JPH0530826B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel intermediates for the preparation of a class of novel substituted phenethylamine derivatives useful as central nervous system antidepressants. The substituted phenethylamine derivative has the following structural formula: [wherein A is the formula: (In the formula, the dotted line means that it may be unsaturated if desired.) R ₁ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₂ is alkyl having 1 to 6 carbon atoms; R ₄ is Hydrogen, alkyl having 1 to 6 carbon atoms, formyl or alkanoyl having 2 to 7 carbon atoms; R ₅ and R ₆ are
Each independently hydrogen, hydroxy, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, and 2 carbon atoms
~7 alkanoyloxy, cyano, nitro, alkylmercapto having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino in which each alkyl group has 1 to 6 carbon atoms, 2 to 7 carbon atoms
alkanamide, halogen or trifluoromethyl, or R ₅ and R ₆ together are methylenedioxy; R ₇ is hydrogen or has 1 to 6 carbon atoms
alkyl; n means an integer of 0 to 4] or a pharmaceutically acceptable salt thereof. More preferred substituted phenethylamine derivatives have the formula: [In the formula, A is the same as above; R ₁ is hydrogen or alkyl having 1 to 3 carbon atoms; R ₂ is alkyl having 1 to 3 carbon atoms; R ₅ is hydrogen, hydroxy, alkoxy having 1 to 3 carbon atoms, chlorine , bromine, trifluoromethyl or alkyl having 1 to 3 carbon atoms; R ₆ is 1 to 3 carbon atoms;
3 alkyl, alkoxy having 1 to 3 carbon atoms, chlorine, bromine, trifluoromethyl or 2 to 3 carbon atoms
3 alkanoyloxy; R ₇ means hydrogen or alkyl having 1 to 3 carbon atoms] or a pharmaceutically acceptable salt thereof. Most preferred are compounds in which R ₅ and R ₆ are in the meta or para position and n is 2. The compounds in which R ₄ is formyl or C 2 -C 7 alkanoyl are not as potent as the corresponding free hydroxy derivatives in the test methods used and disclosed herein. However, in long-term treatment, the acyloxy derivatives may be used in
It acts as a prodrug such that the acyl group is removed in vivo by gastric acid hydrolysis or enzymatically. Pharmaceutically acceptable acid addition salts of the substituted phenethylamine derivatives are conveniently formed by reacting the free base with any acid that forms an equivalent non-toxic salt. Illustrative acids may be organic or inorganic and include hydrochloric, hydrobromic, fumaric, maleic, succinic, sulfuric, phosphoric, tartaric, acetic, citric, oxalic and similar acids. Included. Although the free base of the pharmaceutically acceptable salt can be used for oral or parenteral administration as an antidepressant, for parenteral administration it is preferred to use the water-soluble salt. represents a halogen substituent
R ₅ or R ₆ includes chlorine, bromine, iodine or fluoro substituents. The substituted phenethylamine derivatives are prepared by combining a cycloalkanone or cycloalkenone with the anion of an appropriately substituted (ortho or para)phenylacetonitrile as described by sauvetre et al.
Tetrahedron.Vol34 2135 (1978)), and then the nitrile is reduced (catalytic hydrogenation, borane reducing agent, _LiAlH4, etc.) to a primary amine, and the amine is alkylated. Manufactured. In the presence of cycloaliphatic unsaturation, lithium aluminum hydride is the preferred reducing agent. The subsequent acylation of alpha-alicyclic and phenolic hydroxy groups can be conveniently carried out using formyl reagents such as formyl fluoride or alkanoic acid halides or anhydrides. Symmetric N-methylation was performed by Tilford et al., JACSvol76,
2431 (1954)) using a large excess of water. Alternatively, using sodium cyanoborohydride and formaldehyde, Borch et al. (Borch and Hassid, J.Org.
Chem. Vol 37, 1653 (1972)) may be used. Asymmetric N-alkylation or monoalkylation is an asymmetric N-alkylation. A. Double Yuu. RAWJohnstone et al., J.Chem.Soc., (c)
2223 (1969)) by the stepwise alkylation of the N-trifluoroacetate. When R ₄ is alkyl, R ₄ is a known O
- introduced before the nitrile is reduced by alkylation. The nitrile has the following structural formula: [Wherein, the dotted line means that it may have unsaturation if desired; R ₄ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₅ and R ₆ are each independently hydrogen, hydroxy , alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aralkoxy having 7 to 9 carbon atoms, alkanoyloxy having 2 to 7 carbon atoms, alkyl mercapto having 1 to 6 carbon atoms, halogen or trifluoromethyl. ortho or para substituent selected from the group; _R7 is hydrogen or alkyl having 1 to 6 carbon atoms; and n is an integer of 0 to 4. The primary amine intermediate produced by reduction of the nitrile has the following structural formula: [Wherein, the dotted line means that it may have unsaturation if desired; R ₄ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₅ and R ₆ are each independently hydrogen, hydroxy , alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aralkoxy having 7 to 9 carbon atoms, alkanoyloxy having 2 to 7 carbon atoms, alkyl mercapto having 1 to 6 carbon atoms, halogen or trifluoromethyl. ortho or para substituent selected from the group; _R7 is hydrogen or alkyl having 1 to 6 carbon atoms; and n is an integer of 0 to 4. Symmetrical N,N-dimethylation can be easily carried out by reacting the primary amine with formaldehyde and formic acid in a large excess of water.
Another intermediate, 3-aza-1-oxaspiro[5.5]undecane, is also produced during the reaction,
Isolation is possible. The intermediate has the following structural formula: [wherein the dotted line means that it may optionally have unsaturation; R ₁ is methyl; R ₅ and
R ₆ is each independently hydrogen, hydroxy, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aralkoxy having 7 to 9 carbon atoms, or having 2 to 7 carbon atoms.
an ortho or para substituent selected from the group consisting of alkanoyloxy, alkylmercapto having 1 to 6 carbon atoms, halogen or trifluoromethyl; R ₇ is hydrogen or alkyl having 1 to 6 carbon atoms;
n means an integer of 0 to 4]. Such oxaspiro[5.5]undecane intermediates have similar activity to the corresponding ring-opened tertiary amino final compounds. For example, the properties of the oxazine produced in Reference Example 3 are later compared with the corresponding dimethylamino final compound of Reference Example 3. The final compound is prepared from the corresponding oxazine by prolonged reflux in the presence of aqueous formic acid. Another preferred method for preparing substituted phenethylamine derivatives which are antidepressants is the method of Sauvetre et al. (ibid.), in which a cycloalkanone or cycloalkenone is replaced with an appropriately substituted phenylacetamide anion. Therefore, there is a method in which the amide is reacted and then, except in the case of alicyclic unsaturation as mentioned above, the amide is reduced using lithium aluminum hydride or a borane reducing agent to form the corresponding amine. The process is preferred because it is extremely easy to handle meta- or halogen-substituted phenylacetamide reactants, which pose some problems when the reaction proceeds through the acetonitrile intermediate. It is also easy to vary the defined R ₁ and R ₂ in the starting reactants in the route to the desired final product. The cyano substituents represented by R ₅ and/or R ₆ are introduced by replacing the R ₅ -R ₆ halogen substituents with cuprous cyanide after all reduction steps have been completed. The amino substituent represented by R ₅ and/or R ₆ is a 1,1,4,4-tetramethyl-
Protected with a protecting group such as 1,4-dichlorosilylethylene. After the series of reactions is completed, the amino group is deprotected and alkylated or acylated by conventional methods to obtain mono- or dialkylamine or alkanamide groups each having 1 to 6 carbon atoms. The nitro substituent represented by R ₅ and/or R ₆ can be obtained by diazotizing the aromatic amine and then treating it with an alkali metal nitrite in the presence of copper or by forming a diazonium tetrafluoroborate salt. It is introduced as an aromatic substituent by reacting with a metal nitrite. Cyano substituents are introduced in a similar manner via diazonium salts using cuprous cyanide. Thus, the intermediate amide of the present invention has the following structural formula: [In the formula, the dotted line means that it can be unsaturated if desired. R ₁ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₂ is alkyl having 1 to 6 carbon atoms; R ₄ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₅ and R ₆
each independently represents hydrogen, hydroxy, or carbon number 1 to
6 alkyl, C1-6 alkoxy, C7-9 aralkoxy, C2-7 alkanoyloxy, C1-6 alkylmercapto, N-protected amino, halogen or trifluoromethyl or together methylenedioxy; R ₇ is hydrogen or alkyl having 1 to 6 carbon atoms;
n means an integer of 0 to 4]. When R ₄ is alkyl, R ₄ is introduced before reduction. Protecting groups used to prevent reaction at the amino substituents represented by R ₅ and/or R ₆ completely inhibit the reaction of primary amino substituents such as 1,2-[bis-dimethylsilylchloride]ethane. Any protective group may be used as long as it can protect the group. Other indirect routes for the synthesis of the antidepressant compounds include cycloalkanones or cycloalkenones optionally substituted with phenylacetic acids, salts,
Examples include a method of reacting with an anion of an ester, aldehyde or alcohol. [wherein B means a carboxyl group, a salt or ester thereof, or a -CHO, CH ₂ OH functional group] The carboxylic acid group is converted into an acid halide, active ester or anhydride and combined with the desired amine. The final product of the invention can be obtained by direct reaction and reduction of the resulting amide. Moreover, the corresponding aldehyde can also be obtained by reducing the carboxylic acid group using diisobutyl aluminum hydride or lithium aluminum hydride. Esters are easily converted to aldehydes using diisobutyl aluminum hydride or alcohols using lithium aluminum hydride. Aldehydes can be condensed with hydroxylamines to form oximes, -CH=NOH; with ammonia or primary amines to form imines, -CH=NR; and with primary or secondary amines to form imines, -CH=NR.

[Formula] can be provided. Alcohols _-CH2OH can be converted to nitro derivatives by preparing organic sulfonates (mesyl esters) or halides followed by displacement with inorganic nitrites. Such intermediates are reduced to provide the desired primary amine intermediate or secondary or tertiary amine end product. the alcohol is converted to mesylate or tosylate;
Reacts with KCN to yield a nitrile, which is converted to an amide and undergoes Hofmann rearrangement with bromine or chlorine and an alkali metal hydrogen oxide. Another route to the desired product is to convert ammonia or HNR ₁ R ₁ to the formula: [In the formula, Z means a leaving group such as a halogen or an organic sulfonyloxy (mesyl, tosyl, etc.) group.] Examples include those which are reacted with a compound represented by K under known conditions. Optionally, the amino reactant is first blocked with a relatively unstable acyl group such as trifluoroacetyl, and then
Reaction with alkylation reactants using highly polar solvents such as KOH and dimethyl sulfoxide provides the tertiary amide, from which the acyl group is easily removed and the _asymmetric N - It is possible to obtain compounds in which alkylation is carried out. Rather than N-alkylation, it is preferable to acylate or react a secondary amine with an aldehyde and then reduce the amide or Schiff base. Similarly, the amine is reacted with an alkyl chloroformate and reduced to give the N-methylated amine. Lithium aluminum hydride is the preferred reducing agent in such processes. aldehyde: The desired end products can also be obtained by reductive amination (Leucart reaction) of with ammonia, primary amines or secondary amines. In the synthetic route of the final compound according to the above method, any hydroxy group represented by -OR ⁴ , R ⁵ or R ⁶ may be in free form or may be protected by a removable protecting group. It may also be in the hydroxy form. The protected form is recommended if the hydroxy group would undergo an undesirable reaction if unprotected, unless of course the hydroxy group is considered to be involved in the reaction. Examples of hydroxy protecting groups include JFW Matsukomie (JFW
Protective Groups in Organic
Chemistry, Chapters 3 and 4, pp. 95-182 (Plenum Press, 1973), and by TWGreene,
“Protective Groups in Organic Chemistry” Chapters 2 and 3, pp. 10-113 (John Wiley
and Sons, 1981). The protecting group can be removed at an appropriate later stage in the synthesis. Similarly, in the synthetic route to the final compound, if preferred, any amino or alkylamino group may be in protected form.
Protecting groups for amino groups are described in Chapter 2 (pages 43-94) of Matsukomie's literature and Chapter 7 of Green's literature (218
- pages 286). The final compounds have one or two asymmetric centers, respectively, depending on the saturated and unsaturated state of the alicyclic ring. Each stereoisomeric form can be obtained or separated by standard methods. For example, resolution of the mixture in the case of amines or carboxylic acids can be carried out by neutralization with a suitable optically active compound to form a salt and separation. Reference Example 31 describes a typical resolution of Compound A, the product of Reference Example 3. The antidepressant activity of the final compound was determined by (1) Raisman et al., Eur.J.Pharmacol.Vol61, 373
~380 (1980)) inhibits ³ H-imipramine binding in brain tissue. (2) Wood et al., J.
According to the test method of Neurochem.Vol37, 795-797, (1981)), it inhibits the intersynaptic uptake of norepinephrine (3H-NE) and serotonin ( ^14C -5-HT),
When tested according to the method of Life Sci. Vol. 725-730 (1963), it is demonstrated by resisting reserpine-induced hypothermia. These test results confirm that the antidepressant activity of the final compound is consistent with the most widely accepted theory of antidepressant activity and is related in activity to known tricyclic depressants. In at least two cases, the dimethylamino product of reference example 3 and the 4-chloro product of reference example 10, the muscarinic receptor ligand, ³ H-quinuclinidyl benzylate (QNB) Binding inhibition does not exhibit the typical undesirable properties of antidepressants, which are observed as anticholinergic properties in inhibiting carbachol-stimulated contractions of the guinea pig ileum. Also, typical antidepressant properties observed as antihistamine-like properties brought about by inhibition of the _H1 -histamine receptor ligand, ^3H -pyrilamine, and in the suppression of histamine-stimulated contractions of the guinea pig ileum. Not found. Examples of typical activities of the final compounds include the dimethylamino form of Reference Example 3 (Compound A), its oxazine form (Compound B), the 4-chloro form of Reference Example 10 (Compound C), and the 4-chloro form of Reference Example 13. - Bromo form (Compound D), 3-chloro form of Reference Example 15 (Compound E), 3-bromo form of Reference Example 14 (Compound F), and Reference Example
Test data for the 3,4-dichloro form of No. 17 (Compound G) are shown below. Inhibition of ^3H -imipramine binding: Compound A (HCl
salt) exhibits an inhibition constant (Ki) of 90 nM for ³ H-imipramine, forming a fairly potent ligand at the imipramine receptor site. Compound B has a Ki of 350 nM and is somewhat less potent. Compound C exhibits a Ki of 100 nM for ³ H-imipramine and is substantially equal in potency to Compound A. Although not as potent as imipramine (Ki = 1.7 nM), these values fall within the range of desmethylimipramine (DMI) (Ki = 130 nM) and other tricyclic antidepressants. Typical antidepressants (non-tricyclic) when tested exhibit Ki values greater than 5000 nM according to this assay. Compound D,
E, F and G are 62, 130, 52 and
37 inhibition constants are shown. Compounds A-G are also representative of other final compounds and are thus comparable to known tricyclic antidepressants in this study. Inhibition of synaptic NE and 5-HT uptake:
The results of inhibition of NE and 5-HT intersynaptic uptake are expressed as the inhibitory concentration at which the uptake rate is reduced by 50% (IC ₅₀ ) and are shown in Table 1 below. Here, the results are compared to values for imipramine, DMI and amitriptyline. IC ₅₀ (μM) Compound NE 5-HT Imipramine 0.26 0.12 DMI 0.15 3.0 Amitriptyline 0.50 0.60 Compound A 0.64 0.21 〃 B 4.7 2.9 〃 C 0.33 0.25 〃 D 0.21 0.11 〃 E 0.16 0.32 〃 F 0.11 0.23 〃 G 0.07 0.08 These results is, compounds A and C to G are
It shows that it has approximately the same efficacy as imipramine in suppressing NE and 5-HT uptake.
