CN114890875A - Preparation method of sevoflurane - Google Patents
Preparation method of sevoflurane Download PDFInfo
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- CN114890875A CN114890875A CN202210732955.0A CN202210732955A CN114890875A CN 114890875 A CN114890875 A CN 114890875A CN 202210732955 A CN202210732955 A CN 202210732955A CN 114890875 A CN114890875 A CN 114890875A
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/68—Preparation of metal alcoholates
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Abstract
A preparation method of sevoflurane, belonging to the technical field of organic fluorine chemical industry. The preparation method of the sevoflurane comprises the steps of firstly preparing hexafluoroisopropanol salt by using hexafluoroisopropanol and alkali as raw materials, and then preparing the sevoflurane by using hexafluoroisopropanol salt and chlorofluoromethane as raw materials. When the hexafluoroisopropanol salt is prepared, the hexafluoroisopropanol is prepared by an excess method, and the excess hexafluoroisopropanol can be removed by a method such as distillation. When preparing sevoflurane, the preparation method adopts an excess method of chlorofluoromethane, and the excess chlorofluoromethane is recovered and used as a raw material for continuous use. The preparation method of sevoflurane has the advantages of simple synthetic route, low cost, high product purity, low raw material consumption, less three-waste emission, high conversion rate, simple synthetic route, easy realization of reaction conditions and the like.
Description
Technical Field
The invention belongs to the technical field of organic fluorine chemical industry, and particularly relates to a preparation method of sevoflurane for anesthesia.
Background
The sevoflurane is chemically named as 1,1,1,3,3, 3-hexafluoro-2-fluoromethoxypropane, is an ideal inhalation anesthetic after halothane, enflurane and isoflurane, is approved by the American FDA to be marketed in 1995, and has the advantages of short induction period, quick recovery, easiness in metabolism, low blood gas distribution coefficient, hemodynamics stability, small adverse reaction to a human body, easiness in anesthesia depth regulation, nonflammability and explosiveness and the like. Sevoflurane is provided by an inhalation route to a warm-blooded animal that breathes air in a mixture with oxygen or a gaseous mixture containing oxygen in an amount sufficient to sustain respiration in an amount of about 1% to about 5% by volume. Sevoflurane is a particularly advantageous inhalation anesthetic because of its rapid loss of consciousness and rapid recovery, which are desirable characteristics of contemporary inhalation anesthetics. Therefore, the method is more and more paid attention and adopted by people in general anesthesia of the operation, and has wide application prospect.
The most commonly used starting material in the prior art sevoflurane synthesis methods is 1,1,1,3,3, 3-hexafluoroisopropanol (hereinafter abbreviated as hexafluoroisopropanol), Bernad M Regan et al report hexafluoroisopropanol, polyoxymethylene and anhydrous hydrogen fluoride in a ratio of 1:2:4 at about 9 ℃ for 2.5 hours in US3683092 and US3689571 to obtain a crystalline product polyether intermediate with a yield of 52%, which is then reacted with anhydrous hydrogen fluoride to obtain sevoflurane.
For example, Chinese patent CN 101337863B discloses a method for preparing intermediate compound methoxy methylene hexafluoroisopropyl ether [ (CF) by reacting hexafluoroisopropanol with dimethoxymethane 3 ) 2 CHOCH 2 OCH 3 ]Then, in the presence of strong acid, methoxy methylene hexafluoroisopropyl ether reacts with fluoride to prepare sevoflurane. Chinese patent CN 101314560B discloses a method for producing bis-hexafluoroisopropanol formal derivatives by reacting hexafluoroisopropanol with trioxymethylene (or paraformaldehyde) in the presence of acid; bis-hexafluoroisopropanol formal derivatives in the presence of anhydrous aluminum trihalides form halomethyl 2,2, 2-trifluoro-1- (trifluoromethyl) ethyl ethers which are reacted with metal fluorides. Chinese patent CN 100590111C discloses a method for synthesizing sevoflurane from hexafluoroisopropanol, trioxymethylene, strong acid, aluminum trichloride, and alkali metal fluoride. Chinese patent CN 1733675A discloses a method for preparing sevoflurane by reacting hexafluoroisopropanol, trioxymethylene and MF3 (such as BF3 and AlF 3).
