CN110862423B - 一种α-芳基半乳烯糖碳苷的合成方法及其在制药中的用途 - Google Patents

一种α-芳基半乳烯糖碳苷的合成方法及其在制药中的用途 Download PDF

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CN110862423B
CN110862423B CN201911096169.0A CN201911096169A CN110862423B CN 110862423 B CN110862423 B CN 110862423B CN 201911096169 A CN201911096169 A CN 201911096169A CN 110862423 B CN110862423 B CN 110862423B
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姚辉
黄年玉
刘明国
邹坤
邓张双
郭志勇
罗华军
冯永奎
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Guangzhou Younan Technology Co.,Ltd.
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Abstract

本发明提供一种α‑芳基半乳烯糖碳苷化合物，结构式为：
Figure DDA0002268406500000011
其制备方法是将催化剂，糖受体硼酸试剂和化合物1中加入溶剂中，在室温条件下进行搅拌反应，TLC检测反应进程，原料完全消失后，终止反应，萃取收集有机相，减压蒸馏除去溶剂得到粗产物，然后采用石油醚/乙酸乙酯溶液作为流动相进行柱层析获得α‑芳基半乳烯糖碳苷。本发明将所述制备得到的产品应用于制备质量乳腺癌、肝癌、胃癌的药物上。

Description

一种α-芳基半乳烯糖碳苷的合成方法及其在制药中的用途
技术领域
本发明主要关于一种α-芳基半乳烯糖碳苷的合成方法及其在制药中的用途
背景技术
糖类广泛存在于自然界与生物体中，它与蛋白质、核酸共同构成了动植物体内最重要的生命物质。糖化学在生命科学与药物开发中均占据着极其重要的地位。碳糖苷比对应的氧糖苷对酸和酶更稳定，因此具有更长的生物半衰期，对于先导化合物的发现具有独特的优势碳苷已被发现具有多种药理活性，例如，抗肿瘤活性、抗病毒和抗菌活性等。
碳糖苷相对于氧糖苷合成更具挑战性，首先一般碳的亲核性比氧弱，难以参与亲核反应；其次，碳不属于异头原子，异头效应大幅度减弱，难以辅助产生高立体选择性。碳糖苷的立体选择性合成仍然是糖化学家的研究热点和难点之一，急需解决。已报道的碳苷合成方法有Ferrier重排反应，但是其通常需要使用当量的活化剂。新加坡的刘学伟小组曾报道使用催化量的催化剂介导分子内的重排反应产生碳糖苷，而此方法需要额外的步骤预先组装糖受体到烯糖3号位。本专利旨在通过采用3,4-O-碳酸酯烯糖供体在温和的条件下立体选择性地获得α-碳苷，开发其作为抗肿瘤药物的用途。
发明内容
针对上述技术问题，本发明提供一种α-芳基半乳烯糖碳苷化合物，及其制备方法和新用途。
一种α-芳基半乳烯糖碳苷化合物，结构式为：
Figure BDA0002268406480000011
其中，PG包括硅基、烷基(C1-C4烷基或者苄基)、芳基(包括苯基，三苯基甲基，吡啶基等)和酯基(苯甲酸酯，吡啶酸酯，喹啉甲酸酯等)；所述的R包括苯基及其衍生物、萘基及其衍生物、蒽及其衍生物。
作为优选方案，所述的PG为叔丁基二苯基氯硅烷，R2为对甲苯。
α-芳基半乳烯糖碳苷化合物的制备方法，具体是将催化剂，糖受体硼酸试剂和化合物1中加入溶剂中，在室温条件下进行搅拌反应，TLC检测反应进程，原料完全消失后，终止反应，萃取收集有机相，减压蒸馏除去溶剂得到粗产物，然后采用石油醚/乙酸乙酯溶液作为流动相进行柱层析获得α-芳基半乳烯糖碳苷，反应式如下
Figure BDA0002268406480000021
所述的化合物1、糖受体硼酸试剂、催化剂的摩尔量之比为1：1.2-2.5：0.01-0.1。
所述的催化剂包括White催化剂或Pd(OAc)2。
所述的溶剂包括四氢呋喃、乙醚、1,4-二氧六环、二氯甲烷、乙腈、N,N-二甲基甲酰胺、二甲基亚砜中的任意一种。
所述的糖受体硼酸试剂为对甲苯硼酸。
作为优选方案，本发明采用3,4-O-环碳酸酯烯糖与对甲基苯硼酸反应进行条件优化，发现醋酸钯在无水无氧条件下可以以94％的产率获得目标产物2，继续筛选不同的溶剂，产率都没有THF高，继续筛选不同的催化剂发现White催化剂可以在非无水无氧的条件下催化反应且产率可以达到95％，醋酸钯也可以催化但是产率下降到60％，零价钯催化剂Pd2(dba)3和Pd(PPh3)4都不能催化原料发生反应如下表所示。因此最优的反应条件是采用White催化剂在室温非无水无氧条件下室温反应。
