CN117285491A - 类氨基酸导向的苯酞类似物及其应用 - Google Patents
类氨基酸导向的苯酞类似物及其应用 Download PDFInfo
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- CN117285491A CN117285491A CN202311223530.8A CN202311223530A CN117285491A CN 117285491 A CN117285491 A CN 117285491A CN 202311223530 A CN202311223530 A CN 202311223530A CN 117285491 A CN117285491 A CN 117285491A
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Abstract
本发明属于药物化学领域,涉及花生白绢病和花生根腐病的防治,特别是指类氨基酸导向的苯酞类似物及其制备方法和应用。该苯酞类似物具有如式A或式B所示的结构通式:、,式中:R和R’选自天然氨基酸或非天然氨基酸,非天然氨基酸为氨基酸的4‑NO2、4‑F或4‑Cl的取代产物。生物活性测定结果表明,所有化合物均具有齐整小核菌菌丝生长抑制活性,其中式A中的4‑硝基苯丙氨酸的5位取代苯酞和精氨酸5位取代苯酞具有明显的抑菌活性,同时,盆栽实验表明4‑硝基苯丙氨酸的5位取代苯酞具有较好的防效。因此,该类氨基酸导向的苯酞类化合物有很好的开发应用前景。
Description
技术领域
本发明属于药物化学领域,涉及花生白绢病和花生根腐病的防治,特别是指类氨基酸导向的苯酞类似物及其应用。
背景技术
在我国,花生分布范围较广。我国花生主产区为山东,辽宁东部,广东雷州半岛,黄淮河地区及东南沿海海滨丘陵,沙土区等。然而,一直以来花生病害的普遍性与严重性都制约着花生产量的增加。花生病害常由病原菌引起的,发生于植物根部或叶部,如根腐病,冠腐病,立枯病,白绢病,早斑病,褐斑病,晚斑病等。当两种或多种病害同时发生时,可能造成50%-70%的产量损失,比如2009年的花生病害统计显示,早期叶斑病造成损失约3.26亿美元,锈病造成损失约4.67亿美元,晚斑病造成损失约5.99亿美元。其中,花生白绢病是由齐整小核菌引起的一种毁灭性的土传真菌病害,这种病害目前在我国各个花生产区的发生日渐严重、分布面积也在逐年增大。据前期调查,在河南花生产区,一般地块发病株率为10%-30%,严重地块达40%以上;一般情况下,发病田块产量损失10%-20%,重病田块产量损失50%以上,甚至导致绝收,成为制约我省花生安全生产的重要因素。目前,防治花生白绢病主要依赖化学手段。从中国农药信息网(http://www.chinapesticide.org.cn)上查询,我国登记在花生白绢病上的化学药剂种类较少,主要是噻呋酰胺、氟酰胺和啶酰菌胺等琥珀酸脱氢酶抑制剂类杀菌剂。该类杀菌剂对非靶标生物具有一定的毒性,长期使用容易造成病原菌抗性的发展。因此,亟需寻找新型绿色防治药剂。
从天然产物中寻找潜在的高活性杀菌剂是可行并有重大意义的。目前登记的香芹酚、丁香酚、大蒜素等杀菌活性成分均来源于植物体内。本课题组长期从事植物源农用活性物质的抑菌活性研究,发现川穹精油中的苯酞类化合物对白绢病具有较好的抑菌离体和活体活性(ZL202110982319.9)。植物精油具有良好的环境相容性和内吸性。对其在花生植株中的吸收与传导性能研究,有利于更好的研究其在花生病害防治上的应用。氨基酸是植物体内维持正常生长发育的必需物质,且氨基酸类农药是许多植物病虫草害防控的特效药。氨基酸类杀菌剂具有高效、低毒、无环境污染、抑菌谱广的特点,并可促进植物生长。活性氨基酸作为杀菌剂有氨基酸及其盐酸盐、氨基酸金属配合物、N-酰基氨基酸、氨基酸酯及含氨基酸结构的杀菌剂。同时,植物体内存在丰富的氨基酸转运蛋白,将氨基酸基团与农药活性分子通过不同的拼接方式形式氨基酸-农药偶合物,借助植物体内丰富的氨基酸转运蛋白对偶合物的转运而达到韧皮部,从而改善农药在作物体内的分布,提高农药的靶向性。
发明内容
