AU2002240242A1 - Processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles - Google Patents
Processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazolesInfo
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- AU2002240242A1 AU2002240242A1 AU2002240242A AU2002240242A AU2002240242A1 AU 2002240242 A1 AU2002240242 A1 AU 2002240242A1 AU 2002240242 A AU2002240242 A AU 2002240242A AU 2002240242 A AU2002240242 A AU 2002240242A AU 2002240242 A1 AU2002240242 A1 AU 2002240242A1
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- Prior art keywords
- process according
- oxidation
- methyl
- formula
- methoxy
- Prior art date
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Links
- 238000000034 method Methods 0.000 title claims description 43
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- HBDKFZNDMVLSHM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfinyl)-1h-benzimidazole Chemical class N=1C2=CC=CC=C2NC=1S(=O)CC1=CC=CC=N1 HBDKFZNDMVLSHM-UHFFFAOYSA-N 0.000 title description 5
- 230000003647 oxidation Effects 0.000 claims description 46
- 238000007254 oxidation reaction Methods 0.000 claims description 46
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 239000007800 oxidant agent Substances 0.000 claims description 15
- -1 thioester compound Chemical class 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 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 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 13
- 150000003568 thioethers Chemical class 0.000 claims description 12
- 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 claims description 10
- 239000006227 byproduct Substances 0.000 claims description 10
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 10
- 125000001174 sulfone group Chemical group 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229960003174 lansoprazole Drugs 0.000 claims description 8
- 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 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 229960005019 pantoprazole Drugs 0.000 claims description 8
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 8
- 229960004157 rabeprazole Drugs 0.000 claims description 8
- 125000005287 vanadyl group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- CQKAPARXKPTKBK-UHFFFAOYSA-N tert-butylazanium;bromide Chemical compound Br.CC(C)(C)N CQKAPARXKPTKBK-UHFFFAOYSA-N 0.000 claims description 6
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 19
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 16
- 229960000381 omeprazole Drugs 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- XURCIPRUUASYLR-UHFFFAOYSA-N Omeprazole sulfide Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 description 9
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 description 5
- 229910052720 vanadium Inorganic materials 0.000 description 5
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 5
- MGUIRBGWJPBAOK-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfinyl)-4h-benzimidazole Chemical class N=1C2=CC=CCC2=NC=1S(=O)CC1=CC=CC=N1 MGUIRBGWJPBAOK-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 4
- IXEQEYRTSRFZEO-UHFFFAOYSA-N Omeprazole sulfone Chemical compound N1C2=CC(OC)=CC=C2N=C1S(=O)(=O)CC1=NC=C(C)C(OC)=C1C IXEQEYRTSRFZEO-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- RMGVZKRVHHSUIM-UHFFFAOYSA-L dithionate(2-) Chemical compound [O-]S(=O)(=O)S([O-])(=O)=O RMGVZKRVHHSUIM-UHFFFAOYSA-L 0.000 description 4
- 231100001261 hazardous Toxicity 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229940001584 sodium metabisulfite Drugs 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 150000004965 peroxy acids Chemical class 0.000 description 3
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 2
- FCJYMBZQIJDMMM-UHFFFAOYSA-N 1H-Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfonyl]- Chemical compound COC1=CC=NC(CS(=O)(=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC FCJYMBZQIJDMMM-UHFFFAOYSA-N 0.000 description 2
- ULUMEOWSBDTGKG-UHFFFAOYSA-N 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-4h-benzimidazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CCC2=N1 ULUMEOWSBDTGKG-UHFFFAOYSA-N 0.000 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 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000007970 thio esters Chemical group 0.000 description 2
