CN117304253A - 一种二氮杂双环拟肽衍生物的制备方法及应用 - Google Patents
一种二氮杂双环拟肽衍生物的制备方法及应用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K38/05—Dipeptides
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
本发明公开了一种二氮杂双环拟肽衍生物的制备方法及其应用,所述制备方法采用磺酰胺作为亲核试剂的分子内亲核取代反应关环合成8元环,再脱除磺酰基合成1,5‑二氮杂双环[6,3,0]十一烷酮氨基酸衍生物;本发明制备方法所制得的衍生物是一类构象控制的模拟二肽的拟肽,可以用于以多肽为先导化合物的新药研发,尤其可以用于IAPs抑制剂Xevinapant的制备。
Description
技术领域
本发明为生物医药领域,涉及一种二氮杂双环拟肽衍生物的制备方法,还涉及其在拟肽合成中的应用,尤其是在IAPs抑制剂Xevinapan的合成中的应用。
背景技术
细胞凋亡是细胞生命活动中的一个重要过程,其主要作用是去除老化、受损和不需要的细胞。凋亡机制失调与很多人类疾病有关,通过不同机制逃避凋亡是癌症的重要特征之一,因此很多在细胞凋亡中起重要调控作用的蛋白都被认为是研发抗癌药物的靶点。凋亡抑制蛋白IAPs是一类细胞凋亡的逆向调节剂,可以通过抑制半胱天冬酶的激活或直接结合并抑制部分半胱天冬酶的活性阻止凋亡的发生。在IAPs中,XIAP、cIAP1和cIAP2在多种肿瘤中过度表达,而且它们的过度表达与肿瘤抗药性的产生密切相关,因此小分子IAPs抑制剂有可能被发展成为新型的抗肿瘤药物。
SM-406是美国密西根大学王少萌课题组研发的一个小分子IAPs抑制剂,可以与XIAP、cIAP1和cIAP2有效结合,而且可以诱导cIAP1和cIAP2的降解(J.Med.Chem.,2011,54,2714-2726)。SM-406于2011年被转让给瑞士制药公司Debiopharm,并被重新命名为Debio1143。2021年,Debio1143被以8.98亿欧元转让给默沙东,并被命名为Xevinapant,目前正在进行三期临床,有望成为首个上市的IAPs抑制剂。
Xevinapant中含有一个1,5-二氮杂双环[6,3,0]十一烷酮的核心骨架,因此1,5-二氮杂双环[6,3,0]十一烷酮氨基酸衍生物是合成Xevinapant的关键中间体。这种1,5-二氮杂双环[6,3,0]十一烷酮氨基酸衍生物也可以作为模拟二肽的拟肽用于其它拟肽药物的研发中,例如最近这类化合物已被用于STAT3抑制剂的研发中。发展有效的合成1,5-二氮杂双环[6,3,0]十一烷酮氨基酸衍生物的方法在拟肽药物的研发领域有重要意义,而且有可能产生重要的经济价值。目前已报道的1,5-二氮杂双环[6,3,0]十一烷酮氨基酸衍生物的合成方法共有两种,均为密西根大学王少萌课题组报道,两种合成方法如下:
方法1:
方法2:
方法1(Tetra.Lett.,2006,47,4769-4770;WO2008/128171;WO2007/130626)步骤繁杂,且由于在合成化合物B时需要在乙酯和叔丁酯之间选择性还原乙酯基,这种方法只能用于合成叔丁酯。因为在叔丁酯存在下无法选择性地脱除Boc保护基,在实际应用时,常需要将化合物B或D中的叔丁酯转化为易于水解的甲酯或乙酯,因此这个中间体在使用时并不方便;方法2(WO2008/128171;WO2007/130626)的路线有所缩短,但其合成的化合物F是两种异构体的混合物,比例大约为3:1,其中主产物为所需的构型,但两种异构体难以分离,不易大量合成;另外化合物F到化合物G的转化需要用到臭氧化,这个反应同样不利于大量合成,因此这种方法难以提供大量的中间体。
在目前已报道的通式I代表的化合物的两种合成方法中,方法2不适于进行大量合成,而方法1中存在两个主要问题:1.用谷氨酸合成中间体B需要7步反应(J.Am.Chem.Soc.1984,106,4539–4547),而将中间体B中的叔丁酯转化为甲酯或乙酯还需一步转化,因此步骤比较繁杂,而且其中部分反应,如硫代酰胺的合成及Eschenmoser偶联反应等,后处理比较困难,产物不易纯化;2.方法1和方法2中均采用催化氢化条件下的分子内还原氨化构建八元环,这种条件下会发生分子间还原氨化形成聚合物,因此产率不稳定,而且产物不易纯化。
发明内容
本发明针对现有技术中存在的问题,提供一种二氮杂双环拟肽衍生物的新的制备方法及其应用。
本发明通式I所示的二氮杂双环拟肽衍生物的制备方法,包括以下步骤:
(1)化合物1与丙烯醇或2-丁烯-1,4-二醇在催化剂的作用下进行烯烃复分解反应合成化合物2;
(2)化合物2在催化剂作用下关环合成化合物3;
(3)化合物3中的双键经硼氢化氧化合成化合物4;
(4)脱除化合物4中氮原子上的保护基后选择性保护羟基,或先保护羟基再脱除氮原子上的保护基制备化合物5;
(5)化合物5与化合物6缩合得到化合物7;
(6)脱除化合物7中的羟基保护基X合成化合物8;
(7)化合物8中的羟基经过活化后与磺酰胺基进行分子内关环合成化合物9;
(8)脱除化合物9中的磺酰基合成通式I所示的二氮杂双环拟肽衍生物;
其中,R1和R2分别选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基;A选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基。
优选的,步骤(1)在化合物1的溶液中,加入丙烯醇或2-丁烯-1,4-二醇,加入催化剂,惰性气体保护下反应制得化合物2。所述催化剂为烯烃复分解反应的催化剂,包括Grubbs 1-3代催化剂、Hoveda-Grubbs一代或二代催化剂。
优选的,步骤(2)在化合物2的溶液中加入催化剂,惰性气体保护下进行关环反应制得化合物3。所述催化剂为Tsuji-Trost反应的常用催化剂,包括Pd(PPh3)4、Pd2(dba)3、Pd(dba)2、Pd(COD)Cl2、双乙腈氯化钯、双苯腈氯化钯等。
优选的,步骤(3),在惰性气体保护下向化合物3的溶液中加入硼氢化试剂,原料反应完后用碱性过氧化氢氧化产生的硼烷合成化合物4。所述硼氢化试剂为硼氢化氧化反应中的常用试剂,包括9-BBN、硼烷-四氢呋喃络合物、硼烷-二甲硫醚络合物及其它单烷基或双烷基硼烷等。
优选的,步骤(4),当化合物4中的R2为叔丁基时,先在酸性条件下脱除Boc保护基,得到的产物与卤代硅烷反应,选择性保护产物中的羟基得到化合物5;所述酸包括三氟醋酸、氯化氢的1,4-二氧六环溶液或氯化氢的甲醇溶液;所述硅烷保护基包括三甲基硅基、三乙基硅基、二甲基叔丁基硅基、二苯基叔丁基硅基等;当化合物4中的R2为苄基时,先用化合物4与卤代硅烷、烷氧基氯甲基醚或酰化试剂反应保护化合物4中的羟基,再通过催化氢化脱除Cbz得到化合物5;所述保护基包括三甲基硅基、三乙基硅基、二甲基叔丁基硅基、二苯基叔丁基硅基、THP、甲氧基甲基、乙氧基甲基等硅醚或醚类保护基,或乙酰基、苯甲酰基等酰基保护基;催化氢化采用的催化剂包括Pd-C、雷尼镍、二氧化铂、氢氧化钯等。
优选的,步骤(5),在化合物5的溶液中,加入缩合剂、有机碱和化合物6进行缩合反应得到化合物7;所述缩合剂为酰化反应中常用的催化剂,包括DCC/HOBt、EDCi/HOBt、HATU、HBTU、BOP、PyBOP等;所述有机碱包括N,N-二异丙基乙基胺、NMP、三乙胺等。
优选的,步骤(6),在化合物7的溶液中,加入含氟试剂、酸或碱脱除保护基合成化合物8;所述含氟试剂包括氢氟酸水溶液、氟化钾、氟化钠、四丁基氟化铵等;所述酸包括三氟醋酸、盐酸、6N以下的硫酸、高氯酸、对甲苯磺酸、樟脑磺酸等;所述碱包括碳酸钾、碳酸铯、碳酸钠、氢氧化钠、氢氧化锂、氢氧化钾。
