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【结 构 式】 
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【药物名称】Lansoprazole, AG-1749, ABT-006, CG-4801, A-65006, Ogast, Lanzor, Lanzo, Agopton, Opiren, Bamalite, Takepron, Lansox, Lansox, Ogastro, Monolitum, Prevacid, Zoton 【化学名称】2-[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethylsulfinyl]-1H-benzimidazole 【CA登记号】103577-45-3 【 分 子 式 】C16H14F3N3O2S 【 分 子 量 】369.36808 |
【开发单位】Takeda (Originator), Almirall Prodesfarma (Licensee), Salvat (Licensee), TAP (Licensee), Wyeth Pharmaceuticals (Licensee) 【药理作用】Agents for Gastritis, Anti-Helicobacter Pylori Agents, Antiulcer Drugs, Esophageal Diseases, Treatment of, Gastric Antisecretory Drugs, Gastroesophageal Reflux Disease, Agents for, GASTROINTESTINAL DRUGS, Non-Ulcer Dyspepsia, Agents for, H+/K+-ATPase Inhibitors |
合成路线1
The condensation of 2,3-dimethyl-4-nitropyridine N-oxide (I) with 2,2,2-trifluoroethanol (II) by means of K2CO3 in hot HMPT gives 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine N-oxide (III), which by isomerization in acetic anhydride at 100 C is converted to 2-(hydroxymethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (IV). The reaction of (IV) with SOCl2 in refluxing CHCl3 affords the corresponding chloromethyl derivative (V), which is condensed with 2-mercaptobenzimidazole (VI) by means of sodium methoxide in refluxing methanol to yield 2-(2-benzimidazolylthiomethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridin (VII). Finally, this compound is oxidized with m-chloroperbenzoic acid in CHCl3.
| 【1】 Makino, T.; Tabata, T.; Hirai, S.; Stabilized pharmaceutical composition comprising a benzimidazole compound, its production and its use as an antiulcer agent.. EP 237200; JP 87277322 . |
| 【2】 Nohara, A.; Maki, Y. (Takeda Chemical Industries, Ltd.); Pyridine derivs. and their production. AU 8545895; EP 0174726; ES 8607288; JP 1986050978; US 4628098; US 4689333 . |
| 【3】 Prous, J.; Castaner, J.; LANSOPRAZOLE < Prop INN >. Drugs Fut 1989, 14, 7, 625. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17888 | m-Chloroperbenzoic acid; 3-Chlorobenzenecarboperoxoic acid | 937-14-4 | C7H5ClO3 | 详情 | 详情 | |
| (I) | 19482 | 2,3-dimethyl-4-nitro-1-pyridiniumolate | 37699-43-7 | C7H8N2O3 | 详情 | 详情 |
| (II) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
| (III) | 19484 | 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)-1-pyridiniumolate | C9H10F3NO2 | 详情 | 详情 | |
| (IV) | 19485 | [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methanol | C9H10F3NO2 | 详情 | 详情 | |
| (V) | 19486 | 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine; 2-(chloromethyl)-3-methyl-4-pyridinyl 2,2,2-trifluoroethyl ether | 127337-60-4 | C9H9ClF3NO | 详情 | 详情 |
| (VI) | 12821 | 2-Mercaptobenzinidiazole; 1H-Benzimidazol-2-ylhydrosulfide; 1H-Benzimidazole-2-thiol; 2-Benzimidazolethiol; o-Phenylenethiourea; 2-Benzimidazolinethione; 1,3-Dihydro-2H-benzimidazole-2-thione | 583-39-1 | C7H6N2S | 详情 | 详情 |
| (VII) | 19488 | 2-[(1H-benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-pyridinyl 2,2,2-trifluoroethyl ether; 2-([[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfanyl)-1H-benzimidazole | 103577-40-8 | C16H14F3N3OS | 详情 | 详情 |
合成路线2
The chlorination of 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine-N-oxide (I) with trichloroisocyanuric acid in hot chloroform gives the 2-chloromethyl derivative (II), which is condensed with 2-mercapto-1H-benzimidazole (III) by means of NaOH in methanol to yield the adduct (IV). The reaction of (IV) with PCl3 and acetic acid eliminates the N-oxide group, affording the sulfanylmethylpyridine (V). Finally, this compound is oxidized with tert-butyl hydroperoxide (VI) in ethanol to provide the target sulfoxide. Alternatively, the intermediate adduct (IV) can also be obtained as follows: The chlorination of 2,3-dimethyl-4-nitropyridine-N-oxide (VII) with trichloroisocyanuric acid as before gives the chloromethyl derivative (VIII), which is condensed with 2-mercapto-1H-benzimidazole (III) as before to yield the adduct (IX). Finally, this compound is treated with 2,2,2-trifluoroethanol (X), benzyltrimethylammonium chloride and K2CO3 in acetonitrile to afford the target intermediate (IV).
| 【1】 Montserrat Vidal, C.; Serra Macia, X. (Laboratorios Salvat SA); Intermediate for the synthesis of lansoprazole and process for obtaining it. ES 2063705 . |
| 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) | 19484 | 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)-1-pyridiniumolate | C9H10F3NO2 | 详情 | 详情 | |
| (II) | 51411 | 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)-1-pyridiniumolate | C9H9ClF3NO2 | 详情 | 详情 | |
| (III) | 12821 | 2-Mercaptobenzinidiazole; 1H-Benzimidazol-2-ylhydrosulfide; 1H-Benzimidazole-2-thiol; 2-Benzimidazolethiol; o-Phenylenethiourea; 2-Benzimidazolinethione; 1,3-Dihydro-2H-benzimidazole-2-thione | 583-39-1 | C7H6N2S | 详情 | 详情 |
| (IV) | 51412 | 2-[(1H-benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-(2,2,2-trifluoroethoxy)-1-pyridiniumolate | C16H14F3N3O2S | 详情 | 详情 | |
| (V) | 19488 | 2-[(1H-benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-pyridinyl 2,2,2-trifluoroethyl ether; 2-([[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfanyl)-1H-benzimidazole | 103577-40-8 | C16H14F3N3OS | 详情 | 详情 |
| (VI) | 37518 | tert-butyl hydroperoxide | 75-91-2 | C4H10O2 | 详情 | 详情 |
| (VII) | 19482 | 2,3-dimethyl-4-nitro-1-pyridiniumolate | 37699-43-7 | C7H8N2O3 | 详情 | 详情 |
| (VIII) | 51413 | 2-(chloromethyl)-3-methyl-4-nitro-1-pyridiniumolate | C7H7ClN2O3 | 详情 | 详情 | |
| (IX) | 51414 | 2-[(1H-benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-nitro-1-pyridiniumolate | C14H12N4O3S | 详情 | 详情 | |
| (X) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |