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组蛋白去乙酰化酶抑制剂及其合成方法和制药用途

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专利汇可以提供组蛋白去乙酰化酶抑制剂及其合成方法和制药用途专利检索,专利查询,专利分析的服务。并且本 发明 包括式Ⅰ所示的组蛋白去乙酰化酶 抑制剂 ,其中R1~R8如 说明书 中所定义;本发明还包括这些化合物的合成方法,以及这些化合物在制备 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。,下面是组蛋白去乙酰化酶抑制剂及其合成方法和制药用途专利的具体信息内容。

1.具有通式I所示的化学结构的环肽化合物,及其药物上可接受的盐、外消旋体或溶剂合物,
其特征在于,其中通式I化合物中的R1、R2、R3、R4、R5、R6、R7、R8选择相应的基团以构成如下化合物:
2.制备权利要求1所述的环肽化合物的方法,其特征在于,该方法包括如下步骤:
(1)将式II化合物、式III化合物和有机在缩合剂的作用下进行缩合反应,得到式IV化合物;反应过程如下所示:
(2)将式IV化合物、式V化合物和有机碱在缩合剂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:
(3)脱去VI化合物上的基保护基P,然后在缩合剂和有机碱的作用下,分子内关环得到式I化合物;反应过程如下所示:
其中,
R1、R2、R3、R4、R5、R6、R7、R8同权利要求1中所述;
P为氨基保护基团。
3.根据权利要求2所述的方法,其特征在于,所述的缩合剂可以为DCC、EDC、HATU、HOAt、HOBt、DEAD、HBTU或PyBOP,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,所述的氨基保护基团P选自Boc、Cbz、Bn、Fmoc、Alloc、Tos、Tfa、Trt或Bn。
4.权利要求1中任一项所述的化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癌症药物中的应用。
5.根据权利要求4所述的应用,其特征在于,所述的“与组蛋白去乙酰化酶调节异常有关的哺乳动物癌症”包括淋巴瘤、癌、胃癌、胰腺癌、乳腺癌前列腺癌、白血病和宫颈癌。

说明书全文

组蛋白去乙酰化酶抑制剂及其合成方法和制药用途

技术领域:

[0001] 本发明属于药物化学领域,具体地涉及一类组蛋白去乙酰化酶抑制剂,以及这些化合物的合成方法和制药用途。背景技术:
[0002] 组蛋白去乙酰化酶(HDACs)是一组在细胞染色平、通过诱导组蛋白去乙酰化来调控包括染色质重组、转录活化或抑制、细胞周期、细胞分化及细胞凋亡等一系列生物学效应的酶,特别是与细胞活化后的基因转录表达调控有关。组蛋白去乙酰化酶抑制剂(HDAC inhibitor,HDACIs)则是一类抑制HDACs活性的化合物。
[0003] 组蛋白乙酰化作用在染色体的DNA转录,复制和修复过程中起着非常重要的作用。组蛋白去乙酰化酶抑制剂过去一直作为情绪稳定剂和抗癫痫药物使用,近年来,人们开始关注组蛋白去乙酰化酶抑制剂在神经变性疾病的靶向治疗作用。染色质的组蛋白乙酰化和去乙酰化是调节基因表达的关键环节之一,而异常的基因表达是肿瘤及一些遗传和代谢疾病发生的分子生物学基础。组蛋白的乙酰化程度,有组蛋白乙酰化酶(HAT)和组蛋白去乙酰化酶(HDAC)协调控制的。实验证明,HDAC抑制剂会使染色质组蛋白乙酰化水平提高,因此导致特定基因激活表达,相应的导致细胞的末端分化或癌细胞的凋亡。因此,HDAC已成为目前肿瘤化疗药物研发领域最热的靶标之一。
[0004] 目前已知组蛋白去乙酰化酶有18个不同的亚型,按种系分为4大类:Ⅰ(HDAC1、2、3、8)、Ⅱ(HDAC4、5、6、7、9、10)、Ⅲ(SIRT1-SIRT7)和Ⅳ(HDAC11)。其中Ⅰ、Ⅱ、Ⅳ为经典
2+
家族,是Zn 依赖性的HDAC。目前临床研究的绝大多数HDAC抑制剂能够抑制HDAC的多个
2+
亚型,这些亚型往往属于Zn 依赖性的HDAC家族。
[0005] 组蛋白去乙酰化酶抑制剂可以抑制细胞内HDAC的活性,使细胞内组蛋白的乙酰化程度增加,提高p21、p53等基因的表达,进而抑制肿瘤细胞的增殖,诱导其分化、凋亡。组蛋白去乙酰化酶抑制剂一般包括锌离子结合区,连接区和表面识别区三个部分。抑制剂与锌离子的直接作用是产生抑制活性所必须的。HDAC抑制剂主要包括以下四类:(1)短链脂肪酸,如丁酸,苯丁酸及其盐类化合物;(2)羟肟酸类,这是迄今研究最广泛的一类HDAC抑制剂,如辛二酰苯胺异羟肟酸(suberoylanilide hydroxamic acid,SAHA)和曲古抑菌素A(trichostatinA,TSA);(3)环四肽类,环肽类化合物是结构最为复杂的一类抑制剂,环肽类抑制剂的分子中基酸大环作为疏水的表面识别区,烷基链作为连接区,烷基链末端连接着一个锌离子结合基团,如trapoxin,HC-toxon,Apicidin,FK228和Largazole等;(4)苯甲酰胺类化合物,这类化合物的活性比一般的羟肟酸类和环肽类化合物低,但是对Ⅰ类HDAC具有较高的选择性。如MS-275,CI-994等。2006年,美国FDA批准默克公司的辛二酰苯胺异羟肟酸(suberoylanilide hydroxamic acid,SAHA)以vorinostat(Zolinza)上市,用于治疗转移性皮肤T细胞淋巴瘤(CTCL),这是第一个面世的组蛋白去乙酰化酶抑制剂类抗肿瘤药物。
[0006] FK228(romidepsin)是从紫色杆菌(Chrombacterium violaceum)的肉汤培养基中分离得到的双环四肽。FK228具有一个独特的双环结构,由4个氨基酸残基(L-Val,L-2-amino-2-butylenoic acid,D-Cys,D-Val)和(3S,4R-3-hydroxy-7-mercapto-4-heptenoic acid)通过二硫键形成双环内酯结构。其对HDAC1和HDAC2的选择性相似。计算机2+
模拟的结果表明,FK228的硫醇基团可以通过一个水分子与Zn 结合。美国FDA于2009年
11月6日批准环肽FK228以注射用药物Istodax(romidepsin)上市,也于治疗皮肤T淋巴细胞瘤(CTCL),成为继Zolinza之后,第二个上市的组蛋白去乙酰化酶抑制剂,其针对慢性淋巴细胞白血病、急性髓样白血病和其他实体瘤的研究正处于临床阶段。
[0007] 由于与组蛋白去乙酰化酶调节异常相关的疾病特别是相关的癌症的发病率高、预后差,并且现有的药物的疗效不确切、毒副作用较大,因此需要一种新的低毒高效的组蛋白去乙酰化酶抑制药物,本发明因此而来。

发明内容

[0008] 本发明提供一种环肽类的组蛋白去乙酰化酶抑制剂,用以解决现有药物疗效不确切、毒副作用较大的缺陷等问题。本发明还提供该种环肽类的组蛋白去乙酰化酶抑制剂的制备方法,以及药物用途。
[0009] 首先,本发明提供了具有通式Ⅰ所示的化学结构的环肽化合物,及其药物上可接受的盐、异构体、外消旋体、前体药物或溶剂合物:
[0010]
[0011] 其中,
[0012] R1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;上述的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,其取代基可以是卤素、氨基、羟基、硝基、氰基、C1-12烷基、C1-12烷基、氨基C1-12烷基、酰基、酰氧基、硫代C1-12烷基、羧基或苯基;
[0013] R2和R3基团独立地选自氢,C1-12烷基,-O-(C1-12烷基),-NH-(C1-12烷基),-S-(C1-12烷基),C6-12芳基或杂芳基;
[0014] R4基团为氢,C1-12烷基,-O-(C1-12烷基),-NH-(C1-12烷基),-S-(C1-12烷基),C6-12芳基或杂芳基;
[0015] R5基团为氢,C1-12烷基,C3-12环烷基,-O-(C1-12烷基),-NH-(C1-12烷基)或-S-(C1-12烷基);
[0016] R6,R7,R8基团独立地选自氢,C1-12烷基或叔丁氧羰基;
[0017] 代表单键或双键;
[0018] X为 其中R9基团是氢,C1-12烷基,-O-(C1-12烷基),-NH-(C1-12烷基),-S-(C1-12烷基),C6-12芳基,杂芳基,卤素,氨基,羟基,硝基,氰基或羧基;
[0019] 或者X为苯环,其上可以含有1个或多个取代基,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、苯基或杂环取代基。
[0020] 进一步地,上述的环肽化合物中
[0021] R2为H,
[0022] 部分是双键,
[0023] R4为氢或C1-12烷基。
[0024] 再进一步,上述的环肽化合物中
[0025] R3为氢或C1-12烷基;
[0026] R5为氢,C1-12烷基或C3-12环烷基;
[0027] R6,R7,R8基团独立地选自氢。
[0028] 再进一步,上述的环肽化合物中
[0029] R3为甲基;
[0030] R6,R7,R8基团均为氢;
[0031] X为 其中R9基团为氢。
[0032] 再进一步,所述化合物选自:
[0033]
[0034]
[0035]
[0036] 本发明还提供制备式Ⅰ所示的环肽化合物的方法,该方法包括如下步骤:
[0037] (1)将式Ⅱ化合物、式Ⅲ化合物和有机在缩合剂的作用下进行缩合反应,得到式Ⅳ化合物;反应过程如下所示:
[0038]
[0039] (2)将式Ⅳ化合物、式Ⅴ化合物和有机碱在缩合剂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:
[0040]
[0041] (3)脱去Ⅵ化合物上的氨基保护基P,然后在缩合剂和有机碱的作用下分子内关环得到式Ⅰ化合物;反应过程如下所示:
[0042]
[0043] 其中,
[0044] R1、R2、R3、R4、R5、R6、R7、R8同权利要求1中所述;
[0045] P为氨基保护基团。
[0046] 进一步地,所述的缩合剂可以为DCC、EDC、HATU、HOAt、HOBt、DEAD、HBTU或PyBOP;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;所述的氨基保护基团P选自Boc、Cbz、Bn、Fmoc、Alloc、Tos、Tfa、Trt或Bn。
[0047] 本发明还提供制备通式Ⅱ化合物的方法,该方法包括如下步骤:
[0048] (1)L-苹果酸经甲酯化、再与氢化钠和醋酸溶液反应得到化合物a,再与叔丁基二甲基氯烷和有机碱反应,替换为三甲基硅乙基保护基得化合物b;反应过程如下所示:
[0049]
[0050] (2)化合物b和樟脑磺酸反应得化合物c,再经氧化后得到的和化合物d,有机碱反应得到化合物e;反应过程如下所示:
[0051]
[0052] (3)化合物e和樟脑磺酸反应得到化合物f,然后化合物f、取代的硫代酸、三苯基膦和缩合剂反应得到化合物g,化合物g和樟脑磺酸反应得通式Ⅱ化合物;
[0053]
[0054] 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、、碳酸钠、碳酸氢钠、碳酸;必要的酸可以选自三氟乙酸、盐酸硫酸硝酸。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)。
[0055] 本发明还提供上述的化合物在制备预防或者治疗与去组蛋白乙酰化酶调节异常有关的哺乳动物疾病药物中的应用。
[0056] 进一步地,所述的与去组蛋白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、疟疾和糖尿病。
[0057] 更进一步地,所述的与去组蛋白乙酰化酶调节异常有关的哺乳动物疾病包括淋巴瘤、癌、胃癌、胰腺癌、乳腺癌前列腺癌、白血病和宫颈癌。
[0058] 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。
[0059] 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。
[0060] 本领域的普通技术人员应当知道下列术语或缩写的含义。
[0061] 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/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。
[0062] 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。
[0063] 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。
[0064] 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。
[0065] 术语“前体药物”指通过在血液中水解而活体内快速转化产生具有上述化学式的母体化合物的化合物。
[0066] 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:
[0067] 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);所述的氨基保护基团P选自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)。

具体实施方式

[0068] 为了更好的说明本发明的技术内容,下面结合具体实例对本发明作进一步阐述。
[0069] 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。
[0070] 实施例1
[0071]
[0072] 0℃条件下,向L-苹果酸(10g,74.6mmol)的甲醇(50mL)溶液中,缓慢滴加二氯亚砜(21.8mL),滴定完全后,室温下搅拌过夜,或者回流4小时。反应液直接旋干甲醇,再用饱和NaHCO3,饱和NaCl依次洗涤,无水NaSO4干燥,过滤,减压旋干直接投下一步,得到粗产品11.49g,产率95%。
[0073] 实施例2
[0074]
[0075] 无水无氧,氩气保护,0℃条件下,将醋酸(2.01mL,35.1mmol)溶解在5mL的THF中,缓慢滴入NaBH4的THF溶液中(20mL),平均两秒一滴。滴完后,反应一小时,再将苹果酸二甲酯(5g,30.5mmol)溶解在10mL的THF中,慢慢滴入反应瓶,然后置于室温下搅拌过夜。甲醇淬灭,硅藻土抽滤,旋干滤液,直接柱层析(石油醚∶乙酸乙酯=1∶1-纯乙酸乙酯),得到二醇3.03g,产率74%。
[0076] 实施例3
[0077]
[0078] 原料(5g,37.3mmol),DMAP(0.5g,0.41mmol)和咪唑(8.6g,126.3mmol)溶于100mL二氯甲烷中配成溶液。在浴下,缓慢滴加TBDMSCl(11.2g,74.6mmol)的二氯甲烷(10mL)溶液。滴完后,室温搅拌过夜。反应液依次用水,饱和食盐水洗涤。有机层用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析得到无色油状物9.2g,产率89%。
[0079] 实施例4
[0080]
[0081] 原料(5.43g,15.0mmol)溶于75mL四氢呋喃中。在冰浴下,缓慢滴加KOH(0.84g,15.0mmol)的水(5mL)溶液。滴完后,室温搅拌1小时。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,硅胶柱层析得到无色油状物4.96g,产率95%。
[0082] 室温搅拌,氩气保护下,上一步得到的化合物(3.48g,10.0mmol),DCC(0.5g,10mmol)和TMSEOH(8.6g,10mmol)溶于100mL二氯甲烷中配成溶液。在冰浴下,缓慢滴加TBDMSCl(11.2g,74.6mmol)的二氯甲烷(10mL)溶液。滴完后,室温搅拌过夜。反应液依次用水,饱和食盐水洗涤。有机层用无水硫酸钠干燥,蒸干溶剂,硅胶柱层析得到无色油状物
9.2g,产率89%。
[0083] [α]23D:-31.7(c = 1,CHCl3).1H NMR(400MHz,CDCl3):δ4.17-4.12(m,3H),3.58(dd,J=9.6,5.2Hz,1H),3.41(dd,J=9.6,7.2Hz,1H),2.61(dd,J=14.8,4.4Hz,
1H),2.33(dd,J = 14.8,8.0Hz,1H),0.98(dd,J = 9.6,7.2Hz,2H),0.89(s,9H),0.86(s,
13
9H),0.05(s,12H),0.04(s,9H)ppm. CNMR(100MHz,CDCl3):δ172.1,70.4,67.0,62.4,+
40.4,25.9,25.8,18.3,18.0,17.3,-4.4,-5.0,-5.4ppm.MS(EI,m/z):449(M+1).[0084] 实施例5
[0085]
[0086] 原料(9.2g,20.5mmol)溶解在50mL 50%的甲醇/二氯甲烷溶液中,冷却至-10℃下,将0.96g樟脑磺酸溶解在0.5mL甲醇中并加入到反应瓶中,保持-10℃,搅拌8小时。用5mL饱和碳酸氢钠淬灭反应,蒸干有机溶剂,二氯甲烷提取3次,水洗,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析纯化(石油醚∶乙酸乙酯=10∶1),得到无色油状物5.5g,
23 1
产 率 82 %。[α] D:-23.8(c = 0.6,CHCl3).H NMR(400MHz,CDCl3):δ4.22-4.17(m,
3H),3.61(m,1H),3.55(m,1H),2.53(dd,J = 6.2,2.2Hz,2H),1.92(dd,J = 7.2,5.6,
13
OH),0.99(t,J = 4.0Hz,2H),0.89(s,9H),0.10(s,3H),0.08(s,3H),0.04(s,9H)ppm. C NMR(100MHz,CDCl3):δ171.3,68.6,66.2,62.9,38.1,25.9,18.3,17.3,-1.52,-5.42ppm.+
MS(EI,m/z):335(M+1).
[0087] 实施例6
[0088]
[0089] 氩气保护,-78℃下,将3mL干燥DMSO缓慢加入到1.8mL重蒸草酰氯的二氯甲烷溶液中,搅拌30分钟后,将溶解有原料(3.5g,10.5mmol)的二氯甲烷溶液缓慢加入反应瓶。搅拌1小时后,缓慢滴加12mL干燥三乙胺,升至室温,反应1小时。饱和氯化铵淬灭,饱和食盐水洗涤,收集有机层,无水硫酸钠干燥,浓缩,得到淡黄色油状物3.32g,产率95%。
[0090] 实施例7
[0091]
[0092] 氩气保护下,原料(3.5g,10.5mmol)和四氮唑化合物(4.02g,10.5mmol)溶于四氢呋喃50mL中,冷却至-78℃,缓慢滴加2M NaHMDS的THF溶液(5.4mL,10.8mmol),反应1小时,饱和氯化铵淬灭,乙酸乙酯提取三次,污水硫酸钠干燥有机层,浓缩,柱层析纯化(5%乙酸乙酯/石油醚),得到无色油状物3.68g,产率72%。23 1
[0093] [α] D:-22.8(c=0.5,CHCl3).H NMR(400MHz,CDCl3):δ5.63(ddd,J=15.6,6.8,6.8Hz,1H),5.49(dd,J = 15.6,6.8Hz,1H),4.54(dd,J = 12.4,7.2Hz,1H),4.14(m,
2H),3.63(t,J=6.8Hz,2H),2.49(dd,J=14.4,8.4Hz,1H),2.38(dd,J=14.4,4.8Hz,
1H),2.22(dt,J = 13.4,6.8Hz,2H),0.98(m,2H),0.89(s,9H),0.85(s,9H),0.07-0.03(m,
13
21H)ppm. C NMR(100MHz,CDCl3):δ171.3,134.0,127.7,126.4(minor),70.7,66.1,62.8,
62.6,62.5,44.2,31.5,26.0,25.8,25.7,18.3,18.0,17.3,-1.5,-4.2,-4.3,-5.0,-5.3ppm+ +
.MS(EI,m/z):489(M+1).HRMS(ESI):calcd forC24H53O4Si3[MH]489.3253,found 489.3258.[0094] 实施例8
[0095]
[0096] 3.68g原料溶解在45mL二氯甲烷溶液中,冷却至-10℃,将0.36g樟脑磺酸溶解在5mL甲醇中并加入到反应瓶中,搅拌8小时。用5mL饱和碳酸氢钠淬灭反应,蒸干有机溶剂,水洗,二氯甲烷提取3次,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(15%乙酸乙酯/石油醚),得到无色油状物1.95g,产率70%。
[0097] 1H NMR(400MHz,CDCl3):δ5.58(m,2H),4.54(dd,J = 12.4,6.6Hz,1H),4.13(m,2H),3.65(m,2H),2.51(dd,J = 14.4,7.2Hz,1H),2.41(dd,J = 14.4,5.8Hz,
1H),2.27(dt,J = 12.4,6.0Hz,2H),0.97(m,2H),0.88(s,9H),0.05(s,15H)ppm.13C NMR(100MHz,CDCl3):δ171.3,135.6,126.9,70.4,62.6,61.7,44.1,35.5,25.8,25.7,
18.1,17.3,-1.5,-4.3,-5.0ppm.MS(EI,m/z):375(M++1).HRMS(ESI):calcd for C18H38NaO4Si2[MNa+]397.2206,found 397.2206.
[0098] 实施例9
[0099]
[0100] 冰浴,氩气保护下,将DEAD(3.74mL,8.23mmol)滴加到三苯基膦(2.16g,8.23mmol)的二氯甲烷溶液中,搅拌15分钟,将原料(1.95g,5.20mmol),硫代正辛酸(1.32g,8.23mmol)依次加入反应瓶,室温搅拌过夜。依次用饱和碳酸氢钠溶液,饱和食盐水洗涤,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(10%乙酸乙酯/石油醚),得到无色油状物2g,产率74%。
[0101] [α]23D:-11.2(c = 0.30,CHCl3).1H NMR(400MHz,CDCl3):δ5.62(m,1H),5.51(dd,J = 15.6,6.4Hz,1H),4.54(dd,J = 13.6,6.0Hz,1H),4.14(m,2H),2.90(t,J = 7.2Hz,2H),2.54-2.46(m,3H),2.38(dd,J = 14.4,5.2Hz,1H),2.27(dd,J = 14.0,
7.2Hz,2H),1.65(t,J = 7.2Hz,2H),1.30-1.27(m,8H),0.99(m,2H),0.96-0.89(12H),
13
0.07-0.03(m,15H)ppm. C NMR(100MHz,CDCl3):δ199.5,199.3(minor),171.3,
171.0(minor),134.3,128.4,127.3(minor),70.4,65.9(minor),62.6,44.2,
43.9(minor),32.0,31.6,28.9,28.3,27.9(minor),25.8,25.7,22.6,18.0,17.3,+
14.0,-1.5,-4.2,-4.4,-5.0ppm.MS(EI,m/z):517(M +1).HRMS(ESI):calcd for C26H52NaO4SSi2[MNa+]539.3023,found 539.3027.
[0102] 实施例10
[0103]
[0104] 冰浴,氩气保护下,将DEAD(3.74mL,8.23mmol)滴加到三苯基膦(2.16g,8.23mmol)的二氯甲烷溶液中,搅拌15分钟,将原料(1.95g,5.20mmol),保护的3-羟基硫代丙酸(1.33g,8.23mmol)依次加入反应瓶,室温搅拌过夜。依次用饱和碳酸氢钠溶液,饱和食盐水洗涤,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(10%乙酸乙酯/石油醚),得到无色油状物3.46g,产率81%。
23 1
[0105] [α] D:-17.4(c = 0.30,CHCl3).H NMR(400MHz,CDCl3):δ5.62(m,1H),5.51(dd,1H),4.54(dd,1H),4.14(t,2H),3.67(t,2H),2.90(t,2H),2.54-2.46(m,4H),
2.38(d,2H),119(s,9H),0.99(m,2H),0.96-0.89(s,9H),0.21(s,6H),0.07-0.03(m,9H)
13
ppm. C NMR(100MHz,CDCl3):δ199.5,173.1,130.1,128.2,81.8,72.6,67.2,62.8,45.3,+
43.9,37.9,31.0,28.2,25.9,22.9,1.8ppm.MS(EI,m/z):519(M+1).
[0106] 实施例11
[0107]
[0108] 原料(2g,3.87mmol)溶解在50%的甲醇/二氯甲烷(20mL)溶液中,冷却至0℃,将0.91g樟脑磺酸溶解在1mL甲醇中并加入到反应瓶中,搅拌过夜。用5mL饱和碳酸氢钠淬灭反应,蒸干有机溶剂,水洗,二氯甲烷提取3次,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(20%乙酸乙酯/石油醚),得到无色油状物1.12g,产率71%。
[0109] [α]23D:-10.1(c = 0.95,CHCl3).1H NMR(400MHz,CDCl3):δ5.70(m,1H),5.55(dd,J=15.5,6.1Hz,1H),4.49(m,1H),4.20(t,J=8.6Hz,2H),2.94(d,J=4Hz,1H),
2.91(t,J = 7.2Hz,2H),2.56-2.45(m,4H),2.30(m,2H),1.65(m,2H),1.29-1.26(m,8H),+
1.00(t,J=8.6Hz,2H),0.88(t,J=6.8Hz,3H),0.03(s,9H)ppm.MS(EI,m/z):403(M+1).+
HRMS(ESI):calcd forC20H38NaO4SSi[M Na]425.2158,found 425.2159.
[0110] 实施例12
[0111]
[0112] 冰浴,氩气保护下,将DEAD(1.12mL,2.74mmol)滴加到三苯基膦(0.65g,2.74mmol)的二氯甲烷溶液中,搅拌15分钟,将原料(0.585g,1.56mmol),硫代乙酸(0.4g,
2.74mmol)依次加入反应瓶,室温搅拌过夜。依次用饱和碳酸氢钠溶液,饱和食盐水洗涤,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(10%乙酸乙酯/石油醚),得到无色油状物
0.948g,产率80%。
[0113] [α]23D:-31.2(c = 0.60,CHCl3).1H NMR(400MHz,CDCl3):δ5.72(m,1H),5.63(dd,1H),4.39(m,1H),4.10(t,2H),2.91(d,1H),2.82(t,2H),2.56-2.45(m,4H),
2.29(m,2H),1.61(m,2H),1.00(t,2H),0.81(t,3H),0.03(s,9H)ppm.MS(EI,m/z):
433(M++1).
[0114] 实施例13
[0115]
[0116] 原料(0.839g,1.94mmol)溶解在50%的甲醇/二氯甲烷(10mL)溶液中,冷却至0℃,将0.455g樟脑磺酸溶解在1mL甲醇中并加入到反应瓶中,搅拌过夜。用5mL饱和碳酸氢钠淬灭反应,蒸干有机溶剂,水洗,二氯甲烷提取3次,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(20%乙酸乙酯/石油醚),得到无色油状物0.481g,产率78%。
[0117] [α]23D:-21.9(c = 0.50,CHCl3).1H NMR(400MHz,CDCl3):δ5.72(m,1H),5.52(dd,1H),4.45(m,1H),4.160(t,2H),2.89(d,1H),2.90(t,2H),2.51-2.43(m,4H),
2.35(m,2H),1.61(m,2H),1.00(t,2H),0.81(t,3H),0.02(s,9H)ppm.MS(EI,m/z):
319(M++1).
[0118] 实施例14
[0119]
[0120] 冰浴,氩气保护下,将DEAD(1.35mL,3.29mmol)滴加到三苯基膦(0.78g,3.29mmol)的二氯甲烷溶液中,搅拌15分钟,将原料(1.102g,1.88mmol),硫代乙酸(0.758g,3.29mmol)依次加入反应瓶,室温搅拌过夜。依次用饱和碳酸氢钠溶液,饱和食盐水洗涤,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(10%乙酸乙酯/石油醚),得到无色油状物1.312g,产率68%。
[0121] [α]23D:-12.9(c = 0.50,CHCl3).1H NMR(400MHz,CDCl3):δ5.67(m,1H),5.54(dd,1H),4.54(dd,6.0Hz,1H),4.12(t,2H),2.91(t,2H),2.54-2.46(m,4H),2.38(dd,
1H),2.27(dd,2H),1.65(t,2H),1.30-1.27(m,20H),0.99(m,3H),0.96-0.89(12H),+
0.07-0.03(m,15H)ppm.MS(EI,m/z):587(M+1).
[0122] 实施例15
[0123]
[0124] 原料(1.172g,2mmol)溶解在50%的甲醇/二氯甲烷(10mL)溶液中,冷却至0℃,将0.52g樟脑磺酸溶解在1mL甲醇中并加入到反应瓶中,搅拌过夜。用5mL饱和碳酸氢钠淬灭反应,蒸干有机溶剂,水洗,二氯甲烷提取3次,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(20%乙酸乙酯/石油醚),得到无色油状物0.766g,产率81%。23 1
[0125] [α] D:-11.0(c = 0.50,CHCl3).H NMR(400MHz,CDCl3):δ5.70(m,1H),5.65(dd,1H),4.42(m,1H),4.09(t,2H),2.90(d,1H),2.83(t,2H),2.51-2.40(m,4H),
2.26(m,2H),1.61(m,2H),1.29-1.21(m,20H),1.00(t,2H),0.82(t,3H),0.03(s,9H)ppm.+
MS(EI,m/z):473(M+1).
[0126] 实施例16
[0127]
[0128] 冰浴,氩气保护下,将DEAD(0.81mL,1.97mmol)滴加到三苯基膦(0.47g,1.97mmol)的二氯甲烷溶液中,搅拌15分钟,将原料(0.66g,113mmol),硫代苯乙酸(0.3g,
1.97mmol)依次加入反应瓶,室温搅拌过夜。依次用饱和碳酸氢钠溶液,饱和食盐水洗涤,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(10%乙酸乙酯/石油醚),得到无色油状物
0.611g,产率61%。
[0129] [α]23D:-21.1(c = 0.50,CHCl3).1H NMR(400MHz,CDCl3):δ7.33(m,2H),7.26(m,1H),7.22(d,2H),5.62(m,1H),5.51(dd,1H),4.52(dd,6.0Hz,1H),4.12(t,2H),
3.66(s,2H),2.51-2.46(m,4H),2.32(dd,1H),2.27(dd,2H),1.62(t,2H),0.91(m,3H),+
0.96-0.81(12H),0.07-0.03(m,15H)ppm.MS(EI,m/z):509(M+1).
[0130] 实施例17
[0131]
[0132] 原料(0.61g,1.2mmol)溶解在50%的甲醇/二氯甲烷(7mL)溶液中,冷却至0℃,将0.3g樟脑磺酸溶解在1mL甲醇中并加入到反应瓶中,搅拌过夜。用5mL饱和碳酸氢钠淬灭反应,蒸干有机溶剂,水洗,二氯甲烷提取3次,收集有机层,无水硫酸钠干燥,浓缩,柱层析纯化(20%乙酸乙酯/石油醚),得到无色油状物0.412g,产率87%。
[0133] [α]23D:-35.0(c=0.50,CHCl3).1H NMR(400MHz,CDCl3):δ7.33(m,2H),7.26(m,1H),7.22(d,2H),5.62(m,1H),5.51(dd,1H),4.52(dd,6.0Hz,1H),4.12(t,2H),3.66(s,
2H),2.51-2.46(m,4H),2.32(dd,1H),2.26(m,2H),1.61(m,2H),1.00(t,2H),0.82(t,3H),+
0.03(s,9H)ppm.MS(EI,m/z):395(M+1).
[0134] 实施例18
[0135]
[0136] 氩气保护,0℃条件下,向原料(0.942g,2.34mmol))的二氯甲烷溶液中,依次加入 Fmoc-L-Val-OH(2.376g,7mmol),EDCI(1.342g,7mmol),DMAP(0.057g,0.468mmol),DIPEA(1.2mL,7mmol),室温下搅拌过夜。饱和NaHCO3溶液,用乙酸乙酯萃取三次,合并有机相,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1)。得到透明液体1.45g,产率86%。
[0137] [α]23D:-13.5(c=0.52,CHCl3).1H NMR(400MHz,CDCl3):δ7.76(d,J=7.6Hz,2H),7.60(m,2H),7.40(dd,J=7.4Hz,2H),7.31(dd,J=7.4Hz,2H),5.84and 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),1.30-1.27(m,8H),0.97-0.83(m,11H),0.03(s,9H)ppm.13C NMR(100MHz,CDCl3):
δ199.2,170.9,169.5,156.2,144.0,141.3,133.3,128.4,127.7,127.6,127.1,125.1,
120.0,71.8,67.1,63.1,58.9,47.1,44.1,39.7,32.2,31.6,31.4,29.7,28.9,28.1,25.6,
23.0,22.6,20.1,19.0,17.4,14.0,-1.30ppm.MS(EI,m/z):723(M++1).HRMS(ESI):calcd forC40H57NNaO7SSi[MNa+]746.3523,found746.3521.
[0138] 实施例19
[0139]
[0140] 氩气保护,0℃条件下,向原料(0.235g,0.58mmol)的二氯甲烷溶液中,依次加入Fmoc-L-Ala-OH(0.363g,1.17mmol),DCC(0.241g,1.17mmol),DMAP(0.014g,0.12mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1)。得到透明液体0.328g,产率81%。
[0141] [α]23D:-18.4(c=0.95,CHCl3).1H NMR(400MHz,MeOD):δ7.75(d,J=7.5Hz,2H),7.59(m,2H),7.39(t,J = 7.4Hz,2H),7.31(t,J = 7.4Hz,2H),5.76(m,1H),5.67(m,
1H),5.6-5.4(m,2H),4.37(m,3H),4.20(m,4H),2.89(m,2H),2.70(dd,J = 7.9Hz,15.7Hz,
1H),2.60(m,1H),2.51(m,2H),2.28(m,2H),1.64(m,3H),1.41(d,J = 7.1Hz,2H),1.27(m,
13
8H),0.98(t,J=8.5Hz,2H),0.87(m,3H)ppm. C NMR(100MHz,CDCl3):δ199.34,172.36,
171.74,169.56,155.52,143.95,141.31,132.75,129.45,128.32,127.68,127.06,125.08,
119.96,71.71,68.55,67.02,63.12,49.68,47.20,44.12,41.62,39.70,32.18,31.59,
28.89,28.18,27.89,25.62,22.55,18.71,17.35,14.01,0.99,-1.54ppm.MS(EI,m/z):
+ +
718(M+Na).HRMS(ESI):calcd for C38H53NO7Ssi[MNa]718.3204,found 718.3203.[0142] 实施例20
[0143]
[0144] 氩气保护,0℃条件下,向原料(0.255g,0.63mmol)的二氯甲烷溶液中,依次加入Fmoc-D-Ala-OH(0.392g,1.26mmol),DCC(0.260g,1.26mmol),DMAP(0.016g,0.13mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1)。得到透明液体0.378g,产率86%。
[0145] [α]23D:-0.29(c = 3.13,CHCl3).1H NMR(400MHz,CDCl3):δ7.75(d,J =7.5Hz,2H),7.59(m,2H),7.39(t,J = 7.4Hz,2H),7.30(d,J = 7.4Hz,2H),5.77(m,
1H),5.66(m,1H),5.6-5.4(m,2H),4.36(m,3H),4.25-4.1(m,4H),2.90(m,2H),2.68(dd,J = 8.6Hz,15.7Hz,1H),2.58(m,1H),2.51(m,3H),2.30(m,2H),1.63(m,2H),1.40(d,J = 7.1Hz,3H),1.27(m,8H),0.98(t,J = 8.6Hz,2H),0.87(m,3H),0.04(s,9H).ppm.13C NMR(125MHz,CDCl3):δ199.23,171.91,169.64,155.54,143.95,143.83,
141.31,132.71,128.23,127.69,127.06,125.10,119.96,71.75,68.56,67.03,63.09,
53.39,49.73,47.19,44.12,41.60,39.68,32.22,31.59,28.89,27.84,25.63,22.56,
18.75,17.39,14.01,1.00,-1.54ppm.MS(EI,m/z):718(M++Na).HRMS(ESI):calcd forC38H53NO7Ssi[MNa+]718.3204,found 718.3206.
[0146] 实施例21
[0147]
[0148] 氩气保护,0℃条件下,向原料(0198g,0.5mmol)的二氯甲烷溶液中,依次加入Fmoc-L-ter-Leu-OH(0.265g,0.75mmol),DCC(0.155g,0.75mmol),DMAP(0.013g,0.1mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1),得到透明液体0.209g,产率57%。
[0149] [α]23D:-11.8(c=0.92,CHCl3).1H NMR(400MHz,CDCl3):δ7.74(d,J=7.4Hz,2H),7.58(d,J = 7.4Hz,2H),7.39(t,J = 7.4Hz,2H),7.31(t,J = 7.4Hz,2H),5.82(m,
1H),5.66(dd,J = 7.1Hz14Hz,1H),5.51(m,1H),5.42(d,J = 9.7Hz,1H),4.45-4,3(m,
3H),4.22(t,J = 7Hz,2H),4.15(m,3H),2.87(m,2H),2.72(dd,J = 7.4Hz 15.6Hz,1H),
2.58(dd,J=6Hz 15.6Hz,1H),2.51(t,J=7.5Hz,2H),1.63(m,3H),1.27(m,8H),1.02(t,
13
2H),0.98(s,9H),0.87(t,J= 6.7Hz,3H).ppm. CNMR(100MHz,CDCl3):δ199.10,170.34,
169.47,155.93,143.82,143.73,141.21,133.60,128.25,127.60,126.97,125.01,71.80,
67.35,66.92,63.00,61.95,53.34,47.13,44.02,39.59,34.96,32.07,31.50,28.80,+
27.79,26.69,25.52,22.47,17.20,13.95ppm.MS(EI,m/z):760(M+Na).HRMS(ESI):calcd +
for C41H59NO7SSi[MNa]760.3674,found 760.3675.
