CN105037207B - 一种(异)亮氨酰胺氨基甲酸酯衍生物及应用 - Google Patents
一种(异)亮氨酰胺氨基甲酸酯衍生物及应用 Download PDFInfo
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Abstract
本发明属于植物杀菌剂领域，涉及一种如通式(I)所示的一种(异)亮氨酰胺氨基甲酸酯衍生物及其药学上可接受的盐，其中取代基R具有说明书中给出的定义，本发明还涉及通式(I)的化合物的制备方法、专门为其制备所开发的中间体以及其在防治植物病害的应用。
Description
技术领域
本发明属于农药领域，特别涉及N-(1-甲基-2-取代乙基)(异)亮氨酰胺氨基甲酸酯衍生物及其作为杀菌剂应用。
背景技术
全世界植物受有害病原微生物种类超过8万种，病原微生物对农业造成巨大危害和损坏，因植物病害导致平均每年粮食减产，甚至导致严重粮食饥荒。据统计，2006年世界用于防治卵菌病害的杀菌剂消费量高达12亿美元，占全世界杀菌剂市场的25％。
卵菌纲属包括腐霉菌、疫霉菌、霜霉菌等。病原菌寄主范围很广，包括蔬菜、水果、花卉、林木、棉、麻等各种作物。卵菌植物病原菌对寄主植物的破坏性强、危害大、潜育期短，短时间迅速四处传播侵染，并难以控制，从而导致农林业上的严重的损失。
国际杀菌剂抗药性行动委员(FRAC)于2005年提出羧酸酰胺类(Carboxylic acidamides,CAAs)杀菌剂，羧酸酰胺类杀菌剂是一类针对卵菌纲病害有优异防治效果的一种杀菌剂。缬氨酰胺氨基甲酸酯类杀菌剂是CAA类杀菌剂重要的一类，是一类防治植物卵菌病害的一类结构新颖的杀菌剂，具有低毒高效、易降解、环境友好等优点，是目前杀菌剂研究的热点，引起了世界各大农化公司的高度关注，纷纷投入巨资用于该类杀菌剂的研发。近期开发研制的缬氨酰胺氨基甲酸酯类杀菌剂主要包括异丙菌胺、苯噻菌、异苯噻菌胺和Valiphenal。
本发明在缬氨酰胺氨基甲酸酯类杀菌剂研究的基础上，按照类同合成法和活性亚结构拼接法设计思路，选取了结构简单、成本低廉的原料，对缬氨酰胺氨基甲酸酯类化合物进行优化，设计合成一系列(异)亮氨酰胺氨基甲酸酯类化合物，经过对多种植物致病细菌杀菌活性测试，结果表明本发明化合物具有良好的杀菌活性。
发明内容
本发明的目的在于提供一种N-(1-甲基-2-取代乙基)(异)亮氨酰胺氨基甲酸酯衍生物。该类化合物具有优异的杀菌活性，制备药物前景广阔。
本发明提供的N-(1-甲基-2-取代乙基)(异)亮氨酰胺氨基甲酸酯衍生物是具有如下通式(I)的化合物或其药学上可接受的盐：
其中，R1是任选1-5个取代基，选自氢、羟基、氰基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C2-6烯氧基、C2-6炔氧基、卤代C1-6烷基、卤代C1-6烷氧基、苄氧基、苯基，所述苄氧基苯环上的氢任选被1-5个选自卤素、羟基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C2-6烯氧基、C2-6炔氧基、卤代C1-6烷基、卤代C1-6烷氧基的取代基取代，R1优选为氢、卤素、甲基、三氟甲基、甲氧基、三氟甲氧基、叔丁基、炔丙氧基、苄氧基、羟基；
R2是氢、C1-6烷基，优选为氢、甲基；
R3是氢、C1-6烷基，优选为氢、甲基。
另外，本发明涉及如式(I)所定义的化合物作为植物杀菌剂的用途。
在本发明中，术语“烷基”指直链或支链的饱和烃。此类取代基的例子包括但不限于甲 基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基、己基。
同样，术语“烷氧基”指直链或支链的饱和烷氧基。此类取代基的例子包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、仲丁氧基、戊氧基、新戊氧基、己氧基。
术语“烯基”指直链或支链的烯基，此类取代基的例子包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1-戊烯基、1-己烯基。
术语“炔基”指直链或支链的炔基，此类取代基的例子包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、1-己炔基。
术语“卤代烷基”为直链或支链烷基，在这些烷基上氢原子可以部分或全部被卤素原子取代；术语“卤代烷氧基”、“卤代烯基”、“卤代炔基”的定义与术语“卤代烷基”类似。
术语“卤素”指氟、氯、溴、碘。
本发明进一步提供农药组合物，其包含有效量的式(I)化合物和载体。本发明还提供农药组合物，其包含有效量的实施例部分所公开的具体化合物之一和载体。
本发明化合物(I)制备路线如下,所有的原料都是通过这些示意式中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商业购买。本发明的全部最终化合物都是通过这些示意式中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。
按照本发明的通式(I)化合物，R1、R2、R3如发明内容所定义。
通式化合物(I)的合成路线为：
通式8和9化合物的合成路线
在合成路线中，将化合物1与一氯丙酮反应得化合物2，化合物2通过甲酰胺或氢气还原得到化合物3，化合物3和6缩合反应得到通式8。同样方法，用化合物3和7缩合反应得到通式9。
本发明还提供所述通式8和9化合物的制备方法，该方法包括如下步骤：
1)苯酚溶于丙酮，加入无水碳酸钾、碘化钾和一氯丙酮，回流反应完毕后，脱溶、水洗、干燥、重结晶，得到淡黄色油状物2。
2)将原料苯氧基丙酮2，甲酰胺和水于蒸馏装置于185℃反应4h。反应完，冷却、水洗、萃取脱溶得到固体，加入水和浓盐酸回流、重结晶得铵盐。加pH＝12的氢氧化钠水溶液游离出淡黄色油状物胺3a-3p。
3)将对苄氧基苯氧基丙酮2q溶于乙醇中，加入盐酸羟胺氢氧化钠，室温反应完，脱溶水洗干燥，得白色固体产物10。将产品10溶于四氢呋喃中，冰水浴分批加入四氢铝锂，加热回流。反应完，依次别加水、氢氧化钠水溶液淬灭四氢铝锂、萃取、干燥、脱溶，得到对苄氧基苯氧基丙胺3q。
将1-甲基-2-对苄氧基苯氧基乙胺3q溶于乙醇，加入钯碳，于高压釜中氢气还原12h。反应完后，过滤、脱溶、水洗、干燥，脱溶得白色固体3r。
4)将NaOH溶于水中，加入L-亮氨酸，0℃下，滴加氯甲酸异丙酯，滴毕室温反应。后处理乙醚洗、盐酸调pH到2～3萃取、干燥、脱溶，得到白色粘状物6。同样方法制得化合物7。
5)4-甲基-2-异丙氧基羰基氨基戊酸6和三乙胺溶于THF溶液中，0℃下，将氯甲酸异丙酯，室温反应。滴加1-甲基-2-苯氧基乙胺3，室温反应。后处理脱溶、水洗、干燥、柱层析纯化，得白色固体8。同样方法选用3和7制得化合物9，状态为白色固体。
本发明提供的结构式(I)化合物是具有优异的杀菌活性的化合物，能用于防治卵菌纲病原菌产生的病害如霜霉病、晚疫病、霜疫病等，具体的如黄瓜霜霉病、葡萄霜霉病、白菜霜霉病、番茄晚疫病、马铃薯晚疫病、辣椒晚疫病、荔枝霜疫霉病、大豆疫霉根腐病等。本发明化合物也可以加上农业上接受的载体使用，也可以和其它杀菌剂复配使用。
具体实施方式
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范围。
实施例1：苯氧基丙酮2a的合成
苯酚(3.00g，33.88mmol)溶于50mL丙酮，加入无水碳酸钾(4.85g，35.03mmol)，室温搅拌0.5h，加入碘化钾(0.53g,3.39mmol)，一氯丙酮(3.44g，35.03mmol)滴加至反应液，回流3h。反应完毕后，脱溶除去丙酮，残余物加入50mL乙酸乙酯，饱和食盐水洗有机层(3×50mL)次，乙酸乙酯反萃取洗水层(3×50mL)，合并有机相，无水硫酸镁干燥。过滤，脱溶。乙醇重结晶得到黄色油状物，收率：99.9％。1H NMR(400MHz,CDCl3)δ7.30–7.21(m,2H,Ar-H),7.01–6.93(m,1H,Ar-H),6.83(d,J＝8.1Hz,2H,Ar-H),4.49(s,2H,CH2),2.21(s,3H,CH3).
