CN112292386A - 作为半乳凝素-3抑制剂的基于四氢吡喃的硫代二糖模拟物 - Google Patents
作为半乳凝素-3抑制剂的基于四氢吡喃的硫代二糖模拟物 Download PDFInfo
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- CN112292386A CN112292386A CN201980039715.9A CN201980039715A CN112292386A CN 112292386 A CN112292386 A CN 112292386A CN 201980039715 A CN201980039715 A CN 201980039715A CN 112292386 A CN112292386 A CN 112292386A
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- pyran
- triazol
- tetrahydro
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- hydroxy
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Abstract
本公开涉及抑制Gal‑3的式(I)的化合物,且包括药学上可接受的盐,包含所述化合物的组合物,以及制备和使用所述化合物和组合物的方法。
Description
发明背景
半乳凝素-3(Gal-3)是约30KDa的β-半乳糖苷结合凝集素(Cell 76:597-598),其参与炎症和纤维化过程的调节。(Immunological Reviews 230:160-171)。在不受控制的炎症和促纤维化的状况下,Gal-3促进成纤维细胞增殖和转化并介导胶原蛋白产生(Circulation 110:3121-3128)。
Gal-3位于许多细胞位置,例如细胞质、细胞核和细胞表面。Gal-3也由各种细胞类型,主要是巨噬细胞和单核细胞分泌到血流中(J Pharmacol Exp Ther 351:336–343)。文献中有许多证据链支持Gal-3参与多个器官如如肺(Am J.Respir.Crit.Care Med.185:537-546)、肝(PNAS 103:5060-5065)和肾(Am.J.Pathol.172:288-298)的纤维化过程的发展。Gal-3也已被鉴定为心力衰竭的生物标记,表明Gal-3的调节在治疗心力衰竭中具有潜在的用途(Curr.Heart Fail.Rep.7:1-8)。Gal-3的调节可被用于治疗癌症,因为Gal-3参与在血管生成、细胞凋亡和转移途径中起关键作用的细胞生长和分化(Galectin-3C:HumanLectin for Treatment of Cancer.ACS Symposium Series,第1115卷第12章,195-23)。最近,Gal-3抑制剂已被证明当用于联合免疫疗法时具有积极的作用(GalectinTherapeutics.Press Release,2017年2月7日)。
一些出版物和专利申请描述了作为抗纤维化剂被研究的Gal-3的合成抑制剂。这些方式的最近实例是WO2005113568、WO2005113569、US2014067986、WO2014067986、WO2017080971、WO2016120403、US20140099319和WO2014067986。
发明描述
本公开涉及抑制Gal-3的本发明的化合物,包括药学上可接受的盐,包含所述化合物的组合物,以及制备和使用这样的化合物和组合物的方法。
本发明的一个方面是式(I)的化合物:
或其药学上可接受的盐,其中:
A是O、NH或N(COCH3);
R2是烷基、(CO2(R5))烷基或(CON(R6)(R7))烷基;
R3是环烷基、四氢吡喃基或Ar1,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N;
R4是烷基、环烷基、二环[2.2.1-2]烷基或Ar2,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5;
R5是氢或烷基;
R6是氢、烷基、烷基羰基或苯基;
R7是氢或烷基;
或(R6)(R7)N一起是氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基或二氧化硫吗啉基,且被0-3个选自以下的取代基取代:卤代基、烷基、羟基和烷氧基;
Ar1是苯基、噻唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基;且
Ar2是苯基、联苯基、萘基、噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉基或喹喔啉基。
本发明的另一个方面是式(Ia)的化合物:
或其药学上可接受的盐,其中:
R2是烷基、(CO2(R5))烷基或(CON(R6)(R7))烷基;
R3是环烷基、四氢吡喃基或Ar1,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N;
R4是烷基、环烷基、二环[2.2.1-2]烷基或Ar2,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5;
R5是氢或烷基;
R6是氢、烷基、烷基羰基或苯基;
R7是氢或烷基;
或(R6)(R7)N一起是氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基或二氧化硫吗啉基,且被0-3个选自以下的取代基取代:卤代基、烷基、羟基和烷氧基;
Ar1是苯基、噻唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基;且
Ar2是苯基、联苯基、萘基、噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉基或喹喔啉基。
本发明的另一个方面是式(I)或(Ia)的化合物,其中R2是烷基。
本发明的另一个方面是式(I)或(Ia)的化合物,其中R2是(CO2(R5))烷基。
本发明的另一个方面是式(I)或(Ia)的化合物,其中R2是(CON(R6)(R7))烷基。
本发明的另一个方面是式(I)或(Ia)的化合物,其中R3是Ar1,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N。
本发明的另一个方面是式(I)或(Ia)的化合物,其中R3是环烷基或四氢吡喃基,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N。
本发明的另一个方面是式(I)或(Ia)的化合物,其中R4是Ar2,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5。
本发明的另一个方面是式(I)或(Ia)的化合物,其中R4是烷基、环烷基或二环[2.2.1-2]烷基,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5。
本发明的另一个方面是式(I)或(Ia)的化合物,其中Ar1是苯基、吡啶基、哒嗪基、嘧啶基或吡嗪基,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N。
本发明的另一个方面是式(I)或(Ia)的化合物,其中Ar2是苯基、吡啶基、哒嗪基、嘧啶基或吡嗪基,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5。
对于式I化合物,包括R1、R2、R3、R4、R5、R6、R7、Ar1和Ar2的可变取代基的任何实例的范围,可独立地与可变取代基的任何其它实例的范围一起使用。因此,本发明包括不同方面的组合。
除非另有说明,否则这些术语具有以下含义。“烷基”是指由1至6个碳组成的直链或支链烷基。“烯基”是指由2至6个碳与至少一个双键组成的直链或支链烷基。“炔基”是指由2至6个碳与至少一个叁键组成的直链或支链烷基。“环烷基”是指由3至7个碳组成的单环环系。具有烃结构部分的术语(例如烷氧基)包括由1至6个碳组成的烃部分的直链和支链异构体。“卤代基”包括氟、氯、溴和碘。“卤代烷基”和“卤代烷氧基”包括从单卤代到全卤代的所有卤代异构体。“芳基”是指具有5-12个碳原子的单环或双环芳族环系,其中一个或两个环是芳族的。芳基的代表性实例包括但不限于茚满基、茚基、萘基、苯基和四氢萘基。“杂芳基”是指具有1-5个独立地选自氮、氧和硫的杂原子的5至7元单环或8至11元双环芳族环系统。在没有指定键合连接位置的情况下,键合可以连接在本领域技术人员所理解的任何适当位置。取代基和键合模式的组合仅仅是本领域技术人员所理解的产生稳定化合物的那些。括号和多括号术语旨在向本领域技术人员阐明键合关系。例如,术语((R)烷基)是指进一步被取代基R取代的烷基取代基。
本发明包括所述化合物的所有药学上可接受的盐形式。药学上可接受的盐是其中的抗衡离子对化合物的生理活性或毒性没有显著贡献并因此作为药理学等价物起作用的那些。这些盐可以根据常规有机技术使用市售试剂制备。一些阴离子盐形式包括乙酸盐、醋硬脂酸盐(acistrate)、苯磺酸盐、溴化物、氯化物、柠檬酸盐、富马酸盐、葡糖醛酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、双羟萘酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐和昔萘酸盐(xinofoate)。一些阳离子盐形式包括铵、铝、N,N'-二苄基乙二胺(benzathine)、铋、钙、胆碱、二乙胺、二乙醇胺、锂、镁、葡甲胺、4-苯基环己基胺、哌嗪、钾、钠、氨丁三醇和锌。
本发明的一些化合物以立体异构形式存在。本发明包括化合物的所有立体异构形式,包括对映异构体和非对映异构体。制备和分离立体异构体的方法是本领域已知的。本发明包括化合物的所有互变异构形式。本发明包括阻转异构体和旋转异构体。
本发明意欲包括本发明化合物中存在的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。作为一般实例而非限制,氢的同位素包括氘和氚。碳的同位素包括13C和14C。同位素标记的本发明化合物通常可通过本领域技术人员已知的常规技术或通过与本文所述的那些类似的方法,使用适当的同位素标记的试剂代替否则使用的非标记的试剂来制备。这些化合物可具有多种潜在用途,例如作为测定生物活性的标准品和试剂。在稳定的同位素的情况下,此类化合物可具有有利地改变生物、药理学或药代动力学性质的潜力。
生物学方法
测定缓冲组合物:在无菌水中制备的25mM HEPES,100mM NaCl,0.005%Tween 20,0.05%BSA(所有试剂均来自Sigma)
对照:
阳性对照:100%DMSO(1μl)+His-标记的hGal-3(20μL)+B-ASF(20μl)+抗-HisTerbium抗体(5μl)+Strep d2抗体(5μl)。
阴性对照:100%DMSO(1μl)+His-标记的hGal-3(20μL)+抗His Terbium抗体(5μl)+Strep d2抗体(5μl)。
储液制备:
方案:Gal-3测定在384白色Opti板中在250-300rpm温和振荡下于室温下(三个复孔)进行。从原始储备液中,制备2.525X工作储备液浓度的His-标记的重组人Gal-3(hGal-3)和B-ASF。从工作储备液中,将20μl hGal-3(15nM)和20μl B-ASF(15nM)加入到板中。在阴性对照中,仅添加hGal-3。制备化合物在100%DMSO中的50x浓度范围的工作储备液。将1μL化合物的等分试样加入到孔中,并与20μl hGal-3/孔预孵育30分钟,然后将20μl B-ASF加入,并再孵育1小时。为了检测信号,加入5μL(最终浓度为1.0nM)铽标记的抗-His抗体并孵育30分钟,随后加入5μL(最终浓度为20nM)链霉抗生物素d2,并再孵育1小时。在Envision2104Multilabel Reader上使用HTRF筛选方案(激发波长=340nm,发射波长=615nm/665nm)检测分析信号。使用Toolset和Curve Master分析数据。结果报告在实验部分(IC50,μM)。
药物组合物和使用方法
本发明的化合物抑制Gal-3。因此,本发明的另一个方面是药物组合物,其包含治疗有效量的本发明的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明的另一个方面是使用本发明的化合物治疗患有疾病或病症的患者的方法,所述疾病或病症选自器官纤维化(包括肝、肾、肺、心脏和皮肤)、肝疾病和病症(包括急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生衰竭、非酒精性脂肪性肝炎(NASH)、肝功能减退和肝血流障碍)、细胞增殖性疾病、癌症和病症(包括实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波西肉瘤、白血病、慢性淋巴细胞性白血病(CLL))和癌细胞的侵袭性转移)、炎性疾病和病症(包括银屑病、肾病和肺炎)、胃肠道疾病和病症(包括肠易激综合征(IBS)、炎性肠病(IBD)和胰腺分泌异常)、肾疾病和病症、尿道相关疾病和病症(包括良性前列腺增生或与神经病性膀胱疾病、脊髓肿瘤、椎间盘突出、椎管狭窄相关的症状和源自糖尿病的症状)、下泌尿道疾病和病症(包括下泌尿道阻塞)、下泌尿道炎性疾病和病症(包括排尿困难和频尿)、胰腺疾病和病症、异常血管发生相关疾病和病症(包括动脉栓塞)、硬皮病、脑相关疾病和病症(包括脑梗塞和脑出血)、神经病性疼痛和周围神经病变、眼疾病和病症(包括年龄相关性黄斑变性(AMD)、糖尿病性视网膜病、增生性玻璃体视网膜病(PVR)、瘢痕性类天疱疮和青光眼滤过手术瘢痕形成)。
本发明的另一个方面是治疗肾纤维化、肺纤维化、肝纤维化、动脉纤维化和系统性硬化病的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗器官纤维化(包括肝、肾、肺、心脏和皮肤)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗肝疾病和病症(包括急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生衰竭、非酒精性脂肪性肝炎(NASH)、肝功能减退和肝血流障碍)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗细胞增殖性疾病、癌症和病症(包括实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波西肉瘤、白血病、慢性淋巴细胞性白血病(CLL))和癌细胞的侵袭性转移)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗炎性疾病和病症(包括银屑病、肾病和肺炎)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗胃肠道疾病和病症(包括肠易激综合征(IBS),炎性肠病(IBD)和胰腺分泌异常)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗肾疾病和病症的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗尿道相关疾病和病症(包括良性前列腺增生或与神经病性膀胱疾病、脊髓肿瘤、椎间盘突出、椎管狭窄相关的症状和源自糖尿病的症状)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗下泌尿道疾病和病症(包括下泌尿道阻塞)、下泌尿道炎性疾病和病症(包括排尿困难和频尿)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗胰腺疾病和病症的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗异常血管发生相关疾病和病症(包括动脉栓塞)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗脑相关疾病和病症(包括脑梗塞和脑出血)的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗神经病性疼痛和周围神经病变的方法,所述方法包括向患者施用本发明的化合物。
本发明的另一个方面是治疗眼疾病和病症(包括年龄相关性黄斑变性(AMD)、糖尿病性视网膜病、增生性玻璃体视网膜病(PVR)、瘢痕性类天疱疮和青光眼滤过手术瘢痕形成)的方法,所述方法包括向患者施用本发明的化合物。
本发明的化合物可用于治疗和/或预防其中Gal-3起作用的病症。
本发明的化合物可用于制备治疗和/或预防病症的药物,在所述病症中抑制Gal-3的生理活性是有用的,所述病症例如是如下疾病:其中Gal-3受体参与该疾病、Gal-3受体涉及该疾病的病因学或病理学、或Gal-3受体与该疾病的至少一种症状相关。
本发明的化合物可以单独使用,与本发明的其它化合物组合使用,或与一种或多种、优选一至两种其它活性剂组合使用。
“治疗有效”是指提供疼痛领域从业者所理解的有意义的患者益处所需的药物的量。
“患者”是指如本领域从业者所理解的患有疼痛并适于治疗的人。
“治疗”、“疗法”、“方案”和相关术语如本领域从业者所理解那样的使用。
本发明的化合物通常以药物组合物的形式给予,该药物组合物包含治疗有效量的本发明的化合物或其药学上可接受的盐和药学上可接受的载体,并且可以含有常规赋形剂。治疗有效量是提供有意义的患者益处所需的量。药学上可接受的载体是那些具有可接受的安全性的常规已知的载体。组合物包括所有常见的固体和液体形式,包括胶囊、片剂、糖锭和粉末以及液体混悬剂、糖浆、酏剂和溶液剂。组合物使用常规的制剂技术制备,并且常规的赋形剂(例如粘合剂和润湿剂)和载体(例如水和醇)通常用于组合物。参见,例如,Remington’s Pharmaceutical Sciences,第17版,Mack Publishing Company,Easton,PA(1985)。
固体组合物通常以剂量单位配制,并且每剂量提供约1至1000mg活性成分的组合物是优选的。剂量的一些实例是1mg、10mg、100mg、250mg、500mg和1000mg。通常,其它抗逆转录病毒药物将以类似于临床使用的该类药物的单位范围存在。通常,这是0.25-1000mg/单位。
液体组合物通常在剂量单位范围内。通常,液体组合物的单位剂量范围将是1-100mg/mL。剂量的一些实例是1mg/mL、10mg/mL、25mg/mL、50mg/mL和100mg/mL。
本发明包括所有常规的施用方式;优选口服和肠胃外方法。通常,施用方案将类似于临床使用的其它药物。通常,日剂量将是1-100mg/kg体重/天。通常,口服需要更多的化合物,而肠胃外需要更少的化合物。然而,具体的施用方案将由医师使用合理的医学判断来确定。
化学方法
本发明的化合物可以通过本领域已知的各种方法制备,包括以下流程和具体实施方案部分中的那些方法。合成方案中所示的结构编号和变量编号与权利要求书或说明书其余部分中的结构或变量编号不同,并且不应与其混淆。流程中的变量仅用于说明如何制备本发明的一些化合物。本公开不限于前述说明性实例,并且应当认为实例在所有方面都是说明性的而非限制性的,应参照的是权利要求而不是前述实例,并且因此意在包括落入权利要求的等同方案的含义和范围内的所有改变。
部分A
对于每个实施例和中间体报告的分析型LC-MS/HPLC保留时间使用了以下通用分析型LC-MS/HPLC条件之一
LC/MS方法:
LC/MS方法1
起始%B=0,最终%B=100,经2分钟梯度;保持在100%B达1分钟
流速=0.8mL/分钟
检测器波长=254nm
溶剂A=90%水,10%甲醇,0.1%TFA
溶剂B=10%水,90%甲醇,0.1%TFA
柱=BEH C18 2.1X 50mm,1.7μm
炉温=40℃
LC/MS方法2
起始%B=0,最终%B=100,经2分钟梯度;保持在100%B达1分钟
流速=0.8mL/分钟
检测器波长=220nm
溶剂A=90%水,10%甲醇,0.1%TFA
溶剂B=10%水,90%甲醇,0.1%TFA
柱=BEH C18 2.1X 50mm,1.7μm
炉温=40℃
LC/MS方法3
条件:起始%B=0,最终%B=100,经4分钟梯度;保持在100%B达1分钟
溶剂A:90%水,10%甲醇,10mM乙酸铵
溶剂B:10%水,90%甲醇,10mM乙酸铵
柱:Phenomenex Luna C18,2.0x 50mm,3μm
流速:0.8mL/分钟
检测器波长:220nm
LC/MS方法4
起始%B=0,最终%B=100,经2分钟梯度;保持在100%B达1分钟
流速=0.8mL/分钟
检测器波长=220nm
溶剂A=90%水,10%乙腈,0.05%TFA
溶剂B=10%水,90%乙腈,0.05%TFA
柱=BEH C18 2.1x 50mm,1.7μm颗粒
制备型HPLC方法
制备型HPLC方法1
起始%B=5,%B=50,经15分钟梯度,最终%B=100,经另外的3分钟梯度;保持在100%B达5分钟
流速=40mL/分钟
检测器波长=254nm
溶剂A=5%乙腈,95%水,0.1%TFA
溶剂B=95%乙腈,5%水,0.1%TFA
柱=Waters Sunfire 30x 150mm,5μm,C18
制备型HPLC方法2
起始%B=5,最终%B=100,经20分钟梯度;保持在100%B达5分钟
流速=40mL/分钟
检测器波长=254nm
溶剂A=5%乙腈,95%水,0.1%TFA
溶剂B=95%乙腈,5%水0.1%TFA
柱=Waters Sunfire 30x 150mm,5μm,C18
制备型HPLC方法3
起始%B=5,%B=60历经15分钟梯度,最终%B=100,经另外的3分钟梯度;保持在100%B达5分钟
流速=40mL/分钟
检测器波长=254nm
溶剂A=5%乙腈,95%水,0.1%TFA
溶剂B=95%乙腈,5%水0.1%TFA
柱=Waters Sunfire 30x 150mm,5μm,C18
制备型HPLC方法4
起始%B=30,最终%B=100,经15分钟梯度;保持在100%B达5分钟
流速=40mL/分钟
检测器波长=220nm
溶剂A=10%甲醇,90%水,0.1%TFA
溶剂B=90%甲醇,10%水,0.1%TFA
柱=Luna Axia 30x 100mm,5μm,C18
制备型MPLC方法
制备型MPLC方法1
起始%B=5,最终%B=100,经18分钟梯度(14柱体积);保持在100%B达4分钟(3柱体积)
流速=40mL/分钟
检测器波长=254nm
溶剂A=5%乙腈,95%水,0.1%TFA
溶剂B=95%乙腈,5%水0.1%TFA
柱=50g Redisep Gold柱,C18
分析型HPLC方法
分析型HPLC方法1
条件:10%B→100%B,经15分钟梯度;保持在100%B达10分钟
溶剂A:5%乙腈,95%水,0.1%TFA
溶剂B:95%乙腈,5%水,0.1%TFA
柱:Waters Sunfire C18,3.0x 150mm,3.5μm
流速:0.5mL/分钟
检测器波长:254nm
分析型HPLC方法2
条件:10%B→100%B,经15分钟梯度;保持在100%B达10分钟
溶剂A:5%乙腈,95%水,0.1%TFA
溶剂B:95%乙腈,5%水,0.1%TFA
柱:Waters Xbridge phenyl,3.0x 150mm,3.5μm
流速:0.5mL/分钟
检测器波长:254nm
分析型HPLC方法3
条件:10%B→100%B,经15分钟梯度;保持在100%B达3分钟
溶剂A:5%乙腈,95%水,0.1%TFA
溶剂B:95%乙腈,5%水,0.1%TFA
柱:Xselect CSH C18,3.0x 150mm,3.5μm
流速:1.0mL/分钟
检测器波长:254nm
分析型HPLC方法4
条件:10%B→100%B,经15分钟梯度;保持在100%B达3分钟
溶剂A:5%乙腈,95%水,0.1%TFA
溶剂B:95%乙腈,5%水,0.1%TFA
柱:Zorbax Bonus RP,3.0x 150mm,3.5μm
流速:1.0mL/分钟
检测器波长:254nm
制备型HPLC(LC/MS监测)方法5
起始%B=10,最终%B=50,经20分钟梯度;保持在100%B达4分钟
流速=20mL/分钟
检测器波长=220nm(由LCMS信号触发的级分收集)
溶剂A=5%乙腈,95%水,0.1%乙酸铵
溶剂B=95%乙腈,5%水0.1%乙酸铵
柱=Xbridge C18,200mm x 19mm,5μm颗粒
制备型HPLC(LC/MS监测)方法6
起始%B=5,最终%B=45,经20分钟梯度;保持在100%B达4分钟
流速=20mL/分钟
检测器波长=220nm(由LCMS信号触发的级分收集)
溶剂A=5%乙腈,95%水,0.1%TFA
溶剂B=95%乙腈,5%水0.1%TFA
柱=Xbridge C18,200mm x 19mm,5μm颗粒
制备型HPLC方法7
起始%B=0,最终%B=100,经10分钟梯度;保持在100%B达2分钟
流速=40mL/分钟
检测器波长=220nm
溶剂A=10%乙腈,90%水,0.1%TFA
溶剂B=90%乙腈,10%水0.1%TFA
柱=Phenomonex Luna AXIA C18,30mm x 100mm,5μm颗粒
分析型LC/MS方法
分析型LC/MS方法1
起始%B=0,最终%B=100,经3分钟梯度;保持在100%B达0.75分钟
流速=1mL/分钟
检测器波长=220nm
溶剂A=5%乙腈,95%水,0.1%乙酸铵
溶剂B=95%乙腈,5%水0.1%乙酸铵
柱=Xbridge C18,2.1mm x 50mm,1.7μm颗粒
温度=50℃
分析型LC/MS方法2
起始%B=0,最终%B=100,经3分钟梯度;保持在100%B达0.75分钟
流速=1mL/分钟
检测器波长=220nm
溶剂A=5%乙腈,95%水,0.1%TFA
溶剂B=95%乙腈,5%水,0.1%TFA
柱=Xbridge C18,2.1mm x 50mm,1.7μm颗粒
温度=50℃
制备中间体(1)
制备1-(二氟甲基)-3-乙炔基苯
在N2下向3-乙炔基苯甲醛(200mg,1.537mmol)在CH2Cl2(4mL)中的搅拌的溶液中加入DAST(0.305mL,2.305mmol)。将该反应混合液在室温搅拌24h。将该混合液转移到含饱和的NaHCO3水溶液(10mL)的分液漏斗。将水层用二氯甲烷萃取(3x 15mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→20%在己烷中的乙酸乙酯;40g柱),得到1-(二氟甲基)-3-乙炔基苯(104mg,0.684mmol,45%收率),为无色油状物。1H NMR(400MHz,氯仿-d)δ7.66(s,1H),7.62(dd,J=7.7,1.1Hz,1H),7.56-7.50(m,1H),7.48-7.42(m,1H),6.65(t,J=56.2Hz,1H),3.15(s,1H);19F NMR(376MHz,氯仿-d)δ-111.50(s,1F);13C NMR(101MHz,氯仿-d)δ134.3(t,J=22.7Hz,1C),133.9(t,J=1.9Hz,1C),128.9(t,J=6.2Hz,1C),128.4,125.4(t,J=6.2Hz,1C),122.5,113.7(t,J=239.3Hz,1C),82.2,77.9。
制备1-(二氟甲氧基)-3-乙炔基苯
向3-乙炔基苯酚(0.264g,2.235mmol)在CH2Cl2(9mL)中的溶液中加入氢氧化钾水溶液(20wt%)(3.13mL,13.41mmol)。然后通过注射器加入(溴二氟甲基)三甲基硅烷(0.556mL,3.58mmol),并将该反应混合液在室温搅拌2h。将该混合液转移到含水(10mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 15mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→20%在己烷中的乙酸乙酯;40g柱),得到1-(二氟甲氧基)-3-乙炔基苯(195mg,1.160mmol,52%收率),为无色油状物。1H NMR(400MHz,氯仿-d)δ7.42-7.32(m,2H),7.28(br s,1H),7.15(dt,J=7.1,2.1Hz,1H),6.53(t,J=73.5Hz,1H),3.14(s,1H);19F NMR(376MHz,氯仿-d)δ-80.98(s,1F);13C NMR(101MHz,氯仿-d)δ150.5,129.4,128.8,123.5,122.7,120.0,115.3(t,J=260.5Hz,1C),82.0,77.9。
制备2-乙炔基-5-氟嘧啶
步骤1.制备5-氟-2-((三甲基硅烷基)乙炔基)嘧啶
将在压力容器中的2-氯-5-氟嘧啶(0.8g,6.04mmol)和乙炔基三甲基硅烷(1.779g,18.11mmol)在甲苯(30mL)中的溶液用N2脱气。然后加入三乙胺(3.37mL,24.15mmol)、碘化铜(I)(0.115g,0.604mmol)和双(三苯基膦)二氯化钯(II)(0.424g,0.604mmol)。密封容器,并将该反应混合液在60℃加热16h。将该混合液冷却至室温,并经Celite垫过滤。将滤液转移到含饱和的NaHCO3水溶液的分液漏斗(25mL)。将水层用乙酸乙酯萃取(3x 50mL)。将合并的有机层用盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(5%→15%在己烷中的乙酸乙酯;120g柱),得到5-氟-2-((三甲基硅烷基)乙炔基)嘧啶(779mg,4.01mmol,66%收率),为黄色固体:1H NMR(400MHz,氯仿-d)δ8.60(s,2H),0.32(s,9H);LC/MS(ESI)m/e 195.0[(M+H)+,计算值C9H12FN2Si 195.1],tR=1.81分钟(方法2)。
步骤2
向5-氟-2-((三甲基硅烷基)乙炔基)嘧啶(760mg,3.91mmol)在MeOH(20mL)中的混合液中加入无水碳酸钾(81mg,0.587mmol)。将该反应混合液在室温搅拌1h。将该混合液用饱和的NH4Cl水溶液(3mL)和1N HCl(0.4mL)处理。然后将该混合液浓缩以除去大部分甲醇。将剩余的液体转移到含水(20mL)和饱和的NaHCO3水溶液(20mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 10mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%→60%在己烷中的乙酸乙酯;80g柱),得到2-乙炔基-5-氟嘧啶(349mg,2.86mmol,73%收率),为棕褐色固体。1H NMR(400MHz,氯仿-d)δ8.62(s,2H),3.15(s,1H);19F NMR(376MHz,氯仿-d)δ-134.28(s,1F);LC/MS(ESI)m/e 123.0[(M+H)+,计算值C6H4FN2 123.0],tR=0.71分钟(方法2)。
制备2-乙炔基-5-甲氧基嘧啶
向5-氟-2-((三甲基硅烷基)乙炔基)嘧啶(310mg,1.596mmol)在MeOH(8mL)中的混合液中加入无水碳酸钾(33.1mg,0.239mmol)。将该反应混合液在室温搅拌14h。LC/MS显示2-乙炔基-5-氟嘧啶与2-乙炔基-5-甲氧基嘧啶一起形成。将该混合液浓缩,并转移到含水(10mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 10mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%→60%在己烷中的乙酸乙酯;40g柱),得到2-乙炔基-5-氟嘧啶(67mg,0.549mmol,34%收率),为棕褐色固体和2-乙炔基-5-甲氧基嘧啶(20mg,0.149mmol,9%收率),为白色泡沫。
2-乙炔基-5-氟嘧啶的数据:
1H NMR(400MHz,氯仿-d)δ8.62(s,2H),3.15(s,1H);LC/MS(ESI)m/e 123.0[(M+H)+,计算值C6H4FN2 123.0],tR=0.50分钟(方法1)。
2-乙炔基-5-甲氧基嘧啶的数据:
1H NMR(400MHz,氯仿-d)δ8.40(s,2H),3.97(s,3H),3.07(s,1H);LC/MS(ESI)m/e135.1[(M+H)+,计算值C7H7N2O 135.1],tR=0.72分钟(方法1)。
制备5-乙炔基-2-甲氧基嘧啶
步骤1.制备2-氟-5-((三甲基硅烷基)乙炔基)嘧啶
在密封的试管中,在氮气下将5-溴-2-氟嘧啶(175mg,0.989mmol)、双(三苯基膦)氯化钯(II)(17.35mg,0.025mmol)、碘化铜(I)(4.71mg,0.025mmol)和二异丙胺(1691μl,11.87mmol)合并。然后加入乙炔基三甲基硅烷(151μl,1.088mmol),并将该反应混合液在40℃搅拌16h。将该反应混合液用水淬灭,并用CH2Cl2萃取(3x 20mL)。将合并的有机层经硫酸镁干燥,并减压浓缩。将粗制的产物经硅胶柱色谱纯化(0%→30%在己烷中的乙酸乙酯;40g柱),得到2-氟-5-((三甲基硅烷基)乙炔基)嘧啶(128mg,0.659mmol,67%收率)。1H NMR(400MHz,氯仿-d)δ8.70(d,J=1.5Hz,2H),0.29(s,9H);LC/MS(ESI)m/e 195.0[(M+H)+,计算值C9H12FN2Si 195.1],tR=1.89分钟(方法2)。
步骤2
在圆底烧瓶中,将氢氧化钾(72.2mg,1.287mmol)加入2-氟-5-((三甲基硅烷基)乙炔基)嘧啶(125mg,0.643mmol)在MeOH(2mL)和CH2Cl2(1.000mL)中的溶液中。将该反应混合液在室温搅拌3h。将该反应用水淬灭(10mL),并用DCM萃取(3x 10mL)。将合并的有机层经硫酸镁干燥,过滤,并真空浓缩。将粗制的产物经硅胶柱色谱纯化(0%→30%在己烷中的乙酸乙酯;40g柱),得到5-乙炔基-2-甲氧基嘧啶(70mg,0.522mmol,81%收率)。1H NMR(400MHz,氯仿-d)δ8.63(s,2H),4.05(s,3H),3.29(s,1H);13C NMR(101MHz,氯仿-d)δ163.9,161.6,111.4,81.9,54.9;LC/MS(ESI)m/e 135.0[(M+H)+,计算值C7H7N2O 135.0],tR=1.39分钟(方法2)。
制备N-(2-乙炔基嘧啶-4-基)乙酰胺
步骤1.制备N-(2-氯嘧啶-4-基)乙酰胺
在圆底烧瓶中,将乙酰氯(0.823mL,11.58mmol)加入2-氯嘧啶-4-胺(750mg,5.79mmol)在吡啶(1.873mL,23.16mmol)和CH2CL2(30mL)中的溶液中。将该反应混合液在室温搅拌16h。将该反应混合液用冷的1N HCl(2x 40mL)、饱和的碳酸氢钠水溶液(50mL)和盐水(50mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%→65%在己烷中的乙酸乙酯;120g柱),得到N-(2-氯嘧啶-4-基)乙酰胺(610mg,3.56mmol,61%收率),为浅黄色固体。1H NMR(400MHz,氯仿-d)δ8.53(d,J=5.8Hz,1H),8.13(d,J=5.8Hz,1H),2.27(s,3H);LC/MS(ESI)m/e 171.9[(M+Na)+,计算值C6H6ClN3ONa 172.1],tR=0.72分钟(方法2)。
步骤2.制备N-(2-((三甲基硅烷基)乙炔基)嘧啶-4-基)乙酰胺
将N-(2-氯嘧啶-4-基)乙酰胺(240mg,1.399mmol)和乙炔基三甲基硅烷(0.233mL,1.678mmol)在甲苯(6mL)中的溶液用N2脱气。然后加入三乙胺(0.780mL,5.59mmol)、碘化铜(I)(26.6mg,0.140mmol)和双(三苯基膦)二氯化钯(II)(98mg,0.140mmol),并将该反应混合液在60℃加热16h。将该混合液冷却至室温,并转移到含饱和的NaHCO3水溶液的分液漏斗(25mL)。将水层用乙酸乙酯萃取(3x 50mL)。将合并的有机层用水(25mL)、盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(5%→50%在己烷中的乙酸乙酯;40g柱),得到N-(2-((三甲基硅烷基)乙炔基)嘧啶-4-基)乙酰胺(120mg,0.514mmol,37%收率)。1H NMR(400MHz,氯仿-d)δ8.62(d,J=5.8Hz,1H),8.28(br s,1H),8.12(d,J=5.8Hz,1H),2.25(s,3H),0.30(s,9H);LC/MS(ESI)m/e 234.0[(M+H)+,计算值C11H16N3OSi 234.1],tR=1.77分钟(方法2)。
步骤3
在密封的小瓶中,将TBAF(1.0M在THF中)(0.321mL,0.321mmol)在0℃加入N-(2-((三甲基硅烷基)乙炔基)嘧啶-4-基)乙酰胺(50mg,0.214mmol)在THF(1.5mL)中的溶液中。将该反应混合液在0℃搅拌1h。将粗制的产物减压浓缩,并将经硅胶柱色谱纯化(20%→80%在己烷中的乙酸乙酯;24g柱),得到N-(2-乙炔基嘧啶-4-基)乙酰胺(22mg,0.137mmol,64%收率)。1H NMR(400MHz,氯仿-d)δ8.63(d,J=5.8Hz,1H),8.16(d,J=5.8Hz,1H),8.03(br s,1H),3.12(s,1H),2.26(s,3H);LC/MS(ESI)m/e 162.0[(M+Na)+,计算值C8H7N3ONa162.1],tR=0.98分钟(方法2)。
制备N-(2-乙炔基-5-甲氧基嘧啶-4-基)乙酰胺
步骤1.制备N-(2-氯-5-甲氧基嘧啶-4-基)乙酰胺
在圆底烧瓶中,将乙酰氯(0.891mL,12.53mmol)加入2-氯-5-甲氧基嘧啶-4-胺(1g,6.27mmol)和吡啶(2.027mL,25.07mmol)在CH2Cl2(30mL)中的溶液中。将该反应混合液在室温搅拌16h。LC/MS显示形成单和二乙酰化产物。将该反应混合液用CH2Cl2(20mL)稀释,并将有机层用1N HCl(50mL)、饱和的碳酸氢钠(50mL)和盐水(50mL)洗涤。将有机层经硫酸镁干燥,并减压浓缩。将粗制的产物经硅胶柱色谱纯化(20%乙酸乙酯(含有5%MeOH)/80%己烷→70%乙酸乙酯(含有5%MeOH)/20%己烷;120g柱),得到N-(2-氯-5-甲氧基嘧啶-4-基)乙酰胺(430mg,2.133mmol,34%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.98(s,1H),3.99(s,3H),2.66(s,3H);LC/MS(ESI)m/e 201.9[(M+H)+,计算值C7H9ClN3O2 202.0],tR=0.99分钟(方法2)。
步骤2.制备N-(5-甲氧基-2-((三甲基硅烷基)乙炔基)嘧啶-4-基)乙酰胺
将N-(2-氯-5-甲氧基嘧啶-4-基)乙酰胺(430mg,2.133mmol)和乙炔基三甲基硅烷(0.355mL,2.56mmol)在甲苯(15mL)中的溶液用N2脱气。然后加入三乙胺(1.189mL,8.53mmol)、碘化铜(I)(40.6mg,0.213mmol)和双(三苯基膦)二氯化钯(II)(150mg,0.213mmol),并将该反应混合液在60℃加热16h。将该混合液冷却至室温,并转移到含饱和的NaHCO3水溶液的分液漏斗(25mL)。将水层用乙酸乙酯萃取(3x 25mL)。将合并的有机层用水(25mL)、盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→80%在己烷中的乙酸乙酯;80g柱),得到N-(5-甲氧基-2-((三甲基硅烷基)乙炔基)嘧啶-4-基)乙酰胺(46mg,0.175mmol,8%收率)。1H NMR(400MHz,氯仿-d)δ8.08(s,1H),4.00(s,3H),2.68(s,3H),0.37-0.25(m,9H);LC/MS(ESI)m/e 264.0[(M+H)+,计算值C12H18N3O2Si264.1],tR=1.71分钟(方法2)。
步骤3
在圆底烧瓶中,在0℃将TBAF(1.0M在THF中)(0.262mL,0.262mmol)加入N-(5-甲氧基-2-((三甲基硅烷基)乙炔基)嘧啶-4-基)乙酰胺(46mg,0.175mmol)的溶液中。将该反应混合液温至室温,并搅拌1h。将粗制的产物减压浓缩,并将经硅胶柱色谱纯化(20%→100%在己烷中的乙酸乙酯;24g柱),得到N-(2-乙炔基-5-甲氧基嘧啶-4-基)乙酰胺(21mg,0.110mmol,63%收率)。1H NMR(400MHz,氯仿-d)δ8.10(s,1H),8.03(br s,1H),4.01(s,3H),3.00(s,1H),2.68(s,3H);LC/MS(ESI)m/e 192.0[(M+H)+,计算值C9H10N3O2 192.1],tR=0.87分钟(方法2)。
制备2-乙炔基噻唑
步骤1.制备2-((三甲基硅烷基)乙炔基)噻唑
将2-溴噻唑(500mg,3.05mmol)和乙炔基三甲基硅烷(0.507mL,3.66mmol)在甲苯(15mL)中的溶液用N2脱气。然后加入三乙胺(1.700mL,12.19mmol)、碘化铜(I)(58.1mg,0.305mmol)和双(三苯基膦)二氯化钯(II)(214mg,0.305mmol),并将该反应混合液在60℃加热16h。将该混合液冷却至室温,并转移到含饱和的NaHCO3水溶液的分液漏斗(25mL)。将水层用乙酸乙酯萃取(3x 25mL)。将合并的有机层用水(25mL)、盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→40%在己烷中的乙酸乙酯;80g柱),得到2-((三甲基硅烷基)乙炔基)噻唑(330mg,1.820mmol,60%收率)。1H NMR(400MHz,氯仿-d)δ7.82(d,J=3.3Hz,1H),7.35(d,J=3.3Hz,1H),0.30(s,9H);LC/MS(ESI)m/e 181.9[(M+H)+,计算值C8H12NSSi 182.0],tR=1.91分钟(方法2)。
