CN113831205A - 一种手性吡唑啉酮化合物的制备方法 - Google Patents

一种手性吡唑啉酮化合物的制备方法 Download PDF

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CN113831205A
CN113831205A CN202111254649.2A CN202111254649A CN113831205A CN 113831205 A CN113831205 A CN 113831205A CN 202111254649 A CN202111254649 A CN 202111254649A CN 113831205 A CN113831205 A CN 113831205A
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孙振亮
王林琳
孙奇奇
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Shanghai University of Medicine and Health Sciences
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Abstract

本发明提供了一种手性吡唑啉酮化合物的制备方法，将吡唑啉酮亚胺与N‑烷基芳胺溶于溶剂中，在手性磷酸催化剂的作用下发生不对称N烷基化反应，制备得到C‑4位双氮杂季碳中心手性吡唑啉酮化合物；手性吡唑啉酮化合物的化学结构式为：

Description

一种手性吡唑啉酮化合物的制备方法
技术领域
本发明属于有机化学领域，涉及一种吡唑啉酮化合物，尤其是一种手性吡唑啉酮化合物的制备方法。
背景技术
具有N,N-缩醛胺片段的分子，即有两个不同的含氮官能团连接到同一个碳原子上，是一类非常重要的手性胺分子化合物，在药物化学和合成化学领域发挥着重要作用。如Bendroflumethiazide是临床上应用广泛的利尿药。光学纯度的咪唑啉酮化合物是有机合成中应用广泛的砌块，常常被设计成各种手性催化剂和手性助剂。而非环系的N,N-缩醛胺结构往往通过引入吸电子基团来稳定电荷的分布，这类结构同样表现出了很多特殊的生理活性，如在多肽链中发现的PMRI可以改变多肽类药物的药理活性和化学性质。由于非环系N,N-缩醛胺结构的不稳定性，其在合成方法上存在很大的挑战。
Figure BDA0003323482590000011
C-4位季碳中心吡唑啉酮化合物的合成，大部分利用的是C-4位的亲核性实现全碳季碳中心的构筑，这一方面的工作已经发展的相当成熟(Chem.Commun.,2015,51,12890-12907，Chem.Commun.,2018,54,11515-11529，Synthesis 2020,52,215-237)。对于含有杂原子取代的手性季碳中心的研究仍存在很多局限性，其原因可能由于含有杂原子的试剂本身就有亲核性，在电性上不匹配。另一方面，简单芳胺化合物的直接官能团化比较困难，这是由于芳胺在反应过程中有多个反应位点，很难通过直接官能团化的方法控制反应的区域选择性。利用预装导向基策略实现氨基邻位的官能团化反应，导向基的引入增加了合成步骤并限制了应用扩展。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种芳胺的直接不对称N烷基化反应，通过有机小分子催化剂实现了C-4位双氮杂季碳中心手性吡唑啉酮化合物的合成，可以很好地控制苯胺反应的区域选择性。
本发明的目的可以通过以下技术方案来实现：
一种手性吡唑啉酮化合物的制备方法，将吡唑啉酮亚胺与N-烷基芳胺溶于溶剂中，在手性磷酸催化剂的作用下发生不对称N烷基化反应，制备得到C-4位双氮杂季碳中心手性吡唑啉酮化合物；
所述吡唑啉酮亚胺的化学结构式为：
Figure BDA0003323482590000021
所述N-烷基芳胺的化学结构式为：
Figure BDA0003323482590000022
所述手性磷酸催化剂的结构式如下所示：
Figure BDA0003323482590000023
其中，R选自H或取代芳基；R1选自芳基；R2选自烷基；R3选自芳基；
所述手性磷酸催化剂、吡唑啉酮亚胺、芳胺化合物的摩尔比为0.02-0.2:1.0:1.0-1.5；
制备得到的手性吡唑啉酮化合物的化学结构式为：
Figure BDA0003323482590000024
进一步的，所述溶剂选自二氯甲烷、二氯乙烷、甲苯或四氢呋喃中的一种或任意两种或以上的组合。所述溶剂优选四氢呋喃。
进一步的，所述的取代芳基为各种卤素(F,Cl,Br)取代的芳基和烷基取代的芳基，所述的芳基为苯基、邻甲苯基、1-萘基或者2-萘基等等，所述的烷基为甲基或者乙基。
