US20070161682A1 - Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for their Preparation - Google Patents
Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for their Preparation Download PDFInfo
- Publication number
- US20070161682A1 US20070161682A1 US11/689,801 US68980107A US2007161682A1 US 20070161682 A1 US20070161682 A1 US 20070161682A1 US 68980107 A US68980107 A US 68980107A US 2007161682 A1 US2007161682 A1 US 2007161682A1
- Authority
- US
- United States
- Prior art keywords
- compound
- methoxy
- tautomer
- single enantiomer
- enantiomerically enriched
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims description 19
- SUBDBMMJDZJVOS-XMMPIXPASA-N (R)-omeprazole Chemical compound C([S@@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-XMMPIXPASA-N 0.000 title 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 claims abstract description 7
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 19
- 229910052719 titanium Inorganic materials 0.000 claims description 19
- 239000010936 titanium Substances 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical group ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 10
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000002035 prolonged effect Effects 0.000 claims description 4
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- LMIZQFMHCPOHAX-UHFFFAOYSA-N 2-[(3,5-dimethyl-4-nitro-1-oxidopyridin-1-ium-2-yl)methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=C(C)C([N+]([O-])=O)=C(C)C=[N+]1[O-] LMIZQFMHCPOHAX-UHFFFAOYSA-N 0.000 claims 1
- PFDONLPWKWJOCD-UHFFFAOYSA-N 2-[(3,5-dimethyl-4-nitropyridin-2-yl)methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C([N+]([O-])=O)=C1C PFDONLPWKWJOCD-UHFFFAOYSA-N 0.000 claims 1
- AVXPKRKFBUYRAV-UHFFFAOYSA-N 2-[(4-chloro-3,5-dimethyl-1-oxidopyridin-1-ium-2-yl)methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=C(C)C(Cl)=C(C)C=[N+]1[O-] AVXPKRKFBUYRAV-UHFFFAOYSA-N 0.000 claims 1
- LZEPUBIBIWJUSW-UHFFFAOYSA-N 2-[(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(Cl)=C1C LZEPUBIBIWJUSW-UHFFFAOYSA-N 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 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 abstract description 21
- 229960000381 omeprazole Drugs 0.000 abstract description 20
- 230000003287 optical effect Effects 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- -1 titanium(IV) compound Chemical class 0.000 description 6
- 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 5
- 239000003446 ligand Substances 0.000 description 5
- OGZMVEWYSAYKAW-UHFFFAOYSA-N CC1=CN=C(C)C(C)=C1C.CC1=C[N+](O)=C(C)C(C)=C1C Chemical compound CC1=CN=C(C)C(C)=C1C.CC1=C[N+](O)=C(C)C(C)=C1C OGZMVEWYSAYKAW-UHFFFAOYSA-N 0.000 description 4
- DTMOJXLUVKLOQE-UHFFFAOYSA-N CCS(=O)C1=NC2=C(C=CC(OC)=C2)N1 Chemical compound CCS(=O)C1=NC2=C(C=CC(OC)=C2)N1 DTMOJXLUVKLOQE-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- LCKIEQZJEYYRIY-UHFFFAOYSA-N Titanium ion Chemical compound [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 159000000011 group IA salts Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 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 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- YSAVZVORKRDODB-WDSKDSINSA-N diethyl tartrate Chemical compound CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC YSAVZVORKRDODB-WDSKDSINSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 150000003608 titanium Chemical class 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UPVARCHBWKDWRW-UHFFFAOYSA-N 2-[(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfanyl]-6-methoxy-1h-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(Cl)=C1C UPVARCHBWKDWRW-UHFFFAOYSA-N 0.000 description 1
