CN114957053B - 一种氧代亚乙基类化合物或其药学上可接受的盐及其制备方法和应用、药物组合物及其应用 - Google Patents
一种氧代亚乙基类化合物或其药学上可接受的盐及其制备方法和应用、药物组合物及其应用 Download PDFInfo
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- CN114957053B CN114957053B CN202210558639.6A CN202210558639A CN114957053B CN 114957053 B CN114957053 B CN 114957053B CN 202210558639 A CN202210558639 A CN 202210558639A CN 114957053 B CN114957053 B CN 114957053B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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Abstract
本发明提供了一种氧代亚乙基类化合物或其药学上可接受的盐及其制备方法和应用、药物组合物及其应用,属于生物医药技术领域。本发明提供的氧代亚乙基类化合物或其药学上可接受的盐,氧代亚乙基类化合物具有式I所示的结构。本发明提供的氧代亚乙基类化合物或其药学上可接受的盐中,氧代亚乙基类化合物能够具有明显的抑制3CL蛋白酶活性以及抗广谱Sarbecovirus亚属冠状病毒活性。毒性研究显示其毒性低、具有良好的成药性,表明该类化合物作为广谱Sarbecovirus亚属冠状病毒的3CL蛋白酶抑制剂和抗病毒药物具有良好的应用前景。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种氧代亚乙基类化合物或其药学上可接受的盐及其制备方法和应用、药物组合物及其应用。
背景技术
冠状病毒属于套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)。根据国际病毒分类委员会(International Committee on Taxonomy ofViruses,ICTV)的标准,冠状病毒科分为两个亚科:冠状病毒亚科(Coronavirinae)和环曲病毒亚科(Torovirinae)。冠状病毒亚科分为α、β、γ和δ四个属,其中β属又分为Embecovirus、Sarbecovirus、Merbecovirus、Nobecovirus和Hibecovirus五个亚属。SARS及其他类似SARS病毒均属于冠状病毒亚科β属Sarbecovirus亚属。
有研究发现SARS-CoV、MERS-CoV和SARS-CoV-2这三种人冠状病毒均起源于不同蝙蝠物种的动物源性病毒。SARS-CoV-2与蝙蝠体内发现的冠状病毒同源性大于95%,这些病毒经变异后通过中间宿主棕榈果子狸、单峰骆驼、马来亚穿山甲等传染给人类。目前在蝙蝠种群中还发现了其他类型的Sarbecovirus亚属SARS样冠状病毒,随着动物源性冠状病毒尤其是Sarbecovirus多样化的增加,通过重组和变异,将极大概率地传播。
广谱Sarbecovirus抑制剂的研究亟需引起高度重视。由于冠状病毒3CL蛋白酶具有高度的序列同源性且在人体内无同源蛋白,因此是广谱抗Sarbecovirus亚属冠状病毒药物研究的理想靶点。然而,抗Sarbecovirus亚属冠状病毒药物的种类还有待丰富。
发明内容
本发明的目的在于提供一种氧代亚乙基类化合物或其药学上可接受的盐及其制备方法和应用、药物组合物及其应用,本发明提供的氧代亚乙基类化合物或其药学上可接受的盐具有显著的抑制Sarbecovirus亚属冠状病毒3CL蛋白酶的活性,抗Sarbecovirus亚属冠状病毒活性高,毒性低,具有良好的成药性。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种氧代亚乙基类化合物或其药学上可接受的盐,所述氧代亚乙基类化合物具有式Ⅰ所示结构:
式I中,M为-CH2-、或不存在;
R1包括C1~C6烷基、C3~C6环烷基或芳杂环取代基;
R2包括 其中,Z包括-CH2-、-O-或-NH-;Z1和Z2独立地包括-O-、-NH-或-CH2-;Z3为=O、=S或不存在;Ra和Rb独立地包括氢或C1~C3烷基;
R3包括 其中n=0或1;L包括=CH-或=N-;Rc包括氢、C1~C6烷基、C3~C6环烷基、C2~C6烯基或C2~C6卤代烯基;Rd包括氢或卤素;Re1包括氢、卤素、硝基、羟基、甲氧基、氨基、甲氨基或二甲氨基;Re2包括C1~C6烷基、C1~C6烷氧基、芳环基、杂环基、苯并杂环;所述R2和R3不相同;
R4包括 其中,A1包括-O-、-S-或-NH-,A2和A3独立地包括=CH-或=N-;D包括=CH-、=CH(CH3)-、
=CH(OCH3)-或=N-,E包括-CH2-、-CH2(CH3)-、-NH-或-O-;H1和H2独立地包括-O-、-S-、-CH2-或-NH-;G1包括-O-、-S-、-CH2-或-NH-;G2包括=CH-或=N-;J1包括=O、=NH或不存在;J2包括C1~C3烷基或C1~C3烷氧基;X包括-CH2-、-O-或-NH-;J3包括=O、-NH2或不存在;Rf、Rg和Rh独立地包括氢、卤素、硝基、羟基、甲氧基、氨基、甲氨基或二甲氨基,所述Rf、Rg和Rh的个数独立地为1或2;Ri包括氢、卤素、羟基、甲氧基、氨基、甲氨基或二甲氨基,所述Ri的个数为1或2;Rj包括羟甲基、氨基、甲氨基、二甲氨基、氰基、C1~C6烷基、C1~C6烷氧基、C1~C6卤代烷基、C1~C6氧代卤代烷基、C1~C6环烷基、C2~C6烯基、C3~C6环烯基、C1~C6烷氧基或C1~C6烷氧烯基
优选的,所述氧代亚乙基类化合物具有式I-1~I-16所示的结构中的任意一个:
优选的,所述药学上可接受的盐包括盐酸盐、硫酸盐、磷酸盐或马来酸盐。
本发明提供了上述技术方案所述的氧代亚乙基类化合物的制备方法,(i)式I中,当R4为且X为-O-或-NH-时,所述氧代亚乙基类化合物的制备方法包括以下步骤:
将化合物II-1、具有式III所示结构的胺衍生物和胺类催化剂混合,进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物;
化合物II-1,其中Rh与式I中相同,X为-O-或-NH-;
其中R1、R2、R3和M与式I中相同;
(ii)式I中,R4为除且X为-O-或-NH-之外的其他取代基时,所述氧代亚乙基类化合物的制备方法包括以下步骤:
将化合物II-2、具有式III所示结构的胺衍生物、碳化二亚胺盐酸盐、1-羟基苯并三唑和4-二甲氨基吡啶混合进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物;
化合物II-2,其中n=0或1。
优选的,所述化合物II-1的制备方法包括以下步骤:将R4H与对硝基苯基氯甲酸酯进行取代反应,得到化合物II-1;
所述R4H为
优选的,所述具有式III所示结构的胺衍生物的制备方法包括以下步骤:
将具有式a所示结构的化合物与具有式b所示结构的化合物进行亲核取代反应,得到具有式c所示结构的中间体;
将所述具有式c所示结构的中间体与戴斯-马丁氧化剂进行氧化反应,得到具有式d所示结构的中间体;
将所述具有式d所示结构的中间体与具有式e所示结构的化合物进行反应,得到具有式f所示结构的中间体;所述具有式e所示结构的化合物为具有式e-1、式e-2、式e-3或e-4所示结构的化合物;所述式f所示结构的中间体为具有式f-1、式f-2、式f-3或式f-4所示结构的化合物;
将所述具有式f所示结构的中间体进行脱保护基,得到具有式III所示结构的胺衍生物;
本发明提供了一种药物组合物,包括氧代亚乙基类化合物和/或其药学上可接受的盐以及药学上可接受的辅料;
所述氧代亚乙基类化合物为上述技术方案所述的氧代亚乙基类化合物或上述技术方案所述制备方法得到的氧代亚乙基类化合物。
优选的,所述药学上可接受的辅料包括载体、赋形剂、稀释剂、吸收促进剂、崩解剂、润滑剂、粘合剂、成栓剂、渗透压调节剂、着色剂、防腐剂、香料、矫味剂、助溶剂、缓冲剂和pH调节剂中的一种或几种。
优选的,所述药物组合物的剂型包括片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、栓剂或冻干粉针剂。
本发明提供了上述技术方案所述的氧代亚乙基类化合物或其药学上可接受的盐、上述技术方案所述制备方法制备得到的氧代亚乙基类化合物或其药学上可接受的盐、上述技术方案所述的药物组合物中的一种或几种在制备Sarbecovirus亚属冠状病毒3CL蛋白酶抑制剂或抗Sarbecovirus亚属冠状病毒药物中的应用。
优选的,所述Sarbecovirus亚属冠状病毒包括SARS-CoV或SARS-CoV-2。
本发明提供了一种氧代亚乙基类化合物或其药学上可接受的盐,所述氧代亚乙基类化合物具有式I所示的结构。本发明提供的氧代亚乙基类化合物或其药学上可接受的盐中,氧代亚乙基类化合物能够与广谱Sarbecovirus亚属冠状病毒的3CL蛋白酶产生氢键、π-π相互作用、疏水作用等多种形式的范德华作用力,从而具有明显的抑制3CL蛋白酶活性以及抗广谱Sarbecovirus亚属冠状病毒活性。毒性研究显示其毒性低、具有良好的成药性,表明该类化合物作为广谱Sarbecovirus亚属冠状病毒的3CL蛋白酶抑制剂和抗病毒药物具有良好的应用前景。实施例经初步药理活性测试可知,本发明提供的氧代亚乙基类化合物对SARS-CoV 3CLpro的IC50值为22~110nM,对SARS-CoV-23CLpro的IC50值为15~92nM,均在nM水平,说明对SARS-CoV和SARS-CoV-2的3CL蛋白酶均具有显著的抑制活性;对293T细胞的CC50值为153.3~321.2μM,细胞毒性低;对SARS-CoV的EC50值为0.052~0.92μM,对SARS-CoV-2的EC50值为0.066~0.73μM,具有显著的抗病毒活性。
本发明提供的氧代亚乙基类化合物或其药学上可接受的盐的制备方法,操作简单,产率高,适宜工业化生产。
本发明提供了一种药物组合物,包括氧代亚乙基类化合物和/或其药学上可接受的盐以及药学上可接受的辅料;所述氧代亚乙基类化合物为上述技术方案所述的氧代亚乙基类化合物或上述技术方案所述制备方法得到的氧代亚乙基类化合物。本发明提供的药物组合物中,氧代亚乙基类化合物具有明显的抑制3CL蛋白酶活性以及抗广谱Sarbecovirus亚属冠状病毒活性。毒性研究显示其毒性低、具有良好的成药性,从而使得药物组合物作为广谱Sarbecovirus亚属冠状病毒的3CL蛋白酶抑制剂和抗病毒药物具有良好的应用前景。
具体实施方式
本发明提供了一种氧代亚乙基类化合物或其药学上可接受的盐,所述氧代亚乙基类化合物具有式Ⅰ所示结构:
在本发明中,所述式I中,M为-CH2-、或不存在。
在本发明中,所述R1包括 C1~C6烷基、C3~C6环烷基或芳杂环取代基;所述C1~C6烷基优选包括甲基、乙基、丙基、丁基、异丁基、直链戊基、支链戊基、直链己基或支链己基;所述C3~C6环烷基优选包括环丙烷、环丁烷、环戊烷或环己烷;所述芳杂环取代基优选包括未取代或取代的苯基、吡啶基或萘基。在本发明中,所述取代的苯基中的取代基优选包括氟、氯、甲基、二氟甲基或三氟甲基。
在本发明中,所述R2包括 其中,Z包括-CH2-、-O-或-NH-;Z1和Z2独立地包括-O-、-NH-、或-CH2-;Z3为=O、=S或不存在;Ra和Rb独立地包括氢或C1~C3烷基;所述C1~C3烷基优选包括甲基、乙基或丙基。
在本发明中,所述R3包括
其中n=0或1;L包括=CH-或=N-;Rc包括氢、C1~C6烷基、C3~C6环烷基、C2~C6烯基或C2~C6卤代烯基;Rd包括氢或卤素;Re1包括氢、卤素、硝基、羟基、甲氧基、氨基、甲氨基或二甲氨基;Re2包括C1~C6烷基、C1~C6烷氧基、芳环基、杂环基、苯并杂环;所述R2和R3不相同;所述C1~C6烷基与C3~C6环烷基的取代基种类优选与前述C1~C6烷基与C3~C6环烷基相同,在此不再赘述;所述C2~C6烯基和C2~C6卤代烯基中的C2~C6烯基独立地优选包括乙烯、丙烯基、烯丙基、直链丁烯、支链丁烯、直链戊烯、支链戊烯、直链己烯或支链己烯;所述C1~C6烷氧基优选包括甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基或异戊氧基;所述卤素和C2~C6卤代烯基中的卤素独立地优选包括氟、氯、溴或碘;所述芳环基优选包括苯基或萘基;所述杂环基优选包括吡啶基、呋喃基、吡喃基、噻唑基、噻吩基、恶唑基、异恶唑基、嘧啶基或吡嗪基;所述苯并杂环优选包括吲哚基、苯并呋喃基、喹啉基、异喹啉基或苯并吡喃。
在本发明中,所述R4包括
其中,A1包括-O-、-S-或-NH-,A2和A3独立地包括=CH-或=N-(氮);D包括=CH-、=CH(CH3)-、=CH(OCH3)-或=N-,E包括-CH2-、-CH2(CH3)-、-NH-或-O-(氧);H1和H2独立地包括-O-、-S-、-CH2-或-NH-;G1包括-O-、-S-、-CH2-或-NH-;G2包括=CH-或=N-;J1包括=O、-NH-或不存在;J2包括C1~C3烷基或C1~C3烷氧基,所述C1~C3烷基优选包括甲基、乙基或丙基,所述C1~C3烷氧基优选包括甲氧基、乙氧基或丙氧基;X包括-CH2-、-O-或-NH-;Rf、Rg和Rh独立地包括氢、卤素、硝基、羟基、甲氧基、氨基、甲氨基或二甲氨基,所述Rf、Rg和Rh的个数独立地为1或2;Ri包括氢、卤素、羟基、甲氧基、氨基、甲氨基或二甲氨基,所述Ri的个数为1或2;Rj包括羟甲基、氨基、甲氨基、二甲氨基、氰基、C1~C6烷基、C1~C6烷氧基、C1~C6卤代烷基、C1~C6环烷基、C2~C6烯基、C3~C6环烯基、C1~C6烷氧基、C1~C6卤代烷氧基或C1~C6烷氧烯基;所述C1~C6烷基、C1~C6烷氧基、C2~C6烯基、C1~C6烷氧基、C3~C6环烷基的取代基种类优选与前述C1~C6烷基与C3~C6环烷基相同,在此不再赘述;所述C1~C6卤代烷基优选包括三氟甲基、三氟乙基、三氟甲氧基、氧代三氟甲基、二氟甲基、二氟乙基、二氟甲氧基或氧代二氟甲基;所述C3~C6环烯基优选包括环戊烯基、环己烯基或甲基环戊烯基;所述C1~C6烷氧烯基优选包括乙烯氧基、丙烯氧基、烯丙基氧基、丁烯氧基、异丁烯氧基、戊烯氧基、异戊烯氧基或己烯氧基。在本发明中,所述,Rf、Rg、Rh、Ri和C1~C6卤代烷基中的卤素独立地优选包括氟、氯、溴或碘。
在本发明中,所述氧代亚乙基类化合物具有式I-1~I-9所示的结构中的任意一个:
在本发明中,所述药学上可接受的盐优选包括盐酸盐、硫酸盐、磷酸盐或马来酸盐。在本发明中,所述氧代亚乙基类化合物的成盐部位为I-7中的吡啶氮原子、I-8中的吡咯氮原子、I-9中的二甲氨基氮原子、I-12中的吲哚氮原子等碱基官能团、I-10中的磺酸基、I-5和I-15中的磷酸羟基酸性官能团。
本发明提供了上述技术方案所述的氧代亚乙基类化合物的制备方法,所述式I中,当R4为且X为-O-或-NH-时,所述氧代亚乙基类化合物的制备方法包括以下步骤:
将化合物II-1、具有式III所示结构的胺衍生物和胺类催化剂混合,进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物;
化合物II-1,其中Rh与式I中相同,X为-O-或-NH-;
其中R1、R2、R3和M与式I中相同。
在本发明中,所述化合物II-1的制备方法优选包括以下步骤:将R4H与对硝基苯基氯甲酸酯进行取代反应,得到化合物II-1。在本发明的具体实施例中,优选将R4H、有机溶剂、催化剂和对硝基苯基氯甲酸酯混合,进行取代反应,得到化合物II-1。
在本发明中,所述R4H为
在本发明中,所述R4H中Rh与A3与所述式I中Rh与A3相同,在此不再赘述。在本发明中,所述R4H与对硝基苯基氯甲酸酯的摩尔比优选为1:(1.2~1.6),更优选为1:(1.15~1.55),最优选为1:(1.2~1.3)。在本发明中,所述有机溶剂优选包括二氯甲烷、四氢呋喃和乙腈中的一种或几种。在本发明中,所述R4H的物质的量与有机溶剂的体积之比优选为1mmol:(2~3)mL,更优选为1mmol:(2.1~2.8)mL,最优选为1mmol:(2.4~2.5)mL。在本发明中,所述催化剂优选包括吡啶和4-二甲氨基吡啶(DMAP)中的一种或两种。在本发明中,所述R4H与催化剂的摩尔比优选为1:(1.0~1.5),更优选为1:(1.1~1.3),最优选为1:1.1。
在本发明中,所述取代反应的温度优选为室温,时间优选为3~4h,更优选为3.5h。完成取代反应后,本发明优选将所得取代反应液进行后处理,所述后处理优选包括以下步骤:将取代反应液依次用饱和氯化铵溶液洗涤、饱和氯化钠溶液洗涤、无水硫酸钠干燥和浓缩,得到化合物II-1。本发明对于所述浓缩没有特殊限定,采用本领域技术人员熟知的浓缩方式即可浓缩至恒重即可,具体如减压浓缩。在本发明中,所述浓缩后无需纯化可直接进行下一步反应;或,将所述浓缩得到的浓缩物进行硅胶柱层析分离纯化,得到化合物II-1,然后再进行下一步反应。在本发明中,所述硅胶柱层析的洗脱剂优选为石油醚和乙酸乙酯的混合溶剂,所述混合溶剂中石油醚和乙酸乙酯的质量比优选为1:(7~11),更优选为1:(8~10),进一步优选为1:9。
所述具有式III1所示结构的胺衍生物的制备方法优选包括以下步骤:
将具有式a所示结构的化合物与具有式b所示结构的化合物进行亲核取代反应,得到具有式c所示结构的中间体;
将所述具有式c所示结构的中间体与戴斯-马丁氧化剂进行氧化反应,得到具有式d所示结构的中间体;
将所述具有式d所示结构的中间体与具有式e所示结构的化合物进行反应,得到具有式f所示结构的中间体;所述具有式e所示结构的化合物为具有式e-1、式e-2、式e-3或e-4所示结构的化合物;所述式f所示结构的中间体为具有式f-1、式f-2、式f-3或式f-4所示结构的化合物;
将所述具有式f所示结构的中间体进行脱保护基,得到具有式III所示结构的胺衍生物;
本发明将具有式a所示结构的化合物与具有式b所示结构的化合物进行亲核取代反应,得到具有式c所示结构的中间体。
在本发明中,所述具有式a所示结构的化合物与具有式b所示结构的化合物的摩尔比优选为1:(1.0~1.5),更优选为1:(1.2~1.3)。本发明对于所述具有式a所示结构的化合物与具有式b所示结构的化合物的来源没有特殊限定,采用本领域技术人员熟知的市售商品,具体如百灵威科技有限公司、伊诺凯科技有限公司或上海毕得医药有限公司。在本发明中,所述亲核取代优选在有机溶剂存在的条件下进行,所述有机溶剂优选为腈类溶剂,更优选为乙腈。在本发明中,所述亲核取代反应的温度优选为75~85℃,更优选为80℃;所述亲核取代反应的时间优选为5~7h,更优选为6h。完成所述亲核取代反应后,本发明优选将所得亲核取代液进行减压浓缩,将所得粗品进行硅胶柱层析分离纯化,得到具有式c所示结构的中间体。在本发明中,所述洗脱剂优选为石油醚与乙酸乙酯的混合溶剂,所述混合溶剂中石油醚与乙酸乙酯的体积比优选为2:1~1:1。
得到具有式c所示结构的中间体后,本发明将所述具有式c所示结构的中间体与戴斯-马丁氧化剂进行氧化反应,得到具有式d所示结构的中间体。