[0150] 实施例22
[0151]
[0152] 氩气保护,0℃条件下,向原料(0.25g,0.63mmol)的二氯甲烷溶液中,依次加入Fmoc-L-Phe-OH(0.728,1.88mmol),EDCI(0.36g,1.88mmol),DMAP(0.015g,0.126mmol),DIPEA(0.3mL,1.88mmol),室温下搅拌过夜。饱和NaHCO3溶液,用乙酸乙酯萃取三次,合并有机相,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1),得到透明液体0.35g,产率72%。
[0153] [α]23D:-21.2(c=0.88,CHCl3).1H NMR(400MHz,CDCl3):δ7.77(d,J=7.6Hz,2H),7.56(m,2H),7.40(dd,J = 7.6Hz,2H),7.31(dd,J = 7.6Hz,2H),7.28-7.25(m,3H),
7.11(d,J = 6.8Hz,2H),5.85and 5.75(m,1H),5.65(dd,J = 14.0,6.8Hz,1H),5.50and
5.37(dd,J = 15.6,7.2Hz,1H),5.27(m,1H),4.63(m,1H),4.43(dd,J = 10.0,7.4Hz,
1H),4.31(m,1H),4.22-4.14(m,3H),3.10(m,2H),2.89(t,J = 7.2Hz,1H),2.68(dd,J= 15.6,7.2Hz,1H),2.57(m,1H),2.52(t,J = 7.6Hz,2H),2.30(dt,J = 13.6,6.8Hz,
2H),1.64(m,2H),1.33-1.26(m,8H),0.97(t,J = 8.6Hz,2H),0.83-0.89(m,3H),0.03(s,
9H)ppm.13C NMR(125MHz,CDCl3):δ199.10,170.42,169.51,155.49,143.87,141.29,
135.73,133.26,129.54,128.46,128.18,127.69,127.05,125.15,119.97,72.03,67.80,
66.95,63.09,60.33,54.71,47.15,44.11,39.61,38.10,32.22,31.60,28.89,28.10,
25.62,22.58,20.97,17.32,14.20,-1.30ppm.MS(EI,m/z):772(M++1).HRMS(ESI):calcd forC44H57NNaO7SSi[MNa+]794.3523,found 794.3524.
[0154] 实施例23
[0155]
[0156] 氩气保护,0℃条件下,向原料(0.26g,0.646mmol)的二氯甲烷溶液中,依次 加 入 Fmoc-3-(1- 基 )-L-丙 氨 酸 (0.596g,1.3mmol),DCC(0.268g,1.3mmol),DMAP(0.016g,0.13mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1),得到透明液体0.397g,产率75%。
[0157] [α]23D:-12.3(c=3.3,CHCl3).1H NMR(400MHz,CDCl3):δ8.15(d,J=8.2Hz,1H),7.86(d,J = 7.9Hz,1H),7.77(m,3H),7.52(m,4H),7.40(m,4H),7.29(m,2H),5.62(m,
2H),5.37(d,J=8.2Hz,1H),5.29(dd,J=7.3Hz,15.4Hz,1H),4.85(dd,J=7Hz,14.5Hz,
1H),4.33(m,2H),4.15(m,3H),3.61(dd,J = 6.8Hz,14.2Hz,1H),3.52(dd,J = 6.8Hz,
14.0Hz,1H),2.86(t,J = 7.2Hz,2H),2.59(dd,J = 7.4Hz,15.6Hz,1H),2.51(m,3H),
2.25(m,2H),1.64(m,3H),1.27(m,8H),0.96(t,J = 8.4Hz,2H),0.88(m,3H),0.02(s,9H).
13
ppm. C NMR(100MHz,CDCl3):δ199.32,170.80,169.57,155.55,143.82,143.77,141.27,
133.89,133.05,132.23,132.16,128.87,128.01,127.70,127.06,126.46,125.79,125.23,
124.85,123.58,119.98,72.15,67.73,63.14,46.87,44.17,39.58,35.74,32.33,28.92,+
28.56,27.87,25.66,22.60,17.32,-1.51ppm.MS(EI,m/z):844(M+Na).HRMS(ESI):calcd +
for C48H59NO7SSi[MNa]844.3674,found 844.3676.
[0158] 实施例24
[0159]
[0160] 氩气保护,0℃条件下,向原料(0.226g,0.56mmol)的二氯甲烷溶液中,依次加入 Fmoc-L-Tyr(tBu)-OH(0.516g,1.12mmol),DCC(0.231g,1.12mmol),DMAP(0.014g,0.112mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=
20∶1-10∶1),得到透明液体0.355g,产率75%。
[0161] [α]23D:-10.4(c 0.62,CHCl3).1H NMR(400MHz,CDCl3):δ7.76(d,J = 7.5Hz,2H),7.57(m,2H),7.40(dd,J=7.4Hz,2H),7.31(dd,J=7.4Hz,2H),7.00(d,J=8.2Hz,
2H),6.88(d,J = 8.2Hz,2H),5.90and 5.76(m,1H),5.63(dd,J = 13.6,6.4Hz,1H),
5.48(dd,J=15.6,7.2Hz,1H),5.27(d,J=8.0Hz,1H),4.60(m,1H),4.43(dd,J=10.4,
7.2Hz,1H),4.31(t,J = 7.2Hz,1H),4.22-4.14(m,3H),3.05(m,2H),2.89(t,J = 7.0Hz,
2H),2.68(dd,J= 15.2,7.2Hz,1H),2.56(m,1H),2.52(t,J = 7.6Hz,2H),2.31(dt,J =
13.6,6.8Hz,2H),1.62(m,2H),1.31(s,9H),1.29-1.26(m,8H),0.98(t,J = 8.0Hz,2H),
13
0.83-0.89(m,3H),0.03(s,9H)ppm. C NMR(100MHz,CDCl3):δ199.11,170.39,169.46,
155.38,154.46,143.83,143.73,141.25,133.33,130.29,129.92,128.13,127.64,127.01,
125.07,123.97,119.91,78.27,72.00,66.91,63.08,54.66,47.12,44.08,39.59,37.48,
32.19,31.84,31.55,28.84,27.79,25.57,22.60,17.28,13.99,-1.58ppm.MS(EI,m/z):
+ +
788(M+1).HRMS(ESI):calcd for C48H65NO8SSi[MNa]866.4098,found 866.4093.[0162] 实施例25
[0163]
[0164] 将100mg(0.25mmol,1eq)原料与148.6mg Fmoc-Gly-OH(0.5mmol,2eq)溶于2ml无水二氯甲烷中,加入5.6mg DMAP(0.05mmol,0.2eq),于0℃下加入103mgDCC(0.5mmol,2eq),0℃下反应1h后过滤除去固体,减压旋干溶剂,柱层析(乙酸乙酯∶石油醚=1∶10)得到无色液体170mg,产率100%.
[0165] (400MHz,CDCl3)δ7.75(d,2-H),7.60(d,2-H),7.39(t,2-H),7.32(t,2-H),5.78(m,1H),5.69(q,1H),5.52(dd,1H),5.37(t,H),4.39(d,2H),
4.22(t,1H),4.20(t,2H),3.98(d,2H),2.89(t,2H),2.70(dd,1H),2.58(dd,1H),2.55(t,
2H),2.29(m,2H),1.64(t,2H),1.28(m,8H),0.99(t,2H),0.87(t,3H),0.02(s,9H);13C NMR(500MHz,CDCl3)δ199.3,169.6,168.9,156.1,143.8,141.2,132.8,128.2,127.6,
127.0,125.0,119.9,71.7,67.1,63.1,47.0,44.1,39.5,32.2,31.5,28.8,27.7,25.6,+
22.5,17.3,14.0,-1.69;MS(ESI)m/z 460.2(100%)(M-Fmoc).
[0166] 实施例26
[0167]
[0168] 将 100mg(0.25mmol,1eq) 原 料 与 162mg Fmoc-N-Me-Gly-OH(0.5mmol,2eq)溶于2ml无水二氯甲烷中,加入5.6mg DMAP(0.05mmol,0.2eq),于0℃下加入
103mgDCC(0.5mmol,2eq),0℃下反应1h后过滤除去固体,减压旋干溶剂,柱层析(乙酸乙酯∶石油醚=1∶10),得到无色液体170mg,产率100%.
[0169] (400MHz,CDCl3)δ7.75(d,2-H),7.60(d,2-H),7.39(t,2-H),7.32(t,2-H),5.78(m,1-H),5.69(q,1-H),5.37(t,1-H),4.91and 4.89(q,
1-H)4.39(d,1-H),4.22(t,1-H),4.20(t,1-H),3.98(d,2-H),2.89(m,5-H),2.70(dd,1-H),
2.58(dd,1-H),2.55(t,2-H),2.29(m,2-H),1.64(t,2-H),1.28(m,8-H),0.99(t,2-H),
0.87(t,3-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.2,170.7,170.5,156.1,143.8,
141.2,132.8,128.2,127.6,127.0,125.0,119.9,71.7,67.8,63.1,54.2,47.0,44.1,42.8,
39.5,32.2,31.5,28.8,27.7,25.6,22.5,17.3,14.0,-1.69;MS(ESI)m/z 488.2(100 % )(M-Fmoc)+.
[0170] 实施例27
[0171]
[0172] 将100mg(0.25mmol,1eq)原料与167mg Fmoc-Abu-OH(0.5mmol,2eq)溶于2ml无水二氯甲烷中,加入5.6mg DMAP(0.05mmol,0.2eq),于0℃下加入103mgDCC(0.5mmol,2eq),0℃下反应1h后过滤除去固体,减压旋干溶剂,柱层析(乙酸乙酯∶石油醚=1∶10)得到无色液体163mg,产率90%.
[0173] (400MHz,CDCl3)δ7.75(d,2-H),7.60(d,2-H),7.39(t,2-H),7.32(t,2-H),5.80(m,1-H),5.69(q,1-H),5.50(t,1-H),5.39(d,1-H),4.38(d,
2-H),4.24(m,1-H),4.19(t,1-H),4.15(t,2-H),2.89(t,2-H),2.70(dd,1-H),2.58(dd,
1-H),2.55(t,2-H),2.29(m,2-H),1.90(m,1-H),1.64(t,2-H),1.60(t,2-H),1.28(m,
8-H),0.99(t,2-H),0.87(m,6-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.2,171.1,
169.6,155.7,143.8(2C),141.2(2C),132.8,128.2,127.6(2C),127.0(2C),125.0(2C),
119.9(2C),71.7,66.9,63.1,54.7,47.0,44.1,39.6,32.1,31.5,28.8(2C),27.7,25.6,+
22.5,17.3,14.0,9.2,-1.58(3C);MS(ESI)m/z 488.1(100%)(M-Fmoc).
[0174] 实施例28
[0175]
[0176] 将150mg(0.375mmol,1eq)原料与278mg Fmoc-Gly-OH(0.75mmol,2eq)溶于4ml无水二氯甲烷中,加入8.4mg DMAP(0.075mmol,0.2eq),于0℃下加入155mgDCC(0.75mmol,2eq),0℃下反应1h后过滤除去固体,减压旋干溶剂,柱层析(乙酸乙酯∶石油醚=
1∶10),得到无色液体270mg,产率95.2%.
[0177] (400MHz,CDCl3)δ7.75(d,2-H),7.60(d,2-H),7.39(t,2-H),7.32(t,2-H),5.80(m,1-H),5.67(q,1-H),5.53(m,2-H),4.48(t,1-H),4.38(d,
2-H),4.16(t,1-H),4.12(t,2-H),2.89(t,2-H),2.70(dd,1-H),2.58(dd,1-H),2.55(m,
4-H),2.14(m,1-H),2.14(s,3-H),1.96(m,1-H),1.62(t,2-H),1.28(m,8-H),0.99(t,
2-H),0.87(t,3-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.1,170.6,169.4,155.7,
143.8(2C),141.2(2C),132.8,128.2,127.6(2C),127.0(2C),125.0(2C),119.9(2C),71.9,
66.8,63.1,53.1,47.0,44.1,39.5,32.1,31.9,31.5,29.7,28.8(2C),27.7,25.5,22.4,+
17.2,15.4,13.9,-1.63(3C);MS(ESI)m/z 778.3(100%)(M+Na).
[0178] 实施例29
[0179]
[0180] 将150mg(0.375mmol,1eq)原料与266mg Fmoc-Leu-OH(0.75mmol,2eq)溶于4ml无水二氯甲烷中,加入8.4mg DMAP(0.075mmol,0.2eq),于0℃下加入155mgDCC(0.75mmol,2eq),0℃下反应1h后过滤除去固体,减压旋干溶剂,柱层析(乙酸乙酯∶石油醚=1∶10)得到无色液体292mg,产率100%.
[0181] (400MHz,CDCl3)δ7.75(d,2-H),7.60(d,2-H),7.39(t,2-H),7.32(t,2-H),5.78(m,1-H),5.65(q,1-H),5.52(dd,1-H),5.21(d,1-H),4.48(t,
1-H),4.38(d,2-H),4.16(t,1-H),4.12(t,2-H),2.87(t,2-H),2.70(dd,1-H),2.58(dd,
1-H),2.50(t,3-H),2.28(q,2-H),1.66(m,6-H),1.28(m,8-H),0.99(m,9-H),0.87(t,
3-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.2,171.8,169.6,155.8,143.9(2C),
141.2(2C),132.9,128.2,127.6(2C),127.0(2C),125.0(2C),119.9(2C),71.7,66.9,63.1,
52.4,47.0,44.1,41.7,39.7,32.1,31.6,31.5,28.8(2C),27.8,25.6,24.7,22.9,22.5,+
21.8,17.2,14.0,-1.58(3C);MS(ESI)m/z 760.3(100%)(M+Na).
[0182] 实施例30
[0183]
[0184] 将 210mg(0.52mmol,1eq) 原 料 与 554mg Fmoc-N-Me-Val-OH(1.57mmol,3eq)溶于10ml无水二氯甲烷中,加入12.6mg DMAP(0.1mmol,0.2eq),于0℃下加入
300mgEDCI(1.57mmol,3eq)和0.26ml DIPEA(1.57mmol,3eq),0℃下反应3h后15ml二氯甲烷稀释,依次用稀HCl(20mlX2),饱和NaCl20mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂,柱层析(乙酸乙酯∶石油醚=1∶10)得到无色液体320mg,产率83.3%.
[0185] (400MHz,CDCl3)δ7.75(d,2-H),7.60(d,2-H),7.39(t,2-H),7.32(t,2-H),5.75(m,1-H),5.60(q,1-H),5.51(dd,1-H),4.48(t,1-H),4.38(d,
1-H),4.26(m,1-H),4.11(m,3-H),2.87(m,5-H),2.70(dd,1-H),2.58(dd,1-H),2.50(t,
3-H),2.28(q,2-H),2.15(m,1-H),1.63(m,2-H),1.28(m,8-H),0.99(d,2-H),0.97(m,
2-H),0.83(t,6-H),0.72(d,1-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.2,169.9,
169.6,155.8,143.9(2C),141.2(2C),132.9,128.2,127.6(2C),127.0(2C),125.0(2C),
119.9(2C),71.1,67.5,64.3,63.1,52.4,47.3,44.1,39.7,32.1,31.6,31.5,28.8(2C),
27.8,25.6,24.7,22.9,22.5,21.8,19.5,18.8,17.2,14.0,-1.58(3C);MS(ESI)m/z +
760.3(100%)(M+Na).
[0186] 实施例31
[0187]
[0188] 氩气保护,0℃条件下,向化合物(0.185g,0.58mmol)的二氯甲烷溶液中,依次加入Fmoc-L-Ala-OH(0.363g,1.17mmol),DCC(0.241g,117mmol),DMAP(0.014g,0.12mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1)。得到透明液体0.252g,产率68%。
[0189] [α]23D:-9.4(c 0.6,CHCl3).1H NMR(400MHz,MeOD):δ7.74(d,2H),7.57(m,2H),7.34(t,2H),7.30(t,2H),5.72(m,1H),5.61(m,1H),5.6-5.4(m,2H),4.37(m,3H),4.20(m,
4H),2.89(m,2H),2.70(dd,1H),2.60(m,1H),2.51(m,2H),2.28(m,2H),1.64(m,3H),
13
1.41(d,2H),0.98(t,2H),0.87(m,3H)ppm. C NMR(100MHz,CDCl3):δ194.9,173.1,171.5,
155.9,143.6,143.2,130.2,126.8,126.4,125.2,120.5,73.8,67.2,61.5,47.1,38.3,+
37.6,30.6,30.4,22.9,18.9.1.8ppm.MS(EI,m/z):662(M+Na).
[0190] 实施例32
[0191]
[0192] 氩气保护,0℃条件下,向化合物(0.331g,0.7mmol)的二氯甲烷溶液中,依次加入Fmoc-L-Ala-OH(0.436g,1.4mmol),DCC(0.29g,1.4mmol),DMAP(0.017g,0.144mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1)。得到透明液体0.394g,产率71%。
[0193] [α]23D:-21.9(c 0.6,CHCl3).1H NMR(400MHz,MeOD):δ7.80(d,2H),7.56(m,2H),7.39(t,2H),7.28(t,2H),5.71(m,1H),5.61(m,1H),5.1(m,2H),4.48(t,1H),4.36(m,
3H),2.87(m,2H),2.70(dd,1H),2.60(m,1H),2.41(m,2H),2.28(m,2H),1.64(m,2H),
13
1.41(d,2H),1.26(m,20H),0.98(t,2H),0.88(m,3H)ppm. C NMR(100MHz,CDCl3):δ199.5,
173.5,172.6,155.8,144.6,144.3,130.2,128.9,125.2,124.3,120.5,73.5,67.5,67.3,
61.2,47.5,44.2,38.5,32.1,29.5,29.3,26.1,22.1,18.6,14.0,1.5ppm.MS(EI,m/z):
+
794(M+1).
[0194] 实施例33
[0195]
[0196] 氩气保护,0℃条件下,向化合物(0.304g,0.77mmol)的二氯甲烷溶液中,依次加入Fmoc-L-Ala-OH(0.48g,1.54mmol),DCC(0.32g,1.54mmol),DMAP(0.019g,0.154mmol),室温下搅拌过夜。过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=20∶1-10∶1),得到透明液体0341g,产率59%。
[0197] [α]23D:-29.5(c 0.6,CHCl3).1H NMR(400MHz,MeOD):δ7.86(d,2H),7.59(m,2H),7.37(t,2H),7.28(m,3H),7.32(m,2H),7.25(m,2H),5.72(m,1H),5.61(m,1H),5.1(m,
2H),4.48(t,1H),4.36(m,3H),3.69(s,2H),2.87(m,2H),2.70(dd,1H),2.60(m,1H),
13
2.42(m,2H),2.28(m,2H),1.41(d,2H),1.26(m,20H),0.98(t,2H),0.88(m,3H)ppm. C NMR(100MHz,CDCl3):δ203.2,173.4,172.1,155.8,144.6,144.3,139.2,130.1,129.4,
128.9,127.6,126.5,125.9,125.2,124.3,120.5,73.5,67.5,67.3,61.2,47.5,44.2,38.5,+
32.1,29.5,29.3,26.1,22.1,18.6,14.0,1.5ppm.MS(EI,m/z):716(M+1).[0198] 实施例34
[0199]
[0200] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1),得到无色液体0.776g,产率78%。
[0201] 氩气保护下,上一步得到的化合物(0.283g,0.57mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.234g,0.69mmol),HATU(0.325g,0.86mmol),HOAt(0.117g,
0.86mmol),DIPEA(0.3ml,1.71mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.378g,产率81%。
23 1
[0202] [α] D:-7.57(c 7.5,CHCl3).H NMR(400MHz,CDCl3):δ8.60(s,1H),8.10(s,1H),6.60(m,2H),5.77(m,1H),5.62(dd,J = 13.7Hz 7.2Hz,1H),5.49(dd,J = 13.7Hz
7.5Hz,1H),5.42(m,1H),4.58(m,3H),4.14(t,J = 8.6Hz,2H),2.85(t,J = 7.2Hz,2H),
2.68(dd,J=15.7Hz 7.7Hz,2H),2.50(t,J=7.5Hz,2H),2.26(q,J=7.1Hz,2H),2.18(m,
1H),1.80(d,J = 7Hz,3H),1.60(m,2H),1.46(m,8H),1.26(m,9H),0.96(m,3H),0.86(t,J
13
=6.1Hz,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.25,170.70,169.55,164.33,
159.26,148.88,133.30,129.39,129.21,128.30,124.75,71.77,63.11,57.16,44.08,
39.63,38.55,32.13,31.59,31.55,28.84,28.28,27.82,25.58,22.52,18.91,17.58,+
17.26,13.99,13.94,0.96,-1.57ppm.MS(EI,m/z):847(M+Na).HRMS(ESI):calcd for +
C39H64N4O9S2Si[MNa]847.3779,found 847.3777.
[0203] 实施例35
[0204]
[0205] 原料(0.328g,0.47mmol)溶解于二氯甲烷中,加入哌啶(0.23ml,2.35mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.178g,产率80%。
[0206] 氩气保护下,上一步得到的化合物(0.218g,0.46mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.188g,0.552mmol),HATU(0.262g,0.69mmol),HOAt(0.094g,
0.69mmol),DIPEA(0.23ml,1.38mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=2∶1),得到固体0.280g,产率76%。
[0207] [α]23D:-7.4(c 2.33,CHCl3).1H NMR(400MHz,CDCl3):δ8.58(s,1H),8.09(s,1H),6.77(d,J = 6.8Hz,1H),6.63(q,J = 7.0Hz,1H),5.73(m,1H),5.61(dd,J = 7Hz,
13.5Hz,1H),5.48(m,2H),4.59(m,3H),4.14(m,2H),2.86(t,J = 7.1Hz,2H),2.68(dd,J= 7.8Hz,15.8Hz,1H),2.57(m,1H),2.50(m,2H),2.27(dd,J = 7Hz,14Hz,2H),1.79(d,J= 7.0Hz,3H),1.62(m,2H),1.47(m,8H),1.40(d,J = 7.1Hz,3H),1.21(m,9H),0.96(t,J
13
= 8.8Hz,2H),0.86(m,3H),0.02(s,9H)ppm. C NMR(100MHz,CDCl3):δ199.24,171.72,
169.61,165.74,163.94,159.25,148.95,132.73,129.68,129.13,128.28,124.78,71.72,
63.14,53.39,48.46,44.12,42.35,39.65,38.58,32.17,31.58,29.66,28.88,28.32,+
27.87,25.62,22.54,18.33,17.33,14.17,-1.54ppm.MS(EI,m/z):797(M++1),819(M+Na).+
HRMS(ESI):calcd for C37H60N4O9S2Si[MNa]819.3463,found 819.3464.
[0208] 实施例36
[0209]
[0210] 原料(0.375g,0.53mmol)溶解于二氯甲烷中,加入哌啶(0.27ml,2.7mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.176g,产率70%。
[0211] 氩气保护下,上一步得到的化合物(0.15g,0.32mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.130g,0.38mmol),HATU(0.183g,0.48mmol),HOAt(0.066g,
0.48mmol),DIPEA(0.16ml,0.96mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=2∶1)。得到固体0.184g,产率72%。
[0212] [α]23D:-15.8(c 1.56,CHCl3).1H NMR(400MHz,CDCl3):δ8.60(s,1H),8.07(s,1H),6.81(d,J=7.2Hz,1H),6.63(m,1H),5.74(m,1H),5.61(dd,J=7.9Hz,12.5Hz,1H),
5.49(m,2H),4.59(m,3H),4.12(t,J = 7.8Hz,2H),2.87(t,J = 7.3Hz,2H),2.66(dd,J = 8.6Hz,15.8Hz,1H),2.56(m,1H),2.51(m,2H),2.27(m,2H),1.78(d,J = 7Hz,3H),
1.62(m,2H),1.46(s,9H),1.38(d,J = 7.1Hz,3H),1.25(m,8H),0.95(t,J = 8.6Hz,2H),
13
0.85(m,3H),0.01(s,9H).ppm. C NMR(125MHz,CDCl3):δ199.41,171.88,169.73,163.96,
159.30,155.63,148.86,132.71,130.00,129.00,128.11,124.89,71.76,63.12,53.39,
48.49,44.11,39.61,38.58,32.19,31.58,28.87,28.30,27.80,25.62,22.55,18.36,+ +
17.34,14.01,0.98,-1.56ppm.MS(EI,m/z):797(M+1),819(M+Na).HRMS(ESI):calcd +
forC37H60N4O9S2Si[MNa]819.3463,found 819.3463.
[0213] 实施例37
[0214]
[0215] 原料(0.29g,0.4mmol)溶解于二氯甲烷中,加入哌啶(0.2ml,2mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。
得到无色液体0.146g,产率71%。
[0216] 氩气保护下,上一步得到的化合物(0.119g,0.23mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.095g,0.28mmol),HATU(0.131g,0.35mmol),HOAt(0.048g,
0.35mmol),DIPEA(0.12ml,0.69mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=2∶1)。得到固体0.151g,产率78%。
23 1
[0217] [α] D:11.8(c 2.5,CHCl3).H NMR(400MHz,CDCl3):δ8.92(s,1H),8.08(s,1H),6.69(d,J = 9.3Hz,1H),6.56(m,1H),5.76(m,1H),5.58(m,2H),5.46(dd,J = 7.8Hz
15.4Hz,1H),4.57(d,J = 5.8Hz,2H),4.44(d,J = 9.3Hz,1H),4.11(t,J = 8.6Hz,2H),
2.83(t,J = 7.2Hz,2H),2.66(dd,J = 7.2Hz 15.6Hz),2.56-2.44(m,3H),2.23(m,2H),
1.77(d,J = 7Hz,3H),1.59(m,2H),1.23(m,8H),0.93(m,11H),0.83(t,3H),-0.03(s,
13
9H).ppm. C NMR(100MHz,CDCl3):δ199.20,170.20,169.54,164.16,159.38,148.88,
133.59,129.57,128.35,124.75,123.81,71.87,63.05,60.24,44.09,39.65,38.56,35.38,
32.13,31.55,28.85,28.30,27.86,25.85,22.51,17.29,13.98,-1.56ppm.MS(EI,m/+ + +
z):839(M+1),861(M+Na).HRMS(ESI):calcd for C40H66N4O9S2Si[MNa]861.3933,found
861.3936.
[0218] 实施例38
[0219]
[0220] 原料(0.221g,0.29mmol)溶解于二氯甲烷中,加入哌啶(0.14ml,1.43mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.142g,产率89%。
[0221] 氩气保护下,上一步得到的化合物(0.142g,0.26mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.106g,0.31mmol),HATU(0.148g,0.39mmol),HOAt(0.053g,
0.39mmol),DIPEA(0.13ml,0.78mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=2∶1),得到固体0.152g,产率67%。
[0222] [α]23D:8.5(c 1.27,CHCl3).1H NMR(400MHz,CDCl3):δ8.50(s,1H),8.11(s,1H),7.20-7.06(m,5H),6.56(m,2H),5.73(m,1H),5.59(dd,J = 14.1Hz 7Hz,1H),5.45(m,
1H),5.30(s,1H),4.89(m,1H),4.61(d,J = 5.8Hz,2H),4.15(t,J = 8.6Hz,2H),3.13(d,J = 5.6Hz,2H),2.88(t,J = 7.2Hz,2H),2.66(m,1H),2.52(m,1H),2.30(m,2H),1.79(d,J=7Hz,3H),1.62(m,8H),1.27(s,9H),0.97(t,J=8.6Hz,2H),0.87(t,J=6.7Hz,3H),
13
0.03(s,9H). C NMR(100MHz,CDCl3):δ199.13,170.28,169.48,164.01,159.16,148.97,
135.68,133.26,129.58,129.16,128.37,126.96,124.69,72.06,63.07,53.36,44.12,
39.61,37.75,32.19,31.56,28.87,28.31,27.83,25.60,22.51,17.34,13.96,-1.55ppm.+ + +
MS(EI,m/z):873(M+1),895(M+Na).HRMS(ESI):calcd for C43H64N4O9S2Si[MNa]895.3776,found895.3778.
[0223] 实施例39
[0224]
[0225] 原料(0.396g,0.68mmol)溶解于二氯甲烷中,加入哌啶(0.24ml,2.4mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.23g,产率80%。
[0226] 氩气保护下,上一步得到的化合物(0.212g,0.35mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.145g,0.42mmol),HATU(0.2g,0.53mmol),HOAt(0.073g,
0.53mmol),DIPEA(0.18ml,1.05mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=2∶1),得到固体0.241g,产率75%。
[0227] [α]23D:5.4(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.47(s,1H),8.13(d,J = 8.4Hz,1H),8.07(s,1H),7.80(d,J = 8.0Hz,1H),7.71(d,J = 8.0Hz,1H),7.45(m,2H),7.26(m,2H),6.73(d,J = 7.5Hz,1H),6.51(m,1H),5.6-5.42(m,3H),5.17(dd,J =
7.4Hz,15.5Hz,1H),4.99(m,1H),4.58(d,J = 5.8Hz,2H),4.09(m,2H),3.61(dd,J =
5.9Hz,14Hz,1H),3.48(m,2H),2.52(m,3H),2.38(dd,J = 6.5Hz,15.6Hz,1H),2.21(m,
2H),1.75(d,J = 7Hz,3H),1.62(m,2H),1.47(s,9H),1.24(m,8H),0.92(t,J = 6.7Hz,
13
2H),0.85(m,3H),0.02(s,9H).ppm. C NMR(100MHz,CDCl3):δ199.10,170.66,170.24,
169.47,165.65,164.37,159.20,155.82,148.83,133.76,132.61,132.26,132.12,130.06,
128.98,128.02,126.30,125.60,125.17,124.62,123.65,71.89,70.98,62.92,61.65,
60.27,53.55,44.05,42.29,39.44,38.51,35.15,32.11,31.52,28.81,28.30,27.78,+
25.56,22.61,17.22,13.97,-1.58ppm.MS(EI,m/z):923(M+1).HRMS(ESI):calcd for +
C47H66N4O9S2Si[MNa]945.3933,found 945.3934.
[0228] 实施例40
[0229]
[0230] 原料(0.464g,0.55mmol)溶解于二氯甲烷中,加入哌啶(0.27ml,2.75mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.2962g,产率87%。
[0231] 氩气保护下,上一步得到的化合物(0.296g,0.48mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.197g,0.576mmol),HATU(0.274g,0.72mmol),HOAt(0.098g,
0.72mmol),DIPEA(0.24ml,1.44mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=2∶1),得到固体0.192g,产率42%。
[0232] [α]23D:4.7(c 0.86,CHCl3).1H NMR(400MHz,CDCl3):δ8.44(s,1H),8.08(s,1H),6.95(d,J = 8.3Hz,2H),6.76(d,J = 8.3Hz,2H),6.58(m,1H),6.50(d,J= 7.0Hz,
1H),5.75(m,1H),5.59(m,2H),5.47(dd,J=7.5Hz,15.3Hz,1H),4.83(m,1H),4.55(m,2H),
4.14(t,J=8.5Hz,2H),3.07(m,2H),2.88(t,J=7.2Hz,2H),2.65(dd,J=7.2Hz,15.6Hz,
1H),2.51(m,3H),2.29(m,2H),1.77(d,J = 7.1Hz,3H),1.62(m,2H),1.47(m,8H),1.28(s,
13
18H),0.96(t,J = 8.6Hz,2H),0.85(m,3H),0.02(s,9H).ppm. CNMR(125MHz,CDCl3):
δ199.15,170.24,169.48,163.80,159.05,154.21,148.74,133.35,130.39,130.01,
128.15,124.071,78.49,72.02,63.09,53.02,44.08,39.58,38.55,36.82,32.19,31.54,+
28.83,28.29,27.79,25.57,22.51,17.27,14.02,-1.60ppm.MS(EI,m/z):945(M+1).+
HRMS(ESI):calcdfor C47H72N4O10S2Si[MNa]967.4351,found 967.4354.
[0233] 实施例41
[0234]
[0235] 将170mg(0.25mmol,1eq)原料溶于2ml无水乙腈中峰回路转入0.1ml哌啶,常温下搅拌2h后减压旋干溶剂,加入5ml无水二氯甲烷,于0℃加入85mg(S)-2-(2-(((tert-butoxycarbonyl)amino)--methyl)thiazole-4-carboxamido)butanoic acid(0.25mmol,1eq),然后依次加入51mgHOAT(0.375mmol,1.5eq),143mg HATU(0.375mmol,1.5eq)与
0.12ml DIPEA(0.75mmol,3eq).投毕,将反应升到常温反应2h后,加入15ml二氯甲烷稀释,依次用稀HCl(20mlX2),饱和NaCl20mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析(乙酸乙酯∶石油醚=1∶2)得到155mg无色液体,产率81.7%.
[0236] (400MHz,CDCl3)δ8.68(s,1-H),7.96(s,1-H),7.11(s,1-H),6.66(q,1-H),5.97(m,1-H),5.66(q,1-H),5.55(q,1-H),5.42(dd,1-H),4.50(d,
2-H),4.07(t,2-H),3.99(t,2-H),2.82(t,2-H),2.70(dd,1-H),2.58(dd,1-H),2.55(t,
2-H),2.22(m,2-H),1.73(d,3-H),1.57(t,2-H),1.55(s,9-H),1.28(m,8-H),0.99(t,2-H),
0.87(t,3-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.2,170.2,169.6,169.0,164.7,
159.6,155.8,148.6,132.7,131.1,128.9,128.1,124.8,80.2,71.7,63.1,60.3,47.0,
44.0,42.2,39.5,38.5,32.1,31.5,28.8(2C),28.3,27.7,25.6,22.5,20.9,17.3,14.9,+
14.0,13.8,-1.69(3C);MS(ESI)m/z 805.2(100%)(M+H).
[0237] 实施例42
[0238]
[0239] 将180mg(0.35mmol,1eq)原料溶于2ml无水乙腈中峰回路转入0.1ml哌啶,常温下搅拌2h后减压旋干溶剂,加入5ml无水二氯甲烷,于0℃加入179mg(S)-2-(2-(((tert-butoxycarbonyl)amino)-methyl)thiazole-4-carboxamido)butanoic acid(0.525mmol,1.5eq),然后依次加入95mgHOAT(0.7mmol,2eq),266mg HATU(0.7mmol,2eq)与0.12ml DIPEA(q.4mmol,4eq).投毕,将反应升到常温反应2h后,加入15ml二氯甲烷稀释,依次用稀HCl(20mlX2),饱和NaCl20mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析(乙酸乙酯∶石油醚=1∶2)得到110mg无色液体,产率81.7%.
[0240] (400MHz,CDCl3)δ8.68(s,1-H),8.85(d,1-H),8.01(s,1-H),5.78(m,1-H),5.60(m,4-H),5.13(q,1-H),4.56(s,2-H),4.13(t,2-H),3.01(s,
2-H),2.88(t,3-H),2.66(m,1-H),2.56(m,3-H),2.50(q,2-H),2.28(m,1-H),1.93(d,3-H),
1.55(s,11-H),1.28(m,8-H),0.99(t,2-H),0.87(t,3-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.3,170.2,169.6,169.0,164.7,159.6,155.8,148.6,132.7,131.1,128.9,
128.1,124.8,80.3,71.4,63.0,47.0,44.1,42.2,39.7,38.5,32.2,31.5,28.8(2C),28.3,+
27.8,25.6,22.5,17.3,14.0,13.8,12.4,-1.69(3C);MS(ESI)m/z 833.2(100%)(M+H).[0241] 实施例43
[0242]
[0243] 将160mg(0.225mmol,1eq)原料溶于2ml无水乙腈中峰回路转入0.1ml哌啶,常温下搅拌2h后减压旋干溶剂,加入5ml无水二氯甲烷,于0℃加入85mg(S)-2-(2-(((tert-butoxycarbonyl)amino)--methyl)thiazole-4-carboxamido)butanoic acid(0.25mmol,1.1eq),然后依次加入5lmgHOAT(0.375mmol,1.5eq),143mg HATU(0.375mmol,1.5eq)与
0.12ml DIPEA(0.75mmol,3eq).投毕,将反应升到常温反应2h后,加入15ml二氯甲烷稀释,依次用稀HCl(20mlX2),饱和NaCl20mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析(乙酸乙酯∶石油醚=1∶2)得到120mg无色液体,产率81.7%.
[0244] (400MHz,CDCl3)δ8.60(s,1-H),8.10(s,1-H),6.72(d,1-H),6.62(q,1-H),5.77(m,1-H),5.64(q,1-H),5.48(q,1-H),5.42(m,1-H),4.60(d,
3-H),4.14(t,2-H),2.86(t,2-H),2.68(dd,1-H),2.56(dd,1-H),2.50(t,2-H),2.27(q,
2-H),1.92(m,1-H),1.83(d,3-H),1.77(m,1-H),1.60(t,1-H),1.55(s,9-H),1.28(m,
8-H),0.99(t,2-H),0.87(q,6-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.3,171.1,
169.6,164.1,159.3,148.9,133.0,129.5,129.2,128.3,124.8,80.2,71.7,63.1,53.5,
44.0,42.2,39.6,38.5,32.1,31.5,28.8(2C),28.3,27.8,25.6,25.5,22.5,17.2,14.0,
9.3,-1.56(3C);MS(ESI)m/z 833.2(100%)(M+H)+.
