CN108658852A - 新化合物吗拉贝胺、其制备方法及用途 - Google Patents
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Abstract
本发明公开一种分子式如式h的新化合物吗拉贝胺(Malabemide)，还涉及其制备方法及在药学上的应用。该新化合物以乙醇胺和5‑氯‑2‑吡啶羧酸为起始原料，分别合成相应的中间体2‑溴乙胺氢溴酸盐和5‑氯‑2‑吡啶甲酰氯，再将这两种中间体反应生成5‑氯‑N‑(2‑溴乙基)‑2‑吡啶甲酰胺，最后与吗啉缩合生成吗拉贝胺h。采用本方法制备吗拉贝胺，原料易得，操作简单，产品纯度较好，收率较高，适用于工业化生产。
Description
技术领域
本发明涉及新化合物吗拉贝胺、其制备方法及用途。
背景技术
吗拉贝胺化学名为5-氯-N-[2-(4-吗啉基)乙基]-2-吡啶甲酰胺，分子式为C12H17ClN3O2，相对分子质量为268.72，熔点162-164℃，为白色结晶体。吗拉贝胺为全新设计合成的新化合物，目前国内外没有相关报道。
吗拉贝胺的分子设计是以吗氯贝胺和拉扎贝胺作为先导化合物，采用生物电子等排体原理和拼合原理设计出全新化合物。把吗氯贝胺苯环上的2位中的碳原子，利用生物电子等排原理替换成氮原子，设计得到吗拉贝胺；或者利用拼合原理，把吗氯贝胺的吗啉基团跟拉扎贝胺的吡啶基团进行拼合，设计出吗拉贝胺。吗拉贝胺在药学上用于制备单胺氧化酶抑制剂，单胺氧化酶抑制剂被用于治疗抑郁症。
经药学试验证明，吗拉贝胺同吗氯贝胺具有相同的活性，但吗氯贝胺的合成路线中涉及有毒性的中间体，并且存在收率低、难以提纯等缺点。
发明内容
本发明的目的之一是提供一种新化合物吗拉贝胺。
所述新化合物吗拉贝胺化学名为5-氯-N-[2-(4-吗啉基)乙基]-2-吡啶甲酰胺，其相对分子质量为268.72，熔点162℃-164℃，为白色结晶体；用核磁共振测量得到的核磁共振氢谱图如图1所示；
其分子式如式h所示：
本发明的目的之二是提供所述新化合物吗拉贝胺的制备方法，合成路线如下：
制备步骤为：
(1)2-溴乙胺氢溴酸盐(b)的合成
将乙醇胺(a)滴加到氢溴酸中，乙醇胺与氢溴酸的摩尔比为1∶9，磁力搅拌，反应体系温度控制在0℃～10℃，滴加时间控制在25～30分钟，滴加完毕后，加入溶剂，升温分水，分水完成后冷却过滤除去溶剂，滤渣用冷丙酮洗涤三次，得到白色结晶产物2-溴乙胺氢溴酸盐(b)；所述溶剂选自二甲苯、苯、甲苯；
(2)5-氯-2-吡啶甲酰氯(e)的合成
先将5-氯-2-吡啶羧酸(d)加入到溶剂中，磁力搅拌均匀，再滴加二氯亚砜，5-氯-2-吡啶羧酸与二氯亚砜的摩尔比为1∶4，反应温度控制在不超过0℃～10℃，滴加时间控制在15～20分；滴加完毕后升温回流反应，待回流完成后，常压除去溶剂，得白色晶体5-氯-2-吡啶甲酰氯(e)；所述溶剂选自二氯甲烷、三氯甲烷、二氯乙烷；
(3)5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)的合成
先将步骤(1)获得的2-溴乙胺氢溴酸盐(b)加入蒸馏水中，磁力搅拌溶解，滴加氢氧化钠溶液中和反应，待滴加完毕后加入溶剂，升温分水，分水完成后，冷却，过滤，收集滤液；再将5-氯-2-吡啶甲酰氯(e)加入到滤液中，2-溴乙胺氢溴酸盐(b)与5-氯-2-吡啶甲酰氯(e)的摩尔比为2∶1，升温回流反应，待反应完成后，冷却，抽滤，甲苯重结晶，得白色晶体5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)；所述溶剂选自甲苯、二甲苯或苯；
(4)吗拉贝胺(h)的合成
将5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)加入到甲苯中，升温溶解后再滴加吗啉，5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)与吗啉的摩尔比为1:3，升温回流反应，待反应完成后，冷却，抽滤，甲苯重结晶，得白色固体吗拉贝胺(h)。
本发明目的之三是提供所述吗拉贝胺在药学上的应用，特别是在制备单胺氧化酶抑制剂及其药物组合的应用。
本发明由于所述技术方案而获得的新化合物吗拉贝胺具有原料易得。合成路线中不含有毒中间体，采用上述方法生产吗拉贝胺，操作简单，产品纯度好，收率较高，适用于工业化生产。
附图说明
附图为采用Brucker ARX-300型核磁共振仪置测得的核磁共振氢谱图。
具体实施方式
本发明以乙醇胺和5-氯-2-吡啶羧酸为起始原料，分别合成相应的中间体2-溴乙胺氢溴酸盐和5-氯-2-吡啶甲酰氯，再这两种中间体反应生成5-氯-N-(2-溴乙基)-2-吡啶甲酰胺，最后与吗啉缩合生成吗拉贝胺。合成路线如下：
实施例1 2-溴乙胺氢溴酸盐(b)的合成
在0-10℃条件下，将乙醇胺滴加到40％氢溴酸中，摩尔比为1:9，磁力搅拌，反应体系温度控制在不超过10℃，滴加乙醇胺时间控制在25-30min。滴加完毕后，再向反应体系中加入溶剂二甲苯，升温分水12h，分水温度为135-145℃。待分水完成后，冷却，过滤除去溶剂，滤渣用冷丙酮洗涤三次，得到白色结晶产物2-溴乙胺氢溴酸盐。收率99％，纯度99.5％，熔点172-174℃。
实施例2 5-氯-2-吡啶甲酰氯(e)的合成
在0-10℃条件下，先将5-氯-2-吡啶羧酸加入到溶剂二氯甲烷中，磁力搅拌均匀，再滴加二氯亚砜，摩尔比1:4，反应体系温度控制在不超过10℃，滴加二氯亚砜时间控制在15-20min。滴加完毕后，升温回流反应7-8h，回流温度为40-45℃，待回流完成后，常压除去溶剂二氯甲烷，冷却，真空干燥，得白色晶体5-氯-2-吡啶甲酰氯。收率92％，纯度99.4％，熔点218-220℃。
实施例3 5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)的合成
先将2-溴乙胺氢溴酸盐加入蒸馏水中，磁力搅拌溶解。滴加氢氧化钠溶液中和反应，待滴加完毕后加入溶剂甲苯，升温分水。待分水完成后，冷却，过滤，收集滤液。再将5-氯-2-吡啶甲酰氯加入到滤液中，摩尔比为2:1，升温回流反应8-10h，回流温度为115-125℃。待反应完成后，冷却，抽滤，甲苯重结晶，得白色晶体5-氯-N-(2-溴乙基)-2-吡啶甲酰胺。收率93％，纯度99.5％，熔点201-203℃。
实施例4 吗拉贝胺(h)的合成
将5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)加入到溶剂甲苯中，先升温让其溶解，待完全溶剂后再滴加吗啉，摩尔比为1:3，升温回流反应10-12h，回流温度为120-125℃。待反应完成后，冷却，抽滤，甲苯重结晶，得白色固体吗拉贝胺。收率46％，纯度99.6％，熔点162-164℃。
经用质谱方法检测其相对分子质量为268.72，熔点162℃-164℃，为白色结晶体；用核磁共振测量得到的核磁共振氢谱图如图1所示。
实施例5 单胺氧化酶抑制实验
实验证明：本发明的新化合物具有抑制单胺氧化酶的活性，能够像吗氯贝胺一样用作制备治疗或预防抑郁症的药物。
实施例6 含新化合物吗拉贝胺的药用组合物
所述的药物组合物的组成为：吗拉贝胺10重量份，药物辅料0～200重量份，所述药物辅料选自药学上能够接受的辅料。
所述的药物组合物的剂型包括但不限于含吗拉贝胺的单方及复方的片剂、胶囊剂、颗粒剂、冻干粉针、无菌粉针、大容量注射剂或小容量注射剂。