进一步的，所述吡唑啉酮亚胺在溶剂中的浓度为0.02～0.2mol/L。
进一步的，反应的温度控制在室温，时间为6～20h。
具体的，合成路线如下：
Figure BDA0003323482590000031
将制备得到的吡唑啉酮化合物I可以经过简单的转化得到新型的螺环吡唑啉酮化合物II，该化合物与具有强心作用的化合物(结构式参考下A)含有类似的核心骨架，为后期药物开发提供了新的思路。
Figure BDA0003323482590000032
与现有技术相比，本发明具有以下特点：
1)本发明采用有机小分子催化剂，无需金属催化剂的参与，有利于后续的分离提纯，简化衍生的步骤。
2)反应条件相对简单，催化剂的用量小，化学产率较高，对映选择性好，为吡唑啉酮类化合物的合成提供了新的思路。
3)本发明可以达到96％的产率和99％的对映选择性。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
本实施方式中，化合物的氢核磁共振谱(1H NMR)由Bruker AVANCE III HD 400或Bruker AVANCE III HD 500测定；质谱(ESI-MS)由Waters ACQUITYTM UPLC&Q-TOF MSPremier测定；所用试剂均为市售试剂。吡唑啉酮化合物根据文献方法(J.Org.Chem.2017,82,7050-7058)合成制备。
本发明的合成方法可以制备如下所示的吡唑啉酮类化合物：这种含有季碳中心结构的吡唑啉酮化合物在临床上应用广泛，结构式参考下结构式B,C，其合成路线相对繁琐，并且无法实现对手性中心的不对称合成(Biochem.Biophys.Res.Commun.2004,320,1351；Cytologia 2010,75,177；J.Heterocycl.Chem.2007,44,49)。但是这类结构的化合物在临床上表现出良好的生理活性，如化合物B显示出良好的抑制伤寒杆菌、金黄色葡萄球菌和大肠杆菌的活性。
Figure BDA0003323482590000041
实施例1
化合物3的制备
Figure BDA0003323482590000051
将手性磷酸(0.7mg,1mol％)，氮甲基苯胺S1-1(10.7mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S-2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物3，产率96％。
Yellow solid.37.8mg,96％yield.96％ee.[α]20 D+92.71(c 1,CHCl3).m.p.99-101℃.HPLC(Daicel Chiralpak AD-H,hexane/i-PrOH＝80:20,1.0mL/min,254nm):tR(major)＝4.9min,tR(minor)＝7.5min.1H NMR(400MHz,Acetone-d6):δ7.83(d,J＝8.0Hz,2H),7.39(t,J＝8.0Hz,2H),7.25-7.14(m,6H),2.98(s,3H),1.89(s,3H),1.33(s,9H).13CNMR(100MHz,Acetone-d6)δ168.95,147.07,138.50,128.80,128.50,127.15,126.75,124.24,118.01,79.76,77.59,36.13,27.38,12.95.HRMS(ESI)m/z:[M+Na]+calculatedfor C22H27N4O3Na 417.1903,found 417.1918.
Figure BDA0003323482590000052
实施例2，化合物4的制备
将手性磷酸(0.7mg,1mol％)，4-甲基氮甲基苯胺S1-2(12.1mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物4。
Figure BDA0003323482590000053
NMR(400MHz,Acetone-d6):δ7.84(d,J＝8.0Hz,2H),7.41-7.37(m,2H),7.18-7.11(m,3H),7.04(d,J＝8.0Hz,2H),2.94(s,3H),2,24(s,3H),1.89(s,3H),1.33(s,9H).13C NMR(100MHz,Acetone-d6)δ169.96,157.85,154.52,154.32,145.42,139.51,137.50,130.30,129.45,128.03,125.15,118.96,118.82,80.53,78.56,37.16,28.31,20.90,13.86.HRMS(ESI)m/z:[M+Na]+calculated for C23H28N4O3Na 431.2059,found 431.2071.
