SCH-400, -Drug Synthesis Database

【结构式】

【药物名称】SCH-400

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

【CA登记号】278785-78-7, 278785-72-1 (diastereomer), 278785-73-2 (diastereomer), 278785-79-8 (diastereomer)

【分子式】C₃₆H₄₅ClN₆O₃

【分子量】645.25145

【开发单位】Schering-Plough (Originator)

【药理作用】ONCOLYTIC DRUGS, Farnesyl Transferase Inhibitors

合成路线1 合成路线2

合成路线1

(R)-Piperazinecarboxylic acid (I) is sequentially protected with 2-(t-butoxycarbonyloxy)imino-2-phenylacetonitrile to produce the 4N-Boc-piperazine (II), and then with cyclohexyl chloroformate, yielding the 1N-cyclohexyl carbamate (III). Selective N-Boc group cleavage in (III) under acidic conditions provides piperazine (IV). This is condensed with the tricyclic chloride (V) to furnish, after chromatographic separation of the isomers, the required intermediate (VI).

参考文献中间体

【1】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. EP 1140904; JP 2002533335; WO 0037458 .
【2】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. US 6362188 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16266	(2S)-hexahydro-2-pyrazinecarboxylic acid; (S)-Piperazine-2-carboxylic acid	C₅H₁₀N₂O₂	详情	详情
(II)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid	C₁₀H₁₈N₂O₄	详情	详情
(III)	51593	(2R)-4-(tert-butoxycarbonyl)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₁₇H₂₈N₂O₆	详情	详情
(IV)	51594	(2R)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₁₂H₂₀N₂O₄	详情	详情
(V)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₄H₁₁Cl₂N	详情	详情
(VI)	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

合成路线2

Reduction of (R)-ethyl nipecotate (VII) with LiAlH4 yields 3-piperidinemethanol (VIII), which is further protected as the N-Boc derivative (IX) by using Boc2O. Treatment of the piperidine alcohol (IX) with p-toluenesulfonyl chloride and pyridine leads to tosylate (X). Condensation of the sodium derivative of 4-methylimidazole (XI) with tosylate (X) gives rise to a mixture of regioisomeric N-alkylated imidazoles, which are chromatographically separated after derivatization with trityl chloride. The desired isomer (XII) is then deprotected under acidic conditions, giving piperidine (XIII). Finally, EDC-mediated coupling between piperidine (XIII) and the piperazinecarboxylic acid (VI) furnishes the title amide.

参考文献中间体

【1】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. EP 1140904; JP 2002533335; WO 0037458 .
【2】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. US 6362188 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	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
(VII)	12453	ethyl (3R)hexahydro-3-pyridinecarboxylate		C₈H₁₅NO₂	详情	详情
(VIII)	57427	(1S)-2,2-dimethylcyclopropanecarbonyl chloride		C₆H₉ClO	详情	详情
(IX)	35221	tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate		C₁₁H₂₁NO₃	详情	详情
(X)	57428	ethyl 3-ethyl-2-pentenoate		C₉H₁₆O₂	详情	详情
(XI)	51586	4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole	822-36-6	C₄H₆N₂	详情	详情
(XII)	58429	tert-butyl (3S)-3-[(4-methyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxylate		C₁₅H₂₅N₃O₂	详情	详情
(XIII)	58430	(3R)-3-[(4-methyl-1H-imidazol-1-yl)methyl]piperidine		C₁₀H₁₇N₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)