CN111072633A - Preparation method of esomeprazole magnesium trihydrate - Google Patents
Preparation method of esomeprazole magnesium trihydrate Download PDFInfo
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- CN111072633A CN111072633A CN201911315546.5A CN201911315546A CN111072633A CN 111072633 A CN111072633 A CN 111072633A CN 201911315546 A CN201911315546 A CN 201911315546A CN 111072633 A CN111072633 A CN 111072633A
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- esomeprazole
- inorganic
- magnesium trihydrate
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- esomeprazole magnesium
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- 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 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 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 claims abstract description 32
- 229960004770 esomeprazole Drugs 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000003756 stirring Methods 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000003446 ligand Substances 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000967 suction filtration Methods 0.000 claims abstract description 16
- 238000001816 cooling Methods 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 13
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000007800 oxidant agent Substances 0.000 claims abstract description 12
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 10
- -1 omeprazole thioether Chemical class 0.000 claims abstract description 10
- 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 abstract description 8
- KOFBRZWVWJCLGM-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazole-2-thione Chemical compound COC1=CC=C2NC(S)=NC2=C1 KOFBRZWVWJCLGM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 159000000003 magnesium salts Chemical class 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- FOFFPEFVSRGLOZ-JIDHJSLPSA-N potassium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [K+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-JIDHJSLPSA-N 0.000 claims description 8
- FSJSYDFBTIVUFD-SUKNRPLKSA-N (z)-4-hydroxypent-3-en-2-one;oxovanadium Chemical compound [V]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FSJSYDFBTIVUFD-SUKNRPLKSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 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 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 4
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical group CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 4
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical group COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 229960000197 esomeprazole magnesium Drugs 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- LKKCSUHCVGCGFA-GEMLJDPKSA-N (1s,2s)-2-aminocyclohexan-1-ol;hydrochloride Chemical compound Cl.N[C@H]1CCCC[C@@H]1O LKKCSUHCVGCGFA-GEMLJDPKSA-N 0.000 claims description 2
- NTHNRYLIXJZHRZ-STQMWFEESA-N (1s,2s)-2-phenylmethoxycyclohexan-1-amine Chemical compound N[C@H]1CCCC[C@@H]1OCC1=CC=CC=C1 NTHNRYLIXJZHRZ-STQMWFEESA-N 0.000 claims description 2
- 229910052787 antimony Inorganic materials 0.000 claims description 2
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- PBYZMCDFOULPGH-UHFFFAOYSA-N tungstate Chemical compound [O-][W]([O-])(=O)=O PBYZMCDFOULPGH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 229960000381 omeprazole Drugs 0.000 abstract description 13
- 238000010438 heat treatment Methods 0.000 abstract description 9
- 238000007254 oxidation reaction Methods 0.000 abstract description 9
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 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 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 6
- FOFFPEFVSRGLOZ-UHFFFAOYSA-N potassium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [K+].N=1C2=CC(OC)=CC=C2[N-]C=1[S+]([O-])CC1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-UHFFFAOYSA-N 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 description 3
- 229940061634 magnesium sulfate heptahydrate Drugs 0.000 description 3
- 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 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical group [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- XURCIPRUUASYLR-UHFFFAOYSA-N Omeprazole sulfide Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940112641 nexium Drugs 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
Images
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a preparation method of esomeprazole magnesium trihydrate, which comprises the following steps: 1) synthesizing omeprazole thioether from 5-methoxy-2-mercaptobenzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride under alkaline condition; 2) taking omeprazole thioether, adding a chiral ligand, a catalyst and an organic solvent, and heating and stirring for reaction to form an omeprazole thioether chiral compound; 3) adding an inorganic oxidant to carry out asymmetric oxidation reaction, and oxidizing omeprazole thioether into esomeprazole; 4) adding an inorganic base organic solution to form esomeprazole inorganic salt from the esomeprazole obtained in the step 3); 5) cooling, crystallizing the esomeprazole inorganic salt obtained in the step 4), and performing suction filtration and drying; 6) dissolving esomeprazole inorganic salt in water, and performing suction filtration; 7) adding inorganic magnesium salt into the inorganic alkaline aqueous solution layer obtained in the step 6), stirring for reaction, and then centrifuging and drying to obtain the esomeprazole magnesium trihydrate. The preparation method has the advantages of high product purity, high yield, simple process, high efficiency, environmental friendliness, low cost and the like.
