A method for refining and purifying etomidate

Abstract

The invention belongs to the field of medicine, and particularly relates to a method for refining and purifying etomidate. The method can overcome the defects of the prior art, control the general single impurities in the etomidate raw material to below 0.10%, and achieve a purity of etomidate of over 99.6%, with no S isomer detected.

Description

Technical Field

[0001] The invention belongs to the field of medicine and specifically provides a method for refining and purifying etomidate. Background Art

[0002] Etomidate (CAS No. 33125-97-2), whose chemical name is R(+)-1-(1-phenylethyl)-1-hydro-imidazole-5-carboxylic acid ethyl ester, is a non-barbiturate intravenous anesthetic. Its structural formula is shown below:

[0003]

[0004] There are two main dosage forms of etomidate in clinical use: (1) aqueous injection: an injection prepared by dissolving etomidate in 35% propylene glycol; the osmotic concentration of the aqueous injection is 464mOsm / L, which is far higher than the physiological osmotic concentration; (2) fat emulsion: such as "Itoli", which is a 20% medium-chain triglyceride emulsion of etomidate. The formula composition is etomidate, soybean oil, medium-chain triglycerides, glycerol, lecithin, sodium oleate, and water for injection. The osmotic concentration of "Itoli" emulsion is 390mOsm / L, which is close to the physiological osmotic concentration range.

[0005] Regarding the preparation process of etomidate API, patents US3354173A and IN2011CH04309 disclose a method for preparing etomidate using R-(+)-α-phenylethylamine as a raw material through condensation, formylation, cyclization, and oxidation reactions. This method is currently a relatively common method. However, in actual industrial production, the raw material R-(+)-α-phenylethylamine typically contains 0.5%-1.5% of S-(-)-α-phenylethylamine. This S-(-)-α-phenylethylamine participates in the reaction, resulting in the S-isomer of etomidate remaining in the etomidate. Since the physical and chemical properties of these enantiomers are generally similar, it is difficult to remove. Furthermore, process impurities generated during the oxidation of 2-mercaptoetomidate to prepare etomidate are also difficult to remove. According to ICH Q3A and the domestic guidelines for drug impurity research, the content of individual impurities in the API should be controlled below 0.10%. The inventors were unable to obtain etomidate API with both the general single isomer and S isomer controlled below 0.10% according to the methods in the above patents and prior art. Therefore, it is urgent to develop a new method for refining and purifying etomidate. Summary of the Invention

[0006] The present invention aims to provide a method for refining and purifying etomidate, which can overcome the defects of the prior art, control the general impurities in the etomidate raw material to below 0.10%, and achieve a purity of etomidate of over 99.6%, with no S isomer detected.

[0007] A method for refining and purifying etomidate, characterized in that it comprises the following steps:

[0008] (1) mixing the crude product of etomidate with an organic solvent A, acidifying the mixture to form a salt, cooling the mixture to precipitate the salt, and separating the crude product of the salt of etomidate;

[0009] (2) mixing the crude salt of etomidate with organic solvent A, heating the mixture until it is completely dissolved, and then cooling the mixture to separate the salt of etomidate;

[0010] (3) Optionally, repeat step (2) above one or more times;

[0011] (4) mixing the separated etomidate acid salt with water, using an alkaline reagent to liberate the etomidate, followed by extraction with an organic solvent B, and removing the organic solvent B to obtain etomidate;

[0012] (5) optionally, recrystallizing the etomidate obtained in step (4);

[0013] The organic solvent A is C2-C7 fatty nitrile, C3-C7 fatty ketone and / or C1-C5 fatty alcohol, preferably one or a mixed solvent of two or more of acetonitrile, ethanol, propanol, isopropanol, acetone and butanone in any ratio, more preferably acetone.

[0014] The organic solvent B is a halogenated alkane and / or aromatic hydrocarbon, preferably one or a mixed solvent of two or more of dichloromethane, chloroform, benzene, toluene, and xylene in any ratio, more preferably dichloromethane.

