4-Piperidinopiperidine -Drug Synthesis Database

【结构式】

【分子编号】10821

【品名】4-Piperidinopiperidine

【CA登记号】4897-50-1

【分子式】C₁₀H₂₀N₂

【分子量】168.28228

【元素组成】C 71.37% H 11.98% N 16.65%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

A more complete synthesis for CPT-11 has been reported: The reaction of camptothecin (I) with propionaldehyde and FeSO4 in water gives 7-ethylcamptothecin (II), which is oxidized with H2O2 in hot acetic acid yielding 7-ethylcamptothecin 1-oxide (III). The isomerization of (III) with UV light (high-pressure Hg lamp) in dioxane-1 N H2SO4 affords 7-ethyl-10-hydroxycamptothecin (IV), which is treated with phosgene and triethylamine in dioxane to give the corresponding chlorocarbonyl derivative (V). Finally, this compound is condensed with 4-piperidinopiperidine (VI) by means of pyridine in dichloromethane.

参考文献中间体

合成目标

【1】 Nokata, K.-I.; Furuta, T.; Yokokura, T.; Okajima, S.; Sawada, S.; Sugino, E.; Miyasaka, T.; Aiyama, R.; Yamaguchi, K.; Synthesis and antitumor activity of 20(S)-camptothecin derivatives: Carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. Chem Pharm Bull 1991, 39, 6, 1446-54.

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)	10816	Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione	7689-03-4	C₂₀H₁₆N₂O₄	详情	详情
(II)	10817	(4S)-4,11-Diethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethylcamptothecin		C₂₂H₂₀N₂O₄	详情	详情
(III)	10818	(4S)-4,11-Diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-6-ium-6-olate; 7-Ethylcamptothecin 1-oxide		C₂₂H₂₀N₂O₅	详情	详情
(IV)	10819	(4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin		C₂₂H₂₀N₂O₅	详情	详情
(V)	10820	(4S)-9-[(Chlorocarbonyl)oxy]-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline		C₂₃H₁₉ClN₂O₆	详情	详情
(VI)	10821	4-Piperidinopiperidine	4897-50-1	C₁₀H₂₀N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 7-ethyl-10-hydroxycamptothecin (I) with phosgene gives 7-ethyl-10-(chlorocarbonyloxy)camptothecin (II), which is then condensed with 4-(1-piperidyl)piperidine.

参考文献中间体

合成目标

【1】 Miyasaka, T.; Mutai, M.; Nokata, K.; Sawada, S.; Sugino, E. (Yakult Honsha Co., Ltd.); New camptothecin derivs. and process for preparing same. EP 0137145; JP 1985019790 .
【2】 Davis, P.D. (Angiogene Pharmaceuticals Ltd.); Benzimidazole vascular damaging agents. EP 1140078; WO 0041669 .

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)	10819	(4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin		C₂₂H₂₀N₂O₅	详情	详情
(II)	10820	(4S)-9-[(Chlorocarbonyl)oxy]-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline		C₂₃H₁₉ClN₂O₆	详情	详情
(III)	10821	4-Piperidinopiperidine	4897-50-1	C₁₀H₂₀N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Esterification of the commercially available carboxylic acid (I) by treatment with oxalyl chloride in DCM followed by reaction with MeOH in CH2Cl2 provides methyl carboxylate (II), which is then brominated with NBS and catalytic dibenzoylperoxide in refluxing acetonitrile to afford 3-bromomethylquinoline derivative (III). Treatment of (III) with secondary amine (IV) and DIEA in THF furnishes compound (V), which is then converted into the desired product by acidic hydrolysis in refluxing HCl followed by coupling with primary amine (VI) by means of HBTU and Et3N in refluxing THF/CH2Cl2.

参考文献中间体

合成目标

【1】 Blaney, F.E.; Artico, M.; Raveglia, L.F.; et al.; Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity and selectivity in quinoline tachykinin receptor antagonists. J Med Chem 2001, 44, 11, 1675.
【2】 Giardina, G.; Grugni, M.; Raveglia, L.F.; Nadler, G.M.M.G.; Farina, C. (SmithKline Beecham SpA); Quinoline derivs. as NK-2 and NK-3 receptor ligands. EP 1131294; WO 0031038 .

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)	50169	3-methyl-2-phenyl-4-quinolinecarboxylic acid		C₁₇H₁₃NO₂	详情	详情
(II)	50170	methyl 3-methyl-2-phenyl-4-quinolinecarboxylate		C₁₈H₁₅NO₂	详情	详情
(III)	50171	methyl 3-(bromomethyl)-2-phenyl-4-quinolinecarboxylate		C₁₈H₁₄BrNO₂	详情	详情
(IV)	10821	4-Piperidinopiperidine	4897-50-1	C₁₀H₂₀N₂	详情	详情
(V)	50172			C₂₈H₃₃N₃O₂	详情	详情
(VI)	30977	(2R)-3,3-dimethyl-2-butanamine; (1R)-1,2,2-trimethylpropylamine		C₆H₁₅N	详情	详情

Extended Information