本发明提出一种类氨基酸导向的苯酞类似物及其制备方法和应用,利用苯酞结构作为骨架,通过对其氨基酸衍生化,能够获得一类新型、安全、高效的氨基酸导向的苯酞类杀菌剂。
本发明的技术方案是这样实现的:
类氨基酸导向的苯酞类似物,其特征在于,具有如式A或式B所示的结构通式:
式中:
R和R’选自天然氨基酸或非天然氨基酸,非天然氨基酸为氨基酸的4-NO2、4-F或4-Cl的取代产物;
氨基酸与苯酞连接的桥键位置为苯环上的4位或5位或6位;
式A中的桥键为羧基苯酞与氨基酸形成酰胺键;式B中的桥键为氨基苯酞与氨基酸形成的酰胺键。
优选的,式A中,R选自5位取代的4-硝基苯丙氨酸、4-氟苯丙氨酸、和精氨酸;优选的,式B中,R`选自6位取代的苯丙氨酸。
本发明所提供的式A和式B化合物,参照固相有机合成法,具体合成步骤如下:
式A所示的苯酞类似物的制备步骤为:
(1)将Rink Amide-AM树脂用二氯甲烷活化后加入50%(V/V)DBU(1,8-二氮杂双环十一碳-7-烯)的二氯甲烷溶液,脱保护反应后,用DMF和DCM洗涤,得活化树脂;
(2)向步骤(1)的活化树脂中加入Fmoc-AA-OH、HBTU、HOBt和DIEA,然后溶于DMF中室温搅拌反应,脱去反应液,用DMF和DCM洗涤,再加入DBU的二氯甲烷溶液进行脱保护反应,用DMF洗涤后得AA-Rink Amide-AM;
(3)向步骤(2)的AA-Rink Amide-AM中加入5-羧基苯酞、HBTU、HOBt和DIEA,然后溶于DMF中室温搅拌反应,脱去反应液,用DMF和DCM洗涤,得5-羧基苯酞-AA-Rink Amide-AM;
(4)以苯酚、水、苯甲硫醚和TFA为切割试剂对步骤(3)的5-羧基苯酞-氨基酸-RinkAmide-AM中进行切割反应后,过滤,除去TFA,加入无水乙醚,离心得白色沉淀,经分离纯化得式A所示的苯酞类似物。
上述Fmoc-AA-OH中的AA指氨基酸,选自甘氨酸、丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、谷氨酸、苏氨酸、精氨酸或4-NO2、4-F、4-Cl取代的苯丙氨酸中的任一种;
步骤(2)中活化树脂、Fmoc-AA-OH、HBTU、HOBt和DIEA当量比的范围为1:3-4:3-4:3-4:6-8;
步骤(3)中AA-Rink Amide-AM、5-羧基苯酞、HBTU、HOBt和DIEA当量比的范围为1:3-4:3-4:3-4:6-8;
步骤(4)中苯酚、水、苯甲硫醚和TFA的体积比为1:2:1:36。
式B所示的苯酞类似物的制备步骤为:
1)将Boc-AA’-OH、4-氨基苯酞、HOBt和DIEA溶于DMF中,室温搅拌反应至完全;
2)向步骤1)得到的反应液中加入水直至析出粘稠固体,然后弃上清液,并用水洗涤固体;
3)经步骤2)处理后的固体溶于DCM,经水洗后,除去水相,旋转蒸发除去DCM,得油状产品;
4)向油状产品中加入盐酸溶液,搅拌至反应完全,旋转蒸出水分,所得粗产品经分离纯化、所得溶液脱去乙腈后,冻干制得式B所示的苯酞类似物。
上述AA’为苯丙氨酸。
步骤1)中Boc-AA’-OH、4-氨基苯酞、HOBt和DIEA当量比的范围为1:3-4:3-4:3-4:6-8。
含有本申请的类氨基酸导向的苯酞类似物的药物,还包括载体,所述载体选自稀释剂、赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂、稳定剂一种或多种。
上述苯酞类似物或药物在防治花生白绢病和花生根腐病中的应用。
本发明化合物的离体生物测定试验采用菌丝生长速率法,测试了式A和式B化合物抑制齐整小核菌(Sclerotium rolfsii)、茄腐镰刀菌(Haematonectria haematococca)、尖孢镰刀菌(Fusarium oxysporum)和层出镰刀菌(Fusarium proliferatum)的离体活性。
本发明化合物的活体生物测定采用盆栽防治试验。本发明的生物活性实验方法均按照专利:藁本内酯及含其的植物精油在防治花生白绢病方面的应用(ZL202110982319.9)进行。
在需要的时候,在所述药物中还可以加入一种或多种农药制剂中可接受的载体,所述载体包括农药制剂中常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂、稳定剂等。制成的药物的剂型也是多样的,可以是粉剂、微乳剂、饵剂、微胶囊剂、乳油等。
