4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one -Drug Synthesis Database

【结构式】

【分子编号】60852

【品名】4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

【CA登记号】

【分子式】C₁₂H₈ClFN₄O

【分子量】278.6729832

【元素组成】C 51.72% H 2.89% Cl 12.72% F 6.82% N 20.1% O 5.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

Condensation of cyano ester (I) with formamidine in the presence of NaOEt afforded the pyrimidinone derivative (II). Acetal hydrolysis of (II) with concomitant intramolecular cyclization under acidic conditions produced the pyrrolopyrimidinone (III), which was further chlorinated to (IV) in refluxing POCl3. Displacement of the 4-chloro of (IV) with 3-chloro-4-fluoroaniline (V) in the presence of silver triflate in hot DMF afforded the anilino pyrrolopyrimidine (VI). Oxidation of (VI) using pyridinium bromide perbromide furnished the alpha,alpha-dibromo lactam (VII). Reductive debromination of (VII) by means of zinc dust in AcOH gave intermediate (VIII).

参考文献中间体

合成目标

【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 .

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)	14789	ethyl 2-cyano-4,4-diethoxybutanoate		C₁₁H₁₉NO₄	详情	详情
(II)	60644	2-[4-bromo-2-(2-fluorobenzoyl)anilino]-2-oxoethyl 4-methylbenzenesulfonate		C₂₂H₁₇BrFNO₅S	详情	详情
(III)	60045	3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one		C₆H₅N₃O	详情	详情
(IV)	60046	4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine	3680-69-1	C₆H₄ClN₃	详情	详情
(V)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(VI)	60850	N-(3-chloro-4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; N-(3-chloro-4-fluorophenyl)-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine		C₁₂H₈ClFN₄	详情	详情
(VII)	60851	5,5-dibromo-4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one		C₁₂H₆Br₂ClFN₄O	详情	详情
(VIII)	60852	4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one		C₁₂H₈ClFN₄O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Vilsmeier-Haack formylation of ethyl 4-methylpyrrole-2-carboxylate (IX) using POCl3 in DMF furnished the pyrrole aldehyde (X). Subsequent basic hydrolysis of the ethyl ester group of (X) gave 5-formyl-4-methylpyrrole-2-carboxylic acid (XI), which was further coupled to cis-2,6-dimethylpiperazine (XII) producing amide (XIII). The title compound was finally prepared by aldol condensation between the pyrrole aldehyde (XIII) and lactam (VIII) in the presence of piperidine.

参考文献中间体

合成目标

【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	60852	4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one	C₁₂H₈ClFN₄O	详情	详情
(IX)	60049	ethyl 4-methyl-1H-pyrrole-2-carboxylate	C₈H₁₁NO₂	详情	详情
(X)	60050	ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate	C₉H₁₁NO₃	详情	详情
(XI)	60051	5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid	C₇H₇NO₃	详情	详情
(XII)	20848	(2R,6S)-2,6-dimethylpiperazine	C₆H₁₄N₂	详情	详情
(XIII)	60853	5-{[(3R,5S)-3,5-dimethylpiperazinyl]carbonyl}-3-methyl-1H-pyrrole-2-carbaldehyde	C₁₃H₁₉N₃O₂	详情	详情

Extended Information