3,4-dihydro-2(1H)-quinolinone -Drug Synthesis Database

【结构式】

【分子编号】18553

【品名】3,4-dihydro-2(1H)-quinolinone

【CA登记号】553-03-7

【分子式】C₉H₉NO

【分子量】147.1766

【元素组成】C 73.45% H 6.16% N 9.52% O 10.87%

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：(II)

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：(I)

Dihydroquinolinone (I) was protected as the tert-butyl carbamate (II) by condensation with di-tert-butyl dicarbonate. Reduction of (II) with NaBH4 in EtOH at -25 C, followed by reaction with ethanolic HCl provided ethoxy compound (III). Subsequent treatment of (III) with 2-silyloxy-1,3-butadiene (V) and trimethylsilyl triflate afforded benzoquinolizinone (VI), through the sequence of Mannich condensation of intermediate N-tert-Boc iminium salt (IV) with silyl enol ether (V), followed by Michael cyclization of the unsaturated ketone. Then, oxidation with mercuric acetate provided the target 4-4a unsaturated compound together with a minor amount of 1,2-unsaturated product.

参考文献中间体

合成目标

【1】 Guarna, A.; Occhiato, E.G.; Scarpi, D.; Tsai, R.; Danza, G.; Comerci, A.; Mancina, R.; Serio, M.; Synthesis of benzo[c]quinolizin-3-ones: Selective non-steroidal inhibitors of steroid 5alpha-reductase 1. Bioorg Med Chem Lett 1998, 8, 20, 2871.

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)	18553	3,4-dihydro-2(1H)-quinolinone	553-03-7	C₉H₉NO	详情	详情
(II)	18554	tert-butyl 2-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate		C₁₄H₁₇NO₃	详情	详情
(III)	18555	tert-butyl 2-ethoxy-3,4-dihydro-1(2H)-quinolinecarboxylate		C₁₆H₂₃NO₃	详情	详情
(IV)	18556	tert-butyl 3,4-dihydro-1lambda(5)-quinoline-1-carboxylate		C₁₄H₁₉NO₂	详情	详情
(V)	18557	1-methylene-2-propenyl trimethylsilyl ether; trimethyl[(1-methylene-2-propenyl)oxy]silane	38053-91-7	C₇H₁₄OSi	详情	详情
(VI)	18558	1,2,4,4a,5,6-hexahydro-3H-pyrido[1,2-a]quinolin-3-one		C₁₃H₁₅NO	详情	详情

Extended Information