P005091的合成

Synthesis of P005091

为改进抗肿瘤药物P005091(1-(5-((2,3-二氯苯基)硫基)-4-硝基-2-噻酚基)-乙酮)的合成方法,以2-氯噻吩为起始原料,乙酰氯为酰化试剂,三氯化铝为催化剂,在2-氯噻吩的5位引入乙酰基,得到2-乙酰基-5-氯噻吩(化合物2),收率为91%;再以浓硫酸为溶剂,以混酸为硝化试剂,与化合物2发生硝化反应得到5-乙酰基-2-氯-3-硝基噻酚(化合物3),收率为64%;再将化合物3与2,3-二氯苯硫酚在N,N-二甲基甲酰胺溶液中及碳酸钾的作用下发生硫醚化反应得到目标产物P005091,收率为76%。目标化合物的结构经熔点(mp)、核磁共振氢谱(1 H-NMR)、核磁共振碳谱(13C-NMR)和质谱(MS)确证,总收率为44%。该合成路线成本低廉,操作简单,与原文献方法相比,避免使用毒性较大的试剂,反应条件更为温和,在保证产品纯度的前提下,收率有了一定的提高。

To improve the synthesis method of P005091 (l-(5-((2,3-dichlorophenyl) thio)-4-nitr〇-2-thienyl) ethanone),with 2-chlorothiophene as the starting material, acetyl chloride as the acetylation reagent and aluminium trichloride as the catalyst,acetyl is introduced in the 5th position of 2-chlorothiophene to get 2-acetyl-5-chlorothiophene (compound 2 ), and the yield is 91%; then with concentrated sulfuric acid as solvent and mixed acid as nitrating agent, 5-acetyl-2-chlor〇-3-nitrothiophene (compound 3) is obtained by nitration reaction with compound 2, and the yield is 64% ; thioetherfication reaction of compound 3 and 2 ,3-dichlorobenzenethiol in DMF solution under the function of potassium carbonate takes place to obtain the target product P005091, and the yield is 76%. The structure of POO5091 is confirmed by mp, 1 H-NMR, 13C-NMR and MS, and the overall yield is 44%. The improved method has the advantages of low cost, simple operation, and a milder reaction condition compared with the former references, avoiding using the reagent with higher toxicity, and high yield on the premise that the product purity is assured.