酶促酯化拆分-化学消旋串联法制备(S)-布洛芬  

Preparation of (S)-ibuprofen by enzymatic esterification resolution-chemical racemization tandem method

作　　者：雷高乙 李红霞 陈中胜[1] 乐长高[1] 谢宗波[1] LEI Gaoyi;LI Hongxia;CHEN Zhongsheng;LE Zhanggao;XIE Zongbo(Jiangxi Province Key Laboratory of Synthetic Chemistry,East China University of Technology,Nanchang 330013,Jiangxi,China)

机构地区：[1]东华理工大学江西省合成化学重点实验室,江西南昌330013

出　　处：《精细化工》2022年第6期1212-1217,1222,共7页Fine Chemicals

摘　　要：以(±)-布洛芬为原料、南极假丝酵母脂肪酶B(CALB)为催化剂,通过对映选择性酯化反应拆分布洛芬,对醇的种类及用量、反应介质、底物物质的量比、酶用量、干燥剂种类及添加量、温度、时间进行了优化。在1 mL环己烷、0.0206 g(0.1 mmol)(±)-布洛芬、0.0444 g(0.6 mmol)异丁醇、添加量为40 g/L 5A分子筛、15 mg CALB、温度60℃、时间48 h的条件下,以56%的收率、100%的对映体过量值得到了纯的(S)-布洛芬。接着对上述拆分时生成的(R)-布洛芬异丁酯进行酸性水解;然后以二异丙基氨基锂为催化剂,对水解生成的(R)-布洛芬进行化学消旋得到(±)-布洛芬,再进行酶促酯化拆分。该酶促酯化拆分-化学消旋串联法可循环进行多次,从而提高(±)-布洛芬的利用率。The resolution of ibuprofen by enantioselective esterification was explored using(±)-ibuprofen as raw material and Candida antarctica lipase B(CALB) as catalyst. The influence of type and dosage of alcohol, reaction medium, molar ratio of substrates, dosage of enzyme, type and dosage of desiccant,reaction temperature and time on enantioselectivity were studied and optimized. Pure(S)-ibuprofen was obtained with a yield of 56% and an enantiomer excess value of 100% under the conditions of 1 m L cyclohexane, 0.0206 g(0.1 mmol)(±)-ibuprofen, 0.0444 g(0.6 mmol) isobutanol, additive amount of 40 g/L 5A molecular sieve as desiccant, 15 mg CALB, 60 ℃ and 48 h. Furthermore,(R)-ibuprofen was obtained through acid hydrolysis of(R)-ibuprofen isobutyl ester generated during the above resolution, and recycled to produce more(±)-ibuprofen as raw material for next enzymatic resolution reaction by chemical racemization using lithium diisopropylamide as catalyst. This enzymatic esterification resolution-chemical racemization tandem method could be cycled multiple times, and improve the utilization rate of(±)-ibuprofen.

关 键 词：(S)-布洛芬 消旋 二异丙基氨基锂 酶促酯化拆分 医药原料 

分 类 号：TQ460.1[化学工程—制药化工]