CN1415622A - 6－烷氧基－2’，3’－双脱氧鸟嘌呤核苷的制备方法 - Google Patents
6－烷氧基－2’，3’－双脱氧鸟嘌呤核苷的制备方法 Download PDFInfo
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Abstract
本发明涉及一种6－烷氧基－2’，3’－双脱氧鸟嘌呤核苷的制备方法，它由价廉易得的鸟嘌呤核苷为起始原料，首先合成2’，3’－脱氧－2’，3’－脱氢－鸟嘌呤核苷，用10％Pd/C常压还原，收率达到80％。接着氯代不经分离进行烷基化，经(1)制备N2－异丁酰鸟苷；(2)制备2’，3’－双脱氧－2’，3’－双脱氢－N2－异丁酰鸟苷；(3)制备2’，3’－双脱氧－鸟苷；(4)制备5’－乙酰氧－2’，3’－双脱氧－鸟苷；(5)制备5’－乙酰氧－6－氯－2’，3’－双脱氧－鸟苷；(6)制备6－烷氧基－2’，3’－双脱氧鸟嘌呤核苷等六步反应制得产物。该路线反应条件温和，原料价格较低，适合大量生产。
Description
技术领域
本发明涉及一种化合物的制备方法，具体说涉及一种6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的制备方法。
背景技术
2′和3′位脱氧核苷可被DNA多聚酶作为底物掺入至DNA链中。由于3′位羟基的缺损，使DNA链的继续延长被终止。这一原理被广泛应用到抗病毒药物的设计中。如齐多夫定(Zidovudine，AZT)、扎西他宾(Zalcitabine，DDC)、司坦夫定(Stavudine，D4T)、地丹诺心(Didannosine，ddI)[Mitsuya H.等人，Science 1990，249，1533-44；Huryn D.M.等人，Chem.Rev.1992，92，1745；De Clereq E.等人，Nucleoside Nucleotide1994，13，1271-95；De Clereq E.等人，J.Med.Chem.1995，38，2491-517；Mansour T.S.等人，Current Pharmac.Design 1997，3，227]
结构式为式(1)的6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的合成方法已有报道(RobinsM.J..等人，J.Org.Chem.1995，60(24)，7902-7908)。采用6-氯-鸟嘌呤核苷作为起始原料，第一步以α-乙酰氧异丁基溴对糖上的羟基溴代和酰化，第二步在醋酸溶液中用锌粉脱除溴生成双健，第三步在氨的甲醇溶液中脱保护得到6-氯-2’，3’-脱氧-2’，3’-脱氢-鸟嘌呤核苷和6-溴-2’，3’-脱氧-2’，3’-脱氢-鸟嘌呤核苷组成的混合物。第四步以Rh·Al2O3为催化剂氢化还原；最后在醇溶液中用烷基醇钠进行取代，得到目标化合物。由于以不稳定的6-氯-鸟嘌呤核苷作为起始原料，第一步中氯原子会被溴所取代，第四步中采用了昂贵的催化剂铷，并且反应中约有20％的核苷发生分解使成产率下降。
发明内容
本发明要解决的技术问题就是现有技术原料难得、合成成本高的问题。
本发明提供了一种制备式(I)6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的新方法。反映路线如下图1。由价廉易得的鸟嘌呤核苷为起始原料，首先合成2’，3’-脱氧-2’，3’-脱氢-鸟嘌呤核苷，用10％Pd/C常压还原，收率达到80％。接着氯代不经分离进行烷基化，经六步反应制得产物。该路线反应条件温和，原料价格较低，适合大量生产。
a.[(CH3)2CH]2CO/HMDSA b.CH3COOC(CH3)2COB/无水乙腈/乙酸乙酯/无水甲醇 c.Zn-Cu齐/甲醇/乙酸乙酯/钠/氯仿甲醇柱层析分离 d.10％Pd/ce.吡啶/醋酐/丙酮 f.TEBA/N，N-二乙基苯胺/无水乙腈/POCI3 g.无水醇/金属钠
具体实施方式
下面具体描述一下本发明的详细工艺过程。
1、制备N2-异丁酰鸟苷
鸟嘌呤(20.0g，70.67mmol)，干燥的DMF(75ml)，加入六甲基二硅胺(110ml)，搅拌12.5小时，冷却到10℃，加入吡啶(100ml)，异丁酸酐(180ml)，反应24小时，降温到0℃，加甲醇(200ml)，反应4小时，浓缩至100ml，加入正己烷和乙醚(1∶1)的混合液(500ml)，放置过夜，过滤得淡黄色固体24g，收率96％。
2、制备2’，3’-双脱氧-2’，3’-双脱氢-N2-异丁酰鸟苷
