Methods for the synthesis of chiral kynurenine compounds
Inventors
Abele, Stefan • Laue, Klaus • BREITENMOSER, Roland A.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10294502-B2
Publication Date
2019-05-21
Expiration Date
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.
Core Innovation
The invention relates to large-scale synthetic methods for preparing chiral kynurenine compounds, including L-4-chlorokynurenine, and other compounds of Formula I and Formula Ia. The methods use a sequence of chemical transformations to generate an acylated kynurenine intermediate, followed by an enzyme-mediated step to obtain the chiral target.
The approach comprises acylating an aniline of Formula II with chloroacetonitrile using aluminum trihalide/boron trihalide to form an acylated aniline of Formula III. The method then includes alkylating with acetamido diethyl malonate to form a diethyl ester of Formula IV and decarboxylating to form the acylated kynurenine of Formula V.
The core chiral step is resolving the acylated kynurenine compound of Formula V, or a related acylated kynurenine acid intermediate of Formula Va, with an acylase enzyme to afford the compound of Formula I or Formula Ia. Enzyme-mediated resolution uses acylase I from Aspergillus melleus and is exemplified with disclosed production scale and quality outcomes including target chemical purity and enantiomeric excess.
Claims Coverage
The document contains two independent claims (clm-00001 and clm-00004). Both independent claims focus on preparing chiral kynurenine compounds by resolving an acylated kynurenine intermediate with an acylase enzyme, with the distinction being the specific acylated kynurenine starting material and the target Formula I vs Formula Ia.
Enzyme-mediated resolving of an acylated kynurenine intermediate with an acylase enzyme to afford Formula I
The method comprising the step of resolving the acylated kynurenine compound of Formula V with an acylase enzyme to afford the compound of Formula I.
Enzyme-mediated resolving of compound of Formula Va with an acylase enzyme to afford Formula Ia
The method comprising the step of resolving 2-acetylamino-4-(2-amino-4-chloro-phenyl)-4-oxo-butyric acid (compound of Formula Va) with an acylase enzyme to the compound of Formula Ia.
Overall, claim coverage centers on resolving an acylated kynurenine intermediate (Formula V or Formula Va) with an acylase enzyme to obtain the chiral kynurenine target (Formula I or Formula Ia), where dependent claims further specify acylase I from Aspergillus melleus and quality constraints such as chemical purity and/or enantiomeric excess.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
Interested in licensing this patent?