CN116265442A - Preparation method of etomidate - Google Patents
Preparation method of etomidate Download PDFInfo
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- CN116265442A CN116265442A CN202111541413.7A CN202111541413A CN116265442A CN 116265442 A CN116265442 A CN 116265442A CN 202111541413 A CN202111541413 A CN 202111541413A CN 116265442 A CN116265442 A CN 116265442A
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- imidazole
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- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 title claims abstract description 55
- 229960001690 etomidate Drugs 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000007864 aqueous solution Substances 0.000 claims abstract description 22
- -1 alpha-methylbenzyl Chemical group 0.000 claims abstract description 18
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 238000010791 quenching Methods 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of etomidate, S1 dissolves (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-sulfydryl-1H-imidazole-5-carboxylic acid ethyl ester in alkaline aqueous solution, and then is mixed with oxidant for temperature control reaction; after the S2 reaction is finished, quenching the reaction, adjusting the pH to be alkaline, extracting with an organic solvent, and concentrating under reduced pressure to obtain a crude etomidate; the method does not use an organic reagent in the oxidation and sulfydryl removal reaction process, is safer and more environment-friendly, and is more suitable for industrial production; compared with the use of organic reagent, the method has the advantages that the side reaction impurities generated in the reaction process are obviously reduced, the purification of the product is facilitated, and the overall yield is higher.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to an industrialized preparation method of etomidate.
Background
Etomidate (Etomidate, structural formula is shown as formula I), its chemical name is R- (+) -1- (1-phenethyl) -1H-imidazole-5-carboxylic acid ethyl ester, CAS number is 33125-97-2, also called mebendazole, belonging to imidazole derivatives. Etomidate is a quick-acting intravenous anesthetic with short duration, and is characterized by high efficiency, low toxicity and slight influence on cardiovascular and respiratory systems.
To date, a variety of methods for preparing etomidate have been reported in the literature. Patent US3354173A, US3991072A, WO2014048568A1 reports a method for preparing etomidate as a target product by taking R (+) -alpha-methylbenzylamine as a raw material and carrying out 5 steps of reactions such as condensation, N acylation, C acylation, cyclization and sulfydryl removal.
In the prior art, nitric acid or hydrogen peroxide is used for oxidative dehydrogenation, and organic reagents such as methylene dichloride, tetrahydrofuran and the like are used as reaction solvents. Oxidation reactions are high-risk reactions, and the use of organic reagents increases the risk during the reaction.
Disclosure of Invention
The purpose of the invention is that: overcomes the defects in the prior art and provides a preparation method of etomidate which has high safety in the reaction process and high product yield and purity and is suitable for industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method of preparing etomidate, the method comprising the steps of:
s1, dissolving (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester in an alkaline aqueous solution, mixing with an oxidant, and controlling the temperature for reaction;
and after the reaction of S2 is finished, quenching the reaction, adjusting the pH to be alkaline, extracting with an organic solvent, and concentrating under reduced pressure to obtain a crude etomidate.
Further, the mixing with the oxidizing agent in the step S1 specifically includes: dropwise adding an oxidant into an alkaline aqueous solution of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester or dropwise adding an alkaline aqueous solution of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester into the oxidant, wherein the temperature is controlled to be not more than 60 ℃ during the dropwise adding period.
Further, in the step S1, the alkaline aqueous solution is any one or a combination of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and ammonia water.
Further, the amount of the base in the alkaline aqueous solution in the step S1 is 1.0 to 5.0 times the molar equivalent of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester.
Further, the molar ratio of the oxidant to (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester is (3-7): 1.
Further, the oxidant is hydrogen peroxide or nitric acid.
Further, the concentration of the hydrogen peroxide is 30%, and the concentration of the nitric acid is 50% -70%.
Further, the reaction temperature in the step S1 is 5-60 ℃.
Further, in the step S2, the pH value is 7-10.
The technical scheme of the invention has the beneficial effects that:
(1) The method does not use an organic reagent in the oxidation and sulfydryl removal reaction process, is safer and more environment-friendly, and is more suitable for industrial production.