在本发明中,所述具有式c所示结构的中间体与戴斯-马丁氧化剂(Dess-Martin)的摩尔比优选为1:(1.1~1.5),更优选为1:(1.2~1.3)。在本发明中,所述氧化反应优选在有机溶剂存在的条件下进行,所述有机溶剂优选为无水卤代烃溶剂,更优选为无水二氯甲烷。在本发明中,所述氧化反应的温度优选为0~25℃,更优选为10~20℃,时间优选为0.5~1.5h,更优选为1h。完成所述氧化反应后,本发明优选在所得氧化反应液中加入饱和硫代硫酸钠溶液进行淬灭反应,卤代烃溶剂萃取,将所得有机相进行无水硫酸钠干燥,浓缩,将所得浓缩物进行硅胶柱层析分离纯化,得到具有式d所示结构的中间体。在本发明中,萃取用卤代烃溶剂优选为二氯甲烷,所述萃取的次数优选为2~4次,更优选为3次。在本发明中,所述硅胶柱层析分离纯化采用的洗脱剂优选石油醚与乙酸乙酯的混合溶剂,所述混合溶剂中石油醚与乙酸乙酯的体积比优选为4:1~3:1。
本发明将所述具有式d所示结构的中间体与具有式e所示结构的化合物进行反应,得到具有式f所示结构的中间体;所述具有式e所示结构的化合物为具有式e-1、式e-2、式e-3或e-4所示结构的化合物;所述式f所示结构的中间体为具有式f-1、式f-2、式f-3或式f-4所示结构的化合物。
本发明将所述具有式d所示结构的中间体与具有式e-1所示结构的化合物进行亲核取代反应,得到具有式f-1所示结构的中间体。
在本发明中,所述具有式d所示结构的中间体与具有式e-1所示结构的化合物的摩尔比优选为1:(1.0~1.2),更优选为1:1.1。在本发明中,所述亲核取代反应优选在有机溶剂和催化剂存在的条件下进行,所述有机溶剂优选为呋喃类溶剂,更优选为四氢呋喃;所述催化剂优选为N,N-二异丙基乙胺和4-二甲氨基吡啶。在本发明中,所述具有式d所示结构的中间体、N,N-二异丙基乙胺与4-二甲氨基吡啶的摩尔比优选为1:(1.1~1.3):(0.05~0.15),更优选为1:1.1:0.1。在本发明的具体实施例中,所述混合的顺序优选先将具有式d所示结构的中间体和呋喃类溶剂混合,然后在冰浴条件下加入催化剂、具有式e-1所示结构的化合物和呋喃类溶剂混合。在本发明中,所述亲核取代反应的温度优选为0℃,所述亲核取代反应的时间优选0.5~1h。在本发明的具体实施例中,优选通过TLC检测亲核取代反应的程度。完成所述亲核取代反应后,本发明优选还包括将所得亲核取代液减压浓缩除去THF,然后采用乙酸乙酯萃取,将萃取所得有机相进行浓缩,将浓缩所得粗品进行硅胶柱纯化,得到具有式f-1所示结构的中间体。在本发明中,所述硅胶柱纯化所采用的洗脱剂优选为乙酸乙酯和石油醚的混合溶剂,所述洗脱剂中乙酸乙酯和石油醚的体积比优选为1:(3~5),更优选为1:4。
本发明将所述具有式d所示结构的中间体与具有式e-2所示结构的化合物进行Abuzov反应,得到具有式f-2所示结构的中间体。
本发明优选将所述具有式d所示结构的中间体与具有式e-2所示结构的化合物和苯甲醇混合进行Arbuzov反应,得到具有式f-2所示结构的中间体。在本发明中,所述具有式e-2所示结构的化合物和具有式d所示结构的中间体的摩尔比优选为1:0.8~1,更优选为1:0.91。在本发明中,所述具有式d所示结构的中间体的物质的量与苯甲醇的体积之比优选为1mmol:0.8~1.2mL,更优选为1mmol:1mL。在本发明中,所述Arbuzov反应优选在有机溶剂和催化剂存在的条件下进行;所述有机溶剂优选为苯,所述催化剂选为N,N-二异丙基乙胺(DIEA)和1-H-四氮唑。在本发明的具体实施例中,优选将具有式e-2所示结构的化合物和1-H-四氮唑溶于苯,在冰浴条件下向所得混合溶液中依次滴加苯甲醇和N,N-二异丙基乙胺(DIEA),进行第一Arbuzov反应、第二Arbuzov反应、第三Arbuzov反应和第四Arbuzov反应;所述第一Arbuzov反应和第三Arbuzov反应的温度优选为-5~5℃,更优选为0℃,所述第一Arbuzov反应和第三Arbuzov反应优选在冰浴条件下进行;所述第一Arbuzov反应和第三Arbuzov反应的时间独立地优选为25~35min,更优选为30min;所述第二Arbuzov反应和第四Arbuzov反应的温度优选为20~35℃,更优选为室温(25℃),所述第二Arbuzov反应的时间优选为2~3h,更优选为2.5h;所述第四Arbuzov反应的时间优选为3~4h,更优选为3.5h。
完成所述Arbuzov反应后,本发明优采用反相柱色谱对所得Arbuzov反应物料进行分离纯化,得到具有式f-2所示结构的中间体。在本发明中,所述反相柱色谱的流动相优选为乙醇和水的混合溶剂,所述流动相中甲醇与水的体积比优选为(4~6):1,更优选为5:1。
本发明将所述具有式d所示结构的中间体与具有式e-3所示结构的化合物进行亲核取代反应,得到具有式f-3所示结构的中间体。
在本发明中,所述亲核取代反应优选在有机溶剂和催化剂存在的条件下进行,所述有机溶剂优选为四氢呋喃、二氯甲烷、甲醇和乙腈中的一种或几种,所述催化剂优选为N,N-二异丙基乙胺。在本发明中,所述具有式d所示结构的中间体、具有式e-3所示结构的化合物和催化剂的摩尔比优选为1:(1.05~1.15):(1.05~1.15),更优选为1:1.1:1.1。在本发明的具体实施例中,优选先将具有式d所示结构的中间体和有机溶剂混合,然后在冰浴条件下加入催化剂和具有式e-3所示结构的化合物,进行亲核取代反应。在本发明中,所述亲核取代反应的温度优选为冰浴(0℃),所述亲核取代反应的时间优选0.5~1h;在本发明的具体实施例中优选通过TLC检测亲核取代反应的程度。完成所述亲核取代反应后,本发明优选将所得亲核取代反应液减压浓缩除去THF,然后采用乙酸乙酯萃取,将萃取所得有机相进行浓缩,将浓缩所得粗品进行硅胶柱纯化,得到具有式f-3所示结构的中间体。在本发明中,所述硅胶柱纯化所采用的洗脱剂优选为乙酸乙酯和石油醚的混合溶剂,所述洗脱剂中乙酸乙酯和石油醚的体积比优选为1:(1.5~3),更优选为1:(2~2.5)。
本发明将所述具有式d所示结构的中间体与具有式e-4所示结构的化合物进行亲核取代反应,得到具有式f-4所示结构的中间体。
在本发明中,所述亲核取代反应优选在有机溶剂和催化剂存在的条件下进行,所述有机溶剂优选为N,N-二甲基甲酰胺(DMF)、无水二氯甲烷和无水四氢呋喃中的一种或几种,所述催化剂优选为碳化二亚胺盐酸盐、1-羟基苯并三唑和4-二甲氨基吡啶。在本发明中,所述具有式d所示结构的中间体、具有式e-4所示结构的化合物、碳化二亚胺盐酸盐、1-羟基苯并三唑和4-二甲氨基吡啶的摩尔比优选为1:(1.05~1.25):(1.2~2.0):(1.05~1.2):(0.05~0.15),更优选为1:1.1:1.5:1.1:0.2。在本发明的具体实施例中,优选将具有式d所示结构的化合物、具有式e-4所示结构的化合物和有机溶剂混合,在冰浴条件和保护气氛下向所得混合溶液中加入碳化二亚胺盐酸盐和1-羟基苯并三唑混合,进行第一亲核取代反应,然后加入4-二甲氨基吡啶混合进行第二亲核取代反应,得到具有式f-4所示结构的中间体。在本发明中,所述第一亲核取代反应的温度优选为0℃,时间优选为0.5~2h,更优选为1h;所述第二亲核取代反应的温度优选为室温,时间优选为1~3h,更优选为2h。
完成所述亲核取代反应后,本发明优选还包括后处理,所述后处理优选包括:将所得亲核取代反应液进行减压浓缩去除DMF,将所得残余物与水混合,采用乙酸乙酯对所得混合物进行萃取,将所得有机相用无水硫酸钠干燥,将干燥后的有机相进行浓缩,将所得粗品进行硅胶制备薄层层析分离纯化,得到具有式f-4所示结构的化合物。在本发明中,所述硅胶制备薄层层析分离纯化采用的洗脱剂优选为乙酸乙酯与石油醚的混合溶剂,所述洗脱剂中乙酸乙酯与石油醚的体积比优选为(2~4):1,更优选为3:1。
得到具有式f所示结构的中间体后,本发明将所述具有式f所示结构的中间体进行脱保护基,得到具有式III所示结构的胺衍生物。
在本发明中,所述脱保护基优选在有机溶剂和催化剂存在的条件下进行,所述有机溶剂优选为CH2Cl2,所述催化剂优选为三氟乙酸。在本发明中,所述式f所示结构的中间体的物质的量与有机溶剂体积和催化剂的体积之比优选为1mmol:1~1.5mL:1~1.5mL,更优选为1mmol:1.25mL:1.25mL。在本发明中,所述脱保护基反应的温度优选为25~35℃,更优选为室温;所述脱保护基反应的时间优选为2~4h,更优选为3h。完成所述脱保护基反应后,本发明优选将所得脱保护基反应液进行浓缩,然后调节pH值至中性,二氯甲烷萃取,无水硫酸钠干燥,浓缩,将所得粗品进行硅胶柱层析分离纯化,得到具有式III所示结构的中间体。本发明对于所述浓缩没有特殊限定,采用本领域技术人员熟知的浓缩方式即可,具体如减压浓缩。在本发明中,所述调节pH值优选利用饱和碳酸氢钠溶液进行。在本发明中,所述柱层析分离所采用的洗脱剂优选为CH2Cl2和MeOH,所述洗脱剂中CH2Cl2和MeOH的体积比优选为(10~15):1,更优选为12:1。
得到化合物II-1和具有式III所示结构的胺衍生物后,本发明将化合物II-1、具有式III所示结构的胺衍生物和胺类催化剂混合,进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物。
在本发明中,所述化合物II-1与具有式III所示结构的胺衍生物的摩尔比优选为1:(0.8~1.0),更优选为1:(0.85~0.95),最优选为1:0.9。在本发明中,所述胺类催化剂优选为N,N-二异丙基乙胺。在本发明中,所述化合物II-1与胺类催化剂的摩尔比优选为1:(1.5~2.5),更优选为1:(1.7~2.2),最优选为1:(1.8~2)。在本发明中,所述缩合反应优选在有机溶剂存在条件下进行;所述有机溶剂优选为无水N,N-二甲基甲酰胺。在本发明中,所述化合物II-1的物质的量与有机溶剂的体积比优选为1mmol:(6~7)mL,更优选为1mmol:(6.2~6.8)mL,最优选为1mmol:(6.5~6.7)mL。
在本发明的具体实施例中,优选将化合物II-1、具有式III所示结构的胺衍生物、有机溶剂和胺类催化剂混合,进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物。在本发明中,所述缩合反应的温度优选为室温,所述缩合反应的时间优选为4.5~5.5h,更优选为5h。
完成缩合反应后,本发明优选还包括后处理,所述后处理优选包括:在所得缩合反应液中加入乙酸乙酯稀释反应液,然后依次用水、饱和氯化钠溶液进行洗涤,将所得有机相用无水硫酸钠干燥后浓缩,将所得浓缩物进行硅胶柱层析分离纯化,得到具有式I所示结构的氧代亚乙基类化合物。本发明对于所述浓缩没有特殊限定,采用本领域技术人员熟知的浓缩方式即可,具体如减压浓缩。在本发明中,所述硅胶柱层析分离纯化采用的洗脱剂优选为石油醚和乙酸乙酯的混合溶剂;所述洗脱剂中石油醚和乙酸乙酯的体积比优选为1:(4~8),更优选为1:(5~6)。
本发明提供了上述技术方案所述的氧代亚乙基类化合物的制备方法,所述式I中,R4为除且X为-O-或-NH-之外的其他取代基(即R4为/> 且X为-CH2)时,所述氧代亚乙基类化合物的制备方法包括以下步骤:
将化合物II-2、具有式III所示结构的胺衍生物、碳化二亚胺盐酸盐、1-羟基苯并三唑和4-二甲氨基吡啶混合进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物;
化合物II-2,其中n=0或1。
本发明对于所述化合物II-2的来源没有特殊限定,采用本领域技术人员熟知的市售商品或本领域技术人员熟知的制备方法制备得到均可。
在本发明中,所述化合物II-2、具有式III所示结构的胺衍生物、碳化二亚胺盐酸盐、1-羟基苯并三唑(HOBt)和4-二甲氨基吡啶(DMAP)的摩尔比优选为1:(1.0~1.1):(1.4~1.6):(1.0~1.2):(0.19~0.21),更优选为1:1.05:1.5:1.1:0.2。在本发明中,所述碳化二亚胺盐酸盐优选为1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(EDCI)。在本发明中,所述缩合反应优选在有机溶剂存在的条件下进行;本发明对于所述有机溶剂的种类没有特殊的限定,采用本领域技术人员熟知的能够使缩合反应顺利进行的有机溶剂即可,具体如二甲基甲酰胺(DMF)。
在本发明的具体实施例中,优选将化合物II-2、具有式III所示结构的胺衍生物和有机溶剂混合,在冰浴和保护气氛下向所得混合溶液中加入碳化二亚胺盐酸盐和1-羟基苯并三唑混合进行第一缩合反应,然后加入4-二甲氨基吡啶进行第二缩合反应,得到具有式I所示结构的氧代亚乙基类化合物。本发明对于所述保护气氛没有特殊限定,采用本领域技术人员熟知的保护气氛即可,具体如氩气或氦气。在本发明中,所述第一缩合反应的温度优选为室温,时间优选为0.5~1.5h,更优选为1h。在本发明中,所述第二缩合反应的温度优选为室温,时间优选为1.5~2.5h,更优选为2h。在本发明中,所述缩合反应过程中发生的反应如下:
完成所述缩合反应后,本发明优选还包括后处理,所述后处理优选包括:将所得缩合反应液进行减压浓缩去除DMF,将所得残余物与水混合,采用乙酸乙酯对所得混合物进行萃取,将所得有机相用无水硫酸钠干燥,将干燥后的有机相进行浓缩,将所得粗品进行硅胶制备薄层层析分离纯化,得到具有式I所示结构的氧代亚乙基类化合物。在本发明中,所述硅胶制备薄层层析分离纯化采用的洗脱剂优选为乙酸乙酯与甲醇的混合溶剂,所述洗脱剂中乙酸乙酯与甲醇的体积比优选(8~12):1,更优选为10:1。
在本发明中,所述氧代亚乙基类化合物的药学上可接受的盐的制备方法优选包括以下步骤:将氧代亚乙基类化合物溶于甲醇或乙醇中,加入过量的盐酸或马来酸等酸,析出固体,过滤,收集滤饼。
本发明提供了一种药物组合物,包括上述技术方案所述的氧代亚乙基类化合物或其药学上可接受的盐和药学上可接受的辅料。
本发明提供了一种药物组合物,包括氧代亚乙基类化合物和/或其药学上可接受的盐以及药学上可接受的辅料;
所述氧代亚乙基类化合物为上述技术方案所述的氧代亚乙基类化合物或上述技术方案所述制备方法得到的氧代亚乙基类化合物。
在本发明中,所述药学上可接受的辅料优选包括载体、赋形剂、稀释剂、吸收促进剂、崩解剂、润滑剂、粘合剂、成栓剂、渗透压调节剂、着色剂、防腐剂、香料、矫味剂、助溶剂、缓冲剂和pH调节剂中的一种或几种。在本发明中,所述载体优选包括水溶性载体、难溶性载体和肠溶性载体中的一种或几种,更优选为水溶性载体;所述水溶性载体优选包括聚乙二醇、聚乙烯吡咯烷酮和有机酸中的一种或几种,所述有机酸优选包括枸橼酸、酒石酸、琥珀酸、胆酸和去氧胆酸中的一种或几种;所述难溶性载体优选包括乙基纤维素和/或胆固醇硬脂酸酯;所述肠溶性载体优选包括醋酸纤维素酞酸酯和/或羧甲乙纤维素。在本发明中,所述赋形剂优选包括黏合剂、填充剂、崩解剂和润滑剂中的一种或几种。在本发明中,所述稀释剂和吸收促进剂独立地优选包括淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土和滑石粉中的一种或几种。在本发明中,所述湿润剂与粘合剂独立地优选包括水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖、液糖、阿拉伯胶、明胶、紫胶、黄蓍胶、羧甲基纤维素钠、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮、米糊或面糊中的一种或几种。在本发明中,所述崩解剂优选包括淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素和乙基纤维素中的一种或几种。在本发明中,所述崩解抑制剂优选包括蔗糖、三硬脂酸甘油酯、可可脂和氢化油中的一种或几种。在本发明中,所述润滑剂优选包括滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡和聚乙二醇中的一种或几种。在本发明中,所述吸收促进剂优选包括季铵盐和十二烷基硫酸钠中的一种或两种。在本发明中,所述成栓剂优选包括肛门栓、阴道栓、尿道栓和牙用栓中的一种或几种。在本发明中,所述渗透压调节剂优选包括氯化钠、葡萄糖和甘油中的一种或几种。
在本发明中,所述药物组合物的剂型优选包括片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、栓剂或冻干粉针剂。在本发明中,当所述剂型为片剂时,所述辅料优选包括稀释剂、吸收剂、湿润剂、粘合剂、崩解剂、崩解抑制剂、润滑剂和吸收促进剂。在本发明中,所述片剂优选包括包衣片、单层片、双层片或多层片,所述包衣片优选包括糖包衣片、薄膜包衣片或肠溶包衣片。在本发明中,当所述剂型为丸剂时,所述辅料优选包括稀释剂、吸收剂、粘合剂和崩解剂。在本发明中,当所述剂型为栓剂时,所述辅料优选包括聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶和半合成甘油酯中的一种或几种。在本发明中,当所述剂型为溶液剂、乳剂、冻干粉针剂或混悬剂时,所述辅料优选包括稀释剂,所述稀释剂优选包括水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇和聚氧乙烯山梨醇脂肪酸酯中的一种或几种。在本发明中,当所述述剂型为等渗注射液时,所述辅料优选包括渗透压调节剂、助溶剂、缓冲剂和pH调节剂。
本发明提供了上述技术方案所述的氧代亚乙基类化合物或其药学上可接受的盐、上述技术方案所述制备方法制备得到的氧代亚乙基类化合物或其药学上可接受的盐、上述技术方案所述的药物组合物中的一种或几种在制备Sarbecovirus亚属冠状病毒3CL蛋白酶抑制剂或抗Sarbecovirus亚属冠状病毒药物中的应用。在本发明中,所述Sarbecovirus亚属冠状病毒包括SARS-CoV或SARS-CoV-2。在本发明中,所述Sarbecovirus亚属冠状病毒3CL蛋白酶抑制剂或抗Sarbecovirus亚属冠状病毒药物的给药方式优选包括口服、外敷、输液、注射给药、腔道给药或呼吸道给药;所述注射给药优选包括皮下注射、静脉注射、肌肉注射、关节内注射或腔内注射;所述腔道给药优选包括直肠给药或阴道给药;所述呼吸道给药优选包括口腔给药、鼻腔给药或粘膜给药。
在本发明中,所述氧代亚乙基类化合物或其药学上可接受的盐在Sarbecovirus亚属冠状病毒3CL蛋白酶抑制剂和抗Sarbecovirus亚属冠状病毒药物中的剂量为0.01~0.50mg/g,更优选为0.02~0.4mg/g。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
1)(S)-2-((叔丁基二甲基硅烷基)氧基)丙胺(中间体2)的合成:将(S)-2-羟基丙胺(1,13.31mmol)和三乙胺(26.62mmol)溶于10mL二氯甲烷中,置于冰浴条件下(0℃)搅拌。将叔丁基二甲基氯硅烷(13.31mmol)(毕得医药有限公司)溶于10mL二氯甲烷中,缓慢滴加入上述反应液中,加毕,转移至室温反应过夜。反应结束后,用10mL饱和氯化铵水溶液淬灭反应,二氯甲烷萃取3次(3×20ml)。合并有机相,用200mL饱和食盐水洗涤,有机相用无水硫酸钠干燥,浓缩,蒸干后得到无色油状液体即为中间体2(2.29g,收率为91%)。中间体2的LC-MS(ESI,M+H+)m/z 190.3。1H NMR(600MHz,CD3OD)δ3.89-3.84(m,1H),2.62(dd,J=12.6,4.2Hz,1H),2.55(dd,J=12.6,6.6Hz,1H),1.13(d,J=6.0Hz,3H),0.91(s,9H),0.10(s,6H);13C NMR(151MHz,CD3OD)δ70.5,50.0,26.5,21.7,19.0,-4.04,-4.41.