本发明具有以下有益效果:
1、本发明的一类氨基酸导向的苯酞类似物,以羧基苯酞或者氨基苯酞为先导,采用活性亚结构拼接方法,通过引入天然和非天然氨基酸,改良化合物得到一类具有导向性苯酞类衍生物,部分化合物的离体活性优于先导羧基苯酞或者氨基苯酞,同时该类似物具有一定的活体活性。本发明的化合物安全高效,合成简便,具有潜在的开发应用前景。
2、本申请化合物的生物活性测定结果表明,所有化合物均具有齐整小核菌菌丝生长抑制活性,其中式A中的4-硝基苯丙氨酸的5位取代苯酞和精氨酸5位取代苯酞具有明显的抑菌活性,同时,盆栽实验表明4-硝基苯丙氨酸的5位取代苯酞化合物具有较好的防效。本发明的类氨基酸导向化合物,对花生植株的根系具有促生活性。因此,该类氨基酸导向的苯酞类化合物有很好的开发应用前景。
3、本申请的氨基酸导向苯酞类化合物是利用多肽固相合成的方法,筛选了合成过程中的脱保护剂的DBU的使用(V/V)比例为50%,有效的避免了易制毒类化合物哌啶的使用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为实施例1制备的A1化合物的1H NMR(400M)谱图。
图2为实施例1制备的A1化合物的质谱(MS)图。
图3为实施例2制备的B1化合物的1H NMR(400M)谱图。
图4为实施例2制备的B1化合物的质谱(MS)图。
图5为A2和多抗霉素花生白绢病的盆栽防治效果。
具体实施方式
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有付出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本申请的式A和式B化合物的制备均按照多肽固相合成的方法制备。其中Fmoc基团的脱保护剂进行了优化。
本申请采用的先导化合物L-1、L-2、L-3和L-4的结构式为:
下面结合具体实施例进行描述:
实施例1
本实施例为化合物A1的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM(二氯甲烷)活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF(N,N-二甲基甲酰胺)和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Phe:加入Fmoc-Phe-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
所得产品的1H NMR(400M)谱图如图1所示、质谱(MS)图如图2所示。
化合物A1:1H NMR(400MHz,DMSO-d6)δ8.84(d,J=8.5Hz,1H),8.03(s,1H),7.99–7.89(m,2H),7.65(s,1H),7.35(d,J=8.2Hz,2H),7.26(t,J=7.5Hz,2H),7.21–7.12(m,2H),5.46(s,2H),4.69(ddd,J=10.6,8.5,4.0Hz,1H),3.15(dd,J=13.8,4.1Hz,1H),2.99(dd,J=13.8,10.8Hz,1H).
实施例2
本实施为化合物A2的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Phe(4-NO2):加入Fmoc-Phe(4-NO2)-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A2:1H NMR(400MHz,DMSO-d6)δ8.94(d,J=8.6Hz,1H),8.19–8.12(m,2H),8.03(s,1H),7.94(q,J=7.9Hz,2H),7.72(s,1H),7.66–7.60(m,2H),7.25(s,1H),5.46(s,2H),4.76(ddd,J=10.6,8.5,3.9Hz,1H),3.29(dd,J=13.6,4.0Hz,1H),3.13(dd,J=13.7,11.0Hz,1H).
