Industrial preparation method of sevoflurane

Abstract

The invention relates to an industrial preparation method of sevoflurane. Specifically, the invention relates to a preparation method of sevoflurane, and the method comprises a step of reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, and a step of preliminary impurity removal and rectification. The sevoflurane prepared by the preparation method disclosed by the invention has the advantages of high purity, high yield and less waste, and is beneficial to industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to an industrial preparation method of sevoflurane. Background Art

[0002] Sevoflurane (fluoromethyl-1, 1, 1, 3, 3, 3-hexafluoroisopropyl ether) is a halogenated volatile anesthetic that is widely used in clinical practice due to its rapid onset of action and few side effects.

[0003] CN108689808A discloses a method for preparing sevoflurane, comprising the steps of preparing chloromethyl hexafluoroisopropyl ether and reacting chloromethyl hexafluoroisopropyl ether with fluoride.

[0004] The current process for preparing sevoflurane generally has a low yield and produces a variety of impurities, some of which have properties similar to those of sevoflurane. Distillation is a commonly used method for refining sevoflurane, but even if the impurities are removed by distillation purification, the sevoflurane product still contains some impurities that are difficult to remove. According to the Chinese Pharmacopoeia, the purity of the main component of medical sevoflurane must be ≥99.9%. The impurity limits for sevoflurane in foreign pharmacopoeias are more stringent. For example, the European Pharmacopoeia stipulates that the content limit of a single impurity in sevoflurane cannot exceed 100ppm.

[0005] In addition, dichloromethane is a unique impurity in the process of synthesizing sevoflurane by catalysis of polyhydroxy compounds. It is produced during the fluorination process and has a boiling point of 39°C. At present, this impurity is mainly removed by distillation fore-fraction, but a large amount of sevoflurane product will be distilled out together with dichloromethane during the distillation process. Therefore, in order to remove this impurity, the fore-fraction containing a large amount of sevoflurane needs to be discarded, resulting in large losses in the distillation operation and low yield.

[0006] CN1177953A discloses a method for purifying sevoflurane by molecular sieves, which comprises further purifying the sevoflurane product after distillation by molecular sieves to improve the purity. The method can significantly remove the bisfluoromethyl ether impurity. However, in actual production, it is found that molecular sieves such as 4A molecular sieves have poor adsorption capacity for other impurities in sevoflurane, and the 4A molecular sieve purification method has limited effect on improving the product quality of sevoflurane.

[0007] CN119019217A discloses a method for purifying sevoflurane by molecular sieve. The method is to further purify the sevoflurane product after distillation by molecular sieve to improve the purity. However, the method cannot improve the distillation yield of sevoflurane.

[0008] ZSM-5 molecular sieve has MFI topological structure, and its Si / Al ratio can be adjusted in a wide range. The three-dimensional ten-membered ring channel structure of ZSM-5 molecular sieve makes it have certain characteristics in the fields of catalysis, adsorption, separation, etc. It also has certain shape selectivity. For example, it can be used for catalytic cracking of light gasoline and catalytic cracking to produce more propylene additives in the fields of petrochemicals and fine chemicals. It can be used for selective catalytic reduction of nitrogen oxides (NOx) in the field of tail gas purification. In addition, it can be used for rapid adsorption of volatile organic compounds (VOCs) in terms of adsorption and can replace activated carbon, etc.

[0009] In recent years, some composite materials of molecular sieves have also appeared to enhance the performance of molecular sieves. For example, PingZhang et al. (Journal of Chemistry, vol. 2022, Article ID 7207403, 7 pages, 2022) disclosed a class of ZSM-5-300 and ZSM-5-360 composite fillers formed by loading molecular sieves onto cordierite honeycomb ceramics by a coating method. Yoon Jong Yoo et al. (Journal of the Korean Ceramic Society Vol. 39, No. 11, pp. 1035 1041, 2002.) disclosed a class of honeycomb composite fillers (hereinafter referred to as ZSM-5-1 composite fillers) prepared by impregnating ZSM-5 molecular sieves into ceramic paper by a coating method. These composite fillers all have good adsorption properties. Summary of the invention

[0010] The present disclosure provides a new industrial preparation method of sevoflurane, which can effectively remove impurities such as dichloromethane in crude sevoflurane, and is more conducive to subsequent distillation operations. The specific method is different from the prior art such as CN119019217A. A new molecular sieve is used to purify the molecular sieve before the distillation of sevoflurane, which significantly improves the distillation yield, and the purity of sevoflurane after distillation is high, meeting medical needs. The prior art has not paid attention to the problem of how to improve the distillation yield, and the present disclosure also proves that the molecular sieves provided by the prior art such as CN119019217A cannot improve the distillation yield.

