CN103044402B - Method for synthesizing esomeprazole sodium - Google Patents
Method for synthesizing esomeprazole sodium Download PDFInfo
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- CN103044402B CN103044402B CN201210590638.6A CN201210590638A CN103044402B CN 103044402 B CN103044402 B CN 103044402B CN 201210590638 A CN201210590638 A CN 201210590638A CN 103044402 B CN103044402 B CN 103044402B
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- esomeprazole sodium
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- 229960000496 esomeprazole sodium Drugs 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 16
- RYXPMWYHEBGTRV-JIDHJSLPSA-N sodium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [Na+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C RYXPMWYHEBGTRV-JIDHJSLPSA-N 0.000 title claims abstract 17
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000003756 stirring Methods 0.000 claims abstract description 64
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000012043 crude product Substances 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 238000001291 vacuum drying Methods 0.000 claims abstract description 12
- 229940043279 diisopropylamine Drugs 0.000 claims abstract description 10
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 claims abstract description 9
- 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 abstract description 9
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 100
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 17
- 238000000605 extraction Methods 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 13
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 9
- 239000008367 deionised water Substances 0.000 claims description 9
- 229910021641 deionized water Inorganic materials 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 238000003809 water extraction Methods 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 8
- 238000007670 refining Methods 0.000 abstract description 5
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 150000003568 thioethers Chemical class 0.000 abstract 2
- FUHSFUQMWWYWSZ-UHFFFAOYSA-N 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-yl)-1-methylsulfanylbenzimidazole Chemical compound N=1C2=CC(OC)=CC=C2N(SC)C=1C1=NC=C(C)C(OC)=C1C FUHSFUQMWWYWSZ-UHFFFAOYSA-N 0.000 abstract 1
- YQHLDYVWEZKEOX-UHFFFAOYSA-N cumene hydroperoxide Chemical compound OOC(C)(C)C1=CC=CC=C1 YQHLDYVWEZKEOX-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 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 description 33
- 239000000243 solution Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 229960004770 esomeprazole Drugs 0.000 description 8
- 238000009835 boiling Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 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 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229960000381 omeprazole Drugs 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 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 description 2
- KOFBRZWVWJCLGM-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazole-2-thione Chemical compound COC1=CC=C2NC(S)=NC2=C1 KOFBRZWVWJCLGM-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- RBSRVLAVTIXANZ-UHFFFAOYSA-N 1-hydroxy-2-methylpent-1-en-3-one Chemical compound CCC(=O)C(C)=CO RBSRVLAVTIXANZ-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (7)
Priority Applications (1)
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CN201210590638.6A CN103044402B (en) | 2012-12-31 | 2012-12-31 | Method for synthesizing esomeprazole sodium |
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CN201210590638.6A CN103044402B (en) | 2012-12-31 | 2012-12-31 | Method for synthesizing esomeprazole sodium |
Publications (2)
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CN103044402A CN103044402A (en) | 2013-04-17 |
CN103044402B true CN103044402B (en) | 2015-01-14 |
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CN201210590638.6A Active CN103044402B (en) | 2012-12-31 | 2012-12-31 | Method for synthesizing esomeprazole sodium |
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Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103242295B (en) * | 2013-05-14 | 2015-11-04 | 山东罗欣药业集团股份有限公司 | Esomeprazole sodium crystal-form compound and synthetic method thereof |
CN104693177A (en) * | 2013-12-09 | 2015-06-10 | 北大方正集团有限公司 | Refining method of esomeprazole sodium |
CN103755685B (en) * | 2014-01-16 | 2015-03-25 | 山东科源制药有限公司 | Purifying and refining method of esomeprazole sodium |
CN103739592A (en) * | 2014-01-24 | 2014-04-23 | 山东科源制药有限公司 | Method for producing esomeprazole sodium |
CN104163814B (en) * | 2014-05-27 | 2016-08-24 | 浙江新东港药业股份有限公司 | A kind of high-purity 5-methoxyl group-2-((S)-((4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl) sulfinyl)-1H-benzimidazole sodium preparation method |
CN105418589B (en) * | 2016-01-17 | 2017-09-26 | 青岛市中心医院 | A kind of esomeprazole magnesium trihydrate preparation method for treating disease of digestive system |
CN106366070B (en) * | 2016-08-10 | 2019-06-11 | 上海万巷制药有限公司 | A kind of preparation method of high-purity esomeprazole sodium |
CN107987058A (en) * | 2017-11-28 | 2018-05-04 | 江苏中邦制药有限公司 | A kind of synthetic method of esomeprazole sodium impurity I |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1157614A (en) * | 1994-07-15 | 1997-08-20 | 阿斯特拉公司 | Process for synthesis of substituted sulphoxides |
CN101538264A (en) * | 2008-03-19 | 2009-09-23 | 中国科学院成都有机化学有限公司 | Novel method for preparing chiral sulphoxide compound |
CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102241670B (en) * | 2011-04-28 | 2013-05-29 | 苏州特瑞药业有限公司 | Preparation method of high-purity chiral sulphoxide compound |
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- 2012-12-31 CN CN201210590638.6A patent/CN103044402B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1157614A (en) * | 1994-07-15 | 1997-08-20 | 阿斯特拉公司 | Process for synthesis of substituted sulphoxides |
CN101538264A (en) * | 2008-03-19 | 2009-09-23 | 中国科学院成都有机化学有限公司 | Novel method for preparing chiral sulphoxide compound |
CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
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CN103044402A (en) | 2013-04-17 |
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Inventor after: Zeng Peian Inventor after: Wu Feng Inventor after: Liu Donghua Inventor after: Zhang Hao Inventor after: Wu Jianmin Inventor after: Zhang Jing Inventor after: He Lian Inventor after: Liu Juan Inventor before: Zeng Peian Inventor before: Wu Feng Inventor before: Liu Donghua Inventor before: Zhang Hao Inventor before: Wu Jianming Inventor before: Zhang Jing Inventor before: He Lian Inventor before: Liu Juan |
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Free format text: CORRECT: INVENTOR; FROM: CENG PEIAN WU FENG LIU DONGHUA ZHANG HAO WU JIANMING ZHANG JING HE LIAN LIU JUAN TO: CENG PEIAN WU FENG LIU DONGHUA ZHANG HAO WU JIANMIN ZHANG JING HE LIAN LIU JUAN |
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Denomination of invention: Synthesis and production method of esomeprazole sodium Effective date of registration: 20210730 Granted publication date: 20150114 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021430000029 |
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Date of cancellation: 20211014 Granted publication date: 20150114 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021430000029 |
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Denomination of invention: Synthesis and production method of esomeprazole sodium Effective date of registration: 20211028 Granted publication date: 20150114 Pledgee: Hunan Hanshou Rural Commercial Bank Co.,Ltd. Pledgor: KAMP PHARMACEUTICALS Co.,Ltd. Registration number: Y2021980011259 |
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