ZA200503911B - Process for preparing (s)-pantoprazole - Google Patents
Process for preparing (s)-pantoprazole Download PDFInfo
- Publication number
- ZA200503911B ZA200503911B ZA200503911A ZA200503911A ZA200503911B ZA 200503911 B ZA200503911 B ZA 200503911B ZA 200503911 A ZA200503911 A ZA 200503911A ZA 200503911 A ZA200503911 A ZA 200503911A ZA 200503911 B ZA200503911 B ZA 200503911B
- Authority
- ZA
- South Africa
- Prior art keywords
- tartaric acid
- zirconium
- acid bis
- process according
- tartrate
- Prior art date
Links
- 229960005019 pantoprazole Drugs 0.000 title claims description 23
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 66
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 35
- 229910052726 zirconium Inorganic materials 0.000 claims description 35
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 34
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 29
- 230000003647 oxidation Effects 0.000 claims description 29
- 238000007254 oxidation reaction Methods 0.000 claims description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- 230000003287 optical effect Effects 0.000 claims description 20
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 14
- 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 12
- 229910052735 hafnium Inorganic materials 0.000 claims description 10
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 claims description 9
- YSAVZVORKRDODB-UHFFFAOYSA-N Diethyl tartrate Chemical compound CCOC(=O)C(O)C(O)C(=O)OCC YSAVZVORKRDODB-UHFFFAOYSA-N 0.000 claims description 7
- XPGAWFIWCWKDDL-UHFFFAOYSA-N propan-1-olate;zirconium(4+) Chemical compound [Zr+4].CCC[O-].CCC[O-].CCC[O-].CCC[O-] XPGAWFIWCWKDDL-UHFFFAOYSA-N 0.000 claims description 6
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 claims description 5
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 claims description 5
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 5
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 5
- YOBOXHGSEJBUPB-MTOQALJVSA-N (z)-4-hydroxypent-3-en-2-one;zirconium Chemical compound [Zr].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O YOBOXHGSEJBUPB-MTOQALJVSA-N 0.000 claims description 4
- PCYQQSKDZQTOQG-NXEZZACHSA-N dibutyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCCCOC(=O)[C@H](O)[C@@H](O)C(=O)OCCCC PCYQQSKDZQTOQG-NXEZZACHSA-N 0.000 claims description 4
- XEBCWEDRGPSHQH-HTQZYQBOSA-N dipropan-2-yl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C XEBCWEDRGPSHQH-HTQZYQBOSA-N 0.000 claims description 4
- HRDRRWUDXWRQTB-UHFFFAOYSA-N hafnium(4+);propan-2-olate Chemical compound [Hf+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-] HRDRRWUDXWRQTB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- ZGSOBQAJAUGRBK-UHFFFAOYSA-N propan-2-olate;zirconium(4+) Chemical compound [Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-] ZGSOBQAJAUGRBK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 3
- WZVIPWQGBBCHJP-UHFFFAOYSA-N hafnium(4+);2-methylpropan-2-olate Chemical compound [Hf+4].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] WZVIPWQGBBCHJP-UHFFFAOYSA-N 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- UARGAUQGVANXCB-UHFFFAOYSA-N ethanol;zirconium Chemical compound [Zr].CCO.CCO.CCO.CCO UARGAUQGVANXCB-UHFFFAOYSA-N 0.000 claims description 2
- SEKCULWEIYBRLO-UHFFFAOYSA-N hafnium(4+);propan-1-olate Chemical compound [Hf+4].CCC[O-].CCC[O-].CCC[O-].CCC[O-] SEKCULWEIYBRLO-UHFFFAOYSA-N 0.000 claims description 2
- PVRATXCXJDHJJN-UHFFFAOYSA-N dimethyl 2,3-dihydroxybutanedioate Chemical compound COC(=O)C(O)C(O)C(=O)OC PVRATXCXJDHJJN-UHFFFAOYSA-N 0.000 claims 3
- GBNDTYKAOXLLID-UHFFFAOYSA-N zirconium(4+) ion Chemical compound [Zr+4] GBNDTYKAOXLLID-UHFFFAOYSA-N 0.000 claims 3
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 claims 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims 2
- LTBRWBUKPWVGFA-UHFFFAOYSA-N butan-1-olate;hafnium(4+) Chemical compound [Hf+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] LTBRWBUKPWVGFA-UHFFFAOYSA-N 0.000 claims 1
- BSDOQSMQCZQLDV-UHFFFAOYSA-N butan-1-olate;zirconium(4+) Chemical compound [Zr+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] BSDOQSMQCZQLDV-UHFFFAOYSA-N 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 37
- IQPSEEYGBUAQFF-SANMLTNESA-N 6-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-SANMLTNESA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- 239000012071 phase Substances 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- -1 4- methoxy-3,5-dimethyl-2-pyridylmethyl Chemical group 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 238000005191 phase separation Methods 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229940126409 proton pump inhibitor Drugs 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 239000004133 Sodium thiosulphate Substances 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
- 235000019345 sodium thiosulphate Nutrition 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003786 synthesis reaction 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
- IQPSEEYGBUAQFF-AREMUKBSSA-N 6-(difluoromethoxy)-2-[(r)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-AREMUKBSSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 3
- 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 3
- 229960004770 esomeprazole Drugs 0.000 description 3
- 229960000381 omeprazole Drugs 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical class OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001226 reprecipitation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 150000004763 sulfides Chemical class 0.000 description 2