Again, Compound B was somewhat less potent. Inhibition of ³ H-QNB binding: In the QNB receptor binding assay, compounds A and CG exhibit _IC50's of ^10-5 molar or higher, so they are essentially inactive. Amipramine and DMI exhibit Ki values of 37 nM and 50 nM, respectively. These results indicate that, unlike tricyclic antidepressants, compounds A and CG do not have any muscarinic anticholinergic effects. Suppression of carbachol-stimulated contractions of guinea pig ileum: At 11 μM, imipramine has a Ki of approximately
100 nM, but Compound A was inactive at 1 μM. This result suggests that Compound A lacks muscarinic anticholinergic effects. Inhibition of ³ H-pyrilamine binding: DMI exhibits a Ki of 124 nM for ³ H-pyrilamine binding, but Compound A was inactive. Compounds D to G exhibited IC ₅₀ 's of 10 ^-5 molar or higher. These results demonstrate that, unlike tricyclic antidepressants, compounds A and D-G
suggests that it has no antihistamine properties. Inhibition of histamine-stimulated contractions in the guinea pig ileum: Imipramine inhibits histamine-stimulated contractions in the guinea pig ileum at 1 μM with a Ki of approximately 8 nM. In contrast, Compound A
No effect was shown at 1 μM. This result suggests the finding that Compound A has no antihistamine effect at all. Antidepressant effect of reserpine-induced hypothermia: related to desmethylimipramine (DMI) in mice (1
The minimum effective doses (MED) of Compounds A to G established in the antidepressant effect of reserpine-induced hypothermia (8 animals per group) are as follows: Compound Dose. mg/Kg. ip DMI 0.4 A 10.0 (po) B 30.0 C 10.0 D 3.0 E 1.0 F 1.0 G 3.0 All mice received reserpine 5 mg/Kg (s.c.) 18 hours before test compound administration DMI and Compounds A-G induced reserpine Shows approximately equal efficacy in reversing hypothermia. In this study, Compound B was less potent than Compound A, Compound C was approximately equal in potency to Compound A, and Compounds D and G were approximately 3 times more potent than Compound A.
Compounds E and F are approximately 10 times more potent than Compound A. The final compound is therefore useful in the treatment of depression, and for this purpose the compound may be administered orally or parenterally in an amount sufficient to alleviate the symptoms of depression. The actual amount of antidepressant to be used may vary depending on the severity and nature of the depression, the animal being treated, and the level of relief desired. For humans, an oral dosage of about 2 to about 50 mg is preferably administered as needed. An intramuscular dose of about 1-25 mg is comparable to the dose prescribed for oral administration. For other antidepressants, treatment should be started at low doses and increased until the desired symptom relief is obtained. The antidepressant compound is administered in the form of a pharmaceutical composition. The active ingredients are formulated into useful oral dosage forms including tablets, capsules, and liquid preparations such as elixirs and suspensions containing various colorants, flavors, stabilizers, and flavor coatings. be able to. To formulate oral dosage forms, the active ingredient may also be mixed with known tabletting materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to aid in the tabletting and encapsulation process. I can do it. If desired, magnesium stearate is added as an additive to provide a lubricating effect. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as sterile water, sterile organic solvent, or a mixture of both. Liquid carriers are particularly suitable for parenteral injection. If the active ingredient is sufficiently soluble, it can be dissolved using physiological saline as a carrier. If the active ingredient is insoluble in saline, it can often be dissolved in a suitable organic solvent, such as an aqueous propylene glycol or polyethylene glycol solution. Aqueous propylene glycol solutions containing 10 to 75% glycol by weight are generally preferred. In other examples, other compositions can be obtained by dispersing the finely divided active ingredient in an aqueous starch, or sodium carboxymethylcellulose solution, or in a suitable oil, such as peanut oil. Liquid pharmaceutical compositions that are sterile solutions or suspensions can be utilized by intramuscular, intraperitoneal, or subcutaneous injection. Preferably, the pharmaceutical composition is in unit dosage form,
For example tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component; the unit dosage form may be a packaged composition, eg, a packaged powder, vials or ampoules. The unit dosage form can itself be a capsule, cachet, or tablet, or it can be the appropriate number of these in packaged form. The amount of active ingredient per unit dose of the composition may be varied or adjusted from 2 mg or less to 50 mg or more depending on individual needs and active ingredient. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 1 1-[cyano(p-methoxyphenyl)methyl]
Cyclohexanol p-methoxyphenylacetonitrile 50g
(0.3 mol) is added to 250 ml of dry tetrahydrofuran and the solution is cooled to -70°C under a stream of nitrogen.
210 ml n-butyllithium in hexane under stirring
(0.3 mol) dropwise. If the temperature is kept below -50°C, a yellow precipitate appears. After the addition is complete, the reaction mixture is kept below -50°C for 30 minutes and 35 ml (0.3 mol) of cyclohexanone is added. After holding below -50°C for an additional 45 minutes, the temperature is raised to 0°C and a saturated ammonium chloride solution is added. Separate the layers and extract the aqueous layer with diethyl ether. The combined organic solutions are washed with brine, dried over magnesium sulphate and evaporated. 25.2 g of product crystallizes out. Melting point 125-127°C Mass spectrometry: Molecular weight 245 [(M+1) ⁺ , CIMS] NMR analysis value: δ7.32, 6.95 (4H, q, p-substituted aromatic); 3.8 (3H, s, O- _CH3 )；3.76(1H,
s, CH-CN); 1.56 (10H, m, aliphatic cyclohexyl) ppm. Reference example 2 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol 1-[cyano(p-methoxy phenyl)methyl]
12 g (0.05 mol) of cyclohexanol are dissolved with warming in a mixture of 250 ml (20% v/v) ammonia-ethanol and hydrogenated with 2.8 g of 5% rhodium on alumina in a Parr apparatus. The catalyst is filtered off, washed thoroughly with ethanol, and the combined filtrates are evaporated and dried under vacuum to give 12 g of an oil. Mass spectrometry value: Molecular weight 249 (M+1 ⁾ enyl)-3-methyl-3
-aza-1-oxaspiro(5.5)undecane and 1-[(2-dimethylamino)-1-(4-
12 g (0.048 mol) of 1-[2-amino-1-(p-methoxyphenyl) ethyl]cyclohexanol, 11 ml of formaldehyde, and 14.5 ml (88 mol) of formic acid.