实例3，化合物5的制备
将手性磷酸(0.7mg,1mol％)，4-甲氧基氮甲基苯胺S1-3(13.7mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物5。
Figure BDA0003323482590000061
(m,2H),7.17-7.15(m,3H),6.77(d,J＝8.0Hz,2H),3.71(s,3H),2.92(s,3H),1.89(s,3H),1.33(s,9H).13C NMR(100MHz,Acetone-d6)δ169.96,159.41,158.00,154.39,140.52,139.50,129.44,129.40,125.13,118.94,115.43,114.75,113.72,80.64,78.64,55.59,37.29,28.31,13.84.HRMS(ESI)m/z:[M+Na]+calculated for C23H28N4O4Na447.2008,found447.2019.
实例4，化合物6的制备
将手性磷酸(0.7mg,1mol％)，4-溴氮甲基苯胺S1-4(18.4mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物6。
Figure BDA0003323482590000062
(m,4H),7.24-7.22(m,2H),7.19-7.15(m,1H),2.96(s,3H),1.95(s,3H),1.33(s,9H).13CNMR(126MHz,Acetone-d6)δ169.69,157.86,154.40,147.29,139.30,132.70,129.98,129.48,125.33,120.20,119.03,80.79,78.45,37.04,28.29,13.84.HRMS(ESI)m/z:[M+Na]+calculated for C22H25BrNaN4O3 495.1008,found 495.1013.
实例5，化合物7的制备
将手性磷酸(0.7mg,1mol％)，4-氯氮甲基苯胺S1-5(14.1mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物7。
Figure BDA0003323482590000071
6.0Hz,2H),7.28(s,4H),7.17(t,J＝6.0Hz,2H),2.96(s,3H),1.95(s,3H),1.33(s,9H).13CNMR(126MHz,Acetone-d6)δ169.72,157.50,154.50,146.83,139.33,132.33,129.70,129.49,125.33,119.04,113.87,80.79,78.52,37.07,28.29,13.84.HRMS(ESI)m/z:[M+Na]+calculated for C22H25ClNaN4O3 451.1513,found 451.1520.
实例6，化合物8的制备
将手性磷酸(0.7mg,1mol％)，3-甲基氮甲基苯胺S1-6(12.1mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物8。
Figure BDA0003323482590000072
7.18-7.10(m,2H),7.04-6.99(m,3H),2.96(s,3H),2.15(s,3H),1.89(s,3H),1.34(s,9H).13C NMR(126MHz,Acetone-d6)δ169.91,157.91,154.49,147.95,139.47,129.50,129.44,128.61,128.46,125.16,118.93,80.52,78.52,36.99,28.31,21.15,13.84.HRMS(ESI)m/z:[M+Na]+calculated for C23H28N4O3Na 431.2059,found 431.2075.
实例7，化合物9的制备
将手性磷酸(0.7mg,1mol％)，3-氯氮甲基苯胺S1-7(14.1mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物9。
Figure BDA0003323482590000073
7.34(s,1H),7.29-7.17(m,4H),2.98(s,3H),1.96(s,3H),1.34(s,9H).13C NMR(126MHz,Acetone-d6)δ169.67,157.85,154.43,149.46,139.24,134.40,131.00,129.48,127.80,127.14,126.34,125.39,119.10,80.80,78.44,37.09,28.29,13.83.HRMS(ESI)m/z:[M+Na]+calculated for C22H25ClNaN4O3 451.1513,found 451.1528.
实例8，化合物10的制备
将手性磷酸(0.7mg,1mol％)，2-甲基氮甲基苯胺S1-8(12.1mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物10。
Figure BDA0003323482590000081
7.17-7.11(m,3H),7.04(d,J＝8.0Hz,3H),2.94(s,3H),2.24(s,3H),1.89(s,3H),1.33(s,9H).13C NMR(100MHz,Acetone-d6)δ169.68,157.78,154.36,148.06,137.09,134.60,129.86,129.71,128.08,127.64,119.05,80.66,78.47,37.06,28.30,20.84,13.85.HRMS(ESI)m/z:[M+Na]+calculated for C23H28N4O3Na 431.2059,found 431.2081.
实例9，化合物11的制备
将手性磷酸(0.7mg,1mol％)，2-氟氮甲基苯胺S1-9(12.1mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物11.
