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【结 构 式】 
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【分子编号】63413 【品名】(6-bromo-3-pyridinyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone 【CA登记号】 |
【 分 子 式 】C13H15BrN2O3 【 分 子 量 】327.17778 【元素组成】C 47.72% H 4.62% Br 24.42% N 8.56% O 14.67% |
合成路线1
该中间体在本合成路线中的序号：(XXXIII)The racemic thiazepinone (XXXIII) has been converted to the pure enantiomer (VIII) through a different strategy. Oxidation of hydroxy lactam (XXXIII) by means of DMSO and Ac2O produced the enol ester (XXXV). Basic hydrolysis of (XXXI) gave rise to the keto lactam (XXXV). This was then subjected to asymmetric reduction utilizing a reducing reagent generated in situ from NaBH4 and (S)-tert-leucine to afford the intermediate thiazepinone (VIII)
| 【1】 Yamada, S.; Mori, Y.; Morimatsu, K.; Ishizu, Y.; Ozaki, Y.; Yoshioka, R.; Nakatani, T.; Seko, H.; Asymmetric reduction of a 1,5-benzothiazepine derivative with sodium borohydride-(S)-alpha-amino acids: An efficient synthesis of a key intermediate of diltiazem. J Org Chem 1996, 61, 24, 8586. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28445 | (2S)-2-amino-3,3-dimethylbutyric acid | C6H13NO2 | 详情 | 详情 | ||
| (VIII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (XXXIII) | 63413 | (6-bromo-3-pyridinyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone | C13H15BrN2O3 | 详情 | 详情 | |
| (XXXIV) | 62452 | 2-(4-methoxyphenyl)-4-oxo-4,5-dihydro-1,5-benzothiazepin-3-yl acetate | C18H15NO4S | 详情 | 详情 | |
| (XXXV) | 62453 | 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione | C16H13NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)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 |