[0015] In step (1), the crude etomidate is prepared from R-(+)-α-phenylethylamine through condensation, formylation, cyclization and oxidation reactions in sequence.

[0016] In step (1), the crude etomidate is prepared by oxidation reaction of 2-mercaptoetomidate.

[0017] In step (1), the acidification salt-forming reagent can be selected from hydrogen chloride gas, an organic solution of hydrogen chloride, 98% sulfuric acid by mass, 98% formic acid or acetic acid by mass, more preferably 98% sulfuric acid by mass.

[0018] In step (1), the organic solution of hydrogen chloride is selected from one or more of an ethyl acetate solution of hydrogen chloride, an ethanol solution of hydrogen chloride, a methanol solution of hydrogen chloride, a methyl tert-butyl ether solution of hydrogen chloride, an isopropanol solution of hydrogen chloride, and an acetone solution of hydrogen chloride, preferably an isopropanol solution of hydrogen chloride.

[0019] In step (1), the mass volume ratio of the crude etomidate and the organic solvent A is 1 g / 1-5 ml, preferably 1 g / 2-3 ml, and more preferably 1 g / 3 ml.

[0020] In step (1), the temperature is lowered to below 15° C., preferably below 10° C., after mixing and before acidification.

[0021] In step (1), during the acidification process, the temperature is controlled below 50°C, preferably below 30°C.

[0022] In step (1), after acidification is completed, the temperature is lowered to below 0°C.

[0023] The mass volume ratio of the crude etomidate in step (1) and the organic solvent A in step (2) is 1 g / 1-5 ml, preferably 1 g / 2-3 ml, more preferably 1 g / 3 ml.

[0024] In step (2), the temperature is raised to reflux.

[0025] In step (2), the temperature is lowered to below 0°C.

[0026] The mass volume ratio of the crude etomidate in step (1) and the water in step (4) is 1g / 3-10ml, preferably 1g / 6-7ml.

[0027] In step (4), the alkaline agent is an alkali metal carbonate, an alkali metal bicarbonate and / or an alkali metal hydroxide, preferably one or a mixture of two or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide, more preferably sodium bicarbonate.

[0028] In step (4), the extraction is performed twice or more, and the extracts are combined.

[0029] In step (4), the organic solvent is removed by concentration under normal pressure or reduced pressure.

[0030] The recrystallization solvent in step (5) is a C5-C8 alkane and / or a C2-C8 fatty ether, preferably one or a mixed solvent of two or more of n-hexane, n-heptane, ethyl ether, propyl ether, and isopropyl ether in any ratio, more preferably isopropyl ether.

[0031] The operating conditions for the recrystallization in step (5) are as follows: mixing the etomidate obtained in step (4) with the recrystallization solvent, heating to reflux, and cooling to below 0° C. after all the mixture is dissolved, to separate the etomidate.

[0032] The separation described in the above steps is suction filtration or centrifugal separation.

[0033] In one embodiment, the method for refining and purifying etomidate comprises the following steps:

[0034] (1) mixing crude etomidate and acetone, cooling to below 10° C., adding dropwise 98% sulfuric acid, controlling the temperature to below 30° C., and cooling to below 0° C. after the addition is complete, separating to obtain crude etomidate sulfate;

[0035] (2) mixing the crude sulfate of etomidate with acetone, heating the mixture to reflux, and cooling the mixture to below 0° C. after the mixture is completely dissolved, to separate the sulfate of etomidate;

[0036] (3) Optionally, repeat step (2) above one or more times;

[0037] (4) mixing the separated sulfate of etomidate with water, adjusting the pH to 7-8 with an alkaline reagent, extracting with dichloromethane, and removing the dichloromethane to obtain etomidate;

[0038] (5) Optionally, the etomidate obtained in step (4) is recrystallized. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1-1 This is the HPLC detection spectrum of related substances of the crude etomidate product in Example 1.

[0040] Figure 1-2 This is the HPLC detection spectrum of the crude S isomer of etomidate in Example 1.

