Method for producing lacosamide and intermediate thereof
The present invention provides a method of industrially and safely producing lacosamide high in diastereomeric excess at a high yield and a low cost. Adopting a particular isomerization-crystallization condition makes it possible to a method of industrially and safely producing lacosamide high in diastereomeric excess at a high yield and a low cost. Additionally, an intermediate efficacious for producing lacosamide is provided.
1. A method for producing lacosamide comprising:
an isomerization-crystallization process that causes racemic N-benzyl-2-amino-3-methoxypropionamide to react with a resolving reagent of at least one selected from a group consisting of
N-acetylamino acid selected from the group consisting of N-acetyl-D-leucine, N-acetyl-D-valine, N-acetyl-D-alanine, and N-acetyl-D-phenylalanine, and
N-formylamino acid selected from the group consisting of N-formyl-L-leucine, N-formyl-L-alanine, and N-formyl-L-phenylalanine
in a solvent in the presence of an aldehyde compound at a temperature lower than 60° C. to selectively crystalize a salt of R-configuration of N-benzyl-2-amino-3-methoxypropionamide and N-acetylamino acid or N-formylamino acid; and
an acetylation process that acetylates the R-configuration N-benzyl-2-amino-3-methoxypropionamide contained in the salt to obtain lacosamide.
2. The method according to claim 1 , wherein, in the isomerization-crystallization process, the resolving reagent is dividedly provided.
3. The method according to claim 1 , wherein the acetylation process comprises:
(i) causing the salt obtained through the isomerization-crystallization process with an acetylating reagent; or
(ii) causing the salt obtained through the isomerization-crystallization process with an acid and causing the obtained R-configuration N-benzyl-2-amino-3-methoxypropionamide to react with the acetylating reagent.
4. The method according to claim 1 , further comprising, an amination process that aminates a compound expressed by a Formula (4) to obtain the racemic N-benzyl-2-amino-3-methoxypropionamide, the amination process being carried out before the isomerization-crystallization process
(where, X represents a leaving group).
5. A method for producing lacosamide comprising:
an isomerization-crystallization process that causes racemic N-benzyl-2-amino-3-methoxypropionamide to react with a resolving reagent of at least one selected from a group consisting of
N-acetylamino acid selected from the group consisting of N-acetyl-D-leucine, N-acetyl-D-valine, N-acetyl-D-alanine, and N-acetyl-D-phenylalanine
in a solvent in the presence of an aldehyde compound at a temperature 60° C. or less to selectively crystalize a salt of R-configuration of N-benzyl-2-amino-3-methoxypropionamide and N-acetylamino acid; and
an acetylation process that acetylates the R-configuration N-benzyl-2-amino-3-methoxypropionamide contained in the salt to obtain lacosamide.
6. The method according to claim 2 , wherein the yield of an R-configuration salt per the resolving reagent of 1MR is 81.0% or more.
7. The method according to claim 1 , wherein the acetylation process comprises:
(i) causing the salt obtained through the isomerization-crystallization process with an acetylating reagent in a solvent consisting of a mixed solvent of ethyl acetate and water, simple water, or an aqueous solution containing water at the concentration of 95 vol % or more in a presence of a base; or
(ii) causing the salt obtained through the isomerization-crystallization process with an acid and causing the obtained R-configuration N-benzyl-2-amino-3-methoxypropionamide to react with the acetylating reagent.