CN109320510B - 一种马罗匹坦游离碱的制备方法 - Google Patents
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及马罗匹坦游离碱的制备方法,反应涉及(2S,3R)‑2‑二苯甲基奎宁环‑3‑醇和R1SO2Cl或(CF3SO2)2O发生反应得到羟基保护的化合物式IV,式IV在碱和溶剂存在下和2‑甲氧基‑5‑叔丁基‑苄胺发生反应得到马罗匹坦游离碱。
Description
技术领域
本发明属于合成原料药方法技术领域，具体涉及原料药马罗匹坦游离碱的制备。
背景技术
柠檬酸马罗匹坦(Maropitant Citrate)是1型神经激肽(NK1)的受体抗结剂，可通过抑制P物质(引起呕吐的关键性神经递质)而作用于中枢神经系统。柠檬酸马罗匹坦属于替代性的喹宁药物的一种，由于疗效显著，2007年FDA批准该药用于预防及治疗犬的急性呕吐，后续同样被批准用于猫的处方外用药。柠檬酸马罗匹坦有两种剂型,注射用的柠檬酸马罗匹坦应用于预防及治疗犬的急性呕吐；片剂柠檬酸马罗匹坦用于预防犬的急性及由于晕动症引起的呕吐；两者均可作为猫的处方外用药。中国农业部2016年5月批准了柠檬酸马罗匹坦的进口注册,同样用于预防及治疗犬的急性呕吐。
柠檬酸马罗匹坦还被称为CJ-11,972，商品名为Cerenia(止吐宁),由辉瑞公司原研开发。柠檬酸马罗匹坦的分子量为678.82,化学名称是(2S,3S)-2-二苯甲基-N-(5-叔丁基-2-甲氧基苄基)-3-氨基-喹宁柠檬酸盐一水合物。其化学结构式如下：
文献WO2004035575、WO2005075473等公开报道了马罗匹坦的合成方法；该方法的合成路线需要8步骤反应实现马罗匹坦游离碱的制备，其中涉及到难以控制的苯基溴化镁格式试剂与溴化亚铜二甲硫醚(CuBr·(CH3)2S)参与的Michael加成反应、多步骤加压氢化反应等。
具体反应式如下：
上述合成马罗匹坦游离碱的方法不仅路线长，收率低下(8步反应总收率仅为10％左右),且反应过程中涉及到使用多种贵重金属，如Ti、Pt、Pd等，不仅成本高，且去除这些贵金属残留需要耗费大量的溶剂和吸附剂。为此，开发一条新的合成马罗匹坦的方法对该药物的产业化生产尤其重要。
发明内容
本发明的目的在于提供一种制备马罗匹坦游离碱的新方法，旨在避免原研专利中大量使用贵金属试剂、手性折分试剂以及总收率低的缺陷。
本发明的合成路线如下：
反应第一步涉及(S)-2-二苯甲基奎宁环-3-酮(式I)在Na/i-PrOH/Toluene条件[0009]下反应生成(2S,3R)-2-二苯甲基奎宁环-3-醇(式II)。
反应第二步是通过式II化合物在碱和溶剂存在下和R1SO2Cl或(CF3SO2)2O发生反应得到羟基保护的化合物式IV。
反应第二步使用的溶剂为CH2Cl2,THF,2-MeTHF,Dioxane,CH3CN。
反应第二步使用的碱为Pyridine,Et3N,DIPEA,Morpholine,DMAP。
式III的R1为甲基,对甲基苯基,苯基。
式IV的R2为甲磺酰基(Ms),对甲苯磺酰基(Ts),三氟甲磺酰基(Tf),苯磺酰基(PhSO2-)。
反应第三步是通过式IV化合物在碱和溶剂存在下和2-甲氧基-5-叔丁基-苄胺发生反应得到马罗匹坦游离碱。
反应第三步所使用的碱为Et3N,DIPEA,Pyridine,Morpholine,DMAP。
反应第三步所使用的溶剂为THF,2-MeTHF,DMF，CH2Cl2，Dioxane，CH3CN，TMBE。
本发明的合成路线短，总收率高，使用的试剂易于商业化大量采购，工艺操作简单，且不涉及使用Pd、Ti、Pt等贵金属，适合马罗匹坦游离碱的工业化放大生产。
具体实施方式
以下典型实施例用来说明本发明，在本领域内的技术人员对本发明所做的简单替换和改进等均属于本发明所保护的技术方案之内。
实施例一:(2S,3R)-2-二苯甲基奎宁环-3-醇(式II)的制备
