CN112876411A - 化合物及其在合成pdl1拮抗剂类药物分子中的应用 - Google Patents
化合物及其在合成pdl1拮抗剂类药物分子中的应用 Download PDFInfo
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- CN112876411A CN112876411A CN202110060576.7A CN202110060576A CN112876411A CN 112876411 A CN112876411 A CN 112876411A CN 202110060576 A CN202110060576 A CN 202110060576A CN 112876411 A CN112876411 A CN 112876411A
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
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- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07—ORGANIC CHEMISTRY
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Abstract
本发明提供了一种化合物,本发明的化合物可以作为中间体用于合成PDL1拮抗剂,本发明化合物作为中间体所制备得到化合物在细胞水平对PD‑1/PD‑L1信号具有较高的抑制活性。
Description
本申请为分案申请,其母案申请号为202080003296.6:母案申请日为2020年02月20日。
本申请要求于2019年2月21日提交中国专利局、申请号为201910130313.1、发明名称为“PD-L1拮抗剂化合物”,以及于2019年7月30日提交中国专利局、申请号为201910695768.8、发明名称为“PD-L1拮抗剂化合物”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种PD-L1拮抗剂化合物及使用其治疗/预防免疫相关病症的方法。
背景技术
肿瘤免疫治疗由于其卓越的疗效和创新性,在2013年被《科学》杂志评为年度最重要的科学突破。肿瘤免疫治疗有望成为继手术、化疗、放疗、靶向治疗后肿瘤治疗领域的一场革新。肿瘤免疫治疗是应用免疫学原理和方法,提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性,激发和增强机体抗肿瘤免疫应答,并应用免疫细胞和效应分子输注宿主体内,协同机体免疫系统杀伤肿瘤、抑制肿瘤生长。肿瘤免疫治疗近来备受关注,是肿瘤治疗领域的焦点。近几年,肿瘤免疫治疗的好消息不断,目前已在一些肿瘤类型如黑色素瘤,非小细胞肺癌等的治疗中展示出了强大的抗肿瘤活性,并已有肿瘤免疫治疗药物获得美国FDA(Food and DrugAdministration,FDA)批准临床应用。
PD-1(程序性死亡受体1,programmed death 1)为CD28超家族成员。以PD-1为靶点的免疫调节在抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等方面均有重要的意义。其配体PD-L1也可作为靶点,相应的抗体也可以起到相同的作用。PD-L1(程序性死亡受体-配体1,programmed cell death-Ligand 1)是大小为40kDa的第一型跨膜蛋白。正常情形下免疫系统会对聚集在淋巴结或脾脏的外来抗原产生反应,促进具有抗原特异性的T细胞增殖。而PD-1与PD-L1结合,可以传导抑制性的信号,减低T细胞的增殖。
肿瘤细胞逃避T细胞摧毁的一种途径是通过在它表面产生PD-L1。当免疫细胞T细胞表面的PD-1识别PD-L1后,可以传导抑制性信号,T细胞就不能发现肿瘤细胞和向肿瘤细胞发出攻击信号。PD-1是通过解除肿瘤细胞逃避免疫系统的新型免疫疗法。PD-1免疫疗法的作用机制是针对PD-1或PD-L1设计特定的蛋白质抗体,阻止PD-1和PD-L1的识别过程,部分恢复T细胞功能,从而使T细胞可以杀死肿瘤细胞。
PD-1表达于活化的T细胞,B细胞及髓系细胞,其有两个配体,即PD-L1和PD-L2。PD-L1/L2在抗原递呈细胞都表达,PD-L1在多种组织也有表达。PD-1与PD-L1的结合介导T细胞活化的共抑制信号,调节T细胞活化和增殖,起到类似于CTLA-4的负调节作用。华裔科学家陈列平实验室首先发现PD-L1在肿瘤组织高表达,而且调节肿瘤浸润CD8 T细胞的功能。因此,以PD-1/PD-L1为靶点的免疫调节对抗肿瘤有重要的意义。
