CN1935779A - N-(n-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物及其制备方法和用途 - Google Patents
N-(n-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN1935779A CN1935779A CN 200610201016 CN200610201016A CN1935779A CN 1935779 A CN1935779 A CN 1935779A CN 200610201016 CN200610201016 CN 200610201016 CN 200610201016 A CN200610201016 A CN 200610201016A CN 1935779 A CN1935779 A CN 1935779A
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- China
- Prior art keywords
- nhco
- nmr
- benzoyl
- phenylalanyl
- dmso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 108010016626 Dipeptides Proteins 0.000 title claims abstract description 16
- XHHGICRKFOUSQV-VXKWHMMOSA-N (2s)-2-[[(2s)-2-benzamido-3-phenylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)C=1C=CC=CC=1)C1=CC=CC=C1 XHHGICRKFOUSQV-VXKWHMMOSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title abstract description 11
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- 239000000460 chlorine Substances 0.000 claims description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
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- 229910052801 chlorine Inorganic materials 0.000 claims description 5
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- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
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- 239000000047 product Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- -1 benzene Propanolamines Chemical class 0.000 description 11
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 9
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 8
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- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
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- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明涉及通式(I)所示的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物及其制备方法和用途,包括其消旋体或光学异构体及其药学上可接受的盐或水合物以及其与一种或多种药学上可接受的载体、赋形剂或稀释剂组成药物组合物;结构通式(I)的化合物具有抑制乙肝病毒(HBV)的活性,且较少出现其它毒副作用,是一类非核苷类抗病毒药,可用于制备治疗病毒性感染药物,尤其是用于制备抗乙肝病毒和抗人免疫缺陷病毒药物。
Description
技术领域:本发明属药物化学技术领域,涉及N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物及其制备方法以及其在制备治疗病毒性感染特别是乙肝病毒(HBV)感染药物中的应用。
技术背景:乙型肝炎病毒(Hepatitis B Virus,HBV)感染是影响人类健康的全球性主要疾病之一,全球目前有4亿多慢性乙型肝炎病毒感染者,其中约75%分布在亚太地区。慢性乙型肝炎的预后不良,可发展为肝硬化和原发性肝癌,全球每年约有100万人死于乙型肝炎病毒感染的相关疾病,占疾病死因的第九位。
共价闭合环状DNA(covalently closed circular.DNA,cccDNA)是HBV DNA在宿主细胞核内的存在形式,是HBV复制和转录的模板,现有药物对核内cccDNA无抑制作用,使得其长期存在于细胞核中难以清除,从而导致HBV DNA可持续复制。而长期用药过程中又容易导致HBV病毒突变株的产生,如HBV DNA聚合酶YMDD(酪氨酸-蛋氨酸-天冬氨酸-天冬氨酸)的突变,Pre-S基因的突变等)及病人的免疫耐受等原因,造成目前抗病毒治疗仅对一小部分患者有效,使得到目前为止,人类在对付乙肝病毒感染的过程中还没有找到一种确实有效的理想方法。从乙肝病毒分子生物学的知识出发,着眼于乙肝病毒循环复制机理,采用多学科合作,筛选不同作用机理和作用形式的创新药物控制乙肝病毒的复制,清除体内乙肝病毒,抑制病毒突变株的产生,避免停药后的“反跳”现象是今后药物化学工作者攻克的方向。在这一研究方向上,从已知具有较强的抗乙肝病毒活性的天然植物中分离提取抗乙肝病毒活性成分并进行结构修饰,发现疗效较理想的药物,然后进行大量的人工合成,是抗乙肝病毒药物研究的重要途径。
发明目的:为研制出新型高效低毒的抗乙肝病毒药物,本发明人以从苗族药马蹄金(Dichondra repens Forst.)中分离得到的具有抗乙肝病毒活性的单体[N-(N-苯甲酰基-L-苯丙氨酰基)-O-乙酰基-L-苯丙氨醇,已获得发明专利,专利号:02160309.X]为母体,对其进行结构修饰和改造设计,合成了一系列结构新颖的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物,并对所合成的化合物进行生物活性测试,发现了部分衍生物的抗乙肝病毒活性比母体化合物好、且较少出现其它毒副作用,从而对该类化合物进行了较为深入的研究,完成了本发明。
发明内容:
本发明涉及结构如通式I所示的化合物和它的制备方法以及应用,包括(2S,2′S)、(2S,2′R)、(2R,2′S)或(2R,2′R)的任何立体异构体或其消旋体或旋光异构体或其混合物,或其药学上可接受的盐或水合物,通式(I)如下:
其中:
R1和R3分别代表氢、氟、氯或溴、-NO2、-NH2、-CN、-NHR、-NRR′、-NHCOR、-OH、(4-OH,3-CH2NRR′)、-OCOR、-OR、-NHCO(CH2)nCOOH、-O(CH2)nNRR′、-O(CH2)nCOOR或-O(CH2)nCOOH;
R2为氢、C1-C6烷基、氟、氯或溴、-NO2、-NH2、-CN、-NHR、-NRR′、-NHCOR、-OH、-OCOR、-OR、-NHCO(CH2)nCOOH、-O(CH2)nNRR′、-O(CH2)nCOOH、-CH2NRR′、
R4为CH2OH、COOR、CH2OCOR、CH2OCO(CH2)2COOH或COONa;
X为CH或N;
R1、R2和R3可分别是单个或多个取代基,并分别处在苯环上的对位和邻位和间位;
R、R′代表相同或不同的C1-C6直链或支链烷基,或C3-C7环烷基;
n为1至4的整数;
所述烷基和环烷基可以被1-2个选自羟基、硝基、卤代、氰基、三氟甲基的取代基任选取代。
根据本发明的化合物可作为活性成分用于制备治疗乙型肝炎病毒感染的药物,本发明包括药物组合物,该组合物含有通式(I)所示的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物,或其药学上可接受的盐或水合物作为活性成分,以及药学上可接受的赋形剂。所述药学上可接受的赋形剂是指任何可用于药学领域的稀释剂、辅助剂或载体。本发明的化合物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应等。
本发明的药物组合可配制成若干种剂型,其中含有药学领域中常用的一些赋形剂;例如,口服剂(如片剂、胶囊剂、溶液或混悬液);可注射的制剂(如可注射的溶液、混悬液或粉针剂);局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药学领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、轿味剂等;可注射制剂用的防腐剂、助溶剂、稳定剂等;局部用药制剂用的基质、稀释剂、润滑剂防腐剂等。药物制剂可以经口服或胃肠外方式(如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的可将其制成肠衣片剂。
以下合成路线I和合成路线II描述了本发明的通式(I)化合物的制备方法。
合成路线I
(I-a).HNO3/H2SO4,rt.;(I-b).MeOH,SOCl2,rt.;(I-c).NaBH4/H2O,0-10℃;
(I-a)以L-苯丙氨酸(或者L-酪氨酸)作为原料,采用混酸(体积比为:硝酸∶硫酸=1.2∶1)于室温对其进行硝化反应,即可得到化合物I-1(产率:~95%);(I-b)将装有90ml甲醇的反应瓶置于冰盐浴中充分冷却搅拌,滴加9.5ml(132mmol)二氯亚砜(SOCl2)。在滴加完毕后,反应升至室温,加入100mmol的化合物I-1,室温搅拌2.5h,水浴回流30min。减压回收溶剂至干,所得残留物以甲醇-***混合溶剂重结晶即可得结晶状化合物I-2(产率:~85%);(I-c)取NaBH41.13g(30mmol)溶于15ml水中,冰盐浴冷却,搅拌下缓慢滴加到15ml含有9.2mmol的化合物I-2的水溶液中,反应自然升至室温(约需2h)后,再于室温反应过夜。次日以乙酯(3×50ml)萃取反应液,合并乙酯层,依次以饱和NaHCO3(20ml)、饱和氯化钠(20ml)洗涤,无水NaSO4干燥,减压回收溶剂至干得淡黄色粉末状中间体I-3 (产率:~70%)。
(I-d).SOCl2,回流;(I-e).2.0M NaOH(aq.);
R2为氢、C1-C6烷基、卤代、-NO2
(I-d)取苯甲酸衍生物I-4加入二氯亚砜中溶解,回流至无氯化氢气体放出,减压蒸干溶剂,即得苯甲酰氯衍生物I-5;(I-e)将苯甲酰氯衍生物I-5加入到置于冰浴中冷却的溶解了L-苯丙氨酸的氢氧化钠溶液中,反应自然升至室温下继续反应2h,所得产物经纯化即得中间体I-7(产率:~90%)。
(I-f).DCC,DMAP,CH2Cl2,rt.;(I-g).1.0M NaOH,rt.;
R1为氢、-NO2或-OH
R2为氢、C1-C6烷基、卤代、-NO2、-NH2、-CN、-NHCOR、-OH等
(I-f)将10mmol的苯甲酸衍生物I-8与10mmol的L-酪氨酸甲酯或苯丙氨酸甲酯的衍生物I-9、二环己基二碳酰亚胺(DCC,2.47g,12mmol)、对二甲氨基吡啶(DMAP,200mg,作为催化剂)混合于反应瓶中,注入无水CH2Cl2 150ml,反应于氮气保护下室温搅拌过夜。次日过滤除去反应产生的二环己基脲(DCU)沉淀,滤液回收溶剂至干,产物经纯化即得中间体I-10(产率:~95%);(I-g)取10mmol的中间体10以适量无水乙醇溶解,加入1.0M的氢氧化钠1.2ml室温水解2h,产物纯化即得中间体I-11(产率:~95%)。
(I-h)氯甲酸异丁酯(IBCF),N-甲基吗啉(NMM),-5-10℃
(I-h)将前述合成的中间体I-12(1.0mmol)、I-13(1.05mmol)与N-甲基吗啉(NMM,23.0mmol)混合溶解于50ml干燥的CH2Cl2中,冰盐浴(-5℃)冷却下,滴加氯甲酸异丁酯(IBCF,1.07mmol),滴加完毕后再继续搅拌反应30min。加水少许终止反应,减压回收溶剂至干,所得固体以适量EtOAc溶解完全,依次以蒸馏水、稀盐酸、蒸馏水、5%NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,减压回收乙酸乙酯至干,所得残留物以经重结晶即得目标产物(产率:~65%)。
合成路线II
(II-a)(t-BuOCO)2O,1.0M NaOH,TBAB;(II-b)CH2Cl2,氯甲酸异丁酯(IBCF),N-甲基吗啉(NMM),-5-10℃;
(II-c)TFA,CH2Cl2,rt,2h;(II-d)DCC,DMAP,CH2Cl2,rt.
(II-a)取L-苯丙氨酸衍生物10.0mmol溶解于20ml 1.0M NaOH溶液中,加入二碳酸二叔丁酯{(t-BuOCO)2O}10.05mmol和四丁基溴化铵(Tetrabutyl ammonium bromide,TBAB,1.0g),室温搅拌过夜。次日以浓盐酸调节反应液至pH2-3,乙酸乙酯萃取,乙酯层以饱和氯化钠洗涤,再经无水硫酸钠干燥,减压回收溶剂至干,即得中间体II-2(产率:~98%);(II-b)其操作步骤与(I-h)操作相似,制备得中间体II-4(产率:88%)
(II-c)取前一步合成所得中间体II-4样品以三氟乙酸(TFA)溶解,室温搅拌2h,向反应瓶中加水适量,以碳酸钠调节至碱性(pH11-12),乙酸乙酯萃取,有机相无以水硫酸钠干燥,减压回收溶剂至干得白色蜡状固体样品II-5(产率:~65%)。
(II-d)将前述合成的中间体II-5(10mmol)与自制苯甲酸衍生物II-6(10mmol)、DCC(2.47g,12mmol)、DMAP(200mg,作为催化剂)混合于反应瓶中,注入无水CH2Cl2200ml,反应于氮气保护下室温搅拌过夜。产物经萃取及重结晶纯化,即得目标产物(产率:~90%)。
其中合成路线I适用于R2为氢、C1-C6烷基、卤代、-NO2、-CN、-NHCOR、-OH、-OCOR、-OR等的衍生物合成;
选择异烟酸衍生物代替苯甲酸衍生物作为合成路线I的反应原料,即可合成制备通式(I)中X为N的衍生物。
分别选择适当的反应底物,如L-苯丙氨酸、D-苯丙氨酸、L-酪氨酸、D-酪氨酸、各种不同取代苯丙氨酸、各种不同取代苯丙氨醇、各种取代的苯甲酸,通过合成路线I或合成路线II以及对所的衍生物进行基团的转换和取代,例如:硝基还原为氨基、芳环氨基(经重氮化中间体)的取代及酰化和烷基化等、苯环上酚羟基的酰化以及烷基化或和其它亲电试剂(如ClCH2(CH2)nNRR′、ClCH2(CH2)nCOOR)的取代等,即可合成通式(I)所代表的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物。
部分所得衍生物的抗乙肝病毒活性结果:
采用2.2.1.5细胞测试其体外抗乙肝病毒活性。
测试原理
以2.2.15细胞为乙型肝炎病毒载体,测定样品抑制乙型肝炎病毒进行DNA复制和产生HBsAg、HBeAg的能力。
测试材料和方法
a.细胞株:2.2.15细胞。
b.样品处理:样品临用前溶于DMSO配成适当浓度,检测时用培养液作3倍稀释,共8个稀释度。
c.阳性对照药:拉米夫定(3TC),由葛兰素威康公司生产。
d.主要试剂:乙肝病毒e抗原及s抗原放免检测试剂盒;a32pdCTP;
e.测试方法:2.2.15细胞种96孔培养板,36小时后按以上稀释度分别加入样品及阳性对照药,同时设细胞对照孔,加药后96小时后分别更换含不同稀释浓度样品的培养液,于加药后第8天分别收集细胞上清及2.2.15细胞,采用RIA法检测细胞上清中HBsAg、HBeAg的分泌量,点杂交的方法检测细胞中HBV DNA复制程度,分别计算IC50及SI。
测试结果见表1:
表1 部分衍生物体外抗乙肝病毒活性测试结果
化合物 | TC50(μg/ml) | 抑制HBsAg | 抑制HBeAg | 抑制DNA复制 | |||
IC50(μg/ml) | SI | IC50(μg/ml) | SI | IC50(μg/ml) | SI | ||
实施例01 | 1101.11 | - | - | - | - | - | - |
实施例02 | 231.12 | - | - | - | - | - | - |
实施例03 | 17.81 | - | - | - | - | 0.63 | 28.27 |
实施例04 | 450.67 | - | - | - | - | 51.78 | 8.70 |
实施例05 | 77.04 | - | - | - | - | 25.19 | 3.06 |
实施例06 | 53.42 | - | - | - | - | - | - |
实施例07 | 28.74 | - | - | - | - | 1.02 | 28.29 |
实施例08 | 166.70 | - | - | - | - | - | - |
实施例09 | 240.38 | - | - | - | - | - | - |
实施例10 | 288.68 | - | - | - | - | - | - |
实施例11 | 500.00 | - | - | - | - | - | - |
实施例12 | 388.03 | - | - | - | - | - | - |
实施例13 | 776.06 | - | - | - | - | - | - |
实施例14 | 53.42 | - | - | - | - | 1.16 | 45.93 |
实施例15 | 45.69 | - | - | - | - | - | - |
实施例16 | 52.34 | - | - | - | - | - | - |
实施例17 | 465.23 | - | - | - | - | - | - |
实施例18 | 45.28 | - | - | - | - | - | - |
实施例19 | 587.06 | - | - | - | - | 103.25 | 5.69 |
实施例20 | 198.46 | - | - | - | - | 48.50 | 4.09 |
实施例21 | 28.74 | - | - | - | - | - | - |
实施例22 | 346.68 | - | - | - | - | 105.88 | 3.27 |
实施例23 | 240.38 | - | - | - | - | 52.00 | 4.62 |
实施例24 | 396.81 | - | - | - | - | 95.98 | 4.13 |
实施例25 | 574.76 | - | - | - | - | 68.70 | 8.37 |
实施例26 | 472.10 | - | - | - | - | - | - |
实施例27 | 441.29 | - | - | - | - | - | - |
实施例27 | 456.75 | - | - | - | - | - | - |
实施例36 | 388.03 | - | - | - | - | 4.56 | 85.09 |
实施例37 | 129.34 | - | - | - | - | 1.43 | 90.45 |
实施例38 | 80.13 | - | - | - | - | 2.39 | 33.53 |
实施例39 | 14.37 | - | - | - | - | 0.34 | 42.26 |
实施例43 | 86.23 | - | - | - | - | 11.67 | 7.39 |
实施例46 | 388.03 | - | - | - | - | 2.41 | 161.01 |
实施例47 | 256.78 | - | - | - | - | - | - |
实施例49 | 86.23 | - | - | - | - | 7.28 | 11.84 |
实施例50 | 64.15 | - | - | - | - | 7.04 | 9.11 |
实施例51 | 78.52 | - | - | - | - | 6.98 | 11.25 |
实施例52 | 89.23 | - | - | - | - | 24.20 | 3.69 |
实施例53 | 354.18 | - | - | - | - | - | - |
实施例54 | 43.11 | - | - | - | - | 0.82 | 52.57 |
实施例55 | 53.42 | - | - | - | - | 4.96 | 10.78 |
实施例56 | 333.33 | - | - | - | - | - | - |
实施例57 | 451.20 | - | - | - | - | 59.48 | 7.59 |
实施例58 | 28.74 | - | - | - | - | - | - |
实施例59 | 258.69 | - | - | - | - | - | - |
实施例63 | 358.02 | - | - | - | - | 53.12 | 6.74 |
实施例64 | 58.54 | - | - | - | - | - | - |
实施例68 | 388.03 | - | - | - | - | 13.12 | 29.57 |
实施例69 | 75.46 | - | - | - | - | - | - |
实施例70 | 17.81 | - | - | - | - | - | - |
实施例71 | 388.03 | - | - | - | - | 6.62 | 58.61 |
实施例72 | 577.35 | - | - | - | - | 87.50 | 6.60 |
实施例74 | >500 | 25.19 | 19.85 | - | - | 32.96 | >15.2 |
实施例75 | 388.03 | 33.51 | 11.58 | 13.51 | 28.72 | 2.41 | 58.60 |
实施例76 | 37.04 | - | - | - | - | - | - |
实施例77 | 160.25 | - | - | - | - | 13.51 | 11.86 |
实施例78 | 257.31 | - | - | - | - | 54.28 | 4.74 |
实施例79 | 86.23 | - | - | - | - | 9.59 | 8.99 |
实施例80 | 388.03 | 150.20 | 2.58 | - | - | 27.28 | 14.22 |
实施例81 | 58.64 | - | - | - | - | - | - |
实施例82 | 59.19 | - | - | - | - | - | - |
实施例83 | >1000 | - | - | - | - | 252.60 | >3.96 |
实施例84 | 86.23 | - | - | - | - | 1.44 | 59.97 |
实施例86 | 130.56 | - | - | - | - | 10.56 | 12.36 |
实施例87 | 43.11 | - | - | - | - | 1.81 | 23.82 |
实施例88 | 388.03 | - | - | - | - | 25.00 | 15.52 |
实施例92 | 379.36 | - | - | - | - | - | - |
实施例93 | 577.35 | - | - | - | - | - | - |
实施例94 | 561.21 | - | - | - | - | - | - |
实施例95 | 79.46 | - | - | - | - | - | - |
实施例96 | 199.67 | - | - | - | - | - | - |
3TC | 786.00 | - | - | - | - | 18.90 | 41.59 |
(续表1 部分衍生物体外抗乙肝病毒活性测试结果)
实施例75所得化合物的抗鸭肝病毒体内实验结果:
试验日期:2006年7-8月,实验方法略,测试结果见表2。
表2 实施例75所得化合物在雏鸭体内对DHBV-DNA的抑制作用和效果
组别 | 实验第5天 | 实验第10天 | 停药第3天 | |||
OD值 | 抑制率 | OD值 | 抑制率 | OD值 | 抑制率 | |
DHBV | 1.33 | 1.09 | 1.08 | |||
实施例75(12.5mg/kg) | 1.11 | 12.87 | 1.11a | 12.92a | 1.09 | 9.23 |
实施例75(25.0mg/kg) | 1.15a | 18.67c | 0.95b | 32.91d | 0.87b | 38.12d |
实施例75(50.0mg/kg) | 0.94a | 36.43c | 0.73b | 54.62d | 0.83b | 42.30d |
3TC(50.0mg/kg) | 0.73b | 53.71d | 0.68b | 57.22d | 1.54 | 0.3 |
注:(1)自身(配对)比较:ap<O.05;bp<0.01;(2)组间(成组)比较:cp<0.05;dp<0.01
与现有技术相比较,本发明提供了一系列结构新颖的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物以及它的制备方法,并对所合成的化合物进行生物活性测试,发现了部分衍生物的抗乙肝病毒活性比母体化合物好、且较少出现其它毒副作用,从而对该类化合物进行了较为深入的研究,达到了本发明的目的。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。所得化合物以400MHz核磁共振仪(INOVA型,带纳克微量探头,Varian Inc.)测定其1H谱和13C谱;惠普公司HP-5973质谱仪测定其分子量;所用试剂均为分析纯或化学纯。