Description
Technical Field
The invention relates to a preparation method of a medicament, and particularly relates to a preparation method of esomeprazole magnesium trihydrate.
Background
Esomeprazole, is an S-isomer of omeprazole with the chemical name: (S) -5-methoxy-2- [ [ 4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1H-benzimidazole is a first global isomer proton pump inhibitor (I-PPI) isolated and synthesized by AstraZeneca (Astra) of Sweden, and the Proton Pump Inhibitor (PPI) is the first choice drug for treating peptic ulcer, gastroesophageal reflux disease (GERD), duodenal ulcer and other diseases. Esomeprazole magnesium is a slow-release oral preparation, is sold in the United states under the trade name of nai xin (NEXIUM), and is approved to be marketed in 10 months 2002 by original manufacturer Aslicon company at present, and is marketed in the national medical insurance catalogue at present as a trihydrate, wherein the structural formula of the product is shown in the figure:
the preparation of esomeprazole magnesium trihydrate mainly comprises the following two methods: (1) synthesizing esomeprazole, purifying the esomeprazole through recrystallization, dissolving the purified esomeprazole in dichloromethane, adding a sodium hydroxide solution to salify and separate out, adding an inorganic magnesium salt for replacement, and drying to obtain an esomeprazole magnesium trihydrate; (2) firstly synthesizing esomeprazole, dissolving esomeprazole in methanol, then adding potassium hydroxide and seed crystal, stirring overnight, precipitating esomeprazole potassium, then dissolving esomeprazole potassium in water, adding inorganic magnesium salt for replacement, and heating and drying to obtain esomeprazole magnesium trihydrate.
At present, the preparation methods of esomeprazole mainly comprise the following steps: (1) resolution of racemate; (2) a biochemical method; (3) asymmetric oxidation process.
Patents WO96/02535, WO9854171, WO2011012957, CN95194956, etc. describe a process for obtaining esomeprazole by oxidation of omeprazole with hydrogen peroxide derivatives in the presence of chiral ligands diethyl tartrate, titanium metal complexes and bases; WO03/089408 discloses a method for obtaining esomeprazole by oxidizing omeprazole with a complex of chiral ligand (S) - (+) -mandelate and titanium or vanadium in the presence of a base, but the above preparation method easily generates a large amount of by-products such as nitrogen oxide and sulfone, which affects the yield and purity of esomeprazole and is not suitable for industrial mass production.
WO9617076 describes the enzymatic catalytic oxidation of omeprazole by using microbial enzymes, and the method has good catalytic oxidation selectivity, but because the microbial enzyme catalytic oxidation influencing factors are complex and difficult to control, the single-batch yield is low, and the large-scale industrial production is difficult. WO9427988, US5714504, CN94190335 describe a synthesis process in which omeprazole is oxidized to esomeprazole by an oxidizing agent, then resolved by a chiral resolving agent, mandelic acid, to obtain a single S-type isomer of omeprazole, then acid hydrolyzed to prepare sodium salt, and finally magnesium ion exchanged to obtain esomeprazole magnesium. The enantiomeric purity of the product prepared by the method is still acceptable (the ee value is 99.8%), but the resolution yield is lower (38%), the product loss is larger, the production cost is higher, and the method is not beneficial to industrial mass production.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of esomeprazole magnesium trihydrate, and the preparation method has the advantages of high product purity, high yield, simple process, high efficiency, environmental friendliness, low cost and the like.
