WO2021062882A1 - 一种络塞维的合成方法 - Google Patents

一种络塞维的合成方法 Download PDF

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WO2021062882A1
WO2021062882A1 PCT/CN2019/110301 CN2019110301W WO2021062882A1 WO 2021062882 A1 WO2021062882 A1 WO 2021062882A1 CN 2019110301 W CN2019110301 W CN 2019110301W WO 2021062882 A1 WO2021062882 A1 WO 2021062882A1
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synthesis method
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李文举
高健
唐鹏飞
庄永忠
李秀珍
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济南山目生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • 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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  • the invention relates to the field of sugar drug synthesis, in particular to a method for preparing the active ingredient Losseville of Rhodiola rosea by a chemical method.
  • Rosavin, ⁇ -(E)-cinnamyl alcohol-O-[6'-O- ⁇ -L-arabinosyl]-D-glucopyranoside is the traditional herbal medicine Rhodiola rosea
  • the main active ingredient has the effects of anti-anoxia, anti-fatigue, delaying aging and treating depression.
  • the commonly used preparation method is extraction from natural plants, but it is difficult to obtain high-purity rosavir products by the method of plant extraction, and the yield is low and the cost is high.
  • the invention patent CN101456885A provides a multi-step synthesis method of rosavir, but the route is long, the total yield is low, and more importantly, it requires multiple treatments of intermediates and The final product is purified by silica gel column, which is difficult to carry out large-scale industrial production.
  • the present invention provides a synthetic method for rosavir, which has easy-to-obtain raw materials, simple synthesis method and high yield.
  • the present invention adopts the following technical solutions.
  • a method for synthesizing rosevi including the following steps:
  • step (1) the dewatering agent is Molecular sieve.
  • the organic solvent is dichloromethane, acetonitrile or a mixture of dichloromethane and acetonitrile.
  • reaction temperature is -25 to -15°C.
  • step (2) the separation step is: raising the reaction system to room temperature, after filtering, washing the filtrate with saturated sodium sulfite solution and saturated brine in sequence, and evaporating the organic solvent to obtain it.
  • the quencher is selected from any one of diethylamine, triethylamine or pyridine.
  • step (3) the separation and purification method is: adding acidic cation exchange resin to the reaction system, adjusting the pH value to neutral, filtering, concentrating the filtrate under reduced pressure, adding 1-1.5 volume times of methyl tert-butyl under stirring Ether (MTBE), filtered after crystallization, the filter cake is rinsed or recrystallized with a solution of methyl tert-butyl ether and methanol in a volume ratio of 2:1, and the final product is obtained after drying.
  • MTBE methyl tert-butyl under stirring Ether
  • the synthetic route is as follows:
  • the present invention uses commercial L-arabinose donors, D-glucose acceptors and beta-(E)-cinnamyl alcohol as raw materials to obtain high-purity rosavir products through a three-step reaction.
  • the intermediates do not need to be purified.
  • the product is obtained by crystallization, with a total yield of more than 70%.
  • the method system of the present invention has clean reaction, the product can be directly crystallized and separated from the system, the product yield is high, and the purity is high, which is beneficial to the large-scale industrial preparation of Losevir.
  • Figure 1 is the HPLC spectrum of the rosavir standard sample
  • Figure 2 is the HPLC spectrum of the Roxavir sample.
  • the filter cake was recrystallized with 10L of methyl tert-butyl ether and methanol solution with a volume ratio of 2:1, and the filtered solid was dried in hot air at 50°C to obtain 723 g of rosacevir.
  • the total yield in three steps The rate is 71.0%.
  • Nuclear magnetic carbon spectrum (CD 3 OD, 100MHz): ⁇ : 138.2, 133.7, 129.6, 128.7, 127.5, 126.7, 105.2, 103.4, 78.0, 76.9, 75.1, 74.2, 72.4, 71.7, 70.9, 69.51, 69.49, 66.7;
  • the purity of the product is determined by high performance liquid chromatography, and the chromatographic conditions are as follows:
  • Figure 1 is a typical HPLC spectrum of Rocevir standard (Sigma-Aldrich), the peak time is 6.711 min, and the area integral purity is 98.120%.
  • Figure 2 is the HPLC spectrum of the prepared sample, the peak time It is 6.714 min, and the area integral purity is 99.073%.
  • step (2) Continue to add 319 grams of beta-(E)-cinnamyl alcohol and 588 grams of NIS to the system of step (1). After the system was stirred at -18°C for 30 minutes, 100 ml of methylene chloride solution containing 7.13 g of TfOH was added dropwise. The system was stirred and reacted at -18°C for 1 hour. The reaction was followed by HPLC until the intermediate product 1 disappeared.
  • the filter cake is rinsed 3 times with a solution of methyl tert-butyl ether and methanol in a volume ratio of 2:1, and then dried in hot air at 60°C to obtain 735 g of rosavic.
  • the yield was 72.2%, and the content detected by HPLC was 98.75%.
  • step (2) Continue to add 319 grams of beta-(E)-cinnamyl alcohol and 588 grams of NIS to the system of step (1). After the system was stirred at -25°C for 30 minutes, 100 ml of methylene chloride solution containing 7.13 g of TfOH was added dropwise. The system was stirred and reacted at -25°C for 1 hour. The reaction was followed by HPLC until the intermediate product 1 disappeared.
  • the filter cake is rinsed 5 times with a solution of methyl tert-butyl ether and methanol in a volume ratio of 2:1, and then dried with hot air at 80°C to obtain 730 g of rosacevir.
  • the yield was 71.6%, and the content detected by HPLC was 98.89%.

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Abstract

一种络塞维的合成方法，步骤为：三氟甲磺酸三甲基硅酯催化2，3，4-三-O-乙酰基-L-呋喃阿拉伯糖三氯乙酰亚胺酯和乙基2，3，4-三-O-乙酰基-beta-D-硫代吡喃葡萄糖苷反应，然后将beta-(E)-肉桂醇、NIS 和TfOH 依次加入继续反应至完全，分离获得中间体粗品。将中间体粗品与甲醇钠在甲醇中反应，分离纯化获得络塞维。

Description

一种络塞维的合成方法 技术领域
本发明涉及糖药物合成领域，具体涉及一种化学方法制备玫瑰红景天活性成分洛塞维的方法。
