CN115611881A - 一种合成新型vhl配体4-f-vh032的方法 - Google Patents
一种合成新型vhl配体4-f-vh032的方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明属化学合成技术领域，涉及一种合成下式1的新型VHL配体4‑F‑VH032的方法。本发明所述制备4‑F‑VH032的技术路线，操作简单，路线简洁，收率较高，所用试剂均为常用试剂。本发明所述VH032是一种VHL配体，用于募集von Hippel‑Lindau(VHL)蛋白。VH032是VHL/HIF‑1α相互作用抑制剂，Kd为185nM。VH032可通过linker与靶蛋白配体连接，形成PROTAC分子。
Description
技术领域
本发明属于化学合成技术领域，涉及一种合成基于VH032的新型VHL配体4-F-VH032(1)的方法。
背景技术
寻找新的小分子工具探索和调控基本的生物过程是当前化学生物学以及药物化学研究的主要内容之一。[1]其中，PROTAC(Proteolysis-targeting chimeras)是利用小分子诱导靶蛋白泛素化，利用泛素化蛋白酶体系统(Ubiquitin-proteasome system,UPS)实现靶蛋白降解的技术。[2]PROTAC是一种具有哑铃型结构的双功能小分子，通过连接链(linker)将靶蛋白配体与E3泛素连接酶配体相连。在体内可以将靶蛋白和E3酶拉近形成三元复合物，使靶蛋白被泛素化，并进一步通过蛋白酶体被降解。靶蛋白降解后，PROTAC分子又可以被释放循环参与到下一个蛋白的降解过程，因此，这种降解作用具有催化效果，较少的药物剂量就可以实现高效的降解(如图1所示)。[3]PROTAC技术已经成为新药研发领域的最热门技术之一。[4]2020年12月14日Arvinas公司公布了PROTAC新药ARV-471和ARV-110的I期临床实验结果，具有良好的口服利用度和良好的安全性和耐受性。[5]随着临床试验逐步完成，PROTAC或将迎来全新的发展。近期Nature Review Drug Discovery期刊发表评论文章，预计今年年底将有至少15款PROTAC药物进入临床阶段。[6]
PROTAC的思路在2001年被Crews，Deshaies等人提出，[7]受限于缺乏具有成药性的小分子E3连接酶配体，PROTAC一直没有受到学术界和工业界广泛的关注。直到耶鲁大学Crews教授设计出了第一例小分子VHL配体后，[8]PROTAC技术才受到了广泛的关注。后续也不断有研究组报道关于VHL配体结构优化的结果，[9]其中VH032及其类似物已经商业化并被用于药物化学以及化学生物学等基础研究当中。[10]关于VHL配体的优化主要集中于左右两个侧链，对其核心羟脯氨酸区域的优化仅有2018年邓迪大学Ciulli教授进行了报道。[11]其研究表明，通过引入2-氟原子得到活性与VH032相当的VHL配体，并且脯氨酸C4-exo构象是VHL保持活性的关键因素。因此，在保留脯氨酸C4-exo构象的基础上，对脯氨酸进行修饰将有可能得到具有新的核心骨架的VHL配体(如图2所示)。
基于现有技术的基础与现状，本申请的发明人拟提供一种合成基于VH032的新型VHL配体4-F-VH032(1)的方法。
参考文献：
[1](a)Schenone,M.；Dancik,V.；Wagner,B.K.；Clemons,P.A.Targetidentification and mechanism of action in chemical biology and drug discoveryNat Chem Biol 2013,9,232-240.(b)Singh,H.；Tiwari,K.；Tiwari,R.；Pramanik,S.K.；Das,A.Small Molecule as Fluorescent Probes for Monitoring IntracellularEnzymatic Transformations Chem.Rev.2019,119,11718-11760.
[2]GeorgeM.Burslemand Craig M.Crews.Proteolysis-Targeting Chimeras asTherapeutics and Tools for Biological Discovery.Cell.2020,181,102-114.
[3](a)Gao,H.；Sun,X.；Rao,Y.PROTAC Technology:Opportunities andChallenges ACS Med.Chem.Lett.2021,10.1021/acsmedchemlett.9b00597.(b)Nalawansha,D.A.；Crews,C.M.PROTACs:An Emerging Therapeutic Modality inPrecision Medicine Cell Chem.Biol.2020,27,998-1014.
