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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、邻二羟基的亚异丙基保护、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(Ⅰ)。对工艺路线中影响收率的关键步骤进行了反应条件优化。结果表明:(R)-N-Boc-丙氨酸异羟肟(Ⅴ)的制备采用(R)-N-Boc-丙氨酸甲酯(Ⅳ)为原料,收率为90.0%;(R)-2-(叔丁氧羰基)氨基-1-[(1S,4R)-2-氧杂-3-氮杂双环[2.2.1]庚-5-烯-3-基]丙-1-酮(Ⅵ)的制备采用Swern氧化和Diels-Alder环加成“一锅”反应,收率为83.1%;(2R)-2-(叔丁氧羰基)氨基-1-[(1S,4R,5R)-5,6-二羟基-2-氧杂-3-氮杂双环[2.2.1]庚-3-基]丙-1-酮(Ⅶ)的制备过程中使用了廉价且低毒的高锰酸钾,收率达85.0%。改进后目标产物的总收率达到了59.8%。
With D-alanine as raw material, esterification, Boc protected amino, ester hydroxylamine, hydroxylamine oxidation, Diels-Alder addition, alkene dihydroxy, o-dihydroisopropylidene protection, de N- (1S, 2R, 3S, 4R) -2,3-O-isopropylidene-4-aminocyclopentane-1,2,3-triol ). The reaction conditions were optimized for the key steps influencing yield in the process route. The results showed that the yield of (R) -N-Boc-alanine oxime (V) was (R) -N-Boc-alanine methyl ester ) -2- (tert-butoxycarbonyl) amino-1 - [(1S, 4R) The ketone (Ⅵ) was prepared by the reaction of Swern oxidation and Diels-Alder cycloaddition in a “one-pot” reaction. The yield was 83.1%. (2R) -2- 4R, 5R) -5,6-dihydroxy-2-oxa-3-azabicyclo [2.2.1] hept-3-yl] propan-1-one (VII) Poisonous potassium permanganate, yield of 85.0%. After the improvement of the total yield of the target product reached 59.8%.