 7,92.

Example 56

(3R-C1S) -3- (acetyloxy) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-7-methoxy-4 ( 4-methoxyphenyl) -4H1-benzazepine-1-monohydrochloride

The title compound is prepared from (3R-cis) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy -4- (4-methoxyo-phenyl) -2H-benzazepin-2-one according to the procedure described in Example 54; Mp> 270 ° C. [a] ₀ = + 95.0 ° (c = l, 0 methanol).

Analysis calculated for C ₂₄ H ₇ N ₂ O ₅ · ₃ HCl 0.72 H ₂ O.:

C 59,19; H 6.09; N, 8.63; Ol 7,28; gef. C 59.36; H 5.75; N 8,46; Cl 7.05.

Example 57

[3R- [1 (J5 *), 3α, 4α]] -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) - 2H-l-benzazepin-2-one monohydrochloride

A. [3R- [I (S *), 3α, 4α]] - l, 3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -1 - [[N- benzyloxycarbonyl) "pyrrolidin-2-yl] methyl] -2H-l-benzazepin-2-one

Prepared from (ice) -1 / ^ 3/4, 5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one (Section E of Example 55) according to the method described for the preparation of the title compound A from Example 38.

B, [3R- [I (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -1- (2- pyrrolidinylmethyl) -2H-1-benzazepin-2-one monohydrochloride

Prepared from [3R- [1 (S *), 3α, 4α]] - l, 3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -1 - [[N- benzyloxycarbonyl) -pyrrolidin-2-yl] -methyl] -2H-1-benzazepin-2-one according to the method described for the preparation of the title compound of Example 16; Mp. 179-181 ⁰ C. [a] ₀ = + 109.4 ° (C = 1.0, methanol).

Analysis for C ₂₄ H ₂₈ N ₂ O ₄ -HCl-O ^ SH ₂ O:

C, 62.55; H, 6.84; N, 6.35; Cl 8.03 C, 62.86; H 6,88; N 6.04; Cl 8,23.

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Example 58

[2S- [2α, 3α, 5 (R *)]] -2, S -dihydro-O-hydroxy-e-methoxy - ^ - (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1, 5-benzothiazepine-4- (5H) -one monohydrochloride

A. [2S- [2a, 3a, 3 (R *)]] - 2,3-dihydro-3- (2-benzyloxycarbonylamino-3-phenyl) -propionyl-e-methoxy - ^ - (4-methoxyphenyl) - !, ö-benzoth ^ azepine ^ - (5H) -one

(2-S) -Carbobenzyloxyaminophenylalanine (6.88 g, 22.99 mmol) is added under argon stirring at room temperature to cis-2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl ) -1,5-benzothiazepine-4- (5H) -one (6.09 g, 18.4 mmol) in dry dimethylformamide (55 mL). Water-soluble carbodiimide (7.05 g, 36.7 mmol) is added, followed by one hour of dimethylaminopyridine (0.45 g, 3.7 mmol). Stirring is continued for 45 minutes, the mixture is diluted with ether (280 mL), washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), and concentrated in vacuo. The mixture is purified by chromatography followed by reverse phase HPLC to give the title compound A (1.30 g).

B. (2S-C1S) -2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl) -l, 5-benzothiazepine-4- (5H) -one

The title compound A (1.30 g, 2.12 mmol) in methanol (21 mL) and water (0.2 mL) is added under argon with 25% sodium hydroxide in methanol (1.0 mL, 4.3 mmol) , Stir for 90 minutes

- 150

$ 84,005

and the mixture diluted with water (100 inl) and stirred for a further 30 minutes. The colorless solid product is separated by filtration; Mp 180-183 ° C (decomp.). [a] _D = + 85.4 ° (c = 0.79, dimethylformamide).

C. [2S- [2a, 3a, 5 (R *)]] -2,3-dihydro-3-hydroxy-8-nethoxy-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1 , 5-benzothiazepin-4- (5H) -one monohydrochloride

The title compound is * ^ aus (2S-cis) -2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4- (5H) -one according to the shown in Example 46, Step B and D; Mp 121-124 ⁰ C (Zers.). [a] ₀ = + 62.9 ° (c = l, 08, methanol).

Analysis calc. For C ₂ H ₂ H ₂₆ N ₂ SO ₄ .HCl-2, 14 H ₂ OC 53.98; H, 6.44; N 5.72; Cl 7,24; S, 6.55;

gef. C 53.99; H 6.02; N 5.71; Cl, 7.57; S 6,65.

Example 59

(2S-C1S) -5- [4,5-dihydro-lH-inu.dazol-2-.yl) methyl] -2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl ) -1,5-benzothiazepin-4- (5H) -one monohydrochloride

The title compound is prepared from (2S-cis) -2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4- (5H) -one according to the procedure described in Example 43 described methods are shown; Mp. 192-199 ⁰ C. [a] ₀ = + 62.9 ° (c = l, 0, methanol).

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28OO O5

Analysis calc. For C ₂ , H _{2 2} N ₃ O ₄ S-HCl-0.66 H ₂ O:

C 54.30; H 5.30; N 9.05; Cl, 8.40; S 6,90; gef. C 54,16; H, 5.52; M 9,19; Cl 8.04; S 6,92.

Example 60

(2S-cis) -S-acetyloxy-S- [4,5-dihydro-lH-imidazol-2 ~ yl) methyl] -2,3-dihydro-8-methoxy-2- (4-methoxyphenyl) -1 , 5-benzothiazepin-4- (5H) -one monohydrochloride

The title compound is prepared from (2S-cis) -5- [4,5-dihydro-1H-imidazol-2-yl) -methyl] -2, S-dihydro-S-hydroxy-e-methoxy-2- (4- methoxyphenyl) -1,5-benzothiazepine-4- (5H) -one (title compound of Example 59) according to the method described in Example 54; M.p. 275 ⁰ C. [a] _D = + 65.19 ° (c = l, 0, methanol).

