具有高同位素丰度氘标记的4'-羟基双氯芬酸的合成

Synthesis of deuterium labelled 4′-hydroxy diclofenac with improved isotopic enrichment

目的设计合成非甾体类抗炎镇痛药双氯芬酸的活性代谢物4'-羟基双氯芬酸的药物标准品——含4个氘原子标记的4'-羟基双氯芬酸。方法以氘标记苯乙酸为起始原料,经取代、酰胺化反应得4个氘原子标记的中间体4;再以苯酚为原料,经2步反应得中间体7;中间体4与中间体7经Ullmann缩合、脱甲基、水解反应得目标产物——氘标记的4'-羟基双氯芬酸。结果与结论目标化合物的总收率为15.1%,其结构经1H-NMR和MS谱确证,最终产物的同位素丰度超过98%;化学纯度经HPLC测定达98.5%。

Diclofenac is a non-steroidal anti-inflammatory drug（NSAID）. 4＇-Hydroxy diclofenac is the principal human metabolite of diclofenac. The synthesis of four-deuterium-labelled 4＇-hydroxy diclofenac in seven steps was described. Five-deuterium-labelled phenyl acetic acid was chosen as the starting material. After substitution and amidation, 2- （ 2-iodo [ 2^ H4 ] phenyl） -N, N-dimethylacetamide （ 4 ） was obtained. 2,6-Dichlo- ro-4-methoxyaniline（7） ,another key intermediate,was synthesized from phenol treated with sodium nitrite in sulphuric acid, followed by continuous passage of dry hydrogen chloride gas into methanol. After Ullmann coupling between 4 and 7, followed by demethylation and hydrolysis, the target compound 4＇-hydroxy di- clofenac was obtained. The total yield was 15. 1% with 98.5% chemical purity and over 98% isotopic enrichment. The structure of the target compound was confirmed by 1^H-NMR and MS. It is used as excellent internal standard for the pharmaceutical studies of diclofenac.