Preparation method of etomidate
By simplifying the preparation process of etomidate, using ethyl 1H-imidazole-4-carboxylate and 1-chlorophenethane as raw materials, the problems of long synthesis steps, poor purity and harsh reaction conditions in the prior art are solved, and high-purity, low-cost and environmentally friendly etomidate preparation is achieved.
Patent Information
- Application Number
- CN202311772000.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-21
- Publication Date
- 2025-06-24
AI Technical Summary
The existing etomidate preparation methods have problems such as long synthesis steps, poor product purity, dark appearance color, long production cycle, harsh reaction conditions and difficult to remove impurities, which are difficult to meet medical needs.
Ethyl 1H-imidazole-4-carboxylate and 1-chlorophenethane are used as raw materials to prepare etomidate through the amine-lysis reaction, separation, freedom and purification process of halogenated hydrocarbons, simplifying the process route, reducing production costs, and improving product purity and stability.
The high purity (>99.9%) and stability of etomidate is achieved, which reduces production costs and process steps, is suitable for industrial production, and has mild process conditions and good environmental protection.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of biomedical technology, and particularly relates to a preparation method of etomidate. Background Art
[0002] Etomidate, with the chemical name of ethyl (+)-1-(α-tolyl)imidazole-5-carboxylate and the English name of etomidate, has the following structural formula: .
[0003] Etomidate was first successfully developed in the 1980s. It was synthesized as a racemate first and then obtained through resolution (Research on the trial production of the hypnotic and sedative anesthetic metomidate [J]. Pharmaceutical Industry, 1979(04):18-20). The etomidate prepared by the existing synthesis method has more impurities and poor stability, and cannot meet the actual medical needs of etomidate.
[0004] Peng Zhenyun provided a preparation method of etomidate (Peng Zhenyun. Direct synthesis of etomidate using the optically active compound R-(+)-α-methylbenzylamine [J]. Chinese Journal of Modern Applied Pharmacy, 1997(01):30-31), and its chemical reaction equation is as follows: .
[0005] At present, most domestic production enterprises use the above method to synthesize etomidate. However, in the actual application process, researchers found that when using isopropyl ether to refine etomidate, the purification effect is very poor, the impurity content is on the high side, and the product color is relatively deep. It needs to be refined repeatedly for many times to control the product quality within the qualified range. After repeated refining for many times, not only the process yield will be significantly reduced, but also the time consumption is long, resulting in a significant increase in the overall production cost. In addition, a large amount of waste liquid will be generated during the production process of this method, which is not conducive to environmental protection.
[0006] Laha, Joydev K et al. proposed a method for preparing etomidate (Laha, Joydev K et al., 2011). Starting from ethyl 1H-imidazole-4-carboxylate and (S)-1-phenylethanol, etomidate was prepared through a one-step reaction, and the reaction yield was 70%. However, the reaction conditions of this method are relatively harsh, and it needs to be carried out under low temperature of -40°C and anhydrous and anaerobic conditions. Moreover, triphenylphosphine needs to be used in the production process, and the generated triphenylphosphine oxide is difficult to remove, which is not conducive to industrial production: .
[0007] In view of the defects of the existing etomidate preparation methods, it is very necessary to develop a green and environmentally friendly process route with a short route and stable product quality. Summary of the Invention
[0008] In view of the problems existing in the existing synthesis methods of etomidate, such as long synthesis steps, poor product purity, relatively dark appearance color, long production cycle, harsh reaction conditions, and impurities that are difficult to remove, the present invention has developed a new preparation method for etomidate. This method has the advantages of a short route, easy operation, stable product quality, and suitability for industrial production.
[0009] The present invention adopts the following technical solutions: A preparation method for etomidate, and its synthesis route is as follows: .
[0010] The etomidate preparation method includes the following process steps: (1) Aminolysis of the halogenated hydrocarbon: Add ethyl 1H-imidazole-4-carboxylate, 1-chloroethylbenzene, and an acid-binding agent to a solvent, heat to 80°C to 120°C, and reflux for 3h to 7h; after the reflux reaction is completed, cool the reaction solution to below 50°C, and obtain an etomidate intermediate through post-treatment; Among them, the post-treatment is: Add purified water to the reaction solution for washing, then form a salt with hydrochloric acid and separate the layers, take the aqueous phase and wash it with a solvent, and then use p an H regulator to adjust the aqueous phase p pH to 6 to 10. After the adjustment is completed, add ethyl acetate for extraction and separation, and retain the organic phase; wash the organic phase with water until it is neutral, concentrate to dryness, add ethyl acetate and n-hexane to the concentrated residue for recrystallization, and obtain an etomidate intermediate.
[0011] (2) Resolution and liberation: Add a resolution reagent to a mixed solvent of ethanol and water, stir to form a salt; add the etomidate intermediate, filter after the reaction is completed, dissolve the filter cake in water and slowly add anhydrous ethanol for crystallization, filter after crystallization, dissolve the obtained filter cake in an appropriate amount of purified water, and use p an H regulator to adjust p the pH to 7 to 10 for liberation, and obtain crude etomidate through filtration, washing, and drying.
[0012] (3) Refining: Add ethyl acetate and n-hexane to the crude etomidate for recrystallization, then filter and dry to obtain pure etomidate.
[0013] Preferably, in step (1), the molar ratio of ethyl 1H-imidazole-4-carboxylate: 1-chloroethylbenzene: acid-binding agent is (0.8 to 1.2): (0.8 to 1.5): (1.0 to 2.0), and more preferably 1: 1.1: 1.2.
[0014] Preferably, the reflux reaction in step (1) is carried out under the condition of 100°C to 120°C, and the reaction time is 5h.
[0015] Preferably, in step (1), the solvent is toluene, xylene, methyl ethyl ketone, cyclohexanone, ethyl acetate, n-heptane or a combination thereof, preferably toluene; the acid-binding agent is triethylamine, sodium carbonate (potassium), sodium bicarbonate (potassium), disodium hydrogen phosphate (potassium), sodium phosphate (potassium), diisopropylethylamine or pyridine, preferably triethylamine; the pH regulator is sodium carbonate, potassium carbonate, sodium bicarbonate (potassium), disodium hydrogen phosphate (potassium), sodium phosphate (potassium) or a combination thereof, preferably sodium carbonate.
[0016] Preferably, in the post-treatment of step (1), the mass ratio of ethyl acetate to n-hexane is 1:(1 - 8), and the recrystallization temperature is -20°C to 20°C; more preferably, the mass ratio of ethyl acetate to n-hexane is 1:2, and the recrystallization temperature is -5°C to 5°C. p The aqueous phase is adjusted with an H regulator p to pH 8 - 9.
[0017] Preferably, the temperature of the resolution reaction in step (2) is -10°C to 30°C, more preferably 10°C to 20°C for reaction for 12 h; the conditions for the free part are: the alkali adjustment temperature is -5°C to 15°C, and the pH for alkali adjustment p is 7 - 10, and the crystallization time is 0.5 h to 4 h. More preferably, the alkali adjustment temperature is 0°C to 10°C, and the pH for alkali adjustment p is 8.5 - 9.5, and the crystallization time is 1 h.
[0018] Preferably, in step (2), the resolution reagent is D-dibenzoyl tartaric acid, D-mandelic acid, D-tartaric acid, D(+)-malic acid, D(-)-quinic acid, D-camphoric acid or any combination thereof, preferably D-dibenzoyl tartaric acid; the molar ratio of the etomidate intermediate to the resolution reagent is 1:0.5 - 1:1.2, preferably 1:0.55.
[0019] Preferably, in step (2), the volume ratio of purified water to ethanol in the ethanol-water mixed solvent is 1:(6 - 12), preferably 1:9; the ethanol-water mixed solvent can be replaced by a mixed solvent of methanol, isopropanol, acetone, N,N-dimethylformamide or N,N-dimethylacetamide and water.
[0020] Preferably, in step (2), the p pH regulator is ammonia water, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, potassium phosphate or a combination thereof, more preferably ammonia water.
[0021] Preferably, in step (3), the volume ratio of ethyl acetate to n-hexane is 1:(2 - 20), preferably 1:10, the crystallization temperature is -20°C to 30°C, and the crystallization time is 1 h to 8 h; preferably, the crystallization temperature is 5°C to 15°C, and the crystallization time is 4 h. Among them, the volume of ethyl acetate and n-hexane is 3 - 15 times that of crude etomidate.
