# US 2021/0276980 A1 · Method for preparing voriconazole l-camphorsulphonate and voriconazole

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- Number: US 2021/0276980 A1
- Document ID: US20210276980A1
- Status: Published application
- Kind: A1
- Application number: 16/330,692
- Filed: 2016-11-10
- Published: 2021-09-09
- Earliest claimed: 2016-09-08
- Assignees: Zhejiang Huahai Pharmaceutical Co., Ltd.
- Applicants: Zhejiang Huahai Pharmaceutical Co. Ltd.
- Inventors: Hu Huang; Wenfeng Huang; Guoliang Tu; Zhongming Xu; Qianghui Wu; Zhaoyang Meng; Yuling Fang
- Web page: https://patentgrep.com/patent/US20210276980A1

## CPC

- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07C 303/22: from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; {from sulfonic halides by reactions not involving the formation of halosulfonyl groups}
- C07C 309/19: of a saturated carbon skeleton containing rings
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07C 2603/66: containing five-membered rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

A method for preparing voriconazole L-camphorsulphonate and voriconazole. The method for preparing voriconazole L-camphorsulphonate comprises: method 1: dissolving (2R,3S)/(2S,3R) isomer mixture and L-camphor sulphonic acid in water and acetone, and performing crystallisation filtration to obtain voriconazole L-camphorsulphonate; method 2: (a) dissolving a mixture of isomer mixture and L-camphor sulphonic acid in a first solvent and then performing crystallisation filtration; or (a′) dissolving L-camphorsulphonate of the isomer mixture in a first solvent and then performing crystallisation filtration; (b) concentrating the filtrate obtained in step (a) or (a′) into a solid; and (c) dissolving the solid obtained in step (b) in a second solvent and performing crystallisation filtration to obtain voriconazole L-camphorsulphonate. Adjusting the resolution solvent effectively reduces production costs and facilitates recycling of the resolution solvent.

## Claims

### Claim 1

A method for preparing voriconazole L-camphorsulfonate, comprising:
Method 1: dissolving a mixture of (2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol and L-camphorsulfonic acid in a mixed solvent of water and acetone, cooling and crystallizing, and filtering to obtain a crystal of voriconazole L-camphorsulfonate;
Method 2: (a) dissolving a mixture of (2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol and L-camphorsulfonic acid in a first solvent, crystallizing, and filtering to remove a crystal enriched with L-camphorsulfonate of (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol; or
(a′) dissolving a mixture of L-camphorsulfonate of (2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol in a first solvent, crystallizing, and filtering to remove a crystal enriched with L-camphorsulfonate of (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol;
(b) concentrating a filtrate obtained in step (a) or (a′) to dryness to obtain a solid; and
(c) dissolving the solid obtained in step (b) in a second solvent and crystallizing to obtain L-camphorsulfonate of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the first solvent is selected from the group consisting of a mixture of C4-C8 ketone solvent and water, isopropanol and ethanol.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the second solvent is selected from the group consisting of a mixed solvent of acetone and water, or a mixed solvent of methanol and acetone.

### Claim 4 (depends on 1)

The method according to claim 1, wherein a volume ratio of the C4-C8 ketone solvent to water is 100:1 to 1:100.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the C4-C8 ketone solvent is butanone, methyl isobutyl ketone or methyl butanone.

### Claim 6 (depends on 5)

The method according to claim 5, wherein a temperature of crystallization in step (a) or (a′) is 0°.

### Claim 7 (depends on 1)

The method according to claim 1, wherein a volume ratio of acetone to water is 100:1 to 1:100.

### Claim 8 (depends on 1)

The method according to claim 1, wherein acetone and water in the method 1 or the second solvent in the method 2 is used in an amount of 10 mL/g to 30 mL/g, with respect to the mixture of (2R,3S)/(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

### Claim 9 (depends on 1)

The method according to claim 1, wherein a temperature of crystallization in the method 1 or in step (c) of the method 2 is 0° C. to 40° C.

### Claim 10 (depends on 1)

A method for preparing voriconazole, comprising adding a base to voriconazole L-camphorsulfonate prepared by the method according to claim 1 to obtain voriconazole.

### Claim 11

A crystal enriched with L-camphorsulfonate of (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, wherein a ratio of L-camphorsulfonate of (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol to L-camphorsulfonate of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol in the crystal is greater than 1.

### Claim 12 (depends on 4)

The method according to claim 4, wherein the volume ratio of the C4-C8 ketone solvent to water is 50:1 to 5:1.

### Claim 13 (depends on 4)

The method according to claim 4, wherein the volume ratio of the C4-C8 ketone solvent to water is 25:1 to 10:1.

### Claim 14 (depends on 6)

The method according to claim 6, wherein the temperature of crystallization in step (a) or (a′) is 15° C. to 25° C.

### Claim 15 (depends on 7)

The method according to claim 7, wherein the volume ratio of acetone to water is 15:1 to 5:1.

### Claim 16 (depends on 8)

The method according to claim 8, wherein acetone and water in the method 1 or the second solvent in the method 2 is used in an amount of 10 mL/g to 15 mL/g, with respect to the mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol and (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

### Claim 17 (depends on 9)

The method according to claim 9, wherein the temperature of crystallization in the method 1 or in step (c) of the method 2 is 15° C. to 30° C.

### Claim 18 (depends on 11)

The crystal according to claim 11, wherein the ratio of L-camphorsulfonate of (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol to L-camphorsulfonate of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol in the crystal is greater than 5.

### Claim 19 (depends on 11)

The crystal according to claim 11, wherein the L-camphorsulfonate of (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol in the crystal has a purity greater than 90%.

### Claim 20 (depends on 11)

The crystal according to claim 11, wherein the L-camphorsulfonate of (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol in the crystal has a purity greater than 98%.