- 150000003899 tartaric acid esters Chemical class 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 150000003754 zirconium Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PWWDEIMGEBPTJL-UHFFFAOYSA-N 1-(pyridin-2-ylmethylsulfinyl)benzimidazole Chemical class C1=NC2=CC=CC=C2N1S(=O)CC1=CC=CC=N1 PWWDEIMGEBPTJL-UHFFFAOYSA-N 0.000 description 1
- CFTKXWOAFYZZEW-UHFFFAOYSA-N 1-methylsulfinyl-2-pyridin-2-ylbenzimidazole Chemical class N=1C2=CC=CC=C2N(S(=O)C)C=1C1=CC=CC=N1 CFTKXWOAFYZZEW-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BGGIUGXMWNKMCP-UHFFFAOYSA-N 2-methylpropan-2-olate;zirconium(4+) Chemical compound CC(C)(C)O[Zr](OC(C)(C)C)(OC(C)(C)C)OC(C)(C)C BGGIUGXMWNKMCP-UHFFFAOYSA-N 0.000 description 1
- ZYPJGOCQEPYWIE-UHFFFAOYSA-N 4-amino-2,3-dihydroxy-4-oxobutanoic acid Chemical class NC(=O)C(O)C(O)C(O)=O ZYPJGOCQEPYWIE-UHFFFAOYSA-N 0.000 description 1
- ZBFDAUIVDSSISP-UHFFFAOYSA-N 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 description 1
- UKILEIRWOYBGEJ-UHFFFAOYSA-N 6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfanyl]-1h-benzimidazole Chemical compound COC1=CC=NC(CSC=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC UKILEIRWOYBGEJ-UHFFFAOYSA-N 0.000 description 1
- 108010059892 Cellulase Proteins 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 150000002362 hafnium Chemical class 0.000 description 1
- 150000002432 hydroperoxides Chemical class 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- NIJDLRJGRCHJDB-UHFFFAOYSA-N propan-2-ol;propan-2-olate;zirconium(4+) Chemical compound [Zr+4].CC(C)O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-] NIJDLRJGRCHJDB-UHFFFAOYSA-N 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950008375 tenatoprazole Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003608 titanium Chemical class 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 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
Description
Process for preparing (S)-pantoprazole
Subject-matter of the invention
The present invention relates to a novel process for preparing the active compound (S)-pantoprazole which can be used for preparing medicaments in the pharmaceutical industry.
Pyridin-2-ylmethylsulphinyl-1H-benzimidazoles and compounds of a closely related structure, as known, for example, from EP-A-0005129, EP-A-0166287, EP-A-0174726 and EP-A-0268956, are, owing to their H*/K*-ATPase-inhibitory action, of considerable importance in the therapy of diseases associated with an increased secretion of gastric acid.
Examples of active compounds from this class of compounds which are commercially available or in clinical development are 5.methoxy-2-[(4-methoxy-3,5-dimethyi-2-pyridinyl)methylsulphinyl]-1 H- benzimidazole (INN: omeprazole), (S)-5-methoxy-2-{(4-methoxy-3,5-dimethyk-2-pyridinyljmethyl- sulphinyll-1H-benzimidazole (INN: esomeprazole), 5-diflucromethoxy-2-{(3,4-dimethoxy-2-pyridin- yhmethylsulphinyi]-1 H-benzimidazole (INN: pantoprazole), 2{3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridinyl)methylsulphiny(]-1 H-benzimidazole (INN: lansoprazole), 2-{[4-(3-methoxypropoxy)-3- methylpyridin-2-yljmethylsulphiny}}-1 H-benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4- methoxy-3,5-dimethyl-2-pyridylmethyl)sulphinyi)-1H-imidazo(4,5-b)pyridine (INN: tenatoprazole).
The abovementioned sulphinyl derivatives which, owing to their mechanism of action, are also referred to as proton pump inhibitors or abbreviated PPI are chiral compounds. The process usually used for preparing the PPI is the oxidation of the corresponding sulphides. This oxidation gives — unless particular measures are taken —a racemic mixture comprising about the same proportions of the two enantiomers (stereoisomers), i.e. the (+)- and (-)-form or the (R)- and (S)-form of the PPI.
Since enantiomers are thermally relatively stable, i.e. they do not racemize on storage — in particular in solid form ~ there has in the past been no lack of efforts to separate PPI enantiomer mixtures or to prepare the PP! enantiomers in more or less pure form.
Prior art
The international patent application W091/12221 describes a process for separating enantiomers using a cellulase enzyme. One of the active compounds mentioned as being separable into the enatiomers with the aid of this process is omeprazole.
The international patent application W092/08716 describes, for the first time, a chemical process which allows the separation of pyridin-2-yimethylsulphinyl-1 H-benzimidazoles into their optical isomers.
Compounds mentioned as having been prepared in an exemplary manner are, inter alia, the compounds (+)- and (-5-dfuoromethoxy-2-{(3 4-dimethoxy-2-pyridinymethylsulphinyl}- H-benzimi- dazole [= (+)- and (-}-pantoprazole]. The international patent application WO92/08716 refers to the fact that the optical isomers of the pyridin-2-yl-methylsulphinyl-1 H-benzimidazoles, i.e. the (+)- and {(-» enantiomers or the (R)- and (S)-enantiomers, are used as active compounds in medicaments for the treatment of gastrointestinal disorders. With respect to the mode of application and the dosage of the active compounds, reference is made inter alia to the European patent 166 287.
The international patent application WO094/27988 describes the separation of racemic omeprazole into the enantiomers, using chiral auxiliaries.
The international patent application WO096/02535 (= USP 5,948,789) describes a process for the enantioselective synthesis of PPI using chiral titanium complexes. What is described is, inter alia, the synthesis of (+)- and (-)- for, expressed in a different way, (R)-and (S)}-pantoprazole, the chiral auxiliary used for the synthesis of (+)-pantoprazole being diethyl (+)-tartrate and the chiral auxiliary used for the preparation of (-}-pantoprazole being diethyl (-}-tartrate.