US patent US4250334 reports the one-pot preparation of sevoflurane by adding polyoxymethylene to 96% sulfuric acid and hydrogen fluoride, heating to 65 c,and (4) dropwise adding hexafluoroisopropanol to react to obtain sevoflurane. One process for the preparation of sevoflurane is reported in US 5811596. Polyether R for the process 1 O(CH 2 O)nR 2 Reacting with 96% sulfuric acid and hydrogen fluoride to obtain sevoflurane. Wherein the polyether Comprises (CF) 3 ) 2 CHO(CH 2 O)nCH(CF 3 ) 2 Wherein n is 1,2, is obtained by reacting hexafluoroisopropanol, 98% sulfuric acid and polyoxymethylene. In US5990359, a method for synthesizing sevoflurane is reported, in which hexafluoroisopropanol is firstly reacted with polyformaldehyde (or 1,3, 5-trioxane) in the presence of an oxidant (aluminum trichloride or phosphorus trichloride) to obtain 2, 2-trifluoro-1- (trifluoromethyl) ethyl ether (hereinafter referred to as chloromethyl ether), and then the chloromethyl ether is reacted with a fluorinating agent (such as potassium fluoride, sodium fluoride, etc.) and distilled to obtain sevoflurane. U.S. Pat. No. 6,459,49 reports the reaction of hexafluoroisopropanol with formal in the presence of zinc Chloride (CF) 3 ) 2 CHOCH 2 OCH 3 Then PEG400 reacts with potassium fluoride under the action of the mixture and the sevoflurane is obtained by distillation. U.S. Pat. No. 4,4996371 reports the reaction of hexafluoroisopropanol with bromoacetic acid under basic conditions to give hexafluoroisopropoxyacetic acid using BrF 3 And carrying out fluorination to prepare the sevoflurane. Chinese patent CN 101381289A discloses a new method for synthesizing sevoflurane by taking hexafluoroisopropanol, formaldehyde equivalent, strong acid, aluminum trichloride and metal fluoride as raw materials. Chinese patent CN 110105178A discloses a new method for synthesizing sevoflurane intermediate chloromethyl-1, 1,1,3,3, 3-hexafluoroisopropyl ether by dissolving hexafluoroisopropanol, anhydrous aluminum trichloride, and paraformaldehyde in acetonitrile, reacting under homogeneous conditions, acidifying with hydrochloric acid solution, standing for separation, and washing with water. Although various methods for synthesizing sevoflurane from hexafluoroisopropanol have been disclosed in the prior art, these methods have various disadvantages such as unsuitability for industrial production, complicated reaction steps, incomplete reaction, low yield, and need to recover the raw materials; the reaction conditions are harsh, such as the equipment needs to resist corrosion; the reaction reagents or solvents are not environmentally friendly, etc. In addition, these methods have the disadvantage that the by-products are more complex in terms of their composition.
The above methods can be summarized into two types according to the difference of the fluorinating agent: one type uses hydrogen fluoride as a fluorinating agent, and the hydrogen fluoride is strong acid with high corrosivity, so the hydrogen fluoride has high corrosivity on equipment, high requirement on operators and high danger, and is gradually eliminated. The other type is alkali metal fluoride, which is used for producing sevoflurane on a large scale, after the sevoflurane is synthesized by the method, feed liquid is in a solid-liquid mixed state containing sevoflurane, excessive metal fluoride, generated metal chloride, unreacted initial substances, impurities generated in the reaction process and the like, and in the existing patent documents, the sevoflurane is extracted by direct distillation after the reaction is finished, and then the sevoflurane finished product is obtained by repeated rectification. Research finds that direct distillation of solid-liquid mixed feed liquid is not beneficial to industrial production: on one hand, the temperature in the distillation kettle gradually rises, the boiling point of the received fraction gradually decreases, which shows that the solid-liquid remained in the kettle has side reaction to generate new impurities with low boiling point, and the content of the impurities increases along with the rise of the temperature, and the retention time of the impurities is close to that of sevoflurane observed from a gas phase map, so that the impurities are difficult to remove in the subsequent rectification process, repeated rectification is needed, the working hours are consumed, the product yield is influenced, and the production cost is increased; on the other hand, most of the kettle residues in the distillation kettle are carbonized solids, cannot be recycled, are difficult to treat and have great pollution to the environment.
Therefore, there is still a need to develop a new method for synthesizing sevoflurane, so as to overcome the defects and shortcomings of the prior art and better realize the industrialization of sevoflurane.
Disclosure of Invention
Aiming at the defects in the prior art, the inventor finds a method for preparing sevoflurane by taking hexafluoroisopropanol and chlorofluoromethane as main raw materials through long-time experiments and exploration, and has the advantages of low raw material consumption, simple and controllable operation, less three-waste discharge, low cost, high conversion rate, simple synthetic route, high product purity, easy realization of reaction conditions and the like.