优选的,步骤(7),在化合物8的溶液中,加入烷基膦或芳基磷试剂和取代的碳二亚胺进行分子内光延反应环化合成化合物9,磷试剂包括三苯基磷、三正丁基磷、三叔丁基磷等;取代的碳二亚胺包括DEAD、DIAD等。
优选的,步骤(7)也可以将化合物8中的羟基转化为甲磺酸酯或卤素原子后再与磺酰胺基进行亲核取代反应合成化合物9,具体为化合物9也可通过将化合物8中的羟基转化为磺酸酯或卤素原子后再与磺酰胺基进行亲核取代反应合成,具体为:在化合物8的溶液中加入有机碱、磺酰氯、磺酸酐或卤化试剂合成磺酸酯或卤代烷;所述有机碱包括三乙胺、NMP、N,N-二异丙基乙基胺等;所述磺酰氯或磺酸酐为甲磺酰氯、甲磺酸酐、三氟甲磺酸酐、苯磺酰氯、对甲苯磺酰氯等;所述卤代试剂为二氯亚砜、液溴、NBS、NCS、I2/PPh3、三氯氧磷、CBr4/PPh3等;上述反应中得到的磺酸酯或卤代烷再重新溶于溶剂中在碱存在下通过分子内亲核取代反应关环合成化合物9,所述碱包括碳酸钾、碳酸铯、氟化钾、磷酸钾、叔丁醇钾等。
优选的,步骤(8),化合物9溶于溶剂中,加入碱和含巯基的试剂进行反应脱除磺酰基合成通式I所示1,5-二氮杂双环[6,3,0]十一烷酮氨基酸衍生物,所述碱包括碳酸钾、氟化钾、磷酸钾、碳酸铯等;含巯基的试剂包括巯基乙醇、巯基乙酸等。
本发明公开了一种二氮杂双环拟肽衍生物的制备方法,将化合物3到化合物8的合成路线替换为:脱除化合物3中胺基上的保护基合成化合物10;化合物10与化合物6缩合合成化合物11;化合物11中的烯基经硼氢化氧化合成化合物8;
具体包括以下步骤:
(1)化合物1与丙烯醇或2-丁烯-1,4-二醇在催化剂的作用下进行烯烃复分解反应合成化合物2;
(2)化合物2在催化剂作用下关环合成化合物3;
(3)脱除化合物3中胺基上的保护基合成化合物10;
(4)化合物10与化合物6缩合合成化合物11;
(5)化合物11中的烯基经硼氢化氧化合成化合物8;
(6)化合物8中的羟基经过活化后与磺酰胺基进行分子内关环合成化合物9;
(7)脱除化合物9中的磺酰基合成通式I所示的二氮杂双环拟肽衍生物;
其中,R1和R2分别选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基;A选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基;X为羟基保护基,包括硅醚、酯、取代的烷氧基甲基醚。
本发明公开的制备方法所制得的二氮杂双环拟肽衍生物,在拟肽化合物合成中应用,进一步的,衍生物在制备IAPs抑制剂Xevinapant中的应用。
发明原理:因为不易形成关环反应所需的构象,八元环的合成通常要比五至七元环的合成困难很多,因此用于构建五至七元环的合成方法不一定适用于构建八元环。合成含氮八元环常用的方法主要包括分子内烯烃复分解反应、内酰胺化反应、七元环酮经Beckmann重排扩环等,分子内取代反应很少被用于合成含氮八元环。本发明是一类含8,5并环骨架的化合物的合成,在这类化合物中因为五元环的构象控制作用,关环前体更易形成合成八元环所需的构象,因此使得采用分子内亲核取代反应合成八元环的可行性提高。磺酰胺中胺基的氢原子具有酸性,在碱性条件下可以形成负离子,在碱性条件下具有较强的亲核性,可以进行亲核取代反应。本发明采用磺酰胺作为亲核试剂通过分子内取代反应合成含多个取代基的含氮八元环,拓展了磺酰胺参与的分子内亲核取代反应在含氮杂环化合物合成中的应用。
有益效果:与现有技术相比,本发明具有如下优点:
(1)本发明提供了一种有效的合成中间体4的方法;中间体4可以替代方法1中的中间体B;这种方法原料易得、条件温和、后处理方便,避免了中间体B的合成中采用的难于进行后处理的硫代酰胺的合成及Eschenmoser偶联反应,更有利于大量合成;
