手性呋喃并α,β-不饱和环酮、其制备方法及应用转让专利
申请号 : CN201210435434.5
文献号 : CN102924465B
文献日 : 2015-02-18
发明人 : 刘丰五 , 孟诗尧 , 贾永康 , 刘宏民
申请人 : 郑州大学
摘要 :
权利要求 :
1.手性呋喃并α,β-不饱和呋喃酮衍生物,其特征在于,具有如下通式:
通式1, 通式2
其中, R 取氢、对甲砜基、间甲氧基,3,4,5-三甲氧基、间氯、3,4-二氟、4-异丙基。
2.依照权利要求1所述手性呋喃并α,β-不饱和呋喃酮衍生物,其特征在于,通式1构型分别为:3S, 4R, 5R, 8R;通式2构型分别为3S, 4R, 5R, 8S ;C1-C7双键为Z式构型。
3.制备权利要求1所述通式1或2所示化合物的方法,其特征在于,将1:4,3:6-二缩水果糖和苯甲醛或取代苯甲醛溶于有机溶剂中,在碱性催化剂存在下,20-100℃反应,反应结束后,柱层析分离依次得到通式1和2所示化合物;有机溶剂为二氯甲烷、氯仿、四氢呋喃、二氧六环、乙腈、乙醇、甲醇、异丙醇、N,N-二甲基甲酰胺中的一种或二种;
所述的取代苯甲醛取代基分别为对甲砜基、间甲氧基,3,4,5-三甲氧基、间氯、3,4-二氟、4-异丙基;所述碱性催化剂为三乙胺、1,8-二氮杂二环-双环(5,4,0)-7-十一烯、吡啶、三丙胺、三乙醇胺、乙醇钠或甲醇钠中的一种,或为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、氟化钾、氟化钠、三氧化二铝中的一种或两种的混和物。
4.按照权利要求3所述的制备通式1或2所示化合物的方法,其特征在于,反应温度选
40-70℃。
5.手性呋喃并α,β-不饱和吡喃酮衍生物,其特征在于,具有如下通式:
通式3
其中, R 取氢、间甲氧基,3,4,5-三甲氧基、间氯、3,4-二氟、4-异丙基。
6.依照权利要求5所述手性呋喃并α,β-不饱和吡喃酮衍生物,其特征在于,所述化合物的立体构型为:3R, 3aR;C5-C8为Z 式构型,C7-C7a为E 式构型。
7.制备权利要求5所述通式3所示化合物的方法,其特征在于,将通式1或2所示化合物或通式1和2所示化合物的混合物溶于有机溶剂中,加入Lewis酸,0-80℃反应,反应结束后,减压浓缩反应液, 柱层析分离得到通式3所示产物;所述有机溶剂为二氯甲烷、氯仿、四氢呋喃、二氧六环、乙腈、乙醇、甲醇、异丙醇、N,N-二甲基甲酰胺中的一种或二种的混合物;所用Lewis酸为无水三氯化铝、无水氯化锌、四氯化锡、三氟甲磺酸三甲基硅酯、三氟化硼乙醚中的一种或两种的混合物。
8.如权利要求1或5所述的手性呋喃并α,β-不饱和环酮衍生物的用途,其特点在于,作为活性成份,用于制备抗菌药物、抗肿瘤药物或作为制备抗肿瘤药物或抗菌药物的先导物使用。
说明书 :
手性呋喃并α,β-不饱和环酮、其制备方法及应用
技术领域
背景技术
发明内容
附图说明
具体实施方式
1中R为氢时所示手性α,β-不饱和酮衍生物(1a)210 mg(收率31%)和通式2中R为氢时所示手性α,β-不饱和酮衍生物(2a)196 mg (收率29%)。
13
H-6a), 3.29 (t, 1H,J = 7.8 Hz, H-6b), 3.26 (m, 1H, H-5). C NMR (100.6 MHz, DMSO-d6) δ 199.2 (C-2), 148.3 (C-1), 140.8, 133.9, 130.8, 129.0,128.9, 128.3,
127.2(aromatic C), 105.3(C-7), 86.7(C-3), 82.2(C-4), 71.4(C-5), 71.2(C-6), +
70.5(C-8). HRMS: Calcd for C20H18O5: 338.1154, found: m/z 339.1228 [M+H].[0049] 2a: 粘稠物, 1H NMR (400.1 MHz, CDCl3): δ 7.67 (d, 2H, J = 7.2 Hz, aromatic H), 7.34 (m, 8H, aromatic H), 6.36 (s, 1H, H-7), 5.25 (s, 1H, H-8),
5.06 (d, 1H, J = 5.2 Hz, H-4), 4.37 (m, 1H, H-5), 4.21(dd, 1H, J = 9.2, 6.8 Hz, H-6a), 3.55 (t, 1H, J = 8.8 Hz, H-6b), 3.46 (br, 1H, 8-OH), 2.57(br, 1H,
13
5-OH). C NMR (100.6MHz, CDCl3): δ197.4 (C-2), 146.6(C-1), 136.5, 132.9,
130.7, 129.3, 128.8, 128.7, 128.6, 126.9(aromatic C), 108.9 (C-7), 88.3 (C-3), 80.9 (C-4), 72.6 (C-5), 72.5 (C-6), 72.2 (C-8). HRMS: Calcd for C20H18O5: +
338.1154, found: m/z 339.1239 [M+H].
