Industrial preparation method of sevoflurane

Abstract

The present disclosure relates to an industrial production method for sevoflurane. Specifically, the present disclosure relates to a method for preparing sevoflurane, comprising the steps of reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, followed by preliminary impurity removal and distillation. The sevoflurane produced by the method described herein has high purity, high yield, and minimal waste, thus facilitating 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 minimal 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 processes for preparing sevoflurane generally have low yields and produce 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 after purification by distillation, the resulting sevoflurane product still contains some difficult-to-remove impurities. According to the Chinese Pharmacopoeia, the purity of the main component of medical sevoflurane must be ≥99.9%. However, foreign pharmacopoeias have even stricter limits on impurities in sevoflurane. For example, the European Pharmacopoeia limits the content of a single impurity in sevoflurane to no more than 100 ppm.

[0005] Furthermore, dichloromethane is a unique impurity in the polyhydroxy compound-catalyzed synthesis of sevoflurane. It is produced during the fluorination process and has a boiling point of 39°C. Currently, this impurity is primarily removed through the distillation fore-fraction, but a large amount of finished sevoflurane is distilled out along with dichloromethane during the distillation process. Therefore, to remove this impurity, the fore-fraction containing a large amount of sevoflurane must be discarded, resulting in significant losses in the distillation operation and low yields.

[0006] CN1177953A discloses a method for purifying sevoflurane using molecular sieves. The method involves further purifying the distilled sevoflurane product through molecular sieves to increase its purity. This method can significantly remove the bisfluoromethyl ether impurity. However, in actual production, it has been found that molecular sieves such as 4A molecular sieve 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 using molecular sieves. This method involves further purifying the distilled sevoflurane product through molecular sieves to increase its purity. However, this method does not improve the distillation yield of sevoflurane.

[0008] ZSM-5 molecular sieve has an MFI topology and a wide adjustable Si / Al ratio. Its three-dimensional, ten-membered ring pore structure lends it unique advantages in catalysis, adsorption, and separation. It also exhibits certain shape selectivity. For example, in the petrochemical and fine chemical industries, it can be used for the catalytic cracking of light gasoline and as a propylene additive in catalytic cracking. In exhaust gas purification, it can be used for the selective catalytic reduction of nitrogen oxides (NOx). Furthermore, in terms of adsorption, it can be used for the rapid adsorption of volatile organic compounds (VOCs), replacing activated carbon.

[0009] In recent years, some molecular sieve composite materials have emerged to enhance the performance of molecular sieves. For example, Ping Zhang 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 via 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 via 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 for sevoflurane, which can effectively remove impurities such as dichloromethane from crude sevoflurane, making it more conducive to subsequent distillation operations. This specific method differs from existing technologies such as CN119019217A in that it utilizes a novel molecular sieve to purify the sevoflurane prior to distillation, significantly improving the distillation yield. The sevoflurane after distillation is of high purity, meeting medical needs. Existing technologies have not addressed the issue of how to improve distillation yield, and the present disclosure demonstrates that the molecular sieves provided by existing technologies such as CN119019217A are also unable to improve distillation yield.

[0011] The present disclosure provides a method for preparing sevoflurane, comprising:

[0012] 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, and 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;

[0013] 2) adding a composite filler adsorbent selected from ZSM-5-300, ZSM-5-360, and ZSM-5-1 to the crude sevoflurane 1, stirring, allowing to stand, and filtering to obtain the crude sevoflurane 2;

[0014] 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;

[0015] Wherein, the crude distillation yield of sevoflurane is greater than 65%.

[0016] The crude sevoflurane distillation yield described in the present disclosure refers to the ratio of the weight of the finished sevoflurane product (having a dichloromethane content of less than 100 ppm) obtained after distillation to the weight of the crude sevoflurane product 1. Direct distillation of the crude sevoflurane product 1 in the prior art yields a relatively low crude distillation yield. However, the crude distillation yield of the crude sevoflurane product 1 treated with a specific molecular sieve in the present disclosure can be increased by over 14%.

[0017] In some embodiments, the crude distillation yield of sevoflurane is greater than 68%, or greater than 70%, or greater than 72%.

[0018] 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.

[0019] In some embodiments, the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol is selected from 1: 0.1-1: 0.5, such as 1: 0.15-1: 0.25, such as 1: 0.17-1: 0.23.

