CN107880085B - 一种利用[Rmim][OSO2OR]-Lewis酸离子液体系合成红景天苷的方法 - Google Patents
一种利用[Rmim][OSO2OR]-Lewis酸离子液体系合成红景天苷的方法 Download PDFInfo
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- CN107880085B CN107880085B CN201711144263.XA CN201711144263A CN107880085B CN 107880085 B CN107880085 B CN 107880085B CN 201711144263 A CN201711144263 A CN 201711144263A CN 107880085 B CN107880085 B CN 107880085B
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- ionic liquid
- reaction
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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Abstract
本发明属于催化合成技术领域,具体涉及一种利用[Rmim][OSO2OR]‑Lewis酸离子液体系合成红景天苷的方法。该方法利用离子液体[Rmim][OSO2OR]合成红景天苷化合物。本发明提供的离子液体的合成仅需一步反应,且在离子液体合成反应中原料的原子得到100%的利用,是一个操作简便的原子经济性反应。本发明提供的方法环境友好、反应条件温和、后处理简单,解决现有离子液体系催化糖基三氯乙酰亚胺酯给体O‑糖苷化过程中所用离子液体的合成繁琐、热能消耗、原子浪费以及非原子经济性反应所造成的环境污染等问题,同时解决了现有有机溶剂中进行红景天苷类药物化学合成所造成的环境污染、后处理繁琐等问题。
Description
技术领域
本发明属于催化合成技术领域,具体涉及一种利用[Rmim][OSO2OR]-Lewis酸离子液体系合成红景天苷的方法。
背景技术
红景天苷(式Ⅰ)是景天属植物的主要生物活性成分,具有抗缺氧、抗疲劳、抗肝纤维化、抗肾损害、抗肿瘤、防辐射等多种药理作用,以红景天苷为主要药效成分的治疗药品、保健食品和药材饮片已经上市。目前,市场销售的红景天苷主要是从景天属植物中提取得到的,由于这些植物多生长于高海拔地区,资源匾乏,且其中红景天苷的含量较低,因此造成红景天苷供不应求,价格昂贵;而利用细胞发酵培养红景天苷不仅含量低,且易造成成分复杂化;因此红景天苷的化学合成研究成为科研人员的重要任务。
红景天苷化学合成中常用的活化糖基给体包括β-五乙酰基葡萄糖、2,3,4,6-四乙酰基-1-β-溴代葡萄糖作为糖基给体。糖基三氯乙酰亚胺酯是常用的活化糖基给体,具有活化程度高、低温下稳定、糖苷化反应立体选择性好等优点。史明明等利用2,3,4,6-四-O-苯甲酰基-ɑ-D-吡喃葡萄糖三氯乙酰亚胺酯为糖基给体,与对羟基苯乙醇进行糖苷化反应,以21.5%的产率得到糖苷化后的红景天苷前体。用2,3,4,6-四-O-苄基ɑ-D-吡喃葡萄糖三氯乙酰亚胺酯作为糖基给体后,与4-苄氧基苯乙醇进行糖苷化反应,反应虽然有较高的产率(82.6%),但是立体选择性偏低(53.0%),且所得ɑ-、β-糖苷异构体难以分离[3](史明明. 红景天苷的合成方法研究[M]. 湖南师范大学硕士学位论文, 2012)。现有技术中,人们通过改变合成路线、改进底物结构和优化反应条件等途径,使红景天苷化学合成的收率有了明显提高,但反应需要消耗大量的有机溶剂。
室温离子液体(Ionic Liquids, ILs)具有优良的热稳定性、可以忽略的蒸汽压、高极性低界面张力、可回收使用等性质,是近年来倍受关注的研究领域之一。作为一种环境友好的新型反应介质,离子液体对有机和无机化合物有良好的溶解性;同时,可以利用其阴阳离子的结构可调性设计合成特定功能化的离子液体用于促进有机化学反应的进行。因此离子液体作为一种环境友好的新型反应介质,不仅可以替代传统的有机溶剂,同时可以为化学反应提供不同于传统有机溶剂的化学环境,从而协助提高反应的效率和选择性。研究表明,一些特殊结构的离子液体对糖苷化反应显示出很好的催化活性,并具有良好的循环使用性质,显示出离子液体中绿色糖苷化反应用于化学工业的巨大潜力;Rencurosi等系统研究了离子液体[Emim][OTf]作为反应溶剂和助剂、TMSOTf催化下,2-位没有邻基参与基团的糖基三氯乙酰亚胺酯给体与醇发生的糖苷化反应(Journal of Organic Chemistry,2005, 70(19): 7765-7768.),但是采用的各种离子液体在合成时,均需要经历N-甲基咪唑与卤代烃烷的烷基化反应、以及卤化烷基咪唑盐与各种盐(KPF6、NaBF4、TfOAg等)的离子交换反应等两步才能完成,合成中需要长时间的加热、操作也较为繁琐。并且从原子经济性的角度出发,这类离子液体合成的原子利用率不是100%,因而不是原子经济性反应,必然造成原子的浪费和环境的污染。红景天苷化学合成中的关键步骤就是葡萄糖1-碳原子与酪醇羟基氧原子间的O-糖苷化反应,因此葡萄糖1-位的活化以及糖苷化反应中催化剂和溶剂的选择至关重要。迄今为止,红景天苷类药物的化学合成仍是在有机溶剂中进行的,利用环境友好的离子液体系催化合成红景天苷类化合物的研究还未见报道,这在绿色化学成为具有战略意义前沿领域的今天,已成为制约其进一步发展的瓶颈,因此进行相关研究具有重要的理论和应用价值。
发明内容
针对现有技术中各类红景天苷化学合成方法存在的多种问题,本发明提供了一种利用[Rmim][OSO2OR]-Lewis酸离子液体系合成红景天苷化合物的方法,发明人对现有离子液体系催化绿色O-糖苷化研究工作进行改进,开发了一类适于O-糖苷化反应的[Rmim][OSO2OR]型离子液体,建立了利用[Rmim][OSO2OR]和Lewis酸组成的离子液体系作为绿色溶剂和催化剂,实施红景天苷类化合物的化学合成新方法。
本发明为了实现上述目的所采用的技术方案为:
本发明提供了一种利用 [Rmim][OSO2OR]-Lewis酸离子液体系合成红景天苷的方法,该离子液体为[Rmim][OSO2OR],其结构如式Ⅱ所示:
本发明所提供的方法具体包括以下步骤:
(1)将N-甲基咪唑与硫酸二烷基酯控温反应,得无色粘稠的离子液体——1,3-二甲基咪唑硫酸单烷基酯[Rmim][OSO2OR]:
(2)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯与4-苄氧基苯乙醇在[Rmim][OSO2OR]离子液体及0.1当量的Lewis酸中进行O-糖苷化反应,再经重结晶纯化后,得到2-(4- 苄氧基苯基) 乙基-(2,3,4,6-O-四-O-乙酰基)-β-D-吡喃葡萄糖苷(式Ⅲ化合物):
(3)式Ⅲ化合物在碱性条件下脱除其中的酰基保护基,然后与氢气在Pd/C催化下氢化脱除苄基保护基,得到红景天苷;
进一步的,步骤(1)中,所述N-甲基咪唑与硫酸二烷基酯的摩尔比为1:1;所述R 选自甲基、乙基、正丙基、异丙基和正丁基。。
进一步的,步骤(2)中,所述2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯同4-苄氧基苯乙醇的摩尔比为1.2:1;所述Lewis酸同4-苄氧基苯乙醇的摩尔比为1:10;所述4-苄氧基苯乙醇在离子液体中的浓度为0.49 mmol/mL。
