WO2000027841A1 - Method of preparing sulfide derivatives - Google Patents
Method of preparing sulfide derivatives Download PDFInfo
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- WO2000027841A1 WO2000027841A1 PCT/KR1998/000354 KR9800354W WO0027841A1 WO 2000027841 A1 WO2000027841 A1 WO 2000027841A1 KR 9800354 W KR9800354 W KR 9800354W WO 0027841 A1 WO0027841 A1 WO 0027841A1
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- WIPO (PCT)
- Prior art keywords
- group
- carbons
- linear
- type
- branched alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 150000003568 thioethers Chemical class 0.000 title claims abstract description 20
- 229920005989 resin Polymers 0.000 claims abstract description 41
- 239000011347 resin Substances 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 9
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 claims description 8
- 229940050176 methyl chloride Drugs 0.000 claims description 8
- 229920001429 chelating resin Polymers 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- CSLNOFLDZPPLKV-UHFFFAOYSA-N 2-(chloromethyl)-n-methyl-n-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CCl CSLNOFLDZPPLKV-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- XURCIPRUUASYLR-UHFFFAOYSA-N Omeprazole sulfide Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- JSSNZRRZJATBLR-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfanylmethyl)-n-methyl-n-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CSC1=NC2=CC=CC=C2N1 JSSNZRRZJATBLR-UHFFFAOYSA-N 0.000 claims description 2
- BSXAHDOWMOSVAP-UHFFFAOYSA-N 2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfanyl]-1h-benzimidazole Chemical compound COCCCOC1=CC=NC(CSC=2NC3=CC=CC=C3N=2)=C1C BSXAHDOWMOSVAP-UHFFFAOYSA-N 0.000 claims description 2
- WKTPBAPTLLDMKZ-UHFFFAOYSA-N 3-[2-(1h-benzimidazol-2-ylsulfanylmethyl)-3-methylpyridin-4-yl]oxypropan-1-ol Chemical compound CC1=C(OCCCO)C=CN=C1CSC1=NC2=CC=CC=C2N1 WKTPBAPTLLDMKZ-UHFFFAOYSA-N 0.000 claims description 2
- KOFBRZWVWJCLGM-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazole-2-thione Chemical compound COC1=CC=C2NC(S)=NC2=C1 KOFBRZWVWJCLGM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims 2
- CCHLMSUZHFPSFC-UHFFFAOYSA-N 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfanyl]-1h-benzimidazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CSC1=NC2=CC=CC=C2N1 CCHLMSUZHFPSFC-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 229910052804 chromium Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- CZHUPOLRFSQPNS-UHFFFAOYSA-N 1-[(3,4-dimethoxypyridin-2-yl)methylsulfanyl]benzimidazole Chemical compound COC=1C(=NC=CC1OC)CSN1C=NC2=C1C=CC=C2 CZHUPOLRFSQPNS-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- PSIREIZGKQBEEO-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfinylmethyl)-n-methyl-n-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CS(=O)C1=NC2=CC=CC=C2N1 PSIREIZGKQBEEO-UHFFFAOYSA-N 0.000 description 1
- HJMVPNAZPFZXCP-UHFFFAOYSA-N 5-(difluoromethoxy)-1,3-dihydrobenzimidazole-2-thione Chemical compound FC(F)OC1=CC=C2NC(=S)NC2=C1 HJMVPNAZPFZXCP-UHFFFAOYSA-N 0.000 description 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 description 1
- PLITYYGQMDTHMM-UHFFFAOYSA-N C(c1ccccn1)Sc1nc(cccc2)c2[nH]1 Chemical compound C(c1ccccn1)Sc1nc(cccc2)c2[nH]1 PLITYYGQMDTHMM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical class [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 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
- 229950007395 leminoprazole Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- -1 methoxyethyl Chemical group 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Chemical group 0.000 description 1
- 239000011591 potassium Chemical group 0.000 description 1
- 239000002243 precursor Substances 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
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Chemical group 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/28—Sulfur atoms
Definitions
- the present invention relates to a method of preparing sulfide derivatives, and more particularly, to a method of preparing sulfide derivatives with high yield.
- Sulfide derivatives are precursors of omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole which have gastric acid secretion inhibition, gastric mucosa protection and antiulcer.
- the sulflde derivatives preparation are classified into three categories.