(一)代表性反应中间体的制备:
1.1 4-硝基-L-苯丙氨酸(4-nitro-L-phenvlalanine,编号:M-05)
试剂及反应条件:HNO3/H2SO4(1.4∶1.1),rt,5h
实验操作:取L-苯丙氨酸16.5g(100mmol)溶解于50ml 85%H2SO4中,搅拌下将其逐滴加入预先配置并冷却至室温的浓HNO3-浓H2SO4(V/V:1.4/1.1)的混酸中,室温搅拌反应5h,反应液以40%NaOH调节pH2-3,产生大量沉淀,过滤、并以水洗涤沉淀至中性、减压烘干即得4-硝基-L-苯丙氨酸(4-nitro-L-phenylalanine,编号:M-05)样品20g(95.2%)。
将反应所用的混酸硝化剂改用稀硝酸(30%),以L-酪氨酸为原料即可合成中间体3-硝基-L-酪氨酸。
1.2 4-硝基-L-苯丙氨醇(4-nitro-L-phenvlalanol,编号:M-12)
试剂及反应条件:(a)MeOH,SOCl2,rt,2.5h,回流30min;(b)NaBH4/H2O,反应过夜
实验操作:(a)将装有90ml甲醇的反应瓶置于冰盐浴中充分冷却搅拌,滴加9.5ml(132mmol)二氯亚砜(SOCl2)。在滴加完毕后,反应升至室温,加入4-硝基-L-苯丙氨酸(4-nitro-L-phenylalanine,编号:M-05)100mmol,室温搅拌2.5h,水浴回流30min。减压回收溶剂至干,所得残留物以甲醇-***混合溶剂重结晶即可得到淡黄色粉末状4-硝基-L-苯丙氨酸甲酯盐酸盐(编号:M-06)样品22.1g(产率:85.0%);(b)取NaBH4 1.13g(30mmol)溶于15ml水中,冰盐浴冷却,搅拌下缓慢滴加到15ml含有2.4g(9.2mmol)M-06的水溶液中,反应自然升至室温(约需2h)后,再于室温反应过夜。次日以乙酯(3×50ml)萃取反应液,合并乙酯层,依次以饱和NaHCO3(20ml)、饱和氯化钠(20ml)洗涤,无水NaSO4干燥,减压回收溶剂至干得淡黄色粉末状样品1.23g,经波谱鉴定其结构与M-12结构一致(产率:68.2%)。
通过类似的合成方法,分别选择L-苯丙氨酸,L-酪氨酸为原料,即可制备L-苯丙氨酸甲酯盐酸盐、L-酪氨酸甲酯盐酸盐、L-苯丙氨醇,L-酪氨醇作为进一步合成的原料。
1.3 4-氯乙酰氨基苯甲酸{4-(2-chloroacetamido)benzoic acid}
试剂及反应条件:1.0M NaOH(aq.),-5℃,2h,再于室温搅拌过夜
实验操作:取4-氨基苯甲酸13.7g(100mmol)溶于220ml 1.0M NaOH中,置冰盐浴中-5℃冷却,滴加氯乙酰氯2-chloroacetyl chloride(12ml,0.15mol),滴加完毕后继续反应2h,再升至室温搅拌反应过夜。次日以浓盐酸调节反应液至pH1-2,过滤沉淀,水洗至近中性,烘干,即得白色粉末状4-氯乙酰氨基苯甲酸{4-(2-chloroacetamido)benzoic acid}样品15.58g(产率:73.0%)
1.4 2-氯-N,N-二甲基乙胺盐酸盐(2-chloro-N,N-dimethylethanaminehydrochloride)
试剂及反应条件:SOCl2,CHCl3,回流4h
实验操作:取2-二甲胺基乙醇{2-(dimethylamino)-ethanol}(5ml,0.05mol)与20mlCHCl3混合,室温搅拌,滴加SOCl2(4.3ml,0.06mol),滴加完毕(约需2h)以后再水浴回流3h,减压回收溶剂至干,将残留物溶解于100ml EtOH中,过滤去除不溶性杂质,滤液蒸干,再将所得固体分散于100ml CH2Cl2中,适当搅拌,过滤,沉淀以适量CH2Cl2洗涤,烘干,即得白色粉末状的中间体2-氯-N,N-二甲基乙胺盐酸盐样品6.18g(产率:85.8%)。
1.5 M-25的合成
试剂及反应条件:(a)NBS,ABIN,CCl4,回流12h;(b)NH(CH3)2稨Cl,K2CO3,KI,无水EtOH,rt,反应过夜;(c)1.0M HCl(aq.),回流8h
实验操作:(a)取对甲基苯甲酸甲酯(4.5g,30mmol),溶解于60ml干燥的CCl4中,加入NBS(6.6g,36.9mmol)和偶氮二异丁腈(azobisisobutyronitrile,ABIN,12mg),将反应瓶置于氩气保护下油浴回流12h。过滤除去反应产生的沉淀,滤液减压回收溶剂至干,即得乳白色油状物4-溴甲基-苯甲酸甲酯(methyl 4-bromomethylbenzoate,编号:M-23)8.58g(理论产量6.87g);(b)取NH(CH3)2·HCl(6.11g,75mmol)、K2CO3(17.25g,125mmol)和KI(1.66g,10mmol)于50ml无水乙醇中混合,氮气保护下滴加M-23(50mmol),室温搅拌反应过夜,次日将反应液经萃取纯化处理,即得无色油状物4-二甲氨甲基苯甲酸甲酯;(C)取前一步所得产物以1.0M HCl溶解回流水解8h,减压蒸馏回收溶剂,烘干即得灰白色粉末状的4-二甲氨甲基苯甲酸盐酸盐(编号:M-25)样品。
按上述合成M-25的方法即可合成下列结构的中间体
(二)目标产物的合成制备
实施例01:N-(N-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸甲酯
试剂及反应条件:(a)2.0M NaOH(aq.),苯甲酰氯,-5℃ to rt,3h,93%;(b)CH2Cl2,氯甲酸异丁酯(isobutyl chloroformate,IBCF),N-甲基吗啉(N-methylmorpholine,NMM),-5℃
实验操作:(a)将1.65g L-苯丙氨酸(10.0mmol)溶解于11ml 2.0M氢氧化钠溶液中,冰盐浴冷却,搅拌下滴加苯甲酰氯10.0mmol。滴加完毕,再将反应升至室温下继续反应2h,反应物以1.8ml(21.6mmol)浓盐酸调节pH5-6,产生的沉淀经过滤,水洗涤至中性,干燥,即得白色粉末状的N-苯甲酰基-L-苯丙氨酸(编号:M-03)样品2.50g(产率:93.0%);(b)将前步合成的中间体M-03(1.0mmol)、M-01(1.05mmol)与N-甲基吗啉(NMM,23.0mmol)混合溶解于50ml干燥的CH2Cl2中,冰盐浴(-5℃)冷却下,滴加氯甲酸异丁酯(IBCF,1.07mmol),滴加完毕后再继续搅拌2h(TLC检测反应进程),加水少许终止反应,减压回收溶剂至干,所得固体以适量EtOAc溶解完全,依次以蒸馏水、稀盐酸、蒸馏水、5%NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,减压回收乙酸乙酯至干,所得残留物以乙酸乙酯重结晶即得白色针状的N-(N-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸甲酯{N-(N-benzoyl-L-phenylalanyl)-L-phenylalanine methyl ester}结晶样品280mg(产率:65.0%)。
光谱数据:EI-MS m/z:430(M+),283,240,128,114,72,59(100),43;1H-NMR(CDCl3,400MHz)δ:7.68(2H,d,J=7.6Hz,H-3″,7″),7.51(1H,m,H-5″),7.42(2H,t,H-4″,6″),7.31-7.13(8H,m,H-5,9,6,8,5′,9′,6′,8′),6.97(2H,m,H-7,7′),6.76(1H,d,J=7.4Hz,NHCO),6.37(1H,d,J=7.6Hz,NHCO),4.85(1H,m,H-2),4.77(1H,m,H-2′),3.70(3H,s,OMe),3.23-2.94(4H,m,H-3,3′);13C-NMR(CDCl3,100 MHz)δ:171.3(C-1),170.4(C-1′),167.0(C-1″),136.4(C-4),135.5(C-4′),133.6(C-2″),131.8(C-5″),129.4(C-6,8),129.1(C-6′,8′),128.7(C-4″,6″),128.6(C-5,9),128.5(C-5′,9′),127.1(C-3″,7″),127.0(C-7,7′),54.5(C-2),53.4(C-2′),52.3(C-COMe),38.0(C-3),37.8(C-3′)。
按照类似于实施例1的合成方法,选择适当的反应原料及中间体,即可分别制得实施例02~18的衍生物。
实施例02:N-(N-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨醇
光谱数据:1H-NMR(CDCl3,400MHz)δ:7.72(2H,d,J=8.0Hz,H-3″,7″),7.53(1H,t,J=7.2Hz,H-5″),7.44(2H,t,H-4″,6″),7.35-7.07(10H,m,H-5-9,5′-9′),6.80(1H,d,J=7.6Hz,NHCO),5.92(1H,d,J=7.6Hz,NHCO),4.77(1H,m,H-2),4.10(1H,m,H-2′),3.42(2H,m,H-1′),3.27(1H,dd,J=5.6,13.6Hz,H-3a),3.04(1H,dd,J=9.2,13.6Hz,H-3b),2.77(1H,dd,J=7.6,13.6Hz,H-3a),2.68(1H,dd,J=6.8,13.6Hz,H-3′b);M(EI)m/z:402(M+),384,311,252,224(100),92。
实施例03:N-(N-4-氟-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸甲酯
光谱数据:1H-NMR(CDCl3,400MHz)δ:7.69-7.72(2H,m,H-3″,7″),7.07-7.28(10H,m,H-5-9,5′-9′),6.96-6.98(2H,m,H-4″,6″),6.80(1H,d,J=7.6Hz,NH),6.34(1H,d,J=7.6Hz,NH),4.76-4.84(2H,m,H-2,2′),3.70(3H,s,OCH3),2.98-3.18(4H,m,H-3,3′),13C-NMR(CDCl3,100MHz)δ:171.24(s),170.41(s),165.97(2×s),136.28(s),135.44(s),129.47(s),129.38(4×d),129.11(2×d),128.69(2×d),128.55(2×d),127.11(2×d),115.74(d),115.52(d),54.56(d),53.44(d),52.38(q),38.13(t),37.82(t)MS(EI)m/z:448(M+),416,389,357,309,286,270,242,218,180,162,147,131,123(100),120,95,91,77,41,28,15。
实施例04:N-(N-苯甲酰基-L-苯丙氨酰基)-L-酪氨酸甲酯,
光谱数据:mp 184.0-186.0℃,1H-NMR(DMSO,400MHz)δ:9.18(1H,s,Ar-OH),8.52(1H,d,J=8.4Hz,NHCO),8.40(1H,d,J=7.6Hz,NHCO),7.77(2H,d,J=7.6Hz,H-3″,7″),7.50(1H,t,H-5″),7.42(2H,t,H-4″,6″),7.33(2H,d,J=7.2Hz,H-5,9),7.24(2H,t,H-6,8),7.16(1H,t,H-7),6.99(2H,d,J=8.4Hz,H-5′,9′),6.62(2H,d,J=8.4Hz,H-6′,8′),4.74(1H,m,H-2),4.45(1H,m,H-2′),3.60(3H,s,OMe),3.11-2.84(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.8(C-1),171.5(C-1′),166.2(C-1″),156.0(C-7′),138.2(C-4),134.0(C-2″),131.1(C-5″),129.9(C-5′,9′),129.1(C-6,8),128.0(×2),127.9(×2),127.3(C-3″,7″),126.8(C-7),126.1(C-4′),115.0(C-6′,8′),54.4(C-2),53.9(C-2′),51.7(C-OMe),36.9(C-3),35.9(C-3′)。
实施例05:N-(N-3-甲基-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨醇
光谱数据:N-(N-3-methyl-benzoyl-L-phenylalanyl)-L-phenylalanol,mp177.0-178.5℃,1H-NMR(DMSO,400MHz)δ:8.44(1H,d,J=8.4Hz,NHCO),7.89(1H,d,J=8.4Hz,NHCO),7.59-7.56(2H,m,H-3″,7″),7.32-7.10(12H,m,H-5″,6″,H-5-9,5′-9′),4.83(1H,t,CH2OH),4.67(1H,m,H-2),3.88(1H,m,H-2′),3.33-3.23(2H,m,H-1),3.04-2.91(2H,m,H-3),2.85(1H,dd,J=5.6,13.6Hz,H-3′a),2.65(1H,dd,J=8.0,13.6Hz,H-3′b),2.33(3H,s,Ar-CH3);13C-NMR(DMSO,100MHz)δ:171.0(C-1),166.2(C-1″),139.0(C-4′),138.5(C-4),137.5(C-4″),134.1(C-2″),131.9(C-5″),129.3(×3,C-6′,8′,6″),128.13(×4,C-5′,9′,C-6,8),128.07(×2,C-5,9),128.0(C-3″),126.2(C-7′),126.0(C-7),124.6(C-7″),62.2(C-1′),54.8(C-2),52.5(C-2′),33.3,36.5,21.0(ArCH3)。
实施例06:N-(N-苯甲酰基-4-硝基-L-苯丙氨酰基)-L-苯丙氨醇
光谱数据:mp 196.0-199.0℃,1H-NMR(DMSO,400MHz)δ:8.62(1H,d,J=8.4Hz,NHCO),8.12(2H,d,J=8.8Hz,H-6,8),8.05(1H,d,J=8.8Hz,NHCO),7.78(2H,d,J=6.4Hz,H-3″,7″),7.59(2H,d,J=8.4Hz,H-5,9),7.51(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.26-7.12(5H,m,H-5′-9′),4.85(1H,t,OH),4.76(1H,m,H-2),3.89(1H,m,H-2′),3.32-3.26(2H,m,H-1′),3.19-3.07(2H,m,H-3),2.92-2.81(2H,m,H-3′);13C-NMR(DMSO,100MHz)δ:170.5(C-1),166.1(C-1″),145.0(C-7),146.2(C-4),139.0(C-4′),133.8(C-2″),131.4(C-5″),130.5(C-5,9),129.2(C-6′,8′),128.2(C-4″,6″),128.1(C-5′,9′),127.4(C-3″,7″),125.9(C-7′),123.2(C-6,8),62.2(C-1′),54.3 (C-2′),52.6(C-2),37.1(C-3′),34.9(C-3)。
实施例07:N-(N-4-氯-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨醇
光谱数据:mp 211.5-214.0℃,1H-NMR(DMSO,400MHz)δ:8.63(1H,d,J=8.4Hz,NHCO),7.93(1H,d,J=8.0Hz,NHCO),7.81(2H,d,J=8.0Hz,H-3″,7″),7.51(2H,d,J=8.0Hz,H-4″,6″),7.12-7.31(10H,m,H-5-9,5′-9′),4.82(1H,s,OH),4.68(H,m,H-2),3.90(1H,m,H-2′),3.29-3.39(2H,m,H-1′),2.49-3.01(4H,m,H-3,3′),13C-NMR(DMSO,100MHz)δ:170.9(C-1),165.1(C-1″),139.0(C-4),138.1(C-4′),136.2(C-5″),132.4(C-2″),129.4(×2),129.2(×2),128.3(×2),128.09(×2),128.07(×2),126.2,125.9,62.2(C-1′),54.9(C-2),52.5(C-2′),37.3(C-3),36.4(C-3′).M(EI)m/z:436(M+),406,345,327,303,286,258,190,139(100),120,111,104,91,73,57,43,28。
实施例08:N-(N-2-氯-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨醇
光谱数据:1H-NMR(CDCl3,400MHz)δ:7.15-7.40(14H,m,H-5-9,5-9′,4″-7″),4.59-4.82(1H,m,H-2),4.07-4.10(1H,m,H-2′),3.41-3.42(2H,m,1′),2.71-3.17(4H,m,H-3,3′),13C-NMR(CDCl3,100MHz)δ:172.81(s),169.53(s),139.61(s),138.42(s),137.02(s),132.27(d),131.96(s),130.92(d),130.45(2×d),130.43(2×d),130.01(d),129.46(2×d),129.42(2×d),127.96(d),127.80(d),127.33(d),63.73(t),56.55(d),54.14(d),38.93(t),37.87(t)MS(EI)m/z:436(M+),418,406,345,327,303,286,258,190,139(100),120,104,91,73,60,43,28,18。
实施例09:N-(N-3-甲基-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp:190.0-192.0℃,1H-NMR(CDCl3,400MHz)δ:7.51(1H,s,H-3″),7.46(1H,d,J=4.4Hz,H-7″),7.31-7.23(6H,m,H-5″,6″,H-6,8,6′,8′),7.16-7.11(4H,m,H-5,9,H-5′,9′),6.99-6.95(2H,m,H-7,7′),6.68(1H,d,J=8.0Hz,NHCO),7.89(1H,d,J=7.4Hz,NHCO),4.80(2H,m,H-2,2′),3.70(3H,s,OCH3),3.23-2.93(4H,m,H-3,3′),2.39(3H,s,Ar-CH3);13C-NMR(CDCl3,100MHz)δ:171.2(C-1),170.3(C-1′),167.2(C-1″),138.4(C-4″),136.4(C-4),135.5(C-4′),133.5(C-2″),132.6(C-5″),129.4(×2),129.1(×2),128.7(×2),128.5(×2),128.4(C-6″),127.7(C-3″),127.0(×2,C-7,7′),124.0(C-7″),54.4(C-2),53.4(C-2′),52.4(OCH3),38.0,37.8。
实施例10:N-(N-2-氯-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp:152.5-153.5℃,1H-NMR(CDCl3,400MHz)δ:7.51(1H,d,J=8.0Hz,H-7″),7.35-7.34(2H,m,H-4″,5″),7.30-7.17(9H,m,H-5,6,8,9,5′,6′,8′,9′,6″),6.97-6.95(2H,m,H-7,7′),6.75(1H,d,J=7.6Hz,NHCO),6.30(1H,d,J=7.6Hz,NH),4.85(1H,m,H-2),4.78(1H,m,H-2),3.67(3H,s,OCH3),3.20-3.00(4H,m,H-3,3′);13C-NMR(CDCl3,100MHz)δ:171.2,169.9,166.1,136.2,135.5,134.1,131.6,130.8,130.3,130.2,129.4(×2),129.2(×2),128.7(×2),128.6(×2),127.14,127.12,127.0,54.9,53.4,52.3,37.9,37.8. M(EI)m/z:464(M+),432,373,309,302,286,258,218,180,162,147,139(100),131,120,112,102,97,91,83,73,60,44,28。
实施例11:N-(N-2-氯-苯甲酰基-L-苯丙氨酰基)-L-酪氨酸甲酯
光谱数据:mp 164.5-167.0℃,1H-NMR(DMSO,400MHz)δ:9.27(1H,s,Ar-OH),8.60(1H,d,J=8.4Hz,NHCO),8.40(1H,d,J=7.2Hz,NHCO),7.42-7.14(9H,m,H-4″-7″,H-5-9),7.03(2H,d,J=8.4Hz,H-5′,9′),6.67(2H,d,J=8.4Hz,H-6′,8′),4.75(1H,m,H-2),4.46(1H,m,H-2′),3.08-2.79(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.9(C-1),171.1(C-1′),166.0(C-1″),156.1(C-7′),137.8(C-4),136.4(C-5″),130.8(C-3″),130.1(C-5′,9′),130.0(C-2″),129.2(4″),129.2(C-6,8),128.9(7″),128.0(C-5,9),126.9(C-6″,C-4′),126.3(C-7),115.1(C-6′,8′),54.0(C-2),51.8(C-2′),37.2,36.0。
实施例12:N-(N-苯甲酰基-4-硝基-L-苯丙氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 202.0-204.5℃,1H-NMR(CDCl3,400MHz)δ:8.09(2H,d,J=8.8Hz,H-6,8),7.71(2H,d,J=7.6Hz,H-3″,7″),7.54(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.38(2H,d,J=8.8Hz,H-5,9),7.13(3H,m,H-6′-8′),6.99(2H,m,H-5′,9′),6.93(1H,br,NHCO),6.56(1H,br,NHCO),4.94(1H,m,H-2),4.80(1H,m,H-2′),3.73(3H,s,OCH3),3.29(1H,dd,J=7.2,13.6Hz,H-3′a),3.22(1H,dd,J=5.6,14.0Hz,H-3′b),3.09(1H,dd,J=5.6,14.0Hz,H-3a),3.01(1H,dd,J=6.4,14.0Hz,H-3b);13C-NMR(CDCl3,100MHz)δ:171.3(C-1),169.8(C-1′),167.1(C-1″),147.0(C-7),144.1(C-4),135.2(C-4′),133.1(C-2″),132.2(C-5″),130.3(C-5,9),129.0(C-6′,8′),128.7(C-5′,9′),128.6(C-4″,6″),127.2(C-7′),127.0(C-3″,7″),123.7(C-6,8),54.0(C-2),53.2(C-2′),52.5(OCH3),38.0,37.8。
实施例13:N-(N-4-甲基-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨醇
光谱数据:mp 200.0-202.0℃,1H-NMR(DMSO,400MHz)δ:8.39(1H,d,J=8.8Hz,NHCO),7.86(1H,d,J=8.8Hz,NHCO),7.68(2H,d,J=8.0Hz,H-3″,7″),7.29-7.11(12H,m,H-4″,6″,H-5′-9′,5-9),4.81(1H,t,OH),4.65(1H,m,H-2),3.88(1H,m,H-2′),3.33-3.24(2H,m,H-1′),3.03-2.90(2H,m,H-3),2.84(1H,dd,J=6.0,13.6Hz,H-3′a),2.65(1H,dd,J=8.0,13.6Hz,H-3′b),2.33(3H,s,Ar-CH3);13C-NMR(DMSO,100MHz)δ:171.0(C-1),166.0(C-1″),141.2(C-5″),139.0(C-4′),138.4(C-4),131.3(C-2″),129.2(×4,C-6,8,C-6′,8′),128.7(C-4″,6″),128.1(C-5′,9′),128.0(C-5,9),127.5(C-3″,7″),126.2(C-7),125.9(C-7′),62.2(C-1′),54.8(C-2′),52.5(C-2),37.3,36.4,21.0(Ar-CH3)。
实施例14:N-(N-苯甲酰基-4-硝基-L-苯丙氨酰基)-L-酪氨酸甲酯
