经典化学合成反应标准操作酯交换为酰胺编者:杜晓行药明康德新药开发有限公司化学合成部药明康德内部保密资料经典合成反应标准操作—酯交换为酰胺药明康德新药开发有限公司目录1.2.3.前言…………………………………………………………………2酯交换为酰胺…………………………………………………………2酯交换为N-取代酰胺…………………………………………………2药明康德内部保密资料Page1of8经典合成反应标准操作—酯交换为酰胺药明康德新药开发有限公司1.前言酯和氨水反应可以很方便地得到酰胺。N-取代酰胺一般可以利用相应的胺与酯直接反应得到,在有些条件下,需要有铝试剂的存在反应才能够顺利进行。2.酯与氨交换一般酯的氨解通过氨的醇溶液或氨水来进行。氨的醇溶剂氨解反应可通过加入适量的甲醇钠和氰化钠来催化。用氨水直接氨解一般需要加热(当该反应温度到100度时,一定要用高压釜做这一反应),这类反应一般可以通过硫酸铜来进行催化。反应的条件选择主要看酯的活性程度,一般脂肪酸酯的交换要比芳香羧酸酯来得容易,甲酯要比乙酯来得快。对脂肪酸酯,α位的位阻大小也决定了反应的快慢。酯通过甲酰胺在乙醇钠的存在下,高温也可得到相应的酰胺。这一方法对各类的酯都比较有效,只是产品的分离比直接氨解稍微麻烦一些,但反应较快。另外近年来,AlMe3-NH4Cl或Me2AlNH2在多官能团及复杂化合物的合成中用的较多,该方法条件较强,各类酯都能很快的氨解。其缺点是AlMe3易自燃,操作不是太方便。2.1氨水用于脂肪羧酸酯氨解示例[1]OOONOOOONH4OHH2NOONToethyl5-ethoxycarbonylmethyl-3-methylisoxazole-4-carboxylate(1.00g,4.15mmol)wasaddedanexcessofconc.aqueousammonia(d=0.88kg·dm-3,5.0cm3)andEtOH(3.0cm3),andthesuspensionwasstirredvigorouslyatroomtemperaturefor14h.Afterthisperiodawhitesolidhadprecipitatedwhichwasfilteredandrecrystallized(EtOAc)toyieldthedesiredproductasawhitesolid(0.81g,92%).OOONOOOOMeNH2/tolueneHNOONPage2of8药明康德内部保密资料经典合成反应标准操作—酯交换为酰胺药明康德新药开发有限公司Preparedasdescribedaboveforethyl5-carbamoylmethyl-3-methylisoxazole-4-carboxylatebutusingmethyl-5-ethoxycarbonyl-3-methylisoxazole-4-carboxylate(1.00g,4.15mmol)andmethylamineintoluene(30%w/v,10.0cm3),toyieldthedesiredproductasawhitesolid(0.93g,99%).2.2氨甲醇氨解脂肪羧酸酯示例[2][3]OONHCOOEtMeNH2/MeOHOONHCONHMeTheester(4.11g,14mmol)wasdissolvedinabsol.methanolicammonia(100ml,20%NH3),andthesolutionwasallowedtostandattemperaturefor3days,thesolventwasthenevaporated,andtheresultingcrystallinewaspurifiedbyrecrystallization.2.3氨水用于芳香羧酸酯氨解示例[4]COOMeNNH4OHNCONH2Toanautoclave,wasaddedmethyl6-methylniconate(500g,3.31mol),sat.aq.NH4OH(500ml)andethanol(500ml).Aftersealing,thereactionwasheatedto80℃for2days.Thecooledreactionmixturewasfiltrated,andthefiltercakewasrecrystallizedtoaffordwhitesolid(247g,54.8%)。2.4HCONH2-NaOEt体系用于酯氨解示例[5]COOEtBocNNaOEt,HCONH2DMF,100oC,2h70%BocNCONH2tert-Butyl4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate(0.60g,2.0mmol,theproductofProductionexample43-1)andformamide(0.27ml,6.7mmol)weredissolvedinN,N-dimethylformamide(1.0ml);sodiumethoxide(0.095g,1.4mmol)wasaddedtheretowhilestirredandheatedat100.deg.C;thereactionmixturewasstirredfor2hoursunder药明康德内部保密资料Page3of8经典合成反应标准操作—酯交换为酰胺药明康德新药开发有限公司nitrogenatmosphere.Aftercooledtoroomtemperature,thereactionmixturewaspartitionedbetweenwaterandethylacetate.Theorganiclayerwaswashedwithbrine,driedoveranhydrousmagnesiumsulfate,andthenthesolventwasdistilledoffunderreducedpressure.Theresiduewaspurifiedbysilicagelchromatography(eluent;hexane-ethylacetate=95:5to85:15).Th...