CN1623996A - N-酰基氨基葡萄糖及其制备方法 - Google Patents
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Abstract
本发明公开了一种N-酰基氨基葡萄糖及其制备方法,是将有机酸与氨基葡萄糖偶联,改造成为N-酰基氨基葡萄糖,可用于治疗高血脂症,高甘油三脂症,低密度脂蛋白(a)血症及高血浆蛋白症,长期应用能减少冠心病、心肌梗塞及其它心脑血管病的发生率。本发明制备技术一是将氨基葡萄糖中的氨基用对-甲氧基苯甲醛保护,以得到完全β-构型的N-酰基氨基葡萄糖;二是将酸或相应的酰卤为原料与β-构型保护的(用乙酰基保护羟基)N-酰基氨基葡萄糖盐酸盐偶联而得到完全β-构型的(用乙酰基保护羟基)氨基葡萄糖;三是所用原料氨基葡萄糖盐酸盐不必去除氯离子而直接进行氨基的保护反应;四是多数反应温度在低温或在稍高于常温下进行,节约能源,并可在稀酸、稀碱或毒性小的丙酮有机溶剂中进行,减少了污染,多数纯化是重结晶,产品纯度高,目标分子的质量与理论计算一致。
Description
技术领域
本发明涉及一种氨基葡萄糖的酰基化技术。
背景技术
烟酸作为一种广谱调节血脂药物。可用于治疗高血脂症,高甘油三脂症,低密度脂蛋白(a)血症及高血浆蛋白症,长期应用能减少冠心病、心肌梗塞及其它心脑血管病的发生率。但烟酸所需治疗量较大(3-6g/d),且易产生面部潮红、瘙痒、诱发溃疡,加重糖尿病及痛风等副作用,限制了其临床的应用。
发明内容
本发明的目的是N-酰基氨基葡萄糖及其制备方法。
本发明的目的是通过如下方式实现的:一种N-酰基氨基葡萄糖,该化合物的结构通式为:
其中R1、R3、R4、R5为-H或CH3CO-,
R2为芳基或杂环基或吡啶基或呋喃基或噻吩基或吡咯基或脱去羧基的氨基酸残基或羧酸中脱去羧基的残基;
R2还可为:
N-酰基氨基葡萄糖的制备方法:
1)、由羧酸制备酰卤:由上列通式中所含R2基的各种羧酸与二氯亚砜或三卤化磷或五卤化磷按重量比为1∶1∽10,在DMF存在下,于-10∽5℃开始反应,然后升温,回流,除去卤化剂,产物经重结晶或蒸馏纯化;
2)、1,3,4,6-四氧乙酰基-2-脱氧-β-D-氨基葡萄糖盐酸盐的制备:用过量1∽10%氨基葡萄糖盐酸盐与对-甲氧基苯甲醛缩合,在5∽20%稀碱溶液中反应1-4小时,过滤,产品经洗涤得到N-保护的氨基葡萄糖;用过量1-5%的乙酸酐与N-保护的氨基葡萄糖在吡啶溶液中于-3∽-8℃反应,10-15小时后,过滤,重结晶,得2-(4-甲氧基亚苄基)-2-脱氧-1,3,4,6-四氧-乙酰基-β-D-氨基葡萄糖;将2-(4-甲氧基亚苄基)-2-脱氧-1,3,4,6-四氧-乙酰基-β-D-氨基葡萄糖溶于有机溶剂中,加入1∽10%的稀盐酸反应,于-3∽10℃温度下结晶,分离,固体物用无水乙醚洗涤,干燥,得1,3,4,6-四氧乙酰基-2-脱氧-β-D-氨基葡萄糖盐酸盐;
3)、将1,3,4,6-四氧乙酰基-2-脱氧-β-D-氨基葡萄糖盐酸盐与酰卤按2∽1∶1摩尔比与CH2Cl2在碱存在下反应,分离,干燥,在混合溶液中重结晶,混合溶液可为乙酸乙酯-吡啶、乙酸乙酯-环己烷、乙酸乙酯-正己烷,制得1,3,4,6-四氧乙酰基-2-脱氧-2-酰胺基-β-D-葡萄糖;
4、将1,3,4,6-四氧乙酰基-2-脱氧-2-酰胺基-β-D-葡萄糖与碱溶液混合,在无水甲醇中回流,将溶液于低温下放置,得固体粉末,分离,干燥,重结晶,得N-酰基氨基葡萄糖。
