Synthesis method of isoflurane

Abstract

The invention discloses a synthesis method of (1-chloro-2,2,2-trifluoroethyl)-difluoromethyl ether (isoflurane, whose structure is as the right figure), belonging to the field of pharmaceutical chemicals. The method takes (2,2,2-trifluoroethyl)-difluoromethyl ether (etherate) as starting material and comprises the following steps of: adding a right amount of water to the etherate; introducing chlorine for chlorination to obtain a mixture of isoflurane, a few impurities and unreacted etherate; carrying out fractionation to obtain the crude isoflurane; reducing the main impurity (1,1-dichloro-2,2,2-trifluoroethyl)-difluoromethyl ether by isopropanol under the sun light to obtain the azeotrope of the isoflurane and the acetone again; combining the collected crude isoflurane and the azeotrope; adding the acetone and carrying out distillation purification to obtain the isoflurane. The method has easy quality control, high yield, low cost and safe and convenient operation and is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of organic compounds, in particular to a synthesis method of (1-chloro-2,2,2-trifluoroethyl)-difluoromethyl ether, belonging to the field of medicine and chemical industry. Background technique [0002] Isoflurane is an inhaled general anesthetic and is the isomer of enflurane. Isoflurane is a colorless, transparent liquid with a special fragrance. The blood / air distribution coefficient is small, the anesthesia induction is stable, rapid and comfortable, the recovery is fast, the muscles relax well, and there is no excitatory effect on the sympathetic nervous system. Occasional nausea and vomiting, is currently commonly used clinical inhalation anesthetics. [0003] The synthetic method bibliographical report of isoflurane is more, and U.S. Patent US3535425 (1970) has reported following synthetic method, obtains corresponding methyl ether with trifluoroethanol and dimethyl sulfate reaction under basic condi...

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Problems solved by technology

[0018] 2. In the chlorination process of the etherified compound, the etherified compound needs to be dried, and a large amount of hydrogen chloride gas is generated after the reaction of chlorine gas, and the escape of the hydrogen chloride gas has a strong effect of carrying material, which requires a cryogenic cold trap for cooling and reflux ( The boiling point of the ether compound is only 29.5°C), which requires a lot of cooling power to be wasted in production

[0019] 3. In order to reduce the formation of by-products in the chlorination process, the molar ratio of ether compounds and chlorine is usually low, about 1:0.3, that is, the conversion rate is low during each chlorination, and too much chlorine will make by-products The product increases significantly, which not only reduces the yield, but also increases the difficulty of separation

[0020] 4. Since the selectivity of the three hydrogen atoms in the ether compound is not high when chlorinated, it is inevitable to generate by-products, among which (1,1-dichloro-2,2,2-trifluoroethane base)-difluoromethyl ether, which not only reduces the yield of isoflurane, but also increases the difficulty of three wastes treatment

[0024] The method solves the high-temperature reaction problem in the process of generating etherified compounds from the reaction of trifluoroethanol and Freon-22 by adding co-solvent NMP, and makes trifluoroethanol and Freon-22 realize equimolar reaction, but also adopts the method of drying ether The way of logical chlorine gas in the compound realizes the chlorination of the ether compound, so there is the same technical defect in the chlorination reaction step disclosed in US3761524, thereby causing the low conversion rate of the ether compound and the high technical problem of production cost (the conversion rate is about 40% , yield 80%)

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