TW201100366A - A process for preparing chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether - Google Patents

Abstract

The present invention relates to a process for preparing chloromethyl-1, 1, 1, 3, 3, 3-hexafluoroisopropyl ether (sevochlorane) which includes the step of reacting hexafluoroisopropanol with either 1, 3, 5-trioxane or paraformaldehyde in the presence of an anhydrous chlorinating Lewis acid as primary catalyst and a chloride as promoter to produce sevochlorane. In particular, the present invention utilizes an inexpensive two-component catalyst system which greatly improves the yield and product purity, and reduces the reaction time compared with the prior art.

Description

201100366,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The main catalyst is catalyzed by == hexa-I perpropanol and U,5·trioxane or oligomerization, and the chlorine-containing compound is used as a catalyst for catalysis. (10) Binary silk (4) I 1 ' 3' 3, 3-hexafluoroisopropyl ether. [Prior Art] 1-Chloroindolyl 1,1,1,3,3,3-hexafluoroisopropyl acid is a syngas methyl, 1' 1' 3' 3' 3-', fluoroisopropyl ether An important intermediate. The latter molecule = 3) 2 (10) (10)' is referred to as the seven-fluoron test. In recent years, studies have shown that the characteristics of induction of anesthesia and wakefulness can also reduce brain resistance, brain metabolic rate, brain oxygen consumption, myocardial contractile function and blood pressure, and irritation to the respiratory tract. ·Below other inhaling anesthetics, it has not seen its liver and kidney toxicity. This is precisely the most desirable property of modern inhalation anesthetics. Heptafluoroscale As a new type of inhaled anesthetic, it has been widely and internationally recognized. US Patent Nos. 4,250,334 and 4,469,898 describe the technical route for the production of sevoflurane, which teaches U,l,3,3,3-hexafluoro-2-propanol (with a molecular formula of (CFOOOH') HFIP) is used as a reaction material. In U.S. Patent No. 4,469,898, HFIP is reacted with furfural and hydrogen fluoride, protonating reagents, dehydrating reagents and fluorinating reagents to form sevoflurane; U.S. Patent No. 4,250,334 describes another technique. By adding HFIp to the amount of 94694 201100366 polymethyl sulfonate and catalyzed hydrogen, while using excess sulfuric acid to absorb the water produced during the reaction. The synthesis methods described in the two US patents, due to by-products The existence of the product requires purification of the product, and these by-products are difficult to remove; the use of highly corrosive gasification gas reagents and sulfuric acid in the production requires higher anti-corrosion requirements for the equipment, and the heptafluorocarbon is improved to some extent. The production cost of the mystery. US Patent No. 6,469, 219 teaches direct fluorination of methyl hexafluoroisopropyl ether. The direct reaction requires the use of an extremely active BrFs reagent to fluorinate methyl hexafluoroisopropyl. 0.5 to 1 mol of BrF3 is required to react with 0.67 mol of methyl hexafluoroisopropyl ether, and the reaction temperature is controlled between 2 Torr and 50 ° C. Direct fluorination can also be carried out under argon gas with fluorine gas. Direct fluorination. U.S. Patent No. 5,705,710 teaches the synthesis of sevoflurane using decyloxymalononitrile and a highly active oxidizing fluorinating agent, bromine trifluoride. Among the numerous patents for the study of sevoflurane, the United States The technical route for the production of sevoflurane described in the patents US Pat. No. 6,100,434, US Pat. No. 6, 245, 949 B1, US Pat. No. 6, 271, 422 and US Pat. No. 6, 303, 831 is the most feasible. The method is most economical and practical. The method uses 1,1,1,3,3,3-hexafluoro-2-propanol, 1,3,5-trioxane or oligomeric oxime and anhydrous gasification. After 20 hours of reaction, 'the intermediate gas thiol-1,1,1,3,3,3-hexafluoroisopropyl ether and the by-product HOAlCh were formed, followed by the addition of 6N HCl to decompose the by-product HOAlCh' and finally from the intermediate chlorine. The thiol-1,1,1,3,3,3-hexa-isopropyl ray is reacted with a chaotic reagent and a solvent to prepare sevoflurane. The advantage is that the raw material is inexpensive and does not carry Button type, the equipment requirements are not high, easy to operate, but the reaction intermediate in the method, chloromercapto 94694 4 201100366 -1,1,1,3,3,3-hexafluoroisopropyl test yield is relatively low, The purity is not high. The recent international patent application 'Publication No. W〇2〇〇8/〇37039 teaches obtaining high purity and high yield of chloromethyl-1,1,1' 3' by adding concentrated sulfuric acid or fuming sulfuric acid. 3' 3-hexafluoroisopropyl 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 hydrazine. The method has high yield (at least 87%) and high purity (at least _, simple reaction process, economical application, non-corrosiveness, and environmental protection requirements. To achieve the above purpose, the technical solution adopted by the present invention is: 1,1'3'3,3-hexafluoro-2-propanol and 1,3,5-trioxacyclohexane 2 oligomeric formic acid fine anhydrous chlorinated Lewis acid as main catalyst, containing gasification = for promoting catalysis _ Binary catalytic system reaction produces gas methyl, I 1,3' 3, 3-hexafluoroisopropyl ether. Coffee ... and gas compound Mo Erbi (5) ar Louis 1 heart = 01 to 1: 5 ° In order to make the reaction proceed better, chlorination 2. 夂3, the molar ratio of the compound should be controlled at 1: 〇. 〇1 to j: # s L]', 3, 3, 3-hexafluoro-&quot ; 2-propanol and 1,3,5-dioxaindole pp $ low poly-methyl-mol ratio is 2;; oxa% is burned or until:: 2. Ub to 1.5' take the molar ratio 1:0.5 is:: ', the molar ratio of fluorine 2 propanol to gasified Lewis acid · 1 · 5 ' is 1 : 〗 〖 to: 94. 94694 5 201100366 The gasified Lewis acid Selected from phosphorus trichloride, aluminum trichloride, ferric chloride or tetrachlorin The chlorine-containing compound is selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, thionyl chloride, thioindigo chloride or aluminum trichloride. The reaction time is controlled to be 5 to 8 hours. The low-cost binary catalyst system greatly improves the conventional method, greatly shortens the reaction time, and greatly increases the yield of chloromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether. The purity of chloromethyl-1,1,3,3,3-hexafluoroisopropyl ether is 98% or more, and the yield is 87% or more.