- SRUQARLMFOLRDN-UHFFFAOYSA-N 1-(2,4,5-Trihydroxyphenyl)-1-butanone Chemical compound CCCC(=O)C1=CC(O)=C(O)C=C1O SRUQARLMFOLRDN-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- OZURYZAHRAPLJF-UHFFFAOYSA-N 2-(phenylsulfanylmethyl)pyridine Chemical class C=1C=CC=NC=1CSC1=CC=CC=C1 OZURYZAHRAPLJF-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- UKILEIRWOYBGEJ-UHFFFAOYSA-N 6-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfanyl]-1h-benzimidazole Chemical compound COC1=CC=NC(CSC=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC UKILEIRWOYBGEJ-UHFFFAOYSA-N 0.000 description 1
- UNFOYLJWLOHUDI-UHFFFAOYSA-N 6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-4h-benzimidazole Chemical compound N=1C2=CC(OC)=CCC2=NC=1S(=O)CC1=NC=C(C)C(OC)=C1C UNFOYLJWLOHUDI-UHFFFAOYSA-N 0.000 description 1
- 102100039386 Ketimine reductase mu-crystallin Human genes 0.000 description 1
- 101000772180 Lithobates catesbeianus Transthyretin Proteins 0.000 description 1
- 239000012425 OXONE® Substances 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- TVMJMCGRSSSSDJ-UHFFFAOYSA-N lansoprazole sulfone Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)(=O)C1=NC2=CC=CC=C2N1 TVMJMCGRSSSSDJ-UHFFFAOYSA-N 0.000 description 1
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002976 peresters Chemical class 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229910000166 zirconium phosphate Inorganic materials 0.000 description 1
Description
PROCESSES FOR THE PRODUCTION OF SUBSTITUTED 2-(2-PYRIDYLMETHYL) SULFINYL-lH-BENZIMIDAZOLES
CROSS-REFERENCE TO RELATED APPLICATION
This invention claims the benefit under 35 U.S.C. §1.119(e) of provisional application Serial No. 60/266,162, filed February 2, 2001.
FIELD OF THE INVENTION The present invention relates to novel processes of preparing substituted 2-(2- pyridylmethyl) suliϊnyl--. H-benzimidazoles .
BACKGROUND OF THE INVENTION Several substituted 2-(2-pyridylmethyl)sulfinyl--. H-benzimidazoles are known gastric proton pump inhibitors. These include omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridyl) methyl] sulfmyl]-iH-benzimidazole), lansoprazole (2-[[[3-methyl-4-(2,2,2- trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]--7H-benzimidazole), pantoprazole (5- (difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-iH-benzimidazole, and rabeprazole (2- [ [ [4-(3 -methoxy-propoxy)-3 -methyl-2-pyidinyl] methyl] sulfinyl] -1 H- benzimidazole. For example, omeprazole is a proton pump inhibitor commercially available for the treatment of gastric ulcers. The compound is disclosed in European Patent No. 5318.
The reported synthesis of these substituted 2-(2-pyridylmethyl)sulfinyl--7H- benzimidazoles principally involves generally an oxidation process of a thioether moiety to form a thioester moiety of the compound of formula A:
A
Various methods employing various different oxidants to perform this oxidation are known. For example, Canadian Patent No. 1,263,119 describes the use of hydrogen peroxide over a vanadium catalyst (such as vanadium pentoxide, sodium vanadate and vanadium acteylacetonate). Canadian Patent No. 1,127,158 similarly describes the use of peracids, peresters, ozone, etc. European Patent Application, Publication No. 533,264 describes the use of magnesium monoperoxyphthalate as the oxidizing agent. PCT Publication No. WO91/18895 describes the use of m-chloroperoxy benzoic acid as the oxidizing agent. GB Pat. No.2,069,492 generally describes this acid and other peroxy acids in the oxidation of substituted (phenylthiomethyl)pyridines.
Use of tert-butyl hydroperoxide (TBHP) as an oxidant has already been suggested for the performance of various organic oxidations. Sharpless et al., Aldrichimica Acta 12:63 (1979) review the use of THBP as an oxidant and compared with hydrogen peroxide and other peracids. Sharpless et al. describe the use of TBHP in the epoxidation of olefinic alcohols in the presence of NO(acac)2 or Mo(CO) catalysts. The oxidation of sulphides, however, is not described.