The intemational patent applications WO96/1 7076 and WO96/17077 describe the enantioselective biooxidation or bioreduction with the use of certain microorganisms for the preparation of enantiomerically pure or enantiomerically enriched PP1L.
The international patent application WO097/02261 describes the enrichment of PPI enantiomers by selective precipitation.
The international patent applications WO94/24867 and W094/25028 claim the use of the compounds (-)- and (+)-pantoprazole for treating stomach disorders in humans. Each of the stereoisomers is said to have medical advantages compared to the respective other stereoisomers.
The enantioselective sulphoxidation for preparing esomeprazole ((S)-omeprazole) on a large scale using a chiral titanium complex is described in Tetrahedron, Asymmetry, (2000), 11, 3819-3825.
The enantioselective sulphoxidation of aryl alkyl sulphides and dialkyl sulphides in the presence of a zirconium catalyst having a polydentate ligand is described in J. Org. Chem., (1999), 64(4), 1327.
The invention provides a process for preparing (-)- or (S)-pantoprazole. The process is characterized in that the oxidation of the comesponding sulphide is carried out in the presence of a chiral zirconium complex or a chiral hafnium complex, the chiral auxiliary used being a (+)-L-tartaric acid derivative.
The fact that, when a chiral zirconium complex or a chiral hafnium complex is used for preparing (-)- or (S)-pantoprazole, it is possible to use, as chiral auxiliary, preferably a (+)-L-tartaric acid derivative instead of a (-)-D-tartaric acid derivative is surprising and particularly advantageous, since (+)-L-tartaric acid derivatives - with respect to naturally considerably more frequently occurring (+)-L-tartaric acid - are considerably less expensive and as a consequence highly suitable in particular for a preparation on an industrial scale. \
The oxidation is advantageously carried out in an organic solvent, such as, for example, ethyl acetate, toluene, dichloromethane, dioxane or, preferably, methyl isobutyl ketone, where it is not necessary for the solvents mentioned to be completely anhydrous or where anhydrous solvents are in each case optionally admixed with a defined proportion of water, for example up to a maximum of 0.5 equivalent.
For reactions with less than 0.5 equivalent of zirconium or hafnium complex, itis preferred to use an anhydrous solvent. The solvents employed may be used in the commericially available quality.
A solvent essentially comprises a specific solvent i it contains at least 50%, preferably at least 90%, in particular at least 95%, of the sald specific solvent. An anhydrous solvent is essentially free of water, having a water content of less than 5%, preferably less than 1%, in particular less than 0.3%.
Suitable oxidizing agents are all anhydrous oxidizing agents customarily used for the synthesis of PPI, where particular mention may be made of hydroperoxides, such as, for example, tert-butyl hydroperoxide or, in particular, cumene hydroperoxide. In general, 0.90 to 1.3 oxidation equivalents, preferably 0.85-1.05 equivalents, of the oxidizing agent are used.
Suitable zirconium complexes are, for example, zirconium(iV) acetylacetonate, zirconium(lV) butoxide, zirconium(iV) tert-butoxide, zirconium(iV) ethoxide and, in particular, zirconium(IV) n-propoxide (preferably as a solution in n-propanol) or zirconium(lV) isopropoxide (preferably in the form of the zirconium(IV) isopropoxide/isopropanol complex). Suitable hafnium complexes are, for example, hafnium(lV) acetylacetonate, hafnium(lV) butoxide, hafnium(IV) n-propoxide, hafnium(iV) isopropoxide (preferably in the form of the hafnium(IV) isopropoxide/isopropanol complex), hafnium(1V) ethoxide and in particular hafnium(IV) tert-butoxide. Preference is given to using a zirconium complex. in general, 0.01-2 equivalents, preferably 0.05-0.9 equivalent, of the zirconium complex or of the hafnium complex are used.
Suitable (+)-L-tartaric acid derivatives are, for example, tartaric acid amides, such as (+)-L-tartaric acid bis-(N,N-diallylamide), (+)-L-tartaric acid bis-(N,N-dibenzylamide), (+)-L-tartaric acid bis<(N,N- diisopropylamide), (+)-L-tartaric acid bis-(N,N-dimethylamide), (+)-L-tartaric acid bis<(N-pyrrolidinamide, (+)-L-tartaric acid bis-(N-piperidinamide), (+)-L-tartaric acid bis-(N-morpholinamide), (+)-L-tartaric acid pis-(N-cycloheptylamide) or (+)-L-tartaric acid bis-(N-4-methyl-N-piperazinamide), or dialkyl tartrates,
such as dibutyl (+)-L-tartrate, di-tert-butyl (+)-L-tartrate, diisopropyl (+)-L-tartrate, dimethy! (+)-L-tartrate and diethyl (+)-L-tartrate. In general, 0.02-4 equivalents, preferably 0.1-2 equivalents, of the (+)-L- tartaric acid derivative are employed.
Particularly preferred tartaric acid derivatives are (+)-L-tartaric acid bis-(N,N-dimethylamide), (+)-L- tartaric acid bis-(N-pyrrolidinamide), (+)-L-tartaric acid bis-(N-morpholinamide).
The oxidation is preferably carried out at temperatures between —20 and 50°C, in particular at room temperature, and optionally in the presence of a base, suitable bases being, in particular, organic bases, preferably a tertiary amine, such as triethylamine or N-ethyldiisopropylamine.