2)叔丁基-((2S,3R)-4-(((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)氨基)-3-羟基-1-苯基丁基-2-基)氨基甲酸酯(中间体3)的合成:将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷(9.65mmol)溶于15mL乙腈中,室温搅拌状态下滴加入中间体2(11.58mmol)。滴加完毕,回流反应6小时,减压浓缩反应溶剂。粗品采用硅胶柱层析进行分离纯化,洗脱剂石油醚-乙酸乙酯2:1至1:1,得到白色粉末固体,即叔丁基-((2S,3R)-4-(((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)氨基)-3-羟基-1-苯基丁基-2-基)氨基甲酸酯(中间体3)(3.62g,收率为83%)。中间体3的LC-MS(ESI,M+H+)m/z 453.3。1H NMR(500MHz,CDCl3)δ7.39(d,J=7.0Hz,2H),7.23-7.19(m,2H),5.58(d,J=8.0Hz,1H),4.36(dd,J=6.5,5.5Hz,1H),3.94(qt,J=6.0,4.0Hz,1H),3.79(s,1H),3.71-3.68(m,2H),2.99(ddd,J=13.5,6.5,4.0Hz,1H),2.93-2.82(m,2H),2.76(ddd,J=13.5,6.5,4.5Hz,1H),2.69(ddd,J=12.5,5.5,4.0Hz,1H),2.60(dd,J=14.0,6.5Hz,1H),1.25(s,9H),1.09(d,J=6.0Hz,3H),0.87(s,7H),0.05(s,4H);13C NMR(125MHz,CDCl3)δ156.5,137.8,130.0,129.1,127.5,79.7,71.3,68.6,56.9,55.8,52.4,36.7,28.4,25.9,21.6,18.2,-4.44。
3)叔丁基-((S)-4-(((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)氨基)-3-氧代-1-苯基丁基-2-基)氨基甲酸酯(中间体4)的合成:将中间体3(6.64mmol)溶于50mL无水二氯甲烷中,置于冰浴下搅拌。在氩气保护下缓慢加入戴斯-马丁氧化剂(7.97mmol)。加料完毕后,转移至室温反应1小时,用饱和硫代硫酸钠溶液淬灭反应,二氯甲烷萃取3次(3×50ml)。合并有机相,用无水硫酸钠干燥,有机相浓缩后采用硅胶柱层析进行分离纯化,洗脱剂石油醚-乙酸乙酯4:1至3:1,得到白色粉末固体,即中间体4(2.84g,收率为95%)。中间体4的LC-MS(ESI,M+H+)m/z 451.3。1H NMR(500MHz,CD3OD)δ7.23-7.19(m,5H),5.49(d,J=7.5Hz,1H),4.44(dt,J=8.0,6.5Hz,1H),3.93(qt,J=6.0,4.0Hz,1H),3.56-3.47(m,2H),3.44-3.36(m,1H),3.08(dd,J=14.0,6.5Hz,1H),2.95-2.86(m,1H),2.83(dd,J=14.0,6.5Hz,1H),2.75-2.66(m,1H),1.25(s,9H),1.09(d,J=6.0Hz,3H),0.87(s,7H),0.05(s,4H);13CNMR(125MHz,CD3OD)δ207.7,155.7,137.7,129.6,128.9,127.2,79.9,68.4,60.1,57.2,56.2,37.9,28.4,25.9,21.6,18.1,-4.44。
4)叔丁基-((S)-4-((N-((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)-2-氯-4-硝基苯基)磺酰胺基)-3-氧代-1-苯基丁基-2-基)氨基甲酸酯(中间体5)的合成:将中间体4(4.95mmol)、四氢呋喃(THF,15mL)加入100mL茄形瓶中,冰浴下缓慢加入N,N-二异丙基乙胺(DIEA,5.45mmol)和4-二甲氨基吡啶(DMAP,0.50mmol),随后加入2-氯-4-硝基苯磺酰氯(5.45mmol)和THF(4mL)的混合溶液。冰浴下搅拌反应0.5小时后移至室温。TLC检测反应完毕后,减压浓缩除去THF,乙酸乙酯萃取(3×15mL),有机相用无水硫酸钠干燥,浓缩。粗品经硅胶柱层析纯化(洗脱剂为石油醚-乙酸乙酯4:1)后得白色固体,即中间体5(2.81g,收率为85%)。中间体5的LC-MS(ESI,M+H+)m/z 670.5。1H NMR(500MHz,CDCl3)δ8.41(s,1H),8.19(dd,J=10.5,2.0Hz,1H),8.03(d,J=10.5Hz,1H),7.25-7.19(m,5H),5.42(d,J=8.0Hz,1H),4.49(dt,J=8.0,6.5Hz,1H),4.27(qt,J=6.5,5.0Hz,1H),4.00(d,J=15.0Hz,1H),3.89(d,J=15.0Hz,1H),3.36(dd,J=12.5,5.0Hz,1H),3.10-3.03(m,2H),2.82(dd,J=14.0,6.5Hz,1H),1.26(s,9H),1.16(d,J=6.5Hz,3H),0.87(s,7H),0.05(s,4H);13C NMR(125MHz,CDCl3)δ201.1,155.7,153.6,139.6,137.7132.3,130.4,129.5,128.9,127.2,126.0,122.8,79.9,67.3,58.2,56.3,51.7,37.8,28.4,25.9,21.7,18.1,-4.45。
5)N-((S)-3-氨基-2-氧代-4-苯基丁基)-2-氯-N-((S)-2-羟丙基)-4-硝基苯磺酰胺(中间体6)的合成:将中间体5(4.0mmol)加入到50mL茄形瓶中,室温下加入5mL CH2Cl2和5mL三氟乙酸。加毕,室温反应3小时。反应完毕后用饱和碳酸氢钠溶液中和反应液,用二氯甲烷萃取3次(3×10mL),合并有机相,用无水硫酸钠干燥,浓缩溶剂,粗品采用硅胶柱层析进行分离纯化,洗脱剂为二氯甲烷-甲醇12:1,得到白色粉末固体,即中间体6(1.27g,收率为70%)。中间体6的LC-MS(ESI,M+H+)m/z 456.3。1H NMR(500MHz,CD3OD)δ8.41(d,J=2.0Hz,1H),8.19(dd,J=10.5,2.0Hz,1H),8.03(d,J=10.5Hz,1H),7.31-7.18(m,4H),4.02-3.96(m,2H),3.99-3.90(m,3H),3.84(d,J=15.0Hz,1H),3.35(dd,J=13.0,5.5Hz,1H),3.12-3.04(m,3H),2.88(dd,J=14.5,6.0Hz,1H),1.24(d,J=7.0Hz,3H);13C NMR(125MHz,CD3OD)δ202.1,153.6,139.6,137.4,132.3,130.4,129.7,129.2,127.5,125.9,122.9,65.2,60.1,56.2,52.0,39.0,20.1。
6)(E)-N-((S)-4-((2-氯-N-((S)-2-羟丙基)-4-硝基苯基)磺酰胺基)-3-氧代-1-苯基丁基-2-基)-3-(3,4-二羟基苯基)丙烯酰胺(I-1,化合物1)的合成:将(E)-3-(3.4-二羟基苯基)丙烯酸(0.10mmol)和中间体6(0.10mmol)溶于2mL无水N,N-二甲基甲酰胺(DMF)中,降温至0℃,在氩气保护下缓慢加入1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(EDCl,0.15mmol),1-羟基苯并三唑(HOBt,0.11mmol),在0℃下继续搅拌10分钟,然后转移至室温反应1小时,加入4-二甲氨基吡啶(DMAP,0.020mmol),继续反应2小时。减压蒸除溶剂,加入4mL水,用乙酸乙酯(3×4mL)萃取,合并有机相,无水Na2SO4干燥,浓缩,采用硅胶柱层析进行分离纯化(所采用的洗脱剂为乙酸乙酯-甲醇15:1),得到白色粉末固体,即化合物1(0.053g,收率为86%)。化合物1:LC-MS(ESI,M+H+)m/z 618.4。1H NMR(500MHz,CD3OD)δ8.60(s,1H),8.41(d,J=2.0Hz,1H),8.19(dd,J=10.5,2.0Hz,1H),8.03(d,J=10.5Hz,1H),7.31-7.27(m,1H),7.25-7.21(m,3H),7.23-7.19(m,1H),6.90-6.88(m,2H),6.83-6.75(m,2H),6.68(d,J=16.5Hz,1H),6.51(d,J=9.0Hz,1H),4.43(dt,J=9.0,6.5Hz,1H),4.08-3.96(m,2H),3.88(d,J=15.0Hz,1H),3.40(dd,J=13.0,5.5Hz,1H),3.18-3.09(m,2H),3.07(d,J=5.5Hz,1H),2.87(ddt,J=14.0,6.5,1.0Hz,1H),1.24(d,J=6.5Hz,3H);13CNMR(125MHz,CD3OD)δ201.5,166.7,153.6,148.4,147.1,142.2,139.6,137.9,132.3,130.4,129.5,129.1,128.9,127.2,126.0,122.9,122.5,121.1,116.4,115.0,65.2,57.7,56.2,51.5,37.8,20.1.
实施例2
1)叔丁基-((2S,3R)-4-(((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)氨基)-1-(3-氟苯基)-3-羟基丁基-2-基)氨基甲酸酯(中间体7)的合成:中间体7的合成与实施例1中中间体3的合成类似,区别仅在于将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-(3-氟苯基)丁烷,得到中间体7(2.57g,收率为85%)。中间体7的LC-MS(ESI,M+H+)m/z471.5。1H NMR(500MHz,CDCl3)δ7.29-7.22(m,1H),7.11-7.06(m,2H),7.00-6.92(m,1H),5.62-5.54(m,1H),4.36(dd,J=6.5,5.5Hz,1H),3.94(dd,J=6.0,4.0Hz,1H),3.72-3.69(m,3H),3.15(dd,J=13.5,6.5Hz,1H),2.99(ddd,J=13.5,6.5,4.0Hz,1H),2.94-2.85(m,2H),2.76(ddd,J=13.5,6.5,4.0Hz,1H),2.69(ddd,J=12.5,5.5,4.0Hz,1H),1.25(s,9H),1.09(d,J=6.0Hz,3H),0.87(s,7H),0.05(s,4H);13C NMR(125MHz,CDCl3)δ164.4,162.5,156.5,139.7,139.6,130.4,130.3,124.6,124.5,116.6,116.4,114.3,114.1,79.7,71.2,68.6,56.9,55.9,52.3,37.1,37.0,28.4,25.9,21.6,18.2,-4.44。
2)叔丁基-((S)-4-(((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)氨基)-3-氧代-1-(3-氟苯基)丁基-2-基)氨基甲酸酯(中间体8)的合成:中间体8的合成方法与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体7,得到中间体8(1.64g,收率为90%)。中间体8的LC-MS(ESI,M+H+)m/z 469.4。1H NMR(500MHz,CDCl3)δ7.31-7.24(m,1H),7.06(dd,J=8.0,2.0Hz,1H),7.00-6.93(m,2H),5.49(d,J=7.5Hz,1H),4.49(dt,J=8.0,6.5Hz,1H),3.93(qt,J=6.0,4.0Hz,1H),3.56-3.47(m,2H),3.44-3.36(m,1H),3.10(dd,J=13.5,6.5Hz,1H),2.89-2.82(m,2H),2.71-2.65(m,1H),1.25(s,9H),1.09(d,J=6.0Hz,3H),0.87(s,7H),0.05(s,4H);13C NMR(125MHz,CDCl3)δ207.7,165.5,163.5,155.7,139.0,138.9,130.5,130.4,125.2,125.1,116.7,116.5,114.3,114.1,79.8,68.4,60.2,57.2,56.2,37.7,37.6,28.4,25.9,21.6,18.2,-4.44。
3)叔丁基-((S)-4-((4-溴-N-((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)苯基)磺酰胺基)-1-(3-氟苯基)-3-氧代丁基-2-基)氨基甲酸酯(中间体9)的合成:中间体9的合成与实施例1中中间体5的合成类似,区别仅在于将2-氯-4-硝基苯磺酰氯替换为4-溴苯磺酰氯,将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-(3-氟苯基)丁烷,得到中间体9(1.58g,收率为83%)。中间体9的LC-MS(ESI,M+H+)m/z 687.3。1H NMR(500MHz,CDCl3)δ7.81-7.70(m,4H),7.31-7.24(m,1H),7.06(dd,J=8.0,2.0Hz,1H),7.00-6.93(m,2H),5.42(d,J=8.0Hz,1H),4.54(dt,J=8.0,6.5Hz,1H),4.27(qt,J=6.5,5.0Hz,1H),3.95(d,J=15.0Hz,1H),3.84(d,J=15.5Hz,1H),3.35(dd,J=12.5,5.0Hz,1H),3.14-3.05(m,2H),2.84(dd,J=13.5,6.5Hz,1H),1.25(s,9H),1.16(d,J=6.5Hz,3H),0.87(s,7H),0.05(s,4H);13C NMR(125MHz,CDCl3)δ201.1,165.4,163.5,155.7,139.0,138.9,137.8,132.4,130.5,130.4,129.2,129.1,125.2,125.1,116.7,116.5,114.2,114.1,79.9,67.3,58.3,56.3,51.7,37.8,37.7,28.4,25.9,21.7,18.2,-4.45。
4)叔丁基-((S)-4-((S)-2-((叔丁基二甲基硅烷基)氧基)丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧合硼-2-基)苯基)磺酰胺基)-1-(3-氟苯基)-3-氧代丁基-2-基)氨基甲酸酯(中间体10)的合成:将中间体9(4.72mmol)、醋酸钾(14.16mmol)、双(频哪醇合)二硼(27.80mmol)和[1,1-双(二苯基磷)二茂铁]二氯化钯(0.472mmol)置于干燥的三口瓶中。减压抽真空,并用氮气置换5次。加入50mL新鲜制备的脱除空气的1,4-二氧六环,反应体系加热至80℃,并在氩气保护下搅拌反应24小时。反应结束后减压抽滤,滤液浓缩后用硅胶柱层析进行分离纯化,洗脱剂为石油醚-乙酸乙酯2:1,得到白色粉末固体,即中间体10(3.85g,收率为90%)。中间体10的LC-MS(ESI,M+H+)m/z 735.4。1H NMR(500MHz,CD3OD)δ7.86-7.80(m,1H),7.73-7.67(m,1H),7.31-7.24(m,1H),7.06(dd,J=8.0,2.0Hz,1H),7.00-6.93(m,2H),5.42(d,J=8.0Hz,1H),4.54(dt,J=8.0,6.5Hz,1H),4.27(qt,J=6.5,5.0Hz,1H),3.94(d,J=15.0Hz,1H),3.82(d,J=15.5Hz,1H),3.35(dd,J=12.5,5.0Hz,1H),3.14-3.05(m,2H),2.84(dd,J=14.0,6.5Hz,1H),1.23(s,9H),1.16(d,J=6.5Hz,2H),0.87(s,5H),0.05(s,3H);13C NMR(125MHz,CD3OD)δ201.1,165.5,163.5,155.6,141.6,139.0,138.9,135.3,130.5,130.4,126.0,125.2,125.1,116.7,116.5,114.3,114.1,84.0,79.8,67.3,58.3,56.3,51.7,37.8,37.7,28.3,25.9,24.8,21.7,18.1,-4.45。
5)、N-((S)-3-氨基-4-(3-氟苯基)-2-氧代丁基)-N-((S)-2-羟丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧合硼-2-基)苯磺酰胺(中间体11)的合成:中间体11的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体10,得到中间体10(2.52g,收率为66%)。中间体11的LC-MS(ESI,M+H+)m/z 521.3。1H NMR(500MHz,CD3OD)δ7.86-7.80(m,2H),7.73-7.67(m,2H),7.31-7.23(m,1H),7.07(dd,J=8.0,2.0Hz,1H),7.01-6.92(m,2H),4.08-3.97(m,2H),3.93(d,J=6.5Hz,2H),3.87(d,J=15.0Hz,1H),3.75(d,J=15.0Hz,1H),3.31(dd,J=13.0,5.5Hz,1H),3.13(dd,J=14.5,6.0Hz,1H),3.06(dd,J=13.0,5.5Hz,2H),2.88(dd,J=14.5,6.0Hz,1H),1.24(d,J=7.0Hz,3H),1.23(s,12H);13CNMR(125MHz,CD3OD)δ202.1,165.4,163.5,141.7,138.9,138.8,135.2,130.4,130.3,126.1,125.3,125.3,116.7,116.5,114.2,114.1,84.0,65.2,60.2,56.2,52.1,38.9,24.8,20.1。
6)(E)-3-(3,4-二羟基苯基)-N-((S)-1-(3-氟苯基)-4-(N-(S)-2-羟丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧合硼-2-基)苯基)磺酰胺基)-3-氧代丁基-2-基)丙烯酰胺(中间体12)的合成:中间体12的合成与实施例1中化合物1的合成类似,区别仅在于将中间体6替换为中间体11,得到中间体12(0.35g,收率为71%)。中间体12的LC-MS(ESI,M+H+)m/z683.5。1H NMR(500MHz,CD3OD)δ8.48(s,1H),7.86-7.80(m,2H),7.73-7.67(m,2H),7.31-7.21(m,1H),7.06(dd,J=8.0,2.0Hz,1H),7.00-6.93(m,2H),6.88(d,J=2.0Hz,2H),6.82-6.76(m,2H),6.69(d,J=16.5Hz,1H),6.51(d,J=9.0Hz,1H),4.51(dt,J=9.0,6.5Hz,1H),4.08-3.93(m,2H),3.85(d,J=15.5Hz,1H),3.31(dd,J=13.0,5.5Hz,1H),3.10-3.06(m,1H),3.09-3.02(m,2H),2.84(dd,J=13.5,6.5Hz,1H),1.24(d,J=7.0Hz,3H),1.23(s,12H);13C NMR(125MHz,CD3OD)δ201.5,166.7,165.4,163.5,148.4,147.1,142.2,141.7,139.4,139.3,138.9,135.2,130.5,130.4,129.1,126.0,125.2,125.1,122.6,120.8,116.7,116.5,116.4,115.0,114.3,114.1,84.0,65.2,57.2,56.2,51.7,37.7,24.8,20.1。
7)4-(N-((S)-3-((E)-3-(3,4-二羟基苯基)丙烯酰胺基)-4-(3-氟苯基)-2-氧代丁基)-N-((S)-2-羟丙基)胺磺酰基)苯基)硼酸(I-2,化合物2)的合成:称取中间体12(0.228mmol)溶于20mL丙酮和水的混合溶剂(V/V 1:1)中,在氩气保护下加入高碘酸钠(0.911mmol)和乙酸铵(0.911mmol)。搅拌反应12小时,反应完毕后减压浓缩反应溶剂,粗品采用反相Flash柱层析进行分离纯化,洗脱剂为甲醇/水65:35,得到白色粉末固体,即化合物2(0.114g,收率为83%)。化合物2:LC-MS(ESI,M+H+)m/z 601.3。1H NMR(500MHz,CD3OD)δ8.48(s,1H),7.96-7.90(m,2H),7.77-7.73(m,2H),7.53(s,2H),7.25-7.21(m,2H),7.06(dd,J=8.0,2.0Hz,1H),7.00-6.95(m,2H),6.88(d,J=2.0Hz,2H),6.80-6.76(m,2H),6.69(d,J=16.0Hz,1H),6.51(d,J=9.0Hz,1H),4.51(dt,J=9.0,6.5Hz,1H),4.08-3.97(m,2H),3.85(d,J=15.5Hz,1H),3.31(dd,J=13.0,5.5Hz,1H),3.13-3.02(m,3H),2.84(ddt,J=13.5,6.5,1.0Hz,1H),1.24(d,J=7.0Hz,3H);13C NMR(125MHz,CD3OD)δ201.5,166.7,165.5,163.5,148.4,147.1,142.2,139.4,139.3,138.9,137.1,134.6,130.5,130.4,129.1,127.1,125.2,125.2,122.6,120.8,116.7,116.5,116.4,115.0,114.3,114.1,65.2,57.8,56.2,51.7,37.8,37.7,20.1.
实施例3
1)叔丁基-((2S,3R)-(1-环丙基-4-((3-(二甲基氨基)-3-氧代丙基)氨基)-3-羟基丁基-2-基)氨基甲酸酯(中间体14)的合成:中间体14的合成与实施例1中中间体3的合成类似,区别仅在于将中间体2替换为3-氨基-N,N-二甲基丙酰胺,将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-环丙基丁烷,得到中间体14(1.83g,收率为90%)。中间体14的LC-MS(ESI,M+H+)m/z 344.5。1HNMR(500MHz,CDCl3)δ5.58(d,J=8.0Hz,1H),3.91(dd,J=7.0,5.0Hz,1H),3.78(dd,J=7.0,5.0Hz,1H),3.69(ddt,J=8.0,7.0,6.0Hz,1H),3.59(d,J=5.0Hz,1H),2.90-2.86(m,3H),2.89(s,5H),2.71(dd,J=14.0,7.0Hz,1H),2.41(t,J=5.5Hz,2H),1.67(ddd,J=13.5,7.5,6.0Hz,1H),1.57-1.50(m,2H),1.49-1.41(m,1H),1.41(s,9H),1.37-1.25(m,3H);13CNMR(125MHz,CDCl3)δ171.9,156.8,79.7,71.3,52.4,52.0,44.5,36.1,35.7,35.0,28.4,9.34,6.26。
2)叔丁基-(S)-(1-环丙基-4-(((二甲氨基)-3-氧代丙基)氨基)-3-氧代丁基-2-基)氨基甲酸酯(中间体15)的合成:中间体15的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体14,得到中间体15(1.21g,收率为92%)。中间体15的LC-MS(ESI,M+H+)m/z 342.5。1H NMR(500MHz,CDCl3)δ5.54(d,J=8.0Hz,1H),4.10(dt,J=8.0,6.0Hz,1H),3.97(dd,J=6.0,5.5Hz,1H),3.49(dd,J=17.0,6.0Hz,1H),3.38(dd,J=17.0,6.0Hz,1H),2.96-2.89(m,2H),2.89(s,5H),2.43(t,J=5.5Hz,2H),1.96-1.87(m,1H),1.70-1.61(m,1H),1.61-1.52(m,2H),1.41(s,9H),1.36-1.25(m,3H);13C NMR(125MHz,CDCl3)δ210.9,171.9,156.0,79.9,58.1,56.9,44.0,37.5,36.1,34.8,28.4,8.84,6.27。
3)1,2,2-三氟乙烯基-(S)-(3-((叔丁基氧羰基)氨基)-4-环丙基-2-氧代丁基)-(3-二甲氨基-3-氧代丙基)氨基磺酸盐(中间体16)的合成:中间体16的合成与实施例1中中间体5的合成类似,区别仅在于将2-氯-4-硝基苯磺酰氯替换为三氟乙烯基氯硫酸盐,将中间体4替换为中间体15,得到中间体16(1.10g,收率为88%)。中间体16的LC-MS(ESI,M+H+)m/z 502.3。1H NMR(500MHz,CDCl3)δ5.41(d,J=8.0Hz,1H),4.18(dt,J=8.0,6.5Hz,1H),3.89(d,J=15.5Hz,1H),3.77(d,J=15.5Hz,1H),3.36(t,J=6.5Hz,2H),2.89(s,6H),2.61(t,J=6.5Hz,2H),1.96-1.87(m,1H),1.71-1.62(m,1H),1.61-1.52(m,2H),1.42(s,9H),1.36-1.25(m,3H);13C NMR(125MHz,CDCl3)δ202.5,171.6,156.0,79.9,56.2,51.7,41.9,37.6,36.2,34.2,28.4,8.85,6.28。
4)1,2,2-三氟乙烯基-(S)-(3-氨基-4-环丙基-2-氧代丁基)-(3-二甲氨基-3-氧代丙基)氨基磺酸盐(中间体17)的合成:中间体17的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体16,得到中间体17(0.74g,收率为87%)。中间体17的LC-MS(ESI,M+H+)m/z 402.3。1H NMR(500MHz,CD3OD)δ4.72(d,J=6.5Hz,2H),3.87(d,J=15.0Hz,1H),3.83-3.73(m,2H),3.41-3.32(m,2H),2.89(s,6H),2.61(t,J=6.5Hz,2H),1.85(ddd,J=14.0,7.0,5.5Hz,1H),1.54-1.48(m,3H),1.31-1.23(m,3H);13C NMR(125MHz,CD3OD)δ203.8,171.6,152.0,151.7,132.7,130.4,56.4,52.3,41.8,38.4,36.2,34.2,8.60,6.39。
5)1,2,2-三氟乙烯基-(S)-(4-环丙基-2-氧代-3-(2,2,2-三氟乙酰胺基)丁基-(3-二甲氨基-3-氧代丙基)氨基磺酸盐(I-3,化合物3)的合成:化合物3的合成与实施例1中化合物1的合成类似,区别仅在于将(E)-3-(3.4-二羟基苯基)丙烯酸替换为三氟乙酸,将中间体6替换为中间体17,得到化合物3(0.25g,收率为85%)。化合物3:LC-MS(ESI,M+H+)m/z498.3。1H NMR(500MHz,CD3OD)δ7.40(dd,J=11.5,2.0Hz,1H),4.33(dd,J=12.0,6.0Hz,1H),3.91(d,J=15.5Hz,1H),3.80(d,J=15.5Hz,1H),3.36(t,J=6.5Hz,2H),2.89(s,5H),2.61(t,J=6.5Hz,2H),1.89(ddd,J=13.5,7.0,6.0Hz,1H),1.58-1.52(m,2H),1.33-1.27(m,3H);13C NMR(125MHz,CD3OD)δ202.6,171.6,157.5,157.2,151.9,151.7,132.7,130.4,117.0,114.7,55.2,55.1,55.0,51.6,41.9,37.5,36.2,34.2,8.94,6.34.