Analysis for C ₂₃ H ₂₅ N ₃ ClSO ₅ -HCl-O ^ H ₂ O:

C 54,29; H, 5.52; N 8.26; Cl 6, 97; S 6,30; gef. C, 54.68; H 5.32; N, 7.72; Cl 7,42; S 5.95.

Example 61

(Ice) -1 - [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-7-methylthio-4- (4-methoxyphenyl ) -2H-l-benzazepin-2-one monohydrochloride

A. 2- [2- (5-Methylthio-2-nitrophenyl) -1- (4-methoxyphenyl) -ethyl] -propanedioic acid dimethyl ester

A solution of dimethyl 4-methoxybenzylidene malonate (13.65 g, 54.6 mmol) and sodium hydride (60% oil dispersion, 3.23 g, 80.8 mmol, 1.5 equiv) in 100 mL of dry dimethylformamide on O ⁰ C

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28 4O O 5

cooled. Over a period of 20 minutes, a solution of 5-methylthio-2-nitrotoluene (10.0 g, 54.6 mmol) in dry dimethylformamide is added. Thereafter, the Eisoad is removed and the reaction mixture is stirred at room temperature. The reaction is continued via power at room temperature.

The reaction mixture is quenched with glacial acetic acid (7 ml) and the slurry is poured onto an ice-water mixture of about 300 ml. The aqueous phase is extracted four times with ethyl acetate and the organic phases are dried (magnesium sulfate). After removal of the solvents in vacuo, a red-brown oil-liquid mixture remains. This mixture is recrystallized from 100 ml of hot isopropanol to give 17.76 g (75%) of bright yellow crystals; Mp. 126-128 ⁰ C.

B. 2- (2- (2-Amino-5-methylthiophenyl) -1- (4-methoxyphenyl) ethyl] -propanedioic acid dimethyl ester

To a solution of stannous chloride-water (47.12 g, 209 mmol, 5.1 equivalents) in 750 mL of 90% methanol / 12M hydrochloric acid is added the title compound A (17.75 g, 40.9 mmol ). The solution is stirred for 60 hours. Celite, ethyl acetate (770 ml), saturated potassium carbonate solution (315 ml) and solid potassium carbonate (200 g) are added to the reaction mixture. The mixture is stirred for 5 minutes and then passed through a filter of porosity C followed by a second filter of porosity M. The reaction mixture is concentrated in vacuo until the product begins to precipitate. The product is filtered off and the clear filtrate is again concentrated in vacuo and

- 153 - ή η ·. ,

gives a second batch of crystals. The two batches are combined and washed with methanol, followed by 70% water / methanol. The crystals are dried in vacuo over P ₂ O _{5 to} yield 13.25 g of a off-white solid; Mp. 126-127 ⁰ C.

C. 1,3,4,5-Tetrahydro-7-methylthio-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

A solution of Title Compound B (12.55 g;

31.1 mmol) in methanol (130 ml) is treated with sodium methoxide (25% solution in methanol, 8.5 ml;

37.2 mmol). The resulting solution becomes

Heated under reflux for 2.5 hours.

The solution is cooled to ⁰ ° C., then 1N hydrochloric acid (130 ml) is added with vigorous stirring. After one hour, the resulting light brown solid is separated and washed with cold water. The solid is dried in vacuo over P ₂ O _{5 to} give 10.51 g (91%) of a light yellow solid; Mp 158-16O ⁰ C.

D. 1,3,4,5-Tetrahydro-3-hydroxy-7-methylthio-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

A solution of the title compound C (3.21 g;

8.6 mmol) in dry dimethylformamide (16 ml) is heated to 6O ⁰ C to complete dissolution.

The solution is first cooled to room temperature, then cooled to -78 ⁰ C. It is (23 ml) was added toluene, and the solution is kept at -78 ⁰ C while potassium-t-amylate (13.8 ml of a 1.8 M solution in

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Toluene; 24.8 mmol) is added. The solution is stirred at -78 ⁰ C, trimethyl phosphite (3.58 g, 28.8 nunol) was added and oxygen bubbled through the solution. With the beginning of the addition of oxygen, the reaction mixture is warmed to ⁰ ° C. and kept at this temperature for 1.5 hours.

The reaction mixture is poured into water (25 ml) and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined and washed with 10% hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated brine. The organic phase is dried (magnesium sulfate) and the solvents removed in vacuo. A clear yellow oil is obtained, which solidifies when pumped off at room temperature.

The crude crystals are recrystallized from ethyl ether to give 2.18 g (65%) of a white powder; Mp. 172-174 ⁰ C.

E. (Ice) -1,3,4,5-Tetrahydro-3-hydroxy-7-methylthio-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

A solution of the title compound D (2.00 g, 5.2 mmol) in a mixture of pyridine and water is cooled to ⁰ ° C. Lithium hydride (2.75 g, 20.6 mmol) is added and the solution is first heated to room temperature, then to reflux (oil bath temperature 12O ⁰ C) for 3 hours. The reaction mixture is poured into water (20 ml) and acidified to pH 2 with 6 N hydrochloric acid. The aqueous phase is extracted twice with ethyl acetate. The united organic

- ¹⁵⁵ -

Phases are dried (magnesium sulfate). After removal of the solvents in vacuo, a yellow solid remains. The crude product is recrystallized from 95% ethanol to give 1.07 g (63%) of the cis isomer as a white solid; Mp 190-191 ° C.

F. (Ice) -1 - [(4,5-Dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hydroxy-7-methylthio-4- (4 -methoxyphenyl) ^ H-benzazepine - ^ - on monohydrochloride

rid ** -.-.

The title compound is prepared from title compound E according to the procedure described in Example 43; Mp 195-198 ⁰ C;

Analysis for C ₂₂ H ₂₅ N ₃ O ₃ S-HCl-0.64 H ₂ O:

C 57.50; H 5.98; N 9.15; Cl 7, 72; S 6,98; gef. C 57.60; H 6,19; N 9.05; Cl, 7.63; S 6,84.