谱数据:mp 200.0-202.0℃,1H-NMR(DMSO,400MHz)δ:9.27(1H,s,Ar-OH),8.67(1H,d,J=8.4Hz,NHCO),8.57(1H,d,J=7.2Hz,NHCO),8.13(2H,d,J=8.4Hz,H-6,8),7.76(2H,d,J=7.2 Hz,H-3″,7″),7.62(2H,d,J=8.4Hz,H-5,9),7.51(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.00(2Hd,J=8.0Hz,H-5′,9′),6.63(2H,d,J=8.0Hz,H-6′,8′),4.83(1H,m,H-2),4.42(1H,m,H-2′),3.57(3H,s,OMe),3.22-2.84(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.9(C-1),171.2(C-1′),166.3(C-1″),156.1(C-7′),146.8(C-7),146.2(C-4),133.8(C-2″),131.4(C-5″),130.6(C-5,9),130.4(C-4′),130.1(C-5′,9′),128.3(C-4″,6″),127.4(C-3″,7″),122.2(C-6,8),115.1(C-6′,8′),54.2(C-2),50.0(C-2′),51.9(C-OMe),36.8(C-3),35.9(C-3′)。
实施例15:N-(N-苯甲酰基-4-硝基-L-苯丙氨酰基)-4-硝基-L-苯丙氨酸甲酯
光谱数据:mp 220.0-221.5℃,1H-NMR(DMSO,400MHz)δ:8.57(1H,d,J=8.0Hz,NHCO),8.52(1H,d,J=8.8Hz,NHCO),8.04(2H,d,J=8.4Hz,H-6′,8′),7.73(2H,d,J=7.6Hz,H-3″,7″),7.49(3H,m,H-5″,H-5′,9′),7.41(2H,t,H-4″,6″),7.31(2H,d,J=7.2Hz,H-5,9),7.23(2H,t,H-6,8),7.14(1H,t,H-7),4.70(1H,m,H-2),4.62(1H,m,H-2′),3.61(3H,s,OCH3),3.25-2.90(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.6(C-1),171.4(C-1′),166.2(C-1″),146.3(C-7′),145.5(C-4′),138.3(C-4),133.9(C-2″),131.4(C-5″),130.6(C-5′,9′),129.2(C-6,8),128.2(×2),128.1(×2),127.4(C-3″,7″),126.3(C-7′),123.2(C-6′,8′),54.5(C-2),52.9(C-2′),52.1(OCH3),36.8,36.2。
实施例16:N-(N-苯甲酰基-L-苯丙氨酰基)-4-硝基-L-苯丙氨醇
光谱数据:mp 192.0-195.0℃,1H-NMR(DMSO,400MHz)δ:8.46(1H,d,J=8.4Hz,NHCO),7.97(2H,d,J=8.0Hz,H-6′,8′),7.92(1H,d,J=8.8Hz,NHCO),7.76(2H,d,J=8.0Hz,H-3″,7″),7.52-7.40(5H,m,H-4″-6″,H-5′,9′),7.29(2H,d,J=7.2Hz,H-5,9),7.23(2H,t,H-6,8),7.14(1H,t,H-7),4.89(1H,t,OH),4.63(1H,m,H-2),4.97(1H,m,H-2′),3.36-3.27(2H,m,H-1′),3.05-2.72(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.0(C-1),166.1(C-1″),147.6(C-7′),145.8(C-4′),138.4(C-4),133.9(C-2″),131.4(C-5″),130.5(C-5′,9′),129.2(C-6,8),128.2(×2),128.0(×2),127.3(C-3″,7″),126.2(C-7′),123.0(C-6′,8′),62.6(C-1′)54.8(C-2),51.9(C-2′),37.0,36.4。
实施例17:N-(N-4-甲基-苯甲酰基-L-苯丙氨酰基)-L-酪氨酸甲酯
光谱数据:mp 207.0-208.5℃,1H-NMR(DMSO,400MHz)δ:9.24(1H,s,Ar-OH),8.45(2H,m,NHCO×2),7.68(2H,d,J=8.0Hz,H-3″,7″),7.33(2H,d,J=7.2Hz,H-5,9),7.22(4H,m,H-4″,6″,H-6,8),7.14(1H,t,H-7),7.00(2H,d,J=8.0Hz,H-5′,9′),6.63(2H,d,J=8.0Hz,H-6′,8′),4.73(1H,m,H-2),4.42(1H,m,H-2′),3.57(3H,s,OCH3),3.08-2.87(4H,m,H-3,3′),2.32(3H,s,Ar-CH3);13C-NMR(DMSO,100MHz)δ:172.0,171.7,166.1(C-1″),156.1(C-7′),141.2(C-5″),138.4(C-4),131.2(C-2″),130.1(C-5′,9′),129.2(C-6,8),128.7(C-4″,6″),128.0(C-5,9),127.4(C-3″,7″),127.0(C-4′),126.2(C-7),115.1(C-6′,8′),54.5(C-2),54.1(C-2′),51.8(OCH3),36.9(C-3),35.9(C-3′),21.0(Ar-CH3)。
实施例18:N-(N-4-甲基-苯甲酰基-4-硝基-L-苯丙氨酰基)-L-酪氨酸甲酯
光谱数据:mp 213.0-215.0℃,1H-NMR(DMSO,400MHz)δ:9.31(1H,s,Ar-OH),8.61-8.57(2H,m,NHCO×2),8.12(2H,d,J=8.8Hz,H-6,8),7.67(2H,d,J=7.6Hz,H-3″,7″),7.60(2H,d,J=8.8Hz,H-5,9),7.23(2H,d,J=8.0Hz,H-4″,6″),7.00(2H,d,J=8.4Hz,H-5′,9′),6.63(2H,d,J=8.0Hz,H-6′,8′),4.81(1H,m,H-2),4.41(1H,m,H-2′),3.56(3H,s,OCH3),3.21-3.06(2H,m,H-3′),2.94-2.84(2H,m,H-3),2.32(3H,s,Ar-CH3);13C-NMR(DMSO,100MHz)δ:172.0(C-1),171.3(C-1′),166.2(C-1″),156.1(C-7′),146.9(C-7),146.2(C-4),141.3(C-5″),131.0(C-2″),130.6(C-5,9),130.1(C-5′,9′),128.8(C-4″,6″),127.4(C-3″,7″),126.9(C-4′),123.2(C-6,8),115.1(C-6′,8′),54.2,53.9,51.9(OCH3),36.8,35.9,21.0(Ar-CH3)。
实施例19:N-(N-4-氯-苯甲酰基-L-酪氨酰基)-L-苯丙氨醇
试剂及反应条件:(1)DCC,DMAP,4-氯苯甲酸,CH2Cl2,rt.Overnight;(2)1.0MNaOH,rt,2h;(3)CH2Cl2,氯甲酸异丁酯(IBCF),N-甲基吗啉(NMM),-5℃
实验操作:(1)将中间体M-29称取2.31g(10mmol)与4-氯苯甲酸1.57g(10mmol)、DCC(2.47g,12mmol)、DMAP(200mg,作为催化剂)混合于反应瓶中,注入无水CH2Cl2 150ml,反应于氮气保护下室温搅拌过夜。次日过滤除去反应产生的二环己基脲(DCU)沉淀,滤液回收溶剂至干,所得固体物以乙酸乙酯100ml溶解完全,依次以蒸馏水、稀盐酸(40ml)、蒸馏水、5%NaHCO3(40ml)和饱和NaCl溶液(40ml)洗涤,无水硫酸钠干燥,减压回收乙酸乙酯至干,即得白色泡沫状的中间体M-75-OMe样品3.18g(产率:95.3%);(2)取前一步合成的M-75-OMe样品3.10g(9.29mmol)于100ml CHCl3中溶解完全,加入1.0M NaOH(2×20ml)对其进行反萃取两次,合并水层,室温搅拌2h后以浓盐酸调节其pH2-3,以EtOAc(2×30ml)萃取两次,合并乙酯层,无水Na2SO4干燥,回收溶剂,减压烘干,得淡黄色泡沫状中间体M-75样品2.82g(产率:95.1%);(3)按照与实施例1的合成步骤(b)类似的实验操作方法,合成得到白色粉末状的目标产物。
光谱数据:mp 217.0-219.0℃,1H-NMR(DMSO,400MHz)δ:9.15(1H,s,Ar-OH),8.54(1H,d,J=8.4Hz,NHCO),7.87(1H,d,J=8.4Hz,NHCO),7.81(2H,d,J=8.4Hz,H-3″,7″),7.53(2H,d,J=8.4Hz,H-4″,6″),7.25-7.12(5H,m,H-5′-9′),7.07(2H,d,J=8.0Hz,H-5,9),6.60(2H,d,J=8.0Hz,H-6,8),4.80(1H,s,OH),4.57(1H,m,H-2),3.88(1H,m,H-2′),3.35-3.24(2H,m,H-1′),2.95-2.60(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:170.9(C-1),164.9(C-1″),155.7(C-7),139.0(C-5″),136.1(C-4′),132.9(C-4),130.1(C-5,9),129.4(×2),129.2(×2),128.33,128.28(×2),128.1(×2),125.9(C-7′),114.8(C-6,8),62.2(C-1′),55.2(C-2),52.5(C-2′),36.5,36.4。
按照类似于实施例19的合成方法,选择适当的反应原料及中间体,分别制得实施例20~48的衍生物。
实施例20:N-(N-4-氯-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 203.5-205.0℃,1H-NMR(DMSO,400MHz)δ:9.16(1H,s,Ar-OH),8.61(1H,d,J=8.4Hz,NHCO),8.53(1H,d,J=8.8Hz,NHCO),7.79(2H,d,J=8.4Hz,H-3″,7″),7.52(2H,d,J=8.4,H-4″,6″),7.26-7.18(5H,m,H-5′-9′),7.10(2H,d,J=8.4Hz,H-5,9),6.61(2H,d,J=8.4Hz,H-6,8),4.64(1H,m,H-2),4.49(1H,m,H-2′),3.58(3H,s,OCH3),3.03-2.80(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.8,171.7,165.1(C-1″),155.7(C-7),137.0(C-4′),136.1(C-5″),132.8(C-2″),130.1(C-5,9),129.4(×2),129.1(×2,C-4),128.3(×4),126.6(C-7′),114.8(C-6,8),54.9(C-2),53.7(C-2′),51.9(C-OMe),36.5(×2)。
实施例21:N-(N-苯甲酰基-L-酪氨酰基)-L-苯丙氨醇
光谱数据:mp 216.0-217.5℃,1H-NMR(DMSO,400MHz)δ:9.18(1H,s,Ar-OH),8.42(1H,d,J=8.4Hz,NHCO),7.86(1H,d,J=8.4Hz,NHCO),7.77(2H,d,J=6.8Hz,H-3″,7″),7.49(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.21-7.11(5H,m,H-5′-9′),7.07(2H,d,J=8.4Hz,H-5,9),6.59(2H,d,J=8.4Hz,H-6,8),4.84(1H,t,OH),4.56(1H,m,H-2),3.87(1H,m,H-2′),3.34-3.22(2H,m,H-1′),2.91-2.61(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.2(C-1),166.1(C-1″),155.7(C-7),139.1(C-4′),134.2(C-2″),131.4(C-5″),130.2(C-5,9),129.3(C-6′,8′),128.4(C-4),128.2(C-4″,6″),128.1(C-5′,9′),127.5(C-3″,7″),126.0(C-7′),114.9(C-6,8),62.3(C-1′),55.3(C-2),52.6(C-2′),36.6,36.5。
实施例22:N-(N-2-氯-苯甲酰基-L-酪氨酰基)-L-苯丙氨醇
光谱数据:mp 168.0-169.0℃,1H-NMR(DMSO,400MHz)δ:9.19(1H,s,Ar-OH),8.50(1H,d,J=8.4Hz,NHCO),7.78(1H,d,J=8.8Hz,NHCO),7.46-7.16(9H,m,H-4″-7″,H-5′-9′),7.04(2H,d,J=8.4Hz,H-5,9),6.65(2H,d,J=8.4Hz,H-6,8),4.83(1H,t,OH),4.56(1H,m,H-2),3.91(1H,m,H-2′),3.34-3.24(2H,m,H-1′),2.91-2.85(2H,m,H-3),2.74-2.63(2H,m,H-3′);13C-NMR(DMSO,100MHz)δ:170.5(C-1),165.8(C-1″),155.7(C-7),139.0(C-4′),136.5(C-5″),130.8(C-4),130.2(C-5,9),130.0(C-2″),129.6(C-3″),129.2(C-6′,8′),128.9(C-4″),128.1(C-5′,9′),127.9(C-7″),126.9(C-6″),125.9(C-7′),114.5(C-6,8),62.1(C-1′),54.8(C-2),52.3(C-2′),36.8,36.4。
实施例23:N-(N-2-氯-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 175.5-177.5℃,1H-NMR(DMSO,400MHz)δ:9.20(1H,s,Ar-OH),8.52(1H,d,J=8.8Hz,NHCO),8.43(1H,d,J=8.0Hz,NHCO),7.46-7.16(9H,m,H-4″-7″,H-5′-9′),7.07(2H,d,J=8.4Hz,H-5,9),6.66(2H,d,J=8.4Hz,H-6,8),4.64(1H,m,H-2),4.53(1H,m,H-2′),3.59(3H,s,OCH3),3.07-2.67(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.8(C-1),171.2(C-1′),165.9(C-1″),155.8(C-7),137.0(C-4′),136.4(C-5″),130.8(C-4),130.2(C-5,9),130.0(C-2″),129.6(C-3″),129.2(C-6,8),128.9(C-4″),128.3(C-5′,9′),127.8(C-7″),126.9(C-6″),126.6(C-7′),114.8(C-6′,8′),54.4(C-2),53.8(C-2′),51.9(OCH3),36.7,36.5。
实施例24:N-(N-4-氟-苯甲酰基-L-酪氨酰基)-L-苯丙氨醇
光谱数据:mp 194.5-195.5℃,1H-NMR(DMSO,400MHz)δ:9.18(1H,s,Ar-OH),8.51(1H,d,J=8.4Hz,NHCO),7.90-7.87(3H,m,NHCO,H-3″,7″),7.31-7.00(6H,m,H-4″,6″,5′,9′,5,9),6.63(2H,d,J=8.4Hz,H-6,8),4.83(1H,t,OH),4.60(1H,m,H-2),3.90(1H,m,H-2′),3.38-3.23(2H,m,H-1′),2.95-2.56(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.3,171.1,165.0(C-1″),162.7(C-5″),155.7(C-7),139.1(C-4′),130.1(C-4),130.0(C-5,9),129.2(C-6′,8′),128.4(C-2″),128.1(C-5′,9′),125.9(C-7′),115.2(×2),115.0(×2),114.8(C-6,8),69.8(C-1′),55.2(C-2),52.5(C-2′),36.5,36.4。
实施例25:N-(N-4-氟-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 186.5-189.0℃,1H-NMR(DMSO,400MHz)δ:9.20(1H,s,Ar-OH),8.55(2H,m,NHCO?),7.86(2H,m,H-3″,7″),7.30-7.13(7H,m,H-4″,6″,5′-9′),7.04(2H,d,J=8.4,H-5,9),7.02(2H,d,J=8.4,H-6,8),4.64(1H,m,H-2),4.50(1H,m,H-2′),3.59(3H,s,OCH3),3.09-2.79(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.84,171.79,165.1(C-1″),162.7(C-5″),155.7(C-7),137.1(C-4′),130.55s,130.52s,130.13(C-4),130.09(C-5,9),130.04d,129.1(C-6′,8′),128.3(C-5′,9′),126.6(C-7′),115.2d,115.0d,114.8(C-6,8),54.9(C-2),53.7(C-2′),51.9(OMe),36.6,36.2。
实施例26:N-(N-4-甲基-苯甲酰基-L-酪氨酰基)-L-苯丙氨醇
光谱数据:mp 193.0-195.0℃,1H-NMR(DMSO,400MHz)δ:9.17(1H,s,ArNHCO),8.36(1H,d,J=8.4Hz,NHCO),7.88(1H,d,J=8.4Hz,NHCO),7.72(2H,d,J=8.0Hz,H-3″,7″),7.26-7.00(9H,m,H-4″,6″,H-5,9,H-5′-9′),6.61(2H,d,J=8.4Hz,H-6,8),4.83(1H,t,OH),4.58(1H,m,H-2),3.88(1H,m,H-2′),3.36-3.25(2H,m,H-1′),2.93-2.62(4H,m,H-3,3′),2.34(3H,s,Ar-CH3);13C-NMR(DMSO,100MHz)δ:171.2(C-1),165.9(1″),155.7(C-7),141.1(5″),139.1(C-4′),131.4(C-2″),130.1(C-5,9),129.2(C-6′,8′),128.7(C-4″,6″),128.4(C-4),128.1(C-5′,9′),127.5(C-3″,7″),125.9(C-7′),114.8(C-6,8),62.2(C-1′),55.2(C-2),52.5(C-2′),36.5,36.4,21.0(Ar-CH3)。
实施例27:N-(N-4-羟基-苯甲酰基-L-苯丙氨酰)-L-苯丙氨醇
光谱数据:mp 223.0-225.0℃,1H-NMR(DMSO,400MHz)δ:9.98(1H,s,Ar-OH),8.22(1H,d,J=8.8Hz,NHCO),7.83(1H,d,J=8.4Hz,NHCO),7.66(2H,d,J=8.8Hz,H-3″,7″),7.29-7.09(10H,m,H-5-9,5′-9),6.76(2H,d,J=8.4Hz,H-4″,6″),4.80(1H,t,J=5.2Hz,OH),4.62(1H,m,H-2),3.87(1H,m,H-2′),3.34-3.22(2H,m,H-1′),3.02-2.92(2H,m,H-3),2.84(1H,dd,J=5.6,13.6Hz,H-3′a),2.64(1H,dd,J=8.0,13.6,Hz,H-3′b);13C-NMR(DMSO,100MHz)δ:171.2(C-1)165.8(C-1″),160.2(C-5″),139.0(C-4′),138.5(C-4),129.4(C-3″,7″),129.23(C-6′,8′),129.21(C-6,8),128.09(C-5′,9′),128.03(C-5,9),126.2(C-7),125.9(C-7′),124.7(C-2″),114.7(C-4″,6″),62.2(C-1′),54.7(C-2),52.5(C-2′),37.2(C-3′),36.5(C-3)。
实施例28:N-(N-4-羟基-苯甲酰基-L-苯丙氨酰)-L-苯丙氨酸甲酯
光谱数据:mp 151.0-153.0℃,1H-NMR(DMSO,400MHz)δ:9.96(1H,s,Ar-0H),8.44(1H,d,J=7.2Hz,NHCO),8.24(1H,d,J=8.0Hz,NHCO),7.64(2H,d,J=8.4Hz,H-3″,7″),7.31-7.12(10H,m,H-5-9,5′-9′),6.75(2H,d,J=8.8Hz,H-4″,6″),4.69(1H,m,H-2),3.49(1H,m,H-2′),3.57(3H,s,OCH3),3.06-2.88(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.8(C-1,1′),165.9(C-1″),160.2(C-5″),139.4(C-4),137.0(C-4′),129.4(C-3″,7″),129.17(×2),129.13(×2),128.3(C-5′,9′),128.0(C-5,9),126.6(C-7′),126.2(C-7),124.7(C-2″),114.7(C-4″,6″),54.4(C-2),53.7(C-2′),51.8(OCH3),36.9,36.6。
实施例29:N-(N-苯甲酰基-3-硝基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 201.0-202.5℃,1H-NMR(DMSO,400MHz)δ:8.61-8.56(2H,m,NHCO×2),7.91(1H,s,H-5),7.76(2H,d,J=8.4Hz,H-3″,7″),7.51-7.41(5H,m,H-9,4″-6″,ArOH),7.26-7.18(5H,m,H-5′-9′),7.03(1H,d,J=8.4Hz,H-8),4.70(1H,m,H-2),4.50(1H,m,H-2′),3.57(3H,s,OCH3),3.07-2.87(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.8,171.3,166.3(C-1″),150.8(C-7),137.0(C-4′),136.4(C-9),136.1(C-6),133.9(C-2″),131.4(C-5″),129.5(C-4),129.1(C-6′,8′),128.3(C-5′,9′),128.2(C-4″,6″),127.4(C-3″,7″),126.6(C-7′),125.4(C-5),118.8(C-8),54.4(C-2),53.8(C-2′),51.9(OCH3),36.6,35.6。
实施例30:N-(N-4-硝基-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 212.0-214.0℃,1H-NMR(DMSO,400MHz)δ:9.17(1H,s,Ar-OH),8.89(1H,d,J=8.4Hz,NHCO),8.60(1H,d,J=7.2Hz,NHCO),8.29(2H,d,J=8.4Hz,H-4″,6″),7.99(2H,d,J=8.8Hz,H-3″,7″),7.26-7.18(5H,m,H-5′-9′),7.11(2H,d,J=8.0Hz,H-5,9),6.61(2H,d,J=8.4Hz,H-6,8),4.68(1H,m,H-2),4.49(1H,m,H-2′),3.57(3H,s,OCH3),3.08-2.78(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.9,171.5,164.5(C-1″),155.8(C-7),149.1(C-5″),139.7(C-2″),137.1(C-4′),130.1(C-5,9),129.1(C-6′,8′),128.9(C-3″,7″),128.3(C-5′,9′),128.1(C-4),126.6(C-7′),123.5(C-4″,6″),114.9(C-6,8),55.1(C-2),53.8(C-2′),51.9(OCH3),36.5,36.3。
实施例31:N-(N-4-甲基-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 190.0-192.5℃,1H-NMR(DMSO,400MHz)δ:9.14(1H,s,Ar-OH),8.46(1H,d,J=7.2Hz,NHCO),8.36(1H,d,J=8.4Hz,NHCO),7.67(2H,d,J=8.8Hz,H-3″,7″),7.27-7.14(7H,m,H-5′-9′,H-4″,6″),7.09(2H,d,J=8.4Hz,H-5,9),6.60(2H,d,J=8.4Hz,H-6,8),4.63(1H,m,H-2),4.48(1H,m,H-2′),3.57(3H,s,OCH3),3.06-2.78(4H,m,H-3,3′),2.33(3H,s,Ar-CH3);13C-NMR(DMSO,100MHz)δ:171.9(s×2,C-1,1′),166.0(C-1″),155.7(C-7),141.2(C-5″),137.0(C-4′),131.3(C-2″),130.1(C-5,9),129.1(C-6′,8′),128.7(C-4″,6″),128.33(C-4),128.28(C-5′,9′),127.4(C-3″,7″),126.6(C-7′),114.8(C-6,8),54.8(C-2),53.7(C-2′),51.9(OCH3),36.6,36.2,21.0(Ar-CH3)。
