HK1159067B

HK1159067B - Method for preparing sevoflurane

Info

Publication number: HK1159067B
Application number: HK11113555.7A
Authority: HK
Inventors: 张富尧; 神小明; 孙飘扬
Original assignee: 江苏盛迪医药有限公司
Filing date: 2011-12-15
Publication date: 2015-01-30

Abstract

The present invention relates to a method for preparing sevoflurane (i.e., fluoromethyl-2,2-trifluoro-1- (trifluoromethyl) ethyl ether), which comprises reacting chloromethyl-2,2,2-trifluoro-1- (trifluoromethyl) ethyl ether with fluoride in the presence of a catalyst. This method is easy to operate, has low cost, high yield, easy solvent recovery, and is suitable for industrial production.

Description

Process for preparing sevoflurane

Technical Field

The present invention relates to a method for the preparation of fluorides and in particular to a method for the preparation of sevoflurane.

Background

Sevoflurane (i.e., fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether) is an inhalation anesthetic, and among the numerous sevoflurane preparation methods, the fluorination reaction of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether is a key step in the preparation of sevoflurane. U.S. Pat. No. 3,683,092 reports the reaction of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with potassium fluoride in sulfolane solvent to form sevoflurane. The method has slow fluorination reaction process and low conversion rate, and the product is not easy to purify. U.S. Pat. No. 6,100,434 reports that chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether reacts with a fluoro reagent (such as KF, NaF) in a solvent PEG-400 to prepare sevoflurane, and the better effect is achieved. EP0901999 and US5,886,239 report a method for preparing sevoflurane by reacting chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with quaternary ammonium hydrogen fluoride salt, but this method cannot achieve chloromethyl-2, 2, 2-trifluoro-1- (tris-phosphonium fluoride)Complete conversion of fluoromethyl) ethyl ether presents difficulties in the purification of sevoflurane. CN1293030 reports that crown ether or polyethylene glycol is used as an activating agent to activate the fluorination reaction of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether. WO2008037040 also reports on iodide (e.g. KI, R)₄N⁺I^-) The catalyst of (2) catalyzes the fluorination reaction of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether to prepare sevoflurane, and achieves better results. WO2006055748 reports that quaternary ammonium salt or quaternary phosphonium salt is used as a phase transfer catalyst to catalyze the fluorination reaction of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, and 5-30% of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether can not be converted in the reaction system, so that the yield of sevoflurane is low and the purification is difficult.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide the method for preparing the fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, which has the advantages of high conversion rate of raw materials, high product yield and easy recovery of a solvent.

The present invention relates to a process for the preparation of sevoflurane [ fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether ], said process comprising reacting chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with fluoride in the presence of a catalyst, wherein said catalyst is a polyol selected from any one or combination of pentaerythritol, 1, 2, 3-propanetriol, tris (2-hydroxyethyl) amine and a polyhydroxylated saccharide compound, preferably pentaerythritol, said polyhydroxylated saccharide compound being selected from mannitol, erythritol or sorbitol; the catalyst is used in an amount of 6% to 60% by weight of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, preferably 20% by weight of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether.

According to the process of the present invention, chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether is reacted in the presence of a catalyst with a fluoride selected from the group consisting of metal fluorides such as calcium fluoride, potassium fluoride, sodium fluoride, cesium fluoride or ammonium fluoride or other fluoride salts which are normally present in solid form, preferably potassium fluoride, to produce sevoflurane. The molar ratio between chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether and fluoride is chosen from 1: 1 to 1: 5, preferably 1: 2.6.

According to the method of the invention, chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether reacts with fluoride in the presence of a catalyst in a solvent, wherein the reaction solvent is selected from any one or combination of sulfolane, N, N '-dimethylformamide, N, N' -dimethylacetamide, dimethyl sulfoxide or water. Preferably a mixture of sulfolane and water; the reaction solvent sulfolane can be recycled by reduced pressure distillation.

According to the method of the present invention, the reaction temperature is not particularly limited, and is 50 to 150 ℃, preferably 80 to 100 ℃; the reaction pressure is not particularly limited, and is generally normal pressure or conducted in a closed reaction vessel.

