化学拆分法制备（S）-普萘洛尔
发布时间：2018-07-16 23:38
【摘要】：普萘洛尔是一种β-受体阻滞剂,可用于治疗心律失常、心绞痛、高血压等病症,且效果良好,目前以消旋体供药。(S)-普萘洛尔的阻滞作用比(R)-普萘洛尔强100倍,因此研究开发(S)-普萘洛尔对于提高药效、降低给药量、减轻毒副作用具有重要的意义。 本论文主要研究在手性拆分剂作用下利用化学拆分法制备(S)-普萘洛尔。 在大量实验的工作基础上,本论文自行制备了两类重要的手性拆分剂拆分混旋体普萘洛尔制备(S)-普萘洛尔。其中一类拆分剂为1-苯基乙磺酸,另一类拆分剂为二苯甲酰酒石酸族手性试剂。 1-苯基乙磺酸的合成以苯乙酮为原料,经硼氢化钠还原生成苯乙醇1-phenylethanol,二氯亚砜氯代生成1-氯代苯乙烷,再与硫脲反应生成1-苯乙硫醇,双氧水氧化1-苯乙硫醇得到消旋体1-苯基乙磺酸钠(PES)。通过左旋对羟基苯甘氨酸拆分制得手性1-苯乙磺酸。 二苯甲酰酒石酸族手性试剂包括O,O’-二苯甲酰-(L)-酒石酸(Di-benzovl tartaricacid,(-)-T1),O,O'-二对甲基苯甲酰-(L)-酒石酸(Di-1,4-toluoyl tartaric acid,(-)-T2),O,O'-二对甲氧基苯甲酰-(L)-酒石酸(Di-p-anisoyl tartaric acid,(-)-T3)。(-)-T1由苯甲酰氯与L-酒石酸制的苯甲酰酒石酸酐,酸酐水解得到目标产物O,O’-二苯甲酰-(L)-酒石酸；(-)-T2由对甲基苯甲酰氯与L-酒石酸制备得到O,O’-二苯甲酰-(L)-酒石酸酐,经水解得到(-)-T2；(-)-T3由对甲基苯甲酰氯与L-酒石酸反应得到O.O’-二对甲氧基苯甲酰-(L)-酒石酸酐,水解得到(-)-T3。产物为光活化合物,并对反应条件进行优化。 本论文利用自行制备的拆分剂(+)-PES对混旋普萘洛尔进行经典化学拆分；同时研究(-)-T1,(-)-T2,(-)-T3对普萘洛尔进行经典拆分以及族拆分。本论文通过实验发现1-苯基乙磺酸作为一种新型强酸性手性拆分剂对普萘洛尔的拆分效果不佳。三种酒石酸衍生物拆分剂的经典拆分中,以O,O’-二苯甲酰-(L)-酒石酸为手性拆分剂得到的目标产物光学纯度,收率较高。 在实验基础上发现,(-)-T1对普萘洛尔的经典拆分较佳拆分条件为：普萘洛尔与(-)-T1摩尔比为1：1,丙酮：甲醇体积比为6：1,溶剂：普萘洛尔液固比为23ml/g,反应时间10h,10%氨水对复盐进行解离,得到(S)-普萘洛尔对映体过量为90%e.e.,收率为87.5%。 二苯甲酰酒石酸族手性试剂进行的族拆分中,拆分效果较好的条件为：普萘洛尔与(-)-T1摩尔比为1：1,甲醇：丙酮=1：6,将35.79g,组合拆分剂配比(-)-T1和(-)-T2的摩尔比为99：1常温反应时间9h,最终所得(S)-普萘洛尔对映体过量为96%e.e.,收率90%。 通过大量实验发现,族拆分制备(S)-普萘洛尔光学纯度高于经典化学拆分所得。少量的第二种拆分剂的加入有抑制成核作用,并且对溶解度较小的非对映异构体效果强于溶解度大的非对映异构体。 本论文采用T族手性试剂运用族拆分法制备(S)-普萘洛尔,取得了比经典拆分更高的收率以及更高的光学纯度,目前该方法未见文献报道,是本论文的重要创新。 通过IR和CSP-HPLC分析发现,拆分法制得的(S)-普萘洛尔结构正确,产品光学纯度高(96% e.e.)。
[Abstract]:Pubinol is a beta - blocker which can be used for the treatment of arrhythmia , angina pectoris , hypertension and other conditions , and has good effect .