实施例32:N-(N-3-硝基-苯甲酰基-L-酪氨酰基)-L-苯丙氨醇
光谱数据:mp 225.5-227.0℃,1H-NMR(DMSO,400MHz)δ:9.15(1H,s,Ar-OH),8.92(1H,d,J=8.0Hz,NHCO),8.62(1H,s,H-3″),8.37(1H,d,J=8.0Hz,H-5″),8.22(1H,d,J=7.6Hz,H-7″),7.94(1H,d,J=8.0Hz,NHCO),7.76(1H,t,H-6″),7.21-7.08(7H,m,H-5′-9′,H-5,9),6.61(2H,d,J=8.0Hz,H-6,8),4.80(1H,t,OH),4.64(1H,m,H-2),3.89(1H,m,H-2′),3.33-3.25(2H,m,H-1′),2.96-2.62(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:170.7(C-1),163.9(C-1″),155.7(C-7),147.6(C-4″),139.0(C-4′),135.6(C-2″),133.9(C-7″),130.1(C-5,9),130.0(C-6″),129.1(C-6′,8′),128.2(C-4),128.0(C-5′,9′),125.8(C-7′,C-5″),122.2(C-3″),114.8(C-6,8),62.2(C-1′),55.3(C-2),52.5(C-2′),36.5,36.4。
实施例33:N-(N-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 200.0-202.0℃,1H-NMR(DMSO,400MHz)δ:9.19(1H,s,Ar-OH),8.52-8.47(2H,m,NHCO×2),7.76(2H,d,J=6.8Hz,H-3″,7″),7.50(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.25-7.18(5H,m,H-5′-9′),7.10(2H,d,J=8.4Hz,H-5,9),6.61(2H,d,J=8.4Hz,H-6,8),4.63(1H,m,H-2),3.78(1H,m,H-2′),3.57(3H,s,OCH3),3.07-2.78(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.93,171.89,166.2(C-1″),155.7(C-7),137.1(C-4′),134.1(C-2″),131.4(C-5″),130.2(C-5,9),129.2(C-6′,8′),128.4(×3,C-4″,6″,C-4),128.3(C-5′,9′),127.5(C-3″,7″),126.7(C-7′),114.9(C-6,8),54.9(C-2),53.8(C-2′),52.0(OCH3),36.6,36.2。
实施例34:N-[N-(4-乙酰氨基-苯甲酰基)-L-苯丙氨酰基]-L-苯丙氨酸甲酯
光谱数据:mp:208.0-209.5,1H-NMR(DMSO,400MHz)δ:10.16(1H,s,ArNHCO),8.51(1H,d,J=7.2Hz,NHCO),8.40(1H,d,J=8.4Hz,NHCO),7.73(2H,d,J=8.8Hz,H-3″,7″),7.61(2H,d,J=8.8Hz,H-4″,6″),7.33-7.14(10H,m,H-5-9,5′-9′),4.72(1H,m,H-2),4.50(1H,m,H-2′),3.57(3H,s,OCH3),3.07-2.90(4H,m,H-3,3′),2.05(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:171.9,171.8,168.7(ArNHCO),165.6(C-1″),142.0(C-5″),138.4(C-4),137.0(C-4′),129.2(×2),129.1(×2),128.3(×4),128.2(C-2″),128.1(×2),126.6(C-7′),126.2(C-7),118.0(C-4″,6″),54.4(C-2),53.7(C-2′),51.9(OCH3),37.0(C-3),36.6(C-3′),24.1(CH3CO)。
实施例35:N-[N-(4-氯乙酰氨基-苯甲酰基)-L-苯丙氨酰基]-L-苯丙氨醇
光谱数据:1H-NMR(DMSO,400MHz)δ:10.55(1H,s,ArNHCO),8.42(1H,d,J=8.4Hz,NHCO),7.90(1H,d,J=8.0Hz,NHCO),7.81(2H,d,J=8.8Hz,H-3″,7″),7.66(2H,d,J=8.8Hz,H-4″,6″),7.33-7.12(10H,m,H-5-9,5′-9′),4.83(1H,t,OH),4.68(1H,m,H-2),4.31(2H,COCH2Cl),3.91(1H,m,H-2′),3.36-3.26(2H,m,H-1′),3.06-2.93(2H,m,H-3),2.88(1H,dd,J=6.0,13.6Hz,H-3′a),2.68(1H,dd,J=7.6,13.6Hz,H-3′b);13C-NMR(DMSO,100MHz)δ:171.0(C-1),165.4(C-1″),165.0(ArNHCO),141.1(C-5″),139.0(C-4′),138.4(C-4),129.2(×4,C-6,8,6′,8′),129.1(C-2″),128.4(C-3″,7″),128.1(×2),128.0(×2),126.2(C-7),125.9(C-7′),118.4(C-4″,6″),62.2(C-1′),54.8(C-2),52.5(C-2′),37.3(C-3),36.4(C-3′)。
实施例36:N-[N-(4-乙酰氨基-苯甲酰基)-L-苯丙氨酰基]-L-酪氨酸甲酯
光谱数据:mp 215.5-217.0℃,1H-NMR(DMSO,400MHz)δ:10.23(1H,s,ArNHCO),9.26(1H,s,ArOH),8.47-8.43(2H,m,NHCO×2),7.73(2H,d,J=8.4Hz,H-3″,7″),7.62(2H,d,J=8.4Hz,H-4″,6″),7.32(2H,d,J=7.2Hz,H-5,9),7.23(2H,t,H-6,8),7.14(1H,t,H-7),6.99(2H,d,J=8.4Hz,H-5′,9′),6.62(2H,d,J=8.0Hz,H-6′,8′),4.71(1H,m,H-2),4.40(1H,m,H-2′),3.56(3H,s,OCH3),3.07-2.86(4H,m,H-3,3′),2.05(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:172.0,171.7,168.7(ArNHCO),165.7(C-1″),156.1(C-7′),142.0(C-5″),138.4(C-4),130.1(C-5′,9′),129.2(C-6,8),128.3(C-3″,7″),128.2(C-4′),128.0(C-5,9),127.O(C-2″),126.2(C-7),117.9(C-4″,6″),115.1(C-6′,8′),54.5(C-2),54.1(C-2′),51.8(OCH3),36.9(C-3),35.9(C-3′),24.1(CH3CO)。
实施例37:N-[N-(4-丙酰氨基-苯甲酰基)-L-苯丙氨酰基]-L-苯丙氨酸甲酯
光谱数据:mp 225.0-227.0℃,1H-NMR(DMSO,400MHz)δ:10.09(1H,s,ArNHCO),8.52(1H,d,J=7.6Hz,NHCO),8.40(1H,d,J=8.4Hz,NHCO),7.74(2H,d,J=8.4Hz,H-3″,7″),7.64(2H,d,J=8.8Hz,H-4″,6″),7.34-7.13(10H,m,H-5-9,5′-9′),4.73(1H,m,H-2),4.52(1H,m,H-2′),3.59(3H,s,OCH3),3.08-2.91(4H,m,H-3,3′),2.35(2H,q,J=7.2Hz,COCH2CH3),1.08(3H,t,J=7.6Hz,COCH2CH3);13C-NMR(DMSO,100MHz)δ:172.4,171.82,171.78,165.7(C-1″),142.1(C-5″),138.4(C-4),137.0(C-4′),129.2(×2),129.1(×2),128.3(×4,C-3″,7″,5′,9′),128.1(C-2″),128.0(C-5,9),126.6(C-7),126.2(C-7′),118.0(C-4″,6″),54.4(C-2),53.7(C-2′),51.9(OCH3),36.9(C-3),36.6(C-3′),29.6(COCH2CH3),9.5(COCH2CH3)。
实施例38:N-[N-(4-丙酰氨基-苯甲酰基)-L-苯丙氨酰基]-4-硝基-L-苯丙氨酸甲酯
光谱数据:mp 221.0-223.0℃,1H-NMR(DMSO,400MHz)δ:10.14(1H,s,ArNHCO),8.61(1H,d,J=7.2Hz,NHCO),8.42(1H,d,J=8.4Hz,NHCO),9.05(2H,d,J=8.0Hz,H-6′,8′),7.72(2H,d,J=7.6 Hz,H-3″,7″),7.63(2H,d,J=8.4Hz,H-5′,9′),7.51(2H,d,J=8.0Hz,H-4″,6″),7.31(2H,d,J=7.2Hz,H-5,9),7.23(2H,t,H-6,8),7.14(1H,t,J=7.2Hz,H-7),4.68-4.59(2H,m,H-2,2′),3.61(3H,s,OCH3),3.25-2.90(4H,m,H-3,3′),2.34(2H,q,J=7.6Hz,COCH2CH3),1.07(3H,t,J=7.6Hz,COCH2CH3);13C-NMR(DMSO,100MHz)δ:172.4(ArNHCO),171.8(C-1),171.4(C-1′),165.7(C-1″),146.3(C-7′),145.5(C-4′),142.2(C-5″),138.3(C-4),130.6(C-5′,9′),129.2(C-6,8),128.3(C-3″,7″),128.1(C-5,9),128.0(C-2″),126.3(C-7),123.2(C-6′,8′),117.9(C-4″,6″),54.5(C-2),52.9(C-2′),52.1(OCH3),36.8(C-3),36.2(C-3′),29.6(COCH2CH3),9.6(COCH2CH3)。
实施例39:N-[N-(4-乙酰氨基-苯甲酰基)-L-苯丙氨酰基]-L-苯丙氨醇
光谱数据:mp 193.0-195.0℃,1H-NMR(DMSO,400MHz)δ:10.16(1H,s,ArNHCO),8.39(1H,d,J=8.4Hz,NHCO),8.26(1H,d,J=8.4Hz,NHCO),7.76(2H,d,J=8.4Hz,H-3″,7″),7.62(2H,d,J=8.8Hz,H-4″,6″),7.32-7.13(10H,m,H-5-9,5′-9′),4.70(1H,m,H-2),4.17(1H,m,H-2′),3.64(1H,dd,J=4.8,11.2Hz,H-1′a),3.52(1H,dd,J=7.0,11.2Hz,H-1′b),3.05-2.78(4H,m,H-3,3′),2.06(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:171.4(C-1),168.7(ArNHCO),165.6(C-1″),142.0(C-5″),138.3(C-4),137.8(C-4′),129.2(×4),128.3(×4),128.2(C-2″),128.0(C-3″,7″),126.4(C-7),126.2(C-7′),118.0(C-4″,6″),54.7(C-2),51.5(C-1′),46.8(C-2′),37.3(C-3),37.0(C-3′),24.1(CH3CO)。
实施例40:N-[N-(4-乙酰氨基-苯甲酰基)-L-酪氨酰基]-L-苯丙氨醇
光谱数据:mp 220.5-223.0℃,1H-NMR(DMSO,400MHz)δ:10.17(1H,s,ArNHCO),9.14(1H,s,ArOH),8.28(1H,d,J=8.0Hz,NHCO),7.83(1H,d,J=8.4Hz,NHCO),7.76(2H,d,J=8.8Hz,H-3″,7″),7.63(2H,d,J=8.4Hz,H-4″,6″),7.22-7.07(7H,m,H-5,9,5′-9′),6.61(2H,d,J=8.0Hz,H-6,8),4.81(1H,t,OH),4.57(1H,m,H-2),3.88(1H,m,H-2′),3.34-3.25(2H,m,H-1′),2.91-2.50(4H,m,H-3,3′),2.07(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:171.2(C-1),168.7(ArNHCO),165.5(C-1″),155.7(C-7),142.0(C-5″),139.0(C-4′),130.1(C-5,9),129.2(6′,8′),128.4(C-4,2″),128.3(C-5′,9′),128.1(C-3″,7″),125.9(C-7′),117.9(C-4″,6″),114.8(C-6,8),62.2(C-1′),55.1(C-2),52.4(C-2′),36.5,36.4,24.2(CH3CO)。
实施例41:N-[N-(4-乙酰氨基-苯甲酰基)-L-酪氨酰基]-L-苯丙氨酸甲酯
光谱数据:mp 225.0-226.0℃,1H-NMR(DMSO,400MHz)δ:10.18(1H,s,ArNHCO),9.16(1H,s,ArOH),8.48(1H,d,J=7.2Hz,NHCO),8.34(1H,d,J=8.4Hz,NHCO),7.75(2H,d,J=8.8Hz,H-3″,7″),7.63(2H,d,J=8.8Hz,H-4″,6″),7.26-7.17(5H,m,5′-9′),7.11(2H,d,J=8.4Hz,H-5,9),6.63(2H,d,J=8.4Hz,H-6,8),4.64(1H,m,H-2),4.50(1H,m,H-2′),3.58(3H,s,OCH3),3.08-2.79(4H,m,H-3,3′),2.07(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:171.9,171.8,168.7(ArNHCO),165.5(C-1″),155.7(C-7),142.0(C-5″),137.0(C-4′),130.1(C-5,9),129.1(6′,8′),128.4(C-4,2″),128.3(×4,C-5′,9′,3″,7″),126.6(C-7′),117.9(C-4″,6″),114.8(C-6,8),54.8(C-2),53.7(C-2′),51.9(OCH3),36.6,36.2,24.1(CH3CO)。
实施例42:N-[N-(4-氯乙酰氨基-苯甲酰基)-L-苯丙氨酰基]-L-苯丙氨酸甲酯
光谱数据:mp 222.5-224.5℃,1H-NMR(DMSO,400MHz)ε:10.64(1H,s,ArNHCO),8.57(1H,d,J=7.6Hz,NHCO),8.50(1H,d,J=8.4Hz,NHCO),7.78(2H,d,J=8.4Hz,H-3″,7″),7.65(2H,d,J=8.8Hz,H-4″,6″),7.34-7.14(10H,m,H-5-9,5′-9′),4.74(1H,m,H-2),4.51(1H,m,H-2′),4.31(2H,s,NHCOCH2Cl),3.59(3H,s,OCH3),3.09-2.92(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.9,171.8,165.6(C-1″),165.0(ArNHCO),141.2(C-5″),138.4(C-4),137.1(C-4′),129.2(C-6,8),129.1(C-6′,8′),129.0(C-2″),128.4(C-3″,7″),128.3(C-5′,9′),128.1(C-5,9),126.6(C-7′),126.2(C-7),118.4(C-4″,6″),54.5(C-2),53.8(C-2′),51.9(OCH3),43.6(COCH2Cl),37.0(C-3),36.6(C-3′)。
实施例43:N-(N-异烟酰基-L-苯丙氨酰)-L-苯丙氨醇
光谱数据:N-(N-4-pyridinyl-formyl-L-phenylalanyl)-L-phenylalanol,mp 199.0-201.0℃,1H-NMR(DMSO,400MHz)δ:8.83(1H,d,J=8.8Hz,NHCO),8.69(2H,d,J=6.4Hz,H-4″,6″),7.96(1H,d,J=8.0Hz,NHCO),7.66(2H,d,J=6.0Hz,H-3″,7″),7.31-7.11(10H,m,H-5-9,5′-9′),4.81(1H,t,J=5.2Hz,OH),4.68(1H,m,H-2),3.89(1H,m,H-2′),3.35-3.25(2H,m,H-1′),3.04(1H,dd,J=4.4,14.0Hz,H-3a),2.95-2.83(2H,m,H-3b,3′a),2.65(1H,dd,J=7.6,13.2Hz,H-3′b);13C-NMR(DMSO,100MHz)δ:170.5(C-1),164.5(C-1″),150.1(C-4″,6″),141.0(C-2″),139.0(C-4′),138.2(C-4),129.2(×4,C-6,8,6′,8′),128.1(×4,C-5,9,5′,9′),126.3(C-7),125.9(C-7′),121.4(C-3″,7″),62.2(C-1′),54.8(C-2),52.5(C-2′),37.3(C-3),36.4(C-3′)。
实施例44:N-(N-异烟酰基-L-苯丙氨酰)-L-苯丙氨酸甲酯
光谱数据:mp 174.0-175.0℃,1H-NMH(CDCl3,400MHz)δ:8.71(2H,d,J=6.0Hz,H-4″,6″),7.52(2H,d,J=5.6Hz,H-3″,7″),7.31-7.17(8H,m,H-5,6,8,9,5′,6′,8′,9′),7.07(1H,br,NHCO),6.99-6.97(2H,m,H-7,7′),6.30(1H,br,NHCO),4.86-4.75(2H,m,H-2,2′),3.72(3H,s,OCH3),3.20(1H,dd,J=6.0,14.0Hz,H-3a),3.14-3.08(2H,m,H-3b,3′a),2.97(1H,dd,J=7.6,13.6Hz,H-3′b);13C-NMR(CDCl3,100MHz)δ:171.2(C-1),170.0(C-1′),165.0(C-1″),150.6(C-4″,6″),140.7(C-2″),136.0,135.3,129.3(C-6′,8′),129.0(C-6,8),128.7(C-5′,9′),128.6(C-5,9),127.24,127.19,120.8(C-3″,7″),54.6(C-2),53.5(C-2′),52.4(OCH3),38.2(C-3),37.8(C-3′)。
实施例45:N-(N-异烟酰基-L-苯丙氨酰)-4-硝基-L-苯丙氨酸甲酯
光谱数据:mp 224.5-225.5,1H-NMR(CDCl3,400MHz)δ:8.77(2H,s,H-4″,6″),8.06(2H,d,J=8.0Hz,H-6′,8′),7.54(2H,s,H-3″,7″),7.29-7.19(7H,m,H-5-9,5′,9′),6.86(1H,br,NHCO),6.29(1H,br,NHCO),4.79(2H,m,H-2,2′),3.72(3H,s,OCH3),3.21-3.08(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:170.5(C-1),170.1(C-1′),165.2(C-1″),150.7(C-4″,6″),147.1(C-7′),143.2(C-4′),140.4(C-2″),135.7(C-4),130.1(C-5′,9′),129.2(C-6,8),128.9(C-5,9),124.4(C-7),123.7(C-6′,8′),120.7(C-3″,7″),54.8(C-2′),53.0(C-2),52.7(OCH3),38.1(C-3′),37.1(C-3)。
实施例46:N-(N-异烟酰基-L-苯丙氨酰)-L-酪氨酸甲酯
光谱数据:mp 216.0-217.0,1H-NMR(DMSO,400MHz)δ:9.26(1H,s,Ar-OH),8.91(1H,d,J=8.8Hz,NHCO),8.70(2H,d,J=5.2Hz,H-4″,6″),8.57(1H,d,J=7.6Hz,NHCO),7.66(2H,d,J=5.2Hz,H-3″,7″),7.35(2H,d,J=7.6Hz,H-5,9),7.25(2H,t,H-6,8),7.16(1H,t,H-7),7.02(2H,d,J=8.0Hz,H-5′,9′),6.64(2H,d,J=8.0Hz,H-6′,8′),4.78(1H,m,H-2),4.44(1H,m,H-2′),3.59(3H,s,OCH3),3.12-2.85(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.0(C-1),171.3(C-1′),164.7(C-1″),156.1(C-7′),150.2(C-4″,6″),140.9(C-2″),138.1(C-4),130.1(C-5′,9′),129.2(C-6,8),128.1(C-5,9),127.0(C-4′),126.3(C-7),121.4(C-3″,7″),115.1(C-6′,8′),54.5(C-2),54.2(C-2′),51.9(OCH3),37.0(C-3),35.8(C-3′)。
实施例47:N-(N-异烟酰基-L-酪氨酰)-L-苯丙氨醇
光谱数据:mp 210.0-212.0℃,1H-NMR(DMSO,400MHz)δ:9.17(1H,s,ArOH),8.79(1H,d,J=8.4Hz,NHCO),8.71(2H,d,J=5.6Hz,H-4″,6″),7.95(1H,d,J=8.0Hz,NHCO),7.69(2H,d,J=5.6Hz,H-3″,7″),7.23-7.09(7H,m,H-5,9,5′-9′),6.63(2H,d,J=8.4Hz,H-6,8),4.82(1H,t,OH),4.62(1H,m,H-2),3.90(1H,m,H-2′),3.37-3.27(2H,m,H-1′),2.96-2.79(3H,m,H-3,3′a),2.66(1H,dd,J=8.0,13.6Hz,H-3′b);13C-NMR(DMSO,100MHz)δ:171.7(C-1),164.5(C-1″),155.7(C-7),150.2(C-4″,6″),141.1(C-2″),139.0(C-4′),130.1(C-5,9),129.2(C-6′,8′),128.2(C-4),128.1(C-5′,9′),125.9(C-7′),121.4(C-3″,7″),1 14.9(C-6,8),62.3(C-1′),55.3(C-2),52.5(C-2′),36.6,36.4。
实施例48:N-(N-异烟酰基-L-酪氨酰)-L-苯丙氨酸甲酯
光谱数据:mp 206.5-209.0℃,1H-NMR(DMSO,400MHz)δ:9.17(1H,s,ArOH),8.82(1H,d,J=8.8Hz,NHCO),8.70(2H,d,J=5.6Hz,H-4″,6″),8.59(1H,d,J=7.6Hz,NHCO),7.67(2H,d,J=5.6Hz,H-3″,7″),7.27-7.18(5H,m,H-5′-9′),7.12(2H,d,J=8.4Hz,H-5,9),6.63(2H,d,J=8.4Hz,H-6,8),4.68(1H,m,H-2),4.50(1H,m,H-2′),3.59(3H,s,OCH3),3.09-2.77(4H,m,H-3,3);13C-NMR(DMSO,100MHz)δ:171.8(C-1),171.4(C-1′),164.6(C-1″),155.7(C-7),150.2(C-4″,6″),141.0(C-2″),137.1(C-4′),130.1(C-5,9),129.1(C-6′,8′),128.3(C-5′,9′),128.1(C-4),126.6(C-7′),121.4(C-3″,7″),114.9(C-6,8),54.9(C-2),53.8(C-2′),51.9(OCH3),38.9,36.5。
实施例49:N-[N-(4-二甲氨甲基-苯甲酰基)-L-苯丙氨酰基]-L-苯丙氨醇
试剂及反应条件:(a)(t-BuOCO)2O,1.0M NaOH,TBAB;(b)CH2Cl2,氯甲酸异丁酯(IBCF),N-甲基吗啉(NMM),-5℃;(c)TFA,CH2Cl2,rt,2h
实验操作:(a)取L-苯丙氨酸(1.65 g,10.0mmol)溶解于20ml 1.0M NaOH溶液中,加入二碳酸二叔丁酯{(t-BuOCO)2O}(2.289g,10.05mmol)和四丁基溴化铵(Tetrabutyl ammonium bromide,TBAB,1.0g),室温搅拌过夜。次日以浓盐酸调节反应液至pH2-3,乙酸乙酯60ml萃取,饱和氯化钠(2?0ml)洗涤,无水硫酸钠干燥,减压回收溶剂至干,即得无色油状样品N-BOC-L-苯丙氨酸(N-BOC-L-Phe)2.63 g(产率:99%);(b)其操作步骤与实施例1的合成步骤(b)类似,制备得白色粉末状的中间体M-32(产率:88%);(c)取前一步合成所得M-32样品以三氟乙酸(TFA)溶解,室温搅拌2h,向反应瓶中加水适量,以碳酸钠调节至碱性(pH11-12),乙酸乙酯萃取,有机相无以水硫酸钠干燥,减压回收溶剂至干得白色蜡状固体样品M-33(产率:65.8%)。
试剂及反应条件:CH2Cl2,DCC,DMAP,rt.
