# US 7,612,210 B2 · Process for selective synthesis of enantiomers of substituted 1-(2-amino-1-phenyl-ethyl)-cyclohexanols

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- Number: US 7,612,210 B2
- Document ID: US7612210B2
- Status: Granted
- Kind: B2
- Application number: 11/633,207
- Filed: 2006-12-04
- Published: 2007-06-14
- Granted: 2009-11-03
- Earliest claimed: 2005-12-05
- Assignees: Wyeth
- Inventors: Paige Erin Mahaney; Madelene Miyoko Antane; Jerry Shunneng Sun
- Web page: https://patentgrep.com/patent/US7612210B2

## CPC

- C07C 213/02: by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 5/24: of the sex hormones
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/10: for impotence
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07C 59/72: containing six-membered aromatic rings and other rings
- C07C 235/34: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 263/26: with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
- C07D 295/092: with aromatic radicals attached to the chain
- C07D 295/096: with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/185: from aliphatic carboxylic acids
- C07B 2200/07: Optical isomers
- C07C 2601/14: The ring being saturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

A process for the enantioselective synthesis of an (S)- or (R)-1-[2-dimethylamino)-1-(methoxyphenyl)ethyl]cyclohexanol and analogues or salt thereof are described. The method involves the steps of (a) reacting an (S) or (R) 4-benzyloxazolidinone with a mixed anhydride of a methyoxyphenylacetic acid under conditions which form a oxazolidinone, (4S)- or (4R)-4-benzyl-3-[methyoxyphenyl]acetyl]-oxazolidin-2-one, (b) treating the (4S)- or (4R)-4-benzyl-3-[(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one with an aprotic amine base and titanium chloride in a chlorinated solvent under conditions which permit formation of the corresponding anion, (c) mixing the corresponding anion with titanium chloride and cylcohexanone under conditions which permit an aldol reaction to form the corresponding (4S)- or (4R)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one,(d) hydrolyzing the (4S)— or (4R)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one to form a chiral acid (2S or 2R)-(1-hydroxycyclohexyl)-methoxyphenyl)acetic acid, (e) coupling the chiral phenylacid to a secondary amine to form an amide, and (f) reducing the amide to form an (S) or (R) 1[2-dimethylamino)-1-(methoxyphenyl)ethyl]cyclohexanol or a salt thereof.

## Claims

### Claim 1

A process for the stereoselective synthesis of a (4S or 4R)-4-benzy-3-[(2R or 2S)-(1-hydroxycyclohexyl)-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one having the structure
wherein X is methoxy or trifluoromethoxy;
comprising the steps of:
treating a (4S or 4R)-4-benzyl-3-[(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one having the structure
wherein X is methoxy or trifluoromethoxy;
with an aprotic amine base and titanium tetrachloride in a chlorinated solvent under conditions which permit formation of the corresponding anion; and
mixing the corresponding anion with titanium tetrachloride and cyclohexanone under conditions which permit an aldol reaction to form said (4S or 4R)-4-benzyl-3-[(2R or 2S)-(1-hydroxycyclohexyl)-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the (4S or 4R)-4-benzyl-3-[(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one is a (4S or 4R)-4-benzyl-3-[(trifluoromethoxyphenyl)acetyl]-1,3-oxazolidin-2-one.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the aprotic amine base is diisopropyethylamine.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the chlorinated solvent is methylene chloride.

### Claim 5

A compound having the structure:

### Claim 6

A process for the stereoselective synthesis of an enantiomer of a 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine or salt thereof having the structure
wherein X is OCH3 or OCF3, R1 and R2 are each independently selected from C1-C3 alkyl, or together with the nitrogen they are attached form a 1,4-piperazine ring wherein said piperazine ring is substituted with from 0 to 2 methyl groups
said method comprising the steps of:
(a) reacting an (S)- or (R)-4-benzyl-1,3-oxazolidin-2-one with a mixed anhydride of a methoxyphenylacetic acid under conditions which form a (4S or 4R)-4-benzyl-3-[(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one having the structure:
wherein X is OCH3 or OCF3;
(b) treating the (4S)- or (4R)-4-benzyl-3-[(methoxyphenyl)acetyl]-1,3-oxazolidin -2-one with an aprotic amine base and titanium tetrachloride in a chlorinated solvent under conditions which permit formation of the corresponding anion;
(c) mixing the corresponding anion with titanium tetrachloride and cyclohexanone under conditions which permit an aldol reaction to form the corresponding (4S)- or (4R)-4-benzyl-3-[(2R or 2S)-2-(1-hydroxycyclohexyl)-2-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one having the formula
wherein X is OCH3 or OCF3;
(d) hydrolyzing the (4S)- or (4R)-4-benzyl-3-[(2R or 2S)-2-(1-hydroxycyclohexyl) -2-(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one to form chiral (2R or 2S)-(1-hydroxycyclohexyl) -methoxyphenyl)acetic acid having the formula
wherein X is OCH3 or OCF3;
(e) coupling the chiral phenylacetic acid with a secondary amine NR1R2 to form an amide having the formula
wherein X is OCH3 or OCF3, R1 and R2 are each independently selected from C1-C3 alkyl, or together with the nitrogen they are attached form a 1,4-piperazine ring wherein said piperazine ring is substituted with from 0 to 2 methyl groups;
(f) reducing the amide to form an (S)- or (R)-2-phenyl-2-(1-hydroxycycloalkyl)ethylamine;
(g) and optionally converting the free base to a salt thereof.

### Claim 7 (depends on 6)

The process according to claim 6, wherein the reacting step (a) comprises reacting the mixed anhydride of a methoxyphenylacetic acid with a lithium anion of benzyl-1,3-oxazolidin-2-one at a temperature from −78° C. to 20° C.

### Claim 8 (depends on 6)

The process of claim 6, wherein the base in step (b) is diisopropylethylamine.

### Claim 9 (depends on 6)

The process of claim 6, wherein the chlorinated solvent of step (b) is methylene chloride.

### Claim 10 (depends on 6)

The process according to claim 6, wherein the coupling step (e) comprises coupling the chiral phenylacetic acid with benzotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate (BOP) in the presence of a base in a chlorinated solvent.

### Claim 11 (depends on 6)

The process according to claim 6, wherein the reduction step (f) comprises reducing the amide formed by step (e) using a borane in tetrahydrofuran at temperatures of 55° C. to 85° C. to form a borane complex, and dissociating the borane complex to provide an enantiomer of 2-phenyl-2-(1-hydroxycycloalkyl)ethylamine.

### Claim 12 (depends on 6)

The process according to claim 6, wherein X is 4-methoxy.

### Claim 13 (depends on 6)

The process according to claim 6, wherein X is 3-trifluoromethoxy.