(2) Compared with the use of organic reagent, the method has the advantages that the side reaction impurities generated in the reaction process are obviously reduced, the purification of the product is facilitated, and the overall yield is higher.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of etomidate concentrate obtained in example 1 of the present invention.
FIG. 2 is a high performance liquid chromatogram of crude etomidate obtained in example 1 of the present invention.
Fig. 3 is a high performance liquid chromatogram of etomidate concentrate obtained in example 1 of the present invention.
FIG. 4 is a high performance liquid chromatogram of crude etomidate obtained in comparative example 1 of the present invention.
Fig. 5 is a high performance liquid chromatogram of etomidate concentrate obtained in comparative example 1 of the present invention.
FIG. 6 is a high performance liquid chromatogram of crude etomidate obtained in comparative example 2 according to the present invention.
Detailed Description
The industrial preparation method of etomidate in the present invention is further described below with reference to specific embodiments.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1:
0.75g of sodium hydroxide and 8.00g of purified water are weighed into a reaction bottle, and dissolved by stirring. 5.00g of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester was weighed into a reaction flask and dissolved by stirring. 8.23g of 30% hydrogen peroxide is added dropwise, and the temperature is controlled to be not more than 50 ℃. After the dripping, the reaction is carried out for 1h at the temperature of about 25 ℃. After the reaction, cooling, dropping 25ml of saturated sodium bisulphite aqueous solution, adjusting the pH to 9 with saturated sodium carbonate aqueous solution, adding methylene dichloride for extraction for 2 times (15 ml multiplied by 2), taking an organic phase, drying with anhydrous sodium sulfate, filtering, washing, concentrating under reduced pressure to dryness, and obtaining 3.99g of crude etomidate with the yield of 90.3% and the purity of 97.197%.
Adding 3.00g of crude etomidate and 5ml of isopropyl ether into a reaction bottle, heating to about 65 ℃, stirring for dissolution, cooling, preserving heat at 10-15 ℃ for crystallization for 2 hours, filtering and washing; adding the obtained filter cake into a reaction bottle, adding 4ml of isopropyl ether, heating to about 65 ℃, stirring for dissolution, cooling, preserving heat at 10-15 ℃ for crystallization for 2 hours, carrying out suction filtration, washing and drying to obtain 2.36g of etomidate, wherein the yield is 78.7%, and the purity is 99.925%.
Characterization of the product:
(1) Nuclear magnetic analysis was performed on etomidate prepared in example 1: 1H-NMR (400 MHz, CDCl 3) delta 7.78 (2H, d), 7.20-7.32 (5H, m), 6.38 (1H, q), 4.28 (2H, m), 1.87 (3H, d), 1.33 (3H, t). The nuclear magnetic hydrogen spectrum of the prepared etomidate is shown in figure 1, and the number and chemical displacement of hydrogen protons on the nuclear magnetic hydrogen spectrum are consistent with the structure of the etomidate.
(2) The etomidate prepared in example 1 was subjected to HPLC under the following conditions: octadecylsilane chemically bonded silica was used as filler (Diamond 5. Mu. m C18, 4.6X1250 mm); taking methanol-0.062% ammonium acetate solution (40:60) as a mobile phase A, and methanol-0.062% ammonium acetate solution (80:20) as a mobile phase B; the detection wavelength is 210nm; the column temperature was 35 ℃.
The detection process comprises the following steps: dissolving the product in ethanol-water (50:50) and diluting to obtain 1mg solution per 1ml as sample solution; precisely measuring 1ml of the sample solution, placing in a 50ml measuring flask, diluting to scale with ethanol-water (50:50), and shaking; then 1mL of the above solution was measured precisely, put into a 20mL measuring flask, diluted to the scale with ethanol-water (50:50), and shaken well to serve as a control solution. Precisely measuring 10 μl of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram to 2 times of the retention time of the main component chromatographic peak.
The high performance liquid chromatogram of the etomidate crude product in this example is shown in fig. 2.
The high performance liquid chromatogram of etomidate concentrate in this example is shown in fig. 3.
