CN103524598A - 一类环肽类化合物、其制备方法、药物组合物及用途 - Google Patents

一类环肽类化合物、其制备方法、药物组合物及用途 Download PDF

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CN103524598A
CN103524598A CN201310393529.XA CN201310393529A CN103524598A CN 103524598 A CN103524598 A CN 103524598A CN 201310393529 A CN201310393529 A CN 201310393529A CN 103524598 A CN103524598 A CN 103524598A
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蒋晟
姚志艺
姚毅武
邱亚涛
卢畅吟
苏琨
姚小明
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Li Shan
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Shanghai Guan Yu Biological Medicine Science And Technology Ltd
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Abstract

本发明涉及一种环肽类化合物、其制备方法、药物组合物及其用途。具体而言，本发明所述环肽类化合物具有通式（I）所示的结构。通式（I）化合物、其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物具有制备预防或者治疗与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病药物中的用途。

Description

一类环肽类化合物、其制备方法、药物组合物及用途
技术领域
本发明涉及药物化学和化学治疗领域。具体而言，本发明涉及一类通式（Ι）所示的环肽类化合物、其制备方法、药物组合物及其在制备治疗与组蛋白去乙酰化酯酶相关的疾病，尤其是癌症、神经变性疾病、疟疾和糖尿病等疾病中的用途。
背景技术
组蛋白去乙酰化酯酶（histonedeacetylase,HDAC）是一类蛋白酶，对染色体的结构修饰和基因表达调控发挥着重要的作用。一般情况下，组蛋白的乙酰化有利于DNA与组蛋白八聚体的解离，核小体结构松弛，从而使各种转录因子和协同转录因子能与DNA结合位点特异性结合，激活基因的转录。在细胞核内，组蛋白乙酰化与组蛋白去乙酰化过程处于动态平衡，并由组蛋白乙酰化转移酶（histoneacetyltransferase,HAT）和组蛋白去乙酰化酶（histonedeacetylase,HDAC）共同调控。
在肿瘤的表观遗传学研究中，组蛋白的乙酰化修饰对肿瘤的发生发展起重要作用。正常细胞体一旦出现核内组蛋白乙酰化与去乙酰化的失衡，即会导致正常的细胞周期与细胞代谢行为的改变而诱发肿瘤。组蛋白去乙酰化酶催化组蛋白的去乙酰化，维系组蛋白乙酰化与去乙酰化的平衡状态，与癌相关基因转录表达、细胞增殖分化及细胞凋亡等诸多过程密切相关。在癌细胞中，HDAC的过度表达导致去乙酰化作用的增强，通过恢复组蛋白正电荷，从而增加DNA与组蛋白之间的引力，使松弛的核小体变得十分紧密，不利于特定基因的表达，包括一些肿瘤抑制基因。
随着生命科学的深入发展，对肿瘤的致病和发病机制的分子生物学研究为开发低毒高效针对特异性分子靶标的抗肿瘤药物提供了基础。组蛋白去乙酰化酶(histonedeacetylases，HDACs)是维持染色体的基本组成单位核小体中组蛋白乙酰化平衡的关键酶类之一，其催化组蛋白的去乙酰化作用，与基因转录抑制密切相关，牵涉到促基因沉默的诸多过程，是抗肿瘤药物设计中的热门靶标。组蛋白去乙酰化酶抑制剂（histonedeacetylaseinhibitors，HDACi）则可通过提高染色质特定区域组蛋白乙酰化，从而调控细胞凋亡及分化相关蛋白的表达和稳定性，诱导细胞凋亡及分化，成为一类新的抗肿瘤药物。HDACi不仅对多种血液***肿瘤和实体瘤具有良好的治疗作用，而且具有肿瘤细胞相对较高选择性和低毒的优点。
发明内容
本发明的一个方面是提供由通式（I）表示的环肽类化合物，及其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物。
本发明的另一个方面是提供制备通式（I）化合物的制备方法。
本发明的另一个方面是提供一种药物组合物，该药物组合物包含治疗有效量的通式（I）所述的化合物、其药学上可接受的盐、结晶水合物及溶剂合物中的一种或多种；以及一种或多种药学上可接受的载体。
本发明再一个方面是提供通式（I）所述的化合物以及其药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物在制备治疗与组蛋白去乙酰化酯酶相关的疾病的药物中的用途。
根据本发明的一个方面，提供了下面通式（I）所示的环肽类化合物，其药学上可接受的盐、结晶水合物或溶剂合物：
其中：R1基团为氢，C1-16烷基，C3-16环烷基，-(C=O)-（C1-16烷基），-(C=S)-（C1-16烷基）或-S-（C1-16烷基）；
R2基团为氢，C1-12烷基，-CH2-O-（C1-12烷基），-CH2-NH-（C1-12烷基），-CH2-S-（C1-12烷基），C6-12芳基，杂芳基，-CH2-（C6-12芳基）或-CH2-杂芳基；所述的C6-12芳基，杂芳基，-CH2-C6-12芳基，-CH2-杂芳基，可以含有1个或多个取代基，所述取代基可以是卤素、氨基、羟基、硝基、氰基、C1-12烷基、C1-12烷氧基、氨基C1-12烷基、酰基、酰氧基、硫代C1-12烷基、羧基或苯基；
R3、R4基团分别独立的选自氢，C1-12烷基，-O-（C1-12烷基），-NH-（C1-12烷基），-S-（C1-12烷基），C6-12芳基和杂芳基；
X和Y中有一个为C，另一个为N，或X和Y都为N；
R5，R6，R7基团分别独立地选自氢，卤素，-S-(C1-12烷基)，C1-12烷基和叔丁氧羰基；
Z为-CH2-、-NH-、-O-、-S-或
Figure BDA0000375704840000022
m为0，1，2，3，4，5，6。
在优选的实施方案中，
R1基团为氢，C1-16烷基，C3-16环烷基，-(C=O)-（C1-16烷基），-(C=S)-（C1-16烷基）或-S-（C1-16烷基）；
R2基团为氢，C1-12烷基，-CH2-O-（C1-12烷基），-CH2-NH-（C1-12烷基），-CH2-S-（C1-12烷基），C6-12芳基，杂芳基，-CH2-（C6-12芳基）或-CH2-杂芳基；
R3、R4基团分别独立的选自氢，C1-12烷基，-O-（C1-12烷基），-NH-（C1-12烷基），-S-（C1-12烷基），C6-12芳基和杂芳基；
X和Y中有一个为C，另一个为N，或X和Y都为N；
R5，R6，R7基团分别独立地选自氢，卤素，-S-(C1-12烷基)，C1-12烷基和叔丁氧羰基；
Z为-O-，-S-或
Figure BDA0000375704840000031
m为0，1或2。
在进一步优选的实施方式中，
R1基团为氢或C1-16烷基；
R2基团为氢，C1-12烷基，或C6-12芳基；
R3、R4基团分别独立的选自氢，C1-12烷基，-O-（C1-12烷基），-NH-（C1-12烷基），-S-（C1-12烷基），C6-12芳基和杂芳基；
X为N；
Y为C；
R5，R6，R7基团分别独立地选自氢，F，-S-(C1-12烷基)；
Z为-S-或
Figure BDA0000375704840000032
m为0，1或2。
在本发明更优选的实施方案中，本发明的通式（I）的化合物优选为如下具体化合物：
Figure BDA0000375704840000033
Figure BDA0000375704840000041
Figure BDA0000375704840000051
Figure BDA0000375704840000071
Figure BDA0000375704840000091
Figure BDA0000375704840000101
Figure BDA0000375704840000111
Figure BDA0000375704840000121
Figure BDA0000375704840000131
Figure BDA0000375704840000141
Figure BDA0000375704840000151
Figure BDA0000375704840000171
Figure BDA0000375704840000181
Figure BDA0000375704840000191
Figure BDA0000375704840000211
Figure BDA0000375704840000221
Figure BDA0000375704840000231
Figure BDA0000375704840000241
Figure BDA0000375704840000251
Figure BDA0000375704840000261
Figure BDA0000375704840000271
Figure BDA0000375704840000281
Figure BDA0000375704840000291
本发明还提供了一种通式（I）表示的化合物的制备方法，其包括如下步骤：
（1）将式（II）化合物在碱的作用下进行水解反应，得到式（III）化合物；反应过程如下所示：
Figure BDA0000375704840000292
（2）将式（III）化合物、式（IV）化合物和有机碱在缩合剂的作用下进行缩合反应，得到式V化合物；反应过程如下所示：
Figure BDA0000375704840000293
（3）将式（V）化合物和MsCl在有机碱的作用下进行缩合反应，得到式（VI）化合物；反应过程如下所示：
（4）将式（VI）化合物进行消除反应，得到式（VII）化合物；反应过程如下所示：
（5）将式（VII）化合物在碱的作用下进行水解反应，得到式（VIII）化合物；反应过程如下所示：
Figure BDA0000375704840000302
（6）将式（VIII）化合物、式（IX）化合物和有机碱在缩合剂的作用下进行缩合反应，得到式（X）化合物；反应过程如下所示：
Figure BDA0000375704840000303
（7）脱去式（X）化合物上的氨基保护基P及羧基保护基Q，然后在缩合剂和有机碱的作用下，分子内关环得到式（XI）化合物；反应过程如下所示：
（8）脱去式（XI）化合物上的保护基T，得到式（XII）化合物；反应过程如下所示：
Figure BDA0000375704840000311
（9）式（XII）化合物与R1-L化合物反应，得到式（XIII）化合物；反应过程如下所示：
其中，R1～R7、X、Y、Z、m的定义均与化合物通式中相同；
P为氨基保护基团；
Q为酸基保护基团；
T为O、S、NH杂原子保护基团；
L选自卤素、OH、OMs、SH、MeO、t-butO。
进一步的，
步骤（2）、（3）、（6）（7）中所述的有机碱均可以选自咪唑、三乙胺、二异丙基乙胺、哌啶、二甲基吡啶、LiHMDS、NaHMDS、KHMDS、N-甲基吗啉、DABCO或吡啶；
步骤（2）、（6）中所述的缩合剂均可以选自DCC、EDC、HATU、HOAt、HOBt、DEAD、HBTU或PyBOP；
所述的氨基保护基团P选自Boc、Cbz、Bn、Fmoc、Alloc、Tos、Trt、或Bn；
所述的酸基保护基团P选自TMSOH、叔丁基、乙基、甲基。
上述的合成反应过程中，必要的有机溶剂可以选自二氯甲烷、四氢呋喃（THF）、二甲基甲酰胺(DMF)、乙二醇二甲醚、1,2-二氯乙烷、邻苯二甲酸二甲酯(DMP)、甲醇、乙醇、石油醚、正己烷或***；必要的无机碱可以选自氢氧化钠、氢氧化锂、碳酸钾、碳酸钠、碳酸氢钠、碳酸钙；必要的酸可以选自三氟乙酸、盐酸、硫酸或硝酸。所述的氧化剂可以是Dess-Martin氧化剂、Swern氧化剂、间氯过氧苯甲酸、氯重铬酸吡啶（PDC）或氯铬酸吡啶（PCC）。
另外，本发明提供了通式（I）化合物、其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物，在制备预防或者治疗与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病药物中的用途。所述与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、疟疾和艾滋病，更具体的包括淋巴瘤、肺癌、胃癌、胰腺癌、乳腺癌、***癌、白血病和***。
本发明还提供一种药物组合物，其含有治疗有效量的通式（I）化合物，或其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物，以及含有一种或多种药学上可接受的载体。其药学上可接受的盐包括与无机酸或有机酸反应形成的无毒盐，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸，所述有机酸包括丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
应当说明的是，本文所使用相关术语诸如“烷基”、“芳基”、“杂芳基”、“卤素”、“酰基”等等与所属领域中所述术语的一般含义无明显不同。
例如，术语“烷基”指直链或支链，C1～n烷基则表示1～n个碳原子的饱和的脂烃基，包括直链和支链，例如“C1～12烷基”指的是该基团为烷基，且烷基的碳链上碳原子的数量在1～12之间。应当说明的是，当没有特别限制其碳原子数时，仅指其中指明的烷基部分的碳原子数，而并不包括烷基的取代基上碳原子数。
本领域的普通技术人员应当知道下列术语或缩写的含义。
术语“药物上可接受的盐”是指在合理医学判断范围内适用于与哺乳动物特别是人的组织接触而无过度毒性、刺激、过敏反应等并与合理的效益/风险比相称的盐，比如胺、羧酸和其它类型化合物的医学上可接受的盐在所属领域中是被熟知的。
术语“异构体”是指分子组成相同、但结构和性质不同的两种或多种化合物。
术语“外消旋体”是指一种具有旋光性的手性分子与其对映体的等摩尔混合物，它由旋光方向相反、旋光能力相同的分子等量混合而成，其旋光性因这些分子间的作用而相互抵消，因而是不旋光的。
术语“溶剂合物”是指化合物与溶剂组成的混合物，例如结晶体即是一种溶剂合物。
权利要求书或说明书中所用的英文缩写所对应的物质分别是：
DCC（N,N'-二环己基碳二亚胺,CasNo.:538-75-0）、EDCI[1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐,CasNo.:25952-53-8]、HATU（CasNo.:148893-10-1）、HOAt（CasNo.:39968-33-7）、HOBt（1-羟基-苯并-三氮唑,CasNo.:2592-95-2）、DEAD（偶氮二甲酸二乙酯，CasNo.:1972-28-7）、HBTU（CasNo.:94790-37-1）,PyBOP（六氟磷酸苯并***-1-基-氧基三吡咯烷基磷,CasNo.:132705-51-2）,DIPEA(N，N-二异丙基乙胺,CAS:7087-68-5)；LiHMDS[二(三甲基硅基)氨基锂]、NaHMDS(六甲基二硅基胺基钠)、KHMDS(六甲基二硅基胺基钾)、DABCO（1,4-二氮杂二环[2.2.2]辛烷）；Boc（叔丁氧羰基）、Cbz（苄氧羰基）、Bn（苄基）、Fmoc（笏甲氧羰基）、Alloc（丙氧羰基）、Tos（对甲苯磺酰基）、Tfa（三氟乙酰基）或Trt（三苯甲基）、OMs（氧甲基磺酰基）、MeO（氧甲基）、t-butO（叔丁氧基）。
具体实施方式
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。
本发明中用到的起始反应物未经特别说明，均为商业购买。
应当说明的是，下述实施例中，常规后处理方法是：反应完成后，在反应液中加入适量的水，分离有机相和水相，合并有机相；如有需要，依次使用5%HCl溶液和/或饱和NaSO4干燥，过滤之后减压选干，得到粗产物，再经过柱层析分离纯化之后得到最终产物。
实施例1
1.1
Figure BDA0000375704840000331
向反应物（2g，7.6mmol）的30mlTHF液中滴加LiOH（456mg，19mmol）的15ml水溶液。滴毕，室温反应2h。反应液用稀盐酸调PH值为3，然后加入乙酸乙酯100mL。有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，得1.86g白色絮状固体，产率97%。1HNMR(400MHz,CDCl3):δ7.96（d,J=8.0Hz,1H）,7.77(t,J=7.6Hz,1H),7.48(d,J=7.8Hz,1H),5.55(s,1H),4.48(d,J=4.2Hz,2H),1.36(s,9H)ppm.
1.2
0℃下，向反应物（0.7g，2.7mmol）中，缓慢加入DIPEA（1.2ml，6mmol），搅拌稍许，再加入S2（456mg，2.7mmol），PyBop（2.5g，4mmol）。室温搅拌过夜。反应液依次用饱和碳酸氢钠溶液，稀盐酸溶液，饱和氯化钠溶液洗涤。无水硫酸钠干燥，旋干溶剂，柱层析得0.7g白色絮状物，产率75%。1HNMR(400MHz,CDCl3):δ8.64(d,J=8.4Hz,1H),8.05(d,J=8Hz,1H),7.81(t,J=8Hz,1H),7.44(d,J=7.6Hz,1H),5.44(s,1H),4.77(d,J=7.2Hz,1H),4.48-4.45(m,J=3H),3.78(s,3H),1.45(s,9H),1.26(d,J=5.6Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ171.1,164.6,157.4,156.0,148.9,137.9,134.6,124.2,121.8,121.0,80.7,79.8,78.7,70.3,68.2,61.1,57.8,52.7,52.2,47.7,32.1,28.3,28.2,28.1,28.0,22.6,19.8ppm.
1.3
0℃下，向反应物（675mg，1.84mmol）的无水DCM（10ml）液中依次加入DMAP(25mg，0.184mmol)，NEt3（0.42ml，3mmol），MsCl（0.186ml，2.4mmol），加毕，提至室温搅拌过夜。旋干，用油泵抽干，直接投下一步。
1.4
Figure BDA0000375704840000341
向上步所得物的无水DCM液（10ml）中加入DABOCO（1g，9.22mmol）。室温搅拌8h。反应液依次用饱和碳酸氢钠液，饱和氯化铵液，饱和氯化钠液洗涤，用无水硫酸钠干燥。过滤，旋干溶剂，柱层析得500mg絮状固体，产率76%。1HNMR(400MHz,CDCl3):δ9.38(s,1H),8.01(d,J=7.6Hz,1H),7.78(t,J=8Hz,1H),7.41(d,J=7.6Hz,1H),6.86(q,J=7.6Hz,1H),5.57(s,1H),4.44(d,J=5.6Hz,2H),3.74(s,9H),1.80(d,J=7.6Hz,3H),1.40(s,9H)ppm.13C NMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9,126.3,124.2,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
1.5
Figure BDA0000375704840000342
向反应物（500mg，1.44mmol）的THF（10ml）液中滴加LiOH（90mg，3.6mmol）的5ml水溶液。三小时后，旋干有机相，加入10ml水和15ml乙酸乙酯稀释，分液，取水相。再加入15ml乙酸乙酯，调酸。分液，有机相用无水硫酸钠干燥。旋干，得453mg白色絮状固体，产率94%。1HNMR(400MHz,CDCl3):δ9.40(s,1H),8.03(d,J=7.6Hz,1H),7.80(t,J=8.2Hz,1H),7.43(d,J=7.8Hz,1H),6.88(q,J=7.8Hz,1H),5.58(s,1H),4.46(d,J=5.8Hz,2H),3.76(s,9H),1.83(d,J=7.8Hz,3H),1.43(s,9H)ppm.13C NMR(100MHz,CDCl3)δ165.3,162.7,157.8,156.2,149.0,148.8,138.3,133.7,126.5,124.5,121.9,121.0,52.5,46.3,28.5,14.8ppm.
1.6
Figure BDA0000375704840000343
0℃下，向反应物（336mg，1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、羧酸(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得750mg白色絮状固体，产率92%。1HNMR(400MHz,CDCl3):δ9.41(s,1H),8.10(d,J=7.6Hz,1H),7.84(t,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
1.7
Figure BDA0000375704840000351
向反应物（750mg，0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。
向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得540mg淡黄色固体，产率82%。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.87(t,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.67(d,J=4.4Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.6,132.0,131.3,126.1,124.7,118.4,111.1,107.1,101.0,97.3,95.2,92.0,90.4,90.3,89.5,89.1,87.5,83.8,39.8,39.5,39.3,34.1,29.1,22.9,19.5ppm.
1.8
Figure BDA0000375704840000352
0℃下，向反应物（150mg，0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得63mg黄色固体，产率63%。[α]20D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.89(t,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例2
Figure BDA0000375704840000361
0℃下，向反应物（60mg，0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体60mg，产率80%。[α]20D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(t,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例3
Figure BDA0000375704840000362
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入庚酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体31mg，产率83%。[α]20D:4.11(c0.7,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.93(t,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),7.08(m,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.48(d,J=10Hz,1H),5.72-5.63(m,2H),5.62-5.45(m,1H),5.15(dd,J=17.2Hz,8Hz,1H),4.75-4.71(m,2H),4.28(d,J=17.2Hz,1H),2.86-2.71(m,4H),2.63-2.62(m,1H),2.50(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.85-1.82(m,3H),1.62-1.59(m,2H),1.26-1.24(m,9H),0.85(m,3H),0.78(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,169.0,163.5,162.1,155.7,148.8,138.6,134.5,132.6,132.1,130.9,128.9,128.5,127.5,125.1,121.3,72.2,71.7,57.3,44.1,43.2,40.9,38.6,33.8,32.2,31.5,30.9,29.7,29.1,28.8,27.7,27.6,25.5,22.5,19.1,18.9,16.4,14.6,14.0ppm.
实施例4
Figure BDA0000375704840000371
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体32mg，产率85%。[α]20D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),8.10(d,J=7.8Hz,1H),7.95(t,J=7.6Hz,1H),7.46(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例5
Figure BDA0000375704840000372
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入戊酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体30mg，产率84%。[α]20D:3.31(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.20(s,1H),8.12(d,J=7.8Hz,1H),7.96(t,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.49(d,J=10.0Hz,1H),5.73-5.69(m,2H),5.51(m,1H),5.15(dd,J=17.2Hz,8.0Hz,1H),4.75-4.73(m,2H),4.29(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.62(m,1H),2.47(t,J=7.8Hz,3H),2.31-2.26(m,3H),1.85-1.83(m,3H),1.62-1.60(m,2H),1.25-1.23(m,5H),0.83(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.2,169.0,163.3,162.2,155.7,148.7,138.9,134.5,132.8,132.1,130.8,128.9,128.5,127.6,125.2,121.3,72.1,71.6,57.8,44.2,43.5,41.3,38.8,33.8,32.6,31.6,30.8,29.9,29.3,28.8,27.6,25.7,22.7,19.1,16.6,14.9,13.8ppm.
实施例6
Figure BDA0000375704840000373
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丁酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体29mg，产率86%。[α]20D:6.51(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.98(t,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.76-5.71(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77-4.74(m,2H),4.27(d,J=17.2Hz,1H),2.88-2.74(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.33-2.28(m,3H),1.86-1.83(m,3H),1.66-1.62(m,2H),1.27-1.24(m,3H),0.86(m,3H),0.79(d,J=7.6Hz,3H),0.56(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.4,169.1,163.5,162.3,155.8,148.8,138.9,134.7,132.9,132.3,130.9,128.9,128.4,127.5,125.3,121.5,72.2,71.7,57.6,44.5,43.6,41.4,38.9,33.9,32.7,31.7,30.9,29.9,29.5,28.9,27.7,25.8,22.9,19.3,15.5,13.8ppm.
实施例7
Figure BDA0000375704840000381
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体35mg，产率88%。[α]20D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.14(d,J=7.8Hz,1H),7.99(t,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.77(d,J=4.4Hz,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例8
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体33mg，产率85%。[α]20D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.98(t,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.79(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例9
Figure BDA0000375704840000391
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入甲酰氯（0.02ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体26mg，产率75%。[α]20D:1.96(c0.1,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),8.16(d,J=7.6Hz,1H),7.88(t,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),7.07(dd,J=14.4Hz,J=7.2Hz,1H),6.56(dd,J=7.6Hz,J=3.6Hz,1H),6.48(d,J=8Hz,1H),5.73(m,2H),5.52(dd,J=15.6Hz,J=6.8Hz,1H),5.12(m,1H),4.76(dd,J=10Hz,J=3.6Hz,1H),4.33(m,1H),2.72(m,2H),2.53(m,2H),2.34-2.29(m,3H),1.38(t,J=7.6Hz,1H),0.82(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ176.5,169.8,169.4,163.6,162.6,155.7,148.8,138.5,134.7,132.5,132.3,130.9,128.8,127.8,125.6,121.8,72.5,71.7,56.9,44.8,43.6,41.5,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例10
10.1
Figure BDA0000375704840000392
将Fmoc-L-Pra（0.976g，3.00mmol），EDCI（584mg，3.05mmol）和DMAP（25mg，0.203mmol）溶于无水二氯甲烷（15mL），在0℃下加入DIPEA（0.50mL，3.05mmol）和醇（526mg，1.02mmol），室温下搅拌12h，加二氯甲烷稀释，反应液用碳酸氢钠溶液洗涤（50mL×3)，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用硅胶柱层析得淡黄色固体化合物（716mg，85%）。1HNMR(400MHz,CDCl3):δ7.77(d,J=7.6Hz,2H),7.61(m,2H),7.42-7.32(m19H),5.85-5.78(m,1H),5.68(dd,J=13.6,7.2Hz,1H),5.55(dd,J=15.2,7.2Hz,1H),5.35(d,J=8.8Hz,1H),4.37(t,J=6.8Hz,2H),4.28(dd,J=9.2,4.4Hz,1H),4.25(t,J=7.2,1H),4.18(t,J=8.4Hz,2H),2.89(t,J=7.2Hz,2H),2.73(dd,J=15.6,7.6Hz,1H),2.61(dd,J=15.6,5.6Hz,1H),2.55(t,J=7.2Hz,2H),2.28(dt,J=13.6,6.8Hz,2H),2.19(m,1H),1.67(m,2H),0.90-0.85(m,4H),0.03(s,9H)ppm.
10.2
Figure BDA0000375704840000393
将反应物（660mg，0.80mmol）溶于乙腈（8mL），加入二乙胺（0.25mL，2.44mmol），搅拌2h，减压旋走乙腈，残留物用硅胶柱层析得无水油状物463mg，产率96%。
1HNMR(400MHz,CDCl3):δ7.41-7.39(m,6H),7.29-7.24(m,6H),7.21-7.18(m,3H),5.69-5.57(m,2H),5.37(dd,J=15.4Hz,7.4Hz,1H),4.15-4.09(m,2H),3.23(d,J=4.8Hz,1H),2.65(dd,J=15.6Hz,8.4Hz,1H),2.54(dd,J=15.6Hz,5.2Hz,1H),2.19-2.16(m,2H),2.07-1.98(m,2H),1.97-1.93(m,1H),0.95(m,1H),0.82(d,J=6.8Hz,3H),0.03(s,9H)ppm.
10.3
Figure BDA0000375704840000401
0℃下，向反应物（603mg，1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、实施例1第1.5步的产物(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得739mg白色絮状固体，产率93%。1HNMR(400MHz,CDCl3):δ9.36(s,1H),8.11(d,J=7.6Hz,1H),7.85(t,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),7.39-7.18(m,12H),6.68-6.63(m,2H),5.66-5.60(m,2H),5.47(s,1H),5.38-5.32(m,1H),4.61(dd,J=8.8Hz,4Hz,1H),4.51(d,J=4.2Hz,2H),4.16-4.11(m,3H),2.67(dd,J=15.6Hz,7.6Hz,1H),2.53(dd,J=15.6Hz,5.6Hz,1H),2.19-2.15(m,3H),2.05(t,J=6.8Hz,4H),1.83(d,J=7.2Hz,3H),1.49(s,9H),1.27(t,J=6.8Hz,2H),0.95-0.91(m,3H),0.82(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.1,170.8,169.6,164.2,162.7,157.4,155.9,148.6,144.7,138.4,133.9,129.7,129.4,129.0,127.6,126.5,124.6,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,0.9,-1.5,-1.6ppm.
10.4
Figure BDA0000375704840000402
向反应物（723mg，0.90mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得537mg淡黄色固体，产率85%。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.87(t,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.67(d,J=4.4Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.64,132.05,131.39,126.08,124.66,118.36,111.05,107.13,100.97,97.27,95.22,91.96,90.37,90.32,89.54,89.11,87.45,83.79,39.76,39.50,39.25,34.06,29.13,22.85,19.48ppm.
10.5
Figure BDA0000375704840000411
0℃下，向反应物（150mg，0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得63mg黄色固体，产率63%。[α]20D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.89(t,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,77.2,76.9,76.7,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例11
Figure BDA0000375704840000412
0℃下，向反应物（60mg，0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体60mg，产率80%。[α]20D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(t,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例12
0℃下，向反应物（60mg，0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体60mg，产率80%。[α]20D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(t,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例13
13.1
将Fmoc-L-Pra（1.033g，3.05mmol），EDCI（584mg，3.045mmol）和DMAP（25mg，0.203mmol）溶于无水二氯甲烷（15mL），在0℃下加入DIPEA（0.50mL，3.045mmol）和化合物2-23（526mg，1.02mmol），室温下搅拌12h，加二氯甲烷稀释，反应液用碳酸氢钠溶液洗涤（50mLx3)，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用硅胶柱层析得淡黄色固体化合物2-24（682mg，80%）。1HNMR(400MHz,CDCl3):δ7.76(d,J=7.6Hz,2H),7.60(m,2H),7.40-7.31(m19H),5.84and5.76(m,1H),5.67(dd,J=13.6,7.2Hz,1H),5.53(dd,J=15.2,7.2Hz,1H),5.32(d,J=8.8Hz,1H),4.39(t,J=6.8Hz,2H),4.29(dd,J=9.2,4.4Hz,1H),4.23(t,J=7.2,1H),4.17(t,J=8.4Hz,2H),2.88(t,J=7.2Hz,2H),2.71(dd,J=15.6,7.6Hz,1H),2.59(dd,J=15.6,5.6Hz,1H),2.52(t,J=7.2Hz,2H),2.29(dt,J=13.6,6.8Hz,2H),2.18(m,1H),1.65(m,2H),0.97-0.83(m,8H),0.03(s,9H)ppm.
13.2
将反应物（682mg，0.81mmol）溶于乙腈（8mL），加入二乙胺（0.25mL，2.44mmol），搅拌2h，减压旋走乙腈，残留物用硅胶柱层析得无水油状物477mg，产率95%。1HNMR(400MHz,CDCl3):δ7.40-7.38(m,6H),7.29-7.25(m,6H),7.22-7.18(m,3H),5.69-5.57(m,2H),5.36(dd,J=15.4Hz,7.4Hz,1H),4.16-4.09(m,2H),3.21(d,J=4.8Hz,1H),2.64(dd,J=15.6Hz,8.4Hz,1H),2.53(dd,J=15.6Hz,5.2Hz,1H),2.19-2.15(m,2H),2.07-1.98(m,2H),1.97-1.93(m,1H),0.98-0.93(m,2H),0.92(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H),0.03(s,9H)ppm.
13.3
Figure BDA0000375704840000431
0℃下，向反应物（336mg，1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、实施例1第1.5步的产物(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得750mg白色絮状固体，产率92%。1HNMR(400MHz,CDCl3):δ9.41(s,1H),8.10(d,J=7.6Hz,1H),7.84(t,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,121.1,79.7,77.2,77.0,76.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
13.4
向反应物（750mg，0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。
向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得540mg淡黄色固体，产率82%。1HNMR(400MHz,CDCl3):δ9.17(s1H),8.10(d,J=7.6Hz,1H),7.87(t,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.67(d,J=4.4Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H)4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H)1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.64,132.05,131.39,126.08,124.66,118.36,111.05,107.13,100.97,97.27,95.22,91.96,90.37,90.32,89.5489.11,87.45,83.79,39.76,39.50,39.25,34.06,29.13,22.85,19.48ppm.
13.5
Figure BDA0000375704840000441
0℃下，向反应物（150mg，0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得63mg黄色固体，产率63%。[α]20D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.89(t,J=7.6Hz,1H),7.45(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,77.2,76.9,76.7,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例14
Figure BDA0000375704840000442
0℃下，向反应物（60mg，0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体60mg，产率80%。[α]20D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(t,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例15
Figure BDA0000375704840000451
0℃下，向反应物（60mg，0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体60mg，产率80%。[α]20D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(t,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例16
16.1
Figure BDA0000375704840000452
向反应物（7.6mmol）的30mlTHF液中滴加LiOH（19mmol）的15ml水溶液。滴毕，室温反应2h。反应液用稀盐酸调PH值为3，然后加入乙酸乙酯100mL。有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，得白色絮状固体。1HNMR(400MHz,CDCl3):δ8.05（s,J=8.0Hz,1H）,7.85(d,J=7.6Hz,1H),7.61(d,J=7.8Hz,1H),5.55(s,1H),4.48(d,J=4.2Hz,1H),1.34(s,9H)ppm.
16.2
Figure BDA0000375704840000453
0℃下，向反应物（2.7mmol），缓慢加入DIPEA（6mmol），搅拌稍许，再加入S2（2.7mmol），PyBop（4mmol）。室温搅拌过夜。反应液依次用饱和碳酸氢钠溶液，稀盐酸溶液，饱和氯化钠溶液洗涤。无水硫酸钠干燥，旋干溶剂，柱层析得白色絮状物。1HNMR(400MHz,CDCl3):δ8.64(d,J=8.4Hz,1H),8.05(d,J=8Hz,1H),7.81(d,J=8Hz,1H),5.44(s,1H),,4.48-4.45(m,J=3H),3.78(s,3H),1.45(s,9H),1.26(d,J=5.6Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ171.1,164.6,157.4,156.0,148.9,137.9,134.6,124.2,121.8,121.0,80.7,79.8,78.7,70.3,68.2,61.1,57.8,52.7,52.2,47.7,32.1,28.3,28.2,28.1,28.0,22.6,19.8ppm.
16.3
Figure BDA0000375704840000461
0℃下，向反应物（1.84mmol）的无水DCM（10ml）液中依次加入DMAP(0.184mmol)，NEt3（3mmol），MsCl（2.4mmol），加毕，提至室温搅拌过夜。旋干，用油泵抽干，直接投下一步。
16.4
Figure BDA0000375704840000462
向上步所得物的无水DCM液（10ml）中加入DABOCO（9.22mmol）。室温搅拌8h。反应液依次用饱和碳酸氢钠液，饱和氯化铵液，饱和氯化钠液洗涤，用无水硫酸钠干燥。过滤，旋干溶剂，柱层析得絮状固体。1HNMR(400MHz,CDCl3):δ9.38(s,1H),8.01(d,J=7.6Hz,1H),7.78(d,J=8Hz,1H),7.41(d,J=7.6Hz,1H),6.86(q,J=7.6Hz,1H),5.57(s,1H),4.44(d,J=5.6Hz,1H),3.74(s,9H),1.80(d,J=7.6Hz,3H),1.40(s,9H)ppm.13CNMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9,126.3,124.2,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
16.5
Figure BDA0000375704840000463
向反应物（1.44mmol）的THF（10ml）液中滴加LiOH（3.6mmol）的5ml水溶液。三小时后，旋干有机相，加入10ml水和15ml乙酸乙酯稀释，分液，取水相。再加入15ml乙酸乙酯，调酸。分液，有机相用无水硫酸钠干燥。旋干，得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.40(s,1H),8.03(d,J=7.6Hz,1H),7.80(d,J=8.2Hz,1H),6.88(q,J=7.8Hz,1H),5.58(s,1H),3.76(s,9H),1.83(d,J=7.8Hz,3H),1.43(s,9H)ppm.13CNMR(100MHz,CDCl3)δ165.3,162.7,157.8,156.2,149.0,148.8,138.3,133.7,126.5,124.5,121.9,121.0,52.5,46.3,28.5,14.8ppm.
16.6
Figure BDA0000375704840000464
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、羧酸、HATU、HOAT。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),8.10(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,1H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
16.7
Figure BDA0000375704840000471
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。
向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得540mg淡黄色固体，产率82%。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.87(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.67(d,J=4.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.6,132.0,131.3,126.1,124.7,118.4,111.1,107.1,101.0,97.3,95.2,92.0,90.4,90.3,89.5,89.1,87.5,83.8,39.8,39.5,39.3,34.1,29.1,22.9,19.5ppm.
16.8
Figure BDA0000375704840000472
0℃下，向反应物（0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.89(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例17
Figure BDA0000375704840000481
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例18
Figure BDA0000375704840000482
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入庚酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.11(c0.7,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.93(d,J=7.6Hz,1H),7.08(m,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.48(d,J=10Hz,1H),5.72-5.63(m,2H),5.62-5.45(m,1H),5.15(dd,J=17.2Hz,8Hz,1H),4.75-4.71(m,2H),4.28(d,J=17.2Hz,1H),2.86-2.71(m,4H),2.63-2.62(m,1H),2.50(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.85-1.82(m,3H),1.62-1.59(m,2H),1.26-1.24(m,9H),0.85(m,3H),0.78(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,169.0,163.5,162.1,155.7,148.8,138.6,134.5,132.6,132.1,130.9,128.9,128.5,127.5,125.1,121.3,72.2,71.7,57.3,44.1,43.2,40.9,38.6,33.8,32.2,31.5,30.9,29.7,29.1,28.8,27.7,27.6,25.5,22.5,19.1,18.9,16.4,14.6,14.0ppm.
实施例19
Figure BDA0000375704840000491
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),8.10(d,J=7.8Hz,1H),7.95(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例20
Figure BDA0000375704840000492
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入戊酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.31(c0.6,CHCl3).1HNMR(400MHzCDCl3):δ9.20(s,1H),8.12(d,J=7.8Hz,1H),7.96(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.49(d,J=10.0Hz,1H),5.73-5.69(m,2H),5.51(m,1H),5.15(dd,J=17.2Hz,8.0Hz,1H)4.75-4.73(m,2H),4.29(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.62(m,1H),2.47(t,J=7.8Hz,3H),2.31-2.26(m,3H),1.85-1.83(m,3H),1.62-1.60(m,2H),1.25-1.23(m,5H),0.83(m,3H),0.78(d,J=7.6Hz,3H),0.58(dJ=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.2,169.0,163.3,162.2,155.7,148.7,138.9,134.5,132.8132.1,130.8,128.9,128.5,127.6,125.2,121.3,72.1,71.6,57.8,44.2,43.5,41.3,38.8,33.8,32.6,31.6,30.8,29.929.3,28.8,27.6,25.7,22.7,19.1,16.6,14.9,13.8ppm.
实施例21
Figure BDA0000375704840000493
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丁酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:6.51(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.98(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.76-5.71(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77-4.74(m,2H),4.27(d,J=17.2Hz,1H),2.88-2.74(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.33-2.28(m,3H),1.86-1.83(m,3H),1.66-1.62(m,2H),1.27-1.24(m,3H),0.86(m,3H),0.79(d,J=7.6Hz,3H),0.56(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.4,169.1,163.5,162.3,155.8,148.8,138.9,134.7,132.9,132.3,130.9,128.9,128.4,127.5,125.3,121.5,72.2,71.7,57.6,44.5,43.6,41.4,38.9,33.9,32.7,31.7,30.9,29.9,29.5,28.9,27.7,25.8,22.9,19.3,15.5,13.8ppm.
实施例22
Figure BDA0000375704840000501
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.14(d,J=7.8Hz,1H),7.99(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.77(d,J=4.4Hz,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例23
Figure BDA0000375704840000502
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.98(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.79(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例24
Figure BDA0000375704840000511
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入甲酰氯（0.02ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:1.96(c0.1,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),8.16(d,J=7.6Hz,1H),7.88(d,J=7.6Hz,1H),7.07(dd,J=14.4Hz,J=7.2Hz,1H),6.56(dd,J=7.6Hz,J=3.6Hz,1H),6.48(d,J=8Hz,1H),5.73(m,2H),5.52(dd,J=15.6Hz,J=6.8Hz,1H),5.12(m,1H),4.76(dd,J=10Hz,J=3.6Hz,1H),4.33(m,1H),2.72(m,2H),2.53(m,2H),2.34-2.29(m,3H),1.38(t,J=7.6Hz,1H),0.82(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ176.5,169.8,169.4,163.6,162.6,155.7,148.8,138.5,134.7,132.5,132.3,130.9,128.8,127.8,125.6,121.8,72.5,71.7,56.9,44.8,43.6,41.5,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例25
25.1
Figure BDA0000375704840000512
向反应物（7.6mmol）的30mlTHF液中滴加LiOH（19mmol）的15ml水溶液。滴毕，室温反应2h。反应液用稀盐酸调PH值为3，然后加入乙酸乙酯100mL。有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，得白色絮状固体。1HNMR(400MHz,CDCl3):δ7.66（d,J=8.0Hz,1H）,7.48(d,J=7.8Hz,1H),5.55(s,1H),4.48(d,J=4.2Hz,2H),3.48(s,3H),1.36(s,9H)ppm.
25.2
0℃下，向反应物（2.7mmol），缓慢加入DIPEA（1.2ml，6mmol），搅拌稍许，再加入S2（2.7mmol），PyBop(4mmol）。室温搅拌过夜。反应液依次用饱和碳酸氢钠溶液，稀盐酸溶液，饱和氯化钠溶液洗涤。无水硫酸钠干燥，旋干溶剂，柱层析得。1HNMR(400MHz,CDCl3):δ8.64(d,J=8.4Hz,1H),8.05(d,J=8Hz,1H),7.44(d,J=7.6Hz,1H),5.44(s,1H),4.77(d,J=7.2Hz,1H),4.48-4.45(m,J=3H),3.78(s,3H),3.48(s,3H),1.45(s,9H),1.26(d,J=5.6Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ171.1,164.6,157.4,156.0,148.9,137.9,134.6,124.2,121.8,121.0,80.7,79.8,78.7,70.3,68.2,61.1,57.8,52.7,52.2,47.7,32.1,28.3,28.2,28.1,28.0,22.6,19.8ppm.
25.3
0℃下，向反应物（1.84mmol）的无水DCM（10ml）液中依次加入DMAP(0.184mmol)，NEt3（0.42ml，3mmol），MsCl（0.186ml，2.4mmol），加毕，提至室温搅拌过夜。旋干，用油泵抽干，直接投下一步。
25.4
Figure BDA0000375704840000522
向上步所得物的无水DCM液（10ml）中加入DABOCO（1g，9.22mmol）。室温搅拌8h。反应液依次用饱和碳酸氢钠液，饱和氯化铵液，饱和氯化钠液洗涤，用无水硫酸钠干燥。过滤，旋干溶剂，柱层析得絮状固体。1HNMR(400MHz,CDCl3):δ9.38(s,1H),8.01(d,J=7.6Hz,1H),7.78(d,J=8Hz,1H),6.86(q,J=7.6Hz,1H),5.57(s,1H),4.44(d,J=5.6Hz,2H),3.74(s,9H),3.48(s,3H),3.48(s,3H),1.80(d,J=7.6Hz3H),1.40(s,9H)ppm.13CNMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9126.3,124.2,123.5,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
25.5
Figure BDA0000375704840000523
向反应物（1.44mmol）的THF（10ml）液中滴加LiOH（90mg，3.6mmol）的5ml水溶液。三小时后，旋干有机相，加入10ml水和15ml乙酸乙酯稀释，分液，取水相。再加入15ml乙酸乙酯，调酸。分液，有机相用无水硫酸钠干燥。旋干，得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.40(s,1H),8.03(d,J=7.6Hz,1H),7.80(d,J=8.2Hz,1H),6.88(q,J=7.8Hz,1H),5.58(s,1H),4.46(d,J=5.8Hz,2H),3.76(s,9H),3.48(s,3H),1.83(d,J=7.8Hz,3H),1.43(s,9H)ppm.13CNMR(100MHz,CDCl3)δ165.3,162.7,157.8,156.2,149.0,148.8,138.3,133.7,126.5,124.5,123.7,121.9,121.0,52.5,46.3,28.5,14.8ppm.
25.6
Figure BDA0000375704840000524
0℃下，向反应物（336mg，1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、羧酸(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),8.10(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),3.48(s,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,123.5,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
25.7
Figure BDA0000375704840000531
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.87(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),3.48(s,3H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.6,132.0,131.3,126.1,124.7,123.3,118.4,111.1,107.1,101.0,97.3,95.2,92.0,90.4,90.3,89.5,89.1,87.5,83.8,39.8,39.5,39.3,34.1,29.1,22.9,19.5ppm.
25.8
Figure BDA0000375704840000532
0℃下，向反应物（150mg，0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.89(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),3.48(s,3H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,123.8,121.4,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例26
Figure BDA0000375704840000541
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),3.48(s,3H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,123.6,121.3,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例27
Figure BDA0000375704840000542
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入庚酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.11(c0.7,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.93(d,J=7.6Hz,1H),7.08(m,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.48(d,J=10Hz,1H),5.72-5.63(m,2H),5.62-5.45(m,1H),5.15(dd,J=17.2Hz,8Hz,1H),4.75-4.71(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.86-2.71(m,4H),2.63-2.62(m,1H),2.50(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.85-1.82(m,3H),1.62-1.59(m,2H),1.26-1.24(m,9H),0.85(m,3H),0.78(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,169.0,163.5,162.1,155.7,148.8,138.6,134.5,132.6,132.1,130.9,128.9,128.5,127.5,125.1,124.1,121.3,72.2,71.7,57.3,44.1,43.2,40.9,38.6,33.8,32.2,31.5,30.9,29.7,29.1,28.8,27.7,27.6,25.5,22.5,19.1,18.9,16.4,14.6,14.0ppm.
实施例28
Figure BDA0000375704840000551
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),8.10(d,J=7.8Hz,1H),7.95(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,124.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例29
Figure BDA0000375704840000552
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入戊酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体30mg，产率84%。[α]20 D:3.31(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.20(s,1H),8.12(d,J=7.8Hz,1H),7.96(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.49(d,J=10.0Hz,1H),5.73-5.69(m,2H),5.51(m,1H),5.15(dd,J=17.2Hz,8.0Hz,1H),4.75-4.73(m,2H),4.29(d,J=17.2Hz,1H),3.48(s,3H),2.89-2.75(m,4H),2.62(m,1H),2.47(t,J=7.8Hz,3H),2.31-2.26(m,3H),1.85-1.83(m,3H),1.62-1.60(m,2H),1.25-1.23(m,5H),0.83(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.2,169.0,163.3,162.2,155.7,148.7,138.9,134.5,132.8,132.1,130.8,128.9,128.5,127.6,125.2,123.1,121.3,72.1,71.6,57.8,44.2,43.5,41.3,38.8,33.8,32.6,31.6,30.8,29.9,29.3,28.8,27.6,25.7,22.7,19.1,16.6,14.9,13.8ppm.
实施例30
Figure BDA0000375704840000553
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丁酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:6.51(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.98(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),6.75(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.76-5.71(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77-4.74(m,2H),4.27(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.74(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.33-2.28(m,3H),1.86-1.83(m,3H),1.66-1.62(m,2H),1.27-1.24(m,3H),0.86(m,3H),0.79(d,J=7.6Hz,3H),0.56(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.4,169.1,163.5,162.3,155.8,148.8,138.9,134.7,132.9,132.3,130.9,128.9,128.4,127.5,125.3,123.9,121.5,72.2,71.7,57.6,44.5,43.6,41.4,38.9,33.9,32.7,31.7,30.9,29.9,29.5,28.9,27.7,25.8,22.9,19.3,15.5,13.8ppm.
实施例31
Figure BDA0000375704840000561
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.14(d,J=7.8Hz,1H),7.99(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),6.77(d,J=4.4Hz,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,124.7,121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例32
Figure BDA0000375704840000562
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.98(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),6.79(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,123.4,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例33
Figure BDA0000375704840000571
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入甲酰氯（0.02ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:1.96(c0.1,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),8.16(d,J=7.6Hz,1H),7.88(d,J=7.6Hz,1H),7.07(dd,J=14.4Hz,J=7.2Hz,1H),6.56(dd,J=7.6Hz,J=3.6Hz,1H),6.48(d,J=8Hz,1H),5.73(m,2H),5.52(dd,J=15.6Hz,J=6.8Hz,1H),5.12(m,1H),4.76(dd,J=10Hz,J=3.6Hz,1H),4.33(m,1H),3.48(s,3H),2.72(m,2H),2.53(m,2H),2.34-2.29(m,3H),1.38(t,J=7.6Hz,1H),0.82(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ176.5,169.8,169.4,163.6,162.6,155.7,148.8,138.5,134.7,132.5,132.3,130.9,128.8,127.8,125.6,123.6,121.8,72.5,71.7,56.9,44.8,43.6,41.5,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例34
34.1
Figure BDA0000375704840000572
将Fmoc-L-Pra（3.00mmol），EDCI（584mg，3.05mmol）和DMAP（25mg，0.203mmol）溶于无水二氯甲烷（15mL），在0℃下加入DIPEA（0.50mL，3.05mmol）和醇（526mg，1.02mmol），室温下搅拌12h，加二氯甲烷稀释，反应液用碳酸氢钠溶液洗涤（50mLx3)，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物用硅胶柱层析得淡黄色固体化合物。1HNMR(400MHz,CDCl3):δ7.77(d,J=7.6Hz,2H),7.61(m,2H),7.42-7.32(m19H),5.85-5.78(m,1H),5.68(dd,J=13.6,7.2Hz,1H),5.55(dd,J=15.2,7.2Hz,1H),5.35(d,J=8.8Hz,1H),4.37(t,J=6.8Hz,2H),4.28(dd,J=9.2,4.4Hz,1H),4.25(t,J=7.2,1H),4.18(t,J=8.4Hz,2H),3.48(s,3H),2.89(t,J=7.2Hz,2H),2.73(dd,J=15.6,7.6Hz,1H),2.61(dd,J=15.6,5.6Hz,1H),2.55(t,J=7.2Hz,2H),2.28(dt,J=13.6,6.8Hz,2H),2.19(m,1H),1.67(m,2H),0.90-0.85(m,4H),0.03(s,9H)ppm.
34.2
Figure BDA0000375704840000573
将反应物（0.81mmol）溶于乙腈（8mL），加入二乙胺（0.25mL，2.44mmol），搅拌2h，减压旋走乙腈，残留物用硅胶柱层析得无水油状物。1HNMR(400MHz,CDCl3):δ7.40-7.38(m,6H),7.29-7.25(m,6H),7.22-7.18(m,3H),5.69-5.57(m,2H),5.36(dd,J=15.4Hz,7.4Hz,1H),4.16-4.09(m,2H),3.21(d,J=4.8Hz,1H),2.64(dd,J=15.6Hz,8.4Hz,1H),2.53(dd,J=15.6Hz,5.2Hz,1H),2.19-2.15(m,2H),2.07-1.98(m,2H),1.97-1.93(m,1H),0.98-0.93(m,2H),0.92(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H),0.03(s,9H)ppm.
34.3
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、实施例16中第16.5步的产物(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),8.10(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,121.1,79.7,77.2,77.0,76.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
34.4
Figure BDA0000375704840000582
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.87(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),,2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.64,132.05,131.39,126.08,124.66,118.36,111.05,107.13,100.97,97.27,95.22,91.96,90.37,90.32,89.54,89.11,87.45,83.79,39.76,39.50,39.25,34.06,29.13,22.85,19.48ppm.
34.5
0℃下，向反应物（0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体，。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.89(d,J=7.6Hz,1H),,7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,77.2,76.9,76.7,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例35
Figure BDA0000375704840000592
0℃下，向反应物(0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.91(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例36
Figure BDA0000375704840000593
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.98(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.79(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例37
37.1
Figure BDA0000375704840000601
向反应物（7.6mmol）的30mlTHF液中滴加LiOH（19mmol）的15ml水溶液。滴毕，室温反应2h。反应液用稀盐酸调PH值为3，然后加入乙酸乙酯100mL。有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，得白色絮状固体。1HNMR(400MHz,CDCl3):δ8.05（s,J=8.0Hz,1H）,7.75(s,1H),7.61(s,1H),5.55(s,1H),4.48(d,J=4.2Hz,2H),1.34(s,9H)ppm.
37.2
Figure BDA0000375704840000602
0℃下，向反应物（2.7mmol），缓慢加入DIPEA（6mmol），搅拌稍许，再加入S2（2.7mmol），PyBop（4mmol）。室温搅拌过夜。反应液依次用饱和碳酸氢钠溶液，稀盐酸溶液，饱和氯化钠溶液洗涤。无水硫酸钠干燥，旋干溶剂，柱层析得白色絮状物。1HNMR(400MHz,CDCl3):δ8.64(d,J=8.4Hz,1H),7.51(s,1H),7.44(s,1H),5.44(s,1H),4.48-4.45(m,J=3H),3.78(s,3H),1.45(s,9H),1.26(d,J=5.6Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ171.1,164.6,157.4,156.0,148.9,137.9,134.6,124.2,121.8,121.0,80.7,79.8,78.7,70.3,68.2,61.1,57.8,52.7,52.2,47.7,32.1,28.3,28.2,28.1,28.0,22.6,19.8ppm.
37.3
Figure BDA0000375704840000603
0℃下，向反应物（1.84mmol）的无水DCM（10ml）液中依次加入DMAP(0.184mmol)，NEt3（3mmol），MsCl（2.4mmol），加毕，提至室温搅拌过夜。旋干，用油泵抽干，直接投下一步。
37.4
Figure BDA0000375704840000611
向上步所得物的无水DCM液（10ml）中加入DABOCO（9.22mmol）。室温搅拌8h。反应液依次用饱和碳酸氢钠液，饱和氯化铵液，饱和氯化钠液洗涤，用无水硫酸钠干燥。过滤，旋干溶剂，柱层析得絮状固体。1HNMR(400MHz,CDCl3):δ9.38(s,1H),7.45(s,1H),7.41(s,1H),6.86(q,J=7.6Hz,1H),5.57(s,1H),4.44(d,J=5.6Hz,1H),3.74(s,9H),1.80(d,J=7.6Hz,3H),1.40(s,9H)ppm.13CNMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9,126.3,124.2,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
37.5
Figure BDA0000375704840000612
向反应物（1.44mmol）的THF（10ml）液中滴加LiOH（3.6mmol）的5ml水溶液。三小时后，旋干有机相，加入10ml水和15ml乙酸乙酯稀释，分液，取水相。再加入15ml乙酸乙酯，调酸。分液，有机相用无水硫酸钠干燥。旋干，得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.40(s,1H),8.03(s,1H),7.11(s,1H),6.88(q,J=7.8Hz,1H),5.58(s,1H),3.76(s,9H),1.83(d,J=7.8Hz,3H),1.43(s,9H)ppm.13CNMR(100MHz,CDCl3)δ165.3,162.7,157.8,156.2,149.0,148.8,138.3,133.7,126.5,124.5,121.9,121.0,52.5,46.3,28.5,14.8ppm.
37.6
Figure BDA0000375704840000613
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、羧酸、HATU、HOAT。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),7.51(s,1H),7.48(s,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,1H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
37.7
Figure BDA0000375704840000621
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得540mg淡黄色固体，产率82%。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(s,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.67(d,J=4.4Hz,1H),6.51(d,J=10.3Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.6,132.0,131.3,126.1,124.7,118.4,111.1,107.1,101.0,97.3,95.2,92.0,90.4,90.3,89.5,89.1,87.5,83.8,39.8,39.5,39.3,34.1,29.1,22.9,19.5ppm.
37.8
Figure BDA0000375704840000622
0℃下，向反应物（0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(s,1H),7.41(s,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(s,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例38
Figure BDA0000375704840000623
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(s,J=7.6Hz,1H),7.91(s,,1H),7.06(m,J=7.2Hz,1H),6.70(s,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例39
Figure BDA0000375704840000631
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入庚酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.11(c0.7,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.93(s,1H),7.08(m,J=7.2Hz,1H),6.73(s,1H),6.48(d,J=10Hz,1H),5.72-5.63(m,2H),5.62-5.45(m,1H),5.15(dd,J=17.2Hz,8Hz,1H),4.75-4.71(m,2H),4.28(d,J=17.2Hz,1H),2.86-2.71(m,4H),2.63-2.62(m,1H),2.50(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.85-1.82(m,3H),1.62-1.59(m,2H),1.26-1.24(m,9H),0.85(m,3H),0.78(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,169.0,163.5,162.1,155.7,148.8,138.6,134.5,132.6,132.1,130.9,128.9,128.5,127.5,125.1,121.3,72.2,71.7,57.3,44.1,43.2,40.9,38.6,33.8,32.2,31.5,30.9,29.7,29.1,28.8,27.7,27.6,25.5,22.5,19.1,18.9,16.4,14.6,14.0ppm.
实施例40
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),8.10(d,J=7.8Hz,1H),7.95(s,1H),7.06(m,J=7.2Hz,1H),6.75(s,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例41
Figure BDA0000375704840000641
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),8.10(d,J=7.8Hz,1H),7.95(s,1H),7.06(m,J=7.2Hz,1H),6.75(s,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例42
Figure BDA0000375704840000642
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丁酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:6.51(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.98(s,1H),7.09(s,1H),6.75(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.76-5.71(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77-4.74(m,2H),4.27(d,J=17.2Hz,1H),2.88-2.74(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.33-2.28(m,3H),1.86-1.83(m,3H),1.66-1.62(m,2H),1.27-1.24(m,3H),0.86(m,3H),0.79(d,J=7.6Hz,3H),0.56(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.4,169.1,163.5,162.3,155.8,148.8,138.9,134.7,132.9,132.3,130.9,128.9,128.4,127.5,125.3,121.5,72.2,71.7,57.6,44.5,43.6,41.4,38.9,33.9,32.7,31.7,30.9,29.9,29.5,28.9,27.7,25.8,22.9,19.3,15.5,13.8ppm.
实施例43
Figure BDA0000375704840000651
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.14(d,J=7.8Hz,1H),7.99(d,J=7.6Hz,1H),7.08(s,1H),6.77(s,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例44
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.98(d,J=7.6Hz,1H),7.09(s,1H),6.79(s,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例45
Figure BDA0000375704840000653
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入甲酰氯（0.02ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:1.96(c0.1,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),8.16(d,J=7.6Hz,1H),7.88(s,1H),7.07(dd,J=14.4Hz,J=7.2Hz,1H),6.56(dd,J=7.6Hz,J=3.6Hz,1H),6.48(s,1H),5.73(m,2H),5.52(dd,J=15.6Hz,J=6.8Hz,1H),5.12(m,1H),4.76(dd,J=10Hz,J=3.6Hz,1H),4.33(m,1H),2.72(m,2H),2.53(m,2H),2.34-2.29(m,3H),1.38(t,J=7.6Hz,1H),0.82(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ176.5,169.8,169.4,163.6,162.6,155.7,148.8,138.5,134.7,132.5,132.3,130.9,128.8,127.8,125.6,121.8,72.5,71.7,56.9,44.8,43.6,41.5,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例46
46.1
Figure BDA0000375704840000661
向反应物（7.6mmol）的30mlTHF液中滴加LiOH（19mmol）的15ml水溶液。滴毕，室温反应2h。反应液用稀盐酸调PH值为3，然后加入乙酸乙酯100mL。有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，得白色絮状固体。1HNMR(400MHz,CDCl3):δ7.77(d,J=7.8Hz,1H),7.56（s,1H）,7.48(s,1H),5.55(s,1H),4.48(d,J=4.2Hz,2H),3.48(s,3H),1.36(s,9H)ppm.
46.2
Figure BDA0000375704840000662
0℃下，向反应物（2.7mmol），缓慢加入DIPEA（1.2ml，6mmol），搅拌稍许，再加入S2（2.7mmol），PyBop(4mmol）。室温搅拌过夜。反应液依次用饱和碳酸氢钠溶液，稀盐酸溶液，饱和氯化钠溶液洗涤。无水硫酸钠干燥，旋干溶剂，柱层析得。1HNMR(400MHz,CDCl3):δ8.64(d,J=8.4Hz,1H),7.95(s,1H),7.81(s,1H),7.44(s,1H),5.44(s,1H),4.77(d,J=7.2Hz,1H),4.48-4.45(m,J=3H),3.78(s,3H),3.48(s,3H),1.45(s,9H),1.26(d,J=5.6Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ171.1,164.6,157.4,156.0,148.9,137.9,134.6,124.2,121.8,121.0,80.7,79.8,78.7,70.3,68.2,61.1,57.8,52.7,52.2,47.7,32.1,28.3,28.2,28.1,28.0,22.6,19.8ppm.
46.3
0℃下，向反应物（1.84mmol）的无水DCM（10ml）液中依次加入DMAP(0.184mmol)，NEt3（0.42ml,3mmol），MsCl（0.186ml，2.4mmol），加毕，提至室温搅拌过夜。旋干，用油泵抽干，直接投下一步。
46.4
Figure BDA0000375704840000671
向上步所得物的无水DCM液（10ml）中加入DABOCO（1g，9.22mmol）。室温搅拌8h。反应液依次用饱和碳酸氢钠液，饱和氯化铵液，饱和氯化钠液洗涤，用无水硫酸钠干燥。过滤，旋干溶剂，柱层析得絮状固体。1HNMR(400MHz,CDCl3):δ9.38(s,1H),7.78(s,1H),7.41(s,1H),6.86(q,J=7.6Hz,1H),5.57(s,1H),4.44(d,J=5.6Hz,2H),3.74(s,9H),3.48(s,3H),3.48(s,3H),1.80(d,J=7.6Hz,3H),1.40(s,9H)ppm.13CNMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9,126.3,124.2,123.5,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
46.5
Figure BDA0000375704840000672
向反应物（1.44mmol）的THF（10ml）液中滴加LiOH（90mg，3.6mmol）的5ml水溶液。三小时后，旋干有机相，加入10ml水和15ml乙酸乙酯稀释，分液，取水相。再加入15ml乙酸乙酯，调酸。分液，有机相用无水硫酸钠干燥。旋干，得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.40(s,1H),7.51(s,1H),7.43(s,1H),6.88(q,J=7.8Hz,1H),5.58(s,1H),4.46(d,J=5.8Hz,2H),3.76(s,9H),3.48(s,3H),1.83(d,J=7.8Hz,3H),1.43(s,9H)ppm.13CNMR(100MHz,CDCl3)δ165.3,162.7,157.8,156.2,149.0,148.8,138.3,133.7,126.5,124.5,123.7,121.9,121.0,52.5,46.3,28.5,14.8ppm.
46.6
0℃下，向反应物（336mg，1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、羧酸(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),7.48(s,1H),7.34(s,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),3.48(s,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,123.5,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
46.7
Figure BDA0000375704840000681
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。
向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.67(s,1H),6.43(s,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),3.48(s,3H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.6,132.0,131.3,126.1,124.7,123.3,118.4,111.1,107.1,101.0,97.3,95.2,92.0,90.4,90.3,89.5,89.1,87.5,83.8,39.8,39.5,39.3,34.1,29.1,22.9,19.5ppm.
46.8
Figure BDA0000375704840000682
0℃下，向反应物（150mg，0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ7.41(s,1H),7.21(s,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),3.48(s,3H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,123.8,121.4,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例47
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),7.24(s,1H),7.11(s,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),3.48(s,3H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,123.6,121.3,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例48
Figure BDA0000375704840000692
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入庚酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.11(c0.7,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),7.33(s,1H),7.25(s,1H),7.08(m,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.48(d,J=10Hz,1H),5.72-5.63(m,2H),5.62-5.45(m,1H),5.15(dd,J=17.2Hz,8Hz,1H),4.75-4.71(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.86-2.71(m,4H),2.63-2.62(m,1H),2.50(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.85-1.82(m,3H),1.62-1.59(m,2H),1.26-1.24(m,9H),0.85(m,3H),0.78(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,169.0,163.5,162.1,155.7,148.8,138.6,134.5,132.6,132.1,130.9,128.9,128.5,127.5,125.1,124.1,121.3,72.2,71.7,57.3,44.1,43.2,40.9,38.6,33.8,32.2,31.5,30.9,29.7,29.1,28.8,27.7,27.6,25.5,22.5,19.1,18.9,16.4,14.6,14.0ppm.
实施例49
Figure BDA0000375704840000693
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),7.45(s,1H),7.16(s,1H),7.06(m,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,124.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例50
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入戊酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体30mg，产率84%。[α]20 D:3.31(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.20(s,1H),7.96(d,J=7.6Hz,1H),7.21(s,1H),7.08(s,1H),6.73(d,J=4.4Hz,1H),6.49(d,J=10.0Hz,1H),5.73-5.69(m,2H),5.51(m,1H),5.15(dd,J=17.2Hz,8.0Hz,1H),4.75-4.73(m,2H),4.29(d,J=17.2Hz,1H),3.48(s,3H),2.89-2.75(m,4H),2.62(m,1H),2.47(t,J=7.8Hz,3H),2.31-2.26(m,3H),1.85-1.83(m,3H),1.62-1.60(m,2H),1.25-1.23(m,5H),0.83(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.2,169.0,163.3,162.2,155.7,148.7,138.9,134.5,132.8,132.1,130.8,128.9,128.5,127.6,125.2,123.1,121.3,72.1,71.6,57.8,44.2,43.5,41.3,38.8,33.8,32.6,31.6,30.8,29.9,29.3,28.8,27.6,25.7,22.7,19.1,16.6,14.9,13.8ppm.
实施例51
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丁酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:6.51(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),7.98(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.09(s,1H),6.75(s,1H),6.47(d,J=10.0Hz,1H),5.76-5.71(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77-4.74(m,2H),4.27(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.74(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.33-2.28(m,3H),1.86-1.83(m,3H),1.66-1.62(m,2H),1.27-1.24(m,3H),0.86(m,3H),0.79(d,J=7.6Hz,3H),0.56(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.4,169.1,163.5,162.3,155.8,148.8,138.9,134.7,132.9,132.3,130.9,128.9,128.4,127.5,125.3,123.9,121.5,72.2,71.7,57.6,44.5,43.6,41.4,38.9,33.9,32.7,31.7,30.9,29.9,29.5,28.9,27.7,25.8,22.9,19.3,15.5,13.8ppm.
实施例52
Figure BDA0000375704840000711
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),7.99(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.08(s,1H),6.77(s,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,124.7,121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例53
Figure BDA0000375704840000712
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),7.98(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.09(s,1H),6.79(s,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,123.4,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例54
Figure BDA0000375704840000713
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入甲酰氯（0.02ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:1.96(c0.1,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),7.18(s,1H),7.02(s,1H),7.07(dd,J=14.4Hz,J=7.2Hz,1H),6.56(dd,J=7.6Hz,J=3.6Hz,1H),6.48(d,J=8Hz,1H),5.73(m,2H),5.52(dd,J=15.6Hz,J=6.8Hz,1H),5.12(m,1H),4.76(dd,J=10Hz,J=3.6Hz,1H),4.33(m,1H),3.48(s,3H),2.72(m,2H),2.53(m,2H),2.34-2.29(m,3H),1.38(t,J=7.6Hz,1H),0.82(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ176.5,169.8,169.4,163.6,162.6,155.7,148.8,138.5,134.7,132.5,132.3,130.9,128.8,127.8,125.6,123.6,121.8,72.5,71.7,56.9,44.8,43.6,41.5,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例55
55.1
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、实施例37第37.5步的产物（mg）、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),7.14(s,1H),7.08(s,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5，124.6,121.1,79.7,77.2,77.0,76.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
55.2
Figure BDA0000375704840000722
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.07(s,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.33(s,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),,2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.64,132.05,131.39,126.08,124.66,118.36,111.05,107.13,100.97,97.27,95.22,91.96,90.37,90.32,89.54,89.11,87.45,83.79,39.76,39.50,39.25,34.06,29.13,22.85,19.48ppm.
55.3
Figure BDA0000375704840000731
0℃下，向反应物（0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体，。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ7.88(d,J=7.6Hz,1H),7.19(s,1H),,7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(s,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,77.2,76.9,76.7,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例56
Figure BDA0000375704840000732
0℃下，向反应物(0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),7.52(d,J=7.6Hz,1H),7.11(s,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.36(s,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例57
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),7.98(d,J=7.6Hz,1H),7.15(d,J=7.8Hz,1H),7.09(m,J=7.8Hz,1H),6.79(s,1H),6.47(s,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例58
58.1
Figure BDA0000375704840000742
向反应物（7.6mmol）的30mlTHF液中滴加LiOH（456mg，19mmol）的15ml水溶液。滴毕，室温反应2h。反应液用稀盐酸调PH值为3，然后加入乙酸乙酯100mL。有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，得白色絮状固体。1HNMR(400MHz,CDCl3):δ7.96（d,J=8.0Hz,1H）,7.47(d,J=7.6Hz,1H),5.55(s,1H),4.48(d,J=4.2Hz,2H),1.36(s,9H)ppm.
58.2
Figure BDA0000375704840000743
0℃下，向反应物（2.7mmol），缓慢加入DIPEA（1.2ml，6mmol），搅拌稍许，再加入S2（2.7mmol），PyBop（2.5g，4mmol）。室温搅拌过夜。反应液依次用饱和碳酸氢钠溶液，稀盐酸溶液，饱和氯化钠溶液洗涤。无水硫酸钠干燥，旋干溶剂，柱层析得白色絮状物。1HNMR(400MHz,CDCl3):δ8.64(d,J=8.4Hz,1H),8.05(d,J=8Hz,1H),7.41(d,J=8Hz,1H),5.44(s,1H),4.77(d,J=7.2Hz,1H),4.48-4.45(m,J=3H),3.78(s,3H),1.45(s,9H),1.26(d,J=5.6Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ171.1,164.6,157.4,156.0,148.9,137.9,134.6,124.2,121.8,121.0,80.7,79.8,78.7,70.3,68.2,61.1,57.8,52.7,52.2,47.7,32.1,28.3,28.2,28.1,28.0,22.6,19.8ppm.
58.3
Figure BDA0000375704840000744
0℃下，向反应物（1.84mmol）的无水DCM（10ml）液中依次加入DMAP(25mg，0.184mmol)，NEt3（0.42ml，3mmol），MsCl（0.186ml，2.4mmol），加毕，提至室温搅拌过夜。旋干，用油泵抽干，直接投下一步。
58.4
向上步所得物的无水DCM液（10ml）中加入DABOCO（1g，9.22mmol）。室温搅拌8h。反应液依次用饱和碳酸氢钠液，饱和氯化铵液，饱和氯化钠液洗涤，用无水硫酸钠干燥。过滤，旋干溶剂，柱层析得絮状固体。1HNMR(400MHz,CDCl3):δ9.38(s,1H),7.88(d,J=8Hz,1H),,7.51(d,J=7.6Hz,1H),6.86(q,J=7.6Hz,1H),5.57(s,1H),4.44(d,J=5.6Hz,2H),3.74(s,9H),1.80(d,J=7.6Hz,3H),1.40(s,9H)ppm.13CNMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9,126.3,124.2,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
58.5
Figure BDA0000375704840000752
向反应物（1.44mmol）的THF（10ml）液中滴加LiOH（90mg，3.6mmol）的5ml水溶液。三小时后，旋干有机相，加入10ml水和15ml乙酸乙酯稀释，分液，取水相。再加入15ml乙酸乙酯，调酸。分液，有机相用无水硫酸钠干燥。旋干，得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.40(s,1H),7.83(d,J=7.6Hz,1H),7.80(d,J=8.2Hz,1H),6.88(q,J=7.8Hz,1H),5.58(s,1H),4.46(d,J=5.8Hz,2H),3.76(s,9H),1.83(d,J=7.8Hz,3H),1.43(s,9H)ppm.13CNMR(100MHz,CDCl3)δ165.3,162.7,157.8,156.2,149.0,148.8,138.3,133.7,126.5,124.5,121.9,121.0,52.5,46.3,28.5,14.8ppm.
58.6
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、羧酸(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),7.91(d,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
58.7
Figure BDA0000375704840000761
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),7.89(d,J=7.6Hz,1H),7.68(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.6,132.0,131.3,126.1,124.7,118.4,111.1,107.1,101.0,97.3,95.2,92.0,90.4,90.3,89.5,89.1,87.5,83.8,39.8,39.5,39.3,34.1,29.1,22.9,19.5ppm.
58.8
0℃下，向反应物（0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例59
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.51(d,1H),7.14(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例60
Figure BDA0000375704840000772
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入庚酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.11(c0.7,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.53(d,J=7.6Hz,1H),7.08(m,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.48(d,J=10Hz,1H),5.72-5.63(m,2H),5.62-5.45(m,1H),5.15(dd,J=17.2Hz,8Hz,1H),4.75-4.71(m,2H),4.28(d,J=17.2Hz,1H),2.86-2.71(m,4H),2.63-2.62(m,1H),2.50(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.85-1.82(m,3H),1.62-1.59(m,2H),1.26-1.24(m,9H),0.85(m,3H),0.78(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,169.0,163.5,162.1,155.7,148.8,138.6,134.5,132.6,132.1,130.9,128.9,128.5,127.5,125.1,121.3,72.2,71.7,57.3,44.1,43.2,40.9,38.6,33.8,32.2,31.5,30.9,29.7,29.1,28.8,27.7,27.6,25.5,22.5,19.1,18.9,16.4,14.6,14.0ppm.
实施例61
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),8.10(d,J=7.8Hz,1H),7.55(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例62
Figure BDA0000375704840000781
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入戊酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.31(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.20(s,1H),8.12(d,J=7.8Hz,1H),7.66(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.49(d,J=10.0Hz,1H),5.73-5.69(m,2H),5.51(m,1H),5.15(dd,J=17.2Hz,8.0Hz,1H),4.75-4.73(m,2H),4.29(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.62(m,1H),2.47(t,J=7.8Hz,3H),2.31-2.26(m,3H),1.85-1.83(m,3H),1.62-1.60(m,2H),1.25-1.23(m,5H),0.83(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.2,169.0,163.3,162.2,155.7,148.7,138.9,134.5,132.8,132.1,130.8,128.9,128.5,127.6,125.2,121.3,72.1,71.6,57.8,44.2,43.5,41.3,38.8,33.8,32.6,31.6,30.8,29.9,29.3,28.8,27.6,25.7,22.7,19.1,16.6,14.9,13.8ppm.
实施例63
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丁酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:6.51(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.98(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),6.75(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.76-5.71(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77-4.74(m,2H),4.27(d,J=17.2Hz,1H),2.88-2.74(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.33-2.28(m,3H),1.86-1.83(m,3H),1.66-1.62(m,2H),1.27-1.24(m,3H),0.86(m,3H),0.79(d,J=7.6Hz,3H),0.56(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.4,169.1,163.5,162.3,155.8,148.8,138.9,134.7,132.9,132.3,130.9,128.9,128.4,127.5,125.3,121.5,72.2,71.7,57.6,44.5,43.6,41.4,38.9,33.9,32.7,31.7,30.9,29.9,29.5,28.9,27.7,25.8,22.9,19.3,15.5,13.8ppm.
实施例64
Figure BDA0000375704840000791
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.14(d,J=7.8Hz,1H),7.51(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.77(d,J=4.4Hz,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例65
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.48(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.79(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例66
Figure BDA0000375704840000793
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入甲酰氯（0.02ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体26mg，产率75%。[α]20 D:1.96(c0.1,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),8.16(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.07(dd,J=14.4Hz,J=7.2Hz,1H),6.56(dd,J=7.6Hz,J=3.6Hz,1H),6.48(d,J=8Hz,1H),5.73(m,2H),5.52(dd,J=15.6Hz,J=6.8Hz,1H),5.12(m,1H),4.76(dd,J=10Hz,J=3.6Hz,1H),4.33(m,1H),2.72(m,2H),2.53(m,2H),2.34-2.29(m,3H),1.38(t,J=7.6Hz,1H),0.82(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ176.5,169.8,169.4,163.6,162.6,155.7,148.8,138.5,134.7,132.5,132.3,130.9,128.8,127.8,125.6,121.8,72.5,71.7,56.9,44.8,43.6,41.5,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例67
67.1
Figure BDA0000375704840000801
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、实施例58中第58.5步的产物(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.36(s,1H),8.11(d,J=7.6Hz,1H),7.55(d,J=7.6Hz,1H),7.39-7.18(m,12H),6.68-6.63(m,2H),5.66-5.60(m,2H),5.47(s,1H),5.38-5.32(m,1H),4.61(dd,J=8.8Hz,4Hz,1H),4.51(d,J=4.2Hz,2H),4.16-4.11(m,3H),2.67(dd,J=15.6Hz,7.6Hz,1H),2.53(dd,J=15.6Hz,5.6Hz,1H),2.19-2.15(m,3H),2.05(t,J=6.8Hz,4H),1.83(d,J=7.2Hz,3H),1.49(s,9H),1.27(t,J=6.8Hz,2H),0.95-0.91(m,3H),0.82(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.1,170.8,169.6,164.2,162.7,157.4,155.9,148.6,144.7,138.4,133.9,129.7,129.4,129.0,127.6,126.5,124.6,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,0.9,-1.5,-1.6ppm.
67.2
Figure BDA0000375704840000802
向反应物（0.90mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.17(d,J=7.6Hz,1H),7.07(q,J=7.2Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.64,132.05,131.39,126.08,124.66,118.36,111.05,107.13,100.97,97.27,95.22,91.96,90.37,90.32,89.54,89.11,87.45,83.79,39.76,39.50,39.25,34.06,29.13,22.85,19.48ppm.
67.3
Figure BDA0000375704840000811
0℃下，向反应物（0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得黄色固体。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.39(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,77.2,76.9,76.7,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例68
Figure BDA0000375704840000812
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例69
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例70
70.1
Figure BDA0000375704840000822
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、实施例1第1.5步的产物(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),8.10(d,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,121.1,79.7,77.2,77.0,76.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
70.2
Figure BDA0000375704840000831
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.47(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.64,132.05,131.39,126.08,124.66,118.36,111.05,107.13,100.97,97.27,95.22,91.96,90.37,90.32,89.54,89.11,87.45,83.79,39.76,39.50,39.25,34.06,29.13,22.85,19.48ppm.
70.3
Figure BDA0000375704840000832
0℃下，向反应物（150mg，0.21mmol）的无水DCM液（5ml）中依次加入TES（0.1ml），TFA（0.65ml）。15min后，直接旋干溶剂，柱层析得63mg黄色固体，产率63%。[α]20 D:6.13(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.18(d,J=7.6Hz,1H),7.49(d,J=7.6Hz,1H),7.06(dd,J=14.4HzJ=7.2Hz,1H),6.58(dd,J=7.6Hz,J=3.6Hz,1H),6.45(d,J=8Hz,1H),5.74-5.64(m,2H),5.50(dd,J=15.6Hz,J=6.8Hz,1H),5.10(m,1H),4.74(dd,J=10Hz,J=3.6Hz,1H),4.34-4.28(m,1H),2.74-2.69(m,2H),2.56-2,50(m,2H),2.34-2.29(m,3H),1.36(t,J=7.6Hz,1H),0.80(d,J=6.8Hz,3H),0.6(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,168.9,163.6,162.9,155.7,148.6,138.3,134.7,132.4,128.6,127.0,124.9,121.4,77.2,76.9,76.7,71.9,56.9,43.3,41.0,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例71
Figure BDA0000375704840000833
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.31(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例72
Figure BDA0000375704840000841
0℃下，向反应物（0.126mmol）的无水DCM（5ml）液中加入重蒸NEt3（0.04ml），搅拌稍许，加入辛酰氯（0.1ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.71(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.21(s,1H),8.10(d,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.70(d,J=4.4Hz,1H),6.46(d,J=10Hz,1H),5.70-5.64(m,2H),5.59-5.46(m,1H),5.13(dd,J=17.2Hz,8Hz,1H),4.73-4.70(m,2H),4.27(d,J=J=17.2Hz,1H),2.85-2.71(m,4H),2.62-2.61(m,1H),2.49(t,J=7.6Hz,3H),2.29-2.23(m,3H),1.84-1.81(m,3H),1.61-1.58(m,2H),1.24(s,11H),0.86-0.57(m,7H),0.53(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ199.5,169.6,169.1,167.6,165.7,163.7,162.3,155.8,148.6,138.5,134.7,132.5,132.2,130.8,128.7,128.2,127.2,124.9,121.3,77.2,77.0,76.7,72.0,71.6,56.9,44.0,43.2,40.8,38.5,33.7,32.1,31.5,30.8,29.6,29.0,28.8,28.8,27.7,27.6,25.5,24.7,22.5,19.0,18.9,16.4,14.6,13.9ppm.
实施例73
73.1
Figure BDA0000375704840000842
向反应物（7.6mmol）的30mlTHF液中滴加LiOH（19mmol）的15ml水溶液。滴毕，室温反应2h。反应液用稀盐酸调PH值为3，然后加入乙酸乙酯100mL。有机相依次用水，饱和食盐水洗涤。有机层用无水硫酸钠干燥，蒸干溶剂，得白色絮状固体。1HNMR(400MHz,CDCl3):δ7.77（d,J=8.0Hz,1H）,7.48(d,J=7.8Hz,1H),5.55(s,1H),4.48(d,J=4.2Hz,2H),3.48(s,3H),1.36(s,9H)ppm.
73.2
0℃下，向反应物（2.7mmol），缓慢加入DIPEA（1.2ml，6mmol），搅拌稍许，再加入S2（2.7mmol），PyBop(4mmol）。室温搅拌过夜。反应液依次用饱和碳酸氢钠溶液，稀盐酸溶液，饱和氯化钠溶液洗涤。无水硫酸钠干燥，旋干溶剂，柱层析得。1HNMR(400MHz,CDCl3):δ8.64(d,J=8.4Hz,1H),8.05(d,J=8Hz,1H),7.81(d,J=8Hz,1H),5.44(s,1H),4.77(d,J=7.2Hz,1H),4.48-4.45(m,J=3H),3.78(s,3H),3.48(s,3H),1.45(s,9H),1.26(d,J=5.6Hz,3H)ppm.13CNMR(100MHz,CDCl3)δ171.1,164.6,157.4,156.0,148.9,137.9,134.6,124.2,123.2，121.8,121.0,80.7,79.8,78.7,70.3,68.2,61.1,57.8,52.7,52.2,47.7,32.1,28.3,28.2,28.1,28.0,22.6,19.8ppm.
73.3
Figure BDA0000375704840000852
0℃下，向反应物（1.84mmol）的无水DCM（10ml）液中依次加入DMAP(0.184mmol)，NEt3（0.42ml，3mmol），MsCl（0.186ml，2.4mmol），加毕，提至室温搅拌过夜。旋干，用油泵抽干，直接投下一步。
73.4
Figure BDA0000375704840000853
向上步所得物的无水DCM液（10ml）中加入DABOCO（1g，9.22mmol）。室温搅拌8h。反应液依次用饱和碳酸氢钠液，饱和氯化铵液，饱和氯化钠液洗涤，用无水硫酸钠干燥。过滤，旋干溶剂，柱层析得絮状固体。1HNMR(400MHz,CDCl3):δ9.38(s,1H),8.01(d,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),6.86(q,J=7.6Hz,1H),5.57(s,1H),4.44(d,J=5.6Hz,2H),3.74(s,9H),3.48(s,3H),3.48(s,3H),1.80(d,J=7.6Hz,3H),1.40(s,9H)ppm.13CNMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9,126.3,124.2,123.5,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
73.5
Figure BDA0000375704840000854
向反应物（1.44mmol）的THF（10ml）液中滴加LiOH（90mg，3.6mmol）的5ml水溶液。三小时后，旋干有机相，加入10ml水和15ml乙酸乙酯稀释，分液，取水相。再加入15ml乙酸乙酯，调酸。分液，有机相用无水硫酸钠干燥。旋干，得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.40(s,1H),8.03(d,J=7.6Hz,1H),7.43(d,J=7.8Hz,1H),6.88(q,J=7.8Hz,1H),5.58(s,1H),4.46(d,J=5.8Hz,2H),3.76(s,9H),3.48(s,3H),1.83(d,J=7.8Hz,3H),1.43(s,9H)ppm.13CNMR(100MHz,CDCl3)δ165.3,162.7,157.8,156.2,149.0,148.8,138.3,133.7,126.5,124.5,123.7,121.9,121.0,52.5,46.3,28.5,14.8ppm.
73.6
Figure BDA0000375704840000861
0℃下，向反应物（1mmol）的DCM液（10ml）中依次加入DIPEA(0.7ml)、羧酸(610mg)、HATU(760mg)、HOAT(326mg)。加毕，提至室温搅拌。8h后，反应液依次用饱和碳酸氢钠溶液、稀盐酸溶液、饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干溶剂，柱层析得白色絮状固体。1HNMR(400MHz,CDCl3):δ9.41(s,1H),8.10(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.39-7.17(m,12H),6.66-6.61(m,2H),5.68-5.59(m,2H),5.46(s,1H),5.38-5.32(m,1H),4.59(dd,J=8.8Hz,4Hz,1H),4.49(d,J=4.2Hz,2H),4.15-4.10(m,3H),3.48(s,3H),2.66(dd,J=15.6Hz,7.6Hz,1H),2.52(dd,J=15.6Hz,5.6Hz,1H),2.18-2.14(m,3H),2.04(t,J=6.8Hz,4H),1.82(d,J=7.2Hz,3H),1.46(s,9H),1.25(t,J=6.8Hz,2H),0.97-0.90(m,5H),0.80(d,J=6.8Hz,3H),0.02(s,9H)ppm.13CNMR(125MHz,CDCl3)δ171.0,170.7,169.5,164.3,162.6,157.3,155.9,148.5,144.7,138.2,133.9,129.6,129.4,129.0,127.7,127.6,126.5,124.6,123.5,121.1,79.7,71.8,66.5,63.0,60.3,57.0,45.6,39.5,31.5,31.2,31.0,28.3,20.9,18.8,17.5,17.2,14.1,13.8,0.9,-1.5,-1.6ppm.
73.7
向反应物（0.92mmol）的重蒸THF液（5ml）中加入四丁基氟化铵的四氢呋喃溶液（1mol/L，2.3ml）。3h后，直接旋干反应液，柱层析得白色色固体。向上一步所得物的DCM液（25ml）中加入三氟醋酸（6ml）。5h后，旋去DCM，向剩余物中加入甲苯（8ml），用油泵抽干有机溶剂，得棕色粘稠物，无需进一步处理，直接投下一步。将上一步所得物用色谱纯乙腈（200ml）溶解，缓慢滴入HATU（3g），DIPEA（4ml）的色谱纯乙腈（550ml）中。24h后，旋干溶剂，用乙酸乙酯（20ml）稀释，依次用饱和碳酸氢钠溶液，烯盐酸溶液，饱和氯化钠溶液洗涤，无水硫酸钠干燥。过滤，旋干，柱层析得淡黄色固体。1HNMR(400MHz,CDCl3):δ9.17(s,1H),8.10(d,J=7.6Hz,1H),7.37-7.16(m,15H),7.07(q,J=7.2Hz,1H),6.67(d,J=4.4Hz,1H),6.43(d,J=10.4Hz,1H),5.62-5.56(m,2H),5.39-5.34(m,1H),5.06(dd,J=17.2Hz,8Hz,1H),4.74(dd,J=6.4Hz,3.6Hz,1H),4.19-4.08(m,2H),3.48(s,3H),2.69-2.64(m,2H),2.30-2.27(m,1H),2.21-2.17(m,2H),1.84(d,J=7.2Hz,3H),0.79(d,J=6.8Hz,3H),0.59(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,DMSO)δ133.6,132.0,131.3,126.1,124.7,123.3,118.4,111.1,107.1,101.0,97.3,95.2,92.0,90.4,90.3,89.5,89.1,87.5,83.8,39.8,39.5,39.3,34.1,29.1,22.9,19.5ppm.
实施例74
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.14(d,J=7.8Hz,1H),7.99(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),6.77(d,J=4.4Hz,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,123.4，121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例75
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体33mg，产率85%。[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.49(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.79(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,123.4，121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例76
Figure BDA0000375704840000873
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入庚酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:4.11(c0.7,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),8.12(d,J=7.8Hz,1H),7.45(d,J=7.6Hz,1H),7.08(dd,J=14.4,7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.48(d,J=10Hz,1H),5.72-5.63(m,2H),5.62-5.45(m,1H),5.15(dd,J=17.2Hz,8Hz,1H),4.75-4.71(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.86-2.71(m,4H),2.63-2.62(m,1H),2.50(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.85-1.82(m,3H),1.62-1.59(m,2H),1.26-1.24(m,9H),0.85(m,3H),0.78(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.5,169.0,163.5,162.1,155.7,148.8,138.6,134.5,132.6,132.1,130.9,128.9,128.5,127.5,125.1,124.1,121.3,72.2,71.7,57.3,44.1,43.2,40.9,38.6,33.8,32.2,31.5,30.9,29.7,29.1,28.8,27.7,27.6,25.5,22.5,19.1,18.9,16.4,14.6,14.0ppm.
实施例77
Figure BDA0000375704840000881
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入己酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.11(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.22(s,1H),8.10(d,J=7.8Hz,1H),7.51(d,J=7.6Hz,1H),7.06(m,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.46(d,J=10.0Hz,1H),5.74-5.68(m,2H),5.50(m,1H),5.17(dd,J=17.2Hz,8.0Hz,1H),4.76-4.73(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.75(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.30-2.25(m,3H),1.84-1.82(m,3H),1.63-1.60(m,2H),1.26-1.24(m,7H),0.84(m,3H),0.79(d,J=7.6Hz,3H),0.59(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.3,169.0,163.2,162.0,155.6,148.9,138.8,134.8,132.7,132.0,130.9,128.9,128.6,127.7,125.3,124.3,121.5,72.3,71.8,57.5,44.3,43.4,41.2,38.9,33.9,32.5,31.7,30.9,29.8,29.2,28.9,27.8,27.6,25.6,22.6,19.0,16.5,14.7,13.9ppm.
实施例78
Figure BDA0000375704840000882
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入戊酰氯（0.04ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:3.31(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.20(s,1H),8.12(d,J=7.8Hz,1H),7.47(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.73(d,J=4.4Hz,1H),6.49(d,J=10.0Hz,1H),5.73-5.69(m,2H),5.51(m,1H),5.15(dd,J=17.2Hz,8.0Hz,1H),4.75-4.73(m,2H),4.29(d,J=17.2Hz,1H),3.48(s,3H),2.89-2.75(m,4H),2.62(m,1H),2.47(t,J=7.8Hz,3H),2.31-2.26(m,3H),1.85-1.83(m,3H),1.62-1.60(m,2H),1.25-1.23(m,5H),0.83(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.2,169.0,163.3,162.2,155.7,148.7,138.9,134.5,132.8,132.1,130.8,128.9,128.5,127.6,125.2,123.1,121.3,72.1,71.6,57.8,44.2,43.5,41.3,38.8,33.8,32.6,31.6,30.8,29.9,29.3,28.8,27.6,25.7,22.7,19.1,16.6,14.9,13.8ppm.
实施例79
Figure BDA0000375704840000891
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丁酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:6.51(c0.5,CHCl3).1HNMR(400MHz,CDCl3):δ9.23(s,1H),8.12(d,J=7.8Hz,1H),7.49(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.75(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.76-5.71(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77-4.74(m,2H),4.27(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.74(m,4H),2.63(m,1H),2.49(t,J=7.8Hz,3H),2.33-2.28(m,3H),1.86-1.83(m,3H),1.66-1.62(m,2H),1.27-1.24(m,3H),0.86(m,3H),0.79(d,J=7.6Hz,3H),0.56(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.4,169.1,163.5,162.3,155.8,148.8,138.9,134.7,132.9,132.3,130.9,128.9,128.4,127.5,125.3,123.9,121.5,72.2,71.7,57.6,44.5,43.6,41.4,38.9,33.9,32.7,31.7,30.9,29.9,29.5,28.9,27.7,25.8,22.9,19.3,15.5,13.8ppm
实施例80
Figure BDA0000375704840000892
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入丙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体。[α]20 D:5.50(c0.3,CHCl3).1HNMR(400MHz,CDCl3):δ9.25(s,1H),8.14(d,J=7.8Hz,1H),7.48(d,J=7.6Hz,1H),7.08(d,J=7.2Hz,1H),6.77(d,J=4.4Hz,1H),6.48(d,J=10.0Hz,1H),5.75-5.72(m,2H),5.55(m,1H),5.19(dd,J=17.2Hz,8.0Hz,1H),4.78-4.75(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.89-2.75(m,4H),2.65(m,1H),2.48(t,J=7.8Hz,3H),2.35-2.29(m,3H),1.88-1.85(m,3H),1.66(m,2H),0.86(m,3H),0.77(d,J=7.6Hz,3H),0.57(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.6,169.2,163.3,162.2,155.9,148.9,138.8,134.8,132.9,132.2,130.8,128.9,128.5,127.6,125.5,124.7,121.6,72.3,71.8,57.8,44.6,43.7,41.5,38.8,33.9,32.8,31.8,30.8,29.9,29.6,28.9,27.8,25.9,22.9,19.5,14.8ppm.
实施例81
Figure BDA0000375704840000901
0℃下，向反应物（0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入乙酰氯（0.05ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体[α]20 D:4.66(c0.6,CHCl3).1HNMR(400MHz,CDCl3):δ9.26(s,1H),8.15(d,J=7.8Hz,1H),7.49(d,J=7.6Hz,1H),7.09(d,J=7.2Hz,1H),6.79(d,J=4.4Hz,1H),6.47(d,J=10.0Hz,1H),5.73-5.70(m,2H),5.53(m,1H),5.18(dd,J=17.2Hz,8.0Hz,1H),4.77(m,2H),4.28(d,J=17.2Hz,1H),3.48(s,3H),2.88-2.78(m,4H),2.67(m,1H),2.49(t,J=7.8Hz,3H),2.36-2.33(m,3H),1.89-1.86(m,3H),0.88(m,3H),0.78(d,J=7.6Hz,3H),0.58(d,J=7.6Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ169.8,169.3,163.5,162.5,155.8,148.8,138.7,134.7,132.8,132.3,130.9,128.8,128.7,127.7,125.6,123.4,121.7,72.5,71.9,57.9,44.7,43.9,41.6,38.9,33.8,32.9,31.9,30.9,29.8,29.5,28.8,27.7,15.0ppm.
实施例82
Figure BDA0000375704840000902
0℃下，向反应物（30mg，0.063mmol）的无水DCM（2ml）液中加入重蒸NEt3（0.02ml），搅拌稍许，加入甲酰氯（0.02ml）。7h后，直接旋干溶剂，柱层析得淡黄色固体26mg，产率75%。[α]20 D:1.96(c0.1,CHCl3).1HNMR(400MHz,CDCl3):δ9.63(s,1H),9.23(s,1H),7.42(d,J=7.6Hz,1H),7.07(dd,J=14.4Hz,J=7.2Hz,1H),6.56(dd,J=7.6Hz,J=3.6Hz,1H),6.48(d,J=8Hz,1H),5.73(m,2H),5.52(dd,J=15.6Hz,J=6.8Hz,1H),5.12(m,1H),4.76(dd,J=10Hz,J=3.6Hz,1H),4.33(m,1H),2.72(m,2H),2.53(m,2H),2.34-2.29(m,3H),1.38(t,J=7.6Hz,1H),0.82(d,J=6.8Hz,3H),0.62(d,J=6.8Hz,3H)ppm.13CNMR(125MHz,CDCl3)δ176.5,169.8,169.4,163.6,162.6,155.7,148.8,138.5,134.7,132.5,132.3,130.9,128.8,127.8,125.6,124.3，121.8,72.5,71.7,56.9,44.8,43.6,41.5,36.0,30.8,23.7,18.9,16.5,14.6ppm.
实施例83HDAC生化活性的测定
1.测定原理：化合物生化活的性测定是根据其抑制HDAC酶的去乙酰化作用程度来确定的。本实验主要测定与肿瘤增殖及转移密切相关的HDAC1，HDAC2，HDAC3，HDAC8，HDAC11五种亚型HDAC酶的去乙酰化作用程度。用荧光标记的含有乙酰化的赖氨酸侧链的底物和HDAC酶作用之后，该荧光底物被去乙酰化。去乙酰化后的荧光标记底物被酶裂解后，释放出荧光物质，该荧光物质在360nm光的激发下产生460nm的发射光。
2.具体步骤：HDAC的底物用反应缓冲液稀释至200M（反应浓度为20M），将HDAC酶稀释至适当浓度，加入不同浓度待测化合物，37℃反应30分钟，然后加入相同体积的2倍浓度底物发展液（developer），室温孵育15分钟，最后用微孔板读板仪测定读数，激发光为360nm，发射光为460nm，数据用Prime4软件处理，结果见表1。本发明实施例中SAHA为辛二酰苯胺异羟肟酸（Suberoylanilidehydroxamicacid）；noactivity表示无活性。
表1HDAC生化活性测试结果
Figure BDA0000375704840000911
Figure BDA0000375704840000931
Figure BDA0000375704840000941
Figure BDA0000375704840000951
Figure BDA0000375704840000961
Figure BDA0000375704840000971
3.检测结果与分析：
上表中IC50是指被抑制一半时抑制剂的浓度（50%inhibitoryconcentration）。
从上表中结果可以看出：上述的化合物与阳性对照（SAHA）相比，具有显著的抑制与肿瘤增殖及转移密切相关的HDAC酶（主要为HDAC1，HDAC2，HDAC3，HDAC8，HDAC11）的去乙酰化作用的活性。而与肿瘤增殖及转移关系不大的HDAC7却没有作用。
本发明化合物结构改进后与专利公开CN102391359A相关化合物相比，结果见表2，显示出显著优势，相差几倍到数百倍不等。
表2本发明与CN102391359A结果比较表
Figure BDA0000375704840000972
Figure BDA0000375704840000981
本发明化合物六元环上有取代基与无取代基的相关化合物相比，在HDAC1上，有取代基显示出显著优势。结果见表3。
表3六元环上有取代基与无取代基的数据结果比较
Figure BDA0000375704840000982
实施例84检测化合物对癌细胞活性实验
实验原理：化合物抑制癌细胞生长用MTT方法来检测。MTT法的原理是，黄色的噻唑兰可透过细胞膜进入细胞内，活细胞线粒体中的琥珀脱氢酶能使外源性MTT还原为难溶于水的蓝紫色的针状Formazan结晶并沉积在细胞中，结晶能被二甲基亚砜（DMSO）溶解，用酶联免疫检测仪在490nm/570nm波长处检测其光吸收值，可间接反映细胞数量。
实验材料：所使用的癌细胞系为Hela（人***细胞），MCF-7（人乳腺癌细胞），BGC-823（人胃癌细胞），A549（人肺癌细胞），HT1080（人纤维肉瘤细胞），A431（人表皮鳞状细胞癌细胞），HUVEC（人脐静脉内皮细胞），DU145（人***癌细胞），lncap（***癌细胞），K562（人白血病细胞），U937（人白血病细胞），Pac-1（人胰腺癌细胞），MOLT-4（人急性淋巴母细胞白血病细胞），KBM-5(人白血病慢性髓细胞)，KBM5-T315I（人白血病慢性髓细胞），SGC-7901（人类胃癌细胞），N-87（人类胃癌细胞），Bel-7402（人肝癌细胞），Huh-7（人肝癌细胞）K562（人白血病细胞），H1975（人非小细胞肺腺癌细），HCC827（人非小细胞肺腺癌细胞），MDA-MB-231(乳腺癌细胞)。分别用DMEM+10%FBS培养基培养或者使用1640+10%FBS培养。
实验方法与结果分析：
实验组：190μl细胞悬液+10μl不同浓度的药物（终浓度为10-5～10-10M）
空白对照组：200μlPBS
阴性对照组：190μl细胞悬液+10μl2%DMSO（DMSO终浓度为0.1%）
阳性对照组：190μl细胞悬液+10μl不同浓度的化合物
a).细胞接种于96孔板，接种量为1500个/孔，190μl/孔，37℃5%的CO2培养箱培养过夜；
b).次日每孔加入10μl不同药物，药物终浓度为10-5～10-10M，设三个平行孔；37℃、5%的CO2培养箱孵育72小时；
c).每孔加入20μl5mg/ml的MTT，37℃5%的CO2培养箱孵育4小时；
d).弃上清，每孔加入100μl的DMSO，振荡；
e).570nm读数，计算细胞存活率，根据结果计算GI50，结果见表4-表5。
表4化合物对癌细胞测试结果（1）
Figure BDA0000375704840000991
Figure BDA0000375704840001001
Figure BDA0000375704840001011
Figure BDA0000375704840001021
Figure BDA0000375704840001031
Figure BDA0000375704840001041
Figure BDA0000375704840001051
表5化合物对癌细249胞测试结果（2）
Figure BDA0000375704840001061
Figure BDA0000375704840001071
Figure BDA0000375704840001081
Figure BDA0000375704840001091
Figure BDA0000375704840001101
Figure BDA0000375704840001111
Figure BDA0000375704840001121
上表中GI50表示的是细胞50%生长抑制所需的药物浓度（50%growth inhibition）。
从上表中结果可以看出：上述的药物与阳性对照（SAHA）相比，具有显著的抑制所列肿瘤细胞生长的活性。
本发明化合物与专利CN102391359A相关化合物相比，显示出显著优势，结果见表6-表7。
表6本发明化合物与专利CN102391359A化合物细胞活性对比（1）
Figure BDA0000375704840001122
表7本发明化合物与专利CN102391359A化合物细胞活性对比（2）
Figure BDA0000375704840001131
应当说明的是，上述的实施例仅用于说明而不是限制本发明的技术方案，任何等同的替换或更改，均应当视为包含在本发明的范围之内。

Claims (10)

1.一种通式（I）表示的化合物，其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物：
Figure FDA0000375704830000011
其中：R1基团为氢，C1-16烷基，C3-16环烷基，-(C=O)-（C1-16烷基），-(C=S)-（C1-16烷基）或-S-（C1-16烷基）；
R2基团为氢，C1-12烷基，-CH2-O-（C1-12烷基），-CH2-NH-（C1-12烷基），-CH2-S-（C1-12烷基），C6-12芳基，杂芳基，-CH2-（C6-12芳基）或-CH2-杂芳基；所述的C6-12芳基，杂芳基，-CH2-C6-12芳基，-CH2-杂芳基，可以含有1个或多个取代基，所述取代基可以是卤素、氨基、羟基、硝基、氰基、C1-12烷基、C1-12烷氧基、氨基C1-12烷基、酰基、酰氧基、硫代C1-12烷基、羧基或苯基；
R3、R4基团分别独立的选自氢，C1-12烷基，-O-（C1-12烷基），-NH-（C1-12烷基），-S-（C1-12烷基），C6-12芳基和杂芳基；
X和Y中有一个为C，另一个为N，或X和Y都为N；
R5，R6，R7基团分别独立地选自氢，卤素，-S-(C1-12烷基)，C1-12烷基和叔丁氧羰基；
Z为-CH2-、-NH-、-O-、-S-或
Figure FDA0000375704830000012
m为0，1，2，3，4，5，6。
2.根据权利要求1所述的通式（I）表示的化合物，其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物，其特征在于：
其中，
R1基团为氢，C1-16烷基，C3-16环烷基，-(C=O)-（C1-16烷基），-(C=S)-（C1-16烷基）或-S-（C1-16烷基）；
R2基团为氢，C1-12烷基，-CH2-O-（C1-12烷基），-CH2-NH-（C1-12烷基），-CH2-S-（C1-12烷基），C6-12芳基，杂芳基，-CH2-（C6-12芳基）或-CH2-杂芳基；
R3、R4基团分别独立的选自氢，C1-12烷基，-O-（C1-12烷基），-NH-（C1-12烷基），-S-（C1-12烷基），C6-12芳基和杂芳基；
X和Y中有一个为C，另一个为N，或X和Y都为N；
R5，R6，R7基团分别独立地选自氢，卤素，-S-(C1-12烷基)，C1-12烷基和叔丁氧羰基；
Z为-O-，-S-或
Figure FDA0000375704830000021
m为0，1或2。
3.根据权利要求1所述的通式（I）表示的化合物，其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物，其特征在于：
其中，
R1基团为氢或C1-16烷基；
R2基团为氢，C1-12烷基，或C6-12芳基；
R3、R4基团分别独立的选自氢，C1-12烷基，-O-（C1-12烷基），-NH-（C1-12烷基），-S-（C1-12烷基），C6-12芳基和杂芳基；
X为N；
Y为C；
R5，R6，R7基团分别独立地选自氢，F，-S-(C1-12烷基)；
Z为-S-或
Figure FDA0000375704830000022
m为0，1或2。
4.根据权利要求1所述的通式（I）表示的化合物，其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物，其特征在于：所述通式（I）表示的化合物选自：
Figure FDA0000375704830000023
Figure FDA0000375704830000031
Figure FDA0000375704830000041
Figure FDA0000375704830000051
Figure FDA0000375704830000061
Figure FDA0000375704830000071
Figure FDA0000375704830000081
Figure FDA0000375704830000091
Figure FDA0000375704830000101
Figure FDA0000375704830000121
Figure FDA0000375704830000131
Figure FDA0000375704830000141
Figure FDA0000375704830000161
Figure FDA0000375704830000171
Figure FDA0000375704830000181
Figure FDA0000375704830000191
Figure FDA0000375704830000201
Figure FDA0000375704830000211
Figure FDA0000375704830000221
Figure FDA0000375704830000261
Figure FDA0000375704830000271
Figure FDA0000375704830000281
5.一种制备权利要求1-4中任一项所述通式（I）表示的化合物的方法，其特征在于，包括以下步骤：
（1）将式（II）化合物在碱的作用下进行水解反应，得到式（III）化合物；反应过程如下所示：
Figure FDA0000375704830000282
（2）将式（III）化合物、式（IV）化合物和有机碱在缩合剂的作用下进行缩合反应，得到式V化合物；反应过程如下所示：
Figure FDA0000375704830000283
（3）将式（V）化合物和MsCl在有机碱的作用下进行缩合反应，得到式（VI）化合物；反应过程如下所示：
Figure FDA0000375704830000284
（4）将式（VI）化合物进行消除反应，得到式（VII）化合物；反应过程如下所示：
Figure FDA0000375704830000291
（5）将式（VII）化合物在碱的作用下进行水解反应，得到式（VIII）化合物；反应过程如下所示：
Figure FDA0000375704830000292
（6）将式（VIII）化合物、式（IX）化合物和有机碱在缩合剂的作用下进行缩合反应，得到式（X）化合物；反应过程如下所示：
Figure FDA0000375704830000293
（7）脱去式（X）化合物上的氨基保护基P及羧基保护基Q，然后在缩合剂和有机碱的作用下，分子内关环得到式（XI）化合物；反应过程如下所示：
Figure FDA0000375704830000294
（8）脱去式（XI）化合物上的保护基T，得到式（XII）化合物；反应过程如下所示：
Figure FDA0000375704830000301
（9）式（XII）化合物与R1-L化合物反应，得到式（XIII）化合物；反应过程如下所示：
Figure FDA0000375704830000302
其中，R1～R7、X、Y、Z、m的定义均与相应权利要求中相同；
P为氨基保护基团；
Q为酸基保护基团；
T为O、S、NH杂原子保护基团；
L选自卤素、OH、OMs、SH、MeO、t-butO。
6.根据权利要求5所述的方法，其特征在于：
所述步骤（2）、（3）、（6）（7）中所述的有机碱选自咪唑、三乙胺、二异丙基乙胺、哌啶、二甲基吡啶、LiHMDS、NaHMDS、KHMDS、N-甲基吗啉、DABCO或吡啶；
所述步骤（2）、（6）中所述的缩合剂均选自DCC、EDC、HATU、HOAt、HOBt、DEAD、HBTU或PyBOP；
所述的氨基保护基团P选自Boc、Cbz、Bn、Fmoc、Alloc、Tos、Trt、或Bn；
所述的酸基保护基团P选自TMSOH、叔丁基、乙基、甲基。
7.一种药物组合物，其包含治疗有效量的选自权利要求1-4中任一项所述的通式（I）表示的化合物、其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物，以及含有一种或多种药学上可接受的载体。
8.权利要求1-4中任一项所述的通式（I）表示的化合物、其异构体、外消旋体、药学上可接受的盐、结晶水合物、溶剂合物或它们的混合物，在制备预防或者治疗与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病药物中的用途。
9.根据权利要求8所述的用途，其特征在于：所述与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括癌症、神经变性疾病、疟疾和艾滋病。
10.根据权利要求9所述的用途，其特征在于：所述与组蛋白去乙酰化酶调节异常有关的哺乳动物疾病包括淋巴瘤、肺癌、胃癌、胰腺癌、乳腺癌、***癌、白血病和***。
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