CN105884692A - 5位取代手性海因的制备方法 - Google Patents
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- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
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Abstract
本发明公开了一种乙内酰脲衍生的环外烯烃的不对称催化氢化直接制备5位取代手性海因化合物的方法。5位取代手性海因化合物的化学结构式用式(I)表示:本发明的化学反应方程式如下:
Description
技术领域
本发明涉及一种5位取代手性海因化合物的制备方法。
背景技术
海因(乙内酰脲)最早由Baeyer于1861年通过尿囊素加氢而获得。科学家通过各种途径发现或者合成了大量海因衍生物,很多这类衍生物具有独特的药理和生物活性,被广泛的应用于医药、农药等领域。近年来。随着手性科学的发展,科学家们也发现和合成了许多具有单一手性的海因衍生物,很多这些化合物都表现出了优异的生物活性。因此高效的合成手性海因化合物不仅具有重要的科学意义,同时还具有重要的应用价值。迄今为止,文献已经报道了几类有效合成手性海因化合物的方法,其中主要包括手性拆分法、酶催化法、定向合成法等(Bulletin des Societes Chimiques Belges,96(6),459-65;1987;Biotechnology Letters,14(2),99-104;1992;Chemistry Letters,32(4),372-373;2003;Journal of Labelled Compounds andRadiopharmaceuticals,54(2),110-114;2011;Journal of Organic Chemistry,79(21),10132-10142;2014)。这些方法反应步骤长,原子利用率低,不易于工业化。
发明内容
本发明提供一种乙内酰脲衍生的环外烯烃的不对称催化氢化直接制备5位取代手性海因化合物的方法。5位取代手性海因化合物的化学结构式如式(I)所示:
式(I)中:
R是H或C1~C8烷基、C1~C8取代烷基、苯基、取代苯基、杂环芳基、取代杂环芳基。5位手性碳原子的构型是R或S,或者是R/S任意比例的混合物。
本发明的化学反应方程式如下:
反应式中化合物(Ⅱ)为乙内酰脲衍生的环外烯烃,其中,R是H、C1~C8烷基、C1~C8取代烷基、苯基、取代苯基、杂环芳基、取代杂环芳基。所述烯烃的构型可以是Z式或E式或Z式E式任何比例的混合物。(Ⅱ)可以由公开报道的文献方法制备(Molecules,18,5142-5154;2013;Tetrahedron,67(45),8639-8647;2011;Journal of Organic Chemistry,80(8),3929-3939;2015)。
反应式中化合物(Ⅲ)为催化剂,催化剂是手性双膦配体的金属配合物。手性双膦配体包括BINAP或BINAPO,H8-BINAP,P-Phos,,MeO-BINAP,SEGPhos,Cn-TunaPhos,SDP。M是金属铑离子或钯离子。配阴离子L是卤素根或醋酸根、三氟醋酸根、四氟硼根、六氟磷根、磷酸根。所述催化剂(Ⅲ)与底物(Ⅱ)的摩尔比是0.01%-10%︰1。催化剂(Ⅲ)可以提前制备,制备方法是将手性配体与相应的金属盐在合适溶剂中配位,配位完毕后脱除溶剂,得到相应催化剂(Ⅲ);催化剂(Ⅲ)也可以在反应体系中原位生成,即将手性配体和相应金属盐直接添加到反应体系中(Journal of Organic Chemistry,59,3064-3076;1994;Journal ofAmerican Chemistry Society,132(26),8909-8911)。手性双膦配体的化学结构式如下:
反应在酸性添加剂存在下有效进行,酸性添加剂包括醋酸或三氟醋酸、樟脑磺酸、磷酸。酸性添加剂与催化剂的摩尔比是0.1-10︰1。
反应在极性溶剂中进行,极性溶剂是指甲醇、乙醇、三氟乙醇、异丙醇、全氟异丙醇、二甲基亚砜中的一种或者两种混合物。
反应温度为10-100℃。反应压力为0.1-10MPa。
本发明通过乙内酰脲衍生的环外烯烃的不对称催化氢化技术,直接制备得到5位取代手性海因化合物。本发明与现有技术相比具有手性增殖、高效高选择性、原子经济性、绿色无污染、易于工业化等特点。
以下通过具体的实施例对本发明上述的内容作进一步的详细说明,但本发明不局限于实施例。
具体实施方式
实施例1