实验操作:将前述合成的中间体M-25(10mmol)与M-33(10mmol)、DCC(2.47g,12mmol)、DMAP(200mg,作为催化剂)混合于反应瓶中,注入无水CH2Cl2 200ml,反应于氮气保护下室温搅拌过夜。产物经萃取及重结晶纯化,即得白色蜡状固体产物1(产率:89%)。
光谱数据:
N-(N-(4-dimethylamino-methyl-benzoyl)-L-phenylalanyl)-L-phenylalanol,mp 196.5-198.0℃,1H-NMR(DMSO,400MHz)δ:8.46(1H,d,J=8.8Hz,NHCO),7.87(1H,d,J=8.4Hz,NHCO),7.75(2H,d,J=8.0Hz,H-3″,7″),7.34(2H,d,J=8.0Hz,H-4″,6″),7.30-7.10(10H,m,H-5′-9′,5-9),4.81(1H,t,OH),4.67(1H,m,H-2),3.87(1H,m,H-2′),3.43(2H,s,ArCH2N(CH3)2),3.34-3.25(2H,m,H-1′),3.02-2.93(2H,m,H-3),2.84(1H,dd,J=5.6,13.6Hz,H-3′a),2.65(1H,dd,J=8.4,13.6Hz,H-3′b),1.14(6H,s,ArCH2N(CH3)2);13C-NMR(DMSO,100MHz)δ:171.0(C-1),165.9(C-1″),143.0(C-5″),139.0(C-4′),138.4(C-4),132.8(C-2″),129.2(?,C-6,8,6′,8′),128.5(C-4″,6″),128.1(C-5′,9′),128.0(C-5,9),127.4(C-3″,7″),126.2(C-7),125.9(C-7′),62.8(ArCH2N(CH3)2),62.2(C-1′),54.8(C-2),52.5(C-2′),44.9(ArCH2N(CH3)2),37.2,36.4。
按照类似于实施例49的合成方法,选择适当的反应原料及中间体,分别制得实施例50~53的衍生物。
实施例50:N-{N-[4-(1-吡咯烷基)甲基-苯甲酰基]-L-苯丙氨酰基}-L-苯丙氨醇
光谱数据:mp 164.0-165.0℃,1H-NMR(DMSO,400MHz)δ:8.44(1H,d,J=8.0Hz,NHCO),7.87(1H,d,J=8.4Hz,NHCO),7.74(2H,d,J=8.4Hz,H-3″,7″),7.35(2H,d,J=8.0Hz,H-4″,6″),7.31-7.09(10H,m,H-5′-9′,5-9),4.81(1H,t,OH),4.67(1H,m,H-2),3.88(1H,m,H-2′),3.58(2H,s,ArCH2N<),3.34-3.24(2H,m,H-1′),3.04-2.91(2H,m,H-3),2.85(1H,dd,J=5.6,13.6Hz,H-3′a),2.65(1H,dd,J=8.0,13.6Hz,H-3′b),2.40(4H,s,ArCH2N(CH2)2),1.67(4H,s,>NCH2CH2CH2CH2N<);13C-NMR(DMSO,100MHz)δ:171.0(C-1),165.9(C-1″),143.0(C-5″),139.0(C-4′),138.4(C-4),132.6(C-2″),129.2(×4,C-6,8,6′,8′),128.14(C-4″,6″),128.08(C-5′,9′),128.04(C-5,9),127.4(C-3″,7″),126.2(C-7),125.9(C-7′),62.2(C-1′),59.2(ArCH2N<),54.8(C-2),53.5(ArCH2N(CH2)2),52.5(C-2′),37.2,36.4,23.1(>NCH2CH2CH2CH2N<)。
实施例51:N-{N-[4-(4-吗啉基)甲基-苯甲酰基]-L-苯丙氨酰基}-L-苯丙氨醇
光谱数据:mp 183.0-184.5℃,1H-NMR(DMSO,400MHz)δ:8.45(1H,d,J=8.4Hz,NHCO),7.87(1H,d,J=8.0Hz,NHCO),7.76(2H,d,J=7.6Hz,H-3″,7″),7.37(2H,d,J=7.6Hz,H-4″,6″),7.31-7.10(10H,m,H-5′-9′,5-9),4.81(1H,t,OH),4.69(1H,m,H-2),3.89(1H,m,H-2′),3.57(4H,s,-CH2OCH2-),3.48(2H,s,ArCH2N<),3.34-3.25(2H,m,H-1′),3.05-2.92(2H,m,H-3),2.86(1H,dd,J=5.2,13.6Hz,H-3′a),2.66(1H,dd,J=8.0,13.6Hz,H-3′b),2.34(4H,s,ArCH2N(CH2)2);13C-NMR(DMSO,100MHz)δ:170.9(C-1),165.9(C-1″),141.4(C-5″),139.0(C-4′),138.4(C-4),132.8(C-2″),129.19(×2),129.17(×2),128.6(C-4″,6″),128.06(×2),128.01(×2),127.4(C-3″,7″),126.2(C-7),125.9(C-7′),66.2(-CH2OCH2-),62.2(C-1′),61.96(ArCH2N<),54.7(C-2),53.2(ArCH2N(CH2)2),52.5(C-2′),37.2,36.4。
实施例52:N-[N-(4-乙氧羰基-苯甲酰基)-L-苯丙氨酰基]-L-苯丙氨醇
光谱数据:mp 188.0-189.5℃,1H-NMR(DMSO,400MHz)δ:8.74(1H,d,J=8.4Hz,NHCO),8.02(2H,d,J=8.0Hz,H-4″,6″),7.97(1H,d,J=8.4Hz,NHCO),7.91(2H,d,J=8.4Hz,H-3″,7″),7.33-7.11(10H,m,H-5-9,5′-9′),4.82(1H,t,OH),4.71(1H,m,H-2),4.34(2H,q,J=7.2Hz,OCH2CH3),3.90(1H,m,H-2′),3.35-3.26(2H,m,H-1′),3.07-2.92(2H,m,H-3),2.87(1H,dd,J=5.6,13.6Hz,H-3′a),2.67(1H,dd,J=8.0,13.6Hz,H-3′b),1.34(3H,t,OCH2CH3);13C-NMR(DMSO,100MHz)δ:171.8(C-1),165.2(×2,C-1″,ArCOOCH2CH3),139.0(C-4′),138.3(C-4),138.1(C-2″),132.1(C-5″),129.2(×4,C-6,8,6′,8′),129.0(C-4″,6″),128.08(×2),128.05(×2),127.8(C-3″,7″),126.2(C-7),125.9(C-7′),62.2(C-1′),61.0(OCH2CH3),54.9(C-2),52.5(C-2′),37.3(C-3),36.4(C-3′),14.2(OCH2CH3)。
实施例53:N-[N-(2-羧基-苯甲酰基)-4-乙酰氨基-L-苯丙氨酰基]-L-苯丙氨醇钠盐
光谱数据:Sodium N-(N-2-carboxybenzoyl-L-phenylalanyl)-L-phenylalanol,1H-NMR(DMSO,400MHz)δ:9.20(1H,d,J=7.2Hz,H-4″),8.50(1H,d,J=8.8Hz,H-7″),7.76(1H,m,H-6″),7.33-7.19(12H,m,H-5-9,5′-9′,NHCO×2),6.65(1H,m,H-5″),4.48-4.39(2H,m,H-2,2′),3.80(1H,br,OH),3.45-3.27(2H,m,H-1′),2.86-2.70(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:170.98,170.94,168.6(C-1″),139.6,139.5,138.4,138.2,129.3(×2,C-4″,7″),129.3(C-6,8),129.0(C-6′,8′),128.2(C-5,9),128.0(C-5′,9′),127.7(C-5″),126.0,125.92,125.87,61.0(C-1′),54.7,54.0,36.6,36.2。
实施例54:N-(N-苯甲酰基-4-乙酰氨基-L-苯丙氨酰基)-O-乙酰基-L-苯丙氨醇
试剂及反应条件:(a)MeOH,H2,Pd/C(20%),rt.,3h;(b)Ac2O,吡啶(pyridine,pyr.),rt.,5h
实验操作:(a)取前述(实施例5)合成的化合物1样品1.788g(4mmol)溶解于100ml MeOH中,经脱气处理后加入20%的Pd/C 21mg,并以氢气置换反应体系中的空气后,以氢气球密封反应体系,于室温搅拌反应过夜。次日过滤除去Pd/C催化剂,滤液减压回收溶剂至干,即得1.876g白色粉末状的化合物2粗品,该产品未经经一步纯化而直接用于下一步的反应。(b)取上一步合成所得化合物2粗品469mg(<1.0mmol)于5ml吡啶中溶解完全,室温搅拌,缓慢滴加乙酸酐(Ac2O)2ml,室温反应5h,加入无水乙醇5ml分解过量的乙酸酐,减压回收溶剂至干,所得固体以适量EtOAc溶解完全,依次以蒸馏水、5%NaHCO3和饱和NaCl溶液洗涤,无水硫酸钠干燥,减压回收乙酸乙酯至干,所得残留物以乙酸乙酯重结晶即得白色粉末状产物300mg(60.0%)。
光谱数据:mp 236.0-237.5℃,1H-NMR(DMSO,400MHz)δ:9.84(1H,s,ArNHCO),8.49(1H,d,J=8.4Hz,NHCO),8.15(1H,d,J=8.4Hz,NHCO),7.80(2H,d,J=7.6Hz,H-3″,7″),7.52(1H,t,H-5″),7.47-7.43(4H,m,H-4″,6″,H-6,8),7.24-7.15(7H,m,H-5′-9′,H-5,9),4.63(1H,m,H-2),4.18(1H,m,H-2′), 4.02(1H,dd,J=4.8,11.2Hz,H-1′a),3.87(1H,dd,J=7.2,11.2Hz,H-1′b),2.96-2.77(4H,m,H-3,3′),1.99(3H,CH3CO),1.98(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:171.2(C-1),170.3(OCOCH3),168.1(ArNHCOCH3),166.1(C-1″),138.0(C-7),137.6(C-4′),134.1(C-2″),132.8(C-4),131.3(C-5″),129.3(C-5,9),129.2(C-6′,8′),128.23(×2),128.18(×2),127.4(C-3″,7″),126.2(C-7′),118.6(C-6,8),64.6(C-1′),55.0(C-2),49.1(C-2′),36.7(C-3′),36.6(C-3),24.0(NHCOCH3),20.6(OCOCH3)。
按照类似于实施例54的合成方法,选择适当的反应原料及中间体,分别制得实施例55~70的衍生物。
实施例55:N-(N-苯甲酰基-L-苯丙氨酰基)-O-乙酰基-L-苯丙氨醇
光谱数据:mp 186-187℃,[酸20 D-35.71(0.028,CHCl3).IR(KBr)cm-1:3314,1725,1661,1631,1533,746,698.EI-MSm/z:444,384,353,311,269,252,224,172,131,105(100),91,77,60.1H-NMR(CDCl3,400MHz)δ:7.69(2H,d,J=8.0Hz,H-3″,7″),7.50(1H,t,H-5″),7.42(2H,t,H-4″,6″),7.30-7.06(10H,m,H-5-9,H-5′-9′),6.76(1H,d,J=7.6Hz,NHCO),5.97(1H,d,J=8.4Hz,NHCO),4.77(1H,m,H-2),4.34(1H,m,H-2′),3.93(1H,dd,J=5.2,11.6Hz,H-1′a),3.81(1H,dd,J=4.0,11.2Hz,H-1′b),3.22(1H,dd,J=5.6,13.6Hz,H-3a),3.06(1H,dd,J=8.4,13.6Hz,H-3b),2.75(2H,m,H-3′),2.03(3H,s,CH3CO);13C-NMR(CDCl3,400MHz)δ:170.6(C-1),170.2(COCH3),167.1(C-1″),136.7(C-4),136.6(C-4′),133.6(C-2″),131.9(C-5″),129.3(C-6,8),129.1(C-6′,8′),128.7(C-4″,6″),128.6(C-5,9),128.5(C-5′,9′),127.1(C-3″,7″),127.0(C-7′),126.7(C-7),64.5(C-1′),54.9(C-2),49.4(C-2′),38.4(C-3),37.4(C-3′),20.77(COCH3)。
实施例56:N-(N-苯甲酰基-L-苯丙氨酰基)-O-(3-羧基-丙酰基)-L-苯丙氨醇
光谱数据:1H-NMR(CDCl3,400MHz)δ:8.61(1H,d,J=7.6Hz,NHCO)7.71(2H,d,H-3″,7″),7.50(1H,t,5″),7.40(2,t,H-4″,6″),7.31-7.08(10H,m,H-5-9,5′-9′),6.47(1H,d,J=8.0Hz,NHCO),5.12(1H,m,H-2),4.32(1H,m,H-2′),4.15-3.94(2H,dd×2,H-3′),3.05-3.01(2H,m,H-3),2.70-2.58(4H,m,-OCOCH2CH2CO-):
实施例57:N-(N-苯甲酰基-乙酰基-L-苯丙氨酰基)-L-苯丙氨酸甲酯
光谱数据:mp 221.0-222.0℃,℃,1H-NMR(DMSO,400MHz)δ:9.84(1H,s,ArNHCO),8.52(2H,m,NHCO×2),7.76(2H,d,J=7.6Hz,H-3″,7″),7.51(1H,t,H-5″),7.46-7.42(4H,m,H-4″,6″,H-6,8),7.26-7.17(7H,m,H-5′-9′,H-5,9),4.71(1H,m,H-2),4.51(1H,m,H-2′),3.59(3H,s,OCH3),3.09-2.85(4H,m,H-3,3′),1.99(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:171.9,171.7,168.1(ArNHCOCH3),166.2(C-1″),137.6(C-7),137.1(C-4′),134.0(C-2″),132.8(C-4),131.3(C-5″),129.4(C-5,9),129.1(C-6′,8′),128.3(C-4″,6″),128.2(C-5′,9′),127.4(C-3″,7″),126.6(C-7′),118.6(C-6,8),54.6(C-2),53.8(C-2′),51.9(OCH3),36.6,36.4,24.0(COCH3)。
实施例58:N-(N-苯甲酰基-L-苯丙氨酰基)-4-氨基-L-苯丙氨酸甲酯盐酸盐
光谱数据:mp 173.0-175.0℃,1H-NMR(DMSO,400MHz)δ:10.25(br,ArNH2·HCl),8.69(1H,d,J=7.6Hz,NHCO),8.62(1H,d,J=8.8Hz,NHCO),7.77(2H,d,J=6.8Hz,H-3″,7″),7.51-7.14(12H,m,H-4″-6″,H-5-9,H-5′,9′,6′,8′),4.71(1H,m,H-2),4.50(1H,m,H-2′),3.58(3H,s,OCH3),3.11-2.82(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.9,171.7,166.3(C-1″),138.4(C-4),137.2(C-7′),134.0(C-2″),131.4(C-5″),130.6(C-4′),130.6 (C-5′,9′),129.3(C-6,8),128.3(×2),128.1(×2),127.5(C-3″,7″),126.3(C-7′),123.1(C-6′,8′),54.8(C-2),53.7(C-2′),52.1(OCH3),37.0,35.9。
实施例59:N-(N-苯甲酰基-L-苯丙氨酰基)-4-乙酰氨基-L-苯丙氨酸甲酯
光谱数据:mp 228.0-229.5℃,1H-NMR(DMSO,400MHz)δ:9.95(1H,s,ArNHCO),8.60(1H,d,J=8.8Hz,NHCO),8.57(1H,d,J=7.6Hz,NHCO),7.77(2H,d,J=6.8Hz,H-3″,7″),7.53-7.14(12H,m,H-4″-6″,H-5-9,H-5′,9′,6′,8′),4.74(1H,m,H-2),4.47(1H,m,H-2′),3.59(3H,s,OCH3),3.09-2.91(4H,m,H-3,3′),2.02(3H,s,COCH3);13C-NMR(DMSO,100MHz)δ:171.9,171.7,168.2(ArNHCOCH3),166.2(C-1″),138.4(C-4),138.0(C-7′),134.0(C-2″),131.4(C-4′),131.3(C-5″),129.4(C-5′,9′),129.2(C-6,8),128.2(C-4″,6″),128.1(C-5,9),127.4(C-3″,7″),126.2(C-7),118.8(C-6′,8′),54.6(C-2),53.9(C-2′),51.9(OCH3),37.0,36.1,24.0(COCH3)。
实施例60:N-[N-(4-甲基-苯甲酰基)-L-苯丙氨酰基]-4-乙酰氨基-L-苯丙氨酸甲酯
光谱数据:mp 221.5-222.0℃,1H-NMR(DMSO,400MHz)δ:9.91(1H,s,ArNHCO),8.53(1H,d,J=7.6Hz,NHCO),8.48(1H,d,J=8.8Hz,NHCO),7.68(2H,d,J=8.8Hz,H-3″,7″),7.48(2H,d,J=8.8Hz,H-6′,8′),7.34(2H,d,J=7.6Hz,H-5,9),7.24(4H,m,H-4″,6″,H-6,8),7.16(3H,m,H-5′,9′,H-7),4.74(1H,m,H-2),4.48(1H,m,H-2′),3.59(3H,s,OCH3),3.09-2.91(4H,m,H-3,3′),2.33(3H,s,Ar-CH3),2.02(3H,s,COCH3);13C-NMR(DMSO,100MHz)δ:171.9,171.8,168.1(ArNHCO),166.1(C-1″),141.2(C-5″),138.4(C-4),138.0(C-7′),131.4(C-2″),131.2(C-4′),129.4(C-5′,9′),129.2(C-6,8),128.7(C-4″,6″),128.0(C-5,9),127.5(C-3″,7″),126.2(C-7),118.9(C-6′,8′),54.5(C-2),53.9(C-2′),37.0,36.1,24.0(NHCOCH3),21.0(Ar-CH3)。
实施例61:N-{N-[4-(3-羧基-丙酰氨基)-苯甲酰基]-L-苯丙氨酰基}-L-苯丙氨醇
光谱数据:1H-NMR(DMSO,400MHz)δ:12.18(1H,COOH),10.21(1H,s,ArNHCO),8.38(1H,d,J=8.4Hz,NHCO),7.88(1H,d,J=8.4Hz,NHCO),7.77(2H,d,J=8.8Hz,H-3″,7″),7.64(2H,d,J=8.4Hz,H-4″,6″),7.31-7.11(10H,m,H-5-9,5′-9′),4.82(1H,t,OH),4.67(1H,m,H-2),3.90(1H,m,H-2′),3.35-3.24(2H,m,H-1′),3.05-2.91(2H,m,H-3),2.86(1H,dd,J=5.6,13.6Hz,H-3′a),2.66(1H,dd,J=8.0,13.6,Hz,H-3′b),2.61-2.50(4H,m,ArNHCOCH2CH2COOH);13C-NMR(DMSO,100MHz)δ:173.9(COOH),171.1(ArNHCO),170.6(C-1),165.6(C-1″),142.0(C-5″),139.0(C-4′),138.5(C-4),129.23(×2),129.21(×2),128.4(C-3″,7″),128.2(C-2″),128.1(×2),128.0(×2),126.2(C-7),125.9(C-7′),117.9(C-4″,6″),62.2(C-1′),54.8(C-2),52.5(C-2′),37.2(C-3′),36.5(C-3),31.1(ArNHCOCH2CH2COOH),28.7(ArNHCOCH2CH2COOH)。
实施例62:N-{N-[4-(3-羧基-丙酰氨基)-苯甲酰基]-L-苯丙氨酰基}-L-苯丙氨酸甲基
光谱数据:1H-NMR(DMSO,400MHz)δ:12.21(1H,br,COOH),10.22(1H,s,ArNHCO),8.55(1H,d,J=7.6Hz,NHCO),8.43(1H,d,J=8.8Hz,NHCO),7.74(2H,d,J=8.8Hz,H-3″,7″),7.63(2H,d,J=8.4Hz,H-4″,6″),7.34-7.13(10H,m,H-5-9,5′-9′),4.73(1H,m,H-2),4.51(1H,m,H-2′),3.59(3H,s,OCH3),3.07-2.91(4H,m,H-3,3′),2.59-2.50(4H,m,ArNHCOCH2CH2COOH);13C-NMR(DMSO,100MHz)δ:173.9(COOH),171.9,171.8,170.6,165.7(C-1″),142.(C-5″),138.4(C-4),137.4(C-4′),129.2(C-6,8),129.2(C-6′,8′),128.4(C-3″,7″),128.3(C-5′,9′),128.12(C-2″),128.07(C-5,9),126.6(C-7′),126.2(C-7),117.9(C-4″,6″),54.4(C-2),53.8(C-2′),51.9(OCH3),36.9(C-3′),36.6(C-3),31.1(ArNHCOCH2CH2COOH),28.7(ArNHCOCH2CH2COOH)。
实施例63:N-(N-苯甲酰基-O-乙酰基-3-乙酰氨基-L-酪氨酰基)-L-苯丙氨酸甲酯
光谱数据:1H-NMR(DMSO,400MHz)δ:9.34(1H,s,ArNHCO),8.58-8.53(2H,m,NHCO×2),7.85(1H,s,H-5),7.77(2H,d,J=8.8Hz,H-3″,7″),7.51(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.25-7.19(5H,m,H-5′-9′),7.09(1H,d,J=8.0Hz,H-8),7.99(1H,d,J=8.0Hz,H-9),4.70(1H,m,H-2),4.51(1H,m,H-2′),3.59(3H,s,OCH3),3.08-2.89(4H,m,H-3,3′),2.24(3H,s,OCOCH3),2.05(3H,s,NHCOCH3);13C-NMR(DMSO,100MHz)δ:171.8,171.7,169.0,166.4(C-1″),140.1(C-7),137.0(C-4′),135.8(C-6),134.2(C-2″),131.3(C-5″),130.1(C-4),129.1(C-6′,8′),128.3(C-5′,9′),128.2(C-4″,6″),127.5(C-3″,7″),126.6(C-7′),125.3,124.7,122.4(C-5),54.5(C-2),53.8(C-2′),51.9(OCH3),36.6,36.5,23.6(NHCOCH3),21.1(OCOCH3)。