[0041] Figure 2-1 This is the HPLC detection spectrum of etomidate-related substances in Example 2.

[0042] Figure 2-2 This is the HPLC detection pattern of etomidate S isomer in Example 2.

[0043] Figure 3-1 This is the HPLC detection spectrum of etomidate-related substances in Example 3.

[0044] Figure 3-2 This is the HPLC detection pattern of etomidate S isomer in Example 3.

[0045] Figure 4-1 This is the HPLC detection spectrum of related substances of crude etomidate in comparative example.

[0046] Figure 4-2 This is the HPLC detection spectrum of the crude S isomer of etomidate in the comparative example.

[0047] Figure 4-3 It is the HPLC detection spectrum of the related substances of etomidate in comparative example.

[0048] Figure 4-4 It is the HPLC detection spectrum of the S isomer of etomidate in comparative example. DETAILED DESCRIPTION

[0049] The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the essence and scope of the present invention are not limited thereto.

[0050] The contents of related substances and etomidate S isomer in the following examples and comparative examples before and after purification of etomidate were determined by high performance liquid chromatography.

[0051] Method 1: HPLC detection method for etomidate-related substances (general impurities)

[0052] Chromatographic column: octadecylsilane bonded silica gel

[0053] Mobile phase A: acetonitrile-0.005 mol / L potassium dihydrogen phosphate solution (15:85 v / v)

[0054] Mobile phase B: acetonitrile-water (90:10 v / v)

[0055] Flow rate: 1.5ml / min

[0056] Detection wavelength: 220nm

[0057] Injection volume: 10 μl

[0058] Method 2: HPLC detection method for etomidate S isomer

[0059] Column: Silica gel coated with cellulose carbamate derivative

[0060] Mobile phase: n-hexane-isopropanol (98:2 v / v)

[0061] Flow rate: 0.8ml / min

[0062] Detection wavelength: 240nm

[0063] Injection volume: 10 μl

[0064] Example 1: Preparation of crude etomidate

[0065]

[0066] To the reaction flask, R-(+)-α-phenylethylamine (145.2g), triethylamine (121.5g), toluene (400ml), and ethyl chloroacetate (147.6g) were added. After the addition was complete, the reaction solution was heated to 70-75°C and reacted for 12 hours. After the reaction was completed, 200ml of water was added to the reaction solution, stirred, and allowed to stand for stratification. The organic layer was then washed twice with 200ml of water each time, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. 98% formic acid (166.8g) was then added to the filtrate. After the addition was complete, the water was separated and reacted at reflux temperature for 12 hours. After the reaction was completed, the pH of the system was adjusted to neutral with saturated sodium bicarbonate aqueous solution, allowed to stand for stratification, the organic phase was washed twice with 150ml of water each time, dried over anhydrous sodium sulfate, and the product was collected by vacuum distillation to obtain 173.7g of a light yellow liquid, i.e., the compound of formula 1.

[0067] Sodium ethoxide (43.9 g) and toluene (600 ml) were added to the reaction flask and stirred. The compound of formula 1 (144 g) was then added, followed by dropwise addition of ethyl formate (136.0 g). The reaction was stirred at room temperature for 6 hours and the reaction endpoint was monitored by TLC. After the reaction was completed, 200 ml of water was added to the system, stirred, allowed to stand for stratification, and the organic phase was then extracted twice with 200 ml of water. The aqueous phases were combined, concentrated hydrochloric acid (151 ml) was added dropwise at room temperature, and then an appropriate amount of ethanol was added to the aqueous phase to make the system homogeneous, followed by addition of potassium thiocyanate (88.5 g), and the reaction was continued at 40 ° C for 12 hours. After the reaction was completed, the temperature was slowly lowered to about 5 ° C, stirred until a solid precipitated, filtered, and the resulting solid was dried with air at 50 ° C to obtain 110 g of solid, i.e., 2-mercaptoetomidate.