实施例4
1)叔丁基-((2R,3S)-2-羟基-5-甲基-1-((吡啶-3-甲基)氨基)己基-3-基)氨基甲酸酯(中间体19)的合成:中间体19的合成与实施例1中中间体3的合成类似,区别仅在于将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-5-甲基己烷,将中间体2替换为3-氨甲基吡啶,得到中间体19(3.35g,收率为73%)。中间体19的LC-MS(ESI,M+H+)m/z 338.5。1H NMR(500MHz,CDCl3)δ8.62(dq,J=2.0,1.0Hz,1H),8.47(dd,J=4.0,2.0Hz,1H),7.72(dt,J=8.0,2.0Hz,1H),7.29-7.24(m,1H),5.39(d,J=7.0Hz,1H),4.14(qd,J=7.0,6.0Hz,1H),4.01-3.94(m,2H),3.77(ddt,J=6.5,5.0,4.0Hz,1H),3.74-3.65(m,1H),3.59(d,J=5.0Hz,1H),3.05(ddd,J=13.5,7.0,4.0Hz,1H),2.82(ddd,J=13.5,7.0,4.0Hz,1H),1.67-1.61(m,2H),1.35(ddd,J=13.5,8.0,6.5Hz,1H),1.31(s,9H),0.97(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3)δ156.9,150.1,148.9,135.7,135.2,124.0,79.7,71.3,53.6,51.7,51.6,39.3,28.4,26.1,22.7。
2)叔丁基-(S)-(5-甲基-2-氧代-1-(吡啶-3-甲基)氨基)己基-3-基)氨基甲酸酯(中间体20)的合成:中间体20的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体19,得到中间体20(2.24g,收率为91%)。中间体20的LC-MS(ESI,M+H+)m/z336.7。1H NMR(500MHz,CDCl3)δ8.62(dq,J=2.0,1.0Hz,1H),8.47(dd,J=4.0,2.0Hz,1H),7.72(dt,J=8.0,2.0Hz,1H),7.30-7.25(m,1H),5.10(d,J=7.0Hz,1H),4.17-4.08(m,3H),3.51(dd,J=17.0,6.0Hz,1H),3.40(dd,J=17.0,6.5Hz,1H),3.30(d,J=6.5Hz,1H),1.69-1.63(m,2H),1.52-1.43(m,1H),1.31(s,9H),0.94-0.86(m,3H),0.82-0.74(m,3H);13C NMR(125MHz,CDCl3)δ210.9,156.0,150.1,148.9,135.7,134.1,124.0,79.9,58.3,56.6,51.2,40.9,28.3,24.9,22.4。
3)叔丁基-(S)-(5-甲基-2-氧代-1-(N-(吡啶-3-甲基)噻唑-2-磺酰胺基)己基-3-基)氨基甲酸酯(中间体21)的合成:中间体21的合成与实施例1中中间体5的合成类似,区别仅在于将2-氯-4-硝基苯磺酰氯替换为2-噻唑磺酰氯,将中间体4替换为中间体20,得到中间体21(2.16g,收率为82%)。中间体21的LC-MS(ESI,M+H+)m/z483.6。1H NMR(500MHz,CDCl3)δ8.70(dq,J=2.0,1.0Hz,1H),8.47(ddd0,J=4.0,2.0Hz,1H),8.02(d,J=4.5Hz,1H),7.94(d,J=4.5Hz,1H),7.74(dt,J=8.0,2.0Hz,1H),7.31-7.25(m,1H),4.98(d,J=7.5Hz,1H),4.47(t,J=1.0Hz,2H),4.20-4.11(m,1H),3.92(d,J=15.5Hz,1H),3.80(d,J=15.5Hz,1H),1.72-1.64(m,2H),1.46-1.41(m,1H),1.32(s,9H),0.94-0.86(m,3H),0.82-0.75(m,3H);13C NMR(125MHz,CDCl3)δ202.4,161.8,156.0,151.6,148.5,142.3,137.3,131.4,124.2,121.4,79.9,56.4,51.8,49.3,40.9,28.4,24.8,22.4。
4)(S)-N-(3-氨基-5-甲基-2-氧代己基)-N-(吡啶-3-甲基)噻唑-2-磺酰胺(中间体22)的合成:中间体22的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体21,得到中间体22(1.75g,收率为80%)。中间体22的LC-MS(ESI,M+H+)m/z383.4。1H NMR(500MHz,CDCl3)δ8.70(dq,J=2.0,1.0Hz,1H),8.47(ddd,J=4.0,2.0,1.0Hz,1H),8.02(d,J=4.5Hz,1H),7.94(d,J=4.5Hz,1H),7.74(ddd,J=8.0,3.0,2.0Hz,1H),7.31-7.25(m,1H),4.47(t,J=1.0Hz,2H),4.26(d,J=6.0Hz,2H),3.88(d,J=15.0Hz,1H),3.80-3.72(m,2H),1.67-1.62(m,2H),1.47(ddd,J=14.0,8.0,6.5Hz,1H),0.96(d,J=7.0Hz,3H),0.86(d,J=7.0Hz,3H);13C NMR(125MHz,CDCl3)δ203.7,161.7,151.6,148.5,142.3,137.3,131.5,124.2,121.4,57.9,51.9,49.2,42.7,25.3,22.5。
5)2-(4-甲氧基-2-氧代吡啶-1(2H))-乙酰溴(中间体24)的合成:将4-甲氧基吡啶-2(1H)-酮(23,2.0mmol)和无水碳酸钾(4.0mmol)溶于4mL无水N,N-二甲基甲酰胺中,在氩气保护下室温搅拌1小时。然后将反应液置于冰浴中,缓慢滴加溴乙酰溴(2.4mmol),滴加完毕,在冰浴中继续搅拌反应0.5小时,然后转移至室温过夜反应。加入10mL饱和碳酸氢钠溶液淬灭反应,用乙酸乙酯萃取3次(3×10mL),合并有机相,用无水硫酸钠干燥,浓缩溶剂,粗品采用硅胶柱层析进行分离纯化,洗脱剂为石油醚-乙酸乙酯1:3,得到白色粉末固体,即中间体24(0.32g,收率为65%)。中间体24的LC-MS(ESI,M+H+)m/z 246.3。1H NMR(500MHz,CD3OD)δ7.74(dt,J=8.0,1.0Hz,1H),6.16(d,J=1.5Hz,1H),6.09(dd,J=8.0,1.5Hz,1H),5.29(d,J=1.0Hz,2H),3.74(s,2H);13C NMR(125MHz,CD3OD)δ167.6,164.6,163.6,138.8,99.4,98.7,55.6,55.5。
6)(S)-2-(4-甲氧基-2-氧代吡啶-1(2H))=N-(5-甲基-2-氧代-1-(N-(吡啶-2-甲基)噻唑-2-磺酰胺基)己基-3-基)乙酰胺(I-4,化合物4)的合成:化合物4的合成与实施例1中化合物1的合成类似,区别仅在于将(E)-3-(3.4-二羟基苯基)丙烯酸替换为2-(4-甲氧基-2-氧代吡啶-1(2H))-乙酰溴,将中间体6替换为中间体22,得到化合物4(0.88g,收率为87%)。化合物4:LC-MS(ESI,M+H+)m/z 548.5。1H NMR(500MHz,CD3OD)δ8.70(dd,J=2.0,1.0Hz,1H),8.47(ddd,J=4.0,2.0,1.5Hz,1H),8.02(d,J=4.5Hz,1H),7.94(d,J=4.5Hz,1H),7.74(dd,J=8.0,3.0Hz,1H),7.68(dt,J=8.0,1.0Hz,1H),7.41(d,J=8.5Hz,1H),7.31-7.25(m,1H),6.16(d,J=1.5Hz,1H),6.09(dd,J=8.01.5Hz,1H),4.52-4.48(m,2H),4.47(t,J=0.8Hz,2H),4.14-4.10(m,1H),4.03(d,J=15.5Hz,1H),3.94(d,J=15.5Hz,1H),3.74(s,2H),1.66-1.64(m,2H),1.42-1.38(m,1H),0.91-0.85(m,3H),0.78-0.74(m,3H);13C NMR(125MHz,CD3OD)δ202.6,169.2,166.7164.2,161.8,151.6,148.5,142.3,138.1,137.3,131.5,124.2,121.4,99.5,98.9,55.7,55.6,51.7,50.0,49.2,40.8,24.9,22.4.
实施例5
1)叔丁基-((2S,3R)-1-环己基-3-羟基-4-((嘧啶-5-甲基)氨基)丁基-2-基)氨基甲酸酯(中间体26)的合成:中间体26的合成与实施例1中中间体3的合成类似,区别仅在于将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-环己基丁烷,将中间体2替换为5-嘧啶甲胺(25),得到中间体26(3.52g,收率为73%)。中间体26的LC-MS(ESI,M+H+)m/z 379.6。1H NMR(500MHz,CDCl3)δ8.90(t,J=1.5Hz,1H),8.51(dt,J=1.5,1.0Hz,2H),5.58(d,J=8.0Hz,1H),4.77(d,J=7.0Hz,1H),4.17(dt,J=7.0,1.0Hz,2H),3.80(ddt,J=7.5,5.0,4.0Hz,1H),3.68(dq,J=8.0,7.0Hz,1H),3.59(d,J=5.0Hz,1H),3.05(ddd,J=13.5,7.0,3.5Hz,1H),2.82(ddd,J=13.5,7.0,4.0Hz,1H),1.67(dd,J=8.0,5.5Hz,1H),1.52-1.49(m,1H),1.48-1.46(m,1H),1.44-1.41(m,4H),1.41(s,9H),1.41-1.38(m,3H),1.28(s,9H),1.17(ddt,J=13.0,8.5,6.0Hz,2H);13C NMR(125MHz,CDCl3)δ157.3,156.9,154.6,131.4,79.7,71.4,53.5,51.6,48.8,36.5,33.7,33.1,28.4,26.3,26.1。
2)叔丁基-(S)-(1-环己基-3-氧代-4-((嘧啶-5-甲基)氨基)丁基)-2-基)氨基甲酸酯(中间体27)的合成:中间体27的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体26,得到中间体27(2.87g,收率为91%)。中间体27的LC-MS(ESI,M+H+)m/z 377.5。1H NMR(500MHz,CDCl3)δ8.90(t,J=1.5Hz,1H),8.51(d,J=1.5Hz,2H),5.54(d,J=8.0Hz,1H),4.18-4.13(m,2H),4.09(dt,J=8.0,7.0Hz,1H),3.52(dd,J=17.0,6.0Hz,1H),3.40(dd,J=17.0,6.0Hz,1H),3.20(tt,J=7.5,6.0Hz,1H),1.89(ddd,J=13.5,8.0,7.0Hz,1H),1.67-1.60(m,2H),1.55-1.41(m,5H),1.41(s,9H),1.34-1.28(m,2H),1.26(s,9H),1.19(ddt,J=13.0,8.5,6.0Hz,2H);13C NMR(125MHz,CDCl3)δ210.8,157.3,156.0,154.5,130.3,79.9,58.1,56.6,48.5,37.4,33.9,33.2,28.4,26.3,25.9。
3)叔丁基-((2S)-4-((苄氧基-4-硝基苯基)磷酰基)-(嘧啶-5-甲基)氨基)-1-环己基-3-氧代丁基-2-基)氨基甲酸酯(中间体28)的合成:将4-硝基苯基膦酰二氯(4.16mmol)(北京伊诺凯科技有限公司)、1-H-四氮唑(0.038mmol)(北京伊诺凯科技有限公司)溶于8mL干燥的苯中,将反应瓶置于冰浴中,在氩气保护下依次缓慢滴加入苯甲醇(3.78mmol)、DIEA(4.16mmol)。加毕,在冰浴中搅拌反应0.5小时,然后转移至室温下继续反应2.5小时。将反应瓶置于冰浴中,依次缓慢加入中间体27(3.78mmol)、DIEA(4.16mmol),冰浴中搅拌反应0.5小时,后转移至室温下继续反应3.5小时。过滤,滤液浓缩后采用反相柱色谱进行分离纯化(MeOH/H2O:5/1),得白色粉末即中间体28(1.65g,收率为67%)。中间体28的LC-MS(ESI,M+H+)m/z 652.5。1H NMR(500MHz,CDCl3)δ8.90(t,J=2.0Hz,1H),8.53(dt,J=2.0,1.0Hz,2H),8.29-8.22(m,2H),7.35-7.26(m,6H),7.11-7.03(m,2H),5.41(d,J=8.0Hz,1H),4.96(dt,J=8.5,1.0Hz,2H),4.74(d,J=1.0Hz,2H),4.15(dt,J=8.0,7.0Hz,1H),3.89(d,J=14.0Hz,1H),3.78(d,J=14.0Hz,1H),1.89(ddd,J=13.5,8.0,7.0Hz,1H),1.73-1.58(m,2H),1.55-1.28(m,8H),1.41(s,9H),1.19(ddt,J=13.0,8.5,6.0Hz,2H);13CNMR(125MHz,CDCl3)δ206.9,206.8,157.3,156.0,154.0,149.7,136.7,136.6,133.2,132.2,132.0,131.9,131.8,131.7,128.7,128.6,128.2,122.8,122.7,79.9,68.3,55.7,49.5,49.2,37.1,33.8,33.2,28.4,26.3,26.0。
4)苄基-N-((S)-3-氨基-4-环己基-2-氧代丁基)-P-(4-硝基苯基)-N-(嘧啶-5-甲基)磷酰胺(中间体29)的合成:中间体29的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体28,得到中间体29(0.89g,收率为73%)。中间体29的LC-MS(ESI,M+H+)m/z 552.4。1H NMR(500MHz,CD3OD)δ8.53(d,J=2.0Hz,1H),8.29-8.22(m,1H),7.33-7.26(m,2H),7.11-7.03(m,1H),4.96(dt,J=8.5,1.0Hz,1H),4.74(s,1H),4.61(d,J=6.5Hz,1H),3.71-3.68(m,1H),1.62-1.56(m,1H),1.35-1.28(m,4H),1.18(ddt,J=12.5,8.5,6.0Hz,1H);13C NMR(125MHz,CD3OD)δ207.4,207.3,157.3,154.0,149.7,136.7,136.6,133.2,132.2,132.0,131.9,131.8,131.7,128.7,128.6,128.2,122.8,122.7,68.3,57.8,49.5,49.0,37.3,34.2,33.1,26.3,25.9。
5)苄基-N-((S)-4-环己基-3-(4-甲氧基-1H-吲哚-2-甲酰胺基)-2-氧代丁基)-P-(4-硝基苯基)-N-(嘧啶-5-甲基)磷酰胺(中间体30)的合成:中间体30的合成与实施例1中化合物1的合成类似,区别仅在于将(E)-3-(3.4-二羟基苯基)丙烯酸替换为4-甲氧基-1H-吲哚-2-甲酰氯,将中间体6替换为中间体29,得到中间体30(0.64g,收率为86%)。中间体30的LC-MS(ESI,M+H+)m/z 725.6。1H NMR(500MHz,CD3OD)δ9.94(s,1H),8.90(t,J=2.0Hz,1H),8.53(d,J=2.0Hz,2H),8.29-8.22(m,2H),7.78(s,1H),7.69(d,J=8.5Hz,1H),7.37-7.26(m,6H),7.18(t,J=8.0Hz,1H),7.11-7.03(m,2H),6.92-6.87(m,1H),4.96(dt,J=8.5,1.0Hz,2H),4.74(s,2H),4.26(dt,J=8.5,7.0Hz,1H),3.93(d,J=14.0Hz,1H),3.93(s,3H),3.82(d,J=14.0Hz,1H),1.91(ddd,J=14.0,8.0,7.0Hz,1H),1.67-1.61(m,2H),1.45-1.37(m,6H),1.32-1.27(m,2H),1.19(ddt,J=13.0,8.5,6.0Hz,2H);13C NMR(125MHz,CD3OD)δ206.9,206.8,162.1,158.5,157.3,154.0,149.7,136.7,136.6,136.1,133.2,132.3,132.0,131.9,131.8,131.7,130.6,128.7,128.6,128.2,126.3,122.8,122.7,115.7,106.9,104.8,102.0,68.3,56.3,55.8,49.5,49.3,37.1,33.7,33.2,26.3,25.9。
6)N-((S)-4-环己基-3-(4-甲氧基-1H-吲哚-2-甲酰胺基)-2-氧代丁基)-P-(4-硝基苯基)-N-(嘧啶-5-甲基)膦酰胺酸(I-5,化合物5)的合成:将中间体30(0.17mmol)、1mL四氢呋喃、10%Pd/C(湿度37%)(0.10g,w/w 0.37:1)加入到氢化反应瓶中,在氩气保护下剧烈搅拌均匀,然后用氢气置换3次,在40psi压力下室温催化反应4小时。反应液用微孔滤膜过滤,滤液置于冰浴中,用2M HCl调节pH至5.0,搅拌0.5小时,用乙酸乙酯(3×5mL)萃取,有机相用无水硫酸钠干燥,浓缩,采用反相Flash柱层析进行分离纯化,洗脱剂为甲醇/水70:30,得到白色粉末固体,即化合物5(0.093g,收率为86%)。化合物5:LC-MS(ESI,M+H+)m/z635.5。1H NMR(500MHz,CD3OD)δ9.94(s,1H),9.76(s,1H),8.90(t,J=2.0Hz,1H),8.53(dt,J=2.0,1.0Hz,2H),8.26-8.22(m,2H),7.78(s,1H),7.69(d,J=8.5Hz,1H),7.36-7.30(m,1H),7.21-7.13(m,2H),7.13(d,J=1.5Hz,1H),6.92-6.87(m,1H),4.77(q,J=0.5Hz,2H),4.26(dd,J=8.5,7.0Hz,1H),3.93(s,3H),3.83(d,J=14.0Hz,1H),1.91(ddd,J=14.0,8.0,7.0Hz,1H),1.67-1.61(m,2H),1.35-1.27(m,3H),1.19(ddd,J=13.0,8.5,6.0Hz,2H);13C NMR(125MHz,CD3OD)δ207.0,206.9,162.1,158.5,157.3,154.0,149.7,136.1,136.0,135.0,131.8,131.7,131.6,130.6,126.3,122.8,122.7,115.7,106.9,104.8,102.5,56.3,55.8,48.9,48.8,48.6,48.5,37.1,33.7,33.2,26.3,25.9.
