CN110314165B - 一种手性噁唑啉钯配合物晶体的用途 - Google Patents

一种手性噁唑啉钯配合物晶体的用途 Download PDF

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CN110314165B
CN110314165B CN201910640369.1A CN201910640369A CN110314165B CN 110314165 B CN110314165 B CN 110314165B CN 201910640369 A CN201910640369 A CN 201910640369A CN 110314165 B CN110314165 B CN 110314165B
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罗梅
彼得·史唐
李国雄
谢蓝
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Hefei University of Technology
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Abstract

一种手性钯配合物晶体(I)的用途,其可用作抗癌试剂在A549(肺癌)、KB(鼻咽癌)、白血病HL‑60、肝癌SMMC‑7721、结肠癌SW480、肺癌(A549),人口腔癌细胞及人乳腺癌细胞MCF‑7试验中均显示出较强的抑制活性,其化学式如下：
Figure DDA0002131642400000011

Description

一种手性噁唑啉钯配合物晶体的用途
一、技术领域
本发明涉及一种金属有机配位化合物(配合物)的用途，特别涉及含氮的手性金属有机配合物的用途，确切地说是一种手性噁唑啉钯金属有机配合物的用途。
二、背景技术
随着有机化学的发展,金属有机化合物在有机合成及医药领域中的应用愈来愈广,20世纪60年代后期出现的使用手性配体与过渡金属络合物催化的不对称合成反应大大加速了手性药物的发展，近年来手性噁唑啉钯金属配合物在有机反应及抗癌等活性中取得了较好的应用。
参考文献：
1G.C.Hargaden,P.J.Guiry,Chem.Rev.2009,109,2505.
2G.Desimoni,G.Faita,K.A.
Figure BDA0002131642380000012
Chem.Rev.2006,106,3561.
3.G.Desimoni,G.Faita,K.A.
Figure BDA0002131642380000013
Chem.Rev.2011,111,PR284.
三、发明内容
本发明旨在提供一种Pd-N金属有机配合物以应用于医药领域，所要解决的技术问题是合成手性催化剂并应用于抗癌试剂的研发。
本发明所称的手性钯氮配合物是由以下化学式(I)所示的配合物：
Figure BDA0002131642380000011
化学名称：：双{[1,4-(4S)-二异丙基－2－噁唑啉基苯]氯化钯}配合物，简称配合物(I)。
Figure BDA0002131642380000021
本手性配合物(I)的合成方法包括反应、分离和纯化，其特征是由1，4-二氰基苯39.2mmol和L-缬氨醇16.2075g在无水无氧条件下和催化剂无水ZnCl2(26.4mol％)于氯苯溶剂中回流反应60小时，然后分离、纯化，反应结束后脱去氯苯，将粗产品用石油醚/二氯甲烷(4:1)柱层析,得白色噁唑啉晶体,再按照噁唑啉与氯化钯摩尔比0.7：1，以氯苯为溶剂反应，用三氯甲烷及乙醇进行重结晶，得红褐色双核氯化钯配合物单晶。
该手性配合物在在白血病HL-60,肝癌SMMC-7721，结肠癌SW-480,肺癌A549,人口腔癌细胞KB及人乳腺癌细胞MCF-7A试验中均显示出较强的抑制活性。
四、附图说明
图1是配合物(I)的单晶衍射图。
五、具体实施方式
1.手性配合物的制备
(1)[1,4-(4R)-二异丙基－2－噁唑啉基]苯的制备