[4](a)Lai,A.C.；Crews,C.M.Induced protein degradation:an emerging drugdiscovery paradigm Nat.Rev.Drug.Discov.2017,16,101-114.(b)
M.；Yoon,H.；Koeppel,J.；Nitsch,L.；Roy Burman,S.S.；Di Genua,C.；Donovan,K.A.；Sperling,A.S.；Hunkeler,M.；Tsai,J.M.；Sharma,R.；Guirguis,A.；Zou,C.；Chudasama,P.；Gasser,J.A.；Miller,P.G.；Scholl,C.；
S.；Nowak,R.P.；Fischer,E.S.；Ebert,B.L.Small-molecule-induced polymerization triggers degradation of BCL6 Nature 2020,588,164-168.
[5](a)Trial of ARV-110 in Patients With Metastatic CastrationResistant Prostate Cancer,https://clinicaltrials.gov,(b)A Phase 1/2 Trial ofARV-471 Alone and in Combination With Palbociclib
in PatientsWith ER+/HER2-Locally Advanced or Metastatic Breast Cancer,https:// clinicaltrials.gov.
[6]Targeted protein degraders crowd into the clinicNat.Rev.Drug.Discov.2021,10.1038/d41573-021-00052-4
[7]Sakamoto,K.M.；Kim,K.B.；Kumagai,A.；Mercurio,F.；Crews,C.M.；Deshaies,R.J.Protacs:Chimeric molecules that target proteins to the Skp1–Cullin–F boxcomplex for ubiquitination and degradation Proc.Natl.Acad.Sci.USA2001.988554-8559.
[8](a)Buckley,D.L.；Van Molle,I.；Gareiss,P.C.；Tae,H.S.；Michel,J.；Noblin,D.J.；Jorgensen,W.L.；Ciulli,A.；Crews,C.M.Targeting the von Hippel-Lindau E3Ubiquitin Ligase Using Small Molecules to Disrupt the VHL/HIF-1αInteraction.J.Am.Chem.Soc.2012,134,4465-4468.(b)Galdeano,C.；Gadd,M.S.；Soares,P.；Scaffidi,S.；Van Molle,I.；Birced,I.；Hewitt,S.；Dias,D.M.；Ciulli,A.Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau(VHL)E3 ubiquitin ligaseandthe hypoxia inducible factor(HIF)alpha subunit with in vitro nanomolaraffinities J.Med.Chem.2014,57,8657-8663.
[9](a)Ishida,T.；Ciulli,A.E3 Ligase Ligands for PROTACs:How They WereFound and How to Discover New Ones SLAS Discov 2020,2472555220965528.(b)Morreale,F.E.；Walden,H.Types of Ubiquitin Ligases Cell 2016,165,248-248e241.
[10](a)Blaquiere,N.；Villemure,E.；Staben,S.T.Medicinal Chemistry ofInhibiting RING-Type E3 Ubiquitin Ligases J.Med.Chem.2020,63,7957-7985.
[11]Testa,A.；Lucas,X.；Castro,G.V.；Chan,K.H.；Wright,J.E.；Runcie,A.C.；Gadd,M.S.；Harrison,W.T.A.；Ko,E.J.；Fletcher,D.；Ciulli,A.3-Fluoro-4-hydroxyprolines:Synthesis,Conformational Analysis,and StereoselectiveRecognition by the VHL E3 Ubiquitin Ligase for Targeted Protein DegradationJ.Am.Chem.Soc.2018,140,9299-9313.。
发明内容
本发明的目的是基于现有技术的基础与现状，提供一种合成基于VH032的新型VHL配体4-F-VH032(1)的方法。
本发明的合成路线的特点是:反应条件简单，选择性高，可以进行大量制备，为VHL类似物的不对称合成奠定了基础。
本发明的具体技术路线如下，在下文的陈述实施例中，中间体通式是根据结构式中的编号，用阿拉伯数字表示，其中OTBS是指叔丁基二甲基硅氧基，Boc是指叔丁氧羰基。
上述合成路线包括以下合成步骤：
