WO2015027959A1 - 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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WO2015027959A1
WO2015027959A1 PCT/CN2014/085705 CN2014085705W WO2015027959A1 WO 2015027959 A1 WO2015027959 A1 WO 2015027959A1 CN 2014085705 W CN2014085705 W CN 2014085705W WO 2015027959 A1 WO2015027959 A1 WO 2015027959A1
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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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上海冠宇生物医药科技有限公司
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Priority to US14/915,740 priority patent/US10065990B2/en
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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(histone deacetylase,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(histone acetyltransferase,HAT)和组蛋白去乙酰化酶(histone deacetylase,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(histone deacetylases，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(histone deacetylase inhibitors，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不仅对多种血液系统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：
Figure PCTCN2014085705-appb-000001
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 PCTCN2014085705-appb-000002
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 PCTCN2014085705-appb-000003
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 PCTCN2014085705-appb-000004
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 PCTCN2014085705-appb-000005
Figure PCTCN2014085705-appb-000006
Figure PCTCN2014085705-appb-000007
Figure PCTCN2014085705-appb-000008
Figure PCTCN2014085705-appb-000009
Figure PCTCN2014085705-appb-000010
Figure PCTCN2014085705-appb-000011
Figure PCTCN2014085705-appb-000012
Figure PCTCN2014085705-appb-000013
Figure PCTCN2014085705-appb-000014
Figure PCTCN2014085705-appb-000015
Figure PCTCN2014085705-appb-000016
Figure PCTCN2014085705-appb-000017
Figure PCTCN2014085705-appb-000018
Figure PCTCN2014085705-appb-000019
Figure PCTCN2014085705-appb-000020
Figure PCTCN2014085705-appb-000021
Figure PCTCN2014085705-appb-000022
Figure PCTCN2014085705-appb-000023
Figure PCTCN2014085705-appb-000024
Figure PCTCN2014085705-appb-000025
Figure PCTCN2014085705-appb-000026
Figure PCTCN2014085705-appb-000027
Figure PCTCN2014085705-appb-000028
Figure PCTCN2014085705-appb-000029
Figure PCTCN2014085705-appb-000030
Figure PCTCN2014085705-appb-000031
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 PCTCN2014085705-appb-000032
(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 PCTCN2014085705-appb-000033
(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 PCTCN2014085705-appb-000034
(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 PCTCN2014085705-appb-000035
(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 PCTCN2014085705-appb-000036
(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 PCTCN2014085705-appb-000037
(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 PCTCN2014085705-appb-000038
(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 PCTCN2014085705-appb-000039
(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 PCTCN2014085705-appb-000040
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、正己烷或乙醚；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、前列腺癌、白血病和宫颈癌。
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,Cas No.:538-75-0)、EDCI[1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐,Cas No.:25952-53-8]、HATU(Cas No.:148893-10-1)、HOAt(Cas No.:39968-33-7)、HOBt(1-羟基-苯并-三氮唑,Cas No.:2592-95-2)、DEAD(偶氮二甲酸二乙酯，Cas No.:1972-28-7)、HBTU(Cas No.:94790-37-1),PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷,Cas No.: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 PCTCN2014085705-appb-000041
向反应物(2g，7.6mmol)的30ml THF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％。1H NMR(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
Figure PCTCN2014085705-appb-000042
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％。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000043
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 PCTCN2014085705-appb-000044
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％。1H NMR(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 PCTCN2014085705-appb-000045
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％。1H NMR(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 PCTCN2014085705-appb-000046
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％。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000047
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％。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000048
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(c 0.5,CHCl3).1H NMR(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＝14.4Hz J＝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.13C  NMR(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 PCTCN2014085705-appb-000049
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000050
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(c 0.7,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000051
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000052
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000053
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000054
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000055
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000056
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(c 0.1,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000057
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％)。1H NMR(400MHz,CDCl3):δ7.77(d,J＝7.6Hz,2H),7.61(m,2H),7.42-7.32(m 19H),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 PCTCN2014085705-appb-000058
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％。
1H NMR(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 PCTCN2014085705-appb-000059
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％。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000060
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％。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000061
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(c 0.5,CHCl3).1H NMR(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＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000062
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000063
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000064
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(50mL x 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2-24(682mg，80％)。1H NMR(400MHz,CDCl3):δ7.76(d,J＝7.6Hz,2H),7.60(m,2H),7.40-7.31(m 19H),5.84 and 5.76(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
Figure PCTCN2014085705-appb-000065
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％。1H NMR(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 PCTCN2014085705-appb-000066
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％。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000067
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％。1H NMR(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.13C NMR(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.
13.5
Figure PCTCN2014085705-appb-000068
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(c 0.5,CHCl3).1H NMR(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＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000069
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000070
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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16
16.1
Figure PCTCN2014085705-appb-000071
向反应物(7.6mmol)的30ml THF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。1H NMR(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 PCTCN2014085705-appb-000072
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000073
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 PCTCN2014085705-appb-000074
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。1H NMR(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.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.
