CN113135914B - 一种消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法及其应用 - Google Patents

一种消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法及其应用 Download PDF

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CN113135914B
CN113135914B CN202110384967.4A CN202110384967A CN113135914B CN 113135914 B CN113135914 B CN 113135914B CN 202110384967 A CN202110384967 A CN 202110384967A CN 113135914 B CN113135914 B CN 113135914B
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王海飞
邓启福
张凯强
陈知刚
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Hunan Jiuwei Biopharmaceutical Co.,Ltd.
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Abstract

本发明公开了一种消旋体3,6‑二氮杂二环[3.2.1]辛烷衍生物的制备方法及其应用,所述消旋体3,6‑二氮杂二环[3.2.1]辛烷衍生物通过催化剂和强碱催化偶氮甲碱叶立德和α‑取代的末端烯烃酰胺一步法反应合成。本发明所述制备方法步骤简单,原料廉价易得,腐蚀度低以及毒性较小,而且反应条件简单易实现。根据所述消旋体3,6‑二氮杂二环[3.2.1]辛烷衍生物的制备方法得到的消旋体3,6‑二氮杂二环[3.2.1]辛烷衍生物可应用于药物抑制剂或药物中间体。

Description

一种消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法 及其应用
技术领域
本发明涉及辛烷衍生物合成技术领域,更具体地,涉及一种消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法及其应用。
背景技术
消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物不仅具有重要的医学研究价值(如在抑制凝血酶活性以及作为丝氨酸蛋白酶结构的片段抑制剂等方面),而且其衍生物也是合成喹诺酮类抗菌药物、降血压药物、降糖药物及抗肿瘤药物的关键中间体。关于3,6-二氮杂二环[3.2.1]辛烷骨架的构造己经引起众多有机化学家的重视,据文献报道,1988年Kleinman小组利用环戊二烯和亚胺为原料,通过 Diels-Alder反应,臭氧开环,Mannich反应以及氰基硼氢化钠还原等4步合成3,6- 二氮杂二环[3.2.1]辛烷类衍生物(参考文献:J.Org.Chem.,1988,53(4),896-899)。 2010和2014年,Kudryavtsev小组报道了利用1,3-偶极环加成、脱酯化、酰胺缩合以及氰化亚铜催化环化等步骤实现了3,6-二氮杂二环[3.2.1]辛烷类衍生物的合成(参考文献:Russian Journal of Organic Chemistry,2010,46(3),372-379; Tetrahedron,2014,70(43),7854-7864)。但是,上述方法不仅步骤较长,原料腐蚀性及毒性较大,而且反应条件苛刻如低温零下78℃等,因此,发展高效、简洁合成此类化合物的方法十分重要。
发明内容
本发明要解决的技术问题是针对现有技术中制备消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物存在反应步骤较长,原料腐蚀性及毒性较大,而且反应条件苛刻的不足,提供一种消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法。
本发明要解决的另一技术问题是提供制备消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的应用。
本发明的目的通过以下技术方案予以实现:
一种消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物,其特征在于,所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物通过银催化剂和有机碱或无机碱催化偶氮甲碱叶立德和α-取代的末端烯烃酰胺一步法反应合成,合成路径如式Ⅰ:
Figure BDA0003014401980000021
进一步地,所述R1~R4为烷基、芳基、杂芳基的一种或多种。
通过上述方法,可合成的化合物包括:
Figure BDA0003014401980000022
进一步地,所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物制备步骤包括:
S1.将银催化剂、碱物质溶于有机溶剂中,然后加入偶氮甲碱叶立德与α-取代的末端烯烃酰胺,室温下搅拌2~12h,待反应完全;
S2.在步骤S1反应完全的溶液中加入氯化钠溶液,加入萃取剂萃取,得到有机相;
S3.将步骤S2所得有机相干燥,过滤,减压浓缩,洗脱过柱,得到消旋体产物。
进一步地,所述银催化剂为氧化银(Ag2O)、碳酸银(Ag2CO3)、乙酸银 (AgOAc)、三氟乙酸银(AgOTf)、苯甲酸银(PhCOOAg),氟化银(AgF) 等银盐的一种或多种。
进一步地,所述有机碱为1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)、7-甲基 -1,5,7-三氮杂二环[4.4.0]癸-5-烯(MTBD)、三乙胺(Et3N)、4-二甲氨基吡啶 (DMAP)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)的一种或多种。无机碱为碳酸铯(Cs2CO3)、碳酸钾(K2CO3)、叔丁醇钾(tBuOK)、叔丁醇钠(tBuONa) 的一种或多种。
进一步地,所述步骤S1中还可以加入α-取代的末端烯烃酰胺摩尔量的2~4%的叔膦物质。
进一步地,所述膦物质为三苯基膦(PPh3),二甲基苯基膦(PPhMe2),三甲基膦(PMe3)等叔磷的一种或多种。
进一步地,所述偶氮甲碱叶立德和α-取代的末端烯烃酰胺的摩尔比为1~2:1。
进一步地,所述银催化剂的添加量为α-取代的末端烯烃酰胺摩尔量的2~4%。
进一步地,所述碱物质的添加量为α-取代的末端烯烃酰胺摩尔量的10~20%。
进一步地,步骤S1中有机溶剂为甲苯。
进一步地,步骤S2中所述氯化钠溶液为饱和氯化钠溶液,所述萃取剂为 CH2Cl2
进一步地,步骤S3中所述有机相干燥用无水Na2SO4干燥;所述洗脱过柱采用乙酸乙酯和石油醚洗脱过柱。
根据上述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物应用于药物抑制剂或药物中间体。
与现有技术相比,有益效果是:
本发明创造性的以不同系列的偶氮甲碱叶立德与α-取代的末端烯烃酰胺为原料,通过一价银盐为催化剂和有机或无机碱的结合,一步实现了消旋体3,6- 二氮杂二环[3.2.1]辛烷衍生物的合成。本发明所述制备方法步骤简单,原料相对现有合成材料廉价易得,腐蚀度低以及毒性较小,而且反应条件简单易实现。根据所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法得到的消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物应用于药物抑制剂或药物中间体。
附图说明
图1是化合物(I)-a的氢谱图;图2是化合物(I)-a的碳谱图;图3是化合物(I)-b 的氢谱图;图4是化合物(I)-b的碳谱图;图5是化合物(I)-c的氢谱图;图6是化合物(I)-c的碳谱图;图7是化合物(I)-d的氢谱图;图8是化合物(I)-d的碳谱图;图9是化合物(I)-e的氢谱图;图10是化合物(I)-e的碳谱图;图11是化合物(I)-f 的氢谱图;图12是化合物(I)-f的碳谱图;图13是化合物(I)-g的氢谱图;图14 是化合物(I)-g的碳谱图;图15是化合物(I)-h的氢谱图;图16是化合物(I)-h的碳谱图;图17是化合物(I)-i的氢谱图;图18是化合物(I)-i的碳谱图;图19是化合物(I)-j的氢谱图;图20是化合物(I)-j的碳谱图;图21是化合物(I)-k的氢谱图;图22是化合物(I)-k的碳谱图;图23是化合物(I)-l的氢谱图;图24是化合物(I)-l的碳谱图;图25是化合物(I)-m的氢谱图;图26是化合物(I)-m的碳谱图;图27是化合物(I)-n的氢谱图;图28是化合物(I)-n的碳谱图;图29是化合物(I)-o 的氢谱图;图30是化合物(I)-o的碳谱图;图31 是化合物(I)-p的氢谱图;图32 是化合物(I)-p的碳谱图。