This paper mainly studies the preparation of ( S ) - prodinol by chemical resolution method under the action of chiral resolving agent .
On the basis of a great deal of experiments , two kinds of important chiral resolving agents were prepared by ourselves .
The synthesis of 1 - phenylethanesulfonic acid takes acetophenone as the raw material , and is reduced by sodium borohydride to generate 1 - chlorophenylethane , 1 - chlorophenylethane is generated by reaction with thiourea , 1 - phenylethanedithiol is generated by reaction with thiourea , 1 - phenylethanedithiol is oxidized to obtain racemic 1 - phenylethanesulfonic acid ( PES ) , and the chiral 1 - phenylethanesulfonic acid is prepared by the separation of L - p - hydroxyphenylglycine .
The dibenzoyltartaric acid chiral reagent includes O , O ' - dibenzoyl - ( L ) - tartaric acid ( Di - divl tartaric acid , ( - ) - T1 ) , O , O ' - di - p - methylbenzoyl - ( L ) - tartaric acid ( Di - 1,4 - dihydroxy phosphonic acid , ( - ) - T2 ) , O , O ' - di - p - methoxybenzoyl - ( L ) - tartaric acid ( Di - p - dimethyyl phosphonic acid , ( - ) - T3 ) . ( - ) - T1 is hydrolyzed by benzoyl chloride and L - tartaric acid to obtain the target product O , O ' - dibenzoyl - ( L ) - tartaric acid ;
( - ) - T2 is prepared from p - methylbenzoyl chloride and L - tartaric acid to obtain O , O ' - dibenzoyl - ( L ) - tartaric acid anhydride , and is hydrolyzed to obtain ( - ) - T2 ;
( - ) - T3 is obtained by reacting p - methylbenzoyl chloride with L - tartaric acid to obtain O . O ' - di - p - methoxybenzoyl - ( L ) - tartaric acid anhydride , and hydrolyzing to obtain ( - ) - T3 . The product is a photoactive compound , and the reaction conditions are optimized .
In this paper , using the self - prepared splitter ( + ) - PES , the classical chemical resolution was carried out on the mixture .
In this paper , we found that 1 - phenylethanesulfonic acid was used as a new type of strong acid chiral resolving agent . The results showed that 1 - phenylethanesulfonic acid was used as a new kind of strong acid chiral resolving agent .
Based on the experimental results , it was found that ( - ) - T1 had better separation conditions for the classical resolution of protolyllol : the molar ratio of protolyllol to ( - ) - T1 was 1 : 1 , the volume ratio of acetone to methanol was 6 : 1 , the ratio of the solvent to the ratio of methanol to methanol was 23 ml / g , the reaction time was 10 h , the reaction time was 10 % , and the reaction time was 10 % . The enantiomeric excess was 90 % e.e . and the yield was 87.5 % .
In the family resolution of the chiral reagent of dibenzoyltartaric acid , the condition that the splitting effect is better is that the mole ratio of the protolyllol to the ( - ) - T1 molar ratio of 1 : 1 , the methanol : acetone = 1 : 6 , the molar ratio of the combined resolving agent ( - ) - T1 and ( - ) - T2 is 99 : 1 at normal temperature and the reaction time is 9 hours , and finally the obtained ( S ) - preneol enantiomer has an enantiomeric excess of 96 % e.e . , and the yield is 90 % .
A large number of experiments have found that the optical purity of ( S ) - protolyllol is higher than that of the classical chemical resolution . The addition of a small amount of the second resolving agent has the effect of inhibiting the nucleation , and the diastereoisomer with a small solubility is stronger than that of the diastereoisomer with large solubility .
In this paper , we use the chiral reagent of the group T to prepare ( S ) - Pubinol , which has achieved higher yield and higher optical purity than the classical resolution . At present , this method is not reported in the literature , which is an important innovation in this paper .
By IR and CSP - HPLC analysis , it was found that the ( S ) - Pubinol structure was correct and the optical purity of the product was high ( 96 % e.e . ) .
【学位授予单位】：河北科技大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：TQ463.2
[Abstract]:Pubinol is a beta - blocker which can be used for the treatment of arrhythmia , angina pectoris , hypertension and other conditions , and has good effect .
This paper mainly studies the preparation of ( S ) - prodinol by chemical resolution method under the action of chiral resolving agent .
On the basis of a great deal of experiments , two kinds of important chiral resolving agents were prepared by ourselves .
The synthesis of 1 - phenylethanesulfonic acid takes acetophenone as the raw material , and is reduced by sodium borohydride to generate 1 - chlorophenylethane , 1 - chlorophenylethane is generated by reaction with thiourea , 1 - phenylethanedithiol is generated by reaction with thiourea , 1 - phenylethanedithiol is oxidized to obtain racemic 1 - phenylethanesulfonic acid ( PES ) , and the chiral 1 - phenylethanesulfonic acid is prepared by the separation of L - p - hydroxyphenylglycine .
The dibenzoyltartaric acid chiral reagent includes O , O ' - dibenzoyl - ( L ) - tartaric acid ( Di - divl tartaric acid , ( - ) - T1 ) , O , O ' - di - p - methylbenzoyl - ( L ) - tartaric acid ( Di - 1,4 - dihydroxy phosphonic acid , ( - ) - T2 ) , O , O ' - di - p - methoxybenzoyl - ( L ) - tartaric acid ( Di - p - dimethyyl phosphonic acid , ( - ) - T3 ) . ( - ) - T1 is hydrolyzed by benzoyl chloride and L - tartaric acid to obtain the target product O , O ' - dibenzoyl - ( L ) - tartaric acid ;
( - ) - T2 is prepared from p - methylbenzoyl chloride and L - tartaric acid to obtain O , O ' - dibenzoyl - ( L ) - tartaric acid anhydride , and is hydrolyzed to obtain ( - ) - T2 ;
( - ) - T3 is obtained by reacting p - methylbenzoyl chloride with L - tartaric acid to obtain O . O ' - di - p - methoxybenzoyl - ( L ) - tartaric acid anhydride , and hydrolyzing to obtain ( - ) - T3 . The product is a photoactive compound , and the reaction conditions are optimized .
In this paper , using the self - prepared splitter ( + ) - PES , the classical chemical resolution was carried out on the mixture .
In this paper , we found that 1 - phenylethanesulfonic acid was used as a new type of strong acid chiral resolving agent . The results showed that 1 - phenylethanesulfonic acid was used as a new kind of strong acid chiral resolving agent .
Based on the experimental results , it was found that ( - ) - T1 had better separation conditions for the classical resolution of protolyllol : the molar ratio of protolyllol to ( - ) - T1 was 1 : 1 , the volume ratio of acetone to methanol was 6 : 1 , the ratio of the solvent to the ratio of methanol to methanol was 23 ml / g , the reaction time was 10 h , the reaction time was 10 % , and the reaction time was 10 % . The enantiomeric excess was 90 % e.e . and the yield was 87.5 % .
In the family resolution of the chiral reagent of dibenzoyltartaric acid , the condition that the splitting effect is better is that the mole ratio of the protolyllol to the ( - ) - T1 molar ratio of 1 : 1 , the methanol : acetone = 1 : 6 , the molar ratio of the combined resolving agent ( - ) - T1 and ( - ) - T2 is 99 : 1 at normal temperature and the reaction time is 9 hours , and finally the obtained ( S ) - preneol enantiomer has an enantiomeric excess of 96 % e.e . , and the yield is 90 % .
A large number of experiments have found that the optical purity of ( S ) - protolyllol is higher than that of the classical chemical resolution . The addition of a small amount of the second resolving agent has the effect of inhibiting the nucleation , and the diastereoisomer with a small solubility is stronger than that of the diastereoisomer with large solubility .
In this paper , we use the chiral reagent of the group T to prepare ( S ) - Pubinol , which has achieved higher yield and higher optical purity than the classical resolution . At present , this method is not reported in the literature , which is an important innovation in this paper .
By IR and CSP - HPLC analysis , it was found that the ( S ) - Pubinol structure was correct and the optical purity of the product was high ( 96 % e.e . ) .
【学位授予单位】：河北科技大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：TQ463.2
【参考文献】
相关期刊论文 前10条
1 杨忠华,姚善泾,赵s，
本文编号：2128066
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