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Preparation method for voriconazole and voriconazole intermediate

A technology of voriconazole and intermediates, which is applied in the field of preparation of voriconazole and its intermediates, can solve the problems of being unable to meet the requirements of industrial production cost control, unable to greatly improve the utilization rate of raw and auxiliary materials, expensive transition metal catalysts, etc., and achieve easy scale The effect of industrial production, low cost, and short synthesis steps

Inactive Publication Date: 2019-05-03
ZHEJIANG HUAHAI LICHENG PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Another existing technology such as CN1919846A and CN103788073 is by adding a transition metal catalyst and a chiral ligand (reagent) in the condensation process to carry out an asymmetric induction reaction, but there are also the following problems at present. One is that the asymmetric synthesis needs to use When it comes to transition metal catalysts that are expensive and difficult to obtain in large quantities, this method is still in the stage of small-scale preparation of voriconazole samples in the laboratory, which cannot meet the requirements of industrial production for cost control
Second, due to the selectivity problem of asymmetric synthesis, the improvement range is limited, and the content of isomer impurities in the product still occupies a certain proportion, so the final subsequent purification still needs to be resolved.
[0010] To sum up, voriconazole or its intermediate compound 2 is prepared according to the prior art method. Due to the limitation of theory and large-scale production on cost control, although some parameters can be optimized, the utilization rate of raw materials and auxiliary materials cannot be greatly improved in the process of industrial production.

Method used

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  • Preparation method for voriconazole and voriconazole intermediate
  • Preparation method for voriconazole and voriconazole intermediate
  • Preparation method for voriconazole and voriconazole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of 4-chloro-6-ethyl-5-fluoropyrimidine and 2'4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone

[0032] Add 38.3 g of 2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1,2,4-triazol-1-yl)butan- 2-alcohol (configuration 2S, 3S / 2R, 3R, containing a small amount of 2R, 3S / 2S, 3R), in 500ml of 1mol / L dilute hydrochloric acid, heat up to 60-70°C for 6-7 hours, and the reaction is over After cooling down to 0°C, adjust the pH value to 7-8 with ionic membrane liquid alkali, extract with dichloromethane to obtain a mixture of compound 3 and compound 4, and distill under reduced pressure to obtain 22g of compound 4 with a purity of 92% and a yield of 98.7% . The collected fractions were subjected to atmospheric distillation to remove the solvent, and then vacuum distillation to obtain 14.2 g of compound 3 with a purity of 99.1% and a yield of 88.4%.

Embodiment 2

[0034] Preparation of 4-chloro-6-ethyl-5-fluoropyrimidine and 2'4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone

[0035] Add 38.3 g of 2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1,2,4-triazol-1-yl)butan- 2-alcohol (configuration 2S, 3S / 2R, 3R, containing a small amount of 2R, 3S / 2S, 3R), in 380ml 3mol / L sulfuric acid, heat up to 40-50°C for 10 hours, cool down to room temperature after the reaction , ionic membrane liquid base to adjust the pH value to 7-8, extracted with ethyl acetate to obtain a mixture of compound 3 and compound 4, and concentrated to obtain 21 g of compound 4 with a purity of 90% and a yield of 94.2%. The collected fractions were subjected to atmospheric distillation to remove the solvent, and then vacuum distillation to obtain 13.6 g of compound 3 with a purity of 99.0% and a yield of 84.6%.

Embodiment 3

[0037] Preparation of 4-chloro-6-ethyl-5-fluoropyrimidine and 2'4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone

[0038] Add 38.3 g of 2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1,2,4-triazol-1-yl)butan- 2-alcohol (configuration 2S, 3S / 2R, 3R, with a small amount of 2R, 3S / 2S, 3R), add 380ml dioxane, 11.5g trifluoroacetic acid, heat up to 70-90°C for 3-5 hours After the reaction was completed, the temperature was lowered to room temperature, and the pH value was adjusted to 7-8 by ion-exchange membrane liquid alkali. The mixture of compound 3 and compound 4 was obtained by extraction with dichloromethane, and concentrated to obtain 20 g of compound 4 with a purity of 91% and a yield of 89.6%. The collected fractions were subjected to atmospheric distillation to remove the solvent, and then vacuum distillation to obtain 13.7 g of compound 3 with a purity of 99.3% and a yield of 85.3%.

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Abstract

The invention discloses a preparation method for voriconazole and a voriconazole intermediate. According to the invention, with a voriconazole condensate isomer as a raw material, 4-chloro-6-ethyl-5-fluoropyrimidine and 2'4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone are obtained through recovery under an acidic condition, and can be further used for preparation of the voriconazole. By adoption of the method provided by the invention, the utilization rates of raw and auxiliary materials for preparation of the voriconazole in the prior art can be greatly improved; and cost is reduced.

Description

technical field [0001] The invention relates to a preparation method of voriconazole and an intermediate thereof, belonging to the technical field of medicine. Background technique [0002] The chemical name of voriconazole is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidine)-1-(1H-1,2,4-triazole-1 -base)-2-butanol, its chemical formula is as follows: [0003] [0004] Voriconazole is a broad-spectrum triazole antifungal indicated for the following: treatment of invasive aspergillosis; treatment of severe invasive infections caused by fluconazole-resistant Candida species (including Candida krusei); treatment of Serious infections caused by Actinomycetes and Fusarium species; [0005] The methods for preparing voriconazole reported in the literature mainly consist of two approaches, one of which is to prepare the (2R,3S / 2S,3R) racemate first, and then split it. The second route is direct preparation by asymmetric condensation using chiral reagents (catalysts or ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D249/10C07D239/30
CPCC07D403/06C07D239/30C07D249/08
Inventor 周文祥黄文锋胡佳兴
Owner ZHEJIANG HUAHAI LICHENG PHARMA CO LTD
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