Methods for the synthesis of chiral kynurenine compounds
Inventors
Abele, Stefan • Laue, Klaus • BREITENMOSER, Roland A.
Assignees
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Publication Number
US-9834801-B2
Publication Date
2017-12-05
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 preparation of chiral kynurenine compounds of Formula I, including pharmaceutically acceptable salts, polymorphs, hydrates, solvates, tautomers, and stereoisomers, by an in-sequence chemistry route. The route acylates an aniline compound of Formula II with chloroacetonitrile in the presence of aluminum trihalide and boron trihalide to afford an acylated aniline of Formula III, followed by alkylation with acetamido diethyl malonate to form a diethyl ester of Formula IV. The method then decarboxylates the diethyl ester to afford an acylated kynurenine compound of Formula V.
The sequence continues with resolving the acylated kynurenine of Formula V with an acylase enzyme to afford the compound of Formula I. In the described embodiments, the acylase enzyme is acylase I from Aspergillus melleus, and the document targets production of high chemical purity and high chiral purity suitable for scale-up. The partial content indicates assessment of purity and enantiomeric excess for the produced compound of Formula I.
A corresponding in-sequence chemistry method is described for preparing a compound of Formula Ia, including its pharmaceutically acceptable salt, polymorph, hydrate, solvate, tautomer, or stereoisomer. The method acylates 3-chloroaniline (IIa) with chloroacetonitrile using aluminum trihalide and boron trihalide to afford I-(2-amino-4-chloro-phenyl)-2-chloro-ethanone (IIia), then alkylates IIia with acetamido diethyl malonate to afford the diethyl ester intermediate (IVa), followed by decarboxylation to the butyric acid derivative (Va). The resulting oxo-butyric acid derivative is then resolved with an acylase enzyme to afford Formula Ia.
Claims Coverage
The partial content includes two independent claims that cover two related targets (Formula I and Formula Ia) using the same in-sequence chemistry workflow with acylation, alkylation, decarboxylation, and acylase resolution. Across the dependent claims, inventive features are refined by specifying an acylase enzyme source and by adding production-scale thresholds and narrowed process conditions.
In-sequence acylation, alkylation, decarboxylation, and acylase resolution to prepare Formula I
A method of preparing a compound of Formula I, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, tautomer, or stereoisomer thereof by: acylating an aniline compound of Formula II with chloroacetonitrile in the presence of aluminum trihalide and boron trihalide to afford an acylated aniline of Formula III; alkylating the acylated aniline of Formula III with acetamido diethyl malonate to afford a diethyl ester of Formula IV; decarboxylating the diethyl ester of Formula IV to afford an acylated kynurenine of Formula V; and resolving the acylated kynurenine of Formula V with an acylase enzyme to afford the compound of Formula I.
In-sequence acylation, alkylation, decarboxylation, and acylase resolution to prepare Formula Ia
A method of preparing a compound of Formula Ia, or a pharmaceutically acceptable salt, polymorph, hydrate, solvate, tautomer, or stereoisomer thereof by: 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); alkylating 1-(2-amino-4-chloro-phenyl)-2-chloro-ethanone (IIia) with acetamido diethyl malonate to afford a diethyl ester compound (IVa); 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 resolving 2-acetylamino-4-(2-amino-4-chloro-phenyl)-4-oxo-butyric acid (Va) with an acylase enzyme to the compound of Formula Ia.
Using acylase I from Aspergillus melleus for resolution
The method is characterized in that resolving the acylated kynurenine compound (Formula V for Formula I, or Va for Formula Ia) is performed with acylase I from Aspergillus melleus.
Scale-up production threshold for Formula I
The method is specified such that producing at least 10 g, and further that producing at least 500 g, of the compound of Formula I.
Scale-up production threshold for Formula Ia
The method is specified such that producing at least 10 g of the compound of Formula Ia, and further that producing at least 500 g, of the compound of Formula Ia.
Acylation solvent and two-stage temperature staging
The acylation step is performed by adding chloroacetonitrile to a toluene solution containing the relevant aniline compound together with boron trihalide and aluminum trihalide at 0 to 10°C, and then heating to 55 to 60°C.
Using sodium iodide as the alkali metal salt in alkylation
The alkylation step is carried out using an alkali metal salt, preferably sodium iodide, as specified in the dependent claim language.
Overall, the claims cover preparation of chiral kynurenine compounds of Formula I and Formula Ia through a defined in-sequence workflow (acylation, alkylation, decarboxylation, and acylase resolution). The partial content further narrows key aspects by specifying acylase I from Aspergillus melleus, adding production-scale minimums, and including specified acylation staging and sodium iodide for the alkylation step.
Stated Advantages
Use of commercially available reagents.
Avoidance of highly toxic/reactive reagents and extensive purification.
Production of high chemical purity and high chiral purity with scale-up.
Documented Applications
Preparation of chiral kynurenine compounds, including L-4-chlorokynurenine (Formula I/Ia), at large scale.
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