A method for preparing sevoflurane and its intermediates

Abstract

The present disclosure relates to a method for preparing sevoflurane and its intermediates. Specifically, the present disclosure relates to a method for preparing sevoflurane, which includes steps such as reacting hexafluoroisopropanol with dimethoxymethane in the presence of a Lewis acid catalyst to prepare methoxymethylidene hexafluoroisopropyl ether. The sevoflurane prepared by this method has high purity and few impurities.

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a method for preparing sevoflurane and its intermediates. Background Art

[0002] Sevoflurane (fluoromethyl 1,1,1,3,3,3 - hexafluoroisopropyl ether) is a halogenated volatile anesthetic and is widely used in clinical practice due to its advantages of rapid onset and low side effects. As an inhaled anesthetic, sevoflurane has extremely high purity requirements and strict compliance with pharmacopoeias and medical standards is necessary to ensure safety and effectiveness. According to the provisions of the Chinese Pharmacopoeia, the main component purity of medical sevoflurane should be ≥99.9%.

[0003] CN1431986A discloses a method for synthesizing sevoflurane, in which hexafluoroisopropanol reacts with dimethoxymethane in the presence of zinc chloride to obtain methoxymethylene hexafluoroisopropyl ether, and then further reacts to prepare sevoflurane. In this method, the catalyst cannot be completely dissolved in the reaction system, the catalytic effect is general, the yield of the first - step reaction is 55%, the yield of the second - step reaction is 51%, and the overall yield of the two - step reaction is only 28.1%.

[0004] CN101337863A reports an optimized method for preparing sevoflurane. Hexafluoroisopropanol reacts with dimethoxymethane in the presence of p - toluenesulfonic acid, and the obtained intermediate reacts with metal fluoride or other fluoride salts that exist in solid form under normal conditions in the presence of strong acid to prepare sevoflurane. Among them, the yield of the first - step reaction is 39%, the yield of the second - step reaction is 72.5%, and the overall yield of the two - step reaction is only 28.2%.

[0005] Currently, the processes for preparing sevoflurane generally have low yields and produce various impurities. Some of the impurities have properties similar to those of sevoflurane, and rectification is a commonly used purification method for sevoflurane. In addition, improving the purity of reaction intermediates is of great significance, which facilitates subsequent reactions and rectification separation, and the purity of sevoflurane after rectification is higher.

[0006] Traditional nitrogen - containing compounds are generally regarded as Lewis bases, while nitrogen - containing compounds with Lewis acidity are very rare. Nitrenium cations are a new type of nitrogen - based Lewis acid. Currently, there are literature reports that a class of nitrenium cations (structures shown in Compound 1) have good catalytic activity, are soluble in organic solvents, and show remarkable stability to moisture.

[0007] . Summary of the Invention

[0008] The present disclosure provides a new preparation method of sevoflurane. This method uses a new Lewis acid catalyst to catalyze the reaction, and the product has a higher purity. The yield of the first-step reaction is over 75%, the yield of the second-step reaction is over 70%, and the overall yield of the two-step reaction reaches over 53%, which is twice the reaction yield of the prior art. In addition, the purity of the sevoflurane product obtained in the present disclosure can reach over 99%, which is much higher than the purity of the products obtained by the prior art similar preparation methods, meets the sevoflurane standard for medical use, eliminates the operation of repeated purification, and is more conducive to industrial production.

[0009] The present invention provides a method for preparing sevoflurane, and the method includes:

[0010] (1) Reacting hexafluoroisopropanol with dimethoxymethane in the presence of catalyst compound 1 to prepare methoxymethylene hexafluoroisopropyl ether, wherein the molar ratio of hexafluoroisopropanol to dimethoxymethane is 1:1 - 1:1.2, and the molar ratio of hexafluoroisopropanol to compound 1 is 1:0.01 - 1:0.1, and the reaction temperature is 20 - 25 °C;

[0011] (2) Reacting methoxymethylene hexafluoroisopropyl ether with potassium fluoride in the presence of a strong acid to prepare sevoflurane, wherein the molar ratio of methoxymethylene hexafluoroisopropyl ether to potassium fluoride is 1:1 - 1:5, and the molar ratio of methoxymethylene hexafluoroisopropyl ether to the strong acid is 1:5 - 1:20, and the reaction temperature is 40 - 100 °C,

[0012] ;

[0013] In some embodiments, the molar ratio of hexafluoroisopropanol to dimethoxymethane in step (1) is 1:1 - 1:1.1, such as 1:1.1.

[0014] In some embodiments, the molar ratio of hexafluoroisopropanol to compound 1 in step (1) is 1:0.01, 1:0.04 or 1:0.1, such as 1:0.04.

[0015] In some embodiments, the reaction temperature of step (1) is 20 - 50 °C, such as 20 - 25 °C.

[0016] In some embodiments, the strong acid in step (2) is selected from one or more of fuming sulfuric acid, concentrated sulfuric acid, and sulfuric anhydride, such as fuming sulfuric acid.

