|
【结 构 式】 
|
【药物名称】Omeprazole, H-168/68, SAN-15, Omez, Nuclosina, Parizac, Omapren, Audazol, Omepradex, Losec, Prilosec, Omeprazon, Omepral, Antra, Mopral, Miol 【化学名称】5-Methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl)-1H-benzimidazole 【CA登记号】73590-58-6, 95510-70-6 (Na salt) 【 分 子 式 】C17H19N3O3S 【 分 子 量 】345.42328 |
【开发单位】AstraZeneca (Originator), Dr. Reddy's Laboratories (Not Determined), Valeant (Not Determined), Ferrer (Licensee), Fujisawa (Licensee), Lacer (Licensee), Mitsubishi Pharma (Licensee), Vita (Licensee), Santarus (Formulation) 【药理作用】Anti-Helicobacter Pylori Agents, Antiulcer Drugs, Esophageal Diseases, Treatment of, Gastric Antisecretory Drugs, Gastroesophageal Reflux Disease, Agents for, GASTROINTESTINAL DRUGS, ABCC3 Expression Enhancers, H+/K+-ATPase Inhibitors |
合成路线1
The condensation of 5-methoxy-2-mercaptobenzimidazole (I) with 2-chloromethyl-3,5dimethyl-4-methoxypyridine (II) by means of NaOH in refluxing ethanol gives 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (III), which is then oxidized with m-chloroperbenzoic acid (IV) in chloroform. Benzimidazole (I) is obtained by cyclization of 4-methoxy-o-phenylenediamine (V) with potassium ethylxanthate (VI). Pyridine (II) is obtained by reaction of 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine (VII) with SOCl2.
| 【1】 Junggren, U.K.; Sjöstrand, S.E. (Hässle Läkemedel AB); Substd. pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation. CA 1129417; EP 0005129; US 4255431 . |
| 【2】 Blancafort, P.; Neuman, M.; Castaner, J.; Serradell, M.N.; Omeprazole. Drugs Fut 1983, 8, 2, 129. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 29924 | 5-Methoxy-1H-benzimidazol-2-ylhydrosulfide; 2-Mercapto-5-methoxybenzimidazole; 5-Methoxy-1H-benzimidazole-2-thiol; 5-Methoxy-2-mercaptbenzimidazole; 5-Methoxy-2-Benzimidazolethiol | 37052-78-1 | C8H8N2OS | 详情 | 详情 |
| (II) | 16521 | 2-(chloromethyl)-3,5-dimethyl-4-pyridinyl methyl ether; 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine; 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine | 86604-75-3 | C9H12ClNO | 详情 | 详情 |
| (III) | 29925 | 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-[[(5-methoxy-1H-benzimidazol-2-yl)sulfanyl]methyl]-3,5-dimethyl-4-pyridinyl methyl ether | 73590-85-9 | C17H19N3O2S | 详情 | 详情 |
| (V) | 29922 | 2-amino-4-methoxyphenylamine; 4-methoxy-1,2-benzenediamine | 102-51-2 | C7H10N2O | 详情 | 详情 |
| (VI) | 29923 | o-Ethylxanthic acid potassium salt; Potassium ethyl xanthogenate; potassium 1-(carbodithioatooxy)ethane | 140-89-6 | C3H5KOS2 | 详情 | 详情 |
| (VII) | 18785 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methanol | C9H13NO2 | 详情 | 详情 |
合成路线2
The deoxygenation of 3.5-dimethyl-4-nitropyridine N-oxide (I) gives the corresponding pyridine (II), which is treated with trimethylksilyl cyanide to yield 3,5-dimethyl-4-nitropyridine-2-carbonitrile (III). The hydrolysis of (III) affords the corresponding carboxylic acid (IV), which by a nucleophillic substitution of the NO2 group with sodium methoxide gives 4-methoxy-3,5-dimethylpyridine-2-carboxylic acid (V). The reduction of (V) with borane or LiAlH4 yields the carbinol (VI), which by reaction with SOCl2 is converted into the chloromethylpyridine (VII). The condensation of (VII) with 5-methoxy-1H-benzimidazole-2-thiol (VIII) by means of NaOH in refluxing water affords the thioether (IX), which is finally oxidized to the target sulfoxide by means of MCPBA or peracetic acid.