具体实施方式
下面结合实施例进一步解释和阐明,但具体实施例并不对本发明有任何形式的限定。若未特别指明,实施例中所用的方法和设备为本领常规方法和设备,所用原料均为常规市售原料。
实施例1
本实施例提供消旋体3,6-二氮杂二环[3.2.1]辛烷(I)-a的合成,步骤如下:
Figure BDA0003014401980000041
PMB为4-MeOC6H4CH2
S1.将摩尔量为α-取代的末端烯烃酰胺的2~4mol%银催化剂、摩尔量为α-取代的末端烯烃酰胺的10~20mol%碱物质和摩尔量为α-取代的末端烯烃酰胺的2~4 mol%银催化剂叔膦溶于甲苯中,搅拌5分钟后,依次加入偶氮甲碱叶立德和α- 苯基取代的丙烯酰胺,所述偶氮甲碱叶立德和α-取代的末端烯烃酰胺的摩尔比为 1~2:1,在常温下搅拌,TLC板检测原料消耗完全;
S2.向步骤S1反应完全的溶液体系中加入饱和的食盐水溶液,用CH2Cl2萃取 3次,合并有机相;
S3.向步骤S2所得有机相中加入无水Na2SO4干燥,过滤减压浓缩,用乙酸乙酯和石油醚洗脱过柱,分离得到产物。
实施例2
本实施例根据实施例1提供的方法按照下表所列物质剂参数制备消旋体3,6- 二氮杂二环[3.2.1]辛烷,如下表1所示:
表1
序号 银催化剂 叔膦 碱物质 溶剂 搅拌时间(h) 产品收率(%)
1 Ag<sub>2</sub>O PPh<sub>3</sub> Et<sub>3</sub>N 甲苯 12 29
2 Ag<sub>2</sub>O PPh<sub>3</sub> DBU 甲苯 8 48
3 Ag<sub>2</sub>O PPh<sub>3</sub> DMAP 甲苯 12 31
4 Ag<sub>2</sub>O PPh<sub>3</sub> KO<sup>t</sup>Bu 甲苯 3 53
5 Ag<sub>2</sub>O PPh<sub>3</sub> Cs<sub>2</sub>CO<sub>3</sub> 甲苯 10 27
6 Ag<sub>2</sub>O PPh<sub>3</sub> K<sub>2</sub>CO<sub>3</sub> 甲苯 10 22
7 Ag<sub>2</sub>O PPh<sub>3</sub> TBD 甲苯 2 92
8 Ag<sub>2</sub>O PPh<sub>3</sub> TBD 甲苯 2 92
9 Ag<sub>2</sub>O PPh<sub>3</sub> MTBD 甲苯 2 84
10 Ag<sub>2</sub>CO<sub>3</sub> PPh<sub>3</sub> TBD 甲苯 3 90
11 AgOTf PPh<sub>3</sub> TBD 甲苯 2 45
12 AgOAc PPh<sub>3</sub> TBD 甲苯 2 56
13 AgF PPh<sub>3</sub> TBD 甲苯 2 89
14 PhCO<sub>2</sub>Ag PPh<sub>3</sub> TBD 甲苯 2 83
15 Ag<sub>2</sub>O PPh<sub>3</sub> TBD CH<sub>2</sub>Cl<sub>2</sub> 2 87
16 Ag2O PPh3 TBD THF 5 67
17 Ag<sub>2</sub>O PPh<sub>3</sub> TBD AcOEt 2 83
18 Ag<sub>2</sub>O PPh<sub>3</sub> TBD 1,4-dioxane 3 80
19 Ag<sub>2</sub>O PMe<sub>3</sub> TBD 甲苯 2 83
20 Ag<sub>2</sub>O PPhMe<sub>2</sub> TBD 甲苯 2 86
21 Ag<sub>2</sub>O / TBD 甲苯 2 89
实施例3
根据实施例1记载的制备方法和实施例2序号7所用物质和参数合成以下物质:
Figure BDA0003014401980000061
计算各物质的产品收率如表2:
表2
序号 产品收率(%) 序号 产品收率(%)
(I)-a 92 (I)-i 89
(I)-b 90 (I)-j 94
(I)-c 76 (I)-k 98
(I)-d 82 (I)-l 96
(I)-e 83 (I)-m 90
(I)-f 89 (I)-n 80
(I)-g 90 (I)-o 74
(I)-h 95 (I)-p 91
将上述制备消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物进行氢谱和碳谱表征,所述的产物结构式和表征数据如下:
化合物(I)-a的表征数据