%) and 125 ml of water and heated at 100° C. for 5 hours. The reaction mixture is cooled and extracted with ethyl acetate. Discard the extract. The aqueous residue is placed in an ice bath, made basic by the addition of solid potassium hydroxide, saturated with sodium chloride and extracted three times with ethyl acetate. The extracted layer was washed with brine, dried over anhydrous potassium carbonate, and evaporated to an oily residue of 8 g.
get. The mixture of products was chromatographed on 1 kg of Mallinckrodt silicar cc7 silica gel, and the chromatography was developed using ethanol: 2N ammonia: ethyl acetate: cyclohexane = 45:8:
Monitored by thin layer chromatography using a system configured at 100:100 (v/v). The fractions containing the desired product are combined and 4-N-
Generate the hydrochloride salt using isopropanolic HCl. The yields of the free base were 1.4 g (spiro compound) and 4.6 g (dimethylamine), respectively. Compound B 5-(4-methoxyphenyl)-3-methyl-3
-Aza-1-oxaspiro (5.5) undecane Melting point: 242-244°C Mass spectrometry value: Molecular weight 275 (M+1) ⁺ , CIMS NMR analysis value: δ7.22, 6.96 (4H, q, p-substituted aromaticity); 4.78 (2H, q, O- _CH2 - _NCH3 )3.8
(4H, O- _CH3 , CH- _CH2 - _NCH3 ); 3.3
(2H, m, CH-CH ₂ -NCH ₃ ); 2.8 (3H,
_NCH3 ) 0.9-1.8 (10H, broad m, aliphatic cyclohexyl) ppm. Compound A 1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride: Melting point 215-217 °C Mass spectrometry: Molecular weight 279 (M+1) ⁺ , CIMS (free base) NMR analysis: δ7.32, 6.98 (4H, q, p-substituted aromatic); 3.78 (3H, O-CH ₃ ); 3.64 ( 2H, m,
_CH2N ( _CH3 ) ₂ ); 3.06(1H, m, CH− _CH2
(NCH ₃ ) ₂ ); 2.74 (6H, N(CH ₃ ) ₂ ); 1.38 (10H,
Broad m, aliphatic cyclohexyl) ppm. Reference example 4 1-[(α-aminomethyl)benzyl]cyclohexanol 10 g (0.08 mol) of phenylacetonitrile was added to 100 ml of dry THF, and the solution was cooled to -70°C under nitrogen. do. When 64 ml (0.1 mol) of n-butyllithium in hexane is added dropwise while maintaining the temperature below -40 DEG C., a yellow precipitate appears. After the addition, the reaction mixture is kept at around -70°C for 30 minutes and 10g (0.1 mole) of cyclohexanone is added. After holding at -70°C for a further 45 minutes, the temperature is raised to 0°C and a saturated ammonium chloride solution is added. Separate the layers and extract the aqueous layer with diethyl ether. The combined organic solutions are washed with brine, dried over magnesium sulphate and evaporated. The product, 1-[α-
4.93 g of cyanobenzyl]cyclohexanol crystallized. Melting point 100-102℃. Mass spectrometry value: Molecular weight 215 (M ⁺ ) NMR analysis value: δ7.4 (5H, s, aromatic); 3.8 (1H,
s, CH-CN); 1.6 (10H, m, aliphatic cyclohexyl) ppm. 60ml of methanol and ammonia mixture
(9:1v/v), 1-(α-cyanobenzyl)
A solution of 3.43g (0.02mol) of cyclohexanol
Hydrogenate with 2 g of 5% rhodium on alumina in a Parr apparatus. Filter the catalyst and evaporate the filtrate. The residue is dissolved in ethyl acetate, washed with brine, dried over magnesium sulphate and then evaporated. 1.2 g of the hydrochloride (melting point 220 DEG -222 DEG C.) is crystallized from diethyl ether-acetone. Elemental analysis value: C ₁₄ H ₂₁ NO・HCl Calculated value (%): C, 64.29; H, 8.67; N, 5.47 Actual value (%): C, 65.74; H, 8.51; N, 5.56 NMR analysis value ( DMSO): δ7.73 (5H, s, aromatic); 3.46 (2H, m, _CH2 - _NH2 ), 3.0 (1H,
m, CH- _CH2NH2 ); 0.9-1.7 (10H, m, aliphatic cyclohexyl) ppm. Mass spectrometry value ₍ by chemical ionization): 220 (M+
H) ⁺ (molecular weight 219) (free base) Reference example 5 1-{α-[(dimethylamino)methyl]benzyl}cyclohexanol 1.38 g (0.006 mol) of 1-{α-[aminomethyl]benzyl}cyclohexanol Dissolve in a mixture of 2 ml of formaldehyde, 2.6 ml of formic acid and 2.5 ml of water and reflux at 95°C for 18 hours. The reaction mixture is cooled, made basic with solid KOH, and extracted with methylene chloride. The extract layer is washed with brine, dried over magnesium sulfate and evaporated. Hydrochloride (melting point
225-227 °C) using 3N isopropanolic HCl. Yield 589 mg Elemental analysis value: C ₁₆ H ₂₅ as NO・HCl Calculated value (%): C, 67.36; H, 9.12; N, 4.88 Actual value (%): C, 67.7; H, 9.23; N, 4.93 Mass Analytical value: Molecular weight 247 (M ⁺ , free base) NMR analytical value (DMSO): δ7.4 (5H, s, aromaticity); 3.68 (2H, m, _CH2 -N( _CH3 ) ₂ ; 3.18
(1H, m, CH- _CH2N- ( _CH3 ) ₂ ); 2.68 (6H,
N(CH ₃ ) ₂ ); 0.9 to 1.7 (10H, m, aliphatic cyclohexyl) ppm. Reference example 6 1-{α-[(methylamino)methyl]benzyl}
Cyclohexanol 1-[α-(aminomethyl)benzyl[1.59 g (0.007 mol) of cyclohexanol is dissolved in 10 ml of diethyl ether and cooled to 5°C. 2 g of trifluoroacetic anhydride was added, and the mixture was heated at 0°C for 30
Stir for a minute. The mixture is made neutral using saturated sodium bicarbonate solution and the layers are separated. The organic layer is washed with brine, dried over magnesium sulfate and evaporated. crystalline trifluoroacetamide
Get 975mg. Melting point 78-80℃. 975 mg of the trifluoroacetamide are dissolved in 20 ml of dry acetone and treated with 2 g of methyl iodide. The solution is warmed to reflux temperature and 1 g of dry powdered potassium hydroxide is added followed by excess methyl iodide. The mixture is refluxed for 5 minutes, then cooled and the acetone evaporated. 20 ml of water are added and the mixture is refluxed for 15 minutes. Cool and extract with ethyl acetate. The extracted layer was washed with water and brine,
Dry over magnesium sulfate and evaporate to obtain a crystalline product. Melting point 92-94℃. The product is converted to the hydrochloride salt using 3N isopropanolic HCl. Yield 235mg. Melting point 208-210℃. NMR analysis value (CHCl ₃ ): δ7.3 (7H, aromatic, HCl
and NH・CH ₃ ); 3.9 (1H, m, CH−
CH ₂ NH ₂ ); 3.25 (2H, m, CH ₂ −NH ₂ ); 2.6
(3H, s, NH-CH ₃ ); 0.8-1.9 (10H, m, aliphatic cyclohexyl) ppm. Mass spectrometry value: Molecular weight by chemical ionization/M.
