Synthesis of 4-chlorokynurenines and intermediates

A method for the preparation of L-4-chlorokynurenine (8a) according to Scheme

• wherein Ts is a tosyl group and comprising the steps of:
• Step 1, reacting a BOC-L-serine methyl methyl ester (1a) with 1 to 2 molar equivalents of toluenesulfonyl chloride under suitable reaction conditions to convert the BOC-L-serine methyl ester (1a) to its corresponding tosylate (2a),
• Step 2, reacting the tosylate (2a) with sodium iodide or potassium iodide under an inert atmosphere in the absence of light under suitable reaction conditions to replace the tosyl group with iodide and form the corresponding iodo intermediate (3a),
• Step 3, converting the iodo intermediate (3a) in situ to a zinc reagent (4a) in the absence of light under suitable reaction conditions and forming a BOC-protected methyl ester compound (6a) via a carbonylation reaction and reacting the zinc reagent (4a) with a 5-chloro-iodo aniline compound (5a) in the presence of a palladium (0) catalyst [Pd] and while maintaining a sustained dissolved CO concentration either by continuous subsurface CO addition and/or CO pressure,
• optionally purifying the protected ester compound (6a), and
• Step 4, deprotecting the BOC protected ester compound (6a) in the absence of light under suitable reaction conditions to remove the protecting group to form the methyl ester (7a) taking precautions to avoid exposing the isolated solids to air or moisture, and then deprotecting the methyl ester (7a) in the absence of light without exposure to air under suitable reaction conditions to form 4-chlorokynurenine (8a) after adjustment to an acidic pH, wherein the deprotecting reactions are done in a single step or in two steps.

A method of preparing a compound 6 from a compound 3

• wherein
• R is a C1-C12 alkyl group, a C1-C12 alk-aryl group, an aryl group, or a heteroaryl group;
• * indicates an asymmetric carbon which may be a single enantiomer or a mixtures of enantiomers which is maintained throughout;
• PG is an amino protecting group;
• Ts is a tosyl group;
• R1 is NH2, NH(PG) or NO2;
• and
• X is Cl, Br, I, triflate or tosylate;
• and
• comprising the steps of:
• converting the iodo intermediate (3) in situ to a zinc reagent (4) in the absence of light under suitable reaction conditions and forming a protected ester compound (6) via a carbonylation reaction reacting the zinc reagent (4) with a compound (5) in the presence of a palladium (0) catalyst [Pd] under suitable reaction conditions and while maintaining a sustained dissolved CO concentration either by continuous subsurface CO addition and/or CO pressure, and
• optionally purifying the protected ester compound (6).