一种新型磷酸二酯酶4抑制剂Crisaborole的合成方法

New Method for Synthesis of Phosphodiesterase 4 Inhibitor Crisaborole

选择3-溴甲基-4-溴苯酚为起始原料,经取代、酰化、酯化、水解成环四步反应制备目标产品Crisaborole,其结构经~1HNMR、^(13)CNMR和MS确证。实验探讨了反应pH值、析晶时间、析晶温度及溶剂对目标产品收率的影响,获得了最佳工艺参数:反应pH值为2.0~4.0,析晶时间为6h,析晶温度为0℃,混合溶剂n (乙酸乙酯):n (二氯甲烷)=1:1。同时获得了目标产品的中试极限条件为湿品45~55℃干燥8 h。该合成方法路线操作简单、反应条件温和。

By using 3-bromomethyl-4-bromo phenol as original material, the target product crisaborolewas obtained from four stepreaction of substitution, acylation, esterification, hydrolytic-cyclization. The structure of the target product was confirmed by using 1H NMR, 13 C NMR and MS. The effects of reaction pH, crystallization time, crystallization temperature and solvent to the target productwere studied from experiment, and optimum process parameters were determined. It showed that the optimum reaction condition asfollows: the reaction pHvalue is 2.0~4.0, crystallization time is 6 h, crystallization temperature is 0 ℃, and the ratio of mixed solventsis n(ethyl acetate):n(dichloromethane)=1∶1.The critical condition of target productin semi-works productionwasalso obtained:thedrying time of wet product is no more than 8 h at 45 ~55 ℃. The synthetic route iseasy in preparation and has mildreaction conditions.