[0020] In some embodiments, the reaction solvent for the reaction of chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol is sulfolane.

[0021] In some embodiments, the reaction temperature is reflux reaction, for example, 70-110° C., to achieve reflux temperature.

[0022] 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%.

[0023] 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.

[0024] 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.

[0025] In some embodiments, the content of dichloromethane in the finished sevoflurane product is less than 50 ppm, or less than 40 ppm.

[0026] In some embodiments, the method comprises:

[0027] 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, and adding water and distilling after the reaction to obtain a crude sevoflurane product 1, wherein the dichloromethane content 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 to 1:3.5, and the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol is selected from 1:0.15 to 1:0.25, and the reaction solvent is sulfolane;

[0028] 2) adding ZSM-5-300 composite filler to crude sevoflurane 1, stirring, allowing to stand, and filtering to obtain crude sevoflurane 2, wherein the weight ratio of crude sevoflurane 1 to the composite filler is selected from 1:0.01 to 1:0.1;

[0029] 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;

[0030] Wherein, the yield of the distillation operation of sevoflurane is greater than 70%.

[0031] The sevoflurane preparation method disclosed herein significantly reduces the content of low-boiling-point impurities such as dichloromethane by adding a composite filler for preliminary impurity removal prior to the distillation operation. Subsequent distillation significantly improves the purity of the sevoflurane-containing distillate, eliminating the need to discard the fore-fraction. The overall sevoflurane yield is significantly increased by over 14%, which is of great significance for industrial production. Furthermore, when ZSM-5-300 composite filler is used for preliminary impurity removal, the dichloromethane impurity content in the sevoflurane distillate is significantly below 100 ppm, fully meeting the content limits for individual impurities in sevoflurane as specified in various pharmacopoeias. Existing preparation methods contain a high concentration of low-boiling-point impurities in crude sevoflurane. Removing these low-boiling-point impurities through distillation results in a significant loss of sevoflurane product, resulting in significant waste.

[0032] 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

[0033] The present disclosure will be explained in detail below with reference to 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.

[0034] Example 1: Preparation of chloromethyl hexafluoroisopropyl ether

[0035] Add 700g of chloromethyl hexafluoroisopropyl ether and 1030g of aluminum chloride to a reaction flask, cool to -5°C to 0°C, and add 1000g of hexafluoroisopropanol dropwise with stirring. Continue stirring for 0.5 hours after the addition is complete. Then add 190g of paraformaldehyde and stir until the reaction is complete. Cool to below 0°C, add 2L of 6mol / L hydrochloric acid dropwise, separate the organic layer, and wash twice with water. After removing the initial solvent, 1205g of chloromethyl hexafluoroisopropyl ether is obtained with a GC purity of 99.3%.

[0036] Example 2: Treatment with ZSM-5-300 molecular sieve

[0037] A reaction flask was charged with 2250 g of sulfolane, 525 g of potassium fluoride, and 150 g of pentaerythritol, followed by 700 g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125 g of purified water. The mixture was heated to reflux for 5 hours, cooled naturally to room temperature, and 800 mL of purified water was added. The mixture was distilled to obtain 542 g of crude sevoflurane, with a dichloromethane content of 176 ppm as measured by GC. 27 g of ZSM-5-300 composite filler was then added to the crude distillate, stirred for 1 hour, allowed to stand for 0.5 hours, and filtered. The filtrate was then purified by distillation. The fore-fraction was collected at approximately 58°C to obtain 401 g of the fore-fraction, which contained 99.990% sevoflurane purity and 24 ppm dichloromethane. The sevoflurane met the required purity standards and was used as the positive component. The crude product distillation yield was 73.9%, with an overall yield of 62% (based on chloromethyl hexafluoroisopropyl ether).

[0038] Example 3: Treatment with ZSM-5-360 molecular sieve

[0039] A reaction flask was charged with 2250 g of sulfolane, 525 g of potassium fluoride, and 150 g of pentaerythritol, followed by 700 g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125 g of purified water. The mixture was heated to reflux for 5 hours, cooled naturally to room temperature, and 800 mL of purified water was added. The crude product of sevoflurane was distilled to obtain 546 g of crude product, with a dichloromethane content of 174 ppm as measured by GC. 28 g of ZSM-5-360 composite filler was then added to the crude product, stirred for 1 hour, allowed to stand for 0.5 hours, and filtered. The filtrate was then purified by distillation. The fore-fraction was collected at approximately 57.9°C to obtain 408 g of the fore-fraction, which had a sevoflurane purity of 99.985% and a dichloromethane content of 84 ppm. The sevoflurane met the required purity standards and was thus used as the positive component. The crude product distillation yield was 74.7%, and the overall yield was 63.1% (based on chloromethyl hexafluoroisopropyl ether).

