CN1040438C - 一釜法制备硫丙麦角林 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一釜法由8,9-二氢野麦角碱生产硫丙麦角林,其中8,9-二氢野麦角碱相继与1-碘丙烷、磺酰卤以及碱金属甲硫醇盐反应而不分离中间产物。
Description
正如Kornfeld和Bach在美国专利第4166182中所公开的,硫丙麦角林,是一个众所周知的特别是用于治疗帕金森氏病的药物。本发明提供用安全和易得的成分快速经济地合成高纯度和高收率的硫丙麦角林的方法。本发明属于有机化学和药物化学领域。
本发明提供好的廉价的原料和中间体化合物,并提供高收率的纯产物,本发明最特别的优点在于能够避免中间体的分离,该分离在处理和操作中难于控制并存在公害,因此,本发明提供在对操作者和环境的安全方面极为有利的方法。
本发明提供制备硫丙麦角林的一釜法,它包括:8,9-二氢野麦角碱于高温及钙、镁或碱金属碳酸氢盐或碳酸盐存在下并选自N-甲基吡咯烷酮、六甲基磷酰胺、二甲基亚丙基脲和二甲基亚乙基脲的溶剂中与1-碘丙烷反应直至8,9-二氢野麦角碱基本上已消耗掉,制得第一中间体混合物;用大量的选自吡啶、甲基吡啶和二甲基吡啶的碱性溶剂稀释第一中间体混合物,将稀释后的混合物冷至低温,将其与甲苯-或C1-C3链烷磺酰卤混合并于低温继续反应至第一中间体混合物基本上已消耗掉,制得第二中间体混合物;将冷的第二中间体混合物与冷的碱金属甲硫醇盐溶液混合并于高温继续反应直至第二中间体混合物基本上已消耗掉,制得粗的硫丙麦角林混合物;用水稀释粗的硫丙麦角林混合物得到固体硫丙麦角林,用水洗涤后得纯度至少为90%的硫丙麦角林。
若无另外说明,本发明中所有的数量、比例、比率等均以重量单位表示。所有的温度均以℃表示。
本发明方法用8,9-二氢野麦角碱开始,该化合物由Kornfeld和Bach在美国专利第4166182中公开。目前该化合物由匈牙利布达佩斯的GedeonRichter和日本东京Kawaken Fine Chemicals Co.,Ltd销售。
该方法通过下述反应来完成:使原料化合物与1-碘丙烷反应制得第一中间体,然后使第一中间体与 甲苯-或C1-C3链烷磺酰卤反应生成第二中间体,然后使第二中间体与碱金属甲硫醇盐反应制得硫丙麦角林,该产物通过简单的用水洗涤来分离和纯化。该方法由下列合成路线简要说明:
硫丙麦角林
如上所述,第一和第二中间体未被分离,而只是将反应剂加到相继的中间体混合物中进行连续反应。
该方法开始时是将原料,略过量的1-碘丙烷、碳酸氢盐或碳酸盐以及溶剂在适当大小的反应器中混合,溶剂优选N-甲基吡咯烷酮。过量的1-碘丙烷使用范围在约1.05-2当量,最好在约1.1-13当量范围内,而碱的用量很小,例如约0.01-0.3当量。优选的碱是碳酸钠,但钙、镁、钠、钾和锂的碳酸氢盐和碳酸盐也适用。
由于在这个阶段的反应可被完全浓缩,因此要限制溶剂的用量。例如,当用N-甲基吡咯烷酮作溶剂时,仅需要相当于8,9-二氢野麦角碱的体积的约1-4体积溶剂,最好为约2体积。
反应器中应保持有惰性气氛如干燥氮气,并且将反应混合物加热至高温,例如约50-100°,最好为约65-85°。反应混合物保持高温,最好同时搅拌,直至原料基本上都被消耗掉,有代表性的是该过程于约75°需约3-5小时。反应的进程可以通过下述层析方法来监控:用腈处理过的硅胶柱,用含水乙腈缓冲液洗脱。反应最好一直进行到当用层析法测定约99%的原料已消失的时候。
