(R)-(–)-3-奎宁环醇的合成工艺优化  

Process Optimization for Synthesis of(R)-(–)-3-Quinuclidinol

作　　者：吴泽农 蔡青峰 张福利[2] 陈少欣[2] 余俊 WU Zenong;CAI Qingfeng;ZHANG Fuli;CHEN Shaoxin;YU Jun(School of Pharmacy,Fudan University,Shanghai 201203;Shanghai Institute of Pharmaceutical Industry,China State Institute of Pharmaceutical Industry,Shanghai 201203;Taizhou Dachen Pharmaceutical Co.,Ltd.,Taizhou 317016)

机构地区：[1]复旦大学药学院,上海201203 [2]中国医药工业研究总院上海医药工业研究院,上海201213 [3]台州达辰药业有限公司,浙江台州317016

出　　处：《中国医药工业杂志》2021年第11期1472-1475,共4页Chinese Journal of Pharmaceuticals

摘　　要：对阿地溴铵和索利那新的手性中间体(R)-(–)-3-奎宁环醇(1)的合成工艺进行了改进。以4-哌啶甲酸(7)为起始原料,在氯化氢催化下与乙醇发生酯化反应,蒸除部分溶剂和氯化氢后,在反应液中加入碳酸钠与氯乙酸乙酯,反应完毕经简单后处理制得1-(2-乙氧-2-氧代乙基)哌啶-4-甲酸乙酯(6)。以甲苯∶N,N-二甲基甲酰胺(5∶1)为溶剂,在叔丁醇钾作用下,6发生Dieckmann缩合,再经水解、脱羧制得3-奎宁环酮(2)盐酸盐。质量浓度为200 g/L的2盐酸盐经3-奎宁酮还原酶不对称催化还原制得1,纯度99.92%,ee值大于99.99%。总收率达65.3%。The synthetic process of(R)-(–)-3-quinuclidinol(1),a key chiral intermediate of aclidinium bromide and solifenacin was improved.The esterification of the starting material 4-piperidinecaboxylic acid(7)and ethanol was catalyzed by hydrogen chloride,and then after a part of ethanol and HCl were removed by evaporation,sodium carbonate and ethyl chloroacetate were added to the reaction mixture.After the reaction finished,ethyl 1-(2-ethoxy-2-oxoethyl)piperidine-4-carboxylate(6)was obtained through simple work-up operations.With toluene∶DMF(5∶1)as solvents,6 experienced Dieckmann condensation in the presence of potassium tert-butoxide.Then after the hydrolysis and decarboxylation,3-quinuclidinone hydrochloride(2·HCl)was obtained.Compound 2·HCl(200 g/L)experienced asymmetric reduction catalyzed by 3-quinuclidinone reductase(QNR)to produce 1 with 99.92%of purity and up to 99.99%ee.The total yield reached 65.3%.

关 键 词：阿地溴铵 索利那新 (R)-(–)-3-奎宁环醇 3-奎宁环酮盐酸盐 羰基还原酶 工艺改进 

分 类 号：O626.322[理学—有机化学] TQ463[理学—化学]