步骤2
向2-((三甲基硅烷基)乙炔基)噻唑(330mg,1.820mmol)在MeOH(20mL)中的混合液中加入无水碳酸钾(37.7mg,0.273mmol)。将该反应混合液在室温搅拌1h。将该混合液用饱和的NH4Cl水溶液(5mL)和1N HCl(3mL)处理。然后将该混合液浓缩以除去大部分甲醇。将剩余的液体转移到含水(20mL)和饱和的NaHCO3水溶液(20mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 10mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→50%在己烷中的乙酸乙酯;40g柱),得到2-乙炔基噻唑(82mg,0.751mmol,41%收率),为棕褐色固体。1H NMR(400MHz,氯仿-d)δ7.85(d,J=3.3Hz,1H),7.39(d,J=3.5Hz,1H),3.50(s,1H);LC/MS(ESI)m/e 109.9[(M+H)+,计算值C5H4NS110.0],tR=1.08分钟(方法2)。
制备5-乙炔基-2-(三氟甲基)嘧啶
步骤1.制备2-(三氟甲基)-5-((三甲基硅烷基)乙炔基)嘧啶
将5-溴-2-(三氟甲基)嘧啶(230mg,1.013mmol)和乙炔基三甲基硅烷(0.168mL,1.216mmol)在甲苯(8mL)中的溶液用N2脱气。然后加入三乙胺(0.565mL,4.05mmol)、碘化铜(I)(19.30mg,0.101mmol)和双(三苯基膦)二氯化钯(II)(71.1mg,0.101mmol),并将该反应混合液在60℃加热16h。将该混合液冷却至室温,并转移到含饱和的NaHCO3水溶液的分液漏斗(25mL)。将水层用乙酸乙酯萃取(3x 50mL)。将合并的有机层用水(25mL)、盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→75%在己烷中的乙酸乙酯;40g柱),得到2-(三氟甲基)-5-((三甲基硅烷基)乙炔基)嘧啶(230mg,0.941mmol,93%收率)。1H NMR(400MHz,氯仿-d)δ8.91(s,2H),0.30(s,9H);LC/MS(ESI)m/e 245.0[(M+H)+,计算值C10H12F3N2Si 245.1],tR=2.13分钟(方法2)。
步骤2
向2-(三氟甲基)-5-((三甲基硅烷基)乙炔基)嘧啶(130mg,0.532mmol)在MeOH(5mL)中的混合液中加入无水碳酸钾(11.03mg,0.080mmol)。将该反应混合液在室温搅拌1h。将该混合液用饱和的NH4Cl水溶液(10mL)和1N HCl(1mL)处理。然后将该混合液浓缩以除去大部分甲醇。将剩余的液体转移到含水(20mL)和饱和的NaHCO3水溶液(20mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 10mL)。将合并的有机层用盐水(20mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→40%在己烷中的乙酸乙酯;24g柱),得到5-乙炔基-2-(三氟甲基)嘧啶(25mg,0.145mmol,27%收率)。1H NMR(400MHz,氯仿-d)δ8.98(s,2H),3.57(s,1H);LC/MS(ESI)m/e 173.0[(M+H)+,计算值C7H4F3N2 173.0],tR=1.51分钟(方法2)。
制备((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
步骤1.制备(2S,4aR,6S,7R,8R,8aR)-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7,8-二醇
向(2R,3R,4S,5R,6S)-2-(羟基甲基)-6-(苯硫基)四氢-2H-吡喃-3,4,5-三醇(Ohlsson,J.,Magnusson,G.Carbohydr.Res.,2000,329,49)(29.5g,102mmol)在MeCN(204ml)(用N2脱气(2x))中的溶液中加入1-(二甲氧基甲基)-4-甲氧基苯(22.54ml,132mmol)。加入对甲苯磺酸一水合物(1.937g,10.18mmol),并将该反应混合液在N2下搅拌18h。最初的均相溶液变成非均相混合液。将该混合液浓缩至约1/3体积,然后用1N K2HPO4(水溶液)(200mL)稀释。通过真空过滤收集所得沉淀,用水洗涤,并通过用乙醚研磨进一步纯化产物。通过真空过滤收集固体,并将产物在真空下干燥,得到(4aR,6S,7R,8R,8aR)-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7,8-二醇(28.0g,71.7mmol,70%收率),为白色固体。1H NMR(500MHz,甲醇-d4)δ7.70-7.63(m,2H),7.41(d,J=8.8Hz,2H),7.33-7.26(m,3H),6.92(d,J=8.5Hz,2H),5.55(s,1H),4.61(d,J=9.1Hz,1H),4.25-4.18(m,2H),4.10(dd,J=12.4,1.4Hz,1H),3.83(s,3H),3.73-3.58(m,3H);LC/MS(ESI)m/e 391.1[(M+H)+,计算值C20H23O6S 391.1];tR=3.29分钟(方法3)。
步骤2.制备(4aR,6S,7R,8S,8aS)-乙酸2-(4-甲氧基苯基)-6-(苯硫基)-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯
向(4aR,6S,7R,8R,8aR)-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7,8-二醇(40.0g,102mmol)在CH2Cl2(427ml)中的溶液中加入吡啶(33.1ml,410mmol)。将该反应混合液冷却至-10℃。然后滴加Tf2O(24.23ml,143mmol)。将该反应混合液保持在-10℃达1h,然后使其缓慢温至室温。2h后,LCMS显示约75%转化。将该反应混合液冷却至0℃,然后滴加乙酰氯(8.74ml,123mmol),并使该反应混合液达到室温过夜。将该混合液转移到分液漏斗,用1N HCl(3x 150mL)、1M K2HPO4(150mL)、盐水洗涤,经Na2SO4干燥,过滤,并浓缩。使用最小量的CH2Cl2研磨以混悬固体来纯化得到的半固体。然后加入乙醚,并将该混合液搅拌直至固体块状物破碎。通过真空过滤分离产物,并在真空下干燥,得到(4aR,6S,7R,8S,8aS)-乙酸2-(4-甲氧基苯基)-6-(苯硫基)-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(33.04g,58.5mmol,57%收率),为白色固体。将滤液浓缩,并将残余物经硅胶色谱纯化(120g柱;A=己烷,B=乙酸乙酯;60分钟梯度;0%B至100%B流速=120mL/分钟)。合并级分,浓缩,并在真空下干燥,得到另外的(4aR,6S,7R,8S,8aS)-乙酸2-(4-甲氧基苯基)-6-(苯硫基)-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(6.2g,10.98mmol,11%收率),为浅黄色固体。总收率为39.24g(68%收率)。1H NMR(400MHz,DMSO-d6)δ7.58-7.50(m,2H),7.41-7.32(m,3H),7.31-7.25(m,2H),7.01-6.93(m,2H),5.72-5.66(m,2H),5.22-5.17(m,2H),4.66(d,J=3.3Hz,1H),4.16(dd,J=3.3,1.3Hz,2H),3.96(s,1H),3.79(s,3H),2.09(s,3H);LC/MS(ESI)m/e 565.0[(M+H)+,计算值C23H24F3O9S2 565.1],tR=4.10分钟(方法3)。
步骤3.制备(4aR,6S,7R,8R,8aR)-乙酸8-羟基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯
向1L圆底烧瓶中加入(4aR,6S,7R,8S,8aS)-乙酸2-(4-甲氧基苯基)-6-(苯硫基)-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(15.8g,28.0mmol)、亚硝酸钾(11.82g,139mmol和DMF(347ml)。将该反应混合液加热至50℃达18h。将该混合液冷却,用水(1L)稀释,并用EtOAc萃取(2x 500mL)。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将残余物经硅胶色谱纯化(330g柱;A=己烷,B=乙酸乙酯;45分钟梯度;0%B至100%B流速=120mL/分钟)。合并级分,浓缩,并在真空下干燥,得到(4aR,6S,7R,8R,8aR)-乙酸8-羟基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(24.0g,42.2mmol,61%收率),为浅黄色固体。1H NMR(400MHz,DMSO-d6)δ7.56-7.49(m,2H),7.37-7.28(m,5H),7.01-6.90(m,2H),5.73(d,J=4.2Hz,1H),5.55(s,1H),5.20(d,J=10.3Hz,1H),4.77(dd,J=10.3,3.1Hz,1H),4.14-4.01(m,3H),3.98-3.93(m,1H),3.86(s,1H),3.78(s,3H),2.03(s,3H);LC/MS(ESI)m/e 433.1[(M+H)+,计算值C22H25O7S 433.1];tR=3.68分钟(方法3)。
步骤4.制备(4aR,6S,7R,8R,8aS)-乙酸2-(4-甲氧基苯基)-6-(苯硫基)-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯
向(4aR,6S,7R,8R,8aR)-乙酸8-羟基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(3.00g,6.94mmol)在CH2Cl2(50mL)中的溶液中加入吡啶(2.81mL,34.7mmol)。将该反应混合液冷却至-10℃,通过注射器缓慢加入三氟甲磺酸酐(2.344mL,13.87mmol)。将该反应混合液搅拌3h,同时使其升温至0℃。将该混合液转移到含冷的1N HCl(50mL)的分液漏斗。将水层用二氯甲烷萃取(3x 50mL)。将合并的有机层用饱和的NaHCO3水溶液(25mL)、盐水(25mL洗涤,经MgSO4干燥,过滤,并浓缩,得到(4aR,6S,7R,8R,8aS)-乙酸2-(4-甲氧基苯基)-6-(苯硫基)-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(3.93g,6.96mmol,100%收率),为琥珀色泡沫。将产物不经进一步纯化直接用于下一步骤。1H NMR(400MHz,氯仿-d)δ7.66-7.61(m,2H),7.39-7.29(m,5H),6.93-6.89(m,2H),5.52(s,1H),5.22-5.18(m,1H),5.15(dd,J=10.3,3.0Hz,1H),5.06(d,J=10.0Hz,1H),4.42(dd,J=12.5,1.5Hz,1H),4.24(dd,J=3.6,0.9Hz,1H),4.09(dd,J=12.7,1.6Hz,1H),3.86(s,3H),3.85(d,J=1.3Hz,1H),2.17(s,3H);LC/MS(ESI)m/e 587.1[(M+Na)+,计算值C23H23F3O9S2Na 587.1],tR=2.21分钟(方法1)。
步骤5.制备(4aR,6S,7R,8S,8aR)-乙酸8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯
将(4aR,6S,7R,8R,8aS)-乙酸2-(4-甲氧基苯基)-6-(苯硫基)-8-(((三氟甲基)磺酰基)氧基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(3.93g,6.96mmol)和叠氮化四丁基铵(5.94g,20.88mmol)在DMF(35mL)中的混合液在50℃加热3h。将该混合液转移到含水(25mL)和饱和的NaHCO3水溶液(25mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 100mL)。将合并的有机层用盐水(50mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%→50%在己烷中的乙酸乙酯;220g柱),得到(4aR,6S,7R,8S,8aR)-乙酸8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(1.35g,2.95mmol,42%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.65-7.58(m,2H),7.41-7.29(m,5H),6.93-6.87(m,2H),5.55(s,1H),5.36(t,J=9.9Hz,1H),4.71(d,J=9.8Hz,1H),4.40(dd,J=12.4,1.6Hz,1H),4.34(d,J=2.8Hz,1H),4.07(dd,J=12.5,1.5Hz,1H),3.85(s,3H),3.56(d,J=1.0Hz,1H),3.41(dd,J=10.3,3.3Hz,1H),2.19(s,3H);LC/MS(ESI)m/e 480.1[(M+Na)+,计算值C22H23N3O6SNa 480.1],tR=1.83分钟(方法1)。
步骤6.制备(2S,4aR,6S,7R,8R,8aR)-8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-醇
在0℃向(2S,4aR,6S,7R,8S,8aR)-乙酸8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基酯(4.2g,9.18mmol)在甲醇(6mL)和THF(42mL)中的溶液中加入甲醇钠(25%wt甲醇溶液)(8.40mL,36.7mmol)。将该反应混合液在室温搅拌1h。将该反应混合液冷却至0℃,并用1N HCl(100mL)处理。将该混合液转移到分液漏斗,并将水层用乙酸乙酯萃取(3x 60mL)。将合并的有机层用饱和的NaHCO3水溶液(100mL)、盐水(100mL)洗涤,经MgSO4干燥,过滤,并浓缩。然后将固体风干,随后在真空下干燥,得到(2S,4aR,6S,7R,8R,8aR)-8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-醇(3.81g,9.18mmol,100%收率),为白色固体。将产物不经进一步纯化直接用于下一步骤。1H NMR(400MHz,氯仿-d)δ7.70(dd,J=8.0,1.3Hz,2H),7.40-7.30(m,5H),6.92-6.87(m,2H),5.52(s,1H),4.57(d,J=9.3Hz,1H),4.40(dd,J=12.4,1.6Hz,1H),4.24(d,J=2.8Hz,1H),4.06(dd,J=12.4,1.6Hz,1H),3.99(t,J=9.5Hz,1H),3.85(s,3H),3.57(d,J=1.0Hz,1H),3.49(dd,J=10.0,3.3Hz,1H);LC/MS(ESI)m/e 438.1[(M+Na)+,计算值C20H21N3O5SNa438.1],tR=1.69分钟(方法1)。
步骤7.制备(2S,4aR,6S,7R,8S,8aR)-8-叠氮基-7-甲氧基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯
在0℃向(2S,4aR,6S,7R,8R,8aR)-8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-醇(3.8g,9.15mmol)在DMF(75mL)中的溶液中加入氢化钠(0.915g,22.87mmol)。移去冷却浴,并将该混合液在室温搅拌30分钟。然后加入碘代甲烷(2.288mL,36.6mmol),并将该反应混合液搅拌1h。将该混合液转移到含饱和的NaHCO3水溶液的分液漏斗(200mL)和水(200mL)。将水层用乙酸乙酯萃取(3x 200mL)。将合并的有机层用盐水(250mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%→50%在己烷中的乙酸乙酯;330g柱),得到(2S,4aR,6S,7R,8S,8aR)-8-叠氮基-7-甲氧基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯(3.7g,8.61mmol,94%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.76-7.67(m,2H),7.51-7.40(m,2H),7.36-7.22(m,3H),7.00-6.87(m,2H),5.54(s,1H),4.58(d,J=9.3Hz,1H),4.39(dd,J=12.5,1.5Hz,1H),4.24(d,J=2.5Hz,1H),4.05(dd,J=12.4,1.6Hz,1H),3.85(s,3H),3.68-3.63(m,1H),3.62(s,3H),3.54-3.46(m,2H);LC/MS(ESI)m/e 452.1[(M+Na)+,计算值C21H23N3O5SNa 452.1],tR=1.98分钟(方法1)。
步骤8.制备(2R,3R,4S,5R,6S)-4-叠氮基-2-(羟基甲基)-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-3-醇
将(2S,4aR,6S,7R,8S,8aR)-8-叠氮基-7-甲氧基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯(3.7g,8.61mmol)溶于80%AcOH(50mL)中,并在40℃加热2.5h。将该混合液浓缩,然后从庚烷再浓缩(2x)。将产物经硅胶柱色谱纯化(10%→75%在己烷中的乙酸乙酯;120g柱),得到(2R,3R,4S,5R,6S)-4-叠氮基-2-(羟基甲基)-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-3-醇(2.6g,8.35mmol,97%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.62-7.54(m,2H),7.39-7.30(m,3H),4.66-4.61(m,1H),4.06(t,J=2.3Hz,1H),4.01-3.93(m,1H),3.91-3.83(m,1H),3.70(s,3H),3.59-3.48(m,3H),2.69(d,J=3.0Hz,1H),2.09(dd,J=7.4,5.4Hz,1H);LC/MS(ESI)m/e 334.0[(M+Na)+,计算值C13H17N3O4SNa334.0],tR=1.74分钟(方法1)。
步骤9.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯
向(2R,3R,4S,5R,6S)-4-叠氮基-2-(羟基甲基)-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-3-醇(0.580g,1.86mmol)在吡啶(15mL)中的溶液中加入乙酸酐(1.055mL,11.18mmol)和DMAP(0.023g,0.186mmol)。将该反应混合液在室温搅拌16h。将该混合液转移到含乙酸乙酯(150mL)的分液漏斗。将有机层用冷4N HCl(2x 50mL)、饱和的NaHCO3水溶液(25mL)和盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(10%→30%在己烷中的乙酸乙酯;40g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯(0.735g,1.86mmol,100%收率),为无色油状物。1H NMR(400MHz,氯仿-d)δ7.63-7.56(m,2H),7.40-7.31(m,3H),5.37(dd,J=3.3,1.0Hz,1H),4.62(d,J=9.5Hz,1H),4.12(d,J=6.5Hz,2H),3.85(td,J=6.5,1.0Hz,1H),3.69(s,3H),3.60(dd,J=9.7,3.4Hz,1H),3.46-3.36(m,1H),2.17(s,3H),2.06(s,3H);LC/MS(ESI)m/e418.0[(M+Na)+,计算值C17H21N3O6SNa 418.1],tR=2.01分钟(方法1)。
步骤10.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-5-甲氧基-6-(苯硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯(375mg,0.948mmol)和5-乙炔基-1,2,3-三氟苯(296mg,1.897mmol)溶于DMF(15mL)和水(5mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(188mg,0.948mmol)和五水合硫酸铜(II)(189mg,0.759mmol)(预溶于1mL水中),并将该反应混合液在室温搅拌14h。将该混合液经Celite垫过滤,并将滤液转移到含饱和的NaHCO3水溶液的分液漏斗(25mL)。将水层用二氯甲烷萃取(3x 50mL)。将合并的有机层用盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将滤液浓缩,并将经硅胶柱色谱纯化(30%→70%在己烷中的乙酸乙酯;40g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-5-甲氧基-6-(苯硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(483mg,0.876mmol,92%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.79(s,1H),7.67-7.61(m,2H),7.46(dd,J=8.3,6.5Hz,2H),7.40-7.35(m,3H),5.52(dd,J=2.9,0.9Hz,1H),4.75(d,J=9.5Hz,1H),4.65(dd,J=10.2,3.1Hz,1H),4.37-4.29(m,1H),4.21(qd,J=11.3,6.4Hz,2H),4.09-4.03(m,1H),3.38(s,3H),2.10(s,3H),2.06(s,3H);LC/MS(ESI)m/e 574.1[(M+Na)+,计算值C25H24F3N3O6SNa574.1],tR=2.18分钟(方法1)。
步骤11
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-5-甲氧基-6-(苯硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(250mg,0.453mmol)在CH2Cl2(5mL)中的溶液中(经分子筛预干燥)滴加溴(10%在CH2Cl2中的储备溶液)(0.467mL,0.907mmol)。将该反应混合液在0℃搅拌1h。通过加入饱和的NaHCO3水溶液和饱和的Na2S2O3水溶液(1mL:3mL)淬灭过量溴(红色消失)。将该混合液转移到含水(10mL)的分液漏斗。将水层用二氯甲烷萃取(3x 15mL)。将合并的有机层用盐水(10mL)洗涤,经Na2SO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%→40%在己烷中的乙酸乙酯;24g柱),得到((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(195mg,0.373mmol,82%收率),为白色固体。将产物储存在冰箱中直到使用。1H NMR(400MHz,氯仿-d)δ7.82(s,1H),7.46(dd,J=8.4,6.4Hz,2H),6.87(d,J=3.8Hz,1H),5.60(dd,J=2.9,1.4Hz,1H),5.01(dd,J=10.8,3.0Hz,1H),4.67-4.59(m,1H),4.49(dd,J=10.8,3.8Hz,1H),4.25(dd,J=11.8,6.3Hz,1H),4.18(dd,J=11.5,6.8Hz,1H),3.40(s,3H),2.11(s,3H),2.09(s,3H);LC/MS(ESI)m/e 522.0[(M+H)+,计算值C19H20BrF3N3O6522.0],tR=1.80分钟(方法1)。
制备(–)-(3S,4R,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇和(+)-(3S,4R,5S)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇
步骤1.制备1-(烯丙基氧基)丁-3-烯-2-醇
在压力烧瓶中,将2-乙烯基环氧乙烷(7.00g,100mmol)和丙-2-烯-1-醇(13.58mL,200mmol)溶于DMF(200mL)中,并将该溶液冷却至0℃。将氢化钠(7.99g,200mmol)加入该反应混合液中,然后将其在0℃搅拌20分钟。然后密封压力烧瓶,并将该反应混合液在50℃搅拌16h。将该反应混合液冷却至室温,并用1N HCl(200mL)淬灭。将该混合液转移到分液漏斗,并将水层用乙醚萃取(3x 150mL)。将合并的有机层用盐水(200mL)洗涤,经硫酸镁干燥,并减压浓缩。将粗制的产物经硅胶柱色谱纯化(0%→20%在己烷中的乙酸乙酯;220g柱),得到1-(烯丙基氧基)丁-3-烯-2-醇(10.8g,84mmol,84%收率),为无色油状物。1H NMR(400MHz,氯仿-d)δ5.99-5.80(m,2H),5.43-5.19(m,4H),4.38-4.32(m,1H),4.06(dt,J=5.8,1.4Hz,2H),3.53(dd,J=9.7,3.4Hz,1H),3.36(dd,J=9.7,7.9Hz,1H),2.47-2.22(m,1H)。
步骤2.制备(((1-(烯丙基氧基)丁-3-烯-2-基)氧基)甲烷三基)三苯
在圆底烧瓶中,将DBU(45.0mL,298mmol)加入1-(烯丙基氧基)丁-3-烯-2-醇(15.3g,119mmol)和(氯甲烷三基)三苯(69.9g,251mmol)在CH2Cl2(250mL)中的溶液中。将该反应混合液在室温搅拌2天。将该反应混合液减压浓缩,并将经硅胶柱色谱纯化(0%→15%在己烷中的乙酸乙酯;330g柱,3次运行),得到(((1-(烯丙基氧基)丁-3-烯-2-基)氧基)甲烷三基)三苯(34.2g,92mmol,77%收率)。1H NMR(400MHz,氯仿-d)δ7.60-7.53(m,6H),7.34-7.23(m,9H),5.88-5.66(m,2H),5.25-5.10(m,2H),5.03-4.85(m,2H),4.22-4.13(m,1H),3.89-3.79(m,2H),3.14-3.00(m,2H);LC/MS(ESI)m/e 393.2[(M+Na)+,计算值C26H26O2Na 393.2]tR=1.67分钟(方法1)。
步骤3.制备3-(三苯甲基氧基)-3,6-二氢-2H-吡喃
在5L 3颈烧瓶中,将(((1-(烯丙基氧基)丁-3-烯-2-基)氧基)甲烷三基)三苯(34.2g,92mmol)加入(1,3-二基咪唑烷-2-亚基)(2-异丙氧基亚苄基)氯化钌(VI)(0.578g,0.923mmol)在CH2Cl2(4L)中的溶液中。将该反应混合液在室温搅拌16h。将乙基乙烯基醚(50mL)加入该反应混合液中以分解催化剂,并将该反应混合液减压浓缩。将粗制的产物经硅胶柱色谱纯化(0%→10%在己烷中的乙酸乙酯;330g柱,3次运行),得到3-(三苯甲基氧基)-3,6-二氢-2H-吡喃(28.05g,82mmol,89%收率)。1H NMR(400MHz,氯仿-d)δ7.57-7.52(m,6H),7.36-7.25(m,9H),5.81-5.72(m,1H),5.40(dq,J=10.5,2.6Hz,1H),4.14-4.06(m,2H),3.97-3.89(m,1H),3.22(dd,J=5.1,1.4Hz,2H);LC/MS(ESI)m/e 364.8[(M+Na)+,计算值C24H22O2Na365.2]tR=2.33分钟(方法2)。
步骤4.制备(1R,5R,6R)-5-(三苯甲基氧基)-3,7-二氧杂二环[4.1.0]庚烷和(1S,5R,6S)-5-(三苯甲基氧基)-3,7-二氧杂二环[4.1.0]庚烷
在氮气下,在圆底烧瓶中,将碳酸氢钠(8.26g,98mmol)加入3-(三苯甲基氧基)-3,6-二氢-2H-吡喃(28.05g,82mmol)在CH2Cl2(950mL)中的溶液中。将该反应混合液冷却至0℃,并将mCPBA(36.7g,164mmol)加入该反应混合物中。将该反应混合液缓慢升至室温,并搅拌16h。将该反应混合液用饱和的Na2S2O3水溶液(400mL)洗涤以破坏过量的mCPBA。将有机层用1N NaOH(400mL)和盐水(400mL)洗涤,经硫酸钠干燥,并减压浓缩。将粗制的产物经硅胶柱色谱纯化(0%→15%在己烷中的乙酸乙酯;330g柱,3次运行),得到(1R,5R,6R)-5-(三苯甲基氧基)-3,7-二氧杂二环[4.1.0]庚烷(主要)和(1S,5R,6S)-5-(三苯甲基氧基)-3,7-二氧杂二环[4.1.0]庚烷(次要)的不可分离的混合物(23.8g,66.4mmol,81%收率)(2.5:1比率)。1H NMR(400MHz,氯仿-d)δ7.61-7.50(m,6H),7.40-7.23(m,9H),4.00(ddd,J=9.3,5.8,2.0Hz,1H,次要),3.97-3.89(m,2H,主要),3.87-3.80(m,1H),3.77-3.71(m,1H,次要),3.31(dd,J=11.5,5.3Hz,1H,主要),3.27-3.21(m,2H,次要),3.05(dt,J=4.0,0.8Hz,1H,主要),3.03-2.99(m,1H,次要),2.96(dd,J=11.4,7.9Hz,1H,主要),2.70(d,J=4.0Hz,1H,主要),2.66-2.62(m,1H,次要);
LC/MS(ESI)m/e 380.8[(M+Na)+,C24H22O3Na计算值381.2]tR=2.18分钟(方法1)。
步骤5.制备(3S,4R,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇和(3R,4S,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇
在密封的小瓶中,将叠氮化钠(8.60g,132mmol)加入(1R,5R,6R)-5-(三苯甲基氧基)-3,7-二氧杂二环[4.1.0]庚烷和(1S,5R,6S)-5-(三苯甲基氧基)-3,7-二氧杂二环[4.1.0]庚烷的外消旋混合物(23.7g,66.1mmol)在MeOH(500mL)和水(55.6mL)中的溶液中。将该反应混合液在80℃搅拌16h。将该反应混合液在水(300mL)和CH2Cl2(300mL)之间分配。将水层用CH2Cl2(3x 200mL)洗涤。将合并的有机层经硫酸钠干燥,并减压浓缩。将产物经硅胶柱色谱纯化(0%→35%在己烷中的乙酸乙酯;330g柱,3次运行),得到产物(3S,4R,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(9.30g,23.17mmol,35%收率)和(3R,4S,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(5.30g,13.20mmol,20%收率)。
(3S,4R,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(化合物A)的数据:1HNMR(400MHz,氯仿-d)δ7.55-7.45(m,6H),7.40-7.24(m,9H),3.87-3.76(m,2H),3.41-3.22(m,3H),3.17-2.97(m,2H),2.37(s,1H);LC/MS(ESI)m/e 423.7[(M+Na)+,C24H23N3O3Na计算值424.2]tR=2.18分钟(方法2)。
(3R,4S,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(化合物B)的数据:1HNMR(400MHz,氯仿-d)δ7.56-7.48(m,6H),7.41-7.25(m,9H),3.96-3.80(m,2H),3.68-3.55(m,2H),3.45(td,J=11.2,4.1Hz,2H),2.95-2.75(m,1H),2.46(d,J=3.3Hz,1H);LC/MS(ESI)m/e423.7[(M+Na)+,C24H23N3O3Na计算值424.2]tR=2.17分钟(方法2)。
步骤6A.制备(–)-(3S,4R,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇
使用了以下描述的条件,通过制备型SFC手性色谱法分离来自以上的化合物A的外消旋混合物(9.3g):
制备型手性HPLC条件:
随后使用了以下条件通过手性HPLC进行单个对映异构体的分析:
分析型手性HPLC条件:
峰1(不期望的):(+)-(3R,4S,5S)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(3.8g):手性HPLC tR=5.44分钟;[α]D 22+11.5,(c=0.755,MeOH)。
峰2(期望的):(–)-(3S,4R,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(3.6g):手性HPLC tR=6.06分钟;[α]D 22–11.9,(c=0.575,MeOH)。
步骤6B.制备(+)-(3S,4R,5S)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇
使用了以下描述的条件通过制备型SFC手性色谱法分离来自以上的化合物B的外消旋混合物(5.3g),:
制备型手性HPLC条件:
随后使用了以下条件通过手性HPLC进行单个对映异构体的分析:
分析条件:
峰1(期望的):(+)-(3S,4R,5S)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(2.6g):手性HPLC tR=4.81分钟;[α]D 22+32.1,(c=0.575,MeOH)。
峰2(不期望的):(–)-(3R,4S,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(2.41g):手性HPLC tR=6.89分钟;[α]D 22–29.4,(c=0.575,MeOH)。
制备(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(方法1)
步骤1.制备(–)-(3S,4R,5R)-乙酸3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-基酯
在氮气下将乙酰氯(1.240mL,17.44mmol)加入(–)-(3S,4R,5R)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(3.50g,8.72mmol)和吡啶(2.115mL,26.2mmol)在CH2Cl2(100mL)中的溶液中。将该反应混合液在室温搅拌16h。将该反应混合液用CH2Cl2(20mL)稀释,并将有机层用1N HCl(50mL)、饱和的碳酸氢钠(50mL)和盐水(50mL)洗涤。将有机层经MgSO4干燥,过滤,并真空浓缩,得到(–)-(3S,4R,5R)-乙酸3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-基酯(3.73g,8.41mmol,96%收率)。将产物未经进一步纯化地用于下一个步骤。[α]D 22–8.8,(c=0.340,CHCl3);1H NMR(400MHz,氯仿-d)δ7.55-7.46(m,6H),7.38-7.22(m,9H),5.34(t,J=9.2Hz,1H),3.85(dd,J=11.4,5.1Hz,1H),3.58-3.44(m,1H),3.42-3.32(m,1H),3.30-3.10(m,3H),2.03(s,3H);LC/MS(ESI)m/e 465.7[(M+Na)+,C26H25N3O4计算值466.2],tR=2.31分钟(方法2)。
步骤2.制备(–)-(3S,4R,5R)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯
将(–)-(3S,4R,5R)-乙酸3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-基酯(1.6g,3.61mmol)加入甲酸(4mL,104mmol)和Et2O(6mL)的溶液中。将该反应混合液在室温搅拌过夜。通过TLC监测反应过程(Hanessian染色)。将该混合液减压浓缩,并经硅胶柱色谱纯化(20%→70%在己烷中的乙酸乙酯;80g柱),得到(–)-(3S,4R,5R)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯(570mg,2.83mmol,79%收率)。[α]D 22–58.4,(c=0.290,CHCl3);1HNMR(400MHz,氯仿-d)δ4.84(t,J=8.9Hz,1H),4.05-3.93(m,2H),3.73-3.64(m,1H),3.63-3.53(m,1H),3.21(ddd,J=11.7,10.0,8.7Hz,2H),2.18(s,3H);13C NMR(101MHz,氯仿-d)δ171.7,77.9,70.2,68.8,67.8,58.6,20.6。
步骤3.制备(+)-(3S,4R,5S)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯
在-10℃将三氟甲磺酸酐(0.846mL,5.01mmol)加入(–)-(3S,4R,5R)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯(0.840g,4.18mmol)和吡啶(1.013mL,12.53mmol)在CH2Cl2(40mL)中的溶液中。将该反应混合液在-10℃搅拌1.5h。通过TLC监测反应过程(Hanessian染色)。将该反应混合液用CH2Cl2(20mL)稀释,并用1N HCl(30mL)、饱和的碳酸氢钠(30mL)和盐水(30mL)洗涤。将有机层经MgSO4干燥,过滤,并真空浓缩,得到(3S,4R,5R)-乙酸3-叠氮基-5-(((三氟甲基)磺酰基)氧基)四氢-2H-吡喃-4-基酯(1.39g,4.18mmol,100%收率)。将产物未经进一步纯化地使用。
在压力容器中,将四丁基亚硝酸铵(3.62g,12.54mmol)加入来自上步骤的粗制的(3S,4R,5R)-乙酸3-叠氮基-5-(((三氟甲基)磺酰基)氧基)四氢-2H-吡喃-4-基酯(1.39g,4.18mmol)在DMF(40mL)中的溶液中。密封容器,并将该反应混合液在50℃加热1.5h。通过TLC监测反应过程(Hanessian染色)。将该反应混合液冷却至室温,并减压浓缩。将产物经硅胶柱色谱纯化(10%→70%在己烷中的乙酸乙酯;80g柱),得到(+)-(3S,4R,5S)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯(0.46g,2.267mmol,54%收率)。[α]D 22+34.7,(c=0.325,CHCl3);1H NMR(400MHz,氯仿-d)δ4.88(dd,J=9.4,3.1Hz,1H),4.13-4.09(m,1H),4.07-3.91(m,3H),3.56(dd,J=12.4,1.6Hz,1H),3.22(dd,J=11.3,9.8Hz,1H),2.43(brs,1H),2.20(s,3H);13C NMR(101MHz,氯仿-d)δ169.8,74.5,69.8,67.9,66.5,56.1,20.7。
步骤4.制备(+)-(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-叠氮基四氢-2H-吡喃-4-基酯
