WO2010054540A1

WO2010054540A1 - A method for preparing chloromethyl-1,1,1,3,3,3- hexafluoroisopropyl ether

Info

Publication number: WO2010054540A1
Application number: PCT/CN2009/070530
Authority: WO
Inventors: 孙飘扬; 童达君; 李迎宾; 卢长娟; 刘潇; 梅杰
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2008-11-17
Filing date: 2009-02-25
Publication date: 2010-05-20
Also published as: CN101735026A

Abstract

Disclosed is a method for preparing chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, which is combining hexafluoroisopropanol and either 1,3,5-trixane or paraformaldehyde in the presence of a binary catalyst system to produce chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, where in the binary catalyst system is consisted of an anhydrous chlorinating Lewis acid as the main catalyst and a chlorine-containing compound as the cocatalyst.

Description

Process for the preparation of chloromethyl-1,U,3,3,3-hexafluoroisopropyl ether

The present invention relates to a process for the preparation of hexafluoroisopropyl ether, in particular to a process for the preparation of chloromethyl-1,1,3,3,3-hexafluoroisopropyl ether, from 1,1, 1,3, Binary catalytic system of 3,3-hexafluoro-2-propanol and 1,3,5-trioxanthene or paraformaldehyde in the main catalyst with anhydrous chlorinated Lewis acid and chlorine-containing compound as cocatalyst The reaction takes place to form chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether. technical background

Chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether is an important intermediate for the synthesis of fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether . The latter formula (CF ₃ ) ₂ CHOCH ₂ F, referred to as sevoflurane. In recent years, studies have found that sevoflurane has the characteristics of induction of anesthesia and rapid recovery, but also reduces cerebral vascular resistance, brain metabolic rate, brain oxygen consumption, myocardial contractile function and blood pressure, and is significantly less irritating to the respiratory tract. Other inhaled anesthetics have not seen liver and kidney toxicity. This is precisely the most desirable nature of modern inhalation anesthetics. As a new type of inhaled anesthetic, sevoflurane has received extensive attention and attention internationally.

U.S. Patent No. US4,250,334 and US4,469,898 describes the production of sevoflurane technical route, have taught with 1,1,1,3,3,3-hexafluoro-2-propanol (formula (CF ₃₎ ₂ CHOH , hereinafter referred to as HFIP) as a raw material for the reaction. U.S. Patent No. 4,469,8,98, the disclosure of HFIP to form sevoflurane with formaldehyde and hydrogen fluoride, protonating reagents, dehydrating reagents and fluorinating reagents; U.S. Patent 4,250,334 describes another technical route for the addition of HFIP to excess polymerization. The reaction is carried out in formaldehyde and hydrogen fluoride, while excess sulfuric acid is used to absorb the water generated during the reaction. The synthesis methods described in these two U.S. patents require the purification of the product due to the presence of by-products, and these by-products are difficult to remove; the use of highly corrosive hydrogen fluoride reagents and sulfuric acid in the production requires corrosion protection of the equipment. High, to some extent, increase the production cost of sevoflurane.

U.S. Patent No. 6,469,219 teaches direct fluorination of methyl hexafluoroisopropyl ether. Direct reaction requires the use of an extremely active BrF ₃ reagent to fluorinate methyl hexafluoroisopropyl ether. In this anti 0.5-lmol of BrF _{3 is} required to react with 0.67 mol of methyl hexafluoroisopropyl ether, and the reaction temperature is controlled between 20 and 50 °C. Direct fluorination can also be carried out directly with fluorine gas under argon protection. U.S. Patent No. 5,705,710 teaches the synthesis of sevoflurane using methoxymalononitrile and a highly active oxidizing fluorinating agent, bromine trifluoride.

Among the numerous patents for the study of sevoflurane, the technical routes for the production of sevoflurane described in U.S. Patent Nos. 6,100,434, 6,245,949 B1, US 6,271,422 and US 6,303,831 are most feasible. Among them, the method described in US 6,100,434 is the most economical and practical. The method is reacted with 1,1,1,3,3,3-hexafluoro-2-propanol, 1,3,5-trioxanthene or paraformaldehyde and anhydrous aluminum chloride for 20 hours. The intermediate chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether and the by-product H0A1C1 _{2 are formed} , followed by the addition of 6N HCl to remove the by-product H0A1C1 ₂ , and finally the intermediate chloromethyl group - 1,1,1,3,3,3-hexafluoroisopropyl ether is reacted with a fluorinating reagent or a solvent to obtain sevoflurane. Its advantage is that the raw materials are inexpensive and non-corrosive, and the equipment requirements are not high and the operation is simple. However, the reaction intermediate of the method, chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, has a relatively low yield and a low purity.

