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A kind of synthetic method of voriconazole intermediate

A synthesis method and voriconazole technology are applied in the field of synthesis of voriconazole intermediates, can solve problems such as being unfavorable to large-scale industrial production, and achieve the effects of eliminating danger, reducing the generation of impurity A, and mild and controllable reaction conditions

Active Publication Date: 2021-03-05
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] However, after zinc powder is in contact with air, it is relatively easy to oxidize. In the process of preparing zinc reagent, there are problems of initiation and activation. In the previous activated zinc powder technology, lead powder was mostly involved, and lead is a highly toxic metal. Elements are strictly controlled in the pharmaceutical process, which is not conducive to large-scale industrial production

Method used

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  • A kind of synthetic method of voriconazole intermediate
  • A kind of synthetic method of voriconazole intermediate
  • A kind of synthetic method of voriconazole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Under nitrogen protection, at 20±5°C, add THF (160g) and compound III (20g) into the flask, stir until dissolved, then add ZnCl 2 (13.6g), zinc powder (8.6g), dropwise the THF (160g) solution of iodine (2.0g) and compound IV (30g), after reacting for 3 hours, add dropwise acetic acid (5.6g) and water (160mL) The mixed solution was quenched, concentrated under reduced pressure, then added dichloromethane (208g), water (100mL), acetic acid (5.8g), stirred and left to separate layers, the aqueous layer was washed once with dichloromethane (110g), and the organic Mutually. The organic phase was washed with aqueous sodium bicarbonate solution, dried and concentrated, then hydrochloric acid was added dropwise to form a salt and crystallized to obtain a solid, which was dried under vacuum at 50°C to obtain (2R,3S / 2S,3R)-3-(6-chloro-5-fluoropyrimidine -4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride (24.5g, yield Rate 65.1%), the crude product l...

Embodiment 2

[0042] Under nitrogen protection, at 20±5°C, add THF (80g) and compound III (10g) into the flask, stir until dissolved, then add ZnCl 2 (6.8g), zinc powder (4.3g), dropwise the THF (80g) solution of iodine (2.0g) and compound IV (15g), after reacting 3 hours and finish, aftertreatment is the same as embodiment 1, obtains crude product (11.7g , yield 62.3%), liquid phase detection showed that the content of impurity A was 0.72%.

Embodiment 3

[0044] Under nitrogen protection, at 20±5°C, add THF (80g) and compound III (10g) into the flask, stir until dissolved, then add ZnCl 2 (6.8g), zinc powder (4.3g), dropwise the THF (80g) solution of iodine (1.0g) and compound IV (11.8g), after reacting 3 hours and finish, aftertreatment is the same as embodiment 1, obtains crude product (12.3 g, yield 65.3%), liquid phase detection showed that the content of impurity A was 0.72%.

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Abstract

The present invention provides a novel synthesis method of voriconazole intermediate condensate represented by formula II or its acid addition salt, which is prepared from compound formula III and formula IV. The feeding method is adjusted, and the reaction conditions are mild and controllable, reducing The formation of impurity A is controlled within 0.74%, while avoiding the use of highly toxic metal lead, eliminating the danger of highly toxic metal residues in the drug; making the product more pure and having great industrial application value .

Description

technical field [0001] The invention relates to a method for synthesizing an important intermediate condensate hydrochloride of voriconazole. Background technique [0002] Voriconazole (Voriconazole, VRC, UK109496) is a new type of antifungal drug synthesized by Pfizer based on fluconazole. It is mainly used for patients with progressive and fatal immunocompromised patients. Because voriconazole has a wide antifungal spectrum, strong antibacterial efficacy, and good safety, and the demand for antifungal drugs in the domestic market is growing rapidly, the market prospect is huge. [0003] Voriconazole, whose chemical name is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-tri Azol-1-yl)-2-butanol, the structural formula is as shown in formula I: [0004] [0005] As an important intermediate, voriconazole condensate has a chemical name: (2R,3S / 2S,3R)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06
CPCC07D403/06C07D239/30
Inventor 黄虎黄文锋涂国良刘节根徐中明吴强晖孟昭旸方玉玲
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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