2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide -Drug Synthesis Database

【结构式】

【分子编号】40926

【品名】2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

【CA登记号】

【分子式】C₁₂H₁₁BrN₂O₂

【分子量】295.13562

【元素组成】C 48.84% H 3.76% Br 27.07% N 9.49% O 10.84%

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：(III)

Condensation of 5-bromoindole (I) with oxalyl chloride produced (5-bromo-3-indolyl)glyoxyl chloride (II), which was subsequently treated with dimethylamine to give amide (III). Conversion of (III) to the tributylstannyl derivative (IV) was achieved by reaction with hexabutylditin in the presence of tetrakis(triphenylphosphine) palladium in refluxing dimethoxyethane. Palladium-catalyzed coupling of stannyl indole (IV) with 5-bromo-2-thiophenecarboxaldehyde (V) furnished the thienyl indole (VI). Finally, reduction of (VI) with LiAlH4 in boiling THF produced a mixture of the desired 5-methylthiophene derivative along with the 5-(hydroxymethyl) analogue (VII), that were separated by column chromatography.

参考文献中间体

合成目标

【1】 Kamboj, R.; Slassi, A.; Mazzocco, L.; Meng, C.Q.; Lee, D.K.H.; Dyne, K.; McCallum, K.L.; Rakhit, S.; 5-Thienyltryptamine derivatives as serotonin 5-HT1B/1D receptor agonists: Potential treatments for migraine. Bioorg Med Chem Lett 2000, 10, 9, 903.
【2】 Meng, Q.; Slassi, A.; Rakhit, S. (NPS Allelix Corp.); Thiophene- and furan-tryptamine derivs.. WO 9743281 .

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)	13309	5-Bromo-1H-indole; 5-Bromoindole	10075-50-0	C₈H₆BrN	详情	详情
(II)	40925	2-(5-bromo-1H-indol-3-yl)-2-oxoacetyl chloride		C₁₀H₅BrClNO₂	详情	详情
(III)	40926	2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide		C₁₂H₁₁BrN₂O₂	详情	详情
(IV)	40927	N,N-dimethyl-2-oxo-2-[5-(tributylstannyl)-1H-indol-3-yl]acetamide		C₂₄H₃₈N₂O₂Sn	详情	详情
(V)	40928	5-bromo-2-thiophenecarbaldehyde	4701-17-1	C₅H₃BrOS	详情	详情
(VI)	40929	2-[5-(5-formyl-2-thienyl)-1H-indol-3-yl]-N,N-dimethyl-2-oxoacetamide		C₁₇H₁₄N₂O₃S	详情	详情
(VII)	40930	(5-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-2-thienyl)methanol		C₁₇H₂₀N₂OS	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Condensation between 5-bromoindole (I) in ether and oxalyl chloride (II) in dichloromethane followed by treatment with dimethylamine provides N,N-dimethyaminoglyoxyl derivative (III), which is then reduced with LiAlH4 in THF to yield compound (IV). Coupling of (IV) with benzoyl chloride (V) by means of Et3N and DMAP in dichloromethane affords benzoylindole derivative (VI), which is then subjected to reaction with tributylstannyl derivative (VII) in toluene in the presence of Pd(PPh3)4 to furnish compound (VIII). Treatment of (VIII) with NaOH in refluxing MeOH gives indole (IX), which is converted into the final product by reduction with LiAlH4 in refluxing THF) and treatment with HCl for the formation of the corresponding hydrochloride salt. Alternatively, the target compound can be obtained as follows: treatment of (IV) with KH in ether and tert-butyllithium in pentane followed by reaction with N-methylpiperidinone (X) affords hydroxy derivative (XI), which is finally converted into the desired product.

参考文献中间体

合成目标

【1】 Arora, J.; et al.; 5-Bicyclopiperidinetryptamine derivatives as selective 5-HT1D agonists. Soc Neurosci Abst 2000, 26, Part 1, Abst 145.14.
【2】 Slassi, A.; Edwards, L.; Meng, Q.; Rakhit, S. (NPS Allelix Corp.); 5-Cyclo indole cpds. as 5-HT1D receptor ligands. EP 0944595; JP 2001504501; WO 9823587 .
【3】 Rakhit, S.; Edwards, L.; Slassi, A.; Meng, Q. (NPS Allelix Corp.); 5-Cyclo indole cpds.. US 5998438 .

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)	13309	5-Bromo-1H-indole; 5-Bromoindole	10075-50-0	C₈H₆BrN	详情	详情
(II)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(III)	40926	2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide		C₁₂H₁₁BrN₂O₂	详情	详情
(IV)	49717	N-[2-(5-bromo-1H-indol-3-yl)ethyl]-N,N-dimethylamine; 2-(5-bromo-1H-indol-3-yl)-N,N-dimethyl-1-ethanamine		C₁₂H₁₅BrN₂	详情	详情
(V)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(VI)	49718	[5-bromo-3-[2-(dimethylamino)ethyl]-1H-indol-1-yl](phenyl)methanone		C₁₉H₁₉BrN₂O	详情	详情
(VII)	49719	tert-butyl 4-(tributylstannyl)-3,6-dihydro-1(2H)-pyridinecarboxylate		C₂₂H₄₃NO₂Sn	详情	详情
(VIII)	49720	tert-butyl 4-[1-benzoyl-3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate		C₂₉H₃₅N₃O₃	详情	详情
(IX)	49721	tert-butyl 4-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate		C₂₂H₃₁N₃O₂	详情	详情
(X)	10919	1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one	1445-73-4	C₆H₁₁NO	详情	详情
(XI)	49722	4-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-1-methyl-4-piperidinol		C₁₈H₂₇N₃O	详情	详情

Extended Information