In an effort to develop a method for the selective oxidation of sulphides to sulphoxides, Choudray et al., J. Mol. Catalysts, 75:L7-L12 (1992) describe the use of TBHP in the presence of vanadium pillared clay. The results demonstrated selectivity for the oxidation to sulphoxide in preference to the sulphone far superior to that of known TBHP/vanadium catalysts. The use of NO(acac)2 or N2O5 resulted in sulphones rather than sulfoxide predominating in the final product.
There has been a long felt need for efficient and safe methods for the selective oxidation of a thioether moiety of formula B to a thioester moiety of formula A. The present invention provides efficient and safe methods of preparing various substituted 2-(2- pyridylrnethyi) sulfmyl-iH-benzimidazoles.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing a thioester compound of formula A:
A
wherein Rj, R2, and - 4 are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R3 is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising reacting a thioether compound of formula B
B
wherein Ri. through 4 are as in formula A, with an oxidizing agent to produce selective oxidation of the thioether compound of formula B to form the thioester compound of formula A.
The present invention further provides a process for preparing a thioester compound of compound of formula A, comprising reacting a thioether compound of formula B with Oxone (Oxone monopersulphate).
The present invention further provides a process for preparing a thioester compound of compound of formula A, comprising reacting a thioether compound of formula B with tert-
butyl hydroperoxide (TBHP) in the presence of a catalyst selected from the group consisting of vanadyl (IN) acetylacetonate, sodium metavanadate and vanadium pentoxide.
The substituted 2-(2-pyridylmethyl)sulfmyl-iH-benzimidazoles prepared according to the process of the present invention yield the desired products in a relatively high yield with only small amounts of the corresponding sulphone as by-product.
An object of the present invention is to provide an improved process of selective oxidation of 5-methoxy-2-[[(4-methoxy-3 ,5-dimethyl-2-pyridyl)methyl]thio]-iH- benzimidazole (MPB) that utilizes a non-hazardous oxidant and results in the selective production of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfmyl]-iH- benzimidazole (omeprazole), i.e., the corresponding sulphoxide, with only minor amounts of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphonyl]benzimidazole.
Another object of the present invention is to provide an improved process of selective oxidation of 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]thio]- H- benzimidazole that utilizes a non-hazardous oxidant and results in the selective production of 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]--7H-benzimidazole (lansoprazole), i.e., the corresponding sulphoxide, with only minor amounts of 2-[[[3-methyl- 4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulphonyl]-iH-benzimidazole.
Another object of the present invention is to provide an improved process of selective oxidation of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-iH- benzimidazole that utilizes a non-hazardous oxidant and results in the selective production of 5 -(difluoromethoxy)-2- [ [(3 ,4-dimethoxy-2-pyridinyl)methyl] sulfinyl] -iH-benzimidazole
(pantoprazole), i.e., the corresponding sulphoxide, with only minor amounts of 5- (difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulphonyl]-iH-benzimidazole.
Another object of the present invention is to provide an improved process of selective oxidation of 2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyidinyl]methyl]thio]-iH- benzimidazole that utilizes a non-hazardous oxidant and results in the selective production of
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-7H-benzimidazole (rabeprazole), i.e., the corresponding sulphoxide, with only minor amounts of 5-methoxy- 2 [[(4-methoxy-3 , 5 -dimethyl-2-pyridyl)methyl] sulphonyl] -i H-benzimidazole.
Another object of the present invention is to provide an improved process of preparing omeprazole while the amount of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] sulphonyl]-iH-benzimidazole (SOMP) as by-product when the reaction proceeds to completion, is typically within the range of about 1 to about 4.5% by weight of the crude product mixture.
