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New synthetic method of sevoflurane

A sevoflurane, a new synthesis technology, applied in ether preparation, organic chemistry and other directions, can solve the problems of decreased yield and purity, unsuitable for industrial production, raw materials need to be recovered, etc., and achieves easy operation, easy control of reaction conditions, and three wastes discharge. less effect

Active Publication Date: 2010-02-17
福安药业集团重庆博圣制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it is disclosed in these two patent international applications that concentrated sulfuric acid, hexafluoroisopropanol, formaldehyde equivalents, and chlorinating reagents are reacted together to obtain chloromethyl ether, but Ogari Pacheco limits the chlorinating reagents to oxalyl chloride, tris Phosphorus chloride, phosphorus pentachloride, phosphorus oxychloride, and thionyl chloride; in addition, Ogari Pacheco et al. believe that the reaction is carried out under atmospheric humidity conditions, and aluminum trichloride is a very hygroscopic solid. Lower the yield and purity of the reaction
[0017] Although a variety of methods for synthesizing sevoflurane with hexafluoroisopropanol as raw materials have been disclosed in the prior art, there are still many deficiencies in these methods, such as not being suitable for industrial production, incomplete reaction, relatively low yield, and raw materials requiring Recycling; harsh reaction conditions such as pressurized, corrosion-resistant equipment; non-environmentally friendly reaction reagents or solvents
In addition, these methods also have the disadvantage of many by-products and complex components.

Method used

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  • New synthetic method of sevoflurane
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  • New synthetic method of sevoflurane

Examples

Experimental program
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Effect test

Embodiment 1

[0065] Add 400g of hexafluoroisopropanol, 84g of paraformaldehyde, and 30ml of concentrated sulfuric acid into a 500ml flask, stir and heat to 45-50°C, react for 2 hours, stop stirring, cool to room temperature, and set aside.

[0066] Add 300.0g of crude sevoflurane and 340g of anhydrous aluminum trichloride into a 3000ml three-necked bottle, cool down to 0°C and add the reaction solution to be used in Example 1 dropwise with stirring, control the temperature of the reaction solution to not exceed 10°C, add Complete the reaction at 0°C for 0.5 hours, heat up to 25-30°C, add polyethylene glycol 1000ml after reacting for 10 hours, add anhydrous potassium fluoride 232g while stirring, heat and reflux under normal pressure for 4 hours; normal pressure distillation, All fractions were collected to obtain a total of 661.5 g of crude sevoflurane (GC97.36%, yield 70.1%). The crude product was subjected to rectification to obtain 584.7 g of sevoflurane (GC 99.998%, yield 88.4%).

Embodiment 2

[0068] Add 400g of hexafluoroisopropanol, 84g of paraformaldehyde, and 40ml of concentrated sulfuric acid into a 500ml flask, stir and heat to 45-50°C, react for 2 hours, stop stirring, cool down to room temperature, and separate the lower layer of concentrated sulfuric acid for later use.

[0069] Add 300.0g of crude sevoflurane and 340g of anhydrous aluminum trichloride into a 3000ml three-necked bottle, cool down to 0°C and add the reaction solution to be used in Example 1 dropwise with stirring, control the temperature of the reaction solution to not exceed 10°C, add Complete the reaction at 0°C for 0.5 hours, heat up to 25-30°C, add polyethylene glycol 1000ml after reacting for 10 hours, add anhydrous potassium fluoride 232g while stirring, heat and reflux under normal pressure for 4 hours; normal pressure distillation, All fractions were collected to obtain a total of 676.5 g of crude sevoflurane (GC97.36%, yield 73.2%). The crude product was subjected to rectification t...

Embodiment 3

[0072] Add 300.0g of crude sevoflurane, 340g of anhydrous aluminum trichloride, 400g of hexafluoroisopropanol, and 84g of paraformaldehyde into a 3000ml three-necked bottle, cool down to 0°C and add 40ml of concentrated sulfuric acid dropwise with stirring to control the reaction liquid. The temperature does not exceed 10°C. After the addition, react at 0°C for 0.5 hours, heat up to 25-30°C, add 1000ml of polyethylene glycol after 10 hours of reaction, add 232g of anhydrous potassium fluoride while stirring, and heat to reflux under normal pressure. 4 hours; Atmospheric distillation, all fractions were collected to obtain 636.5 g of crude sevoflurane (GC97.36%, yield 65.3%). The crude product was subjected to rectification to obtain 542.3 g of sevoflurane (GC99.998%, yield 85.2%).

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Abstract

The invention discloses a method for applying methylating halogen, which is a new method to use hexafluoro isopropanol, formaldehyde equivalent, strong acid, alchlor and metal fluoride as raw materials to react so as to synthesize high-purity and high-yield sevoflurane. The method is characterized in that the reaction condition is easy to control without unnecessary intermediate processes of separation and purification, the post-treatment is simple, mostly raw materials and auxiliary materials can be recovered and used repeatedly so that the yield of the 'three wastes' is quite little, the product yield is high, the production time of single batch is shortened greatly, and the production efficiency is improved, thus the method is applicable to large-scale industrial production.

Description

technical field [0001] The present invention relates to the synthetic method of inhalable anesthetic, more specifically, relates to a new synthetic method of sevoflurane. Background technique [0002] Sevoflurane, chemical name: fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, was first approved for marketing in the United States in 1995, and is used for general anesthesia induction and maintenance of inhalation anesthesia medicine. [0003] Since sevoflurane is an α-fluoroalkyl ether, there are many difficulties in its chemical synthesis, among which different synthesis processes often lead to low yields, different by-products, and harsh reaction conditions. In the synthesis method of sevoflurane, the most commonly used raw material is 1,1,1,3,3,3-hexafluoroisopropanol (hereinafter referred to as hexafluoroisopropanol). Bernad M.Regan et al. reported in U.S. Patents US3683092 and US3689571 that hexafluoroisopropanol, polyoxymethylene and anhydrous hydrogen flu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C43/12C07C41/01
Inventor 汪天祥蒋晨郭子维
Owner 福安药业集团重庆博圣制药有限公司
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