The method has the advantages that the method adopts safe and cheap catalyst to carry out catalytic reaction, has the characteristics of simple operation, high raw material conversion rate, easy solvent recovery, environmental protection and the like, has low production cost, is suitable for industrial production, and has remarkable social benefit and economic benefit.

Detailed Description

The present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only used for illustrating the technical scheme of the present invention and do not limit the present invention in any way.

Example 1

In a 250mL three-necked flask, 100 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether (prepared according to the reference USP 3683092), 328 g of sulfolane, 16 g of water, 20 gPentaerythritolAnd 70 g of potassium fluoride,heating to 100 deg.C, stirring at 100 deg.C for 10 hr, analyzing to contain sevoflurane 91.8%, conversion rate is greater than 99.0%, after reaction, distilling to obtain 68.0 g product with purity of 95.9% and yield of 73.4%.

Example 2

In a 100mL three-necked flask, 20.0 grams of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 65.5 grams of sulfolane, 3.2 grams of water, 8.0 grams of 1, 2, 3-propanetriol, and 14.0 grams of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 8-9 hours, which was analyzed to contain 91.6% sevoflurane and a conversion of greater than 99.0%. After the reaction, 12.5 g of product is obtained by distillation, the purity is 97.6 percent, and the yield is 67.5 percent.

Example 3

In a 100mL three-necked flask, 20.0 grams of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 65.5 grams of sulfolane, 3.2 grams of water, 3.7 grams of erythritol, and 14.0 grams of potassium fluoride were added, heated to 100 ℃, and stirred at 100 ℃ for 6 hours, which was analyzed to contain 84.8% sevoflurane, with a conversion of greater than 99.0%. After the reaction, 13.0 g of product is obtained by distillation, the purity is 92.2 percent, and the yield is 70.2 percent.

Example 4

In a 50mL three-necked flask, 5.0 grams of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 16.4 grams of sulfolane, 0.8 grams of water, 2.7 grams of mannitol, and 3.5 grams of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6 hours, which was analyzed to contain 79.6% sevoflurane with a conversion of greater than 99.0%. After the reaction, 3.0 g of product is obtained by distillation, the purity is 94.1 percent, and the yield is 64.8 percent.

Example 5

In a 50mL three-necked flask, 5.0 grams of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 16.4 grams of sulfolane, 0.8 grams of water, 2.7 grams of sorbitol and 3.5 grams of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6 hours, which was analyzed to contain 69.0% sevoflurane and a conversion of greater than 99.0%. After the reaction, 2.6 g of product is obtained by distillation, the purity is 90.3 percent, and the yield is 56.2 percent.

Example 6

In a 50mL three-necked flask, 5.0 grams of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 16.4 grams of sulfolane, 2.3 grams of tris (2-hydroxyethyl) amine, and 3.5 grams of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6 hours, which was analyzed to contain 58.8% sevoflurane, with a conversion of greater than 97.0%. After the reaction, 2.2 g of product was obtained by distillation, purity 82.9% and yield 47.5%.

Example 7

In a 50mL three-necked flask, 5.0 grams of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 13.0 grams of N, N' -dimethylformamide, 0.8 grams of water, 2.0 grams of pentaerythritol, and 3.5 grams of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6 hours, which was analyzed to contain 85.6% sevoflurane and a conversion of greater than 98.0%. After the reaction, 3.1 g of product is obtained by distillation, the purity is 93.1 percent, and the yield is 66.9 percent.

Example 8

In a 50mL three-necked flask, 5.0 grams of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 13.0 grams of N, N' -dimethylacetamide, 0.8 grams of water, 2.0 grams of pentaerythritol, and 3.5 grams of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6 hours, which was analyzed to contain 95.5% sevoflurane and a conversion of greater than 99.0%. After the reaction, 3.4 g of product is obtained by distillation, the purity is 97.5 percent, and the yield is 73.4 percent.

Example 9

In a 50mL three-necked flask, 20.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 53.0 g of dimethyl sulfoxide, 3.2 g of water, 4.0 g of pentaerythritol and 14.0 g of potassium fluoride were added, and the mixture was heated to 100 ℃ and stirred at 100 ℃ for 3 to 4 hours to achieve a conversion of 98.7%. After the reaction, 5.0 g of product was obtained by distillation, purity 82.6% and yield 27.0%.