按照实施例1的方法，选择合适的原料和试剂，分别制得2b至2q的化合物。应该理解的是，精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例2：4-氟苯氧基丙酮2b的合成
淡黄色油状物，收率：99.1％。1H NMR(400MHz,CDCl3)δ6.98(ddd,J＝9.6,4.1,2.0Hz,2H,Ar-H),6.89–6.75(m,2H,Ar-H),4.51(s,2H,CH2),2.26(s,3H,CH3).
实施例3：3-氟苯氧基丙酮2c的合成
淡黄色油状物，收率：98.7％。1H NMR(400MHz,CDCl3)δ7.26(td,J＝8.2,4.4Hz,1H,Ar-H),6.76–6.60(m,3H,Ar-H),4.55(s,2H,CH2),2.29(s,3H,CH3).
实施例4：4-氯苯氧基丙酮2d的合成
淡黄色油状物，收率：99.3％。1H NMR(400MHz,CDCl3)δ7.25(d,J＝9.0Hz,2H,Ar-H),6.87–6.82(m,2H,Ar-H),4.50(s,2H,CH2),2.25(s,3H,CH3).
实施例5：3-氯苯氧基丙酮2e的合成
淡黄色油状物，收率：97.6％。1H NMR(400MHz,CDCl3)δ7.24(t,J＝8.2Hz,1H,Ar-H),7.01(d,J＝8.1Hz,1H,Ar-H),6.91(t,J＝5.7Hz,1H,Ar-H),6.80(dd,J＝8.3,2.3Hz,1H,Ar-H),4.56(s,2H,CH2),2.30(s,3H,CH3).
实施例6：2-氯苯氧基丙酮2f的合成
淡黄色油状物，收率：99.3％。1H NMR(400MHz,CDCl3)δ7.40(d,J＝7.7Hz,1H,Ar-H),7.21(t,J＝7.9Hz,1H,Ar-H),6.95(t,J＝7.7Hz,1H,Ar-H),6.79(d,J＝8.2Hz,1H,Ar-H),4.55(s,2H,CH2),2.35(s,3H,CH2).
实施例7：4-溴苯氧基丙酮2g的合成
淡黄色液体,收率：98.0％。1H NMR(300MHz,CDCl3)δ7.35(t,J＝18.8Hz,2H,Ar-H),6.81(dd,J＝28.4,8.7Hz,2H,Ar-H),4.51(s,2H,CH2),2.32(d,J＝34.2Hz,3H,CH3).
实施例8：4-甲基苯氧基丙酮2h的合成
淡黄色油状物，收率：98.8％。1H NMR(400MHz,CDCl3)δ7.06(dd,J＝27.9,7.1Hz,2H,Ar-H),6.76(dd,J＝16.3,7.8Hz,2H,Ar-H),4.51(s,2H,CH2),2.29(d,J＝4.3Hz,3H,Ar-CH3),2.27(s,3H,CH3).
实施例9：4-甲氧基苯氧基丙酮2i的合成
淡黄色油状物，收率：99.0％。1H NMR(300MHz,CDCl3)δ6.89-6.82(m,4H,Ar-H),4.51(s,2H,CH2),3.79(s,3H,OCH3),2.29(s,3H,CH3).
实施例10：2-甲氧基苯氧基丙酮2j的合成
淡黄色油状物，收率：94.6％。1H NMR(400MHz,CDCl3)δ6.92(m,3H,Ar-H),6.77(dd,J＝8.0,1.1Hz,1H,Ar-H),4.58(s,2H,CH2),3.88(d,J＝1.1Hz,3H,OCH3),2.28(d,J＝5.5Hz,3H,CH3).
实施例11：4-叔丁基苯氧基丙酮2k的合成
淡黄色油状物，收率：95.8％。1H NMR(400MHz,CDCl3)δ7.30(t,J＝13.4Hz,2H,Ar-H),6.86(dd,J＝33.7,6.7Hz,2H,Ar-H),4.55(s,2H,CH2),2.28(s,3H,CH3),1.31(s,9H,Ar-p-C(CH3)3).
实施例12：4-三氟甲基苯氧基丙酮2l的合成
淡黄色油状物，收率：95.8％。1H NMR(400MHz,CDCl3)δ7.57(d,J＝8.6Hz,2H,Ar-H),6.99(d,J＝25.0Hz,2H,Ar-H),4.60(s,2H,CH2),2.29(s,3H,CH3).
实施例13：3-三氟甲基苯氧基丙酮2m的合成
淡黄色油状物，收率：96.7％。1H NMR(400MHz,CDCl3)δ7.43(t,J＝8.0Hz,1H,Ar-H),7.28(d,J＝7.7Hz,1H,Ar-H),7.15(s,1H,Ar-H),7.07(d,J＝8.1Hz,1H,Ar-H),4.61(s,2H,CH2),2.31(s,3H,CH3).
实施例14：2-三氟甲基苯氧基丙酮2n的合成
淡黄色油状物，收率：98.1％。1H NMR(400MHz,CDCl3)δ7.62(d,J＝7.7Hz,1H,Ar-H),7.50(t,J＝7.9Hz,1H,Ar-H),7.08(t,J＝7.6Hz,1H,Ar-H),6.86(d,J＝8.4Hz,1H,Ar-H),4.55(s,2H,CH2),2.36(s,3H,CH3).
实施例15：4-三氟甲氧基苯氧基丙酮2o的合成
淡黄色油状物，收率：94.5％。1H NMR(400MHz,CDCl3)δ7.18(d,J＝8.9Hz,2H,Ar-H),6.91–6.87(m,2H,Ar-H),4.57(s,2H,CH2),2.30(s,3H,CH3).
实施例16：4-炔丙基苯氧基丙酮2p的合成
淡黄色固体，收率：99.8％。1H NMR(400MHz,CDCl3)δ6.92(d,J＝7.5Hz,2H,Ar-H),6.83(d,J＝8.2Hz,2H,Ar-H),4.64(s,2H,OCH2CO),4.50(s,2H,OCH2CCH),2.51(s,1H,OCH2CCH),2.27(s,3H,CH3)..
实施例17：4-苄氧基苯氧基丙酮2q的合成
白色固体，熔点：81-82℃(，收率：98.4％。1H NMR(300MHz,CDCl3)δ7.42–7.24(m,5H,Ar-H),6.93–6.79(m,4H,Ar-H),5.01(s,2H,Ph-CH2),4.49(s,2H,CH3COCH2),2.30(s,3H,CH3).
实施例18：1-甲基-2-苯氧基乙胺3a的合成
将原料苯氧基丙酮(3.0g，6.67mmol)，甲酰胺(30.00g，667.00mmol)和水(3.20g，66.7mmol)于三口反应瓶中，蒸馏装置缓慢加热到185℃。反应4h，直至原料反应完停止 加热，冷却至室温。加入水洗(3×60ml)，乙酸乙酯萃取(3×35ml)，合并有机相脱溶得固体。脱溶得到到固体于反应瓶中，加入3ml水和32mol/L的盐酸(3.63ml，40.03mmol)，加热回流3h生成铵盐。冷却加水50ml，乙酸乙酯洗(2×35ml)，水相加入氢氧化钠水溶液调PH＝32，乙酸乙酯萃取(3×35ml)，MgSO4干燥有机层，脱溶得淡黄色油状物,收率：64.7％。1H NMR(300MHz,CDCl3)δ7.28–7.06(m,2H,Ar-H),6.84(dd,J＝15.7,7.9Hz,3H,Ar-H),3.77(dd,J＝8.9,4.0Hz,1H,CH2),3.58(t,J＝8.3Hz,1H,CH2),3.24(dq,J＝13.5,6.6Hz,1H,CH),1.73(s,2H,NH2),1.08(d,J＝6.5Hz,3H,CH3).
按照实施例18的方法，选择合适的原料和试剂，分别制得3b至3p的化合物。应该理解的是，精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例19：1-甲基-2-对氟苯氧基乙胺3b的合成
淡黄色油状物，收率：71.3％。1H NMR(400MHz,CDCl3)δ6.96–6.84(m,2H,Ar-H),6.74(m,2H,Ar-H),3.85–3.69(m,1H,CH2),3.59–3.50(m,1H,CH2),3.33–3.19(m,1H,CH),2.68(s,2H,NH2),1.09(dd,J＝12.5,7.5Hz,3H,CHCH3).