A preparation method of esomeprazole magnesium trihydrate comprises the following steps:
a. taking 5-methoxy-2-mercaptobenzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride to obtain a compound with a structure (I) in an alkaline environment;
b. taking a compound with a structure shown in a formula (I), and adding a catalyst, a chiral ligand, an organic base and an oxidant to obtain a compound with a structure shown in a formula (II);
c. adding an inorganic base organic solution to enable the compound with the structure of the formula (II) to form esomeprazole inorganic salt, cooling, crystallizing, filtering and drying;
d. c, recrystallizing the esomeprazole inorganic salt obtained in the step c
e. D, dissolving the esomeprazole inorganic salt obtained in the step d with water, performing suction filtration, slowly dropwise adding an inorganic magnesium aqueous solution into the solution, stirring for reaction, performing suction filtration, and drying to obtain the esomeprazole magnesium trihydrate. The water is preferably purified water.
In the preparation of formula (I), preferably, the inorganic base is one or more selected from potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide;
in the preparation of formula (II), preferably, the organic base is selected from N, N-diisopropylethylamine, triethylamine, 4-methylmorpholine;
in the preparation of formula (II), preferably, the chiral ligand is selected from the group consisting of diethyl D-tartrate, (+) -l-di-tert-butyl tartrate, (1S,2S) - (+) -2-aminocyclohexanol hydrochloride, propionamide D-tartrate, (1S,2S) - (+) -2-benzyloxycyclohexylamine;
in the preparation of formula (II), preferably, the catalyst is selected from tetraisopropyl titanate, Mn-supported sandwich antimony tungstate (Cat-Mn), Mo (OiPr)4And vanadyl acetylacetonate.
In the preparation of formula (II), preferably, the oxidant is selected from cumene hydroperoxide, hydrogen peroxide and tert-butyl hydroperoxide;
in the preparation of formula (II), preferably, in the step b, at 50-55 ℃, the chiral ligand and the catalyst form a chiral ligand catalyst, and then the chiral ligand catalyst is complexed with the formula (I) to form a chiral complex with a specific spatial configuration.
In the preparation of formula (II), preferably, in the step b, an oxidant is added into the organic solvent at-5 to 0 ℃.
In the preparation of formula (ii), preferably, in step b, the organic solvent is one or more selected from toluene, ethyl acetate and tetrahydrofuran.
In the preparation of formula (II), preferably, in step b, the reaction time is 1-4 hours.
In the preparation of the esomeprazole salt, preferably, in the step c, the inorganic base is selected from one or two of potassium hydroxide and sodium hydroxide.
In the preparation of the esomeprazole salt, preferably, in the step c, the organic solvent is one or more selected from acetonitrile, methanol, ethanol and acetone.
In the preparation of esomeprazole salt, preferably, in step c, the reaction temperature is selected from 30 ± 5 ℃, preferably 30 ± 3 ℃.
In the preparation of esomeprazole salt, preferably, in the step e, the inorganic magnesium salt is anhydrous magnesium sulfate, magnesium sulfate heptahydrate or magnesium chloride.
Compared with the prior art, the preparation method takes 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 2-mercapto-5-methoxy-benzimidazole as starting materials, prepares esomeprazole potassium through condensation and improved sharpless asymmetric oxidation, and finally obtains the high-purity esomeprazole magnesium trihydrate through salt replacement. The preparation method has the advantages of mild reaction conditions, simple operation, good reproducibility, high yield, easy industrial production and stable form, and can meet the requirements of medicine.