If the process is carried out in a suitable manner, (-)- or (S)-pantoprazole is obtained in an optical purity of >95%. By further steps, such as, for example, pH-controlled reprecipitation and/or recrystallization in a suitable solvent, such as, for example, isopropanol, it is possible to further increase the optical purity considerably. Reprecipitation is carried out via intermediate preparation of suitable salts, such as, for example, via the sodium salt (for other possible salts, see, for example, EP-A-166287).
The invention is illustrated in more detail by the examples below, but not limited in any way. The abbreviation h stands for hour(s).
Examples 1. (15. Difiuoromethoxy.2(3 A-dimethoxy-2-pyridinylimethylsulphinyll-1H-benzimidazole [= (--pantoprazole or (S)-pantoprazole] with diethyl (+1. tartrate and Zirconium{[V} isopropoxide/lsopropanol
A) At room temperature, 20.29 of 5 difluoromethoxy-2-{(3,4-dimethoxy-2-pyridinyhmethyithic}-1H- benzimidazole together with 17.9 g of diethyl (+)-tartrate, 13.4 g of zirconium(IV) isopropoxide/isopropanol and 0.1 mi of water are suspended in 100 ml of methyl isobuty! ketone. The mixture is heated at 40°C for one hour, resulting in the formation of an almost clear solution. After cooling to room temperature, 4.1 mi of N-ethyldiisopropylamine are added. 11 mi of cumene hydroperoxide are then slowly metered in. Stirring at room temperature is continued until the oxidation process has ended (monitored by TLC). The clear solution is quenched with 0.9 g of sodium thiosulphate in 54 m| of water and 30.3 g of 40% (w/w) of NaOH and stirred for another 14 h. After addition of 25 g of sodium chloride, the phases are separated. The aqueous phase is extracted with 50 ml of methyl isobutyl ketones. The combined organic phases are washed together using 25 mi of saturated sodium chloride solution. 150 mi of water are added to the methyl! isobutyl ketone solution, and the pH is adjusted to 13 using 10% (wiw) NaOH. The phases are separated and the methyl isobuty! ketone phase is extracted once more with 50 ml of water at pH 13. The aqueous phases are combined and, at 40°C and under reduced pressure, subjected to incipient distillation. At 40-50°C, (-)-pantoprazole is precipitated by addition of 10% strength acetic acid to pH 9. Under pH control, stirring is continued for another 12 h. The beige crystals are filtered off and washed with 50 ml of water.
This gives the title compound in an optical purity of >90%.
To increase the purity, (-)-pantoprazole is dissolved in water/NaOH and again precipitated by addition of acetic acid to pH 9. Drying gives a beige powder of melting point 145°C (decomposition) and an optical purity of >95%. If this powder is recrystallized from 2-PrOH, a clear crystal of melting point 147- 149°C (decomposition) with an optical rotation of ap = -140 (c=0.5, MeOH) is obtained.
B) Alternatively, the reaction described in Example 1A can be carried out in 100 mil of toluene instead of methyl isobutyl ketone. If the reaction is carried out in toluene, the zirconium salts have to be filtered off after quenching and the reaction product ((S)-pantoprazole as sodium salt) is directly extracted into the aqueous phase. From the aqueous phase, it can then be precipitated under controlled pH as (S)- pantoprazole. This gives beige crystals of an optical purity of > 95%.
© () pantoprazole of (S)-pantoprazolel with (+L tagtaric acid bie-(N.N-dimethylamide) and zirconlum(IV) sopropoxidefisopropanol
At room temperature, 20.2 g of 5.-difluoromethoxy-2-{(3,4-dimethoxy-2-pyridinyl)methylthio}-1 H- benzimidazole are suspended in 100 ml of methyl isobuty! ketone together with 18.0 g of (+)-L-tartaric acid bis-(N,N-dimethylamide) and 13.4 9 of zirconium(iV) isopropoxide-isopropanol. The mixture is heated at 40°C for one hour, resulting in the formation of a solution which is almost clear. After cooling to room temperature, 4.1 ml of N-ethyldiisopropylamine are added. 11 ml of cumene hydroperoxide are then slowly metered in. The mixture is stirred at room temperature until the oxidation has ended (5-10 hours, monitored by TLC). The clear solution is diluted with 100 ml of methyl isobutyl ketone and quenched with 1.8 g of sodium thiosulphate in 140 ml of water and stirred for a further 14 hours. After phase separation, 55 ml of saturated sodium bicarbonate solution and 55 ml of methyl isobutyl ketone are added to the aqueous phase, and the phases are separated. Another 55 mi of saturated sodium bicarbonate solution and 55 ml of methyl isobutyl ketone are added to the aqueous phase, and the phases are separated. The combined methyl isobutyl ketone phases are then washed twice with 55 ml of saturated sodium bicarbonate solution. 150 ml of water are added to the methyl isobutyl ketone phase, and the pH is adjusted to pH = 13 using a 40% by weight strength aqueous solution of sodium hydroxide. After phase separation, the methyl isobutyl ketone phase is extracted with another 50 ml of water at pH = 13. The aqueous phases are combined and, at 40°C, subjected to incipient distillation under reduced pressure. At 40-45°C, (-)-pantoprazole is precipitated by addition of 10% strength acetic acid to pH = 9.0. The mixture is stirred for another 12 hours during which the pH is monitored. The beige crystals are filtered off and washed with 50 mi of water. The title compound is obtained in a yield of about 15 g (73% of theory) and an optical purity of >95%. 1
To increase the purity, (-)-pantoprazole is dissolved in water/aqueous sodium hydroxide solution at pH = 13 and re-precipitated with acetic acid (10%) at pH = 9.0. 3. (-)-5-Difluoromethoxy-2-I(3.4-dimethoxy-2-pyridiny)methyisulphinyfl-1 H-benzimidazole [= (-)-pantoprazole or (S)-pantoprazole] with (+)-1-tartaric acid bis-{N.N-pyrrolidinamide) and zirconiym(V) isopropoxide/isopropanol
At room temperature, 20.2 g of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methyithio}-1 H- benzimidazole are suspended in 100 ml of methyl isobutyl ketone together with 22.6 g of (2R,3R)-(+)-
L-tartaric acid bis-(N-pyrrolidinamide) and 13.4 g of zirconium(lV) isopropoxide-isopropanol. The mixture is heated at 40°C for one hour, resulting in the formation of a solution which is almost clear.
