5-bromo-1-methyl-1H-indole -Drug Synthesis Database

【结构式】

【分子编号】29521

【品名】5-bromo-1-methyl-1H-indole

【CA登记号】

【分子式】C₉H₈BrN

【分子量】210.07326

【元素组成】C 51.46% H 3.84% Br 38.04% N 6.67%

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：(II)

The methylation of 5-bromo-1H-indole (I) with methyl iodide and NaH in DMSO gives the 1-methyl derivative (II), which is acylated with 4-fluorobenzoyl chloride (III) and AlCl3 in dichloromethane yielding the 3-acyl derivative (IV). The reduction of (IV) with NaBH4 in methanol affords the corresponding carbinol (V), which is finally treated with carbonyl diimidazole (VI) in THF.

参考文献中间体

合成目标

【1】 Marchand, P.; Robert, J.-M.; Palzer, M.; Delovoye-Seiller, B.; Hartmann, R.W.; Le Baut, G.; Le Borgne, M.; New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles. Bioorg Med Chem Lett 1999, 9, 3, 333.

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)	29521	5-bromo-1-methyl-1H-indole		C₉H₈BrN	详情	详情
(III)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(IV)	29522	(5-bromo-1-methyl-1H-indol-3-yl)(4-fluorophenyl)methanone		C₁₆H₁₁BrFNO	详情	详情
(V)	29523	(5-bromo-1-methyl-1H-indol-3-yl)(4-fluorophenyl)methanol		C₁₆H₁₃BrFNO	详情	详情
(VI)	11353	1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole)	530-62-1	C₇H₆N₄O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Reaction of 3,4-dichlorobenzalzehyde (I) with methyl 3-mercaptopropionate in the presence of K2CO3 in hot DMF afforded the thioether (II). Subsequent condensation of (II) with malonic acid under Knoevenagel conditions produced the substituted cinnamic acid (III), which was further converted to the corresponding acid chloride (IV) upon treatment with oxalyl chloride and a catalytic amount of DMF. Coupling of acid chloride (IV) with N-acetylpiperazine (V) furnished amide (VI). Treatment of (VI) with potassium tert-butoxide caused the elimination of methyl acrylate, producing the potassium thiolate (VII). Thiolate (VII) was then condensed with 1-methyl-7-bromoindole (VIII) to give the title compound.

参考文献中间体

合成目标

【1】 Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 .
【2】 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 .

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)	18122	3,4-Dichlorobenzaldehyde	6287-38-3	C₇H₄Cl₂O	详情	详情
(II)	48173	methyl 3-[(2-chloro-4-formylphenyl)sulfanyl]propanoate		C₁₁H₁₁ClO₃S	详情	详情
(III)	48174	(E)-3-[3-chloro-4-[(3-methoxy-3-oxopropyl)sulfanyl]phenyl]-2-propenoic acid		C₁₃H₁₃ClO₄S	详情	详情
(IV)	48175	methyl 3-([2-chloro-4-[(E)-3-chloro-3-oxo-1-propenyl]phenyl]sulfanyl)propanoate		C₁₃H₁₂Cl₂O₃S	详情	详情
(V)	20674	N-Acetyl piperazine; 1-(1-piperazinyl)-1-ethanone	13889-98-0	C₆H₁₂N₂O	详情	详情
(VI)	48176	methyl 3-([4-[(E)-3-(4-acetyl-1-piperazinyl)-3-oxo-1-propenyl]-2-chlorophenyl]sulfanyl)propanoate		C₁₉H₂₃ClN₂O₄S	详情	详情
(VII)	48177	potassium 4-[(E)-3-(4-acetyl-1-piperazinyl)-3-oxo-1-propenyl]-2-chlorobenzenethiolate		C₁₅H₁₆ClKN₂O₂S	详情	详情
(VIII)	29521	5-bromo-1-methyl-1H-indole		C₉H₈BrN	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The intermediate silyl sulfide (II) was prepared by palladium-catalyzed displacement of 5-bromo-1-methylindole (I) with potassium (triisopropylsilyl)sulfide. Alternatively, 5-iodoindole (III) was N-methylated with iodomethane and NaH, yielding 5-iodo-1-methylindole (IV), which was then reacted with potassium (triisopropylsilyl)sulfide to give (II). Condensation of silyl sulfide (II) with the aryl triflate (V) in the presence of CsF as the desilylating reagent furnished the diaryl sulfide (VI). Knoevenagel condensation of aldehyde (VI) with malonic acid (VII) gave rise to the cinnamic acid derivative (VIII). This was then coupled with ethyl isonipecotate (IX), producing amide (X). The ethyl ester of (X) was finally hydrolyzed with NaOH to yield the title sodium carboxylate salt.

参考文献中间体

合成目标

【1】 Reilly, E.B.; Liu, G.; Winn, M.; et al.; Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationships of substituents on the benzene ring of the cinnamide. J Med Chem 2001, 44, 25, 4393.
【2】 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 .
【3】 Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 .

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)	29521	5-bromo-1-methyl-1H-indole		C₉H₈BrN	详情	详情
(II)	53020	1-methyl-5-[(triisopropylsilyl)sulfanyl]-1H-indole; 1-methyl-1H-indol-5-yl triisopropylsilyl sulfide	n/a	C₁₈H₂₉NSSi	详情	详情
(III)	40983	5-iodo-1H-indole		C₈H₆IN	详情	详情
(IV)	53021	5-iodo-1-methyl-1H-indole	n/a	C₉H₈IN	详情	详情
(V)	52029	2,3-dichloro-4-formylphenyl trifluoromethanesulfonate		C₈H₃Cl₂F₃O₄S	详情	详情
(VI)	53022	2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]benzaldehyde	n/a	C₁₆H₁₁Cl₂NOS	详情	详情
(VII)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(VIII)	53023	(E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid	n/a	C₁₈H₁₃Cl₂NO₂S	详情	详情
(IX)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(X)	53024	ethyl 1-((E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoyl)-4-piperidinecarboxylate	n/a	C₂₆H₂₆Cl₂N₂O₃S	详情	详情

Extended Information