CpCH2CI CF3CHCF3 OH CF3CHCF3 Paraformaldehyde or 1,3,5-trioxinium binary catalyst The reaction of the technical scheme is an exothermic reaction. When 1,3,5-trioxane is used, the reaction proceeds slowly, and the process can be controlled relatively smoothly. When oligodecanal is used, 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 chlorinated Lewis acid to the reaction is used to start 1,3,5-trioxane or paraformaldehyde and is used as a chlorinating group. The HFIP (purity 99%) and 1,3,5-trioxane or oligomeric furfural molar ratio added in the reaction is 1:0.5 to 1:5; HFIP and Lewisine acid chloride The molar ratio is 1: 0. 1 to 1: 5. Among them, chlorinated Lewis acid is a kind of 6 94694 201100366 among three gasified phosphorus, aluminum trichloride, three gas iron, and four gas tin. The reaction can be carried out under the conditions of -20 ° C to 5 、, and the w p gas-containing compound is sodium carbonate, potassium chloride or lithium chloride. Gas, trichlorinated in the species. The gasification of Lewis acid and sulfur-containing brewing ratio is (4) ^ in order to make the reaction better ^^^ The molar ratio of the amine acid and the chlorine-containing compound should be controlled to. The by-product HOAlCh is chlorine in the reaction. Methyl-i'丨丄1,2° hexafluoroisopropyl ether has certain toxicity and can cause chloroform, 3 〇-1,1,1,3,3, 3-hexafluoroisopropyl ether Degradation. In particular, the chloride ion in the product acts as a Lewis acid, which causes the degradation of the gas-based "1,1' ύ, d,3-hexafluoroiso-diyl ether. Therefore, it is preferable to remove the produced H〇A1Ch. The removal method is also very simple, and the method of the prior art can be used, for example, dilute hydrochloric acid can be added to decompose it, and the recovered H0A1Ch can be further prepared to prepare the raw material chlorinated Lewis acid required for the reaction. 〇 and 250ml dry three-necked flask were added 27. 〇g(〇2〇m〇1) anhydrous Aich 8. 5g (〇'2〇m〇l) LiCl, stirred to cool to -5 ° C, add 2 滴. 5ml • 20 η 〇 1) ι,1,1,3, 3, 3- hexafluoro-2-propanol (drip time ι〇 points. After the completion of the dropwise addition, continue to stir for 15 minutes, add 9. 0g (0 30m〇1 The low-concentration hydrazine was removed from the cold bath, and the white mixture was stirred at room temperature for 8 hours. After the reaction was completed, it was returned to -5 ° C, 10 〇 mi 5N hydrochloric acid and 20 ml of water were added dropwise, stirred for 1 hour, and then allowed to stand. Og(〇. 2〇mol) 。 。 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 Waterless 7 946 94 201100366 A1C13 'Co-mixed to _5 it, drop 9n 9 series; ^/ 罔 add 20.5ml (0·20mol) l,l,l,3,3,3- パiL-2-propylate (drip Add time rn A (] m 1 Λ匕 U knife in). Then add 28.4ml (0·40πιο1) sulphur sulfoxide. Drop (r, qn, χ, ', $ for 15 minutes, add 9. Og (〇.30raol) oligomeric furfural, shift, ^ eve, 'cold heart', stir the white mixture at room temperature for 6 small dozens. After the reaction, cool down, Ί,,, Wang' drop add l〇〇ml 5Ν hydrochloric acid and 40ml Sound: After the rest of the %, the organic phase (lower layer) is separated, 37.2 § no soil; = yield is 87. 2%. The purity of gas chromatography is 9 Example 3 25 Ο π 1 dry three bottles Knowing people / n 7, rn Π1 〇中力入27. 5§(〇·20πι〇1) Anhydrous PC13 and .5; (.丨:. Trace continued, eight in gas and 2' propanol (drip time 10 Minutes. After the completion of the drop, stir 15 knives, add 9._.3 〇 _ stir the white mixture for 8 hours at room temperature. After the r reaction, cool to -5 ° C, add 150ffil 5N hydrochloric acid and _ water, 3%。 After mixing for 1 hour, the mixture was allowed to stand. The separation was = = = 37.9g of colorless liquid, the yield was 88.1%. The purity of gas chromatography was 99.3% Example 4 10 0 0m 1 dry can be bottled into the bottle Τ Add 86.3g (0.65mol) of anhydrous A!Ch and 1 · 2g (0. 02m〇l) gasification of sodium, the mixture is cold, dripping Μ.—(0. 