Detailed Description
The invention provides a preparation method of esomeprazole magnesium trihydrate, which comprises the following steps:
1) taking 5-methoxy-2-mercaptobenzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride to obtain a compound with a structure (I) in an alkaline environment;
2) taking a compound with a structure shown in a formula (I), and adding a catalyst, a chiral ligand, an organic base and an oxidant to obtain a compound with a structure shown in a formula (II);
3) adding an inorganic base organic solution to enable the compound with the structure of the formula (II) to form esomeprazole inorganic salt, cooling, crystallizing, filtering, and drying;
4) recrystallizing the esomeprazole inorganic salt obtained in the step 3);
5) and 4) dissolving the esomeprazole inorganic salt obtained in the step 4) with purified water, performing suction filtration, slowly dropwise adding an inorganic magnesium aqueous solution into the filtrate, stirring for reaction, performing suction filtration, and drying to obtain the esomeprazole magnesium trihydrate.
The preparation method comprises the steps of uniformly stirring 5-methoxy-2-mercaptobenzimidazole and ethanol, cooling to 10-15 ℃, adding an inorganic alkaline aqueous solution, dissolving, adding dichloromethane, and cooling to 0-5 ℃. 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride was added thereto, and after stirring thoroughly, the mixture was heated to reflux. Reflux was timed for 3 hours. After the reaction is finished, cooling the materials to 20-25 ℃, and then extracting, concentrating and crystallizing to obtain the compound with the structure of the formula (I). The molar ratio of 2-mercapto-5-methoxy-benzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride in the reaction for preparing formula (I) is preferably 1: 1.05-1.20, the reaction time is preferably 2-5 hours, and the inorganic base is preferably one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and more preferably sodium hydroxide.
After the compound with the structure of the formula (I) is obtained, firstly, adding an organic solvent into the compound, heating and stirring, then, adding a chiral ligand D-diethyl tartrate for dissolving at 50-55 ℃, then, adding vanadyl acetylacetonate, continuing to stir at the maintained temperature for 1-1.5 hours after the addition is finished to form a compound, cooling to room temperature, adding triethylamine, stirring for 20 minutes, then, dropwise adding an oxidant organic solution into a reaction system, and continuing to stir for 2-4 hours after the dropwise addition is finished, thus obtaining the compound with the structure of the formula (II). Adding potassium hydroxide methanol solution with the total amount of about 1/2 into reaction liquid containing the compound with the structure of formula (II), heating to 30 +/-5 ℃, continuously dropwise adding the residual potassium hydroxide methanol solution, and after dropwise adding, crystallizing at low temperature and performing suction filtration to obtain esomeprazole potassium salt.
In order to improve the purity of esomeprazole potassium salt and the subsequently prepared esomeprazole magnesium salt, after the esomeprazole sodium salt is prepared by the above method, the sodium salt may be subjected to recrystallization treatment with an organic solvent. Meanwhile, the treatment can also reduce the residual quantity of other organic solvents.
And (3) dissolving recrystallized esomeprazole potassium salt in water, performing suction filtration, removing solid impurities, heating to 35-40 ℃, slowly dropwise adding a magnesium sulfate heptahydrate aqueous solution, stirring for growing crystals after dropwise adding, performing suction filtration and drying to obtain the high-purity esomeprazole magnesium trihydrate.
The preparation process route of the esomeprazole magnesium trihydrate provided by the invention is as follows:
in the preparation method, the chiral ligand and the catalyst form the chiral ligand catalyst in the presence of an organic solvent, and then are complexed with the omeprazole thioether to form an omeprazole thioether chiral compound with a specific spatial configuration; then carrying out oxidation reaction under the action of an organic oxidant to obtain chiral esomeprazole; then adding an inorganic base organic solution for replacement, and crystallizing esomeprazole in the form of an inorganic salt, thereby performing separation and purification; and finally, adding inorganic magnesium salt and water to form esomeprazole magnesium trihydrate.
The preparation method of esomeprazole magnesium trihydrate provided by the invention has the following advantages:
1. the method comprises the steps of taking D-diethyl tartrate as a chiral ligand, taking vanadyl acetylacetonate as a catalyst, forming the chiral ligand catalyst under the condition that an organic solvent exists, complexing with omeprazole thioether to form a chiral compound with a specific spatial configuration, and adding an oxidant to perform asymmetric oxidation reaction to obtain chiral esomeprazole.
