新型羟基双氢青蒿素衍生物及其应用_2

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M+Na]+(calcdforC33H34F2Na08,619. 2114).
[0071] 实施例4 :9a,12a-二_(对氯肉桂酸)双氢青蒿素酯的制备
[0072] 按照实施例1的方法,用原料对氯肉桂酸代替实施例1中的原料肉桂酸而制备标 题化合物。
[0073] 白色粉末,产率 50%。4NMR(400MHz,Chloroform-d)S= 7. 72(d,J= 16. 0, lH),7.65(d,J= 16.0,lH),7.46(dd,J= 8.4,5.9,4H),7.40-7.33(m,4H),6.45(d,J =16.0,1H),6.40 (d,J= 16.0,1H),5.92 (d,J= 9.8,1H),5.59 (s,lH),4.62 (td,J= 10. 8,4. 4, 1H),2. 76-2. 60(m,1H),2. 51-2. 37(m,1H),2. 21-2. 03(m,2H),2. 00-1. 87(m, 2H),1. 72-1. 51(m,4H),1. 45(s,3H),1. 00(d,J= 6. 2,3H),0? 89(d,J= 7. 1,3H).13C 匪R(101MHz,Chloroform-d)S= 166.24,165.18,144.76,143.86,136.51,136.42, 132. 76,132. 74,129. 37,129. 29,129. 24, 118. 44,118. 03,104. 61,91. 88,91. 20,79. 09, 75. 60,49. 04,42. 74,41. 36, 36. 07, 31. 67, 27. 54, 25. 90, 24. 57,15. 43,12. 03.HRES頂Sm/z 651. 1517 [M+Na]+(calcdforC33H34Cl2Na08,651. 15 2 3).
[0074] 实施例5 :9a,12a-二_(对溴肉桂酸)双氢青蒿素酯的制备
[0075] 按照实施例1的方法,用原料对溴肉桂酸代替实施例1中的原料肉桂酸而制备标 题化合物。
[0076] 白色粉末,产率 42%。4NMR(400MHz,Chloroform-d)S= 7. 73(d,J= 16. 0, 1H),7. 65 (d,J= 16. 0,1H),7. 58-7. 51 (m,4H),7. 42 (dd,J= 8. 4, 5. 8,4H),6. 49 (d,J= 16. 0,1H),6. 44 (d,J=16. 0,1H),5. 95 (d,J=9. 8,1H),5. 61(s,1H),4. 65 (td,J=10. 8, 4. 4,1H),2. 70(dtt,J= 14. 3,7. 1,3. 8,1H),2. 51-2. 39(m,1H),2. 15(ddd,J= 21. 8, 11. 8,7. 7,2H),1. 94(dt,J= 9. 1,4. 5,2H),1. 62(m,4H),1. 48(s,3H),1. 03(d,J= 6. 2, 3H),0? 92(d,J= 7. 1,3H).13CNMR(101MHz,Chloroform-d)S= 166. 23,165. 17,144. 84, 143. 93,133. 16,132. 22,129. 57,129. 50, 118. 55,118. 14,104. 62,91. 88,91. 20,79. 09, 75. 61,49. 04,42. 74,41. 36, 36. 07, 31. 67, 27. 54, 25. 90, 24. 57,15. 44,12. 03.HRES頂Sm/z 739. 0499 [M+Na] +(calcdforC33H34Br2Na08, 7 39 . 05 1 3).
[0077] 实施例6 :9a,12a-二_(对甲氧基肉桂酸)双氢青蒿素酯的制备
[0078] 按照实施例1的方法,用原料对甲氧基肉桂酸代替实施例1中的原料肉桂酸而制 备标题化合物。
[0079] 白色粉末,产率 44%。4NMR(400MHz,Chloroform-d)S= 7. 73(d,J= 16. 0, 1H),7. 66 (d,J= 16. 0,1H),7. 49 (dd,J= 8. 6,6. 0,4H),7. 01-6. 81 (m,4H),6. 35 (d,J= 16. 0,1H),6. 30 (d,J= 16. 0,1H),5. 93 (d,J= 9. 8,1H),5. 59 (s,1H),4. 62 (td,J= 10. 8, 4. 4,1H),3. 84 (s,3H),3. 84 (s,3H),2. 76-2. 61 (m,1H),2. 51-2. 36 (m,1H),2. 13 (ddd,J= 21. 2,10. 6,4. 2, 2H),2. 01-1. 83 (m,2H),1. 70-1. 51 (m,4H),1. 46 (s,3H),1. 00 (d,J= 6. 2, 3H),0? 89(d,J= 7. 1,3H).13CNMR(101MHz,Chloroform-d)S= 166. 84,165. 72,161. 61, 161. 55,145. 90,144. 96,129. 92,129. 82,127. 04,115. 32,114. 90,114. 39,104. 56,91. 66, 91. 21,79. 19,75. 22,55. 38,49. 10,42. 79,41. 42,36. 11,31. 74, 27. 61,25. 92,24. 59, 15. 44,12. 04.HRESIMSm/z643. 2506 [M+Na]+(calcdforC35H40Na010,643. 2514).
