CN103772241B - 一种磺化去氢松香酸盐的制备方法 - Google Patents
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Abstract
本发明公开了一种磺化去氢松香酸盐的制备方法，该方法的特征包括室温下将五水硝酸铋溶于甘油∶水＝1∶3的混合溶剂中，全溶后，过滤，再将磺化去氢松香酸溶解到的乙醇中，全溶后，滴入硝酸铋的甘油水溶液中，室温下反应30min，离心，再用纯水打浆，滤饼60℃真空干燥24小时，得磺化去氢松香酸铋。
Description
技术领域
本发明涉及磺化去氢松香酸盐的制备方法及其为一种可用于治疗消化道溃疡、急慢性胃炎及糜烂性胃炎等疾病的药物。
背景技术
消化性胃溃疡是由于胃酸、胃蛋白酶的消化作用引起的溃疡性疾病，多发于胃和十二指肠，该类疾病容易反复发作，容易引起癌变。常用治疗药物有抗酸剂碳酸氢钠、磷酸铝，抗胃酸分泌药物泌素、西咪替丁、雷尼替丁，胃粘膜保护剂硫糖铝、复方次硝酸铋、替普瑞酮，促动力药甲氧氯普胺、多潘立酮、莫沙必利等。抗酸剂使用过多，容易引起胃酸过少，从而明显降低胃蛋白酶的消化活性，引起消化不良；胃粘膜保护剂如生胃酮可引起水肿、血压升高等症状，而一些促动力药如甲氧氯普胺引起中枢的不良反应较大。目前治疗消化性溃疡的首选药物就是抗胃酸分泌药物，常用抗胃酸分泌药物西咪替丁会引起心脏传导阻滞等副作用。因此，急需研究开发新型的抗胃酸分泌药。
本发明中涉及的磺化去氢松香酸盐早在80年代日本田边制药株式会社就对其进行了研究，发现这些化合物具有显著的胃粘膜保护、胃蛋白酶活性的抑制和抗胃酸分泌、无耐药性杀灭幽门螺旋杆菌的作用等，可用作消化溃疡以及各种胃炎的治疗药物。
现有技术中，将磺化去氢松香酸制备成磺化去氢松香酸盐反应溶剂为C1-6的脂肪醇，水、DMF和DMSO中的一种溶剂，反应体系为液-匀浆反应，不利于反应，易形成混合物。且反应需要高温，导致有关物质明显增加，生产效率低，耗能大，故该制备方法在工业化生产中意义不是很大。
发明内容
为了克服现有技术中的不足，本发明的目的在于提供一种磺化去氢松香酸盐新的制备方法。
具体讲，为实现本发明的目的，采用如下的技术方案：本发明磺化去氢松香酸盐制备的方法如下：
室温下磺化去氢松香酸在选自由C1-C10的脂肪族醇和水组成的混合溶媒中，与硝酸铋盐、次硝酸铋、氯化铋或氢氧化铋，通过反应制得通式(1)表示的磺化去氢松香酸盐。
其中，R为或或2BiO、或1/2Zn H
n＝0-10。
(式1)
进一步优选的制备方法为：1)室温下将五水硝酸铋溶于多元醇和水组成的混合溶剂中，过滤得a溶液；2)再将磺化去氢松香酸在C1-C10的脂肪族醇中溶解，待全部溶解后，滴入步骤1所得a溶液中，室温下反应，离心干燥即得。其中，多元醇为甘油、甘露醇、木糖醇、山梨醇，优选甘油。C1-C10的脂肪族醇优选C1-C4的脂肪醇，进一步优选甲醇、乙醇、异丙醇，更进一步优选乙醇。
更优选的制备方法为：室温下将五水硝酸铋溶于甘油∶水＝1∶3的混合溶剂中，全溶后，过滤，再将磺化去氢松香酸溶解到的乙醇中，全溶后，滴入五水硝酸铋的甘油水溶液中，室温下反应30min，离心，再用纯水打浆，滤饼60℃真空干燥24小时，得磺化去氢松香酸铋。