The technical scheme adopted by the invention for achieving the purpose is as follows:
a preparation method of sevoflurane comprises the steps of firstly preparing hexafluoroisopropanol salt by taking hexafluoroisopropanol and alkali as raw materials, and then preparing sevoflurane by taking hexafluoroisopropanol salt and chlorofluoromethane as raw materials, and is characterized by comprising the following steps:
(1) adding alkali into hexafluoroisopropanol to react, and distilling the reaction solution under reduced pressure after the reaction is finished until no fraction is generated to obtain hexafluoroisopropanol salt;
(2) reacting hexafluoroisopropanolate prepared in the step (1) with chlorofluoromethane, carrying out solid-liquid separation after the reaction is finished, and distilling organic phase filtrate to obtain a sevoflurane crude product;
(3) and purifying the crude sevoflurane to obtain sevoflurane.
The synthetic route is as follows:
preferably, the alkali is NaOH or CH 3 ONa、KOH、Na 2 CO 3 、K 2 CO 3 、CH 3 CH 2 ONa, and the like.
Preferably, the molar ratio of hexafluoroisopropanol to base in step (1) is 1.5-10: 1.
Preferably, the reaction temperature in the step (1) is 50-90 ℃, the reaction pressure is 0.1-1.0Mpa, and the reaction time is 4-12 h.
Preferably, the mole ratio of the chlorofluoromethane to the hexafluoroisopropoxide in step (2) is 1.1-5: 1.
Preferably, the reaction temperature in the step (2) is 60-80 ℃, the reaction pressure is 0.2-0.8Mpa, and the reaction time is 6-10 h.
Preferably, a high-pressure reaction kettle is used as the reaction vessel in the step (2).
Preferably, the reaction system in step (2) uses an aprotic polar solvent as a reaction solvent.
Preferably, in the reaction system of step (2), any one of acetonitrile, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, DMI and NMP is used as a reaction solvent.
Preferably, in the step (2), the chlorofluoromethane is filled into the high-pressure reaction kettle according to the specified quality by cooling the reaction kettle.
Preferably, the solid-liquid separation in the step (2) is performed by filtration with a suction filtration method.
Preferably, the organic phase filtrate distillation in the step (2) is carried out by adopting a negative pressure distillation mode.
Preferably, the crude sevoflurane in step (3) is purified by distillation.
The preparation method of the sevoflurane comprises the steps of preparing hexafluoroisopropanol salt by taking hexafluoroisopropanol and alkali as raw materials, and preparing sevoflurane by taking hexafluoroisopropanol salt and chlorofluoromethane as raw materials. In the production of hexafluoroisopropanol, hexafluoroisopropanol was produced in excess, and the excess hexafluoroisopropanol was removed by distillation or the like, see the production method of hexafluoroisopropanol disclosed in CN 11281207A. When preparing sevoflurane, the preparation method adopts an excess method of chlorofluoromethane, and the excess chlorofluoromethane is recovered and used as a raw material for continuous use.
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation method of the sevoflurane has the advantages that the raw material of the chlorofluoromethane is easy to obtain, the hexafluoroisopropanol and the chlorofluoromethane which are completely converted can be directly reused, and the recovery and purification operations are reduced.
2. The preparation method of sevoflurane is convenient to operate, reduces the production cost, and is safe and environment-friendly.
3. The preparation method of sevoflurane has the advantages of low raw material consumption, simple and controllable operation, less three-waste discharge, low cost, high conversion rate, simple synthetic route, high product purity, easy realization of reaction conditions and the like.
Detailed Description
The present invention will be further described with reference to the following specific examples, but the present invention is not limited to these examples. It will be appreciated by those skilled in the art that the present invention encompasses all alternatives, modifications and equivalents as may be included within the scope of the claims.
Example 1
Preparation of sodium hexafluoroisopropoxide: adding excessive hexafluoroisopropanol into a reactor, adding NaOH in batches while stirring, and reacting for 2-6h at 50 ℃. And then distilling the reaction solution under reduced pressure until no fraction is generated, and drying the obtained solid at 70 ℃ for 6-8h to obtain the sodium hexafluoroisopropoxide.
Example 2
Preparing sevoflurane: 500.0g of acetonitrile and 190.0g of sodium hexafluoroisopropoxide are added into a 1L high-pressure reaction kettle, the reaction kettle is cooled to minus 7 ℃ by a refrigerating machine under the condition of stirring, and 100.0g of chlorofluoromethane is filled. Slowly heating to 70 ℃, reacting for 8 hours, stopping heating, cooling to room temperature, and collecting unreacted chlorofluoromethane through a vent valve of the reaction kettle. And (4) carrying out suction filtration to realize liquid-solid separation, and carrying out reduced pressure distillation on the organic phase to obtain a crude sevoflurane product.
And (3) adding the crude sevoflurane product into a rectifying device for rectifying to obtain 165.04g of qualified sevoflurane product, wherein the yield is 78.50% (calculated according to sodium hexafluoroisopropoxide), and the purity is as follows: 99.995% (GC method).