Another object of the present invention is to provide an improved process of preparing lansoprazole while the amount of 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl] methyl]sulphonyl]--.H-benzimidazole as by-product when the reaction proceeds to completion, is typically within the range of about 1 to about 4.5% by weight of the crude product mixture.
Another object of the present invention is to provide an improved process of preparing pantoprazole while the amount of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]sulphonyl]-iH-benzimidazole as by-product when the reaction proceeds to completion, is typically within the range of about 1 to about 4.5% by weight of the crude product mixture.
Another object of the present invention is to provide an improved process of preparing rabeprazole while the amount of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulphonyl]-iH-benzimidazole as by-product when the reaction proceeds to completion, is typically within the range of about 1 to about 4.5% by weight of the crude product mixture.
DETAILED DESCRIPTION OF THE INVENTION
Definitions: As used herein, the following abbreviations are used: "NO(acac)2" is vanadium bis acetylacetonate; "TBHP" is tert-butyl hydroperoxide; "ΝaNO " is sodium meta-vanadate; "N2O5" is vanadium pentoxide; "MPB" is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]thio]benzimidazole; "OMP" is omeprazole; "SOMP" is 5-methoxy-2-[[(4- methoxy-3,5-dimethyl-2-pyridyl)methyl]sulphonyl]-lH-benzimidazole; "Oxone® refers to a trademark name of an oxidizing agent under Du Pont for an acidic, white, granular, free- flowing solid containing the active ingredient potassium peroxymonosulfate; "TBAB" is tert- butyl ammonium bromide which is a quaternary ammonium salt that is one of the most common phase transfer catalysts; "substantially free" refers to sulphone by-product less than about 1 to about 4.5% by weight of the crude product mixture.
The present invention provides a process for preparing a thioester compound of formula A:
A
wherein Rls R , and P are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R3 is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising reacting a thioether compound of formula B
B
wherein Ri through 4 are as in formula A, with an oxidizing agent to produce selective oxidation of the thioether compound of formula B to form the thioester compound of formula A.
Preferably, the present invention provides the preparation of substituted 2-(2- pyridylmethyl)sulfinyl-iH-benzimidazoles of formula A, wherein Ri is methyl; R2 is methoxy; R3 is methyl and R-t is methoxy. The compound is omeprazole.
Preferably, the present invention provides the preparation of substituted 2-(2- pyridylmethyl)sulfinyl-iH-benzimidazoles of formula A, wherein Ri. is methyl; R2 is
2-trifluoroethoxy; R3 is hydrogen and R4 is hydrogen. The compound is lansoprazole.
Preferably, the present invention provides the preparation of substituted 2-(2- pyridylmethyl)sulfinyl--. H-benzimidazoles of formula A, wherein Ri is methoxy; R2 is methoxy; R3 is hydrogen and is difluoromethoxy. The compound is pantoprazole.
Preferably, the present invention provides the preparation of substituted 2-(2- pyridylmethyl)sulfinyl-iH-benzimidazoles of formula A, wherein Ri. is methyl; R2 is MeOCΗ2CΗ2CΗ O, R3 is hydrogen and R is hydrogen. The compound is rabeprazole.
According to one embodiment, the oxidation is performed with tert-butyl hydroperoxide (TBHP) in the presence of a catalyst selected from the group consisting of vanadyl bis-acetylacetonate, sodium meta-vanadate and vanadium pentoxide. Preferably, the catalyst is vanadyl bis-acetylacetonate.
According to another embodiment, the molar ratio of tert-butyl hydroperoxide (TBHP) to a compound of formula B, is in the range of about 1.15 to about 4.5. Preferably, the compound of formula A includes 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]thio]-lH-benzimidazole, 2[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2- pyridinyl]methyl]thio]-lH-benzimidazole, 5-(difluoromethoxy)-2-[[3,4-dimethoxy-2-
pyridinyl)methyl]thio]-lH-benzimidazole, and 2-[[[4-(3-methoxy-propoxy)-3-methyl-2- pyridinyl]methyl]thio]-lH-benzimidazole.