5L反应瓶中加入(S)-2-二苯甲基奎宁环-3-酮(式I)(130g,446mmol,1.0eq.)和甲苯(1.8L),加入完毕后体系加热回流分水，去除反应体系中少量的水。然后体系回流状态下缓慢加入切成小块的金属Na(50g,2175mmol)，加入完毕后回流状态下缓慢加入i-PrOH(450mL)。体系回流反应1.5小时后自然降温至室温，反应体系加入甲醇(1L)淬灭反应。体系高真空减压浓缩去除溶剂，残余物加入H2O(2L)和CH2Cl2(1L),体系搅拌3小时后静置，分出有机相，水相CH2Cl2(3×500mL)萃取三次，合并有机相，有机相高真空减压浓缩去除溶剂，残余物柱层析纯化得到(2S,3R)-2-二苯甲基奎宁环-3-醇(式II)(浅黄色固体，94.3g,72.1％)。
实施例二:(2S,3R)-2-二苯甲基-3-甲磺酰氧基-奎宁(式IV,R2＝Ms)的制备
向反应瓶中加入(2S,3R)-2-二苯甲基奎宁环-3-醇(式II)(5.0g,17mmol)和CH2Cl2(15mL)。反应体系冰盐浴冷却至5℃，然后缓慢通过滴液漏斗加入Pyridine(25mL)和MsCl(4.0g,34.9mmol)。加入完毕后体系自然升温至室温搅拌5小时后，体系加热至回流反应2小时，然后体系自然降温至室温。体系加入HCl溶液(2N in H2O)调节体系pH值至8-9，然后加入CHCl3(3×120mL)萃取三次，合并有机相，有机相高真空减压浓缩去除溶剂，残余物柱层析纯化得到(2S,3R)-2-二苯甲基-3-甲磺酰氧基-奎宁(式IV,R2＝Ms)(5.15g,81.5％)。
实施例三:马罗匹坦游离碱的制备
反应瓶中加入(2S,3R)-2-二苯甲基-3-甲磺酰氧基-奎宁(式IV,R2＝Ms)(4.5g,12.11mol)和DMF(20mL)。加入完毕后，向体系中加入三乙胺(4.9g,48.42mmol,4.0eq.)和2-甲氧基-5-叔丁基-苄胺(3.50g,18.11mol)。加入完毕后体系升温至100℃反应至TLC跟踪起始原料消失。体系自然降温至室温，体系高真空减压脱除有机溶剂，残余物加入CH2Cl2(60mL)和H2O(60mL),分出有机相，水相用CH2Cl2萃取(3×30mL)。合并有机相，有机相饱和食盐水洗涤(50mL)，无水Na2SO4干燥后减压脱溶，残余物柱层析纯化得马罗匹坦游离碱(4.94g,87.1％)。
实施例四:(2S,3R)-2-二苯甲基-3-三氟甲磺酰氧基-奎宁(式IV,R2＝Tf)的制备
向反应瓶中加入(2S,3R)-2-二苯甲基奎宁环-3-醇(式II)(12.2g,41.6mmol)和无水THF(40mL)。反应体系冰盐浴冷却至5℃左右，然后缓慢通过滴液漏斗加入DIPEA(50mL)和Tf2O(23.5g,83.3mmol)。加入完毕后体系自然升温至室温搅拌24小时。体系加入HCl溶液(2N in H2O)调节体系pH值至8-9，然后加入CHCl3(3×200mL)萃取三次，合并有机相，有机相高真空减压浓缩去除溶剂，残余物柱层析纯化得到(2S,3R)-2-二苯甲基-3-三氟甲磺酰氧基-奎宁(式IV,R2＝Tf)(13.48g,76.2％)。
实施例五:马罗匹坦游离碱的制备
反应瓶中加入(2S,3R)-2-二苯甲基-3-三氟甲磺酰氧基-奎宁(式IV,R2＝Tf)(12.0g,28.2mol)和2-MeTHF(50mL)。加入完毕后，向体系中加入DMAP(10.34g,84.64mmol)和2-甲氧基-5-叔丁基-苄胺(6.55g,33.89mol)。加入完毕后体系升温至回流反应至TLC跟踪起始原料消失。体系自然降温至室温，体系高真空减压脱除有机溶剂，残余物加入CH2Cl2(120mL)和H2O(120mL),分出有机相，水相CH2Cl2萃取(3×60mL)。合并有机相，有机相饱和食盐水洗涤(120mL)，无水Na2SO4干燥后减压脱溶，残余物柱层析纯化得马罗匹坦游离碱(10.92g,82.6％)。
Claims (2)
1.制备马罗匹坦游离碱的方法,反应式如下：
2.如权利要求1所述制备马罗匹坦游离碱的方法，反应使用的碱为三乙胺，N,N-二异丙基乙胺，吡啶，吗啉，4-二甲氨基吡啶；反应所使用的溶剂为四氢呋喃，2-甲基四氢呋喃，N,N-二甲基甲酰胺，二氯甲烷，二氧六环，乙腈，甲基叔丁基醚。
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