[0017] In some embodiments, the molar ratio of methoxymethylene hexafluoroisopropyl ether to potassium fluoride in step (2) is 1:1 - 1:2, such as 1:2.

[0018] In some embodiments, the molar ratio of methoxymethylene hexafluoroisopropyl ether to the strong acid in step (2) is 1:10 - 1:11.

[0019] In some embodiments, the reaction temperature in step (2) is 40 - 50 °C.

[0020] In some embodiments, the method comprises:

[0021] (1) Reacting hexafluoroisopropanol with dimethoxymethane in the presence of catalyst compound 1 to prepare methoxymethylidene hexafluoroisopropyl ether, wherein the molar ratio of hexafluoroisopropanol to dimethoxymethane is 1:1.1, the molar ratio of hexafluoroisopropanol to compound 1 is 1:0.04, and the reaction temperature is 20 - 25 °C;

[0022] (2) Reacting methoxymethylidene hexafluoroisopropyl ether with potassium fluoride in the presence of fuming sulfuric acid to prepare sevoflurane, wherein the molar ratio of methoxymethylidene hexafluoroisopropyl ether to potassium fluoride is 1:2, the molar ratio of methoxymethylidene hexafluoroisopropyl ether to fuming sulfuric acid is 1:10 - 1:11, and the reaction temperature is 40 - 50 °C.

[0023] In some embodiments, methoxymethylidene hexafluoroisopropyl ether is obtained by fractional distillation after the reaction in step (1).

[0024] In some embodiments, sevoflurane is obtained by fractional distillation after the reaction in step (2).

[0025] The impurity content in the sevoflurane described in the present disclosure can be detected by gas chromatography. The detection method can refer to the methods disclosed in the prior art or national pharmacopoeias, such as the methods described in EP1165478B, CN103635451A, etc.

[0026] Advantages of the invention:

[0027] The method for preparing sevoflurane described in the present disclosure uses a new Lewis acid catalyst to prepare the intermediate methoxymethylidene hexafluoroisopropyl ether. The whole reaction system is a homogeneous system, with better catalytic effect, more complete reaction of raw materials, less catalyst consumption, higher yield and purity of the prepared intermediate, fewer impurities, and better reaction effect compared with some similar catalysts. The higher purity of the intermediate enables the purity of the finally obtained sevoflurane to reach more than 99%, and the purity of sevoflurane prepared by some reactions can reach more than 99.9%, meeting the medical - grade sevoflurane standard, eliminating the need for repeated purification operations, and being more conducive to industrial production. The existing methods for preparing methoxymethylidene hexafluoroisopropyl ether generally have a low yield and low product purity. Detailed implementation manners

[0028] The following will explain the present disclosure in detail with specific examples, so that those skilled in the art can understand the present disclosure more comprehensively. 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.

[0029] Example 1:

[0030]

[0031] The first step

[0032] Add 42 g of hexafluoroisopropanol, 20.9 g of dimethoxymethane (1.1 eq), and 8.7 g (0.04 eq) of Compound 1 (prepared according to the literature Mehta M, Goicoechea J M. Angewandte Chemie International Edition, 2020, 59(7): 2715 - 2719) into the reaction flask, and stir the reaction at room temperature for 24 h. After the reaction is completed, add 60 ml of water for washing, wash with saturated brine, and separate the organic layer. Fractionate the obtained organic layer to obtain 40.8 g of methoxymethylene hexafluoroisopropyl ether, with a yield of 77% and a GC purity of 99.60%.

[0033] The second step

[0034] Add 21.2 g of the methoxymethylene hexafluoroisopropyl ether prepared in the first step, 116 g of potassium fluoride, and 100 g of fuming sulfuric acid into a 200 - ml stainless - steel reactor, slowly heat up to 50 °C, collect the vapor generated by the reaction with a water trap, wash the obtained organic layer with water to obtain the crude product. Fractionate the obtained crude product to obtain 14.2 g of sevoflurane finished product, with a yield of 71% and a GC purity of 99.93%.

[0035] Example 2: Screening of the catalyst feeding amount

[0036] Put 42 g of hexafluoroisopropanol, 20.9 g of dimethoxymethane, and 2.2 g (0.01 eq) of Compound 1 into the reaction flask, and stir the reaction at room temperature for 24 h. After the reaction is completed, add 60 ml of water for washing, wash with saturated brine, and separate the organic layer. Fractionate the obtained organic layer to obtain 37.7 g of methoxymethylene hexafluoroisopropyl ether, with a yield of 71% and a GC purity of 98.63%.

[0037] Put 21.2 g of the prepared methoxymethylene hexafluoroisopropyl ether, 116 g of potassium fluoride, and 100 g of fuming sulfuric acid into a 200 - ml stainless - steel reactor, slowly heat up to 50 °C, collect the vapor generated by the reaction with a water trap, wash the obtained organic layer with water to obtain the crude product. Fractionate the obtained crude product to obtain 13 g of sevoflurane, with a yield of 65% and a GC purity of 99.65%.

