CN113698389A - Synthetic method of esomeprazole - Google Patents
Synthetic method of esomeprazole Download PDFInfo
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- CN113698389A CN113698389A CN202110990882.0A CN202110990882A CN113698389A CN 113698389 A CN113698389 A CN 113698389A CN 202110990882 A CN202110990882 A CN 202110990882A CN 113698389 A CN113698389 A CN 113698389A
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- esomeprazole
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- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 title claims abstract description 35
- 229960004770 esomeprazole Drugs 0.000 title claims abstract description 34
- 238000010189 synthetic method Methods 0.000 title claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000008367 deionised water Substances 0.000 claims abstract description 42
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 42
- 238000003756 stirring Methods 0.000 claims abstract description 42
- 239000013078 crystal Substances 0.000 claims abstract description 28
- 238000002156 mixing Methods 0.000 claims abstract description 27
- 238000001914 filtration Methods 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 25
- 229960000381 omeprazole Drugs 0.000 claims abstract description 23
- 239000012043 crude product Substances 0.000 claims abstract description 22
- -1 omeprazole thioether Chemical class 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 19
- 238000007670 refining Methods 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 16
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 claims abstract description 16
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 claims abstract description 16
- 238000005406 washing Methods 0.000 claims abstract description 10
- 239000012153 distilled water Substances 0.000 claims abstract description 6
- 238000003828 vacuum filtration Methods 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 26
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 18
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 12
- LCJDHJOUOJSJGS-UHFFFAOYSA-N 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridin-1-ium;chloride Chemical compound Cl.COC1=C(C)C=NC(CCl)=C1C LCJDHJOUOJSJGS-UHFFFAOYSA-N 0.000 claims description 10
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 claims description 10
- KOFBRZWVWJCLGM-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazole-2-thione Chemical compound COC1=CC=C2NC(S)=NC2=C1 KOFBRZWVWJCLGM-UHFFFAOYSA-N 0.000 claims description 10
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 10
- 238000007792 addition Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000012545 processing Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 8
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- KWORUUGOSLYAGD-YPPDDXJESA-N esomeprazole magnesium Chemical compound [Mg+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-YPPDDXJESA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 229960000197 esomeprazole magnesium Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 2
- 229960002337 magnesium chloride Drugs 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 229960000496 esomeprazole sodium Drugs 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- MQEUGMWHWPYFDD-JIDHJSLPSA-N magnesium;6-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound [Mg].C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C MQEUGMWHWPYFDD-JIDHJSLPSA-N 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthetic method of esomeprazole, which comprises the following steps: firstly, preparing omeprazole thioether; secondly, preparing a crude product by taking omeprazole thioether and the like as raw materials; refining the obtained crude product for 3 times to obtain a refined intermediate; and thirdly, mixing the refined intermediate with deionized water, filtering, adding esomeprazole as a seed crystal, mixing magnesium chloride hexahydrate and deionized water, stirring, cooling, stirring for 30min, carrying out vacuum filtration, washing the obtained crystal with distilled water, and drying to obtain the esomeprazole. The preparation process is refined for three times, so that the yield and the purity in the subsequent processing process are improved under the condition of ensuring that the yield in the refining process is 90%, and the problems of low total yield, increased production cost and inconvenience for industrial production caused by unsatisfactory improvement of the purity in the existing method are solved.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthetic method of esomeprazole.
Background
Proton pump inhibitors, the pure levorotatory isomer of omeprazole, are useful for the initial and long-term treatment of gastroesophageal reflux disease (GORD), including erosive reflux esophagitis, including erosive esophagitis, for long-term maintenance therapy of esophagitis and prevention of GORD recurrence, and for symptomatic treatment of GORD disease. The methods for preparing esomeprazole have been disclosed in the patent documents WO9617076, WO9617077, WO9208716, WO9602535 and the like in succession. CN1110477A discloses a method for producing esomeprazole magnesium salt by reacting magnesium chloride with esomeprazole sodium, but magnesium chloride is dissolved in water and alcohol solvent, which brings great difficulty to the subsequent separation and purification, and the method for purifying and refining esomeprazole magnesium is not disclosed in the patent. In addition, these processes often yield esomeprazole magnesium trihydrate or other unstable forms of esomeprazole magnesium, rather than the more stable dihydrate of esomeprazole magnesium.
Disclosure of Invention
The invention provides a synthetic method of esomeprazole.