步骤1：向化合物2的四氢呋喃溶液中加入1-溴-4-(异氰甲基)苯、一种路易斯酸，在-78℃-室温反应12小时后，再经过饱和碳酸氢钠水溶液处理，萃取分液、干燥浓缩、柱层析纯化得到化合物3；这里所说的一种路易斯酸是指三氟甲磺酸锌，三氟甲磺酸铁，三氟甲磺酸镍，三氟甲磺酸铜，三氟甲磺酸镧，三氟甲磺酸钪，三氟化硼乙醚，三氟甲磺酸三甲基硅脂。
步骤2：将上述化合物3溶于二氯甲烷中，于0℃下加入一种氟化试剂，室温搅拌12小时，经饱和碳酸氢钠水溶液淬灭、萃取分液，干燥浓缩，柱层析纯化后得到化合物4；这里所说的一种氟化试剂是指氟化钾，氟化铯，四丁基氟化铵，四氟化硫，二乙胺基三氟化硫，1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)。
步骤3：将上述化合物4溶于二氯甲烷中，室温加入三氟乙酸，搅拌10小时后，浓缩。随后将浓缩物溶解于二氯甲烷中，加入(S)-2-((叔丁氧羰基)氨基)-3,3-二甲基丁酸，一种缩合剂和一种碱，室温反应10小时候淬灭后经柱层析纯化得到化合物5；这里所说的一种缩合剂是指二环己基碳二亚胺，N,N'-二异丙基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，N,N'-羰基二咪唑，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，1-羟基苯并三唑，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。一种碱是指三乙胺，二乙胺，N,N-二异丙基乙胺，咪唑。
步骤4：将上述化合物5溶于二氯甲烷中，室温加入三氟乙酸，搅拌10小时后，浓缩。随后将浓缩物溶解于二氯甲烷中，加入乙酸酐和一种碱室温反应10小时候，淬灭后经柱层析纯化得到化合物6；这里所说的一种碱是指三乙胺，二乙胺，N,N-二异丙基乙胺。
步骤5：将上述化合物6溶于N,N-二甲基乙酰胺中，加入醋酸钯，醋酸钾和4-甲基噻唑，回流反应12小时，淬灭后经柱层析纯化得到化合物1；
本发明提供了一种合成基于VH032的新型VHL配体4-F-VH032(1)的方法。本发明所述VH032是一种VHL配体，用于募集von Hippel-Lindau(VHL)蛋白。VH032是VHL/HIF-1α相互作用抑制剂，Kd为185nM。VH032可通过linker与靶蛋白配体连接，形成PROTAC分子。本发明所述的合成4-F-VH032的方法，其技术路线操作简单，路线简洁，收率较高，所用的试剂均为常用试剂，而且，可适合大规模制备。
附图说明
图1.PROTAC技术基本原理。
图2.VHL配体的结构特征及代表性化合物。
具体实施方式
实施例1
步骤1：合成化合物3
(2S，4S)-2-((4-溴苯基)氨甲酰基)-4-羟基吡咯烷-1-羧酸叔丁酯在-78℃将化合物2(1.0mmol)、1-溴-4-(异氰甲基)苯(1.0mmol)溶解于四氢呋喃(5mL)中，然后添加Cu(OTf)2(0.2mmol)。反应在-78℃搅拌至室温过夜，然后用饱和碳酸氢钠水溶液淬灭并用乙酸乙酯(30mL×3)萃取。合并的有机层用盐水洗涤、干燥、过滤和浓缩。通过硅胶(石油醚/乙酸乙酯＝1:1)上的快速色谱法纯化残余物，得到目标产物3(259mg,65％)1H NMR(400MHz,CD3OD)δ6.73-6.59(m,2H),6.53-6.39(m,2H),3.65-3.40(m,4H),2.82-2.75(m,1H),2.67-2.60(m,1H),1.69-1.56(m,1H),1.25-1.17(m,1H),0.68(s,3.5H),0.55(s,5.5H)ppm.
步骤2：合成化合物4
(2S，4R)-2-((4-溴苯基)氨甲酰基)-4-氟吡咯烷-1-羧酸叔丁酯将3(400mg，1.0mmol)存于二氯甲烷(3mL)中之溶液于0℃添加至二乙胺基三氟化硫(0.67mL，5mmol)。在0℃至室温搅拌4h后，加入饱和碳酸氢钠水溶液，用二氯甲烷(10mL×3)萃取。合并的有机层用盐水洗涤、干燥、过滤和浓缩。通过硅胶(石油醚/乙酸乙酯＝1:1)上的快速色谱法纯化，得到所需产物4(188mg,47％)1H NMR(400MHz,CD3OD,mixture of rotamers)δ7.51-7.44(m,2H),7.30-7.21(m,2H),5.35-5.15(m,1H),4.45-4.27(m,3H),3.90-3.78(m,1H),3.72-3.53(m,1H),2.64-2.48(m,1H),2.24-2.01(m,1H),1.50(s,3.5H),1.36(s,5.5H)ppm；
步骤3：合成化合物5
叔丁基((S)-1-((2S，4R)-2-((4-溴苯基)氨甲酰基)-4-氟吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)氨基甲酸酯在室温下将4(150mg，0.37mmol)存于三氟乙酸/二氯甲烷(1/1mL)中的溶液搅拌1h。在减压下蒸发混合物以得到相应的中间体进一步纯化。将相应的中间体溶解于二甲基甲酰胺(1mL)，加入(S)-2-((叔丁氧羰基)氨基)-3,3-二甲基丁酸(86mg，0.37mmol)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(156mg，0.41mmol)和二异丙基乙基胺(0.26mL，1.48mmol)。室温搅拌3h后，加水，用乙酸乙酯(10ml×3)萃取。合并的有机层用盐水洗涤、干燥、过滤和浓缩。残渣在硅胶(石油醚/乙酸乙酯＝1:1)上通过快速色谱法纯化，得到目标产物5(158mg,83％)1H NMR(400MHz,CD3OD,mixtureof rotamers)δ7.49-7.43(m,2H),7.33-7.24(m,2H),5.46-5.26(m,1H),4.61-4.53(m,1H),4.51-4.43(m,1H),4.35-4.20(m,3H),3.95-3.78(m,1H),2.63-2.48(m,1H),2.28-2.08(m,1H),1.46(s,9H),1.03(s,9H)ppm.
