CN1309732C - 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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- 238000000034 method Methods 0.000 title claims abstract description 7
- 229940029575 guanosine Drugs 0.000 title abstract description 11
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- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 title abstract 4
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
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- OXTYJSXVUGJSGM-HTVVRFAVSA-N N-Isobutyrylguanosine Chemical compound C1=2NC(NC(=O)C(C)C)=NC(=O)C=2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OXTYJSXVUGJSGM-HTVVRFAVSA-N 0.000 claims abstract description 5
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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’-双脱氧-2’，3’-双脱氢-N2-异丁酰鸟嘌呤核苷，用10%钯炭常压还原，收率达到80%，接着氯代不经分离进行烷基化。共经(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，反应路线如下图1.：由价廉易得的鸟嘌呤核苷为起始原料，首先合成2’，3’-双脱氧-2’，3’-双脱氢-N2-异丁酰鸟嘌呤核苷，用10％钯炭常压还原，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)CH]2CO/六甲基二硅胺b.CH3COOC(CH3)2COBr/无水乙腈/乙酸乙酯/无水甲醇
c.锌-铜齐/甲醇/乙酸乙酯/钠/氯仿甲醇柱层析分离 d.10％钯炭 e.吡啶/醋酐/丙酮
f.三乙基苄基氯化铵/N，N-二乙基苯胺/无水乙腈/三氯氧磷 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
鸟嘌呤核苷(20.0g，770.67mmol)，干燥的N，N-二甲基甲酰胺(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(体积比为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，再加入乙酰氧异丁酰溴，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，加入新制的锌-铜剂，剧烈搅拌5分钟，过滤，滤饼用甲醇洗涤，合并滤液并旋干，加入乙酸乙酯250ml，用水洗到中性，干燥后旋干，加入甲醇l00ml，再加20mmol的甲醇钠溶液，室温搅拌l0分钟，然后加乙酸中和到中性，柱层析分离(氯仿∶甲醇体积比为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，室温搅拌至硅胶薄层层析显示反应完全。过滤，以丙酮洗涤滤饼，干燥后得产品。
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)、三乙基苄基氯化铵(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，加入新蒸的三氯氧磷(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100ml萃取四次，干燥萃取液后浓缩的油状物，经柱层析分离得目的物4.1g，收率73％。
6、制备6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷
500ml茄型瓶中加入250ml无水醇，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)，室温搅拌至薄层层析显示反应完全，减压蒸出溶剂，柱层析分离制得目的物231mg，收率91％。
Claims (3)
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’-双脱氧-2’，3’-双脱氢-鸟嘌呤核苷，用10％钯炭常压还原，接着氯代不经分离进行烷基化，经以下六步反应制得产物：
1)制备N2-异丁酰鸟苷
A.取鸟嘌呤核苷和干燥的N，N-二甲基甲酰胺，加入六甲基二硅烷，搅拌12.5小时，冷却到10℃；
B.加入吡啶和异丁酸酐，反应24小时，降温到0℃；
C.加甲醇，反应4小时，浓缩；
D.加入正己烷和乙醚的混合液，放置过夜，过滤到淡黄色固体；
2)制备2’，3’-双脱氧-2’，3’-双脱氢-N2-异丁酰鸟苷
A.取N2-异丁酰鸟苷和干燥乙腈，加水，再加入乙酰氧异丁酰溴，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.加入新制的锌—铜剂，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，用水洗至中性，干燥后旋干；
E.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，氯仿甲醇柱层析分离，得目的物；
3)制备2’，3’-双脱氧-鸟苷
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，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；
4)制备5’-乙酰氧-2’，3’-双脱氧-鸟苷
A.2’，3’-双脱氧-鸟苷和吡啶和乙酸酐加入反应瓶，室温搅拌至硅胶薄层层析显示反应完全；
B.过滤，以丙酮洗涤滤饼，干燥后以定量得产品；
5)制备5’-乙酰氧-6氯-2’，3’-双脱氧-鸟苷
A.在反应瓶中加入5’-乙酰氧-2’，3’-双脱氧-鸟苷和三乙基苄基氯化铵和干燥的N，N-二乙基苯胺和无水乙腈，室温搅拌10分种；
B.加入新蒸的三氯氧磷，加热回流，冷却后减压蒸出溶剂；
C.将剩余的油状物加入冰水，以二氯甲烷萃取，干燥萃取液后浓缩的油状物，经柱层析分离得目的物；
6)制备6-烷氧基-2’，3’-双脱氧鸟嘌呤核苷
A.在茄形瓶中加入无水醇，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，室温搅拌至硅胶薄层层析显示反应完全；
C.减压蒸出溶剂，柱层析分离制得目的物。
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，其特征在于步骤1)的D步骤中的正己烷和乙醚的混合液中正己烷和乙醚的体积比为1∶1。
3、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，其特征在于步骤2)的E步骤中氯仿和甲醇的体积比为9∶1。
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| 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 |
Citations (2)
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| CN1033701C (zh) * | 1987-08-15 | 1997-01-01 | 惠尔康基金会集团公司 | 9-(2-羟基乙氧基甲基)鸟嘌呤衍生物的制备方法 |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1033701C (zh) * | 1987-08-15 | 1997-01-01 | 惠尔康基金会集团公司 | 9-(2-羟基乙氧基甲基)鸟嘌呤衍生物的制备方法 |
| 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 |
Non-Patent Citations (4)
| Title |
|---|
| 2-氨基-6-氯嘌呤的合成方法及用途 战佩英等，化学工业与工程，第18卷第2期 2001 * |
| 2-氨基-6-氯嘌呤的合成方法及用途 战佩英等，化学工业与工程，第18卷第2期 2001;nucleic acid related compound morris j. Robings,et al,J Org Chem,Vol.60 No.24 1995;新法合成6-烷氧基和6-氨基鸟嘌呤核苷衍生物 林紫云等，有机化学，第20卷第4期 2000 * |
| nucleic acid related compound morris j. Robings,et al,J Org Chem,Vol.60 No.24 1995 * |
| 新法合成6-烷氧基和6-氨基鸟嘌呤核苷衍生物 林紫云等，有机化学，第20卷第4期 2000 * |
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