- PFDONLPWKWJOCD-VWLOTQADSA-N 2-[(s)-(3,5-dimethyl-4-nitropyridin-2-yl)methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound C([S@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C([N+]([O-])=O)=C1C PFDONLPWKWJOCD-VWLOTQADSA-N 0.000 description 1
- LZEPUBIBIWJUSW-QHCPKHFHSA-N 2-[(s)-(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound C([S@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(Cl)=C1C LZEPUBIBIWJUSW-QHCPKHFHSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- RPPHUAOJICTCLN-UHFFFAOYSA-N C.COC1=CC2=C(C=C1)NC(SCC1=C(C)C(C)=C(C)C=[N+]1[O-])=N2.C[O-].C[O-].[CH][S@](O)(CC1=C(C)C(C)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(C)=C(C)C=[N+]1[O-])C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(OC)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(OC)=C(C)C=[N+]1[O-])C1=NC2=C(C=CC(OC)=C2)N1 Chemical compound C.COC1=CC2=C(C=C1)NC(SCC1=C(C)C(C)=C(C)C=[N+]1[O-])=N2.C[O-].C[O-].[CH][S@](O)(CC1=C(C)C(C)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(C)=C(C)C=[N+]1[O-])C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(OC)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(OC)=C(C)C=[N+]1[O-])C1=NC2=C(C=CC(OC)=C2)N1 RPPHUAOJICTCLN-UHFFFAOYSA-N 0.000 description 1
- BEQAUZKBVGGOEY-UHFFFAOYSA-N CC1=CN=C(C)C(C)=C1C.CC1=C[N+]([O-])=C(C)C(C)=C1C.CCSC1=NC2=C(C=CC(OC)=C2)N1.CC[S@](C)(O)C1=NC2=C(C=CC(OC)=C2)N1.I.II Chemical compound CC1=CN=C(C)C(C)=C1C.CC1=C[N+]([O-])=C(C)C(C)=C1C.CCSC1=NC2=C(C=CC(OC)=C2)N1.CC[S@](C)(O)C1=NC2=C(C=CC(OC)=C2)N1.I.II BEQAUZKBVGGOEY-UHFFFAOYSA-N 0.000 description 1
- CZSQXDMMIUJHSK-UHFFFAOYSA-N CCSC1=NC2=C(C=CC(OC)=C2)N1 Chemical compound CCSC1=NC2=C(C=CC(OC)=C2)N1 CZSQXDMMIUJHSK-UHFFFAOYSA-N 0.000 description 1
- JHBOHAXBDJLMKL-UHFFFAOYSA-N COC1=CC2=C(C=C1)NC(S(=O)CC1=NC=C(C)C(Cl)=C1C)=N2.COC1=CC2=C(C=C1)NC(S(=O)CC1=NC=C(C)C([N+](=O)[O-])=C1C)=N2.COC1=CC2=C(C=C1)NC(S(=O)CC1=[N+]([O-])C=C(C)C(Cl)=C1C)=N2.COC1=CC2=C(C=C1)NC(S(=O)CC1=[N+]([O-])C=C(C)C([N+](=O)[O-])=C1C)=N2 Chemical compound COC1=CC2=C(C=C1)NC(S(=O)CC1=NC=C(C)C(Cl)=C1C)=N2.COC1=CC2=C(C=C1)NC(S(=O)CC1=NC=C(C)C([N+](=O)[O-])=C1C)=N2.COC1=CC2=C(C=C1)NC(S(=O)CC1=[N+]([O-])C=C(C)C(Cl)=C1C)=N2.COC1=CC2=C(C=C1)NC(S(=O)CC1=[N+]([O-])C=C(C)C([N+](=O)[O-])=C1C)=N2 JHBOHAXBDJLMKL-UHFFFAOYSA-N 0.000 description 1
- JXKVDNQNCWMSFH-UHFFFAOYSA-N COC1=CC2=C(C=C1)NC(SCC1=C(C)C(C)=C(C)C=N1)=N2.C[O-].[CH][S@](O)(CC1=C(C)C(C)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(OC)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1 Chemical compound COC1=CC2=C(C=C1)NC(SCC1=C(C)C(C)=C(C)C=N1)=N2.C[O-].[CH][S@](O)(CC1=C(C)C(C)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1.[CH][S@](O)(CC1=C(C)C(OC)=C(C)C=N1)C1=NC2=C(C=CC(OC)=C2)N1 JXKVDNQNCWMSFH-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1cnc(C)c(C)c1* Chemical compound Cc1cnc(C)c(C)c1* 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- YSAVZVORKRDODB-PHDIDXHHSA-N diethyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC YSAVZVORKRDODB-PHDIDXHHSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 235000020094 liqueur Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Definitions
- the present invention is directed to new compounds of high optical purity, a process for their preparation and their use as intermediates in the synthesis of the S- or R-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole.
