CN105315159B - 一种化合物的拆分方法 - Google Patents

一种化合物的拆分方法 Download PDF

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CN105315159B
CN105315159B CN201410415353.8A CN201410415353A CN105315159B CN 105315159 B CN105315159 B CN 105315159B CN 201410415353 A CN201410415353 A CN 201410415353A CN 105315159 B CN105315159 B CN 105315159B
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韩波
彭成
谢欣
黄维
李想
杨磊
冷海军
王彪
赵倩
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Chengdu University of Traditional Chinese Medicine
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Abstract

本发明提供了一种化合物的拆分方法。本发明拆分方法，操作简便，无需特别使用具备光学异构的中间体进行反应，就可以简单有效地拆分得到(S)‑3手性化合物，为相关化合物的手性拆分提供了新的选择。

Description

一种化合物的拆分方法
技术领域
本发明涉及一种化合物的拆分方法。
背景技术
手性因素在生物学、化学及其他多领域中都具有极其重要的影响力。随着有机化学和生物化学的发展，化合物的手性特征已开始受到越来越多的重视。众多研究表明，不同的光学异构体可能具有截然不同的生理活性、转运机制、代谢速率和毒性，在吸收、分布和***方面也不尽相同。
手性拆分(Chiral resolution)，亦称光学拆分(Optical resolution)或外消旋体拆分，为立体化学上，用以分离外消旋化合物成为两个不同的镜像异构物的方法。通常使用的拆分方法有结晶拆分法、化学拆分法、酶解法和柱色谱分离法等，其中，化学拆分法常使用一个纯的光活性异构体参加反应，形成非对映体，再将非对映体逆向反应脱去纯的光活性异构体即可。然而并非所有化合物都能够找到适合的光活性异构体参与反应，若能够找到一种不使用特定光活性异构体就能够拆分化合物的方法，将会为手性拆分方法提供新的思路和选择。
发明内容
本发明的目的在于提供一种化合物的手性拆分方法。
具体地，本发明提供了如下所示(S)-3化合物的拆分方法，反应途径如下：
Rac-3为的外消旋体；
R1选自苯环、取代苯环或五元或六元杂环，R2选自C1-C4烷基，R3选自H或C1-C4烷基。
进一步地，所述取代苯基的取代基选自卤素或硝基，取代基数量为1～3个。
更进一步地，所述卤素选自F、Cl或Br。
更进一步地，取代基数量为1个或2个。
进一步地，所述C1-C4烷基选自甲基或乙基。
进一步地，具体操作步骤如下：
取Rac-3加入醛4，二苯基脯氨醇硅醚IIa和冰醋酸，反应在室温下进行，用TLC监测至反应结束，浓缩并硅胶柱层析(PE/EA＝10：1)先后分离得到MBH产物(S)-3和手性四氢吡喃醇产物5。
进一步地，Rac-3的制备方法为：
其中，Rac-3制备方法的具体操作步骤如下：
硝基烯烃1和羰基化合物2在DMAP存在下，以MeCN做溶剂，室温搅拌得到MBH加成产物rac-3。
MBH即贝里斯-希尔曼反应。
更进一步地，式1所示硝基烯烃：式2所示羰基化合物：DMAP：式4所示醛：催化剂：冰醋酸＝0.5-1.0mmol:1.0mmol：0.05-0.2mmol：1.0-2.0mmol：0.1-0.3mmol：0.1-0.2mmol。
优选地，式1所示硝基烯烃:式2所示羰基化合物：DMAP：式4所示醛：催化剂：冰醋酸＝0.5mmol:1.0mmol：0.05mmol：1.0mmol：0.1mmol：0.1mmol。
本发明拆分方法，操作简便，无需特别使用具备光学异构的中间体进行反应，就可以简单有效地拆分得到(S)-3手性化合物，为相关化合物的手性拆分提供了新的选择。
以下通过具体实施方式对本发明作进一步的详细描述，但并不限制本发明，本领域技术人员可以根据本发明作出各种改变和变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
具体实施方式
实施例1 本发明拆分方法
硝基烯烃1(0.5mmol)和具有活性的羰基化合物2(1.0mmol)在DMAP(6.1mg,0.05mmol)的存在下，以MeCN做溶剂，室温搅拌30min得到MBH加成产物rac-3。接着一锅法加入醛4(1.0mmol)，二苯基脯氨醇硅醚IIa(32.5mg,0.1mmol)和冰醋酸(6.0mg,0.1mmol)。反应在室温下进行，用TLC监测反应进程。浓缩并硅胶柱层析(PE/EA＝10：1)先后分离得到MBH产物(S)-3和手性四氢吡喃醇产物5。
拆分的各具体化合物如下：