实施例64:N-(N-苯甲酰基-L-苯丙氨酰基)-4-丙酰氨基-L-苯丙氨酸甲酯
光谱数据:mp 244.5-246.0℃,1H-NMR(DMSO,400MHz)δ:9.89(1H,s,ArNHCO),8.60-8.57(2H,m,NHCO×2),7.76(2H,d,J=7.6Hz,H-3″,7″),7.51-7.47(3H,m,H-5″,H-6′,8′),7.41(2H,t,H-4″,6″),7.32(2H,d,J=7.6 Hz,H-5,9),7.33(2H,t,H-6,8),7.15-7.13(3H,m,H-7,H-5′,9′),4.73(1H,m,H-2),4.46(1H,m,H-2′),3.57(3H,s,OCH3),3.08-2.92(4H,m,H-3,3′),2.28(2H,q,J=7.6,Hz,NHCOCH2CH3),1.05(3H,t,J=7.6Hz,NHCOCH2CH3);13C-NMR(DMSO,100MHz)δ:171.96,171.93,171.8,166.3(C-1″),138.4(C-4),138.1(C-7′),134.1(C-2″),131.4(C-5″,C-4′),129.4(C-5′,9′),129.2(C-6,8),128.2(C-4″,6″),128.1(C-5,9),127.5(C-3″,7″),126.3(C-7),118.9(C-6′,8′),54.7(C-2),54.0(C-2′),51.9(OCH3),37.0,36.1,29.6(NHCOCH2CH3),9.8(NHCOCH2CH3)。
实施例65:N-[N-(4-二甲氨基甲基-苯甲酰基)-L-苯丙氨酰基]-O-乙酰基-L-苯丙氨醇
光谱数据:1H-NMR(CDCl3,400MHz)δ:7.68(2H,d,J=8.4Hz,H-3″,7″),7.40(2H,d,J=8.0Hz,H-4″,6″),7.30-7.06(10H,m,H-5′-9′,5-9),6.76(1H,br,NHCO),6.07(1H,br,NHCO),4.78(1H,m,H-2),4.35(1H,m,H-2′),3.92(1H,dd,J=4.8,11.6Hz,H-1′a),3.81(1H,dd,J=4.0,11.6Hz,H-1′b),3.49(2H,s,ArCH2N(CH3)2),3.22(1H,dd,J=5.6,13.6Hz,H-3a),3.06(1H,dd,J=8.4,13.2Hz,H-3b),2.76-2.73(2H,m,H-3′),2.26(6H,s,ArCH2N(CH3)2),2.03(3H,s,COCH3);13C-NMR(CDCl3,100MHz)δ:170.8(C-1),170.2(OCOCH3),166.9(C-1″),143.0(C-5″),136.7,136.6,132.5(C-2″),129.3(×4,C-6,8,6′,8′),129.1(C-4″,6″),128.7(C-5′,9′),128.5(C-5,9),127.1(C-3″,7″),126.7(C-7,7′),64.5(C-1′),63.8(ArCH2N(CH3)2),54.9(C-2),49.3(C-2′),45.3(ArCH2N(CH3)2),38.4,37.4,20.8(OCOCH3)。
实施例66:N-[N-(4-二甲氨基甲基-苯甲酰基)-L-苯丙氨酰基]-O-丙酰基-L-苯丙氨醇
光谱数据:1H-NMR(CDCl3,400MHz)δ:7.70(2H,d,J=8.0Hz,H-3″,7″),7.44(2H,d,J=7.6Hz,H-4″,6″),7.30-7.06(10H,m,H-5′-9′,5-9),6.83(1H,br,NHCO),6.13(1H,br,NHCO),4.78(1H,m,H-2),4.34(1H,m,H-2′),3.93(1H,dd,J=5.2,11.6Hz,H-1′a),3.85-3.81(1H,m,H-1′b),3.59(2H,s,ArCH2N(CH3)2),3.22(1H,dd,J=7.0,13.6Hz,H-3a),3.06(1H,dd,J=8.4,13.6Hz,H-3b),2.80-2.70(2H,m,H-3′),2.33(6H,s,ArCH2N(CH3)2),2.29(2H,q,J=7.6,COCH2CH3),1.13(3H,t,J=7.6,COCH3); 13C-NMR(CDCl3,100MHz)δ:173.9(OCOCH2CH3),169.9(C-1),166.5(C-1″),143.0(C-5″),136.4,136.2,132.6(C-2″),129.2(C-6,8),128.9(C-6′,8′),128.8(C-4″,6″),128.4(C-5′,9′),128.2(C-5,9),126.9(C-3″,7″),126.7(C-7),126.4(C-7′),64.0(C-1′),63.4(ArCH2N(CH3)2),54.6(C-2),49.1(C-2′),44.6(ArCH2N(CH3)2),38.1,37.1,27.0(OCOCH2CH3),8.7(OCOCH2CH3)。
实施例67:N-{N-[4-(4-吗啉基)甲基-苯甲酰基]-L-苯丙氨酰基}-O-丙酰基-L-苯丙氨醇
光谱数据:1H-NMR(DMSO,400MHz)δ:8.68(1H,d,J=8.0Hz,NHCO),8.30(1H,d,J=7.6Hz,NHCO),7.78(2H,d,J=8.4Hz,H-3″,7″),7.36(2H,d,J=8.0Hz,H-4″,6″),7.31-7.13(10H,m,H-5′-9′,5-9),4.65(1H,m,H-2),4.18(1H,m,H-2′),4.03(1H,dd,J=4.8,11.2Hz,H-1′a),3.87(1H,dd,J=6.8,11.2Hz,H-1′b),3.57(4H,t,J=4.4Hz,-CH2OCH2-),3.49(2H,s,ArCH2N<),2.96(2H,d,J=7.2Hz,H-3),2.79(2H,d,J=6.8Hz,H-3′),2.34(4H,s,ArCH2N(CH2)2),2.26(2H,q,J=7.6Hz,COCH2CH3),0.98(3H,t,J=7.6Hz,COCH2CH3);13C-NMR(DMSO,100MHz)δ:173.5(COEt),171.3(C-1),165.9(C-1″),142.3(C-5″),138.4(C-4),138.1(C-4′),132.8(C-2″),129.2(×2),129.1(×2),128.5(C-4″,6″),128.2(C-5,9),128.0(C-5′,9′),127.4(C-3″,7″),126.2(C-7,7′),66.2(-CH2OCH2-),64.5(C-1′),62.0(ArCH2N<),55.1(C-2),53.2(ArCH2N(CH2)2),49.2(C-2′),37.2,36.6,26.7(COCH2CH3),8.9(COCH2CH3)。
实施例68:N-[N-(4-甲基-苯甲酰基)-4-乙酰氨基-L-苯丙氨酰基]-O-乙酰基-L-酪氨酸甲酯
光谱数据:mp 222.0-223.0℃,1H-NMR(DMSO,400MHz)δ:9.84(1H,s,ArNHCO),8.55(1H,d,J=7.2Hz,NHCO),8.42(1H,d,J=8.4Hz,NHCO),7.69(2H,d,J=8.0Hz,H-3″,7″),7.44(2H,d,J=8.4Hz,H-6,8),7.27-7.23(6H,m,H-5,9,5′,9′,4″,6″),6.98(2H,d,J=8.4Hz,H-6′,8′),4.71(1H,m,H-2),4.52(1H,m,H-2′),3.59(3H,s,OCH3),3.07-2.86(2H,m,H-3,3),2.34(3H,s,Ar-CH3),2.24(3H,s,OCOCH3),1.99(3H,s,NHCOCH3);13C-NMR(DMSO,100MHz)δ:171.4(×2,C-1,1′),169.2(ArOCO),168.1(ArNHCO),166.0(C-1″),149.2(C-7′),141.2(C-5″),137.6(C-7),134.5(C-4′),132.8(C-4),131.2(C-2″),130.1(C-5′,9′),129.4(C-5,9),128.7(C-4″,6″),127.4(C-3″,7″),121.6(C-6′,8′),118.7(C-6,8),54.5(C-2),53.7(C-2′),51.9(OCH3),36.5,35.9,24.0(OCOCH3),21.0(ArCH3),20.9(NHCOCH3)。
实施例69:N-(N-苯甲酰基-L-苯丙氨酰基)-4-乙酰基-L-苯丙氨醇
光谱数据:mp 235.5-238.0℃,1H-NMR(DMSO,400MHz)δ:9.85(1H,s,ArNHCO),8.54(1H,d,J=8.0Hz,NHCO),7.95(1H,d,J=8.4Hz,NHCO),7.77(2H,d,J=7.6Hz,H-3″,7″),7.50(1H,t,H-5″),7.44-7.40(4H,m,H-4″-6″,6′,8′),7.31(2H,d,J=7.6Hz,H-5,9),7.23(1H,t,H-6,8),7.15-7.12(3H,m,H-7,5′,9′),4.84(1H,t,OH),4.67(1H,m,H-2),3.86(1H,m,H-2′),3.34-3.27(2H,m,H-1′),3.05-2.92(2H,m,H-3),2.79(1H,dd,J=6.0,13.2Hz,H-3′a),2.61(1H,dd,J=7.6,13.2Hz,H-3′b),2.00(3H,s,COCH3);13C-NMR(DMSO,100MHz)δ:171.0(C-1),168.1(ArNHCO),166.2(C-1″),138.5(C-4),137.4(C-7′),134.1(C-2″),133.5(C-4′),131.3(C-5″),129.4(C-5′,9′),129.2(C-6,8),128.2(C-4″,6″),128.1(C-5,9),127.4(C-3″,7″),126.2(C-7′),118.8(C-6′,8′),62.1(C-1′),55.0(C-2),52.6(C-2′),37.4(C-3),35.8(C-3′),24.0(COCH3)。
实施例70:N-[N-(4-氯-苯甲酰基)-4-丙酰氨基-L-苯丙氨酰基]-L-苯丙氨酸甲酯
光谱数据:1H-NMR(DMSO,400MHz)δ:9.75(1H,s,ArNHCO),8.52(2H,m,NHCO×2),7.78(2H,m,H-3″,7″),7.53-7.42(4H,m,H-4″,6″,6,8),7.24-7.19(7H,m,H-5,9,H-5′-9′),4.70(1H,m,H-2),4.51(1H,m,H-2′),3.59(3H,s,OCH3),3.09-2.87(4H,m,H-3,3′),2.26(2H,q,J=7.6Hz,COCH2CH3),1.05(3H,t,J=7.6Hz,COCH2CH3),13C-NMR(DMSO,100MHz)δ:171.83,171.77,166.1(ArNHCO),165.1(C-1″),137.6(C-7),137.0(C-4′),136.1(C-5″),134.0(C-4),132.7(C-2″),129.4(C-3″,7″),129.1(C-6′,8′),128.3(C-4″,6″),128.2(C-5,9),127.4(C-5′,9′),126.6(C-7′),118.7(C-6,8),54.6,53.7,51.9(OCH3),36.6,36.4,29.5(COCH2CH3),9.73(COCH2CH3)。
实施例71:N-(N-苯甲酰基-L-苯丙氨酰基)-O-甲基-L-酪氨酸甲酯
试剂及反应条件:CH3I,K2CO3,DMF,rt.,反应过夜
实验操作:取前述(见实施例3)合成的化合物1样品446mg(1.0mmol)溶解于5ml无水DMF中,加入276mg无水K2CO3(2.0mmol),于氩气保护下,将160靗典乙烷(CH3CH2I,2.0mmol)注入反应瓶,室温搅拌反应过夜。次日将反应物分散于70ml EtOAc和30ml10%的Na2CO3水溶液体系中,萃取分层,有机层以饱和氯化钠(2×20ml)洗涤,加入适量无水Na2SO4干燥,过滤,滤液经减压回收溶剂至干得白色粉末状样品468mg,经波谱鉴定其结构与设计结构化合物2一致(产率:98.7%)。
光谱数据:mp 170.0-172.0℃,1H-NMR(CDCl3,400MHz)δ:7.69(2H,d,J=7.6Hz,H-3″,7″),7.51(1H,t,H-5″),7.42(2H,t,H-4″,6″),7.31-7.20(5H,m,H-5-9),6.86(2H,d,J=8.4Hz,H-5′,9′),6.76(1H,br,NHCO),6.66(2H,d,J=8.4Hz,H-6′,8′),6.29(1H,br,NHCO),4.84(1H,m,H-2),4.72(1H,m,H-2′),3.90(2H,m,ArOCH2CH3),3.70(3H,s,OMe),3.21(1H,dd,J=6.0,14.0Hz,H-3′a), 3.12(1H,dd,J=7.6,14.0Hz,H-3′b),3.02(1H,dd,J=5.6,13.6Hz,H-3a),2.90(1H,dd,J=6.4,13.6Hz,H-3b),1.36(3H,t,ArOCH2CH3);13C-NMR(CDCl3,100MHz)δ:171.7(C-1),170.6(C-1′),167.3(C-1″),158.3(C-7′),136.7(C-4),133.9(C-2″),132.2(C-5″),130.4(C-5′,9′),129.8(C-6,8),129.0(×2),128.9(×2),127.5(C-4′),127.4(C-7),127.3(C-3″,7″),114.8(C-6′,8′),63.5(ArOCH2CH3),54.8(C-2),53.8(C-2′),52.7(C-OMe),38.4(C-3),37.3(C-3′),15.1(ArOCH2CH3)。
采用类似于实施例71的合成方法,选择适当的碘代烷、及自制中间体2-氯-N,N-二甲基乙胺盐酸盐等作为反应原料对前述部分实施例化合物中苯环羟基、或氨基进行亲电取代反应;或者选择二甲胺、二乙胺、吡咯烷或***啉等作为亲核试剂对含有氯代基团的化合物(RNHCOCH2Cl)中氯原子进行取代,分别制得实施例72~84的衍生物。
实施例72:N-(N-苯甲酰基-L-苯丙氨酰基)-O-正丁基-L-酪氨酸甲酯
光谱数据:mp 177.0-178.0℃,1H-NMR(CDCl3,400MHz)δ:7.69(2H,d,J=7.6Hz,H-3″,7″),7.51(1H,t,H-5″),7.42(2H,t,H-4″,6″),7.31-7.23(5H,m,H-5-9),6.85(2H,d,J=8.4Hz,H-5′,9′),6.76(1H,br,NHCO),6.66(2H,d,J=8.4Hz,H-6′,8′),6.31(1H,br,NHCO),4.83(1H,m,H-2),4.72(1H,m,H-2′),3.82(2H,m,ArOCH2CH2CH2CH3),3.70(3H,s,OMe),3.21(1H,dd,J=5.6,14.0Hz,H-3′a),3.12(1H,dd,J=7.2,13.6Hz,H-3′b),3.01(1H,dd,J=5.6,14.0Hz,H-3a),2.90(1H,dd,J=6.8,14.0Hz,H-3b),1.70(2H,m,ArOCH2CH2CH2CH3),1.45(2H,m,ArOCH2CH2CH2CH3),0.96(2H,t,J=7.6Hz,ArOCH2CH2CH2CH3);13C-NMR(CDCl3,100MHz)δ:171.4(C-1),170.3(C-1′),167.0(C-1″),158.2(C-7′),136.4(C-4),133.6(C-2″),131.8(C-5″),130.1(C-5′,9′),129.4(C-6,8),128.7(C-5,9),128.6(C-4″,6″),127.04(C-4′,C-7),127.01(C-3″,7″),114.5(C-6′,8′),63.5(ArOCH2CH2CH2CH3),54.5(C-2),53.5(C-2′),52.3(OMe),38.1(C-3),36.9(C-3′),31.3(ArOCH2CH2CH2CH3),19.2(ArOCH2CH2CH2CH3),13.8(ArOCH2CH2CH2CH3)。
实施例73:N-(N-苯甲酰基-L-苯丙氨酰基)-O-乙基-L-酪氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.85(1H,br,COOH),8.55(1H,d,J=8.4Hz,NHCO),8.24(1H,d,J=8.0Hz,NHCO),7.76(2H,d,J=7.6Hz,H-3″,7″),7.52 (1H,t,H-5″),7.43(2H,t,H-4″,6″),7.33(2H,d,J=7.6Hz,H-5,9),7.23(2H,t,J=7.6Hz,H-6,8),7.15-7.10(3H,m,J=8.4Hz,H-7,H-5′,9′),6.70(2H,d,J=8.4Hz,H-6′,8′),4.73 (1H,m,H-2),4.41(1H,m,H-2′),3.87(2H,m,ArOCH2CH3),3.10-2.84(4H,m,H-3′,3),1.26(3H,t,ArOCH2CH3);13C-NMR(DMSO,100MHz)δ:172.9(C-1′),171.4(C-1),166.2(C-1″),157.2(C-7′),138.4(C-4),134.0(C-2″),131.4(C-5″),130.2(C-5′,9′),129.2(C-6,8),129.0(C-4′),128.2(C-4″,6″),128.1(C-5,9),127.4(C-3″,7″),126.2(C-7),114.1(C-6′,8′),62.8(ArOCH2CH3),54.5(C-2′),53.8(C-2),36.8(C-3),35.9(C-3′),14.7(ArOCH2CH3)。
实施例74:N-(N-苯甲酰基-L-苯丙氨酰基)-O-正丁基-L-酪氨酸钠盐
光谱数据:1H-NMR(DMSO,400MHz)δ:8.82(1H,d,J=8.4Hz,NHCO),7.78(2H,d,J=7.2Hz,H-3″,7″),7.51-7.47(2H,m,H-5″,NHCO),7.41(2H,t,H-4″,6″),7.30(2H,d,J=7.6Hz,H-5,9),7.22(2H,t,H-6,8),7.12(1H,t,H-7),6.99(2H,d,J=8.4Hz,H-5′,9′),6.55(2H,d,J=8.0Hz,H-6′,8′),4.57(1H,m,H-2),3.94(1H,m,H-2′),3.75(2H,t,J=6.4Hz,ArOCH2CH2CH2CH3),3.12-2.85(4H,m,H-3,3′),1.61(2H,m,ArOCH2CH2CH2CH3),1.37(2H,m,ArOCH2CH2CH2CH3),0.89(2H,t,J=7.6Hz,ArOCH2CH2CH2CH3);13C-NMR(DMSO,100MHz)δ:172.5(C-1′),169.6(C-1),166.0(C-1″),156.6(C-7′),138.7(C-4),134.1(C-2″),131.0(C-5″),130.9(C-4′),130.5(C-5′,9′),128.9(C-6,8),127.93,127.87,127.3(C-3″,7″),125.9(C-7),113.4(C-6′,8′),66.8(ArOCH2CH2CH2CH3),55.4,55.3,36.6,36.3,30.7(ArOCH2CH2CH2CH3),18.6(ArOCH2CH2CH2CH3),13.5(ArOCH2CH2CH2CH3)。
实施例75:N-[N-苯甲酰基-O-(2-二甲氨基-乙基)-L-酪氨酰基]-L-苯丙氨醇盐酸盐
光谱数据:mp 158.5-161.0℃,1H-NMR(DMSO,400MHz)δ:10.57(1H,br,CH2CH2N+H(CH3)2·Cl-),8.57(1H,d,J=8.4Hz,NHCO),8.03(1H,br,NHCO),7.83(2H,d,J=7.6Hz,H-3″,7″),7.52(1H,t,H-5″),7.45(2H,t,H-4″,6″),7.28-7.11(7H,m,H-5′-9′,H-5,9),6.88(2H,d,J=8.8Hz,H-6,8),4.88(1H,br,OH),4.63(1H,m,H-2),4.28(2H,t,J=4.8Hz,ArOCH2CH2N(CH3)2HCl),3.89(1H,m,H-2′),3.44(2H,t,J=4.8Hz,ArOCH2CH2N(CH3)2HCl),3.34-3.27(2H,m,H-1′),3.00-2.85(3H,m,H-3,3′a),2.79(6H,s,N(CH3)2),2.71-2.66(1H,dd,J=8.0,13.6Hz,3′b);13C-NMR(DMSO,100MHz)d:171.0(C-1),166.0(C-1″),156.0(C-7),139.1(C-4′),134.0(C-2″),131.3(C-5″,C-4),130.3(C-5,9),129.2(C-6′,8′),128.2(C-4″,6″),128.1(C-5′,9′),127.5(C-3″,7″),125.9(C-7′),114.2(C-6,8),62.2,62.1,55.2(×2),52.6(C-2′),42.7(×2),36.4(×2)。
实施例76:N-[N-4-(二甲氨基-乙酰氨基)-苯甲酰基-L-苯丙氨酰基]-L-苯丙氨醇
光谱数据:mp 162.5-164.0℃,1H-NMR(DMSO,400MHz)δ:9.94(1H,s,ArNHCO),8.39(1H,d,J=8.8Hz,NHCO),7.89(1H,d,J=8.4Hz,NHCO),7.77(2H,d,J=8.8Hz,H-3″,7″),7.73(2H,d,J=8.8Hz,H-4″,6″),7.31-7.1 1(10H,m,H-5-9,5′-9′),4.82(1H,t,OH),4.67(1H,m,H-2),3.89(1H,m,H-2′),3.35-3.24(2H,m,H-1′),3.09(2H,COCH2N<),3.07-2.91(2H,m,H-3),2.86(1H,dd,J=5.6,13.6Hz,H-3′a),2.66(1H,dd,J=7.6,13.6Hz,H-3′b),2.28(6H,s,-N(CH3)2);13C-NMR(DMSO,100MHz)δ:171.0(C-1),169.1(ArNHCO),165.5(C-1″),141.4(C-5″),139.0(C-4′),138.5(C-4),129.2(×4,C-6,8,6′,8′),128.6(C-2″),128.2(C-3″,7″),128.1(×2),128.0(×2),126.2(C-7),125.9(C-7′),118.5(C-4″,6″),63.3(COCH2N<),62.2(C-1′),54.8(C-2),52.5(C-2′),45.4(×2,-N(CH3)2),37.3(C-3),36.4(C-3′)。
实施例77:N-[N-4-(2-二甲氨基-乙氧基)-苯甲酰基-L-苯丙氨酰基]-L-苯丙氨醇
光谱数据:1H-NMR(CDCl3,400MHz)δ:7.67(2H,d,J=8.8Hz,H-3″,7″),7.31-7.07(10H,m,H-5-9,5′-9′),6.92(2H,d,J=8.8Hz,H-4″,6″),6.78(1H,d,J=7.6Hz,NHCO),6.28(1H,d,J=8.0Hz,NHCO),4.80(1H,m,H-2),4.11-4.07(3H,m,ArOCH2,H-2′),3.42(2H,m,H-1′),3.23(1H,dd,J=6.4,13.6Hz,H-3a),3.06(1H,dd,J=8.4,13.6Hz,H-3b),2.80-2.66(4H,m,H-3′,CH2N(CH3)2),2.34(6H,s,-N(CH3)2);13C-NMR(CDCl3,100MHz)δ:171.0(C-1),166.8(C-1″),161.8(C-5″),137.4(C-4),136.8(C-4′),129.3(C-3″,7″),129.1(C-6,8),128.9(C-6′,8′),128.8(C-5′,9′),128.5(C-5,9),127.1(C-7),126.5(C-7′),125.8(C-2″),114.4(C-4″,6″),66.2(ArOCH2),63.4(C-1′),58.1(CH2N(CH3)2),55.1(C-2),52.9(C-2′),45.9(-N(CH3)2),38.6(C-3′),36.8(C-3)。
实施例78:N-[N-4-(2-二甲氨基-乙氧基)-苯甲酰基-L-苯丙氨酰基]-L-苯丙氨酸甲酯
光谱数据:1H-NMR(CDCl3,400MHz)δ:7.64(2H,d,J=8.8Hz,H-3″,7″),7.30-6.95(10H,m,H-5-9,5′-9′),6.92(2H,d,J=8.8Hz,H-4″,6″),6.58(1H,d,J=7.6Hz,NHCO),6.35(1H,d,J=7.2Hz,NHCO),4.83-4.76(2H,m,H-2,2′),4.10(2H,t,J=6.0Hz,ArOCH2),3.70(3H,s,OCH3),3.21-2.93(4H,m,H-3,3′),2.75(2H,t,J=6.0Hz,CH2N(CH3)2),2.35(6H,s,-N(CH3)2);13C-NMR(CDCl3,100MHz)δ:171.3(C-1),170.5(C-1′),166.6(C-1″),161.7(C-5″),136.4(C-4),135.5(C-4′),129.4(C-3″,7″),129.1(C-6,8),128.8(C-6′,8′),128.7(C-5′,9′),128.5(C-5,9),127.0(C-7,7′),125.9(C-2″),114.3(C-4″,6″),66.1(ArOCH2),58.1(CH2N(CH3)2),54.4(C-2),53.4(C-2′),52.3(OCH3),45.9(-N(CH3)2),38.0,37.8。
实施例79:N-(N-苯甲酰基-L-苯丙氨酰基)-O-甲基-L-酪氨酸钠盐
光谱数据:1H-NMR(DMSO,400MHz)δ:8.81(1H,d,J=8.4Hz,NHCO),7.78(2H,d,J=7.2Hz,H-3″,7″),7.48(2H,m,H-5″,NHCO),7.42(2H,t,H-4″,6″),7.30(2H,d,J=8.4Hz,H-5,9),7.22(2H,t,H-6,8),7.13(1H,t,H-7),7.01(2H,d,J=8.4Hz,H-5′,9′),6.57(2H,d,J=8.4Hz,H-6′,8′),4.57(1H,m,H-2),3.95(1H,m,H-2′),3.59(3H,s,ArOCH3),3.13-2.86(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.7(C-1′),169.9(C-1),166.2(C-1″),157.3(C-7′),138.9(C-4),134.1(C-2″),131.3(C-5″),131.0(C-4′),130.7(C-5′,9′),129.1(C-6,8),128.2(C-4″,6″),128.1(C-5,9),127.4(C-3″,7″),126.1(C-7),112.9(C-6′,8′),55.6(×2),54.7(ArOCH3),36.7,36.3。
实施例80:N-[N-苯甲酰基-O-羧甲基-L-酪氨酰基]-L-苯丙氨醇钠盐
光谱数据:1H-NMR(DMSO,400MHz)δ:8.65(1H,br,NHCO),8.30(1H,br,NHCO),7.82(2H,d,J=8.0Hz,H-3″,7″),7.50(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.23-7.17(5H,m,H-5′-9′),7.12(2H,d,J=8.0Hz,H-5,9),6.69(2H,d,J=8.4Hz,H-6,8),5.17(1H,br,OH),4.59(1H,m,H-2),4.08(2H,s,ArOCH2COONa),3.87(1H,m,H-2′),3.33-3.27(2H,m,H-1′),2.93-2.66(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:171.2(C-1,COONa),166.0(C-1″),157.4(C-7),139.2(C-4′),134.2(C-2″),131.2(C-5″),129.7(C-5,9),129.4(C-4),129.2(C-6′,8′),128.1(C-4″,6″),128.0(C-5′,9′),127.4(C-3″,7″),125.8(C-7′),114.0(C-6,8),67.8(ArOCH2COONa),62.1(C-1′),55.5(C-2),52.6(C-2′),36.4(C-3,3′)。
实施例81:N-[N-4-(二甲氨基-乙酰氨基)-苯甲酰基-L-苯丙氨酰基]-L-苯丙氨酸甲酯
光谱数据:mp 192.5-194.0℃,1H-NMR(DMSO,400MHz)δ:9.92(1H,s,ArNHCO),8.52(1H,d,J=7.6Hz,NHCO),8.41(1H,d,J=8.4Hz,NHCO),7.71(4H,m,H-3″,7″,4″,6″),7.33-7.14(10H,m,H-5-9,5′-9′),4.72(1H,m,H-2),4.50(1H,m,H-2′),3.57(3H,s,OCH3),3.07(2H,s,NHCOCH2N<),3.06-2.89(4H,m,H-3,3′),2.26(6H,s,-N(CH3)2);13C-NMR(DMSO,100MHz)δ:172.5,172.4,169.8(ArNHCO),165.3(C-1″),142.1(C-5″),139.0(C-4),137.7(C-4′),129.83(C-6,8),129.78(C-6′,8′),129.1(C-2″),128.9(C-5′,9′),128.8(C-3″,7″),128.7(C-5,9),127.2(C-7′),126.9(C-7),119.1(C-4″,6″),63.9(COCH2N<),55.1(C-2),54.4(C-2′),52.5(OCH3),46.0(-N(CH3)2),37.6(C-3),37.2(C-3′)。
实施例82:N-{N-[4-(1-吡咯烷基)乙酰氨基-苯甲酰基]-L-苯丙氨酰基}-L-苯丙氨酸甲酯
光谱数据:1H-NMR(DMSO,400MHz)δ:9.93(1H,s,ArNHCO),8.53(1H,d,J=7.2Hz,NHCO),8.43(1H,d,J=8.8Hz,NHCO),7.75(2H,d,J=8.8Hz,H-3″,7″),7.69(2H,d,J=8.8Hz,H-4″,6″),7.34-7.15(10H,m,H-5-9,5′-9′),4.74(1H,m,H-2),4.52(1H,m,H-2′),3.59(3H,s,OCH3),3.26(2H,COCH2N<),3.07-2.94(4H,m,H-3,3′),2.59(4H,m,COCH2N(CH2)2),1.74(4H,m,>NCH2CH2CH2CH2N<);13C-NMR(DMSO,100MHz)δ:171.8,171.7,169.2(ArNHCO),165.6(C-1″),141.4(C-5″),138.3(C-4),137.0(C-4′),129.2(×2),129.1(×2),128.5(C-2″),128.3(×2),128.2(×2),128.0(×2),126.6(C-7′),126.2(C-7),118.5(C-4″,6″),59.5(COCH2N<),54.4(C-2),53.73(C-2′),53.69(COCH2N(CH2)2),51.9(OCH3),36.9(C-3),36.6(C-3′),23.5(>NCH2CH2CH2CH2N<)。
实施例83:N-[N-苯甲酰基-4-(3-羧基-丙酰氨基)-L-苯丙氨酰基]-L-苯丙氨醇
光谱数据:1H-NMR(DMSO,400MHz)δ:11.31(1H,s,ArNHCO),8.96(1H,d,J=8.4Hz,NHCO),8.37(1H,d,J=8.0Hz,NHCO),7.79(2H,m,H-3″,7″),7.46(2H,m,H-4″,6″),7.40(2H,d,J=8.4Hz,H-6,8),7.24-7.11(7H,m,H-5′-9′,H-5,9),5.05(1H,br,OH),4.58(1H,m,H-2),3.87(1H,m,H-2′),3.36-2.95(2H,m,H-1′),2.94-2.65(4H,m,H-3,H-3′),2.33(2H,m,CH2COONa),2.21(2H,t,ArNHCOCH2),13C-NMR(DMSO,100MHz)δ:176.1(CH2COONa),172.0(ArNHCOCH2),171.1(C-1),165.0(C-1″),139.2(C-4′),138.0(C-7),135.9(C-5″),132.9(C-4),132.3(C-2″),129.34(C-3″,7″),129.30(C-5,9),129.2(C-6′,8′),128.2(C-4″,6″),128.0(C-5′,9′),125.8(C-7′),118.3(C-6,8),62.2(C-1′),55.6(C-2),52.6(C-2′),36.8,36.4,34.6(CH2COONa),33.9(ArNHCOCH2)。
实施例84:N-(N-苯甲酰基-4-二甲氨基-L-苯丙氨酰基)-L-苯丙氨醇
光谱数据:1H-NMR(DMSO,400MHz)δ:7.74(2H,d,J=7.2Hz,H-3″,7″),7.52(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.21-7.08(7H,m,H-5′-9′,H-5,9),6.90(1H,d,J=7.2Hz,NHCO),6.62(2H,d,J=8.4Hz,H-6,8),5.96(1H,d,J=7.6Hz,NHCO),4.70(1H,m,H-2),4.09(1H,m,H-2′),3.49-3.35(2H,m,H-1′),3.32(4H,q,J=7.2Hz,N(CH2CH3)2),3.19(1H,dd,J=5.6,13.2Hz,H-3a),2.88(1H,dd,J=9.2,13.6Hz,H-3b),2.77(1H,dd,J=7.6,13.6Hz,H-3′a),2.68(1H,dd,J=7.2,13.6Hz,H-3′b),2.18(1H,t,OH),1.14(6H,t,J=7.2Hz,N(CH2CH3)2);13C-NMR(DMSO,100MHz)δ:171.1(C-1),167.1(C-1″),146.9(C-7),137.4(C-4′),133.7(C-2″),131.8(C-5″),130.2(C-5,9),129.1(C-6′,8′),128.6(×2),128.5(×2),127.1(C-3″,7″),126.5(C-7′),122.7(C-4),111.9(C-6,8),63.4(C-1′),55.5(C-2),52.8(C-2′),44.3(N(CH2CH3)2),37.9(C-3′),36.8(C-3),12.5(N(CH2CH3)2)。
实施例85:N-(N-苯甲酰基-L-苯丙氨酰基)-L-酪氨酸及其钠盐
试剂及反应条件:(a)NaOH,DMF,rt,5h;(b)NaOH/EtOH-CHCl3
实验操作:(a)取前述(见实施例3)合成的化合物1样品2.0mmol于5ml DMF与10mlEtOH的混合溶剂中溶解完全,搅拌下加入5M NaOH溶液1ml,室温反应过夜,所得反应液以浓盐酸调节pH2-3后,将其分散到150ml EtOAc和50ml 10%Na2CO3水溶液中,萃取分层,有机层以饱和氯化钠2×30ml洗涤,无水硫酸钠干燥,减压回收溶剂至干,即得白色粉末状的N-(N-苯甲酰基-L-苯丙氨酰基)-L-酪氨酸(化合物2)样品674mg(产率:78.0%);(b)取前一步合成所得化合物2样品235mg(0.48mmol)于10ml EtOH与5ml CHCl3的混合溶剂中溶解完全,搅拌下滴加1.0M NaOH溶液0.48ml,室温反应过夜,回收溶剂至干,所得固体物以乙酸乙酯重结晶,即得白色粉末状的N-(N-苯甲酰基-L-苯丙氨酰基)-L-酪氨酸钠盐133mg(产率:61.2%)。
光谱数据:N-(N-benzoyl-L-phenylalanyl)-L-tyrosine,1H-NMR(DMSO,400MHz)δ:12.75(COOH),9.22(1H,s,Ar-OH),8.55(1H,d,J=8.4Hz,NHCO),8.23(1H,d,J=7.6Hz,NHCO),7.76(2H,d,J=7.6Hz,H-3″,7″),7.51(1H,t,H-5″),7.43(2H,t,H-4″,6″),7.34(2H,d,J=7.2Hz,H-5,9),7.24(2H,t,H-6,8),7.15(1H,t,H-7),7.02(2H,d,J=8.4Hz,H-5′,9′),6.61(2H,d,J=8.4Hz,H-6′,8′),4.74(1H,m,H-2′),4.38(1H,m,H-2),3.11-2.82(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.9(C-1′),171.5(C-1),166.3(C-1″),156.0(C-7′),138.4(C-4),134.0(C-2″),131.3(C-5″),130.1(C-5′,9′),129.2(C-6,8),128.2(C-4″,6″),128.0(C-5,9),127.4(C-3″,7″),127.3(C-4′),126.2(C-7),115.0(C-6′,8′),54.6(C-2′),53.9(C-2),36.9(C-3),35.9(C-3′)。
采用类似于实施例85的操作方法,对前述实施例中部分化合物中的羧基甲酯或醇羟基的酰化产物进行水解、及其钠盐的制备等,分别制得实施例86~106的衍生物。
实施例86:N-(N-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.81(1H,br,COOH),8.53(1H,d,J=8.4Hz,NHCO),8.31(1H,d,J=8.0Hz,NHCO),7.74(2H,d,J=7.6Hz,H-3″,7″),7.46(1H,t,H-5″),7.40(2H,t,H-4″,6″),7.33-7.12(10H,m,H-5-9,5′-9′),4.72(1H,m,H-2),4.46(1H,m,H-2′),3.10-2.90(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.8(C-1′),171.5(C-1),166.2(C-1″),138.4(C-4),137.4(C-4′),134.0(C-2″),131.3(C-5″),129.2(×4,C-6,8,C-6′,8′),128.2(×4,C-4″,6″,C-5′,9′),128.1(C-5,9),127.4(C-3″,7″),126.5(C-7′),126.2(C-7),54.6(C-2),53.6(C-2′),36.9(C-3),36.7(C-3′)。
实施例87:N-(N-苯甲酰基-4-乙酰氨基-L-苯丙氨酰基)-L-苯丙氨酸
光谱数据:mp 233.5-235.5℃, 1H-NMR(DMSO,400MHz)δ:9.84(1H,s,ArNHCO),8.46(1H,d,J=8.4Hz,NHCO),7.89(1H,d,J=8.0Hz,NHCO),7.79(2H,d,J=7.6Hz,H-3″,7″),7.52(1H,t,H-5″),7.47-7.42(4H,m,H-4″,6″,H-6,8),7.23-7.11(7H,m,H-5′-9′,H-5,9),4.83(1H,t,OH),4.64(1H,m,H-2),3.90(1H,m,H-2′),3.34-3.25(2H,m,H-1′),3.00-2.64(4H,m,H-3,3′),1.99(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:170.9(C-1),168.0(ArNHCOCH3),166.0(C-1″),139.0(C-7),137.5(C-4′),134.1(C-2″),132.9(C-4),131.3(C-5″),129.4(C-5,9),129.2(C-6′,8′),128.2(×2),128.1(×2),127.4(C-3″,7″),125.9(C-7′),118.6(C-6,8),62.2(C-1′),54.9(C-2),52.5(C-2′),36.7(C-3′),36.4(C-3),24.0(NHCOCH3)。
实施例88:N-(N-苯甲酰基-4-硝基-L-苯丙氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.85(1H,COOH),8.54(1H,d,J=8.8Hz,NHCO),8.42(1H,d,J=8.4Hz,NHCO),8.14(2H,d,J=8.8Hz,H-6,8),7.77(2H,d,J=6.8Hz,H-3″,7″),7.63(2H,d,J=8.4Hz,H-5,9),7.52(1H,t,H-5″),7.45(2H,t,H-4″,6″),7.26-7.18(5H,m,H-5′-9′),4.85(1H,m,H-2),4.49(1H,m,H-2′),3.24-2.94(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.7(C-1′),171.0(C-1),166.3(C-1″),146.8(C-7),146.2(C-4),137.4(C-4′),133.8(C-2″),131.4(C-5″),130.5(C-5,9),129.2(C-6′,8′),128.2(×4,C-4″,6″,5′,9′),127.4(C-3″,7″),126.5(C-7′),123.2(C-6,8),53.9(C-2′),53.6(C-2),36.8,36.6。
实施例89:N-(N-苯甲酰基-L-苯丙氨酰基)-4-乙酰氨基-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.80(1H,br,COOH),9.87(1H,s,ArNHCO),8.55(1H,d,J=8.4Hz,NHCO),8.32(1H,d,J=8.0Hz,NHCO),7.75(2H,d,J=7.2Hz,H-3″,7″),7.51-7.13(12H,m,H-4″-6″,H-5-9,H-5′,9′,6′, 8′),4.73(1H,m,H-2),4.44(1H,m,H-2′),3.10-2.88(4H,m,H-3,3′),2.02(3H,s,COCH3);13C-NMR(DMSO,100MHz)δ:172.9(C-1′),171.6(C-1),168.1(ArNHCOCH3),166.3(C-1″),138.5(C-4),137.9(C-7′),134.1(C-2″),131.8(C-4′),131.3(C-5″),129.4(C-5′,9′),129.2(C-6,8),128.2(C-4″,6″),128.1(C-5,9),127.4(C-3″,7″),126.3(C-7′),118.8(C-6′,8′),54.6(C-2),53.7(C-2′),37.0(C-3),36.1(C-3′),24.0(COCH3)。
实施例90:N-(N-4-甲基-苯甲酰基-L-苯丙氨酰基)-4-乙酰氨基-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:10.02(1H,s,ArNHCO),8.70(1H,d,J=8.4Hz,NHCO),7.64(2H,d,J=8.0Hz,H-3″,7″),8.49(1H,d,J=6.4Hz,NHCO),7.33-7.27(4H,m,H-6′,8′,H-5,9),7.21-7.17(4H,m,H-4″,6″,H-6,8),7.10(1H,t,H-7),7.00(2H,d,J=8.4Hz,H-5′,9′),4.50(1H,m,H-2),3.95(1H,m,H-2′),3.12-2.88(4H,m,H-3,3′),2.29(3H,s,Ar-CH3),1.94(3H,s,COCH3);13C-NMR(DMSO,100MHz)δ:172.8(C-1′),170.1(C-1),168.0(ArNHCO),166.2(C-1″),141.1(C-5″),139.0(C-4),137.2(C-7′),133.6(C-2″),131.3(C-4′),129.9(C-5′,9′),129.1(C-6,8),128.7(C-4″,6″),128.1(C-5,9),127.5(C-3″,7″),126.1(C-7),118.5(C-6′,8′),55.9(C-2′),55.5(C-2′),36.9,36.5,23.9(NHCOCH3),21.0(Ar-CH3)。
实施例91:N-(N-4-羟基-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸钠盐
光谱数据:1H-NMR(DMSO,400MHz)δ:8.45(1H,d,J=8.4Hz,NHCO),7.62(2H,d,J=8.4Hz,H-3″,7″),7.44(1H,br,NHCO),7.29-7.05(10H,m,H-5-9,5′-9′),6.76(3H,m,ArOH,H-4″,6″),4.50(1H,m,H-2),4.02(1H,m,H-2′),3.11-2.92(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:170.2(C-1,1′),166.0(C-1″),160.6(C-5″),139.1,139.0,129.8(C-3″,7″),129.4(C-6,8),129.1(C-6′,8′),128.1(C-5′,9′),127.5(C-5,9),126.1(C-7),125.5(C-7′),124.5(C-2″),114.7(C-4″,6″),55.7(C-2′),55.4(C-2),37.2,36.8。
实施例92:N-[N-4-(3-羧基-丙酰氨基)-苯甲酰基-L-苯丙氨酰基]-L-苯丙氨酸钠盐