[0068] Add 701 g of 30% aqueous hydrogen peroxide to the reaction flask and stir. Warm the system to approximately 25°C-35°C. Then, add 100 g of 2-mercaptoetomidate in portions, maintaining the temperature at ≤50°C. After addition, incubate the system for 30 minutes and monitor the reaction endpoint by TLC.

[0069] After the reaction, the pH of the system was adjusted to approximately 7 with a saturated aqueous sodium bicarbonate solution, followed by the addition of 300 ml of dichloromethane, stirring, and separation. The organic layer was collected. The aqueous phase was further extracted with 300 ml of dichloromethane, and the organic phases were combined. The organic phase was washed once with 150 ml of water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 80.4 g of crude etomidate.

[0070] Test results:

[0071] Table 1-1 HPLC detection results of etomidate-related substances in Example 1

[0072] Peak Retention time area high area% Theoretical plate number tailing factor Separation 1 2.929 11917 2749 0.039 8226 1.15 -- 2 3.557 104549 22133 0.345 10289 1.11 4.66 3 5.467 59321 8327 0.196 12283 1.09 11.32 4 11.366 11655 1511 0.038 44136 0.96 28.51 5 11.623 10966 1774 0.036 68330 1.04 1.30 6 13.135 41687 5210 0.138 67378 -- 7.96 7 13.696 52950 4965 0.175 33749 1.09 2.24 8 14.666 10741 1144 0.035 48467 -- 3.44 9 15.578 23973 2978 0.079 76859 0.97 3.72 10 17.658 52781 5066 0.174 74855 1.50 8.61 11 19.512 103796 9915 0.343 72428 1.55 6.76 12 20.219 12871 987 0.042 48114 -- 2.15 13 20.845 248324 24834 0.820 93247 1.03 1.95 14 21.488 11857 1226 0.039 105516 1.18 2.39 15 22.364 565291 53326 1.866 96034 -- 3.17 16 22.735 950113 87391 3.136 94978 -- 1.27 17 23.211 15663 1629 0.052 120734 1.12 1.69 18 23.656 19059 1909 0.063 116498 1.05 1.64 19 25.486 45761 3893 0.151 99974 1.01 6.10 20 27.096 24879 1966 0.082 103018 0.90 4.88

[0073] (Continued Table 1-1)

[0074] Peak Retention time area high area% Theoretical plate number tailing factor Separation 21 29.673 124133 7117 0.410 62466 1.00 6.34 22 30.155 31995 2803 0.106 146846 1.30 1.22 23 30.795 40724 3123 0.134 118299 -- 1.90 24 31.165 32625 2472 0.108 117199 -- 1.02 25 34.960 12142 958 0.040 161548 0.95 10.66 26 36.150 27273651 1611914 90.021 93608 0.71 2.90 27 39.500 16658 837 0.055 93765 1.06 6.78 28 40.155 11378 888 0.038 207982 1.00 1.51 29 41.396 19709 1537 0.065 246462 1.25 3.62 30 42.614 10094 930 0.033 340344 1.16 3.90 31 45.614 59889 6036 0.198 505193 -- 10.93 32 46.275 76344 2118 0.252 37107 -- 1.09 33 48.281 111265 12357 0.367 611092 1.08 3.32 34 48.788 26067 1779 0.086 231990 1.03 1.55 35 51.171 11807 1049 0.039 400293 -- 6.54 36 51.555 34062 2527 0.112 372541 -- 1.16 37 58.784 26306 1955 0.087 416147 1.05 20.58 total 30297002 100.000

[0075] Table 1-2 HPLC detection results of etomidate S isomer in Example 1

[0076] Peak Retention time area high area% Theoretical plates Separation tailing factor 1 6.986 57857 7953 0.170 19060 -- 1.072 2 7.750 4560 385 0.013 10183 3.00 0.891 3 9.923 3207 191 0.009 9838 6.14 1.409 4 11.081 4232 285 0.012 4137 2.13 -- 5 11.431 8803 372 0.026 4200 0.50 -- 6 12.317 203680 11994 0.598 11855 1.53 1.063 7 13.807 33172832 1563535 97.356 10136 2.98 1.169 8 15.170 574288 7621 1.685 514 0.84 -- 9 16.767 30766 1208 0.090 5105 0.88 -- 10 17.433 7675 342 0.023 9942 0.81 -- 11 17.916 5791 227 0.017 7075 0.62 -- total 34073692 100.000

