Process for the preparation of D(-) and L(+)-3,3-diphenylalanine and D(-) and L(+)-substituted 3,3-diphenylalanines and derivatives thereof
AssigneeWarner-Lambert Company
InventorsVladimir Beylin, Huai G. Chen, Om P. Goel, John G. Topliss
Life of this patent
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Abstract
A process for the preparation of D(-) and L(+)-3,3-diphenylalanine and D(-) and L(+)-substituted 3,3-diphenylalanines is described where N-protected DL-3,3-diphenylalanine or N-protected-DL-substituted 3,3-diphenylalanine are treated with (-)cinchonidine and the resulting salt resolved into the desired enantiomers, as well as derivatives thereof and valuable intermediates used in the process.
Claims12
A process for the preparation of the D(-) and L(+) enantiomers of a compound of Formula I ##STR17## and pharmaceutically acceptable salts thereof wherein R is hydrogen, chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, 2,4-dichloro, or 2,4-difluoro
- which comprises:
- step (a) treating a racemic compound of Formula II ##STR18## wherein R.sup.1 is a lower alkyl,
- CX.sub.3 wherein X is hydrogen or halogen or aryl and R is as defined above;
- wherein (-) cinchonidine is a solvent selected from the group consisting of methanol, ethanol, propanol, and butanol to afford a racemic compound of Formula III;
- ##STR19## wherein R and R.sup.1 are as defined above;
- Step (b) resolving a compound of Formula III wherein R and R.sup.1 are as defined above by fractional crystallization into D(-) and L(+) enantiomers;
- ##STR20## Step (c) treating a compound of Formula D(-)IIIa or Formula L(+)IIIb wherein R and R.sup.1 are as defined above with an acid in a solvent selected from the group consisting of ethyl acetate, dichloromethane, chloroform, toluene, tetrahydrofuran and diethyl ether to afford a compound of Formula D(-)IIa or Formula L(+)IIb:
- ##STR21## Step (d) heating a compound of Formula D(-) IIa or Formula L(+)IIb wherein R and R.sup.1 are as defined above with an acid to afford the D(-)Ia or L(+) Ib enantiomers of Formula I;
- Step (e) and, if desired, converting a compound of Formula D(-)Ia or Formula L(+)Ib to a corresponding pharmaceutically acceptable salt and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula D(-)Ia or Formula L(+)Ib.
A compound selected from the group consisting of ##STR22## and ##STR23## wherein `R is hydrogen
- chloro,
- bromo,
- fluoro,
- methyl,
- trifluoromethyl,
- methoxy,
- 2. 4-dichloro, or
- 2,4-difluoro and
- R.sup.1 is lower alkyl,
- CX.sub.3 wherein X is hydrogen or halogen or aryl.
A compound selected from the group consisting of ##STR24## wherein R is hydrogen chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, 2,4-dichloro, or 2,4-difluoro and
- R.sup.1 is lower alkyl,
- CX.sub.3 wherein X is hydrogen or halogen or aryl and
- pharmaceutically acceptable salts thereof.
A compound selected from the group consisting of ##STR25## wherein R.sub.a is chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, 2,4-dichloro, or 2,4-difluoro
- and pharmaceutically acceptable salts thereof.
A compound selected from the group consisting of ##STR26## wherein R is hydrogen, chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, 2,4-dichloro, or 2,4-difluoro
- and pharmaceutically acceptable salts thereof.
A compound selected from the group consisting of ##STR27## wherein Z is benzyloxycarbonyl,
- R is hydrogen chloro, bromo, fluoro, methyl, trifluoromethyl, methoxy, 2,4-dichloro, or 2,4-difluoro, and
- pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.