实施例3
本实施为化合物A3的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Phe(4-F):加入Fmoc-Phe(4-F)-OH(4倍当量),HBTU(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3.5倍当量),(3.5倍当量),HOBt(3.5倍当量),DIEA(7倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A3:1H NMR(400MHz,DMSO-d6)δ8.84(d,J=8.5Hz,1H),8.03(s,1H),7.94(q,J=8.0Hz,2H),7.65(s,1H),7.37(dd,J=8.3,5.6Hz,2H),7.19(s,1H),7.09(t,J=8.9Hz,2H),5.46(s,2H),4.66(ddd,J=10.4,8.6,4.0Hz,1H),3.13(dd,J=13.8,4.0Hz,1H),2.97(dd,J=13.8,10.8Hz,1H).
实施例4
本实施为化合物A4的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Phe(4-Cl):加入Fmoc-Phe(4-Cl)-OH(4倍当量),HBTU(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A4:1H NMR(400MHz,DMSO-d6)δ8.90(dd,J=16.4,8.7Hz,1H),8.10–7.91(m,3H),7.69(d,J=16.7Hz,1H),7.43–7.23(m,5H),5.55–5.45(m,2H),4.80–4.58(m,1H),3.20–3.13(m,1H),3.01(d,J=13.0Hz,1H).
实施例5
本实施为化合物A5的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Tyr:加入Fmoc-Tyr-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A5:1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.68(d,J=8.4Hz,1H),7.96(s,1H),7.87(q,J=8.0Hz,2H),7.52(s,1H),7.05(d,J=8.2Hz,3H),6.55(d,J=8.0Hz,2H),5.39(s,2H),4.51(ddd,J=10.3,8.4,4.0Hz,1H),2.94(dd,J=13.8,4.1Hz,1H),2.79(dd,J=13.8,10.6Hz,1H).
实施例6
本实施为化合物A6的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Tyr:加入Fmoc-Tyr-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接Pro:加入Fmoc-Pro-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(4)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(5)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(6)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A6:1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.10–7.54(m,4H),7.44–6.51(m,6H),5.48(s,1H),5.44–5.25(m,1H),4.53–4.08(m,2H),3.51–3.35(m,2H),3.06–2.74(m,1H),2.61(td,J=13.8,7.2Hz,1H),2.15–1.98(m,1H),1.85–1.55(m,3H).
实施例7
本实施为化合物A7的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Arg:加入Fmoc-Arg-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A7:1H NMR(400MHz,DMSO-d6)δ8.75(d,J=7.9Hz,1H),8.15(s,1H),8.07(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.66(t,J=5.7Hz,1H),7.53(s,1H),7.30(s,1H),7.15(s,2H),6.97(s,1H),5.49(s,2H),4.42(td,J=8.5,4.9Hz,1H),3.13(q,J=6.7Hz,2H),1.83(td,J=10.5,9.7,4.6Hz,1H),1.72(dd,J=14.3,9.6Hz,1H),1.56(td,J=15.7,13.7,8.0Hz,2H).
实施例8
本实施为化合物A8的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Gln:加入Fmoc-Gln-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A8:1H NMR(400MHz,DMSO-d6)δ8.82(d,J=7.7Hz,1H),8.15(s,1H),8.07(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.47(s,1H),7.36(s,1H),7.10(s,1H),6.85(s,1H),5.49(s,2H),4.36(td,J=8.7,4.9Hz,1H),2.27–2.12(m,2H),2.11–1.84(m,2H).
实施例9
本实施为化合物A9的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mL DCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Glu:加入Fmoc-Glu-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A9:1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.71(d,J=7.8Hz,1H),8.15(s,1H),8.07(d,J=8.0Hz,1H),7.95(d,J=7.9Hz,1H),7.49(s,1H),7.13(s,1H),5.49(s,2H),4.40(td,J=8.7,4.9Hz,1H),2.38–2.25(m,2H),2.13–1.99(m,1H),1.99–1.85(m,1H).实施例10
本实施为化合物A10的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mLDCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Asn:加入Fmoc-Asn-OH(3倍当量),HBTU(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(3倍当量),(3倍当量),HOBt(3倍当量),DIEA(6倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A10:1H NMR(400MHz,DMSO-d6)δ8.80(d,J=7.8Hz,1H),8.11(s,1H),8.03(d,J=8.0Hz,1H),7.96(dd,J=8.0,1.6Hz,1H),7.43(s,1H),7.35(s,1H),7.12(s,1H),6.93(s,1H),5.49(s,2H),4.72(td,J=8.1,5.4Hz,1H),2.68–2.52(m,2H).