光谱数据:1H-NMR(DMSO,400MHz)δ:11.38(1H,s,ArNHCO),9.92(1H,br,ArOH),8.60(1H,d,J=8.0Hz,NHCO),7.73(2H,d,J=8.8Hz,H-3″,7″),7.62(2H,d,J=8.4Hz,H-4″,6″),7.50(1H,d,J=6.0Hz,NHCO),7.13-7.05(7H,m,H-5-9,5′,9′),6.62(2H,d,J=8.4Hz,H-6,8),4.45(1H,m,H-2),4.04(1H,m,H-2′),3.14-2.79(4H,m,H-3,3′),2.46(2H,t,J=6.4Hz,ArNHCOCH2CH2COONa),2.27(2H,t,J=6.0Hz,ArNHCOCH2CH2COONa);13C-NMR(DMSO,100MHz)δ:176.4(COONa),173.2,172.7,170.4,165.7(C-1″),156.0(C-7),142.4(C-5″),139.0(C-4′),129.9(C-5,9),129.8(C-6′,8′),128.5(C-4),128.3(C-5′,9′),127.9(C-2″),127.5(C-3″,7″),125.5(C-7′),117.8(C-4″,6″),115.0(C-6,8),56.1(C-2),55.4(C-2′),37.3(C-3′),36.5(C-3),34.4,33.5。
实施例93:N-(N-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.79(1H,br,COOH),9.12(1H,s,Ar-OH),8.44(1H,d,J=8.8Hz,NHCO),8.26(1H,d,J=7.6Hz,NHCO),7.73(2H,d,J=6.8Hz,H-3″,7″),7.48(1H,t,H-5″),7.41(2H,t,H-4″,6″),7.25-7.13(5H,m,H-5′-9′),7.09(2H,d,J=8.4Hz,H-5,9),6.58(2H,d,J=8.4Hz,H-6,8),4.61(1H,m,H-2),4.43(1H,m,H-2′),3.08-2.76(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.8(C-1′),171.7(C-1),166.2(C-1″),155.7(C-7),137.4(C-4′),134.1(C-2″),131.3(C-5″),130.1(C-5,9),129.2(C-6′,8′),128.4(C-4),128.2(×4,C-4″,6″,C-5′,9′),127.4(C-3″,7″),126.5(C-7′),1 14.9(C-6,8),55.0(C-2),53.5(C-2′),36.7,36.2。
实施例94:N-(N-苯甲酰基-L-苯丙氨酰基)-4-丙酰氨基-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.78(1H,br,COOH),9.81(1H,s,ArNHCO),8.56(1H,d,J=8.4Hz,NHCO),8.33(1H,d,J=8.0Hz,NHCO),7.75(2H,d,J=7.2Hz,H-3″,7″),7.50-7.48(3H,m,H-5″,H-6′,8′),7.42(2H,t,H-4″,6″),7.34(2H,d,J=7.2Hz,H-5,9),7.23(2H,t,H-6,8),7.17-7.12(3H,m,H-7,H-5′,9′),4.73(1H,m,H-2),4.44(1H,m,H-2′),3.10-2.86(4H,m,H-3,3′),2.28(2H,q,J=7.6Hz,NHCOCH2CH3),1.06(3H,t,J=7.6Hz,NHCOCH2CH3);13C-NMR(DMSO,100MHz)δ:172.9(C-1′),171.9,171.6,166.3(C-1″),138.5(C-4),138.0(C-7′),134.1(C-2″),131.7(C-4′),131.3(C-5″),129.4(C-5′,9′),129.2(C-6,8),128.2(C-4″,6″),128.1(C-5,9),127.5(C-3″,7″),126.3(C-7),118.9(C-6′,8′),54.7(C-2),53.7(C-2′),37.0,36.1,29.6(NHCOCH2CH3),9.8(NHCOCH2CH3)。
实施例95:N-(N-苯甲酰基-L-酪氨酰基)-4-乙酰氨基-L-苯丙氨酸钠盐
光谱数据:1H-NMR(DMSO,400MHz)δ:9.95(1H,s,ArNHCO),9.47(1H,s,ArOH),8.86(1H,d,J=8.4Hz,NHCO),7.78-7.74(3H,m,H-3″,7″,NHCO),7.48(3H,m,H-6′,8′,H-5″),7.34(2H,t,H-4″,6″),7.08(2H,d,J=8.4Hz,H-5,9),7.01(2H,d,J=8.8Hz,H-5′,9′),6.61(2H,d,J=8.4Hz,H-6,8),4.44(1H,m,H-2),3.95(1H,m,H-2′),3.09-2.78(4H,m,H-3,3′),1.97(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:172.6(C-1′),170.0(C-1),168.0(ArNHCO),165.3(C-1″),155.8(C-7),137.2 (C-7′),136.0(C-2″),133.6(C-4′),132.9(C-5″),130.0(C-5,9),129.9(C-5′,9′),129.4(C-4″,6″),128.7(C-4),128.3(C-3″,7″),118.4(6′,8′),115.0(C-6,8),56.4(C-2′),5.5(C-2),36.5,36.1,23.9(CH3CO)。
实施例96:N-(N-4-甲基-苯甲酰基-L-酪氨酰基)-4-乙酰氨基-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.79(1H,br,COOH),9.86(1H,s,ArNHCO),9.14(1H,s,Ar-OH),8.36(1H,d,J=8.8Hz,NHCO),8.23(1H,d,J=7.6Hz,NHCO),7.66(2H,d,J=8.0Hz,H-3″,7″),7.44(2H,d,J=8.4Hz,H-6′,8′),7.23(2H,d,J=7.6Hz,H-4″,6″),7.14(2H,d,J=8.4Hz,H-5′,9′),7.10(2H,d,J=8.4Hz,H-5,9),6.60(2H,d,J=8.4Hz,H-6,8),4.61(1H,m,H-2),4.41(1H,m,H-2′),3.00-2.82(4H,m,H-3,3′),2.32(3H,s,Ar-CH3),2.01(3H,s,COCH3);13C-NMR(DMSO,100MHz)δ:172.8(C-1′),171.7(C-1),168.1(ArNHCO),166.0(C-1″),155.7(C-7),141.2(C-5″),137.8(C-7′),131.8(C-4′),131.3(C-2″),130.1(C-5,9),129.4(C-5′,9′),128.7(C-4″,6″),128.5(C-4),127.4(C-3″,7″),118.8(C-6′,8′),114.8(C-6,8),55.0(C-2),53.6(C-2′),52.1(OCH3),36.2(t×2),24.0(COCH3),21.0(Ar-CH3)。
实施例97:N-(N-4-氯-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)d:12.83(1H,br,COOH),8.67(1H,d,J=8.4Hz,NHCO),8.39(1H,d,J=8.0Hz,NHCO),7.79(2H,d,J=8.8Hz,H-3″,7″),7.53(2H,m,H-4″,6″),7.34-7.13(10H,m,H-5-9,5′-9′),4.75(1H,m,H-2),4.48(1H,m,H-2′),3.13-2.88(4H,m,H-3,3′),13C-NMR(DMSO,100MHz)δ:172.8(C-1′),171.5(C-1),165.1(C-1″),138.4(C-4),137.4(C-4′),136.2(C-5″),132.7(C-2″),129.4(×2),129.2(×4),128.3(×2),128.2(×2),128.1(×2),126.5,126.3,54.6(C-2),53.6(C-2′),36.9,36.6。
实施例98:N-(N-4-氯-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸钠盐
光谱数据:1H-NMR(DMSO,400MHz)δ:8.92(1H,br,NHCO),7.79(2H,d,J=8.8Hz,H-3″,7″),7.51(3H,m,H-4″,6″,NHCO),7.31-7.05(10H,m,H-5-9,5′-9′),4.52(1H,m,H-2),3.90(1H,m,H-2′),3.13-3.09(2H,m,H-3),2.98-2.89(2H,m,H-3′),13C-NMR(DMSO,100MHz)δ:179.0(C-1′),169.7(C-1),165.1(C-1″),139.3(C-4),138.8(C-4′),136.0(C-5″),132.8(C-2″),129.8(×2),129.4(×2),129.1(×2),128.2(×2),128.1(×2),127.4(×2),126.1,125.4,55.9(C-2),55.5(C-2′),37.2,36.8。
实施例99:N-(N-2-氯-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.82(1H,br,COOH),8.56(1H,d,J=8.4Hz,NHCO),8.23(1H,d,J=7.6Hz,NHCO),7.43-7.12(14H,m,H-5-9,H-4″-7″,H-5′-9′),4.74(1H,m,H-2),4.52(1H,m,H-2′),3.14-2.78(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.6(C-1′),170.9(C-1),165.9(C-1″),137.8(C-4),137.3(C-4′),136.4(C-5″),130.7(C-3″),129.9(C-2″),129.5(C-4″),129.21(C-6′,8′),129.17(C-6,8),128.8(C-7″),128.2(C-5,9),128.0(C-5′,9′),126.8(C-6″),126.5(C-7),126.2(C-7′),54.1,53.5,37.2,36.8。
实施例100:N-(N-4-硝基-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:9.19(1H,br,Ar-OH),8.90(1H,d,J=8.8Hz,NHCO),8.42(1H,d,J=7.6Hz,NHCO),8.30(2H,d,J=8.8Hz,H-4″,6″),7.99 (2H,d,J=8.8Hz,H-3″,7″),7.27-7.18(5H,m,H-5′-9′),7.13(2H,d,J=8.4Hz,H-5,9),6.63(2H,d,J=8.4Hz,H-6,8),4.70(1H,m,H-2),4.47(1H,m,H-2′),3.14-2.80(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.9(C-1′),171.4(C-1),164.5(C-1″),155.8(C-7),149.1(C-5″),139.7(C-2″),137.6(C-4′),130.1(C-5,9),129.2(C-6′,8′),128.9(C-3″,7″),128.2(C-5′,9′),128.2(C-4),126.5(C-7′),123.5(C-4″,6″),114.9(C-6,8),55.2(C-2),53.7(C-2′),36.6,36.3。
实施例101:N-(N-4-乙酰氨基-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.82(1H,br,COOH),10.16(1H,s,ArNHCO),8.42(1H,d,J=8.4Hz,NHCO),8.32(1H,d,J=8.0Hz,NHCO),7.73(2H,d,J=8.8Hz,H-3″,7″),7.62(2H,d,J=8.8Hz,H-4″,6″),7.34-7.14(10H,m,H-5-9,5′-9′),4.72(1H,m,H-2),4.47(1H,m,H-2′),3.12-2.91(4H,m,H-3,3′),2.06(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:172.8(C-1′),171.6(C-1),168.7(ArNHCO),165.7(C-1″),142.0(C-5″),138.5(C-4),137.4(C-4′),129.4(C-6,8),129.2(C-6′,8′),128.3(C-3″,7″),128.2(C-2″),128.2(C-5′,9′),128.1(C-5,9),126.5(C-7′),126.2(C-7),117.9(C-4″,6″),54.5(C-2),53.6(C-2′),36.9(C-3),36.7(C-3′),24.1(CH3CO)。
实施例102:N-(N-异烟酰基-L-苯丙氨酰基)-L-酪氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.78(1H,br,COOH),9.23(1H,s,Ar-OH),8.89(1H,d,J=8.8Hz,NHCO),8.70(2H,m,H-4″,6″),8.36(1H,d,J=8.0Hz,NHCO),7.65(2H,d,J=5.2Hz,H-3″,7″),7.34(2H,d,J=6.8Hz,H-5,9),7.25(2H,t,H-6,8),7.16(1H,t,H-7),7.03(2H,d,J=8.4Hz,H-5′,9′),6.62(2H,d,J=8.0Hz,H-6′,8′),4.77(1H,m,H-2),4.38(1H,m,H-2′),3.13-2.82(4H,m,H-3,3′);13C-NMR(DMSO,100MHz)δ:172.9(C-1′),171.1(C-1),164.7(C-1″),156.0(C-7′),150.2(C-4″,6″),140.9(C-2″),138.2(C-4),130.1(C-5′,9′),129.2(C-6,8),128.1(C-5,9),127.4(C-4′),126.3(C-7),121.4(C-3″,7″),115.0(C-6′,8′),54.6(C-2),54.0(C-2′),37.0(C-3),35.8(C-3′)。
实施例103:N-(N-4-乙酰氨基-苯甲酰基-L-苯丙氨酰基)-L-酪氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.77(1H,br,COOH),10.18(1H,s,ArNHCO),9.23(1H,s,ArOH),8.43(1H,d,J=8.4Hz,NHCO),8.24(1H,d,J=7.6Hz,NHCO),7.73(2H,d,J=8.8Hz,H-3″,7″),7.63(2H,d,J=8.8Hz,H-4″,6″),7.34(2H,d,J=7.2Hz,H-5,9),7.24(2H,t,H-6,8),7.15(1H,t,H-7),7.02(2H,d,J=8.4Hz,H-5′,9′),6.61(2H,d,J=8.8Hz,H-6′,8′),4.72(1H,m,H-2),4.39(1H,m,H-2′),3.10-2.84(4H,m,H-3,3′),2.07(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:172.9(C-1′),171.5(C-1),168.7(ArNHCO),165.7(C-1″),156.0(C-7′),142.0(C-5″),138.5(C-4),130.1(C-5′,9′),129.2(C-6,8),128.3(C-3″,7″),128.2(C-4′),128.0(C-5,9),127.3(C-2″),126.2(C-7),118.0(C-4″,6″),115.0(C-6′,8′),54.5(C-2),53.9(C-2′),36.9(C-3),36.0(C-3′),24.1(CH3CO)。
实施例104:N-(N-4-丙酰氨基-苯甲酰基-L-苯丙氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.81(1H,br,COOH),10.09(1H,s,ArNHCO),8.40(1H,d,J=8.4Hz,NHCO),8.31(1H,d,J=7.6Hz,NHCO),7.73(2H,d,J=9.2Hz,H-3″,7″),7.63(2H,d,J=8.8Hz,H-4″,6″),7.34-7.13(10H,m,H-5-9,5′-9′),4.72(1H,m,H-2),4.48(1H,m,H-2′),3.11-3.05(2H,m,H-3),2.99-2.91(2H,m,H-3′),2.34(2H,q,J=7.6Hz,COCH2CH3),1.08(3H,t,J=7.6Hz,COCH2CH3);13C-NMR(DMSO,100MHz)δ:172.8(C-1′),172.4,171.6,165.7(C-1″),142.1(C-5″),138.5(C-4),137.4(C-4′),129.2(×4,C-6,8,6′,8′),128.3(C-3″,7″),128.2(C-5′,9′),128.1(C-2″),128.0(C-5,9),126.5(C-7),126.2(C-7′),118.0(C-4″,6″),54.5(C-2),53.5(C-2′),36.9(C-3),36.6(C-3′),29.6(COCH2CH3),9.5(COCH2CH3)。
实施例105:N-(N-4-乙酰氨基-苯甲酰基-L-酪氨酰基)-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.79(1H,br,COOH),10.16(1H,s,ArNHCO),9.14(1H,s,ArOH),8.32(1H,d,J=8.8Hz,NHCO),8.27(1H,d,J=7.6Hz,NHCO),7.73 (2H,d,J=8.4Hz,H-3″,7″),7.62(2H,d,J=8.4Hz,H-4″,6″),7.25-7.17(5H,m,5′-9′),7.11(2H,d,J=8.4Hz,H-5,9),6.61(2H,d,J=8.8Hz,H-6,8),4.62(1H,m,H-2),4.46(1H,m,H-2′),3.11-2.73(4H,m,H-3,3′),2.07(3H,CH3CO);13C-NMR(DMSO,100MHz)δ:172.8(C-1′),171.8(C-1),168.7(ArNHCO),165.6(C-1″),155.7(C-7),142.0(C-5″),137.4(C-4′),130.1(C-5,9),129.2(6′,8′),128.4(C-4,2″),128.3(C-3″,7″),128.2(C-5′,9′),126.5(C-7′),117.9(C-4″,6″),114.8(C-6,8),54.9(C-2),53.5(C-2′),36.7,36.2,24.2(CH3CO)。
实施例106:N-(N-异烟酰基-L-酪氨酰基)-4-硝基-L-苯丙氨酸
光谱数据:1H-NMR(DMSO,400MHz)δ:12.96(1H,br,COOH),9.17(1H,s,ArOH),8.79(1H,d,J=8.4Hz,NHCO),8.69(2H,d,J=5.6Hz,H-4″,6″),8.50(1H,d,J=8.4Hz,NHCO),8.08(2H,d,J=8.8Hz,H-6′,8′),7.65(2H,m,H-3″,7″),7.52(2H,d,J=8.4Hz,H-5′,9′),7.11(2H,d,J=8.8Hz,H-5,9),6.62(2H,d,J=8.4Hz,H-6,8),4.67-4.54(2H,m,H-2,2′),3.26(1H,dd,J=5.2,13.6Hz,H-3′a),3.08(1H,dd,J=9.2,13.6Hz,H-3′b),2.98-2.73(2H,m,H-3);13C-NMR(DMSO,100MHz)δ:172.4(C-1′),171.3(C-1),164.5(C-1″),155.8(C-7),150.2(C-4″,6″),146.2(C-7′),145.9(C-4′),140.9(C-2″),130.6(C-5′,9′),130.1(C-5,9),128.1(C-4),123.2(C-6′,8′),121.3(C-3″,7″),114.9(C-6,8),55.0(C-2),52.9(C-2′),36.3,36.1。
Claims (8)
1.N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物,其特征在于:结构如通式I所示的化合物,或其药学上可接受的盐或水合物。
通式(I)
其中
R1和R3分别代表氢、氟、氯或溴、-NO2、-NH2、-CN、CH2NRR′、-NHR、-NRR′、-NHCOR、-OH、(4-OH,3-CH2NRR′)、-OCOR、-OR、-NHCO(CH2)nCOOH、-O(CH2)nNRR′、-O(CH2)nCOOR或-O(CH2)nCOOH;
R2为氢、C1-C6烷基、氟、氯或溴、-NO2、-NH2、-CN、-NHR、-NRR′、-NHCOR、-OH、-OCOR、-OR、-NHCO(CH2)nCOOH、-O(CH2)nN RR′、-O(CH2)nCOOH、-CH2NRR′、
R4为CH2OH、COOR、CH2OCOR、CH2OCO(CH2)2COOH或COONa;
X为CH或N;
R1、R2和R3可分别是单个或多个取代基,并分别处在苯环上的对位和邻位和间位;
R、R′代表相同或不同的C1-C6直链或支链烷基,或C3-C7环烷基;
n为1至4的整数。
2.根据权利要1所述的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物,其特征在于:所述烷基和环烷基可以被1-2个羟基、硝基、卤代、氰基、三氟甲基的取代基取代。
3.根据权利要1所述的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物,其特征是包括(2S,2′S)、(2s,2′R)、(2R,2′s)或(2R,2′R)的任何立体异构体或其消旋体或旋光异构体或其混合物。
5.如权利要1所述的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物的制备方法,其特征在于:
合成路线II如下:
(II-a)(t-BuOCO)20,1.0 M NaOH,TBAB;(II-b)CH2Cl2,氯甲酸异丁酯(IBCF),N-甲基吗啉(NMM),-5~10℃;(II-c)TFA,CH2Cl2,rt,2h;(II-d)DCC,DMAP,CH2Cl2,rt.
6.如权利要求1所述的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物在制备药物中的应用,其特征在于:所述的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨衍生物或其消旋体或旋光异构体或差向异构体或其药学上可接受的盐制备成适宜的给药剂型,可加入附加剂或赋形剂。
7.如权利要求1所述的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物作为制备治疗病毒性感染的药物。
8.如权利要求1所述的N-(N-苯甲酰基-苯丙氨酰基)-苯丙氨酸二肽衍生物作为制备***病毒感染的药物。
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