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【结 构 式】 
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【分子编号】27246 【品名】3,5-dimethyl-4-nitro-1-pyridiniumolate 【CA登记号】 |
【 分 子 式 】C7H8N2O3 【 分 子 量 】168.1522 【元素组成】C 50% H 4.8% N 16.66% O 28.54% |
合成路线1
该中间体在本合成路线中的序号：(I)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2
该中间体在本合成路线中的序号：(X)Condensation of methyl 3-amino-4-methoxybenzoate (I) with cyclopropyl cyanide (II) in the presence of p-toluenesulfonic acid at 180 C gave amidine (III). Subsequent reaction of (III) with sodium hypochlorite in methanolic HCl, followed by treatment of the intermediate chloroimine with aqueous Na2CO3, furnished the benzimidazole (IV). The ester group of (IV) was reduced to alcohol (V) with DIBAL-H, and then oxidized to aldehyde (VI) using activated MnO2. Protection of the imidazole N-H of (VI) was effected by means of 2-(trimethylsilyl)ethoxymethyl chloride (VII) and NaH to afford the 1-(2-trimethylsilyl)ethoxymethylimidazole (VIII) accompanied by some amounts of the 3-substituted analogue. The Baeyer-Villiger rearrangement of the formyl group employing m-chloroperbenzoic acid then produced phenol (IX), together with the 3-protected imidazole. The pyridylmethanol derivative (XIII) was obtained from 4-nitro-3,5-dimethylpyridine N-oxide (X) through conversion to the bromopyridine (XI) with PBr3, followed by lithium-halogen exchange and condensation with DMF to give aldehyde (XII), and then reduction of (XII) with NaBH4 to (XIII). Condensation of the hydroxybenzimidazole (IX) with pyridylmethanol (XIII) using diisopropylazodicarboxylate and triphenylphosphine gave ether (XIV), which was finally deprotected with HCl in boiling aqueous methanol to yield the target compound.
| 【1】 Cox, P.J.; Bower, S.; Aldous, D.J.; Astles, P.C.; McGarry, D.G.; Hulme, C.; Regan, J.R.; Huang, F.-C.; Djuric, S.W.; Moriarty, K.J.; Mathew, R.M.; Poli, G.B. (Aventis Pharma SA); Substd. azabicyclic cpds. and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase. EP 0934307; JP 2000509719; WO 9748697 . |
| 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) | 25130 | methyl 3-amino-4-methoxybenzoate | 24812-90-6 | C9H11NO3 | 详情 | 详情 |
| (II) | 27238 | cyclopropanecarbonitrile | 5500-21-0 | C4H5N | 详情 | 详情 |
| (III) | 27239 | methyl 3-[[cyclopropyl(imino)methyl]amino]-4-methoxybenzoate | C13H16N2O3 | 详情 | 详情 | |
| (IV) | 27240 | methyl 2-cyclopropyl-4-methoxy-1H-benzimidazole-7-carboxylate | C13H14N2O3 | 详情 | 详情 | |
| (V) | 27241 | (2-cyclopropyl-4-methoxy-1H-benzimidazol-7-yl)methanol | C12H14N2O2 | 详情 | 详情 | |
| (VI) | 27242 | 2-cyclopropyl-4-methoxy-1H-benzimidazole-7-carbaldehyde | C12H12N2O2 | 详情 | 详情 | |
| (VII) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
| (VIII) | 27244 | 2-cyclopropyl-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-benzimidazole-7-carbaldehyde | C18H26N2O3Si | 详情 | 详情 | |
| (IX) | 27245 | 2-cyclopropyl-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-benzimidazol-7-ol | C17H26N2O3Si | 详情 | 详情 | |
| (X) | 27246 | 3,5-dimethyl-4-nitro-1-pyridiniumolate | C7H8N2O3 | 详情 | 详情 | |
| (XI) | 27247 | 4-bromo-3,5-dimethylpyridine | C7H8BrN | 详情 | 详情 | |
| (XII) | 27248 | 3,5-dimethylisonicotinaldehyde | C8H9NO | 详情 | 详情 | |
| (XIII) | 27249 | (3,5-dimethyl-4-pyridinyl)methanol | C8H11NO | 详情 | 详情 | |
| (XIV) | 27250 | [2-cyclopropyl-7-[(3,5-dimethyl-4-pyridinyl)methoxy]-4-methoxy-1H-benzimidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether | C25H35N3O3Si | 详情 | 详情 |