SCH-226374, -Drug Synthesis Database

【结构式】

【药物名称】SCH-226374

【化学名称】4-[8-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(S)-yl]-2(R)-[N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]carbamoyl]piperazine-1-carboxylic acid cyclohexyl ester

【CA登记号】279233-71-5

【分子式】C₄₀H₄₇ClN₆O₃

【分子量】695.31199

【开发单位】Pharmacopeia (Originator), Schering-Plough (Originator)

【药理作用】ONCOLYTIC DRUGS, Farnesyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways

合成路线1 合成路线2

合成路线1

The alkylation of 4-methylimidazole (I) with N-(3-bromopropyl)phthalimide (II) produced a mixture of N-alkylated regioisomers (III) and (IV). After selective derivatization of the undesired 5-methyl isomer (III) with trityl chloride, the 4-methyl derivative was isolated by flash chromatography and subsequently subjected to phthaloyl group hydrazinolysis to yield amine (V). Reductive condensation of amine (V) with benzaldehyde (VI) in the presence of NaBH4 afforded the N-benzyl amine (VII).

参考文献中间体

【1】 Guzi, T.; Taveras, A.G.; Ferreira, J.A.; Desai, J.A.; Wang, J.J.S.; Lalwani, T.; Alvarez, C.; Afonso, A.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Weinstein, J.; Cooper, A.B.; Chao, J.; Rane, D.F.; Aki, C.J.; Kelly, J.M. (Schering Corp.); Tricyclic farnesyl protein transferase inhibitors. EP 1140902; WO 0037459 .

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)	51586	4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole	822-36-6	C₄H₆N₂	详情	详情
(II)	15216	N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione	5460-29-7	C₁₁H₁₀BrNO₂	详情	详情
(III)	51587	2-[3-(5-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione		C₁₅H₁₅N₃O₂	详情	详情
(IV)	51588	2-[3-(4-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione		C₁₅H₁₅N₃O₂	详情	详情
(V)	51589	3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; 3-(4-methyl-1H-imidazol-1-yl)propylamine		C₇H₁₃N₃	详情	详情
(VI)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(VII)	51590	N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amine		C₁₄H₁₉N₃	详情	详情

合成路线2

(R)-Piperazine-2-carboxylic acid, obtained by resolution of the racemic piperazine (VIII) with (-)-camphorsulfonic acid, was regioselectively protected with Boc-ON at the 4-N atom, yielding the tert-butyl carbamate (IX). Subsequent treatment with cyclohexyl chloroformate (X) produced the bis-carbamate (XI), which was further subjected to selective Boc group cleavage under acidic conditions. The resultant piperazine (XII) was condensed with the tricyclic alkyl chloride (XIII), producing a diastereomeric mixture of N-alkylated adducts from which the required isomer (XIV) was isolated by flash chromatography. Finally, coupling of acid (XIV) with the intermediate amine (VII) by means of EDC and HOBt gave rise to the title compound.

参考文献中间体

【1】 Guzi, T.; Taveras, A.G.; Ferreira, J.A.; Desai, J.A.; Wang, J.J.S.; Lalwani, T.; Alvarez, C.; Afonso, A.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Weinstein, J.; Cooper, A.B.; Chao, J.; Rane, D.F.; Aki, C.J.; Kelly, J.M. (Schering Corp.); Tricyclic farnesyl protein transferase inhibitors. EP 1140902; WO 0037459 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	51590	N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amine		C₁₄H₁₉N₃	详情	详情
(VIII)	25933	2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid		C₅H₁₀N₂O₂	详情	详情
(IX)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid		C₁₀H₁₈N₂O₄	详情	详情
(X)	51592	Carbonochloridic acid, cyclohexyl ester; Cyclohexyl chloroformate	13248-54-9	C₇H₁₁ClO₂	详情	详情
(XI)	51593	(2R)-4-(tert-butoxycarbonyl)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₁₇H₂₈N₂O₆	详情	详情
(XII)	51594	(2R)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₁₂H₂₀N₂O₄	详情	详情
(XIII)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₄H₁₁Cl₂N	详情	详情
(XIV)	51595	(2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₂₆H₃₀ClN₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)