S.233 (M+1, 234, free base) Reference example 7 1-{α-[(dimethylamino)methyl]benzyl}cyclohexanol acetate 1-{α-[(dimethylamino)methyl]benzyl}cyclohexanol 0.5 g (0.0025 mol) with 1 mm of acetic anhydride and 3 ml of pyridine and the mixture is left overnight at room temperature. The reaction mixture is poured into water, made basic with solid KOH and extracted with ethyl acetate. The extracted layer was washed with water and brine,
Dry over magnesium sulfate and evaporate to give an oil. After azeotropic distillation with toluene to remove traces of pyridine, the oil is treated with 3N isopropanolic HCl to give 70 mg of the title compound as the crystalline hydrochloride salt. Melting point 163-165℃. NMR analysis value (CHCl ₃ ): δ7.35 (5H, s, aromatic); 4.2 (1H, m, CHCH ₂ N(CH ₃ ) ₂ ); 3.6
(2H, m, CH ₂ -N(CH ₃ ) ₂ ); 2.65 (6H, s,
N( _CH3 ) ₂ ); 2.1(3H, s, -O-C- _CH3 );
0.9-1.7 (10H, m, aliphatic cyclohexyl)
ppm. Mass spectrometry value: Molecular weight 289 (M ⁺ , free base) Reference example 8 1-[cyano(p-chlorophenyl)methyl]
Cyclohexanol In Reference Example 1, p-methoxyphenylacetonitrile was replaced with 1 molar equivalent of p-chlorophenylacetonitrile to obtain 13.7 g of 1-[cyano(p-chlorophenyl)methyl]cyclohexanol. Melting point 115-117℃. Mass spectrometry value: Molecular weight 249 (M+1) ⁺ , CIMS Reference example 9 1-[2-amino-1-[4-chlorophenyl]
Ethyl]cyclohexanol 3.5 g of lithium aluminum hydride is suspended in 125 ml of ice-cold tetrahydrofuran, and 2.5 ml of concentrated sulfuric acid is carefully added while stirring. After 1 hour, 15 g (0.06 mol) of 1-[cyano(p-chlorophenyl)methyl]cyclohexanol was added to tetrahydrofuran.
Dissolve in 100 ml, stir vigorously, and quickly add dropwise while cooling. After a further 2 hours, 30 ml of a tetrahydrofuran-water mixture (1:1) and then 50 ml of a 10% aqueous sodium hydroxide solution were added. The tetrahydrofuran is decanted and the residue is thoroughly washed with diethyl ether and ethyl acetate. The combined organic solutions are dried over anhydrous potassium carbonate and evaporated to give 12 g of an oil. Mass spectrometry value: Molecular weight 253 (M+1) ⁺ , CIMS Reference example 10 1-[1-(4-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol 1-[2-amino-1-(4-chlorophenyl)
12 g (0.04 mol) of cyclohexanol, 13.7 ml of formaldehyde, 18.1 ml of formic acid and water.
Treat with 160 ml of the mixture and reflux for 4 hours at 100°C. The reaction mixture is cooled and thoroughly extracted with ethyl acetate, and the extract layer is discarded. Cool the aqueous residue on ice;
Make basic by adding solid potassium hydroxide, saturate with sodium chloride and extract three times with ethyl acetate. The extract layer is washed with brine, dried over anhydrous potassium carbonate and evaporated. Filter off 3 g of crystalline solid. The solid is converted to the hydrochloride salt using 4N isopropanolic HCl. Yield: 4.7g. Melting point 241-243
℃. Mass spectrometry value: Molecular weight 281 (M+1) ⁺ , CIMS NMR analysis value: δ7.35 (4H, s, 4-chloro substitution); 3.65 (2H, m, _CH2 -CHN( _CH3 ) ₂ ), 3.0
(1H, m, CH ₂ CHN (CH ₃ ) ₂ ); 1.4 (10H, m,
Reference example 11 1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol In Reference example 6, 1-[α-(aminomethyl)benzyl]cyclohexanol was 1 molar equivalent of 1-
By replacing with [2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol, 1-[1-(4-methoxyphenyl)-2-methylamino)ethyl]cyclohexanol hydrochloride is obtained. . Melting point 164-166℃. Mass spectrometry value: Molecular weight 263 (M+1) ⁺ , CIMS NMR analysis value: δ7.28, 6.92 (4H, q, p-substituted aromaticity); 3.76 (3H, s, OMe); 3,4 (2H,
m, _CH2 -CHN( _CH3 ) ₂ ); 2.9(1H, m,
_CH2CHN ( _NH3 ) ₂ );2.54(3H, _NCH3 );1.4
(10H, broad m, aliphatic cyclohexyl)
ppm. Reference example 12 4-Bromo-N,N-dimethylbenzeneacetamide Dissolve 50 g (0.233 mol) of p-bromophenyl acetic acid in 500 ml of methylene chloride and treat with 23.3 ml (0.27 mol) of oxalyl chloride and 0.5 ml of DMF at room temperature. do. The mixture is stirred for 4 hours until gas evolution ceases. The solvent is evaporated and the residue is dried under vacuum to remove excess oxalyl chloride. The residue is dissolved in 300 ml of methylene chloride and treated with excess gaseous dimethylamine. The mixture is stirred overnight and the solvent is evaporated. The residue was redissolved in methylene chloride and the solution was dissolved in saturated sodium bicarbonate solution, N-
Wash with hydrochloric acid, water, brine, dry over magnesium sulfate and evaporate. Filter the tan crystals with hexane and air dry. Yield: 51.2g. Melting point 73-76
℃. Elemental analysis value: C ₁₀ H ₁₂ Calculated value (%) as NOBr: C, 49.59; H, 4.96; N, 5.79 Actual value (%): C, 48.98; H, 5.14; N, 5.77 NMR analysis value (CHCl ₃ ): δ7.55 (4H, q, aromatic); 3.65 (2H, s); 2.95 (6H, s, N
(CH ₃ ) ₂ ) ppm. Example 1 1-[(4-bromophenyl)[(dimethylamino)carbonyl]methyl]cyclohexanol 15 g (0.06 mol) of 4-bromo-N,N-dimethylbenzeneacetamide was added to 250 ml of dry THF. and cool the solution to −78° C. under nitrogen. 43.3 ml (0.06 mol) n-butyllithium in hexane
is added dropwise while maintaining the temperature at -70°C. An orange precipitate forms. After addition, the reaction mixture was heated to -70°C.
Hold near 7.5ml of cyclohexane for 20 minutes
(0.07 mol) is added. After a further 50 minutes, at -78°C, the reaction mixture is poured into a stirred saturated ammonium chloride solution. Separate the layers and extract the aqueous layer with diethyl ether. The combined organic solutions are washed with brine, dried over magnesium sulphate and evaporated. The product crystallizes out and is then filtered with isopropanol. Yield: 9.8g. Melting point 140-144℃. Elemental analysis value: C ₁₆ H ₂₂ NO ₂ Br Calculated value (%): C, 56.47; H, 6.47; N, 4.12 Actual value (%): C, 57.22; H, 6.66; N, 4.21 NMR analysis value ( CHCl ₃ ): δ7.35 (4H, aromatic);
3.63 (1H, s, CH-CON(CH ₃ ) ₂ ); 2.95 (6H,
s, N-(CH ₃ ) ₂ ); 1.45 (10H, m, aliphatic cyclohexyl) ppm. Reference example 13 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol Aluminum hydride 0.7 g of lithium is suspended in 25 ml of dry THF cooled to 0° C. and 0.5 ml of concentrated sulfuric acid is carefully added to the as-prepared aluminum hydride. The mixture was stirred at 0°C for 1 hour, and 4 g of the amide, 1-[(4-bromophenyl)[dimethylaminocarbonyl]methyl]cyclohexanol
(0.012 mol) was dissolved in 35 ml of THF and immediately added dropwise. The reaction mixture is stirred at 0° C. for 1 hour.