The technical problems to be solved by the invention are as follows:
the products prepared in the prior art have obvious impurities, including various intermediates and reaction byproducts, which remain therein; the purity is not improved ideally, the total yield is low, the production cost is increased, and the industrial production is not facilitated. The purity of the raw material drug directly influences the safety of the drug, and the yield directly influences the cost of producing the drug, so that the development of a preparation process of esomeprazole with higher purity and yield is necessary.
The purpose of the invention can be realized by the following technical scheme:
a synthetic method of esomeprazole comprises the following steps:
firstly, mixing methanol, 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride solution and 2-mercapto-5-methoxy-1H-benzimidazole, then adding sodium hydroxide and deionized water, controlling the temperature of dripping to be 0-30 ℃, and reacting for 1H at the temperature of 20-30 ℃ after finishing dripping; after the reaction is finished, carrying out post-treatment; the post-treatment comprises the following specific steps: adding toluene with 2 times of the volume of the reaction solution into the obtained reaction solution, then regulating the pH value to 12-12.5 by using an acetic acid solution, stirring for 10min, standing for 10min, separating liquid, washing a toluene layer for 2-4 times by using a potassium carbonate solution, then adding seed crystal omeprazole thioether, stirring for 12h at 0-30 ℃, stirring for 30min at 0-5 ℃, filtering, and drying a filter cake for 2h at 40 ℃ to obtain the omeprazole thioether;
the reaction process is as follows:
secondly, mixing omeprazole thioether, toluene, D- (-) -diethyl tartrate and deionized water, heating to 48-54 ℃, adding tetraisopropyl titanate, stirring for 50min, cooling to 28-34 ℃, adding N, N-diisopropylethylamine, dropwise adding cumene hydroperoxide, reacting for 60-120min after the addition, adding ammonia water and sodium bisulfite, and reacting for 6h at 12-30 ℃; after the reaction is finished, post-treatment is carried out, and the specific process of the post-treatment is as follows: adjusting pH of the reaction solution to 12.5-12.9 with sodium hydroxide solution, stirring for 10min, standing for 10min for liquid separation, removing a toluene layer, then adding toluene and dichloromethane, adjusting pH to 9-9.2 with glacial acetic acid, heating to 38-43 ℃, stirring for 10min, standing for 10min for liquid separation, removing a water layer, and drying the toluene layer with anhydrous magnesium sulfate to obtain a crude product;
refining the obtained crude product for 3 times to obtain a refined intermediate;
the reaction process is as follows:
and thirdly, mixing the refined intermediate with deionized water, dissolving, filtering, adding esomeprazole as a seed crystal at the temperature of 30-40 ℃, mixing magnesium chloride hexahydrate with deionized water, dropwise adding the mixture within 1h, stirring for 12h, cooling to 0-5 ℃, stirring for 30min, carrying out vacuum filtration, washing obtained crystals with distilled water, and drying obtained wet products to constant weight at the temperature of 40 ℃ and 2-4kPa to obtain esomeprazole.
The reaction process is as follows:
further, in the first step, the ratio of the amount of methanol, 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride, 2-mercapto-5-methoxy-1H-benzimidazole, sodium hydroxide and deionized water was 42L: 12 kg: 9.8-9.9 kg: 5.4 kg: 24L.
Furthermore, the dosage ratio of omeprazole thioether, toluene, diethyl D- (-) -tartrate, deionized water, tetraisopropyl titanate, N-diisopropylethylamine, cumene hydroperoxide, ammonia water and sodium bisulfite is 15.6-15.7 kg: 65.8L: 1.96-1.97 kg: 31.32 mL: 1.35-1.36 kg: 0.9-1L: 9 kg; 51-52L: 2.47 kg; wherein the mass fraction of the ammonia water is 15-18%.
Further, the ratio of the amount of the purified intermediate to the deionized water in the third step was 11.8 kg: 47L; the dosage ratio of the magnesium chloride hexahydrate to the deionized water is 3.35-3.6 kg: 68.8-69L; the dosage ratio of the refined intermediate, the magnesium chloride hexahydrate and the esomeprazole seed crystal is 11.8 kg: 3.35 kg: 144.9 g.