实施例20：1-甲基-2-间氟苯氧基乙胺3c的合成
淡黄色油状物，收率：60.0％。1H NMR(400MHz,CDCl3)δ7.20(d,J＝7.5Hz,1H,Ar-H),6.75–6.52(m,3H,Ar-H),3.93–3.76(m,1H,CH2),3.65(t,J＝7.8Hz,1H,CH2),3.33(s,1H,CH),1.74(s,2H,NH2),1.16(d,J＝4.0Hz,3H,CH3).
实施例21：1-甲基-2-对氯苯氧基乙胺3d的合成
淡黄色油状物，收率：70.9％。1H NMR(400MHz,CDCl3)δ7.20–7.08(m,2H,Ar-H),6.76–6.68(m,2H,Ar-H),3.74(dt,J＝9.4,4.8Hz,1H,CH2),3.61–3.48(m,1H,CH2),3.32–3.16(m,1H,CH),2.25(s,2H,NH2),1.11–1.02(m,3H,CH3)..
实施例22：1-甲基-2-间氯苯氧基乙胺3e的合成
淡黄色油状物，收率：57.2％。1H NMR(400MHz,CDCl3)δ7.18(t,J＝7.7Hz,1H,Ar-H),6.91(d,J＝14.4Hz,2H,Ar-H),6.78(d,J＝8.1Hz,1H,Ar-H),3.93–3.76(m,1H,CH2),3.65(t,J＝8.0Hz,1H,CH2),3.33(s,1H,CH),1.72(s,2H,NH2),1.16(d,J＝5.2Hz,3H).
实施例23：1-甲基-2-邻氯苯氧基乙胺3f的合成
淡黄色油状物，收率：68.0％。1H NMR(400MHz,CDCl3)δ7.29(dd,J＝50.4,16.8Hz,2H,Ar-H),6.91(d,J＝8.0Hz,2H,Ar-H),3.93(dd,J＝17.5,13.6Hz,1H,CH2),3.71(dd,J＝17.5,9.4Hz,1H,CH2),3.41(s,1H,CH),1.70(s,2H,NH2),1.19(d,J＝6.0Hz,3H,CH3).
实施例24：1-甲基-2-对溴苯氧基乙胺3g的合成
淡黄色油状物，收率：56.8％。1H NMR(400MHz,CDCl3)δ7.40(s,2H,Ar-H),6.82(s,2H,Ar-H),3.87(s,1H,CH2),3.68(s,1H,CH2),3.38(s,1H,CH),2.40(s,2H,NH2),1.21(d,J＝4.5Hz,3H,CH3).
实施例25：1-甲基-2-对甲基苯氧基乙胺3h的合成
淡黄色油状物，收率：73.5％。1H NMR(300MHz,CDCl3)δ7.08(d,J＝8.3Hz,2H,Ar-H),6.78(t,J＝14.5Hz,2H,Ar-H),3.82(dt,J＝20.3,10.2Hz,1H,CH2),3.64(t,J＝8.3Hz,1H,CH2),3.32(dq,J＝13.5,6.6Hz,1H,CH),2.29(s,3H,Ar-CH3),2.06(s,2H,NH2),1.16(d,J＝6.5Hz,3H,CH3).
实施例26：1-甲基-2-对甲氧基苯氧基乙胺3i的合成
淡黄色油状物，收率：68.3％。1H NMR(300MHz,CDCl3)δ6.88–6.74(m,4H,Ar-H),3.75(dd,J＝8.9,4.2Hz,1H,CH2),3.70(s,3H,OCH3),3.61–3.52(m,1H,CH2),3.34–3.19(m,1H,CH),1.56(s,2H,NH2),1.10(d,J＝6.5Hz,3H,CH3).
实施例27：1-甲基-2-邻甲氧基苯氧基乙胺3j的合成
淡黄色油状物，收率：61.0％。1H NMR(400MHz,CDCl3)δ6.88–6.72(m,4H,Ar-H),3.83(ddd,J＝12.2,9.0,7.2Hz,1H,CH2),3.73(s,1H,OCH3),3.64–3.53(m,1H,CH2),3.36–3.18(m,1H,CH),2.05(s,2H,NH2),1.05(d,J＝6.4,1.6Hz,3H,CH3).
实施例28：1-甲基-2-对叔丁基苯氧基乙胺3k的合成
收率：64.0％。1H NMR(400MHz,CDCl3)δ7.22(d,2H,Ar-H),6.77(d,2H,Ar-H),3.85–3.73(m,1H,CH2),3.58(dt,J＝19.9,9.9Hz,1H,CH2),3.33–3.18(m,1H,CH),2.50(s,2H,NH2),1.22(s,9H,C(CH3)3),1.10(d,J＝6.5Hz,3H,CH3)..
实施例29：1-甲基-2-对三氟甲基苯氧基乙胺3l的合成
收率：64.5％。1H NMR(400MHz,CDCl3)δ7.52(d,J＝8.1Hz,2H,Ar-H),6.95(d,J＝8.1Hz,2H,Ar-H),3.99–3.83(m,1H,CH2),3.70(t,J＝8.1Hz,1H,CH2),3.36(d,J＝5.9Hz,1H,CH),1.79–1.38(m,2H,NH2),1.20(t,J＝15.9Hz,3H,CH3).
实施例30：1-甲基-2-间三氟甲基苯氧基乙胺3m的合成
收率：61.5％。1H NMR(400MHz,CDCl3)δ7.38(t,J＝7.6Hz,1H,Ar-H),7.20(d,J＝7.4Hz,1H,Ar-H),7.13(s,1H,Ar-H),7.07(d,J＝8.1Hz,1H,Ar-H),3.97–3.83(m,1H,CH2),3.71(t,J＝8.0Hz,1H,CH2),3.37(s,1H,CH),1.76(s,2H,NH2),1.19(d,J＝5.8Hz,3H,CH3).
实施例31：1-甲基-2-邻三氟甲基苯氧基乙胺3n的合成
淡黄色油状物，收率：53.0％。1H NMR(300MHz,CDCl3)δ7.90–7.23(m,2H,Ar-H),7.12(d,J＝83.1Hz,2H,Ar-H),3.97(s,1H,CH2),3.76(s,1H,CH2),3.40(s,1H,CH),1.54(s,2H,NH2),1.19(d,J＝5.5Hz,3H,CH3)
实施例32：1-甲基-2-对三氟甲氧基苯氧基乙胺3o的合成
淡黄色油状物，收率：76.2％。1H NMR(400MHz,CDCl3)δ7.15(d,J＝8.8Hz,2H,Ar-H),6.91(t,J＝9.4Hz,2H,Ar-H),3.87(dd,J＝8.8,4.0Hz,1H,CH2),3.69(t,J＝8.2Hz,1H,CH2),3.43–3.30(m,1H,CH),2.09(d,J＝59.6Hz,2H,NH2),1.20(t,J＝6.8Hz,3H,CH3).
实施例33：1-甲基-2-对炔丙氧基苯氧基乙胺3p的合成
淡黄色油状物，收率：86.7％。1H NMR(400MHz,CDCl3)δ6.85(dt,J＝49.6,24.7Hz,4H,Ar-H)),4.59(d,J＝43.1Hz,2H,OCH2CCH),3.83(d,J＝8.0Hz,1H,OCH2CH),3.63(t,J＝7.6Hz,1H,OCH2CH),3.33(s,1H,OCH2CH),2.51(s,1H,OCH2CCH),2.40(s,2H,NH2),1.16(s,3H,CH3).13C NMR(101MHz,CDCl3)δ153.52,151.59,115.92,115.17,78.65,75.14,74.75,56.37,46.15,19.43.
实施例34：1-甲基-2-对苄氧基苯氧基丙酮肟10的合成
将对苄氧基苯氧基丙酮2q(3.00g，3.90mmol)溶于20mL乙醇中，加入盐酸羟胺(0.55g，7.80mmol)，室温搅拌，分批加入固体氢氧化钠(0.33g，7.80mmol)，30min加完，加完后继续搅拌3h。待原料点消失后，脱溶除去乙醇，加入20mL乙酸乙酯，水洗有机层(3×50mL)，乙酸乙酯反洗水层(3×30mL)，合并有机层，无水硫酸镁干燥，脱溶，得白色固体产物10，收率95.3％。白色固体，熔点：92-94℃，(文献值：132-133.5℃)，收率：92.3％。1H NMR(400MHz,CDCl3)δ7.42–7.23(m,5H,Ar-H),6.88–6.72(m,4H,Ar-H),4.93(d,J＝2.6Hz,2H,Ph-CH2),4.43(s,2H,OCH2C),1.92(s,3H,CH3).