2. Acid generated by the chiral auxiliary agent can be neutralized by adding a proper amount of acid-binding agent (triethylamine), so that the pH value of the reaction system is relatively stable. Meanwhile, triethylamine is used, the reaction can be carried out at room temperature, the cost is low, and the operation is simple and convenient.
3. The method uses vanadyl acetylacetonate as a metal center of the catalyst, and because vanadyl acetylacetonate does not react with water, the sensitivity of the reaction to moisture is greatly reduced, a commercial analytical reagent can be directly used as a related reagent, the water content of raw materials is not required to be measured, the operation of the experiment is simplified, and the requirement on the experimental condition is reduced.
4. In the process of converting the esomeprazole potassium salt into the esomeprazole magnesium salt, water is used as a reaction solvent, so that the esomeprazole magnesium salt can be directly crystallized without secondary purification, and meanwhile, the water is used as the reaction solvent, so that the method is environment-friendly, has no pollution to the environment, and can reduce the organic solvent residue in the product.
Drawings
FIG. 1 is a mass spectrum of esomeprazole magnesium trihydrate;
FIG. 2 is of esomeprazole magnesium trihydrate1An H-NMR spectrum;
FIG. 3 is an infrared spectrum of esomeprazole magnesium trihydrate;
figure 4 is an HPLC spectrum of esomeprazole magnesium trihydrate.
In order to further illustrate the present invention, the following examples are given to describe the preparation of esomeprazole magnesium trihydrate provided by the present invention in detail.
Example 1
Preparation of 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -lH-benzimidazole
Adding 5-methoxy-2-mercaptobenzimidazole (36.06g, 0.200mol) and absolute ethyl alcohol (80.17g,1.740mol) into a three-necked bottle (1000ml), stirring, cooling to 10-15 ℃, adding a sodium hydroxide solution (90.31 g of water and 16.16g of sodium hydroxide), stirring for 20 minutes, and adding 268.31g of dichloromethane. And continuously cooling to 0-5 ℃, adding 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (46.14g, 0.208mol) into the reaction system, continuously stirring for 40-60 minutes after the addition is finished, and heating to reflux. The time is 3 hours. TLC monitors the reaction end point (the developing solvent is ethyl acetate: n-heptane 1:1), stops heating, naturally cools to room temperature, and extracts and concentrates. Adding acetone (64.41g) into the concentrate, slowly stirring with the temperature of minus 5-0 ℃ for crystallization for 8 hours, after the crystallization is finished, carrying out suction filtration, and finally drying the product at the temperature of 40-50 ℃ under reduced pressure to obtain about 60g of a white powdery product.
Example 2
Preparation of esomeprazole potassium salt
Toluene (134.11g), thioether (25.31g) was placed in a 1L four-necked flask. Heating to 50-55 deg.C. After stirring for 10 minutes, diethyl D-tartrate (9.53g) was added thereto, the mixture was further stirred for 20 minutes, vanadyl acetylacetonate (6.13g) was added thereto, and the mixture was stirred for 1 hour after dissolution and clarification. After the stirring reaction is finished, cooling the materials to room temperature, adding triethylamine (2.36g), stirring for 20 minutes, dripping a toluene solution I of cumene hydroperoxide (15.34g) is dissolved in toluene (43.59g) for 40 minutes, after the dripping is finished, continuously stirring for 2-4 hours, adding a methanol solution of potassium hydroxide (7.56g) with the total amount of about 1/2) into methanol (261.11g), heating to 30 +/-5 ℃, continuously dripping the residual methanol solution of potassium hydroxide, slowly cooling to 0 +/-2 ℃, keeping the temperature at 0 +/-3 ℃, stirring for 1 hour for crystal growth, performing suction filtration, washing a filter cake with cold methanol (52.69g), performing suction filtration until no feed liquid drips out, then placing the product in a vacuum drying box, performing vacuum drying at 45-50 ℃ to obtain white-like powder, namely crude esomeprazole potassium (about 29g), directly used for the next refining.
