Process for production of β-amino-α-hydroxy carboxamide derivative
View Patent ↗Provided is a process for production of a β-amino-α-hydroxy carboxamide derivative that is important in production of drugs or the like. In the presence of a predetermined solvent, a β-(N-protected)amino-α-hydroxycarboxylic acid is reacted with an amine to conversion to a β-(N-protected)amino-α-hydroxy carboxamide derivative; then the derivative is deprotected for conversion to a β-amino-α-hydroxy carboxamide derivative; and the derivative is crystallized using a protic solvent to obtain a crystal. The high-purity β-amino-α-hydroxy carboxamide derivative can be stably produced on an industrial scale by the process.
1. A process for production of a β-amino-α-hydroxy carboxamide derivative (1) of the following general formula (1);
(wherein R represents an alkyl group having 1 to 6 carbon atoms and optionally having a substituent, or an aralkyl group having 7 to 15 carbon atoms and optionally having a substituent;
P 1 and P 2 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms and optionally having a substituent, an aralkyl group having 7 to 15 carbon atoms and optionally having a substituent, or a carboxyl group; HX represents a mineral acid, a sulfonic acid, or a carboxylic acid)
characterized in that the β-amino-α-hydroxy carboxamide derivative (1) is obtained as a crystal by a crystallization step using a solvent containing a protic solvent.
2. The process for production according to claim 1 , comprising a step of deprotecting a β-(N-protected)amino-α-hydroxy carboxamide derivative of the following general formula (4);
(wherein R, P 1 and P 2 are the same group as above; P 3 and P 4 each independently represent a hydrogen atom or a protective group for the amino group, or are joined together to form a phthaloyl group)
for conversion to the β-amino-α-hydroxy carboxamide derivative (1).
3. The process for production according to claim 2 , wherein the deprotection is attained with an acid.
4. The process for production according to claim 3 , wherein an amount of the acid to be used is not less than 1 time by mol relative to the β-(N-protected)amino-α-hydroxy carboxamide derivative (4).
5. The process for production according to claim 1 , wherein the protic solvent is an alcohol or a mixed solvent of an alcohol and water.
6. The process for production according to claim 1 , wherein cooling crystallization at a cooling speed of not less than 1° C./hr is carried out in the crystallization step.
7. The process for production according to claim 1 , wherein the compound of the formula (1) is obtained by deprotecting a β-(N-protected)amino-α-hydroxy carboxamide derivative of the following general formula (4);
(wherein R, P 1 and P 2 are the same group as above; P 3 and P 4 each independently represent a hydrogen atom or a protective group for the amino group, or are joined together to form a phthaloyl group),
and the β-(N-protected)amino-α-hydroxy carboxamide derivative (4) is produced by the reaction of a β-amino-α-hydroxycarboxylic acid of the following general formula (2);
(wherein R, P 3 and P 4 are the same as above)
with a condensing agent and an amine of the general formula (3);
P 1 P 2 NH (3)
(wherein P 1 and P 2 are the same as above)
in the presence of one or more solvents of aliphatic esters, ethers, nitriles and sulfur-containing solvents.
8. The process for production according to claim 2 , wherein an absolute configuration of the 2-position and 3-position in the compound of the formula (4) is (2S,3S) or (2R,3R).
9. The process for production according to claim 1 , wherein R is an n-propyl group.
10. The process for production according to claim 1 , wherein one of P 1 and P 2 is a hydrogen atom and the other is a cyclopropyl group.
11. The process for production according to claim 2 , wherein one of P 3 and P 4 is a hydrogen atom and the other is a tert-butoxycarbonyl group.
12. The process for production according to claim 1 , wherein HX is hydrogen chloride.