16.5
Figure PCTCN2014085705-appb-000075
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。1H NMR(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.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.
16.6
Figure PCTCN2014085705-appb-000076
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。1H NMR(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＝15.6 Hz,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.13C NMR(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 PCTCN2014085705-appb-000077
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％。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000078
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.18(d,J＝7.6Hz,1H),7.89(d,J＝7.6Hz,1H),7.06(dd,J＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000079
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000080
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(c 0.7,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000081
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000082
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(c 0.6,CHCl3).1H NMR(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),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.13C NMR(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21
Figure PCTCN2014085705-appb-000083
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000084
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000085
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000086
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(c 0.1,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000087
向反应物(7.6mmol)的30ml THF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。1H NMR(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
Figure PCTCN2014085705-appb-000088
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。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000089
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 PCTCN2014085705-appb-000090
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。1H NMR(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＝7.6Hz,3H),1.40(s,9H)ppm.13C NMR(100MHz,CDCl3)δ164.8,162.1,157.4,156.0,148.9,148.8,138.1,133.9,126.3,124.2,123.5,121.7,121.0,79.7,52.1,45.9,28.3,14.6ppm.
25.5
Figure PCTCN2014085705-appb-000091
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000092
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000093
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000094
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.18(d,J＝7.6Hz,1H),7.89(d,J＝7.6Hz,1H),7.06(dd,J＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000095
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000096
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(c 0.7,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000097
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000099
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000100
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000101
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000102
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(c 0.1,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000103
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(50mL x 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。1H NMR(400MHz,CDCl3):δ7.77(d,J＝7.6Hz,2H),7.61(m,2H),7.42-7.32(m 19H),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 PCTCN2014085705-appb-000104
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。1H NMR(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
Figure PCTCN2014085705-appb-000105
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000106
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。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000107
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.18(d,J＝7.6Hz,1H),7.89(d,J＝7.6Hz,1H),,7.06(dd,J＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000108
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000109
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000110
向反应物(7.6mmol)的30ml THF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。1H NMR(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 PCTCN2014085705-appb-000111
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000112
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 PCTCN2014085705-appb-000113
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。1H NMR(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.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.
37.5
Figure PCTCN2014085705-appb-000114
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。1H NMR(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.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.
37.6
Figure PCTCN2014085705-appb-000115
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000116
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％。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000117
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.18(s,1H),7.41(s,1H),7.06(dd,J＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000118
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000119
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(c 0.7,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000120
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(c 0.3,CHCl3).1H NMR(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.13C  NMR(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 PCTCN2014085705-appb-000121
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000122
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000123
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000124
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000125
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(c 0.1,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000126
向反应物(7.6mmol)的30ml THF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。1H NMR(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 PCTCN2014085705-appb-000127
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。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000128
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 PCTCN2014085705-appb-000129
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000130
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。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000131
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000132
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000133
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ7.41(s,1H),7.21(s,1H),7.06(dd,J＝14.4Hz J＝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.13C NMR(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
Figure PCTCN2014085705-appb-000134
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000135
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(c 0.7,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000136
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(c 0.3,CHCl3).1H NMR(400 MHz,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.13C NMR(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
Figure PCTCN2014085705-appb-000137
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000138
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000139
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000140
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000141
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(c 0.1,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000142
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000143
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000144
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ7.88(d,J＝7.6Hz,1H),7.19(s,1H),,7.06(dd,J＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000145
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000146
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000147
向反应物(7.6mmol)的30ml THF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。1H NMR(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 PCTCN2014085705-appb-000148
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000149
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
Figure PCTCN2014085705-appb-000150
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。1H NMR(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.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.
58.5
Figure PCTCN2014085705-appb-000151
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。1H NMR(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.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.