[0022] Preferably, in steps (1) and (3), the crystallization reagent ethyl acetate can be replaced by ethyl formate, isopropyl acetate, dichloromethane, dichloroethane, acetone or a combination thereof; the n-hexane can be replaced by petroleum ether, n-heptane, cyclohexane or a combination thereof.
[0023] The present invention provides a preparation method of etomidate: using ethyl 1H-imidazole-4-carboxylate and 1-chloro-2-phenylethane as raw materials, and successively obtaining etomidate through the aminolysis reaction of halogenated hydrocarbons, resolution, liberation, and purification processes. It has the following advantages: (1) High product purity and stable quality: The obtained etomidate is in the form of white crystals, with single impurity and total impurity both less than 0.1%, purity > 99.9%, and optical purity up to 100%, fully meeting the quality requirements related to drug declaration; the pure etomidate prepared by the method of the present invention has very little quality difference between different batches, has excellent stability, and can have only one impurity, showing broad prospects in the medical field; (2) Low cost and high yield: The raw materials used, ethyl 1H-imidazole-4-carboxylate and 1-chloro-2-phenylethane, are both bulk chemicals, with low prices and easy commercial access; the production time is greatly shortened, and the yield of the prepared etomidate is over 90%, further effectively reducing the cost; (3) Mild synthesis conditions, green and environmental protection: Compared with the mainstream domestic route, this route has shorter synthesis steps, does not require relatively harsh reaction conditions such as low temperature, anhydrous and anaerobic conditions, which is beneficial to reducing the production difficulty; the overall process has a relatively single solvent selection, which can be recycled, reducing the generation of waste liquid, reducing the environmental burden, and at the same time avoiding the use of triphenylphosphine that is difficult to remove, making it a green and environmental protection route. Description of the Drawings
[0024] Figure 1 It is the system suitability chromatogram for the detection of etomidate finished product isomers.
[0025] Figure 2 It is the enantiomer detection chromatogram of the etomidate finished product in Example 1.
[0026] Figure 3 It is the related substance detection chromatogram of the etomidate finished product in Example 1.
[0027] Figure 4 It is the enantiomer detection chromatogram of the etomidate finished product in Example 2.
[0028] Figure 5 It is the detection chromatogram of related substances of etomidate finished product in Example 2.
[0029] Figure 6 It is the detection chromatogram of enantiomers of etomidate finished product in Example 3.
[0030] Figure 7 It is the detection chromatogram of related substances of etomidate finished product in Example 3. Detailed implementation manners
[0031] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs.
[0032] The experimental methods without specific conditions in the following embodiments are usually operated according to conventional conditions. The reagents or instruments without indicating the manufacturer can be obtained as conventional products through commercial purchase.
[0033] Example 1 A preparation method of etomidate: Step 1: Add 2.50 kg of ethyl 1H-imidazole-4-carboxylate and 6.5 kg of butanone into a 50 L reaction kettle, start stirring, then add 2.17 kg of triethylamine and 2.51 kg of 1-chloroethylbenzene, heat up to 100 °C - 120 °C and react for 5 h. After the reaction is completed, cool the reaction solution to below 50 °C, add 7.5 kg of purified water, adjust the temperature to 20 - 30 °C, wash and separate the liquid. Control the temperature at 20 °C - 30 °C, add the prepared dilute hydrochloric acid to the organic phase, stir and separate the liquid, and wash the aqueous phase once with 2.5 kg of butanone. Control the temperature at 20 °C - 30 °C, adjust the pH of the aqueous phase with anhydrous sodium carbonate p to 8 - 9. After the adjustment, add 10.0 kg of ethyl acetate for extraction and separation, and retain the organic phase. Wash the organic phase twice with purified water, 10.0 kg each time. After the washing is completed, concentrate the organic phase under reduced pressure until there is basically no liquid flowing out, then add 3.11 kg of ethyl acetate and 9.33 kg of n-hexane to the concentrated residue, heat up to dissolve clearly and then cool down to -5 °C - 5 °C for crystallization for 2 h, filter, and dry at 60 °C to constant weight to obtain 4.08 kg of etomidate intermediate, with a yield of 89.6% and a purity of 99.23%.