Figure BDA0003014401980000071
1H NMR(400MHz,CDCl3)δ7.45(d,J=8.4Hz,2H),7.33-7.23(m,4H), 7.17-7.14(m,2H),7.08(t,J=7.6Hz,2H),6.89-6.85(m,4H),4.97(d,J=13.2Hz, 1H),4.81(d,J=13.6Hz,1H),4.55(s,1H),4.24(d,J=4.8Hz,1H),3.82(s,3H), 2.83-2.73(m,2H),2.35(brs,1H)。
13C NMR(100MHz,CDCl3)δ174.6,172.2,159.1,137.8,136.4,131.5,128.8,128.5,128.4,127.7,113.8,70.9,60.6,58.9,55.3,42.6,38.9.IR(film)v(cm-1)3366,3043,2946,2347,1732,1680,1611,1511,1450,1295,1247,1145,1031,933.
化合物(I)-b的表征数据
Figure BDA0003014401980000072
1H NMR(400MHz,CDCl3)δ7.52(dd,J=6.2,2.6Hz,2H),7.40-7.22(m,8H), 7.22-7.13(m,2H),7.08(t,J=8.0Hz,2H),6.90(d,J=7.6Hz,2H),5.06(d,J=13.2 Hz,1H),4.88(d,J=13.6Hz,1H),4.59(s,1H),4.29(d,J=4.8Hz,1H),2.87-2.85 (m,2H),2.08(d,J=4.8Hz,2H),1.95(brs,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.2,137.8,136.5,136.3,130.0,128.6,128.5,128.5,128.4,128.3,127.8,127.7,70.9,60.6,58.9,43.3,38.9.IR(film)v(cm-1)3361,3042,2948,2360,1733,1680,1497,1450,1344,1204,1143,1073,934.
化合物(I)-c的表征数据
Figure BDA0003014401980000073
1H NMR(400MHz,CDCl3)δ7.61(s,4H),7.34(d,J=4.8Hz,3H),7.28(d,J=5.4 Hz,2H),7.21(d,J=4.6Hz,2H),7.08(t,J=7.6Hz,2H),6.90(d,J=7.6Hz,2H), 5.07(d,J=13.6Hz,1H),4.91(d,J=13.2Hz,1H),4.65(s,1H),4.30(d,J=4.8Hz, 1H),2.87-2.77(m,2H),2.27(brs,1H).
13C NMR(100MHz,CDCl3)δ174.4,172.3,140.3,137.7,136.1,130.3,130.1,129.7,128.6,128.4,128.3,128.1,127.9,127.8,125.4,125.4,125.4,125.3,122.7,70.4,60.6,58.7,42.7,39.2.IR(film)v(cm-1)3361,3050,2946,2344,1737,1689,1620,1497, 1425,1321,1133,1065,1021,915.
化合物(I)-d的表征数据
Figure BDA0003014401980000081
1H NMR(400MHz,CDCl3)δ7.42(d,J=7.6Hz,2H),7.28-7.34(m,4H),7.18(t, J=6.6Hz,4H),7.10(t,J=7.6Hz,2H),6.92(d,J=7.6Hz,2H),5.02(d,J=13.6 Hz,1H),4.86(d,J=13.2Hz,1H),4.58(s,1H),4.27(d,J=4.8Hz,1H),2.82(dd,J =12.0,4.8Hz,1H),2.78(d,J=12.0Hz,1H),2.40(s,3H),1.73(br.s,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.1,137.8,137.3,136.3,133.5,130.0,129.1,128.5,128.3,127.7,60.6,58.9(d),42.9,38.8,21.1.IR(film):v(cm-1)3428,2939,2352,1734,1720,1680,1447,1344,1226,1126,1042,767,728,585.