[0077] Example 2 Refining of crude etomidate

[0078] To a reaction flask, add 15 g of the crude etomidate prepared in Example 1 and 37.5 ml of acetone. The temperature is cooled to below 10°C in an ice-water bath. Then, 6.28 g of 98% sulfuric acid is added dropwise, maintaining the temperature at ≤ 30°C. After completion of the addition, the reaction mixture is cooled to -5-0°C, stirred for 30 minutes, and filtered. The filter cake is washed with cold acetone to obtain wet etomidate sulfate.

[0079] Add 37.5 ml of acetone to the above-mentioned etomidate sulfate wet product, heat to reflux temperature 50-60°C to dissolve, then slowly cool the system to room temperature, and then further cool to -5-0°C, stir for 30 minutes, filter, and wash the filter cake with cold acetone to obtain etomidate sulfate wet product.

[0080] 100 ml of water was added to the wet product, and then the pH was adjusted to 7-8 with a saturated aqueous sodium bicarbonate solution. The product was then extracted twice with 100 ml of dichloromethane, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated to dryness under reduced pressure and cooled naturally to obtain 11.5 g of etomidate.

[0081] Test results:

[0082] Table 2-1 HPLC detection results of related substances of etomidate in Example 2

[0083] Peak Retention time area high area% Theoretical plate number tailing factor Separation 1 5.471 2028 286 0.020 12146 1.07 -- 2 14.612 1978 302 0.020 99103 -- 47.59 3 17.622 2039 240 0.020 90290 -- 14.32 4 20.840 8062 797 0.080 90992 1.07 12.60 5 22.353 6423 609 0.064 97355 -- 5.38 6 22.717 3633 337 0.036 95732 -- 1.25 7 27.596 2134 167 0.021 101084 1.13 15.23 8 36.004 10072514 682765 99.661 129523 0.84 22.50 9 41.386 3189 261 0.032 251452 0.96 14.74 10 51.170 1615 156 0.016 261442 -- 26.79 11 58.743 3171 227 0.031 389944 1.04 19.50 total 10106786 100.000

[0084] Table 2-2 HPLC detection results of etomidate S isomer in Example 2

[0085] Peak Retention time area high area% Theoretical plates Separation tailing factor 1 14.155 27694243 1294212 100.000 10024 -- 1.128 total 27694243 100.000

[0086] Example 3 Refining of crude etomidate

[0087] To a reaction flask, add 15 g of the crude etomidate prepared in Example 1 and 45 ml of acetone. The temperature is cooled to below 10°C in an ice-water bath. Then, 6.28 g of 98% sulfuric acid is added dropwise, maintaining the temperature at ≤30°C. After completion of the addition, the reaction mixture is cooled to -5-0°C, stirred for 30 minutes, and filtered. The filter cake is washed with cold acetone to obtain wet etomidate sulfate.

[0088] Add 45 ml of acetone to the above-mentioned etomidate sulfate wet product, heat to reflux temperature 50-60°C to dissolve, then slowly cool the system to room temperature, and then further cool to -5-0°C, stir for 30 minutes, filter, and wash the filter cake with cold acetone to obtain etomidate sulfate wet product.

[0089] Repeat the above acetone purification of etomidate sulfate step once.

[0090] 100 ml of water was added to the purified wet product of etomidate sulfate, and then the pH was adjusted to 7-8 with a saturated aqueous sodium bicarbonate solution. The mixture was then extracted twice with 100 ml of dichloromethane, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate. The filtrate was concentrated to dryness under reduced pressure and cooled naturally to obtain 10.5 g of etomidate.