上述 [Rmim][OSO2OR]-Lewis离子液体系中路易斯酸选自三氯化铝、氯化锌、溴化锌、三氟化硼乙醚、四氯化锡、四氯化钛、三氯化铁、三氟甲磺酸三甲基硅酯(TMSOTf)和三氟甲磺酸(TfOH)中的一种或几种。
进一步的,所述路易斯酸选自三氟甲磺酸三甲基硅酯或三氟化硼乙醚。
进一步的,所述重结晶纯化所用的溶剂选自四个碳以内的烷醇及丙酮、乙酸乙酯、乙醚、四氢呋喃、二氧六环、石油醚、正己烷、环己烷或它们的混合物;优选地选自乙醇-正己烷、乙醇-环己烷。
进一步的,步骤(3)中,所述式III化合物与碱的摩尔比为2:1;所述式III化合物与氢气的摩尔比为1:10;所述式III化合物与催化剂Pd/C的摩尔比1:0.1。
本发明的反应中,步骤(2)和(3)均在0-60℃下进行,优选的为室温25℃下。
进一步的,所述碱性条件是指在氢氧化钠、氢氧化及或四个碳以内的烷醇钠。
本发明提供的红景天苷制备方法中,所述4-苄氧基苯乙醇过下列步骤制备:4- 羟基苯乙酸与苄基溴在碱催化下经Williamson反应和成酯反应,得到4-苄氧基苯乙酸苄基酯;4-苄氧基苯乙酸苄基酯在合适溶剂中经氢化锂铝还原,得到4-苄氧基苯乙醇。所述碱选自碳酸钾、碳酸钠、氢氧化钠,优选地选自碳酸钾;所述合适溶剂为四氢呋喃、1,4-二氧六环等。
本发明提供的红景天苷制备方法中,其中,步骤(2) 反应的温度为0-60℃范围内任一温度,优选的温度为室温(25 ℃)。
本发明的有益效果为:
(1)本发明提供的离子液体的合成仅需一步反应,且在离子液体合成反应中原料的原子得到100%的利用,是一个操作简便的原子经济性反应。
(2)本发明利用[Rmim][OSO2OR]和Lewis酸组成的离子液体系作为绿色溶剂和催化剂实施化学合成红景天苷化合物的新方法,该合成方法环境友好、反应条件温和、后处理简单,解决现有离子液体系催化糖基三氯乙酰亚胺酯给体O-糖苷化过程中所用离子液体的合成繁琐、热能消耗、原子浪费以及非原子经济性反应所造成的环境污染等问题,同时解决了现有有机溶剂中进行红景天苷类药物化学合成所造成的环境污染、后处理繁琐等问题。
(3)本发明提供的离子液体可循环使用7次对反应产率没有明显影响,该方法操作简单、环境友好。
附图说明
图1为实施例14制备的2-(4- 苄氧基苯基) 乙基-β-D-吡喃葡萄糖苷的核磁共振氢谱。
图2为实施例15制备的红景天苷化合物的核磁共振氢谱。
具体实施方式
下面结合具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好的理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
室温离子液体1-甲基-3-乙基咪唑硫酸单乙酯[Emim][OSO2OE]的合成:将N-甲基咪唑100 mmol分散于30 mL甲苯中,在0℃下边搅拌边滴加等100 mmol的硫酸二乙酯,期间控制滴加过程中反应体系的温度小于40℃,滴加结束后将反应体系再室温反应,1小时后反应结束,得到两相混合物,分出上层甲苯相,下层离子液体相经乙酸乙酯洗涤三次,然后经旋转蒸发仪旋蒸,真空干燥,得无色粘稠的离子液体——1-甲基-3-乙基咪唑硫酸单乙酯[Emim][OSO2OE],产率98.3%。
实施例2
室温离子液体1,3-二甲基咪唑硫酸单甲酯[Mmim][OSO2OM]的合成:将100 mmolN-甲基咪唑分散于30 mL甲苯中,在0℃下边搅拌边滴加100 mmol的硫酸二甲酯,期间控制滴加过程中反应体系的温度小于40℃,滴加结束后将反应体系再室温反应,1小时后反应结束,得到两相混合物,分出上层甲苯相,下层离子液体相经乙酸乙酯洗涤三次,然后经旋转蒸发仪旋蒸,真空干燥,得无色粘稠的离子液体——1,3-二甲基咪唑硫酸单甲酯[Mmim][OSO2OM],产率97.6%。
实施例3
室温离子液体1-甲基-3-异丙基咪唑硫酸单丙酯[Prmim][OSO2OP]的合成:将100mmol N-甲基咪唑分散于30 mL甲苯中,在0℃下边搅拌边滴加100 mmol的硫酸二丙酯,期间控制滴加过程中反应体系的温度小于40℃,滴加结束后将反应体系再室温反应,1小时后反应结束,得到两相混合物,分出上层甲苯相,下层离子液体相经乙酸乙酯洗涤三次,然后经旋转蒸发仪旋蒸,真空干燥,得无色粘稠的离子液体——1-甲基-3-异丙基咪唑硫酸单丙酯[Prmim][OSO2OP],产率98.2%。
实施例4
室温离子液体1-甲基-3-正丙基咪唑硫酸单异丙酯[i-Prmim][OSO2OP-i]的合成:将100 mmol N-甲基咪唑分散于30 mL甲苯中,在0℃下边搅拌边滴加100 mol的硫酸二异丙酯,期间控制滴加过程中反应体系的温度小于40℃,滴加结束后将反应体系再室温反应,1小时后反应结束,得到两相混合物,分出上层甲苯相,下层离子液体相经乙酸乙酯洗涤三次,然后经旋转蒸发仪旋蒸,真空干燥,得无色粘稠的离子液体——1-甲基-3-异丙基咪唑硫酸单异丙酯[i-Prmim][OSO2OP-i],产率97.8%。
实施例5
室温离子液体1-甲基-3-丁基咪唑硫酸单丁酯[Bmim][OSO2OB]的合成:将100mmol N-甲基咪唑分散于30 mL甲苯中,在0℃下边搅拌边滴加100 mmol的硫酸二丁酯,期间控制滴加过程中反应体系的温度小于40℃,滴加结束后将反应体系再室温反应,1小时后反应结束,得到两相混合物,分出上层甲苯相,下层离子液体相经乙酸乙酯洗涤三次,然后经旋转蒸发仪旋蒸,真空干燥,得无色粘稠的离子液体——1-甲基-3-丁基咪唑硫酸单丁酯[Bmim][OSO2OB],产率98.3%。
实施例6
中间体4- 苄氧基苯乙醇的合成:将10mmol 4-羟基苯乙酸溶于60 mL无水丙酮,再加入30 mmol苄基溴,搅拌下加入30 mmol无水碳酸钾,加热回流10小时;TLC检测发现原料点消失,并有一极性较小的荧光点。以硅藻土滤去溶液中的固体,将滤液浓缩,二氯甲烷稀释,依次用稀盐酸、饱和氯化钠溶液洗涤,无水Na2SO4干燥,蒸除溶剂得微黄色油状液。硅胶柱层析得到3.06克白色粉末状固体4-苄氧基苯乙酸苄基酯,产率92.2%。
称取60 mmol LiAlH4于45 mL无水THF中,0℃时,N2保护下搅拌10分钟,然后用恒压滴液漏斗缓缓滴入15 mmol 4-苄氧基苯乙酸苄基酯的THF溶液,滴完后升至室温,然后加热反应4小时,TLC检测反应完全。冰水浴中慢慢滴入10 mL甲醇,开始有气泡产生,后来无气泡,浑浊液逐渐变澄清,溶液下层及容器壁上有灰色固体产生,继续搅拌15分钟后,灰色固体变为白色泥状固体。停止反应,抽滤除去固体。滤液分别用水及饱和NaCl溶液洗两次,有机相用无水MgSO4干燥过夜后浓缩得黄色液体;该液体经硅胶柱层析得2.89 g白色粉末状固体4-苄氧基苯乙醇,产率84.5%。
1HNMR (500 MHz, CDCl3): δ= 7.43-6.92 (9H, aromatic protons), 5.05 (2H,s, p-PhCH2OCH2OPhCH2CH2OH), 3.83 (2H, t, p-PhCH2OCH2OPhCH2CH2OH), 2.82 (2H, t,p-PhCH2OCH2OPhCH2CH2OH)。
实施例7
2-(4- 苄氧基苯基) 乙基-(2,3,4,6-四-O-乙酰基)-β-D-吡喃葡萄糖苷的制备:取10.0 mL离子液体[Emim][OSO2OE],加入1.0 g(4.1 mmol)4-苄氧基苯乙醇和2.4 g(4.9mmol)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯,氮气换气三次,冷却至0℃,用微量注射器逐滴滴加75 μL TMSOTf(0.4 mmol)。保持温度在0℃左右反应0.5小时左右,然后慢慢升至室温反应2h,TLC检测醇原料消失,用三乙胺中止反应。将反应液用无水乙醚萃取出所生成的糖苷。合并乙醚相,依次用少量的4% Na2CO3、饱和食盐水洗涤,再加入无水Na2SO4干燥,旋蒸除去乙醚后经乙醇-环己烷重结晶得到2-(4- 苄氧基苯基) 乙基-(2,3,4,6-四-O-乙酰基)-β-D-吡喃葡萄糖苷1.83 g,乳白色固体产物,反应产率80.1%。
实施例8
2-(4- 苄氧基苯基) 乙基-(2,3,4,6-O- 四- 乙酰基)-β-D- 吡喃葡萄糖苷的制备:取10.0 mL离子液体[Mmim][OSO2OM],加入1.0 g(4.1 mmol)对苄氧基苯乙醇和2.4 g(4.9 mmol)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯,氮气换气三次,冷却至0 ℃,用微量注射器逐滴滴加75 μL TMSOTf(0.4 mmol)。保持温度在0℃左右反应0.5小时左右,然后慢慢升至室温反应2h,TLC检测醇原料消失,用三乙胺中止反应。将反应液用无水乙醚萃取出所生成的糖苷。合并乙醚相,依次用少量的4% Na2CO3、饱和食盐水洗涤,再加入无水Na2SO4干燥,旋蒸除去乙醚后经乙醇-正己烷重结晶得到纯净的糖苷化产品1.78 g,无色黏状固体产物,反应产率77.9%。
实施例9
2-(4- 苄氧基苯基) 乙基-(2,3,4,6-O- 四- 乙酰基)-β-D- 吡喃葡萄糖苷的制备:取10.0 mL离子液体[Pmim][OSO2OP],加入1.0 g(4.1 mmol)4-苄氧基苯乙醇和2.4 g(4.9 mmol)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯,氮气换气三次,冷却至0 ℃,用微量注射器逐滴滴加75 μL TMSOTf(0.4 mmol)。保持温度在0℃左右反应0.5小时左右,然后慢慢升至室温反应2h,TLC检测醇原料消失,用三乙胺中止反应。将反应液用无水乙醚萃取出所生成的糖苷。合并乙醚相,依次用少量的4% Na2CO3、饱和食盐水洗涤,再加入无水Na2SO4干燥,旋蒸除去乙醚后经乙醇-环己烷重结晶得到纯净的糖苷化产品1.85 g,无色黏状固体产物,反应产率80.9%。
实施例10
2-(4- 苄氧基苯基) 乙基-(2,3,4,6-O- 四- 乙酰基)-β-D- 吡喃葡萄糖苷的制备:取10.0 mL离子液体[i-Pmim][OSO2OP-i],加入1.0 g(4.1 mmol)4-苄氧基苯乙醇和2.4g(4.9 mmol)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯,氮气换气三次,冷却至0 ℃,用微量注射器逐滴滴加75 μL TMSOTf(0.4 mmol)。保持温度在0℃左右反应0.5小时左右,然后慢慢升至室温反应2h,TLC检测醇原料消失,用三乙胺中止反应。将反应液用无水乙醚萃取出所生成的糖苷。合并乙醚相,依次用少量的4% Na2CO3、饱和食盐水洗涤,再加入无水Na2SO4干燥,旋蒸除去乙醚后经乙醇-环己烷重结晶得到纯净的糖苷化产品1.82 g,无色黏状固体产物,反应产率79.6%。
实施例11
2-(4- 苄氧基苯基) 乙基-(2,3,4,6-O- 四- 乙酰基)-β-D- 吡喃葡萄糖苷的制备:取10.0 mL离子液体[Bmim][OSO2OB],加入1.0 g(4.1 mmol)4-苄氧基苯乙醇和2.4 g(4.9 mmol)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯,氮气换气三次,冷却至0 ℃,用微量注射器逐滴滴加75 μL TMSOTf(0.4 mmol)。保持温度在0℃左右反应0.5小时左右,然后慢慢升至室温反应2h,TLC检测醇原料消失,用三乙胺中止反应。将反应液用无水乙醚萃取出所生成的糖苷。合并乙醚相,依次用少量的4% Na2CO3、饱和食盐水洗涤,再加入无水Na2SO4干燥,旋蒸除去乙醚后经乙醇-环己烷重结晶得到纯净的糖苷化产品1.87 g,无色黏状固体产物,反应产率81.8%。
实施例12
2-(4- 苄氧基苯基) 乙基-(2,3,4,6-四-O-乙酰基)-β-D-吡喃葡萄糖苷的制备:取10.0 mL离子液体[Emim][OSO2OE],加入1.0 g(4.1 mmol)对苄氧基苯乙醇和2.4 g(4.9mmol)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯,氮气换气三次,冷却至0℃,用微量注射器逐滴滴加0.94 mL BF3·Et2O(5.0 mmol)。保持温度在0℃左右反应1小时左右,然后慢慢升至室温反应4h,TLC检测醇原料消失,用三乙胺中止反应。将反应液用无水乙醚萃取出所生成的糖苷。合并乙醚相,依次用少量的4% Na2CO3、饱和食盐水洗涤,再加入无水Na2SO4干燥,旋蒸除去乙醚后经乙醇-环己烷重结晶得到2-(4- 苄氧基苯基) 乙基-(2,3,4,6-四-O-乙酰基)-β-D-吡喃葡萄糖苷1.65 g,乳白色固体产物,反应产率72.2%。
实施例13
2-(4- 苄氧基苯基) 乙基-β-D-吡喃葡萄糖苷的制备:取1.89 g (3.4 mmol)1-O-(4-苄氧基)-苯乙基-2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖和0.19g(1.7 mmol) 50%CH3ONa/CH3OH,再加入20 mL无水甲醇,室温搅拌,TLC跟踪反应,3 h后反应基本完成。然后加入732 阳离子交换树脂中和至pH = 7,浓缩得浅黄色蜡状固体粗产物,乙醇重结晶得白色固体1-O-(4-苄氧基)-苯乙基-β-D-吡喃葡萄糖苷产品1.1 g,反应产率83.0%,熔点为100-101℃。
实施例14
2-(4- 苄氧基苯基) 乙基-β-D-吡喃葡萄糖苷的制备:向饱和氢氧化钠溶液中加入甲醇,调pH 至11-12,加入1.89 g (3.4 mmol)1-O-(4-苄氧基)-苯乙基-2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖,室温搅拌,TLC跟踪反应,3 h后反应基本完成。然后加入732 阳离子交换树脂中和至pH = 7,浓缩得浅黄色蜡状固体粗产物,乙醇重结晶得白色固体1-O-(4-苄氧基)-苯乙基-β-D-吡喃葡萄糖苷产品1.17 g,反应产率86.8%。
谱图如图1所示:1H NMR (400 MHz, CD3OD): δ 7.30-7.44(5H, m, -OCH2Ph中苯环上的H), 6.90-7.19(4H, dd, J=8.0Hz), 5.06 (2H, s, -OCH2Ph中CH2上的H), 4.17-4.19 (1H, d, J=8.0 Hz), 3.87-3.93 (1H, m), 3.54-3.68 (2H, m), 3.43(1H, m),2.96-3.14 (4H, m), 2.77-2.80(2H, m).
实施例15
2-(4- 羟基苯基)乙基-β-D-吡喃葡萄糖苷(红景天苷)的制备:取1.1 g(2.8mmol) 1-O-(4-苄氧基)-苯乙基-β-D-吡喃葡萄糖苷和0.1 g的5% Pd/C催化剂,然后反复抽空气充氢气3-5次,并在氢气氛围下加入20 mL无水甲醇,避光,室温搅拌过夜。过滤,减压浓缩至干,经乙醇重结晶得到白色粉末1-(4-羟基)-苯乙基-β-D-吡喃萄萄糖苷,即“红景天苷”,产物重0.78g,产率93%。熔点158-160 ℃。
谱图如图2所示:1H NMR (400 MHz, CD3OD): δ7.03-7.05 (2H, d, J=8.0 Hz),6.57-6.59 (2H, d, J=8.0 Hz), 4.27-4.29 (1H, d, J=8.0 Hz), 4.00-4.03 (1H, m),3.83 (1H, m), 3.66-3.69(2H, m), 3.16-3.35 (4H, m), 2.79-2.84(2H, m).
HRMS(ESI-MS):Found 323.1109[M+Na+],Calc 323.1107[M+Na+]。
Claims (9)
1.一种利用离子液体系合成红景天苷的方法,其特征在于,该离子液体为[Rmim][OSO2OR],其结构如式Ⅱ所示:
具体包括以下步骤:
(1)将N-甲基咪唑与硫酸二烷基酯,加入PhCH3,在0℃至室温下反应,得无色粘稠的离子液体——1,3-二甲基咪唑硫酸单烷基酯[Rmim][OSO2OR]:
(2)2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯与4-苄氧基苯乙醇在[Rmim][OSO2OR]离子液体及0.1当量的Lewis酸中进行O-糖苷化反应,再经重结晶纯化后,得到式Ⅲ化合物:2-(4- 苄氧基苯基) 乙基-(2,3,4,6-O-四-O-乙酰基)-β-D-吡喃葡萄糖苷:
(3)式Ⅲ化合物在碱性条件下脱除其中的酰基保护基,然后与氢气在Pd/C催化下氢化脱除苄基保护基,得到红景天苷:
2.根据权利要求1所述的方法,其特征在于,步骤(1)中,所述N-甲基咪唑与硫酸二烷基酯的摩尔比为1:1;所述R 选自甲基、乙基、正丙基、异丙基和正丁基。
3.根据权利要求1所述的方法,其特征在于,步骤(2)中,所述2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖三氯乙酰亚胺酯同4-苄氧基苯乙醇的摩尔比为1.2:1;所述Lewis酸同4-苄氧基苯乙醇的摩尔比为1:10;所述4-苄氧基苯乙醇在离子液体中的浓度为0.49 mmol/mL。
4.根据权利要求1-3任一项所述的方法,其特征在于,所述Lewis酸选自三氯化铝、氯化锌、溴化锌、三氟化硼乙醚、四氯化锡、四氯化钛、三氯化铁、三氟甲磺酸三甲基硅酯(TMSOTf)和三氟甲磺酸(TfOH)中的一种或几种。
5.根据权利要求4所述的方法,其特征在于,所述Lewis酸选自三氟甲磺酸三甲基硅酯或三氟化硼乙醚。
6.根据权利要求1所述的方法,其特征在于,所述重结晶纯化所用的溶剂选自四个碳以内的烷醇及丙酮、乙酸乙酯、乙醚、四氢呋喃、二氧六环、石油醚、正己烷、环己烷或它们的混合物。
7.根据权利要求1所述的方法,其特征在于,步骤(3)中,所述式III化合物与碱的摩尔比为2:1;所述式III化合物与氢气的摩尔比为1:10;所述式III化合物与催化剂Pd/C的摩尔比1:0.1。
8.根据权利要求1所述的方法,其特征在于,所述步骤(2)和(3)均在0-60℃下进行。
9.根据权利要求1所述的方法,其特征在于,所述碱是指氢氧化钠或四个碳以内的烷醇钠。
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