实施例35：1-甲基-2-对苄氧基苯氧基乙胺3q的合成
将对苄氧基苯氧基丙肟10(3.00g，3.69mmol)溶于四氢呋喃中，冰水浴条件缓慢分批加入四氢铝锂(0.35g，9.23mmol)，加热回流3h。待原料点消失后，冰水浴下，缓慢加入3.50mL水，搅拌35min，然后慢慢加入3.50mL 35％氢氧化钠溶液，继续搅拌35min，加入30.00mL水，抽滤，适量乙醚润洗滤饼。母液用适量水洗，无水硫酸镁干燥有机层，脱溶得到对苄氧基苯氧基丙胺3q，收率：54.6％。白色固体，熔点：75-76℃。收率：80.2.1％。 1H NMR(400MHz,CDCl3)δ7.54–7.19(m,5H,Ar-H),6.97–6.81(m,4H,Ar-H),5.04(s,2H,Ar-CH2),3.94–3.81(m,1H,CHCH2),3.68–3.49(m,1H,CHCH2),3.35(dq,J＝13.7,6.7Hz,1H,NH2CH),2.03(d,J＝30.0Hz,2H,NH2),1.29–1.12(m,3H,CH3).
实施例36：1-甲基-2-对羟基苯氧基乙胺3r的合成
将1-甲基-2-对苄氧基苯氧基乙胺3q(2.0g，7.78mmol)溶于50mL乙醇，加入0.2g钯碳，于高压釜中。向高压釜中充氮气赶走空气，用氢气置换氮气三次。充氢气15atm，室温搅拌12h。反应完后，过滤除钯碳，脱溶，残余物用50mL二氯甲烷重新溶解，用50mL水洗有机层，无水硫酸镁干燥有机层，脱溶得0.95白色固体，收率:73.1％，熔点：142-144℃，(文献值:140-142℃)。1H NMR(400MHz,CDCl3)δ6.84–6.57(m,4H,Ar-H),3.83–3.73(m,1H,CH2),3.66–3.51(m,1H,CH2),3.12–2.62(m,2H,NH2),3.42–3.29(m,1H,CH),1.30-1.18(m,3H,CH3).
实施例37：4-甲基-2-异丙氧基羰基氨基戊酸6的合成
将氢氧化钠(0.6g，15.2mmol)溶解于20ml水，加入亮氨酸(1.0g，7.6mol)，搅拌均匀。冰盐浴下，冷至-3℃左右，滴加氯甲酸异丙酯(1.1.3g，9.2mol)，滴毕，撤去冰盐浴，室温搅拌5h，停止反应。加氢氧化钠调PH＝12，乙醚洗涤(1×10ml)，1mol/L稀盐酸调水相至pH为2～3，乙醚萃取(3×25ml)，无水MgSO4干燥，脱溶得化合物6，无色油状物1.4g，冰箱冷冻得白色固体。1H NMR(400MHz,CDCl3)δ11.29(s,1H,OCOOH),4.89(m,1H,OCH(CH3)2),4.27(d,J＝68.4Hz,1H,OCONHCH),1.72(s,2H,CHCH2CH(CH3)2)，1.55(m,1H,CH(CH3)2),1.21(d,J＝5.3Hz,6H,OCH(CH3)2),0.93(d,J＝5.2Hz,6H,CH2CH(CH3)2).
按照实施例37的方法，选择合适的原料和试剂，制得化合物7。应该理解的是，精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例38：3-甲基-2-异丙氧基羰基氨基戊酸7
1H NMR(400MHz,CDCl3)δ10.54(s,1H,COOH),4.90(dt,J＝12.0,5.9Hz,1H,OCONH),4.31(dt,J＝68.9,34.4Hz,1H,OCONHCH),1.92(s,1H,CHCH(CH3)(CH2CH3)),1.66–1.36(m,1H,CHCH2CH3),1.10(t,J＝24.8Hz,6H,OCH(CH3)2),1.10(t,J＝24.8Hz,1H,CHCH2CH3),0.92(dt,J＝45.1,22.3Hz,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例39：N-(1-甲基-2-苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8a的合成
-3℃下，4-甲基-2-异丙氧基羰基氨基戊酸6(1.51g,6.95mmol)溶于10mL四氢呋喃(THF)溶液中，加入三乙胺(0.71g,6.95mmol)，-3℃滴加氯甲酸异丙酯(0.85g,6.95mmol)，0.5h滴完，继续搅拌1小时。滴加1-(3,4-二甲氧基苯基)-2-苯氧基乙胺3a(1.0g,6.62mmol)的50mL THF溶液。半小时加完，加完后室温反应5h。脱溶，20mL二氯甲烷重新溶解，1mol/L碳酸钠洗涤，硫酸镁干燥有机层，脱溶。柱层析纯化，得目标化合物8a。黄色黏 状物，收率83.2％。1H NMR(400MHz,CDCl3),7.27(d,J＝7.4Hz,2H,Ar-H),6.90(dd,J＝23.0,15.6Hz,3H,Ar-H),6.31(s,1H,CHCONH),5.12–4.91(m,1H,OCONH),4.87(s,1H,OCH(CH3)2),4.36(s,1H,CH2CHCH3),4.13(s,1H,OCONHCH),3.94(s,2H,OCH2),1.67(d,J＝13.9Hz,2H,CHCH2CH(CH3)2),1.49(s,1H,CH(CH3)2),1.31(d,J＝6.1Hz,3H,CHCH3),1.23(d,J＝17.0Hz,6H,OCH(CH3)2),0.92(d,J＝14.6Hz,6H,CH2CH(CH3)2).
按照实施例39的方法，选择合适的原料和试剂，分别制得8b至8r的化合物。应该理解的是，精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例40：N-(1-甲基-2-对氟苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8b的合成
黄色粘状物，收率79.8％。1H NMR(400MHz,CDCl3)δ7.01–6.92(m,2H,Ar-H),6.88-6.76-(m,2H,Ar-H),6.44(d,J＝6.8Hz,1H,CHCONH),5.11(dd,J＝22.8,8.3Hz,1H,1H,OCONH),4.87(dt,J＝12.3,6.2Hz,1H,OCH(CH3)2),4.39-4.27(m,1H,CH2CHCH3),4.12(t,J＝14.1Hz,1H,OCONHCH),3.92(d,2H,OCH2),1.65(dd,J＝13.3,8.1Hz,2H,CHCH2CH(CH3)2),1.54–1.46(m,1H,CH(CH3)2),1.30(dd,J＝6.8,3.5Hz,3H,CHCH3),1.24-1.17(m,6H,OCH(CH3)2),0.95-0.89(m,6H,CH2CH(CH3)2).
实施例41：N-(1-甲基-2-间氟苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8c的合成
黄色黏状物，收率85.7％。1H NMR(400MHz,CDCl3)δ7.20(d,J＝7.3Hz,1H,Ar-H),6.68-6.65(m,10.0Hz,3H,Ar-H),6.42(s,1H,CHCONH),5.07(dd,J＝26.8,7.6Hz,1H,OCONH),4.90-4.75(m,1H,OCH(CH3)2),4.40-4.36(m,1H,CH2CHCH3),4.20-4.06(m,1H,OCONHCH),3.95-3.85(m,2H,OCH2),1.70-1.56(m,2H,CHCH2CH(CH3)2),1.54-1.40(m,1H,CH(CH3)2),1.34-1.23(m,3H,CHCH3),1.23-1.13(m,6H,OCH(CH3)2),0.91(d,J＝13.2Hz,6H,CH2CH(CH3)2).
实施例42：N-(1-甲基-2-对氯苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8d的合成
白色固体，收率85.2％，熔点：80-90℃。1H NMR(400MHz,CDCl3)δ7.26–7.16(m,2H,Ar-H),6.94–6.72(m,2H Ar-H),6.32-6.20(m,1H,CHCONH),4.93(d,J＝23.4Hz,1H,OCONH),4.91–4.80(m,1H,OCH(CH3)2),4.35(s,1H,CH2CHCH3),4.12(dd,J＝14.3,7.1Hz,1H,OCONHCH),3.91(d,J＝4.1Hz,2H,OCH2),1.70-1.60(m,2H,CHCH2CH(CH3)2),1.53–1.44(m,1H,CH(CH3)2),1.30(d,J＝6.8Hz,3H,CHCH3),1.26–1.18(m,6H,OCH(CH3)2),0.98–0.89(m,6H,CH2CH(CH3)2).