(d,J＝7.6Hz,2H),5.35(d,J＝4.8Hz,1H),5.18(dd,J＝9.6Hz,J＝6.0Hz,1H),5.07(d,J＝5.6Hz,1H),4.26-4.20(m,2H),4.03(br s,1H),3.16(t,J＝11.6Hz,1H),1.97-1.94(m,1H),1.24(t,J＝7.2Hz,3H),0.86(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝167.95,137.63,129.11,128.07,128.00,98.15,89.72,69.35,62.29,48.19,39.32,15.50,13.85ppm；ESI HRMS:计算值C15H19NO6+Na 332.1110,实测值332.1112.
[α]D 20+108.4(c＝0.21in CH2Cl2).
1H),7.31-7.19(m,3H),5.30(br s,2H),5.10(d,J＝4.8Hz,1H),4.34(br s,1H),4.30-4.23(m,2H),2.12-2.05(m,1H),1.25(t,J＝6.8Hz,3H),0.88(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝167.89,130.43,130.26,129.13,128.32,127.67,127.40,98.39,95.33,83.64,69.98,68.89,62.38,15.08,13.88ppm；ESI HRMS:calcd.For C15H18ClNO6+Na366.0720,实测值366.0716.
(S)-3b：谱图数据与消旋产物3b一致。收率：39％(55.7mg).高效液相CelluCoat柱测定ee值98％(5％2-propanol/n-hexane,1mL/min),UV 220nm,tminor＝13.24min,tmajor＝14.23min.旋光：[α]D 20+86.2(c＝0.11in CH2Cl2).
7.20(s,1H),7.10-7.08(m,1H),5.34(dd,J＝7.6Hz,J＝4.4Hz,1H),5.13(dd,J＝10.4Hz,J＝6.0Hz,1H),5.04(d,J＝5.6Hz,1H),4.28-4.21(m,2H),3.46(d,J＝4.0Hz,1H),3.21-3.15(m,1H),1.95-1.85(m,1H),1.26(t,J＝7.2Hz,3H),0.87(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝167.64,139.71,135.02,130.40,128.41,128.09,126.32,97.82,88.98,69.60,62.34,47.65,39.49,15.36,13.87ppm；高分辨质谱ESI HRMS:计算值C15H18ClNO6+Na 366.0720,实测值366.0723.
2-propanol/n-hexane,1mL/min),UV 220nm,tminor＝10.13min,tmajor＝19.33min.旋光：[α]D 20+97.6(c＝0.15in CH2Cl2).
δ＝7.35(d,J＝8.0Hz,2H),7.14(d,J＝7.6Hz,2H),5.33(d,J＝6.8Hz,1H),5.13(dd,J＝10.0Hz,J＝6.0Hz,1H),5.06(d,J＝5.6Hz,1H),4.26-4.20(m,2H),4.06(br s,1H),3.15(t,J＝11.2Hz,1H),1.95-1.89(m,1H),1.24(t,J＝7.2Hz,3H),0.85(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝166.80,135.12,132.96,128.34,128.31,96.94,88.37,68.25,61.35,46.58,38.26,14.41,12.82ppm；高分辨质谱ESI HRMS:计算值C15H18ClNO6+Na366.0720,实测值366.0723.
(S)-3d:谱图数据与消旋产物3d一致.收率:38％(54.3mg).高效液相AD-H柱测定ee值98％(10％2-propanol/n-hexane,1mL/min),UV 220nm,tminor＝16.01min,tmajor＝30.78min.旋光：[α]D 20+82.4(c＝0.12in CH2Cl2).
CDCl3):δ＝7.44(s,1H),7.31-7.21(m,2H),5.28(br s,2H),5.07(d,J＝4.4Hz,1H),4.32-4.23(m,2H),4.09(br s,1H),3.92-3.80(m,1H),2.05(br s,1H),1.25(t,J＝7.2Hz,3H),0.87(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝167.68,134.37,130.25,130.08,128.07,127.74,127.67,98.19,95.18,83.25,69.86,69.01,62.44,14.99,13.88ppm；高分辨质谱ESI HRMS:calcd.For C15H17Cl2NO6+Na 400.0331,实测值400.0328.
旋光：[α]D 20+76.9(c＝0.21in CH2Cl2).
CDCl3):δ＝7.45(d,J＝8.4Hz,1H),7.37(s,1H),7.24-7.23(m,1H),7.14(d,J＝7.6Hz,1H),5.32(d,J＝7.2Hz,1H),5.15(dd,J＝9.6Hz,J＝5.6Hz,1H),5.07(d,J＝5.6Hz,1H),4.44(brs,1H),4.25-4.20(m,2H),3.14(t,J＝11.2Hz,1H),1.97-1.89(m,1H),1.24(t,J＝7.2Hz,3H),0.87(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝166.91,139.13,130.29,129.95,129.64,125.83,122.14,96.99,88.27,68.11,61.41,46.89,38.22,14.52,12.82ppm；高分辨质谱ESI HRMS:计算值C15H18BrNO6+Na 410.0215,实测值410.0211.
(S)-3f：谱图数据与消旋产物3f一致。收率：41％(67.7mg).高效液相AD-H柱测定ee值90％(15％2-propanol/n-hexane,1mL/min),UV 220nm,tminor＝9.80min,tmajor＝18.88min.旋光：[α]D 20+65.8(c＝0.16in CH2Cl2).
CDCl3):δ＝7.50(d,J＝7.6Hz,2H),7.08(d,J＝7.6Hz,2H),5.33(d,J＝4.0Hz,1H),5.12(dd,J＝9.6Hz,J＝6.0Hz,1H),5.05(d,J＝5.2Hz,1H),4.25-4.21(m,2H),4.08(br s,1H),3.14(t,J＝11.2Hz,1H),1.95-1.88(m,1H),1.24(t,J＝7.2Hz,3H),0.85(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝166.80,135.66,131.29,128.65,121.05,96.91,88.26,68.27,61.36,46.65,38.23,14.40,12.82ppm；高分辨质谱ESI HRMS:计算值C15H18BrNO6+Na 410.0215,实测值410.0217.
min,tmajor＝32.45min.旋光：[α]D 20+87.2(c＝0.16in CH2Cl2).
CDCl3):δ＝7.19-7.16(m,2H),7.08-7.04(m,2H),5.35-5.33(m,1H),5.13(dd,J＝9.6Hz,J＝6.0Hz,1H),5.06(d,J＝5.6Hz,1H),4.29-4.17(m,3H),3.15(t,J＝11.2Hz,1H),1.96-1.90(m,1H),1.24(t,J＝7.2Hz,3H),0.85(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝167.93,162.36(d,JCF＝246Hz),133.38(d,JCF＝3Hz),129.59(d,JCF＝8Hz),116.14(d,JCF＝21Hz),98.08,89.76,69.19,62.38,47.57,39.35,15.49,13.84ppm；高分辨质谱ESI HRMS:计算值C15H18FNO6+Na 350.1016,实测值350.1011.
(S)-3h:谱图数据与消旋产物3h一致.收率:36％(48.5mg).高效液相AD-H柱测定ee值99％(15％2-propanol/n-hexane,1mL/min),UV 220nm,tminor＝12.73min,tmajor＝24.56min.旋光：[α]D 20+75.4(c＝0.20in CH2Cl2).
7.67(t,J＝7.6Hz,1H),7.51-7.47(m,2H),5.35-5.21(m,2H),5.12(d,J＝5.2Hz,1H),4.32-4.18(m,3H),4.03(br s,1H),2.08(br s,1H),1.25(t,J＝7.2Hz,3H),0.85(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝167.62,133.51,133.05,128.91,128.08,125.19,124.96,97.91,95.17,88.35,83.98,69.70,62.52,13.85,13.43ppm；高分辨质谱ESI HRMS:计算值C15H18N2O8+H355.1141,实测值355.1145.
tmajor＝34.45min.旋光：[α]D 20+91.6(c＝0.16in CH2Cl2).
CDCl3):δ＝8.25(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),5.35(dd,J＝6.8Hz,J＝4.4Hz,1H),5.18(dd,J＝10.0Hz,J＝6.0Hz,1H),5.10(d,J＝5.6Hz,1H),4.31-4.19(m,2H),3.80(d,J＝3.6Hz,1H),3.34(t,J＝11.2Hz,1H),2.01-1.95(m,1H),1.26(t,J＝7.2Hz,3H),0.86(d,J＝6.4Hz,3H)ppm；碳谱13C NMR(100MHz,CDCl3):δ＝167.58,147.73,145.19,129.08,124.39,97.64,88.44,69.45,62.51,47.80,39.45,15.31,13.86ppm；高分辨质谱ESI HRMS:计算值C15H18N2O8+Na 377.0961,实测值377.0958.
min,tmajor＝24.45min.旋光：[α]D 20+65.8(c＝0.22in CH2Cl2).