- R is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; OR 6 ; -O-(CH 2 ) m -OR 7 ; and -NR 8 R 9 , wherein m is an integer of 1 to 6, R 6 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and linear or branched alkyl having 1 to 6 carbons, substituted with 1 to 5 halogen atoms, R 7 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and an usual alcohol protective group, and R 8 and R 9 are same or different and are each selected from the group consisting of hydrogen; and, linear or branched alkyl having 1 to 6 carbons,
- R 2 and R 3 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and OR 6 , and
- R 4 and R 5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR 10 ; and -COOR 6 , wherein R 10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and methyl group substituted with 1 to 3 halogen atoms.
- R ⁇ R 2 , R 3 , R 4 and R 5 have the meanings given above and X represents an usual leaving group.
- R R 2 , R 3 , R 4 and R 5 have the meanings given above and M represents lithium, sodium and potassium, Y represents chlorine, bromine, iodine, methanesulfonyloxy and paratoluenesulfonyloxy, and n is an integer of 0- 1.
- a method of preparing sulfide derivatives of formula 1 including the steps of reacting a compound of formula 5 with a compound of formula 6 or a hydrochloride salt thereof in the presence of a borohydride-based compound selected from the group consisting of a borohydride exchange resin and (R 11 ) 4 N + BH 4 " (wherein R ⁇ is linear or branched lower alkyl having 1 to 6 carbons) in a solvent.
- the present invention provides a method of preparing sulfide derivatives of formula 2 including the steps of reacting a compound of formula 5 with a compound of formula 10 or a hydrochloride salt thereof in the presence of a borohydride-based compound selected from the group consisting of a borohydride exchange resin and (R 11 ) 4 N + BH 4 " (wherein R ⁇ is linear or branched lower alkyl having 1 to 6 carbons) in a solvent, [formula 1]
- R 1 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; R 6 ; -O-(CH 2 ) m -OR 7 ; and -NR 8 R 9 , wherein m is an integer of 1 to 6,
- R 6 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and linear or branched alkyl having 1 to 6 carbons, substituted with 1 to 5 halogen atoms
- R 7 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and an usual alcohol protective group
- R 8 and R g are same or different and are each selected from the group consisting of hydrogen; and linear or branched alkyl having 1 to 6 carbons,
- R 2 and R 3 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and OR 6 ,
- R 4 and R 5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR 10 ; and -COOR 6 , wherein R 10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and methyl group substituted with 1 to 3 halogen atoms, and
- X represents an usual leaving group.
- the present invention provides a method of preparing sulfide derivatives in the presence of borohydride-based compound.
- a compound of formula 5 reacts with a compound of formula 6 or a hydrochloride salt thereof in the presence of a borohydride- based compound selected from the consisting of a borohydride exchange resin or (R 11 ) 4 N + BH 4 " (wherein R ⁇ is linear or branched lower alkyl having 1 to 6 carbons, for example, tetrabuthylammoniumborohydride) in suitable solvent, thereby obtaining sulfide derivatives of formula 1.
- a compound of formula 10 is used instead of the compound of formula 6, sulflde derivatives of formula 2 may be obtained, [formula 1]
- R ⁇ is selected from the group consisting of hydrogen; and, linear or branched alkyl having 1 to 6 carbons; OR 6 ; -O-(CH 2 ) m -OR 7 ; and -
- R 6 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and linear or branched alkyl having 1 to 6 carbons, substituted with 1 to 5 halogen atoms, for example 2,2,2-trifluoroethyl
- R 7 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and an usual alcohol protective group such as trialkylsilyl, benzyl, methoxyethyl, acethyl and benzyloxycarbonyl, and R 8 and R 9 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons,
- R 2 and R 3 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and OR 6 , R 4 and R 5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR 10 ; and -COOR 6 , where R 10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and methyl group substituted with 1 to 3 halogen atoms, and X represents an usual leaving group such as halogen, for example bromine, chlorine, iodine, lower alkylsulfonyloxy and arylsulfonyloxy.
- halogen for example bromine, chlorine, iodine, lower alkylsulfonyloxy and arylsulfonyloxy.
- borohydride-based compound Owing to the use of borohydride-based compound, a pure sulflde derivatives may be obtained without further purification.
- borohydride exchange resin when borohydride exchange resin is used for the borohydride-based compound, a very pure may be obtained.
- the borohydride exchange resin is used for the borohydride-based compound because the yield of the product is very high.
- the borohydride exchange resin is prepared by reacting an amberite IRA 400-X type resin with sodium borohydride (NaBH 4 ) in an aqueous solution according to the conventional method (J. Chem. Soc. Chem. Comm. 1997, 915, U. S. Patent No. 4,107,099).