The recent international patent application, Publication No. WO 2008/037039 teaches obtaining high purity and high yield of chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl by enriching sulfuric acid or fuming sulfuric acid. Ether, but concentrated sulfuric acid or fuming sulfuric acid is very corrosive to equipment. Summary of the invention

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a process for the preparation of chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether. The method has high yield (at least 87%) and high purity (at least 98%). The reaction process is simple, economical, non-corrosive and environmentally friendly.

In order to achieve the above object, the technical solution adopted by the present invention is:

Using 1,1,1,3,3,3-hexafluoro-2-propanol and 1,3,5-trioxanthene or paraformaldehyde in the main catalyst of anhydrous Lewis acid, chlorine The reaction occurs in a binary catalytic system in which the compound is a cocatalyst to form chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether.

Wherein, the molar ratio of the chlorinated Lewis acid to the chlorine-containing compound is from 1:0.01 to 1:5. In order to allow the reaction to proceed better, the molar ratio of the Lewis acid to the chlorine-containing compound should be controlled from 1:0.01 to 1:2.

Molar ratio of 1,1,1,3,3,3-hexafluoro-2-propanol to 1,3,5-trioxanthene or paraformaldehyde The ratio is 1:0.5 to 1:5, and the optimum molar ratio is 1:0.5 to 1:2.

The molar ratio of 1,1,1,3,3,3-hexafluoro-2-propanol to the Lewis acid chloride is 1:0.1 to 1:5, and the optimum molar ratio is 1:0.1 to 1:2.

The chlorinated Lewis acid is selected from the group consisting of phosphorus trichloride, aluminum trichloride, ferric chloride or tin tetrachloride.

The chlorine-containing compound is selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, thionyl chloride, sulfuryl chloride or aluminum trichloride.

Among them, the reaction time is controlled to 5 to 8 hours.

The invention has the advantages of greatly improving the original process by using a low-cost binary catalytic system, greatly shortening the reaction time, and greatly improving the chloromethyl-1,1,1,3,3,3-hexafluoroiso The yield of propyl ether. The purity of chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether was 98% or more, and the yield was 87% or more. Detailed ways

CF ₃ CHCF ₃ CF.qCHCF

The reaction of the binary catalyst technical scheme is an exothermic reaction. When 1,3,5-trioxinium is used, the reaction proceeds slowly, and the process can be controlled relatively smoothly. When using paraformaldehyde, the reaction proceeds relatively quickly, but the exotherm is compared. severe. In theory, both can be used, but it depends on the specific situation and requirements. The addition of a chlorinated Lewis acid to the reaction is used to activate 1,3,5-trioxolane or paraformaldehyde and is used as a chlorinated group. The molar ratio of HFIP (purity 99%) to 1,3,5-trioxin or paraformaldehyde added in the reaction is 1:0.5 to 1:5; the molar ratio of HFIP to Lewis acid is 1 : 0.1 to 1:5. The chlorinated Lewis acid is one of phosphorus trichloride, aluminum trichloride, ferric chloride and tin tetrachloride. The reaction can be controlled at a temperature of from -20 ° C to 50 ° C. The chlorine-containing compound is one of sodium chloride, potassium chloride, lithium chloride, thionyl chloride, sulfuryl chloride, and aluminum trichloride. The molar ratio of the chlorinated Lewis acid to the chlorine-containing compound is from 1:0.01 to 1:5. In order to allow the reaction to proceed better, the molar ratio of the chlorinated Lewis acid to the chlorine-containing compound should be controlled from 1:0.01 to 1:2. The by-product H0A1C1 ₂ produced in the reaction has certain toxicity to chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether, which leads to chloromethyl-1,1,1,3. Degradation of 3,3-hexafluoroisopropyl ether. In particular, chloride ions in the product act as a Lewis acid, causing degradation of chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether. Therefore, it is preferable to remove the generated H0A1C1 ₂ . The method of removal is also simple. The prior art method can be used, for example, by diluting hydrochloric acid to decompose it, and the recovered H0A1C1 ₂ can be further reacted to prepare a raw material for the reaction, which is a chlorinated Lewis acid. Example 1

Add 27.0g (0.20mol) of anhydrous A1C1 ₃ and 8.5g to a 250ml dry three-necked vial

(0.20 mol) LiCl, cooled to -5 °C, and 20.5 ml (0.20 mol) of 1,1,1,3,3,3-hexafluoro-2-propanol (drip time 10 minutes) was added dropwise. After the completion of the dropwise addition, the mixture was continuously stirred for 15 minutes, 9.0 g (0.30 mol) of paraformaldehyde was added, the cooling bath was removed, and the white mixture was stirred at room temperature for 8 hours. After the completion of the reaction, the temperature was lowered to -5 ° C, 100 ml of 5N hydrochloric acid and 20 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to give 37.9 g of a colorless liquid. The purity of the gas chromatographic analysis was 99.3 %.