After cooling to room temperature, 4.1 mi of N-ethyldiisopropylamine are added. 11 ml of cumene hydroperoxide are then slowly metered in. The mixture is stirred at room temperature until the oxidation has ended (5-10 hours, monitored by TLC). The clear solution is diluted with 100 mi of methyl isobutyl ketone and quenched with 1.8 g of sodium thiosulphate in 140 mi of saturated sodium bicarbonate solution and stirred for a further 14 hours. After phase separation, the mixture is washed twice with 55 mi of saturated sodium bicarbonate solution. 150 ml of water are added to the methyl isobutyl ketone phase, and the pH is adjusted to pH = 13 using a 40% by weight strength aqueous solution of sodium hydroxide. After phase separation, the methyl isobutyl ketone phase is extracted with another 50 ml of water at pH = 13. The aqueous phases are combined and, at 40°C, subjected to incipient distillation under reduced pressure. At 40-45°C, (-)-pantoprazole is precipitated by addition of 10% strength acetic acid to pH = 8.0. The mixture is stirred for another 12 hours during which the pH is monitored. The beige crystals are filtered off and washed with 50 mi of water. The title compound is obtained in a yield of about 17 g (80% of theory) and an optical purity of >98%.
To increase the purity, (-}-pantoprazole is dissolved in water/aqueous sodium hydroxide solution at pH = 13 and re-precipitated with acetic acid (10%) at pH = 9.0. 4. {-)-5-Difiuoromethoxy-2-[(3 4-dimethoxy-2-pyridinylimethyisulphinyii-1H-benzimidazole = (-)-pantoprazole or (S)-pantoprazole] with (+}-L. tartaric acld bis-{N.N-pyrrolidinamide) and zirconlum(iV) n-propoxide
At room temperature, 20.2 g of 5-difluoromethoxy-2-{(3,4-dimethoxy-2-pyridinyl)methyithio}-1 H- benzimidazole are suspended in 100 mi of methyl isobutyl ketone together with 22.6 g of (+)-L-tartaric acid bis-(N-pyrrolidinamide) and 16.5 g of zirconium(IV) n-propoxide (70% in propanol). The mixture is heated at 40°C for one hour, resulting in the formation of a solution which is almost clear. After cooling to room temperature, 4.1 mi of N-ethyldiisopropylamine are added. 10 ml of cumene hydroperoxide are then slowly metered in. The mixture is stirred at room temperature until the oxidation has ended (5-24 hours, monitored by TLC). The clear solution is diluted with 100 m! of methyl isobutyl ketone and quenched with 1.8 g of sodium thiosulphate in 140 mi of saturated sodium bicarbonate solution and stirred for a further 14 hours. After phase separation, the mixture is washed twice with 55 mi of saturated sodium bicarbonate solution. 150 ml of water are added to the methyl isobutyl ketone phase, and the pH is adjusted to pH = 13 using a 40% by weight strength aqueous solution of sodium hydroxide. After phase separation, the methyl isobutyl ketone phase is extracted with another 50 ml of water at pH = 13. The aqueous phases are combined and, at 40°C, subjected to incipient distillation under reduced pressure. At 40-45°C, (-)-pantoprazole is precipitated by addition of 10% strength acetic acid to pH = 9.0. The mixture is stirred for another 12 hours during which the pH is monitored. The beige crystals are filtered off and washed with 50 ml of water. The title compound is obtained in a yield of about 16 g (75% of theory) and an optical purity of >98%.
To increase the purity, (-)-pantoprazole is dissolved in water/aqueous sodium hydroxide solution at pH = 13 and re-precipitated with acetic acid (10%) at pH = 9.0.
5. (215-Difluoromethoxy-2-i(3A-dimethoxy-2-pyridinyimethyisulphinyll-1H-benzimidazole [= (-}-pantoprazole or (S}-pantoprazole] with (+)-L tartaric acid ble-NN-pyrrolidinamide) and zirconlupy(IV) n-propoxide
Analogously to Example 4, reaction of 5_difluoromethoxy-2-{(3.4-dimethoxy-2-pyridinyl)methylthiol-1 H- benzimidazole under otherwise identical conditions, but without addition of N-ethyldiisopropylamine, gives the tite compound in a yield of 65% of theory and an optical purity of >98%. 6. (-1-5-Difluoromethoxy-2-i(3.4-dimethoxy-2-pyridinylimethyisuiphiny(}-1H-benzimidazole (N-pyrrolidinamide) and zirconlum{V) n-propoxide
Analogously to Example 4, reaction of 5.difiuoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methyithio}-1 H- benzimidazole under otherwise identical conditions, but with 0.1 equivalent of zirconium n-propoxide, 0.25 equivalent of (+)-L-tartaric acid bis-(N-pyrrolidinamide) and 0.07 equivalents of Honig base gives, after an oxidation time of 48-72 h, the title compound in a yield of 80% of theory and an optical purity of >98%. 7. {)-5-Difluoromethoxy-2-[(34-dimethoxy-2-pyridiny{imethyisulphinyi}-1 H-benzimidazole {N-pyrrolidinamide) and zirconium(lV) n-propoxide
At room temperature, 50.0 g of 5-difluoromethoxy-2-{(3,4-dimethoxy-2-pyridinyl)methylthio}-1 H- benzimidazole and 5.2 g of (+)-L-tartaric acid bis-(N-pyrrolidinamide) (0.15 eq.) are suspended in 360 ml of methy! isobutyl ketone (MIBK). The suspension is heated at 40-45°C and 60 ml of MIBK are distilled off for azeotropic removal of water present in the mixture. At this temperature, 3.2 g of zirconium(IV) n-propoxide (70% in propanol, 0.05 eq.) are added, and the mixture is stirred for 1 hour.
