CN1265393A - 制备n－(氨基－4,6－二卤嘧啶)甲酰胺的方法 - Google Patents

制备n－(氨基－4,6－二卤嘧啶)甲酰胺的方法 Download PDF

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CN1265393A
CN1265393A CN99126244A CN99126244A CN1265393A CN 1265393 A CN1265393 A CN 1265393A CN 99126244 A CN99126244 A CN 99126244A CN 99126244 A CN99126244 A CN 99126244A CN 1265393 A CN1265393 A CN 1265393A
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埃利·赛卡利
瓦尔特·布里登
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Abstract

本发明涉及通式Ⅰ或Ⅱ之N－(氨基－4,6－二卤嘧啶)甲酰胺的新制备方法:其中X是卤原子,其由通式Ⅲ的2,5－二氨基－4,6－二卤嘧啶起始,其中X具有如上所述的含意,与甲酸反应。

Description

制备N-(氨基-4，6-二卤嘧啶)甲酰胺的方法
本发明涉及制备通式I或II之N-(氨基-4，6-二卤嘧啶)-甲酰胺的新方法，其是由通式III的2，5-二氨基-4，6-二卤嘧啶开始。
诸如N-(2-氨基-4，6-二卤嘧啶-5-基)甲酰胺的N-(氨基-4，6-二卤嘧啶)甲酰胺对于制备抗病毒核苷酸衍生物(EP-A 0684 236)是重要的中间体。
目前，已公开了许多制备N-(2-氨基-4，6-二卤嘧啶-5-基)甲酰胺的方法。例如，EP-A 0 684 236公开了由氨基丙二酸酯起始制备N-(2-氨基-4，6-二卤嘧啶-5-基)甲酰胺的方法。在该方法中，氨基丙二酸酯首先在醇盐存在下与胍成环为2，5-二氨基-4，6-二羟基嘧啶，然后由该物质与磷酰氯在二甲基甲酰胺存在下形成4，6-二氯-N′-(二甲基氨基亚甲基)嘧啶-2，5-二胺。随后使用含水丙酸将后者转化为所希望的产物。
该方法的缺陷是，一方面所希望的产物仅有中等产率，另一方面该方法需要经过3个步骤。
迄今为止，还公开了许多制备诸如2，5-二氨基-4，6-二氯嘧啶的2，5-二氨基-4，6-二卤嘧啶的方法。例如，WO 91/01310描述了在磷酰氯和季铵卤或弱碱性叔胺或其盐存在下由2，5-二氨基-4，6-二羟基-嘧啶起始制备2，5-二氨基-4，6-二氯嘧啶的方法。在该方法中，磷酰氯的作用是作为溶剂。该方法的缺陷是，在工业规模上不能重复，而且所希望的最终产物的产率较低。
本发明的目的是提供更简单地制备N-(氨基-4，6-二卤嘧啶)甲酰胺的方法，其中所希望的产物具有良好的产率。
令人惊奇的是，现已发现通式III的2，5-二氨基-4，6-二卤嘧啶其中X是卤原子，与甲酸反应可直接得到通式I或II的最终产物，也就是说不需经过中间体，而且产率非常好。
可使用Cl或Br作为卤原子，优选使用Cl。因此，优选使用2，5-二氨基-4，6-二氯-或2，5-二氨基-4，6-二溴嘧啶作为2，5-二氨基-4，6-二卤嘧啶。
所使用的甲酸至少是浓度为70-98％的甲酸。
为方便起见，如果希望制得通式I的产物，则使用浓度为70-80％的甲酸，而且反应在20-60℃、优选25-55℃下进行。
如果希望制得通式II的产物，则使用浓度为80-98％的甲酸，而且反应在0-30℃、优选10-25℃下进行。
令人惊奇的是，如果通式IV的2，5-二氨基-4，6-二羟基嘧啶或其盐
Figure A9912624400071
在磷酰卤和季铵卤或胺存在下与作为溶剂的卤代烃反应，可制得通式III的起始物2，5-二氨基-4，6-二卤嘧啶，而且产率良好。
2，5-二氨基-4，6-二羟基嘧啶是一种市售化合物。
合适的2，5-二氨基-4，6-二羟基嘧啶也可以是其盐如其氢卤酸盐，如盐酸盐和氢溴酸盐。
所用的磷酰卤可有利地是磷酰氯或磷酰溴。
所用的胺可以是伯胺、仲胺或叔胺或其盐，如其盐酸盐或氢溴酸盐。所用的季铵卤可有利地是氯化铵或溴化铵。通常情况下，以2，5-二氨基-4，6-二羟基嘧啶计，使用过量的胺或季铵卤，优选1摩尔2，5-二氨基-4，6-二羟基嘧啶使用1-10摩尔的胺。
反应可有利地在20℃至适当溶剂的回流温度之间的温度下进行，优选为100-120℃之间。
所用的卤代烃可以是卤代脂族烃。卤代脂族烃的例子是卤代烷烃。所用的卤代烷烃可以是卤代丙烷如1，2，3-三氯丙烷。
                      实施例实施例1制备2，5-二氨基-4，6-二氯嘧啶
将2，5-二氨基-4，6-二羟基嘧啶盐酸盐(0.14mol，25g)填入干燥的反应器中。然后加入干燥的1，2，3-三氯丙烷(51.96ml)，并进行搅拌。随后加入四甲基氯化铵(0.29mol，31.25g)和POCl3(0.54-0.81mol，124.9-183.28g，50.6-75.9ml)。将反应物加热至回流温度(约115℃)24小时。然后将反应物冷却至低于50℃，添加冰水(24.44mol，440.44g)，并使整体保持在低于55℃。使用50％的NaOH(3.12mol，124.92g，163.3ml)将反应物的pH值调节为6.5-7.0之间，并将反应物的温度保持在低于55℃。在50-60℃之间搅拌反应物30分钟。加入四氢呋喃(3.7mol，267.0g，300ml)。为除去非所希望的物质，由Celite过滤整个混合物，并用乙酸乙酯(20.5mol，1806.58g，2002.86ml)洗涤滤饼用于随后的萃取。有机相(四氢呋喃和乙酸乙酯)用水(5.57mol，100.32g，100.32ml)洗涤3次，用碳酸氢钠干燥，然后过滤。真空蒸馏除去乙酸乙酯。在残留的有机物中加入己烷(0.77mol，66.14g，100.36ml)，然后将整个混合物冷却至低于10℃，过滤，并在50℃下真空干燥。得到略呈棕色的固体状的标题化合物(0.09mol，15.71g)，以2，5-二氨基-4，6-二羟基嘧啶计产率为约65％。实施例2制备N-(2-氨基-4，6-二氯嘧啶-5-基)-甲酰胺
在室温下搅拌2，5-二氨基-4，6-二氯嘧啶(0.01mol，2.0g)和水(0.25mol，4.55ml)。然后在反应物中加入浓度为98％的甲酸(0.4mol，18.27g，14.97ml)。随后将反应物加热至50-55℃，并在此温度下保持3小时。
加入甲苯(0.38mol，34.6g，40ml)，用于在50℃和高真空下共沸蒸馏(添加两次甲苯，以确保良好的蒸馏，也就是说总共80ml)。
随后过滤产物，用水洗涤，然后在60℃下真空干燥。得到0.01mol(2.0g)的上述产物，相应于产率为约90％。实施例3制备N-(5-氨基-4，6-二氯嘧啶-2-基)-甲酰胺
在室温下过夜搅拌2，5-二氨基-4，6-二氯嘧啶(0.001mol，2.0g)和浓度为98％的甲酸(0.5mol，22.96g，18.8ml)。添加甲苯(0.94mol，86.76g，18.82ml)，然后将反应物冷却至0-5℃。
过滤出产物，并用水(1.11mol，20.0g，20.0ml)洗涤。在50℃下真空干燥产物。在1H NMR中检测N-(5-氨基-4，6-二氯嘧啶-2-基)-甲酰胺为单一物质。得到0.01mol(1.62g)的上述产物，相应于产率为约70％。

