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US 9,834,801 B2Granted
Methods for the synthesis of chiral kynurenine compounds
AssigneeVistagen Therapeutics, Inc.
InventorsStefan Abele, Klaus Laue, Roland A. Breitenmoser
Life of this patent
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Abstract
Provided are methods for synthesizing compounds, including chiral kynurenine compounds. The methods are suitable for large-scale manufacture and produce the chiral kynurenines compounds in high chemical purity and high chiral purity.
Claims16
A method of preparing a compound of Formula I or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, tautomer, or stereoisomer thereof:
- wherein each R is independently selected from the group consisting of hydrogen, halogen, alkyl, and substituted alkyl;
- and
- wherein n=0-4;
- the method comprising:
- a) acylating an aniline compound of Formula II with chloroacetonitrile in the presence of aluminum trihalide and boron trihalide to afford an acylated aniline compound of Formula III:
- b) alkylating the acylated aniline compound of Formula III with acetamido diethyl malonate to afford a diethyl ester compound of Formula IV:
- c) decarboxylating the diethyl ester compound of Formula IV to afford an acylated kynurenine compound of Formula V:
- and
- d) resolving the acylated kynurenine compound of Form an acylase enzyme to afford the compound of Formula I:
6 more elements
A method of preparing a compound of Formula Ia or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, tautomer, or stereoisomer thereof:
- the method comprising:
- a) acylating 3-chloroaniline (IIa) with chloroacetonitrile in the presence of aluminum trihalide and boron trihalide to afford I-(2-amino-4-chloro-phenyl)-2-chloro-ethanone (IIia):
- b) alkylating 1-(2-amino-4-chloro-phenyl)-2-chloro-ethanone (IIia) with acetamido diethyl malonate to afford 2-acetylamino-2-[2-(2-amino-4-chloro-phenyl)-2-oxo-ethyl]-malonic acid diethyl ester (IV a):
- c) decarboxylating 2-acetylamino-2-[2-(2-amino-4-chloro-phenyl)-2-oxo-ethyl]-malonic acid diethyl ester (IVa) to afford 2-acetylamino-4-(2-amino-4-chloro-phenyl)-4-butyric acid (Va):
- and
- d) resolving 2-acetylamino-4-(2-amino-4-chloro-phenyl)-4-oxo-butyric acid (Va) with an acylase enzyme to the compound of Formula Ia:
3 more elements
Dependencies are inferred from the claim text.