CN115108993A - 一种盐酸右美托咪定的手性催化合成方法 - Google Patents
一种盐酸右美托咪定的手性催化合成方法 Download PDFInfo
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
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- B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
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Abstract
本发明公开了一种盐酸右美托咪定的手性催化合成方法，所述合成方法主要包括以下内容：在有机溶剂中，在加氢催化剂和手性配体的共同作用下，用氢气进行还原，化合物5‑[1‑(2,3‑二甲基苯基)乙烯基]‑1H‑咪唑发生不对称氢化还原反应，得到化合物右美托咪定，再成盐酸盐得到盐酸右美托咪定。本发明采用碳碳加氢还原催化剂和R‑(+)‑2,2’‑双(二苯基膦)‑1,1'‑联萘(R‑BINAP)的组合对5‑[1‑(2,3‑二甲基苯基)乙烯基]‑1H‑咪唑(式I化合物)进行手性催化还原，得到对映体过量百分数可达99.0％的产品，一步产率可达93.0％，相比现有技术产率大幅度提高，且产品无需手性拆分，能避免产品浪费，符合绿色环保理念，适合工业化生产。
Description
技术领域
本发明属于药物制备技术领域，具体而言涉及一种盐酸右美托咪定的手性催化合成方法。
背景技术
盐酸右美托咪定(Dexmedetomidine Hydrochloride)是由Orion Pharma公司(芬兰)/Abott公司(美)合作开发的一种高效的α2肾上腺素受体拮抗剂，通过作用于两种肾上腺素受体而具有抗交感、镇痛和镇静作用。对肾上腺素受体的亲和力比可乐定8倍，半衰期短、有效剂量小，适用于重症监护治疗期间开始插管和使用呼吸机患者的镇静。其化学名为(R)-4-[l-(2,3-二甲基苯基)乙基]-l-H-咪唑单盐酸盐，结构式如下:
目前公开的盐酸右美托咪定的合成方法，以美托咪定作为原料进行手性拆分的方法居多。手性拆分的方法，缺点是成本较高，拆分剩余的另外一个构型左美托咪定成为废弃物，不符合原子经济的原则。
中国专利CN102232公开了用D-(-)-酒石酸拆分美托咪定衍生物的方法，W09715302用L-(+)-酒石酸代替D-(-)-酒石酸，通过重复结晶得到了右美托咪定。这类方法操作过程复杂，不利于工业化放大，且产品质量不稳定。
中国专利CN103694175公开了一种用(+)-二苯甲酰酒石酸拆分美托咪定的方法，但是该方法难以得到高纯度的右美托咪定。
中国专利CN105254567公开了一种用L-(+)-酒石酸拆分美托咪定的方法，尽管该专利公开的方法操作方便，但是收率较低，产业化价值不大。
发明内容
针对现有技术的不足，本发明的目的在于提供一种盐酸右美托咪定的手性催化合成方法，该方法采用高效的手性催化剂，操作简便、产率高、手性纯度高，适合进行工业化应用和生产；克服了传统拆分方法中收率低、手性纯度不高的问题。
本发明解决技术问题所采用的技术方案是：一种盐酸右美托咪定的手性催化合成方法，所述合成方法主要包括以下内容：在有机溶剂中，在加氢催化剂和手性配体的共同作用下，用氢气进行还原，化合物5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑发生不对称氢化还原反应，得到化合物右美托咪定，再成盐酸盐得到盐酸右美托咪定。
进一步地，所述合成方法中，5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑、加氢催化剂、手性配体的用量比为1：0.01～0.015：0.013。
进一步地，所述有机溶剂为甲醇、乙醇、异丙醇中的任意一种，或其中任意两种溶剂任意比例的混合物，或三种溶剂任意比例的混合物。优选地，所述有机溶剂为甲醇。
进一步地，所述加氢催化剂为氯化钯、二氧化铂、三苯基膦氯化钯中的任意一种或多种。优选地，所述加氢催化剂为氯化钯。
进一步地，所述手性配体是R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)。
进一步地，所述氢气的加氢压力为0.1～3Mpa。
