WO2021127965A1 - Method for recycling voriconazole enantiomer - Google Patents

Abstract

Disclosed is a method for recycling a voriconazole enantiomer. The specific steps are as follows: mixing the voriconazole enantiomer with a reaction solvent containing basic substance A; after the reaction ends, concentrating same under reduced pressure; adding organic solvent A and water, stirring and dissolving same, then separating liquid, and collecting an oil layer; continuously adding water, adjusting the pH of the solution with an acidic substance, separating liquid, and concentrating the oil layer; adding a separation solvent, stirring and dissolving same, and then lowering the temperature; and performing crystallization and then subjecting same to suction filtration to obtain formula II; adding organic solvent B to a collected water layer, adjusting the pH value of the solution by using basic substance B; separating liquid, distilling the organic solvent layer under reduced pressure, and then raising the temperature and performing distillation under reduced pressure to obtain formula III. The method has the advantages of a simple process route, convenient operations in the process of processing, little harm to the human body, repeated utilization of waste, being environmentally friendly, not wasting resources, etc.

Description

Method for recovering voriconazole enantiomers Technical field

The invention relates to the field of medicinal chemistry, in particular to a method for recovering voriconazole enantiomers.

Background technique

Voriconazole is a triazole antifungal and a second-generation synthetic derivative of fluconazole. It is the first-line treatment for invasive Aspergillus infection and Candida krusei infection. Its mechanism of action is to inhibit fungal cytochrome P450 (CYP450) end-dependent lanosterol 14α demethylation to exert its antifungal effect, which is a crucial step in the synthesis of fungal cell membrane ergosterol. In vitro tests have shown that voriconazole has a broad-spectrum antifungal effect. It has antibacterial effects on all Candida species (including fluconazole-resistant Candida krusei, Candida glabrata and Candida albicans resistant strains). Fungi of the genus Moulds have bactericidal effects. In addition, voriconazole also has bactericidal effects against other pathogenic fungi in vitro, including those that are less sensitive to existing antifungal drugs, such as Actinomyces and Fusarium. Voriconazole has the advantages of broad antibacterial spectrum and strong antibacterial efficacy, especially for the advantages of good curative effect on invasive Aspergillus infection.

The structural formula of voriconazole is as follows:

Voriconazole (2R, 3S) is a chiral compound with two chiral centers in the structure, with two diastereomers (2R, 3R/2S, 3S) and one enantiomer (2S, 3R) . Among them, the physical and chemical properties of diastereoisomers are generally different, and they are easy to separate and remove during the production process. Enantiomers have the same physical and chemical properties as voriconazole in an achiral environment, and are difficult to separate and remove in the production process.

The reported voriconazole is generally obtained by resolving the voriconazole racemate (2R, 3S/2S, 3R) with a chiral resolving agent. The recovery of the chiral resolving agent is relatively simple and can generally be used repeatedly. The yield of voriconazole (2R, 3S) obtained after resolution using a resolving agent is about 40%, and the voriconazole enantiomer (2S, 3R) obtained by resolution has two treatment methods, one is to Voriconazole isomers (2S, 3R) are converted to voriconazole, but because the voriconazole isomers (2S, 3R) contain two chiral centers for the conversion of isomers, four isomers 2S, 3R, 2R, 3S, 2R, 3R, and 2S, 3S, after the four isomers obtained are separated and resolved, the conversion efficiency of the obtained voriconazole is low, and the process flow is relatively complicated, which is not suitable for industrial production; the other is The enantiomers of voriconazole are treated directly as waste, which not only causes environmental pollution, but also increases production costs. Therefore, there is an urgent need for a method suitable for industrial processing of voriconazole isomers.

Summary of the invention

In order to solve the problems of the above two methods for processing the enantiomers of voriconazole, the present invention discloses a method for recovering the enantiomers of voriconazole. The method has a simple process route, convenient operation in the treatment process, and the reaction process. The substances used are all commonly used substances in the experiment, which have the advantages of low harm to the human body, reuse of waste, environmental friendliness, and no waste of resources, and the substances obtained by the reaction can again become the starting materials for the preparation of voriconazole.

The method for recovering the enantiomers of voriconazole of the present invention includes the following steps: mixing the enantiomers of voriconazole with a reaction solvent containing a basic substance A, heating to temperature I for reaction, and obtaining formula II and formula III after the reaction is completed , The specific reaction is as follows:

In the method for recovering voriconazole enantiomers of the present invention, after the reaction is completed, it is concentrated under reduced pressure, the concentrate is added with organic solvent A and water, the formula III is recovered and separated from the water layer, and the formula II is recovered from the oil layer.