背景技术
络塞维(Rosavin)，β-(E)-肉桂醇基-O-[6’-O-α-L-阿拉伯吡喃糖基]-D-葡萄吡喃糖苷是传统草药玫瑰红景天的主要活性成分，具有抗缺氧、抗疲劳、延缓衰老和治疗抑郁症等功效。目前常用的制备方法为从天然植物中提取，但是植物提取的方法很难得到高纯度的络塞维产品，而且收率低、成本高。
Figure PCTCN2019110301-appb-000001
络塞维的化学结构
目前很少有关络塞维的化学合成文献报道，发明专利CN101456885A给出了一种多步合成络塞维的方法，但是路线长，总收率低，更重要的是需要多次对中间体和终产物进行硅胶柱纯化，很难进行大规模产业化生产。
发明内容
针对现有技术中纯化学合成法制备络塞维路线长、收率低的问题，本发明提供一种络塞维的合成方法，原料易得、合成方法简单、收率高。
为实现上述目的，本发明采用如下技术方案。
一种络塞维的合成方法，包括以下步骤：
(1)在保护气氛中，除水剂存在下，三氟甲磺酸三甲基硅酯催化2,3,4-三-O-乙酰基-L-呋喃阿拉伯糖三氯乙酰亚胺酯和乙基2,3,4-三-O-乙酰基-beta-D-硫代吡喃葡萄糖苷在有机溶剂中反应；
(2)在保护气氛中，将beta-(E)-肉桂醇、NIS(N-碘代丁二酰亚胺)和TfOH(三氟甲磺酸)依次加入步骤(1)的体系中，继续反应，然后加入猝灭剂，分离获得中间体
Figure PCTCN2019110301-appb-000002
粗品；
(3)中间体的粗品和甲醇钠在甲醇中反应，分离纯化获得络塞维。
步骤(1)中，所述除水剂为
Figure PCTCN2019110301-appb-000003
分子筛。
步骤(1)中，所述有机溶剂为二氯甲烷、乙腈或二氯甲烷和乙腈的混合。
步骤(1)和(2)中，所述反应温度为-25～-15℃。
步骤(2)中，所述分离步骤为：将反应体系升至室温，过滤后将滤液依次用饱和亚硫酸钠溶液和饱和食盐水洗涤，蒸除有机溶剂即得。
步骤(2)中，所述猝灭剂选自二乙胺、三乙胺或吡啶中的任意一种。
步骤(3)中，所述分离纯化方法为：反应体系中加入酸性阳离子交换树脂，调节pH值至中性，过滤，滤液减压浓缩，搅拌下加入1-1.5体积倍的甲基叔丁基醚(MTBE)，析晶后过滤，滤饼用体积比为2:1的甲基叔丁基醚和甲醇溶液淋洗或重结晶，干燥后获得终产品。
合成路线如下：
Figure PCTCN2019110301-appb-000004
本发明具有以下优点：
本发明以商品化的L-阿拉伯糖供体、D-葡萄糖受体和beta-(E)-肉桂醇为原料，经三步反应得到高纯度的络塞维产品，中间体不需要纯化，终产品经析晶获得，总收率70％以上。本发明的方法体系反应干净，产物可以直接从体系中析晶分离，产物收率高、纯度高，有利于洛塞维的大规模产业化制备。
附图说明
图1是络塞维标样的HPLC图谱；
图2是络塞维样品的HPLC图谱。
具体实施方式
下面结合实施例和附图对本发明做进一步说明，但本发明不受下述实施例的限制。
实施例1 络塞维的合成
(1)
Figure PCTCN2019110301-appb-000005
搅拌下往10L二氯甲烷中加入1000克L-阿拉伯糖供体2,3,4-三-O-乙酰基-L-呋喃阿拉伯糖三氯乙酰亚胺酯、833克D-葡萄糖受体乙基2,3,4-三-O-乙酰基-beta-D-硫代吡喃葡萄糖苷和活化过的500克
Figure PCTCN2019110301-appb-000006
分子筛，体系在氮气保护和室温条件下搅拌30分钟后降温至-20℃，在氮气保护、低温、搅拌下往体系中滴加5.28克TMSOTf，加料完毕体系在-20℃条件下搅拌30分钟至原料基本无残留(HPLC含量小于1％)；
(2)
Figure PCTCN2019110301-appb-000007
往步骤(1)的体系中继续加入319克beta-(E)-肉桂醇和588克NIS。体系在-20℃下搅拌30分钟后滴加100毫升含有7.13克TfOH的二氯甲烷溶液。体系在-20℃搅拌反应1小时，HPLC跟踪反应至中间体产物1消失，往体系中加入12.0克三乙胺结束反应；将体系升温至室温，过滤后将体系用饱和亚硫酸钠溶液洗涤2次，每次10L，再用10L饱和食盐水洗涤，将有机相减压浓缩，得到1800克粗品中间体产物化合物2，不经纯化直接投入下一步；
(3)
Figure PCTCN2019110301-appb-000008
将化合物2粗品溶于15L干燥甲醇中，室温下搅拌溶清后加入12克甲醇钠至体系pH值达到9，室温下搅拌2小时，经HPLC检测化合物2反应完全；搅拌下，向体系中加入酸性树脂IR-120，调节体系pH值至7，然后过滤，滤液减压浓缩至5L，搅拌下缓慢加入8L甲基叔丁基醚(MTBE)，有白色固体析出，在室温下析晶2小时，然后过滤，滤饼再用10L体积比2:1的甲基叔丁基醚和甲醇溶液重结晶，过滤后的固体在50℃下热风烘干，得络塞维723克，三步总收率71.0％。其核磁氢谱(CD 3OD,400MHz):δ:7.42(d,2H,J＝7.6Hz),7.30(t,2H,J＝7.6Hz),7.21(t,1H,J＝7.1Hz),6.69(d,1H,J＝15.9Hz),6.36(td,1H,J＝6.0,15.9Hz),4.51(dd,1H,J＝5.6,13.1Hz),4.37(d,1H,J＝7.8Hz),4.33(d,1H,J＝6.8Hz),4.35–4.29(m,1H),4.11(d,1H,J＝10.9Hz),3.86(dd,1H,J＝3.0,12.4Hz),3.78–3.76(m,1H),3.74(dd,1H,J＝5.8,11.4Hz),3.61(t,1H,J＝7.1Hz),3.54–3.50(m,2H),3.46–3.44(m,1H),3.37–3.33(m,2H),3.24(t,1H,J＝7.6Hz)；
核磁碳谱(CD 3OD,100MHz):δ:138.2,133.7,129.6,128.7,127.5,126.7,105.2,103.4,78.0,76.9,75.1,74.2,72.4,71.7,70.9,69.51,69.49,66.7；
质谱(FAB)-MS m/z:429.1755；计算值C 20H 29O 10:429.1761(M+1) +；
与络塞维文献数据一致。
采用高效液相色谱对产品的纯度进行测定，色谱条件如下：
色谱柱：Inertsil ODS-3，4.6×250mm，5μm
柱温：40℃
流动相：去离子水:乙腈＝30/70
流速：1.0mL/min
检测器：ELSD
图1中为络塞维标准品(Sigma-Aldrich)的典型HPLC谱图，出峰时间为6.711min，面积积分纯度为98.120％，图2中为制备获得的样品的HPLC谱图，出蜂时间为6.714min，面积积分纯度为99.073％。
实施例2 络塞维的合成
(1)搅拌下往10L乙腈中加入1000克L-阿拉伯糖供体2,3,4-三-O-乙酰基-L-呋喃阿拉伯糖 三氯乙酰亚胺酯、833克D-葡萄糖受体乙基2,3,4-三-O-乙酰基-beta-D-硫代吡喃葡萄糖苷和活化过的500克
Figure PCTCN2019110301-appb-000009
分子筛，体系在氮气保护和室温条件下搅拌30分钟后降温至-18℃，在氮气保护、-18℃、搅拌下往体系中滴加5.28克TMSOTf，加料完毕体系在-18℃条件下搅拌30分钟至原料基本无残留；
(2)往步骤(1)的体系中继续加入319克beta-(E)-肉桂醇和588克NIS。体系在-18℃下搅拌30分钟后滴加100毫升含有7.13克TfOH的二氯甲烷溶液。体系在-18℃搅拌反应1小时，HPLC跟踪反应至中间体产物1消失，往体系中加入12.7克吡啶结束反应；将体系升温至室温，过滤后将体系用饱和亚硫酸钠溶液洗涤2次，每次10L，再用10L饱和食盐水洗涤，将有机相减压浓缩，得到1800克粗品中间体产物化合物2，不经纯化直接投入下一步；
(3)将化合物2粗品溶于15L干燥甲醇中，室温下搅拌溶清后加入12克甲醇钠至体系pH值达到9，室温下搅拌2小时，经HPLC检测化合物2反应完全；搅拌下，向体系中加入酸性树脂IR-120，调节体系pH值至7，然后过滤，滤液减压浓缩至5L，搅拌下缓慢加入8L甲基叔丁基醚(MTBE)，有白色固体析出，在室温下析晶2小时，然后过滤，滤饼再用体积比2:1的甲基叔丁基醚和甲醇溶液淋洗3次，然后在60℃下热风烘干，得络塞维735克，三步总收率72.2％，HPLC检测含量为98.75％。
实施例3 络塞维的合成
(1)搅拌下往10L二氯甲烷与乙腈等体积混合的溶剂中加入1000克L-阿拉伯糖供体2,3,4-三-O-乙酰基-L-呋喃阿拉伯糖三氯乙酰亚胺酯、833克D-葡萄糖受体乙基2,3,4-三-O-乙酰基-beta-D-硫代吡喃葡萄糖苷和活化过的500克
Figure PCTCN2019110301-appb-000010
分子筛，体系在氮气保护和室温条件下搅拌30分钟后降温至-25℃，在氮气保护、-25℃、搅拌下往体系中滴加5.28克TMSOTf，加料完毕体系在-25℃条件下搅拌35分钟至原料基本无残留；
(2)往步骤(1)的体系中继续加入319克beta-(E)-肉桂醇和588克NIS。体系在-25℃下搅拌30分钟后滴加100毫升含有7.13克TfOH的二氯甲烷溶液。体系在-25℃搅拌反应1小时，HPLC跟踪反应至中间体产物1消失，往体系中加入12.7克吡啶结束反应；将体系升温至室温，过滤后将体系用饱和亚硫酸钠溶液洗涤2次，每次10L，再用10L饱和食盐水洗涤，将有机相减压浓缩，得到1800克粗品中间体产物化合物2，不经纯化直接投入下一步；
(3)将化合物2粗品溶于15L干燥甲醇中，室温下搅拌溶清后加入12克甲醇钠至体系pH值达到9，室温下搅拌2小时，经HPLC检测化合物2反应完全；搅拌下，向体系中加入酸 性树脂IR-120，调节体系pH值至7，然后过滤，滤液减压浓缩至5L，搅拌下缓慢加入8L甲基叔丁基醚(MTBE)，有白色固体析出，在室温下析晶2小时，然后过滤，滤饼再用体积比2:1的甲基叔丁基醚和甲醇溶液淋洗5次，然后在80℃下热风烘干，得络塞维730克，三步总收率71.6％，HPLC检测含量为98.89％。

Claims (7)

  1. 一种络塞维的合成方法，其特征在于，包括以下步骤：
    (1)在保护气氛中，除水剂存在下，三氟甲磺酸三甲基硅酯催化2,3,4-三-O-乙酰基-L-呋喃阿拉伯糖三氯乙酰亚胺酯和乙基2,3,4-三-O-乙酰基-beta-D-硫代吡喃葡萄糖苷在有机溶剂中反应；
    (2)在保护气氛中，将beta-(E)-肉桂醇、N-碘代丁二酰亚胺和三氟甲磺酸依次加入步骤(1)的体系中，继续反应，然后加入猝灭剂，分离获得中间体粗品；
    (3)中间体粗品和甲醇钠在甲醇中反应，分离纯化获得络塞维。
  2. 根据权利要求1所述的合成方法，其特征在于，步骤(1)中，所述除水剂为
    Figure PCTCN2019110301-appb-100001
    分子筛。
  3. 根据权利要求1所述的合成方法，其特征在于，步骤(1)中，所述有机溶剂为二氯甲烷、乙腈或二氯甲烷和乙腈的混合。
  4. 根据权利要求1所述的合成方法，其特征在于，步骤(1)和(2)中，所述反应温度为-25～-15℃。
  5. 根据权利要求1所述的合成方法，其特征在于，步骤(2)中，所述猝灭剂选自二乙胺、三乙胺或吡啶中的任意一种。
  6. 根据权利要求1所述的合成方法，其特征在于，步骤(2)中，所述分离步骤为：将反应体系升至室温，过滤后将滤液依次用饱和亚硫酸钠溶液和饱和食盐水洗涤，蒸除有机溶剂即得。
  7. 根据权利要求1所述的合成方法，其特征在于，步骤(3)中，所述分离纯化方法为：反应体系中加入酸性阳离子交换树脂，调节pH值至中性，过滤，滤液减压浓缩，搅拌下加入1-1.5体积倍的甲基叔丁基醚，析晶后过滤，滤饼用体积比为2:1的甲基叔丁基醚和甲醇溶液淋洗或重结晶，干燥后获得终产品。
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