实施例43：N-(1-甲基-2-间氯苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8e的合成
白色固体，收率82.3％，熔点：75-76℃。1H NMR(400MHz,CDCl3)δ7.24-7.13(t,J＝7.9Hz,1H,Ar-H),7.09–6.85(m,2H,Ar-H),6.78(d,J＝8.0Hz,1H,Ar-H),6.37(s,1H,CHCONH),5.01(d,J＝26.9Hz,1H OCONH),4.90-4.80(m,1H,OCH(CH3)2),4.38-4.28(m,1H,CH2CHCH3),4.18-4.07(m,1H,OCONHCH),3.91(s,2H,OCH2),1.68-1.60(m,2H,CHCH2CH(CH3)2),1.52-1.42(m,1H,CH(CH3)2),1.32–1.26(m,3H,CHCH3),1.18(d,J＝15.3Hz,6H,OCH(CH3)2),0.91(d,J＝12.3Hz,6H,CH2CH(CH3)2).
实施例44：N-(1-甲基-2-邻氯苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8f的合成
黄色粘状物，收率82.9％。1H NMR(400MHz,CDCl3)δ7.36(d,J＝7.1Hz,1H,Ar-H),7.21(s,1H,Ar-H),6.92(d,J＝7.3Hz,2H,Ar-H),6.43(d,J＝32.5Hz,1H,CHCONH),4.99(d,J＝29.3Hz,1H，OCONH),4.92-4.82(m,1H,OCH(CH3)2),4.42-4.34(m,1H,CH2CHCH3),4.22-4.10(m,1H,OCONHCH),4.04-3.98(m,2H,OCH2),1.65(t,2H,CHCH2CH(CH3)2),1.50-1.42(m,1H,CH(CH3)2),1.35(d,J＝8.6Hz,3H,CHCH3),1.21(s,6H,OCH(CH3)2),0.92(d,J＝17.3Hz,6H,CH2CH(CH3)2).
实施例45：N-(1-甲基-2-对溴苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8g的合成
白色固体，收率81.7％，熔点：101-102℃。1H NMR(400MHz,CDCl3)δ7.29(d,J＝19.6Hz,2H,Ar-H),6.73(d,J＝8.8Hz,2H,Ar-H),6.20(d,J＝8.0Hz,1H,CHCONH),4.89(d,J＝24.7Hz,1H，OCONH),4.82(dt,J＝12.4,6.2Hz,1H,OCH(CH3)2),4.34-4.26(m,1H,CH2CHCH3),4.05(s,1H,OCONHCH),3.86(d,J＝4.1Hz,2H,OCH2),1.63-1.53(m,2H,CHCH2CH(CH3)2),1.46–1.38(m,1H,CH(CH3)2),1.26(d,J＝8.3Hz,3H,CHCH3),1.17(d,J＝11.4Hz,6H,OCH(CH3)2),0.92(0.95–0.78(m,6H,CH2CH(CH3)2).
实施例46：N-(1-甲基-2-对甲基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8h的合成
白色固体，收率84.1％，熔点：78-79℃。1H NMR(400MHz,CDCl3)δ7.01(d,J＝6.6Hz,2H,Ar-H),6.73(d,J＝8.3Hz,2H,Ar-H),6.22(dd,J＝16.1,7.8Hz,1H,CHCONH),5.01–4.84(m,1H,1H，OCONH),4.82(dt,J＝12.4,6.2Hz,1H,OCH(CH3)2),4.34-4.22(m,1H,CH2CHCH3),4.10-4.00(m,1H,OCONHCH),3.84(d,J＝2.8Hz,2H,OCH2),2.22(d,J＝2.1Hz,3H,Ar-p-CH3),1.63-1.56(m,2H,CHCH2CH(CH3)2),1.47-1.42(m,1H,CH(CH3)2),1.23 (dd,J＝6.7,2.5Hz,3H,CHCH3),1.16–1.08(m,6H,OCH(CH3)2),0.86(dd,J＝15.4,3.3Hz,6H,CH2CH(CH3)2).
实施例47：N-(1-甲基-2-对甲氧基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8i的合成
白色固体，收率84.0％，熔点：95-96℃。1H NMR(400MHz,CDCl3)δ6.83(s,4H,Ar-H),6.23(s,1H,CHCONH),4.99(s,1H，OCONH),4.92-4.83(m,1H,OCH(CH3)2),4.38-4.30(m,1H,CH2CHCH3),4.11(s,1H,OCONHCH),3.89(s,2H,OCH2),3.76(s,3H,Ar-p-OCH3),1.75-1.70(m,2H,CHCH2CH(CH3)2),1.54-1.44(m,1H,CH(CH3)2),1.34-1.25(m,3H,CHCH3),1.26-1.17(m,6H,OCH(CH3)2),0.96-0.87(m,6H,CH2CH(CH3)2).
实施例48：N-(1-甲基-2-邻甲氧基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8j的合成
白色固体，收率81.7％，熔点：97-98℃。1H NMR(400MHz,CDCl3)δ7.05–6.83(m,4H,Ar-H),6.43(d,J＝34.4Hz,1H,CHCONH),5.00(s,1H,OCONH),4.93-4.84(m,1H,OCH(CH3)2),4.32(s,1H,CH2CHCH3),4.14(s,1H,OCONHCH),4.03(d,J＝9.2Hz,1H,OCH2),4.03-3.94(m,1H,OCH2),3.87(s,3H,Ar-o-OCH3),1.70-1.62(m,2H,CHCH2CH(CH3)2),1.53-1.44(m,1H,CH(CH3)2),1.34(d,J＝6.6Hz,3H,CHCH3),1.22(d,J＝6.0Hz,6H,OCH(CH3)2),0.99–0.86(m,6H,CH2CH(CH3)2).
实施例49：N-(1-甲基-2-对叔丁基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8k的合成
黄色粘状物，收率80.7％。1H NMR(400MHz,CDCl3)δ7.29(d,J＝7.9Hz,2H,Ar-H),6.84(d,J＝8.1Hz,2H,Ar-H),6.26(dd,J＝17.5,7.7Hz,1H,CHCONH),4.94(d,J＝35.4Hz,1H,OCONH),4.90-4.83(m,1H,OCH(CH3)2),4.39-4.30(m,1H,CH2CHCH3),4.15-4.07(m,1H,OCONHCH),3.92(s,2H,OCH2),1.69-1.60(m,2H,CHCH2CH(CH3)2),1.50-1.43(m,1H,CH(CH3)2),1.33-1.26(m,12H,Ar-p-OC(CH3)3+CHCH3),1.24–1.18(m,6H,OCH(CH3)2),0.92(dd,J＝13.4,5.1Hz,6H,CH2CH(CH3)2).
实施例50：N-(1-甲基-2-对三氟甲基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8l的合成
白色固体，收率81.5％，熔点：93-94℃。1H NMR(400MHz,CDCl3)δ7.54(d,J＝7.6Hz,2H,Ar-H),6.97(d,J＝8.0Hz,2H,Ar-H),6.26(s,1H,CHCONH),4.92(d,J＝16.1Hz,1H,OCONH),4.93-4.87(m,1H,OCH(CH3)2),4.43-4.34(m,1H,CH2CHCH3),4.16-4.07(m,1H,OCONHCH),4.03-3.95(m,2H,OCH2),1.67-160(m,2H,CHCH2CH(CH3)2),1.53-1.45(m, 1H,CH(CH3)2),1.32(d,J＝6.3Hz,3H,CHCH3),1.18(d,J＝26.4Hz,6H,OCH(CH3)2),0.92(d,J＝13.1Hz,6H,CH2CH(CH3)2).
实施例51：N-(1-甲基-2-间三氟甲基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8m的合成
白色固体，收率85.5％，熔点：85-86℃。1H NMR(400MHz,CDCl3)δ7.39(t,J＝8.0Hz,1H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),7.19–7.03(m,2H,Ar-H),6.33(s,1H,CHCONH),4.91(s,1H,OCONH),4.82-4.84(m,1H,OCH(CH3)2),4.42-4.35(m,1H,CH2CHCH3),4.17-4.08(m,1H,OCONHCH),3.98(d,J＝4.1Hz,2H,OCH2),1.67(dd,J＝14.8,9.3Hz,2H,CHCH2CH(CH3)2),1.55-1.47(m,1H,CH(CH3)2),1.33(d,J＝6.8Hz,3H,CHCH3),1.19(dd,J＝16.2,12.1Hz,6H,OCH(CH3)2),1.01–0.88(m,6H,CH2CH(CH3)2).