Further, the refining operation comprises the steps of:
step S11, mixing the obtained crude product with acetonitrile, heating to 70 ℃, stirring for 15min, filtering while the mixture is hot, adding methanol and a refined intermediate into the filtrate after filtering, taking the refined intermediate as a seed crystal, curing for 1h at the temperature of 65-73 ℃, cooling, crystallizing, filtering to obtain a wet product, and drying for 3h at 40 ℃ and 2-4 kPa; wherein the dosage ratio of the crude product, the acetonitrile, the methanol and the refined intermediate in the step S11 is 17 kg: 96.77L: 10.26L: 7.33 g.
The invention has the beneficial effects that:
omeprazole thioether is added in the first step to serve as seed crystal, refining is carried out for three times in the preparation process in the second step, yield and purity in the subsequent processing process are improved under the condition that yield in the refining process is 90%, and esomeprazole is added in the third step to serve as seed crystal; the total yield is improved in the whole preparation process, the production cost is reduced, the industrial production is facilitated, the operation difficulty and the cost are reduced, and on the other hand, the impurity content in the product is also reduced.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A synthetic method of esomeprazole comprises the following steps:
firstly, mixing methanol, 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride solution and 2-mercapto-5-methoxy-1H-benzimidazole, then adding sodium hydroxide and deionized water, controlling the temperature at the time of dripping to be 0 ℃, and reacting for 1H at the temperature of 20 ℃ after finishing dripping; after the reaction is finished, carrying out post-treatment; the post-treatment comprises the following specific steps: adding toluene with 2 times of the volume of the reaction solution into the obtained reaction solution, then regulating the pH value to 12 by using an acetic acid solution, stirring for 10min, standing for 10min, separating liquid, washing a toluene layer for 2 times by using a potassium carbonate solution, then adding seed crystal omeprazole thioether, stirring for 12h at 0 ℃, stirring for 30min at 0 ℃, filtering, and drying a filter cake for 2h at 40 ℃ to obtain the omeprazole thioether; the yield is 87.99 percent;
secondly, mixing omeprazole thioether, toluene, D- (-) -diethyl tartrate and deionized water, heating to 48 ℃, adding tetraisopropyl titanate, stirring for 50min, cooling to 28 ℃, adding N, N-diisopropylethylamine, dropwise adding cumene hydroperoxide, reacting for 60min after the addition, adding ammonia water and sodium bisulfite, and reacting for 6h at 12 ℃; after the reaction is finished, post-treatment is carried out, and the specific process of the post-treatment is as follows: adjusting pH of the reaction solution to 12.5 with sodium hydroxide solution, stirring for 10min, standing for 10min for liquid separation, removing toluene layer, adding toluene and dichloromethane, adjusting pH to 9 with glacial acetic acid, heating to 38 deg.C, stirring for 10min, standing for 10min, liquid separation, removing water layer, and drying the toluene layer with anhydrous magnesium sulfate to obtain crude product; the yield of the process is 80.4%;
refining the obtained crude product for 3 times to obtain a refined intermediate;
and thirdly, mixing the refined intermediate with deionized water, dissolving, filtering, adding esomeprazole as a seed crystal at the temperature of 30 ℃, mixing magnesium chloride hexahydrate with deionized water, dropwise adding the mixture within 1h, stirring for 12h, cooling to 0 ℃, stirring for 30min, carrying out vacuum filtration, washing obtained crystals with distilled water, and drying the obtained wet product at 40 ℃ and 2kPa to constant weight to obtain esomeprazole. The yield of this process was 92%.
Wherein, in the first step, the dosage ratio of methanol, 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine hydrochloride solution, 2-mercapto-5-methoxyl-1H-benzimidazole, sodium hydroxide and deionized water is 42L: 12 kg: 9.8 kg: 5.4 kg: 24L.
Wherein the dosage ratio of omeprazole thioether, toluene, D- (-) -diethyl tartrate, deionized water, tetraisopropyl titanate, N-diisopropylethylamine, cumene hydroperoxide, ammonia water and sodium bisulfite is 15.6 kg: 65.8L: 1.96 kg: 31.32 mL: 1.35 kg: 0.9L: 9 kg; 51L: 2.47 kg; wherein the mass fraction of the ammonia water is 15 percent.
Wherein, the dosage ratio of the refined intermediate to the deionized water in the third step is 11.8 kg: 47L; the dosage ratio of the magnesium chloride hexahydrate to the deionized water is 3.35 kg: 68.8L; the dosage ratio of the refined intermediate, the magnesium chloride hexahydrate and the esomeprazole seed crystal is 11.8 kg: 3.35 kg: 144.9 g.