13
1H, 3-OH). C NMR (100.6 MHz, CDCl3) δ 179.9 (C-6), 167.1(C-7a), 146.8 (C-5),
133.7, 130.5, 130.0, 129.9, 128.6, 128.0, 127.7, 115.5(C-8), 113.3(C-7), 78.3 (C-2), 76.0(C-3a), 68.7(C-3). HRMS: Calcd for C20H16O4: 320.1049, found: m/z +
321.1128 [M+H].
5.48 (d, 1H, J = 5.2 Hz, 5-OH), 5.11 (d, 1H, J = 4.7 Hz, H-8), 5.06 (d, 1H, J =
4.6 Hz, H-4), 3.46-3.42 (m, 1H, H-5), 3.40-3.35 (dd, 2H, J = 7.6, 6 Hz, H-6),
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3.23 (s, s, 6H, CH3). C NMR (100.6 MHz, DMSO-d6): δ 199.1 (C-2), 149.9 (C-1),
146.5, 140.7, 140.0, 139.0, 131.1, 128.4, 127.6, 126.9 (aromatic C), 103.1 (C-7), 86.1 (C-3), 82.8 (C-4), 72.1 (C-6), 71.1 (C-5), 70.4 (C-8), 44.0, 43.9 +
(CH3). HRMS: Calcd for C22H22O9S2: 494.0705, found: m/z 495.0788 [M+H].[0058] 2b: 粘稠物. 1H NMR (400.1 MHz, DMSO-d6): δ 7.95 (d, 3H, J = 8.4 Hz, aromatic H), 7.84 (d, 3H, J = 8.4 Hz, aromatic H), 7.58 (d, 2H, J = 8.4 Hz, aromatic H), 6.48 (d, 1H, J = 4.4 Hz, 8-OH), 6.14 (s, 1H, H-7), 5.55 (d, J =
4.8 Hz, 1H, 5-OH), 5.38 (d, 1H, J = 4.8 Hz, H-8), 5.08 (d, 1H, J = 4.4 Hz, H-4), 4.49 (m, 1H, H-5), 4.12(dd, 1H, J = 9.2, 4.2 Hz, H-6a), 3.67(dd, 1H, J
13
= 9.2, 4.0 Hz, H-6b), 3.21(s, 3H, CH3), 3.08 (s, 3H, CH3). C NMR (100.6 MHz, DMSO-d 6): δ 198.4 (C-2), 145.6 (C-1), 150.8, 148.2, 145.5, 140.3, 139.8,
139.0, 130.8, 128.9, 127.5, 126.7, 126.6 (Aromatic C), 102.1 (C-7), 86.6 (C-3), 84.9 (C-4), 74.2 (C-5), 72.7 (C-6), 71.4 (C-8), 44.0, 43.9 (CH3). HRMS: +
Calcd for C22H22O9S2: 494.0705, found: m/z 495.0786 [M+H].