(2)本发明中采用磺酰胺作为亲核试剂的分子内亲核反应作为构建八元环的方法,避免了方法1中羟基氧化的反应,而且有效提高了分子内反应的选择性,降低了原来的方法中因发生分子间反应产生的副产物,更有利于进行大量合成。
具体实施方式
下面结合实施例对本发明作进一步描述。
实施例1
化合物21的制备
反应路线如下:
(1)化合物13的制备
化合物12(17g,70mmol)溶于150毫升二氯甲烷中,室温下加入1,4-丁烯二醇(9.2g,105mmol)和Grubbs二代催化剂(890mg,1.05mmol),在氮气保护下室温搅拌60h。减压蒸除溶剂后粗品经硅胶柱层析纯化得到化合物13。1H NMR(300MHz,CDCl3)δ5.70-5.65(m,2H),5.26(brd,J=8.5Hz,1H),4.30(m,1H),4.05-4.10(m,2H),3.74(s,3H),2.78(s,1H),2.18-2.05(m,2H),1.91(m,1H),1.72(m,1H),1.44(s,9H);13C NMR(75MHz,CDCl3)δ173.4,155.4,130.7,130.4,79.9,63.1,52.7,52.3,31.9,28.3,28.0;MS(ESI)m/z:[M+Na]+calcdfor C13H23NO5Na 296.3,found 296.5。
(2)化合物14的制备
化合物13(13.1g,48mmol)溶于100毫升无水四氢呋喃中,加入双乙腈氯化钯(497mg,1.92mmol),反应液在氩气保护下室温搅拌至TLC检测反应完全。减压蒸除溶剂,粗品经硅胶柱层析纯化得到化合物14。1H NMR(300MHz,CDCl3)δ5.88(m,1H),5.36(dd,J=37.7,17.0Hz,1H),5.12(m,1H),4.48–4.20(m,2H),3.74(s,3H),2.22–1.84(m,3H),1.79(m,1H),1.42(s,9H);13C NMR(75MHz,CDCl3)δ173.5,173.3,154.2,153.4,138.8,138.0,115.0,114.7,79.9,60.6,60.1,59.7,51.9,51.8,31.5,30.8,28.7,28.2;MS(ESI)m/z:[M+Na]+calcd for C13H21NO4Na 278.1,found 278.4。
(3)化合物15的制备
化合物14(1.1g,4mmol)溶于15mL无水四氢呋喃中,反应液冷却至0℃,在氮气保护下滴加2mol/L的硼烷二甲硫醚复合物的四氢呋喃溶液(3mL,6mmol),滴加完毕后反应液在室温下搅拌至TLC检测反应完全。反应液重新冷却至0℃,逐滴加入2.7mL的3M氢氧化钠水溶液和4.1mL的30%双氧水溶液,滴加完毕后升至室温搅拌2h,加入15毫升水后用乙酸乙酯萃取三次,有机相合并后用饱和的氯化钠水溶液洗一次,无水硫酸钠干燥,减压蒸除溶剂后粗品用硅胶柱层析纯化得到化合物15。1H NMR(300MHz,CDCl3)δ4.35-4.19(m,2H),3.85-3.58(m,6H),2.28(m,1H),2.08–1.85(m,2H),1.77-1.65(m,2H),1.56(m,1H),1.38(brs,9H);13CNMR(75MHz,CDCl3)δ174.0,155.5,81.0,60.0,58.9,54.6,52.1,37.8,30.7,28.9,28.2;MS(ESI)m/z:[M+Na]+calcd for C13H23NO5Na 296.2,found 296.3。
(4)化合物16的制备
