methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester -Drug Synthesis Database

【结构式】

【分子编号】11920

【品名】methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester

【CA登记号】

【分子式】C₁₀H₁₁BrO₃

【分子量】259.09954

【元素组成】C 46.36% H 4.28% Br 30.84% O 18.53%

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)

Bromination of methyl 3-methoxy-4-methylbenzoate (I) with N-bromosuccinimide in the presence of catalytic amounts of 2,2'-azabisisobutyronitrile in chlorobenzene yields benzylic bromide (II). This compound is coupled with 5-nitroindole via treatment with Ag2CO3 in toluene to afford methyl 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoate (III). N-Methylation of ester (III), using NaH and MeI in DMF, followed by hydrolysis with NaOH in aqueous THF, affords 4-(5-nitro-1-methylindol-3-ylmethyl)-3-methoxybenzoic acid (IV). Conversion of acid (IV) to the sulfonimide derivative (V) is achieved by sequentially treating (IV) with: (i) SOCl2 plus a catalytic amount of DMF in dichloromethane and (ii) o-tolylsulfonamide and 4-(N,N-dimethylamino)pyridine (DMAP). This intermediate sulfonimide is isolated as the DMAP salt (V), which is converted to ICI 204219 via treatment with H2 over Pd/C in alkaline aqueous methoxyethanol, followed by acylation with cyclopentylchloroformate.

参考文献中间体

合成目标

【1】 Brown, F.J.; Bernstein, P.R.; Yee, Y.K.; Matassa, V.G. (AstraZeneca LP); Heterocyclic amide derivs. AU 8656164; EP 0199543; EP 0220066; ES 8801787; ES 8802220; ES 8802493; ES 8802494; JP 1987093274; JP 1987099359; US 4859692; US 4918094; US 5030643; US 5049576; US 5179112 .
【2】 Edwards, M.P.; Sherwood, J.D. (AstraZeneca plc); A physical form of N-[4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, a process for its preparation and pharmaceutical compsns. containing it. EP 0490649; US 5294636 .
【3】 Aharony, D.; Snyder, D.W.; Keith, R.A.; Shapiro, H.S.; Matassa, V.G.; Maduskuie, T.P. Jr.; Hesp, B.; Krell, R.D.; Evolution of a series of peptidoleukotriene antagonists: Synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles. J Med Chem 1990, 33, 6, 1781.
【4】 Bernstein, P.R.; Accolate. Drugs Fut 1994, 19, 3, 217.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	26919	3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indol-5-amine		C₁₄H₁₇N₃	详情	详情
(I)	11919	methyl 3-methoxy-4-methylbenzoate	3556-83-0	C₁₀H₁₂O₃	详情	详情
(II)	11920	methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester		C₁₀H₁₁BrO₃	详情	详情
(III)	11921	methyl 3-methoxy-4-[(5-nitro-1H-indol-3-yl)methyl]benzoate		C₁₈H₁₆N₂O₅	详情	详情
(IV)	11922	3-Methoxy-4-[(1-methyl-5-nitro-1H-indol-3-yl)methyl]benzoic acid		C₁₈H₁₆N₂O₅	详情	详情
(V)	11923	3-Methoxy-4-(1-methyl-5-nitro-1H-indol-3-ylmethyl)-N-(2-methylphenylsulfonyl)benzamide 4-(dimethylamino)pyridine salt		C₃₂H₃₃N₅O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

A modification of Leimgruber-Batcho synthesis of indoles was employed to convert 3-methyl-4-nitrobenzoic acid (I) to the 3,5-disubstituted indole (V)). In this process, the intermediate enamine (II) was alkylated with the bromobenzoate (III) prior to hydrolysis and reductive cyclization to the indole nucleus. Alkylation of (V) with iodomethane under basic conditions, followed by amide formation using (R)-4,4,4-trifluoro-2-methylbutylamine (VII) afforded the key intermediate amidoester (VIII). Hydrolysis of the methyl ester moiety of (VIII) with aqueous lithium hydroxide, followed by sulfonimide formation gave ZD 3523).