在-10℃向(+)-(3S,4R,5S)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯(1.95g,9.69mmol)和吡啶(3.92mL,48.5mmol)在CH2Cl2(50mL)中的溶液中滴加三氟甲磺酸酐(4.09mL,24.23mmol)。将该反应混合液在-10℃搅拌30分钟。通过TLC监测反应过程(Hanessian染色)。将该混合液转移到含二氯甲烷(25mL)的分液漏斗,并用冷的1N HCl(25mL)、饱和的NaHCO3水溶液(50mL)、盐水(50mL)洗涤,经Na2SO4干燥,过滤,并浓缩。然后将粗制的产物溶于干燥的丙酮(50mL)(经分子筛预干燥)中,并将该混合液冷却至-10℃。加入硫代乙酸钾(5.53g,48.5mmol),并将该反应混合液在-10℃搅拌1.5h。通过TLC监测反应过程(Hanessian染色)。将该混合液转移到含水(40mL)的分液漏斗。将水层用二氯甲烷萃取(3x40mL)。将合并的有机层用盐水(40mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→40%在己烷中的乙酸乙酯;120g柱),得到(+)-(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-叠氮基四氢-2H-吡喃-4-基酯(1.92g,7.41mmol,76%收率)。[α]D 22+12.8,(c=0.510,CHCl3);1H NMR(400MHz,氯仿-d)δ4.98(dd,J=10.8,9.3Hz,1H),4.08-4.01(m,1H),3.95(ddd,J=11.5,5.0,0.9Hz,1H),3.71-3.61(m,2H),3.30(t,J=11.3Hz,1H),3.24-3.15(m,1H),2.32(s,3H),2.11(s,3H);13C NMR(101MHz,氯仿-d)δ193.3,169.8,72.1,69.4,68.2,60.4,43.0,30.4,20.4。
步骤5.制备(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇
在-10℃通过注射器向(+)-(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-叠氮基四氢-2H-吡喃-4-基酯(1.92g,7.41mmol)在THF(100mL)中的溶液中滴加甲醇钠(25%,在MeOH中)(8.47mL,37.0mmol)。将该反应混合液在-10℃搅拌15分钟。通过TLC监测反应过程(Hanessian染色)。将该反应混合液转移到含饱和的NH4Cl水溶液(50mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 50mL)。将合并的有机层用盐水(50mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→50%在己烷中的乙酸乙酯;40g柱),得到(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(0.900g,5.14mmol,69%收率)。[α]D 22–107.5,(c=0.255,CHCl3);1H NMR(400MHz,氯仿-d)δ4.06(td,J=11.3,5.0Hz,2H),3.53(ddd,J=10.8,9.3,5.0Hz,1H),3.38-3.29(m,1H),3.18(t,J=11.5Hz,2H),2.96(d,J=1.8Hz,1H),2.90-2.76(m,1H),1.32(d,J=10.0Hz,1H);13C NMR(126MHz,氯仿-d)δ78.8,72.7,69.0,62.3,42.6。
步骤5(可选条件)。制备(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇和(–)-(3S,4R,5R)-乙酸3-叠氮基-5-巯基四氢-2H-吡喃-4-基酯
在-78℃通过注射器向(+)-(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-叠氮基四氢-2H-吡喃-4-基酯(135mg,0.521mmol)在THF(8mL)中的溶液中滴加水合肼(0.126mL,2.60mmol)。然后将冷却浴替换为冰水浴,并将该反应混合液在0℃搅拌15分钟。然后加入乙酸(0.149mL,2.60mmol),并继续搅拌5分钟。将该混合液转移到含水(10mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 10mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(10%→50%在己烷中的乙酸乙酯;24g柱),得到(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(29.2mg,0.167mmol,32%收率)和(–)-(3S,4R,5R)-乙酸3-叠氮基-5-巯基四氢-2H-吡喃-4-基酯(31mg,0.143mmol,27%收率)。
(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇的数据:
[α]D 22–107.51,(c=0.26,CHCl3);1H NMR(500MHz,氯仿-d)δ7.30-7.27(m,1H),4.10-4.00(m,2H),3.58-3.46(m,1H),3.33(br t,J=9.5Hz,1H),3.22-3.13(m,2H),2.98(br s,1H),2.82(ddt,J=8.4,3.2,1.6Hz,1H),1.33(dd,J=9.8,1.3Hz,1H);13C NMR(126MHz,氯仿-d)δ78.8,72.7,69.0,62.3,42.6。
(–)-(3S,4R,5R)-乙酸3-叠氮基-5-巯基四氢-2H-吡喃-4-基酯的数据:
[α]D 22–113.4,(c=0.290,CHCl3);1H NMR(500MHz,氯仿-d)δ4.91-4.82(m,1H),4.11-4.03(m,2H),3.57(ddd,J=10.9,9.6,5.2Hz,1H),3.24(td,J=11.4,9.7Hz,2H),2.88(qd,J=10.5,4.7Hz,1H),2.21(s,3H),1.35(d,J=9.8Hz,1H);13C NMR(126MHz,甲醇-d4)δ170.6,77.5,72.6,68.1,60.8,39.3,19.4。
制备(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(方法2)
步骤1.制备(+)-(3S,4R,5S)-乙酸3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-基酯
在圆底烧瓶中,在氮气下将乙酰氯(1.417mL,19.93mmol)加入(+)-(3S,4R,5S)-3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-醇(4.0g,9.96mmol)和吡啶(2.418mL,29.9mmol)在CH2Cl2(100mL)中的溶液中。将该反应混合液在室温搅拌18h。将该反应混合液用CH2Cl2(20mL)稀释,并将有机层用1N HCl(50mL)、饱和的NaHCO3水溶液(50mL)和盐水(50mL)洗涤。将有机层经MgSO4干燥,过滤,并真空浓缩,得到(+)-(3S,4R,5S)-乙酸3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-基酯(4.42g,9.96mmol,100%收率)。将产物未经进一步纯化地用于下一个步骤。[α]D 22+56.6,(c=0.450,CHCl3);1H NMR(400MHz,氯仿-d)δ7.55-7.48(m,6H),7.38-7.25(m,9H),4.62(dd,J=7.5,3.3Hz,1H),4.07-3.83(m,3H),3.43-3.22(m,2H),3.02(dd,J=12.0,2.8Hz,1H),2.25(s,3H);LC/MS(ESI)m/e 465.7[(M+Na)+,C26H25N3O4计算值466.2],tR=2.36分钟(方法2)。
步骤2.制备(+)-(3S,4R,5S)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯
在圆底烧瓶中,将(+)-(3S,4R,5S)-乙酸3-叠氮基-5-(三苯甲基氧基)四氢-2H-吡喃-4-基酯(4.42g,9.97mmol)在甲酸(19mL,495mmol)和Et2O(30mL)中在室温搅拌16h。将该混合液减压浓缩,并将粗制的产物经硅胶柱色谱纯化(0%→60%在己烷中的乙酸乙酯;40g柱),得到(+)-(3S,4R,5S)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯(1.95g,9.69mmol,97%收率)。[α]D 22+35.1,(c=0.360,CHCl3);1H NMR(400MHz,氯仿-d)δ4.90(dd,J=9.4,3.1Hz,1H),4.14-3.90(m,4H),3.58(dd,J=12.4,1.6Hz,1H),3.23(dd,J=11.3,9.8Hz,1H),2.22(s,3H);13C NMR(101MHz,氯仿-d)δ169.8,74.5,69.8,67.9,66.5,56.1,20.7。
步骤3.制备(+)-(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-叠氮基四氢-2H-吡喃-4-基酯
在-10℃向(+)-(3S,4R,5S)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯(1.95g,9.69mmol)和吡啶(3.92mL,48.5mmol)在CH2Cl2(50mL)中的溶液中滴加三氟甲磺酸酐(4.09mL,24.23mmol)。将该反应混合液在-10℃搅拌30分钟。通过TLC监测反应过程(Hanessian染色)。将该混合液转移到含二氯甲烷(25mL)的分液漏斗,并用冷的1N HCl(25mL)、饱和的NaHCO3水溶液(50mL)、盐水(50mL)洗涤,经Na2SO4干燥,过滤,并浓缩。然后将粗制的产物溶于干燥的丙酮(50mL)(经分子筛预干燥)中,并将该混合液冷却至-10℃。加入硫代乙酸钾(5.53g,48.5mmol),并将该反应混合液在-10℃搅拌1.5h。通过TLC监测反应过程(Hanessian染色)。将该混合液转移到含水(40mL)的分液漏斗。将水层用二氯甲烷萃取(3x40mL)。将合并的有机层用盐水(40mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→40%在己烷中的乙酸乙酯;120g柱),得到(+)-(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-叠氮基四氢-2H-吡喃-4-基酯(1.92g,7.41mmol,76%收率)。[α]D 22+12.8,(c=0.510,CHCl3);1H NMR(400MHz,氯仿-d)δ4.98(dd,J=10.8,9.3Hz,1H),4.08-4.01(m,1H),3.95(ddd,J=11.5,5.0,0.9Hz,1H),3.71-3.61(m,2H),3.30(t,J=11.3Hz,1H),3.24-3.15(m,1H),2.32(s,3H),2.11(s,3H);13C NMR(101MHz,氯仿-d)δ193.3,169.8,72.1,69.4,68.2,60.4,43.0,30.4,20.4。
步骤4
在-10℃通过注射器向(+)-(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-叠氮基四氢-2H-吡喃-4-基酯(1.92g,7.41mmol)在THF(100mL)中的溶液中滴加甲醇钠(25%,在MeOH中)(8.47mL,37.0mmol)。将该反应混合液在-10℃搅拌15分钟。通过TLC监测反应过程(Hanessian染色)。将该反应混合液转移到含饱和的NH4Cl水溶液(50mL)的分液漏斗。将水层用乙酸乙酯萃取(3x 50mL)。将合并的有机层用盐水(50mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→50%在己烷中的乙酸乙酯;40g柱),得到(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(0.900g,5.14mmol,69%收率)。[α]D 22–107.5,(c=0.255,CHCl3);1H NMR(400MHz,氯仿-d)δ4.06(td,J=11.3,5.0Hz,2H),3.53(ddd,J=10.8,9.3,5.0Hz,1H),3.38-3.29(m,1H),3.18(t,J=11.5Hz,2H),2.96(d,J=1.8Hz,1H),2.90-2.76(m,1H),1.32(d,J=10.0Hz,1H);13C NMR(126MHz,氯仿-d)δ78.8,72.7,69.0,62.3,42.6。
制备(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
通过插管向(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(225mg,1.284mmol)在乙酸乙酯(10mL)和碳酸钠溶液(1M,水溶液)(5.14mL,5.14mmol)中的溶液中加入在乙酸乙酯(4mL)中的((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(838mg,1.605mmol)。加入四丁基硫酸氢铵(1744mg,5.14mmol),并将该反应混合液在室温剧烈搅拌2.5h。将该混合液转移到含饱和的NaHCO3水溶液的分液漏斗(20mL)。将水层用乙酸乙酯萃取(3x 25mL)。将合并的有机层用盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(15%→80%在己烷中的乙酸乙酯;40g柱),得到(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(670mg,1.09mmol,85%收率),为白色固体。[α]D 22+37.99,(c=0.240,CHCl3);1H NMR(500MHz,氯仿-d)δ7.81(s,1H),7.47(dd,J=8.2,6.5Hz,2H),5.52(d,J=2.9Hz,1H),4.66-4.59(m,2H),4.28-4.19(m,2H),4.18-4.09(m,3H),4.05-3.96(m,2H),3.67-3.60(m,1H),3.54(ddd,J=10.9,9.1,5.2Hz,1H),3.35(s,3H),3.26(t,J=11.9Hz,1H),3.13(t,J=11.3Hz,1H),2.99(ddd,J=11.9,9.7,5.1Hz,1H),2.15(s,3H),2.12(s,3H);LC/MS(ESI)m/e 617.2[(M+H)+,C24H28F3N6O8S计算值617.1],tR=2.03分钟(方法1)。
制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯
将((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯(70mg,0.177mmol)和1-乙炔基-3-氟苯(63.8mg,0.531mmol)溶于DMF(1.5mL)和水(0.500mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(35.1mg,0.177mmol)和五水合硫酸铜(II)(30.9mg,0.124mmol)(预溶于0.4mL水中),并将该反应混合液在室温搅拌14h。将该混合液经Celite垫过滤,并将滤液转移到含饱和的NaHCO3水溶液(10mL)的分液漏斗。将水层用二氯甲烷萃取(3x 15mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%→80%在己烷中的乙酸乙酯;24g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯(76mg,0.147mmol,83%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.84(s,1H),7.68-7.62(m,2H),7.62-7.53(m,2H),7.45-7.33(m,4H),7.05(tdd,J=8.4,2.5,0.8Hz,1H),5.57-5.51(m,1H),4.76(d,J=9.5Hz,1H),4.69(dd,J=10.2,3.1Hz,1H),4.31(t,J=9.9Hz,1H),4.26-4.14(m,2H),4.10-4.02(m,1H),3.37(s,3H),2.10(s,3H),2.06(s,3H);LC/MS(ESI)m/e 515.7[(M+H)+,C25H276FN3O6S计算值516.2],tR=1.99分钟(方法2)。
步骤2.制备((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯(75mg,0.145mmol)在CH2Cl2(2mL)(经分子筛预干燥)中的溶液中滴加Br2(10%,在DCM中)(0.150mL,0.291mmol)。将该反应混合液在0℃搅拌2h。将粗制的产物经硅胶柱色谱纯化(0%→50%在己烷中的乙酸乙酯;12g柱),得到((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(55mg,0.113mmol,78%收率)。1H NMR(400MHz,氯仿-d)δ7.85(s,1H),7.63-7.54(m,2H),7.45-7.36(m,1H),7.10-7.01(m,1H),6.87(d,J=3.8Hz,1H),5.62(dd,J=3.0,1.3Hz,1H),5.02(dd,J=10.8,3.0Hz,1H),4.64(td,J=6.5,0.9Hz,1H),4.49(dd,J=10.8,3.8Hz,1H),4.29-4.11(m,2H),3.39(s,3H),2.11(s,3H),2.09(s,3H);LC/MS(ESI)m/e 485.6[(M+H)+,C19H22BrFN3O6计算值486.1],tR=1.76分钟(方法2)。
步骤3
向(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(15mg,0.086mmol)在乙酸乙酯(1mL)中的溶液中加入2M碳酸钠(0.171mL,0.342mmol)、((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(52.0mg,0.107mmol)和四丁基硫酸氢铵(116mg,0.342mmol)。将该反应混合液在室温剧烈搅拌1.5h。将该混合液转移到含饱和的NaHCO3水溶液的分液漏斗(20mL)。将水层用乙酸乙酯萃取(3x 25mL)。将合并的有机层用盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(15%→80%在己烷中的乙酸乙酯;24g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(44mg,0.076mmol,89%收率)。1H NMR(400MHz,氯仿-d)δ7.86(s,1H),7.63-7.54(m,2H),7.42(td,J=7.9,6.0Hz,1H),7.07(td,J=8.4,2.5Hz,1H),5.54(d,J=3.0Hz,1H),4.68(dd,J=10.3,3.0Hz,1H),4.65(d,J=9.8Hz,1H),4.27-4.19(m,2H),4.18-4.12(m,3H),4.00(dd,J=11.5,5.3Hz,1H),3.67-3.60(m,1H),3.54(td,J=10.0,5.1Hz,1H),3.34(s,3H),3.26(t,J=11.8Hz,1H),3.13(t,J=11.3Hz,1H),3.00(ddd,J=11.9,9.7,5.0Hz,1H),2.15(s,3H),2.13(s,3H);LC/MS(ESI)m/e 581.1[(M+H)+,C24H30FN6O8S计算值581.2],tR=1.77分钟(方法2)。
制备2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
步骤1.制备2-(((4aR,6S,7R,8S,8aR)-8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基)氧基)乙酸甲酯
向(4aR,6S,7R,8R,8aR)-8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-醇(1.59g,3.83mmol)在DMF(30mL)中的溶液中加入氢化钠(0.459g,11.48mmol)。搅拌15分钟后,将该反应混合液冷却至0℃,并通过注射器加入2-溴乙酸甲酯(1.449mL,15.31mmol)。然后将该反应混合液在室温搅拌1.5h。将该反应混合液冷却至0℃,并通过加入饱和的NaHCO3水溶液(5mL)和水(5mL)淬灭。将该混合液转移到含乙醚(300mL)的分液漏斗。将有机层用水(4x 50mL)和盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%→60%在己烷中的乙酸乙酯;120g柱),得到2-(((4aR,6S,7R,8S,8aR)-8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基)氧基)乙酸甲酯(1.53g,3.14mmol,82%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.73-7.66(m,2H),7.46-7.40(m,2H),7.32-7.20(m,3H),6.96-6.90(m,2H),5.55(s,1H),4.69(d,J=9.3Hz,1H),4.51(d,J=15.6Hz,1H),4.39(dd,J=12.4,1.4Hz,1H),4.32-4.24(m,2H),4.06(dd,J=12.5,1.5Hz,1H),3.86(s,3H),3.80(s,3H),3.78(br t,J=9.4Hz,1H),3.71-3.64(m,1H),3.54(d,J=0.8Hz,1H);LC/MS(ESI)m/e 510.2[(M+Na)+,C23H25N3O7SNa计算值510.1],tR=1.98分钟(方法1)。
步骤2.制备2-(((2S,3R,4S,5R,6R)-4-叠氮基-5-羟基-6-(羟基甲基)-2-(苯硫基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
将2-(((4aR,6S,7R,8S,8aR)-8-叠氮基-2-(4-甲氧基苯基)-6-(苯硫基)六氢吡喃并[3,2-d][1,3]二噁烯-7-基)氧基)乙酸甲酯(1.52g,3.12mmol)溶于80%AcOH(30mL)中,并在40℃加热45分钟。将该混合液浓缩,然后从庚烷(2x)重浓缩。将产物经硅胶柱色谱纯化(30%→100%在己烷中的乙酸乙酯;120g柱),得到2-(((2S,3R,4S,5R,6R)-4-叠氮基-5-羟基-6-(羟基甲基)-2-(苯硫基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(1.06g,2.87mmol,92%收率),为无色粘稠油状物。1H NMR(400MHz,氯仿-d)δ7.57(dd,J=7.3,1.8Hz,2H),7.41-7.30(m,3H),4.72(d,J=9.3Hz,1H),4.59(d,J=15.6Hz,1H),4.40(d,J=15.6Hz,1H),4.11(br s,1H),4.00-3.93(m,1H),3.92-3.86(m,1H),3.80(s,3H),3.77-3.64(m,2H),3.56(t,J=4.9Hz,1H),2.83(br s,1H),2.21(br s,1H);LC/MS(ESI)m/e 392.0[(M+Na)+,C15H19N3O6SNa计算值392.1],tR=1.56分钟(方法1)。
步骤3.制备2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-4-叠氮基-2-(苯硫基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
向2-(((2S,3R,4S,5R,6R)-4-叠氮基-5-羟基-6-(羟基甲基)-2-(苯硫基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(1.02g,2.76mmol)在吡啶(20mL)中的溶液中加入乙酸酐(1.563mL,16.57mmol)和DMAP(0.034g,0.276mmol)。将该反应混合液在室温搅拌16h。将该混合液转移到含乙酸乙酯(150mL)的分液漏斗。将有机层用冷的4N HCl(2x 50mL)、饱和的碳酸氢钠水溶液(25mL)和盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%→50%在己烷中的乙酸乙酯;80g柱),得到2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-4-叠氮基-2-(苯硫基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(1.09g,2.404mmol,87%收率),为无色油状物。1H NMR(400MHz,氯仿-d)δ7.61-7.55(m,2H),7.37-7.32(m,3H),5.41(d,J=2.8Hz,1H),4.71(d,J=9.5Hz,1H),4.59(d,J=15.6Hz,1H),4.37(d,J=15.6Hz,1H),4.13(d,J=6.3Hz,2H),3.89-3.83(m,1H),3.81(s,3H),3.77(dd,J=9.5,3.3Hz,1H),3.58-3.51(m,1H),2.16(s,3H),2.07(s,3H);LC/MS(ESI)m/e 476.1[(M+Na)+,C19H23N3O8SNa计算值476.1],tR=1.86分钟(方法1)。
步骤4.制备2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(苯硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
将2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-4-叠氮基-2-(苯硫基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(1.03g,2.271mmol)和5-乙炔基-1,2,3-三氟苯(0.709g,4.54mmol)溶于DMF(42mL)和水(14mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(0.450g,2.271mmol)和五水合硫酸铜(II)(0.454g,1.817mmol)(预先溶于2mL水中),并将该反应混合液在室温搅拌14h。将该混合液经Celite垫过滤,并将滤液转移到含饱和的NaHCO3水溶液的分液漏斗(50mL)。将水层用二氯甲烷萃取(3x 100mL)。将合并的有机层用盐水(50mL)洗涤,经MgSO4干燥,过滤,并浓缩。将滤液浓缩,并将经硅胶柱色谱纯化(30%→60%在己烷中的乙酸乙酯;80g柱),得到2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(苯硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(1.30g,2.133mmol,94%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.87(s,1H),7.67-7.62(m,2H),7.44(dd,J=8.3,6.5Hz,2H),7.41-7.36(m,3H),5.53(d,J=2.3Hz,1H),4.84(d,J=9.5Hz,1H),4.80(dd,J=10.3,3.0Hz,1H),4.61-4.50(m,2H),4.28-4.15(m,2H),4.09-4.03(m,2H),3.59(s,3H),2.07(s,3H),2.05(s,3H);LC/MS(ESI)m/e 632.1[(M+Na)+,C27H26F3N3O8SNa计算值632.1],tR=2.05分钟(方法1)。
步骤5.制备2-(((2R,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-溴-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
在0℃向2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(苯硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(550mg,0.902mmol)在CH2Cl2(9mL)(经分子筛预干燥)中的溶液中滴加溴(10%在CH2Cl2中的储备溶液)(0.930mL,1.805mmol)。将该反应混合液在0℃搅拌1h。TLC显示原料被消耗。通过加入饱和的NaHCO3水溶液和饱和的Na2S2O3水溶液(2mL:6mL)淬灭过量的溴(红色消失)。将该混合液转移到含水(25mL)的分液漏斗。将水层用二氯甲烷萃取(3x 25mL)。将合并的有机层用盐水(15mL)洗涤,经Na2SO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%→50%在己烷中的乙酸乙酯;40g柱),得到2-(((2R,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-溴-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(447mg,0.770mmol,85%收率),为白色泡沫。将产物储存在冰箱中直到使用。1H NMR(400MHz,氯仿-d)δ8.01(s,1H),7.47(dd,J=8.3,6.5Hz,2H),7.18(d,J=3.5Hz,1H),5.63-5.57(m,1H),5.15(dd,J=10.7,2.9Hz,1H),4.74(dd,J=10.8,3.8Hz,1H),4.65(t,J=6.7Hz,1H),4.27-4.10(m,4H),3.76(s,3H),2.08(s,3H),2.07(s,3H);LC/MS(ESI)m/e580.1[(M+H)+,C21H22BrF3N3O8计算值580.1],tR=2.02分钟(方法1)。
步骤6
通过插管向(–)-(3S,4R,5R)-3-叠氮基-5-巯基四氢-2H-吡喃-4-醇(115mg,0.656mmol)在乙酸乙酯(3mL)和碳酸钠溶液(1M,水溶液)(3mL,3.00mmol)中的溶液中加入2-(((2R,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-溴-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(438mg,0.755mmol)在乙酸乙酯(3mL)。加入四丁基硫酸氢铵(891mg,2.63mmol),并将该反应混合液在室温剧烈搅拌2.5h。将该混合液转移到含饱和的NaHCO3水溶液的分液漏斗(25mL)。将水层用乙酸乙酯萃取(3x25mL)。将合并的有机层用盐水(25mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(40%→70%在己烷中的乙酸乙酯;24g柱),得到2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(445mg,0.660mmol,100%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.86(s,1H),7.45(dd,J=7.5,6.5Hz,2H),5.54(d,J=3.0Hz,1H),4.83-4.72(m,2H),4.57-4.47(m,1H),4.40(d,J=15.8Hz,1H),4.26-4.05(m,5H),4.01(dd,J=11.5,5.0Hz,1H),3.69-3.63(m,1H),3.61(s,3H),3.60-3.50(m,1H),3.24(t,J=11.9Hz,1H),3.12(t,J=11.2Hz,1H),2.99(ddd,J=11.7,9.7,4.9Hz,1H),2.14(s,3H),2.08(s,3H);LC/MS(ESI)m/e 675.2[(M+H)+,C26H30F3N6O10S计算值675.2],tR=2.04分钟(方法1)。
制备最终产物
实施例1.制备(2R,3R,4S,5R,6S)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(((3R,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(((3R,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯
将((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(40mg,0.069mmol)和1-乙炔基-3-氟苯(13.24mg,0.110mmol)溶于DMF(1.5mL)和水(0.500mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(16.38mg,0.083mmol)和五水合硫酸铜(II)(24.08mg,0.096mmol)(预先溶于0.5mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并将水层用5%甲醇的二氯甲烷溶液(4×15mL)萃取(轻轻振动)。将合并的有机层用盐水(15mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%乙酸乙酯(含有5%甲醇)/80%己烷→80%乙酸乙酯(含有5%甲醇)/20%己烷;24g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(((3R,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(45mg,0.064mmol,93%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.94(s,1H),7.88(s,1H),7.62-7.53(m,4H),7.41(tdd,J=7.9,6.0,2.0Hz,2H),7.11-7.02(m,2H),5.53(d,J=3.0Hz,1H),4.76-4.70(m,2H),4.56-4.48(m,1H),4.38(dd,J=11.5,4.8Hz,1H),4.34-4.28(m,2H),4.27-4.22(m,1H),4.20-4.10(m,4H),4.09-4.03(m,1H),3.53(t,J=11.9Hz,1H),3.35(s,3H),3.17(ddd,J=11.8,9.8,5.0Hz,1H),2.11(s,3H),1.93(s,3H);LC/MS(ESI)m/e 701.2[(M+H)+,C32H35F2N6O8S计算值701.2],tR=1.97分钟(方法2)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(((3R,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(45mg,0.064mmol)在THF(0.75mL)和MeOH(0.75mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.073mL,0.321mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。将该混合液加入1N HCl(0.2mL)部分中和。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(((3R,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基四氢-2H-吡喃-3-醇(30mg,0.049mmol,76%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.90(s,1H),8.76(s,1H),7.77(d,J=7.8Hz,1H),7.74-7.68(m,2H),7.67-7.61(m,1H),7.52(tdd,J=8.0,6.1,3.5Hz,2H),7.18(tdd,J=8.2,5.5,2.6Hz,2H),4.95(dd,J=10.5,3.0Hz,1H),4.83(d,J=9.3Hz,1H),4.64-4.55(m,1H),4.25(dd,J=11.6,4.7Hz,1H),4.13(dd,J=11.1,4.9Hz,1H),4.04(t,J=9.9Hz,1H),3.98-3.91(m,2H),3.85-3.77(m,2H),3.58-3.50(m,3H),3.30(dt,J=10.8,5.5Hz,2H),3.25(s,3H);LC/MS(ESI)m/e 617.2[(M+H)+,C28H31F2N6O6S计算值617.2],tR=1.79分钟(方法2);HPLC(方法3):tR=10.01分钟;HPLC(方法4):tR=8.68分钟。hGal-3 IC50=0.060μM。
实施例2.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-叠氮基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯
向(–)-(3S,4R,5R)-乙酸3-叠氮基-5-巯基四氢-2H-吡喃-4-基酯(43mg,0.198mmol)在乙酸乙酯(3mL)中的溶液中加入碳酸钠(0.396mL,0.792mmol)、((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(114mg,0.218mmol)和四丁基硫酸氢铵(269mg,0.792mmol)。将该反应混合液在室温剧烈搅拌1.5h。将该混合液转移到含饱和的NaHCO3水溶液的分液漏斗(5mL)。将水层用乙酸乙酯萃取(3x10mL)。将合并的有机层用盐水(5mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(0%→70%在己烷中的乙酸乙酯;24g柱),得到(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-叠氮基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(101mg,0.153mmol,77%收率)。1H NMR(400MHz,氯仿-d)δ7.81(s,1H),7.46(dd,J=8.3,6.5Hz,2H),5.51(dd,J=3.1,0.9Hz,1H),5.06(dd,J=10.8,9.3Hz,1H),4.69-4.61(m,2H),4.27-4.01(m,6H),3.69(ddd,J=10.7,9.2,5.3Hz,1H),3.59-3.49(m,1H),3.31(s,3H),3.25(t,J=11.2Hz,1H),3.14(td,J=11.0,4.8Hz,1H),2.20(s,3H),2.10(s,3H),2.08(s,3H);LC/MS(ESI)m/e 658.6[(M+H)+,C26H30F3N6O9S计算值659.2],tR=2.10分钟(方法2)。
步骤2.制备(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯
将(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-叠氮基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(101mg,0.153mmol)和1-乙炔基-3-氟苯(55.3mg,0.460mmol)溶于DMF(3mL)和水(1.000mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(30.4mg,0.153mmol)和五水合硫酸铜(II)(26.8mg,0.107mmol)(预溶于0.4mL水中),并将该反应混合液在室温搅拌14h。将该反应混合液经Celite垫过滤,并将滤液转移到含饱和的NaHCO3水溶液(10mL)的分液漏斗。将水层用二氯甲烷萃取(3x 15mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%→75%在己烷中的乙酸乙酯;24g柱),得到(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(85mg,0.109mmol,71%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.91(s,1H),7.83(s,1H),7.65-7.60(m,1H),7.60-7.56(m,1H),7.46(dd,J=8.0,6.3Hz,2H),7.44-7.38(m,1H),7.11-7.04(m,1H),5.61-5.49(m,2H),4.85(td,J=10.2,4.9Hz,1H),4.70(d,J=9.5Hz,1H),4.65(dd,J=10.2,3.1Hz,1H),4.38(t,J=4.0Hz,1H),4.36-4.33(m,1H),4.29-4.21(m,2H),4.17-4.08(m,2H),3.98(t,J=11.2Hz,1H),3.77(t,J=11.8Hz,1H),3.37-3.31(m,1H),3.30(s,3H),2.11(s,3H),2.11(s,3H),2.01(s,3H);LC/MS(ESI)m/e 778.4[(M+H)+,C34H35F4N6O9S计算值779.2],tR=2.12分钟(方法2)。
