# US 2021/0276942 A1 · Synthesis of 4-chlorokynurenines and intermediates

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- Number: US 2021/0276942 A1
- Document ID: US20210276942A1
- Status: Published application
- Kind: A1
- Application number: 16/967,627
- Filed: 2019-02-11
- Published: 2021-09-09
- Earliest claimed: 2018-02-09
- Assignees: Vistagen Therapeutics, Inc.
- Applicants: Vistagen Therapeutics, Inc.
- Inventors: Daniel LEVIN; Peter LEEMING; Emerich EISENREICH; Xuejun Karl LIU
- Web page: https://patentgrep.com/patent/US20210276942A1

## CPC

- C07C 227/18: by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C 227/16: by reactions not involving the amino or carboxyl groups
- C07C 227/20: by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
- C07C 227/32: by stereospecific synthesis
- C07C 227/40: Separation; Purification
- C07C 229/36: with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
- C07C 229/42: with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
- C07C 269/06: by reactions not involving the formation of carbamate groups
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 303/28: by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
- C07F 3/06: Zinc compounds
- C07B 2200/07: Optical isomers
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention relates to an overall enantio-specific synthesis of 4-chlorokynurenine compounds, in particular L-4-chlorokynurenine, with improved yields. Large-scale syntheses are disclosed. The invention also relates to novel intermediates in the synthesis of L-4-chlorokynurenine.

## Claims

### Claim 1

A method for the enantio-specific preparation of 4-chlorokynurenine (8) according to Scheme I,
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:
Step 1, reacting a protected serine ester (1) with toluenesulfonyl chloride under suitable reaction conditions to convert the protected serine ester to its corresponding tosylate (2),
Step 2, reacting the tosylate (2) 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 (3),
Step 3, 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,
optionally purifying the protected ester compound (6), and
Step 4, deprotecting the protected ester compound (6) in the absence of light under suitable reaction conditions to remove any protecting group PG, and, when R1 is NO2, reducing the NO2 group to an NH2 group, to form the ester (7), and deprotecting the ester (7) in the absence of light without exposure to air under suitable reaction conditions to form 4-chlorokynurenine (8) after adjustment to an acidic pH, wherein the deprotecting and reducing reactions are done in a single step or in multiple steps.

### Claim 2 (depends on 1)

A method of claim 1, further comprising at least one of the following:
in Step 1, the presence of a catalytic amount of 4-dimethylaminopyridine and, optionally isolating and recrystallizing the tosylate (2);
in Step 2, an aqueous quench of the reaction mixture into water to precipitate the iodo intermediate (3) and, optionally, recrystallization of the iodo intermediate (3);
in Step 3, the palladium (0) catalyst [Pd] is Pd(0) tetrakis and with a CO pressure ranging from 1 psig to 1,000 psig; and
in Step 4, deprotecting the protected ester compound (6) to remove any protecting group PG using HCl in dioxane and isolating the ester (7) in the absence of light without exposure to air or moisture and, in a separate deprotection step, hydrolyzing (7) at a pH of 12.0 to 12.5 to form 4-chlorokynurenine (8) after adjustment to an acidic pH.

### Claim 3 (depends on 1)

A method of claim 1, further comprising the steps of:
as the pH adjustment, isolating the 4-chlorokynurenine (8) from alkaline solution as a fee acid with aqueous acid to a pH below 6.5,
dissolving the isolated free acid (8) in aqueous acid at a pH below 2,
precipitating the free acid (8) by adjusting the pH of 4.5 to 6.5,
collecting the precipitated free acid (8),
drying the collected free acid (8), and
optionally, triturating the collected free acid (8) using an organic solvent or an organic solvent mixture and drying the triturated free acid (8).

### Claim 4 (depends on 1)

A method of claim 1, wherein
R is a C1-C6 alkyl group;
PG is an amine protecting group selected from BOC, Fmoc, Benzyl, Benzoyl, alkylamine, arylamine, TFA, and CBz; and
X is I.

### Claim 5 (depends on 4)

A method of claim 4, wherein
R is a methyl group,
PG is the amino protecting group BOC, and
X is I.

### Claim 6

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.

### Claim 7 (depends on 6)

A method of claim 6, further comprising at least one of the following:
in Step 1, the presence of a catalytic amount of 4-dimethylaminopyridine and, optionally isolating and recrystallizing the tosylate (2a);
in Step 2, an aqueous quench of the reaction mixture into water to precipitate the iodo intermediate (3a) and, optionally, recrystallization of the iodo intermediate (3a);
in Step 3, the palladium (0) catalyst [Pd] is Pd(0) tetrakis with a CO pressure ranging from 1 psig to 1,000 psig; and
in Step 4, deprotecting the BOC protected ester compound (6a) using HCl in dioxane and isolating the methyl ester (7a) in the absence of light without exposure of the isolated solids to air or moisture and, in a deprotection separate step, hydrolyzing (7a) with aqueous base selected from NaOH, KOH, and LiOH.

### Claim 8 (depends on 6)

A method of claim 6, further comprising the steps of:
as the pH adjustment, isolating the L-4chlorokynurenine (8a) from alkaline solution as a fee acid with aqueous acid to a pH below 6.5,
dissolving the isolated free acid (8a) in aqueous acid at a pH below 2,
precipitating the free acid (8a) by adjusting the pH of 4.5 to 6.5
collecting the precipitated free acid (8a),
drying the collected free acid (8a), and
optionally, triturating the collected free acid (8a) using an organic solvent or an organic solvent mixture and drying the triturated free acid (8a).

### Claim 9

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).

### Claim 10 (depends on 9)

A method of claim 9, wherein the palladium (0) catalyst [Pd] is Pd(0) tetrakis and with a CO pressure ranging from 1 psig to 1,000 psig.

### Claim 11

A method of preparing a compound 6a from a compound 3a
comprising the steps of:
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, and
optionally purifying the protected ester compound (6a).

### Claim 12 (depends on 11)

A method of claim 11, wherein the palladium (0) catalyst [Pd] is Pd(0) tetrakis and with a CO pressure ranging from 1 psig to 1,000 psig.

### Claim 13

A compound of the formula:

### Claim 14

A compound of the formula:
or an acid addition salt thereof.

### Claim 15 (depends on 14)

A compound of claim 14, wherein the acid addition salt is a di-HCl salt.

### Claim 16

A method for the preparation of L-4-chlorokynurenine (8a) from a compound (6a)
comprising the steps of:
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.

### Claim 17 (depends on 15)

A method of claim 15, wherein the deprotection steps comprise
deprotecting the BOC protected ester compound (6a) using HCl in dioxane and isolating the methyl ester (7a) in the absence of light without exposure of the isolated solids to air or moisture and, in a deprotection separate step, hydrolyzing (7a) with aqueous base selected from LiOH, NaOH, and KOH, at a pH of 12.0 to 12.5 to form L-4-chlorokynurenine (8a) after adjustment to an acidic pH.

### Claim 18 (depends on 16)

A method of claim 16, further comprising the steps of:
isolating the free acid (8a) from alkaline solution by pH adjustment with aqueous HCl to a pH of 4.8 to 6.0,
dissolving the isolated free acid (8a) in aqueous acid at a pH of 0.5 to 0.9,
precipitating the free acid (8a) by adjusting the pH to a pH of 4.8 to 6.0,
collecting the precipitated free acid (8a), and
drying the collected free acid (8a).

### Claim 19 (depends on 6)

A method of claim 6, wherein the L-4-chlorokynurenine (8a)
prepared has a chiral purity of ≤0.5% of D-4-chlorokynurenine.