- EP 0 773 940 B1 a process for preparation of the single enantiomers of omeprazole and structurally related sulphoxides is described.
- a pro-chiral sulphide is oxidised with an oxidising agent in the presence of a chiral titanium complex into the corresponding sulphoxide either as a single enantiomer or in enantiomerically enriched form.
- WO 98/28294 discloses S-omeprazole in neutral form that is in a solid state.
- the present invention relates to new crystalline sulphoxides which are stable enough to be directly recrystallised, the preparation of these sulphoxides and their use as intermediates in the synthesis of S- and R-enantiomer of omeprazole.
- the present invention refers to new highly crystalline sulphoxides in enantiomerically enriched form which are chemically stable enough to be directly crystallised from an oxidation reaction mixture, the preparation of these sulphoxides and their use as intermediates in the synthesis of the S- and R-enantiomer of omeprazole and pharmaceutically acceptable salts thereof.
- the new synthetic intermediates are defined by formula I either as a single enantiomer or in enantiomerically enriched form: wherein
- the leaving group X is chloro or nitro as in the compounds of formula Ia, Ib, Ic and Id:
- a further aspect of the invention is the preparation of compounds of formula I, which can be used as intermediates in the synthesis of the S- and R-enantiomer of omeprazole and pharmaceutically acceptable salts thereof.
- the preparation of the compounds of formula I may be carried out as described in EP 0 773 940 B1, and this is also illustrated in Scheme 1 below.
- X is a leaving group such as a halogen (F, Cl, Br, I), NO 2 , N 2 + or —OSO 2 R (R is CH 3 , CF 3 , p-toluene, m-chlorobenzene, p-chlorobenzene).
- a pro-chiral sulphide such as II is oxidised in an organic solvent with an oxidising agent, e.g. cumene hydroperoxide, in the presence of a chiral titanium complex.
- the titanium complex suitable for catalysing the process of the invention is prepared from a chiral ligand and a titanium(IV) compound such as preferably a titanium(IV)alkoxide, and optionally in the presence of water.
- the chiral ligand used in the preparation of the titanium complex is for instance a chiral alcohol such as a chiral diol.
- the oxidation may be performed in the presence of a base, e.g. N,N-diisopropylethylamine.
- the oxidation is carried out in an organic solvent.
- the solvent can be chosen with respect to suitable conditions from an industrial point of view as well as environmental aspects. Suitable organic solvents are for instance toluene, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, diethyl carbonate, tert.butyl methyl ether, tetrahydrofurane, methylene chloride and the like. From an environmental point of view non-chlorinated solvents are preferred.
- the oxidation is preferably carried out in an organic solvent at room temperature or just above room temperature, e.g. between 20-40° C. If the reaction time is varied a reaction temperature may be chosen below as well as above the preferred temperatures 20-40° C. A suitable temperature range is limited only depending on the decomposition of the compounds, and that the reaction time is dramatically shorter at room temperature than at ⁇ 20° C. since the sulphides of interest are oxidised very slowly at such a low temperature.
- An oxidising agent suitable for this asymmetric oxidation may be a hydroperoxide, such as for example tert.-butylhydroperoxide or cumene hydroperoxide, preferably the latter.
- the titanium complex suitable for catalysing the process of the invention is prepared from a chiral ligand and a titanium(IV)compound such as preferably titanium(IV)alkoxide, and optionally in the presence of water.
- An especially preferred titanium(IV)alkoxide is titanium(IV)isopropoxide or -propoxide.