[0011] The present disclosure provides a method for preparing sevoflurane, the method comprising: 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, adding water and distilling after the reaction to obtain a crude sevoflurane product 1, wherein the content of dichloromethane in the crude sevoflurane product 1 is greater than 100 ppm; 2) adding a composite filler adsorbent selected from ZSM-5-300, ZSM-5-360 and ZSM-5-1 to the crude sevoflurane 1, stirring, standing, and filtering to obtain the crude sevoflurane 2; 3) distilling the crude sevoflurane 2 to obtain a finished sevoflurane product, wherein the content of dichloromethane in the finished sevoflurane product is less than 100 ppm; Wherein, the crude distillation yield of sevoflurane is greater than 65%.

[0012] The crude distillation yield of sevoflurane disclosed in the present invention refers to the ratio of the weight of the finished sevoflurane product with a dichloromethane content of less than 100 ppm obtained after the distillation operation to the weight of the crude sevoflurane 1. The crude distillation yield of the crude sevoflurane 1 directly distilled in the prior art is relatively low. However, the crude distillation yield of the crude sevoflurane 1 disclosed in the present invention after being treated with a specific molecular sieve can be increased by more than 14%.

[0013] In some embodiments, the crude distillation yield of sevoflurane is greater than 68%, or greater than 70%, or greater than 72%.

[0014] In some embodiments, the molar ratio of chloromethyl hexafluoroisopropyl ether and potassium fluoride is selected from 1: 1-1: 5, such as 1:2.5-1:3.5, such as 1:2.6-1:3.1.

[0015] In some embodiments, the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol is selected from 1: 0.1-1: 0.5, for example 1: 0.15-1: 0.25, for example 1: 0.17-1: 0.23.

[0016] In some embodiments, the reaction solvent for the reaction of chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol is sulfolane.

[0017] In some embodiments, the reaction temperature is a reflux reaction, for example, 70-110° C., to achieve reflux temperature.

[0018] In some embodiments, the purity of the finished sevoflurane is greater than 99.95%, such as greater than 99.96%, 99.97%, or 99.98%.

[0019] In some embodiments, the weight ratio of the crude sevoflurane 1 to the adsorbent is selected from 1: 0.01-1: 0.1, for example, 1: 0.03-1: 0.06.

[0020] In some embodiments, the ZSM-5-300 composite filler has a Si / Al ratio of 300 and a specific surface area of ​​358 m² / g.

[0021] In some embodiments, the content of dichloromethane in the finished sevoflurane product is less than 50 ppm, or less than 40 ppm.

[0022] In some embodiments, the method comprises: 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, adding water and distilling after the reaction to obtain a crude sevoflurane product 1, wherein the content of dichloromethane in the crude sevoflurane product 1 is greater than 100 ppm, the molar ratio of chloromethyl hexafluoroisopropyl ether to potassium fluoride is selected from 1:2.5-1:3.5, the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol is selected from 1:0.15-1:0.25, and the reaction solvent is sulfolane; 2) adding ZSM-5-300 composite filler to the crude sevoflurane 1, stirring, standing, filtering, and obtaining the crude sevoflurane 2, wherein the weight ratio of the crude sevoflurane 1 to the composite filler is selected from 1: 0.01-1: 0.1; 3) distilling the crude sevoflurane 2 to obtain a finished sevoflurane product, wherein the content of dichloromethane in the finished sevoflurane product is less than 50 ppm; Wherein, the yield of the distillation operation of sevoflurane is greater than 70%.