更进一步地，所述氢气的加氢压力为0.5～2Mpa。
优选地，所述氢气的加氢压力为1.5Mpa。
本发明的合成方法中涉及的反应式如下：
本发明的有益效果是：与现有技术相比，本发明提供的一种盐酸右美托咪定的手性催化合成方法，发明人经过广泛而深入的研究，通过大量筛选和测试，采用碳碳加氢还原催化剂和R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)的组合对5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑(式I化合物)进行手性催化还原，得到对映体过量百分数可达99.0％的产品，一步产率可达93.0％，相比现有技术产率大幅度提高，且产品无需手性拆分，能避免产品浪费，符合绿色环保理念，适合工业化生产。
附图说明
图1为实施例1中得到的产物的HPLC谱图。
图2为实施例1中得到的产物的手性谱图。
图3为实施例2中得到的产物的HPLC谱图。
图4为实施例2中得到的产物的手性谱图。
图5为实施例3中得到的产物的HPLC谱图。
图6为实施例3中得到的产物的手性谱图。
图7为实施例4中得到的产物的HPLC谱图。
图8为实施例4中得到的产物的手性谱图。
图9为实施例5中得到的产物的HPLC谱图。
图10为实施例5中得到的产物的手性谱图。
图11为实施例2中得到的产物的LC-MS谱图。
具体实施方式
下面通过具体实施例来进一步说明本发明。但这些实例仅用于说明本发明而不用于限制本发明的范围。
术语：除非另有定义，否则本文中所用的全部技术术语和科学术语均具有如本发明所属领域普通技术人员通常理解的相同含义。
如本文所用，术语“盐酸右美托咪定”与“式II化合物”可互换使用，指盐酸右美托咪定(右美托咪定盐酸盐)。术语“5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑”与“式I化合物”可互换使用，指5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑。
催化剂组合物包括:碳碳加氢还原催化剂和R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)。
实施例1
将5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑(式I化合物)(10.0g，0.05mol)溶于甲醇(50ml)中，加入氯化钯(0.1g)，R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)(0.13g)，通入氢气(0.1MPa)，25℃搅拌反应4h，HPLC监测反应结束，过滤，收集滤液，减压浓缩至3v体积，再加入15％HCl-EtOH溶液(14.6g，1.2eq)，滴加甲基叔丁基醚(900ml)析晶，过滤得白色固体即为右美托咪定盐酸盐(式II化合物)，烘干得10.06g。收率：85.0％，HPLC纯度99.81％，手性纯度99.96％。元素分析：理论值C，65.95；H，7.24；N，11.83。实测值C，65.97；H，7.23；N，11.83。
实施例2
将式I化合物(10.0g，0.05mol)溶于乙醇(50ml)中，加入氯化钯(0.1g)，R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)(0.13g)，通入氢气(1.5MPa)，25℃搅拌反应4h，HPLC监测反应结束，过滤，收集滤液，减压浓缩至3v体积，再加入15％HCl-EtOH溶液(14.6g，1.2eq)，滴加甲基叔丁基醚(900ml)析晶，过滤得白色固体即为右美托咪定盐酸盐，烘干得11.00g。收率：93.0％，HPLC纯度99.80％，手性纯度99.97。元素分析：理论值C，65.95；H，7.24；N，11.83。实测值C，65.96；H，7.24；N，11.83。
实施例3
将式I化合物(10.0g，0.05mol)溶于甲醇(50ml)中，加入氯化钯(0.1g)，R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)(0.13g)，通入氢气(3MPa)，25℃搅拌反应4h，HPLC监测反应结束，过滤，收集滤液，减压浓缩至3v体积，再加入15％HCl-EtOH溶液(14.6g，1.2eq)，降温至0℃，滴加甲基叔丁基醚(900ml)析晶，过滤得白色固体即为右美托咪定盐酸盐，烘干得10.38g。收率：87.7％，HPLC纯度99.83％，手性99.97％。元素分析：理论值C，65.95；H，7.24；N，11.83。实测值C，65.95；H，7.23；N，11.85。