In the method for recovering voriconazole enantiomers of the present invention, the concentrate is added with organic solvent A and water, stirred and dissolved, and then separated, the oil layer is collected, water is continued to be added to the oil layer, the pH value of the solution is adjusted with acidic substances, and the liquid is separated. Collect oil and water layers.

The method for recovering the enantiomers of voriconazole of the present invention is to concentrate the collected oil layer, add a separating solvent and stir to dissolve, then cool to temperature II, stir and crystallize and filter with suction to obtain formula II; add organic solvent to the collected water layer B. Adjust the pH value of the solution with the alkaline substance B, separate the liquids, collect the organic solvent layer, and distill the organic solvent under reduced pressure, then heat to temperature III and distill under reduced pressure to obtain formula III.

In the method for recovering voriconazole enantiomers of the present invention, the mass ratio of the voriconazole enantiomers of formula I to the reaction solvent is 1:3 to 1:8, and the voriconazole enantiomers of formula I are basic The mass ratio of substance A is 3:1～7:1.

In the method for recovering voriconazole enantiomers of the present invention, the reaction solvent is one or two of methanol, ethanol, propanol, isopropanol, acetone and n-butanol, and the basic substance A is a strong base The strong alkaline substance is one or two of lithium hydroxide, sodium hydroxide and potassium hydroxide.

In the method for recovering voriconazole enantiomers of the present invention, the reaction temperature I of the voriconazole enantiomer of formula I and the basic substance A is 60-85° C., and the reaction time is 10-20 hours.

In the method for recovering the enantiomers of voriconazole of the present invention, the organic solvent A is one or two of toluene, dichloromethane and chloroform, and the acidic substance is hydrochloric acid, sulfuric acid, nitric acid and acetic acid. One or two, the pH of the solution is 1-5.

In the method for recovering voriconazole enantiomers of the present invention, the separation solvent is one or two of acetone, methyl acetate, ethyl acetate, ether and phenol; the temperature II is 0-10°C.

In the method for recovering voriconazole enantiomers of the present invention, the alkaline substance B is one or two of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, lithium hydroxide, sodium hydroxide and potassium hydroxide The organic solvent B is one or two of toluene, dichloromethane and chloroform, and the pH value of the solution is 8-12.

In the method for recovering voriconazole enantiomers of the present invention, the temperature III is 70°C to 90°C, and the pressure is -0.085 to -0.095 MPa.

In the method for recovering the enantiomers of voriconazole of the present invention, the 2,4-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone (formula II) is recovered The rate is 86%-95%, and the 6-ethyl-5-fluoropyrimidine (formula III) is 85%-95%.

The method has the advantages of simple process route, convenient operation in the treatment process, the materials used in the reaction process are all commonly used in the experiment, little harm to the human body, repeated use of waste, environmental friendliness, no waste of resources, etc. The present invention The yields of the obtained products are all above 85%, and some can reach above 90%, and the separation of the products is simple, and the materials obtained by the reaction can be used as starting materials for preparing voriconazole.

Detailed ways

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail. The reagents used in the present invention can be purchased from the market or can be prepared by the method of the prior art or prepared by the method described in the present invention.

In the present invention, °C represents degrees Celsius, g represents grams, Mpa represents megapascals, and h represents hours.

Example 1

Add 100 g of voriconazole enantiomer, 400 g of reaction solvent methanol and 20 g of lithium hydroxide into the reaction flask, and react at 65° C. for 10 hours. After the reaction is completed, the methanol is recovered by concentration under reduced pressure. The concentrate is added with 400g of organic solvent A chloroform and 200g of water after stirring to dissolve, then stand for liquid separation, collect the organic solvent A chloroform layer, and continue to add to the collected chloroform layer 200g water, adjust the pH to 1 with concentrated sulfuric acid, separate the liquids, and collect the oil layer and the water layer.

Concentrate the collected organic solvent A chloroform layer to dryness, add 200g of separation solvent methyl acetate and stir to dissolve, then cool to 3°C, stir and crystallize for 4h, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (compound of formula II), the yield was 86.29%.