- an amberite IRA 416-X type resin For preparing borohydride exchange resin, an amberite IRA 416-X type resin, an amberite IRA 420-X type resin, an amberite IRA 900-X type resin, an amberite IRA 904-X type resin, an amberite IRA 910-X type resin, an amberite CG 400-X type resin, an amberite CG400- ll-X type resin, an amberite IRA 743-X type resin, an amberlyst A-26-X type resin and an amberlyst A-27-X type resin may be used.
- X is selected from the group consisting of Cl “ , Br, F “ , I “ , CN “ , HO “ , NO 2 " , NaCO 3 ⁇ , " SCN and acetate.
- the solvent includes linear or branched lower alcohol having 1 to 6 carbons and it is preferred to use methanol as the solvent.
- the reaction temperature is 0 ° C to reflux temperature of the solvent.
- the yield of compounds of 1 and 2 is very high and it is not required to perform further process such as extraction and purification after terminating reaction. Furthermore, after terminating reaction, the used resin can be repeatedly used by washing it with diluted hydrochloric acid so that the production cost is reduced.
- the molecular structure is confirmed by determining Infrared spectrometry, ultraviolet-visible spectrometry, nuclear resonance spectrometry or mass spectrometry and comparing calculated and found values of elemental analysis.
- 5-methoxy-2-mercaptobenzimidazole (20.28 g, 112.56 mmol)
- a borohydride exchange resin (BER) prepared by IRA400-CI " type resin (46.58 g, 135.07 mmol)
- 3,5-dimethyl-4-methoxypyridyl-2-methylchloride (20.86 g, 112,56 mmol) were added to methanol (550 ml) and reflux-shaken for 1 hour.
- hydrochloride salt thereof instead of 3,5-dimethyl-4-methoxypyridyl-2-methylchloride, instead of 3,5-dimethyl-4-methoxypyridyl-2-methylchloride, hydrochloride salt thereof may be used.
- Example 12 A sulfide derivative was prepared by the same procedure in Example 1 except that (n-Bu) 4 N + CI " was used. The reaction temperature and times, and the yield are shown in Table 1. [Table 1]
- IRA 400-CI " type resin (15.75 g, 45.52 mmol), 3-methyl-4-(2,2,2- trifluoroethoxy)pyridyl-2-methylchloride (6.0 g, 25.04 mmol) were added to methanol (200 ml) and reflux-shaken for 50 minutes. In the step, instead of
- Example 24 A sulfide derivative was prepared by the same procedure in Example 13 except that (n-Bu) 4 N + CI " was used..
- a product was prepared by the same procedure in Example 1 except that 4-(3-methoxypropoxy)-3-methylpyridyl-2-methylchloride and 2- mercaptobenzimidazole were used.
- a hydrochloride salt thereof instead of 4-(3- methoxypropoxy)-3-methylpyridyl-2-methylchioride, a hydrochloride salt thereof may be used.
- Example 27 Preparation of 2-[4-(3-hydroxypropoxy)-3-methyl- 2-pyridyl]methylthio-1 H-benzimidazole A product was prepared by the same procedure in Example 1 except that 4-(3-hydroxypropoxy)3-methyipyridyl-2-methylchloride and 2- mercaptobenzimidazole were used. In the example, instead of 4-(3- hydroxypropoxy)3-methylpyridyl-2-methylchloride, a hydrochloride salt thereof may be used.
- Example 28 Preparation of 2-[2-(N-isobutyl-N-methylamino)benzyl]thio-1 H-benzimidazole A product was prepared by the same procedure in Example 1 except that 2-(N-isobutyl-N-methylamino)benzylchloride and 2- mercaptobenzimidazole were used. In the example, instead of 2-(N-isobutyl- N-methylamino)benzylchloride, a hydrochloride salt thereof may be used.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The method of preparing sulfide derivatives is provided. In the method, a borohydride exchange resin or (R11)4N+BH4- is used so that the sulfide derivatives can be obtained with high yield and simple manufacturing process.
Description
METHOD OF PREPARING SULFIDE DERIVATIVES
BACKGROUND OF THE INVENTION
(a) Field of the Invention The present invention relates to a method of preparing sulfide derivatives, and more particularly, to a method of preparing sulfide derivatives with high yield.
(b) Description of the Related Art
Sulfide derivatives are precursors of omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole which have gastric acid secretion inhibition, gastric mucosa protection and antiulcer.
The methods of preparing sulfide derivatives are disclosed in U. K.
Patent Nos. 1 ,525,958, 2,134,523 and 2,163,747, U. S. Patent Nos.