Example 2

27.0 g (0.20 mol) of anhydrous A1C1 _{3 was} added to a 250 ml dry three-necked flask, and the mixture was cooled to -5 ° C with stirring, and 20.5 ml (0.20 mol) of 1,1,1,3,3,3-hexafluoro-2- was added dropwise. Propanol (addition time 10 minutes). Then, 28.4 ml (0.40 mol) of thionyl chloride was added dropwise. After the completion of the dropwise addition, the mixture was continuously stirred for 15 minutes, 9.0 g (0.30 mol) of paraformaldehyde was added, the cooling bath was removed, and the white mixture was stirred at room temperature for 6 hours. After the reaction, the temperature was lowered to -5 ° C, 100 ml of 5N hydrochloric acid and 40 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to give 37.2 g of a colorless liquid. The purity was 98.2% by gas chromatography.

Example 3

27.5 g (0.20 mol) of anhydrous PC1 ₃ and 0.75 g (O.Olmol) KC1 were added to a 250 ml dry three-necked flask, and the mixture was cooled to -5 ° C with stirring, and 20.5 ml (0.20 mol ) of 1,1,1,3 was added dropwise. 3,3-Hexafluoro-2-propanol (addition time 10 minutes). After the completion of the dropwise addition, the mixture was continuously stirred for 15 minutes, 9.0 g (0.30 mol) of paraformaldehyde was added, the cooling bath was removed, and the white mixture was stirred at room temperature for 8 hours. Reaction After completion, the temperature was lowered to -5 ° C, 150 ml of 5N hydrochloric acid and 20 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to give 37.9 g of a colourless liquid. The purity was 99.3 % by gas chromatography. Example 4

86.3 g (0.65 mol) of anhydrous A1C1 ₃ and 1.2 g (0.02 mol) of sodium chloride were added to a 1000 ml dry three-necked flask, and the mixture was cooled to -10 ° C with stirring, and 58.9 ml (0.56 mol) of 1,1,1,3 was added dropwise. , 3,3-hexafluoro-2-propanol (addition time 20 minutes). After the completion of the dropwise addition, the mixture was continuously stirred for 30 minutes, 19.6 g (0.65 mol) of paraformaldehyde was added, the cooling bath was removed, and the white mixture was stirred at room temperature for 8 hours. After completion of the reaction, the temperature was lowered to -10 ° C, 150 ml of 6N hydrochloric acid and 100 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to give 105.2 g of a colorless liquid with a yield of 87.8% and a purity of 98.6% by gas chromatography. Example 5

1000.lg (0.75mol) anhydrous A1C1 ₃ and 1.4g were added to a 1000 ml dry three-necked flask.

(O.Olmol) sulfuryl chloride, cooled to -10 ° C with stirring, and added 59.3 ml (0.56 mol) of 1,1,1,3,3,3-hexafluoro-2-propanol (dropping time 30 minutes) . After the completion of the dropwise addition, the mixture was continuously stirred for 30 minutes, 61.3 g (0.29 mol) of 1,3,5-trioxinium was added, the cooling bath was removed, and the mixture was stirred at room temperature for 8 hours. After the reaction, the temperature was lowered to -10 ° C, 200 ml of 6N hydrochloric acid and 200 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to obtain 107.8 g of a colorless liquid with a yield of 89.1% and a purity of 98.5% by gas chromatography. Example 6

Add 31.3 g (0.12 mol) of anhydrous SnCl ₄ and 80.1 (0.60 mol) of anhydrous A1C1 _{3 to a} 1000 ml dry three-necked flask, and cool to -5 ° C with stirring, and add 60.0 mK 0.56 mol) 1,1, 1,3. 3,3-Hexafluoro-2-propanol (addition time 30 minutes). After the completion of the dropwise addition, the mixture was continuously stirred for 30 minutes, 25.5 g (0.85 mol) of paraformaldehyde was added, the cooling bath was removed, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the temperature was lowered to -5 ° C, 200 ml of 6N hydrochloric acid and 200 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to obtain 106.6 g of a colorless liquid. The yield was 88.1%, and the purity was 98.2% by gas chromatography. 75.0 g (0.56 mol) of anhydrous A1C1 ₃ and 48.0 g (1.12 mol) of LiCl were added to a 1000 ml dry three-necked flask, and the mixture was cooled to -5 ° C with stirring, and 59.2 ml (0.56 mol ) of 1,1,1,3,3 was added dropwise. , 3-hexafluoro-2-propanol (addition time 25 minutes). After the completion of the dropwise addition, the mixture was continuously stirred for 30 minutes, 15.0 g (0.65 mol) of paraformaldehyde was added, the cooling bath was removed, and the mixture was stirred at room temperature for 6 hours. After the completion of the reaction, the temperature was lowered to -5 ° C, 200 ml of 5N hydrochloric acid and 150 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to give 107.7 g of a colorless liquid. The purity was 98.5% by gas chromatography. Example 8

