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【结 构 式】 
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【分子编号】14036 【品名】5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-([[5-(Difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether 【CA登记号】102625-64-9 |
【 分 子 式 】C16H15F2N3O3S 【 分 子 量 】367.3763264 【元素组成】C 52.31% H 4.12% F 10.34% N 11.44% O 13.07% S 8.73% |
合成路线1
该中间体在本合成路线中的序号：(V)A new synthesis of [14C]-labeled pantoprazole has been described: The cyclization of potassium [14C]-ethylxanthate (I) with the diaminobenzene (II) by means of NaOH gives the imidazole (III), which is condensed with 2-(chloromethyl)-3,4-dimethoxypyridine (IV) by means of NaOH in ethanol to afford the sulfide (V). Finally, this compound is oxidized with m-chloroperbenzoic acid (mcpba) in dichloromethane.
| 【1】 Saunders, D.; Lawrie, K.W.M.; Crowe, A.M.; Johnston, C.E.A.; The synthesis of [14C]pantoprazole - SK&F 96022Z - An H+/K+ ATP inhibitor. J Label Compd Radiopharm 1992, 31, 5, 409. |
| 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) | 14032 | Dithiocarbonic acid O-ethyl ester potassium salt | C3H5KOS2 | 详情 | 详情 | |
| (I) | 45190 | potassium 1-(carbodithioatooxy)ethane | C3H5KOS2 | 详情 | 详情 | |
| (II) | 14033 | 4-(Difluoromethoxy)-1,2-benzenediamine; 2-Amino-4-(difluoromethoxy)phenylamine | C7H8F2N2O | 详情 | 详情 | |
| (III) | 14034 | 5-(Difluoromethoxy)-1H-benzimidazole-2-thiol; 5-(Difluoromethoxy)-1H-benzimidazol-2-ylhydrosulfide; 5-Difluoromethoxy-2-mercapto-1H-benzimidazole | 97963-62-7 | C8H6F2N2OS | 详情 | 详情 |
| (III) | 45191 | 5-(difluoromethoxy)-1H-benzimidazole-2-thiol; 5-(difluoromethoxy)-1H-benzimidazol-2-ylhydrosulfide | C8H6F2N2OS | 详情 | 详情 | |
| (IV) | 14035 | 2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether | 72830-09-2 | C8H10ClNO2 | 详情 | 详情 |
| (V) | 14036 | 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-([[5-(Difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether | 102625-64-9 | C16H15F2N3O3S | 详情 | 详情 |
| (V) | 45192 | 2-([[5-(difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether; 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole | C16H15F2N3O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)3-Methoxy-2-methylpyridine (VII), prepared by methylation of 2-methyl-3-pyridinol (VI), was converted to the N-oxide (VIII) employing peracetic acid. Nitration of the pyridine N-oxide (VIII) with concentrated nitric acid gave the 4-nitro derivative (IX). Subsequent displacement of the nitro group of (IX) by sodium methoxide led to the dimethoxypyridine N-oxide (X). Rearrangement of the N-oxide group of (X) in hot acetic anhydride produced the acetoxymethyl pyridine (XI). After basic hydrolysis of the acetate ester (XI), the resultant hydroxymethyl pyridine (XII) was chlorinated by SOCl2, yielding chloride (XIII). Condensation between mercapto benzimidazole (V) and the chloromethyl pyridine (XIII) in ethanolic NaOH led to the sulfide adduct (XIV). This was finally oxidized to the desired sulfoxide by using meta-chloroperbenzoic acid in CH2Cl2. The oxidation of sulfide (XIV) has also been performed employing sodium perborate, sodium percarbonate in the presence of ammonium molybdate, or tert-butyl hydroperoxide in the presence of vanadyl acetylacetonate.