化合物(I)-e的表征数据
Figure BDA0003014401980000082
1H NMR(400MHz,CDCl3)δ7.51(dd,J=8.2,5.4Hz 2H),7.28-7.34(m,4H), 7.18-7.20(m,2H),7.11(t,J=7.6Hz 2H),7.03(t,J=8.6Hz 2H),6.90(d,J=8Hz 2H), 5.00(d,J=13.6Hz 1H),4.85(d,J=13.6Hz 1H),4.61(s,1H),4.28(d,J=4.8Hz 1H), 2.84(dd,J=12,4.8Hz 1H),2.77(d,J=12Hz 1H),2.15(brs,1H).
13C NMR(100MHz,CDCl3)δ174.5,172.2,163.5,161.1,137.8,136.2,132.3(d),132.0,131.9,128.6,128.5,128.3,128.2,127.8(d),115.3,115.1,60.6,58.8(d),42.5,39.0.IR(film):v(cm-1)3360,3060,2959,2875,1733,1681,1508,1448,1373, 1343,1263。
化合物(I)-f的表征数据
Figure BDA0003014401980000091
1H NMR(400MHz,CDCl3)δ7.33-7.31(m,6H),7.23-7.19(m,4H),4.65(s,1H), 4.22(d,J=5.2Hz,1H),3.88-3.76(m,2H),2.83-2.79(m,1H),2.71(d,J=11.6Hz, 1H),2.37(brs,1H),1.18(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ174.4,172.0,138.2,136.4,128.7,128.5,128.4,128.2,127.8,127.7,70.3,60.6,59.0,39.2,35.1,12.9.IR(film)v(cm-1)3550,3054,2975, 2360,1732,1680,1497,1450,1352,1314,1231,1120,1081,887.
化合物(I)-g的表征数据
Figure BDA0003014401980000092
1H NMR(400MHz,CDCl3)δ7.44(d,J=8.4Hz,2H),7.30(d,J=4.6Hz,3H), 7.21-7.13(m,2H),6.89-6.87(m,4H),6.78(d,J=7.8Hz,2H),4.96(d,J=13.2Hz, 1H),4.82(d,J=13.4Hz,1H),4.53(s,1H),4.23(d,J=4.6Hz,1H),3.83(s,3H), 2.79-6.75(m,2H),2.30(s,3H),2.21(s,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.2,159.0,138.3,136.4,134.7,131.4,129.3,128.8,128.3,128.1,127.7,113.7,70.7,60.5,58.9,58.8,55.2,55.1,42.6,38.7,21.1.IR(film)v(cm-1)3356,3028,2941,1733,1680,1611,1512,1447,1247,1144, 1107,1301,910.
化合物(I)-h的表征数据
Figure BDA0003014401980000093
1H NMR(400MHz,CDCl3)δ7.42(d,J=8.6Hz,2H),7.35-7.29(m,3H), 7.18-7.14(m,2H),6.99(d,J=8.4Hz,2H),6.86(d,J=8.6Hz,2H),6.78(d,J=8.4 Hz,2H),4.95(d,J=13.2Hz,1H),4.75(d,J=13.4Hz,1H),4.55(s,1H),4.24(d,J =3.2Hz,1H),3.84(s,3H),2.84-2.67(m,2H),2.37(s,1H).
13C NMR(100MHz,CDCl3)δ174.3,171.9,159.1,136.4,136.0,134.1,131.6,129.6,128.6,128.5,128.3,127.9,127.8,113.7,69.7,60.5,58.7,55.3,42.6,39.3.IR(film)v(cm-1)3365,2942,2346,1735,1680,1610,1511,1247,1143,1093,1032, 940.