实施例11
本实施为化合物A11的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mLDCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Asp:加入Fmoc-Asp-OH(4倍当量),HBTU(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(4倍当量),(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A11:1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),8.90(d,J=7.8Hz,1H),8.12(s,1H),8.04(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.48(s,1H),7.17(s,1H),5.49(s,2H),4.75(td,J=8.4,5.0Hz,1H),2.80(dd,J=16.4,5.0Hz,1H),2.67(dd,J=16.5,8.9Hz,1H).实施例12
本实施为化合物A12的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mLDCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Ala:加入Fmoc-Ala-OH(4倍当量),HBTU(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mL DMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接5-羧基苯酞:加入5-羧基苯酞(4倍当量),(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A12:1H NMR(400MHz,DMSO-d6)δ8.75(d,J=7.4Hz,1H),8.14(s,1H),8.07(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.46(s,1H),7.06(s,1H),5.49(s,2H),4.43(p,J=7.1Hz,1H),1.35(d,J=7.1Hz,3H).
实施例13
本实施为化合物A13的制备方法:
(1)树脂活化:称取440mg Rink Amide-AM resin,用5mLDCM活化3h,加入50%(V/V)DBU的二氯甲烷溶液脱保护10min,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(2)接Phe:加入Fmoc-Phe-OH(4倍当量),HBTU(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。后加入50%(V/V)DBU二氯甲烷溶液脱保护20min,DMF洗3次。
(3)接6-羧基苯酞:加入6-羧基苯酞(4倍当量),(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于5mLDMF,室温搅拌4h,脱去反应液,DMF和DCM各洗3次,Kaiser’s试剂监测反应。
(4)切割树脂:树脂加入0.25mL苯酚,0.50mL水,0.25mL苯甲硫醚,9.00mL TFA,室温搅拌2.5h,过滤,除去TFA,加入30ml无水乙醚,3000r/min离心5min,得白色沉淀,真空干燥,质谱检测。
(5)粗产品用HPLC分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物A13:1H NMR(400MHz,DMSO-d6)δ8.44(d,J=1.9Hz,1H),8.36(d,J=8.2Hz,1H),7.83(dd,J=8.4,1.8Hz,1H),7.49(dt,J=8.4,1.1Hz,1H),7.30–7.18(m,5H),6.98(d,J=8.4Hz,1H),6.80(d,J=8.4Hz,1H),5.34(t,J=1.1Hz,2H),4.46(dt,J=8.2,6.2Hz,1H),3.01(ddt,J=14.6,6.2,1.0Hz,1H),2.94(ddt,J=14.5,6.2,0.9Hz,1H).
实施例14
本实施例为化合物B1的制备方法:
(1)合成B1:加入Boc-Phe-OH(4倍当量),4-氨基苯酞(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于30mLDMF,室温搅拌4h至反应完全。
(2)后处理:反应液加入大量的水,析出粘稠固体,然后弃去上清液,并用水洗涤固体,将固体加入DCM中溶解,溶解后分层,用水洗3次,除去水相。旋转蒸发除去DCM,在油状产品中加入盐酸水溶液,搅拌至反应完全,旋转蒸出水分,粗产品用制备液相分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
所得产品的1H NMR(400M)谱图如图3所示、质谱(MS)图如图4所示。
化合物B1:1H NMR(400MHz,DMSO-d6)δ10.68(d,J=4.4Hz,1H),8.50(s,2H),7.76(d,J=7.8Hz,1H),7.70(d,J=7.5Hz,1H),7.62(t,J=7.7Hz,1H),7.36(dd,J=8.4,6.2Hz,2H),7.33–7.28(m,3H),5.24–5.10(m,2H),4.30(d,J=7.4Hz,1H),3.17(d,J=7.1Hz,2H).实施例15
本实施为化合物B2的制备方法:
(1)合成B2:加入Boc-Phe-OH(4倍当量),6-氨基苯酞(4倍当量),HOBt(4倍当量),DIEA(8倍当量),溶于30mLDMF,室温搅拌4h至反应完全。
(2)后处理:反应液加入大量的水,析出粘稠固体,然后弃去上清液,并用水洗涤固体,将固体加入DCM中溶解,溶解后分层,用水洗3次,除去水相。旋转蒸发除去DCM,在油状产品中加入盐酸水溶液,搅拌至反应完全,旋转蒸出水分,粗产品用制备液相分离纯化。收集的溶液脱去乙腈后,冻干制得纯产品。色谱柱为C18半制备柱。
化合物B2:1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.37(s,2H),8.07(d,J=1.8Hz,1H),7.66–7.56(m,2H),7.24(d,J=6.8Hz,2H),7.23–7.17(m,3H),5.32(s,2H),4.14(t,J=7.1Hz,1H),3.16–3.01(m,2H).
