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【结 构 式】 
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【药物名称】VX-745 【化学名称】5-(2,6-Dichlorophenyl)-2-(2,4-difluorophenylsulfanyl)-6H-pyrimido[3,4-b]pyridazin-6-one 【CA登记号】209410-46-8 【 分 子 式 】C19H9Cl2F2N3OS 【 分 子 量 】436.26988 |
【开发单位】Vertex (Originator), Kissei (Codevelopment) 【药理作用】Antiarthritic Drugs, Myelodysplastic Syndrome Therapy, Oncolytic Drugs, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Antiinflammatory Drugs, p38 Protein Kinase Inhibitors |
合成路线1
The condensation of 2-(2,6-dichlorophenyl)acetonitrile (I) with 3,6-dichloropyridazin-3-yl)acetonitrile (III), wich is condensed with 2,4-difluorothiophenol (IV) by means of NaH in THF to yield the thioether (V). The partial hydrolysis of the cyano group of (V) with conc. H2SO4 at 100 CC affords the acetamide (VI), wich is finally cyclized with N,N-dimethylformamidedimethylacetal (VII) in refluxing toluene te provide the target pyrimido-pyridazine derivative.
| 【1】 Salituro, F.G.; Duffy, J.P.; Murcko, M.A.; Bemis, G.W.; Su, M.; Wilson, K.P.; Cochran, J.E.; Harrington, E.M.; Galullo, V.P. (Vertex Pharmaceuticals Inc.); Substd. nitrogen containing heterocycles as inhibitors of p38 protein kinase. EP 0951467; JP 2001506266; WO 9827098 . |
| 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) | 18202 | 2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile | 3215-64-3 | C8H5Cl2N | 详情 | 详情 |
| (II) | 11292 | 3,6-Dichloropyridazine | 141-30-0 | C4H2Cl2N2 | 详情 | 详情 |
| (III) | 60561 | 2-(2,6-dichlorophenyl)-2-(6-methyl-3-pyridazinyl)acetonitrile | C13H9Cl2N3 | 详情 | 详情 | |
| (IV) | 60562 | 2,4-difluorobenzenethiol; 2,4-difluorophenylhydrosulfide | C6H4F2S | 详情 | 详情 | |
| (V) | 60563 | 2-(2,6-dichlorophenyl)-2-{6-[(2,4-difluorophenyl)sulfanyl]-3-pyridazinyl}acetonitrile | C18H9Cl2F2N3S | 详情 | 详情 | |
| (VI) | 60564 | 2-(2,6-dichlorophenyl)-2-{6-[(2,4-difluorophenyl)sulfanyl]-3-pyridazinyl}acetamide | C18H11Cl2F2N3OS | 详情 | 详情 | |
| (VII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |