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【结 构 式】 
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【药物名称】LY-335580 【化学名称】2-[5-[2-(2,4-Diamino-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl]-L-glutamic acid 【CA登记号】 【 分 子 式 】C19H24N6O5S 【 分 子 量 】448.50433 |
【开发单位】Lilly (Originator) 【药理作用】Oncolytic Drugs, Dihydrofolate Reductase (DHFR) Inhibitors |
合成路线1
Pyridopyrimidinone (I) was condensed with triazole (II) in the presence of 4-chlorophenyl dichlorophosphate and pyridine to afford (III). Further reaction of (III) with ammonia in dioxan gave amino compound (IV), which was submitted to a Heck reaction with N-(2-bromothien-5-yl)-L-glutamic acid diethyl ester (V) in the presence of palladium catalyst and CuI to provide the disubstituted acetylene (VI). Hydrogenation of both acetylene group and pyridine ring of (VI) over Pd/C gave intermediate (VII). The amide and ester groups of (VII) were finally hydrolyzed with 1 N NaOH to furnish the title compound.
| 【1】 Gossett, L.S.; Habeck, L.L.; Shackelford, K.A.; Mendelsohn, L.G.; Gates, S.B.; Worzalla, J.F.; Self, T.D.; Theobald, K.S.; Andis, S.L.; Schultz, R.M.; Shih, C.; The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents. Bioorg Med Chem Lett 1999, 9, 1, 75. |
| 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) | 14282 | N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C14H14N4O2 | 详情 | 详情 | |
| (II) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (III) | 23132 | N-[6-ethynyl-4-(1H-1,2,4-triazol-1-yl)pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide | C16H15N7O | 详情 | 详情 | |
| (IV) | 23133 | N-(4-amino-6-ethynylpyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C14H15N5O | 详情 | 详情 | |
| (V) | 23137 | diethyl (2S)-2-[[(5-bromo-2-thienyl)carbonyl]amino]pentanedioate | C14H18BrNO5S | 详情 | 详情 | |
| (VI) | 23138 | diethyl (2S)-2-([[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-6-yl]ethynyl)-2-thienyl]carbonyl]amino)pentanedioate | C28H32N6O6S | 详情 | 详情 | |
| (VII) | 23139 | diethyl (2S)-2-([[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)-2-thienyl]carbonyl]amino)pentanedioate | C28H40N6O6S | 详情 | 详情 |