豆腐果苷衍生物或其盐

(19)民国(19)民国家知局(10)(10)CN103059077(43)日(21)(22)(71)申请人大地址610041省市一环路南一24(72)发明人凡(74)专利机构高远知识事人全学荣15/2031/0031/703425/20 权利要求书2页说明书10(57)其结构式如R1选自C1-6的烷基或取代烷基，其中，取代烷基的取代基为C6-10的环烷基或芳R2为-OH或=O。本发明化合物镇静安眠效果明确，其中以化合物b、c1~e1的作CN103059077CN103059077CN103059077权利要求CN103059077R2OH=O物为： CN103059077权利要CN103059077

2/2括如下操作步骤： 豆腐果苷衍生物或其 [0002]豆腐果苷，即4-甲酰苯基-β-D-吡喃(4-fornylphenl-β-D-allopyranosid)是陈维新等在Liebigs.Ann.Chem.,1981,(10)中首次从我国云南山龙眼科植物萝 开号为CN1535690的专利申请中，了豆腐果苷软胶囊及其方法；公开号为 本发明的目的在于提供具有良好生物活性的豆腐果苷衍生物或其盐及其方 R2OH=O。 ： 下操作步骤： 1）按上述方法Ia化合物； [0042]本发明还提供了上述豆腐果苷衍生物或其盐在安眠的药物中的用途[0043]本发明还提供了一种安眠的药物组合物，它是以上述的豆腐果苷衍生物或其[0044]本发明化合物安眠效果明确，其中以化合物bc1~e1的作用更强、持续本发明所说的化合物a-f和a1-f1路线十分简成本较低，产物的收率较能适合于[0050]实施例14-羟乙基苯-(2,3,4,6-四苄氧基)-β-D-吡喃苷(a)的合成[0051]100mL0.11g(30mmol)0.33g(2.3mmol)于20mL无水乙醚中色浑浊后接着反应0.5h然后加入20mL溶解化合物(6)1g(1.6mmol乙醚2h后加30mLNH4Cl搅拌0.5h用乙酸乙Na2SO4a。产率95%,m.p.48-49℃3[0052]1HNMR(CDCl,400MHz)δ:7.18-7.40(m,22H),7.06(dd,J＝2.0Hz,J＝3Hz,2H),5.50(d,J＝7.8Hz,1H),4.78-4.96(m,4H),4.72(dd,J＝2.1Hz,J＝Hz,1H),4.59(dd,J＝1.6Hz,J＝12.2Hz,1H),4.52(s,1H),4.49(s,1H),4.40(dd,J＝Hz,J＝11.5Hz,1H),4.15-4.25(m,2H),3.80(d,J＝10.8Hz,1H),3.64-0-3.95(m,2H),1.72(brs,1H),1.47(d,J＝6.4 2,2967,2864,1610,1508,1453,1377,1088,897,835cm-1;HRMS(ESI)calcdforCHO[M4NH]＋678.3425,found4

42444[0054]100mL0.11g(30.0mmol)0.24g(2.2mmol)于20mL无水乙醚中色浑浊后接着反应0.5h然后加入20mL溶解化合物(6)1g(1.6mmol乙醚2h后加30mLNH4Cl搅拌0.5h用乙酸乙Na2SO4b。产率94%,m.p.47-48℃3 1HNMR(CDCl,400MHz)δ:7.18-7.40(m,22H),7.06(d,J＝3＝7.9Hz,1H),4.91(t,J＝12.5Hz,2H),4.90(d,J＝11.9Hz,1H),4.72(d,J12.1Hz,1H),4.58(d,J＝12.1Hz,1H),4.50-4.56(m,2H),4.49(s,1H),4.39(d,J＝3J＝12.0Hz,2H),1.62-1.88(m,3H),0.88(t,J＝6.0Hz,3H);13CNMR(CDCl362,2918,2865,1611,1510,1454,1382,1236,1091,902,832,740cm-1;HRMS(ESI)calcdCHO[M＋Na]+697.3136,found697.3129,CHO[M＋NH4346 4242 4[0057]100mL0.11g(30.0mmol)0.27g(2.2mmol)于20mL无水乙醚中色浑浊后接着反应0.5h然后加入20mL溶解化合物(6)1g(1.6mmol乙醚2h后加30mLNH4Cl搅拌0.5h用乙酸乙Na2SO4c。产率90%,m.p.38-39℃3[0058]1HNMR(CDCl,400MHz)δ:7.16-7.40(m,22H),7.05(d,J＝7.8Hz,2H),5.45-3,1H),4.90(t,J＝12.2Hz,2H),4.80(d,J＝11.8Hz,1H),4.72(d,J＝＝6.6Hz,2H),4.48(d,J＝12.0Hz,2H),4.38(d,J＝11.5Hz,1H),4.18-7(s,1H),3.79(d,J＝10.7Hz,1H),3.69(dd,J＝4.0Hz,J＝10.2Hz,1H),3.45-H),1.94(brs,1H),1.68-1.80(m,1H),1.55-1.67(m,1H),1.15-1.45(m,3H),0.90(t,J37.2Hz,3H);13CNMR(CDCl39,1510,1454,1382,1308,1093,1060,906,835,737cm-1;HRMS(ESI)calcdforCHO[MNa]＋