[0038] Example 3: Screening of the catalyst feeding amount

[0039] Charge 42 g of hexafluoroisopropanol, 20.9 g of dimethoxymethane and 21.7 g (0.1 eq) of Compound 1 into a reaction flask, and stir the reaction at room temperature for 24 h. After the reaction is completed, add 60 ml of water for washing, wash with saturated brine, and separate the organic layer. Fractionate the obtained organic layer to obtain 39.8 g of methoxymethylene hexafluoroisopropyl ether, with a yield of 75% and a GC purity of 99.25%.

[0040] Charge 21.2 g of the prepared methoxymethylene hexafluoroisopropyl ether, 116 g of potassium fluoride and 100 g of fuming sulfuric acid into a 200 ml stainless steel reactor, slowly heat up to 50 °C, collect the vapor generated by the reaction with a water trap, and wash the obtained organic layer with water to obtain the crude product. Fractionate the obtained crude product to obtain 13.8 g of sevoflurane, with a yield of 69% and a GC purity of 99.80%.

[0041] Comparative Example 1: Screening of other nitrogen cation salt catalysts

[0042]

[0043] Add 42 g of hexafluoroisopropanol, 20.9 g of dimethoxymethane and 10.3 g of Compound 2 (0.1 eq, prepared according to the literature J. Zhou, L. L. Liu, L. L. Cao, D. W. Stephan, Chem. Commun. 2018, 54, 4390–4393) into a reaction flask, and stir the reaction at room temperature for 24 h. Add 60 ml of water for washing, wash with saturated brine, and separate the organic layer. Fractionate the obtained organic layer to obtain 29.2 g of methoxymethylene hexafluoroisopropyl ether, with a yield of 55% and a GC purity of 98.10%.

[0044] Comparative Example 2: Screening of other Lewis acids

[0045] According to the method of CN1431986A, charge 52 g (0.3 mol) of hexafluoroisopropanol, 31.5 mL (0.3 mol) of dimethoxymethane and Lewis acids with different molar ratios, and the reaction results are shown in the following table.

[0046]

[0047] Since the present disclosure has been described in terms of its particular embodiments, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the present disclosure.

Claims

1. A method for preparing sevoflurane, the method comprising: (1) Hexafluoroisopropanol and dimethoxymethane react in the presence of a catalyst compound 1 to prepare methoxymethylene hexafluoroisopropyl ether, wherein the molar ratio of hexafluoroisopropanol to dimethoxymethane is 1:1-1:1.2, the molar ratio of hexafluoroisopropanol to compound 1 is 1:0.01-1:0.1, and the reaction temperature is 20-25°C; (2) preparing sevoflurane by reacting methoxymethylene hexafluoroisopropyl ether with potassium fluoride in the presence of a strong acid, wherein the molar ratio of methoxymethylene hexafluoroisopropyl ether to potassium fluoride is 1:1-1:5, the molar ratio of methoxymethylene hexafluoroisopropyl ether to the strong acid is 1:5-1:20, and the reaction temperature is 40-100°C; Wherein the compound 1 has the following structure, 。 2. The method according to claim 1, wherein the molar ratio of hexafluoroisopropanol to dimethoxymethane in step (1) is 1:1-1:1.

1.

3. The method according to claim 1, wherein in step (1), the molar ratio of hexafluoroisopropanol to compound 1 is 1:0.01, 1:0.04 or 1:0.

1.

4. The method according to claim 1, wherein the strong acid in step (2) is selected from one or more of oleum and concentrated sulfuric acid.

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

2.

6. The method according to claim 1, wherein the molar ratio of methoxymethylene hexafluoroisopropyl ether to the strong acid in step (2) is 1:10-1:

11.

7. The method according to claim 1, wherein the method comprises: (1) Hexafluoroisopropanol and dimethoxymethane react in the presence of a catalyst compound 1 to prepare methoxymethylene hexafluoroisopropyl ether, wherein the molar ratio of hexafluoroisopropanol to dimethoxymethane is 1:1.1, the molar ratio of hexafluoroisopropanol to compound 1 is 1:0.04, and the reaction temperature is 20-25°C; (2) Methoxymethylene hexafluoroisopropyl ether and potassium fluoride are reacted in the presence of fuming sulfuric acid to prepare sevoflurane, wherein the molar ratio of methoxymethylene hexafluoroisopropyl ether to potassium fluoride is 1:2, the molar ratio of methoxymethylene hexafluoroisopropyl ether to fuming sulfuric acid is 1:10-1:11, and the reaction temperature is 40-50°C.

8. The method according to claim 1 or 7, wherein after the reaction in step (1), methoxymethylene hexafluoroisopropyl ether is obtained by fractional distillation, and after the reaction in step (2), sevoflurane is obtained by fractional distillation.

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