Slowly add 6 ml of THF-water mixture (1:1 v/v) followed by 10 ml of 10% sodium hydroxide. The mixture is filtered and the residue is thoroughly washed with ethyl acetate. The combined filtrates are dried over anhydrous potassium carbonate and evaporated to give 3.5 g of an oil, which is converted to the hydrochloride salt using 4N isopropanolic HCl. Elemental analysis value: C ₁₆ H ₂₄ NOBr・HCl Calculated value (%): C, 52.97; H, 6.9; N, 3.86 Actual value (%): C, 52.71; H, 6.63; N, 3.71 NMR analysis value ( DMSO): δ7.4 (4H, aromatic);
3.55 (2H, CH−CH ₂ N(CH ₃ ) ₂ ); 3.05 (1H, t,
CH- _CH2N ( _CH3 ) ₂ ); 2.63(6H, s, N-
(CH ₃ ) ₂ ); 1.30 (10H, m, aliphatic cyclohexyl) ppm. Reference example 14 1-[1-(3-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol In reference example 12, p-bromophenyl 1 acetic acid
replaced with molar equivalent of m-bromophenyl acetic acid,
By the method described in Example 1 and Reference Example 13, 1
-[1-(3-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol is obtained as the hydrochloride. Melting point 198-201℃. Elemental analysis value: C ₁₆ H ₂₄ NOBr・HCl Calculated value (%): C, 52.97; H, 6.90; N, 3.86 Actual value (%): C, 52.84; H, 6.92; N, 3.99 Reference example 15 1 -[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
replaced with a molar equivalent of m-chlorophenylacetic acid,
By the method described in Example 1 and Reference Example 13, 1-[1-(3-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol is obtained as a hydrochloride. Melting point 214-216℃. Elemental analysis value: C ₁₆ H ₂₄ as NOCl/HCl Calculated value (%): C, 60.38; H, 7.86; N, 4.4 Actual value (%): C, 60.07; H, 7.79; N, 3.93 Reference example 13 1 -[1-(2-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
replaced with a molar equivalent of O-chlorophenylacetic acid,
By the method described in Example 1 and Reference Example 13, 1
-[1-(2-chlorophenyl)-2-(dimethylamino)ethyl]cyclohexanol is obtained as the hydrochloride. Melting point 205-206℃. Elemental analysis value: C ₁₆ H ₂₄ as NOCl/HCl Calculated value (%): C, 60.38; H, 7.86; N, 4.4 Actual value (%): C, 60.45; H, 7.71; N, 4.79 Reference example 17 1 -[1-(3,4-dichlorophenyl)-2-
(dimethylamino)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
1-[1-(3,4-dichlorophenyl-2-
(dimethylamino)ethyl]cyclohexanol is obtained as the hydrochloride salt. Melting point 241-244℃. Elemental analysis value: C ₁₆ H ₂₃ NOCl ₂・HCl Calculated value (%): C, 54.47; H, 6.81; N, 3.97 Actual value (%): C, 54.8; H, 6.83; N, 3.99 Reference example 18 1-[1-(3,4-dichlorophenyl)-2-
(dimethylamino)ethyl]cyclohexanol The product of the above reference example is produced in the same manner by the following method. Lithium diisopropylamide is obtained by dissolving 69 ml of diisopropylamine in 500 ml of THF and then adding 325 ml of n-butyllithium. After stirring for 10 minutes, the pale yellow liquid was heated to -78°C.
110.9 g of 3,4-dichloro-N,N-dimethylbenzeneacetamide solution (crude)
Dissolve in 300ml of THF and gradually add. A dark red slurry is obtained. The mixture is stirred for a further 20 minutes and 55.7 ml of cyclohexanone are added. After 60 minutes, at −78° C., the reaction mixture is poured into saturated ammonium chloride solution. The aqueous layer was extracted with diethyl ether, the combined organic layers were washed with brine,
Dry _{with K2CO3} and evaporate. The product, 1-
[(3,4-dichlorophenyl)(dimethylaminocarbonyl)methyl]cyclohexanol crystallizes out and is then filtered. The crystals are washed with isopropanol then petroleum ether and air dried. Yield: 73.6 g, mp 118-120 °C. 1-[(3,4-dichlorophenyl)(dimethylaminocarbonyl)methyl] in THF in an ice-cold solution of 152 ml (152 mmol) of borane-THF complex.
A solution of 30 g (90 mmol) of cyclohexanol is added. The mixture was refluxed for 2 hours, cooled again in an ice bath, 23 ml of 2N HCl was added and the mixture was reduced to 1.5
Reflux for an hour. Let cool overnight. The reaction mixture is made alkaline to pH 14 with solid potassium hydroxide and the layers are separated. The organic layer is washed with brine, dried over magnesium sulfate, and evaporated to a solid. The solid is filtered, washed with diethyl ether and air dried. Yield: 15.4g. Melting point 128-130℃. Conversion of the product into the hydrochloride salt corresponds to the product of Reference Example 17. Reference example 19 1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]cyclohexanol In Reference example 12, p-bromophenyl acetic acid was added to 1
1-[2-(dimethylamino)-1-(3-methoxyphenyl)ethyl]cyclohexanol was converted to hydrochloric acid by the method described in Example 1 and Reference Example 13, substituting a molar equivalent of m-methoxyphenylacetic acid. Obtained as salt. Melting point 166-168℃. Elemental analysis value: C ₁₆ H ₂₅ NO ₂・HCl Calculated value (%): C, 64.11; H, 8.68; N, 4.67 Actual value (%): C, 63.12; H, 8.54; N, 4.46 Reference example 20 1-[1-(3,4-dimethoxyphenyl)-2
-(dimethylamino)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
1-[1-(3,4-dimethoxyphenyl)
-2-(dimethylamino)ethyl]cyclohexanol is obtained as the hydrochloride. Elemental analysis value: _{C16H29NO3 ・ HCl} Calculated value (%): C, 62.88; H, 8.74; N, 4.08 Actual value (%): C, 62.42; H, 8.56; N, 3.98 Reference example 21 1-[2-(dimethylamino)-1-(4-trifluoromethylphenyl)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
1-[2-(dimethylamino)-1-(4
-trifluoromethylphenyl)ethyl]cyclohexanol as the hydrochloride salt. Melting point 238-240
℃. Elemental analysis value: C ₁₇ H ₂₅ NOF ₃・HCl Calculated value (%): C, 58.03; H, 7.16; N, 3.98 Actual value (%): C, 58.47; H, 7.16; N, 4.07 Reference example 22 1-[2-(dimethylamino)-1-(3-trifluoromethylphenyl)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
1-[2-(dimethylamino)-1-(3
-trifluorophenyl)ethyl]cyclohexanol as the hydrochloride salt. Melting point 194-196℃. Elemental analysis value: C ₁₇ H ₂₅ NOF ₃・HCl Calculated value (%): C, 58.03; H, 7.16; N, 3.98 Actual value (%): C, 58.31; H, 7.09; N, 4.09 Reference example 23 1-[2-(dimethylamino)-1-(4-methylphenyl)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
replaced with a molar equivalent of p-methylphenylacetic acid,
By the method described in Example 1 and Reference Example 13, 1
-[2-(dimethylamino)-1-(4-methylphenyl)ethyl]cyclohexanol is obtained as the hydrochloride. Elemental analysis value: C ₁₇ H ₁₇ NO・HCl Calculated value (%): C, 68.54; H, 9.17; N, 4.70 Actual value (%): C, 68.37; H, 9.31; N, 4.83 Reference example 24 1 -[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
1-[1-(4-benzyloxyphenyl)
-2-(dimethylamino)ethyl]cyclohexanol is obtained. Hydrogenolysis of the product to remove the benzyl protecting group from the 4-hydroxyphenyl moiety is carried out by dissolving 1.0 g of the product in 100 ml of ethanol. Add 10% Pd/C and then 5 ml of cyclohexa-1,4-dienone. The mixture is stirred for 90 minutes at room temperature. The catalyst is filtered off and the solvent is removed by evaporation to give 800 mg of solid. the solid,
The 4-hydroxyphenyl product is converted to its fumarate salt via acetone-ethanol solution. melting point
140-142℃. Elemental analysis value: _{C16H25NO2 ・ C4H4O4} Calculated value (%) _: C, _13.30 ; H, _7.70 ; N, 3.69 Actual value (%): C, 62.18; H, 7.90; N , 3.63 Reference Example 25 1-[2-(dimethylamino)-1-(3-hydroxyphenyl)ethyl]cyclohexanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
1-[1-(3-benzyloxyphenyl)
-2-(dimethylamino)ethyl]cyclohexanol is obtained. Hydrogenolysis of 2.3 g of the product is carried out in 200 ml of ethanol using a Parr bomb (300 mg, 10 Pd/C) until hydrogen uptake has ended.
