LU80369A1 - PROCESS FOR OBTAINING DEOXYVINCAMINIC AMIDES - Google Patents

Description

OC 5ο.134

- „Ä ÂRAND-DUCHÉ DE LUXEMBOURG

Patent N ° ............... ^ [) J () of 1.6 .... oc.tob.re ...... 19.7.8 ... Minister of the National Economy and the Middle Classes

Book title: ........................................

giffi Industrial Property Service

LUXEMBOURG

Patent Application I. Application ..... The ... company ..... di.te.ï ...... SYNTHELABO., ...... 1., ... ..avenue ..... & e .... Y.lll.ars, ...... to ..... 75.341 .......... (i) ..... BARIS CEDEX ... α7., France, represented by. Sir ... Cr.ac.ques. of...............

..... Muyser .., ag.is.sant .... en ..... capacity ... de .... mandataire ................ .................................................. ........................ (2) deposits ........ this .seize ..... October ..... 19oo. soix.ant.erdix.r. eight ........................................ .... (3) at ......... 1.5 ........... ... hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: 1 the present request for obtaining a patent for an invention concerning: ...... ”. Px.océdê .... dlob.tentio.n .... dl.am.id.es, ..... dê.s..o.xyv.in.Qâfflinigues "„ ......... (4) declares, assuming responsibility for this declaration, that T (es) inventors) is ( are): ...... see. ... an. back ................................. .................................................. ........................................... (5) 2. the delegation of power, dated ... BARIS ......................................... ..... on the 5th ..... QCtobre. ,,. 197.8 ............

3. description in French ______ language ...................................... of the invention in two copies; 4 ......... U ............. .. drawing boards, in two copies; 5. the receipt of the fees paid to the Luxembourg Registration Office on 16. ... October 19.78 .......................... .................................................. .................................................. .................................................. ..............................

44 ^ 444/4 ^ 4 ~ 4/4 $ 44/44444 444444 4444444 4444444144444414 (6) .............................. .................................................. ................ filed in (7) .......................... .................................................. .................................................. ..

the ................................................. .................................................. .................................................. .................................................. ................... (8) on behalf of ......................... ........................................... (9) takes up residence for him (she) and, if appointed, for his representative, in Luxembourg .................................... ....

....... 35 .., ..... bld. "...... RQY; al ...................... .................................................. .................................................. .............. ao) requests the issuance of an invention patent for the subject described and represented in the abovementioned appendices, - with adjournment of this grant to .11 ... ...................... _______ months.

\ n.e, J.inaAdatJai.rj ^ ......... n ............ h Π. Minutes of Dep & t

The above application for a patent for invention has been filed with the Ministry of National Economy and the Middle Classes, Industrial Property Service in Luxembourg, on: ®Pr. the Minister: onomie Nationale and \ désolasses Moyennes, _77 / _ ID. 5ο.134 *, Description Brief filed in support of a request for

PATENT

at

Luxembourg

formed by: SYNTHELABO

for. "Process for obtaining deoxyvincamine amides".

U

(-1 * t '# · ί J, a present invention relates to the preparation of deoxyvinylamine amides from jabersonine and the intermediate compounds used for this purpose.

The process of the invention consists in preparing the amides corresponding to the formula "R". m — pq ς J iS 1 gf S 20 \ ^ · 10 2, CH3- in which; is and R "each represent, independently of one another, a hydrogen atom, an alkyl radical, a phenyl radical - *, ft alkyl, a cycloalkyl radical or a cycloalkyl radical - '' V * '*' \ Tfr% alkyl, alkyl having 1 to 4 carbon atoms, ie. · '1 R * and R "form with the nitrogen atom a heterocyclic radical / j? which may contain from 4 to 6 carbon atoms and / or one or more hetero atoms G, S or N and which may carry a hydrogen atom or an alkyl on the other nitrogen atom.

These compounds have been the subject of several patents of the Deman- | deresse n ° 72 46386, 74 21210, 74 32095, 75 17670 and 75 18691.