实施例6
1)叔丁基-((2S,3R)-1-(3,5-二氟苯基)-3-羟基-4(((2-氧代-1,2-二氢吡啶-4-基)甲基)氨基)丁基-2-基)氨基甲酸酯(中间体32)的合成:中间体32的合成与实施例1中中间体3的合成类似,区别仅在于将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-(3,5-二氟苯基)丁烷,将中间体2替换为4-(氨甲基)吡啶-2(1H)-酮,得到中间体32(2.51g,收率为72%)。中间体32的LC-MS(ESI,M+H+)m/z 424.5。1H NMR(500MHz,CDCl3)δ7.68(t,J=6.5Hz,1H),6.86(dd,J=12.0,2.0Hz,1H),6.80-6.73(m,2H),6.59(d,J=1.5Hz,1H),5.89(dq,J=7.0,1.0Hz,1H),5.58-5.55(m,1H),4.36(dd,J=6.5,5.0Hz,1H),3.81-3.75(m,2H),3.72(d,J=4.5Hz,1H),3.64-3.57(m,2H),3.23(dd,J=13.5,6.5Hz,1H),3.02-2.93(m,2H),2.75(ddd,J=14.0,6.5,4.0Hz,1H),1.27(s,9H);13C NMR(125MHz,CDCl3)δ164.2,163.0,162.8,161.0,160.8,156.5,146.1,142.6,136.6,112.6,112.5,112.4,112.3,111.1,109.7,101.8,101.6,101.4,79.7,71.1,55.9,53.5,52.0,36.5,36.4,28.4。
2)叔丁基-(S)-(1-(3,5-二氟苯基)-3-氧代-4(((2-氧代-1,2-二氢吡啶-4-基)甲基)氨基)丁基-2-基)氨基甲酸酯(中间体33)的合成:中间体33的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体32,得到中间体33(1.77g,收率为86%)。中间体33的LC-MS(ESI,M+H+)m/z 422.4。1H NMR(500MHz,CDCl3)δ7.68(d,J=6.5Hz,1H),6.86(dd,J=12.0,2.0Hz,1H),6.80(dd,J=12.0,1.5Hz,2H),6.59(q,J=1.5Hz,1H),5.89(dq,J=7.0,1.0Hz,1H),5.50(d,J=7.5Hz,1H),4.49(dt,J=8.0,6.5Hz,1H),3.59(d,J=4.0Hz,2H),3.49-3.46(m,1H),3.38-3.34(m,2H),3.12(dd,J=13.5,6.5Hz,1H),2.87(dd,J=13.5,6.5Hz,1H),1.27(s,9H),;13C NMR(125MHz,CDCl3)δ207.6,164.3,163.6,163.5,161.7,161.5,155.7,146.0,140.2,136.6,113.4,113.3,113.2,111.1,109.6,101.8,101.6,101.4,79.8,60.1,57.0,53.4,37.4,37.3,37.2,28.4。
3)叔丁基-(S)-(4-(氰甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基)-1-(3,5-二氟苯基)-3-氧代丁基-2-基)氨基甲酸酯(中间体34)的合成:将中间体33(4.95mmol)、四氢呋喃(THF,15mL)加入100mL茄形瓶中,冰浴下缓慢加入N,N-二异丙基乙胺(DIEA,5.45mmol),随后加入氯乙腈(5.45mmol)。冰浴下搅拌反应0.5小时后移至室温。TLC检测反应完毕后,减压浓缩除去THF,乙酸乙酯萃取(3×15mL),有机相用无水硫酸钠干燥,浓缩。粗品经硅胶柱层析纯化(洗脱剂为石油醚-乙酸乙酯2:1)后得白色固体,即中间体34(1.98g,收率为87%)。中间体34的LC-MS(ESI,M+H+)m/z461.5。1H NMR(500MHz,CDCl3)δ7.71(d,J=7.0Hz,1H),6.86(dd,J=12.0,2.0Hz,1H),6.80(dd,J=12.0,1.5Hz,2H),6.62(q,J=1.5Hz,1H),5.93(dq,J=7.0,1.0Hz,1H),5.41(d,J=8.0Hz,1H),4.51(dt,J=8.0,7.0Hz,1H),3.89(t,J=1.0Hz,2H),3.60-3.56(m,2H),3.47(d,J=14.0Hz,1H),3.11(dd,J=13.5,7.0Hz,1H),2.87(dd,J=13.5,6.5Hz,1H),1.29(s,9H);13C NMR(125MHz,CDCl3)δ206.4,164.2,163.6,163.5,161.7,161.5,155.7,146.2,140.2,136.8,120.4,117.6,113.4,113.3,113.2,110.7,101.8,101.6,101.4,79.9,59.3,58.5,58.5,42.7,37.5,37.4,37.3,28.3。
4)(S)-2-((3-氨基-4(3,5-二氟苯基)-2-氧代丁基)-92-氧代-1,2-二氢吡啶-4-基)甲基)氨基)乙腈(中间体35)的合成:中间体35的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体34,得到中间体35(1.13g,收率为80%)。中间体35的LC-MS(ESI,M+H+)m/z 361.5。1H NMR(500MHz,CD3OD)δ7.71(d,J=7.0Hz,1H),6.86(dd,J=12.0,2.0Hz,1H),6.82(d,J=2.0Hz,1H),6.80(d,J=2.0Hz,1H),6.62(q,J=1.5Hz,1H),5.93(dq,J=7.0,1.0Hz,1H),4.10-4.01(m,3H),3.89(t,J=1.0Hz,2H),3.64(s,2H),3.55(d,J=14.0Hz,1H),3.44(d,J=14.0Hz,1H),3.10-3.07(m,1H),2.89-2.84(m,1H);13CNMR(125MHz,CD3OD)δ208.9,164.2,163.6,163.5,161.7,161.5,146.2,139.8,139.7,139.6,136.8,120.4,117.7,113.3,113.2,113.1,113.0,110.7,101.8,101.6,101.4,60.5,59.8,58.5,42.6,38.6,38.5,38.3。
5)苯甲基-(4-硝基苯基)碳酸酯(中间体37)的合成:将苄醇(36,2.10mmol)溶于5mL无水二氯甲烷中,置于冰浴条件下搅拌,在氩气保护下缓慢加入DMAP(2.30mmol)和对硝基苯基氯甲酸酯(2.50mmol)。然后转移至室温下反应4小时。反应液依次用饱和氯化铵溶液、饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩得到无色油状物,即中间体37(0.48g,收率为83%)。中间体37的LC-MS(ESI,M+H+)m/z 274.3。1H NMR(500MHz,CDCl3)δ8.20-8.14(m,2H),7.51-7.45(m,2H),7.35(s,1H),7.30(dq,J=7.0,4.5Hz,1H),5.24(s,1H);13C NMR(125MHz,CDCl3)δ155.3,153.0,146.1,134.7,128.7,128.6,128.2,124.2,122.0,70.4。
6)苯甲基-(S)-(1-(4-氰甲基-((2-氧代-1,2-二氢吡啶-4-基)甲基)氨基)-1-(3,5-二氟苯基)-3-氧代丁基-2-基)氨基甲酸酯(I-6,化合物6)的合成:将中间体37(0.15mmol)和中间体35(0.16mmol)溶液1mL无水N,N-二甲基甲酰胺溶剂中,置于冰浴中搅拌,在氩气保护下缓慢加入N,N-二异丙基乙胺(0.30mmol)。然后转移至室温下反应5小时。反应完毕后,加入5mL乙酸乙酯稀释反应液,再依次用水、饱和氯化钠溶液洗涤。有机相用无水硫酸钠干燥,浓缩,用硅胶柱层析进行分离纯化,洗脱剂为石油醚-乙酸乙酯1:5,得到白色粉末固体,即化合物6(0.090g,收率为89%)。化合物6:LC-MS(ESI,M+H+)m/z 495.5。1HNMR(500MHz,CD3OD)δ7.71(t,J=7.0Hz,1H),7.38-7.26(m,3H),6.86(dd,J=12.0,2.0Hz,1H),6.82(dd,J=2.0,1.0Hz,1H),6.79(dd,J=2.0,1.0Hz,1H),6.62(q,J=1.5Hz,1H),5.93(d,J=7.0Hz,1H),5.48(d,J=9.0Hz,1H),5.09(s,2H),4.52(dt,J=9.0,6.5Hz,1H),3.89(t,J=1.0Hz,2H),3.67-3.56(m,3H),3.47(d,J=14.0Hz,1H),3.11(dd,J=13.5,7.0Hz,1H),2.87(dd,J=13.5,6.5Hz,1H);13C NMR(125MHz,CD3OD)δ206.4,164.2,163.6,163.5,161.7,161.5,155.7,146.2,140.3,140.2,140.1,136.8,136.5,128.6,128.2,128.1,120.4,117.6,113.4,113.3,113.2,110.7,101.8,101.6,101.4,66.6,59.3,58.6,58.5,42.7,37.4,37.3.
实施例7
1)(R)-5-氨甲基-2-恶唑烷酮(中间体39)的合成
称取(S)-5-氯甲基-2-恶唑烷酮(38,3.69mmol),在冰浴条件下加入3mL含有饱和氨的甲醇溶液,搅拌均匀后转移至室温,密闭反应6小时。减压整除溶剂,得到无色油状液体,即为中间体39(0.39g,收率为90%)。中间体39的LC-MS(ESI,M+H+)m/z 117.2。1H NMR(500MHz,CDCl3)δ6.72(d,J=4.5Hz,2H),4.63(dd,J=3.5,2.5Hz,2H),3.69-3.62(m,2H),3.42(ddd,J=13.5,4.5,2.5Hz,2H),3.14(ddd,J=13.0,6.5,3.5Hz,2H),2.89(ddd,J=13.0,6.5,3.5Hz,2H),2.23(d,J=13.0Hz,2H);13C NMR(125MHz,CDCl3)δ159.79,77.98,43.57,43.07。
2)叔丁基-((2S,3R)-1-环戊基-3-羟基-4-((((R)-2-氧代恶唑烷酮-5-基)甲基)氨基)丁基-2-基)氨基甲酸酯(中间体40)的合成:中间体40的合成与实施例5中中间体27的合成类似,区别仅在于将(S)-2-((叔丁基二甲基硅烷基)氧基)丙胺替换为(R)-5-(氨甲基)-2-恶唑烷酮,将将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-环戊基丁烷,得到中间体40(0.74g,收率为76%)。中间体40的LC-MS(ESI,M+H+)m/z 372.5。1H NMR(500MHz,CDCl3)δ6.82(d,J=5.0Hz,1H),5.58(d,J=8.0Hz,1H),5.47(dd,J=7.0,6.0Hz,1H),4.73(dd,J=4.0,3.0Hz,1H),3.79(dq,J=7.0,4.5Hz,1H),3.70-3.62(m,2H),3.59(d,J=5.0Hz,1H),3.42(ddd,J=13.5,5.0,3.0Hz,1H),3.20(ddd,J=14.0,6.0,3.5Hz,1H),3.04-2.93(m,2H),2.68(ddd,J=13.5,7.0,4.5Hz,1H),1.62-1.59(m,2H),1.59-1.53(m,4H),1.47-1.38(m,3H),1.41(s,9H),1.27-1.23(m,2H);13C NMR(125MHz,CDCl3)δ158.9,156.9,79.7,76.5,71.4,53.5,52.3,50.4,44.4,37.3,37.1,33.0,28.4,25.1。
3)叔丁基-((S)-1-环戊基-3-氧代-4-((((R)-2-氧代恶唑烷酮-5-基)甲基)氨基)丁基-2-基)氨基甲酸酯(中间体41)的合成:中间体41的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体40,得到中间体41(0.43g,收率为82%)。中间体41的LC-MS(ESI,M+H+)m/z 370.6。1H NMR(500MHz,CDCl3)δ6.82(t,J=5.0Hz,1H),5.54(d,J=8.0Hz,1H),4.72(dd,J=3.5,3.0Hz,1H),4.09(dt,J=8.0,7.0Hz,1H),3.66(dd,J=13.0,4.5Hz,1H),3.55(dd,J=17.0,6.0Hz,1H),3.43-3.38(m,2H),3.18(ddd,J=14.5,6.5,3.5Hz,1H),3.00(ddd,J=14.5,6.5,3.5Hz,1H),2.83(q,J=6.5Hz,1H),1.90(dt,J=14.0,7.0Hz,1H),1.74(dd,J=7.0,5.0Hz,1H),1.59-1.53(m,3H),1.47-1.42(m,2H),1.41(s,9H),1.31-1.25(m,2H);13C NMR(125MHz,CDCl3)δ210.9,156.0,155.9,79.8,76.0,58.1,57.3,50.0,44.4,37.4,36.9,32.7,28.3,25.1。
4)叔丁基-((S)-1-环戊基-3-氧代-4((2,4,5-三氟-N-(((S)-2-氧代恶唑烷酮-5-基)甲基)苯基)-3-磺酰胺基)丁基-2-基)氨基甲酸酯(中间体42)的合成:中间体42的合成与实施例1中中间体5的合成类似,区别仅在于将2-氯-4-硝基苯磺酰氯替换为2,4,5-三氟苯磺酰氯,将中间体4替换为中间体41,得到中间体42(0.55g,收率为88%)。中间体42的LC-MS(ESI,M+H+)m/z 564.5。1H NMR(500MHz,CDCl3)δ7.75(dt,J=12.0,4.5Hz,1H),7.20-7.16(m,1H),6.82(t,J=5.0Hz,1H),5.41(d,J=8.0Hz,1H),5.00(dd,J=5.0,3.0Hz,1H),4.18(dt,J=8.0,7.0Hz,1H),4.03(d,J=15.0Hz,1H),3.92(d,J=15.0Hz,1H),3.76-3.72(m,1H),3.65(dd,J=14.0,5.0Hz,1H),3.48(ddd,J=13.0,5.0,3.0Hz,1H),3.40(dd,J=14.0,5.0Hz,1H),1.89(dt,J=14.0,7.0Hz,1H),1.74(tt,J=7.0,5.0Hz,1H),1.64-1.53(m,4H),1.47-1.42(m,2H),1.41(s,9H),1.37-1.25(m,2H);13C NMR(125MHz,CDCl3)δ202.6,158.9,156.0,119.2,118.9,107.7,107.6,79.9,74.8,56.2,51.7,50.9,43.7,37.5,36.9,32.7,28.4,25.0。
5)N-((S)-3-氨基-4-环戊基-2-氧代丁基)-2,4,5-三氟-N-(((S)-2-2-氧代恶唑烷酮-5-基)甲基)苯磺酰胺(中间体43)的合成:中间体43的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体42,得到中间体43(0.21g,收率为77%)。中间体43的LC-MS(ESI,M+H+)m/z 464.5。1H NMR(500MHz,CD3OD)δ7.75(dt,J=12.0,4.5Hz,1H),7.22-7.16(m,1H),6.82(t,J=5.0Hz,1H),5.00(dd,J=5.0,3.0Hz,1H),4.68(d,J=6.5Hz,2H),3.90(d,J=15.0Hz,1H),3.72-3.69(m,3H),3.65(dd,J=14.0,5.0Hz,1H),3.48(ddd,J=13.0,5.0,3.0Hz,1H),3.40(dd,J=14.0,5.0Hz,1H),1.86(dt,J=14.5,6.5Hz,1H),1.72(dd,J=7.0,5.0Hz,1H),1.65-1.51(m,5H),1.46-1.41(m,2H),1.28-1.21(m,2H);13C NMR(125MHz,CD3OD)δ203.8,158.9,119.2,119.1,119.0,118.9,118.8,107.9,107.8,107.7,107.6,107.5,107.4,74.9,57.6,51.9,50.9,43.7,38.5,37.4,32.9,25.1。
6)3-(5-氯吡啶)甲基-(4-硝基苯基)碳酸酯(中间体45)的合成:中间体45的合成与实施例6中中间体37的合成类似,区别仅在于将苄醇替换为5-氯-3-吡啶甲醇,得到中间体45(0.35g,收率为84%)。中间体45的LC-MS(ESI,M+H+)m/z 309.3。1H NMR(500MHz,CDCl3)δ8.40(d,J=2.0Hz,1H),8.33(d,J=1.5Hz,1H),8.20-8.14(m,2H),7.56(dd,J=2.0,1.0Hz,1H),7.51-7.46(m,2H),5.45(d,J=1.0Hz,2H);13C NMR(125MHz,CDCl3)δ155.2,153.4,147.0,146.5,146.1,133.3,132.9,130.5,124.2,122.0,65.0。
7)5-氯吡啶-3-((S)-1-环戊基-3-氧代-4-((2,4,5-三氟-N-(((S)-2-氧代恶唑烷酮-5-基)甲基)苯基)磺酰胺基)丁基-2-基)氨基甲酸酯(I-7,化合物7)合成:化合物7的合成与实施例6中化合物6的合成方法类似,区别仅在于将中间体35替换为中间体43,将中间体37替换为中间体45,得到化合物7(0.087g,收率为82%)。化合物7:LC-MS(ESI,M+H+)m/z619.3。1H NMR(500MHz,CD3OD)δ8.35(d,J=2.0Hz,1H),8.26(d,J=2.0Hz,1H),7.75(dd,J=12.0,4.5Hz,1H),7.46(d,J=2.0Hz,1H),7.24-7.16(m,1H),6.82(t,J=5.0Hz,1H),5.84(d,J=9.0Hz,1H),5.00(dd,J=4.5,3.0Hz,1H),4.20(dt,J=9.0,7.0Hz,1H),4.03(d,J=15.0Hz,1H),3.92(d,J=15.0Hz,1H),3.66-3.62(m,2H),3.48(ddd,J=13.0,5.0,3.0Hz,1H),3.40(dd,J=14.0,5.0Hz,1H),1.89(dt,J=14.0,7.0Hz,1H),1.74(dd,J=7.0,5.0Hz,1H),1.68-1.53(m,4H),1.51-1.43(m,2H),1.32-1.25(m,2H);13C NMR(125MHz,CD3OD)δ202.6,158.9,153.7,147.6,143.0,140.2,130.7,124.9,124.4,119.2,119.1,119.0,118.9,118.8,107.9,107.8,107.7,107.6,107.5,107.4,74.8,56.2,51.7,50.9,43.7,37.5,36.9,32.7,25.1.
实施例8
1)叔丁基-((2R,3S)-2-羟基-5-甲基-1-((((R)-2-吡咯-3-基)氨基)己基-3-基)氨基甲酸酯(中间体47)的合成:中间体47的合成与实施例1中中间体3的合成类似,区别仅在于将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-5-甲基己烷,将中间体2替换为(S)-(-)-3-氨基吡咯烷,得到中间体47(1.75g,收率为69%)。中间体47的LC-MS(ESI,M+H+)m/z 316.6。1H NMR(500MHz,CDCl3)δ5.39(d,J=7.0Hz,1H),3.91(dt,J=7.0,6.5Hz,1H),3.71-3.66(m,2H),3.57(d,J=4.5Hz,1H),3.17(ddt,J=10.0,4.5,2.5Hz,1H),3.12-3.08(m,1H),3.02-2.94(m,2H),2.87(dd,J=12.5,4.0Hz,1H),2.73(ddd,J=14.0,6.5,4.0Hz,1H),2.63-2.59(m,1H),1.93(dd,J=4.0,3.0Hz,1H),1.84(ddt,J=13.5,4.0,2.0Hz,1H),1.61-1.56(m,3H),1.35(ddd,J=13.5,8.0,6.5Hz,1H),1.25(s,9H),0.97(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3)δ156.9,79.7,71.1,60.6,54.7,53.6,50.0,47.0,39.3,33.8,28.4,26.1,22.7。
2)叔丁基-((S)-5-甲基-2-氧代-1-((((R)-吡咯-3-基)氨基)甲基)己基-3-基)氨基甲酸酯(中间体48)的合成:中间体48的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体47,得到中间体48(1.04g,收率为88%)。中间体48的LC-MS(ESI,M+H+)m/z 314.5。1H NMR(500MHz,CDCl3)δ5.10(d,J=7.0Hz,1H),4.12(t,J=7.0Hz,1H),3.46(dd,J=16.5,6.0Hz,1H),3.41(dt,J=7.0,6.0Hz,1H),3.34(dd,J=16.5,6.0Hz,1H),3.11-3.08(m,2H),3.02-2.97(m,1H),2.91-2.84(m,1H),2.68-2.63(m,1H),1.93(tt,J=4.0,3.0Hz,1H),1.90-1.83(m,1H),1.67-1.59(m,3H),1.52-1.46(m,1H),1.25(s,9H),0.94-0.86(m,3H),0.82-0.74(m,3H);13C NMR(125MHz,CDCl3)δ210.7,156.0,79.9,60.3,58.4,54.8,54.5,47.0,40.9,33.7,28.4,24.9,22.4。
3)叔丁基-((S)-1-(2-(1H-苯并[d][1,2,3]三唑-1-基)-N-(((S)-吡咯-3-基)乙酰胺基)-5-甲基-2-氧代己基-3-基)氨基甲酸酯(中间体49)的合成:将2-(1-苯并三氮唑)乙酸(1.0mmol)和中间体48(1.0mmol)溶于20mL无水DMF中,降温至0℃,在氩气保护下缓慢加入1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(EDCl,1.5mmol),1-羟基苯并三唑(HOBt,1.1mmol),在0℃下继续搅拌10min,然后转移至室温反应1h,加入4-二甲氨基吡啶(DMAP,0.20mmol),继续反应2h。减压蒸除溶剂,加入40mL水,用乙酸乙酯(3×40mL)萃取,合并有机相,无水Na2SO4干燥,浓缩,采用硅胶柱层析进行分离纯化(所采用的洗脱剂为石油醚-乙酸乙酯1:3),得到白色粉末固体,即中间体49(0.41g,收率为81%)。中间体49的LC-MS(ESI,M+H+)m/z 473.5。1H NMR(500MHz,CDCl3)δ8.05(dd,J=7.5,1.5Hz,1H),7.82(dd,J=8.5,1.5Hz,1H),7.56(ddd,J=8.5,7.0,1.5Hz,1H),7.42-7.36(m,1H),5.12-5.05(m,2H),4.99(d,J=7.5Hz,1H),4.24-4.18(m,2H),4.04(d,J=14.5Hz,1H),3.85(dtt,J=6.0,4.0,2.0Hz,1H),3.42-3.37(m,1H),3.07(ddd,J=11.5,6.0,2.5Hz,1H),2.86-2.79(m,1H),2.09(ddd,J=12.5,4.5,2.5Hz,1H),1.89-1.80(m,2H),1.69-1.64(m,2H),1.50-1.46(m,1H),1.25(s,9H),0.92-0.86(m,3H),0.82-0.76(m,3H);13C NMR(125MHz,CDCl3)δ207.9,169.6,156.0,145.3,133.4,127.0,124.8,119.7,110.2,79.9,57.5,56.4,53.7,51.6,50.8,46.4,40.9,31.5,28.4,24.9,22.4。
4)N-((S)-3-氨基-5-甲基-2-氧代己基)-2-(1H-苯并[d][1,2,3]三唑-1-基)-N-(((S)-吡咯-3-基)乙酰胺(中间体50)的合成:中间体50的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体49,得到中间体50(0.28g,收率为86%)。中间体50的LC-MS(ESI,M+H+)m/z 373.5。1H NMR(500MHz,CD3OD)δ8.05(dd,J=7.5,1.5Hz,1H),7.82(dd,J=8.5,1.5Hz,1H),7.56(ddd,J=8.5,7.0,1.5Hz,1H),7.42-7.36(m,1H),5.06(d,J=5.0Hz,2H),4.51(d,J=6.0Hz,2H),4.13(d,J=14.5Hz,1H),4.02(d,J=14.5Hz,1H),3.84(ddd,J=6.0,4.0,2.0Hz,1H),3.81-3.77(m,1H),3.42-3.38(m,1H),3.07(ddd,J=11.5,6.0,2.5Hz,1H),2.82-2.78(m,1H),2.09(ddd,J=12.5,4.5,2.5Hz,1H),1.87-1.80(m,1H),1.73-1.65(m,2H),1.47(ddd,J=14.0,8.0,6.5Hz,1H),0.96(d,J=7.0Hz,3H),0.86(d,J=7.0Hz,3H);13C NMR(125MHz,CD3OD)δ210.1,169.6,145.3,133.4,127.0,124.8,119.7,110.2,58.1,57.4,53.7,51.6,50.3,46.4,42.6,31.5,25.3,22.5。
5)N-((S)-(2-(1H-苯并[d][1,2,3]三唑-1-基)-N-(((S)-吡咯-3-基)乙酰胺基)-5-甲基-2-氧代己基-3-基)-5-甲基异恶唑-3-甲酰胺(I-8,化合物8)的合成:化合物8的合成与实施例1中化合物1的合成类似,区别仅在于将(E)-3-(3.4-二羟基苯基)丙烯酸替换为5-甲基异恶唑-3-甲酰氯,将中间体6替换为中间体50,得到化合物8(0.093g,收率为85%)。化合物8:LC-MS(ESI,M+H+)m/z 482.3。1H NMR(500MHz,CD3OD)δ8.05(dd,J=7.7,1.5Hz,1H),7.82(dd,J=8.5,1.5Hz,1H),7.63(d,J=9.0Hz,1H),7.56(dd,J=8.5,7.0Hz,1H),7.42-7.36(m,1H),6.63(s,1H),5.06(d,J=5.0Hz,2H),4.29(dd,J=9.0,7.0Hz,1H),4.22(d,J=14.5Hz,1H),4.10(d,J=14.5Hz,1H),3.85(dd,J=6.0,4.0Hz,1H),3.42-3.34(m,1H),3.07(dd,J=11.5,6.0Hz,2H),2.80-2.78(m,1H),2.52(s,3H),2.09(dd,J=12.5,4.5Hz,1H),1.79-1.64(m,4H),1.52(ddd,J=13.5,8.0,7.0Hz,1H),0.90(d,J=6.5Hz,3H),0.78(d,J=6.5Hz,3H);13C NMR(125MHz,CD3OD)δ207.8,169.6,167.2,161.6,156.1,145.3,133.4,127.0,124.8,119.7,110.2,101.5,57.5,56.4,53.7,51.6,50.8,46.4,40.8,31.5,24.9,22.4,12.1.
