CN110872251A - N-乙基吡啶甲胺三氟乙酸盐及其晶体、制备工艺和应用 - Google Patents
N-乙基吡啶甲胺三氟乙酸盐及其晶体、制备工艺和应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
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- C07C53/18—Halogenated acetic acids containing fluorine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
本发明公开了一种N‑乙基吡啶甲胺三氟乙酸盐及其晶体、制备工艺和应用。将N‑乙基吡啶甲胺与三氟乙酸制备得到的N‑乙基吡啶甲胺三氟乙酸盐，使用X‑射线粉末衍射，所述晶体在约15.12°，15.45°，17.68°，20.68°，22.62°，23.25°，24.75°，29.54°处有衍射峰。将N‑乙基吡啶甲胺，溶于有机溶剂中，室温或者加热，搅拌至物料完全溶解；缓慢加入三氟乙酸，析晶；保温陈化，过滤，干燥得到N‑乙基吡啶甲胺三氟乙酸盐晶体。方法操作简单，纯化效果明显，结晶制备得到的盐型及晶型杂质含量少，纯度高，有利于工业化生产。
Description
技术领域
本发明涉及一种N-乙基吡啶甲胺的三氟乙酸盐晶体及其制备工艺和应用，属于药物制备技术领域。
背景技术
托品酰胺为抗胆碱药，为副交感神经抑制药，在眼科领域中为眼底检查和诊断用的首选散瞳药，还有睫状肌麻醉的作用。1955年由Roche公司首先合成，在临床商除单独使用外，多以复合剂使用。托品酰胺相比其他散瞳剂具有散瞳迅速，恢复期短等诸多优点。
托品酰胺的理化性质：白色结晶呈粉末状，味苦，溶于乙醇氯仿和丙酮，微溶于水，不溶于石油醚。
目前，公开的最早托品酰胺的合成方法为Siliva Dei等(Life Sciences，Vol，58，No.23,PP.2147-2153)报道的方法，它以水杨酸为原料，先乙酰酯化保护羟基后，再与N-乙基吡啶甲胺反应，最后经过脱乙酰基保护得到托品酰胺，反应路线如式1所示：
上海泰坦科技股份有限公司2017年报道了一种以苯基丙二酸二乙酯为反应原料，经过两步转化后再与N-乙基吡啶甲胺反应，最后还原合成托品酰胺的合成路线(式2)，总收率提高到了65％。
这两种合成路线都以N-乙基吡啶甲胺为关键起始物料，其CAS号为： 33403-97-3，分子式为：C8H12N2：分子量：136.20，其化学结构式如式3所示：
N-乙基吡啶甲胺是一种浅黄色油状液体，其制备工艺多由4-吡啶甲醛与乙胺缩合反应，生成亚胺中间体3，亚胺中间体3经过硼氢化钠还原反应生成N- 乙基吡啶甲胺粗品，粗品经过后处理纯化，进一步得到N-乙基吡啶甲胺产品(如式4所示)。
目前工业化的后处理工艺操作提纯较为困难，往往只能通过精馏纯化，在0.011atm下，N-乙基吡啶甲胺的沸点为103℃，在0.005atm下，亚胺中间体3 的沸点为87℃，两个物料的沸点相差很小，精馏纯化较为困难，提纯率及产率不高，特别的是，精馏能耗及损失较大，成本较高；而且N-乙基吡啶甲胺为胺类化合物，是一种有机碱，长时间存放不稳定，特别是在高温精馏时很容易被氧化，进一步导致产品纯度降低，杂质增多。所以该工艺制备出来的市售产品往往含有较多亚胺中间体3及其他相关杂质，纯度较低，一般不超过95％，但是从托品酰胺的合成路线可见，N-乙基吡啶甲胺是原料药产品申报的关键反应步骤的关键起始物料，它的质量及纯度直接关系到原料药产品的质量及纯度。在现行国家政策对原料药要求越来越严的趋势下，如此低纯度的N-乙基吡啶甲胺很难满足市场的需求。
