【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% |
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 |