[0245] 实施例44
[0246]
[0247] 将270mg(0.357mmol,1eq)原料溶于2ml无水乙腈中峰回路转入0.1ml哌啶,常温下搅拌2h后减压旋干溶剂,加入5ml无水二氯甲烷,于0℃加入134mg(S)-2-(2-(((tert-butoxycarbonyl)amino)-methyl)thiazole-4-carboxamido)butanoic acid(0.393mmol,1.1eq),然后依次加入73mgHOAT(0.536mmol,1.5eq),203mg HATU(0.365mmol,1.5eq)与
0.18ml DIPEA(0.75mmol,3eq).投毕,将反应升到常温反应2h后,加入15ml二氯甲烷稀释,依次用稀HCl(20mlX2),饱和NaCl20mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析(乙酸乙酯∶石油醚=1∶2)得到180mg无色液体,产率58.8%.
[0248] (400MHz,CDCl3)δ8.58(s,1-H),8.10(s,1-H),6.93(d,1-H),6.63(q,1-H),5.77(m,1-H),5.64(q,1-H),5.48(q,1-H),5.42(m,1-H),4.72(q,
1-H),4.60(d,2-H),4.14(t,2-H),2.86(t,2-H),2.78(s,3-H),2.68(dd,1-H),2.56(dd,
1-H),2.50(t,4-H),2.27(q,2-H),2.05(m,1-H),2.01(s,3-H),1.89(m,1-H),1.80(m,5-H),
1.60(m,2-H),1.47(s,9-H),1.26(m,8-H),0.99(t,2-H),0.86(t,3-H),0.02(s,9-H);
13C-NMR(500MHz,CDCl3)δ199.3,171.1,169.6,164.2,159.3,148.9,133.0,130.0,129.0,
128.1,124.8,80.2,72.0,63.1,52.0,44.1,39.6,38.5,32.1,31.5,29.8,28.8(2C),28.3,+
27.8,25.6,25.5,17.3,15.4,14.0,13.9,-1.55(3C);MS(ESI)m/z 857.3(100%)(M+H).[0249] 实施例45
[0250]
[0251] 将292mg(0.375mmol,1eq)原料溶于2ml无水乙腈中峰回路转入0.1ml哌啶,常温下搅拌2h后减压旋干溶剂,加入5ml无水二氯甲烷,于0℃加入141mg(S)-2-(2-(((tert-butoxycarbonyl)amino)-methyl)thiazole-4-carboxamido)butanoic acid(0.412mmol,1.1eq),然后依次加入76.5mgHOAT(0.562mmol,1.5eq),214mg HATU(0.362mmol,1.5eq)与
0.18ml DIPEA(1.125mmol,3eq).投毕,将反应升到常温反应2h后,加入15ml二氯甲烷稀释,依次用稀HCl(20mlX2),饱和NaCl20mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析(乙酸乙酯∶石油醚=1∶2)得到190mg无色液体,产率60.4%.
[0252] (400MHz,CDCl3)δ8.63(s,1-H),8.06(s,1-H),6.67(d,1-H),6.60(q,1-H),5.74(m,1-H),5.58(q,1-H),5.48(q,1-H),5.42(m,1-H),4.72(q,
1-H),4.60(d,2-H),4.14(t,2-H),2.85(t,2-H),2.68(dd,1-H),2.56(dd,1-H),2.50(t,
2-H),2.27(q,2-H),2.07(s,1-H),1.78(s,3-H),1.65(m,6-H),1.45(s,9-H),1.26(m,8-H),
0.99(t,2-H),0.91(t,6-H),0.86(t,3-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.3,
171.7,169.8,164.2,159.3,155.7,132.9,129.8,129.0,128.3,124.8,80.4,71.7,63.1,
51.1,44.1,42.3,41.5,39.6,32.1,31.5,29.8,28.8(2C),27.8,25.6,25.5,24.7,22.8,+
22.5,22.0,17.3,14.04,13.98,-1.57(3C);MS(ESI)m/z 839.3(100%)(M+H).[0253] 实施例46
[0254]
[0255] 将320mg(0.433mmol,1eq)原料溶于10ml无水乙腈中峰回路转入0.4ml哌啶,常温下搅拌2h后减压旋干溶剂,加入5ml无水二氯甲烷,于0℃加入295mg(S)-2-(2-(((tert-butoxycarbonyl)amino)methyl)thiazole-4-carboxamido)butanoic acid(0.866mmol,2eq),然后依次加入118mgHOAT(0.866mmol,2eq),330mg HATU(0.0.866mmol,2eq)与0.29ml DIPEA(1.732mmol,4eq).投毕,将反应升到常温反应2h后,加入15ml二氯甲烷稀释,依次用稀HCl(20mlX2),饱和NaCl20mlX2)萃取.无水硫酸钠干燥,减压旋干溶剂.柱层析(乙酸乙酯∶石油醚=1∶2)得到57mg无色液体,产率15.8%.
[0256] (400MHz,CDCl3)δ8.77(s,1-H),8.03(s,1-H),6.67(d,1-H),6.60(q,1-H),5.74(m,1-H),5.58(q,1-H),5.48(q,1-H),5.42(m,1-H),4.72(q,
1-H),4.60(d,2-H),4.14(t,2-H),2.85(t,2-H),2.68(dd,1-H),2.56(dd,1-H),2.50(t,
2-H),2.27(q,2-H),2.07(s,1-H),1.78(s,3-H),1.65(m,6-H),1.45(s,9-H),1.26(m,8-H),
0.99(t,2-H),0.91(t,6-H),0.86(t,3-H),0.02(s,9-H);13C-NMR(500MHz,CDCl3)δ199.3,
171.7,169.8,164.2,159.3,155.7,132.9,129.8,129.0,128.3,124.8,80.4,71.7,63.1,
51.1,44.1,42.3,41.5,39.6,32.1,31.5,29.8,28.8(2C),27.8,25.6,25.5,24.7,22.8,+
22.5,22.0,17.3,14.04,13.98,-1.57(3C);MS(ESI)m/z 839.3(100%)(M+H).[0257] 实施例47
[0258]
[0259] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0260] 氩气保护下,上一步得到的化合物(0.535g,0.74mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.356g,0.9mmol),HATU(0.0.423g,1.12mmol),HOAt(0.152g,
1.12mmol),DIPEA(0.4ml,2.22mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.455g,产率78%。
23 1
[0261] [α] D:-23.6(c = 5,CHCl3).H NMR(400MHz,CDCl3):δ8.60(s,1H),8.10(s,1H),6.60(m,2H),5.77(m,1H),5.62(dd,J = 13.7Hz 7.2Hz,1H),5.49(dd,J = 13.7Hz
7.5Hz,1H),5.42(m,1H),4.58(m,3H),4.14(t,J = 8.6Hz,2H),2.85(t,J = 7.2Hz,2H),
2.68(dd,J=15.7Hz 7.7Hz,2H),2.50(t,J=7.5Hz,2H),2.26(q,J=7.1Hz,2H),2.18(m,
1H),1.80(d,J = 7Hz,3H),1.60(m,2H),1.46(m,8H),1.26(m,9H),0.96(m,3H),0.86(t,J
13
=6.1Hz,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.25,170.70,169.55,164.33,
159.26,148.88,133.30,129.39,129.21,128.30,124.75,71.77,63.11,57.16,44.08,
39.63,38.55,32.13,31.59,31.55,28.84,28.28,27.82,25.58,22.52,18.91,17.58,+
17.26,13.99,13.94,0.96,-1.57ppm.MS(EI,m/z):831(M+Na).
[0262] 实施例48
[0263]
[0264] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0265] 氩气保护下,上一步得到的化合物(0.593g,0.82mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.452g,0.99mmol),HATU(0.465g,1.23mmol),HOAt(0.167g,
1.23mmol),DIPEA(0.44ml,2.44mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.412g,产率61%。
[0266] [α]23D:-9.1(c=5,CHCl3).1H NMR(400MHz,CDCl3):δ8.60(s,1H),6.60(m,2H),5.77(m,1H),5.66(dd,1H),5.41(m,1H),4.34(m,3H),4.24(t,2H),3.7(m,1H),2.75(t,2H),
2.68(dd,2H),2.50(t,J = 7.5Hz,2H),2.26(q,2H),2.18(m,1H),1.80(d,J = 7Hz,3H),
1.60(m,2H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm.13C NMR(125MHz,CDCl3):δ199.5,170.7,169.4,162.3,159.2,148.8,133.3,129.3,
129.2,128.3,124.7,71.7,63.1,57.6,44.0,39.6,38.5,32.1,31.5,31.5,28.8,28.2,
27.8,25.5,22.5,22.3,18.9,17.5,17.2,13.9,13.9,0.9ppm.MS(EI,m/z):847(M++Na).[0267] 实施例49
[0268]
[0269] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0270] 氩气保护下,上一步得到的化合物(0.412g,0.57mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.352g,0.69mmol),HATU(0.326g,0.86mmol),HOAt(0.117g,
0.86mmol),DIPEA(0.31ml,1.71mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.335g,产率70%。
23 1
[0271] [α] D:-14.3(c = 5,CHCl3).H NMR(400MHz,CDCl3):δ8.60(s,1H),6.60(m,2H),5.77(m,1H),5.66(dd,1H),5.41(m,1H),4.34(m,3H),4.24(t,2H),3.7(m,1H),
2.75(t,2H),2.68(dd,2H),2.50(t,2H),2.26(q,2H),2.18(m,1H),1.80(d,3H),1.60(m,
13
2H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.6,170.7,169.4,162.3,159.2,148.8,133.3,129.3,129.2,
128.3,124.7,71.7,63.1,57.6,44.0,39.5,38.5,32.1,31.5,31.5,28.8,28.2,27.8,25.5,+
22.5,22.3,18.9,17.5,16.2,13.9,13.9,0.9ppm.MS(EI,m/z):863(M+Na).[0272] 实施例50
[0273]
[0274] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0275] 氩气保护下,上一步得到的化合物(0.412g,0.45mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.332g,0.55mmol),HATU(0.261g,0.69mmol),HOAt(0.094g,
0.69mmol),DIPEA(0.25ml,1.37mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.265g,产率73%。
[0276] [α]23D:-21.3(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.60(s,1H),7.55(m,2H),5.77(m,1H),5.66(dd,1H),5.41(m,1H),4.34(m,3H),4.24(t,2H),3.7(m,1H),
3.0(t,2H),2.68(dd,2H),2.50(t,2H),2.26(q,2H),2.18(m,1H),1.80(d,3H),1.60(m,
13
2H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.2,180.3,170.3,169.4,162.3,159.2,148.8,133.3,129.3,
129.2,128.3,124.7,71.7,63.1,57.6,44.0,39.5,38.5,32.1,31.5,31.5,28.8,28.2,+
27.8,25.5,22.5,22.3,18.9,17.5,16.2,13.9,13.9,0.9ppm.MS(EI,m/z):822(M+Na).[0277] 实施例51
[0278]
[0279] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0280] 氩气保护下,上一步得到的化合物(0.412g,0.45mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.313g,0.55mmol),HATU(0.261g,0.69mmol),HOAt(0.094g,
0.69mmol),DIPEA(0.25ml,1.37mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.265g,产率73%。
23 1
[0281] [α] D:-22.1(c = 5,CHCl3).H NMR(400MHz,CDCl3):δ8.60(s,1H),7.55(m,2H),5.77(m,1H),5.66(dd,1H),5.41(m,1H),4.34(m,3H),4.24(t,2H),3.7(m,1H),
3.0(t,2H),2.68(dd,2H),2.50(t,2H),2.26(q,2H),2.18(m,1H),1.80(d,3H),1.60(m,
13
2H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.2,180.3,170.3,169.4,162.3,159.2,148.8,133.3,129.3,
129.2,128.3,124.7,71.7,63.1,57.6,44.0,39.5,38.5,32.1,31.5,31.5,28.8,28.2,+
27.8,25.5,22.5,22.3,18.9,17.5,16.2,13.9,13.9,0.9ppm.MS(EI,m/z):822(M+Na).[0282] 实施例52
[0283]
[0284] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0285] 氩气保护下,上一步得到的化合物(0.412g,0.585mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0485g,0.72mmol),HATU(0.34g,0.9mmol),HOAt(0.122g,0.9mmol),DIPEA(0.33ml,1.78mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.392g,产率82%。
[0286] [α]23D:-39.1(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.40(s,1H),7.84(d,1H),7.75(s,1H),7.41(m,2H),5.79(m,2H),5.66(dd,1H),5.32(m,1H),4.31(m,3H),
4.24(t,2H),3.1(t,2H),2.68(dd,2H),2.50(t,2H),2.26(q,2H),2.18(m,1H),1.80(d,3H),
1.60(m,2H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)
13
ppm. C NMR(125MHz,CDCl3):δ199.3,173.3,171.6,166.8,162.5,156.9,141.9,134.1,
131.5,130.6,130.4,128.9,125.7,125.4,120.3,19.6,73.8,67.8,61.7,44.9,44.6,38.4,
37.9,31.8,30.6,30.4,29.5,28.5,26.3,22.9,22.7,19.8,14.1,13.2,1.5ppm.MS(EI,m/+
z):818(M+1).
[0287] 实施例53
[0288]
[0289] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0290] 氩气保护下,上一步得到的化合物(0.412g,0.76mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.512g,0.936mmol),HATU(0..442g,1.17mmol),HOAt(0.159g,117mmol),DIPEA(0.43ml,2.31mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.46g,产率74%。
[0291] [α]23D:-12.9(c=5,CHCl3).1HNMR(400MHz,CDCl3):δ8.90(d,1H),8.15(s,1H),7.75(s,1H),5.75(m,2H),5.63(dd,1H),5.32(m,1H),4.31(m,3H),4.24(t,2H),3.1(t,2H),
2.68(dd,2H),2.50(t,2H),2.26(q,2H),2.18(m,1H),1.80(d,3H),1.60(m,2H),1.46(m,
13
8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.1,173.3,171.6,166.8,162.5,156.9,156.2,149.2,144.6,131.5,130.6,
130.4,128.9,125.7,125.4,120.3,19.6,73.8,67.8,61.7,44.9,44.6,38.4,37.9,
31.8,30.6,30.4,29.5,28.5,26.3,22.9,22.7,19.8,14.1,13.2,1.5ppm.MS(EI,m/z):
+
819(M+1).
[0292] 实施例54
[0293]
[0294] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0295] 氩气保护下,上一步得到的化合物(0.283g,0.57mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.214g,0.69mmol),HATU(0.325g,0.86mmol),HOAt(0.117g,
0.86mmol),DIPEA(0.3ml,1.71mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.377g,产率80%。
23 1
[0296] [α] D:-22.0(c = 5,CHCl3).H NMR(400MHz,CDCl3):δ8.78(s,1H),5.74(m,1H),5.63(dd,1H),5.32(m,1H),4.31(m,3H),4.24(t,2H),3.1(t,2H),2.68(dd,2H),
2.50(t,2H),2.26(q,2H),2.18(m,1H),1.80(d,3H),1.60(m,2H),1.46(m,8H),1.26(m,9H),
13
1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.5,
173.5,171.8,165.9,161.2,156.3,148.9,130.1,128.6,124.2,79.5,73.9,67.5,61.2,
60.2,44.1,41.5,37.8,31.4,30.7,30.5,29.5,29.1,28.5,26.3,25.3,22.6,22.1,19.5,+
14.2,9.1,1.5ppm.MS(EI,m/z):827(M+1).
[0297] 实施例55
[0298]
[0299] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0300] 氩气保护下,上一步得到的化合物(0.212g,0.43mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.16g,0.52mmol),HATU(0.244g,0.65mmol),HOAt(0.088g,
0.65mmol),DIPEA(0.23ml,1.28mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.306g,产率89%。
[0301] [α]23D:-22.0(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.74(s,1H),5.74(m,1H),5.63(dd,1H),5.32(m,1H),4.31(m,3H),4.24(t,2H),3.1(t,2H),2.68(dd,2H),
2.50(t,2H),2.26(q,2H),2.18(m,1H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,
3H),0.86(t,6H),0.02(s,9H)ppm.13C NMR(125MHz,CDCl3):δ199.5,173.5,171.8,165.9,
161.2,156.3,148.9,130.1,128.6,124.2,79.5,73.9,67.5,61.2,60.2,44.1,41.5,37.8,
31.4,30.7,30.5,29.5,28.5,26.3,25.3,22.6,19.5,14.2,9.1,1.5ppm.MS(EI,m/z):
799(M++1).
[0302] 实施例56
[0303]
[0304] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0305] 氩气保护下,上一步得到的化合物(0.425g,0.86mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.341g,1.04mmol),HATU(0.488g,1.3mmol),HOAt(0.175g,
1.3mmol),DIPEA(045ml,2.67mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1)。得到固体0.446g,产率64%。
[0306] [α]23D:-12.6(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.74(s,1H),5.74(m,1H),5.63(dd,1H),5.45-5.10(m,3H),4.31(m,3H),4.24(t,2H),3.1(t,2H),2.68(dd,2H),
2.50(t,2H),2.26(q,2H),2.18(m,1H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),
13
0.86(t,6H),0.02(s,9H)ppm. CNMR(125MHz,CDCl3):δ199.5,173.5,171.8,165.9,161.2,
156.3,148.9,133.9,130.1,128.6,124.2,104.6,79.5,73.9,67.5,61.2,60.2,44.1,41.5,
37.8,31.4,30.7,30.5,29.5,28.5,26.3,25.3,22.6,19.5,14.2,9.1,1.5ppm.MS(EI,m/z):
+
811(M+1).
[0307] 实施例57
[0308]
[0309] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0310] 氩气保护下,上一步得到的化合物(0.396g,0.798mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.352g,0.966mmol),HATU(0.455g,1.2mmol),HOAt(0.164g,
1.2mmol),DIPEA(0.3ml,0.42mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.581g,产率84%。
[0311] [α]23D:-41.6(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.74(s,1H),5.74(m,2H),5.63(dd,1H),4.31(m,3H),4.24(t,4H),3.1(t,2H),2.68(dd,2H),2.50(t,2H),
2.26(q,2H),2.18(m,2H),2.05(d,3H),1.46(m,8H),1.26(m,9H),1.12(d,6H),0.96(m,
13
6H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.6,173.5,171.6,169.8,
167.4,162.9,155.5,147.6,131.4,130.4,128.1,124.6,120.5,79.6,73.8,60.8,61.5,
60.5,44.0,38.4,37.9,34.5,31.8,30.5,30.1,29.8,28.5,22.5,18.9,18.4,14.2,12.9,+
1.5ppm.MS(EI,m/z):867(M+1).