Wherein the refining operation comprises the steps of:
step S11, mixing the obtained crude product with acetonitrile, heating to 70 ℃, stirring for 15min, filtering while the mixture is hot, adding methanol and a refined intermediate into the filtrate after filtering, taking the refined intermediate as a seed crystal, curing for 1h at the temperature of 65 ℃, cooling, crystallizing, filtering, and drying the wet product for 3h at 40 ℃ and 2 kPa; wherein the dosage ratio of the crude product, the acetonitrile, the methanol and the refined intermediate in the step S11 is 17 kg: 96.77L: 10.26L: 7.33 g. The yield of the refining process was 90%.
Example 2
A synthetic method of esomeprazole comprises the following steps:
firstly, mixing methanol, 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride solution and 2-mercapto-5-methoxy-1H-benzimidazole, then adding sodium hydroxide and deionized water, controlling the temperature at the time of dripping to be 20 ℃, and reacting for 1H at the temperature of 25 ℃ after finishing dripping; after the reaction is finished, carrying out post-treatment; the post-treatment comprises the following specific steps: adding toluene with the volume 2 times that of the obtained reaction solution into the obtained reaction solution, then regulating the pH value to 12 by using an acetic acid solution, stirring for 10min, standing for 10min, separating liquid, washing a toluene layer for 3 times by using a potassium carbonate solution, then adding seed crystal omeprazole thioether, stirring for 12h at the temperature of 20 ℃, stirring for 30min at the temperature of 0 ℃, filtering, and drying a filter cake for 2h at the temperature of 40 ℃ to obtain the omeprazole thioether; the yield is 88.12%;
secondly, mixing omeprazole thioether, toluene, D- (-) -diethyl tartrate and deionized water, heating to 50 ℃, adding tetraisopropyl titanate, stirring for 50min, cooling to 30 ℃, adding N, N-diisopropylethylamine, dropwise adding cumene hydroperoxide, reacting for 90min after the addition, adding ammonia water and sodium bisulfite, and reacting for 6h at 20 ℃; after the reaction is finished, post-treatment is carried out, and the specific process of the post-treatment is as follows: adjusting pH of the reaction solution to 12.5 with sodium hydroxide solution, stirring for 10min, standing for 10min for liquid separation, removing toluene layer, adding toluene and dichloromethane, adjusting pH to 9 with glacial acetic acid, heating to 40 deg.C, stirring for 10min, standing for 10min, liquid separation, removing water layer, and drying the toluene layer with anhydrous magnesium sulfate to obtain crude product; the yield of the process is 80.6 percent;
refining the obtained crude product for 3 times to obtain a refined intermediate;
and thirdly, mixing the refined intermediate with deionized water, dissolving, filtering, adding esomeprazole as a seed crystal at the temperature of 35 ℃, mixing magnesium chloride hexahydrate with deionized water, dropwise adding the mixture within 1h, stirring for 12h, cooling to 0 ℃, stirring for 30min, carrying out vacuum filtration, washing obtained crystals with distilled water, and drying the obtained wet product at 40 ℃ and 3kPa to constant weight to obtain esomeprazole. The yield of this process was 91%.
Wherein, in the first step, the dosage ratio of methanol, 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine hydrochloride solution, 2-mercapto-5-methoxyl-1H-benzimidazole, sodium hydroxide and deionized water is 42L: 12 kg: 9.8 kg: 5.4 kg: 24L.
Wherein the dosage ratio of omeprazole thioether, toluene, D- (-) -diethyl tartrate, deionized water, tetraisopropyl titanate, N-diisopropylethylamine, cumene hydroperoxide, ammonia water and sodium bisulfite is 15.6 kg: 65.8L: 1.96 kg: 31.32 mL: 1.35 kg: 0.9L: 9 kg; 51L: 2.47 kg; wherein the mass fraction of the ammonia water is 15 percent.
Wherein, the dosage ratio of the refined intermediate to the deionized water in the third step is 11.8 kg: 47L; the dosage ratio of the magnesium chloride hexahydrate to the deionized water is 3.35 kg: 68.8L; the dosage ratio of the refined intermediate, the magnesium chloride hexahydrate and the esomeprazole seed crystal is 11.8 kg: 3.35 kg: 144.9 g.