化合物15(471mg,1.72mmol)溶于5mL浓度为1N的氯化氢的甲醇溶液中,室温搅拌至TLC检测反应完全。减压蒸除溶剂后在反应瓶中加入15mL二氯甲烷,在0度搅拌下加入三乙胺(0.7mL,5mmol)和叔丁基二甲基氯硅烷(340mg,2.24mmol),反应液升至室温继续搅拌至TLC检测反应完全。减压浓缩溶剂后粗品用硅胶柱层析纯化得到化合物16。1H NMR(300MHz,CDCl3)δ3.78-3.65(m,6H),3.14(m,1H),2.20-1.95(m,2H),1.94-1.60(m,4H),1.28(m,1H),0.86(s,9H),0.02(s,6H);13C NMR(75MHz,CDCl3)δ175.7,61.6,59.9,57.5,52.1,38.8,31.8,30.1,26.0,18.4,-5.3,-5.2;MS(ESI)m/z:[M+H]+calcd for C14H30NO3Si288.2,found 288.5。
(5)化合物17的制备
(S)-3-氨基-2-(叔丁氧羰基氨基)丙酸(2.04g,10mmol)溶于60mL二氯甲烷溶液中,反应液冷至0℃,在搅拌下加入三乙胺(4.2mL,30mmol),随后缓慢加入邻硝基苯磺酰氯(2.66g,12mmol),继续搅拌2小时,减压蒸除溶剂,粗品经硅胶柱层析纯化得到化合物17。MS(ESI)m/z:[M+H]+calcd for C14H20N3O8S 390.2,found 390.4。
(6)化合物18的制备
化合物17(619mg,1.59mmol)溶于20mL二氯甲烷中,在0度搅拌下依次加入HATU(558mg,1.47mmol)、DIEA(0.6mL,3.66mmol)和化合物16(351mg,1.22mmol),反应液升至室温继续搅拌至TLC检测反应完全。加入30mL二氯甲烷稀释反应液后依次用1N盐酸、饱和NaHCO3水溶液和氯化钠水溶液各洗一次,有机相用无水硫酸钠干燥后减压蒸除溶剂,粗品用硅胶柱层析纯化得到化合物18。MS(ESI)m/z:[M+H]+calcd for C28H47N4O10SSi 659.2,found 659.4。
(7)化合物19的制备
化合物18(559mg,0.85mmol)溶于10mL无水四氢呋喃中,在室温搅拌下向反应液中滴加1mol/L的四丁基氟化铵四氢呋喃溶液(1.28mL,1.28mmol),继续搅拌至TLC检测反应完全。在反应液中加入10毫升饱和氯化铵水溶液,然后用乙酸乙酯萃取三次,每次15毫升,有机相合并后用饱和氯化钠水溶液洗涤一次,用无水硫酸钠干燥后减压蒸除溶剂,粗品用硅胶柱层析纯化得到化合物19。1H NMR(300MHz,CDCl3)δ8.20-8.05(m,1H),7.90-7.80(m,1H),7.80-7.67(m,2H),6.53(brs,0.5H),6.30(brs,0.5H),5.45-5.32(m,1H),4.92-4.42(m,3H),3.97(brs,0.5H),3.85-3.58(m,5H),3.55-3.20(m,2H),2.92(brs,0.5H),2.46-2.26(m,1H),2.20–1.66(m,5H),1.50-1.35(brs,9H);13C NMR(75MHz,CDCl3)δ173.1,172.6,170.7,169.9,155.5,154.9,148.0,133.8,133.8,133.6,133.4,133.0,133.0,131.1,131.0,125.5,125.5,80.7,80.5,59.9,59.6,59.3,59.1,56.3,56.1,53.0,52.6,51.9,50.5,45.5,45.4,37.2,37.1,30.7,29.9,29.4,28.3,27.1;MS(ESI)m/z:[M+H]+calcd forC22H33N4O10S 545.1,found 545.3;HRMS(ESI)m/z:[M+H]+calcd for C22H33N4O10S 545.1917,found 545.1917;IR(neat/KBr):3401,2978,1746,1710,1635,1542,1441,1367,1166,1058,854,588cm-1。