[0312] 实施例58
[0313]
[0314] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1)。得到无色液体0.776g,产率78%。
[0315] 氩气保护下,上一步得到的化合物(0.24g,0.485mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.212g,0.59mmol),HATU(0.276g,0.731mmol),HOAt(0.1g,
0.731mmol),DIPEA(0.255ml,1.45mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.358g,产率88%。
[0316] [α]23D:-8.5(c=5,CHCl3).1H NMR(400MHz,CDCl3):δ8.74(s,1H),5.74(m,2H),5.63(dd,1H),4.31(m,3H),4.24(t,4H),3.1(t,2H),2.68(dd,2H),2.50(t,2H),2.26(q,
2H),2.18(m,2H),2.05(d,3H),1.54(d,3H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,
13
3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.6,173.5,171.6,169.8,
167.4,162.9,155.5,147.6,131.4,130.4,128.1,124.6,120.5,79.6,73.8,60.8,61.5,
60.5,52.6,38.4,37.9,34.5,31.8,30.5,30.1,29.8,28.5,22.5,18.9,18.4,14.2,12.9,+
1.5ppm.MS(EI,m/z):839(M+1).
[0317] 实施例59
[0318]
[0319] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1),得到无色液体0.776g,产率78%。
[0320] 氩气保护下,上一步得到的化合物(0.318g,0.64mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.295g,0.78mmol),HATU(0.366g,0.97mmol),HOAt(0.132g,
0.97mmol),DIPEA(0.34ml,1.92mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.474g,产率81%。
[0321] [α]23D:-12.5(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.94(s,1H),7.40(m,2H),7.29(d,2H),7.25(m,1H),5.74(m,2H),5.63(dd,1H),4.30(m,2H),4.24(t,4H),
3.23(m,2H),2.68(dd,2H),2.50(t,2H),2.26(q,2H),2.18(m,2H),2.05(d,3H),1.54(d,
13
3H),1.46(m,8H),1.26(m,9H),1.12(d,3H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.6,173.5,171.6,169.8,167.4,162.9,155.5,147.6,139.4,
130.4,129.4,128.1,125.9,124.6,120.5,79.6,73.8,60.8,61.5,60.5,52.6,38.4,37.9,
34.5,31.8,30.5,30.1,29.8,28.5,22.5,18.9,18.4,14.2,12.9,1.5ppm.MS(EI,m/z):
+
915(M+1).
[0322] 实施例60
[0323]
[0324] 原料(1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1),得到无色液体0.776g,产率78%。
[0325] 氩气保护下,上一步得到的化合物(0.283g,0.57mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.453g,0.69mmol),HATU(0.325g,0.86mmol),HOAt(0.117g,
0.86mmol),DIPEA(0.3ml,1.71mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.298g,产率53%。
[0326] [α]23D:-42.5(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.94(s,1H),7.18(m,2H),6.95(d,2H),5.74(m,2H),5.63(dd,1H),4.30(m,2H),4.24(t,4H),3.23(m,2H),
2.68(dd,2H),2.50(t,2H),2.26(q,2H),2.18(m,2H),2.05(d,3H),1.54(d,3H),1.46(m,
13
8H),1.26(m,9H),1.12(d,6H),0.96(m,3H),0.86(t,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.6,173.5,171.6,169.8,167.4,162.9,155.5,147.6,139.4,130.4,129.4,
124.6,120.5,79.6,73.8,60.8,61.5,60.5,52.6,38.4,37.9,34.5,31.8,30.5,30.1,29.8,+
28.5,27.6,22.5,18.9,18.4,14.2,12.9,1.5ppm.MS(EI,m/z):987(M+1).[0327] 实施例61
[0328]
[0329] 原料(1.28g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1),得到无色液体0.626g,产率75%。
[0330] 氩气保护下,上一步得到的化合物(0.626g,1.5mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(1.62g,1.56mmol),HATU(0.855g,2.26mmol),HOAt(0.117g,
2.26mmol),DIPEA(0.79ml,4.5mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体1.05g,产率91%。
[0331] [α]23D:-15.3(c = 0.5,CHCl3).1HNMR(400MHz,CDCl3):δ8.60(s,1H),8.10(s,1H),6.60(m,2H),5.77(m,1H),5.62(dd,1H),5.49(dd,1H),5.42(m,1H),4.58(m,3H),
4.14(t,2H),2.85(t,2H),2.68(dd,2H),2.50(t,2H),2.31(s,3H),2.18(m,1H),1.60(m,
13
2H),1.46(m,8H),1.26(m,9H),0.96(m,3H),0.86(t,J = 6.1Hz,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.25,170.70,169.55,164.33,159.26,148.88,133.30,129.39,
129.21,128.30,124.75,71.77,63.11,57.16,44.08,39.63,38.55,30.5,28.84,28.28,
27.82,25.58,22.52,18.91,17.58,17.26,13.99,13.94,0.96,-1.57ppm.MS(EI,m/z):
+
741(M+1).
[0332] 实施例62
[0333]
[0334] 原料(1.587g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1),得到无色液体0.724g,产率65%。
[0335] 氩气保护下,上一步得到的化合物(0.326g,0.57mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.234g,0.69mmol),HATU(0.325g,0.86mmol),HOAt(0.117g,
0.86mmol),DIPEA(0.3ml,1.71mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.428g,产率84%。
[0336] [α]23D:-15.3(c=0.5,CHCl3)..1H NMR(400MHz,CDCl3):δ8.60(s,1H),8.10(s,1H),6.60(m,2H),5.77(m,1H),5.62(dd,J = 13.7Hz 7.2Hz,1H),5.49(dd,J = 13.7Hz
7.5Hz,1H),5.42(m,1H),4.58(m,3H),4.14(t,J = 8.6Hz,2H),2.85(t,J = 7.2Hz,2H),
2.68(dd,J=15.7Hz 7.7Hz,2H),2.50(t,J=7.5Hz,2H),2.26(q,J=7.1Hz,2H),2.18(m,
1H),1.80(d,J= 7Hz,3H),1.60(m,2H),1.46(m,20H),1.26(m,9H),0.91(m,3H),0.86(t,J
13
=6.1Hz,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ199.25,170.70,169.55,164.33,
159.26,148.88,133.30,129.39,129.21,128.30,124.75,71.77,63.11,57.16,44.08,
39.63,38.55,32.13,31.59,31.55,29.6,28.84,28.28,27.82,25.58,22.52,18.91,17.58,+
17.26,13.99,13.94,0.96,-1.57ppm.MS(EI,m/z):895(M+1).
[0337] 实施例63
[0338]
[0339] 原料(1.43g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1),得到无色液体0.711g,产率72%。
[0340] 氩气保护下,上一步得到的化合物(0.281g,0.57mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.234g,0.69mmol),HATU(0.325g,0.86mmol),HOAt(0.117g,
0.86mmol),DIPEA(0.3ml,1.71mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.363g,产率78%。
23 1
[0341] [α] D:-35.1(c=0.5,CHCl3)..H NMR(400MHz,CDCl3):δ8.60(s,1H),8.10(s,1H),7.29(d,2H),7.21(m,1H),7.11(m,1H),6.60(m,2H),5.77(m,1H),5.62(dd,J=13.7Hz
7.2Hz,1H),5.49(dd,J=13.7Hz 7.5Hz,1H),5.42(m,1H),4.58(m,3H),4.14(t,J=8.6Hz,
2H),3.66(s,2H),2.85(t,J=7.2Hz,2H),2.68(dd,J=15.7Hz 7.7Hz,2H),2.50(t,J=
7.5Hz,2H),2.26(q,J = 7.1Hz,2H),2.18(m,1H),1.26(m,9H),0.96(m,3H),0.86(t,J =
13
6.1Hz,6H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):δ202.3,173.7,171.5,167.6,165.5,
162.6,156.2,147.4,138.6,131.4,129.2,127.8,124.3,120.5,79.5,73.7,67.2,61.5,+
41.8,38.3,33.6,30.7,28.4,22.9,18.9,13.1,1.5ppm.MS(EI,m/z):817(M+1).[0342] 实施例64
[0343]
[0344] 原料1.45g,2mmol)溶解于二氯甲烷中,加入哌啶(1ml,10mmol),室温下搅拌2小时。直接旋干,快速柱层析(石油醚∶乙酸乙酯=10∶1,二氯甲烷∶甲醇=10∶1),得到无色液体1.39g,产率84%。
[0345] 氩气保护下,上一步得到的化合物(0.612g,0.74mmol)溶于无水二氯甲烷中,在0℃条件下,依次加入化合物(0.356g,0.9mmol),HATU(0.0.423g,1.12mmol),HOAt(0.152g,
1.12mmol),DIPEA(0.4ml,2.22mmol),1小时后室温下搅拌过夜。依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯=4∶1),得到固体0.391g,产率64%。
[0346] [α]23D:-20.1(c = 5,CHCl3).1H NMR(400MHz,CDCl3):δ8.76(s,1H),8.10(s,1H),6.60(m,2H),5.77(m,1H),5.62(dd,1H),5.42(m,1H),4.28(m,3H),4.14(t,2H),
3.64(t,2H),2.91(t,2H),2.68(m,4H),2.50(t,2H),2.26(q,2H),2.05(d,3H),1.60(m,
13
2H),1.26(m,9H),0.96(m,3H),0.86(t,15H),0.02(s,9H)ppm. C NMR(125MHz,CDCl3):
δ199..5,173.2,171.6,147.4,165.4,162.6,156.1,147.4,131.4,130.2,128.4,124.1,
120.3,81.8,79.5,73.7,67.2,62.6,61.6,45.3,41.8,38.3,37.9,30.7,30.5,28.4,28.2.,+
22.5,18.9,13.0,1.5ppm.MS(EI,m/z):827(M+1).
[0347] 实施例65式1-3化合物的合成
[0348]
[0349] 向实施例34制得的原料(0.34g,0.41mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。
粗产物直接投入下一步。
[0350] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.78g,2.05mmol),HOAt(0.28g,2.05mmol),DIPEA(0.7ml,4.1mmol)的无水DMF溶液中,30℃搅拌
3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.121g固体1-3,产率49%。
[0351] [α]23D:19.2(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.54(s,1H),8.08(s,1H),6.97(q,J = 7Hz,1H),6.82(m,1H),6.51(d,J = 10.1Hz,1H),5.74-5.6(m,2H),5.47(dd,J = 15.5Hz 6.8Hz,1H),5.14(dd,J = 16Hz 8.2Hz,1H),4.70(dd,J = 10.1Hz 3.2Hz,
1H)4.32(dd,J=17.4Hz,3.5Hz,1H),2.82(t,J=7.2Hz,2H),2.75-2.59(m,2H),2.47(t,J=7.5Hz,2H),2.24(m,2H),1.82(d,J=7Hz,3H),1.58(m,2H),1.24(m,8H),0.83(m,3H),
0.74(d,J=6.7Hz,3H),0.55(d,J=6.7Hz,3H)ppm.13C NMR(125MHz,CDCl3):δ199.39,
169.69,169.04,167.46,163.37,158.79,147.85,134.59,132.54,128.20,127.12,124.35,
71.77,56.96,43.98,40.69,40.01,32.10,31.52,28.74,27.67,25.49,22.42,18.90,
16.31,14.53,13.91,0.03ppm.MS(EI,m/z):607(M++1),629(M++Na).HRMS(ESI):calcd forC29H42N406S2[MNa+]629.2438,found 629.2440.
[0352] 实施例66式1-4化合物的合成
[0353]
[0354] 向实施例35制得的原料(0.279g,0.35mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。
粗产物直接投入下一步。
[0355] 氩气保护下,上一步的粗产物用40ml无水DMF溶解,缓慢滴入HATU(0.665g,1.75mmol),HOAt(0.238g,1.75mmol),DIPEA(0.58ml,3.5mmol)的无水DMF溶液中,30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=20∶20∶1),得到0.116g固体1-4,产率58%。
[0356] [α]23D:60.2(c 0.5,CHCl3).1H NMR(400MHz,CDCl3):δ8.67(s,1H),8.07(s,1H),6.95-6.8(m,3H),5.72(m,2H),5.42(dd,J = 7.1Hz,15.5Hz,1H),5.14(dd,J =
7.8Hz,17.4Hz,1H),4.76(m,1H),4.31(dd,J = 4.3Hz,17.4Hz,1H),2.85(m,3H),2.77(m,
1H),2.63(d,J = 16..5Hz,1H),2.50(t,J = 7.5Hz,2H),2.25(dd,J = 7Hz,14Hz,2H),
13
1.79(d,J= 7.1Hz,3H),1.61(m,2H),1.34-1.2(m,11H),0.85(m,3H)ppm. C NMR(125MHz,CDCl3):δ199.40,170.63,169.58,166.86,163.39,157.72,147.88,132.84,128.20,
126.84,124.20,71.54,53.39,48.37,44.05,41.04,39.74,32.14,31.51,28.81,27.72,+
25.56,22.49,17.64,14.92,13.98,0.92ppm.MS(EI,m/z):579(M+1).HRMS(ESI):calcd +
forC27H38N4O6S2[MNa]601.2125,found 601.2129.
[0357] 实施例67式1-5化合物的合成
[0358]
[0359] 向实施例36制得的原料(0.184g,0.32mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。
粗产物直接投入下一步。
[0360] 氩气保护下,上一步的粗产物用40ml无水DMF溶解,缓慢滴入HATU(0.437g,115mmol),HOAt(0.157g,1.15mmol),DIPEA(0.38ml,2.3mmol)的无水DMF溶液中,30℃搅拌
3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.081g固体1-5,产率61%。
[0361] [α]23D:30.8(c 0.86,CHCl3).1H NMR(400MHz,CDCl3):δ8.64(s,1H),8.10(s,1H),6.99(m,1H),6.47(d,J = 8.7Hz,1H),6.33(s,1H),5.85(dd,J = 7.3Hz,15.8Hz,
1H),5.75(m,1H),5.64(m,1H),4.95-4.6(m,3H),2.88(m,2H),2.64(m,2H),2.51(t,J= 7.6Hz,2H),2.28(m,2H),1.85(d,J = 7.4Hz,3H),1.61(m,2H),1.34(d,J = 6.8Hz,
13
3H),1.26(m,8H),0.86(m,3H)ppm. C NMR(125MHz,CDCl3):δ199.42,177.15,169.72,
168.99,166.95,163.07,157.86,148.85,133.68,133.25,128.15,126.39,123.67,
72.49,60.37,49.61,44.11,40.52,39.92,32.13,31.56,29.66,28.86,27.88,25.60,+
22.54,21.02,19.30,15.08,12.16,0.978ppm.MS(EI,m/z):579(M+1).HRMS(ESI):calcd +
forC27H38N406S2[MNa]601.2125,found 601.2127.
[0362] 实施例68式1-6化合物的合成
[0363]
[0364] 向实施例37制得的原料(0.252g,0.3mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。
粗产物直接投入下一步。
[0365] 氩气保护下,上一步的粗产物用40ml无水DMF溶解,缓慢滴入HATU(0.57g,1.5mmol),HOAt(0.204g,1.5mmol),DIPEA(0.5ml,3mmol)的无水DMF溶液中,30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.102g固体1-6,产率55%。
[0366] [α]23D:6.9(c 0.95,CHCl3).1H NMR(400MHz,CDCl3):δ8.49(s,1H),8.12(s,1H),7.03(m,1H),6.75-6.65(m,2H),5.8-5.55(m,3H),5.11(dd,J = 7.6Hz 17.5Hz,
1H),4.57(d,J = 10.5Hz,1H),4.45(dd,J = 3.9Hz 17.4Hz,1H),2.85(t,J = 7.1Hz,
2H),2.67(m,2H),2.27(dd,J = 6.8Hz,13.6Hz,2H),1.87(d,J = 7Hz,3H),1.59(m,2H),
1.23(m,8H),0.9-0.77(m,12H).ppm.13C NMR(125,CDCl3):δ199.45,168.88,168.09,
167.38,163.09,158.99,148.322,135.28,132.29,128.42,127.09,124.45,71.49,60.46,
44.05,41.02,40.68,35.58,32.13,31.52,29.61,28.81,27.80,26.39,25.56,22.49,
14.61,13.98,0.94ppm.MS(EI,m/z):621(M++1),643(M++Na).HRMS(ESI):calcd for C30H44N4O6S2[MNa+]643.2595,found 643.2596.
[0367] 实施例69式1-7化合物的合成
[0368]
[0369] 向实施例38制得的原料(0.151g,0.173mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0370] 氩气保护下,上一步的粗产物用30ml无水DMF溶解,缓慢滴入HATU(0.329g,0.865mmol),HOAt(0.118g,0.865mmol),DIPEA(0.29ml,1.73mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=20∶20∶1),得到0.05g固体1-7,产率44%。
[0371] [α]23D:15.6(c 0.45,CHCl3).1H NMR(400MHz,CDCl3):δ8.24(s,1H),8.10(s,1H),7.09(m,1H),7.05-6.90(m,5H),6.44(d,J = 10.4Hz,1H),5.75-5.65(m,2H),5.78(m,
1H),5.50(m,1H),5.26(m,1H),4.65(dd,J=17.3Hz,6Hz,1H),4.53(dd,J=17.3Hz 5.3Hz,
1H),3.37(dd,J = 13.6Hz 3.4Hz,1H),2.91-2.81(m,3H),2.55-2.45(m,4H),2.26(q,J
13
= 6.8Hz,2H),1.93(d,J = 7.2Hz,3H),1.58(m,2H),1.25(m,8H),0.87(m,3H).ppm. C NMR(100MHz,CDCl3):δ199.29,169.53,168.30,166.72,162.78,158.33,148.35,135.47,
134.59,132.63,129.50,128.29,127.52,126.78,126.35,123.83,52.34,44.00,40.60,
40.36,38.07,32.07,31.50,28.79,27.70,25.53,22.47,14.76,13.95,0.91ppm.MS(EI,+ + +
m/z):655(M+1),677(M+Na).HRMS(ESI):calcd for C33H42N4O6S2[MNa]677.2438,found
677.2437.