Wherein the refining operation comprises the steps of:
step S11, mixing the obtained crude product with acetonitrile, heating to 70 ℃, stirring for 15min, filtering while the mixture is hot, adding methanol and a refined intermediate into the filtrate after filtering, taking the refined intermediate as a seed crystal, curing for 1h at the temperature of 70 ℃, cooling, crystallizing, filtering, and drying the wet product for 3h at 40 ℃ and 2 kPa; wherein the dosage ratio of the crude product, the acetonitrile, the methanol and the refined intermediate in the step S11 is 17 kg: 96.77L: 10.26L: 7.33 g. The yield of the refining process was 90%.
Example 3
A synthetic method of esomeprazole comprises the following steps:
firstly, mixing methanol, 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride solution and 2-mercapto-5-methoxy-1H-benzimidazole, then adding sodium hydroxide and deionized water, controlling the temperature of dripping at 30 ℃, and reacting for 1H at the temperature of 30 ℃ after finishing dripping; after the reaction is finished, carrying out post-treatment; the post-treatment comprises the following specific steps: adding toluene with 2 times of the volume of the reaction solution into the obtained reaction solution, then regulating the pH value to 12.5 by using an acetic acid solution, stirring for 10min, standing for 10min, separating liquid, washing a toluene layer for 4 times by using a potassium carbonate solution, then adding seed crystal omeprazole thioether, stirring for 12h at 30 ℃, stirring for 30min at 5 ℃, filtering, and drying a filter cake for 2h at 40 ℃ to obtain the omeprazole thioether; the yield is 88.21%;
secondly, mixing omeprazole thioether, toluene, D- (-) -diethyl tartrate and deionized water, heating to 54 ℃, adding tetraisopropyl titanate, stirring for 50min, cooling to 34 ℃, adding N, N-diisopropylethylamine, dropwise adding cumene hydroperoxide, reacting for 120min after the addition, adding ammonia water and sodium bisulfite, and reacting for 6h at 30 ℃; after the reaction is finished, post-treatment is carried out, and the specific process of the post-treatment is as follows: adjusting pH of the reaction solution to 12.9 with sodium hydroxide solution, stirring for 10min, standing for 10min for liquid separation, removing toluene layer, adding toluene and dichloromethane, adjusting pH to 9.2 with glacial acetic acid, heating to 43 deg.C, stirring for 10min, standing for 10min, liquid separation, removing water layer, and drying the toluene layer with anhydrous magnesium sulfate to obtain crude product; the yield of the process is 80.4%;
refining the obtained crude product for 3 times to obtain a refined intermediate;
and thirdly, mixing the refined intermediate with deionized water, dissolving, filtering, adding esomeprazole as a seed crystal at the temperature of 40 ℃, mixing magnesium chloride hexahydrate with deionized water, dropwise adding the mixture within 1h, stirring for 12h, cooling to 5 ℃, stirring for 30min, carrying out vacuum filtration, washing obtained crystals with distilled water, and drying the obtained wet product at the temperature of 40 ℃ and 4kPa to constant weight to obtain esomeprazole. The yield of this process was 92%.
Wherein, in the first step, the dosage ratio of methanol, 2-chloromethyl-4-methoxyl-3, 5-dimethylpyridine hydrochloride solution, 2-mercapto-5-methoxyl-1H-benzimidazole, sodium hydroxide and deionized water is 42L: 12 kg: 9.9 kg: 5.4 kg: 24L.
Wherein the dosage ratio of omeprazole thioether, toluene, D- (-) -diethyl tartrate, deionized water, tetraisopropyl titanate, N-diisopropylethylamine, cumene hydroperoxide, ammonia water and sodium bisulfite is 15.7 kg: 65.8L: 1.97 kg: 31.32 mL: 1.36 kg: 1L: 9 kg; 52L: 2.47 kg; wherein the mass fraction of the ammonia water is 18 percent.
Wherein, the dosage ratio of the refined intermediate to the deionized water in the third step is 11.8 kg: 47L; the dosage ratio of the magnesium chloride hexahydrate to the deionized water is 3.6 kg: 69L; the dosage ratio of the refined intermediate, the magnesium chloride hexahydrate and the esomeprazole seed crystal is 11.8 kg: 3.35 kg: 144.9 g.