Figure BDA0002268406480000022
Figure BDA0002268406480000023
Figure BDA0002268406480000031
反应用量0.1mmol的化合物1，0.2mmol的对甲苯硼酸，5mol％的钯催化剂，2mL溶剂，N.R.表示未反应。
附图说明
图1为化合物3的氢谱图。
图2为化合物3的碳谱图。
具体实施方式
实验试剂
White催化剂(96％，日本东京化成工业株式会社TCI)、石油醚(沸程60-90℃，天津市恒兴化学试剂制造有限公司)、乙酸乙酯(分析纯，天津市科密欧化学试剂有限司)、无水硫酸钠(分析纯，国药集团化学试剂有限公司)、氘代氯仿-d(氘原子含量99.8％，TMS含量0.03％V/V，10*0.5mL/盒，瑞士ARMAR公司)；核磁管(5mm 100/pk 2ST500-8，美国Norell公司)。
实验仪器
ZXZ-4型旋片式真空泵(临海市谭氏真空设备有限公司)、DZF-6020型真空干燥箱(上海新苗医疗器械制造有限公司)、SHB-IIIA循环水式多用途真空泵(上海豫康科教仪器设备有限公司)、CL-4型平板磁力搅拌器(郑州长城科工贸有限公司)、EYELA SB-1100旋转蒸发仪(上海爱朗仪器有限公司)、FA2104B分析天平(上海越平科技仪器有限公司)、XRC-1型微熔点测定仪(四川大学科仪厂)、DF-101S集热式恒温加热磁力搅拌器(巩义市英峪予华仪器厂)、GZX-9240MBE数显鼓风干燥箱(上海博迅实业有限公司医疗设备厂)、ZF-6型三用紫外分析仪(上海嘉鹏科技有限公司)、Ultrashied 400MHz Plus核磁共振仪(瑞士Bruker公司)、API 4000LC-MS/MS质谱仪(德国布鲁克道尔顿公司)目标分子的合成
将二乙酸-1,2-双(苯亚磺酰)乙基钯(II)(White催化剂，4.6mg,0.005mmol)和3,4-O-碳酸酯半乳烯糖1(0.1mmol)加入2mL的THF和糖受体硼酸试剂(0.2mmol)。无需严格无水无氧条件，室温搅拌，TLC检测反应进程，直到原料完全消失，终止反应，萃取或者有机相干燥得到粗产物，最后采用石油醚/乙酸乙酯溶液作为流动相进行柱层析获得4-羟基-2,3-不饱和碳苷。合成方法如下：
Figure BDA0002268406480000041
目标分子清单：
Figure BDA0002268406480000042
2.3碳糖苷产物分析与鉴定表征
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-tolyl-D-threo-hex-2-enitol(3)
Figure BDA0002268406480000051
无色油状物；产率95％；1H NMR(400MHz,CD3CN)δ7.68–7.57(m,4H),7.45–7.38(m,2H),7.37–7.32(m,4H),7.30–7.25(m,2H),7.15(d,J＝7.8Hz,2H),6.32–6.20(m,2H),5.31(d,J＝2.7Hz,1H),3.95–3.89(m,1H),3.89–3.80(m,2H),3.71(td,J＝6.2,2.1Hz,1H),2.37(s,3H),1.95(d,J＝9.0Hz,1H),1.02(s,9H)；13C NMR(101MHz,CDCl3)δ137.6,136.1,135.8,135.7,133.5,133.4,131.6,129.8,129.7,129.2,127.9,127.8,127.7,74.1,72.3,63.9,62.6,27.0,21.3,19.3；HRMS(ESI)m/z:calcd.forC29H34O3Si(M+Na)+481.2179,found481.2175；[α]D 20＝-128.3(c＝1.0,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(2-methoxyphenl)-D-threo-hex-2-enitol(4)
Figure BDA0002268406480000052
无色油状物；产率71％；1H NMR(500MHz,CDCl3)δ7.62(ddt,J＝9.5,6.7,1.5Hz,4H),7.44–7.37(m,2H),7.33(qd,J＝7.7,7.0,1.4Hz,6H),6.97–6.86(m,2H),6.24(ddd,J＝10.1,5.4,2.1Hz,1H),6.17(dd,J＝10.2,3.4Hz,1H),5.72(dd,J＝3.3,2.2Hz,1H),3.96(d,J＝5.2Hz,1H),3.94–3.80(m,6H),1.87(s,1H),1.00(s,9H)；13C NMR(126MHz,CDCl3)δ157.7,135.8,135.7,133.6,133.6,131.8,129.7,129.7,129.5,128.6,127.8,127.7,126.4,120.0,111.0,72.7,69.9,63.8,62.7,55.7,26.9,19.2；HRMS(ESI)m/z:calcd.forC29H34O4Si(M+Na)+497.2124,found 497.2127；[α]D 20＝-97.4(c＝1.0,CHCl3)..