步骤3
在0℃向(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(80mg,0.103mmol)在甲醇(1.0mL)和THF(1.0mL)中的溶液中加入甲醇钠(25%wt,在MeOH中)(0.117mL,0.514mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。将该混合液加入1N HCl(0.2mL)部分中和。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(26mg,0.039mmol,38%收率),为白色无定形固体。1H NMR(500MHz,甲醇-d4)δ8.69(s,1H),8.50(s,1H),7.73-7.64(m,3H),7.63-7.57(m,1H),7.47(td,J=8.0,6.0Hz,1H),7.13-7.06(m,1H),4.94(dd,J=10.5,3.0Hz,1H),4.80(d,J=9.3Hz,1H),4.71-4.62(m,1H),4.32(dd,J=12.0,5.0Hz,1H),4.23(dd,J=11.1,5.0Hz,1H),4.13-4.04(m,3H),3.95(t,J=11.1Hz,1H),3.87-3.79(m,2H),3.76-3.70(m,1H),3.62(t,J=11.7Hz,1H),3.35(br d,J=5.3Hz,1H),3.32(s,3H);LC/MS(ESI)m/e 652.5[(M+H)+,C28H29F4N6O6S计算值653.2],tR=1.99分钟(方法2);HPLC(方法3):tR=10.54分钟;HPLC(方法4):tR=9.33分钟。hGal-3 IC50=0.046μM。
实施例3.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(吡啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(吡啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(75mg,0.122mmol)和2-乙炔基吡啶(37.6mg,0.365mmol)溶于DMF(2.1mL)和水(0.7mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(28.9mg,0.146mmol)和五水合硫酸铜(II)(42.5mg,0.170mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入几毫升盐水,并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(40%乙酸乙酯(含有5%甲醇)/60%己烷→100%乙酸乙酯(含有5%甲醇);24g柱),得到(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(吡啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(80.6mg,0.112mmol,92%收率),为白色固体。[α]D 22+31.9,(c=0.245,DMF);1H NMR(500MHz,氯仿-d)δ8.63-8.56(m,1H),8.31(s,1H),8.19(d,J=7.9Hz,1H),7.84-7.78(m,2H),7.47(dd,J=8.1,6.4Hz,2H),7.28-7.24(m,1H),5.51(d,J=3.1Hz,1H),4.70(d,J=9.6Hz,1H),4.65(dd,J=10.2,3.1Hz,1H),4.61-4.52(m,1H),4.38(dd,J=11.6,4.9Hz,1H),4.31(dd,J=11.9,5.0Hz,1H),4.25(t,J=10.0Hz,1H),4.21-4.00(m,5H),3.51(t,J=12.0Hz,1H),3.36(s,3H),3.18(ddd,J=11.9,9.8,5.0Hz,1H),2.10(s,3H),1.93(s,3H);LC/MS(ESI)m/e 720.2[(M+H)+,C31H33F3N7O8S计算值720.2],tR=1.90分钟(方法1)。
步骤2
在0℃向(+)-(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-(吡啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(34.5mg,0.045mmol)在THF(0.7mL)和MeOH(0.7mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.052mL,0.226mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法1)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(+)-(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(吡啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇·TFA(31.3mg,0.041mmol,91%收率),为白色无定形固体。[α]D 22+45.9,(c=0.330,DMF);1H NMR(500MHz,DMSO-d6)δ8.98(s,1H),8.76(s,1H),8.62(br d,J=4.7Hz,1H),8.06(d,J=7.8Hz,1H),7.94(br t,J=7.7Hz,1H),7.89-7.82(m,2H),7.42-7.35(m,1H),5.00-4.96(m,1H),4.85(br d,J=9.3Hz,1H),4.65(td,J=10.3,4.9Hz,2H),4.23(brdd,J=11.7,5.0Hz,2H),4.11(br dd,J=10.5,5.0Hz,2H),4.02-3.93(m,4H),3.88-3.82(m,1H),3.80(br t,J=6.2Hz,1H),3.54(br dd,J=10.1,4.0Hz,3H),3.25(s,3H);LC/MS(ESI)m/e 636.2[(M+H)+,C27H29F3N7O6S计算值636.2],tR=1.74分钟(方法1);HPLC(方法1):tR=5.94分钟;HPLC(方法2):tR=6.06分钟。hGal-3 IC50=0.019μM。
实施例4.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(28mg,0.045mmol)和2-乙炔基嘧啶(9.46mg,0.091mmol)溶于DMF(0.9mL)和水(0.3mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(9.00mg,0.045mmol)和五水合硫酸铜(II)(9.07mg,0.036mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。将该混合液转移到分液漏斗。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL)以及几毫升盐水,导致形成沉淀。用5%在二氯甲烷中的甲醇(4x 10mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(50%乙酸乙酯(含有5%甲醇)/50%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(27.5mg,0.038mmol,84%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ8.84(d,J=5.0Hz,2H),8.42(s,1H),7.83(s,1H),7.47(dd,J=8.3,6.5Hz,2H),7.28-7.23(m,1H),5.51(d,J=3.0Hz,1H),4.74-4.64(m,2H),4.57(td,J=10.3,4.8Hz,1H),4.41(dd,J=11.3,5.0Hz,1H),4.35-4.04(m,8H),3.57-3.47(m,2H),3.36(s,3H),3.17(ddd,J=11.9,9.7,5.0Hz,1H),2.11(s,3H),1.95(s,3H);LC/MS(ESI)m/e 721.2[(M+H)+,C30H32F3N8O8S计算值721.2],tR=1.79分钟(方法1)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(24mg,0.033mmol)在THF(0.7mL)和MeOH(0.7mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.038mL,0.167mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。通过加入1N HCl(0.1mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法1)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(18.6mg,0.029mmol,86%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.80(s,1H),8.05(s,1H),8.00(d,J=7.8Hz,1H),7.89-7.80(m,2H),7.66-7.59(m,1H),7.55(d,J=7.8Hz,1H),7.11(t,J=55.8Hz,1H),4.98(dd,J=10.5,2.9Hz,1H),4.83(d,J=9.3Hz,1H),4.65-4.57(m,1H),4.26(br dd,J=11.7,4.8Hz,1H),4.14(br dd,J=11.0,4.9Hz,1H),4.02-3.93(m,3H),3.85-3.78(m,2H),3.58-3.50(m,3H),3.29(dd,J=10.7,4.7Hz,1H),3.25(s,3H);LC/MS(ESI)m/e 637.2[(M+H)+,C26H28F3N8O6S计算值637.2],tR=1.84分钟(方法1);HPLC(方法1):tR=6.14分钟;HPLC(方法2):tR=5.75分钟。hGal-3 IC50=0.018μM。
实施例5.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-(二氟甲基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-(二氟甲基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(48mg,0.078mmol)和1-(二氟甲基)-3-乙炔基苯(23.69mg,0.156mmol)溶于DMF(0.9mL)和水(0.3mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(15.42mg,0.078mmol)和五水合硫酸铜(II)(15.55mg,0.062mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。将该混合液转移到分液漏斗。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL)以及几毫升盐水,导致形成沉淀。用5%在二氯甲烷中的甲醇(4x 10mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%乙酸乙酯(含有5%甲醇)/70%己烷→70%乙酸乙酯(含有5%甲醇)/30%己烷;12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-(二氟甲基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(56.8mg,0.074mmol,95%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ8.01-7.95(m,3H),7.82(s,1H),7.61-7.44(m,4H),6.72(t,J=56.5Hz,1H),5.52(d,J=2.8Hz,1H),4.73-4.62(m,2H),4.53(td,J=10.3,4.8Hz,1H),4.40(dd,J=11.5,4.8Hz,1H),4.35-4.23(m,3H),4.21-4.04(m,4H),3.57-3.49(m,2H),3.36(s,3H),3.16(ddd,J=11.9,9.7,5.0Hz,1H),2.11(s,3H),1.93(s,3H);LC/MS(ESI)m/e 769.2[(M+H)+,C33H34F5N6O8S计算值769.2],tR=1.96分钟(方法1)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-(二氟甲基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(47mg,0.061mmol)在THF(0.7mL)和MeOH(0.7mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.070mL,0.306mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。将该混合液加入1N HCl(0.2mL)部分中和。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法2)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-(二氟甲基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(38mg,0.055mmol,90%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.80(s,1H),8.05(s,1H),8.00(d,J=7.8Hz,1H),7.89-7.80(m,2H),7.66-7.59(m,1H),7.55(d,J=7.8Hz,1H),7.11(t,J=55.8Hz,1H),4.98(dd,J=10.5,2.9Hz,1H),4.83(d,J=9.3Hz,1H),4.65-4.57(m,1H),4.26(br dd,J=11.7,4.8Hz,1H),4.14(br dd,J=11.0,4.9Hz,1H),4.02-3.93(m,3H),3.85-3.78(m,2H),3.58-3.50(m,3H),3.29(dd,J=10.7,4.7Hz,1H),3.25(s,3H);LC/MS(ESI)m/e 685.2[(M+H)+,C29H30F5N6O6S计算值685.2],tR=2.04分钟(方法1);HPLC(方法1):tR=8.16分钟;HPLC(方法2):tR=7.50分钟。hGal-3 IC50=0.051μM。
实施例6.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-(二氟甲氧基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-(二氟甲氧基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(23.1mg,0.037mmol)和1-(二氟甲氧基)-3-乙炔基苯(12.60mg,0.075mmol)溶于DMF(0.9mL)和水(0.3mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(7.42mg,0.037mmol)和五水合硫酸铜(II)(7.48mg,0.030mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。将该混合液转移到分液漏斗。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL)以及几毫升盐水,导致形成沉淀。用5%在二氯甲烷中的甲醇(4x 10mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%乙酸乙酯(含有5%甲醇)/70%己烷→70%乙酸乙酯(含有5%甲醇)/30%己烷;12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-(二氟甲氧基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(26.7mg,0.034mmol,91%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.94(s,1H),7.83(s,1H),7.67(d,J=7.8Hz,1H),7.61(s,1H),7.51-7.41(m,3H),7.13(dd,J=8.0,2.3Hz,1H),6.60(t,J=73.8Hz,1H),5.51(d,J=3.0Hz,1H),4.72-4.64(m,2H),4.52(td,J=10.5,4.9Hz,1H),4.39(dd,J=11.5,4.8Hz,1H),4.34-4.22(m,3H),4.21-4.01(m,5H),3.53(t,J=11.9Hz,1H),3.36(s,3H),3.16(ddd,J=11.7,10.0,5.1Hz,1H),2.11(s,3H),1.93(s,3H);LC/MS(ESI)m/e 785.1[(M+H)+,C33H34F5N6O9S计算值785.2],tR=2.13分钟(方法1)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-(二氟甲氧基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(25mg,0.032mmol)在THF(0.7mL)和MeOH(0.7mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.036mL,0.159mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。通过加入1N HCl(0.1mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法2)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-(二氟甲氧基)苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(19.6mg,0.028mmol,87%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.99(s,1H),8.78(s,1H),7.86(dd,J=8.9,6.8Hz,2H),7.72(d,J=7.9Hz,1H),7.63(s,1H),7.53(t,J=7.9Hz,1H),7.33(t,J=73.9Hz,1H),7.16(dd,J=8.2,2.1Hz,1H),4.98(dd,J=10.6,2.8Hz,1H),4.83(d,J=9.3Hz,1H),4.63-4.56(m,1H),4.25(dd,J=11.7,5.0Hz,1H),4.13(br dd,J=11.1,5.1Hz,1H),4.01-3.91(m,3H),3.84-3.76(m,2H),3.56-3.49(m,3H),3.32-3.27(m,1H),3.25(s,3H);LC/MS(ESI)m/e 701.2[(M+H)+,C29H30F5N6O7S计算值701.2],tR=2.02分钟(方法1);HPLC(方法1):tR=8.25分钟;HPLC(方法2):tR=7.56分钟。hGal-3 IC50=0.058μM。
实施例7.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(17mg,0.028mmol)和2-乙炔基-5-氟嘧啶(10.10mg,0.083mmol)溶于DMF(0.6mL)和水(0.2mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(5.46mg,0.028mmol)和五水合硫酸铜(II)(5.51mg,0.022mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解附着在搅拌棒上的固体。将该混合液转移到含水(5mL)和饱和的碳酸氢钠水溶液(5mL)的分液漏斗,导致形成沉淀。用5%在二氯甲烷中的甲醇(4x10mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集橙色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(50%乙酸乙酯(含有5%甲醇)/50%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(15.9mg,0.022mmol,78%收率),为白色固体。1H NMR(500MHz,DMSO-d6)δ8.98(s,2H),8.96(s,1H),8.86(s,1H),7.81(dd,J=8.6,6.8Hz,2H),5.72(d,J=7.2Hz,1H),5.39(d,J=2.7Hz,1H),5.27(dd,J=10.5,3.1Hz,1H),5.04(d,J=9.3Hz,1H),4.68(td,J=10.4,5.0Hz,1H),4.35(t,J=6.3Hz,1H),4.21(dd,J=11.7,4.7Hz,1H),4.15(dd,J=10.9,5.0Hz,1H),4.11-4.01(m,4H),3.88(t,J=11.1Hz,1H),3.58(t,J=11.6Hz,1H),3.26(s,3H),3.25-3.20(m,1H),2.04(s,3H),2.03(s,3H);LC/MS(ESI)m/e 739.2[(M+H)+,C30H31F4N8O8S计算值739.1],tR=1.90分钟(方法1)。
步骤2
在-10℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(28mg,0.038mmol)在THF(0.7mL)和MeOH(0.7mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.043mL,0.190mmol)。将该反应混合液在-10℃搅拌1h。通过加入N HCl(0.35mL)将该混合液中和直至酸性。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法1)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(5-氟嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(20.3mg,0.031mmol,81%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.98(s,2H),8.96(s,1H,主要),8.94(s,1H,次要),8.86(s,1H),7.88-7.80(m,2H),5.15(dd,J=10.4,2.9Hz,1H,次要),4.98(dd,J=10.5,2.9Hz,1H),4.84(d,J=9.3Hz,1H),4.70-4.63(m,2H),4.52(br d,J=2.6Hz,1H,次要),4.23(br dd,J=11.9,5.0Hz,2H),4.15-4.08(m,2H),4.03-3.93(m,3H),3.91-3.83(m,1H),3.80(t,J=6.3Hz,1H),3.58-3.51(m,3H),3.25(s,3H,主要),3.29-3.23(m,1H),3.22(s,3H,次要);LC/MS(ESI)m/e 655.2[(M+H)+,C26H27F4N8O6S计算值655.2],tR=1.78分钟(方法1);HPLC(方法1):tR=4.84分钟;HPLC(方法2):tR=4.82分钟。hGal-3 IC50=0.009μM。
实施例8.(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(25.8mg,0.042mmol)和2-乙炔基-5-甲氧基嘧啶(11.23mg,0.084mmol)溶于DMF(0.75mL)和水(0.25mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(8.29mg,0.042mmol)和五水合硫酸铜(II)(8.36mg,0.033mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解附着在搅拌棒上的固体。将该混合液转移到含水(5mL)和饱和的碳酸氢钠水溶液(5mL)的分液漏斗,导致形成沉淀。用5%在二氯甲烷中的甲醇(4x 10mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(50%乙酸乙酯(含有5%甲醇)/50%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(25.3mg,0.034mmol,81%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ8.50(s,2H),8.32(s,1H),7.85(s,1H),7.48(dd,J=8.2,6.4Hz,2H),5.52(d,J=2.8Hz,1H),4.74-4.66(m,2H),4.61-4.52(m,1H),4.40(dd,J=11.7,4.9Hz,1H),4.34-4.20(m,3H),4.19-4.05(m,5H),4.00(s,3H),3.52(t,J=11.9Hz,1H),3.36(s,3H),3.18(ddd,J=11.7,9.7,5.1Hz,1H),2.11(s,3H),1.95(s,3H);LC/MS(ESI)m/e 751.2[(M+H)+,C31H34F3N8O9S计算值751.2],tR=1.90分钟(方法1)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(25.8mg,0.034mmol)在THF(0.7mL)和MeOH(0.7mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.039mL,0.172mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。通过加入1N HCl(0.1mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法1)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(22.8mg,0.034mmol,98%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.77(br s,1H,主要),8.94(s,1H,次要),8.77(br s,1H),8.64(brs,2H),7.85(dd,J=8.9,6.8Hz,2H),5.15(br dd,J=10.2,2.9Hz,1H,次要),4.98(dd,J=10.6,3.0Hz,1H),4.84(d,J=9.3Hz,1H),4.71-4.61(m,2H),4.52(br d,J=3.2Hz,1H,次要),4.26-4.19(m,2H),4.11(br dd,J=10.8,4.8Hz,2H),4.04-3.93(m,3H),3.89-3.82(m,1H),3.80(t,J=6.4Hz,1H),3.58-3.51(m,3H),3.25(s,3H,主要),3.27(br d,J=4.7Hz,1H),3.22(s,1H,次要);LC/MS(ESI)m/e 667.2[(M+H)+,C27H30F3N8O7S计算值667.2],tR=1.79分钟(方法1);HPLC(方法1):tR=5.74分钟;HPLC(方法2):tR=5.44分钟。hGal-3IC50=0.012μM。
实施例9.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(18mg,0.029mmol)和5-乙炔基-2-甲氧基嘧啶(11.75mg,0.088mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(6.94mg,0.035mmol)和五水合硫酸铜(II)(10.20mg,0.041mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%乙酸乙酯(含有5%甲醇)/60%己烷→80%乙酸乙酯(含有5%甲醇)/20%己烷;12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(18mg,0.024mmol,82%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ8.96(s,2H),7.98(s,1H),7.84(s,1H),7.47(dd,J=8.0,6.5Hz,2H),5.52(d,J=3.0Hz,1H),4.72-4.66(m,2H),4.54(td,J=10.3,4.8Hz,1H),4.39(dd,J=11.4,4.9Hz,1H),4.34-4.29(m,1H),4.31-4.22(m,2H),4.19-4.11(m,4H),4.09(s,3H),3.59-3.49(m,1H),3.35(s,3H),3.20-3.11(m,1H),2.10(s,3H),1.95(s,3H);LC/MS(ESI)m/e 751.2[(M+H)+,C31H34F3N8O9S计算值751.2],tR=2.05分钟(方法2)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(18mg,0.024mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.027mL,0.120mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(12.0mg,0.015mmol,62%收率),为白色无定形固体。1H NMR(400MHz,DMSO-d6)δ9.03(s,2H),8.98(s,1H),8.76(s,1H),7.86(dd,J=8.8,7.0Hz,2H),5.72(br s,1H),5.49(br s,1H),4.98(dd,J=10.4,2.6Hz,1H),4.84(d,J=9.3Hz,1H),4.62(td,J=10.4,4.9Hz,1H),4.26(br dd,J=11.4,4.9Hz,1H),4.14(br dd,J=10.9,4.6Hz,1H),3.98(s,3H),3.95(br s,2H),3.86-3.78(m,2H),3.54(br t,J=11.4Hz,4H),3.30(br dd,J=11.0,5.0Hz,1H),3.25(s,3H);LC/MS(ESI)m/e 667.2[(M+H)+,C27H29F3N8O7S计算值667.2],tR=1.92分钟(方法2);HPLC(方法3):tR=8.65分钟;HPLC(方法4):tR=7.44分钟。hGal-3IC50=0.012μM。
实施例10.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(3-羟基苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(3-羟基苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(18mg,0.029mmol)和3-乙炔基苯酚(10.35mg,0.088mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(6.94mg,0.035mmol)和五水合硫酸铜(II)(10.20mg,0.041mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%乙酸乙酯(含有5%甲醇)/60%己烷→80%乙酸乙酯(含有5%甲醇)/20%己烷;12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(3-羟基苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(15mg,0.020mmol,70%收率),为白色固体。1H NMR(400MHz,丙酮)δ8.81(s,1H),8.42(s,1H),7.74(dd,J=9.0,6.8Hz,2H),7.49-7.42(m,1H),7.38-7.34(m,1H),7.30-7.22(m,1H),6.83(ddd,J=8.0,2.5,1.0Hz,1H),5.59(d,J=2.3Hz,1H),5.26(dd,J=10.5,3.0Hz,1H),5.06(d,J=9.5Hz,1H),4.75-4.61(m,1H),4.44(t,J=6.7Hz,1H),4.32-4.12(m,7H),3.98(t,J=11.2Hz,1H),3.64(t,J=11.7Hz,1H),3.36(s,3H),2.10(s,3H),1.99(s,3H);LC/MS(ESI)m/e 735.3[(M+H)+,C32H34F3N6O9S计算值735.2],tR=2.03分钟(方法2)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(3-羟基苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(15mg,0.020mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.023mL,0.102mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(3-羟基苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(11.4mg,0.017mmol,84%收率),为白色无定形固体。1H NMR(400MHz,DMSO-d6)δ9.59(br s,1H),8.98(s,1H),8.60(s,1H),7.86(dd,J=8.9,6.9Hz,2H),7.28(d,J=1.0Hz,1H),7.26-7.21(m,2H),6.77-6.70(m,1H),5.79-5.61(m,1H),5.56-5.43(m,1H),4.98(dd,J=10.4,2.9Hz,1H),4.84(d,J=9.3Hz,1H),4.64-4.50(m,1H),4.29-4.20(m,1H),4.11(br dd,J=10.9,4.9Hz,1H),4.02-3.92(m,3H),3.85-3.76(m,2H),3.56-3.51(m,2H),3.26(s,3H);LC/MS(ESI)m/e 651.2[(M+H)+,C28H30F3N6O7S计算值651.2],tR=1.92分钟(方法2);HPLC(方法3):tR=9.11分钟;HPLC(方法4):tR=8.16分钟。hGal-3 IC50=0.038μM。
实施例11.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(2-氯吡啶-4-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(2-氯吡啶-4-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(20mg,0.032mmol)和2-氯-4-乙炔基吡啶(13.39mg,0.097mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(7.71mg,0.039mmol)和五水合硫酸铜(II)(11.34mg,0.045mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并将水层用5%在二氯甲烷中的甲醇(3x 10mL)萃取。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(40%乙酸乙酯(含有5%甲醇)/60%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(2-氯吡啶-4-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(23mg,0.030mmol,94%收率)。1H NMR(400MHz,氯仿-d)δ8.45(d,J=5.0Hz,1H),8.11(s,1H),7.85(s,1H),7.78(s,1H),7.67(dd,J=5.3,1.3Hz,1H),7.46(dd,J=7.8,6.5Hz,2H),5.52(d,J=3.0Hz,1H),4.73-4.65(m,2H),4.57-4.49(m,1H),4.40(br dd,J=11.5,4.8Hz,1H),4.35-4.29(m,2H),4.29-4.22(m,2H),4.17-4.10(m,2H),4.09-4.02(m,1H),3.52(t,J=11.9Hz,1H),3.35(s,3H),3.15(ddd,J=11.7,10.0,5.1Hz,1H),2.10(s,3H),1.94(s,3H);LC/MS(ESI)m/e 754.2[(M+H)+,C31H32ClF3N7O8S计算值754.2],tR=1.91分钟(方法2)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(2-氯吡啶-4-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(23mg,0.030mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.035mL,0.152mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(2-氯吡啶-4-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇·TFA(14.1mg,0.017mmol,57%收率),为白色无定形固体。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.98(s,1H),8.50(d,J=5.0Hz,1H),7.93(s,1H),7.89-7.81(m,3H),5.74(br dd,J=4.5,1.5Hz,1H),5.50(br d,J=5.5Hz,1H),4.98(dd,J=10.5,2.8Hz,1H),4.84(d,J=9.3Hz,1H),4.62(td,J=10.4,4.9Hz,1H),4.26(br dd,J=11.7,4.6Hz,1H),4.16(dd,J=10.8,4.8Hz,1H),4.02-3.90(m,3H),3.85-3.76(m,2H),3.57-3.51(m,4H),3.34-3.27(m,1H),3.25(s,3H);LC/MS(ESI)m/e 670.1[(M+H)+,C27H28ClF3N7O6S计算值670.1],tR=1.80分钟(方法2);HPLC(方法3):tR=9.75分钟;HPLC(方法4):tR=8.66分钟。hGal-3 IC50=0.037μM。
实施例12.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1。制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(24mg,0.039mmol)和乙炔基苯(11.93mg,0.117mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(9.25mg,0.047mmol)和五水合硫酸铜(II)(13.61mg,0.054mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(40%乙酸乙酯(含有5%甲醇)/60%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(11mg,0.015mmol,39%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.92(s,1H),7.86-7.80(m,3H),7.50-7.41(m,4H),7.40-7.33(m,1H),5.51(d,J=3.0Hz,1H),4.74-4.65(m,2H),4.57-4.48(m,1H),4.38(dd,J=11.5,4.8Hz,1H),4.34-4.03(m,7H),3.53(t,J=11.9Hz,1H),3.36(s,3H),3.18(ddd,J=11.9,9.5,5.0Hz,1H),2.10(s,3H),1.93(s,3H);LC/MS(ESI)m/e 719.3[(M+H)+,C32H34F3N6O8S计算值719.2],tR=2.01分钟(方法2)。
步骤2
