Process for preparing 2,4-diamino-3-hydroxybutyric acid derivatives

1. A process to synthesize compounds of following formula (I):

where:

R 1 and R 2 independently of each other are protective groups of the amine functions;

R 3 is a hydrogen or a protective group of the amine functions and R 4 is a hydrogen or a protective group of the hydroxyl functions, or R 3 and R 4 together form a group selected from among —C(CH 3 ) 2 —, —CH(CH 3 )—, —C((CH 2 ) 4 )—, —C((CH 2 ) 5 )—, —CH(C 6 H 5 )—, —CH((p-OCH 3 )C 6 H 4 )—, —CH((m,p-OCH 3 )C 6 H 3 )— and —C(O)—;

R 5 is a hydrogen, an alkyl radical, aryl radical or heteroaryl radical;

from 5-hydroxyectoine.

2. The synthetic process according to claim 1 comprising the following steps:

(a) base hydrolysis of hydroxyectoine and deacetylation leading to 2,4-diamino-3(S)-hydroxy butyric acid;

(b) regioselective protection by a R 1 group of the primary amine function at position 4 of the 2,4-diamino-3(S)-hydroxybutyric acid obtained at step (a);

(c) protection by an R 2 group of the primary amine function at position 2 of the acid obtained at step (b);

(f) recovering the compound of formula (I) obtained at step (c).

3. The synthesis process according to claim 1 comprising the following steps:

(a) base hydrolysis of hydroxyectoine and deacetylation leading to 2,4-diamino-3(S)-hydroxy butyric acid;

(b) regioselective protection by a R 1 group of the primary amine function at position 4 of the 2,4-diamino-3(S)-hydroxybutyric acid obtained at step (a);

(c) protection by an R 2 group of the primary amine function at position 2 of the acid obtained at step (b);

(d) protection of the hydroxyl function at position 3 by an R 4 group and/or protection of the secondary amine at position 4 by an R 3 group of the compound obtained at step (c) or protection of the hydroxyl function at position 3 and secondary amine function at position 4 to obtain a compound of formula (I) wherein R 3 and R 4 together form a group selected from among —C(CH 3 ) 2 —, —CH(CH 3 )—, —C((CH 2 ) 4 )—, —C((CH 2 ) 5 )—, —CH(C 6 H 5 )—, —CH((p-OCH 3 )C 6 H 4 )—, —CH((m,p-OCH 3 )C 6 H 3 )— and —C(O)—;

(f) recovering the compound of formula (I) obtained at step (d).

4. The synthesis process according to claim 1 comprising the following steps:

(a) base hydrolysis of hydroxyectoine and deacetylation leading to 2,4-diamino-3(S)-hydroxy butyric acid;

(b) regioselective protection by a R 1 group of the primary amine function at position 4 of the 2,4-diamino-3(S)-hydroxybutyric acid obtained at step (a);

(c) protection by an R 2 group of the primary amine function at position 2 of the acid obtained at step (b);

(d) protection of the hydroxyl function at position 3 by an R 4 group and/or protection of the secondary amine at position 4 by an R 3 group of the compound obtained at step (c) or protection of the hydroxyl function at position 3 and secondary amine function at position 4 to obtain a compound of formula (I) wherein R 3 and R 4 together form a group selected from among —C(CH 3 ) 2 —, —CH(CH 3 )—, —C((CH 2 ) 4 )—, —C((CH 2 ) 5 )—, —CH(C 6 H 5 )—, —CH((p-OCH 3 )C 6 H 4 )—, —CH((m,p-OCH 3 )C 6 H 3 )— and —C(O)—;

(e) N-alkylation or N-arylation at position 2 of the compound obtained at step (d) to obtain a compound of formula (I) wherein R 5 is an alkyl radical, aryl radical or heteroaryl radical;

(f) recovering the compound of formula (I) obtained at step (e).

5. The synthesis process according to claim 2 , wherein the hydrolysis and deacetylation at step (a) are performed in the presence of at least 7 molar equivalents of a strong base for at least 18 h at a temperature of 85° C. or higher.

6. The synthesis process according to claim 2 , wherein the hydrolysis at step (a) is performed in the presence of a least one molar equivalent of a strong base for at least 3 h30 at a temperature of 50° C. or higher, followed by deacetylation via acid hydrolysis at a temperature of at least 95° C. for at least 1 hour.

7. The synthesis process according to claim 2 , wherein the regioselective protection of the primary amine function at position 4 at step (b) comprises the following steps:

(b1) preparing a copper complex by placing the 2,4-diamino-3-hydroxybutyric acid obtained at step (a) in the presence of compound selected from among CuSO 4 .5H 2 O, CuSO 4 , Cu 2 (OH) 2 CO 3 , Cu(OAc) 2 and CuCO 3 ;

(b2) protecting the primary amine function at position 4 by an R 1 group.

8. The synthesis process according to claim 2 , wherein the regioselective protection of the primary amine function at position 4 at step (b) comprises the following steps:

(b1) preparing a copper complex by placing the 2,4-diamino-3-hydroxybutyric acid obtained at step (a) in the presence of compound selected from among CuSO 4 .5H 2 O, CuSO 4 , Cu 2 (OH) 2 CO 3 , Cu(OAc) 2 and CuCO 3 ;

(b2) protecting the primary amine function at position 4 by an R 1 group;

(b3) decomplexing the copper to obtain the compound of following formula:

9. The synthesis process according to claim 7 , wherein at step (b2) the primary amine function at position 4 is protected by a Boc group.

10. The synthesis process according to claim 2 , wherein the protection of the primary amine function at position 2 at step (c) is obtained by reaction with FmocOSu.

11. The synthesis process according to claim 2 , wherein the formula (I) compound has the following formula:

12. The synthesis process according to claim 2 , wherein step (d) comprises the reaction of the acid obtained at step (c) with isopropylidene leading to the compound of following formula (Id):

13. The synthesis process according to claim 2 , wherein the formula (I) compound is obtained with diastereoisomeric purity higher than 90%.

14. A process to synthesize 2,4-diamino-3(S)-hydroxycarboxylic acid from 5-hydroxyectoine.

15. The process to synthesize 2,4-diamino-3(S)-hydroxycarboxylic acid according to claim 14 comprising base hydrolysis of hydroxyectoine and deacetylation to lead to 2,4-diamino-3(S)-hydroxy butyric acid.