According to another embodiment, the molar ratio of vanadyl bis-acetylacetonate to the compound of formula B is from about 0.01 to about 0.6.
According to another embodiment, the oxidation by tert-butyl hydroperoxide (TBΗP) in the presence of a catalyst is performed in an organic solvent selected from the group consisting of toluene, lower alkanols and ethyl acetate.
Another preferred embodiment of the present invention is that the oxidation is performed in an organic solvent such as toluene, a lower alkanol, preferably isopropanol or ethyl acetate. Most preferable solvent is toluene or isopropanol.
Preferably, the oxidation of substituted 2-(2-pyridylmethyl)sulfinyl-7H- benzimidazoles of formula A is performed at temperature ranging from about -10 °C to about 30°C.
Preferably, the oxidation of substituted 2-(2-pyridylmethyl)sulfinyl-7H- benzimidazoles of formula A is performed over a period of about 2 to about 10 hours.
According to another embodiment, the oxidation is performed in the presence of Oxone® (Oxone monopersulphate).
According to another embodiment, the molar ratio between Oxone® (Oxone monopersulphate) and the compound of formula B is from about 1.25 to about 1.6:1, most preferably about 1.4 to about 1.6:1.
According to another embodiment, the oxidation by Oxone® (Oxone monopersulphate) is performed in the presence of an aqueous organic solvent. Preferably, the organic solvent is acetone, methanol or in two-phase system (CΗ2C12 / H2O, (ethyl acetate /
H2O) in the presence of phase-transferred catalyst (e.g. TBAB). More preferably, the oxidation is performed in about 5% aqueous methanol.
Preferably, the oxidation of substituted 2-(2-pyridylmethyl)sulfinyl-7H- benzimidazoles of formula A is performed in a two-phase system selected from (CΗ2C12 /
H2O) and (ethyl acetate / H2O).
Preferably, the oxidation of substituted 2-(2-pyridylmethyl)sulfinyl-iH- benzimidazoles of formula A is performed in the presence of tert-butyl ammonium bromide (TBAB).
According to another embodiment, the oxidation by Oxone® (Oxone monopersulphate) is performed at a temperature ranging from about — 10°C to about 30°C over a time period of about 2 to about 10 hours.
The oxidation conditions of the present invention result in the production of the compound of formula A, wherein the amount of sulphone derivative is less than about 0.5% (wt/wt) of the final product preferably less than 0.2% (wt/wt).
Preferably, the pure products prepared in according to the disclosed method include pantoprazole, lansoprazole, omeprazole and rabeprazole.
The invention will now be exemplified by the following non-limiting Examples.
EXAMPLES
Example 1
Selective Oxidation of 5-methoxy-2-["["(4-methoxy-3.5-dimethyl-2-pyridyl methyl]thio]-lH- benzimidazole to form 5-methoxy-2-r["(4-methoxy-3.5-dimethyl-2-pyridyl) methyl] sulfmyl]-
1H- benzimidazole (Omeprazole)
1.5 mg (0.6% molar) NO (acac)2) was dissolved in 12 ml ethanol at room temperature. The solution was stirred and 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridyl)methyl]thio]benzimidazole (MPB) were added. 1.5 ml aqueous tert-butyl
hydroperoxide (TBHP) (70%) was added over a 5-minute period at 16-17°C and the solution was then stirred for 3 hours. After completion of the reaction, the product mixture was cooled to about 15°C and treated with aqueous sodium metabisulphate. The resultant solid was filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79%).
