A method for resolving voriconazole enantiomeric pair B

Abstract

The present invention relates to a method for resolving the enantiomeric pair B of voriconazole. A method for preparing a resolving salt from the enantiomeric pair B of voriconazole, which comprises dissolving L-di-p-toluoyl tartaric acid (L-DTTA) and the enantiomeric pair B of voriconazole in a mixed solvent of ethyl acetate and acetone, heating to 60-65 °C to obtain a clear solution, and stepwise cooling and crystallizing to obtain the resolving salt. The resolving reagent of the present invention is inexpensive and easily available, the resolving method is simple to operate, and only one resolution is required to make the enantiomeric impurity (2S,3R) of voriconazole meet the quality requirements, and the product yield is as high as over 45%, with good optical purity, and has great industrial production value.

Description

Technical Field

[0001] The present invention relates to a method for resolving the enantiomeric pair B of voriconazole by a chemical method, and further obtaining a resolved salt of voriconazole. Background Art

[0002] Voriconazole, with the chemical name of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, is a triazole antifungal drug launched by Pfizer in the United States in August 2002. It is one of the most effective drugs for treating severe fungal infections such as aspergillus in clinical practice, and it is also the only drug with single optical activity among current antifungal drugs.

[0003] Patent WO97 / 06160 reports that four optically active products, namely the enantiomeric pair A (2R,3R / 2S,3S) and the enantiomeric pair B (2R,3S / 2S,3R), are obtained by nucleophilic addition of the triazole intermediate 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone. Among them, the content of the enantiomeric pair B (2R,3S / 2S,3R) accounts for more than 90%. Recrystallization with isopropanol causes the enantiomeric pair B (2R,3S / 2S,3R) with a higher concentration to precipitate, and then it is resolved with L-(-)-10-camphorsulfonic acid in a mixed solvent of methanol and acetone, followed by alkaline hydrolysis and purification with isopropanol to obtain voriconazole (Formula I). However, through multiple experiments, it is found that the optical purity of the obtained resolved salt is not high, ee% ≤ 98.0%. Therefore, it must be resolved multiple times to meet the requirement of optical purity (ee% ≥ 99.0%). As a result, a large amount of reagents and solvents will be wasted, leading to a relatively high production cost. Moreover, the operation is cumbersome and multi-step, and the yield also fails to reach 39% reported in the literature.

[0004]

[0005] Patent WO97 / 06160 reports the reaction formula for resolving the enantiomeric pair B of voriconazole as follows:

[0006] Summary of the Invention

[0007] In order to solve the deficiencies of the prior art, the present invention uses L-di-p-toluoyl tartaric acid (L-DTTA) as a resolving agent, and resolves the enantiomeric pair B of voriconazole once by fractional crystallization in a mixed solvent of ethyl acetate and acetone in a certain proportion. The yield of the obtained resolved salt is above 45%, and the product has high optical purity, ee% ≥ 99.5% (HPLC). This method has simple operation, high yield, good product purity, and is conducive to industrial production.

[0008] The object of the present invention is achieved by the following technical solutions:

[0009] A method for preparing a resolution salt from voriconazole enantiomeric pair B, comprising the following steps:

[0010] Dissolve L-ditoluoyl tartaric acid (L-DTTA) and voriconazole enantiomeric pair B in a mixed solvent of ethyl acetate and acetone, heat to 60-65 °C to obtain a clear solution, and crystallize by stepwise cooling to obtain the resolution salt.

[0011] According to the preparation method of the present invention, the molar ratio of voriconazole enantiomeric pair B to L-ditoluoyl tartaric acid (L-DTTA) is 1:0.1 to 1:2, preferably 1:0.5 to 1:1.

[0012] According to the preparation method of the present invention, the volume ratio of ethyl acetate to acetone is 1:2.0 to 2.0:1, preferably 1:1.2 to 1.2:1. The usage amount of the mixed solvent relative to voriconazole enantiomeric pair B is 20-100 ml / g, preferably 20-30 ml / g.

[0013] According to the preparation method of the present invention, the specific process of stepwise cooling crystallization is as follows: keep warm at 50-55 °C for 1-1.5 hours, cool down to 40-45 °C and keep warm for 1.5-2 hours, cool down to 20-25 °C and keep warm for 3-4 hours, and cool down to 0-5 °C and keep warm for 6-7 hours.

[0014] According to the preparation method of the present invention, the resolution salt is subjected to post-treatment steps of filtration and washing. Preferably, it is washed with a mixed solution of ethyl acetate and acetone.