- the amount of the chiral titanium complex is not critical. An amount of less than approximately 0.50 equivalents is preferred and especially preferred amount is 0.05-0.30 equivalents. Even very low amounts of complex, such as for instance 0.04 equivalents may be used in the processes according to the present invention with excellent result.
- the titanium complex may also be prepared by reacting titanium tetrachloride with a chiral ligand in the presence of a base.
- the chiral ligand used in the preparation of the titanium complex is preferably a chiral alcohol such as a chiral diol.
- the diol may be a branched or unbranched alkyl diol, or an to aromatic diol.
- Preferred chiral diols are esters or tartaric acid, especially (+)-diethyl L-tartrate or ( ⁇ )diethyl D-tartrate are preferred.
- the chiral titanium complex may be prepared in the presence of the pro-chiral sulphide or before the pro-chiral sulphide is added to the reaction vessel.
- the oxidation is carried out in the presence of a base.
- the base may be an inorganic or an organic base, such as for instance a hydrogen carbonate, an amide or an amine.
- Amine includes a guanidine or an amidine.
- Organic bases are preferred and especially suitable bases are amines, preferably triethylamine or N,N-diisopropylethylamine.
- the amount of base added to the reaction mixture is not critical but should be adjusted with respect to the reaction mixture.
- the preparation of the chiral titanium complex is preferably performed in the presence of the pro-chiral sulphide.
- an elevated temperature is meant a temperature above room temperature, such as for instance 30-70° C., preferably 40-60° C.
- a prolonged preparation time is a period of time longer than approximately 20 minutes, preferably 1-5 hours.
- a suitable period of time for the preparation step depends on the preparation temperature and of the pro-chiral sulphide, optionally present during the preparation of the chiral titanium complex.
- Still a further aspect of the invention is the conversion of compounds of formula I into the S- and R-enantiomer of omeprazole and pharmaceutically acceptable salts thereof.
- Scheme 2 and Scheme 3 below describe synthetic routes for converting compound I into the S-enantiomer of omeprazole. The same routes can be applied to convert compund I into the R-enantiomer of omeprazole provided that the chirality of the chiral titanium complex used in the oxidising reaction step is changed to the opposite of that used for making the corresponding S-enantiomer.
- the first step is performed as described above. Nucleophilic substitution of the leaving group X with methoxide, e.g. sodium methoxide, is thereafter performed prior to or after reduction of the pyridine-N-oxide to pyridine.
- methoxide e.g. sodium methoxide
- the compounds of the invention may exist as tautomers. It is to be understood that the present invention encompasses all such tautomers.
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Abstract
The present invention relates to an improved method for the synthesis of the (S)- or (R)-enantiomer of omeprazole, characterized in that 2-[[(4-X-3,5-dimethylpyridin-2-yl)methyl]thio]-5-methoxy-1H-benzimidazole or 2-[[(4-X-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]thio]-5-methoxy-1H-benzimidazole, wherein X is a leaving group, is oxidized into the corresponding sulphoxide which is obtained as a crystalline compound. Recrystallisation of the thus obtained sulphoxide results in a compound of enhanced chemical and optical purity, which is subsequently transformed into the (S)- or (R)-enantiomer of omeprazole.
Description
- The present invention is directed to new compounds of high optical purity, a process for their preparation and their use as intermediates in the synthesis of the S- or R-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole.
- The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole, having the generic name omeprazole, and therapeutically acceptable alkaline salts thereof are described in EP 5129 and EP 124 495, respectively. Omeprazole and its alkaline salts are effective gastric acid secretion inhibitors, and are useful as antiulcer agents. The compounds, being sulphoxides, have an asymmetric center in the sulphur atom, i.e. exist as two optical isomers (enantiomers). It has been shown that the lo magnesium salt of the S-enantiomer of omeprazole has better pharmacokinetic and metabolic properties compared to omeprazole, and this is described in EP 0 652 872 B1. As a result of this the magnesium salt of the S-enantiomer of omeprazole has an improved therapeutic profile such as a lower degree of interindividual variation.
