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【结 构 式】

【分子编号】11923

【品名】3-Methoxy-4-(1-methyl-5-nitro-1H-indol-3-ylmethyl)-N-(2-methylphenylsulfonyl)benzamide 4-(dimethylamino)pyridine salt

【CA登记号】

【 分 子 式 】C32H33N5O6S

【 分 子 量 】615.71012

【元素组成】C 62.42% H 5.4% N 11.37% O 15.59% S 5.21%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(V)

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.

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
Extended Information