在0℃向(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(11mg,0.014mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.017mL,0.072mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(8.1mg,0.012mmol,81%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.98(s,1H),8.68(s,1H),7.89-7.82(m,4H),7.47(t,J=7.7Hz,2H),7.40-7.32(m,1H),5.72-5.66(m,1H),5.49(br d,J=5.5Hz,1H),4.98(dd,J=10.5,2.9Hz,1H),4.84(d,J=9.2Hz,1H),4.63-4.55(m,1H),4.25(dd,J=11.5,5.0Hz,1H),4.12(dd,J=10.7,4.7Hz,1H),4.01-3.92(m,3H),3.84-3.76(m,2H),3.56-3.49(m,3H),3.28(br dd,J=11.0,4.4Hz,1H),3.25(s,3H);LC/MS(ESI)m/e635.2[(M+H)+,C28H30F3N6O6S计算值635.2],tR=1.88分钟(方法2);HPLC(方法3):tR=13.65分钟;HPLC(方法4):tR=11.47分钟。hGal-3 IC50=0.032μM。
实施例13.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-氨基苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1。制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-氨基苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(24mg,0.039mmol)和3-乙炔基苯胺(13.68mg,0.117mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(9.25mg,0.047mmol)和五水合硫酸铜(II)(13.61mg,0.054mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),用5%在二氯甲烷中的甲醇(4x 5mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(40%乙酸乙酯(含有5%甲醇)/60%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-氨基苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(25mg,0.034mmol,88%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.87(s,1H),7.83(s,1H),7.47(dd,J=8.0,6.5Hz,2H),7.28-7.19(m,3H),7.12(d,J=7.5Hz,1H),6.77-6.65(m,1H),5.50(d,J=3.0Hz,1H),4.72-4.65(m,2H),4.55-4.47(m,1H),4.37(dd,J=11.5,4.8Hz,1H),4.32-4.25(m,2H),4.22(br d,J=9.0Hz,1H),4.19-4.11(m,2H),4.09-4.00(m,2H),3.53(t,J=11.9Hz,1H),3.35(s,3H),3.22-3.12(m,2H),2.10(s,3H),1.93(s,4H);LC/MS(ESI)m/e 734.2[(M+H)+,C32H35F3N7O8S计算值734.2],tR=1.79分钟(方法2)。
步骤2
在0℃向(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-(3-氨基苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(25mg,0.032mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.037mL,0.161mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-氨基苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(22.5mg,0.028mmol,87%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.98(s,1H),8.66(s,1H),7.86(dd,J=8.7,6.9Hz,2H),7.57(br s,1H),7.45(br d,J=7.2Hz,1H),7.41-7.34(m,1H),6.99(br d,J=7.5Hz,1H),4.98(dd,J=10.5,2.7Hz,1H),4.84(d,J=9.3Hz,1H),4.59(td,J=10.3,5.0Hz,1H),4.28-4.20(m,1H),4.12(br dd,J=11.1,4.8Hz,1H),4.00-3.92(m,3H),3.84-3.77(m,2H),3.57-3.49(m,3H),3.30-3.26(m,1H),3.25(s,3H);LC/MS(ESI)m/e 650.2[(M+H)+,C28H31F3N7O6S计算值650.2],tR=1.65分钟(方法2);HPLC(方法3):tR=9.63分钟;HPLC(方法4):tR=7.35分钟。hGal-3 IC50=0.022μM。
实施例14.制备N-(3-(1-((3S,4R,5R)-4-羟基-5-(((2S,3R,4S,5R,6R)-5-羟基-6-(羟基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)四氢-2H-吡喃-3-基)-1H-1,2,3-三唑-4-基)苯基)乙酰胺
步骤1.制备(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(3-乙酰氨基苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(24mg,0.039mmol)和N-(3-乙炔基苯基)乙酰胺(18.59mg,0.117mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(9.25mg,0.047mmol)和五水合硫酸铜(II)(13.61mg,0.054mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(40%乙酸乙酯(含有5%甲醇)/60%己烷→100%乙酸乙酯(含有5%甲醇);24g柱),得到(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(3-乙酰氨基苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(28mg,0.036mmol,93%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.96-7.83(m,3H),7.56(br d,J=7.8Hz,1H),7.45(br dd,J=13.3,6.3Hz,3H),7.37-7.31(m,1H),5.51(d,J=2.5Hz,1H),4.89(br s,1H),4.73(br d,J=9.8Hz,2H),4.54-4.45(m,1H),4.38-4.26(m,4H),4.23-4.10(m,2H),4.08-4.00(m,1H),3.56(br t,J=11.9Hz,1H),3.35(s,3H),3.21(td,J=10.8,5.0Hz,1H),2.23(s,3H),2.11(s,3H),1.96(s,3H);LC/MS(ESI)m/e 776.3[(M+H)+,C34H37F3N7O9S计算值776.2],tR=1.92分钟(方法2)。
步骤2
在0℃向(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(3-乙酰氨基苯基)-1H-1,2,3-三唑-1-基)-4-乙酸基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(28mg,0.034mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.039mL,0.171mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到N-(3-(1-((3S,4R,5R)-4-羟基-5-(((2S,3R,4S,5R,6R)-5-羟基-6-(羟基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)四氢-2H-吡喃-3-基)-1H-1,2,3-三唑-4-基)苯基)乙酰胺(24.1mg,0.028mmol,82%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ10.06(s,1H),8.98(s,1H),8.62(s,1H),8.16(s,1H),7.86(dd,J=8.9,6.8Hz,2H),7.54(br d,J=8.2Hz,1H),7.45(d,J=7.8Hz,1H),7.41-7.33(m,1H),4.98(dd,J=10.6,2.8Hz,1H),4.83(d,J=9.3Hz,1H),4.63-4.56(m,1H),4.29-4.20(m,1H),4.11(brdd,J=11.1,4.9Hz,1H),4.01-3.92(m,3H),3.86-3.77(m,2H),3.59-3.49(m,3H),3.31-3.26(m,1H),3.25(s,3H),2.07(s,3H);LC/MS(ESI)m/e 692.2[(M+H)+,C30H33F3N7O7S计算值692.2],tR=1.73分钟(方法2);HPLC(方法3):tR=13.31分钟;HPLC(方法4):tR=11.65分钟。hGal-3 IC50=0.020μM。
实施例15.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(27mg,0.044mmol)和5-乙炔基嘧啶(13.68mg,0.131mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(8.68mg,0.044mmol)和五水合硫酸铜(II)(7.65mg,0.031mmol)(预先溶于0.2mL水中),并将该反应混合液在室温搅拌14h。将该反应混合液经Celite垫过滤,并将滤液转移到含饱和的NaHCO3水溶液(10mL)的分液漏斗。将水层用二氯甲烷萃取(3x 15mL)。将合并的有机层用盐水(10mL)洗涤,经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(10%→100%在己烷中的乙酸乙酯;12g柱),得到(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(12mg,0.017mmol,38%收率),为白色固体。[α]D 22+72.0,(c=0.320,CHCl3);1H NMR(400MHz,氯仿-d)δ9.23(s,1H),9.20(s,2H),8.10(s,1H),7.83(s,1H),7.47(dd,J=8.2,6.4Hz,2H),5.52(d,J=3.0Hz,1H),4.72-4.63(m,2H),4.60-4.51(m,1H),4.41(dd,J=11.7,4.9Hz,1H),4.32(dd,J=12.2,5.1Hz,1H),4.27(t,J=9.9Hz,1H),4.21-4.03(m,4H),3.58-3.48(m,1H),3.36(s,3H),3.15(ddd,J=12.0,9.9,5.0Hz,1H),3.01-2.88(m,1H),2.11(s,3H),1.95(s,3H);LC/MS(ESI)m/e 720.4[(M+H)+,C30H31F3N8O8S计算值721.2],tR=1.81分钟(方法2)。
步骤2
在0℃向(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(23mg,0.032mmol)在甲醇(0.5mL)和四氢呋喃(0.5mL)中的溶液中加入甲醇钠(25%wt,在MeOH中)(0.036mL,0.160mmol)。将该反应混合液在室温搅拌2h。将该反应混合液冷却至0℃,并用1N HCl(0.10mL)部分中和。溶剂的体积在选装蒸发器上减少,将该混合液用甲醇稀释,过滤,并经反相制备型HPLC纯化(方法4)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(+)-(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(11.4mg,0.018mmol,56%收率),为白色无定形固体。[α]D 22+64.3,(c=0.235,DMF);1H NMR(500MHz,丙酮)δ9.24(s,2H),9.13(s,1H),8.77(s,1H),8.73(s,1H),7.76(dd,J=8.9,6.8Hz,2H),5.00(dd,J=10.5,2.9Hz,1H),4.92(d,J=9.3Hz,1H),4.74-4.67(m,1H),4.32-4.22(m,3H),4.18(t,J=9.9Hz,1H),4.08(t,J=10.0Hz,1H),4.01-3.92(m,2H),3.84(dd,J=5.8,3.5Hz,2H),3.62(t,J=11.7Hz,1H),3.37-3.32(m,1H),3.30(s,3H);13C NMR(126MHz,DMSO-d6)δ158.1,153.7,143.8,140.6,125.5,123.5,122.9,110.0,110.0,109.8,82.9,79.6,76.8,72.2,71.7,69.2,67.9,66.5,64.0,60.7,60.1,55.4,46.7;LC/MS(ESI)m/e 637.2[(M+H)+,C26H28F3N8O6S计算值637.2],tR=1.70分钟(方法2);HPLC(方法3):tR=8.32分钟;HPLC(方法4):tR=6.98分钟。hGal-3IC50=0.015μM。
实施例16.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-氯苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-氯苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(18mg,0.029mmol)和1-氯-3-乙炔基苯(11.96mg,0.088mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(6.94mg,0.035mmol)和五水合硫酸铜(II)(10.20mg,0.041mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 10mL)萃取水层(轻轻振动)。将合并的有机层用盐水(20mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(10%乙酸乙酯(含有5%甲醇)/90%己烷→70%乙酸乙酯(含有5%甲醇)/30%己烷;12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-氯苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(21mg,0.028mmol,96%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.94(s,1H),7.84(s,1H),7.81(t,J=1.6Hz,1H),7.71(dt,J=7.5,1.4Hz,1H),7.47(dd,J=8.2,6.4Hz,2H),7.42-7.31(m,2H),5.51(d,J=3.0Hz,1H),4.74-4.66(m,2H),4.58-4.47(m,1H),4.38(dd,J=11.5,4.8Hz,1H),4.34-4.23(m,3H),4.21-4.12(m,4H),4.10-4.01(m,1H),3.53(t,J=12.0Hz,1H),3.35(s,3H),3.16(ddd,J=12.0,9.7,5.1Hz,1H),2.10(s,3H),1.93(s,3H);LC/MS(ESI)m/e 753.2[(M+H)+,C32H33ClF3N6O8S计算值753.2],tR=1.99分钟(方法2)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(3-氯苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(21mg,0.028mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.032mL,0.139mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(3-氯苯基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(15.6mg,0.023mmol,81%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.78(s,1H),7.89(t,J=1.8Hz,1H),7.87-7.79(m,3H),7.54-7.48(m,1H),7.43-7.39(m,1H),4.97(dd,J=10.5,2.9Hz,1H),4.83(d,J=9.3Hz,1H),4.63-4.55(m,1H),4.25(dd,J=11.7,4.7Hz,1H),4.13(dd,J=11.1,5.0Hz,1H),4.01-3.91(m,3H),3.83-3.76(m,2H),3.57-3.49(m,3H),3.29(br dd,J=10.8,4.7Hz,1H),3.25(s,3H);LC/MS(ESI)m/e 669.1[(M+H)+,C28H29ClF3N6O6S计算值669.1],tR=1.90分钟(方法2);HPLC(方法3):tR=15.4分钟;HPLC(方法4):tR=14.1分钟。hGal-3 IC50=0.068μM。
实施例17.制备N-(2-(1-((3S,4R,5R)-4-羟基-5-(((2S,3R,4S,5R,6R)-5-羟基-6-(羟基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)四氢-2H-吡喃-3-基)-1H-1,2,3-三唑-4-基)嘧啶-4-基)乙酰胺
步骤1.制备(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(4-乙酰氨基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(37mg,0.060mmol)和N-(2-乙炔基嘧啶-4-基)乙酰胺(22.24mg,0.138mmol)溶于DMF(1.5mL)和水(0.500mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(14.27mg,0.072mmol)和五水合硫酸铜(II)(20.98mg,0.084mmol)(预先溶于0.5mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(10mL)和饱和的碳酸氢钠水溶液(10mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(20mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%→100%乙酸乙酯(含有5%甲醇)/己烷;24g柱),得到(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(4-乙酰氨基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(35mg,0.045mmol,75%收率),为白色固体。1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.99(s,1H),8.81(s,1H),8.71(d,J=5.8Hz,1H),8.00(d,J=5.8Hz,1H),7.89-7.78(m,2H),5.76(br d,J=6.8Hz,1H),5.40(d,J=2.8Hz,1H),5.28(dd,J=10.5,3.0Hz,1H),5.05(d,J=9.5Hz,1H),4.69(td,J=10.2,4.9Hz,1H),4.35(t,J=6.4Hz,1H),4.26-4.13(m,2H),4.11-3.99(m,4H),3.90(t,J=11.2Hz,1H),3.59(brt,J=11.5Hz,1H),3.27(s,3H),2.18(s,3H),2.05(s,3H),2.04(s,3H);LC/MS(ESI)m/e778.3[(M+H)+,C32H35F3N9O9S计算值778.2],tR=1.90分钟(方法2)。
步骤2
在-20℃(丙酮/干冰浴)向(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(4-乙酰氨基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(15mg,0.019mmol)在THF(0.75mL)和MeOH(0.75mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.022mL,0.096mmol)。移去冷却浴,并将该反应混合液在-20℃搅拌1h。还观测到少量的苯胺副产物。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到N-(2-(1-((3S,4R,5R)-4-羟基-5-(((2S,3R,4S,5R,6R)-5-羟基-6-(羟基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)四氢-2H-吡喃-3-基)-1H-1,2,3-三唑-4-基)嘧啶-4-基)乙酰胺(9.8mg,0.012mmol,62%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ11.13(s,1H),9.01-8.95(m,1H),8.79(s,1H),8.70(d,J=5.6Hz,1H),7.98(d,J=5.8Hz,1H),7.85(br dd,J=8.9,6.9Hz,2H),4.97(dd,J=10.7,2.7Hz,1H),4.84(d,J=9.3Hz,1H),4.67(td,J=10.2,5.0Hz,1H),4.27-4.18(m,2H),4.13(br dd,J=10.7,4.7Hz,2H),4.02-3.93(m,3H),3.91-3.84(m,1H),3.80(br t,J=6.1Hz,1H),3.57-3.49(m,3H),3.25(s,3H),3.29-3.22(m,1H),2.17(s,3H),1.24(s,1H);LC/MS(ESI)m/e 694.2[(M+H)+,C28H31F3N9O7S计算值694.2],tR=1.78分钟(方法2);HPLC(方法3):tR=13.5分钟;HPLC(方法4):tR=11.5分钟。hGal-3 IC50=0.012μM.
实施例18.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(4-氨基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
在室温向(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(4-乙酰氨基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(15mg,0.019mmol)在THF(0.75mL)和MeOH(0.75mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.022mL,0.096mmol)。将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法1)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(4-氨基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(11.6mg,0.015mmol,75%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.89(s,1H),8.14(d,J=6.9Hz,1H),7.91-7.80(m,2H),6.60(br d,J=6.6Hz,1H),5.70(br d,J=1.7Hz,1H),5.47(br s,1H),4.97(dd,J=10.5,3.0Hz,1H),4.84(d,J=9.3Hz,1H),4.78-4.71(m,1H),4.28-4.20(m,1H),4.15(br dd,J=10.9,4.8Hz,1H),4.02-3.93(m,3H),3.89(br t,J=11.1Hz,1H),3.79(br t,J=6.4Hz,1H),3.61-3.51(m,3H),3.30-3.26(m,1H),3.24(s,3H);LC/MS(ESI)m/e 652.2[(M+H)+,C26H29F3N9O6S计算值652.2],tR=1.64min(方法2);HPLC(方法3):tR=12.34分钟;HPLC(方法4):tR=10.03分钟。hGal-3IC50=0.013μM。
实施例19.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-环己基-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-环己基-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(19mg,0.031mmol)和乙炔基环己烷(10.00mg,0.092mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(7.33mg,0.037mmol)和五水合硫酸铜(II)(10.77mg,0.043mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(10mL)和饱和的碳酸氢钠水溶液(10mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%乙酸乙酯(含有5%甲醇)/80%己烷→80%乙酸乙酯(含有5%甲醇)/20%己烷;12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-环己基-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(21mg,0.029mmol,94%收率),为白色固体。1H NMR(400MHz,丙酮)δ8.78(s,1H),7.78(s,1H),7.73(dd,J=9.0,6.8Hz,2H),5.58(dd,J=3.1,0.9Hz,1H),5.26(dd,J=10.4,3.1Hz,1H),5.05(d,J=9.5Hz,1H),4.72(d,J=4.5Hz,1H),4.59-4.50(m,1H),4.46-4.40(m,1H),4.28-4.19(m,2H),4.17-4.10(m,4H),3.89(t,J=11.3Hz,1H),3.59(t,J=11.7Hz,1H),3.35(s,3H),3.32-3.24(m,1H),2.09(s,3H),1.98(s,3H),1.84-1.78(m,2H),1.76-1.68(m,2H),1.50-1.36(m,6H);LC/MS(ESI)m/e 725.3[(M+H)+,C32H40F3N6O8S计算值725.3],tR=2.08分钟(方法2)。
步骤2
在室温向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-环己基-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(21mg,0.029mmol)在THF(0.75mL)和MeOH(0.75mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.033mL,0.145mmol)。将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-环己基-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(8.5mg,0.013mmol,45%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),7.91(s,1H),7.87-7.81(m,2H),4.96(dd,J=10.5,2.7Hz,1H),4.81(d,J=9.3Hz,1H),4.49(td,J=10.4,4.8Hz,1H),4.20(brdd,J=11.4,5.0Hz,1H),4.03-3.92(m,3H),3.88(br t,J=10.1Hz,1H),3.78(br t,J=6.2Hz,1H),3.72(br t,J=11.1Hz,1H),3.55-3.48(m,3H),3.24(s,3H),3.21-3.15(m,1H),2.65(br s,1H),1.96(br d,J=5.8Hz,2H),1.78-1.71(m,2H),1.67(br d,J=12.7Hz,1H),1.36(br t,J=9.8Hz,4H),1.28-1.18(m,2H);LC/MS(ESI)m/e 641.2[(M+H)+,C28H36F3N6O6S计算值641.2],tR=1.99分钟(方法2);HPLC(方法3):tR=11.24分钟;HPLC(方法4):tR=9.99分钟。hGal-3 IC50=0.013μM。
实施例20.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(四氢-2H-吡喃-4-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(四氢-2H-吡喃-4-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(20mg,0.032mmol)和4-乙炔基四氢-2H-吡喃(10.72mg,0.097mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(7.71mg,0.039mmol)和五水合硫酸铜(II)(11.34mg,0.045mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(10%乙酸乙酯(含有5%甲醇)/90%己烷→80%乙酸乙酯(含有5%甲醇)/20%己烷12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(四氢-2H-吡喃-4-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(22mg,0.030mmol,93%收率),为白色固体。1H NMR(400MHz,乙腈-d3)δ8.32(s,1H),7.68-7.61(m,3H),5.47-5.46(m,1H),5.03(dd,J=10.4,3.1Hz,1H),4.88(d,J=9.5Hz,1H),4.52(ddd,J=11.0,9.7,4.9Hz,1H),4.26-4.19(m,3H),4.16-4.04(m,4H),4.00-3.94(m,2H),3.85(t,J=11.2Hz,1H),3.62-3.48(m,3H),3.29(s,3H),3.23(ddd,J=11.5,10.2,4.9Hz,1H),3.00(tt,J=11.6,3.8Hz,1H),2.05(s,3H),1.98(s,3H),1.92(dt,J=13.2,1.9Hz,2H),1.71(qd,J=12.1,4.4Hz,2H);LC/MS(ESI)m/e 727.3[(M+H)+,C31H38F3N6O9S计算值727.2],tR=1.88分钟(方法2)。
步骤2
在室温向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(四氢-2H-吡喃-4-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(22mg,0.030mmol)在THF(0.75mL)和MeOH(0.75mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.035mL,0.151mmol)。将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(四氢-2H-吡喃-4-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(11.2mg,0.016mmol,54%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.95(s,1H,主要),8.94(s,1H,次要),7.99-7.97(m,1H),7.88-7.81(m,2H),5.14(dd,J=10.5,2.8Hz,1H,次要),5.01-4.93(m,1H,主要),4.82(d,J=9.3Hz,1H),4.56-4.44(m,2H),4.24-4.17(m,2H),4.11-4.07(m,2H,次要),4.02(br dd,J=10.6,4.5Hz,1H),3.99-3.86(m,4H),3.80-3.71(m,4H),3.53(dd,J=6.3,2.9Hz,2H),3.50-3.42(m,4H),3.24(s,3H,主要),3.22(s,3H,次要),2.97-2.89(m,1H),1.86(br d,J=13.6Hz,2H),1.67-1.56(m,2H);LC/MS(ESI)m/e 643.2[(M+H)+,C27H34F3N6O7S计算值643.2],tR=1.77分钟(方法2);HPLC(方法3):tR=9.14分钟;HPLC(方法4):tR=7.81分钟。hGal-3 IC50=0.018μM。
实施例21.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(4-氨基-5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(4-乙酰氨基-5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(42mg,0.068mmol)和N-(2-乙炔基-5-甲氧基嘧啶-4-基)乙酰胺(20.84mg,0.109mmol)溶于DMF(1.5mL)和水(0.500mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(16.19mg,0.082mmol)和五水合硫酸铜(II)(23.81mg,0.095mmol)(预先溶于0.5mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 20mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%乙酸乙酯(含有5%甲醇)/己烷→100%乙酸乙酯(含有5%甲醇);24g柱),得到(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(4-乙酰氨基-5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(25mg,0.031mmol,45%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ8.22(s,2H),8.18-8.14(m,1H),7.96(s,1H),7.56-7.44(m,2H),5.52(d,J=2.5Hz,1H),4.85-4.76(m,2H),4.55(td,J=10.3,4.5Hz,1H),4.38-4.25(m,4H),4.25-4.18(m,2H),4.16-4.12(m,1H),4.12-4.07(m,1H),4.03(s,3H),3.59(br t,J=11.8Hz,1H),3.35(s,3H),3.21(td,J=10.9,5.0Hz,1H),2.64(s,3H),2.11(s,3H),1.98(s,3H);LC/MS(ESI)m/e 808.3[(M+H)+,C33H37F3N9O10S计算值808.2],tR=1.85分钟(方法2)。
步骤2
在-20℃(丙酮/干冰浴)向(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-5-(4-(4-乙酰氨基-5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基酯(25mg,0.031mmol)在THF(0.8mL)和MeOH(0.8mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.036mL,0.158mmol)。移去冷却浴,并将该反应混合液在-20℃搅拌1h。通过加入N HCl(0.03mL)将该混合液部分中和。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-5-(4-(4-氨基-5-甲氧基嘧啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(15.4mg,0.022mmol,71%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.79(s,1H),7.87-7.82(m,3H),5.69(br s,1H),5.47(br s,1H),4.97(dd,J=10.5,2.7Hz,1H),4.84(d,J=9.2Hz,1H),4.73(td,J=10.1,5.0Hz,1H),4.29-4.19(m,1H),4.14(br dd,J=10.8,4.9Hz,1H),4.02-3.96(m,2H),3.95(s,3H),3.89(br t,J=11.1Hz,2H),3.79(br t,J=6.3Hz,1H),3.59-3.49(m,3H),3.24(s,3H),3.29-3.21(m,1H);LC/MS(ESI)m/e 682.3[(M+H)+,C27H31F3N9O7S计算值682.2],tR=1.65分钟(方法2);HPLC(方法3):tR=7.59分钟;HPLC(方法4):tR=5.98分钟。hGal-3 IC50=0.023μM。
实施例22.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(噻唑-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(噻唑-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(16mg,0.026mmol)和2-乙炔基噻唑(4.53mg,0.042mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(6.17mg,0.031mmol)和五水合硫酸铜(II)(9.07mg,0.036mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并将水层用5%甲醇的二氯甲烷溶液(4×15mL)萃取(轻轻振动)。将合并的有机层用盐水(15mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(20%乙酸乙酯(含有5%甲醇)/己烷→80%乙酸乙酯(含有5%甲醇)/20%己烷;12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(噻唑-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(16mg,0.022mmol,85%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ8.26(s,1H),7.87(d,J=3.3Hz,1H),7.84(s,1H),7.47(dd,J=8.0,6.5Hz,2H),7.40(d,J=3.3Hz,1H),5.51(d,J=3.0Hz,1H),4.74-4.64(m,2H),4.60-4.52(m,1H),4.45-4.23(m,4H),4.20-4.11(m,4H),3.58-3.48(m,1H),3.35(s,3H),3.18(ddd,J=11.9,9.7,5.0Hz,1H),2.11(s,3H),1.94(s,3H);LC/MS(ESI)m/e726.2[(M+H)+,C29H31F3N7O8S2计算值726.2],tR=1.34分钟(方法2).