步骤4：合成化合物6
(2S，4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-N-(4-溴苯基)-4-氟吡咯烷-2-甲酰胺在室温下将5(150mg，0.29mmol)存于三氟乙酸/二氯甲烷(1/1mL)中的溶液搅拌1h。在减压下蒸发混合物以得到相应的中间体进一步纯化。将相应中间体溶解于二氯甲烷(2mL)中，并向溶液中添加三乙胺(120μL，0.88mmol)。在室温下搅拌混合物10min后，添加醋酸酐(41μL，0.44mmol)，在室温下搅拌反应3h，减压浓缩。通过硅胶(石油醚/乙酸乙酯＝1:1)快速色谱法纯化，得到目标产物6(112mg,85％)1H NMR(400MHz,CD3OD,mixture ofrotamers)δ7.52-7.43(m,2H),7.32-7.27(m,2H),5.43-5.25(m,1H),4.60-4.45(m,3H),4.38-4.24(m,2H),3.95-3.78(m,1H),2.59-2.46(m,1H),2.27-2.09(m,1H),2.02(s,3H),1.06(s,9H)ppm.
步骤5：合成化合物1
(2S，4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-4-氟-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺
在二甲基乙酰胺(2mL)中，将6(100mg，0.22mmol)和醋酸钯(1mg，2mol％)的溶液中添加醋酸钾(43mg，0.44mmol)和4-甲基噻唑(44mg，0.44mmol)。将所得混合物加热至150℃，搅拌12h。用水稀释，二氯甲烷(3×10mL)萃取。将有机相用硫酸镁干燥，减压浓缩。用硅胶(石油醚/乙酸乙酯＝1:1)进行快速层析纯化，得到目标产物1。(70mg,67％)1H NMR(400MHz,CD3OD,mixture of rotamers)δ8.89(s,1H),7.54-7.40(m,4H),5.45-5.28(m,1H),4.62-4.55(m,3H),4.40-4.28(m,2H),3.96-3.81(m,1H),2.65-2.52(m,1H),2.49(s,3H),2.29-2.12(m,1H),2.02(s,3H),1.07(s,9H)ppm.。
实施例2
步骤1：合成化合物3
(2S，4S)-2-((4-溴苯基)氨甲酰基)-4-羟基吡咯烷-1-羧酸叔丁酯在-78℃将化合物2(1.0mmol)、1-溴-4-(异氰甲基)苯(1.0mmol)溶解于乙酸乙酯(5mL)中，然后添加三氟甲磺酸铜(0.2mmol)。反应在-78℃搅拌至室温过夜，然后用饱和碳酸氢钠水溶液淬灭并用乙酸乙酯(30mL×3)萃取。合并的有机层用盐水洗涤、干燥、过滤和浓缩。通过硅胶(石油醚/乙酸乙酯＝1:1)上的快速色谱法纯化残余物，得到目标产物3(301mg,75％)1H NMR(400MHz,CD3OD)δ6.73-6.59(m,2H),6.53-6.39(m,2H),3.65-3.40(m,4H),2.82-2.75(m,1H),2.67-2.60(m,1H),1.69-1.56(m,1H),1.25-1.17(m,1H),0.68(s,3.5H),0.55(s,5.5H)ppm.
