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【结 构 式】 
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【药物名称】 【化学名称】1-[5-[4-Amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyridin-2-yl]piperidin-4-one O-(tetrahydropyran-4-yl)oxime 【CA登记号】265105-63-3 【 分 子 式 】C28H28BrN7O2 【 分 子 量 】574.48506 |
【开发单位】Abbott (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Adenosine Kinase Inhibitors |
合成路线1
6-Chloronicotinic acid (I) was converted to the corresponding acid chloride (II) by treatment with oxalyl chloride. Condensation of acid chloride (II) with diethyl malonate in the presence of MgCl2 and Et3N produced the keto diester (III), which was further decarbethoxylated to ketone (IV) upon heating in moist DMSO. Displacement of the chloride group of (III) with 4-piperidone ethylene ketal (V) furnished the piperidinyl pyridine (VI). Knoevenagel condensation of malononitrile with 3-bromobenzaldehyde (VII) using glycine as the catalyst produced the benzylidene malononitrile (VIII). The dipyridyl derivative (IX) was obtained by condensation of ketone (VI) with dinitrile (VIII) in the presence of ammonium acetate. Cyclization of amino nitrile (IX) in hot formamide gave rise to the pyridopyrimidine system (X). Ketone (XI) was then obtained by acid hydrolysis of the ethylene ketal function of (X). Finally, condensation of ketone (XI) with 4-tetrahydropyranyloxyamine (XII) yielded the title oxime.
| 【1】 Zheng, G.Z.; et al.; Pyridopyrimidine analogues as novel adenosine kinase inhibitors. Bioorg Med Chem Lett 2001, 11, 16, 2071. |
| 【2】 Stewart, A.O.; Perner, R.J.; McKie, J.A.; Zheng, G.Z.; Grillot, A.L.; Cowart, M.D.; Bhagwat, S.S.; Lee, C.-H. (Abbott Laboratories Inc.); 5,7-Disubstd.-4-aminopyrido[2,3-d]pyrimidine cpds.. WO 0023444 . |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 49834 | dimethyl 2-[(6-chloro-3-pyridinyl)carbonyl]malonate | C11H10ClNO5 | 详情 | 详情 | |
| (IV) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (V) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (VI) | 49835 | 1-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]-1-ethanone | C14H18N2O3 | 详情 | 详情 | |
| (VII) | 10477 | 3-Bromobenzaldehyde; m-Bromobenzaldehyde | 3132-99-8 | C7H5BrO | 详情 | 详情 |
| (VIII) | 49836 | 2-(3-bromobenzylidene)malononitrile | C10H5BrN2 | 详情 | 详情 | |
| (IX) | 49837 | C24H22BrN5O2 | 详情 | 详情 | ||
| (X) | 49838 | 5-(3-bromophenyl)-7-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]pyrido[2,3-d]pyrimidin-4-amine; 5-(3-bromophenyl)-7-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]pyrido[2,3-d]pyrimidin-4-ylamine | C25H23BrN6O2 | 详情 | 详情 | |
| (XI) | 49839 | 1-[5-[4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-2-pyridinyl]-4-piperidinone | C23H19BrN6O | 详情 | 详情 | |
| (XII) | 49840 | O-tetrahydro-2H-pyran-4-ylhydroxylamine; 4-(aminooxy)tetrahydro-2H-pyran | C5H11NO2 | 详情 | 详情 |