The catalyst was filtered off and the solvent was evaporated to give a solid product, which was purified using 5N isopropanolic HCl.
Convert to its hydrochloride. Melting point 162-165℃. Elemental analysis value: C ₁₆ H ₂₅ NO ₂・HCl Calculated value (%): C, 64.08; H, 8.74; N, 4.67 Actual value (%): C, 62.78; H, 8.55; N, 4.55 Reference example 26 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclobutanol 1-[1-( 4-bromophenyl)
-2-(dimethylamino)ethyl]cyclobutanol is obtained. Convert this to the hydrochloride. melting point 220
~222℃. Elemental analysis value: C ₁₄ H ₂₀ as NOBr・HCl Calculated value (%): C, 50.22; H, 6.28; N, 4.19 Actual value (%): C, 50.26; H, 6.11; N, 4.13 Reference example 27 1 -[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclopentanol In Reference Example 12, p-bromophenyl acetic acid was added to 1
By replacing the molar equivalent of p-methoxyphenylacetic acid, 4-methoxy-N,N-dimethylbenzeneacetamide is obtained. Next, Example 1
The corresponding cyclopentanol derivatives are obtained by replacing cyclohexanone with 1 molar equivalent of cyclopentanone according to the method outlined in . This intermediate is converted to the hydrochloride salt of the title compound according to the method described in Reference Example 13. Melting point 194. Elemental analysis value: _{C16H25NO2 ・ HCl} Calculated value (%): C, 64.07; H, 8.76; N, 4.67 Actual value (%): C, 64.19; H, 8.72; N, 4.33 Reference example 28 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclopentanol The title compound is obtained as a hydrochloride by replacing cyclopentanone with 1 molar equivalent of cycloheptanone in Reference Example 25. . Melting point 175-177℃. Elemental analysis value: _{C18H29NO2 ・ HCl}・1/ _4H2O Calculated value (%): C, 65.03; H, 9.26; N, 4.21 Actual value (%): C, 65.25; H, 9.16; N, 4.29 Reference Example 29 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclooctanol By replacing cyclopentanone with 1 molar equivalent of cyclooctanone in Reference Example 27,
The title compound is obtained as the hydrochloride salt. Melting point 178-180
℃. Elemental analysis value: _{C19H31NO2 ・ HCl}・1/ _4H2O Calculated value (%): C, 65.87; H, 9.48; N, 4.04 Actual value (%): C, 65.79; H, 9.08; N, 3.95 Reference Example 30 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohex-2-ene In Example 1, 1 mol of 4-bromo-N,N-dimethylbenzeneacetamide By replacing the equivalent amount of 4-methoxy-N,N-dimethylbenzeneacetamide and cyclohexanone with 2-cyclohexen-1-one, the corresponding cyclohexenone derivative is obtained. This intermediate is converted according to the method described in Reference Example 13 to obtain the title compound as a fumarate salt. Melting point 128-130℃. Elemental analysis value: _{C17H25NO2 ・ C4H4O4} Calculated value (%) _: C, _64.4 ; H, 7.31; N, 3.58 Actual value ₍ %): C, 63.8; H, 7.46; N , 3.88 Reference example 31 Racemic 1-[2-(dimethylamino)-1-(4
-Methoxyphenyl)ethyl]cyclohexanol 48.0 g (0.173 mol) of 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethylcyclohexanol dissolved in 350 ml of ethyl acetate is dissolved in 250 ml of ethyl acetate. Dissolved di-p-toluoyl-d
- Treat with 33.5 g (0.082 mol) of tartaric acid. After standing overnight, the solids are filtered off. Three recrystallizations are carried out by dissolving the solid in 300 ml of boiling ethyl acetate and 50 ml of methanol, concentrating by boiling to obtain initial crystallization, and then cooling. Yield 31.7
g. Melting point 126-128℃. [α] ²⁵ _D = -50.51; C = 1.03
Ethanol The salt is converted to its free base by shaking in 2N sodium hydroxide and diethyl ether.
The ether layer is washed with brine, dried over anhydrous sodium carbonate, and evaporated to dryness under vacuum. Yield 16.4g (68.5%) Melting point 104-105°C. [α] ²⁵ _D = +
27.95; C=1.15, 95% ethanol The base is dissolved in 500 ml of ether and treated with 4.5N hydrochloric acid in 20 ml of isopropanol. The resulting hydrochloride is diluted with 400 ml of ether and recrystallized from 75 ml of warm methanol by cooling. Yield 16.6g, melting point 239-240℃. [α] ²⁵ _D = -
4.38; C=1.01, 95% ethanol The filtrate and washings obtained from the original di-p-toluoyl-d-tartrate salt are evaporated to dryness. The solid is shaken with 400 ml of 2N sodium hydroxide, extracted with diethyl ether (3 x 250 ml), the extract is washed with brine and dried to give the free base. Yield: 24.2g. The base is dissolved in 150 ml of ethyl acetate and treated with 16.75 g (0.0435 mol) of di-p-toluoyl-1-tartaric acid dissolved in 150 ml of ethyl acetate. After standing overnight, the salt is filtered and recrystallized twice from 300 ml of ethyl acetate and 50 ml of methanol in the same manner as above. Yield: 29.4g. Melting point 124-127
℃. [α] ²⁵ _D = +50.77; C = 0.845 ethanol The base is obtained by the method described above. Yield 14.7g, melting point
104-105℃. [α] ²⁵ _D = -26.56, C = 1.22%, 95%
Ethanol Converts the free base to the hydrochloride salt. Yield 14.5g Melting point 239-241℃ [α] ²⁵ _D = +4.98C = 1.01, 95% ethanol Reference example 32 1-[1-(4-1-aminophenyl)-2-dimethylaminoethyl]cyclohexanol p-aminophenyl Acetic acid dimethylamide 17.0g
(0.095 mol) was dissolved in 500 ml of tetrahydrofuran, allowed to stand under a nitrogen atmosphere, and cooled to -20°C.
23.6 g (1.15 eq.) of 1,1,4,4-tetramethyl-1,4-dichlorosilylethylene are added, followed by dropwise addition of a solution of 42 g (2.4 eq.) of sodium bis(trimethylsilyl)amide in 250 ml of THF. The mixture is allowed to warm up to room temperature and stirred for 18 hours. The mixture is then cooled to −78° C. and 71.6 ml (1.2 equivalents) of 1.6N n-butyllithium in hexane are added. The reaction was stirred for 45 minutes and 20 ml (2.0 equivalents) of cyclohexanone was added. The mixture was heated to -78℃
The mixture was stirred for an additional 1 hour at 1000 ml, and then poured into a saturated aqueous ammonium chloride solution. The organic layer is removed and the aqueous layer is extracted with diethyl ether. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to give crude 1-[(4-aminophenyl)(dimethylaminocarbonyl)methyl]cyclohexanol.
Get 20g. Column chromatography on silica gel, eluting with 1% methanol in methylene chloride, yields 16 g of a substantially pure white solid. The melting point of the sample recrystallized twice from ethanol is
It has a temperature of 169-170℃ and the following elemental analysis values. Elemental analysis value: C ₁₆ H ₂₄ O ₂ N ₂ Calculated value (%): C, 69.51; H, 8.77; N, 10.14 Actual value (%): C, 69.69; H, 8.96; N, 10.26 Above amide 5.0 Dissolve g (0.018 mol) in 300 ml of dry tetrahydrofuran,
Add dropwise to a mixture of 1.1 g of lithium aluminum hydride and 8.0 ml of concentrated sulfuric acid in 200 ml at 0°C. The mixture is stirred at 0 DEG C. for 5 hours, after which the excess reagent is quenched by dropwise addition of 4 ml of THF-water (50:50), then 4 ml of a 15% aqueous sodium hydroxide solution, and finally 4 ml of water. The mixture is filtered and the precipitate is washed several times with THF. The combined filtrates are evaporated and the residue is recrystallized from isopropanol to give 3.8 g of the title compound as the free base. Treatment with excess oxalic acid in ethyl acetate gives the dioxalate salt. Melting point 105℃ (decomposition). Elemental analysis value: C ₂₀ H ₃₀ N ₂ O ₉ Calculated value (%): C, 54.28; H, 6.84; N, 6.33 Actual value (%): C, 53.96; H, 6.83; N, 6.24 Reference example 33 1-[1-(4-nitrophenyl)-2-dimethylaminoethyl]cyclohexanol 1-[1-(4-aminophenyl)-2-dimethylaminoethyl]cyclohexanol 2.0 g (7.6
mmol) in 50 ml of methylene chloride and added dropwise to a stirred solution of 2.2 g (2.5 equivalents) of nitrosonium tetrafluoroborate. The reaction solution is stirred at room temperature for 4 hours. The methylene chloride is then removed under vacuum and replaced with 100 ml of water. This solution
Add slowly to a mixture of 2.0 g of copper in 200 ml of 1N sodium nitrite, and stir the combined solution at room temperature for 2 hours. Extraction with methylene chloride, drying and evaporation under vacuum yields 2.0 g of the free base of the title compound. The hydrochloride salt is obtained by recrystallization from isopropanolic HCl. Melting point 211-212℃. Elemental analysis value: C ₁₆ H ₂₄ O ₃ N ₂ Calculated value (%): C, 58.42; H, 7.37; N, 8.52 Actual value (%): C, 58.03; H, 7.53; N, 8.69 Reference example 34 1-[(2-dimethylamino)-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol In Reference Example 3, 1-[2-amino-1-(p-
Methoxyphenyl)ethyl]cyclohexanol is replaced with 1 molar equivalent of 1-[2-amino-1-(3-bromo-4-methoxyphenyl)ethyl]cyclohexanol and refluxed overnight to give the title compound. Melting point 218-220℃. Elemental analysis value: C ₁₇ H ₂₆ NO ₂ As Br・HCl Calculated value (%): C, 57.98; H, 6.92; N, 3.56 Actual value (%): C, 51.57; H, 6.79; N, 3.46 Reference example 35 2-[1-(dimethylamino)-2-(4-methoxyphenyl)propyl]cyclohexanol p-methoxyphenylacetonitrile 14.7g
(0.10 mol) is dissolved in 250 ml of dry tetrahydrofuran and placed in a dry water/isopropanol bath under nitrogen flow. 1.6Mn-butyllithium 69.0ml (0.11
mol) was added dropwise over 30 minutes, and the mixture was stirred at -78°C for 1 hour. During this time, the lithium salt of the nitrile precipitates out as a yellow solid. Then 71.0 g (0.50 mol) of methyl iodide is added and stirring is continued for an additional hour at -78°C. The mixture is then poured into saturated ammonium chloride solution and the product is extracted into diethyl ether, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Filter, evaporate, redissolve in methylene chloride and pass through Florisel. Evaporate α-
(p-methoxyphenyl)propionitrile 15.0
g as an orange oil. α-(p-methoxyphenyl) obtained above
Propionitrile was redissolved in 250 ml of tetrahydrofuran and −78
Cool to ℃. 1.6Mn-butyllithium 69.0ml
was added over 30 minutes and the mixture was stirred for 1 hour under nitrogen flow. Then add 20 ml of cyclohexanone and continue stirring at -78°C for an additional hour. The mixture is poured into saturated ammonium chloride solution and the product is extracted with diethyl ether. The extracted layer is washed with water, saturated sodium chloride solution and dried over sodium sulfate. Filtration and evaporation give 21.5 g of white solid. A sample recrystallized twice from benzene had a melting point of 129°C and the following elemental analysis values. Elemental analysis value: C ₁₆ H ₂₁ NO ₂ Calculated value (%): C, 74.10; H, 8.16; N, 5.40 Actual value (%): C, 73.95; H, 8.04; N, 5.29 Obtained above β-hydroxynitrile 4.0g
(15 mmol) in 200 ml of tetrahydrofuran and add 50 ml of 1M boron tetrahydrofuran complex. The mixture is refluxed for 2 hours and cooled.
Add 200 ml of 2NHCl and remove the THF under vacuum. The aqueous solution is made alkaline by addition of solid potassium carbonate and the product is extracted with 500 ml of ethyl acetate, washed with saturated ammonium chloride solution and then dried over sodium sulfate. filter, evaporate,
Treatment with isopropanolic HCl and diethyl ether gives 3.3 g of the primary amine. melting point 209
℃. Elemental analysis value: C ₁₆ H ₂₆ NC ₂ Cl Calculated value (%): C, 64.09; H, 8.74; N, 4.67 Actual value (%): C, 63.70; H, 8.60; N, 4.59 First grade Dissolve 3.0 g (10 mmol) of amine hydrochloride in 200 ml of dehydrated ethanol. 5.0 ml of 37% formaldehyde aqueous solution and 1.0 g of 10% palladium on activated carbon are added and the mixture is treated with 50 psi of hydrogen on a Parr shaker for 3 days. The mixture is then filtered, evaporated, the solvent replaced with 300 ml of water and washed with 300 ml of ethyl acetate. The aqueous solution is made alkaline with solid sodium carbonate and extracted again with ethyl acetate. The organic layer is washed with saturated brine and dried over sodium sulfate. Filter this and
Evaporate the title compound with isopropanolic HCl
It is precipitated as the hydrochloride salt from isopropanol/ether by addition of . Two crystallizations from isopropanol yield 2.0 g of a white solid. Melting point 271
℃. Elemental analysis value: C ₁₈ H ₃₀ NO ₂ Cl Calculated value (%): C, 65.93; H, 9.22; N, 4.27 Actual value (%): C, 65.73; H, 8.93; N, 4.20 Reference example 36 p -(a)3,4- instead of bromophenyl acetic acid
Dibromophenyl acetic acid, (b) 3-methylphenylacetic acid, (c) 4-bromophenyl acetic acid and (d) 3-methoxyphenylacetic acid are used, and the cycloalkanone is (a) cyclohexanone, (b) cyclohexanone, (c) ) Using cyclobutanone and (d) cyclopentanone, Reference Example 12, Example 1 and Reference Example 13
(a) 1-[1-(3,4-dibromophenyl)-2-(dimethylamino)ethyl]
Cyclohexanol, (b) 1-[2-(dimethylamino)-1-(3-methylphenyl)ethyl]cyclohexanol, (c) 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl] Cyclohexanol and (d) 1-[2-(dimethylamino)-
1-(3-methoxyphenyl)ethyl]cyclopentanol is obtained.

Claims (1)

[Claims] 1 Formula: [wherein, the dotted line means that it can be unsaturated if desired; R ₁ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₂ is alkyl having 1 to 6 carbon atoms; R ₄ is hydrogen or alkyl having 1 to 6 carbon atoms; ~6 alkyl; R ₅ and R ₆ are
Each independently hydrogen, hydroxy, carbon number 1-6
alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, aralkoxy having 7 to 9 carbon atoms, alkanoyloxy having 2 to 7 carbon atoms, alkyl mercapto having 1 to 6 carbon atoms, N-protected amino, halogen or trifluoromethyl or R ₅ and R ₆ together are methylenedioxy; R ₇ is hydrogen or has 1 to 6 carbon atoms
alkyl; n means an integer of 0 to 4].