Method for preparing sevoflurane and intermediate thereof

Abstract

The invention relates to a method for preparing sevoflurane and intermediates thereof. Specifically, the invention relates to a preparation method of sevoflurane, which comprises the following steps: reacting hexafluoroisopropanol with dimethoxymethane in the presence of a Lewis acid catalyst to prepare methoxymethylene hexafluoroisopropyl ether, and the like. The sevoflurane prepared by the method has high purity and few impurities.

Description

Technical Field

[0001] The present invention 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, which is widely used in clinical practice due to its rapid onset and few side effects. As an inhaled anesthetic, sevoflurane has extremely high purity requirements and must strictly follow pharmacopoeia and medical standards to ensure safety and effectiveness. According to the Chinese Pharmacopoeia, the purity of the main component of medical sevoflurane must be ≥99.9%.

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

[0004] CN101337863A reports an optimized method for preparing sevoflurane, wherein hexafluoroisopropanol and dimethoxymethane are reacted in the presence of p-toluenesulfonic acid, and the intermediate obtained is reacted with metal fluoride or other fluoride salts that exist in a solid state under normal conditions in the presence of a strong acid to prepare sevoflurane. The first step reaction yield is 39%, the second step reaction yield is 72.5%, and the combined yield of the two steps is only 28.2%.

[0005] The current process for preparing sevoflurane generally has a low yield and produces a variety of impurities, some of which have properties similar to sevoflurane, and distillation is a commonly used method for refining sevoflurane. In addition, it is of great significance to improve the purity of the reaction intermediates, which facilitates subsequent reactions and distillation separation, and the purity of sevoflurane after distillation is higher.

[0006] Traditional nitrogen-containing compounds are usually 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, literature has reported that a type of nitrogen cation salt (structure shown in compound 1) has good catalytic activity, is easily soluble in organic solvents, and exhibits significant stability to water.

[0007] . Summary of the invention

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

[0009] The present invention provides 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) Methoxymethylene hexafluoroisopropyl ether and potassium fluoride react 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, the molar ratio of methoxymethylene hexafluoroisopropyl ether to the strong acid is 1:5-1:20, and the reaction temperature is 40-100°C. .

[0010] In some embodiments, the molar ratio of hexafluoroisopropanol to dimethoxymethane in step (1) is 1:1-1:1.1, for example 1:1.1.

[0011] 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, for example 1:0.04.

[0012] In some embodiments, the reaction temperature of step (1) is 20-50°C, such as 20-25°C.

[0013] 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, for example, fuming sulfuric acid.

[0014] In some embodiments, the molar ratio of methoxymethylene hexafluoroisopropyl ether to potassium fluoride in step (2) is 1:1-1:2, for example 1:2.

[0015] In some embodiments, the molar ratio of methoxymethylene hexafluoroisopropyl ether to the strong acid in step (2) is 1:10-1:11.

[0016] In some embodiments, the reaction temperature of step (2) is 40-50°C.

[0017] In some embodiments, 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.

[0018] In some embodiments, after the reaction in step (1) is completed, methoxymethylene hexafluoroisopropyl ether is obtained by fractional distillation.

[0019] In some embodiments, sevoflurane is obtained by fractional distillation after the reaction in step (2) is completed.

[0020] 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.

[0021] Beneficial effects of the invention:

[0022] The preparation method of sevoflurane disclosed in the present invention uses a new Lewis acid catalysis to prepare the intermediate methoxymethylene hexafluoroisopropyl ether. The entire reaction system is a homogeneous system, the catalytic effect is better, the raw material reaction is more thorough, the catalyst dosage is also less, the yield and purity of the prepared intermediate are higher, and there are fewer impurities, which is better than the reaction effect of some similar catalysts. The higher intermediate purity allows the purity of the final sevoflurane to reach more than 99%, and the purity of the sevoflurane prepared by partial reaction can reach more than 99.9%, which meets the medical grade sevoflurane standard, eliminates the operation of repeated purification, and is more conducive to industrial production. The existing methods for preparing methoxymethylene hexafluoroisopropyl ether generally have low yields and low product purity. DETAILED DESCRIPTION

[0023] 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.