[0091] Test results:

[0092] Table 3-1 is the HPLC detection results of related substances of etomidate in Example 3

[0093] Peak Retention time area high area% Theoretical plate number tailing factor Separation 1 14.618 1354 207 0.010 97547 -- -- 2 17.623 2351 281 0.018 94601 1.11 14.43 3 20.843 1975 200 0.015 91815 1.02 12.77 4 22.356 3542 336 0.027 99540 -- 5.42 5 22.724 1127 105 0.009 99204 -- 1.29 6 27.597 1648 131 0.012 102776 1.09 15.40 7 36.033 13196438 878138 99.827 123343 0.80 22.36 8 41.383 5981 486 0.045 242203 1.03 14.33 9 48.280 1016 109 0.008 639902 0.75 23.87 10 51.161 2272 265 0.017 291014 -- 9.28 11 51.299 1571 189 0.012 12314 -- 0.12 total 13219276 100.000

[0094] Table 3-2 is the HPLC test results of etomidate S isomer in Example 3

[0095] Peak Retention time area Dimension area% Theoretical plates Separation tailing factor 1 13.760 34781147 1617960 100.000 9918 -- 1.178 total 34781147 100.000

[0096] Comparative Example:

[0097] Etomidate was purified by referring to the method disclosed in Indian patent IN2011CH04309. The specific steps are as follows:

[0098]

[0099] 15 g of the crude etomidate obtained in Example 1 was added to 100 ml of toluene and 100 ml of water. The solution was then adjusted to a pH of 3-4 with 15% dilute hydrochloric acid and allowed to stand for separation. The aqueous phase was removed, and the organic phase was further extracted with 100 ml of water. The aqueous phases were combined. The pH of the aqueous phase was adjusted to 7-7.5 with a 20% aqueous sodium bicarbonate solution. A large amount of solid precipitated, which was filtered with suction. The filter cake was washed with 100 ml of water and then dried under forced air at 45° C. for 5 hours to obtain 8.45 g of crude etomidate.

[0100] Test results:

[0101] Table 4-1 Comparative Example Etomidate Crude Product Related Substances HPLC Test Results

[0102] Peak Retention time area high area% Theoretical plate number tailing factor Separation 1 3.557 1178 240 0.008 9851 1.14 -- 2 13.701 1713 140 0.012 27849 1.18 43.o1 3 17.887 8913 867 0.061 65031 0.96 13.75 4 18.770 10084 964 0.069 69371 1.06 3.12 5 19.555 1583 186 0.011 111800 1.02 3.02 6 20.833 19659 1955 0.134 92139 1.05 5.03 7 22.345 31266 2888 0.213 96711 -- 5.38 8 22.707 57186 5164 0.390 92575 -- 1.23 9 23.649 1131 110 0.008 108825 1.14 3.22 10 25.536 1047 63 0.007 49791 1.04 5.07 11 27.588 1964 154 0.013 99684 1.03 5.08 12 29.209 1275 100 0.009 108083 -- 4.60 13 29.676 1210 72 0.008 59353 -- 1.11 14 30.828 1817 120 0.012 86404 -- 2.54 15 31.164 1519 129 0.010 133195 -- 0.89 16 35.170 2584 129 0.018 95981 0.76 10.07 17 36.035 14482277 952980 98.761 120288 0.79 1.99 18 37.722 2476 195 0.017 182111 0.96 4.39 19 38.143 1297 107 0.009 225648 1.18 1.24 20 39.015 3294 208 0.022 138876 -- 2.36

[0103] (Continued Table 4-1)

[0104] Peak Retention time area high area% Theoretical plate number tailing factor Separation 21 39.541 8283 551 0.056 170135 -- 1.31 22 43.568 3413 183 0.023 130506 0.80 9.30 23 45.227 1572 169 0.011 559287 1.11 4.58 24 46.220 3021 175 0.021 204849 -- 3.06 25 48.778 9332 534 0.064 180656 1.01 5.90 26 58.765 1213 94 0.008 443742 0.94 24.60 27 65.137 3726 196 0.025 252315 1.11 14.62 total 14664035 100.000

