Voriconazole synthesis process

Abstract

The present invention discloses a voriconazole bulk drug synthesis process, which comprises: preparing halogenated ethyl fluoropyrimidine, and carrying out a Grignard reaction; oxidizing 2-(2, 4-difluorophenyl)-3-(1, 2, 4-triazole-1-yl)-1, 2-propylene glycol to obtain an epoxypropane compound; and mixing the Grignard reagent with an epoxypropane compound, and reacting to obtain voriconazole. According to the synthesis process provided by the invention, the reaction steps can be simplified, palladium carbon is not needed for dechlorination hydrogenolysis, the reaction period is shortened, in addition, the energy consumption is reduced, the cost is reduced, and the voriconazole and the racemate thereof are obtained at a relatively high yield.

Description

technical field

[0001] The invention relates to the field of drug synthesis, in particular to a synthesis process of voriconazole bulk drug, in particular to a preparation of voriconazole and a racemate thereof. Background technique

[0002] Voriconazole (Voriconazole, VRC, UK109496), 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 is a new type of antifungal drug synthesized by Pfizer based on fluconazole, mainly used for progressive and fatal immune damage patient. Due to the wide antifungal spectrum, strong antibacterial efficacy and good safety of Vorican sleep, and the demand for antifungal drugs in the domestic market is growing rapidly, the market prospect is huge.

[0003] The existing methods or processes for synthesizing voriconazole generally use 2R, 3S / 2S, 3R racemate as the key intermediate, and use specific chiral resolution reagents, such as 1R-(-)-10-camphorsulfonic acid, to form Salt reso...

Examples

Embodiment 1

[0075] In a flask equipped with a double-necked adapter, place 4.8 g of magnesium chips. The main mouth of the interface is equipped with a dropping funnel, and the side mouth is equipped with a reflux condenser of the calcium chloride drying tube. Add dropwise a mixed solution of 0.2mol 4-(1-bromoethyl)-5-fluoropyrimidine and 302mL methyltetrahydrofuran into the bottle, and heat in a water bath at a temperature of 50°C to obtain a solution of Grignard reagent in methyltetrahydrofuran;

[0076] Weigh 0.2mol 2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)-1,2-propanediol and 0.05mol potassium oxide-silica supported catalyst (wherein the loading of potassium oxide is 12wt%), the reaction temperature is 65°C, and the reaction pressure is 2MPa; 2-(2,4-difluorophenyl)-3-(1,2,4-triazole- 1-yl)-1,2-propylene oxide;

[0077] Take 0.1mol of 2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)-1,2-epoxypropane dissolved in 1.2mol of carbon dioxide Add 100 mL of the prepared Grignard reagent i...

Embodiment 2

[0079] 0.05 mol of the voriconazole racemate prepared in Example 1 was dissolved in 73.7 mL of acetone, and 13.9 g of L-(-)-10-camphorsulfonic acid dissolved in 24 mL of methanol was added thereto. The resulting mixture was refluxed for 1 h, and slowly cooled to room temperature, crystallized, filtered, and dried to obtain the camphorsulfonate of voriconazole;

[0080] Voriconazole camphorsulfonate was added to 100 mL of water and dichloromethane at a volume ratio of 1:1, and 40% sodium hydroxide solution was slowly added thereto to adjust the pH to 11-12. The organic layer was separated, dried, and the organic solvent was removed under reduced pressure, crystallized from isopropanol, and dried to obtain 13.7 g of white voriconazole, with a yield of 92%, and the mass spectrum of the obtained voriconazole was as follows: figure 1 shown.

technical field

[0001] The invention relates to the field of drug synthesis, in particular to a synthesis process of voriconazole bulk drug, in particular to a preparation of voriconazole and a racemate thereof. Background technique

[0002] Voriconazole (Voriconazole, VRC, UK109496), 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 is a new type of antifungal drug synthesized by Pfizer based on fluconazole, mainly used for progressive and fatal immune damage patient. Due to the wide antifungal spectrum, strong antibacterial efficacy and good safety of Vorican sleep, and the demand for antifungal drugs in the domestic market is growing rapidly, the market prospect is huge.

[0003] The existing methods or processes for synthesizing voriconazole generally use 2R, 3S / 2S, 3R racemate as the key intermediate, and use specific chiral resolution reagents, such as 1R-(-)-10-camphorsulfonic acid, to form Salt reso...

Examples

Embodiment 1

[0075] In a flask equipped with a double-necked adapter, place 4.8 g of magnesium chips. The main mouth of the interface is equipped with a dropping funnel, and the side mouth is equipped with a reflux condenser of the calcium chloride drying tube. Add dropwise a mixed solution of 0.2mol 4-(1-bromoethyl)-5-fluoropyrimidine and 302mL methyltetrahydrofuran into the bottle, and heat in a water bath at a temperature of 50°C to obtain a solution of Grignard reagent in methyltetrahydrofuran;

[0076] Weigh 0.2mol 2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)-1,2-propanediol and 0.05mol potassium oxide-silica supported catalyst (wherein the loading of potassium oxide is 12wt%), the reaction temperature is 65°C, and the reaction pressure is 2MPa; 2-(2,4-difluorophenyl)-3-(1,2,4-triazole- 1-yl)-1,2-propylene oxide;

[0077] Take 0.1mol of 2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)-1,2-epoxypropane dissolved in 1.2mol of carbon dioxide Add 100 mL of the prepared Grignard reagent i...

Embodiment 2

[0079] 0.05 mol of the voriconazole racemate prepared in Example 1 was dissolved in 73.7 mL of acetone, and 13.9 g of L-(-)-10-camphorsulfonic acid dissolved in 24 mL of methanol was added thereto. The resulting mixture was refluxed for 1 h, and slowly cooled to room temperature, crystallized, filtered, and dried to obtain the camphorsulfonate of voriconazole;

[0080] Voriconazole camphorsulfonate was added to 100 mL of water and dichloromethane at a volume ratio of 1:1, and 40% sodium hydroxide solution was slowly added thereto to adjust the pH to 11-12. The organic layer was separated, dried, and the organic solvent was removed under reduced pressure, crystallized from isopropanol, and dried to obtain 13.7 g of white voriconazole, with a yield of 92%, and the mass spectrum of the obtained voriconazole was as follows: figure 1 shown.

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