4,255,431 , 4,182,766, 4,472,409, 4,808,596 and 5,374,730, Japanese Patent laid-open No. 83-39,622, European Patent Nos. 166,287and 268,956, and
Korean Patent Publication Nos. 88-1714 and 92-2128.
The sulflde derivatives preparation are classified into three categories.
1) Preparation I
[Reaction 1]
(3) (4)
(1) wherein R, is selected from the group consisting of hydrogen; linear or
branched alkyl having 1 to 6 carbons; OR6; -O-(CH2)m-OR7; and -NR8R9, wherein m is an integer of 1 to 6, R6 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and linear or branched alkyl having 1 to 6 carbons, substituted with 1 to 5 halogen atoms, R7 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and an usual alcohol protective group, and R8 and R9 are same or different and are each selected from the group consisting of hydrogen; and, linear or branched alkyl having 1 to 6 carbons,
R2 and R3 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and OR6, and
R4 and R5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR10; and -COOR6, wherein R10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and methyl group substituted with 1 to 3 halogen atoms.
In the preparation I, a compound of formula 4 is unstable and the preparation I is extremely complicate and the yield of a compound of formula 1 is extremely low.
2) Preparation II [Reaction 2]
(5) (6)
(1) wherein R^ R2, R3, R4 and R5 have the meanings given above and X
represents an usual leaving group.
Although the preparation II is generally used, the yield is relatively low (65 — 85%) and purification should be performed in order to obtain a pure compound of formula 1.
3) Preparation
[Reaction 3]
(7) (8)
(9) wherein R R2, R3, R4 and R5 have the meanings given above and M represents lithium, sodium and potassium, Y represents chlorine, bromine, iodine, methanesulfonyloxy and paratoluenesulfonyloxy, and n is an integer of 0- 1.
In the preparation III, it is difficult to obtain the compound of formula 7 and the yield of product is low.
SUMMARY OF THE INVENTION It is an object of the present invention to provide a method of preparing sulfide derivatives with high yield.
It is another object to provide the method of preparing sulfide derivatives with a simple manufacturing process.
These and other objects may be achieved by a method of preparing sulfide derivatives of formula 1 including the steps of reacting a compound of
formula 5 with a compound of formula 6 or a hydrochloride salt thereof in the presence of a borohydride-based compound selected from the group consisting of a borohydride exchange resin and (R11)4N+BH4 " (wherein R^ is linear or branched lower alkyl having 1 to 6 carbons) in a solvent. Furthermore, the present invention provides a method of preparing sulfide derivatives of formula 2 including the steps of reacting a compound of formula 5 with a compound of formula 10 or a hydrochloride salt thereof in the presence of a borohydride-based compound selected from the group consisting of a borohydride exchange resin and (R11)4N+BH4 " (wherein R^ is linear or branched lower alkyl having 1 to 6 carbons) in a solvent, [formula 1]
[formula 2]
[formula 6]
R2 and R3 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and OR6,
R4 and R5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR10; and -COOR6, wherein R10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and methyl group substituted with 1 to 3 halogen atoms, and
X represents an usual leaving group.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of preparing sulfide derivatives in the presence of borohydride-based compound.
In the method, a compound of formula 5 reacts with a compound of formula 6 or a hydrochloride salt thereof in the presence of a borohydride- based compound selected from the consisting of a borohydride exchange resin or (R11)4N+BH4 " (wherein R^ is linear or branched lower alkyl having 1 to 6 carbons, for example, tetrabuthylammoniumborohydride) in suitable solvent, thereby obtaining sulfide derivatives of formula 1.
Alternatively, when a compound of formula 10 is used instead of the compound of formula 6, sulflde derivatives of formula 2 may be obtained, [formula 1]
[formula 2]
[formula 5]
R4
[formula 6]
[formula 10]
NR8R9, wherein m is an integer of 1 to 6, R6 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and linear or branched alkyl having 1 to 6 carbons, substituted with 1 to 5 halogen
atoms, for example 2,2,2-trifluoroethyl, R7 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and an usual alcohol protective group such as trialkylsilyl, benzyl, methoxyethyl, acethyl and benzyloxycarbonyl, and R8 and R9 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons,
R2 and R3 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and OR6, R4 and R5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR10; and -COOR6, where R10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and methyl group substituted with 1 to 3 halogen atoms, and X represents an usual leaving group such as halogen, for example bromine, chlorine, iodine, lower alkylsulfonyloxy and arylsulfonyloxy.
