替卡格雷关键中间体手性氨基环戊三醇的合成

Study on the Synthesis of (1S, 2R, 3S, 4R) -2,3-O- isopropylidene-4-amino- cyclopentane-1,2,3-triol

摘要:

以D-丙氨酸为原料，经酯化、Boc保护氨基、酯基羟胺化、羟胺氧化、Diels-Alder加成、烯烃双羟基化、邻二羟基的异丙基叉保护、脱N-酰基保护基、钯炭催化氢解等反应制备了(1S,2R,3S,4R)-2,3-O-亚异丙基-4-氨基环戊烷-1,2,3-三醇。对工艺路线中影响收率的关键步骤羧基羟胺化、羟胺氧化及Diels-Alder加成、烯烃双羟基化及脱N-酰基等反应条件进行了优化。结果如下：1）化合物Ⅴ的制备采用酯Ⅳ为原料替代N-Boc-丙氨酸，收率由55%提高到90%；2）羟胺的氧化和Diels-Alder加成，采用Swern氧化和环加成在“一锅”内反应，收率由53%提高到83%；3）在烯烃的双羟基化过程中用廉价的高锰酸钾替代了剧毒的四氧化锇，避免了昂贵剧毒试剂的使用。改进后目标产物的总收率达到了59%，较文献收率提高了32%。

Abstract:

(1S,2R,3S,4R)-2,3-O-isopropylidene-4-amino-cyclopentane-1,2,3-triol was prepared from D-alanine by the reaction of esterification, protection of amine group, hydroxylamination of ester group, oxidation of hydroxylamine group and Diels-Alder cycloaddition, dihydroxylation of double bond, protection of hydroxyl group, and de-acyl group and hydrogenation. The reaction conditions of key steps such as hydroxylamination of ester group, oxidation of hydroxylamine and Diels-Alder cycloaddition, dihydroxylation of double bond, and de-acyl group were optimized. The results are as follows: 1) The yield of compoundⅤwas increased from 55% to 90% by using ester Ⅳ instead of N-Boc-alanine as raw maerial; 2) The yield of compound Ⅵ was increased from 53% to 83% by using "one pot" Swern oxidation and the cycloaddition reactions; 3) In the oxidation of double bond, potassium permanganate was used as oxidant instead of highly toxic osmium tetroxide; it avoided using expensive and poisonous reagents. The total yield of the target was 59%, which was increased by 32% compared with the yield in the literature.