Separation and resolution of isomeric forms of 3-(3,4-dihydroxy-phenyl)-serine

Claim 2

AN OPTICAL ANTIPODE SELECTED FROM THE GROUP CONSISTING OF (-)-THREO-, (+)-THREO-, (-)ERYTHRO AND (+)-ERYLTHRO-3-(3,4DIHYDROXYPHENYL)-SERINE AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF ESSENTIALLY FREE OF THE OPTICAL ANTIPODES OF THE REVERSE SIGN.

Claim 3

The optical antipode of claim 1 which is (-)-threo-3-(3,4-dihydroxyphenyl)-serine.

Claim 4

The optical antipode of claim 1 which is (+)-threo-3-(3,4-dihydroxyphenyl)-serine.

Claim 5

The optical antipode of claim 1 which is (-)-erythro-3-(3,4-dihydroxyphenyl)-serine.

Claim 6

The optical antipode of claim 1 which is (+)-erythro-3-(3,4-dihydroxyphenyl)-serine.

Claim 7

A process for preparing the rac-threo and rac-erythro forms of 3-(3,4-dihydroxyphenyl)-serine and the pharmaceutically acceptable salts thereof, which process comprises a. treating an acetonitrile solution of rac-threo/erythro-3-(3, 4-dibenzyloxyphenyl)-N-carbobenzoxy-serine with dicyclohexylamine and isolating the precipitated rac-threo-3-(3,4-benzyloxyphenyl)-N-carbobenzoxy-serine dicyclohexylamine salt; b. acidifying the mother liquor from step (a), replacing the solvent with chloroform and isolating the precipitated rac-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine; and c. producing the desired rac-threo or rac-erythro-3-(3,4-dihydroxyphenyl)-serine by separate catalytic hydrogenolysis of the products of steps (a) and (b), provided however, that the product of step (a) is first converted to the free acid by acidification with aqueous mineral acid.

Claim 8

A process for preparing the rac-threo and rac-erythro forms of 3-(3,4-dihydroxyphenyl)-serine and the pharmaceutically acceptable salts thereof, which process comprises a. treating an acetonitrile solution of rac-threo/erythro-3-(3, 4-dibenzyloxyphenyl)-N-carbobenzoxy-serine with dicyclohexylamine and isolating the precipitated rac-threo-3-(3,4-benzyloxyphenyl)-N-carbobenzoxy-serine dicyclohexylamine salt; b. acidifying the mother liquor from step (a), replacing the solvent with chloroform and isolating the precipitated rac-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine; and c. producing the desired rac-threo or rac-erythro-3-(3,4-dihydroxyphenyl)-serine by separate catalytic hydrogenolysis of the products of steps (a) and (b), provided however, that the product of step (a) is first converted to the free acid by acidification with aqueous mineral acid.

Claim 9

The process of claim 6 wherein the mother liquor from step (b) is concentrated and the solvent replaced by acetonitrile, the resulting solution treated with dicyclohexylamine and the precipitated rac-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine dicyclohexylamine salt is recycled into the process.

Claim 10

A process for resolving rac-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine into its optical antipodes, which process comprises treating said racemic compound with a resolving agent selected from the group consisting of optically active ephedrine and optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol in ethanolic solution, the resulting insoluble diastereomer is collected, the soluble optical antipode in the mother liquor is treated with said resolving agent of opposite sign than used before to precipitate the resulting second insoluble diastereomer and said first and second diastereomers are independently treated with aqueous mineral acid to produce the desired optical antipodes of threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine.

Claim 11

A process for resolving rac-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine into its optical antipodes, which process comprises treating said racemic compound with a resolving agent selected from the group consisting of optically active ephedrine and optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol in ethanolic solution, the resulting insoluble diastereomer is collected, the soluble optical antipode in the mother liquor is treated with said resolving agent of opposite sign than used before to precipitate the resulting second insoluble diastereomer and said first and second diastereomers are independently treated with aqueous mineral acid to produce the desired optical antipodes of threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine.

Claim 12

The resolution process of claim 8 wherein said racemic compound is treated with (+)-ephedrine to thereby precipitate the (+)-ephedrine salt of (-)-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine, and the mother liquor is treated with (-)-ephedrine or (-)-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol to thereby precipitate the Corresponding salt of (+)-threo-3-(3, 4-dibenzyloxyphenyl)-N-carbobenzoxy-serine

Claim 13

A process for the resolution of rac-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine which process comprises treating said racemic compound with optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol in ethanolic solution, isolating the diastereomer which crystallizes out, treating the mother liquor with the opposite antipode of said optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol, isolating the second diastereomer, which crystallizes out, and then independently treating both said diastereomers with mineral acid to produce said optical antipodes of erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine.

Claim 14

A process for the resolution of rac-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine which process comprises treating said racemic compound with optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol in ethanolic solution, isolating the diastereomer which crystallizes out, treating the mother liquor with the opposite antipode of said optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol, isolating the second diastereomer, which crystallizes out, and then independently treating both said diastereomers with mineral acid to produce said optical antipodes of erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine.

Claim 15

The resolution process of claim 10 wherein the diastereomers produced are the (-)-(-) or the (+)-(+) salts.

Claim 16

Rac-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 17

Rac-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 18

Rac-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 19

Rac-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 20

(-)-Threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 21

(-)-Threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 22

(+)-Threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 23

(+)-Threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 24

(-)-Erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 25

(-)-Erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 26

(+)-Erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 27

(+)-Erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and pharmaceutically acceptable salts thereof.

Claim 28

The (+)-ephedrine salt of (-)-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.

Claim 29

The (+)-ephedrine salt of (-)-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.

Claim 30

The (-)-ephedrine or (-)-threo-1-(p-nitrophenyl)-2-amino-1, 3-propanediol salt of (+)-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.

Claim 31

The (-)-ephedrine or (-)-threo-1-(p-nitrophenyl)-2-amino-1, 3-propanediol salt of (+)-threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.

Claim 32

The (-)-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol salt of (-)-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.

Claim 33

The (-)-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol salt of (-)-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.

Claim 34

The (+)-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol salt of (+)-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.

Claim 35

The (+)-threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol salt of (+)-erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxy-serine.