双氯芬酸钠合成工艺研究

以2,6-二氯二苯胺(Ⅳ)和氯乙酰氯为主要原料,经过酰化、分子内付-克烷基化和水解反应,合成了非甾体消炎镇痛药双氯芬酸钠(Ⅰ)。前两步反应均采用无溶剂操作,第3步反应在水溶液中进行,符合绿色化学的原则。各步反应的最佳工艺条件为:①酰化反应,n(Ⅳ)∶n(氯乙酰氯)=1∶1.2,反应温度140℃,中间体Ⅲ的收率为96.6%;②分子内付-克烷基化反应,n(Ⅲ)∶n(A lC l3)=1∶2,反应温度150℃,中间体Ⅱ的收率为91.2%;③水解反应,n(Ⅱ)∶n(NaOH)=1∶2.5,氢氧化钠溶液的质量分数为20%,反应时间6 h,催化剂用量为Ⅱ的质量的2%,Ⅰ的收率为92.5%。三步总收率为81.5%。

Study on the synthetic process of diclofenac sodium

Diclofenac sodium(Ⅰ),a non-steroidal anti-inflammatory drug,was synthesized by 2,6-dichlorodiphenylamine(Ⅳ) and chloroacetyl chloride as raw materials.Synthetic processes included acylation,intramolecular Friedel-Crafts alkylation and hydrolysis.The first and second reactions were carried out in solvent-free process,the third in water which accorded with the principle of green chemistry.The best technical condition for various processes had been found as follows:①acylation,the mole ratio of Ⅳ to chloroacetyl chloride was 1 ∶1.2,reaction temperature 140 ℃,the yield of intermediate Ⅲ was 96.6%;②intramolecular Friedel-Crafts alkylation,the mole ratio of Ⅲ to aluminum chloride was 1 ∶2,reaction temperature 150 ℃,the yield of intermediate Ⅱ was 91.2%;③hydrolysis,the mole ratio of Ⅱ to sodium hydroxide was 1 ∶2.5,mass fraction of sodium hydroxide was 20%,reaction time 6 h,amount of catalyst was 2% of Ⅱ,the yield of Ⅰ was 92.5%.From Ⅳ to Ⅰ,the overall yield reached 81.5%.