多个靶向PD-1/PD-L1相互作用的治疗性单克隆抗体(mAbs)已被美国FDA批准上市。除了开发相关单克隆抗体之外,寻找方便癌症患者的口服小分子化合物用来靶向抑制免疫检查点也是肿瘤免疫疗法的前沿领域。小分子化合物能够穿过细胞膜作用于细胞内靶点,所以应用范围广泛。其次,小分子经化学修饰后往往具有良好的生物利用度和依从性,有效避免消化肠道中酶类的分解失活。最后,在生产工艺、剂型设计和给药方式等多种层面,小分子的研究也颇为成熟。
大多数单克隆抗体(mAbs)的使用途径是高剂量的静脉注射。小分子药物,其更适合口服给药,可以减少严重的免疫相关不良事件。与单克隆抗体相比,小分子药物抑制剂有很多其他好处,例如,制造成本更经济、稳定,且器官和肿瘤的渗透性更好。考虑到小分子药物动力学性质的众多优点,它将会在单一疗法或其它组合方案里体现出剂量上的灵活性。本发明的小分子化合物的可为患者和医生提供一个引人注目的治疗选择。
发明内容
本发明提供了一种用于合成PDL1拮抗剂化合物的中间体I2,其具有以下结构:
除此之外,本发明还提供了用于合成中间体I2的制备方法,其特征包括以下步骤:
中间体I2的合成路线如下:
具体地,本发明提供了中间体I2的制备过程,其特征包括以下步骤:将中间体I1(1.3g,3.68mmol)加入到甲醇(10mL)中,加入原甲酸三甲酯(1.96g,18.42mmol)和对甲苯磺酸(31.73mg,0.184mmol),反应混合物在50℃下搅拌过夜。直接浓缩反应液,将残留物溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(1.53g,11.05mmol),碘化钾(61.17mg,0.368mmol)和4-氯甲基-2-氰基吡啶(1.3g,3.68mmol),反应混合物在70℃下搅拌6小时。将反应液冷却至室温,加入4mol/L盐酸(5mL),持续搅拌20分钟,过滤,滤饼10mL用水洗三次,用10mL乙酸乙酯洗两次,干燥,得到中间体I2。
在本发明的技术方案中,其中中间体I1的合成包括以下步骤:
具体地,中间体I1的合成包括以下步骤:
第一步:将2-溴-3-甲基苯胺(31.5g,169.32mmol)加入到浓盐酸(100mL)中,室温下搅拌20分钟,向体系中加入250g碎冰。冰浴下缓慢加入亚硝酸钠(26.25g,380.43mmol),控制反应液温度低于5℃。加完后保持冰浴搅拌1小时,之后冰浴下缓慢加入碘化钾(112.89g,679.99mmol)。反应液持续搅拌2小时,缓慢升至室温,之后60℃下搅拌1小时。反应液冷却至室温,用200mL亚硫酸氢钠溶液淬灭,用石油醚(3x200mL)萃取,合并有机相,用200mL饱和碳酸氢钠洗一次,再用150mL饱和食盐水洗一次。有机相用无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到2-溴-3-甲基碘苯;
第二步:将2-溴-3-甲基碘苯(33.0g,111.14mmol)溶于四氯化碳(400mL),加入N-溴代丁二酰亚胺(39.6g,222.27mmol)和过氧苯甲酰(5.0g,20.66mmol)。反应混合物在氮气氛围下回流过夜。然后过滤,浓缩滤液,粗产品用快速过柱机分离得到2-溴-3-溴甲基碘苯(28.0g,74.50mmol);
第三步:将2-溴-3-溴甲基碘苯(14.0g,37.25mmol)和5-氯-2,4-二羟基苯甲醛(6.43g,37.25mmol)溶于乙腈(150mL)中,加入碳酸氢钠(10.0g,119.05mmol)。反应混合物搅拌回流过夜。将反应液冷却至室温,搅拌下加入150mL水,持续搅拌20分钟,过滤,滤饼用20mL水洗涤三次,干燥,得到中间体I1。
进一步的,本发明还提供了一种利用中间体化合物I2制备PDL1拮抗剂药物分子1的方法,其中所述的PDL1拮抗剂药物分子1具有如下结构式:
其中,所述的方法包括以下步骤:
第一步:将中间体I2(200mg,0.34mmol)与中间体I6(190.86mg,0.51mmol)溶于1,4-二氧六环(5mL)中,加入碳酸钾(94.73mg,0.68mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(25.08mg,0.034mmol),反应混合物在氮气气氛95℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物1a(80mg,0.11mmol),收率33.3%,淡黄色固体。MS(ESI):m/z 700.3(M+H)+.