Example 2
Selective Oxidation of 5-methoxy-2- |"(4-methoxy-3,5-dimethyl-2-pyridyl methyl]thio]-lH- benzimidazole to form 5-methoxy-2-["["(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl]- lH-benzimidazole (Omeprazole)
15 mg (0.6% molar) NO(acac)2) in 5 ml toluene were added to a suspension of 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) in 30 ml toluene at a temperature of about 5°C. 3.5 ml of tert-butyl hydroperoxide (TBΗP) in toluene (3M, 115%) were added dropwise, while the temperature was maintained between 5 and 7°C. Upon completing the addition of the TBΗP, the temperature rose to
22°C. The reaction was allowed to proceed to completion (about 3 hours), after which the cooled product mixture was treated with aqueous sodium metabisulphite. The solid product was filtered off, washed with cooled ethyl acetate and dried in an oven (yield 80.7%)
Example 3
Selective Oxidation of 2- 3-methyl-4-(2.2.2-trifluoro-ethoxy -2-pyridinyl]methyl]thio]- H- benzimidazole to form 2-r r3-methyl-4-(2,2,2-trifluoro-ethoxy')-2-pyridinyl]metlιyl]sulfinyl]- iH-benzimidazole (Lansoprazole
1.5 mg (0.6% molar) NO (acac)2) is dissolved in 12 ml ethanol at room temperature. The solution is stirred and 3 grams of 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2- pyridinyl]methyl]thio]-iH-benzimidazole are added. 1.5 ml aqueous tert-butyl hydroperoxide (TBΗP) (70%) is added over a 5-minute period at 16-17°C and the solution is then stirred for 3 hours. After completion of the reaction, the product mixture is cooled to about 15°C and treated with aqueous sodium metabisulphate. The resultant solid is filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79%).
Example 4
Selective Oxidation of 5-rdifluoromethoxyV2-[["(3,4-dimethoxy-2-pyridinyl methyl]thio]-7H- benzimidazole to form 5-(difluoromethoxy)-2-[[(3.4-dimethoxy-2-pyridinvDmethyl]sulfinyl]- iH-benzimidazole (Pantoprazole
1.5 mg (0.6% molar) NO (acac)2) is dissolved in 12 ml ethanol at room temperature. The solution is stirred and 3 grams of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]methyl]thio]-iH-benzimidazole are added. 1.5 ml aqueous tert-butyl hydroperoxide (TBΗP) (70%) is added over a 5-minute period at 16-17°C and the solution is then stirred for 3 hours. After completion of the reaction, the product mixture is cooled to about 15°C and treated with aqueous sodium metabisulphate. The resultant solid is filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79%).
Example 5
S elective Oxidation of 2- f [~4-f 3 -methoxy-propoxy)-3 -methyl-2-p vidinyl]me thyl] thio] -1H- benzimidazole to form 2- [ 4-(3-methoxy-propoxy')-3-methyl-2-pyidinyl]methyl]sulfinyl]- iH-benzimidazole (Rabeprazole)
1.5 mg (0.6% molar) NO (acac)2) is dissolved in 12 ml ethanol at room temperature. The solution is stirred and 3 grams of 2-[[[4-(3-methoxy-propxy)-3-methyl-2- pyidinyl]methyl]thio]-7H-benzimidazole are added. 1.5 ml aqueous tert-butyl hydroperoxide (TBΗP) (70%) is added over a 5-minute period at 16-17°C and the solution is then stirred for
3 hours. After completion of the reaction, the product mixture is cooled to about 15°C and treated with aqueous sodium metabisulphate. The resultant solid is filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79%).
Example 6 Changes of Experimental Conditions and Yields
The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results:
Table I
Example 7 Comparison with the Method disclosed by Canadian Patent 1.263,119 4 mg (0.06% molar) NO (acac)2 were added to suspension of 9 grams of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-lH-benzimidazole (MPB) in 66 ml ethanol at room temperature. 35 ml of 35% aqueous hydrogen peroxide (150% mol) was added at room temperature with no visible exotherm, the mixture was then stirred. After 12 hours the reaction mixture still contained 65% of untreated MPB and only 32% omeprazole. Prolongation of the reaction time did not lead to further production of omeprazole.
