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【结 构 式】

【分子编号】66035

【品名】 

【CA登记号】 

【 分 子 式 】C15H16N2O3S

【 分 子 量 】304.36972

【元素组成】C 59.19% H 5.3% N 9.2% O 15.77% S 10.54%

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:(X)

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
Extended Information