[0080] 实施例7 :9a,12a-二-(对硝基肉桂酸)双氢青蒿素酯的制备
[0081] 按照实施例1的方法,用原料对硝基肉桂酸代替实施例1中的原料肉桂酸而制备 标题化合物。
[0082] 黄色粉末,产率 40%。4NMR(400MHz,Chloroform-d)S= 8. 29(dd,J= 8. 7, 3.6,4H),7.83(d,J= 16.1,lH),7.75(d,J= 17.5,1H),7. 72-7. 68(m,4H),6.63(d,J =16.1,1H),6.58 (d,J= 16.0,1H),5.96 (d,J= 9.8,1H),5.62 (s,lH),4.67 (td,J= 10. 8,4. 4, 1H),2. 82-2. 67 (m,1H),2. 55-2. 36 (m,1H),2. 25-2. 08 (m,2H),2. 03-1. 85 (m, 2H),1. 76-1. 53(m,4H),1. 48(s,3H),1. 04(d,J= 6. 2,3H),0? 93(d,J= 7. 1,3H).13C MMR(101MHz,Chloroform-d)S= 165.54,164.54,148.71,148.67,143.22,142.37, 140. 29,140. 23,128. 79,128. 71,124. 23, 122. 11,121. 70,104. 70,92. 16,91. 21,79. 00, 76. 05,48. 99,42. 69,41. 31,36. 03, 31. 61,27. 48, 25. 87, 24. 55,15. 45,12. 03.HRES頂Sm/z 673. 1995 [M+Na]+(calcdforC33H34N2Na012,673. 2004).
[0083] 实施例8 :9a,12a_二_(对三氟甲基肉桂酸)双氢青蒿素酯的制备
[0084] 按照实施例1的方法,用原料对三氟甲基肉桂酸代替实施例1中的原料肉桂酸而 制备标题化合物。
[0085] 白色粉末,产率 53%。4NMR(400MHz,Chloroform-d)S= 7. 79(d,J= 16. 1, 1H),7. 71(d,J= 16. 1,1H),7. 67-7. 58(m,8H),6. 56(d,J= 16. 1,1H),6. 51(d,J= 16. 0, 1H),5. 94 (d,J= 9. 8,1H),5. 60 (s,1H),4. 64 (td,J= 10. 8,4. 4,1H),2. 50-2. 38 (m,1H), 2. 21-2. 07(m,2H),1. 94(dq,J= 12. 1,4. 5,2H),1. 73-1. 51 (m,5H),1. 46(s,3H),1. 02(d, J= 6.2,3H),0.91 (d,J= 7.1,3H).13C匪R(101MHz,Chloroform-d)S= 165.94, 164. 89,144. 34,143. 45,137. 60,137. 56,132. 14,131. 87,128. 33,128. 26,125. 98,125. 95, 125. 91,125. 87,125. 14,122. 43, 120. 41,119. 99, 104. 67,92. 01,91. 21,79. 06,75. 80, 49. 00,42. 71,41. 33,36. 05,31. 65, 27. 51,25. 89,24. 56, 15. 45, 12. 04.HRESIMSm/z719. 2037 [M+Na] +(calcdforC35H34F6Na08, 7 1 9 . 20 5).