(8)化合物20的制备
化合物19(694mg,1.27mmol)溶于15mL无水四氢呋喃中,室温搅拌下加入三苯基膦(399mg,1.52mmol),在氮气保护下向反应液中缓慢滴加DIAD(307mg,1.52mmol),继续搅拌至TLC检测反应完全。减压浓缩溶剂,粗品经硅胶柱层析分离后得到化合物20。MS(ESI)m/z:[M+H]+calcd for C22H31N4O9S 527.2,found 527.4。
(9)化合物21的制备
化合物20(774mg,1.47mmol)溶于15mL DMF中,在室温搅拌下加入碳酸钾(608mg,4.41mmol)和巯基乙醇(138mg,1.76mmol),升温至40℃反应至TLC检测反应完全。反应液用30毫升水稀释后用乙酸乙酯萃取三次,每次30毫升,有机相合并后用饱和的氯化钠水溶液洗涤一次,经无水硫酸钠干燥,减压浓缩溶剂,粗品经硅胶柱层析分离纯化得到化合物21。[α]25D=-20.9(c=0.51,CHCl3);1H NMR(300MHz,CDCl3)δ5.42(brd,J=8.0Hz,1H),4.70(m,1H),4.52(t,J=9.0Hz,1H),4.30(m,1H),3.76(s,3H),3.23-3.15(m,2H),2.90(m,1H),2.72(m,1H),2.38(m,1H),2.20-1.76(m,5H),1.62(m,1H),1.41(s,9H);13C NMR(75MHz,CDCl3)δ173.6,170.7,155.3,79.8,59.6,58.5,55.1,52.6,46.9,37.6,32.3,28.5,27.2;MS(ESI)m/z:[M+H]+calcd for C16H28N3O5 342.0,found 342.2;HRMS(ESI)m/z:[M+H]+calcdfor C16H28N3O5 342.2029,found 342.2050;IR(neat/KBr):3440,3336,2976,2916,1735,1709,1633,1492,1445,1390,1366,1327,1272,1210,1199,1166,1131,1060,1048,1025,746,733,702cm-1。
实施例2
化合物20的制备(方法2)
化合物19(560mg,1.03mmol)溶于20毫升二氯甲烷中,在0℃搅拌下加入三乙胺(0.55mL,4.0mmol),随后缓慢滴入甲磺酰氯(140mg,1.23mmol)的二氯甲烷溶液,继续搅拌至TLC检测反应完全。反应液用30毫升二氯甲烷稀释后用饱和的氯化钠水溶液洗一次,有机相用无水硫酸钠干燥,减压蒸除溶剂,粗品用硅胶柱层析纯化得到化合物22。MS(ESI)m/z:[M+Na]+calcd for C23H34N4O12S2Na 645.2,found 645.4。
化合物22(460mg,0.74mmol)溶于10mL DMF中,加入K2CO3(306mg,2.21mmol),室温搅拌至TLC检测反应完全。分别加入20mL乙酸乙酯和20毫升1N的盐酸,分离有机相后水相用乙酸乙酯萃取三次,每次15毫升,有机相合并后用饱和的氯化钠水溶液洗涤一次,经无水硫酸钠干燥,减压蒸除溶剂,粗品经硅胶柱层析纯化得到化合物20。
实施例3
化合物19的制备,合成路线如下:
(1)化合物23的制备
化合物14(700mg,2.75mmol)溶于10mL氯化氢的甲醇溶液(1M)中,室温搅拌6h,TLC检测反应完全后减压蒸除溶剂得到化合物23,无需纯化,直接用于下一步反应。MS(ESI)m/z:[M+H]+calcd for C8H14NO2 156.2,found 156.4。
