具有抗肿瘤作用的化合物及其制备方法和应用_3

文档序号:9559546阅读:来源:国知局
97 (m,1H,H-18),3. 22 (m,1H,H-3),5. 37 (brs,1H,H-12),7. 38 (m,2H, H-6 ' &H-7 ' ),7. 52 (m,1H,H-8 ' ),8. 05 (d,1H,H-5 ' ),1. 00-2. 30 (22H,methyl-and methylene-of triterpenoid structure). 13C-NMR(CDC13) δ (ppm) :15.51,15.73,17.42, 18. 45,23. 26,23. 60,23. 66,25. 88,27. 31,28. 20,28. 25,30. 79,32. 56,32. 98,33. 07, 33. 81,37. 15,38. 64,38. 90,39. 60,41. 73,42. 04,45. 61,47. 70,47. 75,55. 38,79. 12(C-3), 108. 29 (C-12), 120. 65 (C-13), 124. 05 (C-8 ' ),124.75(05 ' ),128.60(07 '), 128.91(06 ' ),142.24(C-9 ' ),143. 69 (C_4 ' ), 173. 78 (C-28). IR(KBr, cm vnax3432. 85,2940. 47,2862. 98,1811. 19,1630. 87,1464. 26,1445. 19,1386. 49,1281. 08, 1246. 51,1140. 68,1087. 06,1048. 92,1000. 75,958. 57,859. 83,797. 52,782. 25,742. 82. HRMS(ESI)m/z :574. 40155 [M+H]+, calcd. for C36H51N3035 74. 39 6 40.
[0094] 实施例10化合物T0A-X3 (化合物10)的合成
[0095] 圆底瓶中依次加入498. 37mg(lmmol)乙酰基齐墩果酸、4. 85mL(l. 5mmol)TMP_NH2的 CH2C12 溶液、287. 55mg(l. 5mmol)EDCI、625. 49μ L(4. 5mmol)三乙胺和 135. 13mg(lmmol) Η0ΒΤ;再加入20mL二氯甲烷,常温搅拌反应12h。TLC[V(石油醚):V(丙酮)=2 : 1] 检测反应基本完全,反应液用饱和食盐水清洗,干燥,硅胶柱分离得白色固体,收率:51 %, m. p > 21(TC〇
[0096] i-NMlUCDClySOOMHz) δ (ppm) :〇· 85,0.86,0.88,0.93,0.97,0.99,1.21 (s,each, 3H,7 X CH3),2. 05 (s,3H,CHf〇-),2. 20 (m,2H,H-2),2. 97 (m,1H,H-18),4. 50 (m,1H,H-3), 5.37(brs,lH,H-12),7.38(m,2H,H-6,&H-7,),7.52 (m,lH,H-8,),8.05 (d,lH,H-5,), 1. 00-2. 30(20H, methyl-and methylene-〇f triterpenoid structure). 13C-NMR(CDC13) δ (ppm) :15. 57,16. 83,17. 38,18. 32,21. 47,23. 24,23. 59,23. 65,23. 65,25. 83,28. 17, 28. 17,30. 78,32. 55,32. 89,33. 06,33. 80,37. 03,37. 82,38. 30,39. 60,41. 72,42. 01, 45. 55,47. 62,47. 73, 55. 44,80. 98 (C-3),108. 28 (C-12),120. 65 (C-13),123. 95 (C-8 '), 124. 74(C-5/ ), 128. 58(C-7 ; ), 128. 88 (C-6 ; ), 142. 23 (C-9 ; ), 143. 69 (C-4 ;), 171. 19(CH3⑶-),173. 78(C-28). IR(KBr,cm 41,2944. 56, 1803. 74,1729. 92, 1635. 02,1465. 27,1395. 22,1248. 68,1085. 97,1026. 87,1003. 70,857. 79,781. 26,740. 10. HRMS(ESI)m/z :616. 41187[M+H]+, calcd. for C38H53N304 6 1 6 . 40 6 96.
[0097] 实施例11化合物T0A_X4(化合物11)的合成
[0098] 圆底瓶中依次加入 456. 36mg(lmmol)熊果酸、4. 85mL(1. 5mmol)TMP_NH2 的 CH2C12溶液、287. 55mg(l. 5mmol)EDCI、625. 49μ L(4. 5mmol)三乙胺和 135. 13mg(lmmol)H0BT ;再 加入20mL二氯甲烧,常温搅拌反应12hTLC[V(石油醚):V(丙酮)=2 : 1]检测反应基 本完全,反应液用饱和食盐水清洗,无水硫酸钠干燥,硅胶柱分离得白色固体,收率:36%, m. ρ149· 5 ~150. rC〇
[0099] 匪R(CDC13,500MHz) δ (ppm) :〇· 79,0· 90,0· 92,0· 93, 1· 00, 1· 02, 1. 17(s, each,3H,7XCH3),2· 38(m,1Η,Η-18),3· 22(m,1Η,Η-3),5· 37(brs,1Η,Η-12),7· 38(m,2H, Η-6 ' &Η-7 ' ),7· 51(m,1Η,Η-8 ' ),8· 04(d,1Η,Η-5 ' ),1· 00-2. 30(22Η,methyl-and methylene-〇f triterpenoid structure). 13C-NMR(CDC13) δ (ppm) :15.70,15.78,17.05, 17. 67, 18. 43,21. 20,23. 51,23. 53,24. 49, 27. 36,28. 29,28. 53,29. 84, 30. 65,33. 35, 36. 84, 37. 11,38. 85, 38. 90, 39. 19, 39. 83,42. 44,47. 68,49. 26, 53. 14, 55. 40, 79. 16 (C-3), 108. 33(C-12),120. 65(C-13),124. 73(C-8 ' ),127.26(05 ' ),128.53(07 '), 128.89(06 ' ),136.96(C-9 ' ),143. 69 (C_4 ' ),173. 52 (C-28) · IR (KBr,cm_l) vnax3439. 95,2926. 68,2871. 13,1806. 68,1636. 08,1457. 64,1399. 09,1088. 14,1047. 84, 1020. 69,1002. 56,963. 24,781. 44,742. 16. HRMS(ESI)m/z :574. 40125[M+H] + , calcd. for C36H51N303 5 74. 39 6 40.