油状物的N-乙基吡啶甲胺其粘度较大，转移，分装，储存，运输等操作较困难，而且有机胺类易挥发出来的难闻气味对车间操作的工人也极不友好，除此之外，挥发出来的胺类物质极易与空气中的二氧化碳形成烟雾状脲类衍生物固体，污染产品的同时在有气流的情况下极易堵塞管道，造成不必要的事故，因此研发高纯度，低成本的，固化方便操作的N-乙基吡啶甲胺就很有意义和必要；
常用的纯化方法为结晶，但是N-乙基吡啶甲胺熔点很低，不适合结晶，考虑到N-乙基吡啶甲胺本身是一种游离碱，将这种游离碱与酸成盐是固化和提纯的一种有效手段。因此，开发一种成盐的方法，纯化简单，稳定性更好，更绿色环保的起始物料盐型是必要趋势。
发明内容
本发明的目的是提供一种托品酰胺关键起始物料N-乙基吡啶甲胺的三氟乙酸盐及其晶型，利用N-乙基吡啶甲胺的弱碱性，与三氟乙酸反应生成一种稳定性极好的N-乙基吡啶甲胺三氟乙酸盐晶体，该晶体为颗粒性很好的固体，没有有机胺类易挥发的对车间操作工人极不友好的难闻味道，也没有三氟乙酸气的刺激性，同时由于其极易析出颗粒较大的结晶，因此该固体转移，储存，分装等操作方便，特别的是在固体加料过程中，不会出现液体N-乙基吡啶甲胺加料时极易出现的烟雾固体，进而污染产品和堵塞管道的现象，而且由于该晶体颗粒大，不易形成杨尘，减少常规固体加料对操作工人的危害，而且该晶体不易吸潮，长时间存放稳定。
N-乙基吡啶甲胺成盐后除杂效果极好，N-乙基吡啶甲胺三氟乙酸盐纯度及收率较高，如图1中的HPLC谱图所示，市售的N-乙基吡啶甲胺(图1上)在254nm 下，大于0.15％的杂质在10个以上，产品总纯度小于95.0％，其中含有较多亚胺中间体3以及其他与产品结构相似的有机杂质，通过常规纯化手段及精馏很难除去，而N-乙基吡啶甲胺成盐后，其晶体(图1)的纯度在99.8％以上，纯度高，杂质含量少，产品纯化收率大于95％以上，N-乙基吡啶甲胺成盐纯化能极大的降低能耗，提高产品纯度，降低产品成本，提升产品的竞争力，通过对关键起始物料质量及纯度的控制，能有效的提高托品酰胺的原料药质量及纯度，因此，N-乙基吡啶甲胺三氟乙酸盐是纯化N-乙基吡啶甲胺的最优选择。
本发明的另一目的是提供一种托品酰胺关键起始物料N-乙基吡啶甲胺三氟乙酸盐晶体的制备工艺，该工艺操作简单，无需蒸馏精致等大能耗操作，只需室温就能得到稳定晶型，操作方便，适合大规模工业生产制备。
为了实现上述目的，本发明采用的技术方案为：
一种托品酰胺关键起始物料N-乙基吡啶甲胺三氟乙酸盐，是将N-乙基吡啶甲胺溶于有机溶剂中，滴加三氟乙酸，过滤，烘干得到N-乙基吡啶甲胺三氟乙酸盐，其制备路线如式5所示：
所得到的托品酰胺关键起始物料N-乙基吡啶甲胺三氟乙酸盐结构式如式6所示：
一种托品酰胺关键起始物料N-乙基吡啶甲胺三氟乙酸盐的晶体，使用X-射线粉末衍射，所述晶体在约15.12°，15.45°，17.68°，20.68°，22.62°，23.25°， 24.75°，29.54°处有衍射峰；
进一步地，使用X-射线粉末衍射，所述晶体在约15.12°，15.45°，17.68°， 20.68°，20.98°，21.27°，22.62°，23.25°，24.75°，29.54°处有衍射峰。非限制性的，本发明的N-乙基吡啶甲胺三氟乙酸盐的晶体的一个典型的实例具有如图2所示的XRD图谱，该图谱特征见表1。
表1：
所述N-乙基吡啶甲胺三氟乙酸盐晶体的制备方法，包括如下步骤：
1)将N-乙基吡啶甲胺，溶于有机溶剂中，室温或者加热(如果需要)，搅拌至物料完全溶解；
2)缓慢加入三氟乙酸，析晶(如有需要，加晶种并梯度降温至0℃)；