I. • -v'ii ’· | Dexyxyincamides amides are therapeutically active in the cerebrovascular field.

! : t V These amides can exist in two epimeric structures, one of the other ** depending on the position of these radicals COÎK ^ -p ,, and H on the atom I Λ i j. of carbon in position 14.

1 ~ ï 'lÎi; .

1 ‘'... · / -! The epimerization of the unwanted epimer into the desired epimer is part of the invention.

. 2. Λ »* ·

According to the process of the invention, tabersonine is started, in the form of a racemate or "optical isomer, it is transformed into an amide and this amide is subjected to rearrangement.

The reaction scheme is given below.

CcîR

.H C02Me ^. H C0R

t R - - OH (II) 10 (I). · ', R = - Hal or group

'-. reactive ester (I

R = - NR'R "(IV) 5 R- ~ NCO ^ iT ^! .. R NCH, r .. ^ nco Sch f ό j (V).. (VI) i _ j ·: 2o. _ * h> 00 ** ^ 00 (VII) (VIII): L: ·; ·.. 3 ·; ** I · · ¥ * 7

According to the invention, tabersonin is hydrolyzed to tabersoninic acid (II), this acid is transformed into amide (IV) by conventional amidation (either by conversion of the acid to acid halide and reaction of the latter with ammonia or a suitable amine, 3 "either by converting the acid into a reactive ester, such as the pentachlorophenyl ester, and reaction of the latter with ammonia or a suitable amine), then either subject salt of this amide (IV) to an oxidative rearrangement which leads to compounds (V) and (VI), after having dehydrated the compound (VI) into compound (V), this compound (V) is transformed into deoxyvincamine amide by hydrogenation, or the amide is directly subjected to an oxidative rearrangement which leads to the N-oxides of compounds (V) and (VI), after having dehydrated the N-oxide of the compound (VI) to N-oxide of the compound (V ^ -on transforms the latter into N-oxide of deoxyvincaminide amide by hydrogenation 15 and finally the N-oxide group is eliminated by reaction a with triphenylphosphine.

A mixture of the two isomers (VII) and (VIII) epimers is obtained from one another. The epimerization is carried out into the desired isomer.

- The hydrolysis of tabersonine takes place in an alcoholic and / or aqueous solution of potassium hydroxide, - the transformation into acid halide is carried out by "reaction with a usual reagent; the transformation into reactive ester 4 is carried out by reaction with the appropriate compound; .

- the amidification is carried out in a conventional manner by reaction of the active acid derivative with the appropriate amine HNR'R ", - rearrangement of the salt of the amide (IV) (for example the salt obtained by reaction with l perchloric acid) in compounds (V) and (VI) or the amide itself (IV) is carried out using a peroxide, for example, metachloroperbenzoic acid, dehydration of the compound ( VI) in (V) is obtained by dissolving the mixture of the two compounds in acetic acid and heating in the presence of sodium acetate, i ^ Ι · 4 - the hydrogenation of the compound (V) into compounds (VII) and (VIII) takes place catalytically under pressure and at elevated temperature (for example: 100 kg / cm 2 and 100 ° C.), - the epimerization is carried out by heating the unwanted isomer in dimethylformamide in the presence of sodium starch.

The example below illustrates the invention.

SYNTHESIS OF DESOXYVINCAMINAMIDE

. . ’Jÿll, VIII.-R '= R" = H] · The compounds obtained in this example correspond to the stereochemistry 3 S, 16 S.

I - OBTAINING TABERSONINIC ACID (II) SON OF ITS ACID CHLORIDE 10 (III) AND AMIDE (IV)

4/6 g (0.137 mmol) of (-) tabersonine are dissolved in ethanolic potassium hydroxide (0.5 N - 900 ml) and the mixture is heated at reflux for two and a half hours. Distilled water (700 ml) is then added and the reflux is continued for a further 45 minutes. The ethanol is then removed under reduced pressure and the resulting aqueous solution is extracted with ether (4 times 300 ml).

