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

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.

Claims13

Dependent claims

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.

4 more elements

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.

10 more elements

Dependencies are inferred from the claim text.

Process for selective synthesis of enantiomers of substituted 1-(2-amino-1-phenyl-ethyl)-cyclohexanols

Life of this patent

Process for selective synthesis of enantiomers of substituted 1-(2-amino-1-phenyl-ethyl)-cyclohexanols

Life of this patent

Abstract

Claims13