# US 9,434,696 B2 · Process for the preparation of enantiomeric forms of 2,3-diaminopropionic acid derivatives

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- Number: US 9,434,696 B2
- Document ID: US9434696B2
- Status: Granted
- Kind: B2
- Application number: 14/502,141
- Filed: 2014-09-30
- Published: 2015-01-15
- Granted: 2016-09-06
- Earliest claimed: 2010-08-12
- Assignees: Sanofi
- Applicants: Sanofi
- Inventors: Claus-Dieter Graf; Joerg Rieke-Zapp
- Web page: https://patentgrep.com/patent/US9434696B2

## CPC

- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The disclosure relates to a process for the preparation of the enantiomeric forms of 2,3-diaminopropionic acid derivatives of formula I, wherein R1, R2 and R3 are defined as in the disclosure, by racemate resolution. The separation of the racemate into its enantiomers takes place through formation of diastereomeric salts upon addition of an enantiomerically pure auxiliary, and subsequent separation by fractional crystallization.

## Claims

### Claim 1

A process for obtaining a compound of formula IV or a salt thereof:
wherein
R1 is a hydrogen atom, F, Cl, I, Br, (C1-C4)-alkyl or —CN;
R2 is a heteroaryl residue selected from the series consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline and β-carboline, wherein the heteroaryl residue is unsubstituted or is substituted once, twice or three times, independently of each other, by substituents selected from the series consisting of (C1-C5)-alkyl, (C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C1-C4)-alkyl-, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl-, aminocarbonyl- and (C1-C4)-alkoxycarbonyl-, or an aryl residue selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl, wherein the aryl residue is unsubstituted or is substituted once, twice or three times, independently of each other, by substituents selected from the series consisting of (C1-C5)-alkyl, (C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C1-C4)-alkyl-, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl-, am inocarbonyl- and (C1-C4)-alkoxycarbonyl-;
R3 is a hydrogen atom,
or (C1-C4)-alkyl,
or an aryl residue selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl, wherein the aryl residue is unsubstituted or is substituted, independently of each other, once, twice or three times by substituents selected from the series consisting of —NO2, —O—(C1-C4)-alkyl, F, Cl and Br,
or —O—C(CH3)3,
or —O—CH(R7)-aryl, wherein the aryl residue is selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl and is unsubstituted or is substituted, independently of each other, once, twice or three times by substituents selected from the series consisting of —NO2, —O—CH3, F, Cl and Br, and wherein R7 is a hydrogen atom or (C1-C4)-alkyl; and
R5 is —NH2, —N(H)—R6 or —N(R6)2, wherein R6 is (C1-C4)-alkyl or aryl, wherein the aryl residue is selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl;
said process comprising:
a) mixing a compound of formula II:
wherein R1, R2 and R3 are defined as in the compound of formula IV, in an organic solvent or a mixture of organic solvents with an enantiomerically pure auxiliary to form a salt composed of enantiomerically pure auxiliary and compound of formula I:
wherein R1, R2 and R3 are defined as in the compound of formula IV;
b) separating the salt composed of enantiomerically pure auxiliary and compound of formula I, by fractional crystallization;
c) isolating the compound of formula I from the salt composed of enantiomerically pure auxiliary and compound of formula I; and
d) converting the resulting compound of formula I with ammonia or an amine of the formula H2N—R6 or HN(R6)2, wherein R6 is (C1-C4)-alkyl or aryl, wherein the aryl residue is selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl, into the compound of formula IV or a salt thereof.

### Claim 2 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula IV or a salt thereof is obtained wherein
R1 is a hydrogen atom, F, Cl, I or Br;
R2 is phenyl, pyridinyl, pyrimidinyl or thiazolyl, wherein phenyl, pyridinyl, pyrimidinyl and thiazolyl are unsubstituted or substituted by fluorine or chlorine;
R3 is phenyl, methyl or —O—C(CH3)3;
R5 is —NH2, —N(H)—R6 or —N(R6)2, wherein R6 is (C1-C4)-alkyl or aryl, wherein the aryl residue is selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl.

### Claim 3

A compound of formula IV:
wherein
R1 is a hydrogen atom, F, Cl, I, Br, (C1-C4)-alkyl or —CN,
R2 is a heteroaryl residue selected from the series consisting of pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides, triazolones, oxadiazolone, isoxazolone, oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline and β-carboline, wherein the heteroaryl residue is unsubstituted or is substituted once, twice or three times, independently of each other, by substituents selected from the series consisting of (C1-C5)-alkyl, (C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C1-C4)-alkyl-, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl-, aminocarbonyl- and (C1-C4)-alkoxycarbonyl-, or an aryl residue selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl, wherein the aryl residue is unsubstituted or is substituted once, twice or three times, independently of each other, by substituents selected from the series consisting of (C1-C5)-alkyl, (C1-C5)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxy, hydroxy-(C1-C4)-alkyl-, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl-, am inocarbonyl- and (C1-C4)-alkoxycarbonyl-;
R3 is a hydrogen atom,
or (C1-C4)-alkyl,
or an aryl residue selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl, wherein the aryl residue is unsubstituted or is substituted, independently of each other, once, twice or three times by substituents selected from the series consisting of —NO2, —O—(C1-C4)-alkyl, F, Cl and Br, or —O—C(CH3)3,
or —O—CH(R7)-aryl, wherein the aryl residue is selected from the series consisting of phenyl, naphthyl, biphenylyl, anthryl and fluorenyl and is unsubstituted or is substituted, independently of each other, once, twice or three times by substituents selected from the series consisting of —NO2, —O—CH3, F, Cl and Br, and wherein R7 is a hydrogen atom or (C1-C4)-alkyl; and
R5 is —NH2.

### Claim 4 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula IV or a salt thereof is obtained wherein R5 is —NH2 or —N(H)—R6, wherein R6 is (C1-C4)-alkyl or aryl, wherein the aryl residue is selected from the series consisting of phenyl, naphthylbiphenylyl, anthryl and fluorenyl.

### Claim 5 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula IV or a salt thereof is obtained wherein R5 is —NH2.

### Claim 6 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula IV or a salt thereof is obtained wherein R5 is —N(H)—R6 or —N(R6)2, and wherein R6 is (C1-C4)-alkyl.

### Claim 7 (depends on 1)

The process as claimed in claim 1, wherein the compound of formula IV or a salt thereof is obtained wherein R5 is —N(H)—R6 or —N(R6)2, and wherein R6 is methyl.

### Claim 8 (depends on 3)

The compound as claimed in claim 3, wherein R1 is a hydrogen atom, R2 is pyrimidinyl, and R3 is —O—C(CH3)3.