Wherein the refining operation comprises the steps of:
step S11, mixing the obtained crude product with acetonitrile, heating to 70 ℃, stirring for 15min, filtering while the mixture is hot, adding methanol and a refined intermediate into the filtrate after filtering, taking the refined intermediate as a seed crystal, curing for 1h at 73 ℃, cooling, crystallizing, filtering, and drying the wet product for 3h at 40 ℃ and 4 kPa; wherein the dosage ratio of the crude product, the acetonitrile, the methanol and the refined intermediate in the step S11 is 17 kg: 96.77L: 10.26L: 7.33 g. The yield in the purification process was 91%.
Comparative example 1
Compared with the example 1, the yield of the third step is 78 percent without three refining operations and the rest processes are kept unchanged.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing is illustrative and explanatory only and is not intended to be exhaustive or to limit the invention to the precise embodiments described, and various modifications, additions, and substitutions may be made by those skilled in the art without departing from the scope of the invention or exceeding the scope of the claims.
Claims (5)
1. A synthetic method of esomeprazole is characterized by comprising the following steps:
firstly, mixing methanol, 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride solution and 2-mercapto-5-methoxy-1H-benzimidazole, then adding sodium hydroxide and deionized water, controlling the temperature of dripping to be 0-30 ℃, and reacting for 1H at the temperature of 20-30 ℃ after finishing dripping; after the reaction is finished, carrying out post-treatment; obtaining omeprazole thioether;
secondly, mixing omeprazole thioether, toluene, D- (-) -diethyl tartrate and deionized water, heating to 48-54 ℃, adding tetraisopropyl titanate, stirring for 50min, cooling to 28-34 ℃, adding N, N-diisopropylethylamine, dropwise adding cumene hydroperoxide, reacting for 60-120min after the addition, adding ammonia water and sodium bisulfite, and reacting for 6h at 12-30 ℃; after the reaction is finished, carrying out post-treatment to obtain a crude product; refining the obtained crude product for 3 times to obtain a refined intermediate;
and thirdly, mixing the refined intermediate with deionized water, dissolving, filtering, adding esomeprazole as a seed crystal at the temperature of 30-40 ℃, mixing magnesium chloride hexahydrate with deionized water, dropwise adding the mixture within 1h, stirring for 12h, cooling to 0-5 ℃, stirring for 30min, carrying out vacuum filtration, washing obtained crystals with distilled water, and drying obtained wet products to constant weight at the temperature of 40 ℃ and 2-4kPa to obtain esomeprazole.
2. The process for the synthesis of esomeprazole according to claim 1, wherein the refining operation comprises the steps of:
mixing the obtained crude product with acetonitrile, heating to 70 ℃, stirring for 15min, filtering while the mixture is hot, adding methanol and a refined intermediate into the filtrate after filtering, taking the refined intermediate as a seed crystal, curing for 1h at the temperature of 65-73 ℃, cooling, crystallizing, filtering to obtain a wet product, and drying for 3h at the temperature of 40 ℃ and 2-4 kPa; wherein, the dosage ratio of the crude product, the acetonitrile, the methanol and the refined intermediate is 17 kg: 96.77L: 10.26L: 7.33 g.
3. The method for synthesizing esomeprazole according to claim 1, wherein the using amount ratio of methanol, 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride solution, 2-mercapto-5-methoxy-1H-benzimidazole, sodium hydroxide and deionized water in the first step is 42L: 12 kg: 9.8-9.9 kg: 5.4 kg: 24L.
4. The method for synthesizing esomeprazole according to claim 1, wherein the dosage ratio of omeprazole thioether, toluene, diethyl D- (-) -tartrate, deionized water, tetraisopropyl titanate, N-diisopropylethylamine, cumene hydroperoxide, ammonia water and sodium bisulfite in the second step is 15.6-15.7 kg: 65.8L: 1.96-1.97 kg: 31.32 mL: 1.35-1.36 kg: 0.9-1L: 9 kg; 51-52L: 2.47 kg; the mass fraction of the ammonia water is 15-18%.
5. The method for synthesizing esomeprazole according to claim 1, wherein the ratio of the amount of the refined intermediate to the deionized water in the third step is 11.8 kg: 47L; the dosage ratio of the magnesium chloride hexahydrate to the deionized water is 3.35-3.6 kg: 68.8-69L; the dosage ratio of the refined intermediate, the magnesium chloride hexahydrate and the esomeprazole seed crystal is 11.8 kg: 3.35 kg: 144.9 g.
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