Claims (7)

1、制备通式I或II之N-(氨基-4，6-二卤嘧啶)甲酰胺的方法其中X是卤原子，该方法包括通式II的2，5-二氨基-4，6-二卤嘧啶其中X具有如上所述的含意，与甲酸反应，形成通式I或II的最终产物。
2、如权利要求1所述的方法，其特征在于，制备通式I的产物时使用浓度为70-80％的甲酸，反应在20-60℃的温度下进行。
3、如权利要求1所述的方法，其特征在于，制备通式II的产物时使用浓度为80-90％的甲酸，反应在0-30℃的温度下进行。
4、如权利要求1-3之一所述的方法，其特征在于，通式III的2，5-二氨基-4，6-二卤嘧啶是如下制备的：
Figure A9912624400031
使通式IV的2，5-二氨基-4，6-二羟基嘧啶或其盐
Figure A9912624400032
在作为溶剂的卤代烃中与磷酰卤和季铵卤反应。
5、如权利要求4所述的方法，其特征在于，所述反应是在20℃至适当溶剂的回流温度之间的温度下进行的。
6、如权利要求4或5所述的方法，其特征在于，所用溶剂是卤代烷烃。
7、制备通式III之2，5-二氨基-4，6-二卤嘧啶的方法
Figure A9912624400041
其中X是卤原子，该方法包括使通式IV的2，5-二氨基-4，6-二羟基嘧啶或其盐在作为溶剂的卤代烃中与磷酰卤和季铵卤或胺反应。
CNB991262441A 1998-12-21 1999-12-17 制备n-（氨基-4，6-二卤嘧啶）甲酰胺的方法 Expired - Fee Related CN1156449C (zh)

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ATE228508T1 (de) 2002-12-15
US6271376B1 (en) 2001-08-07
SK178499A3 (en) 2000-09-12
EP1013647A2 (de) 2000-06-28
JP3543709B2 (ja) 2004-07-21
HUP9904608A2 (hu) 2000-08-28
SK283681B6 (sk) 2003-11-04
CZ296753B6 (cs) 2006-06-14
NO996325D0 (no) 1999-12-20
EP1188750A1 (de) 2002-03-20
DE59903535D1 (de) 2003-01-09
JP2000191647A (ja) 2000-07-11
CZ9904598A3 (cs) 2001-03-14
PL337354A1 (en) 2000-07-03
EP1013647B1 (de) 2002-11-27
US20010031868A1 (en) 2001-10-18
ES2187112T3 (es) 2003-05-16
EP1013647A3 (de) 2000-10-04
HUP9904608A3 (en) 2001-03-28
DE59907401D1 (de) 2003-11-20

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