实施例4
将式I化合物(10.0g，0.05mol)溶于乙醇(50ml)中，加入二氧化铂(0.15g)，R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)(0.13g)，通入氢气(1.5MPa)，25℃搅拌反应4h，HPLC监测反应结束，过滤，收集滤液，减压浓缩至3v体积，再加入15％HCl-EtOH溶液(14.6g，1.2eq)，降温至0℃，滴加甲基叔丁基醚(900ml)析晶，过滤得白色固体即为右美托咪定盐酸盐，烘干得9.71g。收率：82.0％，HPLC纯度99.60％，手性纯度99.95％。元素分析：理论值C，65.95；H，7.24；N，11.83。实测值C，65.95；H，7.22；N，11.86。
实施例5
将式I化合物(10.0g，0.05mol)溶于乙醇(50ml)中，加入三苯基膦氯化钯(0.1g)，R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)(0.13g)，通入氢气(1.5MPa)，25℃搅拌反应4h，HPLC监测反应结束，过滤，收集滤液，减压浓缩至3v体积，再加入15％HCl-EtOH溶液(14.6g，1.2eq)，降温至0℃，滴加甲基叔丁基醚(900ml)析晶，过滤得白色固体即为右美托咪定盐酸盐，烘干得9.60g。收率：81.1％，HPLC纯度99.61％，手性99.95％。元素分析：理论值C，65.95；H，7.24；N，11.83。实测值C，65.94；H，7.23；N，11.85。
综上，本发明的盐酸右美托咪定制备方法中，采用碳碳双键加氢还原催化剂和R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)的组合物对式I化合物进行手性催化，能得到对映体过量百分数可达99.0％的产品，一步产率可达93.0％，能有效节约成本，提高产率，且产品无需手性拆分，后处理简单，能避免产品浪费，符合绿色环保理念，适合工业化生产。
以上实施方式仅用于说明本发明，而并非对本发明的限制，有关技术领域的普通技术人员，在不脱离本发明的精神和范围的情况下，还可以做出各种变化和变型，因此所有等同的技术方案也属于本发明的范畴，本发明的专利保护范围应由权利要求限定。
Claims (8)
1.一种盐酸右美托咪定的手性催化合成方法，其特征在于，所述合成方法主要包括以下内容：在有机溶剂中，在加氢催化剂和手性配体的共同作用下，用氢气进行还原，化合物5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑发生不对称氢化还原反应，得到化合物右美托咪定，再成盐酸盐得到盐酸右美托咪定。
2.如权利要求1所述的一种盐酸右美托咪定的手性催化合成方法，其特征在于：所述合成方法中，5-[1-(2,3-二甲基苯基)乙烯基]-1H-咪唑、加氢催化剂、手性配体的用量比为1：0.01～0.015：0.013。
3.如权利要求1所述的一种盐酸右美托咪定的手性催化合成方法，其特征在于：所述有机溶剂为甲醇、乙醇、异丙醇中的任意一种，或其中任意两种溶剂任意比例的混合物，或三种溶剂任意比例的混合物。
4.如权利要求1所述的一种盐酸右美托咪定的手性催化合成方法，其特征在于：所述加氢催化剂为氯化钯、二氧化铂、三苯基膦氯化钯中的任意一种或多种。
5.如权利要求1所述的一种盐酸右美托咪定的手性催化合成方法，其特征在于：所述手性配体是R-(+)-2,2’-双(二苯基膦)-1,1'-联萘(R-BINAP)。
6.如权利要求1所述的一种盐酸右美托咪定的手性催化合成方法，其特征在于：所述氢气的加氢压力为0.1～3Mpa。
7.如权利要求6所述的一种盐酸右美托咪定的手性催化合成方法，其特征在于：所述氢气的加氢压力为0.5～2Mpa。
8.如权利要求7所述的一种盐酸右美托咪定的手性催化合成方法，其特征在于：所述氢气的加氢压力为1.5Mpa。
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