Example 2
1.00g of potassium hydroxide and 5.00g of purified water are weighed into a reaction flask, and dissolved by stirring. 5.00g of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester was weighed into a reaction flask and dissolved by stirring. 7.20g of 30% hydrogen peroxide and 5.00g of purified water are weighed into another reaction bottle, and (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester potassium hydroxide aqueous solution is added dropwise, wherein the temperature is controlled to be no more than 60 ℃ in the dropping process. After the dripping, controlling the temperature to be about 35 ℃ for 3 hours. Cooling after the reaction, dropwise adding 20ml of saturated sodium bisulphite aqueous solution, regulating the pH to 7 by using saturated sodium carbonate aqueous solution, adding toluene for extraction for 2 times (20 ml multiplied by 2), taking an organic phase, drying by using anhydrous sodium sulfate, filtering, washing, concentrating under reduced pressure to dryness, and obtaining 4.16g of crude etomidate with the yield of 94.1% and the purity of 97.311%.
Example 3
2.63g of ammonia water, 15g of purified water and 5.00g of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester are weighed into a reaction flask, stirred and dissolved. 10.00g of nitric acid is added dropwise, and the temperature is controlled to be not more than 60 ℃ in the dropping process. After the dripping, the temperature is raised to about 40 ℃ for reaction for 1h. After the reaction, cooling, dropping 30ml of saturated sodium bisulphite aqueous solution, adjusting the pH to 10 with saturated sodium carbonate aqueous solution, adding methylene dichloride for extraction for 2 times (20 ml multiplied by 2), taking an organic phase, drying with anhydrous sodium sulfate, filtering, washing, concentrating under reduced pressure to dryness, and obtaining 4.08g of crude etomidate with the yield of 92.3% and the purity of 97.003%.
Comparative example 1
5.00g of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester was weighed into a reaction flask, 10ml of acetic acid was measured, and the mixture was stirred and dissolved. 8.23g of 30% hydrogen peroxide and 5.00g of purified water are weighed into another reaction bottle, and (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester tetrahydrofuran solution is dripped, wherein the temperature is controlled to be not more than 60 ℃ in the dripping process. After the dripping, the temperature is raised to 30 ℃ for reaction for 2 hours. After the reaction, the temperature was lowered, 25ml of a saturated aqueous sodium bisulphite solution was added dropwise, and the pH was adjusted to 8 with a saturated aqueous sodium carbonate solution. The mixture was separated and the aqueous phase was extracted once with 15ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, washed and concentrated to dryness under reduced pressure to give 3.77g of crude etomidate in 85.3% yield and 93.169% purity.
Adding 3.00g of crude etomidate and 5ml of isopropyl ether into a reaction bottle, heating to about 65 ℃, stirring for dissolution, cooling, preserving heat at 10-15 ℃ for crystallization for 2 hours, filtering and washing; adding the obtained filter cake into a reaction bottle, adding 4ml of isopropyl ether, heating to about 65 ℃, stirring for dissolution, cooling, preserving heat at 10-15 ℃ for crystallization for 2 hours, carrying out suction filtration, washing and drying to obtain 2.16g of etomidate, wherein the yield is 72.0%, and the purity is 99.014%.
The high performance liquid chromatogram of the etomidate crude product in this example is shown in fig. 4.
The high performance liquid chromatogram of etomidate concentrate in this example is shown in fig. 5.
Comparative example 2
5.00g of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester was weighed into a reaction flask, 10ml of methylene chloride was measured, and the mixture was dissolved by stirring. 8.23g of 30% hydrogen peroxide is added dropwise, and the temperature is controlled to be not more than 40 ℃ in the dropping process. After the dripping, controlling the temperature to be about 30 ℃ for 2 hours. After the reaction, the temperature was lowered, 25ml of a saturated aqueous sodium bisulphite solution was added dropwise, and the pH was adjusted to 8 with a saturated aqueous sodium carbonate solution. The mixture was separated and the aqueous phase was extracted once with 15ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, washed and concentrated to dryness under reduced pressure to give 3.68g of crude etomidate in 83.3% yield and 92.936% purity.
The high performance liquid chromatogram of the etomidate crude product in this example is shown in fig. 6.