- In EP 0 773 940 B1 a process for preparation of the single enantiomers of omeprazole and structurally related sulphoxides is described. In this process, a pro-chiral sulphide is oxidised with an oxidising agent in the presence of a chiral titanium complex into the corresponding sulphoxide either as a single enantiomer or in enantiomerically enriched form.
- Single enantiomers of omeprazole in neutral form are difficult to obtain in crystalline state and thus these compounds are most frequently obtained as non crystalline products. In for instance WO 92/08716 the neutral form of the R enantiomer of omeprazole is obtained as an amorphous solid and in WO 94/27988 both of the enantiomers of omeprazole—in their neutral forms—are obtained in the form of syrups or oils. In WO 94/27988 is also described the preparation of alkaline salts of the single enantiomers, which are obtainable as crystalline products. These can be purified by recrystallisation resulting in products of very high optical purity. Furthermore, optically pure salts of the S-enantiomer of omeprazole are stable towards racemization both in neutral pH and basic pH.
- WO 98/28294 discloses S-omeprazole in neutral form that is in a solid state.
- It would be desirable to perform the oxidation of pro-chiral sulphides yielding highly crystalline sulphoxide intermediates, thus making it possible to directly recrystallise the crude sulphoxides in its neutral form in order to increase the optical purity as well as to increase the chemical purity. The purified enantiomerically enriched sulphoxide intermediates could then be converted into the S- or R-enantiomer of omeprazole and thereafter optionally into pharmaceutically acceptable salts thereof. An advantage of such a process is that a requisite chemical and optical purification step would not involve the addition of an alkaline medium to a titanium containing reaction mixture, which process is associated with problems with the formation of inorganic titanium salts that are difficult to work with. A further advantage is if the titanium catalyzed reaction step occurrs earlier in the synthesis of the enantiomerically enriched compounds thereby reducing a possible risk of contamination of the final product by titanium salts.
- The present invention relates to new crystalline sulphoxides which are stable enough to be directly recrystallised, the preparation of these sulphoxides and their use as intermediates in the synthesis of S- and R-enantiomer of omeprazole.
- The present invention refers to new highly crystalline sulphoxides in enantiomerically enriched form which are chemically stable enough to be directly crystallised from an oxidation reaction mixture, the preparation of these sulphoxides and their use as intermediates in the synthesis of the S- and R-enantiomer of omeprazole and pharmaceutically acceptable salts thereof.
-
- Het is
and X is a leaving group such as a halogen (F, Cl, Br, I), NO2, N2 + or —OSO2R (R is CH3, CF3, p-toluene, m-chlorobenzene, p-chlorobenzene). -
- The compounds Ia-Id, and their corresponding tautomers, exist either as a single enantiomer or in an enantiomerically enriched form.
- A further aspect of the invention is the preparation of compounds of formula I, which can be used as intermediates in the synthesis of the S- and R-enantiomer of omeprazole and pharmaceutically acceptable salts thereof. The preparation of the compounds of formula I may be carried out as described in EP 0 773 940 B1, and this is also illustrated in Scheme 1 below.
and X is a leaving group such as a halogen (F, Cl, Br, I), NO2, N2 + or —OSO2R (R is CH3, CF3, p-toluene, m-chlorobenzene, p-chlorobenzene). - In this process, a pro-chiral sulphide such as II is oxidised in an organic solvent with an oxidising agent, e.g. cumene hydroperoxide, in the presence of a chiral titanium complex. The titanium complex suitable for catalysing the process of the invention is prepared from a chiral ligand and a titanium(IV) compound such as preferably a titanium(IV)alkoxide, and optionally in the presence of water. The chiral ligand used in the preparation of the titanium complex is for instance a chiral alcohol such as a chiral diol. The oxidation may be performed in the presence of a base, e.g. N,N-diisopropylethylamine.
- The oxidation is carried out in an organic solvent. The solvent can be chosen with respect to suitable conditions from an industrial point of view as well as environmental aspects. Suitable organic solvents are for instance toluene, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, diethyl carbonate, tert.butyl methyl ether, tetrahydrofurane, methylene chloride and the like. From an environmental point of view non-chlorinated solvents are preferred.