步骤2
在室温(丙酮/干冰浴)向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(噻唑-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(16mg,0.022mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.025mL,0.110mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(噻唑-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(13.3mg,0.020mmol,92%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ8.96(s,1H),8.79(s,1H),7.94(d,J=3.4Hz,1H),7.85(dd,J=8.9,6.7Hz,2H),7.78(d,J=3.2Hz,1H),4.97(dd,J=10.5,3.1Hz,1H),4.84(d,J=9.3Hz,1H),4.70-4.61(m,1H),4.23(br dd,J=11.8,4.8Hz,1H),4.12(dd,J=10.8,5.0Hz,1H),4.03-3.93(m,4H),3.84(br t,J=11.1Hz,1H),3.80(br t,J=6.4Hz,1H),3.58-3.49(m,4H),3.25(s,3H),3.29-3.22(m,1H);LC/MS(ESI)m/e 642.2[(M+H)+,C25H27F3N7O6S2计算值642.1],tR=1.82分钟(方法2);HPLC(方法3):tR=9.76分钟;HPLC(方法4):tR=8.54分钟。hGal-3 IC50=0.005μM。
实施例23.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(2-(三氟甲基)嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(2-(三氟甲基)嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(20mg,0.032mmol)和5-乙炔基-2-(三氟甲基)嘧啶(8.93mg,0.052mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(7.71mg,0.039mmol)和五水合硫酸铜(II)(11.34mg,0.045mmol)(预先溶于0.5mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(10mL)和饱和的碳酸氢钠水溶液(10mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并用5%在二氯甲烷中的甲醇(4x 10mL)萃取水层(轻轻振动)。将合并的有机层用盐水(20mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(25%乙酸乙酯(含有5%甲醇)/75%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(2-(三氟甲基)嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(12mg,0.015mmol,47%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ9.36(s,2H),8.22(s,1H),7.84(s,1H),7.47(dd,J=8.0,6.5Hz,2H),5.53(d,J=3.0Hz,1H),4.74-4.65(m,2H),4.58(td,J=10.3,4.8Hz,1H),4.43(dd,J=11.4,4.9Hz,1H),4.33(br dd,J=11.9,5.1Hz,1H),4.27(t,J=10.0Hz,2H),4.16-4.13(m,3H),3.54(t,J=12.0Hz,2H),3.36(s,3H),3.15(ddd,J=11.9,9.8,5.1Hz,1H),2.11(s,3H),1.97(s,3H);LC/MS(ESI)m/e 789.3[(M+H)+,C31H31F6N8O8S计算值789.2],tR=2.13分钟(方法2)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(2-(三氟甲基)嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(12mg,0.015mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.017mL,0.076mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。加入1N HCl(0.18mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法3)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(2-(三氟甲基)嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(7.3mg,9.84μmol,65%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.49(s,2H),9.08(s,1H),8.99(s,1H),7.85(br dd,J=8.8,6.8Hz,2H),6.53(s,1H),5.76(d,J=7.0Hz,1H),5.49(d,J=6.3Hz,1H),4.97(dd,J=10.5,2.7Hz,1H),4.85-4.79(m,2H),4.73-4.65(m,1H),4.27-4.22(m,1H),4.17(br dd,J=11.1,4.9Hz,1H),4.02-3.97(m,1H),3.96-3.92(m,2H),3.89-3.83(m,1H),3.83-3.77(m,1H),3.55-3.51(m,3H),3.25(s,3H);LC/MS(ESI)m/e 705.2[(M+H)+,C27H27F6N8O6S计算值705.2],tR=1.92分钟(方法2);HPLC(方法3):tR=10.58分钟;HPLC(方法4):tR=9.38分钟。hGal-3 IC50=0.041μM。
实施例24.制备6-(1-((3S,4R,5R)-4-羟基-5-(((2S,3R,4S,5R,6R)-5-羟基-6-(羟基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)四氢-2H-吡喃-3-基)-1H-1,2,3-三唑-4-基)吡啶甲酸甲酯
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(6-氰基吡啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(20mg,0.032mmol)和6-乙炔基2-氰基吡啶(12.47mg,0.097mmol)溶于DMF(0.9mL)和水(0.300mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(7.71mg,0.039mmol)和五水合硫酸铜(II)(11.34mg,0.045mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(5mL)和饱和的碳酸氢钠水溶液(5mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并将水层用5%在二氯甲烷中的甲醇(3x 10mL)萃取。将合并的有机层用盐水(10mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(40%乙酸乙酯(含有5%甲醇)/60%己烷→100%乙酸乙酯(含有5%甲醇);12g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(6-氰基吡啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(22mg,0.030mmol,91%收率)。1H NMR(400MHz,氯仿-d)δ8.41-8.39(m,1H),8.42(br d,J=1.0Hz,1H),7.94(t,J=7.9Hz,1H),7.87(s,1H),7.65(dd,J=7.8,1.0Hz,1H),7.47(dd,J=8.0,6.5Hz,2H),5.51(d,J=2.5Hz,1H),4.74-4.67(m,2H),4.61-4.52(m,1H),4.40(dd,J=11.5,4.8Hz,1H),4.34-4.22(m,3H),4.19-4.03(m,5H),3.51(t,J=11.9Hz,1H),3.35(s,3H),2.10(s,3H),1.96(s,3H);LC/MS(ESI)m/e 745.2[(M+H)+,C32H32F3N8O8S计算值745.2],tR=1.86分钟(方法2)。
步骤2
在室温向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-(4-(6-氰基吡啶-2-基)-1H-1,2,3-三唑-1-基)-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(22mg,0.030mmol)在THF(0.5mL)和MeOH(0.5mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.034mL,0.148mmol),并将该混合液搅拌1h。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相HPLC纯化(方法4)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到6-(1-((3S,4R,5R)-4-羟基-5-(((2S,3R,4S,5R,6R)-5-羟基-6-(羟基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)四氢-2H-吡喃-3-基)-1H-1,2,3-三唑-4-基)吡啶甲酸甲酯(4.5mg,0.0054mmol,18%收率),为白色无定形固体。1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.82(s,1H),8.28(dd,J=7.9,0.9Hz,1H),8.12(t,J=7.8Hz,1H),8.02(dd,J=7.7,0.9Hz,1H),7.86(dd,J=8.8,7.0Hz,2H),6.57(br s,1H),5.69(d,J=7.0Hz,1H),5.49(d,J=6.3Hz,1H),4.98(dd,J=10.7,2.6Hz,1H),4.84(d,J=9.3Hz,1H),4.79(br s,1H),4.69(td,J=10.4,5.0Hz,1H),4.27-4.20(m,1H),4.11(br dd,J=10.7,4.9Hz,1H),4.05(br d,J=7.3Hz,1H),4.01-3.94(m,2H),3.93(s,3H),3.91-3.86(m,1H),3.80(t,J=6.3Hz,1H),3.54(br d,J=11.3Hz,3H),3.26(s,3H);LC/MS(ESI)m/e694.2[(M+H)+,C29H31F3N7O8S计算值694.2],tR=1.76分钟(方法2);HPLC(方法3):tR=14.01分钟;HPLC(方法4):tR=12.10分钟。hGal-3 IC50=0.014μM。
实施例25.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(吡嗪-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(吡嗪-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
将(+)-((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(62mg,0.101mmol)和2-乙炔基吡嗪(16.75mg,0.161mmol)溶于DMF(3mL)和水(1.000mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(23.90mg,0.121mmol)和五水合硫酸铜(II)(35.2mg,0.141mmol)(预先溶于0.5mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(10mL)和饱和的碳酸氢钠水溶液(10mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入盐水(10mL),并将水层用5%甲醇的二氯甲烷溶液(4×15mL)萃取(轻轻振动)。将合并的有机层用盐水(15mL)洗涤。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(30%乙酸乙酯(含有5%甲醇)/己烷→100%乙酸乙酯(含有5%甲醇)/己烷;24g柱),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(吡嗪-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(65mg,0.090mmol,90%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ9.44(d,J=0.8Hz,1H),8.55(s,2H),8.35(s,1H),7.83(s,1H),7.47(dd,J=8.0,6.5Hz,2H),5.51(d,J=2.8Hz,1H),4.74-4.64(m,2H),4.62-4.52(m,1H),4.40(dd,J=11.5,5.0Hz,1H),4.32(dd,J=11.8,5.0Hz,1H),4.26(t,J=9.9Hz,1H),4.20-4.09(m,4H),4.09-4.03(m,1H),3.52(t,J=11.9Hz,1H),3.36(s,3H),3.17(ddd,J=11.8,9.8,5.0Hz,1H),2.10(s,3H),1.94(s,3H);LC/MS(ESI)m/e 721.2[(M+H)+,C30H32F3N8O8S计算值721.2],tR=1.88分钟(方法2)。
步骤2
在0℃向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-4-羟基-5-(4-(吡嗪-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(65mg,0.090mmol)在THF(2mL)和MeOH(2mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.103mL,0.451mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。将该混合液加入1N HCl(0.2mL)部分中和。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相HPLC纯化(方法4)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-(吡嗪-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇(46mg,0.072mmol,80%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.26(d,J=1.1Hz,1H),8.96(s,1H),8.87(s,1H),8.73-8.67(m,1H),8.63(d,J=2.4Hz,1H),7.90-7.80(m,2H),5.74-5.61(m,1H),5.46(br d,J=1.2Hz,1H),4.98(dd,J=10.6,2.8Hz,1H),4.84(d,J=9.3Hz,1H),4.68(td,J=10.4,4.9Hz,1H),4.24(br dd,J=11.4,4.7Hz,1H),4.13(dd,J=10.9,5.0Hz,1H),4.04-3.93(m,3H),3.86(t,J=11.1Hz,1H),3.80(t,J=6.3Hz,1H),3.59-3.51(m,3H),3.25(s,3H),3.29-3.22(m,1H);LC/MS(ESI)m/e 637.2[(M+H)+,C26H28F3N8O6S计算值637.2],tR=1.77分钟(方法2);HPLC(方法3):tR=8.84分钟;HPLC(方法4):tR=7.54分钟。hGal-3 IC50=0.016μM。
实施例26.制备2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸
步骤1.制备2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
将2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(101mg,0.150mmol)和5-乙炔基嘧啶(31.2mg,0.299mmol)溶于DMF(2.7mL)和水(0.9mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(29.7mg,0.150mmol)和五水合硫酸铜(II)(29.9mg,0.120mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(10mL)和饱和的NaHCO3水溶液(10mL),导致形成沉淀。将该混合液经Celite垫过滤,并将滤饼用5%甲醇的二氯甲烷溶液冲洗。将滤液转移到分液漏斗。加入几毫升盐水,并将水层用5%甲醇的二氯甲烷溶液(4×15mL)萃取(振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(50%乙酸乙酯(含有5%甲醇)/50%己烷→100%乙酸乙酯(含有5%甲醇);24g柱),得到2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(81.2mg,0.104mmol,70%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ9.23(s,1H),9.21(s,2H),8.13(s,1H),7.87(s,1H),7.45(dd,J=7.8,6.8Hz,2H),5.55(d,J=3.0Hz,1H),4.85-4.75(m,2H),4.61-4.49(m,2H),4.44-4.28(m,4H),4.21(td,J=9.8,2.3Hz,1H),4.16(s,3H),4.14-4.02(m,2H),3.62(s,3H),3.53(t,J=11.9Hz,1H),3.19-3.08(m,1H),2.98(s,1H),2.91(s,1H),2.08(s,3H),2.01(s,3H);LC/MS(ESI)m/e 779.2[(M+H)+,C32H34F3N8O10S计算值779.3],tR=1.91分钟(方法1)。
步骤2
在0℃向2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(80mg,0.103mmol)在THF(2mL)和MeOH(2mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.117mL,0.514mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。通过加入1N HCl(0.1mL)部分中和该混合物。将该混合液浓缩,溶于二噁烷/甲醇/水中,过滤,并经反相制备型HPLC纯化(方法1)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(66.5mg,0.098mmol,95%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.24(s,2H),9.18(s,1H),8.91(d,J=3.8Hz,2H),7.80(dd,J=8.8,6.8Hz,2H),5.88-5.66(m,1H),5.52-5.37(m,1H),5.05(dd,J=10.5,2.8Hz,1H),4.86(d,J=9.3Hz,1H),4.65(td,J=10.3,5.0Hz,1H),4.47(d,J=16.2Hz,1H),4.30-4.19(m,2H),4.15(br dd,J=10.8,5.0Hz,1H),4.00-3.88(m,3H),3.86-3.78(m,2H),3.54-3.45(m,2H),3.26(td,J=10.8,4.9Hz,1H);LC/MS(ESI)m/e 681.2[(M+H)+,C27H28F3N8O8S计算值681.1],tR=1.58分钟(方法1);HPLC(方法1):tR=5.07分钟;HPLC(方法2):tR=4.74分钟。hGal-3IC50=0.015μM。
实施例27.制备2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
在0℃向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(16.5mg,0.024mmol)在CH2Cl2(0.9mL)和MeOH(0.3mL)中的溶液中加入三甲基硅烷基重氮甲烷(0.077mL,0.048mmol)。将该反应混合液在室温搅拌2.5h。将该混合液浓缩。用乙醚研磨产物,并真空干燥,得到2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(12.5mg,0.016mmol,65%收率),为白色固体。1H NMR(500MHz,DMSO-d6)δ9.24(s,2H),9.18(s,1H),8.91(d,J=3.8Hz,2H),7.80(dd,J=8.6,6.9Hz,2H),5.81(d,J=6.9Hz,1H),5.48(d,J=6.3Hz,1H),5.07(dd,J=10.5,2.6Hz,1H),4.85(d,J=9.3Hz,1H),4.81(t,J=5.5Hz,1H),4.69-4.61(m,1H),4.58(d,J=16.0Hz,1H),4.28-4.21(m,2H),4.15(br dd,J=11.0,5.0Hz,1H),4.07(d,J=16.0Hz,1H),3.95(br dd,J=5.7,2.4Hz,1H),3.93-3.87(m,1H),3.85-3.80(m,2H),3.57-3.46(m,3H),3.39(s,3H),3.29-3.23(m,1H);LC/MS(ESI)m/e 695.2[(M+H)+,C28H30F3N8O8S计算值695.2],tR=1.69分钟(方法1);HPLC(方法1):tR=5.86分钟;HPLC(方法2):tR=5.54分钟。hGal-3 IC50=0.017μM。
实施例28.制备2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-1-吗啉代乙-1-酮
向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(17mg,0.025mmol)和吗啉(4.31μl,0.050mmol)在DMF(0.8mL)中的溶液中加入N,N-二异丙基乙胺(0.022mL,0.125mmol),随后加入HATU(18.99mg,0.050mmol)。将该反应混合液在室温搅拌14h。将该混合液用乙腈和少量水稀释,过滤,并经反相制备型HPLC纯化(方法1)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-1-吗啉代乙-1-酮(15.1mg,0.020mmol,80%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.25(s,2H),9.18(s,1H),8.93-8.88(m,2H),7.84-7.74(m,2H),5.25(br dd,J=10.4,2.7Hz,1H,次要),5.11-5.03(m,2H),4.89(d,J=9.3Hz,1H),4.68-4.60(m,1H),4.56(d,J=12.4Hz,1H),4.52(dd,J=7.7,4.8Hz,1H),4.28-4.19(m,2H),4.18-4.12(m,1H),4.09(br d,J=10.7Hz,1H,次要),4.05-4.00(m,1H),3.99-3.92(m,2H),3.89-3.80(m,2H),3.57-3.49(m,3H),3.41-2.97(m,10H);LC/MS(ESI)m/e 750.2[(M+H)+,C31H35F3N9O8S计算值750.2],tR=1.57分钟(方法1);HPLC(方法1):tR=5.18分钟;HPLC(方法2):tR=4.93分钟。hGal-3 IC50=0.010μM。
实施例29.制备2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-N-甲基-N-苯基乙酰胺
向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(16mg,0.024mmol)和N-甲基苯胺(5.09μl,0.047mmol)在DMF(0.8mL)中的溶液中加入N,N-二异丙基乙胺(0.021mL,0.118mmol),随后加入HATU(17.88mg,0.047mmol)。将该反应混合液在室温搅拌14h。将该混合液用乙腈和少量水稀释,过滤,并经反相制备型HPLC纯化(方法2)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-N-甲基-N-苯基乙酰胺(4.6mg,5.92μmol,25%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.26(s,2H),9.19(s,1H),8.95-8.89(m,1H),8.81(br s,1H),7.78-7.68(m,2H),7.30-7.16(m,3H),7.12-7.00(m,2H),5.82-5.76(m,1H,次要),5.70(br s,1H,主要),5.39(br d,J=4.0Hz,1H,主要),5.23-5.14(m,1H,次要),5.04-4.95(m,1H),4.84(br d,J=8.9Hz,1H,主要),4.80-4.71(m,1H,次要),4.68-4.57(m,1H),4.49(br s,1H,次要),4.25-3.76(m,9H),3.49(br t,J=11.6Hz,3H),3.22-3.13(m,1H),2.95(s,3H,主要),2.93(br s,3H,次要);LC/MS(ESI)m/e 770.2[(M+H)+,C34H35F3N9O7S计算值770.2],tR=1.80分钟(方法1);HPLC(方法1):tR=6.43分钟;HPLC(方法2):tR=6.10分钟。hGal-3 IC50=0.025μM。
实施例30.制备2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸
步骤1.制备2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯
将2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-5-叠氮基-4-羟基四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(250mg,0.371mmol)和5-乙炔基-2-甲氧基嘧啶(99mg,0.741mmol)溶于DMF(6mL)和水(2mL)的预先除气的溶液中,并将该混合液置于氩气下。加入抗坏血酸钠(73.4mg,0.371mmol)和五水合硫酸铜(II)(74.0mg,0.296mmol)(预先溶于0.3mL水中),并将该反应混合液在室温搅拌14h。通过加入二氯甲烷和甲醇溶解混合物和附着在搅拌棒上的固体。加入水(15mL)和饱和的碳酸氢钠水溶液(15mL),导致形成沉淀。用5%在二氯甲烷中的甲醇(4x 25mL)萃取水层(轻轻振动)。将合并的有机层用盐水(10mL)洗涤。将含盐水的分液漏斗用二氯甲烷(2x)冲洗以收集黄色残余物,并将该有机层与原始有机萃取物合并。将有机层经MgSO4干燥,过滤,并浓缩。将产物经硅胶柱色谱纯化(50%乙酸乙酯(含有5%甲醇)/50%己烷→100%乙酸乙酯(含有5%甲醇);40g柱),得到2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(260mg,0.321mmol,87%收率),为白色固体。1H NMR(400MHz,DMSO-d6)δ9.04(s,2H),8.89(s,1H),8.76(s,1H),7.78(dd,J=8.8,6.8Hz,2H),5.83(d,J=6.8Hz,1H),5.40(d,J=2.8Hz,1H),5.36(dd,J=10.4,2.9Hz,1H),5.05(d,J=9.5Hz,1H),4.64(td,J=10.4,4.9Hz,1H),4.54(d,J=16.1Hz,1H),4.40-4.31(m,2H),4.24-4.14(m,2H),4.11-4.01(m,3H),3.98(s,3H),3.96-3.81(m,2H),3.53(br t,J=11.5Hz,1H),3.38(s,3H),3.25(td,J=10.8,4.8Hz,1H),2.03(s,3H),2.02(s,3H);LC/MS(ESI)m/e 809.3[(M+H)+,C33H36F3N8O11S计算值809.2],tR=1.89分钟(方法1)。
步骤2
在0℃向2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸甲酯(217mg,0.268mmol)在THF(3mL)和MeOH(3mL)中的混悬液中加入甲醇钠(25%wt甲醇溶液)(0.307mL,1.342mmol)。移去冷却浴,并将该反应混合液在室温搅拌1h。通过加入N HCl(1mL)将该混合液部分中和。将该混合液部分浓缩以除去THF,溶于二噁烷/甲醇/水中,过滤,并经反相制备型MPLC使用C18 Redisep Gold柱(2次进样)(方法1)纯化。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(162.5mg,0.226mmol,84%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ12.36(br s,1H),9.05-9.00(m,2H),8.89(s,1H),8.75(s,1H),7.85-7.72(m,2H),5.71(brd,J=6.6Hz,1H),5.42(d,J=6.1Hz,1H),5.05(dd,J=10.4,2.4Hz,1H),4.85(d,J=9.3Hz,1H),4.77(br t,J=5.2Hz,1H),4.62(td,J=10.3,5.0Hz,1H),4.46(d,J=15.9Hz,1H),4.28-4.18(m,2H),4.13(br dd,J=10.8,4.9Hz,1H),3.97(s,3H),3.96-3.88(m,3H),3.85-3.78(m,2H),3.56-3.46(m,3H),3.29-3.21(m,1H);LC/MS(ESI)m/e 711.2[(M+H)+,C28H30F3N8O9S计算值711.2],tR=1.60分钟(方法1);HPLC(方法1):tR=5.78分钟;HPLC(方法2):tR=5.45分钟。hGal-3 IC50=0.008μM。
实施例31.制备2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-1-吗啉代乙-1-酮
向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(24mg,0.034mmol)和吗啉(5.83μl,0.068mmol)在DMF(0.8mL)中的溶液中加入N,N-二异丙基乙胺(0.029mL,0.169mmol),随后加入HATU(25.7mg,0.068mmol)。将该反应混合液在室温搅拌14h。将该混合液用乙腈和少量水稀释,过滤,并经反相制备型HPLC纯化(方法2)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-1-吗啉代乙-1-酮(25.1mg,0.031mmol,93%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.03(s,2H),8.90(s,1H,主要),8.88(s,1H,次要),8.75(s,1H),7.84-7.77(m,2H),5.25(dd,J=10.2,2.7Hz,1H,次要),5.09-5.02(m,1H),4.88(d,J=9.2Hz,1H),4.62(td,J=10.3,5.0Hz,1H),4.55(d,J=12.4Hz,1H),4.53-4.48(m,1H),4.27-4.20(m,3H),4.18-4.10(m,2H),4.04-3.99(m,1H),3.97(s,3H),3.96-3.91(m,1H),3.83(td,J=11.1,7.2Hz,2H),3.55-3.48(m,3H),3.41-2.98(m,10H);LC/MS(ESI)m/e 780.3[(M+H)+,C32H37F3N9O9S计算值780.3],tR=1.68分钟(方法1);HPLC(方法1):tR=5.94分钟;HPLC(方法2):tR=5.66分钟。hGal-3 IC50=0.013μM。
实施例32.制备1-(2,6-二甲基吗啉代)-2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙-1-酮
向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(23mg,0.032mmol)和2,6-二甲基吗啉(7.46mg,0.065mmol)在DMF(0.8mL)中的溶液中加入N,N-二异丙基乙胺(0.028mL,0.162mmol),随后加入HATU(24.61mg,0.065mmol)。将该反应混合液在室温搅拌14h。将该混合液用乙腈和少量水稀释,过滤,并经反相制备型HPLC纯化(方法2)。存在两个具有正确质量的峰。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到1-(2,6-二甲基吗啉代)-2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙-1-酮(4.1mg,4.91μmol,15%收率)(异构体1),为白色无定形固体和1-(2,6-二甲基吗啉代)-2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙-1-酮(21.5mg,0.026mmol,80%收率)(异构体2),为白色无定形固体。分离主峰(异构体2)并表征。1H NMR(500MHz,DMSO-d6)δ9.02(s,2H),8.93-8.86(m,1H),8.75(s,1H),7.85-7.74(m,2H),5.25(br d,J=10.1Hz,1H,次要),5.06(br d,J=10.7Hz,1H),4.87(br t,J=9.4Hz,1H),4.65-4.48(m,3H),4.28-3.99(m,5H),3.97(s,3H),3.96-3.88(m,3H),3.86-3.79(m,2H),3.55-3.48(m,3H),3.41-3.15(m,5H),2.44-2.32(m,1H),2.09-1.94(m,1H),0.96-0.89(m,6H);LC/MS(ESI)m/e 808.3[(M+H)+,C34H41F3N9O9S计算值808.3],tR=1.84分钟(方法1);HPLC(方法1):tR=6.59分钟;HPLC(方法2):tR=6.21分钟。hGal-3 IC50=0.019μM。
实施例33.制备1-(1,1-二氧化硫吗啉代)-2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙-1-酮
向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(23mg,0.032mmol)和硫吗啉-1,1-二氧化物(8.75mg,0.065mmol)在DMF(0.8mL)中的溶液中加入N,N-二异丙基乙胺(0.028mL,0.162mmol),随后加入HATU(24.61mg,0.065mmol)。将该反应混合液在室温搅拌14h。将该混合液用乙腈和少量水稀释,过滤,并经反相制备型HPLC纯化(方法2)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到1-(1,1-二氧化硫吗啉代)-2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙-1-酮(25.5mg,0.030mmol,92%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.03(s,2H),8.91(s,1H,主要),8.89(s,1H,次要),8.75(s,1H,主要),8.74(s,1H,次要),7.85-7.76(m,2H),5.29-5.24(m,1H,次要),5.08(dd,J=10.5,2.7Hz,1H),5.04(d,J=9.5Hz,1H,次要),4.87(d,J=9.2Hz,1H),4.67-4.58(m,2H),4.57-4.52(m,1H,次要),4.29-4.05(m,6H),3.97(s,3H),3.96(br d,J=3.1Hz,1H),3.94-3.90(m,1H),3.86-3.79(m,2H),3.73-3.59(m,3H),3.56-3.45(m,5H),3.28(td,J=10.8,5.0Hz,1H),3.12-2.86(m,4H);LC/MS(ESI)m/e 828.2[(M+H)+,C32H37F3N9O10S2计算值828.2],tR=1.57分钟(方法1);HPLC(方法1):tR=5.94分钟;HPLC(方法2):tR=5.71分钟。hGal-3 IC50=0.012μM。