Add 200g of organic solvent B chloroform to the water layer, adjust the pH to 8 with sodium acetate solution, separate the layers, collect the organic solvent B chloroform layer, and distill the organic solvent B chloroform under reduced pressure at 30°C, then reduce pressure at 70°C To -0.095Mpa, 6-ethyl-5-fluoropyrimidine (compound of formula III) was obtained by distillation, and the yield was 85.33%.

Example 2

Add 100 g of voriconazole enantiomer, 400 g of acetone as the reaction solvent, and 20 g of potassium hydroxide into the reaction flask, and react with reflux at 75°C for 20 hours. After the reaction is completed, the acetone is recovered by concentration under reduced pressure. The concentrate is mixed with 400g of organic solvent A toluene and 200g of water and stirred to dissolve, then stand for liquid separation, collect the organic solvent A toluene layer, continue to add 200g of water to the toluene layer, adjust the pH with concentrated nitric acid To 5, separate liquid, collect oil layer and water layer.

The toluene layer of the organic solvent A collected at the end was concentrated to dryness. After adding 200g of the separating solvent ether and stirring to dissolve, the temperature was lowered to 8°C, stirred and crystallized for 4h, and filtered with suction to obtain 2,4-difluoro-2-[1-(1H -1,2,4-triazolyl)] crude acetophenone (compound of formula II), the yield was 88.27%.

Add 200 g of organic solvent B toluene to the water layer, adjust the pH to 12 with 25% potassium hydroxide solution, separate the layers, collect the organic solvent B toluene layer, distill the organic solvent B toluene off under reduced pressure at 30°C, and then reduce pressure at 90°C to- 0.085Mpa, distilled to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III), the yield was 87.52%.

Example 3

Add 100 g of voriconazole enantiomer, 400 g of ethanol as the reaction solvent, and 20 g of sodium hydroxide into the reaction flask, and reflux for 15 hours at 85°C. After the reaction is over, the ethanol is recovered by concentration under reduced pressure. The concentrate is mixed with 400g of organic solvent A dichloromethane and 200g of water after stirring to dissolve, then stand for liquid separation, collect the dichloromethane layer of organic solvent A, and continue to add 200g of water to the dichloromethane layer , Adjust the pH to 3 with concentrated hydrochloric acid, separate the liquids, and collect the oil and water layers.

Concentrate the last collected dichloromethane layer of organic solvent A to dryness, add 200 g of the separating solvent ethyl acetate and stir to dissolve, then cool to 3°C, stir and crystallize for 4 hours, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (compound of formula II), the yield was 93.84%.

Add 200g of organic solvent B dichloromethane to the water layer, adjust the pH to 10 with 25% sodium hydroxide solution, separate the layers, collect the dichloromethane layer, distill the dichloromethane under reduced pressure at 30°C, and then reduce pressure to-at 80°C 0.09Mpa, distilled to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III), the yield was 91.37%.

Example 4

Add 100 g of voriconazole enantiomer, 400 g of reaction solvent methanol and 20 g of sodium carbonate into the reaction flask, and reflux at 65° C. for reaction for 10 hours. After the reaction, the methanol was recovered by concentration under reduced pressure. The concentrate was added with 400g of organic solvent A dichloromethane and 200g of water after stirring to dissolve, then stood still for liquid separation, collected the dichloromethane layer of organic solvent A, and continued to add 200g of water to the dichloromethane layer , Adjust the pH to 1 with concentrated sulfuric acid, separate the liquids, and collect the oil and water layers.

Concentrate the last collected dichloromethane layer of organic solvent A to dryness, add 200 g of the separation solvent ethyl acetate and stir to dissolve, then cool to 0°C, stir and crystallize for 4 hours, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (compound of formula II) has a yield of 50.96%.

Add 200 g of organic solvent B dichloromethane to the water layer, adjust the pH to 9 with 25% sodium hydroxide solution, separate the layers, collect the dichloromethane layer, distill the dichloromethane under reduced pressure at 30°C, and then reduce pressure to-at 70°C 0.095Mpa, distilled to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III), the yield was 43.58%.

Example 5

Add 100 g of voriconazole enantiomers, 400 g of ethanol as the reaction solvent and 20 g of sodium acetate into the reaction flask, and react with reflux at 80° C. for 15 hours. After the reaction is over, the ethanol is recovered by concentration under reduced pressure. The concentrate is mixed with 400g of organic solvent A dichloromethane and 200g of water after stirring to dissolve, then stand for liquid separation, collect the dichloromethane layer of organic solvent A, and continue to add 200g of water to the dichloromethane layer , Adjust the pH to 3 with concentrated sulfuric acid, separate the liquids, and collect the oil and water layers.