- The oxidation is preferably carried out in an organic solvent at room temperature or just above room temperature, e.g. between 20-40° C. If the reaction time is varied a reaction temperature may be chosen below as well as above the preferred temperatures 20-40° C. A suitable temperature range is limited only depending on the decomposition of the compounds, and that the reaction time is dramatically shorter at room temperature than at −20° C. since the sulphides of interest are oxidised very slowly at such a low temperature.
- An oxidising agent suitable for this asymmetric oxidation may be a hydroperoxide, such as for example tert.-butylhydroperoxide or cumene hydroperoxide, preferably the latter. The titanium complex suitable for catalysing the process of the invention is prepared from a chiral ligand and a titanium(IV)compound such as preferably titanium(IV)alkoxide, and optionally in the presence of water. An especially preferred titanium(IV)alkoxide is titanium(IV)isopropoxide or -propoxide. The amount of the chiral titanium complex is not critical. An amount of less than approximately 0.50 equivalents is preferred and especially preferred amount is 0.05-0.30 equivalents. Even very low amounts of complex, such as for instance 0.04 equivalents may be used in the processes according to the present invention with excellent result.
- The titanium complex may also be prepared by reacting titanium tetrachloride with a chiral ligand in the presence of a base.
- The chiral ligand used in the preparation of the titanium complex is preferably a chiral alcohol such as a chiral diol. The diol may be a branched or unbranched alkyl diol, or an to aromatic diol. Preferred chiral diols are esters or tartaric acid, especially (+)-diethyl L-tartrate or (−)diethyl D-tartrate are preferred.
- The chiral titanium complex may be prepared in the presence of the pro-chiral sulphide or before the pro-chiral sulphide is added to the reaction vessel.
- According to one aspect of the invention, the oxidation is carried out in the presence of a base. The base may be an inorganic or an organic base, such as for instance a hydrogen carbonate, an amide or an amine. Amine includes a guanidine or an amidine. Organic bases are preferred and especially suitable bases are amines, preferably triethylamine or N,N-diisopropylethylamine. The amount of base added to the reaction mixture is not critical but should be adjusted with respect to the reaction mixture.
- The preparation of the chiral titanium complex is preferably performed in the presence of the pro-chiral sulphide.
- Other essential features in the preparation of the chiral titanium complex is that the preparation of the complex is performed during an elevated temperature and/or a prolonged time. With an elevated temperature is meant a temperature above room temperature, such as for instance 30-70° C., preferably 40-60° C. A prolonged preparation time is a period of time longer than approximately 20 minutes, preferably 1-5 hours. A suitable period of time for the preparation step depends on the preparation temperature and of the pro-chiral sulphide, optionally present during the preparation of the chiral titanium complex.
- Yet a further aspect of the invention is the conversion of compounds of formula I into the S- and R-enantiomer of omeprazole and pharmaceutically acceptable salts thereof. Scheme 2 and Scheme 3 below describe synthetic routes for converting compound I into the S-enantiomer of omeprazole. The same routes can be applied to convert compund I into the R-enantiomer of omeprazole provided that the chirality of the chiral titanium complex used in the oxidising reaction step is changed to the opposite of that used for making the corresponding S-enantiomer.
- In Scheme 2, the first step is performed as described above. The obtained sulphoxide I may be recrystallised in order to enhance chemical and optical purity. Finally, a substitution reaction with methoxide, e.g. sodium methoxide, yields the S-enantiomer of omeprazole, which may be converted to a pharmaceutically acceptable salt thereof.
- In Scheme 3, the first step is performed as described above. Nucleophilic substitution of the leaving group X with methoxide, e.g. sodium methoxide, is thereafter performed prior to or after reduction of the pyridine-N-oxide to pyridine.
- The compounds of the invention may exist as tautomers. It is to be understood that the present invention encompasses all such tautomers.
- The invention is illustrated by the following non-limiting examples.