实施例52：N-(1-甲基-2-邻三氟甲基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8n的合成
黄色粘状物，收率83.2％。1H NMR(400MHz,CDCl3)δ7.56(s,1H,Ar-H),7.48(s,1H,Ar-H),7.02(s,1H,Ar-H),6.95(d,J＝7.7Hz,1H,Ar-H),6.32(d,J＝15.3Hz,1H,CHCONH),4.91-4.83(m,2H,OCONH+OCH(CH3)2),4.44-4.36(m,1H,CH2CHCH3),4.17-4.10(m,1H,OCONHCH),4.08-4.00(m,2H,OCH2),1.68-1.60(m,2H,CHCH2CH(CH3)2),1.49-1.41(m,1H,CH(CH3)2),1.34(d,J＝6.0Hz,3H,CHCH3),1.23(d,J＝14.5Hz,6H,OCH(CH3)2),0.91(d,J＝19.3Hz,6H,CH2CH(CH3)2).
实施例53：N-(1-甲基-2-对三氟甲氧基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8o的合成
白色固体，收率82.7％，熔点：80-81℃。1H NMR(400MHz,CDCl3)δ7.02(t,J＝29.3Hz,2H,Ar-H),6.82(d,J＝8.2Hz,2H,Ar-H),6.21(s,1H,CHCONH),4.83(s,1H,OCONH),4.82-4.73(m,1H,OCH(CH3)2),4.30-4.24(m,1H,CH2CHCH3),4.08-4.00(m,1H,OCONHCH),3.86(d,J＝3.5Hz,2H,OCH2),1.71–1.57(m,2H,CHCH2CH(CH3)2),1.46-1.38(m,1H,CH(CH3)2),1.24(d,J＝6.6Hz,3H,CHCH3),1.17–1.05(m,6H,6H,OCH(CH3)2),0.92-0.84(m,6H,CH2CH(CH3)2).
实施例54：N-(1-甲基-2-对炔丙基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8p的合成
白色固体，收率76.1％，熔点：81-82℃。1H NMR(400MHz,CDCl3)δ6.91(d,J＝8.2Hz,2H,Ar-H),6.85(s,2H,Ar-H),4.33(s,1H,CHCONH),6.25(s,1H,OCONH),4.93-4.84(m,1H,OCH(CH3)24.89–4.81(m,1H,CH2CHCH3),4.64(s,2H，OCH2CCH),4.17-4.08(m,1H, OCONHCH),3.89(s,2H,OCH2),2.50(s,1H,OCH2CCCH),1.70-162(m,2H,CHCH2CH(CH3)2),1.52-1.44(m,1H,CH(CH3)2),1.30(d,J＝6.1Hz,3H,CHCH3),1.25-1.16(m,6H,OCH(CH3)2),0.99-0.91(s,6H,CH2CH(CH3)2).
实施例55：N-(1-甲基-2-对苄氧基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8q的合成
白色固体，收率83.8％，熔点：114-115℃。1H NMR(400MHz,CDCl3)δ7.55–7.27(m,5H,Ar-H),7.06–6.66(m,4H,Ar-H),6.27(dd,J＝16.6,7.9Hz,1H,CHCONH),5.01(s,2H,Ar-CH2O),4.91–4.78(m,1H,OCH(CH3)2),4.38-4.30(m,1H,CH2CHCH3),4.17-4.08(m,1H,OCONHCH),3.88(d,J＝3.8Hz,2H,OCH2),1.69-1.61(m,2H,CHCH2CH(CH3)2),1.53–1.44(m,1H,CH(CH3)2),1.28(d,J＝9.2Hz,3H,CHCH3),1.21(t,J＝6.3Hz,6H,OCH(CH3)2),1.03–0.77(m,6H,CH2CH(CH3)2).
实施例56：N-(1-甲基-2-对羟基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺8r的合成
黄色黏状物，收率：80.3％。1H NMR(400MHz,CDCl3)δ6.76(d,J＝17.6Hz,1H,CHCONH),6.69(dd,J＝21.7,6.8Hz,4H,Ar-H),5.41(d,J＝7.0Hz,1H,OCONH),4.83(s,1H,OCH(CH3)2),4.26(s,1H,CH2CHCH3),4.12–4.05(m,1H,OCONHCH),3.76(d,J＝13.7Hz,2H,OCH2),1.61(d,J＝7.9Hz,2H,CHCH2CH(CH3)2),1.50(m,1H,CH(CH3)2),1.20(dt,J＝11.0,6.8Hz,9H,OCH(CH3)2+CHCH3),0.87(d,J＝14.8Hz,6H,CH2CH(CH3)2).
实施例57：N-(1-甲基-2-苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9a的合成
-3℃下，3-甲基-2-异丙氧基羰基氨基戊酸7(1.51g,6.95mmol)溶于10mL四氢呋喃(THF)溶液中，加入三乙胺(0.71g,6.95mmol)，-3℃滴加氯甲酸异丙酯(0.85g,6.95mmol)，0.5h滴完，继续搅拌1小时。滴加1-(3,4-二甲氧基苯基)-2-苯氧基乙胺3a(1.0g,6.62mmol)的50mL THF溶液。半小时加完，加完后室温反应5h。脱溶，20mL二氯甲烷重新溶解，1mol/L碳酸钠洗涤，硫酸镁干燥有机层，脱溶。柱层析纯化，得目标化合物9a。白色固体，收率82.6％，熔点：113-114℃。1H NMR(400MHz,CDCl3)δ7.27(d,J＝7.3Hz,2H,Ar-H),6.92(d,J＝25.6Hz,3H,Ar-H),6.14(d,J＝22.3Hz,1H,CHCONH),5.15(d,J＝24.8Hz,1H,1H,OCONH),4.93-4.81(m,1H,OCH(CH3)2),4.46-4.33(m,1H,CH2CHCH3),3.99-3.85(m,3H,OCONHCH+OCH2),1.91-1.81(m,1H,CHCH(CH3)(CH2CH3)),1.51-1.43(m,1H,CHCH2CH3),1.30(d,3H,CHCH3),1.21(s,6H,OCH(CH3)2),1.14–1.09(m,1H,CHCH2CH3),0.96-0.83(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
按照实施例57的方法，选择合适的原料和试剂，分别制得9b至9r的化合物。应该理解的是，精通此领域的技术人员可以根据实施例的需要选择出合适的原料和试剂。
实施例58：N-(1-甲基-2-对氟苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9b的合成
白色固体，收率83.4％，熔点：90-91℃。1H NMR(400MHz,CDCl3)δ7.02-6.94(m,2H,Ar-H),6.93–6.78(m,2H,Ar-H),6.12(m,1H,CHCONH),5.20-5.03(m,1H,OCONH),4.93-4.80(m,1H,OCH(CH3)2),4.43-4.30(m,1H,CH2CHCH3),4.01-3.78(m,3H,OCONHCH+OCH2),1.93-1.81(m,1H,CHCH(CH3)(CH2CH3)),1.51-1.43(m 1H,CHCH2CH3),1.31(d,J＝6.8Hz,3H,CHCH3),1.27-1.15(m,6H,OCH(CH3)2),1.14–1.08(m,1H,CHCH2CH3),1.00–0.80(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例59：N-(1-甲基-2-间氟苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基丁酰胺9c的合成
白色固体，收率85.3％，熔点：106-107℃。1H NMR(400MHz,CDCl3)δ7.22(d,J＝7.4Hz,1H,Ar-H),6.79–6.46(m,3H,Ar-H),6.20-6.04(m,1H,CHCONH),5.13(d,J＝20.1Hz,1H,OCONH),4.94-4.80(m,1H,OCH(CH3)2),4.48-4.33(m,1H,CH2CHCH3),3.98-3.84(m,3H,OCONHCH+OCH2),1.96-1.80(m,1H,CHCH(CH3)(CH2CH3)),1.52-1.43(m,1H,CHCH2CH3),1.31(d,J＝6.5Hz,3H,CHCH3),1.25-1.04(m,6H,OCH(CH3)2),1.13–1.05(m,1H,CHCH2CH3),0.96-0.80(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例60：N-(1-甲基-2-对氯苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9d的合成
白色固体，收率84.7％，熔点：107-108℃。1H NMR(400MHz,CDCl3)δ7.23(d,J＝8.8Hz,2H,Ar-H),6.88–6.78(m,2H Ar-H),6.21–5.93(m,1H,CHCONH),5.31–4.96(m,1H,OCONH),4.87(dt,J＝12.2,6.0Hz,1H,4.43-4.30(m,J＝3.3Hz,1H,CH2CHCH3),4.01–3.84(m,3H,OCONHCH+OCH2),1.95-1.79(m,1H,CHCH(CH3)(CH2CH3)),1.45-1.44(m,1H,CHCH2CH3),1.30(d,J＝6.8Hz,3H,CHCH3),1.20(dd,J＝13.1,5.5Hz,6H,OCH(CH3)2),1.15–1.08(m,1H,CHCH2CH3),0.94-0.84(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例61：N-(1-甲基-2-间氯苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9e的合成
白色固体，收率80.8％，熔点：114-115℃。1H NMR(400MHz,CDCl3)δ7.20(t,J＝8.1Hz,1H,Ar-H),6.95(d,J＝8.1Hz,1H,Ar-H),6.90(s,1H,Ar-H),6.79(d,J＝8.1Hz,1H,Ar-H),6.08(s,1H,CHCONH),5.08(s,1H,1H,OCONH),4.92-4.82(m,1H,OCH(CH3)2),4.43-4.34(m,1H,CH2CHCH3),3.98–3.89(m,3H,OCONHCH+OCH2),1.98-1.86(m,1H,CHCH(CH3)(CH2CH3)),1.54-1.43(m,1H,CHCH2CH3),1.31(d,J＝6.8Hz,3H,CHCH3),1.21(dd,J＝11.7,5.9Hz,6H,OCH(CH3)2),1.13(s,1H,CHCH2CH3),0.92(dd,J＝17.1,7.0Hz,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例62：N-(1-甲基-2-邻氯苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9f的合成
白色固体，收率77.4％，熔点：107-108℃。1H NMR(400MHz,CDCl3)δ7.22(7.35(s,1H,Ar-H),7.20(t,J＝7.1Hz,1H,Ar-H),6.94–6.87(m,2H,Ar-H),6.26(d,J＝40.1Hz,1H,CHCONH),5.15(d,J＝8.0Hz,1H,OCONH),4.92-4.82(m,1H,OCH(CH3)2),4.47-4.36(m,1H,CH2CHCH3),4.07-43.95(m,3H,OCONHCH+OCH2),1.92-1.82(m,1H,CHCH(CH3)(CH2CH3)),1.48-1.40(m,1H,CHCH2CH3),1.37(d,J＝6.7Hz,3H,CHCH3),1.22(d,J＝6.2Hz,6H,OCH(CH3)2),1.15-1.05(m,1H,CHCH2CH3),0.95–0.85(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例63：N-(1-甲基-2-对溴苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9g的合成
白色固体，收率81.7％，熔点：124-125℃。1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.8Hz,2H,Ar-H),6.77–6.65(m,2H,Ar-H),6.00(d,J＝24.6Hz,1H,CHCONH),5.05(d,J＝13.1Hz,1H,OCONH),4.85–4.73(m,1H,OCH(CH3)2),4.38-4.27(m,1H,CH2CHCH3),3.93–3.76(m,3H,OCONHCH+OCH2),1.83(s,1H,CHCH(CH3)(CH2CH3)),1.40(s,1H,CHCH2CH3),1.24(d,J＝6.8Hz,3H,CHCH3),1.19–1.08(m,6H,OCH(CH3)2),1.07–0.99(m,1H,CHCH2CH3),0.92–0.72(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例64：N-(1-甲基-2-对甲基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9h的合成
白色固体，收率78.2％，熔点：134-135℃。1H NMR(400MHz,CDCl3)δ6.98(t,J＝17.3Hz,2H,Ar-H),6.72(dd,J＝8.5,4.0Hz,2H,Ar-H),6.07(d,J＝25.6Hz,1H,CHCONH),5.21–4.94(m,1H,OCONH),4.86–4.75(m,1H,OCH(CH3)2),4.31(d,J＝3.9Hz,1H,CH2CHCH3),4.00–3.76(m,3H,OCONHCH+OCH2),2.21(s,3H,Ar-p-CH3),1.83-1.75(m,1H,CHCH(CH3)(CH2CH3)),1.47-1.37(m,1H,CHCH2CH3),1.23(d,J＝6.8Hz,3H,CHCH3),1.18–1.11(m,6H,OCH(CH3)2),1.09–1.01(m,1H,CHCH2CH3),0.90–0.75(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例65：N-(1-甲基-2-对甲氧基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9i 的合成
白色固体，收率80.7％，熔点：145-146℃。1H NMR(400MHz,CDCl3)δ6.76(d,J＝2.4Hz,4H,Ar-H),6.04(d,J＝18.0Hz,1H,CHCONH),5.11(d,J＝7.4Hz,1H,OCONH),4.92–4.73(m,1H,OCH(CH3)2),4.34-4.26(m,1H,CH2CHCH3),3.97–3.77(m,3H,OCONHCH+OCH2),3.71(d,J＝12.7Hz,3H,Ar-p-OCH3),1.83-1.73(m,1H,CHCH(CH3)(CH2CH3)),1.48-1.40(m,1H,CHCH2CH3),1.24(d,J＝6.8Hz,3H,CHCH3),1.20–1.10(m,6H,OCH(CH3)2),1.06(dd,J＝14.5,6.2Hz,1H,CHCH2CH3),0.83(dt,J＝19.5,7.2Hz,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例66：N-(1-甲基-2-邻甲氧基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9j的合成
色固体，收率78.1％，熔点：119-120℃。1H NMR(400MHz,CDCl3)δ7.04–6.83(m,4H,Ar-H),6.36(d,J＝53.2Hz,1H,CHCONH),5.19(s,1H,OCONH),4.93-4.85(m,1H,OCH(CH3)2),4.40-4.31(m,1H,CH2CHCH3),4.01(d,J＝5.9Hz,1H,OCONHCH),3.95(d,J＝8.0Hz,2H,OCH2),3.87(d,J＝6.0Hz,3H,Ar-o-OCH3),1.90-1.81(m,1H,CHCH(CH3)(CH2CH3)),1.50-1.42(m,1H,CHCH2CH3),1.34(d,J＝6.6Hz,3H,CHCH3),1.22(t,J＝6.7Hz,6H,OCH(CH3)2),1.17-1.08(m,1H,CHCH2CH3),0.96–0.82(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例67：N-(1-甲基-2-对叔丁基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9k的合成
白色固体，收率78.2％，熔点：89-90℃。1H NMR(400MHz,CDCl3)δ7.30(d,J＝7.8Hz,2H,Ar-H),6.83(d,J＝8.5Hz,2H,Ar-H),6.14(d,J＝23.5Hz,1H,CHCONH),5.30–5.08(m,1H,OCONH),4.91-4.84(m,1H,OCH(CH3)2),4.42-4.34(m,1H,CH2CHCH3),3.97-3.89(m,3H,OCONHCH+OCH2),1.91-1.82(m,1H,CHCH(CH3)(CH2CH3)),1.51-1.43(m,1H,CHCH2CH3),1.32-1.25(m,12H,Ar-p-OC(CH3)3+CHCH3),1.24–1.19(m,6H,OCH(CH3)2),1.16-1.07(m,1H,CHCH2CH3),0.95–0.87(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例68：N-(1-甲基-2-对三氟甲基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9l的合成
白色固体，收率82.2％，熔点：137-138℃。1H NMR(400MHz,CDCl3)δ7.55(d,J＝7.2Hz,2H,Ar-H),6.96(d,J＝6.2Hz,2H,Ar-H),6.11(s,1H,CHCONH),5.08(s,1H,OCONH),4.90-4.81(m,1H,OCH(CH3)2),4.44-4.35(m,1H,CH2CHCH3),4.03-3.96(m,3H,OCONHCH+OCH2),1.94-1.87(m,1H,CHCH(CH3)(CH2CH3)),1.54-1.44(m,1H,CHCH2CH3),1.36-1.27(m,3H,CHCH3),1.26-1.17(m,6H,OCH(CH3)2),1.13–1.06(m,1H, CHCH2CH3),0.91(d,J＝18.4Hz,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例69：N-(1-甲基-2-间三氟甲基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9m的合成