本发明所取得的有益效果为：五水硝酸铋室温即溶于多元醇和水的混合溶剂中，解决了五水硝酸铋在水中迅速形成不溶性的碱式硝酸铋的问题；磺化去氢松香酸室温溶于乙醇解决了高温下溶于水而导致有关物质增加的问题，且将磺化去氢松香酸的乙醇溶液滴入甘油水溶液中不易析出；乙醇-甘油-水混合溶剂解决了磺化去氢松香酸铋盐的不溶问题，且液-液反应体系不必加热就能成盐完全，更容易实现工业生产。
本发明的制备方法大大降低了原料成本，且减少了副产物的生成，能耗降低，反应收率有很大的提高，适合大规模工业化生产。
具体实施方式
现通过以下实施例对本发明的技术方案作进一步说明
[实施例1]
五水硝酸铋溶解度研究
(1)取500mg五水硝酸铋，加入5ml甘油∶水＝1∶1的混合溶液中，稍微加热，该盐全部溶解，自然降至室温过夜，无固体析出。
(2)取500mg五水硝酸铋，加入5ml甘油∶水＝1∶2的混合溶液中，超声全部溶解，放置过夜，溶液澄清无固体析出。
(3)取500mg五水硝酸铋，加入5ml甘油∶水＝1∶3的混合溶液中，无需超声就能迅速溶解，放置过夜，溶液澄清无固体析出。
(4)取500mg五水硝酸铋，加入5ml甘油∶水＝1∶4的混合溶液中，超声迅速溶解，放置过夜，溶液有少量固体析出。
(5)取500mg五水硝酸铋，加入5ml甘油∶水＝1∶5的混合溶液中，超声一段时间固体全部溶解，放置一段时间有少量固体析出，放置过夜，有大量固体析出。
表1 甘油水的混合溶液中甘油∶水的体积比筛选表
| 甘油水体积比 | 1∶1 | 1∶2 | 1∶3 | 1∶4 | 1∶5 |
| 溶解处理方法 | 加热 | 超声 | -- | 超声 | 超声 |
| 有无固体析出 | 无 | 无 | 无 | 有少量 | 有大量 |
注：甘油在甘油水混合溶液中的含量越高，溶液的粘稠度也越高，可操作性越差，且生产成本越高。水在甘油水混合溶液中的含量越高，越容易形成不溶性的碱式硝酸铋。
结论：五水硝酸铋溶于甘油∶水＝1∶3的混合溶剂中溶解度最佳，且放置过夜无固体析出。
[实施例2]
将1.654kg五水硝酸铋溶于28L甘油∶水＝1∶3的混合溶剂中，全溶后，过滤，再将1.42kg磺化去氢松香酸溶解到2.8L75％的乙醇中，全溶后，滴入硝酸铋的甘油水溶液中，反应30min，离心，再用纯水25L*3次打浆，滤饼60℃真空干燥24小时，得磺化去氢松香酸铋盐1.6kg，经HPLC检测其纯度为99.90％。
[实施例3]
将45g五水硝酸铋溶于800mL甘油∶水＝1∶3的混合溶剂中，全溶后，过滤，再将40g磺化去氢松香酸溶解到80mL75％的乙醇中，全溶后，滴入硝酸铋的甘油水溶液中，反应30min，离心，再用纯水800mL*3次打浆，滤饼60℃真空干燥24小时，得磺化去氢松香酸铋盐43.3g，经HPLC检测其纯度为99.92％。
[比较例1]
磺化去氢松香酸成品40g(92mmol)，加水200ml，2L三口瓶中。90℃条件下搅拌加热至全溶解，加入五水硝酸铋匀浆44.64g(92mmol硝酸铋粉末均匀分散在400ml水中)，90℃条件下搅拌反应30分钟，停止加热，放冷，滤过，滤饼以蒸馏水洗涤至滤液PH为5。滤饼60℃烘干24小时，得磺化去氢松香酸铋盐40.1g，经HPLC检测其纯度为90.60％。
[比较例2]
将磺化去氢松香酸成品3.34kg，加入125L水中，90℃条件下搅拌全溶解后，加入五水硝酸铋匀浆(3.77kg硝酸铋粉末均匀分散在19L水中)，不低于90℃条件下搅拌反应30分钟，停止加热，放冷，滤过，滤饼以蒸馏水洗涤至滤液PH为5。滤饼60℃烘干24小时，得磺化去氢松香酸铋盐2.97kg，经HPLC检测其纯度为90.54％。