Owing to the use of borohydride-based compound, a pure sulflde derivatives may be obtained without further purification. In particular, when borohydride exchange resin is used for the borohydride-based compound, a very pure may be obtained. Furthermore, it is preferred that the borohydride exchange resin is used for the borohydride-based compound because the yield of the product is very high.
The borohydride exchange resin is prepared by reacting an amberite IRA 400-X type resin with sodium borohydride (NaBH4) in an aqueous solution according to the conventional method (J. Chem. Soc. Chem. Comm. 1997, 915, U. S. Patent No. 4,107,099). For preparing borohydride exchange resin, an amberite IRA 416-X type resin, an amberite IRA 420-X type resin, an amberite IRA 900-X type resin, an amberite IRA 904-X type resin, an amberite IRA 910-X type resin, an amberite CG 400-X type resin, an amberite CG400- ll-X type resin, an amberite IRA 743-X type resin, an amberlyst A-26-X type
resin and an amberlyst A-27-X type resin may be used. In that case, X is selected from the group consisting of Cl", Br, F", I", CN", HO", NO2 ", NaCO3 ~, " SCN and acetate.
The solvent includes linear or branched lower alcohol having 1 to 6 carbons and it is preferred to use methanol as the solvent. The reaction temperature is 0 °C to reflux temperature of the solvent.
In the present invention, the yield of compounds of 1 and 2 is very high and it is not required to perform further process such as extraction and purification after terminating reaction. Furthermore, after terminating reaction, the used resin can be repeatedly used by washing it with diluted hydrochloric acid so that the production cost is reduced.
The molecular structure is confirmed by determining Infrared spectrometry, ultraviolet-visible spectrometry, nuclear resonance spectrometry or mass spectrometry and comparing calculated and found values of elemental analysis.
The present invention will be now explained in more detail by reference to examples which are not limited to the present invention.
Example 1 Preparation of 5-methoxy-2- [3,5-dimethyl-4-methoxy-2-pyridyl]methylthio-1 H-benzimidazole
5-methoxy-2-mercaptobenzimidazole (20.28 g, 112.56 mmol), a borohydride exchange resin (BER) prepared by IRA400-CI" type resin (46.58 g, 135.07 mmol) and 3,5-dimethyl-4-methoxypyridyl-2-methylchloride (20.86 g, 112,56 mmol) were added to methanol (550 ml) and reflux-shaken for 1 hour. In the step, instead of 3,5-dimethyl-4-methoxypyridyl-2-methylchloride, hydrochloride salt thereof may be used.
The resulting product was cooled to room temperature and filtered to remove the resin. The filtrate was concentrated in vacuum. The concentrated product was dissolved in acetone (50 ml) and petroleum ether (350 ml) was slowly added thereto to crystallize. The crystal was filtered to
obtain white crystal (35.61 g, yield: 96 %). mp: 118 - 120 °C NMR (CDCI3, δ )
: 2.26 (s, 2H), 2.30 (s, 3H), 23.76 (s, 3H), 3.82 (s, 3H), 4.32 (s, 2H), 5.77-6.82 (m, 1 H), 6.89-7.07 (m," 1 H), 7.29-7.45 (m, 1 H),
8.24 (s, 1 H) Elemental analysis
Calculated (%) : C; 61.99, H; 5.81 , N; 12.76, S; 9.73 Found (%) : C ; 61.91 , H; 5.72, N; 12.85. S; 9.53 Examples 2 to 11
Preparation of 5-methoxy-2- [3,5-dimethyl-4-methoxy-2-pyridyl]methylthio-1 H-benzimidazole A sulfide derivative was prepared by the same procedure in Example 1 except that resin types in borohydride exchange resin (BER) was changed as shown in the Table 1. The reaction temperature and times, and the yield are shown in able 1.
Example 12 A sulfide derivative was prepared by the same procedure in Example 1 except that (n-Bu)4N+CI" was used. The reaction temperature and times, and the yield are shown in Table 1. [Table 1]
Example 13
Preparation of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-
2-pyridyl]methylthio-1H-benzimidazole 2-mercaptobenzimidazole (3.42 g, 22.76 mmol), a BER prepared by
IRA 400-CI" type resin (15.75 g, 45.52 mmol), 3-methyl-4-(2,2,2- trifluoroethoxy)pyridyl-2-methylchloride (6.0 g, 25.04 mmol) were added to methanol (200 ml) and reflux-shaken for 50 minutes. In the step, instead of
3-methyl-4-(2,2,2-trifluoroethoxy)pyridyl-2-methylchloride, a hydrochloride salt thereof may be used.
