他达拉非杂质的合成

Synthesis of impurities of tadalafil

目的为了加强对他达拉非原料药及其中间体的质量控制,合成4个新型他达拉非的杂质。方法以(1R,3R)-1-(1,3-苯并二氧戊环-5-基)-1,2,3,4-四氢-9H-吡啶并[3,4-b]吲哚-3-羧酸甲酯盐酸盐为起始原料,经水解、Boc酸酐保护、苄酯保护反应,再经酸催化脱除保护基和异构化制得关键中间体6a、6b,该中间体分别经酰化、氢化脱苄反应合成杂质Ⅰ_1、Ⅰ_2;Ⅰ_1、Ⅰ_2经亲核取代反应制得杂质Ⅱ_1、Ⅱ_2。结果与结论合成的4种杂质及其中间体的结构经NMR、MS谱确证,4种杂质的纯度达到96%以上,可作为他达拉非质量控制的杂质对照品。

To improve the quality control of tadalafil and its intermediates,four new impurities were synthe- sized and reported. The impurities I, and 12 were obtained by acylation and hydrogenated deprotection of benzyl, respectively from （ 1 R, 3R ） -1 -（ 1,3-benzodioxol-5-yl ） -1,2,3,4-tetrahydro-9H-pyrido [ 3,4-b ] in- dole-3 -carboxylic acid benzyl ester and （ 1 S, 3R） -1 - （ 1,3-benzodioxol-5-yl ） -1,2,3,4-tetrahydro-9H-pyrido [ 3,4-b ] indole-3-carboxylic acid benzyl ester which were prepared from （ 1R, 3R ） -1-（ 1,3-benzodioxol-5- yl ） -1,2,3,4-tetrahydro-9H-pyrido [ 3,4-b ] indole-3-carboxylic acid methyl ester hydrochloride by hydrolysis, protection,acid-catalyzed deprotection and isomerization. The impurities II1 and II2 were synthesized from I1 and 12 through nucleophilic substitution reaction,respectively. The structure of the target compounds II,I2 ,II1, II2 and their intermediates was confirmed by NMR and MS. The purity of these target compounds which can be used as reference substances in the research of quality control of tadalafil was over 96%.