[0034] Step 2: Add 7.8 kg of purified water and 93.5 L of methanol into a 100 L reactor. Start stirring, add 3.15 kg of D-benzoyltartaric acid, stir and heat up to 30°C - 40°C, add 3.9 kg of etomidate intermediate, stir for 0.5 h, cool down to 10°C - 20°C and stir for 12 h, filter, rinse the reactor with 2 kg of ethanol, and wash the filter cake with the rinsing solution; Add 3.9 kg of purified water into the reactor, start stirring, heat up to 40°C - 50°C, add the above solid and keep stirring for 20 min, control the temperature at 20°C - 50°C, add 27.6 kg of absolute ethanol, cool down to -5°C - 5°C and crystallize for 3 h, filter, and wash the filter cake with 2 kg of absolute ethanol; Add 11.7 kg of purified water into the reactor, start stirring, add the above filter cake, control the temperature at 20°C - 30°C and stir for 20 min, then cool down, control the temperature at 0°C - 10°C and adjust with p The pH to 8.5 - 9.5. After adjustment, crystallize for 1 h, filter, wash the filter cake with 6.6 kg of purified water, and dry at 60°C for 6 h to obtain 1.75 kg of crude etomidate, with a yield of 44.9%, a purity of 99.73%, and no enantiomers detected.
[0035] Step 3: Add 1.75 kg of crude etomidate into 0.8 L of ethyl acetate and 2.4 L of petroleum ether, heat up to reflux until dissolved clearly, then cool down to 5°C - 15°C, stir and crystallize for 4 h, filter, and dry the filter cake at 60°C for 6 h to obtain 1.60 kg of pure etomidate, with a yield of 81.2%, a purity of 99.939%, and no enantiomers detected.
[0036] Figure 1 It is the system suitability chromatogram for the detection of isomers of etomidate finished product; Figure 2 It is the chromatogram for the detection of enantiomers of etomidate finished product in Example 1; Figure 3 It is the chromatogram for the detection of related substances of etomidate finished product in Example 1. Among them, related substances are terms in pharmaceutical analysis and research, referring to the purity and impurity content of drugs under specific methods.
[0037] Example 2 Step 1: Add 2.50 kg of ethyl 1H-imidazole-4-carboxylate and 6.5 kg of xylene into a 50 L reactor. Start stirring, then add 2.96 kg of potassium carbonate and 2.88 kg of 1-chloroethylbenzene, heat up to 100°C - 120°C and react for 5 h. After the reaction is completed, cool down the reaction solution to below 50°C, add 7.5 kg of purified water, adjust the temperature to 20 - 30°C, and wash and separate the layers; Control the temperature at 20°C - 30°C, add the prepared dilute hydrochloric acid to the organic phase, stir and separate the layers, and wash the aqueous phase with 2.5 kg of xylene once. Control the temperature at 20°C - 30°C, and adjust the aqueous phase with anhydrous sodium carbonate pAdjust the pH to 8 - 9. After the adjustment, add 10.0 kg of ethyl acetate for extraction and liquid separation, and retain the organic phase. Wash the organic phase twice with 10.0 kg of purified water each time. After the washing is completed, concentrate the organic phase under reduced pressure until there is basically no liquid flowing out. Then, add 4.14 kg of ethyl acetate and 8.28 kg of n - hexane to the concentrated residue. Heat it to dissolve clearly and then cool it to 0 °C - 10 °C for crystallization for 3 h. Filter and dry it at 60 °C to constant weight to obtain 4.21 kg of etomidate intermediate, with a yield of 94.2% and a purity of 99.38%.
[0038] Step 2: Add 7.8 kg of purified water and 58.2 L of ethanol to a 100 L reactor. Start stirring, add 4.01 kg of D - benzoyl tartaric acid, stir and heat up to 30 °C - 40 °C, add 3.9 kg of etomidate intermediate, stir for 0.5 h, cool down to 10 °C - 20 °C and stir for 12 h. Filter, and rinse the reactor with 2 kg of ethanol, and wash the filter cake with the rinsing solution. Add 3.9 kg of purified water to the reactor, start stirring, heat up to 40 °C - 50 °C, add the above - mentioned solid and stir for 20 min while controlling the temperature at 20 °C - 50 °C. Then add 27.6 kg of absolute ethanol, cool down to - 5 °C - 5 °C for crystallization for 3 h. Filter, and wash the filter cake with 2 kg of absolute ethanol. Add 11.7 kg of purified water to the reactor, start stirring, add the above - mentioned filter cake, stir for 20 min while controlling the temperature at 20 °C - 30 °C, then cool down, and adjust the pH to 8.5 - 9.5 with ammonia water while controlling the temperature at 0 °C - 10 °C. p After the adjustment, crystallize for 1 h, filter, wash the filter cake with 6.6 kg of purified water, and dry it at 60 °C for 6 h to obtain 1.76 kg of crude etomidate, with a yield of 38% and a purity of 99.73%. No enantiomers are detected.
