1,2,3,4-tetrahydroquinoline -Drug Synthesis Database

【结构式】

【分子编号】23859

【品名】1,2,3,4-tetrahydroquinoline

【CA登记号】635-46-1

【分子式】C₉H₁₁N

【分子量】133.19308

【元素组成】C 81.16% H 8.32% N 10.52%

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：(III)

The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II), which is reduced with LiAlH4 in THF, yielding the tetrahydroquinoline (III). The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV), which is reduced wiith LiAlH4 in THF to the N-amino compound (V). The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII), which is cyclized by means of HCl in refluxing acetic acid, yielding the tetracyclic compound (VIII). The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX), which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI). Finally, this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.

参考文献中间体

合成目标

【1】 Castaner, J.; Rabasseda, X.; Silvestre, J.S.; Graul, A.; Cilansetron. Drugs Fut 1999, 24, 5, 475.
【2】 Haeck, H.H.; Hamminga, D.; Van Wijngaarden, I.; Wouters, W. (Duphar International Research BV); New anellated indole derivs.. AU 8818414; EP 0297651; JP 1989022870; US 4939136 .
【3】 Verbeek, J.-M.; Van der Meij, P.F.C. (Duphar International Research BV); Process for the preparation of enantiomerically pure imidazolyl cpds.. EP 0768309 .
【4】 de Jonge, A.; Tulp, M.T.M.; Olivier, B.; Tipker, J.; van Hes, R.; Mol, F.; Hamminga, D.; Standaar, P.J.; Van Wijngaarden, I.; Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives. 1. J Med Chem 1993, 36, 23, 3693.

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)	23857	1-indanone	83-33-0	C₉H₈O	详情	详情
(II)	18553	3,4-dihydro-2(1H)-quinolinone	553-03-7	C₉H₉NO	详情	详情
(III)	23859	1,2,3,4-tetrahydroquinoline	635-46-1	C₉H₁₁N	详情	详情
(IV)	23860	1-nitroso-1,2,3,4-tetrahydroquinoline		C₉H₁₀N₂O	详情	详情
(V)	23861	3,4-dihydro-1(2H)-quinolinylamine; 3,4-dihydro-1(2H)-quinolinamine		C₉H₁₂N₂	详情	详情
(VI)	11244	1,3-Cyclohexanedione	504-02-9	C₆H₈O₂	详情	详情
(VII)	23863	3-[3,4-dihydro-1(2H)-quinolinylimino]cyclohexanone		C₁₅H₁₈N₂O	详情	详情
(VIII)	23864	5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one		C₁₅H₁₅NO	详情	详情
(IX)	23865	10-[(dimethylamino)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one		C₁₈H₂₂N₂O	详情	详情
(X)	15670	2-Methylimidazole; 2-Methyl-1H-imidazole	693-98-1	C₄H₆N₂	详情	详情
(XI)	23867	10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one		C₂₀H₂₁N₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Condensation of 3-nitrobenzenesulfonyl chloride (I) with tetrahydroquinoline (II) in the presence of pyridine gave sulfonamide (III). Reduction of the nitro group of (III) with stannous chloride produced the aniline derivative (IV). The title compound was then obtained by reductive alkylation of amine (IV) with 4-formylimidazole (V) using sodium triacetoxyborohydride as the reducing reagent.

参考文献中间体

合成目标

【1】 Hunt, J.T.; Manne, V.; Ding, C.Z.; Ricca, C.; 3-Imidazolylmethylaminophenylsulfonyltetrahydroquinolines, a novel series of farnesyltransferase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 273.

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)	41948	3-nitrobenzenesulfonyl chloride	121-51-7	C₆H₄ClNO₄S	详情	详情
(II)	23859	1,2,3,4-tetrahydroquinoline	635-46-1	C₉H₁₁N	详情	详情
(III)	41949	1-[(3-nitrophenyl)sulfonyl]-1,2,3,4-tetrahydroquinoline		C₁₅H₁₄N₂O₄S	详情	详情
(IV)	41950	3-[3,4-dihydro-1(2H)-quinolinylsulfonyl]phenylamine; 3-[3,4-dihydro-1(2H)-quinolinylsulfonyl]aniline		C₁₅H₁₆N₂O₂S	详情	详情
(V)	41951	1H-imidazole-5-carbaldehyde	3034-50-2	C₄H₄N₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIX)

The 2,3-disubstituted maleimide intermediate (X) is prepared by N-alkylation of 1,2,3,4-tetrahydroquinoline (XIX) with ethyl 3-bromopyruvate (XX) in THF to give ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate (XXI), which by intramolecular cyclocondensation by means of MgCl2 in 2-methoxyethanol at 125 °C affords ethyl 5,6-dihydropyrrolo[3,2,1-ij]quinoline-1-carboxylate (XXII). Hydrolysis of ethyl ester (XXII) with NaOH in EtOH/H2O provides the corresponding carboxylic acid (XXIII), which is then decarboxylated to 5,6-dihydropyrrolo[3,2,1-ij]quinoline (lilolidine) (XVII) by heating to 185 °C in quinoline in the presence of CuO·Cr2O3 . Acylation of lilolidine (XVII) with (COCl)2 in Et2O, and subsequent quenching of the resulting glyoxylyl chloride with MeOH or NaOMe/MeOH affords the oxoester (XXIV), which is finally cyclocondensed with indole-3-acetamide (XXV) in the presence of t-BuOK in THF .

参考文献中间体

合成目标

【1】 Li, C.J., Ashwell, M.A., Hill, J., Moussa, M.M., Munshi, N. (ArQule, Inc.). Maleimide derivatives, pharmaceutical compositions and methods for treatment of cancer. CN 10194970, EP 1846406, EP 2289892, JP 2008530026, US 2006223760, US 7713969, WO 2006086484.
【2】 Chan, T.C.K., France, D.S., Ishii, K. (ArQule, Inc.; Kyowa Hakko Kirin Co., Ltd.). Combinational compositions and methods for treatment of cancer. KR 2011118817, US 2010297075, WO 2010093789.
【3】 Reed, D.P., Barnes, N.R., Kane, J.C., Lee, C.A., Chen, J.-X., Redmon, M.P.(ArQule, Inc.). Purified pyrroloquinolinyl-pyrrolidine-2,5-dione compositions and methods for preparing and using same. US 201116022, WO 2011079142.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	68960	3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione		C₂₃H₁₇N₃O₂	详情	详情
(XVII)	68966	5,6-dihydropyrrolo[3,2,1-ij]quinoline;5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline;1,7-Trimethyleneindol;1,8-Trimethyleneindole	5840-01-7	C₁₁H₁₁N	详情	详情
(XIX)	23859	1,2,3,4-tetrahydroquinoline	635-46-1	C₉H₁₁N	详情	详情
(XX)	25183	ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate	70-23-5	C₅H₇BrO₃	详情	详情
(XXI)	68968	ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate		C₁₄H₁₇NO₃	详情	详情
(XXII)	68969	ethyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylate		C₁₄H₁₅NO₂	详情	详情
(XXIII)	68970	5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid		C₁₂H₁₁NO₂	详情	详情
(XXIV)	68971	methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxoacetate		C₁₄H₁₃NO₃	详情	详情
(XXV)	48682	Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl)	879-37-8	C₁₀H₁₀N₂O	详情	详情

Extended Information