在带磁子的玻璃试管中加入188mg 5-亚苄基海因(1mmol),7.5mg(R)-BINAP(0.012mmol),3.3mg三氟醋酸钯(0.01mmol),7.0mg(S)-1,1'-联萘基-2,2'-双磷酸氢酯(0.02mmol)。氮气保护下加入10mL乙醇,充入3MPa氢气,60℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(乙醇/石油醚=1/2,v/v)重结晶。过滤后得产品175mg,收率93.1%,纯度96.6%,对映选择性(ee)为46%。
实施例2
在带磁子的玻璃试管中加入202mg 5-(2-甲基-亚苄基)-海因(1mmol),7.5mg(R)-BINAP(0.012mmol),2.3mg醋酸钯(0.01mmol),12mg(S)-3,3'-(1-萘基)-1,1'-联萘基-2,2'-双磷酸氢酯(0.02mmol)。氮气保护下加入10mL三氟乙醇,充入5MPa氢气,70℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(乙醇/石油醚=1/2,v/v)重结晶。过滤后得产品185mg,收率90.7%,纯度97.2%,对映选择性(ee)为90%。
实施例3
在带磁子的玻璃试管中加入218mg 5-(2-甲氧基-亚苄基)-海因(1mmol),7.0mg(R)-SDP(0.012mmol),3.3mg三氟醋酸钯(0.01mmol),9.2mg(S)-樟脑磺酸(0.04mmol)。氮气保护下加入10mL全氟异丙醇,充入2MPa氢气,80℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(乙醇/石油醚=1/2,v/v)重结晶。过滤后得产品205mg,收率93.2%,纯度95.7%,对映选择性(ee)为88%。
实施例4
在带磁子的玻璃试管中加入189mg 5-(3-吡啶叉基)-海因(1mmol),7.5mg(S)-BINAP(0.012mmol),3.3mg醋酸钯(0.01mmol),72mg醋酸(1.2mmol)。氮气保护下加入10mL二甲基亚砜,充入5MPa氢气,50℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(乙醇/石油醚=1/2,v/v)重结晶。过滤后得产品154mg,收率80.6%,纯度98.1%,对映选择性(ee)为49%。
实施例5
在带磁子的玻璃试管中加入140mg 5-丙叉基海因(1mmol),7.3mg(R)-SEGPhos(0.012mmol),3.3mg三氟醋酸钯(0.01mmol),12mg(S)-3,3'-(1-萘基)-1,1'-联萘基-2,2'-双磷酸氢酯(0.02mmol)。氮气保护下加入10mL全氟异丙醇,充入2MPa氢气,40℃反应6小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(甲醇/石油醚=1/2,v/v)重结晶。过滤后得产品125mg,收率88.0%,纯度93.6%,对映选择性(ee)为67%。
实施例6
在带磁子的玻璃试管中加入204mg 5-(4-羟基-亚苄基)-海因(1mmol),7.5mg(R)-BINAP(0.012mmol),3.3mg三氟醋酸钯(0.01mmol),4.6mg(S)-樟脑磺酸(0.02mmol)。氮气保护下加入10mL全氟异丙醇,充入4MPa氢气,80℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(乙醇/石油醚=1/1,v/v)重结晶。过滤后得产品195mg,收率94.7%,纯度95.5%,对映选择性(ee)为57%。
实施例7
在带磁子的玻璃试管中加入222mg 5-(4-氯-亚苄基)-海因(1mmol),7.5mg(R)-BINAP(0.012mmol),3.3mg三氟醋酸钯(0.01mmol),2.4mg三氟醋酸(0.02mmol)。氮气保护下加入10mL三氟乙醇,充入6MPa氢气,80℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(乙醇/石油醚=1/1,v/v)重结晶。过滤后得产品201mg,收率89.7%,纯度96.8%,对映选择性(ee)为45%。
实施例8
在带磁子的玻璃试管中加入232mg 5-(2-乙氧基-亚苄基)-海因(1mmol),7.5mg(R)-BINAP(0.012mmol),4.1mg双(1,5-环辛二烯)铑四氟化硼盐(0.01mmol),7.0mg(S)-1,1'-联萘基-2,2'-双磷酸氢酯(0.02mmol)。氮气保护下加入10mL三氟乙醇,充入2MPa氢气,50℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(甲醇/石油醚=1/1,v/v)重结晶。过滤后得产品221mg,收率94.4%,纯度93.7%,对映选择性(ee)为62%。