[0039] Step 3: Add 1.75 kg of crude etomidate to 0.8 L of ethyl acetate and 13.6 L of n - heptane. Heat it to reflux until it dissolves clearly, then cool down to 5 °C - 15 °C, stir for crystallization for 4 h. Filter, and dry the filter cake at 60 °C for 6 h to obtain 1.58 kg of pure etomidate, with a yield of 92.1% and a purity of 99.942%. No enantiomers are detected.
[0040] Figure 4 It is the detection chromatogram of enantiomers of the etomidate finished product in Example 2; Figure 5 It is the detection chromatogram of related substances of the etomidate finished product in Example 2.
[0041] Example 3 Step 1: Add 2.50 kg of ethyl 1H-imidazole-4-carboxylate and 6.5 kg of toluene into a 50 L reactor. Start stirring, then add 3.45 kg of potassium dihydrogen phosphate and 2.76 kg of 1-chloroethylbenzene. Heat up to 100 °C - 120 °C and react for 5 h. After the reaction is completed, cool the reaction solution to below 50 °C, add 7.5 kg of purified water, adjust the temperature to 20 - 30 °C, and wash and separate the layers. Control the temperature at 20 °C - 30 °C, add the prepared dilute hydrochloric acid to the organic phase, stir and separate the layers. Wash the aqueous phase once with 2.5 kg of toluene. Control the temperature at 20 °C - 30 °C, and adjust the pH of the aqueous phase p to 8 - 9 with anhydrous sodium carbonate. After adjustment, add 10.0 kg of ethyl acetate for extraction and separation, and retain the organic phase. Wash the organic phase twice with purified water, 10.0 kg each time. After washing, concentrate the organic phase under reduced pressure until there is basically no liquid flowing out. Then add 4.14 kg of ethyl acetate and 8.28 kg of n-hexane to the concentrated residue. Heat up to dissolve clearly and then cool down to -10 °C - -5 °C for crystallization for 2 h. Filter and dry at 60 °C to constant weight to obtain 3.92 kg of etomidate intermediate, with a yield of 98.2% and a purity of 99.52%.
[0042] Step 2: Add 7.8 kg of purified water and 70.2 L of ethanol into a 100 L reactor. Start stirring, add 3.15 kg of D-benzoyltartaric acid, stir and heat up to 30 °C - 40 °C, add 3.9 kg of etomidate intermediate, stir for 0.5 h, cool down to 10 °C - 20 °C and stir for 12 h. Filter, wash the reaction kettle with 2 kg of ethanol, and wash the filter cake with the washing solution. Add 3.9 kg of purified water into the reaction kettle, start stirring, heat up to 40 °C - 50 °C, add the above solid and keep stirring for 20 min. Control the temperature at 20 °C - 50 °C, add 27.6 kg of absolute ethanol, cool down to -5 °C - 5 °C for crystallization for 3 h. Filter and wash the filter cake with 2 kg of absolute ethanol. Add 11.7 kg of purified water into the reaction kettle, start stirring, add the above filter cake, stir at 20 °C - 30 °C for 20 min and then cool down. Control the temperature at 0 °C - 10 °C and adjust the p pH to 8.5 - 9.5 with sodium carbonate. After adjustment, crystallize for 1 h, filter, wash the filter cake with 6.6 kg of purified water, and dry at 60 °C for 6 h to obtain 1.83 kg of crude etomidate, with a yield of 43% and a purity of 99.73%. No enantiomers are detected.
[0043] Step 3: Add 1.75 kg of crude etomidate into 0.8 L of ethyl acetate and 8 L of n-hexane. Heat up to reflux and dissolve clearly, then cool down to 5 °C - 15 °C, stir and crystallize for 4 h. Filter, and dry the filter cake at 60 °C for 6 h to obtain 1.58 kg of pure etomidate, with a yield of 88.5% and a purity of 99.947%. No enantiomers are detected.