| 【1】 Coppi, L.; Berenguer Maimó, R. (Laboratorios del Dr. Esteve, SA); Method for obtaining derivs. of [[pyridyl substd.)methyl]thio]benzimidazol. ES 2171116; WO 0179194 . |
| 【2】 Mendelovici, M.; Avrutov, I. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Processes for the production of substd. 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles. WO 0262786 . |
| 【3】 Coppi, L.; Campon Pardo, J.; Berenguer Maimo, R. (Laboratorios del Dr. Esteve, SA); Method for oxidizing a thioether group into a sulfoxide group. ES 2163372; WO 0168594 . |
| 【4】 Brennan, J.P.; Turner, A.T. (Abbott Laboratories Inc.); Chemical process for the production of sulphinyl derivs. by oxidation of the corresponding co-derivs. with perborates. WO 9947514 . |
| 【5】 Kohl, B.; Sturm, E.; Senn-Bilfinger, J.; Simon, W.A.; Krüger, U.; Schaefer, H.; Rainer, G.; Figala, V.; Klemm, K.; (H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate. J Med Chem 1992, 35, 6, 1049. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 14034 | 5-(Difluoromethoxy)-1H-benzimidazole-2-thiol; 5-(Difluoromethoxy)-1H-benzimidazol-2-ylhydrosulfide; 5-Difluoromethoxy-2-mercapto-1H-benzimidazole | 97963-62-7 | C8H6F2N2OS | 详情 | 详情 |
| (VI) | 29609 | 2-methyl-3-pyridinol | 1121-25-1 | C6H7NO | 详情 | 详情 |
| (VII) | 56496 | 3-methoxy-2-methylpyridine; methyl 2-methyl-3-pyridinyl ether | C7H9NO | 详情 | 详情 | |
| (VIII) | 56497 | 3-methoxy-2-methyl-1-pyridiniumolate | C7H9NO2 | 详情 | 详情 | |
| (IX) | 56498 | 3-methoxy-2-methyl-4-nitro-1-pyridiniumolate | C7H8N2O4 | 详情 | 详情 | |
| (X) | 56499 | 3,4-dimethoxy-2-methyl-1-pyridiniumolate | C8H11NO3 | 详情 | 详情 | |
| (XI) | 56500 | (3,4-dimethoxy-2-pyridinyl)methyl acetate | C10H13NO4 | 详情 | 详情 | |
| (XII) | 56501 | (3,4-dimethoxy-2-pyridinyl)methanol | C8H11NO3 | 详情 | 详情 | |
| (XIII) | 14035 | 2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether | 72830-09-2 | C8H10ClNO2 | 详情 | 详情 |
| (XIV) | 14036 | 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-([[5-(Difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether | 102625-64-9 | C16H15F2N3O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)In an alternative procedure, the nitropyridine N-oxide (IX) was rearranged to the (mesyloxymethyl)pyridine (XIX) by treatment with methanesulfonic anhydride. Condensation of mesylate (XIX) with mercaptobenzimidazole (V), with concomitant nitro group displacement in the presence of sodium methoxide led to the sulfide precursor (XIV). This was then oxidized to the title sulfoxide employing sodium percarbonate and ammonium molybdate. An analogous synthetic route starting from the chloropyridine N-oxide (XX) provided mesylate (XXI), which was condensed with (V) in the presence of Et3N, leading to the sulfide adduct (XXII). The 4-chloro group of (XXII) was then displaced by sodium methoxide producing the dimethoxypyridine derivative (XIV).