44494[0060]100mL0.11g(30.0mmol)0.30g(2.2mmol)于20mL无水乙醚中色浑浊后接着反应0.5h然后加入20mL溶解化合物(6)1g(1.6mmol乙醚2h后加30mLNH4Cl搅拌0.5h用乙酸乙Na2SO4d。产率[0061]1HNMR(CDCl3,400MHz)δ:7.18-7.40(m,22H),7.50(d,J＝＝7.8Hz,1H),4.90(t,J＝12,4Hz,2H),4.80(d,J＝11.9Hz,1H),4.72(d,J＝H),4.55-4.65(m,2H),4.49(d,J＝12.7Hz,2H),4.38(d,J＝11.5Hz,1H),4.22(dd,J4.4Hz,J＝9.6Hz,1H),4.17(s,1H),3.79(d,J＝10.6Hz,1H),3.69(dd,J＝4.6Hz,J10.7Hz,1H),3.53(t,J＝10.2Hz,2H),1.97(brs,1H),1.57-1.82(m,2H),1.12-3,0.86(t,J＝6.6Hz,3H);13CNMR(CDCl3盐片062,2926,1608,1505,1454,1370,1307,1231,1094,911,837,737cm-1;HRMS(ESI)calcdCHO[M＋Na]+725.3449,found725.3450,[M＋NH4550 3[0062]实施例54-羟苯乙基苯-(2,3,4,6-四苄氧基)-β-D-吡喃苷(e)的合成[0063]100mL0.11g(30.0mmol)0.38g(2.2mmol)20mL无水乙醚中室温反出现白色浑浊后接着反应0.5h然后加入20mL溶解化合物萃取无水Na2SO4干燥旋转蒸发除去溶粗品经柱层析分离纯化得油状物e。产率90%。[0064]1HNMR(CDCl,400MHz)δ:7.1-7.4(m,27H),7.04(d,J＝8.4Hz,2H),5.51(dd,J3＝3.1Hz,J＝7.9Hz,1H),4.90(t,J＝11.4Hz,2H),4.76-4.85(m,2H),4.72(d,J＝12.0Hz,1H),4.58(dd,J＝1.6Hz,J＝12.1Hz,1H),4.45-,J＝11.5Hz,1H),4.22(dd,J＝3.2Hz,J＝9.7Hz,1H),4.17(s,1H),3.79(d,J10,8Hz,1H),3.68(dd,J＝4.6Hz,J＝10.7Hz,1H),3.48-3.59(m,2H),2.96(d,J3 3(NaCl 片37cm-1;HRMS(ESI)calcdforCHO[M＋Na]＋759.3292,found759.3291,[M＋NH4848 ＋[0065]实施例6：4-羟异苯-(2,3,4,6-四苄氧基)-β-D-吡喃苷(f)的合成20mL醚中室温反应，出现白色浑浊后05h20mL溶解化合物(6)1g(1.6mmol的乙醚溶室温反应2h后加入30mL和NH4Cl溶液搅拌0.5h用乙酸乙酯萃取，无水Na2SO4干燥，旋转蒸发除去溶剂，粗品经柱层析分离纯化得白色固体f。产率[0067]1HNMR(CDCl3,400MHz)δ:7.15-7.40(m,22H),7.05(d,J＝＝2,7Hz,J＝7.9Hz,1H),4.91(t,J＝12.5Hz,2H),4.80(d,J＝11.9Hz,1H),4.72(d,J12.0Hz,1H),4.58(d,J＝12.1Hz,1H),4.45-4.54(m,2H),4.38(d,J＝11.5Hz,1H),4.2-.3(m,2H),4.17(s,1H),3.80(d,J＝10.7Hz,1H),3.69(dd,J＝4.8Hz,J＝.49-3.58(m,2H),1.83-1.95(m,2H),0.98(d,J＝6.6Hz,3H),0.75(d,J＝1454,1375,1307,1236,1091,1058,931,838,743cm-1;HRMS(ESI)calcdforC44H48O7[MNa]+711.3292,found711.3280,[M＋NH4]＋3[0068]实施例74-乙酰基苯-(2,3,4,6-四苄氧基)-β-D-吡喃苷(a1)的合成[0069]50mL1ga(1.5mmol)2.6(30mmol)25mL二氯甲烷中搅拌回流12h反应结束后过虑除去二氧化有机层用无水Na2SO4干a180%,m.p.51-52℃。[0070]1HNMR(CDCl,400MHz)δ:7.90(d,J＝8.7Hz,2H),7.2-7.4(m,20H),7.09(d,J3＝8.7Hz,2H),5.58(d,J＝7.8Hz,1H),4.87(dd,J＝6.1Hz,J＝11.8Hz2H),4.80(d,J11.4Hz,2H),4.40(d,J＝11.5Hz,1H),4.16-4.28(m,2H),3.80(d,J＝3＝4.8Hz,J＝10.7Hz,1H),3.52-3.60(m,2H),2.55(s,3H);13CNMR(CDCl34242497,1454,1355,1269,1094,1020,975,848,734cm-1;HRMS(ESI)calcdforCHO[M4242681.2823,found681.2842,CHO[M＋42423[0071]实施例84-丙酰基苯-(2,3,4,6-四苄氧基)-β-D-吡喃苷(b1)的合成[0072]50mL1gb(1.5mmol)2.6(30mmol)25mL二氯甲烷中搅拌回流12h反应结束后过虑除去二氧化有机层用无水Na2SO4干b180%,m.p.44-45℃。[0073]1HNMR(CDCl,400MHz)δ:7.91(d,J＝8.4Hz,2H),7.20-7.40(m,20H),7.08(d,3＝11.8Hz,1H),4.72(d,J＝12.1Hz,1H),4.58(d,J＝12.1Hz,1H),4.50(dd,J＝6.2Hz,J＝11.4Hz,2H),4.40(d,J＝11.5Hz,1H),4.25(dd,J＝4.4Hz,J9.6Hz,1H),4.18(s,1H),3.95(d,J＝10.6Hz,1H),3.65-3.75(m,1H),3.56(t,J＝9.5Hz,2H),2.94(dd,J＝7.2Hz,J＝12.5Hz,2H),1.21(t,J＝,733cm-1;HRMS(ESI)calcdforCHO[M＋