The resulting product was cooled to room temperature and filtered to remove the resin and concentrated in vacuum. The concentrated product was crystallized by using ethyl acetate and n-hexane and filtered to obtain white product (7.8 g, yield: 97 %). mp: 148- 150 °C
NMR ( δ , CDCI3): 2.31 (s, 3H), 4.36-4.47 (q, 2H), 4.40 (s, 2H), 6.71 -6.73 (d, 1H), 7.14-7.19 (m, 2H), 7.42-7.53 (b, 2H), 8.39-8.42 (d, 1 H) Examples 14 to 23 Preparation of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-
2-pyridyl]methylthio-1 H-benzimidazole A sulfide derivative was prepared by the same procedure in Example
13 except that types of resin in a BER were changed as shown in Table 2.
Example 24 A sulfide derivative was prepared by the same procedure in Example 13 except that (n-Bu)4N+CI" was used..
[Table 2]
Example 25 Preparation of 5-(difluoromethoxy)-2-
[3,4-dimethoxy-2-pyridyl]methylthio-1 H-benzimidazole A product was prepared by the same procedure in Example 1 except that 5-(difluoromethoxy)2-mercaptobenzimidazole and 3,4-dimethoxypyridyl-2- methylchloride were used. In the example, instead of 3,4-dimethoxypyridyl- 2-methylchloride, a hydrochloride salt thereof may be used, mp: 117- 119 °C NMR (CDCi3, δ ) : 3.92 (s, 3H), 3.94 (s, 3H), 4.40 (s, 2H), 6.51 (t, 1 H),
6.86 (d, 1 H J=5.7 Hz), 6.98 (dd, 1 H), 7.32 (d, 1 H), 7.63 (d, 1 H), 8.26 (d, 1 H), 12.5 (br, 1 H) Example 26 Preparation of 2-[4-(3-methoxypropoxy)- 3-methyl-2-pyridyl]methylthio-1 H-benzimidazole
A product was prepared by the same procedure in Example 1 except that 4-(3-methoxypropoxy)-3-methylpyridyl-2-methylchloride and 2- mercaptobenzimidazole were used. In the example, instead of 4-(3- methoxypropoxy)-3-methylpyridyl-2-methylchioride, a hydrochloride salt thereof may be used.
NMR (CDCI3, δ ) : 2.09 (t, ,2H), 2.26 (s, ,3H), 3.35 (s, 3H), 3.56 (t, 2H),
4.13 (t, 2H), 4.37 (s, 2H), 6.76 (d, J=6.1 Hz, 1 H), 7.1 -7.25 (m, 2H), 7.5 (br, s, 2H), 8.33 (d, J=6.1 Hz, 1 H)
Example 27 Preparation of 2-[4-(3-hydroxypropoxy)-3-methyl- 2-pyridyl]methylthio-1 H-benzimidazole A product was prepared by the same procedure in Example 1 except that 4-(3-hydroxypropoxy)3-methyipyridyl-2-methylchloride and 2- mercaptobenzimidazole were used. In the example, instead of 4-(3- hydroxypropoxy)3-methylpyridyl-2-methylchloride, a hydrochloride salt thereof may be used.
NMR (CDCI3, δ ) : 1.8-2.1 (m, 2H), 2.24 (s, 3H), 3.6 (t, ,2H), 4.2 (t, 2H), 4.7 (s, 2H), 7.0-7.38 (m, 3H),
7.38-7.6 (m, 2H), 8.35 (d, J=6.1 Hz, 1 H) Example 28 Preparation of 2-[2-(N-isobutyl-N-methylamino)benzyl]thio-1 H-benzimidazole A product was prepared by the same procedure in Example 1 except that 2-(N-isobutyl-N-methylamino)benzylchloride and 2-
mercaptobenzimidazole were used. In the example, instead of 2-(N-isobutyl- N-methylamino)benzylchloride, a hydrochloride salt thereof may be used. NMR (CDCI3, δ ): 0.6-2.0 (m, 7H), 2.7-3.1 (m, 2H), 2.88 (s, 3H), 4.42 (s, 2H), 6.8-7.7 (m, 8H) As described above, the present invention can prepare sulfide derivatives with high yield and the manufacturing process is very simple.
While the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art will appreciate that various modifications and substitutions can be made thereto without departing from the spirit and scope of the present invention as set forth in the appended claims.