Example 62

(Cis) -1- [4,5-dihydro-lH-imidazol-2-yl) methyl] -1,3,4,5-tetrahydro-3-hydroxy-7-methylsulfinyl-4- (4-methoxyphenyl) ^ Hl-benzazepin monohydrochloride

A. (Ice) -1,3,4,5-Tetrahydro-3-hydroxy-7-methylsulfinyl-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

A solution of the title E compound of Example 61 (1.0 g; 3.04 mmol) in dry dichloromethane (30 ml) at 5 ⁰ C and m-chloroperbenzoic acid (0.615 q, 3.04 mmol) was added. After 30 minutes, the reaction is complete and the reaction mixture is diluted with ethyl acetate and saturated

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2 8 4 ι) ϋ 5

Sodium bicarbonate solution, water and brine. The organic phase is filtered, concentrated in vacuo to give a solid residue (1.02 g). Trituration with hot ethyl acetate, cooling and filtration gives the product (600 mg); Mp. 214-216 ⁰ C. The mother liquor is concentrated in vacuo and chromatographed on LPS-1 silica gel with dichloromethane / methanol. The product fractions are combined and concentrated in vacuo, and the residue is crystallized from ethyl acetate. Another 200 mg of product are obtained.

For example, (cis) -1 - [(4,5-dihydro-1H-imidazol-2-yl) methyl] -1,3,4,5-tetrahydro-3-hydroxy-7-methylsulfinyl-4- (4 -methoxyphenyl) -Hl-benzazepine-monohydrochloride

The title compound B is prepared from the title compound A according to the method described in Example 43; Mp 195-205 ⁰ C.

Analysis calc. For C ₂ H _{2 6} ClN ₃ O ₄ S- 1, 3 H ₂ O:

C 54.21; H 5.91; N, 8.62; S 6,58; Cl 7,27; gef. C 54.48; H 5.77; N 8:35; S 6,33; Cl 7,62.

Example 63

[3R- [1- (S *), 3a, 4a]] - (1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-azetidinylmethyl] -6- trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

A. (S) -1 - [(1,1-dimethylethoxy) carbonyl] azetidine-2-carboxylic acid

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Di-t-butyl dicarbonate (2.18 g, 9.9 mmol) is added throughout to a stirred mixture of (L) -azetidine-2-carboxylic acid (1.0 g, 9.9 mmol), triethylamine (2.12 ml, 15.0 mmol), 10 ml of acetone and 10 ml of water. The resulting reaction mixture is stirred for 4 hours at room temperature. The mixture is partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase is acidified to pH 3 with 10% citric acid. Extract the resulting acidic mixture with 2x200 mL of ethyl acetate, and dry the combined organic extracts (magnesium sulfate), and give the title compound A (2.0 g) as a colorless oil.

B. (S) -1 - [(1,1-dimethylethoxy) carbonyl] azetidine-2-carboxylic acid methyl ester

A mixture of (S) -1 - [(1,1-dimethylethoxy) carbonyl] azetidine-2-carboxylic acid (2.0 g, 9.9 mmol), potassium carbonate (6.9 g, 50.0 mmol). and methyl iodide (6.25 ml, 100.0 mmol) in 20 ml of dimethylformamide is stirred under argon at room temperature for 1 day. Excess methyl iodide is pumped out into a dry ice-cooled trap, the remaining mixture poured into water and extracted with 300 ml of ethyl ether. The organic extract is washed twice with 150 ml of saturated brine, dried (magnesium sulfate), concentrated to give 1.85 g of the title compound B as a colorless liquid. [a] _D ²⁵ = -114.8 ° (c = 2.5, chloroform).

C. (R, S) -I - [(1,1-Dimethylethoxy) carbonyl] -azetidine-2-carboxylic acid 1,1-dimethylethyl ester

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To a solution of methyl (S) -1- [(1,1-dimethylethoxy) carbonyl] azetidine-2-carboxylate (1.83 g, 8.5 mmol) in 38 ml of t-butanol is added 18 at room temperature Added 8 ml of a 1 M solution of potassium t-butoxide in tetrahydrofuran. The reaction mixture is stirred for 5 hours, during which it is diluted with 200 ml of ethyl ether. The resulting mixture is washed successively with in each case 100 ml of saturated common salt solution, 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated brine. The organic extracts are dried (magnesium sulfate), concentrated to give 1.63 g of the title compound C as a colorless liquid.

D. (R, S) -l - [(1,1-dimethylethoxy) carbonyl] azetidine-2-methanol

Lithium borohydride (0.22 g, 10.5 mmol) is added to a solution of (R, S) -l - [(1,1-dimethylethoxy) carbonyl] -azetidine-2-carboxylic acid 1,1-dimethylethyl ester (1.59 g, 6.19 mmol) in 20 mL of tetrahydrofuran at ⁰ ° C. The reaction mixture is warmed to room temperature, stirred for 18 hours and partitioned between saturated brine and ethyl acetate. The organic extracts are washed with 1N hydrochloric acid and saturated brine, dried (magnesium sulfate), concentrated to give 0.92 g of the title compound D as a colorless oil. [a] _D ²⁵ = 0 °.

E. (R, S) -l - [(1,1-dimethylethoxy) carbonyl] azetidine-2-methyl- (4-methylbenzene) sulfonate

- 159 -

A mixture of (R, S) -l - [(1,1-dimethylethoxy) carbonyl] azetidine-2-methanol (0.9 g, 4.9 mmol) and p-toluenesulfonyl chloride (1.87 g, 9 , 8 mmol) in 10 ml of pyridine is stirred at room temperature for 60 hours, then an additional 0.5 g (2.6 mmol) of p-toluenesulfonyl chloride is added, and the reaction mixture is stirred for a further 2 hours. To the mixture is added 10 ml of saturated sodium bicarbonate solution and stirred for a further 30 minutes. It is then partitioned between 100 ml of ethyl acetate and 100 ml of saturated sodium bicarbonate solution. The organic phase is washed with 2 × 70 ml 1 N hydrochloric acid, 50 ml saturated sodium bicarbonate solution and 50 ml saturated brine, dried (magnesium sulfate) and concentrated. The crude residue is purified by flash chromatography (5x12 cm, 80% hexane / ethyl acetate) to give 1.43 g of the title compound E as a yellow oil.