[0105] Table 4-2 Comparative Example Etomidate Crude S Isomer HPLC Test Results

[0106] Peak Retention time area high area% Theoretical plates Separation tailing factor 1 12.299 127.576 6.4 0.334 10890 1.50 2 14.038 38039.668 1851.8 99.666 10955 3.45 1.19 total 38167.244

[0107] Add 8.25g of crude etomidate to 33ml of n-heptane, heat to 80℃ and dissolve, add 0.1 gActivated carbon, keep warm for 1 hour, filter while hot to obtain a filtrate, cool the filtrate to 0-5°C in an ice-water bath, stir for 30 minutes, filter, wash the filter cake with cold n-heptane, and dry the obtained solid at 45°C with forced air circulation to obtain 7.0g of etomidate. Test results:

[0108] Table 4-3 HPLC test results of related substances of etomidate in comparative example

[0109] Peak Retention time area high area% Theoretical plate number tailing factor Separation 1 3.559 1032 217 0.007 10057 1.13 -- 2 17.009 1189 142 0.008 80036 -- 70.34 3 17.838 1025 114 0.007 76271 -- 3.33 4 19.581 1231 151 0.009 116894 1.03 7.15 5 20.857 19136 1901 0.133 92149 1.06 5.07 6 22.371 30644 2873 0.213 96856 -- 5.38 7 22.733 53436 4833 0.371 92653 -- 1.23 8 23.680 1217 120 0.008 106521 1.06 3.22 9 27.618 1783 143 0.012 100731 1.04 12.34 10 30.862 1070 75 0.007 76176 -- 8.16 11 31.213 1088 90 0.008 139369 -- 0.90 12 35.218 1400 101 0.010 139871 0.95 11.26 13 36.070 14275841 940078 99.049 120967 0.79 2.15 14 37.758 2541 193 0.018 164275 1.00 4.29 15 39.043 3170 197 0.022 130600 -- 3.19 16 39.567 3562 283 0.025 210043 0.97 1.35 17 43.615 1230 67 0.009 160640 -- 10.37 18 45.254 1298 134 0.009 545516 1.02 4.82 19 46.267 1524 84 0.011 192702 -- 3.04 20 48.802 7293 423 0.051 182287 0.93 5.77

[0110] (Continued Table 4-3)

[0111] Peak Retention time area high area% Theoretical plate number tailing factor Separation 21 51.583 1135 31 0.008 86678 -- 4.80 22 58.765 1119 89 0.008 448729 1.19 13.66 total 14412963 100.000

[0112] Table 4-4 Comparative Example Etomidate S Isomer HPLC Test Results

[0113] Peak Retention time area high area% Theoretical plates Separation tailing factor 1 12.286 35.589 1.9 0.094 10716 0.81 2 14.027 37885.541 1847.0 99.906 10953 3.44 1.20 total 37921.130

[0114] Summary of test results:

[0115] The etomidate in Examples 1-3 and the comparative example, and the three impurities (impurities a, b, c The retention time, content and total impurity content of the S isomer are summarized in Table 5 below.

[0116] Table 5 Summary of test results of Examples 1-3 and Comparative Examples

[0117]

[0118] After testing, the above impurities a, b, and c are all impurities generated in the step of preparing etomidate by oxidation of 2-mercaptoetomidate. The method in the prior art (see comparative example) cannot obtain etomidate raw materials that meet the requirements. However, the purification method of the present invention can control the content of general impurities in the etomidate raw materials to below 0.10%, and the purity of etomidate is as high as 99.6% or more, and no S isomer is detected.

[0119] Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and variations may be made to the present invention without departing from the spirit and scope of the present invention. The scope of the present invention is not limited to the detailed description above.