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(p-Methoxyphenyl)-D-threo-hex-2-enitol(5)
Figure BDA0002268406480000061
无色油状物；产率95％；1H NMR(400MHz,CDCl3)δ7.62(dt,J＝7.8,1.3Hz,4H),7.44–7.37(m,2H),7.37–7.29(m,6H),6.87(d,J＝8.4Hz,2H),6.23(q,J＝1.2Hz,2H),5.29(s,1H),3.97–3.89(m,1H),3.88–3.83(m,1H),3.82(d,J＝1.0Hz,3H),3.82–3.78(m,1H),3.67(td,J＝6.2,1.9Hz,1H),1.97(d,J＝8.7Hz,1H),1.02(s,9H)；13C NMR(101MHz,CDCl3)δ159.4,135.8,135.7,133.5,133.4,131.7,131.1,129.8,129.8,129.4,127.8,127.8,113.8,73.9,72.1,63.8,62.6,55.4,26.9,19.3；HRMS(ESI)m/z:calcd.for C29H34O4Si(M+Na)+497.2124,found 497.2127；[α]D 20＝-95.4(c＝1.0,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-phenyl-D-threo-hex-2-enitol(6)
Figure BDA0002268406480000062
无色油状物；产率90％；1H NMR(500MHz,CDCl3)δ7.63(ddd,J＝8.2,4.7,1.5Hz,4H),7.43–7.28(m,12H),6.33–6.19(m,2H),5.35(t,J＝2.5Hz,1H),3.91(d,J＝8.1Hz,1H),3.90–3.82(m,2H),3.71(td,J＝6.2,2.1Hz,1H),1.96(s,1H),1.03(s,9H)；13C NMR(126MHz,CDCl3)δ139.2,135.8,135.7,133.5,133.4,131.5,129.8,129.8,128.5,127.9,127.9,127.8,127.8,74.2,72.6,63.9,62.6,26.9,19.3；HRMS(ESI)m/z:calcd.for C28H32O3Si(M+Na)+467.2018,found 467.2022；[α]D 20＝-147.7(c＝1.0,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(4-(4-methoxybenzyl)phenyl)-D-threo-hex-2-enitol(7)
Figure BDA0002268406480000071
无色油状物；产率70％；1H NMR(500MHz,CDCl3)1H NMR(500MHz,CDCl3)δ7.62(ddd,J＝7.9,3.2,1.4Hz,4H),7.42–7.29(m,10H),6.96–6.89(m,4H),6.23(d,J＝2.8Hz,2H),5.28(s,1H),5.00(s,2H),3.91(dt,J＝8.9,2.3Hz,1H),3.89–3.83(m,1H),3.82(s,3H),3.80–3.78(m,1H),3.67(td,J＝6.1,2.0Hz,1H),1.94(d,J＝9.0Hz,1H),1.01(s,9H)；13CNMR(126MHz,CDCl3)δ159.6,158.7,135.8,135.7,133.5,133.4,131.7,131.3,129.8,129.8,129.4,129.3,129.1,127.8,114.8,114.2,73.9,72.1,70.0,63.8,62.6,55.5,26.9,19.3；HRMS(ESI)m/z:calcd.for C36H40O4SiNa(M+Na)+587.2594,found 587.2585；[α]D 20＝-107.2(c＝1.0,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(o-tolyl)-D-threo-hex-2-enitol(8)