第二步:将化合物1a(80mg,0.11mmol)溶于N,N-二甲基甲酰胺(3mL)和醋酸(0.2mL)的混合物中,加入L-丝氨酸(23.99mg,0.23mmol),反应混合物在45℃下搅拌过夜。之后加入三乙酰氧基硼氢化钠(90.67mg,0.43mmol),继续搅拌3小时。将反应液冷却至室温滴入水淬灭,过滤,滤液用反向制备色谱提纯得到化合物1。
其中,中间体I6具有以下结构:
在本发明的方法中,其中中间体I6的合成方法包括以下步骤:中间体I6的合成路线如下:
具体地,中间体I6的合成方法包括以下步骤:
第一步:将1-溴-3-氯丙烷(5.99g,38.06mmol)和4-溴-1H-吲唑(5.0g,25.38mmol)溶于乙腈(50mL)中,加入碳酸钾(7.01g,50.75mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,浓缩。残留物用快速过柱机分离得到4-溴-1-(4-氯丙基)-1H-吲唑;
第二步:将4-溴-1-(4-氯丙基)-1H-吲唑(1.5g,5.48mmol)和(R)-3-羟基吡咯烷(955.42mg,10.97mmol)溶于乙腈(20mL)中,加入碳酸钾(3.03g,21.93mmol)和碘化钾(0.25g,1.48mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,滤液浓缩后加入50mL乙酸乙酯,用20mL水洗三次,再用20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。得到(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇;
第三步:将(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇(1.78g,5.49mmol)和双联硼酸频那醇酯(2.09g,8.24mmol)溶于1,4-二氧六环(20mL)中,加入醋酸钾(1.62g,16.47mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(401.72mg,0.549mmol)。反应混合物在氮气氛围下90℃搅拌过夜。将反应液冷却至室温,加入100mL乙酸乙酯,经硅藻土过滤,滤液用50mL水洗三次,50mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到中间体I6。
具体实施例
中间体I1:
中间体I1的合成路线如下:
第一步:将2-溴-3-甲基苯胺(31.5g,169.32mmol)加入到浓盐酸(100mL)中,室温下搅拌20分钟,向体系中加入250g碎冰。冰浴下缓慢加入亚硝酸钠(26.25g,380.43mmol),控制反应液温度低于5℃。加完后保持冰浴搅拌1小时,之后冰浴下缓慢加入碘化钾(112.89g,679.99mmol)。反应液持续搅拌2小时,缓慢升至室温,之后60℃下搅拌1小时。反应液冷却至室温,用200mL亚硫酸氢钠溶液淬灭,用石油醚(3x200mL)萃取,合并有机相,用200mL饱和碳酸氢钠洗一次,再用150mL饱和食盐水洗一次。有机相用无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到2-溴-3-甲基碘苯(36.0g,121.23mmol),淡黄色液体,收率71.6%。
第二步:将2-溴-3-甲基碘苯(33.0g,111.14mmol)溶于四氯化碳(400mL),加入N-溴代丁二酰亚胺(39.6g,222.27mmol)和过氧苯甲酰(5.0g,20.66mmol)。反应混合物在氮气氛围下回流过夜。然后过滤,浓缩滤液,粗产品用快速过柱机分离得到2-溴-3-溴甲基碘苯(28.0g,74.50mmol),淡黄色液体,收率67.0%。
第三步:将2-溴-3-溴甲基碘苯(14.0g,37.25mmol)和5-氯-2,4-二羟基苯甲醛(6.43g,37.25mmol)溶于乙腈(150mL)中,加入碳酸氢钠(10.0g,119.05mmol)。反应混合物搅拌回流过夜。将反应液冷却至室温,搅拌下加入150mL水,持续搅拌20分钟,过滤,滤饼用20mL水洗涤三次,干燥,得到中间体I1(17.0g,36.36mmol),白色固体,收率97.6%。MS(ESI):m/z 464.9(M-H)-.