| 【1】 Palomo Coll, A.; Process for the preparation of 4-substd.-2-hydroxymethyl-3,5-dimethylpyridines. ES 2035767 . |
| 【2】 Brandstrom, A.E. (AstraZeneca plc); Improved method for synthesis. US 5386032; WO 9118895 . |
| 【3】 Heleyová, K.; Gattnar, O.; Jezek, L.; Varga, I.; Stalmach, V.; Smahovsky, V.; Oremus, V.; Zlatoidsky, P. (Slovakofarma AS); Method of omeprazole preparation. WO 9809962 . |
| 【4】 Gustavsson, A.; Kallstrom, A. (AstraZeneca plc); Method for the synthesis of a benzimidazole cpd.. JP 2000502101; WO 9722603 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27246 | 3,5-dimethyl-4-nitro-1-pyridiniumolate | C7H8N2O3 | 详情 | 详情 | |
| (II) | 31572 | 3,5-dimethyl-4-nitropyridine | C7H8N2O2 | 详情 | 详情 | |
| (III) | 31573 | 3,5-dimethyl-4-nitro-2-pyridinecarbonitrile | C8H7N3O2 | 详情 | 详情 | |
| (IV) | 31574 | 3,5-dimethyl-4-nitro-2-pyridinecarboxylic acid | C8H8N2O4 | 详情 | 详情 | |
| (V) | 31575 | 4-methoxy-3,5-dimethyl-2-pyridinecarboxylic acid | C9H11NO3 | 详情 | 详情 | |
| (VI) | 18785 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methanol | C9H13NO2 | 详情 | 详情 | |
| (VII) | 16521 | 2-(chloromethyl)-3,5-dimethyl-4-pyridinyl methyl ether; 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine; 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine | 86604-75-3 | C9H12ClNO | 详情 | 详情 |
| (VIII) | 29924 | 5-Methoxy-1H-benzimidazol-2-ylhydrosulfide; 2-Mercapto-5-methoxybenzimidazole; 5-Methoxy-1H-benzimidazole-2-thiol; 5-Methoxy-2-mercaptbenzimidazole; 5-Methoxy-2-Benzimidazolethiol | 37052-78-1 | C8H8N2OS | 详情 | 详情 |
| (IX) | 29925 | 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-[[(5-methoxy-1H-benzimidazol-2-yl)sulfanyl]methyl]-3,5-dimethyl-4-pyridinyl methyl ether | 73590-85-9 | C17H19N3O2S | 详情 | 详情 |
合成路线3
The reaction of ethyl 2-methylacetoacetate (X) with NH3 in ethanol in an autoclave at 80 C gives ethyl 3-amino-2-methylcrotonate (XI), which is cyclized with diethyl 2-methylmalonate (XII) yielding 2,4-dihydroxy-3,5,6-trimethylpyridine (XIII). The reaction of (XIII) with POCl3 at 150 C affords 2,4-dichloro-3,5,6-trimethylpyridine (XIV), which is partially dechlorinated with H2 over Pd/C in ethanol/H2SO4 giving 4-chloro-2,3,5-trimethylpyridine (XV). The reaction of (XV) with sodium methoxide in hot DMSO yields 4-methoxy-2,3,5-trimethylpyridine (XVI), which is oxidized with H2O2 in AcOH affording the corresponding N-oxide (XVIII). The reaction of (XVIII) with acetic anhydride in hot acetic acid provides the acetate ester (XIX), which is finally hydrolyzed in the usual way to the target intermediate the 4-methoxy-3,5-dimethylpyridine-2-methanol (VI). The intermediate 4-chloro-2,3,5-trimethylpyridine (XV), can be oxidized with H2O2 in AcOH as before to give the corresponding N-oxide (XVII), which is treated with sodium methoxide in DMSO/methanol affording the previously described 4-methoxy-2,3,5-trimethylpyridine N-oxide (XVIII).