56mol)l, 1' 1' 3, 3, 3-hexa-2-propanol (addition time 2 〇 minutes). After the completion of the dropwise addition, continue for 30 minutes, add 19 6g (〇.65m (Di) oligomeric f aldehyde, remove the cold bath' and stir the white mixture at room temperature for 8 hours. After the reaction, cool down to -10C, add 150ml 6N The purity of the gas chromatographic chromatography is 87.8%, the yield is 94.8%, the yield is 94.8%, the purity is _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 56mol) 1,1,1,3,3,3-hexafluoro^2-propanol (addition time 30 minutes). After the completion of the dropwise addition, continue to stir for 30 minutes, add 61.3g (0·29mol) l, 3 , 5--trioxane, remove the cold bath, stir the mixture for 8 hours at room temperature. After the reaction, cool down to -10 ° C, add 200 ml of 6N hydrochloric acid and 200 ml of water, stir the mixture for 1 hour and then cool. 5%。 Example 6 was added to a 1000 ml dry three-necked flask. The purity was 98.5%. Example 6 was added to a 1000 ml dry three-necked flask. 3g (0. 12mol) anhydrous SnCh and 80. 1 (0. 60mol) anhydrous AI CI3 'Stir well to -5 ° C, add 60. 0ml (0. 56mol) l, 1,1,3, 3, 3-hexafluoro-2-propanol (addition time 30 minutes). After stirring for 30 minutes, 25. 5 g (0. 85 mol) of an oligomeric hydrazine Q aldehyde was added, the cold bath was removed, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the temperature was lowered to -5 ° C, and 200 ml of 6N hydrochloric acid was added dropwise. 2重量。 Example 7 1000ml Drying After the mixture was stirred for 1 hour, the mixture was allowed to stand for 1 hour. The organic phase was separated (the lower layer) to give 106. 6 g of a colorless liquid, the yield was 88.1%, and the purity was 98.2% by gas chromatography. 5毫升(0. 56摩尔)1,1,1, 3,5,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0 , 3, 3-hexa-H-2-propanol (addition time 25 minutes). After the completion of the dropwise addition, continue to stir for 30 minutes, add 15. 0g (0. 65mol) of low polymethyl 9 94694 201100366 aldehyde, remove the cold bath The mixture is stirred at room temperature for 6 hours. After the reaction is completed, the mixture is cooled to -5 ° C, 200 ml of 5N hydrochloric acid and 150 ml of water are added dropwise, and the mixture is stirred for 1 hour, and then the organic phase (lower layer) is separated to obtain 107. 7 g of a colorless liquid. The rate was 88.9%. 5%。 The purity of the gas chromatography was 98.5%. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Fluor-2-propanol (addition time 10 minutes). Then, 60.2 m (0.5 mol) of disulfoxide was added dropwise. After the completion of the dropwise addition, the mixture was continuously stirred for 30 minutes, and 30. 0 g (1.0 mol) of paraformaldehyde was added, the cold 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 allowed to stand. 8度/〇。 The purity of the purity of 98. 8 ° / 〇. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ l,1,1,3,3,3-hexafluoro-2-propanol (addition time 10 minutes). After the completion of the dropwise addition, the mixture was stirred for 30 minutes, and 25.0 g (0. 84 mol) of the oligomeric furfural was added, the cold bath was removed, and the mixture was stirred at room temperature for 7 hours. After the 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 allowed to stand for 1 hour, and then allowed to stand. 0%。 The organic phase (the lower layer) was obtained. 1%。 The purity of the gas chromatography was 99.1%. Oml (0. 56mol) is added dropwise. 7.5g (0.06 mol) of FeCh and 〇94694 201100366 86. 5g (0. 65mol) of anhydrous A1C13, stirred to -5 ° C, and added dropwise 60. Oml (0. 56mol) l,1,1,3,3,3-hexafluoro-2-propanol (addition time 30 minutes). After the completion of the dropwise addition, the mixture was stirred for 30 minutes, 25. 5 g (0. 84 mol) of the oligomeric formaldehyde was added, the cold bath was removed, and the mixture was stirred at room temperature for 5 hours. After the 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. 3%。 The organic phase (the lower layer) was obtained, 107.5 g of a colorless liquid, a yield of 87.3%. 8%。 The purity of the gas chromatography was 98.8%. [Simple description of the map]