化合物(I)-i的表征数据
Figure BDA0003014401980000101
1H NMR(400MHz,CDCl3)δ7.38(d,J=8.2Hz,2H),7.32(d,J=3.3Hz,3H), 7.25-7.14(m,3H),7.06(s,1H),6.94(t,J=7.8Hz,1H),6.83(d,J=8.4Hz,2H), 6.73(d,J=7.6Hz,1H),4.91(d,J=13.4Hz,1H),4.80(d,J=13.2Hz,1H),4.55(s, 1H),4.23(d,J=4.2Hz,1H),3.80(s,3H),2.80-2.69(m,2H),2.51(s,1H).
13C NMR(100MHz,CDCl3)δ174.2,171.9,159.0,140.2,136.0,134.1,131.1,129.7,129.0,128.7,128.6,128.2,127.9,127.8,125.9,113.7,69.7,60.6,58.7,58.6,55.3,55.2,42.6,39.4.IR(film)v(cm-1)3352,3040,2935,1735,1680,1609,1510, 1430,1247,1142,1031,924.
化合物(I)-j的表征数据
Figure BDA0003014401980000102
1H NMR(400MHz,CDCl3)δ7.42(d,J=8.4Hz,2H),7.31(d,J=4.2Hz,3H), 7.17-7.13(m,4H),6.86(d,J=8.4Hz,2H),6.73(d,J=8.2Hz,2H),4.95(d,J= 13.4Hz,1H),4.75(d,J=13.4Hz,1H),4.55(s,1H),4.24(d,J=3.0Hz,1H),3.84 (s,3H),2.87-2.67(m,2H),2.15(s,1H).
13C NMR(100MHz,CDCl3)δ174.2,171.9,159.2,137.0,136.0,131.6,131.5,130.0,128.6,128.3,127.9,127.9,122.4,113.8,69.8,60.5,58.8,58.7,55.3,55.2,42.6,39.4.IR(film)v(cm-1)3353,2939,1734,1678,1610,1510,1251,1174,1141, 1102,1028,809.
化合物(I)-k的表征数据
Figure BDA0003014401980000111
1H NMR(400MHz,CDCl3)δ7.82(d,J=8.2Hz,1H),7.73(d,J=8.2Hz,1H), 7.62(d,J=8.6Hz,1H),7.46-7.42(m,3H),7.31-7.19(m,3H),7.11(t,J=7.6Hz, 2H),7.04(t,J=7.8Hz,3H),6.95(t,J=7.6Hz,1H),6.87(d,J=8.4Hz,2H),5.53 (s,1H),5.03(d,J=13.4Hz,1H),4.83(d,J=13.4Hz,1H),4.30(d,J=4.8Hz,1H), 3.84(s,3H),2.99-2.95(m,1H),2.86(d,J=11.8Hz,1H),2.03(s,1H).
13C NMR(100MHz,CDCl3)δ174.5,172.9,159.1,135.9,134.0,133.7,132.4,131.5,128.8,128.7,128.6,127.8,127.7,125.9,125.6,125.4,124.5,123.5,113.8,64.8,64.7,60.5,58.8,58.7,55.3,55.2,42.7,39.1.IR(film)v(cm-1)3387,2940, 1733,1678,1612,1511,1323,1246,1143,1033,785.
化合物(I)-l的表征数据
Figure BDA0003014401980000112
1H NMR(400MHz,CDCl3)δ7.78(d,J=7.8Hz,1H),7.55-7.40(m,7H), 7.35-7.23(m,4H),7.18(d,J=7.4Hz,2H),6.95(d,J=8.4Hz,1H),6.84(d,J=8.6 Hz,2H),4.98(d,J=13.4Hz,1H),4.84(d,J=13.6Hz,1H),4.74(s,1H),4.30(d,J =4.8Hz,1H),3.84(s,3H),2.87-2.83(m,1H),2.77(d,J=11.8Hz,1H),2.48(s, 1H).