应用例1:对齐整小核菌菌丝生长的毒力
采用菌丝生长速率法测定。将实施例1-15制备的化合物0.12g溶于0.2mL DMSO和0.2mL吐温-80中,加入9.6mL无菌水定容至10mL并配置成12000mg/L的母液,其中DMSO和吐温-80的体积比分别为2%。再用无菌水稀释成6000、4000、2000、1000、500、250mg/L6个浓度的药液。分别取1mL不同浓度的药液加入到9mL PDA培养基中,制成终浓度为600、400、200、100、50、25mg/L 6种含药培养基,以含0.05% DMSO和0.05%吐温-80的无药培养基为对照,每个浓度重复三次。于28℃光照培养箱中黑暗培养,3d后使用十字交叉法测量各处理的菌落直径。
根据菌丝生长抑制率=[(对照菌落直径-菌饼直径)-(处理菌落直径-菌饼直径)]/(对照菌落直径-菌饼直径)×100;
计算实施例1-15制备的化合物对齐整小核菌菌丝生长的抑制率,并根据机率值分析法求得有效中浓度(EC50)试验结果见表1。
表1式A和式B化合物的结构、质谱数据(MS)、物理性状和抑制齐整小核菌离体活性
表1结果表明:式A化合物可以抑制齐整小核菌(Sclerotium rolfsii)菌丝生长,A1-A5、A7-A12的离体活性要优于先导L-1,A13的活性优于先导L-2、B1、B2的活性分别优于先导L-3、L-4。其中类似物A2、A7的离体活性较之先导提高一个数量级,具有进一步的应用开发价值。
在600mg浓度下检测13种氨基酸抑制齐整小核菌菌丝生长活性,生物活性测定方法为菌丝生长速率法,同上。
表2 600mg/L浓度下13种氨基酸抑制齐整小核菌菌丝生长活性
注:表中数据为平均值±标准误差
由表2可以看出,13种L/D型氨基酸对齐整小核菌的抑制活性较差。结合表1的生测结果,表明将600mg/L浓度下活性较高的L-苯丙氨酸、L-精氨酸、L-谷氨酰胺、L-谷氨酸、L-天冬酰胺、L-天冬氨酸、L-丙氨酸与先导化合物进行结构拼接,有利于活性提升。将活性较低的脯氨酸和酪氨酸引入时,活性提升较差。
应用例2:化合物对茄腐镰刀菌、尖孢镰刀菌和层出镰刀菌菌丝生长的毒力
以A2、A3、A7、A12和B2化合物为例,以先导化合物5-羧基苯酞(L-1)、6-羧基苯酞(L-2)、4-氨基苯酞(L-3)、6-氨基苯酞(L-4)为对照,采用菌丝生长速率法,测试在浓度为600mg/L下,对茄腐镰刀菌(Haematonectria haematococca)、尖孢镰刀菌(Fusariumoxysporum)和层出镰刀菌(Fusarium proliferatum)的菌丝生长抑制活性。结果如表3所示:
表3本发明部分化合物600mg/L浓度下对镰刀菌的抑菌活性
注:表中数据为平均值±标准误差
表3结果表明:所选的部分化物具有一定的抑制镰刀菌的活性,其中类似物A2、A7活性最好,表明该类化合物在防治由茄腐镰刀菌、尖孢镰刀菌和层出镰刀菌引起的花生根腐病具有一定的活性,因此,具有进一步应用开发价值。
应用例3:化合物对花生白绢病的盆栽防治效果
采用喷淋法测试A2对花生白绢病的盆栽防治效果。
试验花生品种为豫花9326,选取颗粒饱满大小一致的花生种子置于盆中,加入无菌水并使水淹没种子的三分之一,并放于培养箱中浸种半天。然后将基质土与蛭石以3:1的体积比例混合,加入无菌水调整土壤含水量为70%后置于盆钵中,将发芽的种子胚根朝下播种。
人工接种病菌:待播种一周后,选取健康、长势、大小一致的植株,每株在茎基部接种1个菌饼,并用土掩埋。当观察到花生植株和土壤上出现菌丝产生后,以600mg/L A2以及300mg/L多抗霉素喷淋植物根茎部及周围土壤,每株药液10mL。以含0.1% DMSO和0.1%吐温-80的无菌水作为对照。每个处理15株植株,重复三次。在施药5d后,检查病情,并计算不同处理的病情指数和防效。结果见表4。防效图如图5所示,由图5可以看出,与对照相比,600mg/L浓度下A2处理后,植株长势良好,地面有少量菌丝。300mg/L商品化药剂多抗霉素处理后,植株长势较好,但地面菌丝较多,防治效果较差于与600mg/L浓度下的A2。说明A2化合物具有较好的活体活性。
表4花生白绢病的盆栽防效
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注:表中数据为平均值±标准误差
从表4可知,A2在600mg/L浓度下的防效分别为50.1%,优于300mg/L对照药剂多抗霉素,表明A2在防治花生白绢病上具有开发前景。
应用例4:化合物对花生的促生效果
供试品种为豫花9326,挑选大小均匀、籽粒饱满的豫花9326种子,放置于0.3%的双氧水溶液中避光状态浸泡6h,浸泡结束后,用去离子水清洗2~3遍,将种子均匀铺在装有脱脂棉的托盘中,让种子在黑暗状态下萌发3~5d,待子叶完全展开且幼根萌发出细小侧根时,取根系粗壮且大小均匀一致的幼苗移植到盛有1.4L去离子水的十二孔水培盒(长20cm,宽15cm,高7cm)中平衡3d,每盆移植20株,待平衡结束后进行试验处理。设置200mg/L浓度下的本发明化合物和清水对照。设置3个重复,每个重复设置2个取样测定时间,分别为16d与24d时,每个重复设置10棵花生植株。
试验结束后,取处理的花生幼苗植株进行检测;每处理每重复取5株花生幼苗,测量主茎高和侧枝长。用剪刀将花生幼苗地上部与地下部分离,每处理每重复取3条完整的根系,利用万深LA-S根系扫描仪扫描,分析花生根系总根长。(见表5)
表5式A和式B化合物400mg/L浓度下对花生的促生效果
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注:表中数据为平均值±标准误差
从表5可知,整个系列对花生的茎和根的生长均具有一定的促进作用,其中A7、A8和A10的促生作用最为明显。表明氨基酸导向苯酞类化合物,具有花生植株促生作用,在防治花生白绢病上具有良好的开发前景。
例如:利用本申请的苯酞类似物结合现有的制药技术制备一种含有本申请的类氨基酸导向的苯酞类似物的药物,还包括载体,所述载体选自稀释剂、赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂、稳定剂一种或多种。
显而易见的,该苯酞类似物或药物在防治花生白绢病和花生根腐病中可以实现应用。
在需要的时候,在所述药物中还可以加入一种或多种农药制剂中可接受的载体,所述载体包括农药制剂中常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂、稳定剂等。制成的药物的剂型也是多样的,可以是粉剂、微乳剂、饵剂、微胶囊剂、乳油等。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (12)
1.类氨基酸导向的苯酞类似物,其特征在于,具有如式A或式B所示的结构通式:
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式中:R和R’选自天然氨基酸或非天然氨基酸,非天然氨基酸为氨基酸的4-NO2、4-F或4-Cl的取代产物。
2.根据权利要求1所述的类氨基酸导向的苯酞类似物,其特征在于:所述R或R’与苯酞连接的桥键位置为苯环上的4位、5位或6位中的任一位置;R或R’与苯环通过酰胺键相连。