Benefit [Main component symbol description] None 11 94694

Claims (1)

201100366 VII, the scope of application for patents: 1. The method for preparing gas methyl], ^ hexafluoroisopropyl silk, L 1 ' 1 ' 3 ' 3 ' 3- hexafluoro ~ 2- propanol and L 3, 5 _Trioxane or oligomethyl is formed, which is characterized in that the reaction is carried out by using anhydrous gasification of Lewis acid as a main catalyst and chlorine-containing compound as a catalytic system. The method of claim 2, wherein the moiré of the gasified Lewis acid and the gas-containing compound is 3. The method of claim 1 is characterized in that: The molar ratio of gasified Lewis acid and chlorine compounds is 丨: please go to 1:2. (For example, the method of applying for the patent (4) is characterized by: :, U, 3, 3, 3-hexafluoro-2-propanol and ι 3, 5_trioxane or paraformaldehyde The ratio is 1: 〇. 5 to J: 5. 5. The method of applying the scope of the patent item is characterized by: 1' 3, 3, 3-hexafluoro | propanol and l 3, 5_ trioxa The molar ratio of cyclohexene or paraformaldehyde is 1: 〇. 5 to 1: 2. 6. The method of applying for the special item, which is characterized by: : 4 1,3,3} hexafluoro- 2-propanol and lanthanum chloride bismuth: 0.1 to 1: 5. ^ 7. The method of applying for a patent is characterized by: HUS'3-hexafluoro-2-propanol and chlorinated Lub 0.1 to 1: 2. The closing ratio is 8. The method of any one of claims 1 to 7 of the patent application, characterized in that the deuterated Lewis acid is selected from the group consisting of trichloroplatin, three The method of any one of claims 1 to 7 wherein the chlorine-containing compound is selected from the group consisting of sodium chloride, Potassium chloride, lithium vapor, thionyl chloride, thioindigo chloride or aluminum trichloride. The method of any one of claims 1 to 7, characterized in that the reaction time of the reaction is 5 to 8 hours. 13 94694 201100366 IV. Designated representative map: There is no schema in this case (1) The representative representative map of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: This case does not represent the chemical formula 94694