实施例9
1)叔丁基-((2R,3S)-1-((氰甲基)氨基)-2-羟基-5-甲基己基-3-基)氨基甲酸酯(中间体52)的合成:中间体52的合成与实施例1中中间体3的合成类似,区别仅在于将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-苯丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-5-甲基己烷,将中间体2替换为氨基乙腈,得到中间体52(1.78g,收率为81%)。中间体52的LC-MS(ESI,M+H+)m/z 286.4。1H NMR(500MHz,CDCl3)δ5.39(d,J=7.0Hz,1H),3.76(ddd,J=6.5,5.0,4.0Hz,1H),3.70-3.63(m,3H),3.59(d,J=5.0Hz,1H),3.03(ddd,J=13.0,7.0,4.0Hz,1H),2.96(dd,J=7.0,3.0Hz,1H),2.80(ddd,J=13.0,7.0,4.0Hz,1H),1.77-1.69(m,2H),1.35(ddd,J=13.5,8.0,6.5Hz,1H),1.26(s,9H),0.97(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3)δ156.9,117.6,79.7,71.2,53.6,51.6,39.3,38.9,28.4,26.1,22.7。
2)叔丁基-(S)-1-((氰甲基)氨基)-5-甲基-2-氧代己基-3-基)氨基甲酸酯(中间体53)的合成:中间体53的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体52,得到中间体53(1.25g,收率为93%)。中间体53的LC-MS(ESI,M+H+)m/z284.5。1H NMR(500MHz,CDCl3)δ5.10(d,J=7.0Hz,1H),4.12(dd,J=7.5,6.5Hz,1H),3.70(d,J=4.0Hz,2H),3.50(dd,J=16.5,6.0Hz,1H),3.39(dd,J=16.5,6.0Hz,1H),2.84(dd,J=6.0,4.0Hz,1H),1.67-1.63(m,2H),1.52-1.48(m,1H),1.26(s,9H),0.94-0.88(m,3H),0.82-0.76(m,3H);13C NMR(125MHz,CDCl3)δ210.8,156.0,117.7,79.9,58.3,56.6,40.9,38.2,28.4,24.9,22.4。
3)叔丁基-(S)-(1-(N-(氰甲基)苯并[d]噻唑-2-磺酰胺基)-5-甲基-2-氧代己基-3-基)氨基甲酸酯(中间体54)的合成:中间体54的合成与实施例1中中间体5的合成类似,区别仅在于将2-氯-4-硝基苯磺酰氯替换为苯并[d]噻唑-2-磺酰氯,将中间体4替换为中间体53,得到中间体54(1.37g,收率为85%)。中间体54的LC-MS(ESI,M+H+)m/z 481.5。1H NMR(500MHz,CDCl3)δ7.98(ddd,J=15.0,7.5,1.5Hz,2H),7.48(dd,J=7.5,1.5Hz,1H),7.45-7.39(m,1H),4.97(d,J=7.5Hz,1H),4.29(s,2H),4.20-4.15(m,1H),3.91(d,J=15.0Hz,1H),3.79(d,J=15.0Hz,1H),1.72-1.67(m,2H),1.50-1.44(m,1H),1.27(s,9H),0.94-0.89(m,3H),0.82-0.77(m,3H);13C NMR(125MHz,CDCl3)δ202.4,166.9,156.0,151.4,136.1,128.0,127.9,124.6,122.7,115.6,79.9,56.4,51.7,40.9,36.7,28.4,24.9,22.4。
4)(S)-N-(3-氨基-5-甲基-2-氧代己基)=N-(氰甲基)苯并[d]噻唑-2-磺酰胺(中间体55)的合成:中间体55的合成方法与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体54,得到中间体55(0.89g,收率为77%)。中间体55的LC-MS(ESI,M+H+)m/z381.5。1H NMR(500MHz,CD3OD)δ7.98(ddd,J=15.0,7.0,1.5Hz,2H),7.48(td,J=7.5,1.5Hz,1H),7.45-7.39(m,1H),4.33-4.23(m,4H),3.97(d,J=14.5Hz,1H),3.85(d,J=14.5Hz,1H),3.80-3.73(m,1H),1.77-1.69(m,2H),1.47(ddd,J=14.0,8.0,6.5Hz,1H),0.96(d,J=7.0Hz,3H),0.86(d,J=7.0Hz,3H);13C NMR(125MHz,CD3OD)δ203.6,166.8,151.4,136.1,128.0,127.9,124.6,122.7,115.6,58.0,51.8,42.7,36.7,25.3,22.5。
5)(S)-N-(1-N-((氰甲基)苯并[d]噻唑-2-磺酰胺基)-5-甲基-2-氧代丁基-3-基)-3-((E)-4-(二甲氨基)苯基)丙烯酰胺(I-9,化合物9)的合成:化合物9的合成与实施例1中化合物1的合成类似,区别仅在于将(E)-3-(3.4-二羟基苯基)丙烯酸替换为(E)-4-(二甲氨基)肉桂酸,将中间体6替换为中间体55,得到化合物9(0.69g,收率为78%)。化合物9:LC-MS(ESI,M+H+)m/z 554.5。1H NMR(500MHz,CD3OD)δ7.98(dd,J=15.0,7.0Hz,2H),7.57-7.52(m,2H),7.55-7.45(m,2H),7.45-7.39(m,1H),6.85-6.79(m,2H),6.64(d,J=16.5Hz,1H),6.27(d,J=8.5Hz,1H),4.29(s,2H),4.21-4.13(m,1H),3.92(d,J=15.0Hz,1H),3.81(d,J=15.0Hz,1H),2.92(s,5H),1.66-1.63(m,2H),1.50-1.46(m,1H),0.94-0.89(m,3H),0.82-0.75(m,3H);13C NMR(125MHz,CD3OD)δ202.4,167.1,166.9,151.5,151.4,141.5,136.1,129.2,128.0,127.9,124.6,122.7,122.2,121.0,115.6,112.1,56.0,51.4,40.8,40.3,36.8,24.9,22.4.
实施例10
1)叔丁基-((2R,3S)-1-苄氨基-2-羟基-5-甲基己基-3-基)氨基甲酸酯(中间体57)的合成:中间体57的合成方法与实施例4中中间体19的合成类似,区别仅在于将中间体18替换为中间体56(苄胺),得到中间体57(2.68g,收率为81%)。中间体57的LC-MS(ESI,M+H+)m/z 337.5。1H NMR(500MHz,CDCl3)δ7.36-7.29(m,4H),7.27-7.23(m,1H),5.39(d,J=7.0Hz,1H),4.19(dd,J=6.0,3.0Hz,2H),4.14-4.08(m,1H),3.77(ddt,J=6.5,5.0,4.0Hz,1H),3.70-3.67(m,1H),3.59(d,J=5.0Hz,1H),3.05(ddd,J=13.5,7.0,4.0Hz,1H),2.82(ddd,J=13.5,7.0,4.0Hz,1H),1.73-1.69(m,2H),1.35(ddd,J=13.5,8.0,6.5Hz,1H),1.24(s,9H),0.97(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3)δ156.9,136.8,128.7,128.3,127.6,79.7,71.3,53.6,53.5,51.7,39.3,28.4,26.1,22.7.
2)叔丁基-(S)-(1-苄氨基-5-甲基-2-氧代己基-3-基)氨基甲酸酯(中间体58)的合成:中间体58的合成方法与实施例4中中间体20的合成类似,区别仅在于将中间体19替换为中间体57),得到中间体58(1.97g,收率为93%)。中间体57的LC-MS(ESI,M+H+)m/z335.5。1H NMR(500MHz,CDCl3)δ7.33(s,1H),7.32-7.27(m,1H),5.10(d,J=7.0Hz,1H),4.12(dt,J=7.0,6.5Hz,1H),4.00(d,J=6.0Hz,2H),3.51(dd,J=17.0,6.0Hz,1H),3.40(dd,J=17.0,6.5Hz,1H),3.20-3.16(m,1H),1.71-1.65(m,2H),1.52-1.48(m,1H),1.25(s,9H),0.94-0.86(m,3H),0.82-0.74(m,3H);13C NMR(125MHz,CDCl3)δ210.9,156.0,139.5,128.8,128.1,127.6,79.9,58.3,56.6,53.7,40.9,28.4,24.9,22.4.
3)三甲基硅基-(S)-苄基-(3-((叔丁氧羰基)氨基)-5-甲基-2-氧代己基)氨基磺酸(中间体59)的合成:中间体59的合成与实施例4中中间体21的合成类似,区别仅在于将2-噻唑磺酰氯替换为三甲基硅基氯磺酸酯,将中间体20替换为中间体58,得到中间体59(1.88g,收率为82%)。中间体59的LC-MS(ESI,M+H+)m/z487.6。1H NMR(500MHz,CD3OD)δ7.35-7.29(m,4H),4.98(d,J=7.5Hz,1H),4.29(d,J=1.0Hz,2H),4.20-4.15(m,1H),3.86(d,J=15.5Hz,1H),3.75(d,J=15.5Hz,1H),1.72-1.69(m,2H),1.50-1.47(m,1H),1.31(m,9H),0.93-0.89(m,3H),0.82-0.78(m,3H),0.24(s,9H);13C NMR(125MHz,CD3OD)δ202.3,156.0,134.5,129.8,129.1,127.8,79.9,56.4,52.8,52.2,40.9,28.4,24.8,22.4.
4)三甲基硅基-(S)-(3-氨基-5-甲基-2-氧代己基)(苄基)氨基磺酸(中间体60)的合成:将中间体59(2.0mmol)加入到50mL干燥茄形瓶中,在冰浴条件下、氩气保护下缓慢滴加入无水三氟乙酸(3.0mmol,1.5eq)。在冰浴中反应0.5小时,减压蒸除三氟乙酸,得到中间体60,无色油状物粗品,0.71g,粗收率92%)。粗品不经纯化,直接进行下一步反应。中间体60的LC-MS(ESI,M+H+)m/z387.4。1H NMR(500MHz,CD3OD)δ7.34-7.31(m,4H),4.30-4.26(m,4H),3.86(d,J=15.0Hz,1H),3.80-3.76(m,2H),1.72-1.66(m,2H),1.47(ddd,J=14.0,8.0,6.5Hz,1H),0.96(d,J=7.0Hz,3H),0.86(d,J=7.0Hz,3H),0.24(s,9H);13C NMR(125MHz,CD3OD)δ203.7,134.4,129.8,129.0,127.5,57.9,52.8,52.7,42.6,25.2,22.4.
5)三甲基硅基-(S)-(3-(6-甲基烟酰胺基)-5-甲基-2-氧代己基)-(苄基)氨基磺酸(中间体61)的合成:中间体61的合成与实施例4中化合物4的合成类似,区别仅在于将2-(4-甲氧基-2-氧代吡啶-1(2H))-乙酰溴替换为6-甲基烟酰氯,将中间体22替换为中间体60,得到中间体61(0.44g,收率为86%)。中间体61的LC-MS(ESI,M+H+)m/z 506.5。1H NMR(500MHz,CD3OD)δ8.81(d,J=2.0Hz,1H),8.03(dd,J=8.0,2.0Hz,1H),7.67(d,J=8.0Hz,1H),7.30-7.24(m,4H),4.29(s,1H),4.25-4.22(m,1H),3.88(d,J=15.5Hz,1H),3.77(d,J=15.5Hz,1H),2.53(d,J=1.0Hz,2H),1.68-1.64(m,1H),1.52(ddd,J=13.5,8.0,7.0Hz,1H),0.90(d,J=6.5Hz,2H),0.78(d,J=6.5Hz,2H),0.24(s,5H);13C NMR(125MHz,CD3OD)δ202.4,166.0,161.4,148.9,134.9,134.5,129.8,129.0,128.0,127.8,122.9,56.5,52.7,52.4,40.8,24.9,24.2,22.4.
6)(S)-苄基-(5-甲基-3-(6-甲基烟酰胺基)-2-氧代己基)氨基磺酸(I-10,化合物10)的合成:将中间体61(0.2mmol)溶于1mL四氢呋喃中,室温下搅拌溶解。将四丁基氟化铵(0.4mmol,2eq)溶于1mL四氢呋喃中,滴加入上述反应液中。室温反应2小时。减压蒸除溶剂,加入5mL二氯甲烷,用水洗涤3次(3×5ml)。有机相用无水硫酸钠干燥,减压浓缩溶剂。采用反相C-18柱层析进行分离纯化,洗脱剂为体积比为65:35甲醇与水混合溶剂,得到白化合物10(色粉末固体,0.063g,收率为73%)。化合物10:LC-MS(ESI,M+H+)m/z 434.5。1H NMR(500MHz,CD3OD)δ8.81(d,J=2.0Hz,1H),8.03(dd,J=8.0,2.0Hz,1H),7.67(d,J=8.0Hz,1H),7.36-7.21(m,6H),6.18(s,1H),4.37(d,J=1.0Hz,2H),4.24(dt,J=8.0,7.0Hz,1H),3.94(d,J=15.5Hz,1H),3.82(d,J=15.5Hz,1H),2.53(d,J=1.0Hz,3H),1.71-1.64(m,2H),1.52(ddd,J=13.5,8.0,7.0Hz,1H),0.90(d,J=6.5Hz,3H),0.78(d,J=6.5Hz,3H);13CNMR(125MHz,CD3OD)δ202.7,165.9,161.4,148.9,135.9,134.9,129.8,129.0,128.2,127.5,122.9,56.6,51.9,51.8,40.8,24.9,24.2,22.4.
实施例11
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1)(R)-2-((叔丁基二甲基硅烷基)氧基)丙胺(中间体63)的合成:中间体63的合成与实施例1中中间体2的合成类似,区别仅在于将(S)-2-羟基丙胺替换为(R)-2-羟基丙胺,得到中间体63(1.58g,收率为89%)。中间体63的LC-MS(ESI,M+H+)m/z 190.3。1H NMR(500MHz,CDCl3)δ3.86(qt,J=5.5,3.5Hz,1H),2.85(ddd,J=11.5,7.0,3.5Hz,1H),2.60(ddd,J=11.5,7.0,3.5Hz,1H),1.50(d,J=14.0Hz,1H),1.12(d,J=56.0Hz,3H),0.87(s,9H),0.21(s,6H);13C NMR(125MHz,CDCl3)δ70.5,50.5,25.9,21.4,18.1,-4.4.
2)叔丁基-((2S,3R)-4-(((R)-2-((叔丁基二甲基硅烷基)氧基)丙基)氨基)-3-羟基-1-苯基丁基-2-基)氨基甲酸酯(中间体64)的合成:中间体64的合成与实施例1中中间体3的合成类似,区别仅在于将中间体2替换为中间体63,得到中间体64(1.02g,收率为86%)。中间体64的LC-MS(ESI,M+H+)m/z 453.3。1H NMR(500MHz,CDCl3)δ7.39(d,J=7.0Hz,2H),7.23-7.19(m,2H),5.58(d,J=7.5Hz,1H),4.36(tt,J=6.5,5.5Hz,1H),3.92(qt,J=6.0,4.5Hz,1H),3.79(s,1H),3.72-3.68(m,2H),2.99(ddd,J=13.5,6.5,4.0Hz,1H),2.90-2.84(m,2H),2.76(ddd,J=13.5,6.5,4.0Hz,1H),2.65-2.58(m,2H),1.27(s,9H),1.09(d,J=6.0Hz,3H),0.87(s,9H),0.05(s,6H);13C NMR(125MHz,CDCl3)δ156.5,137.8,130.0,129.3,127.5,79.7,71.2,68.7,56.9,55.8,52.3,36.7,28.3,25.9,21.6,18.1,-4.44.
3)叔丁基-((S)-4-(((R)-2-((叔丁基二甲基硅烷基)氧基)丙基)氨基)-3-氧代-1-苯基丁基-2-基)氨基甲酸酯(中间体65)的合成:中间体65的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体64,得到中间体65(0.83g,收率为95%)。中间体65的LC-MS(ESI,M+H+)m/z 451.3。1H NMR(500MHz,CDCl3)δ7.31-7.24(m,5H),5.49(d,J=7.5Hz,1H),4.44(dt,J=8.0,6.5Hz,1H),3.92(qt,J=6.0,4.0Hz,1H),3.52-3.47(m,2H),3.44-3.39(m,1H),3.08(dd,J=14.0,6.5Hz,1H),2.90-2.79(m,2H),2.66-2.58(m,1H),1.25(s,9H),0.87(s,9H),1.09(d,J=6.0Hz,3H),0.87(s,9H),0.05(s,6H);13C NMR(125MHz,CDCl3)δ207.67,155.68,137.73,129.56,128.92,127.21,79.86,68.45,60.16,57.22,56.21,37.93,28.35,25.90,21.56,18.15,-4.44.
4)叔丁基-((S)-4-((N-((R)-2-((叔丁基二甲基硅烷基)氧基)丙基)-吡啶-4-磺酰胺基)-3-氧代-1-苯基丁基-2-基)氨基甲酸酯(中间体66)的合成:中间体66的合成与实施例1中中间体5的合成类似,区别仅在于将2-氯-4-硝基苯磺酰氯替换为4-吡啶磺酰氯,将中间体4替换为中间体65,得到中间体66(0.80g,收率为83%)。中间体66的LC-MS(ESI,M+H+)m/z 592.5。1H NMR(500MHz,CDCl3)δ8.77-8.74(m,2H),7.70-7.68(m,2H),7.25-7.19(m,5H),5.42(d,J=8.0Hz,1H),4.49(dt,J=8.0,6.5Hz,1H),4.27(qt,J=6.5,5.0Hz,1H),3.83(d,J=15.0Hz,1H),3.72(d,J=15.0Hz,1H),3.40(dd,J=12.0,5.0Hz,1H),3.15(dd,J=12.0,5.0Hz,1H),3.07(dd,J=14.0,6.5Hz,1H),2.82(dd,J=14.0,6.5Hz,1H),1.25(s,9H),1.16(d,J=6.5Hz,3H),0.87(s,9H),0.05(s,6H);13C NMR(125MHz,CDCl3)δ201.1,155.7,149.9,143.7,137.6,129.6,128.9,127.2,122.3,79.9,67.4,58.2,56.3,51.7,37.9,28.4,25.9,21.7,18.2,-4.45.