[0040] Example 4: Treatment with ZSM-5-1 molecular sieve

[0041] A reaction flask was charged with 2250 g of sulfolane, 525 g of potassium fluoride, and 150 g of pentaerythritol, followed by 700 g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125 g of purified water. The mixture was heated to reflux for 5 hours, cooled naturally to room temperature, and 800 mL of purified water was added. The crude product of sevoflurane was distilled to obtain 538 g of crude product, with a dichloromethane content of 170 ppm as measured by GC. 27 g of ZSM-5-1 composite filler was then added to the crude product, stirred for 1 hour, allowed to stand for 0.5 hours, and filtered. The filtrate was then purified by distillation. The fore-fraction was collected at approximately 57.9°C to obtain 398 g of the fore-fraction, which had a sevoflurane purity of 99.985% and a dichloromethane content of 88 ppm. The sevoflurane met the required purity standards and was thus used as the positive component. The crude product distillation yield was 74%, and the overall yield was 61.5% (based on chloromethyl hexafluoroisopropyl ether).

[0042] Example 5: Amplification reaction

[0043] To a 1000L reactor, add 321.43kg of sulfolane, 75kg of potassium fluoride, and 21.43kg of pentaerythritol, followed by 100kg of chloromethyl hexafluoroisopropyl ether and 17.9kg of purified water. Heat to reflux and stir until the reaction is complete. Cool, add 107kg of purified water, and distill to obtain 78.2kg of crude sevoflurane. Then, add 3.9kg of ZSM-5-300 composite filler to the crude distillate. Stir for 5 hours, let stand for 2 hours, filter, and the filtrate is further distilled to obtain 59.8kg of sevoflurane with a GC purity of 99.988%. This yield is 76.5% and the overall yield is 64.7% (based on chloromethyl hexafluoroisopropyl ether).

[0044] Comparative Example 1: Crude product not treated with molecular sieve

[0045] 2250g of sulfolane, 525g of potassium fluoride and 150g of pentaerythritol were added to the reaction flask, followed by 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water. The mixture was heated to reflux for 5 hours, cooled naturally to room temperature, and 800mL of purified water was added. The crude product was distilled to obtain 537g of crude sevoflurane distillate, of which the dichloromethane content was 180ppm by GC. The crude product was then purified by distillation. First, the front fraction was collected at a temperature of about 56.2°C to obtain 80g of the front fraction, in which the purity of sevoflurane was 99.82% and the dichloromethane content was 1100ppm. The purity of sevoflurane did not meet the standard. Then, the positive component was collected at a temperature of about 58°C to obtain 315g of sevoflurane, with a GC purity of 99.992% and a dichloromethane content of 12ppm. The crude product distillation yield was 58.6%, and the overall yield was 48.7% (based on chloromethyl hexafluoroisopropyl ether).

[0046] 2250g of sulfolane, 525g of potassium fluoride, and 150g of pentaerythritol were added to a reaction flask, followed by 700g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125g of purified water. The mixture was heated to reflux for 5 hours, naturally cooled to room temperature, and 800mL of purified water was added. 550g of crude sevoflurane was obtained by distillation, wherein the dichloromethane content was 170ppm as measured by GC. 28g of 4A molecular sieves were then added to the crude distillate, stirred for 1 hour, allowed to stand for 0.5 hour, filtered, and the filtrate was further purified by rectification. First, a fore-fraction was collected at a temperature of approximately 56.3°C to obtain 85.6g of a fore-fraction with a sevoflurane purity of 99.85% and a dichloromethane content of 990ppm. The purity of sevoflurane did not meet the 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% and a dichloromethane content of 15 ppm. The crude product distillation yield was 60.3%, and the overall yield was 51.3% (calculated as chloromethyl hexafluoroisopropyl ether).

[0047] Comparative Example 3: Crude product treated with 4A-G6 molecular sieve

[0048] A reaction flask was charged with 2250 g of sulfolane, 525 g of potassium fluoride, and 150 g of pentaerythritol, followed by 700 g of chloromethyl hexafluoroisopropyl ether prepared in Example 1 and 125 g of purified water. The mixture was heated to reflux for 5 hours, cooled naturally to room temperature, and 800 mL of purified water was added. The mixture was distilled to obtain 546 g of crude sevoflurane, which contained 182 ppm of dichloromethane as measured by GC. 28 g of 4A-G6 molecular sieve (silicon-aluminum ratio of 400, prepared according to the method disclosed in CN119039100A) was then added to the crude product. The mixture was stirred for 1 hour, allowed to stand for 0.5 hour, and filtered. The filtrate was then purified by distillation. The fore-fraction was collected at approximately 56.6°C to obtain 75.1 g of fore-fraction, which contained 99.87% sevoflurane purity and 730 ppm of dichloromethane, indicating that the sevoflurane purity did 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 an overall yield of 52.6% (calculated as chloromethyl hexafluoroisopropyl ether).

[0049] Comparative Example 4: Crude product treated with ZSM-5 molecular sieve

[0050] 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. The mixture was heated to reflux for 5 hours, naturally cooled to room temperature, and 800mL of purified water was added. The crude product of sevoflurane was distilled to give 540g of sevoflurane, of which GC measured a dichloromethane content of 174ppm. 28g of ZSM-5 molecular sieve was then added to the crude product, stirred for 1 hour, allowed to stand for 0.5 hour, filtered, and the filtrate was purified by rectification. First, a fore-fraction was collected at a temperature of about 57.8°C to give 405g of fore-fraction, wherein the purity of sevoflurane was 99.983% and the dichloromethane content was 103ppm. The purity of sevoflurane was not up to standard, and the sevoflurane product needed to be further purified by secondary purification. The subsequent distillation operation contained substantially no distillate containing sevoflurane.

[0051] Comparative Example 5: First distillation, then molecular sieve treatment of the front fraction

[0052] 50 g of the distillation front fraction from Comparative Example 1 (99.82% sevoflurane purity, 1100 ppm dichloromethane content) was added to 3 g of ZSM-5-300 molecular sieves. The mixture was stirred for 1 hour, allowed to stand for 0.5 hour, and filtered. The sevoflurane purity was 99.94% and the dichloromethane content was 31 ppm. The purity of the treated front fraction was lower than that of the positive component in Comparative Example 1. This is presumably due to the low purity of the crude product before the distillation operation, which resulted in a slight decrease in the stability of sevoflurane during the distillation process and partial degradation. The degraded impurities were concentrated in the front fraction and could not be completely adsorbed by the molecular sieve.

[0053] While the disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to one skilled in the art and are intended to be included within the scope of this disclosure.

Claims

1. A method for preparing sevoflurane, comprising: 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, and adding water and distilling after the reaction to obtain a crude sevoflurane product 1, wherein the dichloromethane content in the crude sevoflurane product 1 is greater than 100 ppm, the molar ratio of chloromethyl hexafluoroisopropyl ether to potassium fluoride is selected from 1:1 to 1:5, and the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol is selected from 1:0.1 to 1:0.5, and the reaction solvent is sulfolane; 2) adding a ZSM-5-300 composite filler adsorbent to the crude sevoflurane product 1, stirring, allowing to stand, and filtering to obtain the crude sevoflurane product 2, wherein the weight ratio of the crude sevoflurane product 1 to the composite filler is selected from 1:0.01 to 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 100 ppm; Wherein, the crude distillation yield of sevoflurane is greater than 65%.

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

3. The preparation method according to claim 1, wherein the method comprises: 1) reacting chloromethyl hexafluoroisopropyl ether with potassium fluoride and pentaerythritol, and adding water and distilling after the reaction to obtain a crude sevoflurane product 1, wherein the dichloromethane content 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 to 1:3.5, the weight ratio of chloromethyl hexafluoroisopropyl ether to pentaerythritol is selected from 1:0.15 to 1:0.25, and the reaction solvent is sulfolane; 2) adding ZSM-5-300 composite filler to crude sevoflurane 1, stirring, allowing to stand, and filtering to obtain crude sevoflurane 2, wherein the weight ratio of crude sevoflurane 1 to the composite filler is selected from 1:0.01 to 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%.