F. [3R- [I (S *), 3 ", 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- [l - [(1, 1-dimethylethoxy) carbonyl] azetidinyl-2-methyl] -6- (trifluoromethyl) -2H-1-benzazepin-2-one and [3R - [(1,1-dimethylethoxy) carbonyl] azetidinyl-2-one methyl] -6- (trifluoromethyl) -2H-l-benzazepin-2-one

A mixture of (R, S) -l - [(1,1-dimethylethoxy) carbonyl] azetidine-2-methyl- (4-methylbenzene) sulfonate (0.492 g, 1.46 mmol), (3R-cis ) -1,3,4,5-Tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one (0.46 g, 1.3 mmol) and cesium carbonate (0.977 g; 30.0 mmol) in 4 ml of dimethylformamide is stirred for 18 hours at 6O ⁰ C and 100 ml of ethyl

- 160 - 28 4

0 O ₅

acetate and 100 ml of water. The organic phases are washed with 2x50 ml of water and 50 ml of saturated brine, dried (magnesium sulfate) and concentrated. The crude pale yellow residue is purified by flash chromatography (5x12 cm; 5 liter 75% hexane / ethyl acetate; 1 liter 50% hexane / ethyl acetate) and the isomers separated. This gives 0.2 g (30%) of [3R- [I (S *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1 - [l - [(1,1-dimethylethoxy) carbonyl] azetidinyl-2-methyl] -6- ('trifluoromethyl) -2H-l- benz / azepin-2-one in the form of a white foam together with 0.232 g (34%) of [3R- [1 (R *), 3α, 4α]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- [1- [ (1,1-dimethylethoxy) carbonyl] -azetidinyl-2-methyl] -6- (trifluoromethyl) -2H-1-benzazepin-2-one also in white white foam and additionally 0.15 g mixed fractions.

G. [3R- [I (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-azetidinylmethyl) -6- (trifluoromethyl) -1H-benzazepine ^ -one, fumaric acid salt (1: 1)

A mixture of [3R- [1 (S *), 3a, 4a]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -l- [l - [(1, 1-dimethylethoxy) carbonyl] -azetidinyl-2-methyl] -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.55 g, 1.06 nanol) and 3.3 mL of trifluoroacetic acid in 3, 3 ml of dichloromethane is stirred for 2 hours at room temperature. The reaction mixture is concentrated under reduced pressure. Toluene is added and the mixture is concentrated again to a yellow oil which is partitioned between ethyl acetate and 1N sodium hydroxide solution. The organic extracts are washed with brine, dried

- 161 -

(Magnesium sulfate), to give 0.424 g of the crude free Ease, which is purified by flash chromatography. Mp. 155 ⁰ C (softening), 162-17O ⁰ C (dec.)

[Ct] ₀ = + 62.8 ° (c = 0.50, methanol).

Analysis Calc. For C ₂₂ H ₂₃ N ₂ F ₃ O ₃ -C ₄ H ₄ O ₄ -O ^ H ₂ O

C 57,26; H 5:17; N 5:14; V 10.45 gef. C 57,24; H5, Ό5; Ν 5.16; F 10.61.

Example 64

[3R- [1 (R *), 3a, 4a]] - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxypheny1) -1- (2-azetidinylmethy1] -6- (trifluoromethyl ) ^ Hl-benzazepin ^ -one, fumaric acid salt (1: 1)

The title compound is prepared from [3R- [1 (R *), 3α, 4α]] - l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -l- [l - [(1 , 1-dimethylethoxy) carbonyl] -azetidinyl-2-methyl] -6- (crifluoromethyl) -1H-benzazepine ^ -one, prepared in Step F of Example 63, according to the procedure described in Step G of Example 63; Mp. 112 ⁰ C (softening), 140-146 ⁰ C (dec.)

[a] ₀ = + 90.2 ° (c = 0.55, methanol).

Analysis for C ₂₂ H ₂₃ N ₂ F ₃ O ₃ .C ₄ H ₄ O ₄ .0.99 H ₂ O:

C 56,33; H 5,27; N 5.05; F 10,28; gef. C 56.21? H 5.22; N 5:17; F 10.55.

Example 65

(3 (R) -cis) -1 - [(1-methyl-4,5-dihydro-imidazol-2-yl) -methyl] -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1. enzazepin-2-one

- 162 -

A. (3 (R) -CX) -1- (cyanomethyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

To a solution of 0.60 g of sodium hydride (14.9 mmol of 60% oil dispersion) in 150 ml of dry tetrahydrofuran is added 5.0 g of (3 (R) -cis) -3-hydroxy-4- (4-methoxyphenyl). -6-trifluoromethyl) -2H-1-benzazepin-2-one. The solution is stirred at room temperature for 15 minutes, cooled to ⁰ ° C., and a solution of 1.03 ml of iodoacetonitrile (14.2 mmol) in 10 ml of dry THF is added dropwise. The solution is warmed to room temperature over a period of 2 hours and partitioned between water and ether. The aqueous phase is washed with ether and the combined ether extracts are washed with brine and dried (magnesium sulfate). The solution is concentrated to about 20 ml, 10 ml of hexane are added and cooled. This gives 0.74 g of (3 (R) -cis) -1- (cyanomethyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one in the form a slightly yellow, crystalline solid * The mother liquor gives another 2.04 g of the product.