本发明是将有机酸与氨基葡萄糖偶联,改造成为N-酰基氨基葡萄糖,可用于治疗高血脂症,高甘油三脂症,低密度脂蛋白(a)血症及高血浆蛋白症,长期应用能减少冠心病、心肌梗塞及其它心、脑血管病的发生率。本发明制备技术一是将氨基葡萄糖中的氨基用对-甲氧基苯甲醛保护,以得到完全β-构型的N-酰基氨基葡萄糖;二是将酸或相应的酰卤为原料与β-构型保护的(用乙酰基保护羟基)氨基葡萄糖盐酸盐偶联而得到完全β-构型的(用乙酰基保护羟基)N-酰基氨基葡萄糖;三是所用原料氨基葡萄糖盐酸盐不必去除氯离子而直接进行氨基的保护反应;四是多数反应温度在低温或在稍高于常温下进行,节约能源,并可在稀酸、稀碱或毒性小的丙酮有机溶剂中进行,减少了污染,多数纯化是重结晶,产品纯度高,目标分子的质量与理论计算一致。
具体实施方式
下面结合实施例对本发明做进一步说明:
实施例:
以2-脱氧-2-烟酰胺基-β-D-葡萄糖及制备方法为例:
2-脱氧-2-烟酰胺基-β-D-葡萄糖的分子结构式为:
其整个反应过程表示于下:
1.烟酰氯盐酸盐的合成
将3-15.0ml SOCl2加入装有HCl气体吸收装置的反应瓶中,在-10∽5℃左右,向其中加入0.4∽15g烟酸,搅拌,滴入数滴无水DMF,在油浴中缓慢升温到60∽85℃,回流3h后,减压蒸除过量的SOCl2,得浅黄色粉末状固体物质(1),产率为81%。
2.1,3,4,6-四氧乙酰基-2-脱氧-β-D-氨基葡萄糖盐酸盐的合成
将定量的氨基葡萄糖盐酸盐在30∽80mL稀NaOH溶液中,与2.5g对甲氧基苯甲醛反应1∽4h,经过滤、洗涤、干燥后得到N-对甲氧基亚苄基保护的氨基葡萄糖A1,mp:165∽166℃。将乙酸酐30∽60mL加入到A1的吡啶溶液中,在温度为-3∽-8℃反应12∽18h,冷却过率,重结晶,得2-(4-甲氧基亚苄基)-2-脱氧-1,3,4,6-四氧-乙酰基-β-D-氨基葡萄糖A2,mp:185.3∽186.5℃。将5-20g A2溶于丙酮中,搅拌,回流,加入稀盐酸,反应0.5∽2h,冷却至室温,于乙醚中低温下放置,结晶,用有机溶剂洗涤,干燥,得A3,产率81%。mp:196.9∽198.1℃。
3.1,3,4,6-四氧乙酰基-2-脱氧-2-烟酰胺基-β-D-葡萄糖的合成
称取0.5∽3.54g A3于一烧瓶中,再加入CH2Cl210∽80mL、有机碱及烟酰氯盐酸盐0.2∽1.5g于-10∽15.0℃下搅拌3h,再将反应液倒入水中,振荡后分液,取下层棕红色有机层,用5%NaHCO3溶液洗涤到无明显气泡放出,再用水洗涤至中性,然后干燥,过滤后减压蒸馏,得一棕红色固体,重结晶得棕红色粉末A4,产率为66.9%。mp:209.1℃,[M+H]+,m/z 453。
4.2-脱氧-2-烟酰胺基-β-D-葡萄糖的合成
称取0.2∽2.0g(A4)及0.5∽8.0mg CH3ONa于100ml圆底烧瓶中,加入30.0∽80mL无水甲醇,搅拌3h,将溶液于-5∽15℃条件下放置,析出大量灰白色粉末,抽滤后干燥得(A5),产率为91%。mp:221.5℃。[M+H]+,m/z285。
Claims (2)
2、根据权利要求1所述的N-酰基氨基葡萄糖的制备方法,其特征在于:
1)、由羧酸制备酰卤:由上列通式中所含R2基的各种羧酸与二氯亚砜或三卤化磷或五卤化磷按重量比为1∶1∽10,在DMF存在下,于-10∽5℃开始反应,然后升温,回流,除去卤化剂,产物经重结晶或蒸馏纯化;