Example 10

In a 50mL three-necked flask, 20.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 65.5 g of sulfolane, 3.2 mL of water, 8.0 g of pentaerythritol and 9.0 g of ammonium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6-8 hours, and the conversion rate reached 98.4%. After the reaction, 12.5 g of product with purity of 80.2% and yield of 67.5% was obtained by distillation.

Example 11

In a 50mL three-necked flask, 20.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 65.5 g of sulfolane, 3.2 mL of water, 4.0 g of pentaerythritol and 14.0 g of potassium fluoride were added, heated to 50 ℃ and reacted at 50 ℃ for 20 hours with a conversion of 16.7%.

Example 12

In a 50mL three-necked flask, 20.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 65.5 g of sulfolane, 3.2 mL of water, 4.0 g of pentaerythritol and 14.0 g of potassium fluoride were added, heated to 150 ℃ and stirred at 150 ℃ for 3-4 hours, and the conversion rate reached 99.4%. After the reaction, 13.5 g of product with purity of 85.9% and yield of 72.9% was obtained by distillation.

Example 13

In a 50mL three-necked flask, 10.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 41.0 g of sulfolane, 2.0 mL of water, 6.0 g of pentaerythritol and 7.0 g of potassium fluoride were added, heated to 80 ℃ and stirred at 80 ℃ for 12 hours, and the conversion rate reached 99.3%. After the reaction, 7.1 g of product was obtained by distillation, with purity 97.2% and yield 76.6%.

Example 14

In a 50mL three-necked flask, 10.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 41.0 g of sulfolane, 2.0 mL of water, 0.6 g of pentaerythritol, and 7.0 g of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 10 hours, giving a conversion of 57.1%.

Example 15

In a 50mL three-necked flask, 20.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 65.5 g of sulfolane, 3.2 mL of water, 4.0 g of pentaerythritol, and 5.3 g of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6 hours, giving a conversion of 73.6%.

Example 16

In a 50mL three-necked flask, 20.0 g of chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether, 65.5 g of sulfolane, 3.2 mL of water, 4.0 g of pentaerythritol and 26.8 g of potassium fluoride were added, heated to 100 ℃ and stirred at 100 ℃ for 6 hours, and the conversion rate reached 99.8%. After the reaction, 13.8 g of product was obtained by distillation, with a purity of 94.9% and a yield of 74.5%.

Example 17: sulfolane recovery

The mixture distilled in the above example 1 was cooled to 50 to 55 ℃ and filtered while it was hot, the obtained filtrate was distilled under reduced pressure, and fractions having a distillation range of 87 to 92 ℃ were collected to obtain 276g of recovered sulfolane. The recovery rate is 84 percent, and the purity of the recovered sulfolane is 99.8 percent.

Since the invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

1. A process for the preparation of fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether comprising reacting chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether with a fluoride in the presence of a catalyst, wherein the catalyst is a polyol selected from the group consisting of pentaerythritol, 1, 2, 3-propanetriol; wherein the reaction is carried out in a solvent which is a mixture of sulfolane and water.

2. The process for producing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 1, wherein the catalyst is pentaerythritol.

3. The process for producing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 1 or 2, wherein the catalyst is used in an amount of 6% to 60% by weight based on the chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether.

4. The process for producing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 3, wherein the catalyst is used in an amount of 20% by weight based on the chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether.

5. The process for the preparation of fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 1 or 2, wherein the molar ratio between chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether and fluoride is selected from 1: 1-1: 5.

6. the process for the preparation of fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 5, wherein the molar ratio between chloromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether and fluoride is 1: 2.6.

7. the process for preparing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 1 or 2, wherein the fluoride is selected from metal fluorides or other fluoride salts which are normally present in solid form.

8. The process for preparing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 7, wherein the fluoride is selected from any one of calcium fluoride, potassium fluoride, sodium fluoride, cesium fluoride or ammonium fluoride or a combination thereof.

9. The process for preparing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 8, wherein the fluoride is potassium fluoride.

10. The process for producing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 1 or 2, wherein the reaction is carried out at a temperature of 50 ℃ to 150 ℃.

11. The process for producing fluoromethyl-2, 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether according to claim 10, wherein the reaction is carried out at a temperature of 80-100 ℃.