步骤2-5:同实施例1。
实施例3
步骤1：合成化合物3
(2S，4S)-2-((4-溴苯基)氨甲酰基)-4-羟基吡咯烷-1-羧酸叔丁酯在-78℃将化合物2(1.0mmol)、1-溴-4-(异氰甲基)苯(1.0mmol)溶解于四氢呋喃(5mL)中，然后添加三氟甲磺酸铁(0.2mmol)。反应在-78℃搅拌至室温过夜，然后用饱和碳酸氢钠水溶液淬灭并用乙酸乙酯(30mL×3)萃取。合并的有机层用盐水洗涤、干燥、过滤和浓缩。通过硅胶(石油醚/乙酸乙酯＝1:1)上的快速色谱法纯化残余物，得到目标产物3(201mg,50％)1H NMR(400MHz,CD3OD)δ6.73-6.59(m,2H),6.53-6.39(m,2H),3.65-3.40(m,4H),2.82-2.75(m,1H),2.67-2.60(m,1H),1.69-1.56(m,1H),1.25-1.17(m,1H),0.68(s,3.5H),0.55(s,5.5H)ppm.
步骤2-5:同实施例1。
实施例4
步骤1同实施例1
步骤2：合成化合物4
(2S，4R)-2-((4-溴苯基)氨甲酰基)-4-氟吡咯烷-1-羧酸叔丁酯将3(400mg，1.0mmol)溶解于二氯甲烷(3mL)中于0℃添加四氟化硫(5mmol)。在0℃至室温搅拌4h后，加入饱和碳酸氢钠水溶液，用二氯甲烷(10mL×3)萃取。合并的有机层用盐水洗涤、干燥、过滤和浓缩。通过硅胶(石油醚/乙酸乙酯＝1:1)快速色谱法纯化，得到所需产物4(220mg,55％)1HNMR(400MHz,CD3OD,mixture of rotamers)δ7.51-7.44(m,2H),7.30-7.21(m,2H),5.35-5.15(m,1H),4.45-4.27(m,3H),3.90-3.78(m,1H),3.72-3.53(m,1H),2.64-2.48(m,1H),2.24-2.01(m,1H),1.50(s,3.5H),1.36(s,5.5H)ppm。
Claims (5)
1.一种合成化合物4-F-VH032的方法，其特征在于，按下述合成路线和步骤：
其中OTBS是指叔丁基二甲基硅氧基，Boc是指叔丁氧羰基；
步骤1：向化合物2的四氢呋喃溶液中加入1-溴-4-(异氰甲基)苯、一种路易斯酸，在-78℃-室温反应12小时后，再经过饱和碳酸氢钠水溶液处理，萃取分液、干燥浓缩、柱层析纯化得到化合物3；
步骤2：将上述化合物3溶于二氯甲烷中，于0℃下加入一种氟化试剂，室温搅拌12小时，经饱和碳酸氢钠水溶液淬灭、萃取分液，干燥浓缩，柱层析纯化后得到化合物4；
步骤3：将上述化合物4溶于二氯甲烷中，室温加入三氟乙酸，搅拌10小时后，浓缩。随后将浓缩物溶解于二氯甲烷中，加入(S)-2-((叔丁氧羰基)氨基)-3,3-二甲基丁酸，一种缩合剂和一种碱，室温反应10小时候淬灭后经柱层析纯化得到化合物5；
步骤4：将上述化合物5溶于二氯甲烷中，室温加入三氟乙酸，搅拌10小时后，浓缩。随后将浓缩物溶解于二氯甲烷中，加入乙酸酐和一种碱室温反应10小时候，淬灭后经柱层析纯化得到化合物6；
步骤5：将上述化合物6溶于N,N-二甲基乙酰胺中，加入醋酸钯，醋酸钾和4-甲基噻唑，回流反应12小时，淬灭后经柱层析纯化得到化合物1(4-F-VH032)。
2.按权利要求1所述的方法，其特征在于，步骤1中所述的一种路易斯酸是三氟甲磺酸锌，三氟甲磺酸铁，三氟甲磺酸镍，三氟甲磺酸铜，三氟甲磺酸镧，三氟甲磺酸钪，三氟化硼乙醚，三氟甲磺酸三甲基硅脂。
3.按权利要求1所述的方法，其特征在于，步骤2中所述的一种氟化试剂是指氟化钾，氟化铯，四丁基氟化铵，四氟化硫，二乙胺基三氟化硫，1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)。
4.按权利要求1所述的方法，其特征在于，步骤3中所述的缩合剂是指二环己基碳二亚胺，N,N'-二异丙基碳二亚胺，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，N,N'-羰基二咪唑，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，1-羟基苯并三唑，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。一种碱是指三乙胺，二乙胺，N,N-二异丙基乙胺，咪唑。
5.按权利要求1所述的方法，其特征在于，步骤4中所述的一种碱是指三乙胺，二乙胺，N,N-二异丙基乙胺。
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