实施例34.制备2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-1-(3-羟基氮杂环丁烷-1-基)乙-1-酮
向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(23mg,0.032mmol)和氮杂环丁烷-3-醇·HCl(7.09mg,0.065mmol)在DMF(0.8mL)中的溶液中加入N,N-二异丙基乙胺(0.028mL,0.162mmol),随后加入HATU(24.61mg,0.065mmol)。将该反应混合液在室温搅拌14h。将该混合液用乙腈和少量水稀释,过滤,并经反相制备型HPLC纯化(方法2)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)-1-(3-羟基氮杂环丁烷-1-基)乙-1-酮(18.7mg,0.024mmol,73%收率),为白色无定形固体。1H NMR(500MHz,DMSO-d6)δ9.03(s,2H),8.95-8.90(m,1H),8.75(s,1H),7.84-7.78(m,2H),5.23(br d,J=10.4Hz,1H,次要),5.05(br dd,J=10.5,1.9Hz,1H),4.86(br dd,J=9.3,2.3Hz,1H),4.62(td,J=10.3,5.0Hz,1H),4.40(br d,J=13.6Hz,1H),4.36-4.08(m,5H),3.97(s,3H),3.96-3.84(m,4H),3.84-3.78(m,3H),3.69(br dd,J=9.7,4.5Hz,1H,次要),3.57-3.48(m,3H),3.41(br dd,J=10.2,3.8Hz,1H),3.31-3.21(m,1H);LC/MS(ESI)m/e 766.2[(M+H)+,C31H35F3N9O9S计算值750.2],tR=1.54分钟(方法1);HPLC(方法1):tR=5.19分钟;HPLC(方法2):tR=4.87分钟。hGal-3 IC50=0.024μM。
实施例35.制备1-(氮杂环丁烷-1-基)-2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙-1-酮
向2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(14mg,0.020mmol)和氮杂环丁烷(9.00mg,0.158mmol)在DMF(0.6mL)中的溶液中加入N,N-二异丙基乙胺(0.017mL,0.099mmol),随后加入HATU(14.98mg,0.039mmol)。将该反应混合液在室温搅拌4h。LC/MS显示仅有约30%转化成产物。将该反应混合液加热至50℃,加入另外的氮杂环丁烷(9.00mg,0.158mmol)和HATU(14.98mg,0.039mmol),并继续搅拌1h。以45分钟的间隔再添加两次另外的氮杂环丁烷(9.00mg,0.158mmol)和HATU(14.98mg,0.039mmol)。大部分原料转化为产物。将该混合液用乙腈和少量水稀释,过滤,并经反相制备型HPLC纯化(方法2)。将有机溶剂在旋转蒸发器上蒸发,将含水混合物冻干,得到1-(氮杂环丁烷-1-基)-2-(((2S,3R,4S,5R,6R)-5-羟基-2-(((3R,4R,5S)-4-羟基-5-(4-(2-甲氧基嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙-1-酮(8.6mg,0.011mmol,57%收率),为白色无定形固体。1HNMR(500MHz,甲醇-d4)δ9.01(s,2H),8.67(s,1H),8.56(s,1H),7.68(dd,J=8.6,6.6Hz,2H),5.02(dd,J=10.5,3.0Hz,1H),4.82(s,1H,部分模糊),4.73-4.66(m,1H),4.46(d,J=14.0Hz,1H),4.38-4.30(m,2H),4.24(dd,J=11.1,4.9Hz,1H),4.15-4.09(m,3H),4.08(s,3H),4.04-3.77(m,8H),3.75-3.70(m,1H),3.61(t,J=11.7Hz,1H),2.19(五重峰,J=7.8Hz,2H);LC/MS(ESI)m/e 750.3[(M+H)+,C31H35F3N9O8S计算值750.2],tR=1.82分钟(方法1);HPLC(方法1):tR=5.87分钟;HPLC(方法2):tR=5.63分钟。hGal-3 IC50=0.032μM。
制备中间体(2)
制备4-乙炔基哒嗪
向200mL梨形烧瓶中加入哒嗪-4-甲醛(0.10g,0.93mmol),K2CO3(0.26g,1.9mmol),和MeOH(9mL)。将该反应混合液搅拌10min,然后加入(1-重氮-2-氧代丙基)膦酸二甲酯(0.19g,0.97mmol)。搅拌18h后,将该混合液用乙醚(50mL)稀释,并依次用1.5M K2HPO4(水溶液)(2x 25mL)和盐水洗涤。将有机相经Na2SO4干燥,过滤,并浓缩。将残余物经硅胶纯化(12g柱;A=Hex,B=EtOAc;15分钟梯度;0%B至70%B;流速=12mL/分钟)。合并级分,浓缩,并在真空下干燥,得到标题化合物(17mg,0.16mmol,18%收率),为棕褐色固体。1H NMR(400MHz,氯仿-d)δ9.16-9.10(m,2H),7.47-7.40(m,1H),3.42(s,1H)。
制备((2R,3R,4S,5R,6R)-乙酸3-乙酸基-4-叠氮基-6-溴-5-甲氧基四氢-2H-吡喃-2-基)甲酯
向250mL圆底烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-5-甲氧基-6-(苯硫基)四氢-2H-吡喃-2-基)甲酯(1.5g,3.7mmol)和DCM(60mL)。将容器冷却至0℃,然后滴加溶于DCM(15mL)中的溴(0.28mL,5.5mmol)。将该反应混合液在以上温度搅拌1h。用1N K2HPO4(水溶液)和饱和的Na2SO4(水溶液)的混合液(1:1,20mL)将过量溴淬灭。将该混合液用水(100mL)进一步稀释,并将各层分离。将水相用DCM萃取(3x50 mL)。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将产物在真空下干燥,得到标题化合物(0.87g,2.4mmol,65%收率),为白色固体,将其直接使用或在冰箱中储存。1H NMR(400MHz,氯仿-d)δ6.72-6.64(m,1H),5.48-5.40(m,1H),4.49-4.35(m,1H),4.24-4.14(m,1H),4.11-4.04(m,1H),4.01-3.91(m,1H),3.59-3.56(m,1H),3.55(s,3H),2.22-2.14(m,3H),2.13-2.04(m,3H)。LC/MS(ESI)m/e 387.5[(M+H2O)+,计算值C11H16BrN3O6 366.2],tR=1.64分钟(方法2)。
制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯
步骤1.制备(3S,4R,5S)-乙酸3-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-基酯
向100mL梨形烧瓶中加入(3S,4R,5S)-乙酸3-叠氮基-5-羟基四氢-2H-吡喃-4-基酯(0.52g,2.6mmol)、乙炔基苯(0.85mL,7.8mmol),随后加入DMF(12mL)和水(4mL)的脱气的混合液。向该混合液中加入溶于水(2mL)中的五水合硫酸铜(II)(0.45g,1.8mmol)和抗坏血酸钠(0.51g,2.6mmol)。将容器抽真空,并用N2净化。搅拌18h后,将该反应混合液过滤,并将滤饼用DCM洗涤。将滤液用1N K2HPO4(水溶液)(200mL)稀释,并将水相用DCM萃取(3x100mL)。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将粗制的产物经快速柱色谱纯化(40g硅胶柱;A=Hex,B=EtOAc;20分钟梯度;0%B至100%B;流速=40mL/分钟)。合并级分,浓缩,并在真空下干燥,得到标题化合物(0.38g,1.3mmol,49%收率),为白色固体。[α]D 22+36.8,(c=1.0,CHCl3);1H NMR(500MHz,甲醇-d4)δ8.49-8.45(m,1H),7.88-7.79(m,2H),7.50-7.42(m,2H),7.42-7.33(m,1H),5.57-5.45(m,1H),5.19-5.07(m,1H),4.26-4.22(m,1H),4.22-4.19(m,1H),4.10-4.02(m,1H),4.01-3.95(m,1H),3.84-3.77(m,1H),2.02-1.91(m,3H);LC/MS(ESI)m/e 304.1[(M+H)+,计算值C15H17N3O4303.3],tR=0.71分钟(方法4)。
步骤2.制备(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-基酯
向100mL梨形烧瓶中加入(3S,4R,5S)-乙酸3-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-基酯(0.37g,1.2mmol)、DCM(24mL)和吡啶(0.40mL,4.9mmol)。将该反应混合液冷却至–10℃,然后经5分钟的时间加入三氟甲磺酸酐(0.41mL,2.4mmol)。将该反应混合液在以上温度搅拌1h。将该混合液用DCM(25mL)稀释,并依次用1M HCl(水溶液)(3x25mL)、1M K2HPO4(水溶液)(25mL)和盐水洗涤。将有机层经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于丙酮(20mL)中,并冷却至–10℃。向该混合液中加入硫代乙酸钾(0.56g,4.9mmol),将该反应混合液温至室温,并搅拌。18h后,将该混合液用水(100mL)稀释,并用DCM萃取(3x 50mL)。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将残余物经快速柱色谱纯化(80g硅胶柱;A=Hex,B=EtOAc;30分钟梯度;0%B至60%B;流速=60mL/分钟)。合并级分,浓缩,并在真空下干燥,得到标题化合物(0.35g,0.97mmol,80%收率),为白色固体。[α]D 22+139.7,(c=1.0,CHCl3);1H NMR(500MHz,氯仿-d)δ7.86-7.79(m,3H),7.45(s,2H),7.40-7.34(m,1H),5.64-5.52(m,1H),4.85(d,J=4.7Hz,1H),4.34(br d,J=5.0Hz,1H),4.23-4.11(m,1H),3.99-3.92(m,1H),3.92-3.84(m,1H),3.62-3.54(m,1H),2.39(s,3H),1.94(s,3H);LC/MS(ESI)m/e 362.2[(M+H)+,计算值C17H19N3O4S 361.4],tR=2.885分钟(方法3)。
步骤3.制备(3R,4R,5S)-3-巯基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-醇
向100mL梨形烧瓶中加入(3R,4R,5S)-乙酸3-(乙酰基硫基)-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-基酯(0.35g,0.97mmol)和THF(13mL)。将该反应混合液冷却至-10℃,然后加入甲醇钠(0.22mL,0.97mmol)(25%w/v在MeOH中的溶液),并将该反应混合液在以上温度搅拌。20分钟后,将溶剂浓缩,并将残余物经快速柱色谱纯化(12g硅胶柱;A=Hex,B=EtOAc;15分钟梯度;0%B至100%B;流速=12mL/分钟)。合并级分,浓缩,并在真空下干燥,得到标题化合物(0.14g,0.52mmol,54%收率),为白色固体。[α]D 22–13.7,(c=1.0,MeOH);1H NMR(500MHz,乙腈-d3)δ8.20-8.17(m,1H),7.91-7.86(m,2H),7.52-7.46(m,2H),7.42-7.36(m,1H),4.57-4.48(m,1H),4.24-4.16(m,1H),4.13-4.07(m,1H),3.91(t,J=11.1Hz,2H),3.88-3.84(m,1H),3.45(t,J=11.6Hz,1H),3.04-2.95(m,1H),1.91-1.79(m,1H);LC/MS(ESI)m/e 278.1[(M+H)+,计算值C13H15N3O2S 277.3],tR=0.75分钟(方法4)。
步骤4
向20mL梨形烧瓶中加入(3R,4R,5S)-3-巯基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-4-醇(0.14g,0.52mmol),((2R,3R,4S,5R,6R)-乙酸3-乙酸基-4-叠氮基-6-溴-5-甲氧基四氢-2H-吡喃-2-基)甲酯(0.20g,0.55mmol)、四丁基硫酸氢铵(0.71g,2.1mmol)和EtOAc(7mL)。向该混合液中加入2M碳酸钠(水溶液)(1.1mL,2.1mmol),并将反应混合液剧烈搅拌。2h后,将该混合液用1M K2HPO4(50mL)稀释,并用EtOAc萃取(3x 25mL)。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将残余物经快速柱色谱纯化(12g硅胶柱;A=Hex,B=EtOAc;15分钟梯度;0%B至100%B;流速=12mL/分钟)。合并级分,浓缩,并在真空下干燥,得到标题化合物(0.240g,0.427mmol,82%收率),为白色固体。[α]D 22+1.2,(c=1.0,MeOH);1H NMR(500MHz,乙腈-d3)δ8.21(s,1H),7.90-7.85(m,2H),7.52-7.45(m,2H),7.42-7.35(m,1H),5.38-5.32(m,1H),4.71(d,J=9.6Hz,1H),4.63-4.53(m,1H),4.24-4.16(m,2H),4.11-3.96(m,3H),3.90(s,1H),3.82-3.75(m,1H),3.61(s,3H),3.58-3.52(m,1H),3.42-3.36(m,1H),3.34-3.28(m,1H),3.24-3.14(m,1H),2.16(s,3H),2.14-2.12(m,3H);LC/MS(ESI)m/e 563.3[(M+H)+,计算值C24H30N6O8S 562.6],tR=3.68分钟(方法3)。
制备(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-4-氨基-5-甲氧基四氢-2H-吡喃-3-基酯
步骤1.制备(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-4-叠氮基-5-甲氧基四氢-2H-吡喃-3-基酯
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(70mg,0.12mmol)、DCM(3mL)和吡啶(20μl,0.25mmol)。向该混合液中加入乙酰氯(11μl,0.15mmol),并将该反应混合液在N2下搅拌。18h后,加入另外的吡啶(25μl,0.31mmol)和乙酰氯(22μl,0.31mmol),并继续反应。18h后,将溶剂浓缩,并将粗制的产物经快速柱色谱纯化(12g硅胶柱;A=Hex,B=EtOAc;10分钟梯度;0%B至100%B;流速=12mL/分钟)。合并级分,浓缩,并在真空下干燥,得到标题化合物(50mg,0.083mmol,67%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.79-7.71(m,3H),7.39-7.32(m,2H),7.30-7.24(m,1H),5.46-5.36(m,1H),5.33-5.26(m,1H),4.80-4.67(m,1H),4.46-4.40(m,1H),4.28-4.18(m,2H),4.06-3.98(m,2H),3.87-3.76(m,2H),3.64-3.56(m,1H),3.52(s,3H),3.51-3.47(m,1H),3.24-3.05(m,2H),2.09(s,3H),2.02(s,3H),1.90(s,3H)。LC/MS(ESI)m/e 605.2[(M+H)+,计算值C26H32N6O9S 604.6],tR=0.94分钟(方法4)。
步骤2
向10mL圆底烧瓶中加入(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-4-叠氮基-5-甲氧基四氢-2H-吡喃-3-基酯(50mg,0.083mmol)、Ph3P(43mg,0.17mmol)、水(30μl,1.7mmol),和THF(3mL)。将该反应混合液在回流下搅拌。18h后,将溶剂浓缩,并将残余物经快速柱色谱纯化(12g硅胶柱;A=Hex,B=EtOAc;15分钟梯度;0%B至100%B;流速=12mL/分钟)。合并级分,浓缩,并在真空下干燥,得到标题化合物(63mg,0.058mmol,70%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.74-7.72(m,1H),7.64-7.56(m,1H),7.51-7.44(m,1H),7.42-7.32(m,2H),7.30-7.24(m,1H),5.43(s,1H),4.94(d,J=3.7Hz,1H),4.79-4.67(m,1H),4.47(dd,J=9.9,1.8Hz,1H),4.30-4.19(m,3H),4.18-4.08(m,2H),4.03(dt,J=4.8,2.2Hz,1H),3.81(t,J=11.2Hz,1H),3.62(t,J=11.9Hz,1H),3.40(s,3H),3.33(s,1H),3.16-3.06(m,1H),2.06(s,3H),1.93(d,J=1.1Hz,3H),1.89(s,3H)。LC/MS(ESI)m/e579.2[(M+H)+,计算值C26H34N4O9S 578.6],tR=0.70分钟(方法4)。
实施例A1.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(吡啶-3-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和3-乙炔基吡啶(8.3mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(11mg,0.020mmol,71%收率)。1HNMR(500MHz,DMSO-d6)δ9.10(s,1H),8.86(s,1H),8.60(s,1H),8.57-8.53(m,1H),8.28-8.19(m,1H),7.84(br d,J=7.6Hz,2H),7.55-7.41(m,3H),7.40-7.31(m,1H),5.00-4.93(m,1H),4.86-4.79(m,1H),4.65-4.55(m,1H),4.28-4.21(m,1H),4.16-4.10(m,1H),4.09-4.03(m,1H),4.00(br s,2H),3.82(br d,J=3.7Hz,2H),3.63-3.50(m,3H),3.42-3.29(m,1H),3.25(s,3H);分析型LC/MS(ESI)m/e 582.1[(M+H)+,计算值C27H31N7O6S 581.7],tR=1.32分钟(方法1);分析型LC/MS(ESI)m/e 582.1[(M+H)+,计算值C27H31N7O6S 581.7],tR=1.17分钟(方法2)。hGal-3 IC50=1.1μM。
实施例A2.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(吡啶-4-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和4-乙炔基吡啶(8.3mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(13mg,0.022mmol,82%收率)。1HNMR(500MHz,DMSO-d6)δ9.07-9.03(m,1H),8.68-8.62(m,3H),7.90-7.86(m,2H),7.86-7.81(m,2H),7.50-7.44(m,2H),7.37-7.32(m,1H),5.73-5.43(m,1H),5.03-4.96(m,1H),4.83(d,J=9.5Hz,1H),4.68-4.55(m,1H),4.29-4.21(m,1H),4.15-4.10(m,1H),4.09-4.02(m,1H),4.00-3.93(m,2H),3.84-3.77(m,2H),3.60-3.52(m,1H),3.48-3.42(m,1H),3.32-3.26(m,1H),3.25(s,3H);分析型LC/MS(ESI)m/e 581.9[(M+H)+,计算值C27H31N7O6S 581.7],tR=1.43分钟(方法1);分析型LC/MS(ESI)m/e 582.2[(M+H)+,计算值C27H31N7O6S 581.7],tR=1.40分钟(方法2)。hGal-3 IC50=1.1μM。
实施例A3.制备(2R,3R,4S,5R,6S)-4-(4-([1,1'-联苯]-4-基)-1H-1,2,3-三唑-1-基)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和4-乙炔基-1,1'-联苯(14mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(8.9mg,0.014mmol,48%收率)。1H NMR(500MHz,DMSO-d6)δ8.84(s,1H),8.70-8.62(m,1H),8.00(d,J=7.9Hz,2H),7.87-7.82(m,2H),7.81-7.76(m,2H),7.75-7.70(m,2H),7.52-7.43(m,4H),7.42-7.32(m,2H),5.70-5.65(m,1H),5.49-5.44(m,1H),4.97-4.92(m,1H),4.87-4.80(m,2H),4.66-4.56(m,1H),4.29-4.22(m,1H),4.16-4.05(m,2H),4.02-3.93(m,2H),3.86-3.77(m,2H),3.60-3.52(m,1H),3.43(br s,1H),3.34-3.27(m,1H),3.26(s,3H),3.18(d,J=5.2Hz,1H);分析型LC/MS(ESI)m/e 657.1[(M+H)+,计算值C34H36N6O6S 656.8],tR=2.02分钟(方法1);分析型LC/MS(ESI)m/e 657.2[(M+H)+,计算值C34H36N6O6S 656.8],tR=2.10分钟(方法2)。hGal-3IC50=>11μM。
实施例A4.制备(2R,3R,4S,5R,6S)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和1-乙炔基-3-氟苯(9.6mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(10mg,0.017mmol,60%收率)。1HNMR(500MHz,DMSO-d6)δ8.79-8.74(m,1H),8.59-8.54(m,1H),7.87-7.80(m,2H),7.77-7.71(m,1H),7.70-7.65(m,1H),7.53-7.42(m,3H),7.38-7.31(m,1H),7.18-7.10(m,1H),5.61-5.33(m,1H),4.98-4.88(m,1H),4.83-4.76(m,1H),4.66-4.55(m,1H),4.26-4.19(m,1H),4.16-4.08(m,1H),3.98(br s,3H),3.80(br d,J=7.4Hz,2H),3.61-3.55(m,2H),3.31-3.25(m,1H),3.24(s,3H);分析型LC/MS(ESI)m/e 598.9[(M+H)+,计算值C28H31FN6O6S598.7],tR=1.64分钟(方法1);分析型LC/MS(ESI)m/e 599.2[(M+H)+,计算值C28H31FN6O6S598.7],tR=1.58分钟(方法2)。hGal-3 IC50=0.026μM。
实施例A5.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(噻唑-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和2-乙炔基噻唑(8.7mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法6)。合并级分,浓缩,并在真空下干燥,得到标题化合物(16mg,0.026mmol,97%收率)。1HNMR(500MHz,DMSO-d6)δ8.83(s,1H),8.70-8.63(m,1H),7.96-7.90(m,1H),7.87-7.81(m,2H),7.80-7.76(m,1H),7.50-7.44(m,2H),7.38-7.31(m,1H),5.68-5.38(m,1H),5.04-4.95(m,1H),4.79(d,J=9.2Hz,1H),4.66-4.55(m,1H),4.27-4.20(m,1H),4.13(br d,J=9.2Hz,2H),4.00-3.89(m,2H),3.84-3.76(m,2H),3.60-3.49(m,1H),3.44-3.34(m,1H),3.25(s,3H),3.04-2.94(m,1H);分析型LC/MS(ESI)m/e 588.2[(M+H)+,计算值C25H29N7O6S2587.7],tR=1.27分钟(方法1);分析型LC/MS(ESI)m/e 588.0[(M+H)+,计算值C25H29N7O6S2587.7],tR=1.35分钟(方法2)。hGal-3 IC50=0.49μM。
实施例A6.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(嘧啶-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和5-乙炔基嘧啶(8.3mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(11mg,0.019mmol,69%收率)。1HNMR(500MHz,DMSO-d6)δ9.33-9.27(m,2H),9.20-9.15(m,1H),9.09-9.04(m,1H),8.70-8.62(m,1H),7.88-7.80(m,2H),7.51-7.43(m,2H),7.40-7.29(m,1H),5.73-5.47(m,1H),5.06-4.99(m,1H),4.88-4.80(m,1H),4.64-4.55(m,1H),4.29-4.21(m,1H),4.16-4.09(m,1H),4.03(s,1H),3.97(br s,2H),3.81(s,2H),3.59-3.51(m,1H),3.48-3.42(m,1H),3.32-3.27(m,1H),3.26(s,3H);分析型LC/MS(ESI)m/e 583.1[(M+H)+,计算值C26H30N8O6S582.6],tR=1.12分钟(方法1);分析型LC/MS(ESI)m/e 583.1[(M+H)+,计算值C26H30N8O6S582.6],tR=1.21分钟(方法2)。hGal-3 IC50=0.36μM。
实施例A7.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(噻唑-5-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和5-乙炔基噻唑(8.7mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(8.5mg,0.014mmol,52%收率)。1HNMR(500MHz,DMSO-d6)δ9.09(s,1H),8.84(s,1H),8.66(s,1H),8.30(s,1H),7.84(br d,J=7.3Hz,2H),7.47(t,J=7.6Hz,2H),7.39-7.31(m,1H),5.72-5.42(m,1H),5.01-4.91(m,1H),4.82(br d,J=9.2Hz,2H),4.65-4.53(m,1H),4.29-4.21(m,1H),4.16-4.09(m,1H),4.06-3.99(m,1H),3.99-3.91(m,2H),3.85-3.75(m,2H),3.58-3.50(m,1H),3.42-3.36(m,1H),3.25(s,3H);分析型LC/MS(ESI)m/e 588.1[(M+H)+,计算值C25H29N7O6S2 587.7],tR=1.33分钟(方法1);分析型LC/MS(ESI)m/e 588.1[(M+H)+,计算值C25H29N7O6S2 587.7],tR=1.26分钟(方法2)。hGal-3 IC50=0.84μM。
实施例A8.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(喹喔啉-6-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和6-乙炔基喹喔啉(12mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法6)。合并级分,浓缩,并在真空下干燥,得到标题化合物(4.4mg,0.007mmol,26%收率)。1HNMR(500MHz,DMSO-d6)δ9.17-9.11(m,1H),9.00-8.96(m,1H),8.96-8.91(m,1H),8.70-8.64(m,1H),8.63-8.58(m,1H),8.48-8.43(m,1H),8.24-8.18(m,1H),7.87-7.81(m,2H),7.50-7.44(m,2H),7.40-7.32(m,1H),5.77-5.45(m,1H),5.06-4.97(m,1H),4.90-4.81(m,1H),4.68-4.54(m,1H),4.30-4.21(m,1H),4.17-4.06(m,2H),4.03-3.93(m,2H),3.88-3.77(m,2H),3.60-3.52(m,1H),3.48-3.40(m,1H),3.34-3.30(m,1H),3.29(s,3H);分析型LC/MS(ESI)m/e 633.1[(M+H)+,计算值C30H32N8O6S 632.7],tR=1.40分钟(方法1);分析型LC/MS(ESI)m/e 633.1[(M+H)+,计算值C30H32N8O6S 632.7],tR=1.44分钟(方法2)。hGal-3 IC50=0.17μM。
实施例A9.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(哒嗪-4-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和4-乙炔基哒嗪(8.3mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法6)。合并级分,浓缩,并在真空下干燥,得到标题化合物(8.4mg,0.014mmol,52%收率)。1HNMR(500MHz,DMSO-d6)δ9.76-9.71(m,1H),9.31-9.24(m,1H),9.20-9.12(m,1H),8.63-8.57(m,1H),8.12-8.06(m,1H),7.88-7.81(m,2H),7.51-7.43(m,2H),7.39-7.31(m,1H),5.07-4.99(m,1H),4.90-4.80(m,1H),4.67-4.52(m,1H),4.29-4.19(m,1H),4.17-4.10(m,1H),4.09-3.94(m,3H),3.82(s,2H),3.58(br d,J=4.8Hz,3H),3.38(s,3H),3.35-3.30(m,1H);分析型LC/MS(ESI)m/e 583.4[(M+H)+,计算值C26H30N8O6S 582.6],tR=1.14分钟(方法1);分析型LC/MS(ESI)m/e 583.3[(M+H)+,计算值C26H30N8O6S 582.6],tR=1.12分钟(方法2)。hGal-3 IC50=1.24μM。
实施例A10.制备(2R,3R,4S,5R,6S)-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基-4-(4-(萘-2-基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-醇
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和2-乙炔基萘(12mg,0.080mmol),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(7.7mg,0.012mmol,46%收率)。1HNMR(500MHz,DMSO-d6)δ8.87-8.82(m,1H),8.63-8.57(m,1H),8.46-8.40(m,1H),8.09-8.03(m,1H),8.03-7.95(m,2H),7.95-7.90(m,1H),7.87-7.81(m,2H),7.59-7.49(m,2H),7.49-7.43(m,2H),7.38-7.31(m,1H),5.58-5.33(m,1H),5.01-4.93(m,1H),4.87-4.80(m,1H),4.68-4.57(m,1H),4.31-4.21(m,1H),4.19-4.06(m,2H),4.05-3.95(m,2H),3.86-3.79(m,2H),3.62-3.57(m,2H),3.39(s,3H),3.37-3.34(m,1H);分析型LC/MS(ESI)m/e631.4[(M+H)+,计算值C32H34N6O6S 630.7],tR=1.76分钟(方法1);分析型LC/MS(ESI)m/e631.4[(M+H)+,计算值C32H34N6O6S 630.7],tR=1.75分钟(方法2)。hGal-3 IC50=0.33μM。
实施例A11.制备4-(1-((2R,3R,4S,5R,6S)-3-羟基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基四氢-2H-吡喃-4-基)-1H-1,2,3-三唑-4-基)二环[2.2.2]辛烷-1-甲酸甲酯
向20mL梨形烧瓶中加入((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-叠氮基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(15mg,0.027mmol)和4-乙炔基二环[2.2.2]辛烷-1-甲酸甲酯(13mg,0.067mmol)(Fukuda,Y等人,WO 2013/003383),随后加入DMF(1mL)和水(0.3mL)。将容器抽真空,并用氮气净化。向该混合液中加入溶于水(0.4mL)中的五水合硫酸铜(II)(9.3mg,0.037mmol)和抗坏血酸钠(6.3mg,0.032mmol)。将容器再次抽真空,并用氮气净化,并搅拌。18h后,将该混合液用EtOAc(20mL)稀释,并过滤。将有机相用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将生成的残余物溶于MeOH(3mL)和THF(3mL)中。向该混合液中加入甲醇钠(12μl,0.053mmol)(25%w/v在MeOH中的溶液)。搅拌45分钟后,将该反应混合液用1N HCl(水溶液)中和直至pH 6-7,并浓缩。将粗制的产物经制备型HPLC纯化(方法5)。合并级分,浓缩,并在真空下干燥,得到标题化合物(11mg,0.017mmol,63%收率)。1H NMR(500MHz,DMSO-d6)δ8.62-8.57(m,1H),7.96-7.91(m,1H),7.85-7.79(m,2H),7.49-7.42(m,2H),7.38-7.31(m,1H),5.76-5.30(m,1H),5.00-4.88(m,1H),4.80-4.75(m,1H),4.73-4.68(m,1H),4.63-4.56(m,1H),4.24-4.16(m,1H),4.13-4.07(m,1H),3.97-3.85(m,2H),3.82-3.74(m,1H),3.71(s,3H),3.58(s,1H),3.54-3.46(m,2H),3.29-3.21(m,1H),3.10(s,3H),1.80(s,12H);分析型LC/MS(ESI)m/e 670.9[(M+H)+,计算值C32H42N6O8S 670.8],tR=1.64分钟(方法1);分析型LC/MS(ESI)m/e 671.2[(M+H)+,计算值C32H42N6O8S 670.8],tR=1.62分钟(方法2)。hGal-3 IC50=1.86μM。
实施例A12.制备3,4,5-三氟-N-((2R,3R,4S,5R,6S)-3-羟基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基四氢-2H-吡喃-4-基)苯甲酰胺
