WO2020048343A1 - 一种6-糠氨基嘌呤的合成方法 - Google Patents

一种6-糠氨基嘌呤的合成方法 Download PDF

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Publication number
WO2020048343A1
WO2020048343A1 PCT/CN2019/102634 CN2019102634W WO2020048343A1 WO 2020048343 A1 WO2020048343 A1 WO 2020048343A1 CN 2019102634 W CN2019102634 W CN 2019102634W WO 2020048343 A1 WO2020048343 A1 WO 2020048343A1
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WIPO (PCT)
Prior art keywords
furfurylaminopurine
purity
furfurylamine
chloropurine
dbu
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PCT/CN2019/102634
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English (en)
French (fr)
Inventor
杨辉
王勇丽
李晓梅
朱辉
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湖北荆洪生物科技股份有限公司
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Publication of WO2020048343A1 publication Critical patent/WO2020048343A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the invention relates to a method for synthesizing high-purity 6-furfurylaminopurine, and belongs to the technical field of organic synthesis.
  • 6-furfurylaminopurine white crystal or white crystalline powder, also known as 6-furfurylaminopurine, kinetin, is a purine-based natural plant endogenous hormone and the first cytokinin discovered by humans. Can be artificially synthesized.
  • Furfuryl aminopurine has the advantages of promoting cell division and tissue differentiation; inducing bud differentiation and lifting the apical advantage; delaying the degradation of proteins and chlorophyll, which has freshness and anti-aging effects; delaying the formation of layers and increasing fruit set.
  • This agent is mainly used for tissue culture, and cooperates with auxin to promote cell division and induce callus and tissue differentiation.
  • 6-furfurylaminopurine are: condensation of adenine and furfuryl chloride under the action of alkali; condensation of methylthiopurine and furfurylamine; condensation of adenine and furfurylamine; condensation of acylpurine and furfuryl chloride to furfurylpurine, Then it is obtained by reduction of lithium aluminum hydride; adenine and furfuryl alcohol are condensed, etc.
  • these methods have problems such as limited raw material sources or low yields.
  • the reaction method using 6-chloropurine and furfurylamine is relatively straightforward, due to the high chlorine activity at the 6-position. It has been reported in the literature that the reaction in ethanol or butanol solvent can easily generate by-products where chlorine is replaced by alcohol, resulting in unqualified single impurities.
  • the invention solves the technical problems of limited raw material sources or unsuitable for scale-up (such as the use of lithium aluminum hydride), low yield, unqualified single impurities, etc. in the existing method.
  • the present invention provides a method for synthesizing high-purity 6-furfurylaminopurine.
  • the high-purity 6-furfurylaminopurine is substituted by high-temperature nucleophilic substitution of 6-chloropurine and furfurylamine, followed by filtration and recrystallization. .
  • the present invention adopts the following technical scheme: in the presence of DBU, furfurylamine and 6-chloropurine are reacted in hexamethyldisilazane to obtain a crude 6-furfurylaminopurine, and recrystallization to obtain high purity 6- Furfuryl aminopurine, HPLC purity is more than 99.5%, single impurity is less than 0.1%.
  • the reaction is preferably carried out by mixing furfurylamine with DBU, heating 6-chloropurine and hexamethyldisilazane to 110-115 ° C, and starting to add the mixture of furfurylamine and DBU dropwise.
  • the molar ratio of the 6-chloropurine to furfurylamine is 1: 1-1.15.
  • the molar ratio of 6-chloropurine to DBU is 1: 1 to 1.2.
  • reaction temperature is 110-130 ° C.
  • a crude 6-furfurylaminopurine is obtained through a nucleophilic substitution reaction of 6-chloropurine and furfurylamine, and high purity 6-furfurylaminopurine is obtained after recrystallization.
  • the purity by HPLC is more than 99.5%, and the single impurity is less than 0.1%.
  • the reaction conditions are mild, the sources of raw materials are wide, and the purity and yield are high.
  • the 6-chloropurine is better dissolved in the reaction solution, and is obtained by nucleophilic substitution reaction Crude 6-furfurylaminopurine.
  • High-purity 6-furfurylaminopurine is obtained after recrystallization from ethanol.
  • the purity by HPLC is more than 99.5%, and the impurity is less than 0.1%.
  • the reaction conditions are relatively mild, the raw materials are all common raw materials available on the market, the obtained products have high purity, and the single impurities can be effectively controlled, which provides a reference for scale-up production.

Abstract

提供了一种6-糠氨基嘌呤的合成方法，在1，8-二氮杂二环十一碳-7-烯(DBU)存在下，将糠胺和6-氯嘌呤在六甲基二硅胺烷回流条件下，进行亲核取代反应，得到6-糠氨基嘌呤粗品，重结晶得到6-糠氨基嘌呤，HPLC纯度99.5％以上，单杂小于0.1％。该方法路线工艺简单，收率高，无废水排放。

Description

[根据细则37.2由ISA制定的发明名称]　一种6-糠氨基嘌呤的合成方法 技术领域
本发明涉及一种高纯6-糠氨基嘌呤的合成方法，属于有机合成技术领域。
 背景技术
6-糠氨基嘌呤，白色结晶或白色结晶性粉未，又称6-糠基氨基嘌呤、激动素，是一种嘌呤类的天然植物内源激素，也是人类发现的第一个细胞分裂素，已能人工合成。糠氨基嘌呤具有促进细胞分裂和组织分化；诱导芽的分化，解除顶端优势；延缓蛋白质和叶绿素降解，有保鲜和防衰作用；延缓离层形成，增加坐果等作用。本剂主要用于组织培养，与生长素配合促进细胞分裂，诱导愈伤组织及组织分化。
目前6-糠氨基嘌呤的合成方法主要有：腺嘌呤与糠氯在碱作用下缩合；甲硫基嘌呤和糠胺缩合；腺嘌呤和糠胺缩合；酰嘌呤和糠酰氯缩合成糠酰嘌呤，然后再氢化铝锂还原得到；腺嘌呤和糠醇缩合等，然而这些方法存在原料来源受限或者收率低等问题，采用6-氯嘌呤与糠胺反应方法较为直接，由于6位氯活性很高，已有文献报道在乙醇或丁醇溶剂中反应，极易生成氯被醇取代副产物，造成单杂不合格。
 技术问题
本发明解决现有方法中原料来源受限或不适合放大规模（如氢化铝锂的使用）、收率低、单杂不合格等技术问题。
 技术解决方案
为了克服现有技术的不足，本发明提供了一种高纯6-糠氨基嘌呤的合成方法，将6-氯嘌呤和糠胺高温亲核取代，过滤重结晶，得到高纯度6-糠氨基嘌呤。
为了实现上述目的，本发明采用如下技术方案：在DBU存在下，糠胺和6-氯嘌呤在六甲基二硅胺烷中反应，得到6-糠氨基嘌呤粗品，重结晶得到高纯6-糠氨基嘌呤，HPLC纯度99.5%以上，单杂小于0.1%。
进一步地，在上述技术方案中，反应优选采用糠胺与DBU混合，将6-氯嘌呤和六甲基二硅胺烷升温至110-115℃，开始滴加糠胺和DBU混合物方式进行。
进一步地，在上述技术方案中，所述6-氯嘌呤与糠胺摩尔比为1：1-1.15。
进一步地，在上述技术方案中，所述6-氯嘌呤与DBU摩尔比为1：1-1.2。
进一步地，在上述技术方案中，所述反应温度在110-130℃。
进一步地，在上述技术方案中，所述重结晶溶剂乙醇。
 有益效果
本发明通过6-氯嘌呤和糠胺亲核取代反应得6-糠氨基嘌呤粗品，重结晶后得到高纯6-糠氨基嘌呤，HPLC纯度99.5%以上，单杂小于0.1%。反应条件温和，原料来源广泛，纯度和收率高。
 本发明的最佳实施方式
向三口烧瓶加入6-氯嘌呤100g和六甲基二硅胺烷180g、升温至110℃，滴加糠胺70g和DBU120g的混合液，滴完，加热回流2h，降温，抽滤，滤饼加入350mL乙醇重结晶，得6-糠氨基嘌呤159g，白色粉末，收率98%，HPLC纯度99.7%，单杂0.02%。
 本发明的实施方式
实施例1：
向三口烧瓶加入6-氯嘌呤100g和六甲基二硅胺烷150g，升温至110℃，滴加糠胺65g和DBU125g的混合液，滴完，加热回流2h，降温至20℃，抽滤，滤饼用330mL乙醇重结晶，得6-糠氨基嘌呤156g，白色粉末，收率96%，HPLC纯度99.7%，单杂0.02%。
实施例2：
向三口烧瓶加入6-氯嘌呤200g和六甲基二硅胺烷300g、升温至110℃，滴加糠胺106g和DBU208g的混合液，滴完，加热回流2h，降温，抽滤，滤饼采用680mL乙醇重结晶，得6-糠氨基嘌呤309g，白色粉末，收率95%，HPLC纯度99.5%，单杂0.03%。
实施例3：
向三口烧瓶加入6-氯嘌呤200g和六甲基二硅胺烷300g、升温至115℃，滴加糠胺106g和DBU200g的混合液，滴完，加热回流2h，降温，抽滤，滤饼采用680mL乙醇重结晶，得6-糠氨基嘌呤311g，白色粉末，收率96%，HPLC纯度99.5%，单杂0.04%。
 工业实用性
本发明通过采用DBU做碱，同时在六甲基二硅胺烷（充当溶剂和反应物）将嘌呤保护后，使得6-氯嘌呤更好地溶解在反应溶液中，通过亲核取代反应后得到6-糠氨基嘌呤粗品，乙醇重结晶后得到高纯6-糠氨基嘌呤，HPLC纯度99.5%以上，单杂小于0.1%。
该反应条件相对温和，原料均为市场上可获得的常见原料，得到的产品纯度高，单杂得以有效控制，为放大规模化生产提供了参考。

Claims (6)

  1. 一种高纯6-糠氨基嘌呤的合成方法，其特征在于，包括如下步骤：在DBU存在下，将糠胺和6-氯嘌呤在六甲基二硅胺烷中反应，得到6-糠氨基嘌呤粗品，重结晶得到高纯6-糠氨基嘌呤，HPLC纯度99.5%以上，单杂小于0.1%。
  2. 根据权利要求书1所述高纯6-糠氨基嘌呤的合成方法，其特征在于：反应采用糠胺与DBU混合，将6-氯嘌呤和六甲基二硅胺烷升温至110-115℃，开始滴加糠胺和DBU混合物方式进行。
  3. 根据权利要求书1或2所述高纯6-糠氨基嘌呤的合成方法，其特征在于：6-氯嘌呤与糠胺的摩尔比为1：1-1.15。
  4. 根据权利要求书1或2所述高纯6-糠氨基嘌呤的合成方法，其特征在于：6-氯嘌呤与DBU摩尔比为 1：1-1.2。
  5. 根据权利要求书1或2所述高纯6-糠氨基嘌呤的合成方法，其特征在于：反应温度在110-130℃。
  6. 根据权利要求书1或2所述高纯6-糠氨基嘌呤的合成方法，其特征在于：重结晶溶剂选自乙醇。
PCT/CN2019/102634 2018-09-08 2019-08-26 一种6-糠氨基嘌呤的合成方法 WO2020048343A1 (zh)

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