| 【1】 Coppi, L.; Berenguer Maimó, R. (Laboratorios del Dr. Esteve, SA); Method for obtaining derivs. of [[pyridyl substd.)methyl]thio]benzimidazol. ES 2171116; WO 0179194 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 14034 | 5-(Difluoromethoxy)-1H-benzimidazole-2-thiol; 5-(Difluoromethoxy)-1H-benzimidazol-2-ylhydrosulfide; 5-Difluoromethoxy-2-mercapto-1H-benzimidazole | 97963-62-7 | C8H6F2N2OS | 详情 | 详情 |
| (IX) | 56498 | 3-methoxy-2-methyl-4-nitro-1-pyridiniumolate | C7H8N2O4 | 详情 | 详情 | |
| (XIV) | 14036 | 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-([[5-(Difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether | 102625-64-9 | C16H15F2N3O3S | 详情 | 详情 |
| (XIX) | 56505 | (3-methoxy-4-nitro-2-pyridinyl)methyl methanesulfonate | C8H10N2O6S | 详情 | 详情 | |
| (XX) | 56506 | 4-chloro-3-methoxy-2-methyl-1-pyridiniumolate | C7H8ClNO2 | 详情 | 详情 | |
| (XXI) | 56507 | (4-chloro-3-methoxy-2-pyridinyl)methyl methanesulfonate | C8H10ClNO4S | 详情 | 详情 | |
| (XXII) | 56508 | 4-chloro-2-({[5-(difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl}methyl)-3-pyridinyl methyl ether; 2-{[(4-chloro-3-methoxy-2-pyridinyl)methyl]sulfanyl}-5-(difluoromethoxy)-1H-benzimidazole | C15H12ClF2N3O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)
| 【1】 Mukarram J, Mohammed S, Naithani PK, et aL 2007. Process for the preparation of pantoprazole and related compounds via oxidation of the corresponding thioethers. W0 2007026188(本专利属于Wockhardt Limited, India) |
合成路线5
该中间体在本合成路线中的序号：(I)
| 【1】 Lieberman A, Singer C,RaiziY. 2004. A process for preparing 2-[ (pyridinyl) methyl] sulfinyl-substituted benzimidazoles and its novel chlorinated derivatives, useful as inhibitors of gastric acid sectetion. WO 2004111029(本专利属于Teva Phttrmaceutical Industries Ltd, Israel; Teva Pharmaceuticals Usa, Inc) |
| 【2】 Kohl B. Mueller B,Weingart RS. 2004. A process for preparing (S)-pantoprazole via stereaselective oxidn. of pyridinylmethylsulfinylbenzimidazole deriv. in the presence of L-tartaric acid deriv. and chiral zircoruum or hafnium catalyst. W0 2004052881(本专利属于Altana Pharma Ag, Germany) |
合成路线6
该中间体在本合成路线中的序号：(I)
| 【1】 Kankan RN, Rao DR, Srinivas PL. 2004. Method for the preparation of pyndinylmethylsulfinylbenzimidazoles which are substantially free of oxidation contaminants for use in pharmaceutical compositions for treatment of gastric ulcers. W0 2004063188（本专利属于Cipla Limited, India；Wain，Christopher Paul） |
合成路线7
该中间体在本合成路线中的序号：(I)
| 【1】 Avrutov I. Mendelovici M, Finkelstein N. 2004. Processes for the production of substituted 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazoles. US 2004138466 |
合成路线8
该中间体在本合成路线中的序号：(III)
| 【1】 Modi PA, Motiwala JK, Durlabhaji C. 1997. A process for the manufacture of 5-(difluorometboxy)-2- [[ (3,4-dimethoxy-2-pyridinyl methyl] sulfinyl] -lH-benzimidazole, i, e, the antiulcer agent pantoprazole, via oxidation of its thio analog. IN 179805(本专利属于Unichem Laboratories Ltd．India) |
| 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) | 66569 | 5-(difluoromethoxy)-1H-benzo[d]imidazole-2(3H)-thione | 97963-62-7 | C8H6F2N2OS | 详情 | 详情 |
| (II) | 14035 | 2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether | 72830-09-2 | C8H10ClNO2 | 详情 | 详情 |
| (III) | 14036 | 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-([[5-(Difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether | 102625-64-9 | C16H15F2N3O3S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)
| 【1】 Avrutov I.Mendelovici M. 2002. Processes for the production of substituted 2-(2-pyridinylmethyl) sulfinyl-lH-benzimidazoles using tert-butyl hydmpermade or oxone. W0 2002062786(本专利属于Teva Pharmaceutical Industries Ltd. Israel; Teva Pharmaceutical USA, Inc) |