[0015] The present invention also provides a method for preparing voriconazole, which comprises the above steps of preparing the resolution salt.

[0016] According to the preparation method of the present invention, the resolution salt is free of alkali to obtain voriconazole.

[0017] According to the preparation method of the present invention, the resolution salt is dissolved in water, the pH is adjusted to 11-13 with an alkali solution, extracted with dichloromethane, the organic phase is distilled under reduced pressure, the residue is dissolved in isopropanol, and voriconazole is obtained by cooling crystallization.

[0018] In the present invention, the reaction formula for preparing the voriconazole resolution salt by resolving voriconazole enantiomeric pair B with L-ditoluoyl tartaric acid (L-DTTA) is as follows:

[0019]

[0020] Beneficial effects:

[0021] The preparation method of the present invention uses L-di-p-toluoyl tartaric acid (L-DTTA) as a resolving agent, and obtains the resolved salt by holding and crystallizing at different temperatures in a mixed solvent of ethyl acetate and acetone. The resolving agent is inexpensive and easily available, and the resolution method is simple to operate. Only one resolution is required to make the enantiomeric impurity (2S,3R) of voriconazole meet the quality requirements (not exceeding 0.5%), and the product yield is as high as over 45%, with good optical purity (ee%≥99.5%), which has great industrial production value. Specific Embodiments

[0022] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only for illustrative and explanatory purposes of the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0023] The experimental methods used in the following embodiments are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the following embodiments can be obtained from commercial sources unless otherwise specified.

[0024] The voriconazole enantiomeric pair B used in the embodiments of the present invention can be purchased and obtained, which exists in a racemic form. Theoretically, the content ratio of voriconazole (2R,3S) to the enantiomeric impurity (2S,3R) is 1:1.

[0025] Example 1

[0026] Take 20 g (0.057 mol) of voriconazole enantiomeric pair B and 11 g (0.028 mol) of L-di-p-toluoyl tartaric acid (L-DTTA), add them to 400 ml of a mixed solvent of ethyl acetate and acetone (1:1), heat up to 60-65 °C and stir to obtain a clear solution, cool down to 50-55 °C and hold for 1-1.5 hours, cool down to 40-45 °C and hold for 1.5-2 hours, cool down to 20-25 °C and hold for 3-4 hours, cool down to 5-10 °C and hold for 6-7 hours, filter to obtain the resolved salt, and detect by HPLC, ee% = 99.8%, yield = 46.9%.

[0027] Dissolve the resolved salt in 250 ml of purified water, adjust the pH to 11 - 13 with 20% sodium hydroxide solution, extract with dichloromethane (220 ml × 2), concentrate the extract (dichloromethane) under reduced pressure to dryness, add 150 ml of isopropanol, heat to 75 ± 5 °C and stir for 15 - 20 minutes, distill off about 1 / 2 of the solvent under reduced pressure, cool the residue to 0 - 5 °C and stir for 4 - 6 hours, filter, and dry to obtain the target compound I. Purity (HPLC): 99.67%, content of enantiomer (2S,3R) (HPLC): 0.08%, yield: 95.6%.

[0028] Example 2

[0029] Take 20 g (0.057 mol) of voriconazole enantiomeric pair B and 16.5 g (0.043 mol) of L - di - p - methylbenzoyl tartaric acid (L - DTTA), add them to a mixed solvent of 400 ml of ethyl acetate and acetone (1:1), heat to 60 - 65 °C and stir until dissolved clearly, cool to 50 - 55 °C and keep for 1 - 1.5 hours, cool to 40 - 45 °C and keep for 1.5 - 2 hours, cool to 20 - 25 °C and keep for 3 - 4 hours, cool to 5 - 10 °C and stir for crystallization for 6 - 7 hours, filter to obtain the resolved salt, detected by HPLC, ee% = 99.62%, yield = 45.6%.

[0030] Example 3

[0031] Take 20 g (0.057 mol) of voriconazole enantiomeric pair B and 22 g (0.057 mol) of L - di - p - methylbenzoyl tartaric acid (L - DTTA), add them to a mixed solvent of 400 ml of ethyl acetate and acetone (1:1), heat to 60 - 65 °C and stir until dissolved clearly, cool to 50 - 55 °C and keep for 1 - 1.5 hours, cool to 40 - 45 °C and keep for 1.5 - 2 hours, cool to 20 - 25 °C and keep for 3 - 4 hours, cool to 5 - 10 °C and stir for crystallization for 6 - 7 hours, filter to obtain the resolved salt, detected by HPLC, ee% = 99.67%, yield = 46.2%.