参考文献中间体

合成目标

【1】 Bernstein, P.R.; Jacobs, R.T.; ZD 3523. Drugs Fut 1995, 20, 12, 1233.
【2】 Jacobs, R.T.; Costello, G.F.; Brook, S.A.; Harrison, P.J. (AstraZeneca plc); A process for the preparation of a 3-alkylated indole, intermediates, and a process for the preparation of a derivative thereof. EP 0489547 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	14771	(4-carboxy-2-methylphenyl)(oxo)-lambda(5)-azanolate	C₈H₈NO₄	详情	详情
(II)	14772	[4-carboxy-2-[(E)-2-(dimethylamino)ethenyl]phenyl](oxo)-lambda(5)-azanolate	C₁₁H₁₃N₂O₄	详情	详情
(III)	11920	methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester	C₁₀H₁₁BrO₃	详情	详情
(IV)	14774	(4-carboxy-2-[1-formyl-2-[2-methoxy-4-(methoxycarbonyl)phenyl]ethyl]phenyl)(oxo)-lambda(5)-azanolate	C₁₉H₁₈NO₈	详情	详情
(V)	14775	3-[2-methoxy-4-(methoxycarbonyl)benzyl]-1H-indole-5-carboxylic acid	C₁₉H₁₇NO₅	详情	详情
(VI)	14776	3-[2-methoxy-4-(methoxycarbonyl)benzyl]-1-methyl-1H-indole-5-carboxylic acid	C₂₀H₁₉NO₅	详情	详情
(VII)	14777	(2R)-4,4,4-trifluoro-2-methyl-1-butanamine; (2R)-4,4,4-trifluoro-2-methylbutylamine	C₅H₁₀F₃N	详情	详情
(VIII)	14778	methyl 3-methoxy-4-[[1-methyl-5-([[(2R)-4,4,4-trifluoro-2-methylbutyl]amino]carbonyl)-1H-indol-3-yl]methyl]benzoate	C₂₅H₂₇F₃N₂O₄	详情	详情
(IX)	14779	3-methoxy-4-[[1-methyl-5-([[(2R)-4,4,4-trifluoro-2-methylbutyl]amino]carbonyl)-1H-indol-3-yl]methyl]benzoic acid	C₂₄H₂₅F₃N₂O₄	详情	详情
(X)	63841	2-methylbenzenesulfonamide	C₇H₉NO₂S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Radical bromination of methyl 3-methoxy-4-methylbenzoate (I) using N-bromosuccinimide and azobisisobutyronitrile gave benzyl bromide (II), which was treated with pyrrolidine to afford the tertiary amine (III). Hydrolysis of the methyl ester group of (III) with LiOH provided carboxylic acid (IV), which was converted to acid chloride (V) upon treatment with SOCl2.

参考文献中间体

合成目标

【1】 Antithrombotic diamines. EP 0863755; US 6025382; WO 9725033 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(I)	11919	methyl 3-methoxy-4-methylbenzoate	3556-83-0	C₁₀H₁₂O₃	详情	详情
(II)	11920	methyl 4-(bromomethyl)-3-methoxybenzoate; 4-(Bromomethyl)-3-methoxy benzoic acid methyl ester		C₁₀H₁₁BrO₃	详情	详情
(III)	31412	methyl 3-methoxy-4-(1-pyrrolidinylmethyl)benzoate		C₁₄H₁₉NO₃	详情	详情
(IV)	31413	3-methoxy-4-(1-pyrrolidinylmethyl)benzoic acid		C₁₃H₁₇NO₃	详情	详情
(V)	31414	3-methoxy-4-(1-pyrrolidinylmethyl)benzoyl chloride		C₁₃H₁₆ClNO₂	详情	详情

Extended Information