[0372] 实施例70式1-9化合物的合成
[0373]
[0374] 向实施例39制得的原料(0.24g,0.26mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。
粗产物直接投入下一步。
[0375] 氩气保护下,上一步的粗产物用40ml无水DMF溶解,缓慢滴入HATU(0.494g,1.3mmol),HOAt(0.177g,1.3mmol),DIPEA(0.43ml,2.6mmol)的无水DMF溶液中。30℃搅拌
3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.077g固体1-9,产率42%。
[0376] [α]23D:-26.5(c 0.78,CHCl3).1H NMR(400MHz,CDCl3):δ8.03(s,1H),7.95(s,1H),7.93(s,1H),7.64(d,J=8.1Hz,1H),7.53(d,J=7.8Hz,1H),7.41(t,J=7.5Hz,1H),
7.32(t,J = 7.5Hz,1H),7.14(m,2H),7.02(m,1H),6.56(d,J = 10.1Hz,1H),5.6-5.4(m,
3H),4.92(m,1H),4.61(dd,J = 6.6Hz,17.2Hz,1H),4.10(m,1H),3.75(dd,J = 3.5Hz,
14.2Hz,1H),3.50(dd,J=5.6Hz,14.2Hz,1H),2.74(t,J=7.1Hz,2H),2.41(t,J=7.5Hz,
2H),2.30(dd,J = 5.2Hz,15.3Hz,1H),2.14(m,2H),1.89(d,J = 7.2Hz,3H),1.54(m,
13
2H),1.22(m,8H),0.84(m,3H),ppm. C NMR(100MHz,CDCl3):δ199.13,169.48,168.09,
166.22,162.85,158.12,148.76,134.27,133.44,132.34,128.52,127.19,126.86,126.26,
125.33,123.82,123.46,71.81,52.68,44.02,40.49,38.57,34.61,32.03,31.55,28.84,+ +
27.74,25.56,22.52,20.98,14.99,13.99,0.97ppm.MS(EI,m/z):705(M+1),727(M+Na).+
HRMS(ESI):calcdfor C37H44N4O6S2[MNa]727.2595,found 727.2596.
[0377] 实施例71式1-8化合物的合成
[0378]
[0379] 向实施例40制得的原料(0.165g,0.175mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0380] 氩气保护下,上一步的粗产物用40ml无水DMF溶解,缓慢滴入HATU(0.333g,0.875mmol),HOAt(0.119g,0.875mmol),DIPEA(0.3ml,1.75mmol)的无水DMF溶液中,30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=20∶20∶1),得到0.075g固体1-8,产率64%。
[0381] [α]23D:7.9(c 0.65,CHCl3).1H NMR(400MHz,MeOD):δ8.20(s,1H),7.67(d,J=9.4Hz,1H),6.83(d,J = 8.3Hz,2H),6.72(m,1H),6.50(d,J = 8.3Hz,2H),5.75-5.65(m,
2H),5.55(dd,J=6.7Hz,15.6Hz,1H),4.97(d,J=17.4Hz,1H),4.39(d,J=17.4Hz,1H),
3.34(s,1H),2.99(m,1H),2.95-2.83(m,4H),2.63(d,J=16.8Hz,1H),2.53(t,J=7.4Hz,
2H),2.26(dd,J=6.9Hz,13.8Hz,2H),1.79(d,J=7.1Hz,3H),1.62(m,2H),1.29(m,8H),
13
0.89(t,J = 6.2Hz,3H)ppm. C NMR(125MHz,MeOD):δ200.92,172.72,171.43,168.56,
165.56,160.83,156.88,149.07,133.91,133.26,131.49,130.06,128.97,128.53,125.67,
116.08,73.22,54.88,44.83,41.76,40.29,37.83,33.37,32.80,30.05,29.94,28.77,+ +
26.78,23.64,14.88,14.42ppm.MS(EI,m/z):671(M+1),693(M+Na).HRMS(ESI):calcd +
forC33H42N4O7S2[MNa]693.2387,found 693.2386.
[0382] 实施例72式1-1化合物的合成
[0383]
[0384] 取实施例41制得的原料155mg(0.198mmol,1eq)溶于5ml无水二氯甲烷,加入1ml三氟乙酸,反应常温下搅拌24小时后,减压旋去溶剂与TFA后,用100ml无水DMF,慢慢滴加入溶有150mg(0.396mmol,2eq)HATU与54mg(0.396mmol,2eq)HOAT与0.2ml(1.188mmol,6eq)DIPEA的DMF溶液(100ml)中.反应于常温下反应72h后,减压旋去DMF,乙酸乙酯(20ml)稀释,用饱和NaCl(20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析(乙酸乙酯)得到22mg白色固体1-1,产率20%.
[0385] (400MHz,CDCl3)δ8.70(s,1-H),8.10(s,1-H),7.11(s,1-H),6.92(q,1-H),6.84(d,1-H),6.61(t,1-H),5.73(t,1-H),5.68(dd,1-H),5.50(dd,
1-H),5.15(dd,1-H),4.68(q,1-H),4.35(dd,1-H),3.65(d,1-H),2.82(t,2-H),2.70(dd,
1-H),2.58(dd,1-H),2.55(t,2-H),2.22(q,2-H),1.95(s,3-H),1.83(d,3-H),1.57(t,
2-H),1.28(m,8-H),0.87(t,3-H);13C-NMR(500MHz,CDCl3)δ199.5,169.6,168.0,166.8,
163.7,157.8,148.1,133.3,132.9,128.1,126.9,124.3,71.7,44.0,42.2,41.0,39.9,+
32.2,31.6,28.9(2C),27.7,25.6,22.5,14.9,14.0,;MS(ESI)m/z 564.72(100%)(M+H).[0386] 实施例73式5-1化合物的合成
[0387]
[0388] 取实施例42制得的原料110mg(0.136mmol,1eq)溶于5ml无水二氯甲烷,加入1ml三氟乙酸,反应常温下搅拌24小时后,减压旋去溶剂与TFA后,用70ml无水DMF,慢慢滴加入溶有207mg(0.544mmol,2eq)HATU与74mg(0.544mmol,4eq)HOAT与0.18ml(1.088mmol,8eq)DIPEA的DMF溶液(70ml)中.反应于常温下反应72h后,减压旋去DMF,乙酸乙酯(20ml)稀释,用饱和NaCl(20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂,柱层析(乙酸乙酯)得到10mg白色固体5-1,产率18%。
[0389] (400MHz,CDCl3)δ8.80(s,1-H),8.07(s,1-H),7.11(s,1-H),6.78(q,1-H),6.40(s,1-H),5.80(m,2-H),5.45(dd,1-H),5.11(s,1-H),4.70(brs,
1-H),4.3(m,1-H),3.65(d,1-H),2.82(t,2-H),2.70(dd,1-H),2.58(dd,1-H),2.55(t,
2-H),2.22(q,2-H),1.95(s,3-H),1.83(d,3-H),1.57(t,2-H),1.28(m,8-H),0.87(t,3-H);
13C-NMR(500MHz,CDCl3)δ199.5,169.6,168.0,166.8,163.7,157.8,148.1,133.3,132.9,
128.1,126.9,124.3,71.7,44.0,42.2,41.0,39.9,32.2,31.6,28.9(2C),27.7,25.6,22.5,+
14.9,14.0,;MS(ESI)m/z 564.72(100%)(M+H).
[0390] 实施例74式1-2化合物的合成
[0391]
[0392] 取实施例43制得的原料120mg(0.148mmol,1eq)溶于5ml无水二氯甲烷,加入1ml三氟乙酸,反应常温下搅拌24小时后,减压旋去溶剂与TFA后,用75ml无水DMF,慢慢滴加入溶有225mg(0.592mmol,4eq)HATU与80mg(0.592mmol,4eq)HOAT与0.2ml(1.184mmol,8eq)DIPEA的DMF溶液(75ml)中.反应于常温下反应72h后,减压旋去DMF,乙酸乙酯(20ml)稀释,用饱和NaCl(20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析(乙酸乙酯)得到40mg白色固体1-2,产率45.6%.
[0393] (400MHz,CDCl3)δ8.64(s,1-H),8.11(s,1-H),6.93(q,1-H),6.74(d,1-H),6.54(brs,1-H),5.76(m,2-H),5.49(dd,1-H),5.16(dd,1-H),4.76(q,
1-H),4.37(dd,1-H),2.88(t,2-H),2.70(dd,1-H),2.60(dd,1-H),2.50(t,2-H),2.28(q,
2-H),1.95(m,1-H),1.83(m,6-H),1.67(m,3-H),1.28(m,8-H),0.87(t,3-H),0.84(t,3-H);
13C-NMR(500MHz,CDCl3)δ199.4,170.0,169.4,166.9,163.5,157.9,148.1,133.3,132.7,
128.2,126.9,124.3,71.4,53.4,44.1,42.2,41.0,40.0,38.6,32.2,31.6,28.9(2C),27.8,+
25.7,25.6,22.5,14.9,14.0,9.6;MS(ESI)m/z 593.2(100%)(M+H).
[0394] 实施例75式1-10化合物的合成
[0395]
[0396] 取实施例44制得的原料180mg(0.21mmol,1eq)溶于5ml无水二氯甲烷,加入1ml三氟乙酸,反应常温下搅拌24小时后,减压旋去溶剂与TFA后,用105ml无水DMF,慢慢滴加入溶有320mg(0.84mmol,4eq)HATU与115mg(0.84mmol,4eq)HOAT与0.28ml(1.68mmol,8eq)DIPEA的DMF溶液(105ml)中.反应于常温下反应72h后,减压旋去DMF,乙酸乙酯(20ml)稀释,用饱和NaCl(20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析(乙酸乙酯)得到28mg白色固体1-10,产率20.9%。
[0397] (400MHz,CDCl3)δ8.65(s,1-H),8.10(s,1-H),7.17(d,1-H),6.97(q,1-H),6.42(brs,1-H),5.76(m,2-H),5.49(dd,1-H),5.13(dd,1-H),4.72(q,
1-H),4.37(dd,1-H),3.72(s,1-H),2.88(t,2-H),2.70(dd,1-H),2.60(dd,1-H),2.50(m,
5-H),2.28(q,2-H),2.17(m,1-H),2.12(m,2-H),1.95(s,3-H),1.83(m,3-H),1.67(m,3-H),
1.28(m,8-H),0.87(t,6-H);13C-NMR(500MHz,CDCl3)δ199.4,170.0,169.2,166.9,163.4,
157.9,148.1,133.3,132.7,128.2,126.9,124.3,71.4,51.6,44.1,41.0,40.0,32.2,31.6,
30.0,29.6,28.9(2C),27.8,25.6,22.5,14.97,14.90,14.0;MS(ESI)m/z 593.2(100 % )+
(M+H)。
[0398] 实施例76式1-11化合物的合成
[0399]
[0400] 取实施例45制得的原料190mg(0.226mmol,1eq)溶于5ml无水二氯甲烷,加入1ml三氟乙酸,反应常温下搅拌24小时后,减压旋去溶剂与TFA后,用115ml无水DMF,慢慢滴加入溶有344mg(0.904mmol,4eq)HATU与123mg(0.904mmol,4eq)HOAT与0.32ml(1.808mmol,8eq)DIPEA的DMF溶液(115ml)中.反应于常温下反应72h后,减压旋去DMF,乙酸乙酯(20ml)稀释,用饱和NaCl(20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析(乙酸乙酯)得到43mg白色固体1-11,产率35.6%.
[0401] (400MHz,CDCl3)δ8.65(s,1-H),8.12(s,1-H),6.93(q,1-H),6.50(d,2-H),6.42(brs,1-H),5.76(m,2-H),5.49(dd,1-H),5.13(dd,1-H),
4.72(q,1-H),4.37(dd,1-H),2.88(t,2-H),2.75(m,2-H),2.50(m,2-H),2.28(q,2-H),
1.95(d,3-H),1.83(m,3-H),1.67(m,3-H),1.50(m,3-H),1.28(m,8-H),0.90(m,6-H);
13C-NMR(500MHz,CDCl3)δ199.4,170.0,169.4,166.8,163.5,157.7,148.1,133.0,132.7,
128.3,127.0,124.3,71.4,50.8,44.1,41.6,40.1,32.2,28.9(2C),27.8,25.6,24.5,22.5,+
21.6,15.0,14.0;MS(ESI)m/z 621.2(100%)(M+H).
[0402] 实施例77式5-2化合物的合成
[0403]
[0404] 向实施例46制得原料(56mg,0.068mmol,1eq)溶于5ml无水二氯甲烷,加入1ml三氟乙酸,反应常温下搅拌24小时后,减压旋去溶剂与TFA后,用115ml无水DMF,慢慢滴加入溶有103mg(0.072mmol,4eq)HATU与37mg(0.072mmol,4eq)HOAT与0.1ml(0.544mmol,8eq)DIPEA的DMF溶液(115ml)中.反应于常温下反应72h后,减压旋去DMF,乙酸乙酯(20ml)稀释,用饱和NaCl(20mlX2)洗涤.无水硫酸钠干燥,,减压旋干溶剂.柱层析(乙酸乙酯)得到4mg白色固体5-2,产率10%.
[0405] (400MHz,CDCl3)δ8.74(s,1-H),8.01(s,1-H),6.26(m,2-H),6.00(t,1-H),5.80(dd,1-H),5.74(dd,1-H),5.06(dd,1-H),4.76(d,1-H),4.30(dd,
1-H),2.88(t,2-H),2.75(m,2-H),2.50(m,2-H),2.28(q,2-H),1.95(d,3-H),1.83(m,3-H),
1.67(m,3-H),1.50(m,3-H),1.28(m,8-H),0.90(m,6-H);13C-NMR(500MHz,CDCl3)δ199.4,
170.0,169.4,166.8,163.5,157.7,148.1,133.0,132.7,128.3,127.0,124.3,71.4,50.8,
44.1,41.6,40.1,32.2,28.9(2C),27.8,25.6,24.5,22.5,21.6,15.0,14.0;MS(ESI)m/z +
621.2(100%)(M+H).
[0406] 实施例78式2-1化合物的合成
[0407]
[0408] 向实施例47制得原料(0.331g,0.41mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。
粗产物直接投入下一步。
[0409] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.78g,2.05mmol),HOAt(0.28g,2.05mmol),DIPEA(0.7ml,4.1mmol)的无水DMF溶液中。30℃搅拌
3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.102g固体2-1,产率42%。
[0410] [α]23D:35.6(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.54(s,1H),8.08(s,1H),6.94(q,1H),6.82(m,1H),6.51(d,1H),5.74-5.6(m,2H),5.47(dd,1H),5.14(dd,
1H),4.70(dd,1H)4.32(dd,1H),2.82(t,2H),2.75-2.59(m,2H),2.47(t,2H),2.24(m,
13
2H),1.82(d,3H),1.58(m,2H),1.24(m,8H),0.83(m,3H),0.74(d,3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):δ199.5,171.5,168.8,168.1,164.5,150.6,141.5,136.2,131.5,
130.1,128.2,120.3,74.5,66.1,44.1,42.4,38.6,37.6,31.9,30.8,30.4,29.1,26.2,+
22.8,18.5,14.1ppm.MS(ESI)m/z 591(100%)(M+H)
[0411] 实施例79式2-2化合物的合成
[0412]
[0413] 向实施例48制得原料(0.412g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0414] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.121g固体2-2,产率40%。
23 1
[0415] [α] D:14.3(c 0.5,CHCl3).H NMR(400MHz,CDCl3):δ6.82(m,1H),6.51(d,1H),5.74-5.6(m,2H),5.45(dd,1H),4.84(dd,1H)4.40(d,1H),3.8(m,1H),3.1(t,2H),
2.75-2.59(m,5H),2.47(t,2H),2.24(m,2H),1.82(d,3H),1.58(m,2H),1.24(m,8H),
13
0.83(m,3H),0.74(d,3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):δ199.5,171.5,168.8,
167.2,164.5,,131.5,130.1,128.2,120.3,83.5,74.8,74.5,66.1,46.8,44.1,42.4,38.6,+
37.6,31.9,30.8,30.4,29.1,26.2,22.8,22.0,18.5,14.1ppm.MS(ESI)m/z 606(M+H)[0416] 实施例80式2-3化合物的合成
[0417]
[0418] 向实施例49制得原料(0.504g,0.6mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0419] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.706g,3mmol),HOAt(0.408g,3mmol),DIPEA(1.05ml,6mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.131g固体2-3,产率35%。
[0420] [α]23D:29.1(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ6.82(m,1H),5.74-5.6(m,2H),5.47(dd,1H),4.79(dd,1H)4.31(dd,1H),2.99(t,2H),2.75-2.59(m,3H),2.47(t,,
2H),2.24(m,5H),1.82(d,3H),1.58(m,2H),1.24(m,11H),0.83(m,3H),0.74(d,3H),
13
0.55(d,3H)ppm. C NMR(125MHz,CDCl3):δ199.4,179.2,171.4,168.4,168.2,131.2,
130.2,129.5,128.1,76.3,74.2,66.4,47.5,44.5,38.4,31.8,30.8,30.5,29.4,29.1,+
26.7,24.5,22.3,21.0,19.3,14.1,13.0ppm MS(ESI)m/z 623(M+H)
[0421] 实施例81式2-4化合物的合成
[0422]
[0423] 向实施例50制得原料(0.404g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0424] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.091g固体2-4,产率31%。
[0425] [α]23D:34.7(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ7.6(d,1H),5.78-5.6(m,2H),5.54(dd,1H),5.11(dd,1H),4.35(d,1H),3.4(dd,2H),2.91(t,2H),2.47(m,2H),
2.24(m,2H),1.82(d,J = 7Hz,3H),1.58(m,2H),1.24(m,8H),0.83(m,3H),0.74(d,3H),
13
0.55(d,3H)ppm. C NMR(125MHz,CDCl3):199.3,180.3,171.7,167.3,166.5,163.7,131.6,
129.4,128.4,74.6,66.2,62.2,46.4,44.0,38.4,30.8,30.5,26.3,22.7,18.9,14.2,+
12.9ppm.MS(ESI)m/z 590(M+H)
[0426] 实施例82式2-5化合物的合成
[0427]
[0428] 向实施例51制得原料(0.404g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0429] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.103g固体2-5,产率35%。
[0430] [α]23D:34.7(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):5.76-5.6(m,2H),5.51(dd,1H),4.87(dd,1H),4.41(d,1H),3.4(d,2H),2.91(t,2H),2.47(m,2H),2.24(m,2H),1.82(d,J = 7Hz,3H),1.58(m,2H),1.4(s,1H),1.24(m,8H),0.83(m,3H),0.74(d,3H),0.55(d,3H)
13
ppm. C NMR(125MHz,CDCl3):199.3,180.3,171.7,167.3,160.3,158.3,,131.6,129.4,
128.4,120.3,74.6,66.2,62.2,46.4,44.0,38.4,30.8,30.5,26.3,22.7,18.9,14.2,+
12.9ppm.MS(ESI)m/z 590(M+H)
[0431] 实施例83式2-6化合物的合成
[0432]
[0433] 向实施例52制得原料(0.409g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0434] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.165g固体2-6,产率55%。
23 1
[0435] [α] D:34.1(c 0.9,CHCl3).H NMR(400MHz,CDCl3):7.84(d,1H),7.74(s,1H),7.40(m,2H),5.76-5.6(m,2H),5.51(dd,1H),4.87(dd,1H),4.41(d,1H),4.3(d,2H),3.4(d,
2H),2.91(t,2H),2.47(m,2H),2.24(m,2H),1.82(d,3H),1.58(m,2H),1.4(s,1H),1.24(m,
13
8H),0.83(m,3H),0.74(d,3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):199.7,171.5,
168.4,164.7,141.8,134.5,130.5,130.2,128.5,125.6,125.3,120.4,74.5,66.5,48.5,
44.5,38.5,37.8,31.5,30.8,30.5,29.1,26.1,22.6,18.9,14.5,13.1ppm.MS(ESI)m/z +
600(M+H)
[0436] 实施例84式2-7化合物的合成
[0437]
[0438] 向实施例53制得原料(0.410g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0439] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.183g固体2-7,产率61%。
[0440] [α]23D:21.9(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):8.93(d,1H),8.16(s,1H),7.56(d,1H),5.8-5.7(m,2H),5.52(dd,1H),4.87(dd,1H),4.79(s,1H),4.41(d,1H),3.4(d,
2H),2.92(t,2H),2.47(m,4H),2.08(d,3H),1.58(m,2H),1.25(m,8H),0.83(m,3H),0.74(d,
13
3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):199.3,180.3,171.7,167.3,160.3,158.3,,
131.6,129.4,128.4,120.3,74.6,66.2,62.2,46.4,44.0,38.4,30.8,30.5,26.3,22.7,+
18.9,14.2,12.9ppm.MS(ESI)m/z601(M+H)
[0441] 实施例85式3-2化合物的合成
[0442]
[0443] 向实施例54制得原料(0.413g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0444] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.128g固体3-2,产率42%。
[0445] [α]23D:28.1(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.94(s,1H),8.08(s,1H),6.51(d,1H),5.74-5.6(m,2H),5.47(dd,1H),4.89(dd,1H),4.5-4.35(m,4H),2.82(t,
2H),2.75-2.59(m,2H),2.47(t,2H),2.24(m,2H),1.82(m,2H),1.24(m,8H),0.92(t,3H),
13
0.83(m,3H),0.74(d,3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):δ199.5,171.6,170.8,
168.6,167.4,165.8,148.9,130.1,128.1,124.5,74.3,66.4,61.8,44.1,38.6,37.8,+
31.7,30.6,29.4,29.2,26.3,25.4,22.8,18.9,14.2,9.4ppm.MS(EI,m/z):609(M+1),+
631(M+Na).
