克立硼罗的合成工艺优化  

Improved Synthetic Process of Crisaborole

作　　者：周昊 史潇瑀 刘梦瑶 刘葵葵 任文杰 ZHOU Hao;SHI Xiaoyu;LIU Mengyao;LIU Kuikui;REN Wenjie(Key Lab.for Biopharmaceuticals Research of Shandong Province,Shandong Academy of Pharmaceutical Science,Jinan 250101)

机构地区：[1]山东省药学科学院,山东省生物药物重点实验室,山东济南250101

出　　处：《中国医药工业杂志》2024年第2期217-220,共4页Chinese Journal of Pharmaceuticals

摘　　要：以2-溴-5-羟基苯甲醛(2)为原料,在对甲苯磺酸和吡啶的催化下与乙二醇进行缩合反应,得4-溴-3-(1,3-二氧杂环戊-2-基)苯酚(3);此步骤中吡啶的加入缓冲了对甲苯磺酸的酸性,解决了反应不完全和聚合物生成的问题。化合物3与4-氟苯甲腈在无水碳酸钾和四丁基溴化铵作用下缩合,得4-[4-溴-3-(1,3-二氧杂环戊-2-基)苯氧基]-苯甲腈(4);相转移催化剂可缩短反应时间至8 h。化合物4脱保护得4-(4-溴-3-甲酰基苯氧基)苯甲腈(5)。化合物5与联硼酸频哪醇酯在[1,1’-双(二苯基膦基)二茂铁]二氯化钯[Pd(dppf)C_(l2)]催化下,发生Miyaura硼化反应得4-[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-3-甲酰基苯氧基]苯甲腈(6),避免使用易燃易爆试剂、不产生易爆中间体,且无严苛操作要求。化合物6在碱性条件下经硼氢化钠还原后成环,得克立硼罗(1);硼氢化钠以水溶液(含5%氢氧化钠)形式滴加,操作简便安全。本工艺总收率51.7%(以2计),1纯度99.9%。4-Bromo-3-(1,3-dioxolane-2-yl)phenol(3)was synthesized by condensation of 2-bromo-5-hydroxybenzaldehyde(2)with ethylene glycol in toluene under the catalysis of p-toluenesulfonic acid and pyridine.The addition of pyridine buffered the acidity of p-toluenesulfonic acid and solved the problems of reversible reaction and polymer formation.4-[4-Bromo-3-(1,3-dioxolane-2-yl)phenoxy]benzonitrile(4)was synthesized from 3 and 4-fluorobenzonitrile under the action of anhydrous potassium carbonate and tetrabutylammonium bromide.The phase transfer catalyst made the reaction faster.4-(4-Bromo-3-formylphenoxy)benzonitrile(5)was obtained by deprotection of 4.Miyaura borylation of 5 with bis(pinacolato)diboron catalyzed by[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium[Pd(dppf)C_(l2)]produced 4-[3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-benzonitrile(6),which avoided the flammable and explosive reagents and intermediates and strict operation conditions.After reduction with sodium borohydride,crisaborole(1)was obtained by cyclization.Sodium borohydride was added dropwise in the form of aqueous solution(containing 5%NaOH)to make the operation safer and more convenient.The total yield of the improved synthesis was 51.7%(based on 2),with the purity more than 99.9%.

关 键 词：克立硼罗 磷酸二酯酶4抑制剂 特异性皮炎 合成 

分 类 号：R758.2[医药卫生—皮肤病学与性病学] TQ460.6[医药卫生—临床医学]