The pH of the aqueous solution cooled to 5 ° C. is adjusted to 7.8 by addition of 0.5 N hydrochloric acid and the mixture is quickly extracted with methylene chloride (3 times 300 ml).

• The combined organic phases are washed with water, dried over ^ £ 20 ^ and the volume is reduced to 500 ml under reduced pressure at 40 ° C. ''

The tabersoninic acid (II) solution is used directly in the next step.

] / U, • · 5, t * ι · * "" m

A freshly distilled solution of oxalyl chloride (8.5 ml) dissolved in methylene chloride (30 ml) is added to the acid solution. After stirring for one hour at room temperature, anhydrous ammonia is bubbled through the solution for 30 minutes. The methylene chloride solution is washed with water and dried over sodium sulfate.

The solvent is removed under reduced pressure. An oil (35 g) is obtained which is chromatographed on silica gel. * Eluted with a 98/2 chloroform / methanol mixture. 10 10 g (23% yield) of 16-carbamoyl-16 methoxycarbonyl tabersonin (IV) are obtained, characterized in the form of its hydrochloride.

P = 184 ° C (decomposition) WD25 = -220 ° (c = 1.07 EtOH] "

Micro-analysis and IR and NMR spectra confirm the structure.

15 ii - OBTAINING OR (2 lû S3 16 S) rD.ESOXÏVINCAMINAMIDE 'AND DU (3 S, 14 R, 16 S) -DESOXYVINCAMINAMIDE 1 To a solution of 3.27 g (0.0093 mole) of carbamoyl-16 demétho - xycarbonyl-16 tabersonine (IV) in 60 ml of methanol, 0.9 ml of 70% perchloric acid is added. After 15 minutes of stirring, 0.01 mole is added to 85% ihetachloroperbenzoic acid. The mixture is stirred at room temperature and in the dark for 24 hours. The excess peroxide is broken down. by addition of aqueous sodium bisulfite. (20%) and dilute the mixture with water (300 ml). After removal of methanol under reduced pressure, the solution is basified with a 28% ammonia solution 'and then extracted with 4 times 300 ml of methylene chloride'. The combined organic extracts are washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure.

2.46 g of an oil are obtained, consisting of a mixture of compounds (V) and (VI).

ο i * I · ί; The dehydration of compound f / I) into compound (V> is carried out by dissolving the oil obtained. In acetic acid (30 ml) and heating the solution at 110 ° C for 5 hours presence of a quantity sodium acetate catalyst.

The reaction mixture is then cooled, diluted with water (30 ml) and 1 g of 10% palladium on carbon is added. .

The mixture is hydrogenated under a pressure of 100 kg / cnr and at 100 ° C. .

After 5 hours, the cooled solution is filtered through celite and the supernatant is evaporated. The d is dissolved in · methylene chloride, the resulting solution is washed with water, dried over sodium sulfate and concentrated. under vacuum. 1.6 g (yield 54%) of a mixture of isoirs are obtained.

(VII) and (VIII) of dexyxyincamine amide.

These isomers are separated by chromatography on çjol de. sil. using an eluent (chloroform / methnnol mixture ^ 8/2).

The isomers of dexyvincaminamide are characterized in ’l: form of their oxalates.

? ° 2H P = 229 -: 30 ° C

2o ^ y C02H

.-TT-nT '.

. ....... COnh; ^ Cil3 oxalate (3 S, 14 R, 16 S) -soxyvincaminamide

at Tpi co2H

CO h F »186 - L5SeC

aJP ‘C0NH ~. . ^ CH3 oxalate (3 S, 14 S, 16 S) -soxyvincaminamide

Micro-analyzes and IR and NMR spectra confirm "the structure" h

• · “I

7 rf III - EPIMERISATION OF THE COMPOUND (VII) IN (VIII) ·: - ~~

150 mg of the compound (VII) are dissolved in 10 ml of dry dimethylformamide and 40 mg of sodium amide are added in portions.

