【结 构 式】 |
【药物名称】Apricoxib, CS-706, R-109339, TG-01, TP-1001, TP-2001, Capoxigem 【化学名称】4-[2-(4-Ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide 【CA登记号】197904-84-0 【 分 子 式 】C19H20N2O3S 【 分 子 量 】356.439 |
【开发单位】Tragara Pharmaceuticals, Inc. (US); licensed from Daiichi Sankyo, Inc. (JP). 【药理作用】Cyclooxygenase-2 (COX-2) Inhibitor, Oncolytic |
合成路线1
In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,N-diisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib (1, 2).
Intermediate (V) can also be prepared by reaction of 1-(4-ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitro derivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).
In an alternative strategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishes N-(4-ethoxybenzylidene)-4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α-amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib (3). Scheme 1.
【1】 Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617. |
【2】 Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078. |
【3】 Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858. |
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) | 66028 | 4'-Ethoxyacetophenone; 1-(4-Ethoxyphenyl)ethan-1-one | 1676-63-7 | C10H12O2 | 详情 | 详情 |
(II) | 66029 | 2-Bromo-1-(4-Ethoxyphenyl)Ethanone; Zinc02649911 | 51012-63-6 | C10H11BrO2 | 详情 | 详情 |
(III) | 66030 | 2-methyl-N-(2-methylpropyl)-N-prop-1-enylpropan-1-amine | 100334-82-5 | C11H23N | 详情 | 详情 |
(IV) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
(V) | 66031 | C18H26O4 | 详情 | 详情 | ||
(VI) | 54719 | 4-Aminobenzenesulfonamide; p-Aminobenzene sulfonyl amide; p-Aminobenzenesulfonamide; p-Anilinesulfonamide; Sulfanilamide | 63-74-1 | C6H8N2O2S | 详情 | 详情 |
(VII) | 66032 | C12H14O2 | 详情 | 详情 | ||
(VIII) | 66033 | C13H17NO4 | 详情 | 详情 | ||
(IX) | 66034 | 4-Ethoxybenzaldehyde; p-Ethoxybenzaldehyde | 10031-82-0 | C9H10O2 | 详情 | 详情 |
(X) | 66035 | C15H16N2O3S | 详情 | 详情 | ||
(XI) | 61447 | Trimethylsilyl cyanide; Cyanotrimethylsilane; TMSCN; Trimethylsilyl carbonitrile; Trimethylsilylnitrile; Cyantrimethylsilan; Trimethylsilylnitrile; Cyanotrimethylsilane; TRIMETHYLSILYLCYANIDE; Cyanotrimethylsilane; (CYANOTRIMETHYLSILANE) | 7677-24-9 | C4H9NSi | 详情 | 详情 |
(XII) | 66036 | C16H17N2O3S | 详情 | 详情 | ||
(XIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |