一种非奈利酮消旋体的制备方法

A preparation method for finerenone racemate

以4-氰基-2-甲氧基苯甲醛和乙酰乙酸叔丁酯为原料,通过缩合、关环、氧烷基化、水解以及氨解反应,得到了非奈利酮消旋体。考察了不同取代酯在碱性条件下的水解,发现常规酯在NaOH等多种碱性条件下均未水解,而在酸性条件下则可发生水解,在三氟乙酸(TFA)的作用下,二氯甲烷(DCM)作溶剂,室温下可实现叔丁基4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-羧酸酯(Ⅶ)的水解,重点优化了中间体Ⅶ的水解条件。结果表明,在n(Ⅶ)∶n(TFA)=1∶10、n(Ⅶ)∶n(DCM)=1∶18、室温(25℃)条件下反应3 h,即可得到收率为68%的4-(4-氰基-2-甲氧基苯基)-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-3-羧酸(Ⅷ)(HPLC纯度98%)。该法突破了常规酯在碱性条件下难以水解的困难,反应放大到百克级,最终以约35%的总收率得到非奈利酮消旋体(HPLC纯度99%)。产物经^(1)HNMR、^(13)CNMR和HRMS确定结构。

Finerenone raceme was obtained from condensation,cyclization,oxyalkylation,hydrolysis and ammolysis reactions of 4-cyano-2-methoxybenzaldehyde and tert-butyl acetoacetate.The hydrolysis of various substituted esters under alkaline conditions was evaluated,and it was found that conventional esters were not hydrolyzed under alkaline conditions such as NaOH,but could be hydrolyzed under acidic conditions.Therefore,under the action of trifluoroacetic acid(TFA),the hydrolysis of tert-butyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylate(Ⅶ)was achieved at room temperature in solvent dichloromethane(DCM),with its hydrolysis conditions optimized.The results showed that under the conditions of n(Ⅶ)∶n(TFA)=1∶10,n(Ⅶ)∶n(DCM)=1∶18,room temperature(25℃)and reaction time 3 h,4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyl-3-carboxylic acid with a yield of 68%(HPLC purity of 98%)was obtained.This method,overcoming the hydrolysis difficulties of conventional esters under alkaline conditions,could be scaled up to the hundred-gram level of finerenone raceme having a total yield of about 35%(HPLC purity of 99%),with the structure determined by ^(1)HNMR,^(13)CNMR and HRMS.