87.0 g (0.66 mol) of anhydrous A1C1 _{3 was} added to a 1000 ml dry three-necked flask, stirred and cooled to -10 ° C, and 20.6 ml (0.2 mol) of 1,1,1,3,3,3-hexafluoro-2-prop was added dropwise. Alcohol (addition time 10 minutes). Then 60.2 ml (0.5 mol) of thionyl chloride was added dropwise. After the completion of the dropwise addition, the mixture was continuously stirred for 30 minutes, 30.0 g (1.0 mol) of paraformaldehyde was added, the cooling bath was removed, and the mixture was stirred at room temperature for 8 hours. After the completion of the reaction, the temperature was lowered to -5 ° C, 150 ml of 6N hydrochloric acid and 200 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to obtain 38.0 g of a colorless liquid, yield: 88.3%, and the purity was 98.8% by gas chromatography. Example 9

Add 14.0 g (1.0 mol) of anhydrous A1C1 ₃ and 240.6 ml to a 1000 ml dry three-necked flask.

(2.02 mol) of thionyl chloride, cooled to -5 ° C with stirring, and 20.5 ml (0.20 mol) of 1,1,1,3,3,3-hexafluoro-2-propanol was added dropwise (dropping time 10 minutes) ). After the completion of the dropwise addition, the mixture was continuously stirred for 30 minutes, 25.0 g (0.84 mol) of paraformaldehyde was added, the cooling bath was removed, and the mixture was stirred at room temperature for 7 hours. After the reaction, the temperature was lowered to -5 ° C, 250 ml of 5N hydrochloric acid and 150 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to give 37.8 g of a colorless liquid, yield: 88.0%. The purity of the gas chromatographic analysis was 99.1%. Example 10

7.5 g (0.06 mol) of FeCl ₃ and 86.5 g (0.65 mol) of anhydrous A1C1 _{3 were} added to a 1000 ml dry three-necked flask, and the mixture was cooled to -5 ° C with stirring, and 60.0 ml (0.56 mol) of 1,1, 1,3 was added dropwise. 3,3-hexafluoro-2-propanol (addition time 30 minutes). After the completion of the dropwise addition, continue to stir for 30 minutes, add 25.5g (0.84mol) Paraformaldehyde was removed, the cold bath was removed, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the temperature was lowered to -5 ° C, 250 ml of 5N hydrochloric acid and 150 ml of water were added dropwise, and the mixture was stirred for 1 hour and then allowed to stand. The organic phase (lower layer) was separated to give 105.7 g of a colourless liquid. The purity was 98.8% by gas chromatography.

Claims

Claims:

CLAIMS 1. A process for the preparation of chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether from 1,1,1,3,3,3-hexafluoro-2-propanol Formed by reacting with 1,3,5-trioxanthene or paraformaldehyde, characterized in that: the reaction is a binary catalyst mainly composed of an anhydrous anhydrous Lewis acid and a chlorine-containing compound as a cocatalyst. In progress.

2. The method according to claim 1, wherein the molar ratio of the chlorinated Lewis acid to the chlorine-containing compound is from 1:0.01 to 1:5.

3. The method according to claim 1, wherein the molar ratio of the Lewis acid chloride to the chlorine-containing compound is from 1:0.01 to 1:2.

4. The method according to claim 1, wherein: 1,1,1,3,3,3-hexafluoro-2-propanol and 1,3,5-trioxanthene or oligomerization The molar ratio of formaldehyde is 1:0.5 to 1:5.

The method according to claim 1, wherein: 1,1,1,3,3,3-hexafluoro-2-propanol and 1,3,5-trioxanthene or oligomerization The molar ratio of formaldehyde is 1:0.5 to 1:2.

The method according to claim 2, wherein the molar ratio of 1,1,1,3,3,3-hexafluoro-2-propanol to the Lewis acid chloride is 1:0.1 to 1:5. .

7. The method according to claim 2, wherein the molar ratio of 1,1,1,3,3,3-hexafluoro-2-propanol to the Lewis acid chloride is 1: 0.1 to 1:2. .

The method according to any one of claims 1 to 7, wherein the chlorinated Lewis acid is selected from the group consisting of phosphorus trichloride, aluminum trichloride, iron trichloride or tin tetrachloride.

9. The method according to any one of claims 1 to 7, wherein the chlorine-containing compound is selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, thionyl chloride, sulfuryl chloride or trichlorination. aluminum.

10. A method according to any one of claims 1-9, characterized in that the reaction time of the reaction is 5 to 8 hours.