Example 8
Selective Oxidation By Oxone" of 5-methoxy-2-r (4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio]-lH-benzimidazole to form 5-methoxy-2-[[(4-methoxy-3.5-dimethyl-2-pyridyl methyl] sulfinyll-lH-benzimidazole (Omeprazole)
A mixture of 3 grams 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] thio]benzimidazole (MPB), 3 grams ΝaΗCO3 and 20 ml aqueous methanol was cooled to -2°C and 3.5 ml (5.69 mmol) Oxone® was added. The mixture was stirred for 4 hours at 0°C and a further lgram (mmol) Oxone® was added and stirring continued for 1.5 hours. A solution of 0.8 gram sodium metabisulfite in 20ml water was added dropwise over 5-10 minutes. After further stirring the resultant precipitate was filtered, washed successively with water and 50% aqueous methanol and dried.
Yield 2.7 grams, 84% (purity 98.1%), SOMP 0.15%.
Example 9 Changes of Experimental Conditions and Yields The above described reaction of Example 8 was repeated while using the conditions given in Table II below, to give the following results:
Table π
Example 10
Selective Oxidation By Oxone® of 2-rrr3-methyl-4-(2,2,2-trifluoro-ethoxy -2- pyridinyl]methyl]thio]-lH-benzimidazole to form of 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxyV
2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole (Lansoprazole)
A mixture of 3 grams 2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl] methyl] thio]-Η-benzimidazole, 3 grams NaHCO3 and 20 ml aqueous methanol is cooled to -2°C and 3.5 ml (5.69 mmol) Oxone® is added. The mixture is stirred for 4 hours at 0°C and a further lgram (mmol) Oxone® is added and stirring continues for 1.5 hours. A solution of 0.8 gram sodium metabisulfite in 20ml water is added dropwise over 5-10 minutes. After further stirring the resultant precipitate is filtered, washed successively with water and 50%> aqueous methanol and dried. Purity is 98.1%.
Example 11
Selective Oxidation By Oxone® of 5-(difluoromethoxy -2-[[(3.4-dimethyoxy-2- pyridiniNDmethyl] thio]-lH-benzimidazole to form 5-(difluoromethoxy)-2-riY3.4- dimethvoxy-2-pyridiniyl)methyl] sulfinyl]- lH-benzimidazole (Pantoprazole)
A mixture of 3 grams 5-(difluoromethoxy)-2-[[(3,4-dimethyoxy-2-pyridinjyl)methyl] thio]-lH-benzimidazole, 3 grams NaΗCO3 and 20 ml aqueous methanol is cooled to -2°C and
3.5 ml (5.69 mmol) Oxone® is added. The mixture is stirred for 4 hours at 0°C and a further lgram (mmol) Oxone® is added and stirring continues for 1.5 hours. A solution of 0.8 gram sodium metabisulfite in 20ml water is added dropwise over 5-10 minutes. After further stirring the resultant precipitate is filtered, washed successively with water and 50% aqueous methanol and dried. Purity is 98.1%.
Example 12
Selective Oxidation By Oxone" of 2- rr4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]methyl1 thiol-lH-benzimidazole to form 2- |"[4-(3-methoxy-propoxy -3-methyl-2-pyridinyl]sulfinvn- lH-benzimidazole (Rabeprazole) A mixture of 3 grams 2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]methyl] thio]-lH-benzimidazole, 3 grams NaΗCO3 and 20 ml aqueous methanol is cooled to -2°C and 3.5 ml (5.69 mmol) Oxone® is added. The mixture is stirred for 4 hours at 0°C and a further lgram (mmol) Oxone is added and stirring continued for 1.5 hours. A solution of 0.8 gram sodium metabisulfite in 20ml water is added dropwise over 5-10 minutes. After further stirring the resultant precipitate is filtered, washed successively with water and 50% aqueous methanol and dried. Purity is 98.1%.