Claims
1. A method of preparing sulfide derivatives of formula 1 comprising the steps of: reacting a compound of formula 5 with a compound of formula 6 or a hydrochloride salt thereof in the presence of a borohydride-based compound selected from the group consisting of a borohydride exchange resin and (R11)4N+BH4 " (wherein R„ is linear or branched lower alkyl having 1 to 6 carbons) in a solvent
[formula 1]
[formula 5]
[formula 6]
R2 and R3 are same or different and each selected from the group
consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and OR6,
R4 and R5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR10; and -COOR6, where R10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and a methyl group substituted with 1 to 3 halogen atoms, and
X represents an usual leaving group.
2. The method of claim 1 wherein the borohydride exchange resin is prepared by reacting a resin with sodium borohydride (NaBH4), the resin being selected from the group consisting of an amberite IRA 400-X type, an amberite IRA-416-X type, an amberite IRA 420-X type, an amberite IRA 900-X type, an amberite IRA 904-X type, an amberite 910-X type, an amberite CG 400-X type, an amberite CG 400-ll-X type, an amberite IRA 743-X type, an amberlyst A-26-X type, an amberlyst A-27-X type, wherein X is selected from the group consisting of Cr, Br, F, I", CN", HO-, NO2 _, NaCO3-, SCN and acetate.
3. The method of claim 1 wherein the solvent includes linear or branched lower alcohol having 1 to 6 carbons.
4. The method of claim 1 wherein the reacting step is performed at room temperature to refulx temperature of the solvent.
5. A method of preparing sulfide derivatives of formula 2 comprising the steps of: reacting a compound of formula 5 with a compound of 10 or a hydrochloride salt thereof in the presence of a borohydride-based compound selected from the group consisting of a borohydride exchange resin and
(R11)4N+BH4 ' (wherein R^ is linear or branched lower alkyl having 1 to 6 carbons) in a solvent
[formula 2]
[formula 5]
[formula 10]
R4 and R5 are same or different and each selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; -OR10; and -COOR6, where R10 is selected from the group consisting of hydrogen; linear or branched alkyl having 1 to 6 carbons; and a methyl group substituted with 1 to 3 halogen atoms, and
X represents an usual leaving group.
6. The method of claim 5 wherein the borohydride exchange
resin is prepared by using resin and sodium borohydride (NaBH4), the resin being selected from the group consisting of an amberite IRA 400-X type, an amberite IRA-416-X type, an amberite IRA 320-X type, an amberite IRA 900- X type, an amberite IRA 904-X type, an amberite 910-X type, an amberite CG 5 400-X type, an amberite CG 400-ll-X type", an amberite IRA 743-X type, an amberlyst A-26-X type, an amberlyst A-27-X type, wherein X is selected from the group consisting of Cl", Br, F, I", CN", HO", NO2 ", NaCO3 ", "SCN and acetate.
7. The method of claim 5 wherein the solvent includes linear or 0 branched lower alcohol having 1 to 6 carbons.
8. The method of claim 5 wherein the reacting step is performed at room temperature to refulx temperature of the solvent.
9. A method of preparing 5-methoxy-2-[3,5-dimethyl-4-methoxy- 2-pyridyl]methylthio-1 H-benzimidazole comprising the step of; 5 reacting 5-methoxy-2-mercaptobenzimidazole with 3,5-dimethyl-4- methoxypyridine-2-methylchloride or a hydrochloride salt thereof in the presence of borohydride exchange resin.
10. A method of preparing 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2- pyridyl]methylthio-1 H-benzimidazole comprising the step of; 0 reacting 2-mercaptobenzimidazole with 3-methyl-4-(2,2,2- trifluoroethoxy)pyridyl-2-methylchoride or a hydrochloride salt thereof in the presence of borohydride exchange resin.
11. A method of preparing 2-[4-(3-methoxypropoxy)-3-methyl-2- pyridyl]methylthio-1 H-benzimidazole comprising the step of; 5 reacting 2-mercaptobenzimidazole with 4-(3-methoxypropoxy)-3- methypyridyl-2-methylchloride or a hydrochloride salt thereof in the presence of borohydride exchange resin.
12. A method of preparing 2-[4-(3-hydroxypropoxy)-3-methyl-2- pyridyl]methylthio-1 H-benzimidazole comprising the step of: 0 reacting 2-mercaptobenzimidazole with 4-(3-hydroxypropoxy)-3-
methylpyridyl-2-methylchloride or a hydrochloride salt thereof in the presence of borohydride exchange resin.