Example 3
The reaction time was changed to 10 hours based on example 2, the reaction conditions were the same as in example 1, and the reaction results are shown in Table 1.
Example 4
The reaction temperature was changed to 80 ℃ on the basis of example 2, the remaining reaction conditions were the same as in example 1, and the reaction results are shown in Table 1.
Example 5
The reaction temperature was changed to 60 ℃ on the basis of example 2, and the reaction conditions were the same as in example 1, and the reaction results are shown in Table 1.
Example 6
The reaction solvent was changed to N, N-dimethylformamide based on example 2, and the reaction conditions were the same as in example 2, and the reaction results are shown in Table 1.
Example 7
The charging amount of chlorofluoromethane was changed from 100.0g to 205.4g based on example 2, and the reaction conditions were the same as in example 2, and the reaction results are shown in Table 1.
Example 8
On the basis of example 2, the acetonitrile feeding amount is changed from 500.0g to 370.0g, the reaction conditions are the same as example 2, and the reaction results are shown in Table 1.
TABLE 1 test results of the contents of the components under different reaction conditions
| Examples | Total yield/% | Purity of sevoflurane/%) |
| 2 | 78.50 | 99.995 |
| 3 | 80.27 | 99.995 |
| 4 | 81.31 | 99.995 |
| 5 | 76.28 | 99.995 |
| 6 | 82.75 | 99.995 |
| 7 | 79.36 | 99.995 |
| 8 | 81.57 | 99.995 |
The above table shows that the preparation method of sevoflurane has the advantages of high conversion rate, simple synthetic route, high product purity and easy realization of reaction conditions. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A preparation method of sevoflurane is characterized by comprising the following steps:
1) adding alkali into hexafluoroisopropanol to react, and distilling the reaction solution under reduced pressure after the reaction is finished until no fraction is generated to obtain hexafluoroisopropanol salt;
2) reacting hexafluoroisopropanolate prepared in the step 1) with chlorofluoromethane, carrying out solid-liquid separation after the reaction is finished, and distilling organic phase filtrate to obtain a sevoflurane crude product;
3) and purifying the crude sevoflurane to obtain sevoflurane.
2. A process for the preparation of sevoflurane according to claim 1, wherein: the alkali in the step 1) is NaOH or CH 3 ONa、KOH、Na 2 CO 3 、K 2 CO 3 、CH 3 CH 2 Any one of ONa.
3. A process for the preparation of sevoflurane according to claim 1, wherein: the molar ratio of the hexafluoroisopropanol to the base in step 1) is 1.5-10: 1.
4. A process for the preparation of sevoflurane according to any one of claims 1-3, wherein: the reaction temperature in the step 1) is 50-90 ℃, the reaction pressure is 0.1-1.0Mpa, and the reaction time is 4-12 h.
5. A process for the preparation of sevoflurane according to claim 1, wherein: the molar ratio of the chlorofluoromethane to the hexafluoroisopropoxide in the step 2) is 1.1-5: 1.
6. A process for the preparation of sevoflurane according to any one of claims 1 or 5, wherein: the reaction temperature in the step 2) is 60-80 ℃, the reaction pressure is 0.2-0.8Mpa, and the reaction time is 6-10 h.
7. A process for the preparation of sevoflurane according to claim 1, wherein: in the step 2), a high-pressure reaction kettle is used as a reaction container, and an aprotic polar solvent is used as a reaction solvent in a reaction system.
8. A process for the preparation of sevoflurane according to any one of claims 1 or 7, characterized by: in the reaction system in the step 2), any one of acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, DMI and NMP is used as a reaction solvent.
9. A process for the preparation of sevoflurane according to claim 1, wherein: and 2) charging the chlorofluoromethane into the high-pressure reaction kettle according to the specified quality in a way of cooling the reaction kettle in the step 2).
10. A process for the preparation of sevoflurane according to claim 1, wherein: and 2) filtering the solid-liquid separation in the step 2) by adopting a suction filtration mode, and distilling the organic phase filtrate by adopting a negative pressure distillation mode.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101314560A (en) * | 2008-07-02 | 2008-12-03 | 鲁南制药集团股份有限公司 | Process for synthesizing Sevoflurane |
| CN101659603A (en) * | 2008-08-27 | 2010-03-03 | 浙江蓝天环保高科技股份有限公司 | Method for preparing fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101314560A (en) * | 2008-07-02 | 2008-12-03 | 鲁南制药集团股份有限公司 | Process for synthesizing Sevoflurane |
| CN101659603A (en) * | 2008-08-27 | 2010-03-03 | 浙江蓝天环保高科技股份有限公司 | Method for preparing fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether |
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