5)N-((S)-3-氨基-2-氧代-4-苯基丁基)-N-((R)-2-羟丙基)吡啶-4-磺酰胺(中间体67)的合成:中间体67的合成与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体66,得到中间体67(0.80g,收率为83%)。中间体66的LC-MS(ESI,M+H+)m/z378.3。1H NMR(500MHz,CD3OD)δ8.77-8.72(m,2H),7.71-7.68(m,2H),7.31-7.24(m,4H),4.05-3.98(m,2H),3.95-3.90(m,2H),3.74(d,J=15.0Hz,1H),3.63(d,J=15.0Hz,1H),3.36(dd,J=12.5,5.5Hz,1H),3.11-3.05(m,3H),2.88(dd,J=14.5,6.0Hz,1H),1.24(d,J=7.0Hz,2H);13C NMR(125MHz,CD3OD)δ202.1,149.9,143.7,137.4,129.7,129.2,127.5,122.3,65.2,60.1,56.2,52.1,38.9,20.1.
6)5-羟基-N-((S)-4-(N-((R)-2-羟丙基)吡啶-4-磺酰胺基)-3-氧代-1-苯基丁基-2-基)-苯并呋喃-2-甲酰胺(I-11,化合物11)的合成:化合物11的合成与实施例1中化合物1的合成类似,区别仅在于将中间体6替换为中间体67,将(E)-3-(3.4-二羟基苯基)丙烯酸替换为5-羟基苯并呋喃-2-甲酸,得到化合物11(0.41g,收率为85%)。化合物11:LC-MS(ESI,M+H+)m/z 538.3。1H NMR(500MHz,CD3OD)δ8.77-8.72(m,2H),7.88(s,1H),7.73-7.68(m,2H),7.63(d,J=2.0Hz,1H),7.25-7.19(m,7H),7.13(t,J=2.0Hz,1H),6.83(dd,J=9.0,2.0Hz,1H),4.51(dt,J=10.5,6.5Hz,1H),4.03(dd,J=7.0,5.5Hz,1H),3.87(d,J=15.0Hz,1H),3.75(d,J=15.0Hz,1H),3.36(dd,J=12.5,5.5Hz,1H),3.12-3.06(m,3H),2.86(dd,J=14.0,6.5Hz,1H),1.24(d,J=7.0Hz,2H);13C NMR(125MHz,CD3OD)δ201.4,161.3,152.7,149.9,149.8,148.6,143.7,138.0,129.5,128.9,127.9,127.2,122.3,114.1,113.4,110.7,106.9,65.2,58.6,56.2,51.6,37.9,20.1.
实施例12
1)叔丁基-(S)-(1-(N-(氰甲基)-2-(1H-吲哚-3-基)-2-氧代乙酰氨基)-5-甲基-2-氧代己基-3-基)-氨基甲酸酯(中间体68)的合成:中间体68的合成与实施例9中中间体54的合成类似,区别仅在于将苯并[d]噻唑-2-磺酰氯替换为吲哚-3-乙醛酰氯,得到中间体68(1.85g,收率为72%)。中间体68的LC-MS(ESI,M+H+)m/z 455.5。
1H NMR(500MHz,CDCl3)δ8.98(d,J=7.5Hz,1H),8.44-8.37(m,1H),7.96(d,J=7.5Hz,1H),7.46-7.40(m,1H),7.32-7.27(m,2H),4.98(d,J=7.5Hz,1H),4.28(s,2H),4.22-4.16(m,1H),4.12(d,J=14.5Hz,1H),4.00(d,J=14.5Hz,1H),1.67-1.64(m,2H),1.50-1.44(m,1H),1.27(s,9H),0.94-0.86(m,3H),0.82-0.74(m,3H);13C NMR(125MHz,CDCl3)δ207.2,179.2,164.3,156.0,138.3,137.8,126.7,123.0,122.8,121.9,116.1,113.9,112.7,79.9,56.4,53.5,40.9,36.8,28.3,24.8,22.4.
2)(S)-N-(3-氨基-5-甲基-2-氧代己基)-N-氰甲基-2-(1H-吲哚-3-基)-2-氧代乙酰胺(中间体69)的合成:中间体69的合成与实施例9中中间体55的合成类似,区别仅在于将中间体54替换为中间体68,得到中间体69(1.03g,收率为80%)。中间体69的LC-MS(ESI,M+H+)m/z 355.5。1H NMR(500MHz,CDCl3)δ8.98(d,J=7.5Hz,1H),8.44-8.37(m,1H),7.96(d,J=7.3Hz,1H),7.47-7.40(m,1H),7.32-7.23(m,2H),4.30-4.24(m,4H),4.09(d,J=13.9Hz,1H),3.97(d,J=14.1Hz,1H),3.82-3.74(m,1H),1.77-1.62(m,2H),1.47(ddd,J=14.0,8.0,6.4Hz,1H),0.96(d,J=6.9Hz,3H),0.86(d,J=7.0Hz,3H);13C NMR(125MHz,CDCl3)δ209.5,179.2,164.2,138.3,137.8,126.7,123.0,122.8,121.9,116.0,113.9,112.7,58.1,52.7,42.6,36.7,25.3,22.5.
3)(S)-4-硝基苯基-((5-氧代四氢呋喃-2-基)-甲基)-碳酸酯(中间体71)的合成:中间体71的合成与实施例6中中间体37的合成类似,区别仅在于将中间体36替换为中间体70,得到中间体71(0.62g,收率为68%)。中间体71的LC-MS(ESI,M+H+)m/z 282.4。1H NMR(500MHz,CDCl3)δ8.20-8.14(m,2H),7.51-7.46(m,2H),5.08(ddd,J=5.5,4.5,3.5Hz,1H),4.46(dd,J=12.0,4.5Hz,1H),4.24(dd,J=12.0,4.5Hz,1H),2.56(ddd,J=12.5,8.0,6.0Hz,1H),2.44(ddd,J=12.5,8.0,6.0Hz,1H),2.33(ddd,J=14.0,8.5,6.0Hz,1H),2.11-2.08(m,1H);13C NMR(125MHz,CDCl3)δ177.1,156.2,153.4,146.0,124.2,122.0,77.0,68.0,27.3,25.6.
4)((S)-5-氧代四氢呋喃-2-基)-甲基-((S)-1-(N-氰甲基-2-(1H-吲哚-3-基)-2-氧代乙酰胺)-5-甲基-2-氧代己基-3-基)-氨基甲酸酯(I-12,化合物12)的合成:化合物12的合成与实施例6中化合物6的合成类似,区别仅在于将中间体35替换为中间体69,将中间体37替换为中间体71,得到化合物12(0.093g,收率为87%)。化合物12:LC-MS(ESI,M+H+)m/z 497.3。1H NMR(500MHz,CDCl3)δ8.98(d,J=7.5Hz,1H),8.45-8.42(m,1H),7.96(d,J=7.5Hz,1H),7.44-7.40(m,1H),7.32-7.28(m,2H),5.03-4.99(m,2H),4.39(dd,J=15.0,4.5Hz,1H),4.28(s,2H),4.23-4.19(m,3H),4.00(d,J=14.5Hz,1H),2.56(ddd,J=12.5,8.0,6.0Hz,1H),2.44(ddd,J=12.5,8.0,6.0Hz,1H),2.33(ddd,J=14.0,8.0,6.0,3.5Hz,1H),2.10-2.05(m,1H),1.67-1.64(m,2H),1.50-1.46(m,1H),0.94-0.86(m,3H),0.82-0.79(m,3H);13C NMR(125MHz,CDCl3)δ207.2,179.1,177.1,164.2,156.6,138.4,137.8,126.7,123.0,122.8,121.9,116.0,113.9,112.7,76.5,67.0,56.4,53.5,40.9,36.8,27.3,25.6,24.8,22.4.
实施例13
1)叔丁基-(S)-(4-(((1,3-二氧戊环-2-基)-甲基)-(3-(二甲氨基)-3-氧代丙基)氨基)-1-环丙基-3-氧代丁基-2-基)-氨基甲酸酯(中间体72)的合成:中间体72的合成与实施例3中中间体16的合成类似,区别仅在于将三氟乙烯基氯硫酸盐替换为2-氯甲基-1,3-二氧戊环,得到中间体72(1.53g,收率为84%)。中间体72的LC-MS(ESI,M+H+)m/z 428.4。1HNMR(500MHz,CDCl3)δ5.42(d,J=8.0Hz,1H),5.22(t,J=2.0Hz,1H),4.16(dt,J=8.0,6.5Hz,1H),3.98-3.90(m,2H),3.81-3.77(m,2H),3.50(d,J=14.5Hz,1H),3.38(d,J=14.5Hz,1H),2.91-2.86(m,9H),2.44(t,J=6.0Hz,2H),1.92(dd,J=13.5,6.5Hz,1H),1.71-1.68(m,1H),1.61-1.52(m,2H),1.36-1.30(m,3H),1.25(s,9H);13C NMR(125MHz,CDCl3)δ209.5,171.8,156.0,102.0,79.8,65.5,61.9,59.1,56.5,50.3,37.5,36.1,33.8,28.3,8.84,6.27.
2)(S)-3-(((1,3-二氧戊环-2-基)-甲基)-(3-氨基-4-环丙基-2-氧代丁基)氨基)-N,N-二甲基丙酰胺(中间体73)的合成:中间体73的合成与实施例10中中间体60的合成类似,在低温无水条件下进行脱除Boc保护基反应,区别仅在于将中间体59替换为中间体72,得到中间体73(0.98g,收率为87%)。中间体73的LC-MS(ESI,M+H+)m/z 328.5。1H NMR(500MHz,CDCl3)δ5.22(t,J=2.0Hz,1H),4.76(d,J=6.5Hz,2H),3.98-3.90(m,2H),3.86-3.82(m,2H),3.79-3.71(m,1H),3.48(d,J=14.0Hz,1H),3.36(d,J=14.5Hz,1H),2.91-2.84(m,9H),2.44(t,J=6.0Hz,2H),1.86(ddd,J=14.0,6.5,6.0Hz,1H),1.52-1.48(m,3H),1.38-1.34(m,3H);13C NMR(125MHz,CDCl3)δ211.9,171.8,102.0,65.5,61.8,59.1,56.6,50.2,38.3,36.1,33.8,8.61,6.45.
3)(R)-N-((S)-4-(((1,3-二氧戊环-2-基)甲基)-(3-二甲氨基-3-丙酰基)氨基)-1-环丙基-3-氧代丁基-2-基)-2-氧代四氢噻唑-4-甲酰胺(中间体74)
中间体74的合成与实施例1中化合物1的合成类似,区别仅在于将中间体6替换为中间体73,将(E)-3-(3.4-二羟基苯基)丙烯酸替换为(R)-2-氧代噻唑烷-4-羧酸,得到中间体74(0.84g,收率为83%)。中间体74的LC-MS(ESI,M+H+)m/z 457.5。1H NMR(500MHz,CD3OD)δ7.74(d,J=9.0Hz,1H),5.57(d,J=6.0Hz,1H),5.22(t,J=2.0Hz,1H),4.22(dt,J=9.0,6.0Hz,1H),4.04(ddd,J=6.0,3.5,1.5Hz,1H),3.98-3.90(m,2H),3.86-3.77(m,2H),3.48(d,J=14.5Hz,1H),3.36(d,J=14.5Hz,1H),3.25(dd,J=14.0,1.5Hz,1H),3.02(dd,J=14.0,3.5Hz,1H),2.91-2.84(m,9H),2.44(t,J=6.0Hz,2H),1.90-1.86(m,1H),1.64-1.57(m,2H),1.36-1.29(m,3H);13C NMR(125MHz,CD3OD)δ209.6,174.5,171.8,171.1,102.0,65.5,61.8,59.1,58.8,54.9,50.2,37.5,36.1,34.4,33.8,9.01,6.34.
4)(R)-N-((S)-1-环丙基-4-((3-二甲氨基-3-丙酰基)-(2-氧代乙基)氨基)-3-氧代丁基-2-基)-2--氧代四氢噻唑-4-甲酰胺(I-13,化合物13)的合成:将中间体74(0.10mmol)溶于2.0mL乙醇中,在搅拌状态下缓慢滴加0.1M的稀盐酸2.0mL,加毕,室温搅拌反应0.5小时,减压蒸除乙醇,加入3mL水,用乙酸乙酯(3×3mL)萃取,合并有机相,无水Na2SO4干燥,浓缩,采用硅胶柱层析进行分离纯化(所采用的洗脱剂体积为乙酸乙酯-甲醇20:1),得到白色粉末固体,即化合物13(0.037g,收率为90%)。化合物13:LC-MS(ESI,M+H+)m/z 413.5。1H NMR(500MHz,CD3OD)δ9.68(t,J=4.5Hz,1H),7.74(d,J=9.0Hz,1H),5.57(d,J=6.0Hz,1H),4.22(dt,J=9.0,6.0Hz,1H),4.04(ddd,J=6.0,3.5,1.5Hz,1H),3.57(d,J=4.5Hz,2H),3.49(d,J=14.5Hz,1H),3.37(d,J=14.5Hz,1H),3.25(dd,J=14.0,1.5Hz,1H),3.02(dd,J=14.0,3.5Hz,1H),2.95(t,J=6.0Hz,2H),2.89(s,5H),2.45(t,J=6.0Hz,2H),1.92-1.88(m,1H),1.66-1.57(m,2H),1.36-1.27(m,3H);13C NMR(125MHz,CD3OD)δ211.0,195.5,174.5,171.8,171.1,61.6,60.5,58.8,54.9,49.1,37.5,36.1,34.4,33.7,9.01,6.34.
实施例14
1)氰基甲酸(中间体75)的合成:将氢氧化钠(15.0mmol)溶于10mL水中,缓慢滴加入盛有氰基甲酸乙酯(中间体74,5.0mmol)的圆底烧瓶中,室温搅拌反应1小时至反应液变澄清。然后将反应瓶置于冰浴中,缓慢滴加4M盐酸调节反应液pH至4.0,继续在冰浴中搅拌0.5小时。静置,抽滤,滤饼用少量冰水洗涤,得到白色粉末固体,即中间体75(0.20g,收率为57%)。中间体75的LC-MS(ESI,M+H+)m/z 72.4。1H NMR(500MHz,DMSO-d6)δ9.16(s,1H);13CNMR(125MHz,DMSO-d6)δ146.9,107.6.
2)((S)-1-(3-氟苯基)-4-(N-(S)-2-羟丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧合硼-2-基)苯基)磺酰胺基)-3-氧代丁基-2-基)氨基甲酰氰(中间体76)的合成:中间体76的合成与实施例2中中间体12的合成类似,区别仅在于将(E)-3-(3.4-二羟基苯基)丙烯酸替换为氰基甲酸,得到中间体76(0.84g,收率为83%)。中间体76的LC-MS(ESI,M+H+)m/z574.5。1H NMR(500MHz,CD3OD)δ7.86-7.80(m,2H),7.75-7.69(m,3H),7.31-7.27(m,1H),7.06(dd,J=8.0,2.0Hz,1H),7.00-6.93(m,2H),4.51(dt,J=7.5,6.0Hz,1H),4.02(ddd,J=12.0,6.5,5.5Hz,1H),3.95(d,J=15.0Hz,1H),3.84(d,J=15.0Hz,1H),3.31(dd,J=13.0,5.5Hz,1H),3.12(dd,J=14.0,6.0Hz,1H),3.09-3.02(m,2H),2.88(dd,J=13.5,6.0Hz,1H),1.24(d,J=7.0Hz,3H),1.23(s,12H);13C NMR(125MHz,CD3OD)δ201.2,165.4,163.5,145.5,141.7,139.4,139.3,138.9,135.3,130.5,130.4,126.0,125.2,125.1,116.7,116.5,114.3,114.1,112.8,84.0,65.2,58.3,56.2,51.6,37.6,37.4,24.8,20.1.
3)(4-(N-((S)-3)3-((氰基羰基)氨基)-4-(3-氟苯基)-2-氧代丁基)-N-((S)-2-羟丙基)氨磺酰基)苯基)硼酸(I-14,化合物14)的合成:化合物14的合成与实施例2中化合物2的合成类似,区别仅在于将中间体12替换为中间体76,得到化合物14(0.062g,收率为78%)。化合物14:LC-MS(ESI,M+H+)m/z 492.4。1H NMR(500MHz,CD3OD)δ7.96-7.90(m,2H),7.77-7.70(m,3H),7.53(s,2H),7.31-7.24(m,1H),7.06(dd,J=8.0,2.0Hz,1H),7.00-6.93(m,2H),4.51(dt,J=7.5,6.0Hz,1H),4.02(ddd,J=12.0,6.5,5.5Hz,1H),3.95(d,J=15.0Hz,1H),3.84(d,J=15.0Hz,1H),3.31(dd,J=13.0,5.5Hz,1H),3.12(dd,J=14.0,6.0Hz,1H),3.09-3.02(m,2H),2.88(dd,J=13.5,6.0Hz,1H),1.24(d,J=7.0Hz,3H);13CNMR(125MHz,CD3OD)δ201.2,165.5,163.5,145.5,139.4,139.3,138.9,137.1,134.6,130.5,130.4,127.1,125.2,125.1,116.7,116.5,114.3,114.0,112.8,65.2,58.3,56.2,51.6,37.6,37.6,20.1.
实施例15
1)叔丁基-((2R,3S)-2-羟基-5-甲基-1-((((R)-2-氧代恶唑烷酮-5-基)甲基)氨基)己基-3-基)氨基甲酸酯(中间体77)的合成:中间体77的合成与实施例7中中间体40的合成类似,区别仅在于将(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-4-环戊基丁烷替换为(2S,3S)-1,2-环氧-3-(叔丁氧基羰基氨基)-5-甲基己烷,得到中间体77(1.44g,收率为82%)。中间体77的LC-MS(ESI,M+H+)m/z 346.5。中间体77:1H NMR(500MHz,CDCl3)δ6.82(t,J=5.0Hz,1H),5.47(tt,J=7.0,6.0Hz,1H),5.39(d,J=7.0Hz,1H),4.73(dd,J=4.0,3.0Hz,1H),3.79-3.69(m,3H),3.59(d,J=5.0Hz,1H),3.42(ddd,J=13.5,5.0,3.0Hz,1H),3.20(ddd,J=14.0,6.0,3.5Hz,1H),3.04-2.98(m,2H),2.68(ddd,J=13.5,7.0,4.5Hz,1H),1.73-1.67(m,2H),1.35(ddd,J=13.5,8.0,6.5Hz,1H),1.27(s,9H),0.97(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3)δ158.9,156.8,79.7,76.5,71.3,53.6,52.3,50.4,44.4,39.3,28.4,26.1,22.7.
2)叔丁基-((S)-5-甲基-2-氧代-1-((((R)-2-氧代恶唑烷酮-5-基)甲基)氨基)己基-3-基)氨基甲酸酯(中间体78)的合成:中间体78的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体77,得到中间体78(1.15g,收率为84%)。中间体78的LC-MS(ESI,M+H+)m/z 344.5。1H NMR(500MHz,CDCl3)δ6.82(t,J=5.0Hz,1H),5.10(d,J=7.0Hz,1H),4.72(dd,J=3.5,3.0Hz,1H),4.12(dt,J=7.5,6.5Hz,1H),3.66(dd,J=13.0,4.5Hz,1H),3.55(dd,J=17.0,6.0Hz,1H),3.42-3.38(m,2H),3.18(ddd,J=14.5,6.5,3.5Hz,1H),3.00(ddd,J=14.5,6.5,3.5Hz,1H),2.83(d,J=6.5Hz,1H),1.67-1.62(m,2H),1.52-1.48(m,1H),1.26(s,9H),0.94-0.86(m,3H),0.82-0.77(m,3H);13C NMR(125MHz,CDCl3)δ210.8,158.9,156.0,79.8,76.0,58.3,57.3,50.0,44.4,40.9,28.3,24.9,22.4.
3)叔丁基-((3S)-1-(((苄氧基)-(4-(三氟甲基)苯基)磷酰基)-(((S)-2-氧代恶唑烷酮-5-基)甲基)氨基)-5-甲基-2-氧代己基-3-基)氨基甲酸酯(中间体79)的合成:中间体79的合成与实施例5中中间体28的合成类似,区别仅在于将中间体27替换为中间体78,将4-硝基苯基膦酰二氯替换为4-三氟甲基苯基膦酰二氯,得到中间体79(0.89g,收率为71%)。中间体79的LC-MS(ESI,M+H+)m/z 642.5。1H NMR(500MHz,CDCl3)δ7.73(dd,J=12.0,4.0Hz,2H),7.37-7.26(m,5H),7.09-6.99(m,2H),6.73(t,J=5.0Hz,1H),5.02(dd,J=3.5,3.0Hz,1H),5.01-4.98(m,2H),4.95(t,J=1.0Hz,1H),4.16-4.11(m,1H),3.88(d,J=14.0Hz,1H),3.76(d,J=14.0Hz,1H),3.69(dd,J=12.5,5.0Hz,1H),3.53(dd,J=12.5,4.0Hz,1H),3.46(ddd,J=13.0,5.0,3.0Hz,1H),3.27(dd,J=13.0,3.5Hz,1H),1.76-1.63(m,2H),1.50-1.41(m,1H),1.27(s,9H),0.94-0.86(m,3H),0.82-0.75(m,3H);13C NMR(125MHz,CDCl3)δ206.7,206.6,158.8,156.0,136.7,136.6,132.9,132.6,131.7,131.6,128.7,128.6,128.5,128.2,127.6,125.5,125.4,124.9,122.7,79.9,75.3,68.3,55.9,49.9,48.9,42.0,40.8,28.3,24.8,22.4.
