酶法制备S-西酞普兰关键中间体及动力学研究
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摘要
西酞普兰对5-羟色胺再摄取的抑制活性主要依赖于S-对映体。S-西酞普兰作为单一对映体药物上市,由于具有低剂量、高疗效等优点,日渐取代消旋西酞普兰,成为最畅销的抗抑郁症药物之一。本文重点研究S-西酞普兰的制备,以西酞普兰关键中间体的拆分为主线,开展了以下四个方面的工作:1.脂肪酶催化转酯化及醇解反应拆分西酞普兰关键中间体,研究拆分过程的动力学并建立模型;2.拆分后底物与产物的分离;3.无效对映体的利用;4.S-西酞普兰的制备及工艺路线放大。
首先,研究有机相中脂肪酶催化转酯化反应与醇解反应两条途径远程拆分西酞普兰二醇中间体,并分别建立动力学模型。结果表明转酯化反应的拆分效果优于醇解反应。
研究脂肪酶催化转酯化反应远程拆分西酞普兰二醇中间体及动力学。通过筛选,确定Novozym 435为实验用酶,乙酸乙烯酯为酰基供体,乙腈为溶剂。考察了各种因素的影响以及酶的重复利用,确定较优的反应条件为:二醇浓度60mmol/L,二醇与乙酸乙烯酯比例为1:5,酶浓度为10 mg/mL,摇床转速250 r/min,温度30℃。反应22 h后,e.e._s可以达到99.1%,S-二醇收率为40.4%,酶的半衰期可达364.8 h。研究无溶剂体系(乙酸乙烯酯为溶剂)中酶催化转酯化反应动力学。通过计算Thiele模量及Biot数,确定该反应体系中可忽略内、外扩散的影响。实验表明,二醇的R-,S-对映体均对酶产生抑制,产物抑制及酶的失活可以忽略。因此,该反应符合具有底物竞争性抑制的双底物双产物乒乓-双双反应机制。根据反应机理推导动力学方程,并考虑自酯化反应的影响,分别得到R-,S-二醇乙酸酯的反应速率方程。利用Matlab程序对不同底物浓度的时间-浓度过程曲线进行拟合得到模型参数。模型计算值与实验数据能较好的吻合,误差为12.8%。所得模型可较准确预测底物浓度对反应选择性的影响。
研究脂肪酶催化醇解反应拆分西酞普兰二醇乙酸酯中间体及其动力学。通过筛选酶、酰基受体及溶剂,确定反应体系为:Novozym 435为实验用酶,异丁醇为酰基受体,溶剂为乙腈与甲基叔丁基醚的混合溶剂(MEBT/MeCN=1:3);考察各种因素对反应的影响,并优化反应条件。研究表明,酶催化醇解反应符合可逆的竞争性底物及产物抑制乒乓-双双反应机理。根据反应机理推导动力学方程,分别得到R-,S-二醇的反应速率方程。对不同底物浓度的时间-浓度过程曲线进行拟合得到模型参数,模型的计算值与实验数据吻合,误差为11.3%。
其次,通过衍生化-萃取法分离拆分所得到的手性二醇及二醇乙酸酯。选用丁二酸酐作为衍生化试剂对二醇进行衍生化,通过筛选确定了甲苯-水相体系为二醇衍生物和二醇乙酸酯的较佳萃取分离体系。考察水相pH值及二醇乙酸酯浓度对分离的影响,得到较优的萃取条件为:水相pH 8.0,二醇乙酸酯初始浓度为10mmol/L,温度25℃。在此萃取条件下,二醇乙酸酯的分配系数为157.7。以S-二醇(ee值为99.5%)与二醇乙酸酯的混合物为原料,经过三次萃取,可分离得到ee值为98.4%的S-二醇,收率为86.0%。该衍生化-萃取法成本低,易放大,可为其他手性芳香胺醇的分离提供思路。
第三,结合二次拆分与构型翻转对无效的R-二醇进行利用。将一次拆分后得到的光学纯度较低的二醇乙酸酯水解为二醇后进行二次转酯化拆分。利用动力学模型预测二次拆分过程,并通过实验验证发现控制反应转化率为20.8%,可得到ee值为91.2%的R-二醇乙酸酯。所得的R-二醇乙酸酯在酸性条件下闭环,构型翻转得到ee值为91.0%的S-西酞普兰,收率为98.0%。以ee值为98.2%的S-二醇为原料,在碱性条件下构型保持闭环合成S-西酞普兰,ee值为98.0%,产率为97.8%。
最后,逐级放大酶催化转酯化反应并研究S-西酞普兰制备总工艺路线的放大。结合动力学模型预测与实验放大,将酶催化转酯化的反应体积逐步放大到1L和14L,实验结果表明酶催化转酯化反应没有明显的放大效应。研究S-西酞普兰制备的总工艺路线并进行小试放大,为工业化生产奠定基础。
Citalopram is a highly selective inhibitor of serotonin(5-HT) reuptake which contains a quaternary chiral center and almost the entire inhibitory activity resides in the S-enantiomer.S-citalporam,the single enantiomer drug with advantage of low dose and high efficacy,is one of the best-selling antidepressant and gradually replace the racemic citalopram.In this dissertation,the enzymatic preparation of citalopram chiral key intermediate was described.The main contents were as follows:1. Lipase-catalyzed remote resolution of citalopram key intermediate and kinetics study; 2.The separation of chiral diol and diol acetate after kinetic resolution;3.The utilization of unwanted R-enantiomer;4.S-citalopram synthesis and scale-up.
Firstly,the lipase-catalyzed kinetic resolution of citalopram intermediate in organic media and its kinetics was studied.The lipase-catalyzed asymmetric transestereaction was superior to the asymmetric alcoholysis.
The lipase-catalyzed remote kinetic resolution of diol,a key intermediate of citalopram,in organic media was studied.Through screening,the preferable system for the asymmetric transestereaction was:Novozym 435 as catalyst,acetonitrile as solvent and vinyl acetate as acyl donor.The influence of temperature,rotation speed, enzyme concentration and substrate concentration on the enzymatic resolution was studied.Reusability study of lipase was also carried out.The optimal condition was as following:60 mmol/L diol,the molar ratio of diol to vinyl acetate,1 to 5,10 mg/mL lipase,250 r/min rotation speed and 30℃.After 22h reaction,the yield of S-diol was 40.4%and the e.e._s was 99.1%.The E value of the reaction was 25.3 and the half-life of the lipase was 364.8 h.The kinetic modeling of Novozym 435 catalyzed remote resolution of diol was studied using vinyl acetate as acylating agent in solvent-free system.The substrate inhibition by each enantiomer of diol was proved.Enzyme deactivation and product inhibition were studied and could be negligible.The diffusion limitation was proved to be negligible by the calculation of Thiele module and Biot number.A kinetic model based on ping-pong bi-bi mechanism with competitive substrates using King-Altman method was proposed.The spontaneous transesterification was also considered.The reaction rate equation of both R- and S-diol acetate were derived.The model parameters were successfully simulated by Matlab program using time-concentration curves of different diol concentrations and the simulated values fitted the experimental values well with an average relative error of 12.8%.Furthermore,the developed model was used to investigate the effect of diol concentration on reaction enantioselectivity.
The lipase-catalyzed asymmetric alcoholysis of diol acetate has been studied. Through screening,the preferable system for the asymmetric reaction was:Novozym 435 as catalyst,isobutyl alcohol as acyl accepter and the mixed solvent(acetonitrile: methyl tert-butyl ether=3:1).The influence of various parameters on the enzymatic resolution was studied and the reaction condition was optimized.A kinetic model based on ping-pong bi-bi mechanism with competitive substrates was proposed.The product inhibition by each enantiomer of diol and substrate inhibition by isobutyl alcohol were also considered.The reaction rate equation of both R- and S- diol were derived.The model parameters were successfully simulated by Matlab program using time-concentration curves of different diol acetate concentrations and the simulated values fitted the experimental values well with an average relative error of 11.3%.
Secondly,a derivatization-extraction method was developed to separate diol from diol acetate after lipase-catalyzed kinetic resolution.It was found that succinic anhydride was the best derivative agent and water/toluene was the optimal extraction system.The effects of pH and initial diol acetate concentration on the total distribution coefficients of diol acetate were investigated.With the extraction conditions of initial diol acetate concentration of 10 mmol/L,pH 8.0 and 25℃,the total distribution coefficient achieved 157.7.The practical extraction process of the mixture of diol(ee value 99.5%) and diol acetate obtained by lipase-catalyzed reaction was carried out,within three extraction stages,the ee value and the yield of S-diol were 98.4%and 86.0%,respectively.This extraction method with anhydrides derivatization is promising in the separation of aromatic amino-alcohols for its low expense and easy scale up.
Thirdly,the unwanted R-enantiomer was converted into S-citalopram by cyclic resolution and stereoinversion.The cyclic resolution of the R-diol with low optical purity obtained from the first resolution was carried out by asymmetric transestereaction.Using the kinetic model to predict the reaction process,R-diol acetate with ee value of 91.2%was obtained by controlling the conversion of cyclic resolution under 20.8%.R-diol was stereoinverted to S-citalopram by cyclization in acidic condition with 98.0%yield and ee value of 91.0%.S-citalopram with ee value of 98.0%was obtained by cyclization of S-diol with ee value of 98.2%in alkaline condition and the yield was 97.8%.
Fourthly,the reaction volume of enzymatic asymmetric transestereaction of diol was scale-uped to 1 L and 14 L,gradually.There was no significant scale-up effect and the kinetic model fitted the result well.Scale-up of S-citalopram synthesis route was carried out for industrial production.
首先,研究有机相中脂肪酶催化转酯化反应与醇解反应两条途径远程拆分西酞普兰二醇中间体,并分别建立动力学模型。结果表明转酯化反应的拆分效果优于醇解反应。
研究脂肪酶催化转酯化反应远程拆分西酞普兰二醇中间体及动力学。通过筛选,确定Novozym 435为实验用酶,乙酸乙烯酯为酰基供体,乙腈为溶剂。考察了各种因素的影响以及酶的重复利用,确定较优的反应条件为:二醇浓度60mmol/L,二醇与乙酸乙烯酯比例为1:5,酶浓度为10 mg/mL,摇床转速250 r/min,温度30℃。反应22 h后,e.e._s可以达到99.1%,S-二醇收率为40.4%,酶的半衰期可达364.8 h。研究无溶剂体系(乙酸乙烯酯为溶剂)中酶催化转酯化反应动力学。通过计算Thiele模量及Biot数,确定该反应体系中可忽略内、外扩散的影响。实验表明,二醇的R-,S-对映体均对酶产生抑制,产物抑制及酶的失活可以忽略。因此,该反应符合具有底物竞争性抑制的双底物双产物乒乓-双双反应机制。根据反应机理推导动力学方程,并考虑自酯化反应的影响,分别得到R-,S-二醇乙酸酯的反应速率方程。利用Matlab程序对不同底物浓度的时间-浓度过程曲线进行拟合得到模型参数。模型计算值与实验数据能较好的吻合,误差为12.8%。所得模型可较准确预测底物浓度对反应选择性的影响。
研究脂肪酶催化醇解反应拆分西酞普兰二醇乙酸酯中间体及其动力学。通过筛选酶、酰基受体及溶剂,确定反应体系为:Novozym 435为实验用酶,异丁醇为酰基受体,溶剂为乙腈与甲基叔丁基醚的混合溶剂(MEBT/MeCN=1:3);考察各种因素对反应的影响,并优化反应条件。研究表明,酶催化醇解反应符合可逆的竞争性底物及产物抑制乒乓-双双反应机理。根据反应机理推导动力学方程,分别得到R-,S-二醇的反应速率方程。对不同底物浓度的时间-浓度过程曲线进行拟合得到模型参数,模型的计算值与实验数据吻合,误差为11.3%。
其次,通过衍生化-萃取法分离拆分所得到的手性二醇及二醇乙酸酯。选用丁二酸酐作为衍生化试剂对二醇进行衍生化,通过筛选确定了甲苯-水相体系为二醇衍生物和二醇乙酸酯的较佳萃取分离体系。考察水相pH值及二醇乙酸酯浓度对分离的影响,得到较优的萃取条件为:水相pH 8.0,二醇乙酸酯初始浓度为10mmol/L,温度25℃。在此萃取条件下,二醇乙酸酯的分配系数为157.7。以S-二醇(ee值为99.5%)与二醇乙酸酯的混合物为原料,经过三次萃取,可分离得到ee值为98.4%的S-二醇,收率为86.0%。该衍生化-萃取法成本低,易放大,可为其他手性芳香胺醇的分离提供思路。
第三,结合二次拆分与构型翻转对无效的R-二醇进行利用。将一次拆分后得到的光学纯度较低的二醇乙酸酯水解为二醇后进行二次转酯化拆分。利用动力学模型预测二次拆分过程,并通过实验验证发现控制反应转化率为20.8%,可得到ee值为91.2%的R-二醇乙酸酯。所得的R-二醇乙酸酯在酸性条件下闭环,构型翻转得到ee值为91.0%的S-西酞普兰,收率为98.0%。以ee值为98.2%的S-二醇为原料,在碱性条件下构型保持闭环合成S-西酞普兰,ee值为98.0%,产率为97.8%。
最后,逐级放大酶催化转酯化反应并研究S-西酞普兰制备总工艺路线的放大。结合动力学模型预测与实验放大,将酶催化转酯化的反应体积逐步放大到1L和14L,实验结果表明酶催化转酯化反应没有明显的放大效应。研究S-西酞普兰制备的总工艺路线并进行小试放大,为工业化生产奠定基础。
Citalopram is a highly selective inhibitor of serotonin(5-HT) reuptake which contains a quaternary chiral center and almost the entire inhibitory activity resides in the S-enantiomer.S-citalporam,the single enantiomer drug with advantage of low dose and high efficacy,is one of the best-selling antidepressant and gradually replace the racemic citalopram.In this dissertation,the enzymatic preparation of citalopram chiral key intermediate was described.The main contents were as follows:1. Lipase-catalyzed remote resolution of citalopram key intermediate and kinetics study; 2.The separation of chiral diol and diol acetate after kinetic resolution;3.The utilization of unwanted R-enantiomer;4.S-citalopram synthesis and scale-up.
Firstly,the lipase-catalyzed kinetic resolution of citalopram intermediate in organic media and its kinetics was studied.The lipase-catalyzed asymmetric transestereaction was superior to the asymmetric alcoholysis.
The lipase-catalyzed remote kinetic resolution of diol,a key intermediate of citalopram,in organic media was studied.Through screening,the preferable system for the asymmetric transestereaction was:Novozym 435 as catalyst,acetonitrile as solvent and vinyl acetate as acyl donor.The influence of temperature,rotation speed, enzyme concentration and substrate concentration on the enzymatic resolution was studied.Reusability study of lipase was also carried out.The optimal condition was as following:60 mmol/L diol,the molar ratio of diol to vinyl acetate,1 to 5,10 mg/mL lipase,250 r/min rotation speed and 30℃.After 22h reaction,the yield of S-diol was 40.4%and the e.e._s was 99.1%.The E value of the reaction was 25.3 and the half-life of the lipase was 364.8 h.The kinetic modeling of Novozym 435 catalyzed remote resolution of diol was studied using vinyl acetate as acylating agent in solvent-free system.The substrate inhibition by each enantiomer of diol was proved.Enzyme deactivation and product inhibition were studied and could be negligible.The diffusion limitation was proved to be negligible by the calculation of Thiele module and Biot number.A kinetic model based on ping-pong bi-bi mechanism with competitive substrates using King-Altman method was proposed.The spontaneous transesterification was also considered.The reaction rate equation of both R- and S-diol acetate were derived.The model parameters were successfully simulated by Matlab program using time-concentration curves of different diol concentrations and the simulated values fitted the experimental values well with an average relative error of 12.8%.Furthermore,the developed model was used to investigate the effect of diol concentration on reaction enantioselectivity.
The lipase-catalyzed asymmetric alcoholysis of diol acetate has been studied. Through screening,the preferable system for the asymmetric reaction was:Novozym 435 as catalyst,isobutyl alcohol as acyl accepter and the mixed solvent(acetonitrile: methyl tert-butyl ether=3:1).The influence of various parameters on the enzymatic resolution was studied and the reaction condition was optimized.A kinetic model based on ping-pong bi-bi mechanism with competitive substrates was proposed.The product inhibition by each enantiomer of diol and substrate inhibition by isobutyl alcohol were also considered.The reaction rate equation of both R- and S- diol were derived.The model parameters were successfully simulated by Matlab program using time-concentration curves of different diol acetate concentrations and the simulated values fitted the experimental values well with an average relative error of 11.3%.
Secondly,a derivatization-extraction method was developed to separate diol from diol acetate after lipase-catalyzed kinetic resolution.It was found that succinic anhydride was the best derivative agent and water/toluene was the optimal extraction system.The effects of pH and initial diol acetate concentration on the total distribution coefficients of diol acetate were investigated.With the extraction conditions of initial diol acetate concentration of 10 mmol/L,pH 8.0 and 25℃,the total distribution coefficient achieved 157.7.The practical extraction process of the mixture of diol(ee value 99.5%) and diol acetate obtained by lipase-catalyzed reaction was carried out,within three extraction stages,the ee value and the yield of S-diol were 98.4%and 86.0%,respectively.This extraction method with anhydrides derivatization is promising in the separation of aromatic amino-alcohols for its low expense and easy scale up.
Thirdly,the unwanted R-enantiomer was converted into S-citalopram by cyclic resolution and stereoinversion.The cyclic resolution of the R-diol with low optical purity obtained from the first resolution was carried out by asymmetric transestereaction.Using the kinetic model to predict the reaction process,R-diol acetate with ee value of 91.2%was obtained by controlling the conversion of cyclic resolution under 20.8%.R-diol was stereoinverted to S-citalopram by cyclization in acidic condition with 98.0%yield and ee value of 91.0%.S-citalopram with ee value of 98.0%was obtained by cyclization of S-diol with ee value of 98.2%in alkaline condition and the yield was 97.8%.
Fourthly,the reaction volume of enzymatic asymmetric transestereaction of diol was scale-uped to 1 L and 14 L,gradually.There was no significant scale-up effect and the kinetic model fitted the result well.Scale-up of S-citalopram synthesis route was carried out for industrial production.
引文
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