3)保温陈化，过滤，干燥得到托品酰胺关键起始物料N-乙基吡啶甲胺三氟乙酸盐晶体。
所使用的酸为三氟乙酸，或三氟乙酸在有机溶剂的溶液。
所述的有机溶剂为醇类或者酯类溶剂等有机溶剂，包括乙腈，二氯甲烷等，所述的醇为C1-C4的醇类的一种或几种。
结晶过程：将N-乙基吡啶甲胺加入到有机溶剂，室温搅拌(如有需要，则加热至溶清)，再滴加三氟乙酸，析出固体后搅拌1-5小时，过滤，用少量有机溶剂淋洗。干燥既得N-乙基吡啶甲胺三氟乙酸盐晶体。
本发明中利用了N-乙基吡啶甲胺的弱碱性与三氟乙酸成盐，避免了蒸馏纯化等大能耗操作及损失，成功开发了托品酰胺关键起始物料N-乙基吡啶甲胺的三氟乙酸盐晶型，该晶体晶型规整均一，杂质含量少，纯度好，收率高，盐型不易潮，长时间存放稳定，并对晶型进行了表征。
本发明的盐型及晶型为首次报道。
有益效果：本发明制备N-乙基吡啶甲胺三氟乙酸盐晶体的方法操作简单，纯化效果明显，结晶制备得到的盐型及晶型杂质含量少，纯度高，有利于工业化生产。
附图说明
图1：N-乙基吡啶甲胺三氟乙酸盐与市售的N-乙基吡啶甲胺的HPLC谱图；
图2：N-乙基吡啶甲胺三氟乙酸盐的XRD谱图；
图3：N-乙基吡啶甲胺三氟乙酸盐的HPLC谱图。
具体实施方式
以下为实施例进一步说明本发明，但不应被理解为对本发明保护的限制。以下实施例采用如式7所示合成路线制备托品酰胺关键起始物料N-乙基吡啶甲胺三氟乙酸盐。
实施例1
制备化合物1：在5000mL的三口瓶中加入157.8g(1.4mol)4-吡啶甲醛， 2000mL无水乙醇，室温搅拌得到澄清溶液，冰水浴控制温度0-10℃，滴加 214.6g(1.5mol)66％浓度的乙胺水溶液，滴完，反应1-2小时，TLC点板中控，原料点消失视为反应完全，分批慢慢加入58.5g(1.5mol)硼氢化钠，加完，控制温度在10-25℃反应1-2小时，滴加300mL纯化水，室温搅拌过夜，TLC 中控，反应完全后，真空浓缩除去溶剂，加入2000mL水，2000mL二氯甲烷萃取，有机相用1500mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液真空浓缩，得到深黄色油状物192.5g，为N-乙基吡啶甲胺粗品，纯度81.5％，粗品收率96.3％。
50.2g粗品经过进一步减压蒸馏，可以得到28.1g浅黄色油状物，为N-乙基吡啶甲胺纯品，纯度94.8％，蒸馏收率为56.2％。
实施例2
制备化合物2：在50mL的三口瓶中加入3.25g(0.024mol)N-乙基吡啶甲胺纯品，20mL乙醇，室温搅拌得到浅黄色澄清溶液，缓慢滴加3.02g(0.026mol) 的三氟乙酸，滴完，室温搅拌1-5小时，过滤，滤饼用乙醇洗涤，真空干燥，得到白色晶体5.72g，纯度99.8％，收率95.8％。所得晶体具有如图2所示的 XRD图谱，该图谱特征见表1。
实施例3
制备化合物2：在50mL的三口瓶中加入3.05g(0.022mol)N-乙基吡啶甲胺纯品，30mL乙酸乙酯，室温搅拌得到浅黄色澄清溶液，缓慢滴加2.81g(0.026mol) 的三氟乙酸，滴完，室温搅拌1-5小时，过滤，滤饼用乙酸乙酯洗涤，真空干燥，得到白色晶体5.35g，纯度99.6％，收率95.5％。
实施例4
制备化合物2：在250mL的三口瓶中加入15.2g N-乙基吡啶甲胺粗品，100mL 乙腈，室温搅拌1小时，加热到60℃，得到黄色澄清溶液，缓慢滴加13.5g 的三氟乙酸，滴完，搅拌3-5小时，梯度降温至室温，搅拌1-3小时，降温至0-5℃，搅拌2-8小时，过滤，滤饼用正庚烷洗涤，真空干燥，得到白色晶体23.1g，纯度99.8％，收率：82.8％。
实施例5