Example 3
Refining of esomeprazole potassium salt
Methanol (288.31g) is added into a 2L reaction kettle in sequence, the crude esomeprazole potassium product is stirred and heated to reflux, and the mixture is stirred until the solution is clear. After dissolving, slowly cooling for about 2 hours, keeping the temperature at 0 +/-2 ℃, and stirring for growing the crystal for 2 hours. After the crystal growth, the mixture is filtered, 52.34g of cold methanol is used for washing a filter cake, and the filter cake is filtered until no feed liquid drips out. The product is then transferred to a double cone. Putting the product in a vacuum drying oven, and vacuum drying at 45-50 ℃. A white-like powder, esomeprazole potassium (about 17g) was obtained.
Example 4
Preparation of esomeprazole magnesium trihydrate
Esomeprazole potassium (17.31g) was dissolved in purified water (102.43g), and the solution was stirred to clear. Suction filtration was performed, and the filtrate was placed in a 1L four-necked flask, and the filter paper and the filter flask were washed with purified water (68.33g) and poured into the four-necked flask. Controlling the temperature to be 35-40 ℃, slowly dropwise adding a magnesium sulfate solution (magnesium sulfate heptahydrate (6.281g) is dissolved in purified water (255.38 g)), dropwise adding for 2-3 h, and stirring for crystal growing for 1 h. After the crystallization is finished, filtering, pulping the filter cake twice by using purified water, and then transferring the product into a vacuum drying oven. Vacuum drying at 55-60 deg.c to water content less than 8%. A white-like powder, esomeprazole magnesium trihydrate (about 14g) was obtained.
The esomeprazole magnesium trihydrate is analyzed by nuclear magnetic resonance, and the result is shown in fig. 1-4, wherein fig. 1 is a mass spectrogram of the esomeprazole magnesium trihydrate provided by the embodiment 4 of the invention; FIG. 2 shows Esomeprazole magnesium trihydrate provided in example 4 of the present invention1An H-NMR spectrum; FIG. 3 is an IR spectrum of esomeprazole magnesium trihydrate provided in example 4 of the present invention; figure 4 is an HPLC chromatogram of esomeprazole magnesium trihydrate provided in example 4 of the invention.
The molecular weight of the anhydrous esomeprazole magnesium trihydrate is 712.2005(M), the esomeprazole magnesium trihydrate is detected by a mass spectrometer, the result is shown in figure 1, figure 1 is a mass spectrogram of the esomeprazole magnesium trihydrate provided by the embodiment 4 of the invention, and the result shows that the M + H of the anhydrous esomeprazole magnesium trihydrate is M + H+Peak (713.2041), molecular weight of said anhydrate of esomeprazole magnesium trihydrate, i.e. with C34H42N6O9S2The molecular weight of Mg is consistent. Meanwhile, the water content is 7.1 percent by performing Karl Fischer water detection on the esomeprazole magnesium trihydrate, and the result shows that the esomeprazole magnesium trihydrate has the advantages of high yield, high stability and the likeThe esomeprazole magnesium trihydrate contains crystal water, and the crystal water meets the moisture requirement of the esomeprazole magnesium trihydrate in the United states pharmacopoeia, and the molecular weight of the esomeprazole magnesium trihydrate is 766.2322 and accords with a theoretical value by combining mass spectrum and moisture.
Meanwhile, the esomeprazole magnesium trihydrate provided by the embodiment 4 of the invention is further subjected to structure detection through a nuclear magnetic resonance hydrogen spectrum and an infrared spectrogram. The nuclear magnetic spectrum data of the esomeprazole magnesium trihydrate are as follows:1H NMR(400MHz,DMSO)δ8.28(s,1H),7.32(d,J＝8.5Hz,1H),7.05(d,J＝18.2Hz,1H),6.71–6.43(m,1H),4.87–4.34(m,2H),3.67(s,3H),2.50(s,3H),2.22(s,3H)。
the infrared spectrum of esomeprazole magnesium trihydrate provided in example 4 was measured using a fourier transform infrared spectrometer (see figure three) and the results are shown in table 1.