B. (3 (R) -cis) -1 - [(1-methyl-4,5-dihydroimidazol-2-yl) -methyl] -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-l-benzazepin-2-one

Hydrogen chloride gas is passed through a solution of 1.95 g of (3 (R) -cis) -1-cyanomethyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2- on (5.0 mmol) in 20 ml of ether and 0.31 ml of absolute ethanol (5.24 mmol) at ^{0 0} C until dissolved in the solid. The solution is locked

- 163 -

28400s

sen and stored for 4 days at 5 ⁰ C and 6 days at -2O ⁰ C. The ether is decanted from the settled thick oily residue, and dry ethor is added to the residue, resulting in the formation of a white solid. The ether is decanted and the white solid washed with ether. The white solid is dissolved in 25 ml of dimethylformamide, and 12.5 ml of this solution are added dropwise at ⁰ ° C. to 0.33 ₍ ml of N-methylethylenediamine (3.75 mmol) in 5 ml of dry dimethylformamide stirred at room temperature, aqueous potassium carbonate is added, and the solution is extracted twice with ether The combined ether extracts are washed twice with water and once with brine, dried (potassium carbonate), concentrated to give 0.77r, a white solid. The solid is dissolved in ether, and addition of hydrogen chloride saturated ether gives a white solid, the solid is filtered, rinsed twice with ether, and dissolved in a homogeneous mixture of aqueous potassium carbonate, ether, and dioxane. Ether is added to achieve phase separation , the aqueous phase washed with more ether, and the combined organic extracts with saturated brine, dried (potassium carbonate), concentrated to give 0.66 g of a white solid. The solid is chromatographed over 3 preparative silica gel plates (pretreated with 5% triethylamine / dichloromethane) with 5% methanol / dichloromethane. The major band is excised and extracted twice with 10% methanol / dichloromethane and the combined solutions concentrated to leave 0.27 g of a light yellow foamy solid. The solid is dissolved in ethyl acetate, and

164 -

Hydrogen chloride saturated ether is added. The result is a waxy solid. The solution is concentrated and stirred with ether. The solid is dissolved in 20 ml of 50% methanol / isopropyl ether and 150 ml of isopropyl ether are added. The solid is filtered, dried in air, giving 235 mg of (3 (R) -cis) -1 - [(1-methyl-4,5-dihydro-imidazol-2-yl) -methyl] -3-hydroxy- 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one as a tan solid; Mp> 240 ° C

[a] ₀ = + 98.2 ° (c = l, methanol).

Analysis for C ₂₃ H _{2 5} N ₃ O ₃ F ₃ Cl-1, 70 H ₂ O:

C, 53.68; H 5.56; N 8,16; F 11.07; Cl 6,89; gef. C 54.08; H 5.46; N 7.90; F, 10.68; Cl 6,90.

Example 66

(3R-C1S) -1 - [{4,5-dihydro-lH-imidazol-2-yl) methyl] -1,3,4,5-tetrahydro-3-hydroxy-6-chloro-4- (4 -methoxyphenyl) -Hl-benzazepine-monohydrochloride

A. (Ice) -I, 3,4,5-Tetrahydro-3 - [(2-carboxyphenyl) -carboxyl] -6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

A stirred suspension of (cis) -l, 3,4,5-tetrahydro-3-hydroxy-6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, prepared according to the method of Example 61, in dichloromethane (100 ml) is added a solution of triethylamine (5.55 g, 55 mmol) in dichloromethane (50 ml), followed by dimethylaminopyridine (1.0 g) and phthalic anhydride (8.2 g, 55 mmol ). The solids dissolve quickly

- 165 -

28 I O O

on, and the resulting solution is stirred for 2 hours at room temperature. The mixture is added portionwise with 1 N hydrochloric acid (83 ml) to give a heavy precipitate. After stirring and cooling for 30 minutes, the product is filtered, washed five times with 25 ml of water, dried, to give the title compound A (22.58 g); Mp. 165-167 ⁰ C. After recrystallization from acetonitrile, a sample melts this Materials'bei 220-222 ⁰ C.

B. (3R-C1S) -1,3,4,5-tetrahydro-3 - [(2-carboxyphenyl) -carboxyl] -6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepine-2 on, (S) - (-) - α-methylbenzylamine aldol

A stirred suspension of (ice) -1,3,4,5-tetrahydro-3 - [(2-carboxyphenyl) -carboxy] -6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepine ~ 2- on (22.17 g, 47.5 mmol) in methanol (250 mL) is warmed and washed with a solution of S - (-) - α-methylbenzylamine (5.80 g, 47.5 mmol) in methanol (50 mL ). The genic is heated to reflux. The result is a solution that then begins to crystallize. After standing at room temperature overnight, the crystalline product is filtered, washed with 3x20 ml of methanol, dried to give the title compound B (12.03 g); Mp 16O ⁰ C.

⁼ -15.5 ° (c = l, 0, acetic acid).

(3R-C1S) -1, 3,4, o -tetrahydro-S-hydroxy-o-chloro - (4-methoxyphenyl) -2H-1-benzazepin-2-one

To a stirred solution of lithium hydroxide hydrate (3.40 g, 81 mmol) in water (113 mL) is added the title compound B (11.85 g, 20.5 mmol). The resulting solution is washed with methanol (11 ml)

- 166

added and heated to reflux. A heavy rainfall settles down. This suspension is heated for one hour at 60 to 7O ⁰ C, diluted with 100 ml of water, cooled and stirred for 2 hours. The solid is filtered, washed with water, dried and gives the title compound C as a colorless solid (5.76 g); Fp. 19.1-193 ⁰ C

[ ⁰ Od ⁼ + 83.4 '(c = l, 0, acetic acid).

D. (3R-cis) -1- [(4,5-dihydro-1H-imidazol-2-yl) -methyl] -1,3,4,5-tetrahydro-3-hv ^r) -oxy-6 -chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one monohydrochloride

Title Compound D was prepared from title compound C according to the procedure described in Example 43; Mp. 196-200 ⁰ C

[a] _D = + 80.4 ° (c = 1.0, methanol).

