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【结 构 式】

【药物名称】Araprofen, Camprofen

【化学名称】(±)-2-[4-(2-Carboxyphenylaminophenyl]propionic acid
      (±)-4-(2-Carboxyphenylamino)-alpha-methylbenzeneacetic acid
      (±)-p-(o-Carboxyanilino)hydratropic acid

【CA登记号】15250-13-2

【 分 子 式 】C16H15NO4

【 分 子 量 】285.30225

【开发单位】University Sciences in Philadelphia (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Non-Opioid Analgesics, Non-Steroidal Antiinflammatory Drugs

合成路线1

Camprofen has been synthesized previously by Picciola as a chemical intermediate in the preparation of an indazolylpropionic acid, but was apparently not itself evaluated for antiinflammatory activity during that study. The synthetic approach (scheme 16191901a), begins with 1-chloro-4-nitrobenzene (I), which is readily available commercially. Treatment of (I) with the carbanion derived from diethyl methylmalonate (using sodium hydride as base, in N,N-dimethylformamide) provides the intermediate diethyl ester (II), which is saponified in situ and then acidified to the acid (IIIa). Crude (IIIa) is then esterified to the methyl ester (IIIb), purified by column chromatography, the sequence being analogous to that of Hino et al. The nitrophenyl ester (IIIb) is dissolved in 95% ethanol and hydrogenated in the presence of palladium catalyst to provide the 4-aminophenyl compound (IV). Finally, an Ullmann-Jourdan condensation of (IV) with 2-chlorobenzoic acid in the presence of anhydrous potassium carbonate, activated copper powder and N,N-methylformamide provides camprofen. This synthetic scheme uses cheap and readily available reagents and provides racemic camprofen in an overall yield of 52% based on 1-chloro-4-nitrobenzene (I).

1 Appleton, R.A.; Brown, K.; Conformational requirements at the prostaglandin cyclooxygenase receptor site: A template for designing non-steroidal anti-inflammatory drugs. Prostaglandins 1979, 18, 29.
2 Hino, K.; Nakamura, H.; Nagai, Y.; Uno, H.; Nishimura, H.; Non-steroidal anti-inflammatory agents. 2.[(heteroarylamino)phenyl]alkanoic acids. J Med Chem 1983, 26, 222.
3 Taraporewala, I.B.; Kauffman, J.M.; Synthesis and structure activity relationships of anti-inflammatory 9,10-dihydro-9-oxo-2-acridine-alkanoic acids and 4-(2-carboxyphenyl)aminobenzenealkanoic acids. J Pharm Sci 1990, 79, 2, 173.
4 Kauffman, J.M.; Taraporewala, I.B.; Synthesis of the p-nitrophenyl ester of acridine-2-acetic acid. J Heterocycl Chem 1982, 19, 1557.
5 Picciola, G.; Heterocyclic compounds containing 4-aminophenyl-alkanoic acid residues with potential antiinflammatory activity. III. Derivatives of 3-hydroxyindazole. Boll Chim Farm 1981, 120, 8, 458.
6 Taraporewala, I.B.; Kauffman, J.M.; CAMPROFEN. Drugs Fut 1990, 15, 6, 563.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10203 o-Chlorobenzoic acid; 2-Chlorobenzoic acid 118-91-2 C7H5ClO2 详情 详情
33989   C8H13NaO4 详情 详情
(III-b) 13911 methyl 2-(4-nitrophenyl)propanoate C10H11NO4 详情 详情
(III-a) 52520 2-(4-nitrophenyl)propanoic acid C9H9NO4 详情 详情
(I) 13909 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene 100-00-5 C6H4ClNO2 详情 详情
(II) 13910 diethyl 2-methyl-2-(4-nitrophenyl)malonate C14H17NO6 详情 详情
(IV) 13912 methyl 2-(4-aminophenyl)propanoate 39718-97-3 C10H13NO2 详情 详情
Extended Information