| 【1】 Junek, H.; Mittelbach, M.; Schmidt, H.-W.; Uray, G. (Hassle Lakemedel AB); Chemical intermediates and method for their preparation. EP 0226558 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 18785 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methanol | C9H13NO2 | 详情 | 详情 | |
| (X) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (XI) | 31576 | ethyl (Z)-3-amino-2-methyl-2-butenoate | C7H13NO2 | 详情 | 详情 | |
| (XII) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
| (XIII) | 31577 | 3,5,6-trimethyl-2,4-pyridinediol | C8H11NO2 | 详情 | 详情 | |
| (XIV) | 31578 | 2,4-dichloro-3,5,6-trimethylpyridine | C8H9Cl2N | 详情 | 详情 | |
| (XV) | 31579 | 4-chloro-2,3,5-trimethylpyridine | C8H10ClN | 详情 | 详情 | |
| (XVI) | 31580 | 4-methoxy-2,3,5-trimethylpyridine; methyl 2,3,5-trimethyl-4-pyridinyl ether | C9H13NO | 详情 | 详情 | |
| (XVII) | 31582 | 4-chloro-2,3,5-trimethyl-1-pyridiniumolate | C8H10ClNO | 详情 | 详情 | |
| (XVIII) | 31581 | 4-methoxy-2,3,5-trimethyl-1-pyridiniumolate | 86604-80-0 | C9H13NO2 | 详情 | 详情 |
| (XIX) | 31583 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl acetate | C11H15NO3 | 详情 | 详情 |
合成路线4
The reaction of 2-methylpropane-1,3-dial (XX) first with methanesulfonyl chloride and then with NaOMe gives 3-methoxy-2-methyl-2-propenal (XXI), which is cyclized with 1-(tert-butyldimethylsilyloxy)-2-butanone (XXII) in basic medium to yield the dihydropyridine (XXIII). Finally, this compound is dehydrogenated with DDQ and desilylated to afford the target intermediate 4-methoxy-3,5-dimethylpyridine-2-methanol (VI).
| 【1】 Bekhazi, M.; Zoghbi, M. (PDi-Research Laboratories, Inc. ); Synthesis of omeprazole-type pyridine derivs. and intermediates thereof. WO 9729103 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 18785 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methanol | C9H13NO2 | 详情 | 详情 | |
| (XX) | 31584 | 2-methylmalonaldehyde | C4H6O2 | 详情 | 详情 | |
| (XXI) | 31585 | (E)-3-methoxy-2-methyl-2-propenal | C5H8O2 | 详情 | 详情 | |
| (XXII) | 31586 | 1-[[tert-butyl(dimethyl)silyl]oxy]-2-butanone | C10H22O2Si | 详情 | 详情 | |
| (XXIII) | 31587 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methoxy-3,5-dimethyl-1,4-dihydropyridine; tert-butyl(dimethyl)silyl (4-methoxy-3,5-dimethyl-1,4-dihydro-2-pyridinyl)methyl ether | C15H29NO2Si | 详情 | 详情 |
合成路线5
The reaction of 1-hydroxy-2-butanone (XXIV) with tosyl chloride gives the tosylate (XXV), which is condensed with 5-methoxy-1H-benzimidazole-2-thiol (VIII) yielding 5-methoxy-2-(2-oxobutylsulfanyl)-1H-benzimidazole (XXVI). The reaction of (XXVI) with 3-methoxy-2-methyl-2-propenal (XXI) in basic medium affords the 5-oxohexanal derivative (XXVII), which is cyclized by means of NH4OAc and NH3 to give the dihydropyridine (XXVIII). Finally, this compound is dehydrogenated and oxidized to the target sulfinyl derivative.
| 【1】 Bekhazi, M.; Zoghbi, M. (PDi-Research Laboratories, Inc. ); Synthesis of omeprazole-type pyridine derivs. and intermediates thereof. WO 9729103 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 29924 | 5-Methoxy-1H-benzimidazol-2-ylhydrosulfide; 2-Mercapto-5-methoxybenzimidazole; 5-Methoxy-1H-benzimidazole-2-thiol; 5-Methoxy-2-mercaptbenzimidazole; 5-Methoxy-2-Benzimidazolethiol | 37052-78-1 | C8H8N2OS | 详情 | 详情 |
| (XXI) | 31585 | (E)-3-methoxy-2-methyl-2-propenal | C5H8O2 | 详情 | 详情 | |
| (XXIV) | 31588 | 1-hydroxy-2-butanone | 5077-67-8 | C4H8O2 | 详情 | 详情 |
| (XXV) | 31589 | 2-oxobutyl 4-methylbenzenesulfonate | C11H14O4S | 详情 | 详情 | |
| (XXVI) | 31590 | 1-[(5-methoxy-1H-benzimidazol-2-yl)sulfanyl]-2-butanone | C12H14N2O2S | 详情 | 详情 | |
| (XXVII) | 31591 | 3-methoxy-6-[(5-methoxy-1H-benzimidazol-2-yl)sulfanyl]-2,4-dimethyl-5-oxohexanal | C17H22N2O4S | 详情 | 详情 | |
| (XXVIII) | 31592 | 2-[[(5-methoxy-1H-benzimidazol-2-yl)sulfanyl]methyl]-3,5-dimethyl-1,4-dihydro-4-pyridinyl methyl ether; 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-1,4-dihydro-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole | C17H21N3O2S | 详情 | 详情 |
合成路线6
The reaction of tosylate (XXV) with potassium ethylxanthate (XXIX) gives the adduct (XXX), which is cyclized with 3-methoxy-2-methyl-2-propenal (XXI) by means of t-BuOK, NH4Cl and NH3 in THF yielding the dihydropyridine (XXXI). The oxidation of (XXXI) with MCPBA in chloroform affords the pyridine (XXXII), with simultaneous formation of the sulfinyl group. Finally, this compound is cyclized with 4-methoxyphenylene-1,2-diamine (XXXIII) by means of TFA in refluxing toluene.
| 【1】 Bekhazi, M.; Zoghbi, M. (PDi-Research Laboratories, Inc. ); Synthesis of omeprazole-type pyridine derivs. and intermediates thereof. WO 9729103 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 31585 | (E)-3-methoxy-2-methyl-2-propenal | C5H8O2 | 详情 | 详情 | |
| (XXV) | 31589 | 2-oxobutyl 4-methylbenzenesulfonate | C11H14O4S | 详情 | 详情 | |
| (XXIX) | 29923 | o-Ethylxanthic acid potassium salt; Potassium ethyl xanthogenate; potassium 1-(carbodithioatooxy)ethane | 140-89-6 | C3H5KOS2 | 详情 | 详情 |
| (XXX) | 31593 | O-ethyl S-(2-oxobutyl) carbonodithioate | C7H12O2S2 | 详情 | 详情 | |
| (XXXI) | 31594 | S-[(4-methoxy-3,5-dimethyl-1,4-dihydro-2-pyridinyl)methyl] O-methyl carbonodithioate | C11H17NO2S2 | 详情 | 详情 | |
| (XXXII) | 31595 | O-methyl [(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl](oxo)-lambda(4)-sulfanecarbothioate | C11H15NO3S2 | 详情 | 详情 | |
| (XXXIII) | 29922 | 2-amino-4-methoxyphenylamine; 4-methoxy-1,2-benzenediamine | 102-51-2 | C7H10N2O | 详情 | 详情 |
合成路线7
An improved process for the synthesis of omeprazole has been developed that incorporates the oxidation of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfanyl)-1H-benzimidazole (I) by means of meta-chloroperbenzoic acid in ethyl acetate cooled below 0 C and keeping the temperature below 5 C during the addition of the oxidant.
| 【1】 Hafner Milac, N.; Jereb, D. (LEK Pharmaceutical and Chemical Co.); Improved process of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl-1H-benzimidazole. WO 0002876 . |
合成路线8
An improved process for the synthesis of omeprazole has been developed that incorporates the oxidation of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfanyl)-1H-benzimidazole (I) by means of meta-chloroperbenzoic acid in dichloromethane or toluene/ethanol cooled below 0 C and keeping the temperature below 5 C during the addition of the oxidant.
