1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】19324

【品名】1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone

【CA登记号】

【分子式】C₁₀H₁₀BrNO₂

【分子量】256.09894

【元素组成】C 46.9% H 3.94% Br 31.2% N 5.47% O 12.49%

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：(V)

Friedel-Crafts acylation of 1-acetylindoline (I) with acetyl chloride and AlCl3 afforded ketone (II). Subsequent Baeyer-Villiger rearrangement using peracetic acid yielded acetate ester (III), which was hydrolyzed with NaOH to give phenol (IV). Bromination of (IV) with NBS in AcOH then provided bromo hydroxy indoline (V). Alkylation with 1-methyl-tetrahydropyridine-4-methanol (VI) under Mitsunobu conditions produced ether (VII). This was cyclized to the spirocyclic compound (VIII) using AIBN and tributyltin hydride in refluxing benzene. Then, amide hydrolysis in hydroalcoholic HCl gave (IX), which was finally condensed with acid chloride (X) to provide the desired amide.

参考文献中间体

合成目标

【1】 Gaster, L.M.; et al.; The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function b. J Med Chem 1998, 41, 8, 1218.
【2】 Gaster, L.; et al.; SB-224289 - a highly selective 5-HT1B receptor inverse agonist. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.259.

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)	19320	1-(2,3-dihydro-1H-indol-1-yl)-1-ethanone	16078-30-1	C₁₀H₁₁NO	详情	详情
(II)	19321	1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-1-ethanone		C₁₂H₁₃NO₂	详情	详情
(III)	19322	1-acetyl-2,3-dihydro-1H-indol-5-yl acetate		C₁₂H₁₃NO₃	详情	详情
(IV)	19323	1-(5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone		C₁₀H₁₁NO₂	详情	详情
(V)	19324	1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone		C₁₀H₁₀BrNO₂	详情	详情
(VI)	19325	(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)methanol		C₇H₁₃NO	详情	详情
(VII)	19326	1-[6-bromo-5-[(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)methoxy]-2,3-dihydro-1H-indol-1-yl]-1-ethanone		C₁₇H₂₁BrN₂O₂	详情	详情
(VIII)	19327	5-Acetyl-1'-methyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]		C₁₇H₂₂N₂O₂	详情	详情
(IX)	19328	1'-Methyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]		C₁₅H₂₀N₂O	详情	详情
(X)	19329	2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carbonyl chloride		C₁₇H₁₃ClN₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Quaternization of 4-pyridylcarbinol (I) by means of iodoethane provided pyridinium salt (II), which was reduced with NaBH4 to the tetrahydropyridine (III). Subsequent Mitsunobu coupling of (III) with 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (IV) afforded ether (V). Intramolecular cyclization of (V) to the spiro compound (VI) was effected by treatment with tributyltin hydride and azobis(isobutyronitrile). The acetamide function of (VI) was then hydrolyzed by refluxing with HCl in H2O-EtOH to furnish intermediate diamine (VII).

参考文献中间体

合成目标

【1】 Gaster, L.M.; King, F.D.; Wyman, P.A. (GlaxoSmithKline plc); Tetracyclic spiro cpds., process for their preparation and their use as 5HT1D receptor antagonists. EP 0799226; JP 1998510821; US 5972951; WO 9619477 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10925	Iodoethane;ethyl iod	75-03-6	C₂H₅I	详情	详情
(I)	32835	4-pyridinylmethanol	586-95-8	C₆H₇NO	详情	详情
(II)	32836	1-ethyl-4-(hydroxymethyl)pyridinium iodide		C₈H₁₂INO	详情	详情
(III)	32837	(1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methanol		C₈H₁₅NO	详情	详情
(IV)	19324	1-(6-bromo-5-hydroxy-2,3-dihydro-1H-indol-1-yl)-1-ethanone		C₁₀H₁₀BrNO₂	详情	详情
(V)	32838	1-[6-bromo-5-[(1-ethyl-1,2,3,6-tetrahydro-4-pyridinyl)methoxy]-2,3-dihydro-1H-indol-1-yl]-1-ethanone		C₁₈H₂₃BrN₂O₂	详情	详情
(VI)	32839	1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]; 5-Acetyl-1'-ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]		C₁₈H₂₄N₂O₂	详情	详情
(VII)	32844	1'-Ethyl-3,5,6,7-tetrahydro-2H-spiro[furo[2,3-f]indole-3,4'-piperidine]		C₁₆H₂₂N₂O	详情	详情

Extended Information