13C NMR(100MHz,CDCl3)δ174.5,172.2,159.1,136.2,135.1,133.2,132.9,131.4,128.4,128.3,128.2,128.1,127.8,127.7,127.5,126.3,126.1,125.3,113.8,70.9,60.6,58.9,55.2,42.7,39.0.IR(film)v(cm-1)3352,3036,2946,2251,1732, 1676,1608,1503,1436,1326,1026,921.
化合物(I)-m的表征数据
Figure BDA0003014401980000121
1H NMR(400MHz,CDCl3)δ7.44(d,J=8.4Hz,2H),7.28-7.22(m,2H), 7.12-7.06(m,3H),7.01-6.94(m,2H),6.89-6.81(m,4H),4.97(d,J=13.2Hz,1H), 4.80(d,J=13.6Hz,1H),4.47(s,1H),4.26(d,J=4.8Hz,1H),3.82(s,3H), 2.83-2.78(m,1H),2.72(d,J=12.0Hz,1H),2.48(brs,1H).
13C NMR(100MHz,CDCl3)δ174.3,172.0,163.4,161.0,159.1,137.3,131.9,131.5,130.2,130.1,128.9,128.6,128.5,128.3,114.6,114.4,113.7,71.4,59.9,58.8,55.3,42.7,38.7.IR(film)v(cm-1)3381,3038,2942,2539,1736,1679,1608,1512, 1247,1148,1108,1028,934.
化合物(I)-n的表征数据
Figure BDA0003014401980000122
1H NMR(400MHz,CDCl3)δ7.44(d,J=8.4Hz,2H),7.23(d,J=7.4Hz,1H), 7.08(t,J=7.6Hz,2H),6.88-6.85(m,4H),6.73(d,J=8.0Hz,1H),6.65(d,J=8.4 Hz,1H),6.58(s,1H),5.97-5.84(m,2H),4.96(d,J=13.6Hz,1H),4.79(d,J=13.2 Hz,1H),4.48(s,1H),4.20(d,J=4.4Hz,1H),3.82(s,3H),2.76-2.66(m,2H),2.53 (s,1H).
13C NMR(100MHz,CDCl3)δ174.4,172.2,159.1,147.0,146.9,137.8,131.4,130.1,128.7,128.6,128.5,128.3,121.1,113.7,109.8,107.4,101.0,71.3,60.3,58.8,55.2,42.6,39.1.IR(film)v(cm-1)3364,2925,1732,1679,1611,1509,1436,1342, 1245,1146,1034,929.
化合物(I)-o的表征数据
Figure BDA0003014401980000131
1H NMR(400MHz,CDCl3)δ7.35(d,J=8.4Hz,2H),7.28-7.32(m,6H),7.17(t,J =7.6Hz,2H),7.05(d,J=7.6Hz,2H),6.86(d,J=8.4Hz,2H),4.82(d,J=13.2Hz, 1H),4.71(d,J=13.2Hz,1H),4.45(s,1H),4.09(d,J=4.8Hz,1H),3.85(s,3H), 3.50(d,J=13.6Hz,1H),2.82(d,J=14Hz,1H),2.45(brs,1H),2.18(dd,J=12, 4.2Hz,1H),2.06(d,J=12Hz,1H).
13C NMR(100MHz,CDCl3)δ174.4,172.7,158.9,137.6,137.2,131.1,130.4,129.1,128.4,128.2,126.7,113.6,69.3,58.9,58.9,55.2,42.0,37.8,36.9.IR(film)v(cm-1)3358,3038,2934,1733,1679,1610,1511,1450,1348,1246,1175,1028, 965.