[0446] 实施例86式3-3化合物的合成
[0447]
[0448] 向实施例55制得原料(0.399g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0449] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.154g固体3-3,产率53%。
[0450] [α]23D:19.1(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.94(s,1H),8.08(s,1H),5.74-5.6(m,2H),5.47(dd,1H),4.89(dd,1H),4.5-4.35(m,4H),3.85(t,2H),2.82(t,
2H),2.75-2.59(m,2H),2.47(t,2H),2.24(m,2H),1.82(m,2H),1.24(m,8H),0.92(t,3H),
13
0.74(d,3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):δ199.5,171.6,168.6,168.2,
165.8,148.9,130.1,128.1,124.5,74.3,66.4,44.1,42.2,38.6,37.8,31.7,30.6,29.4,+
29.2,26.3,25.4,22.8,18.9,14.2ppm.MS(EI,m/z):581(M+1),
[0451] 实施例87式3-1化合物的合成
[0452]
[0453] 向实施例56制得原料(0.405g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0454] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.136g固体3-1,产率46%。
[0455] [α]23D:14.1(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.94(s,1H),8.08(s,1H),5.74-5.6(m,2H),5.45(d,1H),5.13(d,1H),4.89(dd,1H),4.5-4.35(m,3H),2.82(t,
2H),2.75-2.59(m,2H),2.47(t,2H),2.24(m,2H),1.82(m,2H),1.24(m,8H),0.92(t,3H),
13
0.74(d,3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):δ199.5,171.6,168.6,168.2,
165.8,148.9,138.1,130.2,128.1,124.5,104.6,74.3,66.4,44.1,42.2,38.6,37.8,31.7,+
30.6,29.4,29.2,26.3,25.4,22.8,14.2ppm.MS(EI,m/z):593(M+1),
[0456] 实施例88式4-1化合物的合成
[0457]
[0458] 向实施例57制得原料(0.433g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0459] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.085g固体4-1,产率26%。
[0460] [α]23D:6.9(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.95(s,1H),5.91(q,1H),5.74-5.6(m,2H),4.87-4.81(m,1H),,4.40(d,1H),2.82(m,2H),2.75-2.59(m,2H),2.47(t,
2H),2.24(m,2H),1.82(d,J = 7Hz,3H),1.58(m,2H),1.24(m,8H),0.83(m,3H),0.74(d,
13
6H),0.55(d,6H)ppm. C NMR(125MHz,CDCl3):δ199.5,171.5,169.4,168.2,168.0,164.3,
147.4,131.5,130.2,128.5,124.2,120.3,74.3,.66.2,63.8,44.2,38.9,34.6,31.8,30.7,+
30.4,29.8,29.4,26.1,22.7,18.9,18.6,14.2,13.1ppm.MS(EI,m/z):649(M+1)[0461] 实施例89式4-2化合物的合成
[0462]
[0463] 向实施例58制得原料(0.419g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0464] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.059g固体4-2,产率19%。
[0465] [α]23D:17.3(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.95(s,1H),5.91(q,1H),5.74-5.6(m,2H),4.87-4.81(m,1H),,4.40(d,1H),2.82(m,2H),2.75-2.59(m,2H),2.47(t,
2H),2.24(m,2H),1.82(d,J = 7Hz,3H),1.58(m,2H),1.48(d,3H),1.24(m,8H),0.83(m,
13
3H),0.74(d,3H),0.55(d,3H)ppm. CNMR(125MHz,CDCl3):δ199.5,171.5,169.4,168.2,
168.0,164.3,147.4,131.5,130.2,128.5,124.2,120.3,74.3,.66.2,63.8,53.6,44.0,
38.9,34.6,31.8,30.7,30.4,29.8,29.4,26.1,22.7,18.9,14.2,13.1ppm.MS(EI,m/z):
+
621(M+1)
[0466] 实施例90式4-3化合物的合成
[0467]
[0468] 向实施例59制得原料(0.457g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0469] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.059g固体4-3,产率17%。
[0470] [α]23D:48.3(c 0.9,CHCl3).1HNMR(400MHz,CDCl3):δ8.95(s,1H),7.41(m,2H),7..28(m,3H),5.91(q,1H),5.74-5.6(m,2H),4.87-4.81(m,1H),,4.40(d,1H),2.82(m,2H),
2.75-2.59(m,2H),2.47(t,2H),2.24(m,2H),1.82(d,J = 7Hz,3H),1.58(m,2H),1.48(d,
13
3H),1.24(m,8H),0.83(m,3H),0.74(d,3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):
δ199.5,171.5,169.4,168.2,168.0,164.3,147.4,131.5,130.2,128.5,128.4,127.7,
124.2,120.3,74.3,.66.2,63.8,53.6,44.0,38.9,34.6,31.8,30.7,30.4,29.8,29.4,+
26.1,22.7,18.9,14.2,13.1ppm.MS(EI,m/z):697(M+1)
[0471] 实施例91式4-4化合物的合成
[0472]
[0473] 向实施例60制得原料(0.493g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0474] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.039g固体4-4,产率11%。
[0475] [α]23D:5.1(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.95(s,1H),7.12(d,2H),6.7(d,2H),5.91(q,1H),5.74-5.6(m,2H),5.3(s,1H),4.87-4.81(m,1H),,4.40(d,1H),
2.82(m,2H),2.75-2.59(m,2H),2.47(t,2H),2.24(m,2H),1.82(d,J = 7Hz,3H),1.58(m,
2H),1.48(d,3H),1.24(m,8H),0.83(m,3H),0.74(d,3H),0.55(d,3H)ppm.13C NMR(125MHz,CDCl3):δ199.5,171.5,169.4,168.2,168.0,164.3,147.4,132.1,130.2,128.5,128.4,
115.8,120.3,74.3,.66.2,63.8,53.6,44.0,38.9,34.6,31.8,30.7,30.4,29.8,29.4,+
26.1,22.7,18.9,14.2,13.1ppm.MS(EI,m/z):713(M+1)
[0476] 实施例92式6-2化合物的合成
[0477]
[0478] 向实施例61制得原料(0.370g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0479] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.125g固体6-2,产率48%。
[0480] [α]23D:28.1(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.95(s,1H),5.91(q,1H),5.74-5.6(m,2H),4.87-4.81(m,3H),,4.40(d,1H),2.82(m,2H),2.75-2.59(m,2H),2.47(t,
2H),2.24(m,5H),1.82(d,3H),1.58(m,2H),1.48(d,3H),0.83(m,3H),0.74(d,3H),0.55(d,
13
3H)ppm. C NMR(125MHz,CDCl3):δ194.5,171.5,168.4,165.5,164.2,147.4,131.4,
130.0,128.1,124.2,120.3,74.2,66.1,44.5,36.6,37.6,30.7,30.5,30.1,18.9,13.1ppm +
MS(EI,m/z):523(M+1)
[0481] 实施例93式6-3化合物的合成
[0482]
[0483] 向实施例62制得原料(0.447g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0484] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.142g固体6-3,产率42%。
[0485] [α]23D:28.1(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.95(s,1H),5.91(q,1H),5.74-5.6(m,2H),4.87-4.81(m,3H),,4.40(d,1H),2.82(m,2H),2.75-2.59(m,2H),
2.47(t,2H),2.24(m,2H),1.82(d,3H),1.58(m,2H),1.48(d,3H),0.83(m,20H),0.74(d,
13
3H),0.55(d,3H)ppm. C NMR(125MHz,CDCl3):δ194.5,171.5,168.4,165.5,164.2,147.4,
131.4,130.0,128.1,124.2,120.3,74.2,66.1,44.5,36.6,37.6,30.7,30.5,30.1,29.6,+
29.3,22.7,18.9,14.1,13.1ppm MS(EI,m/z):677(M+1)
[0486] 实施例94式6-4化合物的合成
[0487]
[0488] 向实施例63制得原料(0.408g,0.5mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。粗产物直接投入下一步。
[0489] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.588g,2.5mmol),HOAt(0.34g,2.5mmol),DIPEA(0.87ml,5mmol)的无水DMF溶液中。30℃搅拌3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.132g固体6-4,产率44%。
23 1
[0490] [α] D:32.8(c 0.9,CHCl3).H NMR(400MHz,CDCl3):δ8.95(s,1H),7.33(m,2H),7.23(m,3H),5.91(q,1H),5.74-5.6(m,2H),4.87-4.81(m,3H),,4.40(d,1H),3.66(s,
2H),2.82(m,2H),2.75-2.59(m,2H),2.47(t,2H),2.24(m,2H),1.82(d,3H),1.58(m,2H),
13
1.48(d,3H),0.74(d,6H),ppm. C NMR(125MHz,CDCl3):δ194.5,171.5,168.4,165.5,
164.2,147.4,138.2,131.4,130.1,129.2,127.6,124.5,120.3,74.3,66.3,44.5,38.5,+
37.4,33.9,30.4,30.1,19.8,13.0ppm MS(EI,m/z):599(M+1)
[0491] 实施例95式6-5化合物的合成
[0492]
[0493] 向实施例64制得原料(0.339g,0.41mmol)的无水二氯甲烷(5ml)溶液中,加入1ml三氟乙酸,室温下搅拌24小时。减压旋干,加入5ml甲苯再旋干,除去大量三氟乙酸。
粗产物直接投入下一步。
[0494] 氩气保护下,上一步的粗产物用50ml无水DMF溶解,缓慢滴入HATU(0.78g,2.05mmol),HOAt(0.28g,2.05mmol),DIPEA(0.7ml,4.1mmol)的无水DMF溶液中。30℃搅拌
3天。反应液体系浓度为0.001mol/L。减压旋干DMF,乙酸乙酯溶解,依次用稀盐酸洗涤,饱和NaCl洗涤,无水Na2SO4干燥,过滤,减压旋干后柱层析(石油醚∶乙酸乙酯∶甲醇=
20∶20∶1),得到0.144g固体6-5,产率52%。
[0495] [α]23D:11.3(c 0.9,CHCl3).1H NMR(400MHz,CDCl3):δ8.64(s,1H),8.08(s,1H),6.97(q,J = 7Hz,1H),6.82(m,1H),6.51(d,J = 10.1Hz,1H),5.74-5.6(m,2H),5.47(dd,J = 15.5Hz 6.8Hz,1H),5.14(dd,J = 16Hz 8.2Hz,1H),4.70(dd,J = 10.1Hz 3.2Hz,
1H)4.32(dd,J = 17.4Hz,3.5Hz,1H),3.86(m,1H),3.65(s,1H),2.82(t,J = 7.2Hz,2H),
2.75-2.59(m,2H),2.47(t,J=7.5Hz,2H),2.24(m,2H),1.82(d,J=7Hz,3H),1.58(m,2H),
0.74(d,J=6.7Hz,3H),0.55(d,J=6.7Hz,3H)ppm.
[0496] 13C NMR(125MHz,CDCl3):δ199.5,171.5,168.5,165.5,164.3,147.4,131.4,130.0,128.0,124.2,120.3,74.3,66.2,58.9,46.9,44.5,37.9,30.7,30.5,18.9,13.0ppm.+
MS(EI,m/z):553(M+1),
[0497] 实施例96式6-1化合物的合成
[0498]
[0499] 向实施例65制得的式1-3化合物(0.26g,0.43mmol)的乙腈(50ml)溶液中加入氨水(28.9%,5ml)。室温下反应12小时,反应完毕后减压浓缩,残留物直接柱层析,乙酸乙酯∶甲醇=10∶1,得到0.17g产6-1,收率79%。
[0500] [α]23D:25.4(c 0.6,CHCl3)1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.18(d,J =9.2Hz,1H),6.64(dd,J=8.8,3.2Hz,1H),5.89(ddd,J=15.6,6.8,6.8Hz,1H),5.69(dd,J = 6.8,6.8Hz,1H),5.54(dd,J = 15.6,6.8Hz,1H),5.25(dd,J = 17.6,9.2Hz,1H),
4.61(dd,J=9.6,3.6Hz,1H),4.21(dd,J=17.6,3.2Hz,1H),4.03(d,J=11.2Hz,1H),
3.28(d,J=11.2Hz,1H),2.87(dd,J=16.4,10.0Hz,1H),2.71(dd,J=6.8,6.8Hz,1H),
2.68-2.75(m,1H),2.44(ddd,J = 7.2,7.2,7.2Hz,2H),2.07-2.13(m,1H),1.86(s,3H),
0.70(d,J=6.8Hz,1H),0.53(d,J=6.8Hz,1H),IR(neat)3374.5,3305.1,2961.8,2929.1,
2851.4,1731.6,1666.2,1596.7,1502.7,1237.0,1179.8,1114.4,1020.4cm-1;MS(EI,m/+
z):481(M+1).
[0501] 实施例97式6-6化合物的合成
[0502]
[0503] 0℃条件下,向实施例96制得的式6-1(0.96g,2mmol)化合物的200ml无水二氯甲烷中,加入三乙胺(1ml,4mmol)和酰氯(10mmol),室温下反应2小时。加入哌啶(10mmol),反应1小时,反应完全后,降温至0℃,甲醇淬灭,柱层析,得到0.88g式6-6化合物,产率23 1
80%。[α] D:18.6(c 0.9,CHCl3).H NMR(400MHz,CDCl3):δ8.69(s,1H),8.08(s,1H),
6.97(q,J = 7Hz,1H),6.82(m,1H),6.51(d,J = 10.1Hz,1H),5.74-5.6(m,2H),5.47(dd,J = 15.5Hz 6.8Hz,1H),5.40(dd,J = 16Hz 8.2Hz,1H),4.68(dd,J = 10.1Hz 3.2Hz,
1H)4.32(dd,J = 17.4Hz,3.5Hz,1H),3.86(m,1H),3.65(s,1H),2.82(t,J = 7.2Hz,2H),
2.75-2.59(m,2H),2.47(t,J=7.5Hz,2H),2.24(m,2H),1.82(d,J=7Hz,3H),1.58(m,2H),
13
0.74(d,J = 6.7Hz,3H),0.55(d,J = 6.7Hz,3H)ppm. C NMR(125MHz,CDCl3):δ198.5,
171.5,168.4,165.5,164.3,147.4,131.4,130.0,128.0,124.2,120.3,74.3,66.2,58.9,+
46.9,44.5,37.9,30.7,30.5,18.9,13.0ppm.MS(EI,m/z):552(M+1),
[0504] 实施例98HDAC生化活性的测定
[0505] 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。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。
[0506] 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。
[0507] 3.检测结果与分析:
[0508]
[0509]
[0510] 上表中IC50是指被抑制一半时抑制剂的浓度(50%inhibitory concentration)。
[0511] 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HDAC酶的去乙酰化作用的活性。
[0512] 实施例99检测化合物对癌细胞活性实验
[0513] 1.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。
[0514] 2.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),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);分别用DMEM+10%FBS培养基培养或者使用1640+10%FBS培养。
[0515] 3.实验方法与结果分析:
[0516] 实验组:190μl细胞悬液+10μl不同浓度的药物(终浓度为10-5~10-10M)[0517] 空白对照组:200μl PBS
[0518] 阴性对照组:190μl细胞悬液+10μl 2%DMSO(DMSO终浓度为0.1%)
[0519] 阳性对照组:190μl细胞悬液+10μl不同浓度的化合物
[0520] 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;
[0521] 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;
[0522] c).每孔加入20μl 5mg/ml的MTT,37℃5%的CO2培养箱孵育4小时;
[0523] d).弃上清,每孔加入100μl的DMSO,振荡;
[0524] e).570nm读数,计算细胞存活率,根据结果计算GI50,得下表。
[0525]
[0526] 上表中GI50表示的是细胞50%生长抑制所需的药物浓度(50%growthinhibition)。
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