CN102887858B - 3-氯-5-氨基-1h-吡唑-4-甲酸乙酯的合成方法 - Google Patents
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Abstract
本发明涉及3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成方法，以3,5-二氨基-1H-吡唑-4-甲酸乙酯为原料，经过与1,1,3,3-四甲氧基丙烷缩合得到2-氨基吡唑啉[1,5-α]吡嘧啶-3-酸乙酯,在氯化亚铜和盐酸存在下和亚硝酸钠反应得到2-氯吡唑啉[1,5-α]吡嘧啶-3-酸乙酯,最后在乙醇中和水合肼反应得到3-氯-5-氨基-1H-吡唑-4-甲酸乙酯。原料易得成本低、路线简洁,操作和后处理方便,总收率高,易于放大,可进行大规模生产的3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成方法。
Description
技术领域
本发明涉及一种3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成方法。
背景技术
3-氯-5-氨基-1H-吡唑-4-甲酸乙酯是有机合成的重要中间体，在许多药物候选分子结构中也含有该化合物的衍生结构(WO2006133261;WO200746548;WO20084698;WO20113065)。其具有优越的可修饰特性：（1）分子中的氯原子,是一个高活性的反应位点,可以和一些含杂原子的片段或中间体发生取代反应，通过氯原子和相邻的酯基与脲或硫脲的衍生物反应能合成非常良好生物活性的嘧啶并吡唑类化合物(Eur.J.Med.Chem.,2011,46(2),631等)；（2）分子中的氨基也可进行修饰也能得到一系列不同的有机化合物和候选药物活性分子，
3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成,目前报道得很少，而其衍生物的合成主要是通过3-溴-5-氨基-1H-吡唑-4-甲酸乙酯的衍生物与丁基锂反应后与N-氯代丁二酰亚胺反应生成3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的衍生物。3-溴-5-氨基-1H-吡唑-4-甲酸乙酯的衍生物是一个非商业化的试剂,制备此原料合成路线长，成本高；与丁基锂反应中,反应的活性位点多,致使反应复杂,副产物多,后处理麻烦,收率低。
发明内容
本发明的目的在于提供3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成工艺,避免具有路线试剂难得,反应复杂,后处理麻烦,收率低,不易于放大等缺点。
本发明采用的技术方案的反应原理如下：以3,5-二氨基-1H-吡唑-4-甲酸乙酯为原料，经过与1,1,3,3-四甲氧基丙烷缩合得到2-氨基吡唑啉[1,5-α]吡嘧啶-3-酸乙酯,在氯化亚铜和盐酸存在下和亚硝酸钠反应得到2-氯吡唑啉[1,5-α]吡嘧啶-3-酸乙酯,最后在乙醇中和水合肼反应得到3-氯-5-氨基-1H-吡唑-4-甲酸乙酯。
反应式如下:
具体工艺如下：
步骤（1）为缩合反应,反应物为3,5-二氨基-1H-吡唑-4-甲酸乙酯和1,1,3,3-四甲氧基丙烷,两者之间的摩尔比是1.1:1,反应溶剂为2M盐酸,反应温度为55℃,反应时间1小时；
步骤（2）为芳香杂环胺的Sandmeyer反应.所用试剂为亚硝酸钠和氯化亚铜,反应溶剂为盐酸,反应时间为室温搅拌2小时；
步骤（3）为与水合肼的反应,反应溶液为乙醇 ,反应温度为室温,反应时间为过夜。
本发明提供了的合成方法,原料易得成本低、路线简洁,操作和后处理方便,总收率高,易于放大,可进行大规模生产的3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成方法。
具体实施方式
所有原料均购自上海达瑞精细化学品有限公司。
实施例
第一步: 2-氨基吡唑啉[1,5-α]吡嘧啶-3-酸乙酯
在55℃下将1,1,4,4-四甲氧基丙烷（25.7 g，156 mmol）加入到3,5-二氨基-1H-吡唑-4-甲酸乙酯（29.6 g，173 mmol）的2M盐酸水溶液(120 mL)中.混合物在此温度下搅拌1小时后冷却.加入饱和碳酸氢钠水溶液至pH=9后溶液用乙酸乙酯萃取.有机相用无水硫酸钠干燥后拉干. 残留物经柱层析后得到2-氨基吡唑啉[1,5-α]吡嘧啶-3-酸乙酯(28.7g,89%)。
1HNMR(400MHz, CDCl3): 1.46 (t, 3 H), 4.50 (m, 2 H), 5.52 (s, 2 H), 6.84 (m, 1 H), 8.45 (d, 1 H), 8.57 (d, 1 H)。
第二步: 2-氯吡唑啉[1,5-α]吡嘧啶-3-酸乙酯的合成
在0-5℃,将亚硝酸钠（8.46 g，123 mmol）的水溶液(24 mL)滴加到2-氨基吡唑啉[1,5-α]吡嘧啶-3-酸乙酯（23 g，112 mmol）和20% 盐酸水溶液(230mL)的混合液中并继续搅拌30分钟.将此混合液加到冷却的CuCl （27.8g , 279mmol） 和20%盐酸水溶液(230 mL)的混合液中后再继续反应2小时。溶液用乙酸乙酯萃取.有机相用饱和碳酸氢钠水溶液洗涤, 无水硫酸钠干燥后拉干. 残留物经柱层析后得到2-氯吡唑啉[1,5-α]吡嘧啶-3-酸乙酯(7.6 g,30%)
1HNMR(400MHz, DMSO-d6): 1.33 (t, 3 H), 4.33 (m, 2 H), 7.36 (m, 1 H) , 8.87 (m, 1 H), 9.24 (m, 1 H)。
第三步: 3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成
将2-氯吡唑啉[1,5-α]吡嘧啶-3-酸乙酯(4.5 g, 20 mmol),水合肼(80%,90 mL)和 EtOH (20 mL)的混合物室温搅拌过夜。混合物旋干后将残留物经柱层析后得3-氯-5-氨基-1H-吡唑-4-甲酸乙酯(3.5 g,92%)。
1HNMR(400MHz, DMSO-d6): 1.26( t, 3 H) , 4.20 (m, 2 H), 6.24 (s, 2 H), 12.00 (s, 1 H)。
Claims (1)
1.3-氯-5-氨基-1H-吡唑-4-甲酸乙酯的合成方法，其特征在于按下式反应：
其中，步骤（1）3,5-二氨基-1H-吡唑-4-甲酸乙酯和1,1,3,3-四甲氧基丙烷的摩尔比是1.1:1，反应溶剂为2M盐酸,反应温度为50℃-55℃,反应时间1小时；
步骤（2）为芳香杂环胺的Sandmeyer反应，所用试剂为亚硝酸钠和氯化亚铜,反应溶剂为盐酸,室温搅拌2小时；
步骤（3）为与水合肼的反应,反应溶液为乙醇,反应温度为室温,反应时间为过夜。
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| CN101932583A (zh) * | 2007-12-19 | 2010-12-29 | 沃泰克斯药物股份有限公司 | 用作JAK2抑制剂的吡唑并[1,5-a]嘧啶类 |
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| CN101932583A (zh) * | 2007-12-19 | 2010-12-29 | 沃泰克斯药物股份有限公司 | 用作JAK2抑制剂的吡唑并[1,5-a]嘧啶类 |
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