中间体I2:
中间体I2的合成路线如下:
将中间体I1(1.3g,3.68mmol)加入到甲醇(10mL)中,加入原甲酸三甲酯(1.96g,18.42mmol)和对甲苯磺酸(31.73mg,0.184mmol),反应混合物在50℃下搅拌过夜。直接浓缩反应液,将残留物溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(1.53g,11.05mmol),碘化钾(61.17mg,0.368mmol)和4-氯甲基-2-氰基吡啶(1.3g,3.68mmol),反应混合物在70℃下搅拌6小时。将反应液冷却至室温,加入4mol/L盐酸(5mL),持续搅拌20分钟,过滤,滤饼10mL用水洗三次,用10mL乙酸乙酯洗两次,干燥,得到中间体I2(0.97g,2.07mmol),淡黄色固体,收率56.1%。MS(ESI):m/z583.3(M+H)+.
中间体I6:
中间体I6的合成路线如下:
第一步:将1-溴-3-氯丙烷(5.99g,38.06mmol)和4-溴-1H-吲唑(5.0g,25.38mmol)溶于乙腈(50mL)中,加入碳酸钾(7.01g,50.75mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,浓缩。残留物用快速过柱机分离得到4-溴-1-(4-氯丙基)-1H-吲唑(3.0g,10.97mmol),淡黄色液体,收率43.2%。MS(ESI):m/z 273.4(M+H)+.
第二步:将4-溴-1-(4-氯丙基)-1H-吲唑(1.5g,5.48mmol)和(R)-3-羟基吡咯烷(955.42mg,10.97mmol)溶于乙腈(20mL)中,加入碳酸钾(3.03g,21.93mmol)和碘化钾(0.25g,1.48mmol)。反应混合物于60℃下搅拌过夜。将反应液冷却至室温,过滤,滤液浓缩后加入50mL乙酸乙酯,用20mL水洗三次,再用20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。得到(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇(1.78g,5.49mmol),淡黄色液体,收率100%。MS(ESI):m/z 324.4(M+H)+.
第三步:将(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇(1.78g,5.49mmol)和双联硼酸频那醇酯(2.09g,8.24mmol)溶于1,4-二氧六环(20mL)中,加入醋酸钾(1.62g,16.47mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(401.72mg,0.549mmol)。反应混合物在氮气氛围下90℃搅拌过夜。将反应液冷却至室温,加入100mL乙酸乙酯,经硅藻土过滤,滤液用50mL水洗三次,50mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到中间体I6(1.38g,3.74mmol),淡黄色液体,收率68.1%。MS(ESI):m/z372.4(M+H)+.
化合物1的合成
第一步:将中间体I2(200mg,0.34mmol)与中间体I6(190.86mg,0.51mmol)溶于1,4-二氧六环(5mL)中,加入碳酸钾(94.73mg,0.68mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(25.08mg,0.034mmol),反应混合物在氮气气氛95℃下搅拌过夜。将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩。残留物用快速过柱机分离得到化合物1a(80mg,0.11mmol),收率33.3%,淡黄色固体。MS(ESI):m/z 700.3(M+H)+.
第二步:将化合物1a(80mg,0.11mmol)溶于N,N-二甲基甲酰胺(3mL)和醋酸(0.2mL)的混合物中,加入L-丝氨酸(23.99mg,0.23mmol),反应混合物在45℃下搅拌过夜。之后加入三乙酰氧基硼氢化钠(90.67mg,0.43mmol),继续搅拌3小时。将反应液冷却至室温滴入水淬灭,过滤,滤液用反向制备色谱提纯得到化合物1(4.6mg,5.82umol),收率5.1%,白色固体。MS(ESI):m/z 789.3(M+H)+.1H NMR(500MHz,d6-DMSO)δ8.75(d,J=5.0Hz,1H),8.17(s,1H),7.89(d,J=5.0Hz,1H),7.74(d,J=8.5Hz,1H),7.70(d,J=10.0Hz,2H),7.56(q,J=7.0,5.5Hz,2H),7.53–7.43(m,2H),7.09(d,J=7.0Hz,1H),7.04(s,1H),5.39(d,J=4.5Hz,2H),5.33(s,2H),4.83(s,1H),4.49(s,3H),4.21(s,1H),4.03(s,2H),3.77–3.60(m,2H),3.21(s,1H),2.72(d,J=7.5Hz,3H),2.36(s,1H),2.10–1.91(m,5H),1.59(s,1H).
细胞水平PD-1/PD-L1信号抑制的生物活性检测
本检测方法用于本发明所述化合物1的细胞水平生物学活性评价。
实验原理
本检测方法采用荧光素酶报告基因法检测化合物对细胞水平PD-1/PD-L1信号抑制的生物活性。PD-1/NFAT-Reporter-Jurkat细胞稳定表达人PD-1,且表达由NFAT元件调控的荧光素酶报告基因;TCR activator/PD-L1-CHO细胞稳定表达人PD-L1和TCR激活元件。当两株细胞共培养时,PD-1/PD-L1的结合会抑制TCR信号通路,从而抑制下游NFAT控制的荧光素酶报告基因表达。当加入PD-1/PD-L1抗体或者抑制剂,这种抑制作用被反转,荧光素酶表达,从而可以检测PD-1/PD-L1抑制剂对荧光素酶活性影响。
实验材料与设备
PD-1/NFAT-Reporter-Jurkat细胞(货号60535)以及TCR activator/PD-L1-CHO细胞(货号60536)购自BPS Bioscience公司;PD-L1抗体(Atezolizumab,货号A2004)购自Selleck公司;荧光素酶检测试剂(ONE-GloTM Luciferase Assay System,货号E6120)购自Promega公司;多功能微孔板检测仪(型号SpectraMax i3x)购自Molecular Devices公司。
实验主要过程
按常规细胞培养实验操作流程培养PD-1/NFAT-Reporter-Jurkat细胞和TCRactivator/PD-L1-CHO细胞。
收集TCR activator/PD-L1-CHO细胞并按照35000个/每孔,接种到96孔培养板中,培养基体积为100微升,37℃孵育过夜。第二天,弃去培养基,加入化合物孵育30分钟,同时设置溶剂对照(二甲基亚砜,DMSO,终浓度0.1%)和PD-L1抗体(Atezolizumab,终浓度约10nM)阳性对照。再加入PD-1/NFAT-reporter-Jurkat细胞。继续培养6小时后,按荧光素酶检测试剂说明书检测荧光素酶活性。
以PD-L1抗体作为阳性对照,计算测试化合物的PD-1/PD-L1结合抑制率(%)=(化合物处理孔化学发光值/溶剂对照孔化学发光值平均值–1)/(PD-L1抗体孔化学发光值平均值/溶剂对照孔化学发光值平均值–1)×100%。
根据上述检测方法,对本发明所述化合物1进行细胞水平生物学活性评价,试验结果如下。
化合物编号 | Absolute EC50(μM) |
1 | 0.34 |
Claims (10)
3.如权利要求2所述的方法,其特征在于包括以下步骤:将中间体I1加入到甲醇中,加入原甲酸三甲酯和对甲苯磺酸,反应混合物在50℃下搅拌过夜,直接浓缩反应液,将残留物溶于N,N-二甲基甲酰胺,加入碳酸钾,碘化钾和4-氯甲基-2-氰基吡啶,反应混合物在70℃下搅拌6小时,将反应液冷却至室温,加入4mol/L盐酸,持续搅拌,过滤,滤饼用水洗三次,用乙酸乙酯洗两次,干燥,得到中间体I2。
5.如权利要求4所述的方法,其中中间体I1的制备过程包括如下步骤:
第一步:将2-溴-3-甲基苯胺加入到浓盐酸中,室温下搅拌20分钟,向体系中加入250g碎冰,冰浴下缓慢加入亚硝酸钠,控制反应液温度低于5℃,加完后保持冰浴搅拌1小时,之后冰浴下缓慢加入碘化钾,反应液持续搅拌2小时,缓慢升至室温,之后60℃下搅拌1小时,反应液冷却至室温,用200mL亚硫酸氢钠溶液淬灭,用石油醚(3x200mL)萃取,合并有机相,用200mL饱和碳酸氢钠洗一次,再用150mL饱和食盐水洗一次,有机相用无水硫酸钠干燥,过滤,浓缩,残留物用快速过柱机分离得到2-溴-3-甲基碘苯;
第二步:将2-溴-3-甲基碘苯溶于四氯化碳,加入N-溴代丁二酰亚胺和过氧苯甲酰,反应混合物在氮气氛围下回流过夜,然后过滤,浓缩滤液,粗产品用快速过柱机分离得到2-溴-3-溴甲基碘苯;
第三步:将2-溴-3-溴甲基碘苯和5-氯-2,4-二羟基苯甲醛溶于乙腈中,加入碳酸氢钠,反应混合物搅拌回流过夜,将反应液冷却至室温,搅拌下加入150mL水,持续搅拌20分钟,过滤,滤饼用20mL水洗涤三次,干燥,得到中间体I1。
8.如权利要求7所述的应用,其中包括以下步骤:
第一步:将中间体I2与中间体I6溶于1,4-二氧六环中,加入碳酸钾和[1,1'-双(二苯基膦基)二茂铁]二氯化钯,反应混合物在氮气气氛95℃下搅拌过夜,将反应液冷却至室温,加入30mL乙酸乙酯,经硅藻土过滤,滤液用10mL水洗三次,10mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩,残留物用快速过柱机分离得到化合物1a;
其中所述的中间体I6具有以下结构:
第二步:将化合物1a溶于N,N-二甲基甲酰胺和醋酸的混合物中,加入L-丝氨酸,反应混合物在45℃下搅拌过夜,之后加入三乙酰氧基硼氢化钠,继续搅拌3小时,将反应液冷却至室温滴入水淬灭,过滤,滤液用反向制备色谱提纯得到化合物1。
10.如权利要求9所述的应用,其中所述的中间体I6的合成方法包括以下步骤:
第一步:将1-溴-3-氯丙烷和4-溴-1H-吲唑溶于乙腈中,加入碳酸钾,反应混合物于60℃下搅拌过夜,将反应液冷却至室温,过滤,浓缩,残留物用快速过柱机分离得到4-溴-1-(4-氯丙基)-1H-吲唑;
第二步:将4-溴-1-(4-氯丙基)-1H-吲唑和(R)-3-羟基吡咯烷溶于乙腈中,加入碳酸钾和碘化钾,反应混合物于60℃下搅拌过夜,将反应液冷却至室温,过滤,滤液浓缩后加入50mL乙酸乙酯,用20mL水洗三次,再用20mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩,得到(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇;
第三步:将(R)-1-(4-(4-溴-1H-吲唑-1-基)丙基)吡咯烷-3-醇和双联硼酸频那醇酯溶于1,4-二氧六环中,加入醋酸钾和[1,1'-双(二苯基膦基)二茂铁]二氯化钯,反应混合物在氮气氛围下90℃搅拌过夜,将反应液冷却至室温,加入100mL乙酸乙酯,经硅藻土过滤,滤液用50mL水洗三次,50mL饱和食盐水洗一次,无水硫酸钠干燥,过滤,浓缩,残留物用快速过柱机分离得到中间体I6。
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Effective date of registration: 20211125 Address after: 361000 floor 3-5, No. 188, Pingcheng South Road, Haicang street, Haicang District, Xiamen City, Fujian Province Applicant after: Xiamen Baotai Biotechnology Co.,Ltd. Address before: 311100 Building 8, 1008 Xiangxiang street, Cangqian street, Yuhang District, Hangzhou City, Zhejiang Province Applicant before: Hangzhou Arnold Biomedical Technology Co.,Ltd. |
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Application publication date: 20210601 |