(2)化合物24的制备
化合物17(1.35g,3.5mmol)溶于25mL二氯甲烷中,在0度搅拌下依次加入HATU(1.25g,3.3mmol)、DIEA(1.4mL,8.3mmol)和化合物23的盐酸盐(0.53g,2.75mmol),反应液升至室温,继续搅拌至TLC检测反应完全。反应液用30mL二氯甲烷稀释,随后依次用1N盐酸、饱和NaHCO3水溶液和饱和的氯化钠水溶液各洗一次,有机相用无水硫酸钠干燥,减压蒸除溶剂,粗品经硅胶柱层析纯化得到化合物24。1H NMR(300MHz,CDCl3)δ8.06(m,1H),7.84(m,1H),7.75–7.69(m,2H),6.22(brs,1H),5.89(m,1H),5.46(m,1H),5.31(brd,J=9.2Hz,1H),5.18(m,1H),4.73(m,1H),4.55(m,1H),4.42(m,1H),3.70(s,3H),3.42(m,1H),3.20(m,1H),2.24–2.09(m,2H),2.02–1.79(m,2H),1.38(s,9H);13C NMR(75MHz,CDCl3)δ172.1,170.3,155.3,148.0,137.9,133.7,133.6,132.9,131.0,125.6,117.4,80.5,61.1,59.9,52.5,50.0,45.4,32.4,28.3,27.1;MS(ESI)m/z:[M+H]+calcd for C22H31N4O9S 527.2,found527.5;HRMS(ESI)m/z:[M+H]+calcd for C22H31N4O9S 527.1812,found 527.1812;IR(neat/KBr):3362,2981,1748,1710,1646,1542,1440,1367,1168,854,785,588cm-1。
(3)化合物19的制备
化合物24(1.22g,2.3mmol)溶于20mL无水四氢呋喃中,反应液冷至0℃,在氮气保护下滴加0.5mol/L的9-BBN的四氢呋喃溶液(8mL,4mmol),滴加完毕后反应液在室温下搅拌至TLC检测反应完全。反应液冷却至0℃,逐滴加入1.5mL的3M氢氧化钠水溶液和2.4mL的30%双氧水溶液,滴加完毕后在室温下搅拌2h。在反应液中加入20毫升水后用乙酸乙酯萃取三次,每次30毫升,有机相合并,用饱和的氯化钠水溶液洗一次,无水硫酸钠干燥,减压蒸除溶剂,粗品经硅胶柱层析纯化得到化合物19。
Claims (10)
1.一种二氮杂双环拟肽衍生物的制备方法,其特征在于,包括以下步骤:
(1)化合物1与丙烯醇或2-丁烯-1,4-二醇在催化剂的作用下进行烯烃复分解反应合成化合物2;
(2)化合物2在催化剂作用下关环合成化合物3;
(3)化合物3中的双键经硼氢化氧化合成化合物4;
(4)脱除化合物4中氮原子上的保护基后选择性保护羟基,或先保护羟基再脱除氮原子上的保护基制备化合物5;
(5)化合物5与化合物6缩合得到化合物7;
(6)脱除化合物7中的羟基保护基X合成化合物8;
(7)化合物8中的羟基经过活化后与磺酰胺基进行分子内关环合成化合物9;
(8)脱除化合物9中的磺酰基合成通式I所示的二氮杂双环拟肽衍生物;
其中,R1和R2分别选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基;A选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基;羟基保护基X包括硅醚、酯或取代的烷氧基甲基醚。
2.根据权利要求1所述的制备方法,其特征在于,步骤(1)具体为,在化合物1的溶液中,加入丙烯醇或2-丁烯-1,4-二醇,加入催化剂,惰性气体保护下反应制得化合物2,所述催化剂为烯烃复分解反应的催化剂,包括Grubbs 1-3代催化剂、Hoveda-Grubbs一代或二代催化剂;