13. A method of preparing 2-[2-(N-isobutyl-N- methylamino)benzyl]thio-1 H-benzimidazole comprising the step of: reacting 2-mercaptobenzimidazole with 2-(N-isobutyl-N- methylamino)benzylchloride or a hydrochloride salt thereof in the presence of borohydride exchange resin.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR1998/000354 WO2000027841A1 (en) | 1998-11-06 | 1998-11-06 | Method of preparing sulfide derivatives |
| AU10548/99A AU1054899A (en) | 1998-11-06 | 1998-11-06 | Method of preparing sulfide derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR1998/000354 WO2000027841A1 (en) | 1998-11-06 | 1998-11-06 | Method of preparing sulfide derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000027841A1 true WO2000027841A1 (en) | 2000-05-18 |
Family
ID=19531159
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR1998/000354 WO2000027841A1 (en) | 1998-11-06 | 1998-11-06 | Method of preparing sulfide derivatives |
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| Country | Link |
|---|---|
| AU (1) | AU1054899A (en) |
| WO (1) | WO2000027841A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008102145A3 (en) * | 2007-02-21 | 2008-11-13 | Cipla Ltd | Process for the preparation of esomeprazole magnesium dihydrate |
| CN102675285A (en) * | 2012-06-02 | 2012-09-19 | 大连理工大学 | Method for pure water phase preparation of rabeprazole sodium |
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| SU509595A1 (en) * | 1974-01-04 | 1976-04-05 | Ордена Трудового Красного Знамениинститут Органического Синтезаан Латвийской Сср | Method for preparing tetrahydropyridine derivatives |
| US4107099A (en) * | 1977-02-10 | 1978-08-15 | Ventron Corporation | Borohydride exchange resins and their uses as reducing agents and in preparation of volatile metal hydrides |
| US4255431A (en) * | 1978-04-14 | 1981-03-10 | Aktiebolaget Hassle | Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion |
| GB2134523A (en) * | 1983-02-11 | 1984-08-15 | Haessle Ab | Novel pharmacologically active compounds |
| US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
| GB2163747A (en) * | 1984-08-31 | 1986-03-05 | Nippon Chemiphar Co | Benzimidazole derivatives |
| EP0204215A1 (en) * | 1985-05-24 | 1986-12-10 | G.D. Searle & Co. | 2-[(1H-benzimidazol-2-ylsulfinyl)methyl]-benzenamines |
| KR900001164B1 (en) * | 1987-07-09 | 1990-02-27 | 주식회사 삼양사 | Method of purificating tetra hyarofuran |
-
1998
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU509595A1 (en) * | 1974-01-04 | 1976-04-05 | Ордена Трудового Красного Знамениинститут Органического Синтезаан Латвийской Сср | Method for preparing tetrahydropyridine derivatives |
| US4107099A (en) * | 1977-02-10 | 1978-08-15 | Ventron Corporation | Borohydride exchange resins and their uses as reducing agents and in preparation of volatile metal hydrides |
| US4255431A (en) * | 1978-04-14 | 1981-03-10 | Aktiebolaget Hassle | Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion |
| US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
| GB2134523A (en) * | 1983-02-11 | 1984-08-15 | Haessle Ab | Novel pharmacologically active compounds |
| GB2163747A (en) * | 1984-08-31 | 1986-03-05 | Nippon Chemiphar Co | Benzimidazole derivatives |
| EP0204215A1 (en) * | 1985-05-24 | 1986-12-10 | G.D. Searle & Co. | 2-[(1H-benzimidazol-2-ylsulfinyl)methyl]-benzenamines |
| KR900001164B1 (en) * | 1987-07-09 | 1990-02-27 | 주식회사 삼양사 | Method of purificating tetra hyarofuran |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008102145A3 (en) * | 2007-02-21 | 2008-11-13 | Cipla Ltd | Process for the preparation of esomeprazole magnesium dihydrate |
| JP2010519284A (en) * | 2007-02-21 | 2010-06-03 | シプラ・リミテッド | Method for preparing esomeprazole magnesium dihydrate |
| US8394963B2 (en) | 2007-02-21 | 2013-03-12 | Cipla Limited | Process for the preparation of esomeprazole magnesium dihydrate |
| KR101522865B1 (en) * | 2007-02-21 | 2015-05-26 | 시플라 리미티드 | Process for the preparation of form a of esomeprazole magnesium dihydrate |
| CN102675285A (en) * | 2012-06-02 | 2012-09-19 | 大连理工大学 | Method for pure water phase preparation of rabeprazole sodium |
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| AU1054899A (en) | 2000-05-29 |
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