CN116375650A - 一种替戈拉生中间体的制备方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明提供一种替戈拉生中间体化合物的新的制备方法，以化合物5为原料，通过简单的化学反应可以得到中间体化合物1，进一步通过一步反应得到替戈拉生，反应步骤少，收率高。
Description
技术领域
本发明属于药物化学领域，具体涉及一种替戈拉生中间体的制备。
背景技术
替戈拉生，由CJ Health Care在韩国研发并于2018年7月在韩国成功上市销售，主要用于治疗胃食管反流疾病和糜烂性食管炎的治疗。替戈拉生的化学名为7-[[(4S)-5,7-二氟-3,4-二氢-2H-1-苯并吡喃-4-基]氧基]-N,N,2-三甲基-1H-苯并咪唑-5-甲酰胺，CAS号为942195-55-3，化学结构如下：
专利CN111303131A公开一种替戈拉生的制备方法，反应瓶中加入4-溴-N,N,2-三甲基-1H-苯并[d]咪唑-6-甲酰胺、(S)-5,7-二氟-3,4-二氢-2H-色原烯-4-醇、碘化亚铜、叔丁醇钠和N1,N2-双(苯基乙基)草酰二胺，氮气置换三次，然后加入无水N,N-二甲基甲酰胺,反应体系再次氮气置换三次。随后，搅拌加热至85℃反应24h。反应结束后，自然降至室温。加入乙酸乙酯稀释，剧烈搅拌0.5小时后通过硅藻土过滤。滤液减压下脱溶去除有机溶剂。残余物柱层析纯化(乙酸乙酯/庚烷)得到替戈拉生。具体合成路线如下：
在上述专利的替戈拉生合成过程中，并没有公开中间体4-溴-N,N,2-三甲基-1H-苯并[d]咪唑-6-甲酰胺的合成方法，现有技术中也没有记载该化合物的合成。因此需要开发一种合成该中间体的方法。
发明内容
基于上述技术问题，本发明提供一种替戈拉生中间体的制备方法，该中间体可用于合成替戈拉生，减少反应步骤，降低成本。
本发明提供一种替戈拉生中间体化合物的制备方法，中间体化合物为4-溴-N,N,2-三甲基-1H-苯并[d]咪唑-6-甲酰胺，结构式如式1所示：
中间体化合物式1的制备方法如下所示，包括化合物5经溴代、成环、中和反应得到化合物1。
优选的，溴代反应通过溴代试剂进行，溴代试剂包括N-溴代丁二酰亚胺。
优选的，成环反应为化合物4和乙酸在氯化亚锡作用下进行。
优选的，化合物3与二甲胺或其盐进行中和反应得到化合物1。
优选的，化合物3经水解反应得到化合物2后，再与二甲胺反应得到化合物1。
优选的，化合物3在碱性条件进行水解反应。
本发明提供的中间体化合物1可用于合成替戈拉生，包括将化合物1与化合物7，(S)-5,7-二氟-3,4-二氢-2H-色原烯-4-醇，反应得到替戈拉生。
本发明提供一种替戈拉生中间体式1的制备方法，可用于合成替戈拉生，相较于化合物专利合成替戈拉生的制备方法，减少反应步骤，降低成本，提高收率，有利于工业化生产。
附图说明
图1为化合物1的HPLC图谱；
图2为替戈拉生的HPLC图谱。
具体实施方式
以下结合附图实施例对本发明作进一步详细描述。
实施例1：
化合物4的合成：
在化合物6(10g)的乙腈(200mL)溶液中加入N-溴代丁二酰亚胺(10.02g)，此混合液在80℃下搅拌反应3小时，待反应完全后，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干得到黄色固体化合物5(12.98g,)。收率：92.6％。
实施例2：
化合物3的合成：
在化合物4(14.3g)的乙酸(50mL)溶液中加入氯化亚锡(29.57g),此混合液在80℃下搅拌反应5小时，待反应完全后，加入饱和碳酸氢钠调节pH至7-8，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤、旋干得到固体化合物3(12.51g)。收率：89.4％。
实施例3：
化合物2的合成
在化合物3(25g)的四氢呋喃/水/甲醇(350mL,4:2:1)溶液中加入NaOH(11.15g)，此混合液在60℃下搅拌反应过夜，加入6M HCl(55mL)调节pH至3，有大量固体析出，搅拌20min，过滤烘干，得到灰白色固体化合物2(22.46g)。收率：94.8％。
实施例4：
化合物1的合成：
在化合物2(23.7g)的二氯甲烷(600mL)溶液中加入三乙胺(28.21g)、2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯(52.99g)和盐酸二甲胺(9.09g)，此混合液在室温下搅拌反应过夜，用二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干得到浅黄色固体化合物1(23.60g)。收率：90.3％。
实施例5：
化合物1的合成：
在化合物3(25g)的四氢呋喃/水/甲醇(350mL,4:2:1)溶液中加入二甲胺(8.98g)、甲醇钠(27.5g)和氨基钠(28.7g)，在室温下搅拌反应过夜，用二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，旋干得到浅黄色固体化合物1(22.5g)。收率：88.7％
实施例6：
替戈拉生的合成：
在反应瓶中加入化合物1(2.4g)、化合物7(2.3g)、碘化亚铜(100mg)、叔丁醇钠(1.5g)和N,N-双(苯基乙基)草酰二胺(150mg)，在氮气气氛下，加入无水的N,N-二甲基甲酰胺(15mL)，搅拌加热至85℃，反应24h。反应结束后，降至室温，加入乙酸乙酯搅拌，硅藻土过滤，减压蒸馏除去溶剂，柱层析纯化得到白色固体替戈拉生。收率：87％。
Claims (9)
1.一种替戈拉生中间体化合物的制备方法，其特征在于化合物5经溴代、成环、中和反应得到化合物1，
2.根据权利要求1所述的制备方法，其特征在于，化合物5与溴代试剂进行溴代反应得到化合物4。
3.根据权利要求2所述的制备方法，其特征在于，溴代试剂包括N-溴代丁二酰亚胺。
4.根据权利要求1所述的制备方法，其特征在于，化合物4和乙酸在氯化亚锡作用下进行成环反应得到化合物3。
5.根据权利要求1所述的制备方法，其特征在于，化合物3与二甲胺或盐反应得到化合物1。
6.根据权利要求5所述的制备方法，其特征在于，化合物3经水解反应得到化合物2后，再与二甲胺反应得到化合物1。
7.根据权利要求1所述的制备方法，其特征在于，化合物3在碱性条件进行水解反应。
8.根据权利要求1所述的制备方法制备得到的化合物1用于制备替戈拉生的用途。
9.一种替戈拉生的制备方法，其特征在于使用根据权利要求1所述的制备方法得到的化合物1与化合物7进行反应，
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