[0032] Example 4

[0033] Take 20 g (0.057 mol) of voriconazole enantiomeric pair B and 11 g (0.028 mol) of L - di - p - methylbenzoyl tartaric acid (L - DTTA), add them to a mixed solvent of 600 ml of ethyl acetate and acetone (1:1), heat to 60 - 65 °C and stir until dissolved clearly, cool to 50 - 55 °C and keep for 1 - 1.5 hours, cool to 40 - 45 °C and keep for 1.5 - 2 hours, cool to 20 - 25 °C and keep for 3 - 4 hours, cool to 5 - 10 °C and keep for 6 - 7 hours, filter to obtain the resolved salt, detected by HPLC, ee% = 99.8%, yield = 46.3%

[0034] Comparative Example 1

[0035] Take 20 g (0.057 mol) of voriconazole enantiomeric pair B and dissolve it in 450 ml of acetone. Add a methanol solution of L-(-)-camphorsulfonic acid [13.3 g (0.057 mol) of L-(-)-camphorsulfonic acid dissolved in 150 ml of methanol]. Heat under reflux to obtain a homogeneous solution. Cool to 20 °C and stir to crystallize overnight. Filter, wash with acetone to obtain the resolution salt. Detect by HPLC, ee% = 96.6%, yield = 35.5%.

[0036] Comparative Example 2

[0037] Take 20 g (0.057 mol) of voriconazole enantiomeric pair B and dissolve it in 450 ml of acetone. Add a methanol solution of L-di-p-toluoyl tartaric acid (L-DTTA) [22 g (0.057 mol) of L-di-p-toluoyl tartaric acid (L-DTTA) dissolved in 150 ml of methanol]. Heat under reflux to obtain a homogeneous solution. Cool to 20 °C and stir to crystallize overnight. Filter, wash with acetone to obtain the resolution salt. Detect by HPLC, ee% = 95.4%, yield = 26.5%.

[0038] Comparative Example 3

[0039] Take 20 g (0.057 mol) of voriconazole enantiomeric pair B and 22 g (0.057 mol) of L-di-p-toluoyl tartaric acid (L-DTTA) and add them to a mixed solvent of 400 ml of ethyl acetate and acetone (1:1). Heat to 60 - 65 °C and stir until dissolved clearly. Cool to 20 °C and stir to crystallize overnight. Filter, wash with a mixed solvent of ethyl acetate and acetone (1:1) to obtain the resolution salt. Detect by HPLC, ee% = 96.5%, yield = 34.3%.

[0040] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing a resolution salt from voriconazole enantiomeric pair B, which comprises the following steps: dissolving L-ditoluoyl tartaric acid (L-DTTA) and voriconazole enantiomeric pair B in a mixed solvent of ethyl acetate and acetone, heating to 60-65 °C to obtain a clear solution, and stepwise cooling for crystallization to obtain the resolution salt; The volume ratio of the ethyl acetate to the acetone is 1:1.2-1.2:1; The specific process of the stepwise cooling for crystallization is as follows: keep the temperature at 50-55 °C for 1-1.5 hours, cool down to 40-45 °C and keep the temperature for 1.5-2 hours, cool down to 20-25 °C and keep the temperature for 3-4 hours, and cool down to 0-5 °C and keep the temperature for 6-7 hours.

2. The method for preparing a resolution salt according to claim 1, wherein the molar ratio of voriconazole enantiomeric pair B to L-ditoluoyl tartaric acid (L-DTTA) is 1:0.1-1:

2.

3. The method for preparing a resolution salt according to claim 1, wherein the usage amount of the mixed solvent is 20-100 ml / g relative to voriconazole enantiomeric pair B.

4. The method for preparing a resolution salt according to claim 1, wherein the resolution salt is subjected to post-treatment steps of filtration and washing.

5. The method for preparing a resolution salt according to claim 4, wherein a mixed solution of ethyl acetate and acetone is used for washing.

6. A method for preparing voriconazole, which comprises the method for preparing a resolution salt according to any one of claims 1-5.

7. The preparation method according to claim 6, wherein the resolution salt is free of alkali to obtain voriconazole.

8. The preparation method according to claim 6, wherein the resolution salt is dissolved in water, the pH value is adjusted to 11-13 with an alkali solution, extracted with dichloromethane, the organic phase is distilled under reduced pressure, the residue is dissolved in isopropanol, and cooled for crystallization to obtain voriconazole.

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