Figure BDA0003323482590000082
(s,1H),7.30-7.25(m,1H),7.20-7.10(m,2H),7.09-7.05(m,1H),2.96(s,3H),1.88(s,3H),1.33(s,9H).13C NMR(126MHz,Acetone-d6)δ169.66,161.74,159.28,139.52,135.08,134.97,130.95,129.74,129.66,129.48,125.39,125.35,125.23,118.97,117.32,117.10,80.76,78.27,36.58,28.31,13.39.HRMS(ESI)m/z:[M+Na]+calculated for C22H25FNaN4O3435.1808,found 435.1819.
实例10，化合物12的制备
将手性磷酸(0.7mg,1mol％)，2-溴氮甲基苯胺S1-10(18.4mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物12。
Figure BDA0003323482590000091
7.27-7.16(m,5H),5.10(s,1H),2.92(s,3H),2.02(s,3H),1.36(s,9H).13C NMR(100MHz,Acetone-d6)δ169.65,157.84,154.39,149.59,139.21,131.28,130.73,130.10,129.47,126.80,125.39,122.37,119.13,80.86,78.21,37.09,28.28,13.82.HRMS(ESI)m/z:[M+Na]+calculated for C22H25BrNaN4O3 495.1008,found 495.1014.
实例11，化合物13的制备
将手性磷酸(0.7mg,1mol％)，氮乙基苯胺S1-11(12.1mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物13。
Figure BDA0003323482590000092
(400MHz,Acetone-d6):δ7.81(d,J＝8.0Hz,2H),7.39(t,J＝8.0Hz,2H),7.28-7.14(m,6H),3.63-3.54(m,1H),3.36-3.27(m,1H),1.86(s,3H),1.33(s,9H),0.84(t,J＝8.0Hz,3H).13CNMR(100MHz,Acetone)δ169.27,144.27,138.68,129.08,128.80,128.60,127.55,124.30,118.12,78.17,42.08,27.48,13.34,13.14.HRMS(ESI)m/z:[M+Na]+calculated forC23H28N4O3Na 431.4918,found 431.4932.
实例12，化合物14的制备
将手性磷酸(0.7mg,1mol％)，氮苯基甘氨酸乙酯S1-12(17.9mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物14。
Figure BDA0003323482590000093
7.27-7.17(m,6H),4.67(d,J＝16.0Hz,1H),4.10(q,J＝8.0Hz,2H),4.03(d,J＝16.0Hz,1H),1.74(s,3H),1.34(s,9H),1.18(t,J＝8.0Hz,3H).13C NMR(100MHz,Acetone-d6)δ172.60,170.50,157.56,154.43,146.50,139.34,129.89,129.61,129.51,128.30,125.41,119.13,80.73,77.40,61.58,51.41,28.26,14.32,14.09.HRMS(ESI)m/z:[M+Na]+calculated for C25H30N4O5Na 489.2114,found 489.2120.
实例13，化合物15的制备
将手性磷酸(0.7mg,1mol％)，氮烯丙基苯胺S1-13(13.3mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物15。
Figure BDA0003323482590000101
7.22-7.16(m,6H),5.77-5.68(m,1H),4.94-4.82(m,2H),4.26(dd,J1＝4.0Hz,J2＝16.0Hz,1H),3.91(dd,J1＝8.0Hz,J2＝16.0Hz,1H),1.87(s,3H),1.33(s,9H).13C NMR(100MHz,Acetone-d6)δ170.05,157.60,154.43,145.33,139.42,136.68,129.78,129.49,129.43,128.20,125.19,118.97,117.23,80.73,78.69,52.03,28.29,13.97.HRMS(ESI)m/z:[M+Na]+calculated for C24H28N4O3Na 443.2059,found 443.2073.
实例14，化合物16的制备
将手性磷酸(0.7mg,1mol％)，2-苯胺基乙醇S1-14(13.7mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物16。
Figure BDA0003323482590000102
7.27-7.22(m,5H),7.16(t,J＝8.0Hz,1H),4.45(s,1H),4.15-4.08(m,1H),3.51-3.42(m,2H),3.11(d,J＝16.0Hz,1H),1.90(s,3H),1.37(s,9H).13C NMR(100MHz,Acetone)δ171.37,146.46,139.43,129.93,129.89,129.47,128.55,125.23,119.05,77.76,60.15,52.36,28.35,13.93.HRMS(ESI)m/z:[M+Na]+calculated for C23H28N4O4Na 447.2008found447.2017.
