化學拆分法制備（S）-普萘洛爾
發(fā)布時間：2018-07-16 23:38
【摘要】：普萘洛爾是一種β-受體阻滯劑,可用于治療心律失常、心絞痛、高血壓等病癥,且效果良好,目前以消旋體供藥。(S)-普萘洛爾的阻滯作用比(R)-普萘洛爾強100倍,因此研究開發(fā)(S)-普萘洛爾對于提高藥效、降低給藥量、減輕毒副作用具有重要的意義。 本論文主要研究在手性拆分劑作用下利用化學拆分法制備(S)-普萘洛爾。 在大量實驗的工作基礎上,本論文自行制備了兩類重要的手性拆分劑拆分混旋體普萘洛爾制備(S)-普萘洛爾。其中一類拆分劑為1-苯基乙磺酸,另一類拆分劑為二苯甲酰酒石酸族手性試劑。 1-苯基乙磺酸的合成以苯乙酮為原料,經(jīng)硼氫化鈉還原生成苯乙醇1-phenylethanol,二氯亞砜氯代生成1-氯代苯乙烷,再與硫脲反應生成1-苯乙硫醇,雙氧水氧化1-苯乙硫醇得到消旋體1-苯基乙磺酸鈉(PES)。通過左旋對羥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試劑包括O,O’-二苯甲酰-(L)-酒石酸(Di-benzovl tartaricacid,(-)-T1),O,O'-二對甲基苯甲酰-(L)-酒石酸(Di-1,4-toluoyl tartaric acid,(-)-T2),O,O'-二對甲氧基苯甲酰-(L)-酒石酸(Di-p-anisoyl tartaric acid,(-)-T3)。(-)-T1由苯甲酰氯與L-酒石酸制的苯甲酰酒石酸酐,酸酐水解得到目標產物O,O’-二苯甲酰-(L)-酒石酸；(-)-T2由對甲基苯甲酰氯與L-酒石酸制備得到O,O’-二苯甲酰-(L)-酒石酸酐,經(jīng)水解得到(-)-T2；(-)-T3由對甲基苯甲酰氯與L-酒石酸反應得到O.O’-二對甲氧基苯甲酰-(L)-酒石酸酐,水解得到(-)-T3。產物為光活化合物,并對反應條件進行優(yōu)化。 本論文利用自行制備的拆分劑(+)-PES對混旋普萘洛爾進行經(jīng)典化學拆分；同時研究(-)-T1,(-)-T2,(-)-T3對普萘洛爾進行經(jīng)典拆分以及族拆分。本論文通過實驗發(fā)現(xiàn)1-苯基乙磺酸作為一種新型強酸性手性拆分劑對普萘洛爾的拆分效果不佳。三種酒石酸衍生物拆分劑的經(jīng)典拆分中,以O,O’-二苯甲酰-(L)-酒石酸為手性拆分劑得到的目標產物光學純度,收率較高。 在實驗基礎上發(fā)現(xiàn),(-)-T1對普萘洛爾的經(jīng)典拆分較佳拆分條件為：普萘洛爾與(-)-T1摩爾比為1：1,丙酮：甲醇體積比為6：1,溶劑：普萘洛爾液固比為23ml/g,反應時間10h,10%氨水對復鹽進行解離,得到(S)-普萘洛爾對映體過量為90%e.e.,收率為87.5%。 二苯甲酰酒石酸族手性試劑進行的族拆分中,拆分效果較好的條件為：普萘洛爾與(-)-T1摩爾比為1：1,甲醇：丙酮=1：6,將35.79g,組合拆分劑配比(-)-T1和(-)-T2的摩爾比為99：1常溫反應時間9h,最終所得(S)-普萘洛爾對映體過量為96%e.e.,收率90%。 通過大量實驗發(fā)現(xiàn),族拆分制備(S)-普萘洛爾光學純度高于經(jīng)典化學拆分所得。少量的第二種拆分劑的加入有抑制成核作用,并且對溶解度較小的非對映異構體效果強于溶解度大的非對映異構體。 本論文采用T族手性試劑運用族拆分法制備(S)-普萘洛爾,取得了比經(jīng)典拆分更高的收率以及更高的光學純度,目前該方法未見文獻報道,是本論文的重要創(chuàng)新。 通過IR和CSP-HPLC分析發(fā)現(xiàn),拆分法制得的(S)-普萘洛爾結構正確,產品光學純度高(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 . ) .
【學位授予單位】：河北科技大學
【學位級別】：碩士
【學位授予年份】：2011
【分類號】：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 . ) .
【學位授予單位】：河北科技大學
【學位級別】：碩士
【學位授予年份】：2011
【分類號】：TQ463.2
【參考文獻】
相關期刊論文 前10條
1 楊忠華,姚善涇,趙s，
本文編號：2128066
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