CN102432549B - 一种抑制血管生成、肿瘤发生和增殖疾病的药物中间体1,3-二环己基巴比妥酸的制备方法 - Google Patents
一种抑制血管生成、肿瘤发生和增殖疾病的药物中间体1,3-二环己基巴比妥酸的制备方法 Download PDFInfo
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Abstract
本发明公开了一种抑制血管生成、肿瘤发生和增殖疾病的药物中间体1,3-二环己基巴比妥酸的制备方法，该合成方法包括以下工艺步骤：由N,N'-二环己基脲（DCU）跟丙二酸在乙酸做溶剂条件下，乙酸酐脱水产生1,3-二环己基巴比妥酸，本发明工艺简单，易操作，产品收率高，产品纯度大于99.5％。
Description
技术领域
本发明涉及一种抑制血管生成、肿瘤发生和增殖疾病的药物中间体1,3-二环己基巴比妥酸的合成方法，属于有机化学和药物合成技术领域。
背景技术
1,3-二环己基巴比妥酸是抑制血管生成、肿瘤发生和增殖疾病的巴比妥酸类药物关键中间体, 化学结构式：
化学结构名称 ：1,3-二环己基L嘧啶-2,4,6(1H,3H,5H)-三酮，分子式为C16H24N2O3，分子量为 292.37。本发明涉及抗增殖化合物领域且更具体地涉及抑制HIF-1活性（例如HIF-1α与p300之间的相互作用）并因而抑制血管生成、肿瘤发生和增殖性疾病入癌症的活性化合物。 几个用于证明的细胞系支持了HIF-1作为血管生成中的可行资料目标的重要性。HIF-1α小白鼠呈现胚胎致死表型，其特征在于缺乏头侧血管化。由HIF-1α小白鼠产生的畸胚瘤比野生型肿瘤小75%，尺寸的降低由细胞程序死亡水平增加引起。此外，ARNT在小白鼠肝癌细胞系中的失活导致血管生成和肿瘤生长受阻。其他研究已经记载了高度转移性和侵袭性肿瘤表型的HIF-1α水平，例如在具有高水平HIF-1α且极具转移性的人前列腺细胞系PC3中。最近已采用转基因小白鼠方法来证明HIF-1α/p300相互作用对肿瘤发生的重要性。
近年来采用几种方法对血管生成抑制的研究清楚的表明该过程的有效抑制可以在动物模型中阻断肿瘤生长。使用抗血管源性策略在实验条件下诱导肿瘤消退的可能最惊人的例子最近已由使用天然多肽-血管抑素(angiostatin)和内皮抑素(endostatin)的研究提供。这些研究除了明显有效外，还没有出现毒性且未获得抗药性。此外，有前景的抗血管源性策略出现在使用定向于血管生长的几个方面的小分子的临床开发中，例如VEGF/VEGF受体，整联蛋白(ανβ3)：玻连蛋白相互作用或基质金属蛋白酶的抑制。目前对抗血管源性策略已确定的唯一清楚的不利副作用是雌性生育能力可逆丧失。
目前合成该中间体的主要方法为美国化学学会数据库ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986，Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich。主要是从N'N-二环己基碳二亚胺的四氢呋喃溶液跟丙二酸的四氢呋喃溶液搅拌脱水反应得到1,3-二环己基巴比妥酸。
发明内容
本发明的目的在于提供一种工艺简单，单耗低，收率高的不同工艺路线合成1,3-二环己基巴比妥酸方法。
本发明的技术解决方案是：一种抑制血管生成、肿瘤发生和增殖疾病的药物中间体1,3-二环己基巴比妥酸的制备方法，其特征在于：由下列反应组成：
N’N-二环己基脲和丙二酸在溶剂和脱水剂存在下反应得到1,3-双环己基巴比妥酸。
进一步地，在反应中，所述溶剂为乙酸。
进一步地，所述脱水剂指常用的乙酸酐、丙酸酐类酸酐。
进一步地，反应温度为0～150℃；N’N-二环己基脲：丙二酸：脱水剂：溶剂（摩尔比）=1：1.1：4.4：9.0。
本发明的优点在于：工艺简单，易操作，成本低，产品收率高。
下面结合实施例对本发明作进一步说明：
具体实施方式：
本发明的反应具体如下：
N,N'-二环己基脲（DCU）跟丙二酸在乙酸做溶剂条件下，乙酸酐脱水产生1,3-二环己基巴比妥酸。反应式如下：
N’N-二环己基脲：丙二酸：脱水剂：溶剂（摩尔比）=1：1.1：4.4：9.0，在0-150℃，优选0～90℃条件下反应直到完全转化，减压蒸去溶剂加入无水乙醇回流，冷却到0～10℃，搅拌过滤得到产品。