HO[M43444NH4

4242[0074]实施例94-丁酰基苯-(2,3,4,6-四苄氧基)-β-D-吡喃苷(c1)的合成[0075]50mL1gc(1.5mmol)2.6(30mmol)25mL二氯甲烷中搅拌回流12h反应结束后过虑除去二氧化有机层用无水Na2SO4干c182%,m.p.39-40℃。[0076]1HNMR(CDCl3,400MHz)δ:7.90(d,J＝7.9Hz,2H),7.37-7.42(m,20H),7.09(d,J＝8.0Hz,2H),5.59(d,J＝7.7Hz,1H),4.88(dd,J＝7Hz,J＝＝11.8Hz,1H),4.72(d,J＝12.1Hz,1H),4.58(d,J＝12.6Hz,1H),4.50(dd,J6.1Hz,J＝11.3Hz,2H),4.40(d,J＝11.5Hz,1H),4.22-1(d,J＝10.8Hz,1H),3.70(dd,J＝4.2Hz,J＝＝7.2Hz,2H),1.75(dd,J＝7.3Hz,J＝14.5Hz,,2H),0.99(t,J 9,734cm-1;HRMS(ESI)calcdforCHO[M＋Na]＋44463[0077]实施例104-戊酰基苯-(2,3,4,6-四苄氧基)-β-D-吡喃苷(d1)的合成[0078]50mL1gd(1.5mmol)2.6(30mmol)25mL二氯甲烷中搅拌回流12h反应结束后过虑除去二氧化有机层用无水Na2SO4干d192%,m.p.31-32℃。[0079]1HNMR(CDCl,400MHz)δ:7.81(d,J＝7.7Hz,2H),7.18-7.32(m,20H),6.99(d,3J＝7.5Hz,2H),5.50(d,J＝7.8Hz,1H),4.78(dd,J＝6.5Hz,J＝＝11.4Hz,2H),4.31(d,J＝11.5Hz,1H),4.13-4.20(m,1H),4.10(s,1H),3.72(d,J10.7Hz,1H),3.60(dd,J＝4.6Hz,J＝10.6Hz,1H),3.43-3.52(m,2H),2.80(t,J＝32H),1.55-1.67(m,2H),1.25-1.37(m,2H),0.86(t,J＝7.2Hz,3H);13CNMR(CDCl32,731cm-1;HRMS(ESI)calcdforCHO[M＋Na]+723.3292,found723.3285,[M＋NH]

4548 3[0081]50mL1ge(1.5mmol)2.6(30mmol)25mL二氯甲烷中搅拌回流12h反应结束后过虑除去二氧化有机层用无水Na2SO4干e183%,m.p.35-36℃[0082]1HNMR(CDCl,400MHz)δ:7.9-8.0(m,2H),7.0-7.45(m,27H),5.55-5.65(m,1H),334.35-4.95(m,12H),