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【结 构 式】 
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【药物名称】AR-C102222 【化学名称】5-(4'-Amino-5',8'-difluoro-1',2'-dihydrospiro[piperidine-4,2'-quinazoline]-1-ylcarbonyl)pyridine-2-carbonitrile 【CA登记号】253771-21-0, 190010-48-1 (diHCl) 【 分 子 式 】C19H16F2N6O 【 分 子 量 】382.37577 |
【开发单位】AstraZeneca Charnwood (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Inducible Nitric Oxide Synthase (NOS-2) Inhibitors |
合成路线1
Displacement of the 2-fluoro group in 2,3,6-trifluorobenzonitrile (I) with aqueous ammonia leads to 2-amino-3,6-difluorobenzonitrile (II). Addition of hydroxylamine to the nitrile (II) in the presence of NaOMe affords benzamidoxime (III). Subsequent catalytic hydrogenation of (III) over Raney nickel furnishes benzamidine (IV).
| 【1】 Tinker, A.C.; Beaton, H.G.; Boughton-Smith, N.; Cook, T.R.; Cooper, S.L.; Fraser-Rae, L.; Hallam, K.; Hamley, P.; McInally, T.; Nicholls, D.J.; Pimm, A.D.; Wallace, A.V.; 1,2-Dihydro-4-quinazolinamines: Potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo. J Med Chem 2003, 46, 6, 913. |
| 【2】 Hamley, P.R.J.; Pimm, A.D.; Tinker, A.C.; Beaton, H.G.; McInally, T. (AstraZeneca plc); Pharmaceutically active quinazoline cpds.. EP 0858451; JP 1999513679; WO 9714686 . |
| 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) | 63408 | 2,3,6-trifluorobenzonitrile | 136514-17-5 | C7H2F3N | 详情 | 详情 |
| (II) | 63409 | 2-amino-3,6-difluorobenzonitrile | 190011-81-5 | C7H4F2N2 | 详情 | 详情 |
| (III) | 63410 | 2-amino-3,6-difluoro-N'-hydroxybenzenecarboximidamide | C7H7F2N3O | 详情 | 详情 | |
| (IV) | 63411 | 2-amino-3,6-difluorobenzenecarboximidamide | C7H7F2N3 | 详情 | 详情 |
合成路线2
4-Piperidone ethylene ketal (V) is acylated with 6-bromonicotinic acid (VI) employing 1,1'-carbonyldiimidazole to yield amide (VII). The bromide group of (VII) is then displaced with CuCN in hot DMF producing nitrile (VIII). Finally, condensation between N-acylpiperidone (VIII) and amidine (IV) in refluxing EtOH leads to the target spiro quinazoline.
| 【1】 Tinker, A.C.; Beaton, H.G.; Boughton-Smith, N.; Cook, T.R.; Cooper, S.L.; Fraser-Rae, L.; Hallam, K.; Hamley, P.; McInally, T.; Nicholls, D.J.; Pimm, A.D.; Wallace, A.V.; 1,2-Dihydro-4-quinazolinamines: Potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo. J Med Chem 2003, 46, 6, 913. |
| 【2】 Hamley, P.R.J.; Pimm, A.D.; Tinker, A.C.; Beaton, H.G.; McInally, T. (AstraZeneca plc); Pharmaceutically active quinazoline cpds.. EP 0858451; JP 1999513679; WO 9714686 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 63411 | 2-amino-3,6-difluorobenzenecarboximidamide | C7H7F2N3 | 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) | 63412 | 6-bromonicotinic acid | C6H4BrNO2 | 详情 | 详情 | |
| (VII) | 63413 | (6-bromo-3-pyridinyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone | C13H15BrN2O3 | 详情 | 详情 | |
| (VIII) | 63414 | 5-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-2-pyridinecarbonitrile | C14H15N3O3 | 详情 | 详情 |