CN104402910B - 一种噻唑吡啶类化合物及其制备方法 - Google Patents

一种噻唑吡啶类化合物及其制备方法 Download PDF

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CN104402910B
CN104402910B CN201410227515.5A CN201410227515A CN104402910B CN 104402910 B CN104402910 B CN 104402910B CN 201410227515 A CN201410227515 A CN 201410227515A CN 104402910 B CN104402910 B CN 104402910B
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thiourea
thiazole
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CN104402910A (zh
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姚庆佳
徐扬军
武思民
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Sphinx Drug Development (tianjin) Ltd By Share Ltd
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Abstract

本发明涉及一种噻唑吡啶类化合物及其制备方法，该化合物为噻唑并(4，5‑b)吡啶，制备方法如下：(1)以化合物13‑溴‑2‑氨基吡啶为起始原料，在苯甲酰氯及硫氰酸铵存在下得到苯甲酰基保护的含硫脲的衍生物化合物2；(2)化合物2经过水解得到硫脲衍生物化合物3；(3)化合物3在NaH作用下关环生成化合物4；(4)化合物4用亚硝酸异戊酯脱氨基得到目标产物化合物5；该方法原料便宜易得，合成方法简单，适合规模化工业生产的需要。

Description

一种噻唑吡啶类化合物及其制备方法
技术领域
本发明涉及化合物生产领域，尤其是一种噻唑吡啶类化合物及其制备方法。
背景技术
噻唑吡啶类化合物广泛应用于药物分子中，以该化合物合成的衍生物，在治疗癌症方面具有巨大的临床药物应用价值。由于其良好的药理活性及潜在药用价值，用该化合物做母体能进一步进行合成更为复杂的衍生物，将为更广泛地研究该类化合物性质提供条件。
发明内容
本发明所要解决的技术问题在于提供一种噻唑吡啶类化合物。
本发明所要解决的另一技术问题在于提供上述噻唑吡啶类化合物的制备方法。
为解决上述技术问题，本发明的技术方案是：
一种噻唑吡啶类化合物，噻唑并(4，5-b)吡啶，其结构式为(Ⅰ)所示，
优选的，上述噻唑吡啶类化合物，噻唑并(4，5-b)吡啶为黄色固体，其核磁共振氢谱数据为1H-NMR(DMSO；400HZ)7.54(q,1H)8.76(dd,1H)，8.72(dd,1H)，9.73(s,1H)。
上述噻唑吡啶类化合物的制备方法，具体步骤如下：
(1)以化合物1 3-溴-2-氨基吡啶为起始原料，在苯甲酰氯及硫氰酸铵存在下得到苯甲酰基保护的含硫脲的衍生物化合物2；
(2)化合物2经过水解得到硫脲衍生物化合物3；
(3)化合物3在NaH作用下关环生成化合物4；
(4)化合物4用亚硝酸异戊酯脱氨基得到目标产物化合物5；其中，
优选的，上述噻唑吡啶类化合物的制备方法，所述步骤(2)中水解为碱性条件下水解。
优选的，上述噻唑吡啶类化合物的制备方法，所述化合物3、4作为中间产物，为新的化合物。
上述噻唑吡啶类化合物的制备方法的具体反应方程式如下：
本发明的有益效果是：
上述噻唑吡啶类化合物的制备方法，原料便宜易得，合成方法简单，适合规模化工业生产的需要。
附图说明
图1为噻唑并(4，5-b)吡啶的HNMR谱图。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施方式对本发明所述技术方案作进一步的详细说明。
实施例1
噻唑并(4，5-b)吡啶的制备方法，具体步骤如下：
(1)在4室温下，将22.7g苯甲酰氯滴入14.9g硫氰酸铵的400ml丙酮溶液(30min滴完)，升温至60℃回流，将20g化合物13-溴-2-氨基吡啶分批投入体系；14h后，TLC检测，原料消失，体系冷却至室温，过滤，滤饼乙酸乙酯洗涤(50mL*3)至无产品残留，母液旋干，得到粗品(化合物2)50g；TLC信息：原料Rf＝0.6，产品Rf＝0.5。展开剂：石油醚：乙酸乙酯＝3：1。
(2)将50g化合物2溶于250ml MeOH(甲醇)中，室温下，加入250ml4N NaOH的水溶液，70度回流2h；TLC检测反应完全，旋干甲醇，体系加适量水至溶清，10度下浓盐酸滴入至PH＝9，白色固体析出，过滤烘干得20.3g粗品(化合物3)，两步收率75.7％，直接用于下一步。TLC信息：原料Rf＝0.5，产品Rf＝0.3。展开剂：石油醚：乙酸乙酯＝3：1。
(3)将11.0g氢化钠(60％)在0度下投入200ml DMF(二甲基甲酰胺)中，20.3g化合物3分批加入体系(约0.5h)，而后升温至90度过夜；14h后，TLC检测反应完全，体系冷却至室温，300mL冰水加入体系，二氯甲烷：异丙醇3:1的混合溶剂萃取300mL×3，有机相干燥旋干，经柱纯化(200-300目硅胶柱子)，得纯品(化合物4)8.6g；(二氯甲烷：甲醇＝20:1)。TLC信息：原料Rf＝0.6，产品Rf＝0.2。展开剂：石油醚：乙酸乙酯＝1：1。得纯品8.6g，收率65.0％。
(4)在0度下，将15.7g亚硝酸异戊酯滴入8.1g化合物4的160ml无水四氢呋喃溶液(20min)，而后升温至65度回流4h；TLC检测反应应终止，降至室温，滤出不容物，滤饼乙酸乙酯(50mL*3)洗涤，旋干体系，经柱纯化(200-300目硅胶柱子)石油醚：乙酸乙酯＝1:1)，得纯品(化合物5)3.4g，收率46.6％。TLC信息：原料Rf＝0.3，产品Rf＝0.8。展开剂：二氯甲烷：甲醇＝10：1。
如图1所示，化合物5结构确认：1H-NMR(DMSO；400HZ)7.54(q,1H)8.76(dd,1H)，8.72(dd,1H)，9.73(s,1H)。
应用试验例
用小白鼠做抗肿瘤实验，8只小鼠腋下接种S180肉瘤细胞，制作鼠源肉瘤模型。将实施例1所得100mg化合物溶于20ml丙二醇溶液中溶解后，再加入30ml注射用水稀释后进行瘤内注射，每只0.5毫升，每天一次，用药疗程为7天，试验结果显示，平均抑瘤率为63.4％。
上述参照具体实施方式对该一种噻唑吡啶类化合物及其制备方法进行的详细描述，是说明性的而不是限定性的，可按照所限定范围列举出若干个实施例，因此在不脱离本发明总体构思下的变化和修改，应属本发明的保护范围之内。

Claims (2)

1.一种噻唑吡啶类化合物5的制备方法，其特征在于：具体步骤如下：
(1)以化合物1即3-溴-2-氨基吡啶为起始原料，在苯甲酰氯及硫氰酸铵存在下得到苯甲酰基保护的含硫脲的衍生物化合物2；
(2)化合物2经过水解得到硫脲衍生物化合物3；
(3)化合物3在NaH作用下关环生成化合物4；
(4)化合物4用亚硝酸异戊酯脱氨基得到目标产物化合物5；其中，所述化合物1至化合物5的结构式如下：
2.根据权利要求1所述的噻唑吡啶类化合物5的制备方法，其特征在于：所述步骤(2)中水解为碱性条件下水解。
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