(R)-(+)-和(S)-(-)磷酸苯并哌林对映体的合成新方法

A New Method for Synthesis of (R)-(+)- and (S)-(-)-Benproperine Phosphate Enantiomers

报道了(R)-和(S)-磷酸苯丙哌林对映体的合成新方法.以邻苄基苯酚和(S)-(+)-环氧氯丙烷为原料,通过成醚、选择性还原开环两步反应简捷高效地制得重要中间体(R)-1-(2-苄基苯氧基)-2-丙醇(2).中间体2与对甲苯磺酰氯酰化,制得中间体(R)-1-(2-苄基苯氧基)-2-丙醇对甲苯磺酸酯(3),该中间体与哌啶发生一次SN2反应直接得到(S)-(-)-苯丙哌林,该中间体与溴化锂和哌啶发生两次SN2反应制得(R)-(+)-苯丙哌林.然后它们分别与磷酸成盐制得相应的(S)-(-)-和(R)-(+)-磷酸苯丙哌林,其结构通过1H NMR和HRMS进行了表征.该合成方法路线短,反应条件温和,易于操作,且收率好,适合工业化生产.

A new and practical procedure is described for the preparation of benproperine phosphate enantiomers.Starting from the source of o-benzylphenol and（S）-（＋）-epichlorohydrin,the key intermediate（R）-1-（2-benzylphenoxy） propan-2-ol（2） was prepared by etherification,selective ring opening reaction in a simple and efficient step.（R）-1-（2-Benzylphenoxy）propan-2-yl 4-methylbenzenesulfonate（3） was obtained with p-toluenesulfonate,then followed by the SN2-type reaction with piperdine furnishing（S）-（-）-benproperine,while（R）-（＋）-benproperine was obtained by submitting the same tosylate to two consecutive SN2-type reaction with LiBr and piperidine.The（S）-（-）-and（R）-（＋）-benproperine phosphates were recrystallized by ethanol,respectively.And the enantiomers of benproperine phosphate were character-rized by 1H NMR and HRMS techniques.The improved method presented here features mild reaction conditions,simple operation,easy separation of product,high yield and was suitable for manufacturing in commercial scale.