The stirred mixture is heated at 95 ° C for one hour. The cooled reaction mixture is then diluted with water (100 ml) and extracted with methylene chloride.

The organic extract is washed with distilled water saturated with NaCl, dried and the solvent is removed. An oil (140 mg) is obtained. Thin layer chromatography and spectral analysis 10. (IR and NMR) confirm that it is the compound (VIII) q i.e. c (3 S, 14 R, 16 S) -déssoxyvincaminamide ·

/ 'X

The

Claims (8)

8 1. Process for obtaining the deoxyvincamine amides corresponding to the formula "5; . R ^ N-C07k> f ^ H ch3 in which 10 or R 'and R "each represent / independently of one another, a hydrogen atom, an alkyl radical, a phenylalkyl radical, a cycloalkyl radical or a cycloalkylalkyl radical, the alkyls having from 1 to 4 carbon atoms, ie, R ′ and R ′ form with the nitrogen atom a heterocyclic radical which may contain from 4 to 6 carbon atoms and / or another hetero atom O, S or N and being able to carry a hydrogen atom 4-20. or an alkyl on the other nitrogen atom, process characterized in that the tabersonine is hydrolyzed under! form of racemate or optical isomer in tabersoninic acid (II)? this acid is transformed into a reactive derivative (III) to obtain the amide (IV) 'by conventional amidation, -then either this amide is subjected (IV ) to an oxidative rearrangement which leads to compounds (V) and (VI), after having dehydrated the compound (VI) into compound (V), this compound (V) is transformed into deoxyvincaminic amide by> hydrogenation according to the following reaction scheme , either the amide is subjected directly to an oxidative rearrangement which leads to the N-oxides of the compounds (V) and (VI), after having dehydrated the N-oxide of the compound (VI) to N-oxide of the compound. V), the latter is transformed into N-oxide of deoxyvincamine amide by hydrogenation and finally the N-oxide group is eliminated by reaction with triphenylphosphine. Λ 9 »m oéïplr 'oé ^ 3 CO2Me COR R = - OH (II) (I) R = - Hal or aroupe reactive ester (III) 10 R = - NR'R "'(IV) i5 —3» OcjC'Xv, ï- CLjGl H "> ° C ^ Lc„ 3 (V)' (VI) 20 \ f * \ [Γ ^ ί VI T j r-> nc «pJ î J 30 (VII) (VIII) i ·, I · 1U | 2. Method according to claim 1, characterized in that the rearrangement of the salt of the amide (IV) as a mixture of the compounds (V) and (VI) is carried out using peroxides. j. 3. Method according to claim 2, characterized in that the peroxide used is metachloroperbenzoic acid. 4. Method according to any one of claims 1 to 3, charac terized in that the hydrogenation of the compound (V) to deso-ί xyvincamine amide is carried out catalytically under pressure. 5. Method according to any one of claims 1 to 4, characterized in that one carries out the epimerization of the unwanted isomer 1. into the desired isomer of the deoxyvincamine amide by heating the isomer unwanted in dimethylformamide in the presence of sodium amide. 6. Compounds useful as intermediates in the process for obtaining deoxyoxyamine amides of claim 1, compounds sc in the form of racemate or optical isomer, characterized in that they correspond to the formula ' 20 H '' C0R in which R represents a halogen atom or a reactive ester group or a radical NR'R "in which either 'R' and R" each represent, independently of one another, an atom of hydrogen, an alkyl radical, a phenylalkyl radical, a cycloalkyl radical, a cycloalkylalkyl radical, alkyls having from 1 to 4 carbon atoms, "· * A- K 11 4, · 0, '. ♦ or R * and R "form, with the nitrogen atom, a heterocyclic radical which may contain from 4 to 6 carbon atoms and / or another heteroatom 0, S or N and which may carry one hydrogen atom or one alkyl on the other nitrogen atom. '. t 'r i a \ I ^ * w r