向10mL梨形烧瓶中加入(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-4-氨基-5-甲氧基四氢-2H-吡喃-3-基酯(28mg,0.041mmol)、3,4,5-三氟苯甲酸(15mg,0.083mmol)、吡啶(10μl,0.12mmol)和DMF(1mL)。向该混合液中加入1-丙烷膦酸酐(50%在EtOAc中的溶液)(0.049mL,0.083mmol),并将该反应混合液在N2下搅拌。18h后,将该混合液用水(25mL)稀释,并用EtOAc萃取(2x15 mL)。将有机相合并,用盐水洗涤,经Na2SO4干燥,过滤,并浓缩。将残余物经制备型HPLC纯化(方法7)。合并级分,并浓缩。将生成的残余物溶于THF(0.1mL)和MeOH(0.1mL)中。向该混合液中加入甲醇钠(25%w/v在MeOH中)(2.8μl,0.012mmol),并搅拌该反应混合液。1小时后,加入1M HCl直至pH 7。将溶剂浓缩,并将残余物经制备型HPLC纯化(方法6)。合并级分,浓缩,并在真空下干燥,得到标题化合物(6.2mg,0.010mmol,25%收率)。1H NMR(500MHz,DMSO-d6)δ8.59(s,1H),8.57-8.50(m,1H),7.93-7.86(m,2H),7.84(brd,J=7.4Hz,2H),7.46(s,2H),7.38-7.31(m,1H),5.48(d,J=6.5Hz,1H),5.04(d,J=5.5Hz,1H),4.66(d,J=9.4Hz,1H),4.62-4.51(m,1H),4.22(br dd,J=11.6,4.8Hz,1H),4.16-4.07(m,2H),4.02-3.93(m,1H),3.86-3.76(m,2H),3.64-3.49(m,4H),3.44(s,3H)。分析型LC/MS(ESI)m/e 611.1[(M+H)+,计算值C27H29F3N4O7S 610.6],tR=1.55分钟(方法1)。分析型LC/MS(ESI)m/e 611.1[(M+H)+,计算值C27H29F3N4O7S 610.6],tR=1.55分钟(方法2)。hGal-3 IC50=1.4μM。
实施例A13.制备2,3,5,6-四氟-N-((2R,3R,4S,5R,6S)-3-羟基-6-(((3R,4R,5S)-4-羟基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(羟基甲基)-5-甲氧基四氢-2H-吡喃-4-基)-4-甲氧基苯甲酰胺
向10mL梨形烧瓶中加入2,3,5,6-四氟-4-甲氧基苯甲酸(15mg,0.068mmol)、DMF(0.4μl,5.1μmol)和DCM(1mL)。向该混合液中加入乙二酰氯(6.0μl,0.068mmol),并将该反应混合液在N2下搅拌。2h后,将溶剂(在室温)浓缩,将残余物溶于DCM(1mL)中,并加入(2R,3R,4S,5R,6S)-乙酸6-(((3R,4R,5S)-4-乙酸基-5-(4-苯基-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)硫基)-2-(乙酸基甲基)-4-氨基-5-甲氧基四氢-2H-吡喃-3-基酯(23mg,0.034mmol)和DMAP(4.2mg,0.034mmol)溶于DCM(1mL)中的溶液中。将该反应混合液在N2下搅拌。18h后,将溶剂浓缩,并将粗制的中间体经制备型HPLC纯化(方法7)。合并级分,并浓缩。将生成的残余物溶于THF(0.5mL)和MeOH(0.5mL)中。向该混合液中加入甲醇钠(25%w/v在MeOH中)(1.7μl,0.0077mmol),并搅拌该反应混合液。1小时后,加入1M HCl直至pH 7。将溶剂浓缩,并将残余物经制备型HPLC纯化(方法6)。合并级分,浓缩,并在真空下干燥,得到标题化合物(0.9mg,0.0014mmol,4%收率)。1H NMR(500MHz,DMSO-d6)δ9.05-8.95(m,1H),8.71-8.60(m,1H),7.87-7.78(m,2H),7.51-7.43(m,2H),7.39-7.30(m,1H),5.65-5.48(m,1H),5.19-5.02(m,1H),4.72-4.64(m,1H),4.59-4.50(m,1H),4.24-4.16(m,1H),4.10-4.07(m,2H),4.09(s,3H),3.98-3.89(m,1H),3.85-3.72(m,2H),3.64-3.56(m,1H),3.56-3.46(m,2H),3.43(s,3H),2.56-2.53(m,1H)。分析型LC/MS(ESI)m/e 658.9[(M+H)+,计算值C28H30F4N4O8S 658.6],tR=1.68分钟(方法1)。分析型LC/MS(ESI)m/e 659.0[(M+H)+,计算值C28H30F4N4O8S 658.6],tR=1.65分钟(方法2)。hGal-3 IC50=0.57μM。
部分B
对于每个实施例和中间体报告的分析型LC-MS/HPLC保留时间使用了以下通用分析型LC-MS/HPLC条件之一:
LCMS条件:
方法A:
柱:XBridge BEH XP C18(50x 2.1)mm,2.5μm;
流动相A:10mM NH4OAc,水:乙腈(95:5)
流动相B:10mM NH4OAc,水:乙腈(5:95)
梯度=0-100%B,经3分钟
温度:50℃;
流速:1.1mL/分钟
检测:UV在220nm
方法B:
柱:XBridge BEH XP C18(50x 2.1)mm,2.5μm
流动相A:0.1%在水中的TFA,乙腈(95:5)
流动相B:0.1%在水中的TFA,乙腈(5:95)
梯度=0-100%B,经3分钟
温度:50℃
流速:1.1mL/分钟
检测:UV在220nm
方法C:
柱-KINETEX-XB-C18(75x 3mm-2.6μm)
流动相A:10mM NH4OAc,水:乙腈(98:2)
流动相B:10mM NH4OAc,水:乙腈(2:98)
梯度=20-100%B,经5分钟
流速:1.5mL/分钟
检测:UV在254nm
方法D:
柱:Waters Acquity UPLC BEH C18(2.1x 50mm),1.7μm
流动相A:10mM NH4OAc,水:乙腈(95:5)
流动相B:10mM NH4OAc,水:乙腈(5:95)
梯度=20-90%B,经1.1分钟,然后在90%B保持0.6分钟
温度:50℃
流速:0.7mL/分钟
检测:UV在220nm
方法E:
柱-ZORBAX-SB-C18(50x 4.6mm),6μm
流动相A:10mM NH4OAc,水:乙腈(98:2)
流动相B:10mM NH4OAc,水:乙腈(2:98)
梯度=30-100%B,经5分钟
流速:1.5mL/分钟
检测:UV在254nm
制备型-HPLC条件:
方法A:
柱:Waters XBridge C18,(19x 150mm),5μm颗粒
流动相A:10mM乙酸铵水溶液
流动相B:乙腈
梯度:15-50%B,经20分钟,然后在100%B保持5分钟
流速:15mL/分钟
方法B:
柱:Inertsil ODS(250x 19mm),5μm颗粒
相A:10mM乙酸铵水溶液
流动相B:乙腈
梯度:40-65%B,经20分钟,然后在100%B保持5分钟
流速:20mL/分钟
方法C:
柱:Sunfire C18(19x 150mm),5μm颗粒
流动相A:10mM乙酸铵水溶液
流动相B:乙腈
梯度:40-45%B,经12分钟,然后在100%B保持5分钟
流速:20mL/分钟
方法D:
柱:Sunfire C18(19x 150mm),5μm颗粒
流动相A:10mM乙酸铵水溶液
流动相B:乙腈
梯度:30-75%B,经12分钟,然后在100%B保持5分钟
流速:20mL/分钟
方法E:
柱:Sunfire C18(19x 150mm),5μm颗粒
流动相A:10mM乙酸铵水溶液
流动相B:乙腈
梯度:20-60%B,经20分钟,然后在100%B保持5分钟
流速:15mL/分钟
方法F:
柱:Inertsil ODS(250x 19)mm,5μm颗粒
相A:10mM乙酸铵水溶液
流动相B:乙腈
梯度:40-75%B,经20分钟,然后在100%B保持5分钟
流速:17mL/分钟
方法G:
柱:YMC trart C18,19x 150mm,5-μm颗粒
流动相A:10mM乙酸铵,pH 4.5,含有TFA
流动相B:乙腈
梯度:20-60%B,经15分钟,然后在100%B保持5分钟
流速:20mL/分钟
制备中间体
制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)-6-((三异丙基硅烷基)硫基)四氢-2H-吡喃-2-基)甲酯
将((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(350mg,0.670mmol)在干燥的乙腈(15mL)中的搅拌的溶液用氩气净化10分钟。然后加入碳酸钾(278mg,2.010mmol),随后加入三异丙基硅烷硫醇(0.216mL,1.005mmol)。将该反应混合液在室温搅拌4h,然后减压浓缩。将残余物用CH2Cl2萃取(3x 30mL),用水(20mL)、盐水(20mL)洗涤,经Na2SO4干燥,并浓缩。将粗制的残余物经硅胶柱色谱纯化(20%→50%在己烷中的乙酸乙酯),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)-6-((三异丙基硅烷基)硫基)四氢-2H吡喃-2-基)甲酯(300mg,0.467mmol,69%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.76(s,1H),7.56-7.37(m,2H),5.48(d,J=2.5Hz,1H),4.62(d,J=9.2Hz,1H),4.58(dd,J=10.4,3.2Hz,1H),4.26-4.03(m,3H),3.99-3.89(m,1H),3.43(s,3H),2.08(s,3H),2.04(s,3H),1.36–1.35(m,3H),1.17(d,J=7.3Hz,18H);LC/MS[M+H]+=632.2,tR=4.19分钟(方法C)。
制备2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)-2-((三异丙基硅烷基)硫基)四氢-2H-吡喃-3-基)氧基)乙酸乙酯
将2-(((2R,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-溴-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸乙酯(300mg,0.505mmol)在干燥的乙腈(15mL)中的搅拌的溶液用氩气净化10分钟。然后加入碳酸钾(209mg,1.514mmol),随后加入三异丙基硅烷硫醇(0.163mL,0.757mmol),并将该反应混合液在室温搅拌4h。然后将该反应混合液减压浓缩。将残余物用CH2Cl2萃取(3x 50mL),用水(30mL)、盐水(30mL)洗涤,经Na2SO4干燥,并浓缩。将粗制的残余物经硅胶柱色谱纯化(50%→100%在己烷中的乙酸乙酯),得到2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)-2-((三异丙基硅烷基)硫基)四氢-2H-吡喃-3-基)氧基)乙酸乙酯(80mg,0.078mmol,16%收率),为无色液体。1H NMR(400MHz,氯仿-d)δ7.85(s,1H),7.47-7.35(m,2H),5.51(d,J=2.5Hz,1H),4.78-4.62(m,2H),4.55-4.40(m,1H),4.19-4.05(m,4H),4.03-3.82(m,3H),2.07(s,3H),2.04(s,3H),1.42-1.21(m,3H),1.20-1.06(m,18H);LC/MS[M+H]+=704.2,tR=4.25分钟(方法C)。
制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基-6-((三异丙基硅烷基)硫基)四氢-2H-吡喃-2-基)甲酯
将((2R,3R,4S,5R,6R)-乙酸3-乙酸基-6-溴-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(400mg,0.823mmol)在干燥的乙腈(15mL)中的搅拌的溶液用氩气净化10分钟。加入碳酸钾(341mg,2.468mmol),随后加入三异丙基硅烷硫醇(0.216mL,1.005mmol),并将该反应混合液在室温搅拌4h。将该反应混合液减压浓缩。将残余物用CH2Cl2萃取(3x 30mL),用水(20mL)、盐水(20mL)洗涤,经Na2SO4干燥,并浓缩。将粗制的残余物经硅胶柱色谱纯化(20%→50%在己烷中的乙酸乙酯),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基-6-((三异丙基硅烷基)硫基)四氢-2H-吡喃-2-基)甲酯(70mg,0.108mmol,13%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ7.80(s,1H),7.60-7.47(m,2H),7.39(d,J=6.0Hz,1H),7.03(d,J=1.2Hz,1H),5.50(d,J=2.4Hz,1H),4.64-4.54(m,2H),4.19-4.06(m,3H),3.97(d,J=6.4Hz,1H),3.43(s,3H),2.08(s,3H),2.06(s,3H),1.39-1.21(m,21H);[NMR具有EtOAc作为溶剂残余物峰];LC/MS[M+H]+=596.2,tR=4.29分钟(方法C)。
制备(-)-(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯
步骤1。制备(1S,5R,6R)-5-羟基-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯
在0℃在氮气下向N-Boc-3-羟基-1,2,3,6-四氢吡啶(500mg,2.51mmol)在CH2Cl2(25mL)中的溶液中加入碳酸氢钠(211mg,2.51mmol),随后加入在CH2Cl2(3mL)中的mCPBA(928mg,3.76mmol)。使该反应混合液温至室温,并搅拌24h。将该反应混合液用CH2Cl2(100mL)稀释,经Celite垫过滤,并将滤液用饱和的Na2SO3(2x50 mL)、饱和的NaHCO3(2x50mL)和饱和的NaCl(25mL)洗涤。将有机层经Na2SO4干燥,过滤,浓缩,并将粗制的残余物经硅胶色谱纯化(40%→50%在己烷中的乙酸乙酯),得到(1S,5R,6R)-5-羟基-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯(430mg,2.002mmol,80%收率),为白色固体。1H NMR(400MHz,氯仿-d)δ4.01(br.s,1H),3.92-3.44(m,5H),3.10(dd,J=12.8,7.2Hz,1H),1.29(s,9H)(旋转异构体混合物)。
步骤2。制备(1S,5S,6R)-5-叠氮基-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯
向(1S,5R,6R)-5-羟基-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯(325mg,1.510mmol)在THF(50mL)中的搅拌的溶液中加入三苯基膦制备(792mg,3.02mmol)。将该反应混合液冷却至0℃。在氮气下依次加入DEAD(0.478mL,3.02mmol)和DPPA(0.651mL,3.02mmol)。使该反应混合液温至室温,并搅拌16h。减压除去溶剂,并将粗制的残余物经硅胶色谱纯化(10%→15%在己烷中的乙酸乙酯),得到(1S,5S,6R)-5-叠氮基-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯(230mg,0.957mmol,64%收率),为浅黄色油状物。1HNMR(400MHz,DMSO-d6)δ4.09-3.82(m,2H),3.62-3.38(m,4H),3.17(dd,J=13.1,3.3Hz,1H),1.40(s,9H)(旋转异构体混合物)。
步骤3。制备(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯
在室温向(1R,5R,6S)-5-叠氮基-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯(1.6g,6.66mmol)在DMF(30mL)和水(7.50mL)中的溶液中依次加入抗坏血酸钠(1.319g,6.66mmol)、五水合硫酸铜(II)(1.496g,5.99mmol)和3-氟苯基乙炔(3.08mL,26.6mmol)。将该反应混合液用N2脱气5分钟,并加热至85℃达30分钟。将该混合液冷却至室温,用冰冷的水(100mL)稀释,并搅拌15分钟得到固体。将固体过滤,混悬于CH2Cl2(100mL)中,经celite垫过滤,并用过量的CH2Cl2洗涤。将滤液经硫酸钠干燥,并浓缩。将残余物经硅胶纯化(40%→80%在己烷中的乙酸乙酯),得到(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯(1.1g,3.03mmol,46%收率),为白色固体。1HNMR(400MHz,氯仿-d)δ7.83(br.s,1H),7.59-7.55(m,2H),7.42-7.38(m,1H),7.10-7.07(m,1H),5.18-5.06(m,1H),4.34-4.29(m,1H),3.93-3.45(m,5H),1.47-1.11(m,9H)(旋转异构体混合物);LC/MS,[M+H]+=361.0,tR=2.01分钟(方法E)。
步骤4。制备(-)-(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯
使用了以下描述的条件通过制备型SFC手性色谱分离来自以上的化合物A的外消旋混合物(1.1g)
制备型手性HPLC条件:
峰-1采取以下步骤
分析型手性HPLC条件:
峰1(期望的):0.3g:手性HPLC tR=2.45分钟;[α]D 22-72.0,(c=0.1,MeOH)。
峰2(不期望的):0.5g:手性HPLC tR=3.07分钟;[α]D 22+58.0,(c=0.1,MeOH)。
制备1-((1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚-3-基)乙-1-酮
步骤1。制备(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷
在0℃向(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯(200mg,0.555mmol)在CH2CL2(10mL)中的搅拌的溶液中滴加活化的MS(0.4g)和BF3·OEt2(0.211mL,1.665mmol)。将该混合液在0℃搅拌15分钟。然后将该反应混合液用MeOH(2mL)淬灭,用CH2Cl2(30mL)稀释,用水、10%NaHCO3洗涤,经Na2SO4干燥,并浓缩,得到(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷(110mg,0.335mmol,60%收率),为白色固体,将其未经进一步纯化地用于下一个步骤。LC/MS[M+H]+=261.2,tR=0.86分钟(方法D)。
步骤2
在室温向(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷(110mg,0.423mmol)在CH2Cl2(4mL)中的搅拌的溶液中依次加入三乙胺(0.177mL,1.268mmol)、乙酸酐(0.060mL,0.634mmol)和DMAP(5.16mg,0.042mmol),并将该混合液搅拌16h。将该反应混合液用CH2Cl2萃取(3x 30mL),用水、盐水洗涤,经Na2SO4干燥,并浓缩,得到1-((1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚-3-基)乙-1-酮(100mg,0.32mmol,75%收率),为棕色液体,将其未经进一步纯化地用于下一个步骤。LC/MS[M+H]+=303.0,tR=1.30分钟(方法C)。
制备最终产物
实施例B1.制备(3S,4R,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(((2S,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-基)硫基)哌啶-4-醇
步骤1.制备(3R,4R,5S)-3-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-1-甲酸叔丁基酯
向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)-6-((三异丙基硅烷基)硫基)四氢-2H-吡喃-2-基)甲酯(20mg,0.032mmol)在乙腈(2mL)中的搅拌的溶液中加入在乙腈(2mL)中的(1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚烷-3-甲酸叔丁基酯(11.41mg,0.032mmol)。将该溶液用氩气净化10分钟。滴加TBAF(0.032mL,0.032mmol),并将该混合液在室温在氩气下搅拌10分钟。减压除去溶剂,得到(3R,4R,5S)-3-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-1-甲酸叔丁基酯(30mg,0.020mmol,65%收率),将其未经进一步纯化地用于下一个步骤。LC/MS[M+H]+=836.0,tR=3.47分钟(方法C)。
步骤2
向(3R,4R,5S)-3-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-3-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)硫基)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-1-甲酸叔丁基酯(30mg,0.036mmol)在CH2Cl2(5mL)中的溶液中加入TFA(2.77μl,0.036mmol),并将该反应混合液搅拌1h。然后减压除去溶剂。将残余物溶于甲醇(2mL)中,随后加入甲醇钠(0.194mg,3.59μmol)。将该混合液在室温搅拌30分钟。将该反应混合液用AcOH(0.1mL)酸化,浓缩,并经制备型HPLC纯化(方法A),得到(3S,4R,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(((2S,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-基)硫基)哌啶-4-醇(3mg,4.47μmol,13%收率)(实施例B1)。1H NMR(400MHz,甲醇-d4)δ8.66(s,1H),8.53(s,1H),7.70-7.60(m,4H),7.52-7.46(m,1H),7.15-7.10(m,1H),4.94-4.80(m,3H),4.19-4.12(m,3H),3.89-3.76(m,6H),3.45-3.32(m,2H),3.32(s,3H,被溶剂峰遮盖);LC/MS[M+H]+=652.3,tR=1.63分钟(方法A)。hGal3 IC50=0.067μM。
实施例B2.制备(3S,4R,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(((2S,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-基)硫基)哌啶-4-醇
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯
向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)-6-((三异丙基硅烷基)硫基)四氢-2H-吡喃-2-基)甲酯(30mg,0.047mmol)在乙腈(2mL)中的搅拌的溶液中加入在乙腈(2mL)中的1-((1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚-3-基)乙-1-酮(14.36mg,0.047mmol)。将该溶液用氩气净化10分钟。然后滴加TBAF(0.032mL,0.032mmol),并将该混合液在室温在氩气下搅拌10分钟。减压除去溶剂,并将产物经制备型HPLC纯化(方法C),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(8mg,10.29μmol,22%收率),为白色固体。LC/MS,[M+H]+=778.2,tR=2.68分钟(方法C)。
步骤2
向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-5-甲氧基-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-2-基)甲酯(7mg,9.00μmol)在甲醇(2mL)中的搅拌的溶液中加入甲醇钠(25%wt,在甲醇中)(1.945mg,9.00μmol),并将该混合液在室温搅拌30分钟。将该反应混合液用AcOH(0.1mL)酸化,浓缩,并经制备型HPLC纯化(方法A),得到((3S,4R,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(((2S,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-基)硫基)哌啶-4-醇(2.3mg,3.32μmol,37%收率)(实施例B2)。1H NMR(400MHz,甲醇-d4)δ8.75,8.70*(s,1H),8.52(s,1H),7.77-7.63(m,4H),7.51-7.45(m,1H),7.13-7.07(m,1H),4.96-4.94(m,1H),4.77(d,J=9.2Hz,1H),4.58-4.48(m,2H),4.26-4.17(m,1H),4.15-4.05(m,2H),3.86-3.77(m,3H),3.76-3.71(m,1H),3.45-3.37(m,3H),3.32(s,3H,被溶剂峰遮盖),2.31,2.23*(s,3H)(*旋转异构体混合物);LC/MS[M+H]+=694.3,tR=1.71分钟(方法A)。hGal3IC50=0.037μM。
实施例B3.制备1-((3S,4R,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(((2S,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-基)硫基)-4-羟基哌啶-1-基)乙-1-酮
步骤1.制备((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯
向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基-6-((三异丙基硅烷基)硫基)四氢-2H-吡喃-2-基)甲酯(20mg,0.034mmol)在乙腈(2mL)中的搅拌的溶液中加入在乙腈(2mL)中的1-((1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚-3-基)乙-1-酮(10.15mg,0.034mmol)。将该溶液用氩气净化10分钟。然后滴加TBAF(0.034mL,0.034mmol),并将该混合液在室温在氩气下搅拌10分钟。减压除去溶剂。将残余物经制备型-HPLC纯化(方法B),得到((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(7mg,9.44μmol,28%收率),为白色固体。LC/MS[M+H]+=742.0,tR=2.40分钟(方法C)。
步骤2
向((2R,3R,4S,5R,6S)-乙酸3-乙酸基-6-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-甲氧基四氢-2H-吡喃-2-基)甲酯(7mg,9.44μmol)在甲醇(2mL)中的搅拌的溶液中加入甲醇钠(25%wt,在甲醇中)(2.0mg,9.44μmol),并将该混合液在室温搅拌30分钟。将该反应混合液用AcOH(0.1mL)酸化,浓缩,并经制备型HPLC纯化(方法A),得到1-((3S,4R,5R)-3-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-(((2S,3R,4S,5R,6R)-4-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-5-羟基-6-(羟基甲基)-3-甲氧基四氢-2H-吡喃-2-基)硫基)-4-羟基哌啶-1-基)乙-1-酮(2.76mg,4.11μmol,44%收率)(实施例B3)。1H NMR(400MHz,甲醇-d4)δ8.58,8.53*(s,1H),8.39(s,1H),7.60-7.39(m,4H),7.38-7.01(m,2H),7.01-6.95(m,2H),4.83-4.78(m,2H),4.65-4.47(m,1H),4.41-4.01(m,3H),3.99-3.93(m,2H),3.77-3.62(m,4H),3.38-3.03(m,2H),3.32,3,25*(s,3H,被溶剂峰遮盖),2.19,2.11*(s,3H)(*旋转异构体混合物);LC/MS[M+H]+=658.0,tR=1.86分钟(方法C)。hGal3 IC50=0.054μM。
实施例B4.制备2-(((2S,3R,4S,5R,6R)-2-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-5-羟基-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸
步骤1.制备2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸乙酯
向2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)-2-((三异丙基硅烷基)硫基)四氢-2H-吡喃-3-基)氧基)乙酸乙酯(40mg,0.057mmol)在乙腈(2mL)中的搅拌的溶液中加入在乙腈(2mL)中的((1S,5S,6R)-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-7-氧杂-3-氮杂二环[4.1.0]庚-3-基)乙-1-酮(17.18mg,0.057mmol)。将该溶液用氩气净化10分钟。TBAF(0.057mL,0.057mmol)然后滴加,并将该混合液在室温在氩气下搅拌10分钟。减压除去溶剂。将残余物经制备型HPLC纯化(方法D),得到2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸乙酯(12mg,0.013mmol,23%收率),为白色固体。LC/MS[M+H]+=850.2,tR=2.82分钟(方法C)。
步骤2
在室温向2-(((2S,3R,4S,5R,6R)-5-乙酸基-6-(乙酸基甲基)-2-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸乙酯(11mg,0.013mmol)在THF(2mL)中的搅拌的溶液中加入水(0.500mL)和LiOH(0.930mg,0.039mmol),并将该混合液搅拌1h。然后减压除去溶剂,并将残余物经制备型HPLC纯化(方法E),得到2-(((2S,3R,4S,5R,6R)-2-(((3R,4R,5S)-1-乙酰基-5-(4-(3-氟苯基)-1H-1,2,3-三唑-1-基)-4-羟基哌啶-3-基)硫基)-5-羟基-6-(羟基甲基)-4-(4-(3,4,5-三氟苯基)-1H-1,2,3-三唑-1-基)四氢-2H-吡喃-3-基)氧基)乙酸(2.3mg,3.09μmol,24%收率)(实施例B4)。1HNMR(400MHz,甲醇-d4)δ8.69,8.65*(s,1H),8.53,8.52*(s,1H),7.69-7.60(m,4H),7.50-7.43(m,1H),7.13-7.06(m,1H),5.15-4.94(m,2H),4.95(d,J=9.2Hz,1H),4.59-4.42(m,5H),4.17-4.06(m,3H),3.93-3.74(m,4H),3.50-3.44(m,1H),2.30,2.23*(s,3H)(*旋转异构体混合物);LC/MS[M-H]+=736.0,tR=1.11分钟(方法C)。hGal3 IC50=0.032μM。
对于本领域技术人员来说,显然本公开不限于上述说明性示例,并且在不脱离其基本属性的情况下,可以以其它具体形式来实施本公开。因此,在所有方面,实施例应当被认为是说明性的而非限制性的,应参照的是所附权利要求而不是前述实施例,并且因此意图涵盖在权利要求的等同含义和范围内的所有变化。
Claims (14)
1.式(I)的化合物
或其药学上可接受的盐,其中:
A是O、NH或N(COCH3);
R2是烷基、(CO2(R5))烷基或(CON(R6)(R7))烷基;
R3是环烷基、四氢吡喃基或Ar1,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N;
R4是烷基、环烷基、二环[2.2.1-2]烷基或Ar2,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5;
R5是氢或烷基;
R6是氢、烷基、烷基羰基或苯基;
R7是氢或烷基;
或(R6)(R7)N一起是氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基或二氧化硫吗啉基,且被0-3个选自以下的取代基取代:卤代基、烷基、羟基和烷氧基;
Ar1是苯基、噻唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基;且
Ar2是苯基、联苯基、萘基、噻唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉基或喹喔啉基。
4.权利要求1或权利要求2的化合物,其中R2是烷基。
5.权利要求1或权利要求2的化合物,其中R2是(CO2(R5))烷基或(CON(R6)(R7))烷基。
6.权利要求1或权利要求2的化合物,其中R3是Ar1,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N。
7.权利要求1或权利要求2的化合物,其中R3是环烷基或四氢吡喃基,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N。
8.权利要求1或权利要求2的化合物,其中R4是Ar2,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5。
9.权利要求1或权利要求2的化合物,其中R4是烷基、环烷基或二环[2.2.1-2]烷基,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5。
10.权利要求1或权利要求2的化合物,其中Ar1是苯基、吡啶基、哒嗪基、嘧啶基或吡嗪基,且被0-3个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基、CO2R5和(R6)(R7)N。
11.权利要求1或权利要求2的化合物,其中Ar2是苯基、吡啶基、哒嗪基、嘧啶基或吡嗪基,且被0-5个选自以下的取代基取代:氰基、卤代基、烷基、卤代烷基、羟基、烷氧基、卤代烷氧基和CO2R5。
12.组合物,其包含治疗有效量的权利要求1至11中任一项的化合物或其药学上可接受的盐和药学上可接受的载体。
13.治疗器官纤维化(包括肝、肾、肺、心脏和皮肤)、肝疾病和病症(包括急性肝炎、慢性肝炎、肝纤维化、肝硬化、门静脉高压、再生衰竭、非酒精性脂肪性肝炎(NASH)、肝功能减退和肝血流障碍)、细胞增殖性疾病、癌症和病症(包括实体瘤、实体瘤转移、血管纤维瘤、骨髓瘤、多发性骨髓瘤、卡波西肉瘤、白血病、慢性淋巴细胞性白血病(CLL))和癌细胞的侵袭性转移)、炎性疾病和病症(包括银屑病、肾病和肺炎)、胃肠道疾病和病症(包括肠易激综合征(IBS)、炎性肠病(IBD)和胰腺分泌异常)、肾疾病和病症、尿道相关疾病和病症(包括良性前列腺增生或与神经病性膀胱疾病、脊髓肿瘤、椎间盘突出、椎管狭窄相关的症状和源自糖尿病的症状)、下泌尿道疾病和病症(包括下泌尿道阻塞)、下泌尿道炎性疾病和病症(包括排尿困难和频尿)、胰腺疾病和病症、异常血管发生相关疾病和病症(包括动脉栓塞)、硬皮病、脑相关疾病和病症(包括脑梗塞和脑出血)、神经病性疼痛和周围神经病变、眼疾病和病症(包括年龄相关性黄斑变性(AMD)、糖尿病性视网膜病、增生性玻璃体视网膜病(PVR)、瘢痕性类天疱疮和青光眼滤过手术瘢痕形成)的方法,所述方法包括向患者施用治疗有效量的权利要求1至11中任一项的化合物或其药学上可接受的盐。
14.权利要求13的方法,其中,所述疾病或病症是肾纤维化、肺纤维化、肝纤维化、动脉纤维化或系统性硬化病。
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- 2019-06-13 WO PCT/US2019/036877 patent/WO2019241461A1/en unknown
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- 2019-06-13 JP JP2020569778A patent/JP7190513B2/ja active Active
- 2019-06-13 US US17/251,964 patent/US11970511B2/en active Active
- 2019-06-13 CN CN201980039715.9A patent/CN112292386B/zh active Active
- 2019-06-13 EP EP19740100.3A patent/EP3807290B1/en active Active
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ES2912499T3 (es) | 2022-05-26 |
JP7190513B2 (ja) | 2022-12-15 |
EP3807290B1 (en) | 2022-03-30 |
JP2021527102A (ja) | 2021-10-11 |
US11970511B2 (en) | 2024-04-30 |
WO2019241461A1 (en) | 2019-12-19 |
KR20210021015A (ko) | 2021-02-24 |
EP3807290A1 (en) | 2021-04-21 |
CN112292386B (zh) | 2024-06-11 |
US20210323991A1 (en) | 2021-10-21 |
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