3.77 (dd, 1H, J = 8.2, 6.0 Hz, H-6a), 3.41 (m, 2H, H-5, H-6b), 2.88 (br s, 1H,
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5-OH), 2.30 (br s, 1H, 8-OH). C NMR (100.6 MHz, CDCl3): δ 198.0(C-2), 146.8 (C-1), 159.6, 159.5, 140.2, 134.3, 129.7, 129.3, 123.4, 118.7, 115.6, 115.0,
113.9, 112.1 (aromatic C), 108.7 (C-7), 86.8 (C-3), 81.4 (C-4), 72.2 (C-5),
71.6 (C-6), 70.4 (C-8), 55.3. HRMS: Calcd for C22H22O7: 398.1366, found: m/z +
399.1440 [M+H].
8.2, 6.0 Hz, H-6a), 3.77 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.56 (t, 1H, J = 8.8
13
Hz, H-6b), 3.55 (br s, 1H, 5-OH), 2.66 (br s, 1H, 8-OH). C NMR (100.6 MHz, CDCl3): δ 197.4 (C-2), 146.8 (C-1), 159.7, 159.6, , 138.2 , 134.1 , 129.7 ,
123.4 , 119.2, 115.7, 114.9, 112.7 (aromatic C), 108.6 (C-7), 88.2 (C-3), 81.2 (C-4), 72.6 (C-5), 72.3 (C-6), 72.2 (C-8), 55.3 (OCH3). HRMS (ESI): Calcd for +
C22H22O7: 398.1366, found: m/z 399.1438 [M+H].
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H-2a), 4.59 (dd, J = 10.6, 1.4 Hz, H, H-2b), 3.85 (s, 6H, OCH3). C NMR (100.6 MHz, CDCl3): δ 179.7 (C-6), 167.1 (C-7a), 146.90 (C-5), 159.5, 159.2, 134.9,
131.2, 129.5, 128.9, 123.1, 122.4, 116.1, 113.9 , 113.6, 113.3 (aromatic C),
115.44 (C-8), 115.39 (C-7), 78.3 (C-2), 76.1 (C-3a), 68.7 (C-3), 55.3 (OCH3). +
HRMS: Calcd for C22H20O6: 380.1260, found: m/z: 381.1338[M+H].
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2H, H-5, H-6b), 3.05 (br, 1H, 5-OH), 2.50 (br, 1H, 8-OH). C NMR (100.6 MHz, CDCl3): δ197.8, (C-2), 146.3(C-1), 153.1, 153.0, 139.0, 137.7, 134.3, 128.7,
107.9, 103.4 (aromatic C), 108.9(C-7), 87.0(C-3), 81.3(C-4), 72.3(C-5),
71.5(C-6), 70.5(C-8), 60.9, 56.2, 56.0 (OCH3). HRMS: Calcd for C26H30O11: +
518.1788, found: m/z 519.1860 [M+H].
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6.2 Hz, H-6b). C NMR (100.6 MHz, CDCl3): δ 197.3 (C-2), 146.2 (C-1),153.3,
153.1, 139.2, 137.7, 132.2, 128.4, 107.9, 103.9 (aromatic C), 109.0 (C-7),
88.3 (C-3), 81.2 (C-4), 72.7 (C-5), 72.3 (C-8), 72.0(C-6), 60.9, 60.8, 56.1, +
56.0 (OCH3). HRMS: Calcd for C26H30O11: 518.1788, found: m/z 519.1862 [M+H].[0073] 实施例7:制备通式3所示R为3,4,5-三甲氧基(3,4,5-triOCH3)时手性α,β-不饱和吡喃酮衍生物(3d)
3.8 Hz, 1H, 3-OH), 5.45 (d, J = 4.3 Hz, 1H, H-3a), 4.72 – 4.62 (m, 2H, H-3, H-2a), 4.47 (d, J = 10.0 Hz, 1H, H-2b), 3.83 (s, 6H, OCH3), 3.76 (s, 6H, OCH3),
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3.70 (s, 3H, OCH3), 3.69 (s, 3H, OCH3). C NMR (100.6 MHz, DMSO-d6): δ 179.6 (C-6), 170.6 (C-7a), 147.7 (C-5), 153.1, 152.7, 138.2, 137.2, 129.9, 126.8,
108.3, 108.0 (aromatic C),113.1(C-8), 111.4 (C-7), 80.6 (C-2), 76.8 (C-3a),
68.4 (C-3), 60.55 (OCH3), 60.51 (OCH3), 56.36 (OCH3), 56.33 (OCH3). HRMS: Calcd +
for C26H28O10: 500.1683, found: m/z 501.1760 [M+H].