实例15，化合物17的制备
将手性磷酸(0.7mg,1mol％)，吲哚啉S1-14(11.9mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物17。
Figure BDA0003323482590000111
J＝8.0Hz,1H),3.54(q,J＝8.0Hz,1H),3.34(q,J＝8.0Hz,1H),2.95-2.85(m,2H),2.17(s,3H),1.38(s,9H).13C NMR(126MHz,Acetone-d6)δ168.98,147.59,139.19,132.04,129.52,127.30,125.50,125.36,121.06,118.84,114.17,77.34,49.69,28.41,28.32,14.67.HRMS(ESI)m/z:[M+Na]+calculated for C23H26N4O3Na 429.1903,found 429.1905.
实例16，化合物18的制备
将手性磷酸(0.7mg,1mol％)，氮苄基苯胺S1-15(18.3mg,0.1mmol,1.0equiv.)，吡唑啉酮亚胺S2(31.6mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物18。
Figure BDA0003323482590000112
Hz,2H),7.42(t,J＝8.0Hz,2H),7.30(d,J＝4.0Hz,2H),7.21-7.08(m,9H),4.80(d,J＝16.0Hz,1H),4,57(d,J＝16.0Hz,1H),1.89(s,3H),1.35(s,9H).13C NMR(100MHz,Acetone)δ170.01,145.26,139.48,139.18,129.87,129.50,129.38,128.64,128.18,127.54,125.27,119.07,79.13,52.46,28.33,14.18.HRMS(ESI)m/z:[M+Na]+calculated for C28H30N4O3493.2116found 493.2132.
实例17，化合物19的制备
将手性磷酸(0.7mg,1mol％)，氮甲基苯胺S1-1(10.7mg,0.1mmol,1.0equiv.)，3-乙基-1-苯基吡唑啉酮亚胺S2-1(33.1mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物19。
Figure BDA0003323482590000113
mL/min,254nm):tR(major)＝4.4min,tR(minor)＝6.6min.1H NMR(400MHz,Acetone-d6):δ7.85(d,J＝8.0Hz,2H),7.40(t,J＝8.0Hz,2H),7.26-7.14(m,6H),2.97(s,3H),2.38-2.21(m,1H),1.33(s,9H),1.04(t,J＝8.0Hz,3H).13C NMR(100MHz,Acetone)δ169.21,147.27,138.77,128.89,128.61,127.27,126.83,124.31,118.17,79.85,77.76,36.28,27.49,20.83,9.00.HRMS(ESI)m/z:[M+Na]+calculated for C28H28N4O3Na431.2059,found431.2068.
实例18，化合物20的制备
将手性磷酸(0.7mg,1mol％)，氮甲基苯胺S1-1(10.7mg,0.1mmol,1.0equiv.)，3-甲基-5-对甲苯基吡唑啉酮亚胺S2-2(33.1mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物20.
Figure BDA0003323482590000121
＝8.0Hz,2H),7.25-7.17(m,7H),2.97(s,3H),2.31(s,3H),1.88(s,3H),1.33(s,9H).13CNMR(100MHz,Acetone)δ169.68,157.78,154.27,148.06,137.09,134.60,129.86,129.71,128.08,127.64,119.05,80.55,78.47,37.06,28.30,20.84,13.85.HRMS(ESI)m/z:[M+Na]+calculated for C23H28N4O3Na 431.2059,found 431.2062.
实例19，化合物21的制备
将手性磷酸(0.7mg,1mol％)，氮甲基苯胺S1-1(10.7mg,0.1mmol,1.0equiv.)，3-甲基-5-对甲氧基苯基吡唑啉酮亚胺S2-3(34.9mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物21.
Figure BDA0003323482590000122
J＝8.0Hz,2H),7.25-7.17(m,5H),6.96(d,J＝8.0Hz,2H),3.83(s,3H),2.97(s,3H),1.88(s,3H),1.34(s,9H).13C NMR(100MHz,Acetone)δ169.49,157.58,148.06,132.74,129.67,128.04,127.60,120.86,114.53,80.55,78.37,55.65,37.04,28.30,13.83.HRMS(ESI)m/z:[M+Na]+calculated for C23H28N4O4Na 447.2008found 447.2009.