当反应达到所需的完全程度时,将反应混合物冷至30°以下。尽管可以立即进行该方法的下一步反应,但并非必须,因为第一中间体是十分稳定的。因此,在进行该方法的其余反应之前,第一中间体混合物可在惰性气氛中于室温储存长达几星期。
将第一中间体混合物仍置惰性气氛中用大量的吡啶,甲基吡啶或二甲基吡啶来稀释。以第一中间体混合物中的溶剂的体积为基准,碱性溶剂的体积应该在约3-10体积范围内,使用约4-7体积为佳,特别是约5体积碱性溶剂剂。优选的碱性溶剂是吡啶。然后将稀释后的中间体混合物冷却至低温约-50°-0°范围内,最好为约-10°。当该温度被维持并且肯定没升高到约0°以上时,缓慢加入磺酰卤。最优选的卤化物是甲磺酰氯,但任何甲苯磺酰-、甲磺酰-、乙磺酰-和正丙烷磺酰溴、氯和碘都可以使用,特别是磺酰氯,更特别的是C1-C2链烷磺酰氯。酰卤的用量实际上过量,最好为约2.5当量,但一般在约1.5-5当量范围内。
由于需要低温,加入磺酰卤必须缓慢,并且当一加入磺酰卤时第二中间体混合物中的大部分反应就会发生。因此常发现该加入步骤结束后仅需要约1-3小时的附加反应时间就能使第一中间体基本上完全消耗掉。反应的进程可用上述层析方法追踪。
第二中间体特别不稳定,因此在进行该方法的最终步骤之前,第二中间体混合物的贮存不应超过1或2天。若第二中间体需要贮存时,应将其贮存在上述的低温条件下。
第二中间体经与甲硫醇的钠、钾或锂盐反应转化成硫丙麦角林。所用的甲硫醇盐远远过量,以原料化合物的用量为基准,甲硫醇盐的用量在约5-15当量范围内,优选约8-14当量,最好为约12当量。通过甲硫醇与碱金属甲醇盐原位反应制备甲硫醇盐很方便,该反应容易进行,反应最好在上述的低温条件下进行。若原位反应制备甲硫醇盐,重要的是要用少量到中等过量的甲硫醇,以确保无残留的甲醇盐进入反应混合物中。
该反应不被水的存在所防碍,因此可以加入甲硫醇盐水溶液,在含水溶剂或无水有机溶剂中更方便。优选的溶剂与第一中间体混合物中所用的溶剂相同,或可以选自酰胺类例如二甲基甲酰胺和二甲基乙酰胺,醚类例如四氢呋喃,链烷醇类以及其它可与水混溶的溶剂。
将甲硫醇盐溶液于低温与冷的第二中间体混合物混合,两者均处于上述定义的低温条件下,但最好是在约-10°。在将一种加到另一种中时要控制速度以使最终的混合物的温度保持在环境温度以下。加完后可以升温,可立即将该混合物加热至上述定义的高温,最好为约80°根据反应混合物的浓度,可以多加一些溶剂以利于更好地搅拌混合物。反应一直持续到第二中间体基本上都消耗掉并转化成硫丙麦角林,这需要几小时,例如于约80°需约1-4小时,当然,正如有机反应通常显示的那样,温度越低需要的反应时间越长,该最终反应的进程可用上述层析方法追踪。
当第二中间体已被消耗并且反应已达到所需的完全程度时,将粗的硫丙麦角林混合物用水稀释,仅需要适量的水,最好约为粗的硫丙麦角林混合物体积的1-1.5倍,但水的用量并不特别重要,因为硫丙麦角林基本上不溶于水,硫丙麦角林立即沉淀,按常规方法洗涤,将其从洗涤水中分出,并且再洗涤得到基本上纯的硫丙麦角林,经层析分析确定其纯度至少为90%。
硫丙麦角林在市场上销售并以其甲磺酸盐的形式用作药物。当该一釜法结束时,其硫丙麦角林产物最好用层析方法纯化,然后将其转化成甲磺酸盐,即可用于药用用途,正如Misner的美国专利第4782152中所述。
本发明将由下列实施例进一步解释,以确保读者能充分理解本发明。
下列实施例将进一步说明本发明的操作,以使读者能成功地实施本发明。
实施例
第一中间体
将12.8g 8,9-二氢野麦角碱(Kawaken)、10.6g 1-碘丙烷、0.42g无水碳酸钠和25ml经分子筛干燥的N-甲基吡咯烷酮加到搅拌的烧瓶中。将混合物置氮气气氛保护下搅拌并加热至75°。