After cooling to 30°C, 0.9 mi of N-ethyldiisopropylamine are added. 27.1 g of cumene hydroperoxide (80% in cumene) are then slowly metered in. Stirring is continued at 30°C until the exothermic oxidation process has ended (20 hours, monitored by TLC or HPLC). The suspension is diluted with 60 ml of 2-propanol and quenched with 1.69 g of sodium thiosulphate in 100 mi of saturated sodium bicarbonate solution and stirred for at least 2 hours. After phase separation, the mixture is washed twice with 50 ml of saturated sodium bicarbonate solution. 150 mi of water are added to the methyl isobutyl ketone phase, and the pH is adjusted to 12.5-13 using 10 ml of aqueous sodium hydroxide solution (40% (w/w)). After phase separation, the methyl isobutyl ketone phase is extracted 2 more times with 100 ml of water and 2 ml of aqueous sodium hydroxide solution (40% (w/w)) at pH = 12.6- 413. The combined aqueous phases are reextracted twice with 50 mi of methyl isobutyl ketone and subjected to incipient distillation at 40°C under reduced pressure. At 40-45°C, (-)-pantoprazole is precipitated by addition of 10% strength acetic acid to pH = 9.0. Under pH control, stirring is continued for another 12 hours. The beige crystals are filtered off and washed twice with 50 mi of water.
This gives the title compound in a yield of 82% of theory in a chemical purity of 95% and an optical purity of > 95%.
To increase the purity, (-)-pantoprazole is dissolved in water/aqueous sodium hydroxide solution at pH =13 and again precipitated at pH = 9.0 using acetic acid (10%). This gives the title compound in a yield of 75% of theory in a chemical purity of > 97% and an optical purity of > 98%. 8. (1-5-Difiucromethoxy-2-{(3 4-dimethoxy.2-pyridinylimethyisuiphinyil-1H: benzimidazole [= (-}pantoprazole or (S)-pantoprazole] with catalytic amounts of (+)- tartaric acid ble: {N-pyrrolidinamide) and zircoplum(IV) isopropoxidefisopropanol
At room temperature, 10.0 g of 5.difiucromethoxy-2-{(3 4-dimethoxy-2-pyridinyl)methyithio}-1 H- benzimidazole and 1.05 g of (+)-L-tartaric acid bis-(N-pyrrolidinamide) (0.15 eq.) are suspended in 72 mi of methyl isobutyl! ketone. The suspension is heated at 40-45°C and 12 ml of MIBK are distilled off for azeotropic removal of water present in the mixture. At this temperature, 0.53 g of zirconium(lV) isopropoxide isopropanol (0.05 eq.) is added and the mixture is stirred for 1 hour. After cooling to 30°C, 0.16 mi of N-ethyldiisopropylamine is added. 5.5 g of cumene hydroperoxide (80% in cumene) are then slowly metered in. Stirring is continued at 30°C until the exothermic oxidation process has ended (20 hours, monitored by TLC or HPLC). HPLC of the reaction shows 82% of title compound in an optical purity of > 95%. 9. (-1-5-Difluoromethoxy-2-4(34-dimethoxy-2-pyridinylimethylsulphinyl}-1H-benzlmidazole [ = (-}-pantoprazole or (S)-pantoprazole] with catalytic amounts of (+)-L-tartaric acid bis- (N-pyrrolidinamide) and zirconlum({V} n-propoxide
At room temperature, 50.0 g of 5-difluoromethoxy-2-{(3,4-dimethoxy-2-pyridinyl)methyithio]-1 H- benzimidazole and 13.9 g of (+)-L-tartaric acid bis~(N-pyrrolidinamide) (0.40 eq.) are suspended in 360 ml of methyl isobutyl ketone. The suspension is heated at 40-45°C and 60 mi of MIBK are distilled off for azeotropic removal of water present in the mixture. At this temperature, 6.4 g of zirconium(lV) n-propoxide (70% in propanol, 0.10 eq.) are added, and the mixture Is stirred for 1 hour. After cooling to 30°C, 1.8 mi of N-ethyldiisopropylamine are added. 27.1 g of cumene hydroperoxide (80% in cumene) are then slowly metered in. Stirring is continued at 30°C until the exothermic oxidation process has ended (20 hours, monitored by TLC or HPLC: chemical purity: 90% of pantoprazole sulphoxide). The suspension is diluted with 120 ml of 2-propanol and quenched with 1.69 g of sodium thiosulphate in 100 mi of saturated sodium bicarbonate solution and stirred for at least 2 hours. After phase separation, the mixture is washed twice with 50 m! of saturated sodium bicarbonate solution. 350 mi of water are added to the methyl isobutyl ketone phase, and the pH is adjusted to 12.5-13 using 40 m) of aqueous sodium hydroxide solution (40% (w/w). After phase separation, the methyl isobutyl ketone phase is extracted 2 more times with 100 ml of water and 2 mi of aqueous sodium hydroxide solution (40% (wi/w)) at pH = 12.5-13. The combined aqueous phases are reextracted twice with 50 ml of methyl isobutyl ketone and subjected to incipient distillation at 40°C under reduced pressure. At 40- 45°C, (-}-pantoprazole is precipitated by addition of 10% strength acetic acid to pH = 9.0. Under pH control, stirring is continued for another 42 hours. The beige crystals are filtered off and washed twice with in each case 50 ml of water.
