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Synthesis method and application of voriconazole

A voriconazole and synthetic method technology, applied in the field of drug synthesis, can solve problems such as voriconazole purification difficulties, voriconazole hydrolysis, and increased production costs of enterprises

Active Publication Date: 2021-06-04
HAINAN JINRUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] At present, the systems for synthesizing voriconazole in the prior art are all under strong alkaline conditions, which easily cause the hydrolysis of voriconazole, making the purification of voriconazole difficult and the yield reduced. In order to achieve the standard purity of the preparation of drugs, it is often necessary to prepare a large amount of voriconazole , This undoubtedly increases the production cost of the enterprise and causes a large amount of waste in the preparation of raw materials, so it is very necessary to develop a high-yield voriconazole synthetic method

Method used

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  • Synthesis method and application of voriconazole
  • Synthesis method and application of voriconazole
  • Synthesis method and application of voriconazole

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1 A kind of synthetic method of voriconazole

[0029] The present embodiment provides a kind of synthetic method of voriconazole, and its chemical reaction equation is:

[0030]

[0031] Weigh 60g of (2R,3S)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-1-(1H-1,2,4- Triazol-1-yl)-2-butanol was dissolved in 200ml of methanol, 5g of zinc powder was added, and 14g of glacial acetic acid was added dropwise for substitution and reduction reaction. After the reaction was monitored by TLC, 500ml of water was added, and triethylamine (TEA) was used to Adjust the pH value to be between 7.5~8.5, preferred pH value is 8.0, in the process of adjusting pH, a large amount of solids are separated out, filter, after washing the filter cake with water, dry, obtain 50g voriconazole (HPLC such as figure 1 Shown), the yield is 93%, and the purity is 99.86%.

[0032] It should be noted that the organic base used in this embodiment is triethylamine, which is only...

Embodiment 2

[0033] Embodiment 2 A kind of preparation method of voriconazole tablet

[0034] This embodiment takes the voriconazole synthesized in Example 1 as a raw material, and provides a preparation method of voriconazole tablets, the preparation method comprising the following steps:

[0035] 1) Weigh 50g voriconazole and place it in a hammer mill equipped with a 100-mesh stainless steel screen for pulverization to control the particle size D of voriconazole 90 55 μm, then weigh 70g of lactose, 20g of pregelatinized starch and 12g of croscarmellose sodium, mix and pulverize them, pass through a 60-mesh sieve, and mix with pulverized voriconazole to obtain the mixed material A;

[0036] 2) Weigh 3g of povidone K30 and add it into purified water, and stir until the aqueous solution becomes clear to obtain an aqueous binder solution;

[0037] 3) Add the mixed material A to the wet mixing granulator and stir for 5 minutes, then add the binder aqueous solution, stir and chop, and then ge...

Embodiment 3～6

[0040] The preparation method of embodiment 3~6 voriconazole sheet X2~X5

[0041] Embodiments 3 to 6 respectively provide a preparation method of voriconazole tablets, the preparation method is basically the same as that of Example 2, the only difference is that some process parameters are different, and the specific process parameter data are shown in Table 1.

[0042] Table 1: Parameters of the preparation method of voriconazole tablets X2~X5

[0043]

[0044] Other processing parameters are all identical with embodiment 1.

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Abstract

The invention belongs to the field of medicine synthesis, and discloses a synthesis method and application of voriconazole. The synthesis method of the voriconazole provided by the invention comprises the steps: (2R,3S)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol is subjected to dechlorination reduction under an acidic condition to generate the voriconazole; and the voriconazole tablet is prepared from the obtained voriconazole, auxiliary materials and an adhesive through the steps of crushing, sieving, mixing, granulating, drying, granulating, tabletting, coating and the like. According to the invention, on the basis of ensuring the purity of voriconazole, the yield of voriconazole is improved, and the production cost is reduced; and the prepared voriconazole tablet also has high dissolution rate of voriconazole, and has a good medical effect. The method is suitable for synthesis of voriconazole and preparation of the voriconazole tablet, and is particularly suitable for synthesis of high-yield voriconazole and preparation of the high-dissolution voriconazole tablet.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a synthesis method and application of voriconazole, specifically a synthesis method and application of high-yield voriconazole. Background technique [0002] Voriconazole (Voriconazole) is a new type of broad-spectrum triazole antifungal drug synthesized by Pfizer on the basis of the structure of fluconazole. It has the advantages of good pharmacokinetic characteristics and broad antibacterial spectrum. The first-line treatment drug for the disease, its chemical name is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2 , 4-triazol-1-yl)-2-butanol, its structural formula is as follows: [0003] [0004] At present, the systems for synthesizing voriconazole in the prior art are all under strong alkaline conditions, which easily cause the hydrolysis of voriconazole, making the purification of voriconazole difficult and the yield reduced. In order to achieve the stan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61K9/28A61K47/38A61K47/36A61K47/26A61K31/506A61P31/10
CPCC07D403/06A61K9/2806A61K9/2054A61K9/2059A61K9/2018A61K31/506A61P31/10
Inventor 黄月娜王进宇潘淑华王寿春
Owner HAINAN JINRUI PHARMA
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