制备托品酰胺(化合物7)：在250mL的三口瓶中加入20.4g(0.123mol)托品酸(化合物4),50mL甲苯,加热到50℃,加入0.3g(0.003mol)三乙胺,滴加 19.0g(0.24mol)乙酰氯,50℃反应3小时，滴加20.5g(0.17mol)二氯亚砜,继续反应5小时，真空浓缩至小体积，加入甲苯50mL，冷却至室温；在另一个500mL三口瓶中加入18.2g(0.134mol)N-乙基吡啶甲胺纯品(化合物1), 13.7g(0.136mol)三乙胺，100mL甲苯，冷却至0℃，滴加乙酰托品酸的溶液，0-10℃反应过夜，加入饱和食盐水80mL洗涤五次，有机相加入27g(0.23mol)31％盐酸，加热至90℃，反应过夜，分液，有机相分别用氨水，稀盐酸，饱和食盐水，纯化水洗涤，有机相50℃真空浓缩，浓缩液用乙酸乙酯/正庚烷重结晶，滤饼用正庚烷洗涤，真空干燥，得到26.5g托品酰胺，纯度98.8％，收率75.9％。
实施例6
制备托品酰胺(化合物7)：在250mL的三口瓶中加入14.5g(0.087mol)托品酸(化合物4),60mL甲苯,加热到50℃,加入0.2g(0.002mol)三乙胺,滴加13.7g (0.14mol)乙酰氯,50℃反应3小时，滴加14.8g(0.124mol)二氯亚砜,继续反应5 小时，真空浓缩至小体积，加入甲苯60mL，冷却至室温；在另一个500mL三口瓶中加入20.7g(0.087mol)N-乙基吡啶甲胺三氟乙酸盐(化合物2),8.8g(0.087mol) 三乙胺，80mL甲苯，冷却至0℃，滴加乙酰托品酸的溶液，0-10℃反应过夜，加入饱和食盐水60mL洗涤五次，有机相加入10.2g(0.14mol)31％盐酸，加热至 90℃，反应过夜，分液，有机相分别用氨水，稀盐酸，饱和食盐水，纯化水洗涤，有机相50℃真空浓缩，浓缩液用乙酸乙酯/正庚烷重结晶，滤饼用正庚烷洗涤，真空干燥，得到21.7g托品酰胺，纯度99.5％，收率87.5％。
Claims (9)
1.N-乙基吡啶甲胺三氟乙酸盐，其特征在于：是将N-乙基吡啶甲胺与三氟乙酸制备得到的N-乙基吡啶甲胺三氟乙酸盐，结构式如下所示：
2.N-乙基吡啶甲胺三氟乙酸盐的晶体，其特征在于：使用X-射线粉末衍射，所述晶体在约15.12°，15.45°，17.68°，20.68°， 22.62°，23.25°，24.75°，29.54°处有衍射峰。
3.权利要求2所述的N-乙基吡啶甲胺三氟乙酸盐的晶体，其特征在于：使用X-射线粉末衍射，所述晶体在约15.12°，15.45°，17.68°，20.68°，20.98°，21.27°，22.62°，23.25°，24.75°，29.54°处有衍射峰。
4.权利要求2或3所述的N-乙基吡啶甲胺三氟乙酸盐晶体的制备工艺，其特征在于：
1）、 将N-乙基吡啶甲胺，溶于有机溶剂中，室温或者加热，搅拌至物料完全溶解；
缓慢加入三氟乙酸，析晶；
2）、保温陈化，过滤，干燥得到N-乙基吡啶甲胺三氟乙酸盐晶体。
5.根据权利要求4所述的制备工艺，其特征在于：所述有机溶剂为醇类或者酯类溶剂。
6.根据权利要求4所述的制备工艺，其特征在于：步骤1）中所述N-乙基吡啶甲胺与有机溶剂的用量重量比范围为 1:2至1:20。
7.根据权利要求4所述的制备工艺，其特征在于：步骤2）中三氟乙酸的用量为N-乙基吡啶甲胺的0.5-1.5摩尔当量。
8.根据权利要求5所述的制备工艺，其特征在于：所述醇类溶剂为C1-C4的醇的一种或几种。
9.权利要求2或3所述的N-乙基吡啶甲胺三氟乙酸盐晶体在制备托品酰胺中的应用。
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