4)苄基-N-((S)-3-氨基-5-甲基-2-氧代己基)-N-(((S)-2-氧代恶唑烷酮-5-基)甲基-P-(4-(三氟甲基)苯基)磷酰胺(中间体80)的合成:中间体80的合成与实施例5中中间体29的合成类似,区别仅在于将中间体28替换为中间体79,得到中间体80(0.57g,收率为82%)。中间体80的LC-MS(ESI,M+H+)m/z 542.3。1H NMR(500MHz,CDCl3)δ7.73(dd,J=12.0,4.0Hz,2H),7.32-7.26(m,5H),7.05-6.99(m,2H),6.73(t,J=5.0Hz,1H),5.02(dd,J=4.0,3.0Hz,1H),4.96(dt,J=8.5,1.0Hz,2H),4.38(d,J=6.0Hz,2H),3.88-3.76(m,4H),3.53(dd,J=12.5,4.0Hz,1H),3.46(ddd,J=13.0,5.0,3.0Hz,1H),3.27(dd,J=12.5,3.5Hz,1H),1.67-1.63(m,2H),1.47(ddd,J=14.0,8.0,6.5Hz,1H),0.96(d,J=7.0Hz,3H),0.86(d,J=7.0Hz,3H);13C NMR(125MHz,CDCl3)δ207.5,207.4,158.8,136.7,136.6,132.9,132.6,131.7,131.6,128.7,128.6,128.5,128.2,127.6,125.5,125.4,124.9,122.7,75.3,68.3,57.9,49.9,48.9,42.1,42.0,25.2,22.4.
5)苄基-N-((S)-5-甲基-2-氧代-3-(3-苯基丙酰胺基)己基)-N-(((S)-2-氧代恶唑烷酮-5-基)甲基-P-(4-(三氟甲基)苯基)磷酰胺(中间体81)的合成:中间体81的合成与实施例5中中间体30的合成类似,区别仅在于将中间体29替换为中间体80,将4-甲氧基-1H-吲哚-2-甲酰氯替换为3-苯丙酸,得到中间体81(0.35g,收率为84%)。中间体81的LC-MS(ESI,M+H+)m/z 674.5。1H NMR(500MHz,CD3OD)δ7.73(dd,J=12.0,4.0Hz,2H),7.37-7.19(m,7H),7.15(dd,J=6.5,2.5Hz,2H),7.07(s,1H),7.05-7.00(m,2H),6.73(t,J=5.0Hz,1H),5.02(dd,J=3.5,3.0Hz,1H),4.96(dt,J=8.5,1.0Hz,2H),4.17-4.09(m,1H),3.89(d,J=14.0Hz,1H),3.77(d,J=14.0Hz,1H),3.73-3.66(m,1H),3.53(dd,J=12.5,3.5Hz,1H),3.46(ddd,J=13.0,5.0,3.0Hz,1H),3.27(dd,J=12.5,3.5Hz,1H),2.87-2.78(m,2H),2.62-2.57(m,2H),1.73-1.66(m,2H),1.48-1.39(m,1H),0.94-0.86(m,3H),0.82-0.75(m,3H);13C NMR(125MHz,CD3OD)δ206.7,206.64172.9,158.8,140.3,136.7,136.7,132.9,132.6,131.7,131.6,128.8,128.7,128.6,128.5,128.2,127.6,126.5,125.5,125.4,124.9,122.7,75.3,68.3,56.0,49.9,48.7,42.1,40.8,33.9,31.2,24.9,22.4.
6)N-((S)-5-甲基-2-氧代-3-(3-苯基丙酰胺基)己基)-N-(((S)-2-氧代恶唑烷酮-5-基)甲基-P-(4-(三氟甲基)苯基)磷酰胺酸(I-15,化合物15)的合成:化合物15的合成与实施例5中化合物5的合成类似,区别仅在于将中间体30替换为中间体81,得到化合物15(0.088g,收率为82%)。化合物15:LC-MS(ESI,M+H+)m/z 584.5。1H NMR(500MHz,CD3OD)δ9.61(s,1H),7.72(dq,J=11.5,1.5Hz,2H),7.30-7.25(m,3H),7.16-7.09(m,4H),7.06(d,J=8.0Hz,1H),6.73(t,J=5.0Hz,1H),5.01(dd,J=3.5,3.0Hz,1H),4.12-4.09(m,1H),3.88(d,J=14.0Hz,1H),3.77(d,J=14.0Hz,1H),3.69(dd,J=12.5,5.0Hz,1H),3.54(dd,J=12.5,4.0Hz,1H),3.46(ddd,J=13.0,5.0,3.0Hz,1H),3.29(dd,J=12.5,4.0Hz,1H),2.87-2.78(m,2H),2.62-2.57(m,2H),1.76-1.73(m,2H),1.42-1.38(m,1H),0.94-0.86(m,3H),0.82-0.75(m,3H);13C NMR(125MHz,CD3OD)δ207.1,207.0,172.9,158.8,140.3,132.9,132.7,131.5,131.5,131.4,131.3,131.2,131.1,130.5,128.8,128.7,126.5,125.4,125.3,125.2,125.1,125.0,124.9,122.7,75.5,75.4,56.0,55.9,49.4,49.3,48.1,48.0,42.1,40.8,33.9,31.2,24.9,22.4.
实施例16
1)叔丁基-((2S,3R)-1-环己基-3-羟基-4-((((S)-四氢呋喃-2-基)甲基)氨基)丁基-2-基)氨基甲酸酯(中间体83)的合成:中间体83的合成与实施例5中中间体26的合成类似,区别仅在于将中间体25替换为中间体82,得到中间体83(2.58g,收率为81%)。中间体83的LC-MS(ESI,M+H+)m/z 371.4。1H NMR(500MHz,CDCl3)δ5.58(d,J=8.0Hz,1H),4.93(dd,J=7.0,6.0Hz,1H),3.91(ddd,J=6.0,4.0,2.0Hz,1H),3.79(ddd,J=9.0,7.0,5.0Hz,2H),3.70-3.63(m,2H),3.59(d,J=5.0Hz,1H),2.92-2.89(m,2H),2.73-2.64(m,2H),2.06-1.88(m,3H),1.80-1.72(m,2H),1.62-1.45(m,9H),1.41(s,9H),1.17(ddt,J=13.0,8.5,6.0Hz,2H);13C NMR(125MHz,CDCl3)δ156.8,79.7,79.2271.4,68.7,53.5,52.8,52.4,36.5,33.7,33.2,30.5,28.4,26.3,26.1,25.1.
2)叔丁基-((S)-1-环己基-3-氧代-4-((((S)-四氢呋喃-2-基)甲基)氨基)丁基-2-基)氨基甲酸酯(中间体84)的合成:中间体84的合成与实施例1中中间体4的合成类似,区别仅在于将中间体3替换为中间体83,得到中间体84(2.58g,收率为81%)。中间体84的LC-MS(ESI,M+H+)m/z 369.5。1H NMR(500MHz,CDCl3)δ5.54(d,J=8.0Hz,1H),4.09(dt,J=8.0,7.0Hz,1H),3.91(ddd,J=7.5,4.0,3.5Hz,1H),3.80(ddd,J=10.5,5.0,2.0Hz,1H),3.73-3.69(m,1H),3.55(dd,J=16.5,7.0Hz,1H),3.52-3.49(m,1H),3.41-3.39(m,1H),2.95(ddd,J=13.5,6.5,3.5Hz,1H),2.74(ddd,J=13.5,6.5,3.5Hz,1H),2.06-1.94(m,4H),1.80-1.76(m,1H),1.73-1.69(m,2H),1.55-1.43(m,8H),1.41(s,9H),1.19(ddt,J=13.0,8.5,6.0Hz,2H);13C NMR(125MHz,CDCl3)δ210.8,156.0,79.8,79.0,68.6,58.1,57.2,52.2,37.3,33.8,33.2,30.5,28.3,26.3,25.9,25.1.
3)叔丁基-((S)-1-环己基-4-((4-硝基-N-(((S)-四氢呋喃-2-基)甲基)苯基)磺酰胺基)-3-氧代丁基-2-基)氨基甲酸酯(中间体85)的合成:中间体85的合成与实施例1中中间体5的合成类似,区别仅在于将中间体4替换为中间体84,将2-氯-4-硝基苯磺酰氯替换为4-硝基苯磺酰氯,得到中间体85(1.73g,收率为79%)。中间体85的LC-MS(ESI,M+H+)m/z554.5。1H NMR(500MHz,CDCl3)δ8.17-8.11(m,2H),7.95-7.88(m,2H),5.41(d,J=8.0Hz,1H),4.22(ddd,J=7.0,4.5,2.0Hz,1H),4.18(dt,J=8.0,7.0Hz,1H),3.94(d,J=15.0Hz,1H),3.86-3.79(m,2H),3.68(dddd,J=9.0,6.0,4.0,2.0Hz,1H),3.44(dd,J=13.0,4.5Hz,1H),3.19(dd,J=13.0,4.5Hz,1H),2.05-1.94(m,2H),1.91-1.83(m,2H),1.81-1.76(m,1H),1.74-1.68(m,2H),1.55-1.47(m,5H),1.41-1.38(m,2H),1.24-1.19(m,2H);13C NMR(125MHz,CDCl3)δ202.6,156.0,150.0,142.4,128.2,124.5,79.9,77.9,68.4,56.2,52.7,51.6,37.3,33.9,33.2,29.6,28.3,26.3,25.9,25.6.
4)N-((S)-3-氨基-4-环己基-2-氧代丁基)-4-硝基-N-(((S)-四氢呋喃-2-基)甲基)苯磺酰胺(中间体86)的合成:中间体86的合成与实施例1中中间体6的合成类似,区别仅在于将中间体5替换为中间体85,得到中间体86(1.21g,收率为80%)。中间体86的LC-MS(ESI,M+H+)m/z 454.5。1H NMR(500MHz,CDCl3)δ8.17-8.11(m,2H),7.95-7.88(m,2H),4.68(d,J=6.5Hz,2H),4.22(dd,J=4.5,2.0Hz,1H),3.87(d,J=15.0Hz,1H),3.83-3.74(m,4H),3.43(dd,J=13.0,4.5Hz,1H),3.18(dd,J=13.0,4.5Hz,1H),2.04-1.97(m,1H),2.00-1.92(m,3H),1.72-1.58(m,10H),1.18(ddt,J=12.5,8.5,6.0Hz,2H);13C NMR(125MHz,CDCl3)δ203.8,150.0,142.4,128.1,124.5,78.0,68.4,57.6,52.7,51.9,38.5,34.3,33.1,29.6,26.3,25.9,25.6.
5)2-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酸(中间体88)的合成:将尿嘧啶(2.0mmol)和无水碳酸钾(4.0mmol)加入到干燥的反应瓶中,加入3.0mL无水DMF。在氩气保护下剧烈反应1小时,然后缓慢滴加入溴乙酸乙酯(2.4mmol),室温下搅拌反应过夜。次日。将氢氧化钠(6.0mmol)溶于5mL水中,缓慢滴加入反应液中,室温搅拌1小时。将反应瓶置于冰浴中,用4M盐酸调节pH至4.0,冰浴下继续搅拌反应0.5小时。过滤,滤饼用少量冰水洗涤,得到白色粉末固体,即中间体88(0.22g,65%)。中间体88的LC-MS(ESI,M+H+)m/z 171.4。1HNMR(500MHz,DMSO-d6)δ9.73(s,1H),9.63(s,1H),7.29-7.25(m,1H),5.81(d,J=7.5Hz,1H),4.27(d,J=1.0Hz,2H);13C NMR(125MHz,DMSO-d6)δ170.9,164.0,150.1,142.5,102.3,48.7.
6)N-((S)-1-环己基-4-((4-硝基-N-(((S)-四氢呋喃-2-基)甲基)苯基)磺酰胺基)-3-氧代丁基-2-基)-2-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酰胺(I-16,化合物16)的合成:化合物16的合成与实施例1中化合物1的合成类似,区别仅在于将(E)-3-(3.4-二羟基苯基)丙烯酸替换为2-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)乙酸,将中间体6替换为中间体86,得到化合物16(0.47g,收率为83%)。化合物16:LC-MS(ESI,M+H+)m/z 606.5。1HNMR(500MHz,CD3OD)δ9.77(s,1H),8.17-8.11(m,2H),7.95-7.88(m,2H),7.74(d,J=9.0Hz,1H),7.33-7.27(m,1H),5.83(d,J=7.5Hz,1H),4.42-4.36(m,2H),4.22(dd,J=4.5,2.0Hz,1H),4.13(dt,J=9.5,7.0Hz,1H),3.89-3.74(m,4H),3.44(dd,J=13.0,4.5Hz,1H),3.19(dd,J=13.0,4.5Hz,1H),2.05-1.94(m,2H),1.94-1.85(m,5H),1.55-1.37(m,9H),1.19(ddt,J=13.0,8.5,6.0Hz,2H);13C NMR(125MHz,CD3OD)δ202.6,169.0,164.0,150.0,149.5,142.4,142.3,128.2,124.5,102.3,77.9,68.4,55.4,52.7,51.6,49.8,37.3,34.2,33.2,29.6,26.3,25.9,25.6.
测试例1
(1)将实施例1~16制备的化合物I-1~I-16均用DMSO溶解,并用双蒸水进行梯度稀释得到不同浓度的溶液作为样品,按照下述方法测定上述化合物对SARS-CoV和SARS-CoV-2的3CL蛋白酶抑制活性和细胞毒性,其中,细胞和病毒均来源于大肠杆菌BL21(DE3)细胞。
(1.1)3CL蛋白酶抑制活性测试:对SARS-CoV-23CL蛋白酶的抑制活性:首先将3CL片段构建到pGEX-6p-1载体上。以3CL序列为模板,利用引物(上游引物:5′-CGG GAT CCGCGG TACAGAGTG GTTTCAGGAAAATGG CA-3′,下游引物:5′-CCG CTC GAG TTAGTG GTG GTGGTG GTG GTG GGG TCC GAAGGTAAC TCC-3′)扩增3CL片段。将所扩增片段利用BamHI/Xhol进行双酶切,经琼脂糖凝胶电泳及胶回收后,利用T4连接酶将目的片段与BamHI/Xhol线性化的pGEX-6P-1载体连接,构建表达质粒(pGEX-SARS-3CL)。将pGEX-SARS-3CL转化至原核表达菌株BL21感受态,转化后的大肠杆菌涂布于含有终浓度100μg/mL氨苄西林的Luria-Bertani(LB)固体培养基上,37℃过夜培养。次日,取5mL菌液加至200mL LB液体培养基中,培养至菌液OD600为0.4~0.6。向培养基中加入终浓度为1mmol/L的异丙基硫代-β-D-半乳糖苷诱导蛋白酶的表达。25℃培养6小时后,6000×g离心5分钟,收集菌体,进行纯化。利用荧光能量共振转移技术设计并合成3CL蛋白酶的荧光底物(参考文献:李萍,陈子诺,崔清华,杜瑞坤.中医药来源2019新型冠状病毒3CL蛋白酶抑制剂的筛选[J].中华中医药杂志,2021,36(10),6154-6157.)。在黑色透明的96孔板中加入40μL500nmol/L蛋白溶液、10μL50μmol/L的待测药物,震荡孵育30min,然后加入50μL浓度为50μmol/L的底物,在37℃、200次/分钟条件下震荡孵育5s,进行荧光检测。SARS-CoV 3CL蛋白酶抑制活性测试与SARS-CoV-23CL蛋白酶抑制活性的测试方法类似。测试结果如表1所示。
(1.2)细胞毒性测试:化合物细胞毒性采用试剂盒Cell CountingKit-8(CCK-8试剂盒)测定。用96孔板对化合物进行细胞毒性测试,每孔加入293T细胞2万个,在37℃条件下孵育24h后加入1μL样品,继续孵育24h,加入10μL CCK-8,孵育2h后测定在450nm下的吸光度,计算出各个浓度存活细胞的百分率,用Graphpad软件计算得到CC50值,以DMSO为空白对照。测试结果如表1所示。
(2)实施例1~9制备的化合物I-1~I-9对SARS-CoV和SARS-CoV-2的抗病毒活性。测试方法:将Huh7、Huh7.5、H460及C3A等细胞分别按照细胞数每孔2.5×104、2.5×104、2.0×104及3.0×104个接种到96孔培养板,在37℃下培养24h后,用含2%FBS(体积分数)的DMEM培养基按浓度梯度稀释药物并加入到96孔培养板继续培养,给药48h后,加入PrestoBlue进行细胞增殖率测定。
表1化合物I-1~I-16的对SARS-CoV、SARS-CoV-2的3CL蛋白酶抑制活性和抗病毒活性以及细胞毒性测试结果
由表1可知:(1)化合物I-1~I-16对SARS-CoV和SARS-CoV-2的3CL蛋白酶抑制活性分别为12~154nM和8~108nM。表明,化合物I-1~I-9对SARS-CoV和SARS-CoV-2的3CL蛋白酶具有显著的抑制活性,且均在nM水平。(2)化合物I-1~I-16均具有较低的细胞毒性。(3)化合物I-1~I-16对SARS-CoV和SARS-CoV-2的抗病毒活性分别为0.052~1.03μM和0.043~0.85μM。表明,化合物I-1~I-16对SARS-CoV和SARS-CoV-2均具有显著的抗病毒活性。
综上所述,本发明提供的具有式I所示结构的包含氧代亚乙基类化合物或其药学上可接受的盐具有显著的SARS-CoV和SARS-CoV-23CL蛋白酶抑制活性和抗病毒活性;毒性研究显示其具有良好的成药性,表明该类化合物作为广谱抗Sarbecovirus亚属冠状病毒药物具有良好的应用前景。根据实验数据可知,本发明提供的的化合物对SARS-CoV和SARS-CoV-23CL蛋白酶具有显著的抑制活性,对SARS-CoV和SARS-CoV-2具有明显的抗病毒活性,而且均具有较低的细胞毒性。表明,本发明提供的含氧代乙基类化合物或其药学上可接受的盐有望成为一种新的广谱Sarbecovirus亚属冠状病毒3CL蛋白酶抑制剂。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种氧代亚乙基类化合物或其药学上可接受的盐,所述氧代亚乙基类化合物具有式I所示结构:
所述式I中:
化合物I-1:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-2:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-4:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-7:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-8:当M为时,R1为/>R2为/>R3为/>R4为/>
化合物I-9:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-10:当M为时,R1为/>R2为/>R3为-OH,R4为/>
化合物I-11:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-12:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-14:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-15:当M为时,R1为/>R2为/>R3为/>R4为
化合物I-16:当M为时,R1为/>R2为/>R3为/>R4为
2.根据权利要求1所述的氧代亚乙基类化合物或其药学上可接受的盐,其特征在于,所述药学上可接受的盐选自盐酸盐、硫酸盐、磷酸盐或马来酸盐。
3.权利要求1所述的氧代亚乙基类化合物的制备方法,(i)式I中,当R4为时,所述氧代亚乙基类化合物的制备方法包括以下步骤:
将化合物II-1、具有式III所示结构的胺衍生物和胺类催化剂混合,进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物;
其中R1、R2、R3和M与式I中相同;
(ii)式I中,R4为除之外的其他取代基时,所述氧代亚乙基类化合物的制备方法包括以下步骤:
将化合物II-2、具有式III所示结构的胺衍生物、碳化二亚胺盐酸盐、1-羟基苯并三唑和4-二甲氨基吡啶混合进行缩合反应,得到具有式I所示结构的氧代亚乙基类化合物;
化合物II-2,其中n=0或1。
4.根据权利要求3所述的制备方法,其特征在于,所述具有式III所示结构的胺衍生物的制备方法包括以下步骤:
将具有式a所示结构的化合物与具有式b所示结构的化合物进行亲核取代反应,得到具有式c所示结构的中间体;
将所述具有式c所示结构的中间体与戴斯-马丁氧化剂进行氧化反应,得到具有式d所示结构的中间体;
将所述具有式d所示结构的中间体与具有式e所示结构的化合物进行反应,得到具有式f所示结构的中间体;所述具有式e所示结构的化合物为具有式e-1、式e-2或e-4所示结构的化合物;所述式f所示结构的中间体为具有式f-1、式f-2或式f-4所示结构的化合物;
将所述具有式f所示结构的中间体进行脱保护基,得到具有式III所示结构的胺衍生物;
5.一种药物组合物,包括氧代亚乙基类化合物和/或其药学上可接受的盐以及药学上可接受的辅料;
所述氧代亚乙基类化合物和/或其药学上可接受的盐为权利要求1~2任一项所述的氧代亚乙基类化合物和/或其药学上可接受的盐或权利要求3~4任一项所述制备方法得到的氧代亚乙基类化合物。
6.根据权利要求5所述的药物组合物,其特征在于,所述药学上可接受的辅料包括载体和赋形剂中的一种或几种。
7.根据权利要求5或6所述的药物组合物,其特征在于,所述药物组合物的剂型包括片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、透皮剂、栓剂或冻干粉针剂。
8.权利要求1~2任一项所述的氧代亚乙基类化合物或其药学上可接受的盐、权利要求3~4任一项所述制备方法制备得到的氧代亚乙基类化合物和权利要求5~7任一项所述的药物组合物中的一种或几种在制备Sarbecovirus亚属冠状病毒3CL蛋白酶抑制剂或抗Sarbecovirus亚属冠状病毒药物中的应用。
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