2)、1,3,4,6-四氧乙酰基-2-脱氧-β-D-氨基葡萄糖盐酸盐的制备:用过量1∽10%氨基葡萄糖盐酸盐与对-甲氧基苯甲醛缩合,在5∽20%稀碱溶液中反应1-4小时,过滤,产品经洗涤得到N-保护的氨基葡萄糖;用过量1-5%的乙酸酐与N-保护的氨基葡萄糖在吡啶溶液中于-3∽-8℃反应,10-15小时后,过滤,重结晶,得2-(4-甲氧基亚苄基)-2-脱氧-1,3,4,6-四氧-乙酰基-β-D-氨基葡萄糖;将2-(4-甲氧基亚苄基)-2-脱氧-1,3,4,6-四氧-乙酰基-β-D-氨基葡萄糖溶于有机溶剂中,加入1∽10%的稀盐酸反应,于-3∽10℃温度下结晶,分离,固体物用无水乙醚洗涤,干燥,得1,3,4,6-四氧乙酰基-2-脱氧-β-D-氨基葡萄糖盐酸盐;
3)、将1,3,4,6-四氧乙酰基-2-脱氧-β-D-氨基葡萄糖盐酸盐与酰卤按2∽1∶1摩尔比与CH2Cl2在碱存在下反应,分离,干燥,在混合溶液中重结晶,混合溶液可为乙酸乙酯-吡啶、乙酸乙酯-环己烷、乙酸乙酯-正己烷,制得1,3,4,6-四氧乙酰基-2-脱氧-2-酰胺基-β-D-葡萄糖;
4)、将1,3,4,6-四氧乙酰基-2-脱氧-2-酰胺基-β-D-葡萄糖与碱溶液混合,在无水甲醇中回流,将溶液于低温下放置,得固体粉末,分离,干燥,重结晶,得N-酰基氨基葡萄糖。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100463923C (zh) * | 2006-06-29 | 2009-02-25 | 中国海洋大学 | 对乙酰氨基苯甲酰壳聚糖化合物及其制备方法 |
CN101234118B (zh) * | 2008-03-05 | 2010-10-27 | 北京诚创康韵医药科技有限公司 | 一种治疗心脑血管疾病的药物组合物 |
CN101735286B (zh) * | 2009-12-14 | 2012-02-29 | 西南大学 | 氨基酸修饰的氨基葡萄糖及其制备方法和应用 |
CN105920612A (zh) * | 2016-06-12 | 2016-09-07 | 浙江大学 | 一种氨基葡萄糖-山嵛酸嫁接物及制备方法 |
CN109879967A (zh) * | 2017-12-15 | 2019-06-14 | 苏州和锐生物科技有限公司 | 一种乙酰氨基葡萄糖偶联物的制备方法及应用 |
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2004
- 2004-03-19 CN CN 200410023021 patent/CN1623996A/zh active Pending
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100463923C (zh) * | 2006-06-29 | 2009-02-25 | 中国海洋大学 | 对乙酰氨基苯甲酰壳聚糖化合物及其制备方法 |
CN101234118B (zh) * | 2008-03-05 | 2010-10-27 | 北京诚创康韵医药科技有限公司 | 一种治疗心脑血管疾病的药物组合物 |
CN101735286B (zh) * | 2009-12-14 | 2012-02-29 | 西南大学 | 氨基酸修饰的氨基葡萄糖及其制备方法和应用 |
CN105920612A (zh) * | 2016-06-12 | 2016-09-07 | 浙江大学 | 一种氨基葡萄糖-山嵛酸嫁接物及制备方法 |
CN109879967A (zh) * | 2017-12-15 | 2019-06-14 | 苏州和锐生物科技有限公司 | 一种乙酰氨基葡萄糖偶联物的制备方法及应用 |
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