Claims (4)

1.如下所示(S)-3化合物的拆分方法，其特征在于：反应途径如下：
Rac-3为的外消旋体；
R1选自苯环、取代苯环或五元或六元杂环，R2选自C1-C4烷基，R3选自H或C1-C4烷基；
其中，所述取代苯基的取代基选自卤素或硝基；所述卤素选自F、Cl或Br；取代基数量为1个或2个；
具体操作步骤如下：
取Rac-3加入醛4，二苯基脯氨醇硅醚和冰醋酸，反应在室温下进行，用TLC监测至反应结束，浓缩并经过硅胶柱层析，石油醚/乙酸乙酯＝10：1洗脱分离得到MBH产物(S)-3和手性四氢吡喃醇产物5；
Rac-3的制备方法为：
硝基烯烃1和羰基化合物2在DMAP存在下，以MeCN做溶剂，室温搅拌得到MBH加成产物Rac-3。
2.根据权利要求1所述的拆分方法，其特征在于：所述C1-C4烷基选自甲基或乙基。
3.根据权利要求1所述的拆分方法，其特征在于：式1所示硝基烯烃：式2所示羰基化合物：DMAP：式4所示醛：二苯基脯氨醇硅醚：冰醋酸＝0.5-1.0mmol:1.0mmol：0.05-0.2mmol：1.0-2.0mmol：0.1-0.3mmol：0.1-0.2mmol。
4.根据权利要求3所述的拆分方法，其特征在于：式1所示硝基烯烃:式2所示羰基化合物：DMAP：式4所示醛：二苯基脯氨醇硅醚：冰醋酸＝0.5mmol:1.0mmol：0.05mmol：1.0mmol：0.1mmol：0.1mmol。
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CN105315248A (zh) * 2014-06-26 2016-02-10 成都中医药大学 一种四氢吡喃醇系列手性化合物及其合成方法和用途

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Asymmetric One-Pot Four-Component Coupling Reaction: Synthesis of Substituted Tetrahydropyrans Catalyzed by Diphenylprolinol Silyl Ether;Hayato Ishikawa等;《Angew. Chem.》;20110324;第123卷;3858-3863 *

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