TABLE 1 purity detection results for crude etomidate of examples 1-3 and comparative examples 1-2
As is clear from the above table, the crude etomidate obtained in examples 1 to 3 is superior to that obtained in comparative examples 1 to 2 in both purity and yield. The crude etomidate obtained in the example 1 is adopted, and the etomidate meeting the standard requirement can be obtained through refining twice; and the crude etomidate obtained in comparative example 1 can not meet the standard requirements after two times of refining.
It should be understood that while the present description describes embodiments, not every embodiment contains only one independent claim, and that this manner of description is for the sake of clarity only, and that any steps recited in any method or process claims may be executed in any order, and are not limited to the orders set forth in the claims. Those skilled in the art will recognize that the technical solutions of the embodiments may be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims (9)
1. A method for preparing etomidate, which is characterized in that: the preparation method comprises the following steps:
s1, dissolving (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester in an alkaline aqueous solution, mixing with an oxidant, and controlling the temperature for reaction;
and after the reaction of S2 is finished, quenching the reaction, adjusting the pH to be alkaline, extracting with an organic solvent, and concentrating under reduced pressure to obtain a crude etomidate.
2. A process for the preparation of etomidate according to claim 1, characterized in that: the step S1 is specifically mixed with an oxidant: dropwise adding an oxidant into an alkaline aqueous solution of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester or dropwise adding an alkaline aqueous solution of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester into the oxidant, wherein the temperature is controlled to be not more than 60 ℃ during the dropwise adding period.
3. A process for the preparation of etomidate according to claim 1, characterized in that: the alkaline aqueous solution in the step S1 is any one or combination of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and ammonia water.
4. A process for the preparation of etomidate according to claim 1, characterized in that: the amount of the alkali in the alkaline aqueous solution in the step S1 is 1.0-5.0 times of molar equivalent of (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester.
5. A process for the preparation of etomidate according to claim 1, characterized in that: the molar ratio of the oxidant to (+) -1- [ (1R) - (alpha-methylbenzyl) ] -2-mercapto-1H-imidazole-5-carboxylic acid ethyl ester is (3-7): 1.
6. A process for the preparation of etomidate according to claim 1, characterized in that: the oxidant is hydrogen peroxide or nitric acid.
7. A method for preparing etomidate according to claim 6, wherein: the concentration of the hydrogen peroxide is 30%, and the concentration of the nitric acid is 50% -70%.
8. A process for the preparation of etomidate according to claim 1, characterized in that: the reaction temperature in the step S1 is 5-60 ℃.
9. A process for the preparation of etomidate according to claim 1, characterized in that: the pH value in the step S2 is 7-10.
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| US20180297958A1 (en) * | 2015-10-10 | 2018-10-18 | Jiangsu Nhwaluokang Pharmaceutical Research And Development Co., Ltd. | Etomidate derivative and intermediate, preparation method and use thereof |
| CN110922361A (en) * | 2019-11-21 | 2020-03-27 | 武汉大安制药有限公司 | Etomidate oxidation impurity and preparation method thereof |
| CN111533695A (en) * | 2020-05-25 | 2020-08-14 | 武汉大安制药有限公司 | Etomidate preparation method |
| CN116262729A (en) * | 2021-12-15 | 2023-06-16 | 燃点(南京)生物医药科技有限公司 | Etomidate impurity compound, preparation method and application thereof |
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| US20180297958A1 (en) * | 2015-10-10 | 2018-10-18 | Jiangsu Nhwaluokang Pharmaceutical Research And Development Co., Ltd. | Etomidate derivative and intermediate, preparation method and use thereof |
| CN110922361A (en) * | 2019-11-21 | 2020-03-27 | 武汉大安制药有限公司 | Etomidate oxidation impurity and preparation method thereof |
| CN111533695A (en) * | 2020-05-25 | 2020-08-14 | 武汉大安制药有限公司 | Etomidate preparation method |
| CN116262729A (en) * | 2021-12-15 | 2023-06-16 | 燃点(南京)生物医药科技有限公司 | Etomidate impurity compound, preparation method and application thereof |
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