A number of embodiments of the invention have been described. The present invention is not to be limited in scope by the specific embodiments described herein. It will be understood that various modifications may be made without departing from the spirit and scope of the invention. Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties.
Claims (1)
- WHAT IS CLAIMED IS:1. A process for preparing a thioester compound of formula A:Awherein Ri, R2, and Ri are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower alkoxy; and R3 is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl, comprising reacting a thioether compound of formula BBwherein Ri through R are as in formula A, with an oxidizing agent to produce selective oxidation of the thioether compound of formula B to form the thioester compound of formula A.The process according to claim 1, wherein the oxidation is performed at a temperature from about -10°C to about 30°C.The process according to claim 1, wherein the oxidation is performed for about 2 hours to about 10 hours.The process according to claim 1, wherein Rj is methyl; R2 is methoxy; R3 is methyl and P^ is methoxy.The process according to claim 1, wherein is methyl; R2 is 2-trifluoroethoxy; R3 is hydrogen and ^ is hydrogen.6. The process according to claim 1, wherein Ri is methoxy; R2 is methoxy; R3 is hydrogen and i is difluoromethoxy.7. The process according to claim 1, wherein Rj is methyl; R2 is MeOCH2CH2CH2O; R3 is hydrogen and R-t is hydrogen. 8. The process according to claim 1, wherein the oxidizing agent is tert-butyl hydroperoixde in the presence of a catalyst. 9. The process according to claim 8, wherein the catalyst is selected from the group consisting of vanadyl bis-acetylacetonate, sodium meta-vanadate and vanadium pentoxide. 10. The process according to claim 8, wherein the molar ratio of tert-butyl hydroperoxide to the compound of formula B is in the range of about 1.15 to about 4.5.11. The process according to claim 8, wherein the catalyst is vanadyl bis-acetylacetonate.12. The process according to claim 8, wherein the vanadyl bis-acetylacetonate and the compound of formula B is in the molar ratio of about 0.01 to about 0.6. 13. The process according to any one of claims 8-12, wherein the oxidation is performed in an organic solvent.14. The process according to claim 13, wherein the organic solvent is selected from the group consisting of toluene, lower alkanols and ethyl acetate.15. The process according to claim 13, wherein the oxidation is performed in an organic solvent in the presence of water.16. The process according to claim 1, wherein the oxidizing agent is Oxone®.17. The process according to claim 16, wherein the molar ratio between Oxone® and the compound of formula B is from about 1.25-1.6 to about 1.18. The process according to claim 16, wherein the molar ratio between Oxone and the compound of formula B is from about 1.4-1.6 to about 1.19. The process according to claim 16, wherein the oxidation is performed of an aqueous organic solvent.20. The process according to claim 16, wherein the oxidation is performed in the presence any one or more of acetone and methanol. 21. A process according to claim 16, wherein the oxidation is performed in about 5% aqueous methanol.22. The process according to claim 16, wherein the oxidation is performed in a two-phase system selected from (CH Cl2/H2O) and (ethyl acetate/H2O).23. The process according to claim 16, wherein the oxidation is performed in the presence of phase-transferred catalyst. 24. The process according to claim 16, wherein the oxidation is performed in the presence of tert-butyl ammonium bromide.25. Omerprazole substantially free of sulphone by-product prepared as in any one of claims 1, 4, 8 or 16.26. Lansoprazole substantially free of sulphone by-product prepared as in any one of claims 1, 5, 8 or 16.27. Pantoprazole substantially free of sulphone by-product prepared as in any one of claims 1, 6, 8 or 16.28. Rabeprazole substantially free of sulphone by-product prepared as in any one of claims, 1, 7, 8 or 16.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/266,162 | 2001-02-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2002240242A1 true AU2002240242A1 (en) | 2002-08-19 |
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