This gives the title compound in a yield of 85% of theory in a chemical purity of 95% and an optical purity of > 95%. To increase the purity, (-)-pantoprazole is dissolved in water/aqueous sodium hydroxide solution at pH = 13 and again precipitated at pH = 9.0 using acetic acid (10%). This gives the title compound in a yield of 75-80% of theory in a chemical purity of > 98% and an optical purity of > 99%. 10. ()-5-Difiuoromethoxy-2-{(34-dimethoxy-2-pyridinylimethyisulohinyll-1H-benzimidazole [ = (-}-pantoprazole or (S)-pantoprazole] with (+)-L-tartaric acid bis-(N.N-pyrrolidinamide} and hafnlum(IV) tert-butoxide
At room temperature, 3.67 g of 5-difluoromethoxy-2-{(3,4-dimethoxy-2-pyridinyl)methyithio}-1 H- benzimidazole, 4.10 g of (+)-L-tartaric acid bis-(N,N-pyrrolidinamide) and 2.60 mi of hafnium(IV) tert- butoxide are suspended in 18.5 m! of methyl isobutyl ketone. The mixture is heated at 40°C for 1 hour, during which an almost clear solution is formed. After cooling to room temperature, 0.74 mi of N-ethyl- diisopropylamine is added. 2.2 ml of cumene hydroperoxide are then slowly metered in. Stirring is continued at room temperature until the oxidation process has ended (48 hours, monitored by TLC).
The clear solution is diluted with 20 mi of methyl isobutyl ketone and quenched with 0.3 g of sodium thiosulphate in 25 ml of saturated sodium bicarbonate solution and stirred for a further 14 hours. After phase separation, the methyl isobutyl ketone phase is washed two more times with 10 mi of saturated sodium bicarbonate solution. 30 mi of water are added to the methyl isobutyl ketone, phase and the pH is adjusted to 13 using 40% strength (wiw) aqueous sodium hydroxide solution. After phase separation, the methyl isobutyl ketone phase is once more extracted with 10 mi of water at pH = 13. The aqueous phases are combined and, at 40°C and under reduced pressure, subjected to incipient distillation. At 40-45°C, (-)-pantoprazole is precipitated by addition of 10% strength acetic acid to pH 9.0. Under pH control, stirring is continued for another 12 hours. The beige crystals are filtered off and washed with 10 mi of water. This gives the title compound in a yield of 2.5 g (65% of theory) in an optical purity of > 95%. To increase the purity, (-)-pantoprazole is dissolved in water/aqueous sodium hydroxide solution at pH = 13 and again precipitated at pH = 9.0 using acetic acid (10%).
Claims (20)
1. Process for preparing (S)-pantoprazole in enantiomerically pure or enantiomerically enriched form by oxidation of 5 ifluoromethoxy-2-(3.4-dimethoxy-2-pyridiny)methyithio}-1H-benzimidazole. characterized in that the oxidation is carried out in the presence of a chiral zirconium complex or a chiral hafnium complex.
2. Process for preparing (S)-pantoprazole in enantiomerically pure or enantiomerically enriched form by oxidation of 5. difiuoromethoxy-2-{(3.4-dimethoxy-2-pyridiny)methytthio}-1 H-benzimidazole, characterized in that the oxidation is carried out in the presence of a chiral zirconium complex.
3. Process according to Claim 1, characterized in that (S)-pantoprazole is obtained in an optical purity of > 90%.
4. Process according to Claim 1, characterized in that the oxidation Is carried out using cumene hydroperoxide.
5. Process according to Claim 1, characterized in that zirconium(lV) acetylacetonate, zirconium(iV) butoxide, zirconium(lV) tert-butoxide, zZirconium(iV) ethoxide, zirconium(iV) n-propoxide, zirconium(IV) isopropoxide or Zzirconium(fV) isopropoxide/isopropanol complex or hafnium(lV) acetylacetonate, hafnium(IV) butoxide, hafnium(iV) tert-butoxide, hafnium(lV) ethoxide, hafnium(IV) n-propoxide, hafnium(iV) isopropoxide or hafnium(IV) isopropoxide/isopropanol complex is used.
6. Process according to Claim 2, characterized in that zirconium(IV) acetylacetonate, 2zirconium(iV) butoxide, zirconium(lV) tert-butoxide, zirconium(lV) ethoxide, zirconium({V) n-propoxide, zirconium(IV) isopropoxide or zirconium(IV) isopropoxidefisopropanol complex is used.
7. Process according to Claim 1, characterized in that the chiral auxiliary used is a (+)-L-tartaric acid derivative.
8. Process according to Claim 1, characterized in that the chiral auxiliary used is (+)-L-tartaric acid bis-(N,N-diallylamide), (+)-L-tartaric acid bis-(N,N-dibenzylamide), (+)-L-tartaric acid bis-(N,N- diisopropylamide), (+)-L-tartaric acid bis-(N,N-dimethylamide), (+)-L-tartaric acid bis-(N- pyrrolidinamide), (+)-L-tartaric acid bis-(N-piperidinamide), (+)-L-tartaric acid bis-(N-morpholinamide), (+)-L-tartaric acid bis-(N-cycloheptylamide), (+)-L-tartaric acid bis-(N-4-methyl-N-piperazinamide), dibutyl (+)-L-tartrate, di-tert-butyl (+)-L-tartrate, diisopropyl (+)-L-tartrate, dimethyl (+)-L-tartrate or diethyl (+)-L-tartrate.