Analysis for C ₂₁ H ₂₂ Cl ₂ N ₃ Oj-1 H ₂ O:

C 55,38; H 5.56; N 9,23; Cl 15.57; gef. C 54.98; H 5.15; N 8,87; Cl 15.95.

Example 67

[3R- [1 (R *), 3a, 4a]] - 3-acetyloxy-l, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6-trifluoromethyl 2H-l-benzazepin-2-one monohydrochloride

The title compound is prepared from RI- (t-butoxycarbonyl) -2 - [(4-methylphenylsulfonyloxy) methyl] pyrrolidine and (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4 methoxyphenyl) -6-

- 167 -

(trifluoromethyl) -2H-1-benzazepin-2-one according to that described in Example 46. Method presented; Mp 153-157 ⁰ C

[a] ₀ = + 104.8 ° (c = 1.0, methanol).

Analysis for C ₂₅ H ₂ / N ₂ O ₄ F ₃ .HCl-0.32 H ₂ O:

C 57.88; H, 5.57; N 5.40; Cl 6,83; F 10.99;

gef. C 5 * 7.78; H 5.89; N 5.50; Cl 6,88; F 10.61.

Claims (17)

P Λ T I- 'N T Λ N S P R ϋ C H E 1. A process for the preparation of benzazepine and benzothiazopine derivatives of the general formula I. and pharmaceutically acceptable salts thereof, wherein X represents one of the groups -CH ₂ - or -S-; R _{1 represents} one of the radicals -CH or -OY, if X is the group -CH ₂ -ReSt, the radical R ₂ (CH ₂ ) _n
CH-CH vf CH- I
N CH ₂ - (CH ₂ J _n Y ₅ -C Y, Y, (CHa) _n , NY ₁₅ V ₇ CH-Y CH- (CH ₀₎ ^ Y _14, CH N-CH, 4 (CHj) L- (CHa) _n (CH ₂ ) _n , N N Ye; means; if X is the (Jruppo -.S-, R ₂ dor Roaü (CHa) _n ,
CH-CH (CH ₉ ) CH-CH ₂
.N. (CH,) _n , CH-Y ₄ .CH. CH ₀ ^ CH ^Υ 6 ^Υ 7 (CHa) _n ,
CH (CH ₉ ) 2'- Y, -CH CH ₀ 28 CH- ^"Υ 4 (CH,) _{/ ηη} od «f J ^ L (CH ₂ ) _n LJ means; R ₃ and fy each independently represent a hydrogen or halogen atom, an alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy, -O-C-NY ₈ Y ₉ , fluoro-substituted alkoxy, fluoro-substituted alkyl, (cycloalkyl) alkoxy, -NO ₂ -, 0 -NY ₁₀ Y ₁₁ -, -S (O) _m alkyl, -S (0) _m aryl, -CY, ₂ - or -0-CY ₁₃ -ReSt mean;
η and η 'are independently 0, I, 2 or 3 to have; m is 0, 1 or 2; Y ₁ and Y ₂ each independently represent a hydrogen atom or an alkyl radical, or Y _{1 represents} a hydrogen atom and Y ₂ denotes an alkenyl, alkynyl, aryl, heteroaryl or cycloalkyl radical, or Y ₁ and Y ₂ together with the carbon atom, to which they are attached, a cycloalkyl radical; Yj oin hydrogen atom, an alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl or O
-C-NY ₈ Y ₉ -ReSt means; Y ₄ and Y ₅ . each independently represents a hydrogen atom or an alkyl, aryl or arylalkyl group, and in the case of the presence of both of these groups, they are not both a hydrogen atom or when both are bonded to the same carbon atom, neither of which is a hydrogen atom; Y ₆ and Y ₇ each independently represent a hydrogen atom, an alkyl, cycloalkyl or arylalkyl radical or Y ₆ and Y ₇ together with the nitrogen atom to which they are attached denote an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group ; Each of Y ₈ and Y ₉ independently represents a hydrogen atom, an alkyl, aryl or heteroaryl group or Y ₈ and Y ₉ together with the nitrogen atom to which they are attached represent a pyrrolidinyl, piperidinyl or morphilinyl group; Y ₁₀ and Y ₁ ! each independently a hydrogen atom, an alkyl, alkanoyloyl, arylcarbonyl, heteroarylcarbonyl or O
-C-NY ₈ Y ₉ -ReSt; Y _{12 represents} a hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino radical; Y _{13 represents} an alkyl, alkoxy or aryloxy radical; and 284 Y ^ _{4 represents} a hydroxy, alkoxy, aryloxy or arylalkoxy radical; which is characterized in that a compound of general formula II in a solvent with a base and subsequently the eo obtained compound with a compound of the formula R ₂ -L or a protected form thereof, wherein L is a leaving group such as a halogen or toeyoxy group A method according to claim 1, characterized in that R ^ -CH
I means _e 284 Process according to claim 1, characterized in that R. -O-Y_ means. 4. The method according to claim 1, characterized in that R _? CH-Y I
-CH-Y- I ^b N
/ \ YY ^T 6 ^Y 7 means _e 5 «method according Anepruch 1, characterized in that R" (CH ₂ Jn. ' / S YY ^Y 6 ^Y 7 meant
6e ^ experience according to claim 1, characterized in that CH-CH ₂ CH-CH ₉ means _β YY ^Y 6 ^Y 7 A method according to claim I _1, characterized in that ^ CH ₂ -CH ₂ YY