3.根据权利要求1或2所述的类氨基酸导向的苯酞类似物,其特征在于:所述R或R’为甘氨酸、丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、天冬氨酸、谷氨酸、苏氨酸、精氨酸或4-NO2、4-F或4-Cl取代后的非天然氨基酸中的任意一种。
4.权利要求1-3任一项所述的类氨基酸导向的苯酞类似物的制备方法,其特征在于,式A所示的苯酞类似物的制备步骤为:
(1)将Rink Amide-AM树脂用二氯甲烷活化,加入50%(V/V)DBU的二氯甲烷溶液进行脱保护反应,用DMF和DCM洗涤,得活化树脂;
(2)向步骤(1)的活化树脂中加入Fmoc-AA-OH、HBTU、HOBt和DIEA,然后溶于DMF中室温搅拌反应,脱去反应液,用DMF和DCM洗涤,再加入50%(V/V)DBU的二氯甲烷溶液进行脱保护反应,用DMF洗涤后得AA-Rink Amide-AM;
(3)向步骤(2)的AA-Rink Amide-AM中加入5-羧基苯酞、HBTU、HOBt和DIEA,然后溶于DMF中室温搅拌反应,脱去反应液,用DMF和DCM洗涤,得5-羧基苯酞-AA-Rink Amide-AM;
(4)以苯酚、水、苯甲硫醚和TFA为切割试剂对步骤(3)的5-羧基苯酞-氨基酸-RinkAmide-AM中进行切割反应后,过滤,除去TFA,加入无水乙醚,离心得白色沉淀,经分离纯化冻干制得式A所示的苯酞类似物。
5.根据权利要求4所述的类氨基酸导向的苯酞类似物的制备方法,其特征在于:所述Fmoc-AA-OH中的AA指氨基酸;步骤(1)中的DBU的体积分数为0.5;步骤(2)中活化树脂、Fmoc-AA-OH、HBTU、HOBt和DIEA当量比的范围为1:3-4:3-4:3-4:6-8;步骤(3)中AA-RinkAmide-AM、5-羧基苯酞、HBTU、HOBt和DIEA当量比的范围为1:3-4:3-4:3-4:6-8;步骤(4)中苯酚、水、苯甲硫醚和TFA的体积比为1:2:1:36。
6.权利要求1-3中任一项所述的类氨基酸导向的苯酞类似物的制备方法,其特征在于,式A所示的苯酞类似物的制备步骤为:
1)将Boc-AA’-OH、氨基苯酞、HOBt和DIEA溶于DMF中,室温搅拌反应至完全;
2)向步骤1)得到的反应液中加入水直至析出粘稠固体,然后弃上清液,并用水洗涤固体;
3)经步骤2)处理后的固体溶于DCM,经水洗后,除去水相,旋转蒸发除去DCM,得油状产品;
4)向油状产品中加入盐酸溶液,搅拌至反应完全,旋转蒸出水分,所得粗产品经分离纯化、所得溶液脱去乙腈后,冻干制得式B所示的苯酞类似物。
7.根据权利要求6所述的类氨基酸导向的苯酞类似物的制备方法,其特征在于,所述AA’为氨基酸;步骤1)中Boc-AA’-OH、4-氨基苯酞或者6-氨基苯酞、HOBt和DIEA当量比的范围为1:3-4:3-4:3-4:6-8。
8.权利要求1-3所述的类氨基酸导向的苯酞类似物在制备防治花生白绢病药物中的应用。
9.权利要求1-3所述的类氨基酸导向的苯酞类似物在制备防治花生根腐病药物中的应用。
10.一种药物,其特征在于:包含权利要求1-3任一项所述的类氨基酸导向的苯酞类似物。
11.根据权利要求10所述的药物,其特征在于:还包括载体,所述载体选自稀释剂、赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂、稳定剂中的一种或一种以上。
12.根据权利要求10所述的药物,其特征在于:所述药物的剂型为粉剂、微乳剂、饵剂、微胶囊剂和乳油中的任一种。
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