表2 制备磺化去氢松香酸铋实施例和比较例工艺对照表
表3 制备磺化去氢松香酸铋盐实施例和比较例两种工艺产量和纯度对照表
| 磺化去氢松香酸投料量 | 产量 | 纯度(％) | |
| 实施例2 | 1.42kg | 1.6kg | 99.90 |
| 实施例3 | 40g | 43.3g | 99.92 |
| 比较例1 | 40g | 40.1g | 90.60 |
| 比较例2 | 3.34kg | 2.97kg | 90.54 |
Claims (4)
1.一种通式(1)表示的磺化去氢松香酸铋的制备方法，室温条件下，磺化去氢松香酸在甘油-水-乙醇组成的混合溶媒中，与硝酸铋通过反应制得通式(1)表示的磺化去氢松香酸铋，
其中，R为Bi(OH)++，或2BiO，n＝0-10，甘油-水的比例为1∶3，其特征在于：1)室温下将五水硝酸铋溶于甘油∶水＝1∶3的混合溶剂中，过滤得a溶液；2)再将磺化去氢松香酸在乙醇中溶解，待全部溶解后，滴入步骤1所得a溶液中，室温下反应，后离心干燥即得。
2.如权利要求1所述的磺化去氢松香酸铋的制备方法，其特征在于：室温下将五水硝酸铋溶于甘油∶水＝1∶3的混合溶剂中，全溶后，过滤，再将磺化去氢松香酸溶解到乙醇中，全溶后，滴入五水硝酸铋的甘油水溶液中，室温下反应30min，离心，再用纯水打浆，滤饼60℃真空干燥24小时，得磺化去氢松香酸铋。
3.一种磺化去氢松香酸铋的制备方法，其特征在于：将1.654kg五水硝酸铋溶于28L甘油∶水＝1∶3的混合溶剂中，全溶后，过滤，再将1.42kg磺化去氢松香酸溶解到2.8L75％的乙醇中，全溶后，滴入硝酸铋的甘油水溶液中，反应30min，离心，再用纯水25L*3次打浆，滤饼60℃真空干燥24小时，得磺化去氢松香酸铋盐1.6kg。
4.一种磺化去氢松香酸铋的制备方法，其特征在于：将45g五水硝酸铋溶于800mL甘油∶水＝1∶3的混合溶剂中，全溶后，过滤，再将40g磺化去氢松香酸溶解到80mL75％的乙醇中，全溶后，滴入硝酸铋的甘油水溶液中，反应30min，离心，再用纯水800mL*3次打浆，滤饼60℃真空干燥24小时，得磺化去氢松香酸铋盐43.3g。
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| EP0078152A1 (en) * | 1981-10-22 | 1983-05-04 | Tanabe Seiyaku Co., Ltd. | Salts of sulfodehydroabietic acid and treatment of gastro-intestinal diseases |
| GB2107584A (en) * | 1981-10-22 | 1983-05-05 | Tanabe Seiyaku Co | Treatment of gastro-intestinal diseases |
| CN1396154A (zh) * | 2001-07-16 | 2003-02-12 | 中国医药研究开发中心 | 磺化去氢松香酸盐及其制备方法和其用途 |
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