N2-异丁酰鸟苷(6.74g，20mmol)，干燥乙腈(80ml)，加水0.4ml，再加入乙酰氧异丁基溴，室温搅拌1小时，过滤，滤液加入乙酸乙酯(200ml)，用水洗至中性，用无水硫酸镁干燥后浓缩至50ml，加入新制的Zn-Cu剂，剧烈搅拌5分钟，过滤，滤饼用甲醇洗涤，合并滤液并旋干，加乙酸乙酯250ml，用水洗到中性，干燥后旋干，加入甲醇100ml，再加20mmol的甲醇钠溶液，室温搅拌10分钟，然后加乙酸中和到中性，柱层析分离(氯仿∶甲醇＝9∶1)，得目的物2.4g，收率45％。
3、制备2’，3’-双脱氧-鸟苷
2’，3’-双脱氧-2’，3’-双脱氢-N2-异丁酰鸟苷(6.38g，20mmol)，加入甲醇(150ml)，10％钯碳0.03g，常压氢化到不吸氢为止，过滤，滤饼用甲醇洗涤，浓缩滤液得目的物5.10g，收率88％。
4、制备5’-乙酰氧-2’，3’-双脱氧-鸟苷
2’，3’-双脱氧-鸟苷(3.94g，0.0157mol)，吡啶(4ml)和乙酸酐(60ml)加入反应瓶，室温搅拌至TLC显示反应完全。过滤，以丙酮洗涤滤饼，干燥后几乎以定量得产品。
5、制备5’-乙酰氧-6-氯-2’，3’-双脱氧-鸟苷
150ml反应瓶中加入5’-乙酰氧-2’，3’-双脱氧-鸟苷(4.4g，0.015mol)、EDTA(6g，0.026mol)干燥的N，N-二乙基苯胺(2.8ml，0.0176mol)和无水乙腈100ml，室温搅拌10分钟，加入新蒸的POCI3(8ml，0.086mol)，加热回流，冷却后减压蒸出溶剂。将剩余油状物加入冰水，以二氯甲烷(4×100ml)萃取，干燥萃取液后浓缩的油状物，经柱层次分离得目的物4.1g，收率73％。
6、制备6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷
50ml茄型瓶中加入250ml无水5’-乙酰氧-6-氯-2’，3’-双脱氧-鸟苷醇，并加入金属钠(100mg，4.35mmol)，室温搅拌至无气体产生，加入5’-乙酰氧-6-氯-2’，3’-双脱氧-鸟苷(262Mg，0.84mmol)，室温搅拌至TLC显示反应完全，减压蒸出溶剂，柱层析分离制得目的物231mg，收率91％
Claims (8)
1、一种6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的制备方法，其特征在于它是以鸟嘌呤核苷为起始原料，首先合成2’，3’-脱氧-2’，3’-脱氢-鸟嘌呤核苷，用10％Pd/C常压还原；接着氯代不经分离进行烷基化，经六步反应制得产物。
2、如权利要求1所述的6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的制备方法，其特征在于包括如下步骤：
(1)制备N2-异丁酰鸟苷；
(2)制备2’，3’-双脱氧-2’，3’-双脱氢-N2-异丁酰鸟苷；
(3)制备2’，3’-双脱氧-鸟苷；
(4)制备5’-乙酰氧-2’，3’-双脱氧-鸟苷；
(5)制备5’-乙酰氧-6-氯-2’，3’-双脱氧-鸟苷；
(6)制备6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷；
3、如权利要求2所述的6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的制备方法，其特征在于所述的步骤(1)包括如下步骤：
A.取鸟嘌呤、干燥的DMF，加入六甲基二硅胺，搅拌12.5小时，冷却到10℃；
B.加入吡啶、异丁酸酐，反应24小时，降温到0℃；
C.加甲醇，反应4小时，浓缩；
D.加入正己烷和乙醚(1∶1)的混合液，放置过夜，过滤得淡黄色固体。
4、如权利要求2所述的6-烷氧基-2’，3’-脱氧鸟嘌呤核苷的制备方法，其特征在于所述的步骤(2)包括如下步骤：
A.取N2-异丁酰鸟苷、干燥乙腈，加水，再加入乙酰氧异丁基溴，室温搅拌1小时；
B.过滤，滤液加入乙酸乙酯，用水洗至中性，用无水硫酸镁干燥后浓缩；
C.加入新制的Zn-Cu剂，剧烈搅拌5分钟，过滤，滤饼用甲醇洗涤；
D.合并滤液并旋干，加乙酸乙酯，用水洗到中性，干燥后旋干；
F.加入甲醇，再加甲醇钠溶液，室温搅拌10分钟，然后加乙酸中和到中性，柱层析分离(氯仿∶甲醇＝9∶1)，得目的物。
5、如权利要求2所述的6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的制备方法，其特征在于所述的步骤(3)包括如下步骤：
A.取2’，3’-双脱氧-2’，3’-双脱氢-N2-异丁酰鸟苷，加入甲醇，10％钯碳0.03g，常压氢化到不吸氢为止；
B.过滤，滤饼用甲醇洗涤，浓缩滤液得目的物。
6、如权利要求2所述的6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的制备方法，其特征在于所述的步骤(4)包括如下步骤：
A.取2’，3’-双脱氧-鸟苷、吡啶(4m1)和乙酸酐加入反应瓶，室温搅拌至TLC显示反应完全；
B.过滤，以丙酮洗涤滤饼，干燥后几乎以定量得产品。
7、如权利要求2所述的6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷的制备方法，其特征在于所述的步骤(5)包括如下步骤：
A.在反应瓶中加入5’-乙酰氧-2’，3’-双脱氧-鸟苷、EDTA、干燥的N，N-二乙基苯胺和无水乙腈，室温搅拌10分钟；
B.加入新蒸的POCI3，加热回流，冷却后减压蒸出溶剂；
C.将剩余油状物加入冰水，以二氯甲烷萃取，干燥萃取液后浓缩的油状物，经柱层次分离得目的物。
8、如权利要求2所述的6-烷氧基-2’，3，-双脱氧鸟嘌呤核苷的制备方法，其特征在于所述的步骤(6)包括如下步骤：
A.在茄型瓶中加入无水5’-乙酰氧-6-氯-2’，3’-双脱氧-鸟苷醇，并加入金属钠，室温搅拌至无气体产生；
B.加入5’-乙酰氧-6-氯-2’，3’-双脱氧-鸟苷，室温搅拌至TLC显示反应完全；
C.减压蒸出溶剂，柱层析分离制得目的物。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009089702A1 (fr) | 2008-01-17 | 2009-07-23 | Nanjing Changao Pharmaceutical Science & Technology Co., Limited | 6-méthoxy-2',3'-didésoxyguanosine stable, son procédé de préparation et composition pharmaceutique la contenant |
| CN117586307A (zh) * | 2024-01-19 | 2024-02-23 | 凯莱英生命科学技术(天津)有限公司 | Pmo鸟苷单体的合成方法 |
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| AP160A (en) * | 1987-08-15 | 1991-11-18 | The Wellcome Foundation Ltd | Therapeutic acyclic nucleosides. |
| CN1091445C (zh) * | 1999-12-29 | 2002-09-25 | 湖北省医药工业研究院 | 抗病毒药物中间体、它们的制备及应用 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009089702A1 (fr) | 2008-01-17 | 2009-07-23 | Nanjing Changao Pharmaceutical Science & Technology Co., Limited | 6-méthoxy-2',3'-didésoxyguanosine stable, son procédé de préparation et composition pharmaceutique la contenant |
| US8349811B2 (en) | 2008-01-17 | 2013-01-08 | Nanjing Changao Pharmaceutical Science & Technology Co., Limited | Stable 6-methoxy-2′,3′-dideoxyguanosine, method for preparing the same and pharmaceutical composition containing the same |
| CN117586307A (zh) * | 2024-01-19 | 2024-02-23 | 凯莱英生命科学技术(天津)有限公司 | Pmo鸟苷单体的合成方法 |
| CN117586307B (zh) * | 2024-01-19 | 2024-04-16 | 凯莱英生命科学技术(天津)有限公司 | Pmo鸟苷单体的合成方法 |
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