Figure BDA0002268406480000072
白色固体；产率70％；1H NMR(400MHz,CDCl3)δ7.57(ddd,J＝8.1,5.0,1.5Hz,4H),7.42–7.35(m,2H),7.31(t,J＝7.3Hz,4H),7.25–7.14(m,3H),6.37–6.29(m,1H),6.15(dd,J＝10.2,3.6Hz,1H),5.51(dd,J＝3.7,2.0Hz,1H),4.03–3.93(m,1H),3.87–3.72(m,2H),3.61(td,J＝6.1,2.0Hz,1H),2.46(s,3H),2.06(d,J＝8.5Hz,1H),0.96(s,9H)；1.01(s,9H)；13C NMR(101MHz,CDCl3)δ138.8,135.9,135.7,135.6,133.5,133.4,131.8,131.2,129.8,129.8,128.5,128.5,128.5,127.8,125.1,77.5,77.2,76.8,72.4,71.9,63.9,63.0,26.9,19.4,19.2；HRMS(ESI)m/z:calcd.for C29H34O3Si(M+Na)+481.2175,found 481.2180；[α]D 20＝-12.8(c＝0.6,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(3,5-dimethyl-phenyl)-D-threo-hex-2-enitol(9)
Figure BDA0002268406480000081
无色油状物；产率90％；1H NMR(400MHz,CDCl3)δ7.63(ddd,J＝8.1,4.6,1.5
Hz,4H),7.45–7.30(m,6H),6.98(s,2H),6.96(s,1H),6.30–6.19(m,2H),5.27(s,1H),4.01–3.92(m,1H),3.92–3.80(m,2H),3.73(td,J＝6.2,2.2Hz,1H),2.31(s,6H),1.99(d,J＝8.8Hz,1H),1.01(s,9H)；13C NMR(101MHz,CDCl3)δ138.9,138.0,135.8,135.7,133.5,133.5,131.7,129.8,129.8,129.7,127.8,127.7,125.9,74.3,72.2,63.8,62.6,26.9,21.5,19.3；HRMS(ESI)m/z:calcd.for C30H36O3Si(M+Na)+495.2331,found 495.2331；[α]D 20＝-122.9(c＝1.0,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(naphthalen-2-yl)-D-threo-hex-2-enitol(10)
Figure BDA0002268406480000082
无色油状物；产率92％；1H NMR(400MHz,CDCl3)δ7.89–7.76(m,3H),7.73(d,J＝1.6Hz,1H),7.62–7.53(m,5H),7.54–7.48(m,2H),7.39–7.27(m,3H),7.29–7.19(m,3H),6.40(dd,J＝10.2,3.5Hz,1H),6.32(ddd,J＝10.2,5.2,1.8Hz,1H),5.52–5.45(m,1H),3.96(ddd,J＝8.8,5.2,2.1Hz,1H),3.87(qd,J＝10.7,6.2Hz,2H),3.68(td,J＝6.2,2.1Hz,1H),2.02(d,J＝8.9Hz,1H),1.00(s,9H)；13C NMR(101MHz,CDCl3)δ136.5,135.7,135.6,133.4,133.4,133.1,133.1,131.4,129.8,129.7,128.4,128.3,128.3,127.8,127.7,126.8,126.3,126.3,126.3,74.3,72.3,63.8,62.6,26.9,19.3；HRMS(ESI)m/z:calcd.forC32H34O3SiNa(M+Na)+517.2175,found 517.2194；[α]D 20＝-167.2(c＝0.47,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(4-(trifluoromethyl)phenyl)-D-threo-hex-2-enitol(11)
Figure BDA0002268406480000091