在100mL两口瓶中,无水无氧条件下,加入无水ZnCl21.4054g(10.64mmol),40ml氯苯,1,4-二氰基苯5.0236g(39.2mmol),L-缬氨醇16.2075g,将混合物在高温下回流60h,停止反应,减压以除去溶剂,,将剩余物用水溶解,并用CHCl3(20mLx2)萃取,有机相用无水硫酸钠干燥,旋转除去溶剂,将粗产品用石油醚/二氯甲烷(4:1)柱层析,得浅绿色粘稠状液体,产率52％；白色晶体,熔点:48-50°C,[a]5 D＝+111.9°(c＝0.429,CHCl3)；1HNMR(500MHz,CDCl3,27℃),δ(ppm)＝7.97(s,4H),4.39～4.43(t,3.18Hz,1H),4.09～4.15(m,2H),1.85～1.86(m,1H),(d,J＝6.24Hz,6H),0.86～0.96(d,J＝6.24Hz,6H).13CNMR 18.13,19.03,32.85,70.26,72.76,128.10,128.16,130.32,162.82.IR:3273,2976,2960,2932,2889,2869,1643,1512,1469,1408,1382,1366,1350,1320,1296,1276,1214,1180,1108,1077,1047,1014,971,955,900,891,838,726,698,675,659,540.HRMS(EI):m/z(％):calcd forC18H24N2O2:300.1838；found:300.1833。
双{[1,4-(4S)-二异丙基－2－噁唑啉基苯]氯化钯}配合物的制备100mL两口瓶中,无水无氧条件下,加入氯化钯1.5603g(4.92mmol),1,4-(4R)-二异丙基－2－噁唑啉基苯1.0435g(3.48mmol)，氯苯30mL将混合物在高温下回流48h,停止反应,减压以除去溶剂,,将剩余物三氯甲烷及乙醇溶解，自然挥发，得红褐色配合物得晶体，产率：92％；m.p.:>200℃,[a]5 D＝+512.8°(c0.0564,CH3OH)；1H NMR(600MHz,CDCl3),δ`ppm 8.81(s,8H,ArH),4.61-4.63(m,4H,CH×4),4.53(t,J＝9.6Hz,4H,CH×4),4.44(t,J＝8.5Hz,4H,CH×4),3.07-3.10(m,4H),1.18and 1.15(dd,J＝6.7,7.2Hz,24H,CH3×4)；13C NMR(150MHz,CDCl3)δppm 166.8,130.1(×2),129.3,72.0,69.1,30.7,19.0,15.6；νmax(cm-1)3487,3049,2957,2929,2872,1642,1609,1572,1509,1480,1464,1416,1379,1331,1288,1246,1178,1141,1123,1099,1045,1018,959,933,899,854,804,770,722,693,438；Elemental analysisfor C36H48N4Cl4O4Pd2,found C 45.26％,H 5.06％,N5.86％；requires C 45.32％,H5.24％,N 5.48％；
其晶体数据如下：
Figure BDA0002131642380000031
Figure BDA0002131642380000041
表1晶体的键长数据
Figure BDA0002131642380000042
Figure BDA0002131642380000051
Figure BDA0002131642380000061
Figure BDA0002131642380000071
表2晶体的键角数据
Figure BDA0002131642380000072
Figure BDA0002131642380000081
Figure BDA0002131642380000091
Figure BDA0002131642380000101
Figure BDA0002131642380000111
2.抗癌活性应用
本发明依据活性天然产物的结构设计合成的钯配合物在多种癌细胞如：白血病HL-60,肝癌SMMC-7721，结肠癌SW480,肺癌A549,人口腔癌细胞-KB及人乳腺癌细胞MCF-7试验中均显示出较强的抑制活性，因此，预期本发明的化合物可用于治疗多种癌症，例如白血病、肝癌癌及结肠癌，本发明化合物的部分抗癌活性测试结果见表1及2。
表1.钯配合物(I)的抗癌活性数据
Figure BDA0002131642380000112
表2钯配合物(I)的抗癌活性数据
Figure BDA0002131642380000121

Claims (1)

1.一种手性钯配合物晶体(I)在制备抗癌试剂中的用途,所述的抗癌试剂在 针对肝癌SMMC-7721，结肠癌SW-480,肺癌A549,人口腔癌细胞KB及人乳腺癌细胞MCF-7A几种癌症细胞种类试验中均显示出抑制活性,其化学式如下：
Figure FDA0003148288400000011
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