Concentrate the last collected dichloromethane layer of organic solvent A to dryness, add 200 g of the separating solvent ethyl acetate and stir to dissolve, then cool to 3°C, stir and crystallize for 4 hours, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (compound of formula II), the yield was 41.78%.

Add 200g of organic solvent B dichloromethane to the water layer, adjust the pH to 12 with sodium acetate solution, separate the layers, collect the dichloromethane layer, distill the dichloromethane under reduced pressure at 30°C, reduce pressure at 80°C to -0.09Mpa, and distill 6-ethyl-5-fluoropyrimidine (compound of formula III) was obtained with a yield of 37.62%.

Example 6

Add 100 g of voriconazole enantiomer, 400 g of reaction solvent methanol and 20 g of sodium hydroxide into the reaction flask, and reflux for 15 hours at 30°C. After the reaction is over, the ethanol is recovered by concentration under reduced pressure. The concentrate is mixed with 400g of organic solvent A dichloromethane and 200g of water after stirring to dissolve, then stand for liquid separation, collect the dichloromethane layer of organic solvent A, and continue to add 200g of water to the dichloromethane layer , Adjust the pH to 3 with concentrated sulfuric acid, separate the liquids, and collect the oil and water layers.

Concentrate the last collected dichloromethane layer of organic solvent A to dryness, add 200 g of the separating solvent ethyl acetate and stir to dissolve, then cool to 3°C, stir and crystallize for 4 hours, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (compound of formula II), the yield was 39.84%.

Add 200 g of organic solvent B dichloromethane to the water layer, adjust the pH to 9 with 25% sodium hydroxide solution, separate the layers, collect the dichloromethane layer, distill the dichloromethane under reduced pressure at 30°C, and then reduce pressure to-at 70°C 0.095Mpa, distillation to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III), the yield was 33.71%.

Example 7

Add 100 g of voriconazole enantiomers, 400 g of reaction solvent methanol and 20 g of sodium hydroxide into the reaction flask, and reflux for 15 hours at 50°C. After the reaction is completed, the methanol is recovered by concentration under reduced pressure. The concentrate is mixed with 400g of organic solvent A dichloromethane and 200g of water after stirring to dissolve, then stand for liquid separation, collect the organic solvent A dichloromethane layer, and continue to add 200g of water to the dichloromethane layer , Adjust the pH to 3 with concentrated sulfuric acid, separate the liquids, and collect the oil and water layers.

Concentrate the last collected dichloromethane layer of organic solvent A to dryness, add 200 g of the separating solvent ethyl acetate and stir to dissolve, then cool to 3°C, stir and crystallize for 4 hours, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (compound of formula II), the yield was 58.64%.

Add 200 g of organic solvent B dichloromethane to the water layer, adjust the pH to 12 with 25% sodium hydroxide solution, separate the liquids, collect the dichloromethane layer, distill the dichloromethane under reduced pressure at 30°C, and then reduce pressure to-at 80°C 0.09Mpa, distilled to obtain 6-ethyl-5-fluoropyrimidine (the compound of formula III), the yield was 51.47%.

Example 8

Add 100 g of the voriconazole enantiomer, 400 g of ethanol as the reaction solvent, and 20 g of sodium hydroxide into the reaction flask, and react with reflux at 20° C. for 15 hours. After the reaction, the methanol was recovered by concentration under reduced pressure. The concentrate was added with 400g of organic solvent A dichloromethane and 200g of water after stirring to dissolve, then stood still for liquid separation, collected the dichloromethane layer of organic solvent A, and continued to add 200g of water to the dichloromethane layer , Adjust the pH to 3 with concentrated sulfuric acid, separate the liquids, and collect the oil and water layers.

Concentrate the last collected dichloromethane layer of organic solvent A to dryness, add 200 g of the separating solvent ethyl acetate and stir to dissolve, then cool to 3°C, stir and crystallize for 4 hours, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (compound of formula II), the yield was 38.71%.

Add 200 g of organic solvent B dichloromethane to the water layer, adjust the pH to 12 with 25% sodium hydroxide solution, separate the liquids, collect the dichloromethane layer, distill the dichloromethane under reduced pressure at 30°C, and then reduce pressure to-at 80°C 0.09Mpa, distilled to obtain 6-ethyl-5-fluoropyrimidine (compound of formula III), the yield was 33.71%.