Claims

1. A method for refining and purifying etomidate, characterized in that: The steps include: (1) mixing the crude product of etomidate with an organic solvent A, acidifying the mixture to form a salt, cooling the mixture to precipitate the salt, and separating the crude product of the salt of etomidate; (2) mixing the crude salt of etomidate with organic solvent A, heating the mixture until it is completely dissolved, and then cooling the mixture to separate the salt of etomidate; (3) Optionally, repeat step (2) above one or more times; (4) mixing the separated etomidate acid salt with water, using an alkaline reagent to liberate the etomidate, followed by extraction with an organic solvent B, and removing the organic solvent B to obtain etomidate; (5) optionally, recrystallizing the etomidate obtained in step (4); The organic solvent A is one or both of acetone and butanone; The organic solvent B is one or a mixture of two or more of dichloromethane, chloroform, benzene, toluene, and xylene in any ratio; The reagent used for acidification and salt formation in step (1) is sulfuric acid with a mass fraction of 98%.

2. The method according to claim 1, wherein In step (1), the temperature is lowered to below 15° C. after mixing and before acidification; during the acidification process, the temperature is controlled below 50° C.; after the acidification is completed, the temperature is lowered to below 0° C.

3. The method according to claim 2, wherein In step (1), the temperature is lowered to below 10° C. after mixing and before acidification; during the acidification process, the temperature is controlled below 30° C.

4. The method according to any one of claims 1 to 3, wherein: In step (2), the temperature is raised to reflux and then lowered to below 0°C.

5. The method according to claim 4, wherein The steps include: (1) mixing crude etomidate and acetone, cooling to below 10° C., adding dropwise 98% sulfuric acid, controlling the temperature to below 30° C., and cooling to below 0° C. after the addition is complete, separating to obtain crude etomidate sulfate; (2) mixing the crude sulfate of etomidate with acetone, heating the mixture to reflux, and cooling the mixture to below 0° C. after the mixture is completely dissolved, to separate the sulfate of etomidate; (3) Optionally, repeat step (2) above one or more times; (4) mixing the separated sulfate of etomidate with water, adjusting the pH to 7-8 with an alkaline reagent, extracting with dichloromethane, and removing the dichloromethane to obtain etomidate; (5) Optionally, the etomidate obtained in step (4) is recrystallized.

6. The method according to claim 1 or 5, wherein: In step (4), the alkaline reagent is an alkali metal carbonate, an alkali metal bicarbonate and / or an alkali metal hydroxide.

7. The method according to claim 6, wherein the alkaline reagent in step (4) is one or a mixture of two or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide.

8. The method according to claim 7, wherein In step (4), the extraction is performed twice or more, and the extracts are combined; and the organic solvent is removed by concentration under normal pressure or reduced pressure.

9. The method according to any one of claims 1 to 3, wherein: The mass volume ratio of the crude etomidate in step (1) to the organic solvent A is 1 g / 1-5 ml; the mass volume ratio of the crude etomidate in step (1) to the organic solvent A in step (2) is 1 g / 1-5 ml; and the mass volume ratio of the crude etomidate in step (1) to the water in step (4) is 1 g / 3-10 ml.

10. The method according to claim 9, wherein The mass volume ratio of the crude etomidate in step (1) to the organic solvent A is 1 g / 2-3 ml; the mass volume ratio of the crude etomidate in step (1) to the organic solvent A in step (2) is 1 g / 2-3 ml; and the mass volume ratio of the crude etomidate in step (1) to the water in step (4) is 1 g / 6-7 ml.

11. The method according to claim 1, wherein The solvent for recrystallization in step (5) is one or a mixed solvent of two or more of n-hexane, n-heptane, diethyl ether, dipropyl ether and isopropyl ether in any ratio.

12. The method according to claim 11, wherein The operating conditions for the recrystallization in step (5) are as follows: mixing the etomidate obtained in step (4) with the recrystallization solvent, heating to reflux, and cooling to below 0° C. after all the solvents are dissolved, to separate the etomidate.

13. The method according to any one of claims 1 to 3, 5 and 12, wherein: The separation is by suction filtration or centrifugal separation.

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