[0023] The preparation method of sevoflurane disclosed in the present invention is to add a composite filler for preliminary impurity removal before the distillation operation, which greatly reduces the content of low-boiling impurities such as dichloromethane. When the distillation operation is performed later, the purity of the distillate containing sevoflurane is significantly improved, and there is no need to discard the front fraction. The overall yield of sevoflurane is significantly increased by more than 14%, which is of great significance for industrial production. Moreover, when the ZSM-5-300 composite filler is used for preliminary impurity removal, the dichloromethane impurity content in the sevoflurane distillate is significantly lower than 100ppm, which can fully meet the content limit requirements for a single impurity in sevoflurane in the pharmacopoeias of various countries. In the existing preparation method, there are many low-boiling impurities in the crude sevoflurane product, and a large amount of sevoflurane product will be lost when the low-boiling impurities are removed by distillation operation, resulting in great waste.

[0024] The impurity content in the sevoflurane disclosed in the present invention can be detected by gas chromatography. The detection method can refer to the existing technology or the methods disclosed in the pharmacopoeias of various countries, such as the methods described in EP1165478B, CN103635451A, etc. DETAILED DESCRIPTION

[0025] The present disclosure will be explained in detail below in conjunction with specific examples so that those skilled in the art can have a more comprehensive understanding of the present disclosure. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

[0026] Example 1: Preparation of chloromethyl hexafluoroisopropyl ether Add 700g of chloromethyl hexafluoroisopropyl ether and 1030g of aluminum chloride to the reaction bottle, cool to -5℃~0℃, add 1000g of hexafluoroisopropanol dropwise while stirring, continue stirring for 0.5 hours after the dropwise addition, then add 190g of paraformaldehyde, and stir to react until the reaction is complete. Cool to below 0℃, add 2L of 6mol / L hydrochloric acid dropwise, separate the organic layer, wash twice with water, remove the solvent initially added to the reaction, and obtain 1205g of chloromethyl hexafluoroisopropyl ether with a GC purity of 99.3%.

[0027] Example 2: Treatment with ZSM-5-300 molecular sieve 2250g of sulfolane, 525g of potassium fluoride and 150g of pentaerythritol were added to the reaction flask, and then 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water were added. Heat to reflux reaction for 5 hours, cool naturally to room temperature, add 800mL of purified water, and distill to obtain 542g of crude sevoflurane distillation product, and GC measured the dichloromethane content of 176ppm. Then 27g of ZSM-5-300 composite filler was added to the crude distillation product, stirred for 1 hour, allowed to stand for 0.5 hours, filtered, and the filtrate was purified by distillation. First, the fore fraction was collected at a temperature of about 58°C to obtain 401g of the fore fraction, wherein the purity of sevoflurane was 99.990%, the content of dichloromethane was 24ppm, and the purity of sevoflurane was up to standard, which could be used as a positive component, the crude product distillation yield was 73.9%, and the comprehensive yield was 62% (in terms of chloromethyl hexafluoroisopropyl ether).

[0028] Example 3: Treatment with ZSM-5-360 molecular sieve 2250g of sulfolane, 525g of potassium fluoride and 150g of pentaerythritol were added to the reaction flask, and then 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water were added. Heat to reflux reaction for 5 hours, cool naturally to room temperature, add 800mL of purified water, and distill to obtain 546g of crude distillation product of sevoflurane, and GC measured the content of dichloromethane therein as 174ppm. Then 28g of ZSM-5-360 composite filler was added to the crude distillation product, stirred for 1 hour, allowed to stand for 0.5 hours, filtered, and the filtrate was purified by distillation. First, the fore fraction was collected at a temperature of about 57.9°C to obtain 408g of the fore fraction, wherein the purity of sevoflurane was 99.985%, the content of dichloromethane was 84ppm, and the purity of sevoflurane was up to standard, which could be used as a positive component, the crude product distillation yield was 74.7%, and the comprehensive yield was 63.1% (in terms of chloromethyl hexafluoroisopropyl ether).

[0029] Example 4: Treatment with ZSM-5-1 molecular sieve 2250g of sulfolane, 525g of potassium fluoride and 150g of pentaerythritol were added to the reaction flask, and then 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water were added. Heat to reflux reaction for 5 hours, cool naturally to room temperature, add 800mL of purified water, and distill to obtain 538g of crude distillation product of sevoflurane, and GC measured the dichloromethane content of 170ppm. Then 27g of ZSM-5-1 composite filler was added to the crude distillation product, stirred for 1 hour, allowed to stand for 0.5 hours, filtered, and the filtrate was purified by distillation. First, the fore fraction was collected at a temperature of about 57.9°C to obtain 398g of the fore fraction, wherein the purity of sevoflurane was 99.985%, the content of dichloromethane was 88ppm, and the purity of sevoflurane was up to standard, which could be used as a positive component, the crude product distillation yield was 74%, and the comprehensive yield was 61.5% (in terms of chloromethyl hexafluoroisopropyl ether).