无色油状物；产率64％；1H NMR(500MHz,CDCl3)1H NMR(500MHz,Chloroform-d)δ7.66–7.61(m,4H),7.58(d,J＝8.2Hz,3H),7.51(d,J＝8.1Hz,3H),7.41(tdd,J＝6.1,3.9,2.0Hz,2H),7.39–7.30(m,4H),6.35–6.20(m,2H),5.36(d,J＝2.1Hz,1H),3.89(ddd,J＝14.6,6.8,2.9Hz,3H),3.59(td,J＝6.1,2.1Hz,1H),1.93(d,J＝9.0Hz,1H),1.03(s,9H)；13CNMR(126MHz,CDCl3)δ143.4,135.7,135.7,133.4,133.3,130.6,129.9,129.9,128.5,127.9,127.8,127.8,125.5,125.5,125.4,125.4,77.4,73.4,73.1,63.8,62.4,26.9,19.3；HRMS(ESI)m/z:calcd.for C29H31F3O3Si(M+Na)+535.1982,found 535.1907；[α]D 21＝-114.1(c＝0.73,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-(tert-butyldiphenylsilyl)-1-C-(4-(hydroxymethyl)phenyl)-D-threo-hex-2-enitol(12)
Figure BDA0002268406480000101
无色油状物；产率64％；1H NMR(400MHz,CDCl3)δ7.63(dq,J＝6.7,1.4Hz,4H),7.43–7.30(m,10H),6.32–6.20(m,2H),5.34(s,1H),4.71(s,2H),3.91(d,J＝8.0Hz,1H),3.89–3.81(m,2H),3.69(td,J＝6.1,2.1Hz,1H),1.94(d,J＝9.0Hz,1H),1.02(s,9H)；13CNMR(126MHz,CDCl3)δ140.5,138.6,135.8,135.7,135.7,133.4,133.4,131.4,129.8,129.8,128.1,127.9,127.8,127.2,73.9,72.5,65.2,63.9,62.6,26.9,19.3；HRMS(ESI)m/z:calcd.for C29H34O4Si(M+Na)+497.2124,found497.2133；[α]D 21＝-42.1(c＝0.56,CHCl3).
(1S)-1,5-anhydro-2,3-dideoxy-6-O-methyl-1-C-(p-tolyl)-D-threo-hex-2-enitol(13)
Figure BDA0002268406480000102
无色油状物；产率89％；1H NMR(400MHz,CDCl3)δ7.36–7.26(m,2H),7.16(d,J＝7.7Hz,2H),6.24(t,J＝4.6Hz,2H),5.32(s,1H),3.92(d,J＝8.1Hz,1H),3.76(td,J＝5.8,2.3Hz,1H),3.68–3.55(m,1H),3.33(s,3H),2.34(s,3H),2.20(d,J＝8.6Hz,1H)；13C NMR(101MHz,CDCl3)δ137.9,135.7,131.5,129.2,128.1,127.7,74.3,72.5,70.2,63.0,59.4,21.3；HRMS(ESI)m/z:calcd.for C14H18O3(M+Na)+257.1154,found 257.156；[α]D 21＝-248.4(c＝0.59,CHCl3)。

Claims (4)

1.α-芳基半乳烯糖碳苷化合物的制备方法，其特征在于，包括如下步骤：将催化剂，糖受体硼酸试剂和化合物1中加入溶剂中，在室温条件下进行搅拌反应，TLC检测反应进程，原料完全消失后，终止反应，萃取收集有机相，减压蒸馏除去溶剂得到粗产物，然后采用石油醚/乙酸乙酯溶液作为流动相进行柱层析获得α-芳基半乳烯糖碳苷，所述的催化剂为White催化剂，反应式如下：
Figure FDA0004105989020000011
PG为叔丁基二苯基硅基TBDPS，则R为苯基、对甲苯基、邻甲氧基苯基、对甲氧基苯基或萘基中的任意一种；
PG为甲基，则R为对甲苯基。
2.根据权利要求1所述的α-芳基半乳烯糖碳苷化合物的制备方法，其特征在于，化合物1、糖受体硼酸试剂、催化剂的摩尔量之比为1：1.2-2.5：0.01-0.1。
3.根据权利要求1所述的α-芳基半乳烯糖碳苷化合物的制备方法，其特征在于，所述的溶剂为四氢呋喃、乙腈、N,N-二甲基甲酰胺中的任意一种。
4.根据权利要求1所述的α-芳基半乳烯糖碳苷化合物的制备方法，其特征在于，所述的糖受体硼酸试剂为对甲苯硼酸。
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