反应于恒温持续进行约18小时,然后在Zorbax CN柱上以甲醇:0.1M乙酸铵(4∶1)洗脱,用290nm检测器进行液相层析分析(Zorbax CN得自杜邦公司)。在反应混合物中未检出8,9-二氢野麦角碱,说明该化合物完全转化成第一中间体。
将体积为约39ml的反应混合物分成5等分用于进一步实验。
第二中间体
在干燥氮气下将上述制得的第一中间体混合物中的一个等分与39ml经分子筛干燥的吡啶在100ml烧瓶中混合,该烧瓶备有氮气入口、冰浴、温度计和搅拌器。将该溶液冷却至0°并向其中滴加2.86g甲磺酰氯,注意反应混合物的温度不要超过5°,滴加时间约为8分钟。
如上述步骤所释反应混合物,用液相层析法监控,于0°搅拌1小时后发现混合物含5.9%第一中间体。2.5小时后,第一中间体的含量降至约4%,使该反应混合物进行本方法的下一步反应。
甲硫醇钠
将30ml经分子筛干燥的N-甲基吡咯烷酮在氮气氛下加到烧瓶中并冷至-5°。然后加入6.2ml甲硫醇和4.0g粉末状氢氧化钠。立即将混合物的温度升至5°,将混合物冷却并搅拌1小时,维持温度为约-2°。
硫丙麦角林
将第二中间体混合物加到上述混合物中,经放热使温度升至21°。将混合物于室温搅拌15分钟,然后加热至80°于该温度搅拌2小时。然后通过加入60ml水将反应骤冷。将含水混合物冷却至5°并过滤。固体用60ml水洗涤并在真空烘箱中于50°干燥过夜。干燥固体的分析表明其为94.1纯度的硫丙麦角林,产量为2.86g,基于原料8,9-二氢野麦角碱的收率为90.8%。
Claims (6)
1.用于制备硫丙麦角林的一釜法,它包括:8,9-二氢野麦角碱于50-100℃的温度及钙、镁或碱金属碳酸氢盐或碳酸盐存在下并在选自N-甲基吡咯烷酮、六甲基磷酰胺、二甲基亚丙基脲和二甲基亚乙基脲的溶剂中与1.05-2当量的1-碘丙烷反应直至8,9-二氢野麦角碱基本上已消耗掉,制得第一中间体混合物;用3-10体积的选自吡啶、甲基吡啶和二甲基吡啶的碱性溶剂稀释第一中间体混合物,将稀释后的混合物冷至-50-0℃的低温,将其与1.5~5当量的甲苯-或C1-C3链烷磺酰卤在1-3小时的一段期间慢慢混合并于低温继续反应至第一中间体混合物基本上已消耗掉,制得第二中间体混合物;将冷的第二中间体混合物与冷的5-15当量的碱金属甲硫醇盐溶液混合并于50-100℃的温度继续反应1-4小时的一段期间直至第二中间体混合物基本上已消耗掉,制得粗的硫丙麦角林混合物;用水稀释粗的硫丙麦角林混合物得到固体硫丙麦角林,用以粗的硫丙麦角林混合物的体积计为1-1.5倍的水洗涤硫丙麦角林,得色谱分析纯度至少为90%的硫丙麦角林。
2.权利要求1的方法,其中碱金属碳酸盐存在于第一中间体混合物中。
3.权利要求1的方法,其中在第一中间体混合物中,溶剂是N-甲基吡咯烷酮。
4.权利要求1的方法,其中在第二中间体混合物中,碱性溶剂是吡啶。
5.权利要求1的方法,其中在第二中间体混合物中,磺酰卤是磺酰氯。
6.权利要求1的方法,其中在硫丙麦角林混合物中,碱金属甲硫醇盐是甲硫醇钠。
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US6388079B1 (en) | 2000-08-29 | 2002-05-14 | Scinopharm Singapore Pte Ltd. | Process for preparing pergolide |
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