9. Process according to Claim 1, characterized in that the chiral auxifiary used is (+)-L-tartaric acid bis<(N,N-dimethylamide), (+)-L-tartaric acid bis-(N-pyrrolidinamide) or (+)-L-tartaric acid bis-(N- morpholinamide).
10. Process according to Claim 1, characterized in that the oxidation is carried out in the presence of an organic base.
41. Process according to Claim 1, characterized in that the oxidation is carried out in the presence ofa tertiary amine.
12. Process according to Claim 1, characterized in that the oxidation is carried out in organic solvents.
13. Process according to Claim 1, characterized in that the oxidation is carried out in organic solvents comprising 0 to 0.3% by volume of water.
14. Process according to Claim 1, characterized in that the oxidation is carried out in solvents of commercially available quality.
15. Process according to Claim 1, characterized in that the oxidation is carried out in an organic solvent which essentially comprises methyl isobutyl ketone.
16. Process according to Claim 1, characterized in that the zirconium component used is zirconium(IV) acetylacetonate, zirconium(lV) butoxide, zirconium(lV) tert-butoxide, zirconium(lV) ethoxide, zirconium(IV) n-propoxide, zirconium(lV) isopropoxide, or zirconium(iV) isopropoxidefisopropanol complex, that the chiral auxiliary used is (+)-L-tartaric acid bis<(N,N-diallylamide), (+)-L-tartaric acid bis- (N,N-dibenzylamide), (+)-L-tartaric acid bis-(N,N-diisopropylamide), (+)-L-tartaric acid bis(N,N- dimethylamide), (+)-L-tartaric acid bis-(N-pyrrolidinamide), (+)-L-tartaric acid bis-(N-piperidinamide), (+)-L-tartaric acid bis-(N-morpholinamide), (+)-L-tartaric acid bis-(N-cycloheptylamide), (+)-L-tartaric acid bis-(N-4-methyl-N-piperazinamide), dibutyl (+)-L-tartrate, di-tert-butyl (+)-L-tartrate, diisopropyl (+)- L-tartrate, dimethyl (+)-L-tartrate or diethyl (+)-L-tartrate.
47. Process according to Claim 1, characterized in that the zirconium component used is zirconium(IV) acetylacetonate, zirconium(lV) butoxide, zirconium(lV) tert-butoxide, zirconium(iV) ethoxide, zirconium(lV) n-propoxide, zirconium(lV) isopropoxide, or zirconium(lV) isopropoxide/isopropanol complex, that the chiral auxiliary used is (+)-L-tartaric acid bis~(N,N-diallylamide), (+)-L-tartaric acid bis- (N,N-dibenzylamide), (+)-L-tartaric acid bis-(N,N-diisopropylamide), (+)-L-tartaric acid bis-(N,N- dimethylamide), (+)-L-tartaric acid bis-(N-pyrrolidinamide), (+)-L-tartaric acid bis-(N-piperidinamide), (+)-L-tartaric acid bis-(N-morpholinamide}), (+)-L-tartaric acid bis-(N-cycloheptylamide), (+)-L-tartaric acid bis-(N-4-methyl-N-piperazinamide), dibutyl (+)-L-tartrate, di-tert-butyl (+)-L-tartrate, diisopropyl (+) L-tartrate, dimethyl (+)-L-tartrate or diethyl (+)-L-tartrate, and that the oxidation is carried out in the presence of an organic base.
18. Process according to Claim 1, characterized in that the zirconium component used is zirconium(lv) n-propoxide, zirconium(lV) isopropoxide or zirconium(IV) isopropoxidefisopropanol complex, that the chiral auxiliary used is (+)-L-tartaric acid bis-(N,N-dimethylamide), (+)-L-tartaric acid bis-(N- pyrrolidinamide) or (+)-L-tartaric acid bis-(N-morpholinamide) and that the oxidation is carried out using cumene hydroperoxide.
19. Process according to Claim 1, characterized in that the zirconium component used is zircontum(lV) n-propoxide, zirconlum(iV) isopropoxide or zircanium(IV) isopropoxide/isopropano! tomplex, that the chiral auxiliary used is (+)-L-tartaric-25d bis-(N,N-dimethylamide), (+)-L-tartaric acid bis-(N- pyrrolidinamide) or (+)-L-tartaric acid bis<(N-morpholinamide) and that the oxidation is carried out using cumene hydroperoxide in the presence of a tertiary amine.
20. (S)-pantoprazole prepared by the process according to Claim 1.
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CN101012141B (en) * | 2007-02-02 | 2012-05-23 | 沈阳药科大学 | Method of manufacturing chiral sulfoxide compounds |
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 |
CN102807560B (en) * | 2011-06-21 | 2014-07-23 | 寿光富康制药有限公司 | New method for synthesizing esomeprazole through asymmetrically catalytic oxidation |
CN102603716B (en) * | 2012-03-31 | 2014-04-16 | 广东华南药业集团有限公司 | Method for preparing (S)-pantoprazole in high-enantioselectivity way |
CN103880819B (en) * | 2012-12-20 | 2017-02-08 | 四川海思科制药有限公司 | Preparation method of optically pure lansoprazole |
CN106632249A (en) * | 2016-09-30 | 2017-05-10 | 青岛云天生物技术有限公司 | Method for preparing (S)-pantoprazole sodium |
CN106632248A (en) * | 2016-09-30 | 2017-05-10 | 青岛云天生物技术有限公司 | Preparation process of (S)-pantoprazole sodium |
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