阿托伐他汀关键中间体的合成工艺优化  

Synthesis Process Optimization of the Atorvastatin Key Intermediate

作　　者：陈伟荣 吕志卿 周刚 肖玉峰 王宇 CHEN Weirong;LV Zhiqing;ZHOU Gang;XIAO Yufeng;WANG Yu(Zhejiang Hisoar Chuannan Pharmaceutical Company Limited,Taizhou 317000,China)

机构地区：[1]浙江海翔川南药业有限公司,浙江台州317000

出　　处：《化学反应工程与工艺》2023年第2期145-151,共7页Chemical Reaction Engineering and Technology

摘　　要：以对氟苯甲醛和4-甲基-3-氧-N-苯-2-(苯亚甲基)戊酰胺为起始原料,噻唑溴化物和三乙胺作为催化剂,通过Stetter反应合成阿托伐他汀关键中间体2-[2-(4-氟苯基)-2-氧代-1-苯基乙基]-4-甲基-3-氧代-N-苯基戊酰胺。根据可能的反应机理,从质子、非质子溶剂和不同极性大小的溶剂中寻找合适的溶剂提高Stetter反应收率和产品质量。研究了溶剂类型、反应温度、溶剂用量、催化剂种类和反应时间等因素对反应的影响,得到的优化工艺条件为:以四氢呋喃作为反应溶剂,用量为原料质量的2.7倍,以溴化3-乙基-5-(2-羟基乙基)-4-甲基噻唑和三乙胺作为催化剂,在65℃下反应16h。在上述条件下,阿托伐他汀关键中间体2-[2-(4-氟苯基)-2-氧代-1-苯基乙基]-4-甲基-3-氧代-N-苯基戊酰胺的纯度大于99.5%,收率高于88%,产品质量和收率大幅提高,明显减少了脱氟杂质(Des-fluoro)及其他副反应,有利于提高产品的竞争力。The atorvastatin key intermediate,2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide,was synthesized by Stetter reaction using p-fluorophenaldehyde and(Z)-2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide as starting materials and thiazolium bromide and triethylamine as catalysts.According to the possible reaction mechanism,suitable solvents were searched from protic or aprotic solvent,and solvents of different polarity to improve Stetter reaction yield and product quality.The effects of solvent type,reaction temperature,solvent dosage,catalyst type and reaction time on the reaction were studied,the optimized conditions were as follows:tetrahydrofuran as the reaction solvent,the amount was 2.7 times mass ratio that of 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide,3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide and triethylamine as the catalysts,and the reaction time was 16 hours at 65.Under the℃above conditions,the purity of the atorvastatin key intermediate,2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide was above 99.5%,and the yield was above 88%,which greatly improved the product quality and yield,and reduced Des-fluoro impurity and other side reactions.It is beneficial to improve the competitiveness of products.

关 键 词：Stetter反应 极性非质子溶剂 亲核试剂 四氢呋喃 

分 类 号：TQ073[化学工程] TQ463.4