TABLE 1 Infrared spectra of esomeprazole magnesium trihydrate
Remarking: v telescopic vibration, delta bending vibration, s strong absorption, m medium absorption and w weak absorption
The purity of the product is detected by liquid chromatography, and the content of the esomeprazole magnesium trihydrate is 99.87%. The measurement results of the mass spectrum, the nuclear magnetic resonance spectrogram and the infrared spectrogram show that the final product obtained by the method is esomeprazole magnesium trihydrate, and the purity of the product is ensured by HPLC detection, so that the method meets the requirements of pharmacopoeia.
The above-mentioned embodiments only express one embodiment of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (9)
1. A preparation method of esomeprazole magnesium trihydrate comprises the following steps:
a. taking 5-methoxy-2-mercaptobenzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride to obtain a compound with a structure (I) in an alkaline environment;
b. taking a compound with a structure shown in a formula (I), and adding a catalyst, a chiral ligand, an organic base and an oxidant to obtain a compound with a structure shown in a formula (II);
c. adding an inorganic base organic solution to enable the compound with the structure of the formula (II) to form esomeprazole inorganic salt, cooling, crystallizing, filtering and drying;
d. d, recrystallizing the esomeprazole inorganic salt obtained in the step c;
e. d, dissolving the esomeprazole inorganic salt obtained in the step d with water, performing suction filtration, slowly dropwise adding an inorganic magnesium aqueous solution into the solution, stirring for reaction, performing suction filtration, and drying to obtain the esomeprazole magnesium trihydrate.
2. The preparation method of esomeprazole magnesium trihydrate according to claim 1, wherein in step a, the alkaline environment uses one or more inorganic bases selected from potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.
3. The method as claimed in claim 1, wherein in step b, the chiral ligand is selected from the group consisting of diethyl D-tartrate, (+) -l-Di-tert-butyl tartrate, (1S,2S) - (+) -2-aminocyclohexanol hydrochloride, D-tartaric acid propionamide, (1S,2S) - (+) -2-benzyloxycyclohexylamine; the oxidant is selected from cumene hydroperoxide, hydrogen peroxide and tert-butyl hydroperoxide; the organic base is selected from N, N-diisopropylethylamine, triethylamine and 4-methylmorpholine; the catalyst is selected from tetraisopropyl titanate, Mn-loaded sandwich type antimony tungstate (Cat-Mn), Mo (OiPr)4And vanadyl acetylacetonate.
4. The process for preparing esomeprazole magnesium trihydrate according to claim 1, wherein in step b, the chiral ligand and the catalyst form a chiral ligand catalyst in the presence of an organic solvent at 50-55 ℃, and then complex with formula (i) to form a chiral complex with a specific spatial configuration.
5. The process for preparing esomeprazole magnesium trihydrate according to claim 1, wherein in said step b, an oxidizing agent is added to the organic solvent at room temperature; the organic solvent is toluene, ethyl acetate or tetrahydrofuran; the reaction time is 1-4 hours.
6. The method for preparing esomeprazole magnesium trihydrate according to claim 1, wherein in the step c, the inorganic base is one or two selected from sodium hydroxide and potassium hydroxide.
7. The method for preparing esomeprazole magnesium trihydrate according to claim 1, wherein a final product is prepared, and in the step e, the reaction temperature is 35-40 ℃.
8. A preparation method of esomeprazole magnesium trihydrate comprises the following steps:
and (3) reacting esomeprazole potassium with an inorganic magnesium salt in water to obtain esomeprazole magnesium, and performing suction filtration and drying to obtain an esomeprazole trihydrate.
9. The process for producing esomeprazole magnesium trihydrate according to claim 8, wherein the reaction solvent uses only water as the reaction solvent.
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