[0024] Embodiment 1:

[0025]

[0026] first step

[0027] 42g hexafluoroisopropanol, 20.9g dimethoxymethane (1.1eq) and 8.7g (0.04eq) compound 1 (prepared according to the literature Mehta M, Goicoechea J M. Angewandte Chemie International Edition, 2020, 59(7): 2715-2719) were added to the reaction flask, and the reaction was stirred at room temperature for 24h. After the reaction was completed, 60ml of water was added for washing, saturated brine was used for washing, and the organic layer was separated. The obtained organic layer was fractionated to obtain 40.8g methoxymethylene hexafluoroisopropyl ether, with a yield of 77% and a GC purity of 99.60%.

[0028] Step 2

[0029] 21.2 g of methoxymethylene hexafluoroisopropyl ether prepared in the first step, 116 g of potassium fluoride and 100 g of fuming sulfuric acid were added to a 200 ml stainless steel reactor, and the temperature was slowly raised to 50°C. The vapor produced by the reaction was collected with a water trap, and the obtained organic layer was washed with water to obtain a crude product. The obtained crude product was fractionated to obtain 14.2 g of finished sevoflurane, with a yield of 71% and a GC purity of 99.93%.

[0030] Example 2: Catalyst feed amount screening

[0031] 42g hexafluoroisopropanol, 20.9g dimethoxymethane and 2.2g (0.01eq) compound 1 were added to the reaction flask and stirred at room temperature for 24h. After the reaction was completed, 60ml of water was added for washing, saturated brine was used for washing, and the organic layer was separated. The obtained organic layer was fractionated to obtain 37.7g methoxymethylene hexafluoroisopropyl ether with a yield of 71% and a GC purity of 98.63%.

[0032] In a 200ml stainless steel reactor, 21.2g of the prepared methoxymethylene hexafluoroisopropyl ether, 116g of potassium fluoride and 100g of fuming sulfuric acid were added, and the temperature was slowly raised to 50°C. The steam produced by the reaction was collected with a water trap, and the obtained organic layer was washed with water to obtain a crude product. The obtained crude product was fractionated to obtain 13g of sevoflurane, with a yield of 65% and a GC purity of 99.65%.

[0033] Example 3: Catalyst feed amount screening

[0034] 42g hexafluoroisopropanol, 20.9g dimethoxymethane and 21.7g (0.1eq) compound 1 were added to the reaction flask and stirred at room temperature for 24h. After the reaction was completed, 60ml of water was added for washing, saturated brine was used for washing, and the organic layer was separated. The obtained organic layer was fractionated to obtain 39.8g methoxymethylene hexafluoroisopropyl ether, with a yield of 75% and a GC purity of 99.25%.

[0035] In a 200 ml stainless steel reactor, 21.2 g of the prepared methoxymethylene hexafluoroisopropyl ether, 116 g of potassium fluoride and 100 g of fuming sulfuric acid were added, and the temperature was slowly raised to 50°C. The steam produced by the reaction was collected with a water trap, and the obtained organic layer was washed with water to obtain a crude product. The obtained crude product was fractionated to obtain 13.8 g of sevoflurane, with a yield of 69% and a GC purity of 99.80%.

[0036] Comparative Example 1: Screening of other nitrogen cation salt catalysts

[0037]

[0038] Add 42g hexafluoroisopropanol, 20.9g dimethoxymethane and 10.3g compound 2 (0.1eq, prepared according to J. Zhou, LL Liu, LL Cao, DW Stephan, Chem. Commun. 2018, 54, 4390–4393) to the reaction flask, stir and react at room temperature for 24h. Add 60ml water for washing, wash with saturated brine, and separate the organic layer. Fractionate the obtained organic layer to obtain 29.2g methoxymethylene hexafluoroisopropyl ether, with a yield of 55% and a GC purity of 98.10%.

[0039] Comparative Example 2: Screening of other Lewis acids

[0040] According to the method of CN1431986A, 52 g (0.3 mol) of hexafluoroisopropanol, 31.5 mL (0.3 mol) of dimethoxymethane and Lewis acid in different molar ratios were added. The reaction results are shown in the following table.

[0041]

[0042] 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) 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 fuming sulfuric acid, concentrated sulfuric acid, and sulfuric anhydride.

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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