| 【1】 Liu, H.; McManus, J.W.; Anousis, N.; Banks, B.N.; Zhou, L. (Merck & Co., Inc.); Improved omeprazole process and compsns. thereof. US 6191148; WO 0009497 . |
合成路线9
An improved process for the synthesis of omeprazole has been developed that incorporates the oxidation of 5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridylmethylsulfanyl)-1H-benzimidazole (I) by means of magnesium monoperoxyphthalate (MMPP) in water cooled at -5 C to 0 C and keeping the temperature in this range during the addition of the oxidant. The oxidation can also be performed with the same oxidant in either water/toluene/methanol cooled at -5 C to -10 C, methanol/water cooled at -10 C, or dichloromethane cooled at 0 C to 4 C.
| 【1】 Weinstock, L.M.; Shinkai, I.; Hoerrner, R.S.; Liu, T.M.-H.; Amato, J.S.; Friedman, J.J. (Merck & Co., Inc.); Process for the preparation of antiulcer agents. EP 0533264; US 5391752 . |
合成路线10
The acetylation of 2,3,5-trimethyl-4-nitropyridine N-oxide (I) with acetic anhydride in hot acetic acid gives the 2-(acetoxymethyl)-3,5-dimethyl-4-nitropyridine (II), which, without isolation, is treated with NaOH in hot dichloromethane/water, yielding the corresponding 2-(hydroxymethyl) derivative (III). This compound, also without isolation, is treated with SOCl2 to afford 2-(chloromethyl)-3,5-dimethyl-4-nitropyridine (IV), which is condensed with 6-methoxy-1H-benzimidazole-2-thiol (V) by means of tetrabutylammonium bromide and NaOH in dichloromethane/water, providing the corresponding thioether (VI). The reaction of (VI) with sodium methoxide and K2CO3 in refluxing methanol yields 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethylsulfanyl)-1H-benzimidazole (VII), which is finally oxidized to the target sulfoxide with peracetic acid (VIII) in ethyl acetate.
| 【1】 Hamied, Y.K.; Kankan, R.N.; Rao, D.R. (Cipla Ltd.); Omeprazole synthesis. EP 1085019 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 54909 | 2,3,5-trimethyl-4-nitro-1-pyridiniumolate | C8H10N2O3 | 详情 | 详情 | |
| (II) | 54910 | (3,5-dimethyl-4-nitro-2-pyridinyl)methyl acetate | C10H12N2O4 | 详情 | 详情 | |
| (III) | 54911 | 3,5-Dimethyl-2-hydroxymethyl-4-nitropyridine | C8H10N2O3 | 详情 | 详情 | |
| (IV) | 54912 | 2-(chloromethyl)-3,5-dimethyl-4-nitropyridine | C8H9ClN2O2 | 详情 | 详情 | |
| (V) | 54913 | 6-methoxy-1H-benzimidazol-2-ylhydrosulfide; 6-methoxy-1H-benzimidazole-2-thiol | C8H8N2OS | 详情 | 详情 | |
| (VI) | 54914 | 2-{[(3,5-dimethyl-4-nitro-2-pyridinyl)methyl]sulfanyl}-1H-benzimidazol-6-yl methyl ether; 2-{[(3,5-dimethyl-4-nitro-2-pyridinyl)methyl]sulfanyl}-6-methoxy-1H-benzimidazole | C16H16N4O3S | 详情 | 详情 | |
| (VII) | 54915 | 2-{[(6-methoxy-1H-benzimidazol-2-yl)sulfanyl]methyl}-3,5-dimethyl-4-pyridinyl methyl ether; 6-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfanyl}-1H-benzimidazole | C17H19N3O2S | 详情 | 详情 | |
| (VIII) | 54916 | Peracetic acid; Peroxyacetic acid | 79-21-0 | C2H4O3 | 详情 | 详情 |