实施例9
在带磁子的玻璃试管中加入260mg 5-(2-丁氧基-亚苄基)-海因(1mmol),7.8mg(R)-BINAPO(0.012mmol),4.1mg双(1,5-环辛二烯)铑四氟化硼盐(0.01mmol),6.0mg醋酸(0.1mmol)。氮气保护下加入10mL甲醇,充入10MPa氢气,10℃反应24小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(甲醇/石油醚=1/1,v/v)重结晶。过滤后得产品244mg,收率93.1%,纯度94.9%,对映选择性(ee)为67%。
实施例10
在带磁子的玻璃试管中加入222mg 5-(3-氯-亚苄基)-海因(1mmol),7.0mg(S)-MeOBIPHEP(0.012mmol),3.3mg三氟醋酸钯(0.01mmol),7.0mg(R)-1,1'-联萘基-2,2'-双磷酸氢酯(0.02mmol)。氮气保护下加入10mL异丙醇,充入0.1MPa氢气,60℃反应8小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(甲醇/石油醚=1/1,v/v)重结晶。过滤后得产品201mg,收率89.7%,纯度96.6%,对映选择性(ee)为48%。
实施例11
在带磁子的玻璃试管中加入222mg 5-(2-氯-亚苄基)-海因(1mmol),7.7mg(R)-P-Phos(0.012mmol),3.3mg三氟醋酸钯(0.01mmol),7.0mg(S)-1,1'-联萘基-2,2'-双磷酸氢酯(0.02mmol)。氮气保护下加入10mL三氟乙醇,充入5MPa氢气,100℃反应6小时。反应结束后,自然冷却至室温,小心放掉氢气,脱去大部分有机溶剂,加入5mL溶剂(甲醇/石油醚=1/1,v/v)重结晶。过滤后得产品211mg,收率94.2%,纯度97.8%,对映选择性(ee)为52%。
Claims (2)
1.制备5位取代手性海因化合物的方法,其特征在于通过乙内酰脲衍生的环外烯烃的不对称催化氢化法直接制备得到,5位取代手性海因化合物的化学结构式如式(I)所示:
式(I)中:
R是H或C1~C8烷基、C1~C8取代烷基、苯基、取代苯基、杂环芳基、取代杂环芳基;5位手性碳原子的构型是R或S,或者是R/S任意比例的混合物,
化学反应方程式如下:
反应式中化合物(Ⅱ)为乙内酰脲衍生的环外烯烃,其中,R是H、C1~C8烷基、C1~C8取代烷基、苯基、取代苯基、杂环芳基、取代杂环芳基;
反应式中化合物(Ⅲ)为催化剂,催化剂是手性双膦配体的金属配合物,手性双膦配体包括BINAP或BINAPO,H8-BINAP,P-Phos,,MeO-BINAP,SEGPhos,Cn-TunaPhos,SDP;M是金属铑离子或钯离子;配阴离子L是卤素根或醋酸根、三氟醋酸根、四氟硼根、六氟磷根、磷酸根;手性双膦配体的化学结构式如下:
所述催化剂(Ⅲ)与乙内酰脲衍生的环外烯烃(II)的投料摩尔比是0.0.01%-10%︰1;
反应在酸性添加剂存在下进行,所述酸性添加剂包括醋酸或三氟醋酸、樟脑磺酸、磷酸,酸性添加剂与催化剂的投料摩尔比是0.1-10︰1;
反应在极性溶剂中进行,所述极性溶剂是指甲醇、乙醇、三氟乙醇、异丙醇、全氟异丙醇、二甲基亚砜中的一种或者两种混合物;
反应温度为10-100℃,反应压力为0.1-10MPa。
2.根据权利要求1所述制备5位取代手性海因化合物的方法,其特征在于所述烯烃的构型是Z式或E式或Z式E式任何比例的混合物。
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CN112574014A (zh) * | 2019-09-29 | 2021-03-30 | 中国科学院大连化学物理研究所 | 一种钯催化不对称还原合成手性β-羟基酮的方法 |
CN112574014B (zh) * | 2019-09-29 | 2022-03-11 | 中国科学院大连化学物理研究所 | 一种钯催化不对称还原合成手性β-羟基酮的方法 |
CN112358379A (zh) * | 2020-11-09 | 2021-02-12 | 南方科技大学 | 一种光学纯s构型1,1-双-(4-氟苯基)-2-丙醇的制备方法 |
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