[0100] 实施例12化合物T0A-X5 (化合物12)的合成
[0101] 圆底瓶中依次加入 468. 32mg (lmmol) 3-氧代甘草次酸、4. 85mL (1. 5mmol) TMP_NH2的 CH2C12 溶液、287. 55mg(l. 5mmol)EDCI、625. 49μ L(4. 5mmol)三乙胺和 135. 13mg(lmmol) HOBT;再加入20mL二氯甲烷,常温搅拌反应12h。TLC[V(石油醚):V(丙酮)=2 : 1] 检测反应基本完全,反应液用饱和食盐水清洗,干燥,硅胶柱分离得白色固体,收率:64%, m. p > 21(TC〇
[0102] i-NMlUCDClySOOMHz) δ (ppm) :0·79,1·05,1·09,1· 14,1· 19,1.25,1.37(s,each, 3Η,7 X CH3),2· 26&2· 35 (m,2Η,Η-2),2· 45 (s,1Η,Η-9),2· 46 (s,3Η,CH3-5 ' ),2· 50 (s,3Η, CH3-6 ' ),2· 55(s,3H,CH3-3 ' ),2· 95(m,1H,Η-18),4· 50(m,2H,CH2-2 ' ),5· 74(brs, 1H, H-12),7. 51(s,1H, N-H),1. 00-2. 30(17H, methyl-and methylene-〇f triterpenoid structure) .13C-匪R(CDC13) δ (ppm) :15. 74,18. 60,18. 88,23. 61,26. 48,26. 53,26. 62, 28. 68,28. 68, 29. 80,31. 57,32. 03,32. 23,34. 35,36. 80,37. 66,39. 88,41. 05,43. 46, 44. 04,45. 34,47. 91,48. 11,55. 57,61. 20,128. 50(C-12), 169. 96(C-13), 175. 92 (C-30), 199. 35(C-11) ,217. 28(C-3) ;pyrazine ring :20. 05(CH3-3 ; ), 21. 56 (CH3-5 ;), 21. 79 (CH3-6, ),42. 11 (-CH2-2, ),145. 01 (C-3' ),147. 65 (Οδ' ),148. 25 (C-6'), 149. 81(C-2 ; ). IR(KBr, cm vnax3431. 81,2956. 00, 2866. 57,1704. 48,1667. 60,1647. 33, 1517. 07, 1451. 93, 1402. 71,1387. 07, 1327. 95, 1279. 36, 1246. 25, 1203. 45,1182. 01, 1109. 80,997. 94. HRMS(ESI)m/z :602. 43152 [M+H]+, calcd. for C38H55N303 602. 42770.
[0103] 实施例13化合物T0A-X6 (化合物13)的合成
[0104] 圆底瓶中依次加入 470. 34mg(lmmol)甘草次酸、4. 85mL(1. 5mmol)TMP-NH2 的 CH2C12 溶液、287. 55mg(l. 5mmol)EDCI、625. 49μ L(4. 5mmol)三乙胺和 135. 13mg(lmmol) Η0ΒΤ;再加入20mL二氯甲烷,常温搅拌反应12h。TLC[V(石油醚):V(丙酮)=2 : 1] 检测反应基本完全,反应液用饱和食盐水清洗,无水硫酸钠干燥,硅胶柱分离得白色固体, 收率:67%,m.p > 21(TC。
[0105] i-NMlUCDClySOOMHz) δ (ppm) :0·77,0·79,0·99,1·09,1· 11,1· 19,1.39(s,each, 3H,7XCH3),2.35(s,1H,H-9),2.47(s,3H,CH3-5 ' ),2.50(s,3H,CH3-6 ' ),2.55(s,3H, CH3-3 ' ),2. 77(m,1H,H-18),3. 22(m,1H,Η-3),4· 41&4. 54(m,2H,CH2-2 ' ),5. 69(brs, 1H, H-12),7. 52(s,1H, N-H),1. 00-2. 30(19H, methyl-and methylene-〇f triterpenoid structure) .13C-匪R(CDC13) δ (ppm) :15. 72,16. 47,17. 58,18. 73, 23. 67,26. 54, 26. 56, 27. 40,28. 21,28. 64,29. 80,31. 54,32. 02,32. 85,37. 116,37. 67,39. 26,39. 29,41. 02, 43. 34,44. 05,45. 50,48. 10,55. 06,61. 96,78. 85(C-3), 128. 58(C-12), 169. 46(C-13), 175. 98(C-30) ,200. 08(C-11) ;pyrazine ring :20. 03(CH3-3 ; ), 21. 53 (CH3-5 ;), 21.76(CH3-6/ ), 42. 07 (-CH2-2 ; ), 145. 04 (C-3 ; ), 147. 64 (C-5 ; ), 148. 30 (C-6 ;), 149. 82(C-2 ; ). IR(KBr, cm 1)vnax3422. 62,2949. 6
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