化合物(I)-p的表征数据
Figure BDA0003014401980000132
1H NMR(400MHz,CDCl3)δ7.33(d,J=8.4Hz,2H),7.18(t,J=7.2Hz,1H), 7.07(t,J=7.4Hz,2H),6.95(d,J=7.6Hz,2H),6.82(d,J=8.4Hz,2H),4.79(s, 1H),4.76-4.65(m,2H),4.15(d,J=5.0Hz,1H),4.04(d,J=10.8Hz,1H),3.95(d,J =10.8Hz,1H),3.81(s,3H),2.53(dd,J=11.8,5.2Hz,1H),2.13(d,J=11.8Hz, 1H),1.19-1.05(m,21H),0.97(d,J=3.6Hz,1H).
13C NMR(100MHz,CDCl3)δ174.6,172.8,159.0,137.9,131.2,129.1,128.4,127.9,126.5,113.6,63.4,60.5,59.3,58.9,55.2,41.8,36.0,18.0,11.9.IR(film)v (cm-1)3377,2993,2949,2358,1724,1674,1613,1512,1460,1381,1244,1177, 1079,1030,932.
显然,本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明权利要求的保护范围之内。

Claims (7)

1.一种消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法,其特征在于,所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物通过银催化剂和碱物质催化偶氮甲碱叶立德和α-取代的末端烯烃酰胺一步法反应合成,合成路径如式Ⅰ:
Figure 981437DEST_PATH_IMAGE001
式Ⅰ所述R1~R4任选自烷基、芳基、杂芳基的一种或多种;
所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物制备步骤包括:
S1.将银催化剂、碱物质溶于有机溶剂中,然后加入偶氮甲碱叶立德与α-取代的末端烯烃酰胺,室温下搅拌2~12h,待反应完全;
S2.在步骤S1反应完全的溶液中加入氯化钠溶液,加入萃取剂萃取,得到有机相;
S3.将步骤S2所得有机相干燥,过滤,减压浓缩,洗脱过柱,得到消旋体产物;
所述银催化剂为氧化银、碳酸银、乙酸银、三氟乙酸银、苯甲酸银、氟化银的一种或多种;所述碱物质为1,5,7-三氮杂二环[4.4.0]癸-5-烯、7-甲基-1,5,7-三氮杂二环[4.4.0]癸-5-烯、三乙胺、4-二甲氨基吡啶、1,8-二氮杂二环[5.4.0]十一碳-7-烯、碳酸铯、碳酸钾、叔丁醇钾、叔丁醇钠的一种或多种。
2.根据权利要求1所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法,其特征在于,所述步骤S1中还可以加入α-取代的末端烯烃酰胺摩尔量的2~4%的膦物质。
3.根据权利要求2所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法,其特征在于,所述膦物质为三苯基膦,二甲基苯基膦,三甲基膦的一种或多种。
4.根据权利要求1所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法,其特征在于,所述偶氮甲碱叶立德和α-取代的末端烯烃酰胺的摩尔比为1~2:1。
5.根据权利要求1所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法,其特征在于,所述银催化剂的添加量为α-取代的末端烯烃酰胺摩尔量的2~4%。
6.根据权利要求1所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法,其特征在于,所述碱物质的添加量为α-取代的末端烯烃酰胺摩尔量的10~20%。
7.根据权利要求1所述消旋体3,6-二氮杂二环[3.2.1]辛烷衍生物的制备方法,其特征在于,步骤S1中有机溶剂为甲苯;步骤S2中所述氯化钠溶液为饱和氯化钠溶液,所述萃取剂为CH2Cl2;步骤S3中所述有机相干燥用无水Na2SO4干燥;所述洗脱过柱采用乙酸乙酯和石油醚洗脱过柱。
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"Synthesis of novel bridged dinitrogen heterocycles and their evaluation as potential fragments for the design of biologically active compounds";Konstantin V. Kudryavtsev et al.;《Tetrahedron》;20141231;第70卷;第7854-7864页 *

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