^r 6 7 means " 8. The method according to claim 1, characterized in that CH - (CH ₂ ) _n Y ₁ . -CH CH ₀ means. 9β The method according to claim 1, characterized in that CH-Y. 4 CH-CH, (CH.) x \ N-CH, I means ο 10. The method according to claim 1, characterized in that R_ is a methoxy or trifluoromethyl group, R ₄ bound in the 4-position de9 phenyl ring iat and R _{4 represents} an alkoxy radical 11 »Process according to claim 1, characterized in that R. means a 4-methoxy group» 12o Method according to claim 1, characterized in that R, a methoxy «or trifluoromethyl group meant 13. The method according to claim 1, characterized in that / 3R- / 1 (S *), 3ot, 4cV / -3- (Ace ty loxy) -1, 3,4,5-1 et rahydro-4- (4 -methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one or a pharmaceutically acceptable salt thereof. 14 »Process according to Claim 1, characterized in that / 3 (R) - / 1 (S" *), 3 *, 4 (*) / - 1, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one or a pharmaceutically acceptable salt thereof. 15 »Process according to claim 1, characterized in that / 3R- / 1 (S ^K ), 3oi, 4 * V / -6-chloro-l, 3,4,5-tetrahydro-3-hydroxy-4- (4 -methoxyphenyl) -I- (2-pyrrolidinylmethyl) -1H-benzazepin-2-one is produced Process according to Claim 1, characterized in that / 3R-Z 1 (S 3), 3iX, 4eC // - 3- (acetyloxy) -6-chloro-1, 3,4,5-tetrahydro-4- (4 -methoxyphenyl) -l- (2-pyrrolidinylmethyl) -2H-benzazepine-2-one is produced « 28 17. The method according to claim 1, characterized in that / 3R-l (2S *), 3 # <, 4 »V / -l - / (2-dimethyl-amino) -l-phenylpropyl / -1,3,4,5 tetrahydro-3-hydroxy-4- (4-methoxy-phonono) -6- (trifluoromethyl) -2H-1-benzazepin ~ 2-one monohydrochloride, isomer B is prepared ₀ 18. The method according to claim 1, daduch in that (3 (R) -cis) -L ~ / 2- (Dimethylamine) -l-phenylethyl / -l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluormethyI) -2H-1-benzazepin-2-one monohydrochloride, isomer B is produced 19. The method according to claim 1, characterized in that ^ (R) - /! ^^ *) / ^ *, ^ / -! - ^ - (Dimethylamine) -l-phenylpropyl / -l, 3,4,5- tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride, isomer A is produced Process according to claim 1, characterized in that / 3-1 (R '* ^f (, 3 <*, 4iV / -l, 3,4,5-tetrahydro-3-hydroxy-4- (4-methoxy. phenyl) -l- (3-pyrrolidinyl) -6- (trifluoromethyl) -2H-1-benzazep - '. n-2-one, fumaric acid salt (II) is prepared 21. The method according to claim 1, characterized in that / 3R- / l (2S ^K , 4R ⁱ * ") _# 3 ^, 4iV / -l, 3,4,5-tetrahydro-3-hydroxy-4 ~ (4 -methoxyphenyl) -l-4- (phenylmethoxy) -2-pyrrolidinyl / -methyl / -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride. 22 «Process according to Claim 1, characterized in that / 3R- / 1 (2S ^{i <} , 4R ^ '), 3 ^, 4'-yl, 3,4,5-tetrahydro-3-hydroxy 1- (4-hydroxy-2-pyrrolidinyl) -ethyl / -4- (4-methoxyphenyl) -6- (trifluorometh-1) -2H-1-benzazepine-2-one monohydrochloride. A method according to claim 1, characterized in that / 3R- / 1 (2S *, 4S *), 3p <, W / -l »3 * 4,5-tetrahydro-3-hydroxy-1 - / (4 hydroxy-2-pyrrolidinyl) -methyl / -4- (4-riethoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one monohydrochloride 24. A method according to claim 1, characterized in that (3R-cis) -l - / (4,5-dihydro-lH-imidazol-2-yl) methyl / -l, 3,4,5-tetrahydro-3-hydroxy -4- (4-methoxyphenyl) -6- (trifluoromethyl) .2H-1-benzazepin-2-one monohydrochloride is prepared 25. The method according to claim 1, characterized in that / 2S- / 2i *, 3Ä, 5 (ä *) // - 3 ~ (acetoxy) -2,3-dlhydro-8-methoxy-2- (4- methoxyphenyl) »5- (2-pyrrolidinylmethyl) -I, 5-benzothiazepine-4- (5H) -one monohydrochloride. Process according to Claim 1, characterized in that / 2S- / 2 *, 3 *, 5 (1 '), - 2,3-dihydro-2- (4-methoxyphenyl) -3- (2-methyl-) 1-oxopropoxy) -5- (2-pyrrolidinylmethyl) -l, 5-benzothiazepine-4- (5H) -one monohydrochloride A process according to claim 1, characterized in that / 3R- / 1 (S), 3 ^, 4C ^ / - 3- (acetyloxy) -1,3,4,5-tetrahydro-7-methoxy-4- ( 4-methoxyphenyl) -I- (2-pyrrolidinylmethyl) -2H-1-benzazepin-2-one monohydrochloride. 28. The method according to claim 1, characterized in that (3R-cis) -3- (acetyloxy) -1 - / (4,5-dihydro-lH-imidazol-2-yl) -methyl / -l, 3.4 , 5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one mimohydrochloride is prepared » 8 * 005 29. Method according to claim 1, characterized in that (3R-cis) -1- (4,5-dihydro-1H-imidazol-2-yl) -methyl-L, 3,4,5-tetrahydro ~ 3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -2H-benzazepine-2-one monohydrochloride is prepared, 3Oe method of claim 1, characterized in that (3R «ci8) -3- (acetyloxy) -l ^ / (4,5-dihydro-lH-imidazol-2-yl), me thy 1 / -1.3 4,5'-t et rahydro-7-inethoxy '' - (4-metoxyphenyl) -2H-1-benzazepin ~ 2-one monohydrochloride. 31- Process according to claim 1, characterized in that / 3R- / 1 (S *), 3fl, 4 <V / - l »3,4,5-T8-tetrahydro-3-hydroxy-7-methoxy-4- ( 4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -2H-1-benzazepln-2-one monohydrochloride. A method according to claim 1, characterized in that / 2S- / 2 ^, 3 «< _i 5 (R ^) // - 2,3-dihydro-3-hydroxy-8-.ethoxy-2- (4-methoxyphenyl ) -5- (2-pyrrolidinylmethyl) -l, 5 "-benzothiazepin-4 - (5H) -one monohydrochloride. 