[0030] Example 5: Amplification reaction In a 1000L reactor, add 321.43kg sulfolane, 75kg potassium fluoride and 21.43kg pentaerythritol, then add 100kg chloromethyl hexafluoroisopropyl ether and 17.9kg purified water. Heat to reflux, stir until the reaction is complete, cool, add 107kg purified water, and distill to obtain 78.2kg of crude sevoflurane. Then add 3.9kg ZSM-5-300 composite filler to the distilled crude product, stir for 5 hours, let stand for 2 hours, filter, and distill the filtrate to obtain 59.8kg of sevoflurane, with a GC purity of 99.988%, a crude product distillation yield of 76.5%, and a comprehensive yield of 64.7% (based on chloromethyl hexafluoroisopropyl ether).

[0031] Comparative Example 1: Crude product without molecular sieve treatment 2250g of sulfolane, 525g of potassium fluoride and 150g of pentaerythritol were added to the reaction flask, and then 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water were added. Heat to reflux reaction for 5 hours, cool naturally to room temperature, add 800mL of purified water, and distill to obtain 537g of crude distillation product of sevoflurane, and GC measured the dichloromethane content of 180ppm. The crude product was then purified by distillation, and the front fraction was first collected at a temperature of about 56.2°C to obtain 80g of the front fraction, wherein the purity of sevoflurane was 99.82%, the dichloromethane content was 1100ppm, and the purity of sevoflurane was not up to standard. Then the positive component was collected at a temperature of about 58°C to obtain 315g of sevoflurane, GC purity was 99.992%, the dichloromethane content was 12ppm, the crude product distillation yield was 58.6%, and the comprehensive yield was 48.7% (in terms of chloromethyl hexafluoroisopropyl ether).

[0032] Add 2250g of sulfolane, 525g of potassium fluoride and 150g of pentaerythritol to the reaction flask, and then add 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water. Heat to reflux reaction for 5 hours, cool naturally to room temperature, add 800mL of purified water, and distill to obtain 550g of crude sevoflurane distillation product, and GC measures the dichloromethane content of 170ppm. Then add 28g of 4A molecular sieve to the crude distillation product, stir for 1 hour, let stand for 0.5 hour, filter, and purify the filtrate by rectification. First, collect the fore fraction at a temperature of about 56.3°C to obtain 85.6g of the fore fraction, wherein the purity of sevoflurane is 99.85%, the content of dichloromethane is 990ppm, and the purity of sevoflurane is not up to standard. Then the positive component was collected at a temperature of about 58°C to obtain 332 g of sevoflurane with a GC purity of 99.991%, a dichloromethane content of 15 ppm, a crude product distillation yield of 60.3%, and a comprehensive yield of 51.3% (calculated as chloromethyl hexafluoroisopropyl ether).

[0033] Comparative Example 3: Crude product treated with 4A-G6 molecular sieve Add 2250g sulfolane, 525g potassium fluoride and 150g pentaerythritol to the reaction flask, and then add 700g chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g purified water. Heat to reflux reaction for 5 hours, cool naturally to room temperature, add 800mL purified water, and distill to obtain 546g of crude sevoflurane distillation product, and GC measures the dichloromethane content of 182ppm. Then add 28g 4A-G6 molecular sieve (silicon-aluminum ratio of 400, prepared according to the method disclosed in CN119039100A) to the crude distillation product, stir for 1 hour, stand for 0.5 hour, filter, and purify the filtrate by rectification. First, collect the fore fraction at a temperature of about 56.6°C to obtain 75.1g of the fore fraction, wherein the purity of sevoflurane is 99.87%, the dichloromethane content is 730ppm, and the purity of sevoflurane does not meet the standard. Then the positive component was collected at a temperature of about 58°C to obtain 340 g of sevoflurane with a GC purity of 99.992%, a dichloromethane content of 13 ppm, a crude product distillation yield of 62.2%, and a comprehensive yield of 52.6% (calculated as chloromethyl hexafluoroisopropyl ether).