实例20，化合物22的制备
将手性磷酸(0.7mg,1mol％)，氮甲基苯胺S1-1(10.7mg,0.1mmol,1.0equiv.)，3-甲基-5-对氯苯基吡唑啉酮亚胺S2-4(35.3mg,0.11mmol,1.1equiv.)置于干燥的反应管内,室温下反应，薄层色谱板监测，直至反应结束。将反应液旋干，柱层析纯化(PE:EA＝20:1)得到化合物22.
Figure BDA0003323482590000131
7.41(d,J＝8.0Hz,2H),7.24-7.17(m,5H),2.98(s,3H),1.90(s,3H),1.33(s,9H).13C NMR(100MHz,Acetone)δ169.12,157.59,153.61,147.06,137.36,128.98,128.88,128.69,127.27,127.02,119.42,80.16,77.81,36.25,27.54,13.11.HRMS(ESI)m/z:[M+Na]+calculated for C22H26ClNaN4O3 451.1513,found 451.1532.
实例21，化合物23的制备
Figure BDA0003323482590000132
取化合物16(84.8mg,0.2mmol,1.0equiv.)于干燥的反应管中，加入四氢呋喃溶液(2mL)，冰浴条件下加入三苯基磷(52.4mg,0.2mmol,1.0equiv)，DEAD(34.8mg,0.2mmol.1.0equiv.)。薄层色谱法检测反应进程。待反应完全后，蒸出溶剂，柱层析纯化(PE:EA＝20:1)得到反应产物23，产率99％。
White solid.1H NMR(400MHz,CDCl3):δ7.80(d,J＝8.0Hz,2H),7.36(t,J＝8.0Hz,2H),7.18-7.14(m,3H),6.89(t,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,2H),4.10-4.04(m,1H),3.94-3.80(m,2H),3.64-3.58(m,1H),2,07(s,3H),1.27(s,9H).13C NMR(100MHz,Acetone)δ13C NMR(101MHz,CDCl3)δ169.62,158.41,151.50,143.25,137.86,129.42,128.86,124.94,122.09,118.10,116.64,82.73,80.56,46.77,44.40,28.03,12.96.HRMS(ESI)m/z:[M+Na]+calculated for C23H26N4O3Na 429.1903,found 429.1911.
相比于之前的方法(Org.Lett.2019,21,5719，Org.Biomol.Chem.,2019,17,8374)，本发明利用了生理活性更高的吡唑啉酮骨架，增加了吡唑啉酮化合物的结构多样性，制备得到的吡唑啉酮衍生物可以很好的转化，为后续的药物筛选提供丰富的分子库。
上述对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述实施例，本领域技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。

Claims (5)

1.一种手性吡唑啉酮化合物的制备方法，其特征在于：将吡唑啉酮亚胺与N-烷基芳胺溶于溶剂中，在手性磷酸催化剂的作用下发生不对称N烷基化反应，制备得到C-4位双氮杂季碳中心手性吡唑啉酮化合物；
所述吡唑啉酮亚胺的化学结构式为：
Figure FDA0003323482580000011
所述N-烷基芳胺的化学结构式为：
Figure FDA0003323482580000012
所述手性磷酸催化剂的结构式如下所示：
Figure FDA0003323482580000013
其中，R选自H或取代芳基；R1选自芳基；R2选自烷基；R3选自芳基；
所述手性磷酸催化剂、吡唑啉酮亚胺、芳胺化合物的摩尔比为0.02-0.2:1.0:1.0-1.5；
制备得到的手性吡唑啉酮化合物的化学结构式为：
Figure FDA0003323482580000014
2.根据权利要求1所述的一种手性吡唑啉酮化合物的制备方法，其特征在于：所述溶剂选自二氯甲烷、二氯乙烷、甲苯或四氢呋喃中的一种或任意两种或以上的组合。
3.根据权利要求1所述的一种手性吡唑啉酮化合物的制备方法，其特征在于：所述吡唑啉酮化合物的芳基取代基为卤代芳基或者烷基取代的芳基。
4.根据权利要求1所述的一种手性吡唑啉酮化合物的制备方法，其特征在于：所述吡唑啉酮亚胺在溶剂中的浓度为0.02～0.2mol/L。
5.根据权利要求1所述的一种手性吡唑啉酮化合物的制备方法，其特征在于：反应的温度控制在室温，时间为6～20h。
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Application publication date: 20211224