- 1.2 g (3.6 mmol) of 2-{[(4-chloro-3,5-dimethyl-2-pyridinyl)methyl]thio}-5-methoxy-1H-benzimidazole was mixed with toluene (40 mL). The mixture was concentrated until half to the volume was left. Water (38 mg, 2.1 mmol), (S,S)-diethyl tartrate (1.85 g, 9.0 mmol) and titanium tetraisopropoxide (1.0 g, 3.6 mmol) were added in the given order while stirring. The mixture was then stirred at 50° C. for an hour and then N,N-diisopropylethylamine (0.46 g, 3.6 mmol) was added at room temperature. After 15 minutes cumene hydroperoxide (80% in cumene, 0.69 g, 3.6 mmol) was added dropwise is and stirring was then continued for 2 h at room temperature. The optical purity of crude sulfoxide turned out to be 75% ee as determined by chiral HPLC analysis of the solution. The mixture was washed with water and then evaporated. The product was purified by chromatography on silica gel using methanol/dichloromethane as eluent (gradient, 1-7% MeOH) and this afforded 1.0 g of a crude product as a solid. Recrystallisation from hot acetonitrile gave 0.35 g of a white solid with an enantiomeric excess of 51%. Next, the mother liqueur from the filtration was concentrated and this material was then also recrystallised from acetonitrile to give 0.35 g of the title compound as a crystalline product with an enantiomeric excess of 92.5%.
- 1H NMR of the most enriched fraction (92.5% ee) in chloroform-d; 2.3 (s, 3H), 2.4 (s, 3H), 3.8 (s, 3H), 4.8 (AB-system, 2H), 7.0 (dd, 1H), 7.0 (b, 1H), 7.5 (b, 1H), 8.2 (s, 1H).
- In an analogous experiment as in Example 1—starting from 1.2 g of (S)-2-[[(4-nitro-3,5-dimethyl-2-pyridinyl)methyl]thio]5-methoxy-1H-benzimidazole—1.0 g of the title compound as a crystalline product was obtained. The enantiomeric excess of this crude product was determined to be 48% by chiral HPLC analysis.
Claims (17)
2. The compound 2-[[(4-chloro-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.
3. The compound 2-[[(4-nitro-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.
4. The compound 2-[[(4-chloro-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.
5. The compound 2-[[(4-nitro-3,5-dimethyl-1-oxidopyridin-2-yl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the enantiomerically enriched form of the compound.
6. A process for enantioselective synthesis of a sulphoxide of formula I in the form of a single enantiomer, a tautomer of the single enantiomer, an enantiomerically enriched form of the compound, or a tautomer of the entiomerically enriched form of the compound,
wherein Het is
and X is a leaving group, wherein the process comprises oxidizing a pro-chiral sulphide of the formula II,
wherein Het is defined above, in an organic solvent with an oxidising agent and in the presence of a chiral titanium complex and optionally a base.
8. The compound S-5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole prepared according to the process of claim 6 or 7 .
9. A pharmaceutical formulation comprising S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole and a pharmaceutically acceptable carrier or diluent, wherein the S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole is prepared according to claim 6 or 7 .
10. The compound according to claim 1 , wherein the leaving group X is selected from the group consisting of halogen, NO2, N2 +, and OSO2R, wherein R is CH3, CF3, p-toluene, m-chlorobenzene, or p-chlorobenzene.
11. The process according to claim 6 , wherein the leaving group X is selected from the group consisting of halogen, NO2, N2 +, and OSO2R, wherein R is CH3, CF3, p-toluene, m-chlorobenzene, or p-chlorobenzene.
12. The process according to claim 6 , wherein the process is carried out in the presence of a base.
13. The process according to claim 6 , wherein the titanium complex is prepared in the presence of the pro-chiral sulphide.
14. The process according to claim 6 , wherein the titanium complex is prepared at an elevated temperature and/or during a prolonged preparation time.
15. The process according to claim 6 , wherein the titanium complex is prepared in the presence of the pro-chiral sulphide and at an elevated temperature and/or during a prolonged preparation time.