步骤(2)具体为,在化合物2的溶液中加入催化剂,惰性气体保护下进行分子内Tsuji-Trost反应关环制得化合物3,所述催化剂为Tsuji-Trost反应中使用的催化剂;
步骤(3)具体为,在惰性气体保护下向化合物3的溶液中加入硼氢化试剂,原料反应完后用碱性过氧化氢氧化产生的硼烷合成化合物4,所述硼氢化试剂为硼氢化氧化反应中的常用试剂,包括9-BBN、硼烷-四氢呋喃络合物、硼烷-二甲硫醚络合物及其它单烷基或双烷基硼烷。
3.根据权利要求1所述的制备方法,其特征在于,步骤(4)具体为,脱除化合物4中氮原子上的保护基后选择性保护羟基:当化合物4中的R2为叔丁基时,先在酸性条件下脱除Boc保护基,得到的产物与卤代硅烷反应,选择性保护产物中的羟基得到化合物5;
先保护羟基再脱除氮原子上的保护基制备化合物5:当化合物4中的R2为苄基时,先用化合物4与卤代硅烷、烷氧基氯甲基醚或酰化试剂反应保护化合物4中的羟基,再通过催化氢化脱除Cbz得到化合物5。
4.根据权利要求1所述的制备方法,其特征在于,步骤(5)具体为,在化合物5的溶液中,加入缩合剂、有机碱和化合物6进行缩合反应得到化合物7;所述缩合剂为酰化反应中常用的缩合剂。
5.根据权利要求1所述的制备方法,其特征在于,步骤(6)具体为,在化合物7的溶液中,加入含氟试剂、酸或碱脱除保护基合成化合物8;所述含氟试剂包括氢氟酸水溶液、氟化钾、氟化钠或四丁基氟化铵;所述酸包括三氟醋酸、盐酸、6N以下的硫酸、高氯酸、对甲苯磺酸或樟脑磺酸;所述碱包括碳酸钾、碳酸铯、碳酸钠、氢氧化钠、氢氧化锂、氢氧化钾。
6.根据权利要求1所述的制备方法,其特征在于,步骤(7)具体为,在化合物8的溶液中,加入烷基膦或芳基磷试剂和偶氮二甲酸酯进行分子内光延反应环化合成化合物9。
7.根据权利要求1所述的制备方法,其特征在于,步骤(7)中,化合物9也可通过将化合物8中的羟基转化为磺酸酯或卤素原子后再与磺酰胺基进行亲核取代反应合成,具体为:在化合物8的溶液中加入三级胺、磺酰氯、磺酸酐或卤化试剂合成磺酸酯或卤代烷;所述磺酰氯或磺酸酐为甲磺酰氯、甲磺酸酐、乙磺酰氯、乙磺酸酐、三氟甲磺酸酐、苯磺酰氯、对甲苯磺酰氯;所述卤代试剂为二氯亚砜、液溴、NBS、NCS、I2/PPh3、三氯氧磷、CBr4/PPh3;上述反应中得到的磺酸酯或卤代烷再重新溶于溶剂中在碱存在下通过分子内亲核取代反应关环合成化合物9。
8.根据权利要求1所述的制备方法,其特征在于,步骤(8)具体为,化合物9溶于溶剂中,加入碱和含巯基的试剂进行反应脱除磺酰基合成通式I所示的二氮杂双环拟肽衍生物。
9.一种二氮杂双环拟肽衍生物的制备方法,其特征在于,包括以下步骤:
(1)化合物1与丙烯醇或2-丁烯-1,4-二醇在催化剂的作用下进行烯烃复分解反应合成化合物2;
(2)化合物2在催化剂作用下关环合成化合物3;
(3)脱除化合物3中胺基上的保护基合成化合物10;
(4)化合物10与化合物6缩合合成化合物11;
(5)化合物11中的烯基经硼氢化氧化合成化合物8;
(6)化合物8中的羟基经过活化后与磺酰胺基进行分子内关环合成化合物9;
(7)脱除化合物9中的磺酰基合成通式I所示的二氮杂双环拟肽衍生物;
其中,R1和R2分别选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基;A选自任意取代或非取代的烷基、任意取代或非取代的环烷基、任意取代或非取代的芳基、取代或非取代的杂环芳基;X为羟基保护基,包括硅醚、酯、取代的烷氧基甲基醚。
10.权利要求1或9的制备方法所制得的二氮杂双环拟肽衍生物在拟肽合成中应用,其特征在于,所述衍生物在制备IAPs抑制剂Xevinapant中的应用。
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