新化合物吗拉贝胺在制备单胺氧化酶抑制剂及其制剂中以及产品说明书中使用英文名Malabemide。
本发明化合物吗拉贝胺明采用以乙醇胺、5-氯-2-吡啶羧酸和吗啉为主要原料制备新型单胺氧化酶抑制剂吗拉贝胺，原料易得。采用上述方法生产吗拉贝胺，操作简单，产品纯度好，收率较高，适用于工业化生产。
Claims (8)
1.一种新化合物吗拉贝胺，其特征是：所述新化合物吗拉贝胺化学名为5-氯-N-[2-(4-吗啉基)乙基]-2-吡啶甲酰胺，英文名为Malabemide，其相对分子质量为268.72，熔点162℃-164℃，为白色结晶体；用核磁共振测量得到的核磁共振氢谱图如图1所示；其分子式如式h所示：
2.一种如权利要求1所述新化合物吗拉贝胺的制备方法，合成路线如下：
制备步骤为：
(1)2-溴乙胺氢溴酸盐(b)的合成
将乙醇胺(a)滴加到氢溴酸中，乙醇胺与氢溴酸的摩尔比为1∶9，磁力搅拌，反应体系温度控制在0℃～10℃，滴加时间控制在25～30分钟，滴加完毕后，加入分水溶剂，升温分水，分水完成后冷却过滤除去溶剂，滤渣用冷丙酮洗涤三次，得到白色结晶产物2-溴乙胺氢溴酸盐(b)；所述溶剂选自二甲苯、苯或甲苯；
(2)5-氯-2-吡啶甲酰氯(e)的合成
先将5-氯-2-吡啶羧酸(d)加入到溶剂中，磁力搅拌均匀，再滴加二氯亚砜；5-氯-2-吡啶羧酸与二氯亚砜的摩尔比为1∶4，反应温度控制在0℃～10℃，滴加时间控制在15～20分；滴加完毕后升温回流反应，待回流完成后，常压除去溶剂，得白色晶体5-氯-2-吡啶甲酰氯(e)；所述溶剂选自二氯甲烷、三氯甲烷、二氯乙烷；
(3)5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)的合成
先将步骤(1)获得的2-溴乙胺氢溴酸盐(b)加入蒸馏水中，磁力搅拌溶解，滴加氢氧化钠溶液中和反应，待滴加完毕后加入溶剂，升温分水，分水完成后，冷却，过滤，收集滤液；再将5-氯-2-吡啶甲酰氯(e)加入到滤液中；2-溴乙胺氢溴酸盐(b)与5-氯-2-吡啶甲酰氯(e)的摩尔比为2∶1，升温回流反应，待反应完成后，冷却，抽滤，甲苯重结晶，得白色晶体5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)；所述溶剂选自甲苯、二甲苯或苯；
(4)吗拉贝胺(h)的合成
将5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)加入到甲苯中，升温溶解后再滴加吗啉，5-氯-N-(2-溴乙基)-2-吡啶甲酰胺(f)与吗啉的摩尔比为1:3升温回流反应，待反应完成后，冷却，抽滤，重结晶，得白色固体吗拉贝胺(h)；重结晶溶剂选自二甲苯、苯、甲苯、异丙醇、乙醇、二氯甲烷、三氯甲烷或二氯乙烷。
3.根据权利要求2所述新化合物吗拉贝胺的制备方法，其特征在于步骤(1)中所述氢溴酸浓度为40％；分水温度为135-145℃，分水时间为12h。
4.根据权利要求2所述新化合物吗拉贝胺的制备方法，其特征在,步骤(2)中的回流温度为40-45℃，回流时间为7-8h。
5.根据权利要求2所述新化合物吗拉贝胺的制备方法，其特征在于步骤(3)中回流温度为115-125℃，回流时间为8-10h。
6.根据权利要求2所述新化合物吗拉贝胺的制备方法，其特征在于步骤(4)中回流温度为120-125℃，回流时间为10-12h。
7.权利要求1或2所述的新化合物吗拉贝胺在制备单胺氧化酶抑制剂及其制剂的用途。
8.一种药物组合物，其特征是：含有权利要求1或2所述新化合物吗拉贝胺。
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