16. The process according to claim 7 , wherein the leaving group X is selected from the group consisting of halogen, NO2, N2 +, and OSO2R, wherein R is CH3, CF3, p-toluene, m-chlorobenzene, or p-chlorobenzene.
17. The process according to claim 7 , wherein the leaving group X is replaced prior to or after a reduction step during which the oxidopyridine is reduced to pyridine.
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US20090253911A1 (en) * | 2004-02-20 | 2009-10-08 | Sverker Von Unge | New Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for Their Preparation |
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WO2010011856A2 (en) * | 2008-07-23 | 2010-01-28 | Board Of Regents Of The University Of Nebraska | Stereospecificity of methylsulfinyl reduction |
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ES2187248B1 (en) | 2000-08-25 | 2004-01-16 | Sint Quimica Sa | NEW PROCEDURE FOR OBTAINING DERIVATIVES OF 2- (2-PIRIDINILMETILSULFINIL) -1H-BENZIMIDAZOL. |
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2004
- 2004-02-20 SE SE0400410A patent/SE0400410D0/en unknown
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2005
- 2005-02-17 CA CA2553877A patent/CA2553877C/en not_active Expired - Fee Related
- 2005-02-17 US US11/060,138 patent/US20050187256A1/en not_active Abandoned
- 2005-02-17 EP EP05711081A patent/EP1718636B1/en not_active Expired - Lifetime
- 2005-02-17 US US10/588,056 patent/US20080255199A1/en not_active Abandoned
- 2005-02-17 WO PCT/SE2005/000221 patent/WO2005080374A1/en not_active Application Discontinuation
- 2005-02-17 ES ES05711081T patent/ES2378237T3/en not_active Expired - Lifetime
- 2005-02-17 JP JP2006554057A patent/JP2007523160A/en active Pending
- 2005-02-17 AT AT05711081T patent/ATE541838T1/en active
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2007
- 2007-03-22 US US11/689,801 patent/US20070161682A1/en not_active Abandoned
- 2007-05-07 HK HK07104871.9A patent/HK1098474A1/en not_active IP Right Cessation
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2008
- 2008-12-05 US US12/329,077 patent/US8697880B2/en not_active Expired - Fee Related
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US5948789A (en) * | 1994-07-15 | 1999-09-07 | Astra Aktiebolag | Process for synthesis of substituted sulphoxides |
US7169799B2 (en) * | 2000-05-15 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Process for producing crystal |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090253911A1 (en) * | 2004-02-20 | 2009-10-08 | Sverker Von Unge | New Compounds Useful for the Synthesis of S- and R-Omeprazole and a Process for Their Preparation |
US8697880B2 (en) | 2004-02-20 | 2014-04-15 | Astrazeneca Ab | Compounds useful for the synthesis of S- and R-omeprazole and a process for their preparation |
US20070203195A1 (en) * | 2006-02-24 | 2007-08-30 | Wheelock Kenneth S | Transition metal mediated oxidation of hetero atoms in organic molecules coordinated to transition metals |
US7579476B2 (en) * | 2006-02-24 | 2009-08-25 | Praktikatalyst Pharma, Llc | Transition metal mediated oxidation of hetero atoms in organic molecules coordinated to transition metals |
Also Published As
Publication number | Publication date |
---|---|
US20090253911A1 (en) | 2009-10-08 |
WO2005080374A1 (en) | 2005-09-01 |
SE0400410D0 (en) | 2004-02-20 |
EP1718636B1 (en) | 2012-01-18 |
ES2378237T3 (en) | 2012-04-10 |
US20050187256A1 (en) | 2005-08-25 |
HK1098474A1 (en) | 2007-07-20 |
US8697880B2 (en) | 2014-04-15 |
CA2553877C (en) | 2012-07-31 |
US20080255199A1 (en) | 2008-10-16 |
JP2007523160A (en) | 2007-08-16 |
ATE541838T1 (en) | 2012-02-15 |
CA2553877A1 (en) | 2005-09-01 |
EP1718636A1 (en) | 2006-11-08 |
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