Example 9

Add 100 g of voriconazole enantiomer, 400 g of ethanol as the reaction solvent, and 20 g of sodium hydroxide into the reaction flask, and reflux for 15 hours at a temperature of 40°C. After the reaction is over, the ethanol is recovered by concentration under reduced pressure. The concentrate is mixed with 400g of organic solvent A dichloromethane and 200g of water after stirring to dissolve, then stand for liquid separation, collect the dichloromethane layer of organic solvent A, and continue to add 200g of water to the dichloromethane layer , Adjust the pH to 3 with concentrated nitric acid, separate the liquids, and collect the oil and water layers.

Concentrate the last collected dichloromethane layer of organic solvent A to dryness, add 200 g of the separating solvent ethyl acetate and stir to dissolve, then cool to 3°C, stir and crystallize for 4 hours, and filter with suction to obtain 2,4-difluoro-2-[ The crude product of 1-(1H-1,2,4-triazolyl)]acetophenone (the compound of formula II), the yield was 49.21%.

Add 200 g of organic solvent B dichloromethane to the water layer, adjust the pH to 10 with 25% sodium hydroxide solution, separate the layers, collect the dichloromethane layer, distill the dichloromethane under reduced pressure at 30°C, and then reduce the pressure to-at 70°C 0.095Mpa, distilled to obtain 6-ethyl-5-fluoropyrimidine (the compound of formula III), the yield was 43.85%.

Claims (10)

A method for recovering the enantiomers of voriconazole, which is characterized in that it comprises the following steps: mixing the enantiomers of voriconazole with a reaction solvent containing a basic substance A, heating to temperature I for reaction, and obtaining formula II after the reaction is completed And formula III, the specific reaction is as follows:

The method for recovering the enantiomers of voriconazole according to claim 1, characterized in that, after the reaction is completed, it is concentrated under reduced pressure, the concentrate is added to the organic solvent A and water, and the aqueous layer is recovered and separated by formula III, Formula II is recovered in the oil layer. The method for recovering the enantiomers of voriconazole according to claim 2, characterized in that the concentrate is added with organic solvent A and water, stirred and dissolved, and then separated, the oil layer is collected, and water is continuously added to the oil layer. The substance adjusts the pH value of the solution, separates the liquid, and collects the oil and water layers. The method for recovering the enantiomers of voriconazole according to claim 3, characterized in that the collected oil layer is concentrated, a separating solvent is added and stirred to dissolve, the temperature is lowered to temperature II, the crystallization is stirred and then suction filtered to obtain the formula II; Add organic solvent B to the collected water layer, adjust the pH value of the solution with alkaline substance B, separate liquids, collect the organic solvent layer, distill under reduced pressure to remove the organic solvent, heat to temperature III and distill under reduced pressure to obtain formula III. The method for recovering voriconazole enantiomers according to claim 4, wherein the mass ratio of the voriconazole enantiomers of formula I to the reaction solvent is 1:3 to 1:8, and the formula I. The mass ratio of the enantiomer of voriconazole and the basic substance A is 3:1-7:1; or the reaction temperature I of the voriconazole enantiomer of formula I and the basic substance A is 60-85°C, The reaction time is 10-20 hours. The method for recovering voriconazole enantiomers according to claim 5, wherein the reaction solvent is one or two of methanol, ethanol, propanol, isopropanol, acetone and n-butanol The alkaline substance A is a strong alkaline substance, and the strong alkaline substance is one or two of lithium hydroxide, sodium hydroxide and potassium hydroxide. The method for recovering voriconazole enantiomers according to any one of claims 1 to 6, wherein the organic solvent A is one or two of toluene, dichloromethane and chloroform The acidic substance is one or two of hydrochloric acid, sulfuric acid, nitric acid and acetic acid, and the pH value of the solution is 1-5. The method for recovering voriconazole enantiomers according to any one of claims 1 to 6, characterized in that, or the separation solvent is one of acetone, methyl acetate, ethyl acetate, ethyl ether and phenol One or two kinds, the temperature II is 0-10°C. The method for recovering voriconazole enantiomers according to any one of claims 1 to 6, wherein the alkaline substance B is sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, lithium hydroxide , One or two of sodium hydroxide and potassium hydroxide, the organic solvent B is one or two of toluene, dichloromethane and chloroform, and the pH of the solution is 8-12. The method for recovering voriconazole enantiomers according to any one of claims 1 to 6, wherein the temperature III is 70°C to 90°C, and the pressure is -0.085 to -0.095 MPa.