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3.31 (d, 1H, J = 4.2 Hz, 5-OH), 2.44 (br, 1H, 8-OH). C NMR (100.6 MHz, CDCl3): δ 198.0 (C-2), 147.3 (C-1) , 140.7, 134.8, 134.6, 134.4, 130.1, 129.9, 129.5,
129.0, 128.8, 128.6, 126.6, 124.8 (aromatic C), 107.1(C-7), 86.5 (C-3), 81.6 (C-4), 72.1(C-5), 71.6 (C-6), 69.9(C-8). HRMS (ESI): Calcd for C20H16Cl2O5: +
406.0375, found: m/z 407.0449 [M+H].
H-6b), 2.85 (br, 1H, 5-OH). C NMR (100.6 MHz, CDCl3): δ 197.3 (C-2), 147.3 (C-1), 138.6, 134.7, 134.5, 130.1, 129.9, 129.9, 129.1, 128.9, 128.8, 127.0,
125.3 (aromatic C), 107.2 (C-7), 88.0 (C-3), 81.4 (C-4), 72.6 (C-5), 72.5 (C-6), 72.0 (C-8). HRMS: Calcd for C20H16Cl2O5: 406.0375, found: m/z 407.0442 +
[M+H].
4.56 (dd, 1H, J = 10.7, 2.4 Hz, H-2b), 2.89 (br, 1H, 3-OH). C NMR (100.6 MHz, CDCl3): δ 179.2 (C-6), 167.8 (C-7a), 147.2 (C-5), 135.3, 134.4, 133.8,
131.6, 129.88, 129.86, 129.8, 129.2, 128.7, 128.6, 128.0, 127.8 (aromatic C),
114.2 (C-8), 112.1 (C-7), 78.6 (C-2), 76.3 (C-3a), 68.6 (C-5). HRMS: Calcd for +
C20H14Cl2O4: 388.0269, found: m/z 389.0347 [M+H].
1:3),依次得到通式1所示R为3,4-二氟时手性α,β-不饱和酮衍生物(1f) 312 mg(收率38%)和通式2所示R为3,4-二氟时手性α,β-不饱和酮衍生物(2f) 271 mg(收率
33%)。
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5.4 Hz, H-6b). C NMR (100.6 MHz, DMSO-d6): δ 199.0 (C-2), 148.5(C-1), 150.8,
150.7, 148.5, 148.3, 138.6, 131.7, 128.0, 124.2, 118.9, 118.2, 117.3, 116.4 (aromatic C), 103.2 (C-7), 86.3 (C-3), 82.4 (C-4), 71.8 (C-5), 71.2 (C-6), +
69.7 (C-8). HRMS: Calcd for C20H14F4O5: 410.0777, found: m/z 411.0857 [M+H].[0089] 2f: 粘稠状物.1H NMR (400.1 MHz, CDCl3): δ 7.57 (dt, 1H, J = 7.8,1.8 Hz, aromatic H), 7.31 (m, 1H, aromatic H), 7.27 (m, 1H, aromatic H), 7.16-7.02 (m, 3H, aromatic H), 6.23(s, 1H, H-7), 5.17 (s, 1H, H -8), 5.04 (d, 1H, J = 4.0 Hz, H -4), 4.46 (m, 1H, H-5), 4.23 (dd, 1H, J = 9.4, 6.2 Hz, H-6a), 3.64 (dd,
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1H, J = 9.2, 7.9 Hz, H-6), 3.60 (br s, 1H, 8-OH), 2.66 (br, 1H, 5-OH). C NMR (100.6 MHz, CDCl3): δ 197.1 (C-2), 149.2 (C-1), 151.6, 151.4, 149.3, 149.0,
146.7, 133.5, 129.8, 127.5, 123.2, 118.8, 117.5, 116.1 (aromatic C), 106.8 (C-7), 88.0 (C-3), 81.2 (C-4), 77.4 (C-5), 77.1 (C-6), 71. 5 (C-8). HRMS: Calcd +
for C20H14F4O5: 410.0777, found: m/z 411.0850 [M+H].