[0034] Comparative Example 4: Crude product treated with ZSM-5 molecular sieve 2250g sulfolane, 525g potassium fluoride and 150g pentaerythritol were added to the reaction flask, and then 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water were added. The mixture was heated to reflux for 5 hours, cooled naturally to room temperature, 800mL of purified water was added, and 540g of crude sevoflurane distillation product was obtained by distillation, and GC measured a dichloromethane content of 174ppm. Then 28g of ZSM-5 molecular sieve was added to the crude distillation product, stirred for 1 hour, allowed to stand for 0.5 hours, filtered, and the filtrate was purified by distillation. First, the fore fraction was collected at a temperature of about 57.8°C to obtain 405g of fore fraction, wherein the purity of sevoflurane was 99.983%, the content of dichloromethane was 103ppm, and the purity of sevoflurane was not up to standard, and the sevoflurane product needed to be further purified by secondary purification operation. There was basically no distillate containing sevoflurane in the subsequent distillation operation.

[0035] Comparative Example 5: First distillation, then use molecular sieve to treat the front fraction Take 50g of the front fraction of the distillation in Comparative Example 1 (sevoflurane purity 99.82%, dichloromethane content 1100ppm), add 3g of ZSM-5-300 molecular sieve thereto, stir for 1 hour, let stand for 0.5 hour, filter, and measure the purity of sevoflurane to be 99.94%, and the dichloromethane content to be 31ppm. The purity of the front fraction after treatment is lower than that of the positive component of Comparative Example 1. It is speculated that the purity of the crude product before the distillation operation is low, resulting in a slight decrease in the stability of sevoflurane during the distillation process, partial degradation, and the degradation impurities are enriched in the front fraction and cannot be completely adsorbed by the molecular sieve.

[0036] Since the disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalent changes will be apparent to one skilled in the art and are intended to be included within the scope of the disclosure.

Claims

1. A method for preparing sevoflurane, the method comprising: 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, adding water and distilling after the reaction to obtain a crude sevoflurane product 1, wherein the content of dichloromethane in the crude sevoflurane product 1 is greater than 100 ppm; 2) adding a composite filler adsorbent selected from ZSM-5-300, ZSM-5-360 and ZSM-5-1 to the crude sevoflurane 1, stirring, standing, and filtering to obtain the crude sevoflurane 2; 3) distilling the crude sevoflurane 2 to obtain a finished sevoflurane product, wherein the content of dichloromethane in the finished sevoflurane product is less than 100 ppm; Wherein, the crude product distillation yield of sevoflurane is greater than 65%.

2. The preparation method according to claim 1, wherein the molar ratio of chloromethyl hexafluoroisopropyl ether to potassium fluoride in step (1) is selected from 1: 1-1:

5.

3. The preparation method according to claim 1, wherein the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol in step (1) is selected from 1: 0.1-1: 0.

5.

4. The preparation method according to claim 1, wherein the reaction solvent in step (1) is sulfolane.

5. The preparation method according to claim 1, wherein the weight ratio of the crude sevoflurane 1 to the adsorbent in step (2) is selected from 1: 0.01-1: 0.

1.

6. The preparation method according to claim 1, wherein the content of dichloromethane in the finished sevoflurane product is less than 50 ppm.

7. The preparation method according to claim 1, wherein the method comprises: 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, adding water and distilling after the reaction to obtain a crude sevoflurane product 1, wherein the content of dichloromethane in the crude sevoflurane product 1 is greater than 100 ppm, the molar ratio of chloromethyl hexafluoroisopropyl ether to potassium fluoride is selected from 1:2.5-1:3.5, the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol is selected from 1:0.15-1:0.25, and the reaction solvent is sulfolane; 2) adding ZSM-5-300 composite filler to the crude sevoflurane 1, stirring, standing, filtering, and obtaining the crude sevoflurane 2, wherein the weight ratio of the crude sevoflurane 1 to the composite filler is selected from 1: 0.01-1: 0.1; 3) distilling the crude sevoflurane 2 to obtain a finished sevoflurane product, wherein the content of dichloromethane in the finished sevoflurane product is less than 50 ppm; Wherein, the crude distillation yield of sevoflurane is greater than 70%.