实施例1：
在三口烧瓶中，加入150.0ml的冰醋酸，65.0g的N'N-二环己基脲及33.0g的丙二酸，升温，80℃滴加120ml的乙酸酐，保温反应4h，减压蒸馏，加入500ml无水乙醇，回流，冷却到0-5℃搅拌析晶，过滤得到75.0g产品，含量99.5%以上。
实施例2：
在三口烧瓶中，加入150.0ml的冰醋酸，65.0g的N'N-二环己基脲及33.0g的丙二酸，升温，100℃滴加120ml的乙酸酐，保温反应4h，减压蒸馏，加入500ml无水乙醇，回流，冷却到0-5℃搅拌析晶，过滤得到78.0g产品，含量99.5%以上。
实施例3：
在三口烧瓶中加入150.0ml的冰醋酸，65.0g的N'N-二环己基脲及33.0g的丙二酸，升温，滴加120ml的乙酸酐，保温反应4h，减压蒸馏，加入100.0ml水及60.0ml浓盐酸，加热回流，冷却过滤，得到59.0g，含量99.0%以上。
Claims (2)
1.一种抑制血管生成、肿瘤发生和增殖疾病的药物中间体1,3-二环己基巴比妥酸的制备方法，其特征在于：在三口烧瓶中，加入150.0ml的冰醋酸，65.0g的N,N'-二环己基脲及33.0g的丙二酸，升温，80℃滴加120ml的乙酸酐，保温反应4h，减压蒸馏，加入500ml无水乙醇，回流，冷却到0-5℃搅拌析晶，过滤得到75.0g产品，含量99.5%以上。
2.一种抑制血管生成、肿瘤发生和增殖疾病的药物中间体1,3-二环己基巴比妥酸的制备方法，其特征在于：在三口烧瓶中，加入150.0ml的冰醋酸，65.0g的N,N'-二环己基脲及33.0g的丙二酸，升温，100℃滴加120ml的乙酸酐，保温反应4h，减压蒸馏，加入500ml无水乙醇，回流，冷却到0-5℃搅拌析晶，过滤得到78.0g产品，含量99.5%以上。
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| CN105801490B (zh) * | 2016-05-05 | 2019-08-23 | 傅晓倩 | 一种制备阿格列汀中间体的方法 |
| IT202100020591A1 (it) * | 2021-07-30 | 2023-01-30 | Dipharma Francis Srl | Preparazione di un intermedio di un agente per il trattamento dell'anemia |
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| US7074925B1 (en) * | 1998-05-26 | 2006-07-11 | Rimma Lliinichna Ashkinazi | N-substituted derivatives of 5-oxyiminobarbituric acid |
| CN101190898A (zh) * | 2006-11-30 | 2008-06-04 | 上海三爱思试剂有限公司 | 一种1,3-二甲基巴比妥酸的制备方法 |
| CN101505752A (zh) * | 2006-06-23 | 2009-08-12 | 史密丝克莱恩比彻姆公司 | 脯氨酸羟化酶抑制剂 |
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| US7074925B1 (en) * | 1998-05-26 | 2006-07-11 | Rimma Lliinichna Ashkinazi | N-substituted derivatives of 5-oxyiminobarbituric acid |
| CN101505752A (zh) * | 2006-06-23 | 2009-08-12 | 史密丝克莱恩比彻姆公司 | 脯氨酸羟化酶抑制剂 |
| CN101190898A (zh) * | 2006-11-30 | 2008-06-04 | 上海三爱思试剂有限公司 | 一种1,3-二甲基巴比妥酸的制备方法 |
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