[0086] 实施例9 :9a,12a_二_(邻甲氧基肉桂酸)双氢青蒿素酯的制备
[0087] 按照实施例1的方法,用原料邻甲氧基肉桂酸代替实施例1中的原料肉桂酸而制 备标题化合物。
[0088] 白色粉末,产率 44%。4NMR(400MHz,Chloroform-d)S= 8. 07(d,J= 16. 3, lH),8.02(d,J= 16.2,lH),7.53(ddd,J= 10.0,7.7,1.7,2H),7.38(dddd,J= 8.4, 7.4,4.5,1.7,2H),7.04-6.90(m,4H),6.63(d,J= 16.2,lH),6.55(d,J= 16.2,1H), 5. 97 (d,J=9. 8,1H),5. 62(s,1H),4. 66 (td,J=10. 8,4. 4,1H),3. 93(s,3H),3. 91(s,3H), 2. 45(s,1H),2. 25-2. 04 (m,2H),1. 95 (dt,J=15. 0, 4. 4, 2H),1. 78-1. 52 (m,5H),1. 49(s, 3H),1.03(d,J= 6.2,3H),0.92 (d,J= 7.1,3H).13CNMR(101MHz,Chloroform-d)S= 167. 05,165. 99,158. 58,158. 44,141. 79,140. 72,131. 68,131. 63,129. 39,129. 10,123. 29, 120. 73, 120. 70, 118. 41,118. 10, 111. 17, 104. 55,91. 67,91. 24, 79. 23,75. 20,55. 50, 55. 45,49. 11,42. 81,41. 41,36. 12,31. 77,27. 62,25. 95,24. 59,15. 45,12. 06.HRESIMSm/z 643. 2503 [M+Na] +(calcdforC35H40Na010,643. 2514).
[0089] 实施例10 :9a,12a_二_(邻氯肉桂酸)双氢青蒿素酯的制备
[0090] 按照实施例1的方法,用原料邻氯肉桂酸代替实施例1中的原料肉桂酸而制备标 题化合物。
[0091] 白色簇状结晶,产率 50%。4NMR(400MHz,Chloroform-d)S= 8. 19(d,J= 16. 0,1H),8. 14 (d,J= 16. 0,1H),7. 65 (ddd,J= 9. 7, 7. 4, 2. 0, 2H),7. 45 (ddd,J= 7. 5, 5. 7,1. 6,2H),7. 33(dddd,J= 11. 1,9. 4,5. 0,2. 6,4H),6. 52(d,J= 16. 0,1H),6. 46(d,J= 16. 0,1H),5. 95 (d,J=9. 8,1H),5. 62 (s,1H),4. 66 (td,J=10. 9,4. 5,1H),2. 77-2. 65 (m, 1H),2. 52-2. 38 (m,1H),2. 25-2. 05 (m,2H),1. 96 (dt,J= 14. 3,4. 5,2H),1. 80-1. 54 (m, 4H),1. 48(s,3H),1. 04(d,J= 6. 2,3H),0? 94(d,J= 7. 1,3H).13CNMR(101MHz, Chloroform-d)S= 166. 05,164. 99,142. 04,141. 11,135. 11,135. 06,132. 55,131. 28, 131. 22,130. 22,127. 78,127. 70,127. 13, 120. 47,120. 10,104. 62,91. 96,91. 21,79. 12, 75. 71,49. 06,42. 75,41. 33,36. 08,31. 66,27. 52,25. 93,24. 55,15. 44,12. 08.HRESIMSm/z 651. 1517 [M+Na] +(calcdforC33H34Cl2Na08,651. 15 2 3).
[0092] 实施例11 :9a,12a_二_(邻氟肉桂酸)双氢青蒿素酯的制备
[0093] 按照实施例1的方法,用原料邻氟肉桂酸代替实施例1中的原料肉桂酸而制备标 题化合物。
[0094] 白色粉末,产率 60%。4NMR(400MHz,Chloroform-d)S= 7. 90(d,J= 16. 2, 1H),7. 83 (d,J= 16. 2,1H),7. 55 (qd,J= 7. 9,1. 5, 2H),7. 37 (dddd,J= 10. 2,8. 5, 3. 3, 1.7,2H),7.22-7.06(m,4H),6.60(d,J= 16.2,1H),6.54 (d,J= 16.2,1H),5.94 (d,J =9. 8,1H),5. 60 (s,1H),4. 64 (td,J= 10. 8,4. 4,1H),2. 76-2. 63 (m,1H),2. 50-2. 36 (m, 1H),2. 17 (dt,J= 12. 8,4. 4,1H),2. 08 (dd,J= 14. 8,4. 0,1H),1. 94 (dt,J= 14. 7, 4.5,2H),1.73-L51(m,5H),L46(s,3H),1.01(d,J= 6.2,3H),0.91(d,J= 7. 1,3H).13C 匪R(101MHz,Chloroform-d)S= 166. 36,165. 27,162.72,162.67,160.19,160. 1
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