A kind of purification method of voriconazole

A voriconazole and purification method technology, applied in the field of voriconazole purification, can solve the problems of increasing process operation steps and production costs, unstable ee value of levocamphorsulfonate, voriconazole is difficult to meet medical needs, etc., to reduce process costs , few process factors and low cost

Active Publication Date: 2020-12-18
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, the ee value of the left-handed camphorsulfonate obtained by the prior art is unstable (the ee value of the left-handed camphorsulfonate in the patent CN106432198A is 99.3% to 99.8%). The free voriconazole is difficult to meet the medicinal needs. If the ee value of the product needs to be further improved, it is necessary to dissociate the levocamphorsulfonate and then split it
Causes a large loss of yield, increases process operation steps and production cost

Method used

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  • A kind of purification method of voriconazole
  • A kind of purification method of voriconazole
  • A kind of purification method of voriconazole

Examples

Experimental program
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Effect test

Embodiment 1

[0045]Voriconazole L-camphorsulfonate 109g, ee value 71.90%, add 1090g water, 2014g dichloromethane, cool to 0-10°C, adjust pH=10.52 with 10wt% NaOH aqueous solution. Liquid separation. The methylene chloride layer was washed with 3*545g of water, separated liquids, and spin-dried to obtain 64.6g of crude voriconazole. Add 290g of tert-butyl methyl ether to the crude voriconazole, heat to 50°C, stir for 2.5h, lower the temperature to 0-10°C, filter, and dry to obtain 62.5g of voriconazole. ee%=99.96%, and the yield is 96.7%.

Embodiment 2

[0047] 120 g of voriconazole L-camphorsulfonate, ee value 73.78%, add 1200 g of water and 2500 g of dichloromethane, cool to 0-10°C, adjust pH=10.71 with 10wt% NaOH aqueous solution. Liquid separation. The methylene chloride layer was washed with 3*600g of water, separated liquids, and spin-dried to obtain 70.2g of crude voriconazole. Add 351 g of isopropyl ether to the crude voriconazole, raise the temperature to 50° C., stir for 2.5 h, lower the temperature to 0-10° C., filter, and dry to obtain 68.6 g of voriconazole. ee%=99.96%, and the yield is 97.7%.

Embodiment 3

[0049]Voriconazole L-camphorsulfonate 227g, ee value 63.82%, 2270g water and 4600g methylene chloride were added, the temperature was reduced to 0-10°C, and the pH was adjusted to 10.41 with 10wt% NaOH aqueous solution. Liquid separation. The dichloromethane layer was washed with 3*1100g water, separated, the dichloromethane layer was spin-dried to obtain 135.4g crude voriconazole, added with tert-butyl methyl ether 542g, heated to 50℃, stirred for 2.5h, cooled to 0~10℃, filtered and dried Dry, 130.4g of voriconazole was obtained. ee%=99.96%, yield 96.3%.

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Abstract

The invention discloses a purification method of voriconazole. The method comprises the following processes: adding voriconazole to be purified to an ether solvent; washing and starching; filtering; drying. According to the method, the production technology is stabilized; the production cost is decreased; the productivity is improved; the industrial production value is extremely high.

Description

Technical field[0001]The present invention relates to the field of methods for eliminating enantiomers, in particular to a method for purifying voriconazole.Background technique[0002]Voriconazole, a fluconazole derivative, is a second-generation triazole broad-spectrum antifungal drug developed by Pfizer. Voriconazole specifically inhibits 14α-sterol demethylase, has a better inhibitory effect on ergosterol biosynthesis, and has obvious antibacterial activity against Candida, Aspergillus and other pathogenic bacteria such as Fusarium, Actinomycetes, etc. Enhanced, its in vitro anti-candida activity is 10-100 times that of fluconazole. It also has obvious antibacterial effect on fluconazole-resistant Candida such as Candida krusei. It is mainly used clinically to treat acute and potentially life-threatening infections in patients with immunodeficiency.[0003]The structural formula of voriconazole is as follows:[0004][0005]Voriconazole (2R, 3S) is a chiral compound with two chiral cent...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06
CPCC07B2200/07C07D403/06
Inventor 黄浩喜段锴黄俊崔阳文李英富苏忠海
Owner CHENGDU BRILLIANT PHARMA CO LTD
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