33. The method according to claim 1, characterized in that (2S-cis) -5- / 4,5-dihydro-lH-imidazol-2-yl) methyl / -2,3-dihydro-3-hydroxy-8-methoxy-2- (4 ~ methoxyphenyl) -l , 5-benzothiazepine-4- (5H) -one monohydrochloride was prepared A process as claimed in claim I _4, characterized in that (2S-cis) -3-acetyloxy-5- / 4,5-dihydro-1H-imidazol-2-yl) -ethyl / -2,3-dihydro-8-tnethoxy 2- (4-methoxyphenyl) -l, 5-benzothiazepine-4- (5H) -one monohydrochloride. 35. The method according to claim 1, characterized in that (ice) -l - / (4,5-dihydro-lH-imidazol-2-yl) -methyl / -l, 3,4,5- 2 8 4 0 0g tetrahydro-3-hydroxy-7-methyl-4- (4-methylthyphenyl) -2H-benzazepine-2-one monohydrochloride is obtained 36o Method according to claim 1, characterized in that (cis) -l- / (4,5-dihydro-1H-imidazol-2-.yl) -methyl / -l, 3,4,5-tetrahydro-3-hydroxy 7-methyl-8-sulfinyl-4- (4-methoxy -phanyl) -2H-.1-bp-azepin-2-one monohydrochloride. 37. The method according to claim 1 *, characterized in that / 3R- / l (S *), 3flU4cV / -l # 3,4,5-tetrahydro-3-hydroxy-4- (4-inet hoxyphenyl) -l- ( 2-azet id inylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid (1 * 1). 38. The method according to claim 1, characterized in that / 3R- / l (R *), 3 <*, 4ey / -l, 3,4,5-tetrahydro-3 ~ hydroxy-4- (4-methoxyphenyl) - l- (2-azet-idinylmothyi) -6- (t rif luormethyl) -2H-lb ^ n ^ azepin-2-one, fumaric acid salt (IjI) is prepared A method according to claim 1, characterized in that (3 (R) -cis) -1- / (1-methyl-4,5-dihydro-imidazol-2-yl) -methyl / 3-hydroxy-4- (4-methoxy-5-phenyl) -6- (trifluoromethyl) -2H-benzazepine-2-one. 40. The method according to claim 1, characterized in that (3R-cis) -l - / (4,5-dihydro-lH-in.idazol-2-yl) -methyl / -l, 3,4,5-tetrahydro 3-hydroxy-6-chloro-4- (4-meth-3-phenyl) -2H-benzazepine-2-one monohydrochloride. 4L ancestors according to claim 1, characterized / 3R- / 1 (R *), 3 *, 4 "V / 3-acetoxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6-trifluoromethyl- 2H-1-benzazepin-2-one monohydrochloride is prepared · 42o Process according to claim 1 for the preparation of benzazepine derivatives of the general formula and pharmaceutically acceptable salts thereof, wherein Ϊ1 R _{1 represents} one of the radicals -CH or -O-Y_; J. (O one of the leftovers R ₂ is CH-Y ₄ CH-Y ₅ N ' Y Y ^Y 6 ^Y 7 YY ^T 6 ^T 7 CH-CH, CH-CH ₂ N CH,
I ^c
C ' CH ₀ - CH, CH "- Yi-- CH CH, or means; R ₃ and R ₄ each independently represent a hydrogen or halogen atom, an alkyl / alkoxy ,. Aryloxy, arylalkoxy, diarylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy, -O-C-NY ₈ Y ₉ , fluoro-substituted alkoxy, fluoro-substituted alkyl, (cycloalkyl) alkoxy, -NO ₂ -, O -NY ₁₀ Y _n -, -S (O) _m alkyl, -S (O) _n , aryl, -CY ₁₂ - or Mean -OCY ₁₃ radical;
η is 0, 1, 2 or 3; m is 0, 1 or 2; Y, and Y ₂ each independently represent a hydrogen atom or an alkyl group, or Y _{1 represents} a hydrogen atom and Y _{2 represents} an alkenyl, alkynyl, aryl, heteroaryl or cycloalkyl group, or Y ₁ and Y ₂ together with the carbon atom to which they are bonded, a cycloalkyl radical; Y _{3 represents} a hydrogen atom, an alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl or 0 IlC-NY ₈ Y ₉ -ReSt means; Yz ₁ and Y ₅ each independently represent a hydrogen atom or an alkyl, aryl or -W- 28 40C Arylalkyl group, wherein in the case of the presence of both of these groups, they are not both a hydrogen atom or when both are bonded to the same carbon atom, neither of which is a hydrogen atom; Each of Y ₆ and Y ₇ independently represents a hydrogen atom, an alkyl, cycloalkyl or arylalkyl group or Y ₆ and Y ₇ together with the nitrogen atom to which they are attached represent an azetidinyl, pyrrolidinyl, piperidinyl "or morpholinyl group; Each of Y ₈ and Y ₉ independently represents a hydrogen atom, an alkyl, aryl, or hauroaryaryl group, or Y ₈ and Y ₉ together with the nitrogen atom to which they are attached represent a pyxrolidinyl, piperidine, '''or morphilinyl group; Y ₁₀ and Y _n each independently represent a hydrogen atom, an alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl or O
-C-NY ₈ Y ₉ -ReSt; Y _{12 represents} a hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino radical? Y _{13 is} an alkyl, alkoxy or aryloxy radical I means; dadurcli characterized in that one is a compound of the general formula 28 in a solvent with a base and then the compound thus obtained with a compound of the formula ' R, -L or a protected form thereof, wherein L is a leaving group such as a halogen or
Tosyloxygruppe is.