[0044] Figure 6 It is the detection chromatogram of enantiomers of the etomidate finished product in Example 3; Figure 7 It is the detection chromatogram of related substances of the etomidate finished product in Example 3.
[0045] The purity and isomer detection results of etomidate obtained in Examples 1-3 are shown in Table 1.
[0046]
[0047] The "Chinese Pharmacopoeia 2020 Edition" stipulates that the quality standard of etomidate is: single impurity ≤ 0.3%, total impurities ≤ 0.5%. It can be seen from the above table that the purity of etomidate obtained in Examples 1-3 fully meets the requirements of the Chinese Pharmacopoeia.
[0048] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention. In addition, the technical solutions between various embodiments can be combined with each other, but it must be based on the realization by those of ordinary skill in the art; when the combination of technical solutions conflicts with each other or cannot be realized, it should be considered that such a combination of technical solutions does not exist and is not within the protection scope required by the present invention.
Claims
1. A method for preparing etomidate, characterized in that, Taking ethyl 1H-imidazole-4-carboxylate and 1-chloroethylbenzene as raw materials, etomidate is prepared through the amination reaction of halogenated hydrocarbon, resolution, liberation and purification processes in sequence. The synthetic route is as follows: 。 2. The preparation method of etomidate according to claim 1, characterized in that, The amination of the halogenated hydrocarbon is as follows: Add ethyl 1H-imidazole-4-carboxylate, 1-chloroethylbenzene and an acid-binding agent into a solvent, heat up to 80°C to 120°C for reflux reaction. After the reaction is completed, cool the reaction solution to below 50°C, and obtain the etomidate intermediate through post-treatment. The splitting and liberation are as follows: A resolving agent is added to a mixed solvent of ethanol and water, and stirred to form a salt; etomidate intermediate is added, and after the reaction is completed, it is filtered. The filter cake is dissolved in water, and anhydrous ethanol is slowly added for crystallization. After crystallization, it is filtered. The obtained filter cake is dissolved in an appropriate amount of purified water, and the p pH is adjusted with a p pH regulator to 7 - 10 for liberation. After filtration, washing and drying, crude etomidate is obtained.
3. The preparation method of etomidate according to claim 1, wherein The purification is as follows: Add ethyl acetate and n-hexane to the crude etomidate for recrystallization, then filter and dry to obtain the pure etomidate.
4. The preparation method of etomidate pure product according to claim 2, characterized in that, The post-treatment is as follows: adding purified water to the reaction solution for washing, then separating the layers after salifying with hydrochloric acid, washing the aqueous phase with a solvent, and then using p an H regulator to adjust the aqueous phase p pH to 6 - 10. After the adjustment is completed, adding ethyl acetate for extraction and separation of layers, and retaining the organic phase; Wash the organic phase with water until neutral, concentrate to dryness, add ethyl acetate and n-hexane to the concentrated residue for recrystallization to obtain the etomidate intermediate.
5. The preparation method of etomidate according to claim 2, wherein, The resolution reagent is D-dibenzoyl tartaric acid, D-mandelic acid, D-tartaric acid, D(+)-malic acid, D(-)-quinic acid, D-camphoric acid or any combination thereof.
6. The preparation method of etomidate according to claim 2, characterized in that, The solvent is toluene, xylene, butanone, cyclohexanone, ethyl acetate, n-heptane or a combination thereof; the acid-binding agent is one of triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, potassium phosphate, diisopropylethylamine or pyridine.
7. The preparation method of etomidate according to claim 2, characterized in that, The molar ratio of ethyl 1H-imidazole-4-carboxylate: 1-chloroethylbenzene: acid-binding agent is (0.8 to 1.2): (0.8 to 1.5): (1.0 to 2.0).
8. The preparation method of etomidate according to claim 2, characterized in that, The molar ratio of the etomidate intermediate to the resolution reagent is 1: (0.5 to 1.2).
9. The preparation method of etomidate according to claim 3, characterized in that, The volume ratio of ethyl acetate to n-hexane is 1: (2 to 20).
10. The preparation method of etomidate according to claim 4, characterized in that, The mass ratio of ethyl acetate to n-hexane is 1: (1 to 8).