10.7, 2.0 Hz, H-2b), 2.82 (s, 1H, 3-OH). C NMR (100.6 MHz, CDCl3): δ 179.0 (C-6), 167.5 (C-7a), 151.4, 151.1, 151.0, 150.8, 148.9, 148.4, 146.6 (C-5),
127.31, 127.28, 127.25, 126.25, 126.19, 126.15, 119.08, 118.90, 118.65,
118.47, 117.47, 117.30, 116.78, 116.61 (aromatic C), 113.7 (C-8), 111.5 (C-7),
78.7 (C-2), 76.3 (C-3a), 68.6 (C-3). HRMS: Calcd for C20H14F4O4: 392.0672, found: +
m/z: 393.0753 [M +H].
2所示R为4-异丙基时手性α,β-不饱和酮衍生物(2g) 218 mg(收率26%)。
1H, J = 8.0Hz, H-4), 3.79 (t, 1H, J = 6.0, H-5), 3.38 (m, 1H, H-6a), 3.54 (t,
1H, J = 4.8Hz, H-6b), 2.49 (d, 1H, J = 4.0Hz, 8-OH), 2.95 (m, 2H, CH), 2.19
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(d, 1H, J = 9.6Hz, 5-OH), 1.29 (d, 12H, J = 6.8Hz, -CH3). C NMR (100.6 MHz, CDCl3): δ 197.9(C-2), 146.2 (C-1), 150.5, 149.3, 135.8, 130.9, 130.7, 127.0,
126.5, 126.4 (aromatic C), 109.1 (C-7), 86.9 (C-3), 81.2(C-4), 72.4 (C-5),
72.3 (C-6),70.5 (C-8), 34.1 (-CH), 33.8 (-CH), 24.0 (-CH3), 23.8 (-CH3). HRMS: +
Calcd for C26H30O5: 423.2123, found: m/z 424.2215 [M+H].
1H, J = 9.2, 6.8Hz, H-5), 3.54 (t, 1H, J = 4.8Hz, H-6b), 3.20 (s, 1H, 8-OH),
2.89 (m, 1H, -CH), 2.38 (d, 1H, J = 9.6Hz, 5-OH), 1.26 (d, 6H, J = 6.8Hz,
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-CH3), 1.20(d, 6H, J = 6.8Hz, -CH3). C NMR (100.6 MHz, CDCl3): δ 197.2(C-2),
146.1(C-1), 150.6, 149.1, 133.8, 130.8, 130.5, 127.0, 126.9, 126.7 (aromatic C), 109.2 (C-7), 88.3 (C-3), 81.0 (C-4), 72.7 (C-5), 72.3 (C-6), 72.1 (C-8),
34.1 (-CH), 33.8 (-CH), 23.8 (-CH3), 23.7 (-CH3). HRMS: Calcd for C26H30O5: +
423.2123, found: m/z 424.2210 [M+H].
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6H, J = 2. 8Hz, -CH3). CNMR(100.6 MHz, CDCl3) : δ 180.1 (C-6), 166.7 (C-7a),
149.6 (C-5), 148.2, 146.4, 131.3, 130.5, 129.9, 127.3, 126.6, 126. 1(aromatic C), 115.6 (C-8), 113.3 (C-7), 78.2 (C-2), 76.1 (C-3a), 68.6(C-3), 34.1 (-CH),
34.0 (-CH), 23.9 (-CH3), 23.8(-CH3). HRMS: Calcd for C26H28O4: 404.1963, found: m/+
z 405.2072 [M+H].
1a 0.65 24.35
2a 108.22 >128
3a >128 13.03
1b >128 >128
2b >128 >128
1c >128 44.04
2c 0.93 5.52
3c >128 1.36
1d 0.61 >128
2d 59.22 >128
3d 13.74 19.70
1e >128 9.92
2e 60.50 17.57
3e >128 7.99
1f 5.26 6.02
2f 63.67 20.81
3f 0.76 0.74
1a>128 >128 >128 >128
2a>128 >128 >128 >128
3a>128 85.60 >128 >128
1c>128 >128 >128 >128
2c>128 75.00 >128 >128
3c9.15 9.32 16.32 7.02
1d>128 >128 >128 >128
2d>128 >128 >128 >128
3d>128 94.92 >128 >128
1e16.92 27.67 26.32 31.85
2e7.15 15.31 16.36 31.67
3e23.01 18.40 12.40 9.17
1f64.12 66.46 59.35 78.95
2f82.96 >128 >128 >128
3f1.66 6.40 9.66 4.25