58.6
Figure PCTCN2014085705-appb-000152
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000153
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。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000154
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.18(d,J＝7.6Hz,1H),7.49(d,J＝7.6Hz,1H),7.06(dd,J＝14.4Hz J＝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.13C NMR(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
Figure PCTCN2014085705-appb-000155
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000156
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(c 0.7,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000157
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000158
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000159
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000160
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000161
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000162
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(c 0.1,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000163
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000164
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000165
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.18(d,J＝7.6Hz,1H),7.39(d,J＝7.6Hz,1H),7.06(dd,J＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000166
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000167
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000168
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000169
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000170
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(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.18(d,J＝7.6Hz,1H),7.49(d,J＝7.6Hz,1H),7.06(dd,J＝14.4Hz J＝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.13C NMR(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 PCTCN2014085705-appb-000171
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000172
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000173
向反应物(7.6mmol)的30ml THF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。1H NMR(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
Figure PCTCN2014085705-appb-000174
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000175
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 PCTCN2014085705-appb-000176
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000177
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。1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000178
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。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000179
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。1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000180
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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
Figure PCTCN2014085705-appb-000181
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000182
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(c 0.7,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000183
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000184
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(c 0.6,CHCl3).1H NMR(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＝4.4 Hz,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.13C NMR(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 PCTCN2014085705-appb-000185
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(c 0.5,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000186
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(c 0.3,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000187
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(c 0.6,CHCl3).1H NMR(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.13C NMR(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 PCTCN2014085705-appb-000188
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(c 0.1,CHCl3).1H NMR(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.13C NMR(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Prime 4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(Suberoylanilide hydroxamic acid)；no activity表示无活性。
表1 HDAC生化活性测试结果
Figure PCTCN2014085705-appb-000189
Figure PCTCN2014085705-appb-000190
Figure PCTCN2014085705-appb-000191
Figure PCTCN2014085705-appb-000192
Figure PCTCN2014085705-appb-000193
Figure PCTCN2014085705-appb-000194
Figure PCTCN2014085705-appb-000195
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％inhibitory concentration)。
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 PCTCN2014085705-appb-000196
Figure PCTCN2014085705-appb-000197
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 PCTCN2014085705-appb-000198
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(人宫颈癌细胞)，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(人前列腺癌细胞)，lncap(前列腺癌细胞)，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：200μl PBS
阴性对照组：190μl细胞悬液+10μl 2％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20μl 5mg/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 PCTCN2014085705-appb-000199
Figure PCTCN2014085705-appb-000200
Figure PCTCN2014085705-appb-000201
Figure PCTCN2014085705-appb-000202
Figure PCTCN2014085705-appb-000203
Figure PCTCN2014085705-appb-000204
Figure PCTCN2014085705-appb-000205
表5 化合物对癌细249胞测试结果(2)
Figure PCTCN2014085705-appb-000206
Figure PCTCN2014085705-appb-000207
Figure PCTCN2014085705-appb-000208
Figure PCTCN2014085705-appb-000209
Figure PCTCN2014085705-appb-000210
Figure PCTCN2014085705-appb-000211
Figure PCTCN2014085705-appb-000212
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 PCTCN2014085705-appb-000213
表7 本发明化合物与专利CN102391359A化合物细胞活性对比(2)
Figure PCTCN2014085705-appb-000214
Figure PCTCN2014085705-appb-000215
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 PCTCN2014085705-appb-100001
    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 PCTCN2014085705-appb-100002
    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 PCTCN2014085705-appb-100003
    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 PCTCN2014085705-appb-100004
    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 PCTCN2014085705-appb-100005
    Figure PCTCN2014085705-appb-100006
    Figure PCTCN2014085705-appb-100007
    Figure PCTCN2014085705-appb-100008
    Figure PCTCN2014085705-appb-100009
    Figure PCTCN2014085705-appb-100010
    Figure PCTCN2014085705-appb-100011
    Figure PCTCN2014085705-appb-100012
    Figure PCTCN2014085705-appb-100013
    Figure PCTCN2014085705-appb-100014
    Figure PCTCN2014085705-appb-100015
    Figure PCTCN2014085705-appb-100016
    Figure PCTCN2014085705-appb-100017
    Figure PCTCN2014085705-appb-100018
    Figure PCTCN2014085705-appb-100019
    Figure PCTCN2014085705-appb-100020
    Figure PCTCN2014085705-appb-100021
    Figure PCTCN2014085705-appb-100022
    Figure PCTCN2014085705-appb-100023
    Figure PCTCN2014085705-appb-100024
    Figure PCTCN2014085705-appb-100025
    Figure PCTCN2014085705-appb-100026
    Figure PCTCN2014085705-appb-100027
    Figure PCTCN2014085705-appb-100028
    Figure PCTCN2014085705-appb-100029
    Figure PCTCN2014085705-appb-100030
    Figure PCTCN2014085705-appb-100031
  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 PCTCN2014085705-appb-100032
    (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 PCTCN2014085705-appb-100033
    (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 PCTCN2014085705-appb-100034
    (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 PCTCN2014085705-appb-100035
    (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 PCTCN2014085705-appb-100036
    (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 PCTCN2014085705-appb-100037
    (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 PCTCN2014085705-appb-100038
    (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 PCTCN2014085705-appb-100039
    (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 PCTCN2014085705-appb-100040
    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、前列腺癌、白血病和宫颈癌。
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CN107708719A (zh) * 2016-05-20 2018-02-16 恩库勒公司 作为组蛋白脱乙酰酶抑制剂的大环硫代酸酯前体药物
JP2019523750A (ja) * 2016-05-20 2019-08-29 オンキュアー，インコーポレイテッド ヒストンデアセチラーゼの阻害剤としての大環状分子のチオエステルプロドラッグ
JP2020125315A (ja) * 2016-05-20 2020-08-20 オンキュアー，インコーポレイテッド ヒストンデアセチラーゼの阻害剤としての大環状分子のチオエステルプロドラッグ
US11203602B2 (en) 2016-05-20 2021-12-21 Onkure, Inc. Thioester prodrugs of macrocycles as inhibitors of histone deacetylases

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US20160280736A1 (en) 2016-09-29
CN103524598A (zh) 2014-01-22
JP2016530286A (ja) 2016-09-29
CN106800589A (zh) 2017-06-06
US10065990B2 (en) 2018-09-04
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