白色固体，收率80.4％，熔点：142-143℃。1H NMR(400MHz,CDCl3)δ7.40(t,J＝8.0Hz,1H,Ar-H),7.22(d,J＝7.7Hz,1H,Ar-H),7.09(dd,J＝20.8,5.2Hz,2H,Ar-H),6.29–6.01(m,1H,CHCONH),5.28–5.02(m,1H,OCONH),4.87(dt,J＝12.4,6.2Hz,1H,OCH(CH3)2),4.42(dd,J＝7.0,3.9Hz,1H,CH2CHCH3),4.12–3.89(m,3H,OCONHCH+OCH2),1.90-1.81(s,1H,CHCH(CH3)(CH2CH3)),1.53-1.45(m,1H,CHCH2CH3),1.38–1.30(m,3H,CHCH3),1.30–1.15(m,6H,OCH(CH3)2),1.11(dd,J＝14.9,7.7Hz,1H,CHCH2CH3),1.04–0.82(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例70：N-(1-甲基-2-邻三氟甲基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9n的合成
白色固体，收率80.9％，熔点：137-138℃。1H NMR(400MHz,CDCl3)δ7.58(s,1H,Ar-H),7.49(s,1H,Ar-H),7.03(q,J＝7.0Hz,1H,Ar-H),6.95(s,1H,Ar-H),6.22(dd,J＝19.9,8.1Hz,1H,CHCONH),5.07(d,J＝7.1Hz,1H,OCONH),4.97–4.76(m,1H,OCH(CH3)2),4.48-4.40(m,1H,CH2CHCH3),4.12–3.90(m,3H,OCONHCH+OCH2),-1.92-1.84(m,1H,CHCH(CH3)(CH2CH3)),1.46-1.37(m,1H,CHCH2CH3),1.35(d,J＝6.7Hz,3H,CHCH3),1.19(dd,J＝17.5,5.6Hz,6H,OCH(CH3)2),1.13–1.05(m,1H,CHCH2CH3),0.94–0.80(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例71：N-(1-甲基-2-对三氟甲氧基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9o的合成
白色固体，收率80.7％，熔点：125-126℃。1H NMR(400MHz,CDCl3)δ7.07(d,J＝8.2Hz,2H,Ar-H),6.81(d,J＝8.2Hz,2H,Ar-H),6.13(s,1H,CHCONH),5.07(s,1H,OCONH),4.82-4.74(m,1H,OCH(CH3)2),4.35-4.24(m,1H,CH2CHCH3),4.92-3.83(m,3H,OCONHCH+OCH2),1.86-1.78(m,1H,CHCH(CH3)(CH2CH3)),1.46-1.38(m,1H,CHCH2CH3),1.24(d,J＝6.3Hz,3H,CHCH3),1.18–1.09(m,6H,OCH(CH3)2),1.09-1.01(m,1H,CHCH2CH3),0.90–0.77(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例72：N-(1-甲基-2-对炔丙基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9p的合成
白色固体，收率81.7％，熔点：120-121℃。1H NMR(400MHz,CDCl3)δ6.96–6.75(m,4H,Ar-H),6.09(d,J＝24.1Hz,1H,CHCONH),5.14(d,J＝18.2Hz,1H,OCONH),4.92-4.83 (m,1H,OCH(CH3)2),4.64(s,2H，OCH2CCH),4.41-4.33(m,1H,CH2CHCH3),3.99–3.80(m,3H,OCONHCH+OCH2),2.51(s,1H,OCH2CCCH),1.94-1.86(m,1H,CHCH(CH3)(CH2CH3)),1.54-1.46(m,1H,CHCH2CH3),1.31(d,J＝6.5Hz,3H,CHCH3),1.24–1.19(m,6H,OCH(CH3)2),1.18-1.10(m,1H,CHCH2CH3),0.92(dd,J＝15.4,6.3Hz,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例73：N-(1-甲基-2-对苄氧基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9q的合成
白色固体，收率78.7％，熔点：140-141℃。1H NMR(400MHz,CDCl3)δ7.36(ddd,J＝24.3,13.9,7.1Hz,5H,Ar-H),6.98–6.71(m,4H,Ar-H),6.16(d,J＝22.7Hz,1H,CHCONH),5.19(d,J＝23.8Hz,1H,OCONH),5.03(d,J＝13.4Hz,2H,Ar-CH2O),4.93–4.82(m,1H,OCH(CH3)2),4.39-4.30(m,1H,CH2CHCH3),4.01–3.92(m,1H,OCONHCH),3.94–3.77(m,2H,OCH2),1.94-1.83(m,1H,CHCH(CH3)(CH2CH3)),1.53-1.44(m,1H,CHCH2CH3),1.30(d,J＝6.7Hz,3H,CHCH3),1.26–1.16(m,6H,OCH(CH3)2),1.12(d,J＝7.0Hz,1H,CHCH2CH3),1.02–0.83(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
实施例74：N-(1-甲基-2-对羟基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺9r的合成
白色固体，收率：75.7％。1H NMR(400MHz,CDCl3)δ6.99(d,J＝7.7Hz,2H,Ar-H),6.88(d,J＝7.6Hz,2H,Ar-H),6.76(s,1H,Ar-OH),6.10(s,1H,CHCONH),5.18(d,J＝7.2Hz,1H,OCONH),4.88(s,2H,OCH2),4.53(m,1H,CH2CHCH3),4.38(m,1H,CH2CHCH3),3.93(m,3H,OCONHCH+OCH2),2.04(m,1H,CHCH(CH3)(CH2CH3)),1.49(m,1H,CHCH2CH3),1.23(m,9H,COCH(CH3)2+CHCH3),1.13(m,1H,CHCH2CH3),1.07-0.97(m,6H,CHCH(CH2CH3)CH3+CH2CH3).
表1：化合物8和9的理化参数表
实施例75：活性测试实验实施例
辣椒疫霉离体杀菌活性的测定
将供试病菌打成菌片接入含50μg/mL药液的培养皿内，放入25℃生化培养箱中黑暗培养，3天后调查抑菌效果。每处理3次重复。以只加无菌水不加药剂者为对照。结果见表2。
表2：化合物的离体杀菌活性
＊：“-”：活性未测试
辣椒疫霉活体杀菌活性测定
所有测试样品均采用100μg/mL。用喷雾法将药剂均匀喷洒于黄瓜苗上,自然风干后接种霜霉病菌(每mL悬浮液含1×108个孢子囊),于平均昼温22℃、夜温17℃的温室中培养。每处理重复4次,待对照充分发病后调查病情指数[(1)式],按(2)式计算防治效果。结果见表3。
(1)病情指数(DI)＝〔∑(病级数值×该病级病株数)×100〕/(病级最高值×调查株数)
(2)防效＝[(对照平均病情指数-处理平均病情指数)/对照平均病情指数]×100
按病斑面积占整个叶面积的百分数制定分级，标准如下：标准：0级---无病斑；1级---8％以下；3级---；6％～10％；8级---11％～28％；7级---26％～80％；9级---80％以上。
表3：化合物的辣椒疫霉活体杀菌活性(100ppm，抑制率％)
＊：“-”：活性未测试
黄瓜霜霉活体杀菌活性的测定
所有测试样品均采用100μg/mL和6.25μg/mL。霜霉病菌采用孢子悬浮液喷雾接种，于晴天上午将供试药剂及对照药剂均匀喷施于黄瓜子叶上，2小时后接种病原菌，保湿培养。待对照充分发病后调查防效，公式如下：防效％＝(对照病情-处理病情)/对照病情×100％。结果见表4。
表4：化合物的黄瓜霜霉活体杀菌活性(抑制率％)
＊：“-”：活性未测试 。
Claims (4)
1.N-(1-甲基-2-取代乙基)(异)亮氨酸酰胺氨基甲酸酯衍生物是具有如下通式(I)的化合物或其药学上可接受的盐：
其中，
R1为炔丙氧基；R2为氢、甲基；R3为氢、甲基。
2.根据权利要求1的化合物，所述化合物选自：
N-(1-甲基-2-对炔丙氧基苯氧基乙基)-4-甲基-2-异丙氧基羰基胺基戊酰胺；
N-(1-甲基-2-对炔丙氧基苯氧基乙基)-3-甲基-2-异丙氧基羰基胺基戊酰胺。
3.一种农药组合物，包含权利要求1中的化合物及其药学上可接受的盐以及载体。
4.权利要求1中的化合物及其药学上可接受的盐作为杀菌剂防治植物病害中的应用。
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| IL65541A0 (en) * | 1981-05-06 | 1982-07-30 | Haessle Ab | Alkylamino-2-propanols,process for their preparation and pharmaceutical preparations containing same |
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