Quy trình chung
Một hỗn hợp của NH2O-THP (60 mg; 1eq; 0,51 mmol), 65a-g (1,0 eq), EDC.HCl (97,0 mg; 0,51 mmol; 1 eq), DMAP (30,5 mg; 0,25 mmol; 0,5 eq) trong CH2Cl2 (15 mL) được khuấy ở nhiệt độ phòng trong 6 giờ. Kiểm tra tiến trình phản ứng bằng TLC hệ dung môi CH2Cl2: MeOH = 30: 1. Phản ứng sau đó được pha loãng với CH2Cl2 (15 mL), chiết với H2O. Pha hữu cơ được tách ra, làm khan bằng Na2SO4, bốc hơi dung môi dưới áp suất giảm thu được cặn tương ứng. Cặn sau đó được hòa trong EtOH (5 mL), làm lạnh bằng nước đá. Nhỏ vào hỗn hợp 2 giọt benzoylchloride và khuấy tiếp 3 giờ. Hỗn hợp phản ứng sau đó được pha loãng với
H2O (10 mL), chiết với CH2Cl2 (2×15 mL). Pha hữu cơ được tách ra, làm khan với Na2SO4, bốc hơi dung môi dưới áp suất giảm thu được cặn phản ứng. Cặn sau đó được tách bằng cột silica gel, hệ dung môi CH2Cl2: MeOH (10:1) cho 67a-g.
Sơ đồ 20. Tổng hợp các dẫn xuất artemisinin chứa nhóm hydroxamic axit
(i) (CH3)3SiCl, NaN3, KI, CH2Cl2, 0 C, 2.5 giờ, 45%; (ii) Ph3P, THF/H2O (1:1), 65 oC, 8 giờ, 81%; (iii) succinic anhydride, glutaric anhydride, 3,3- dimethylglutaric anhydride, maleic anhydride, naphthalic anhydride, EDC.HCl, DMAP, CH2Cl2, nhiệt độ phòng, 12–15 giờ, 70–86%; (iv) adipic acid monomethyl ester, suberic acid monomethyl ester, EDC.HCl, DMAP, CH2Cl2, rt, 12-15 giờ; (v) NaOH 0.2 N trong MeOH, CH2Cl2: MeOH (9: 1), 20 giờ, 74-80% (2 bước); vi) O- (tetrahydro-2H-pyran-2-yl)hydroxylamine (H2N-O-THP), EDC.HCl, DMAP, CH2Cl2, 6 giờ; vii) EtOH, benzoylchloride (2 giọt), 3 giờ, 35–50% (hai bước).
N1-hydroxy-N4-((3R, 6R, 9R, 10S, 12R, 12aR)-3,6,9-trimethyldecahydro-3H- 3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)succinamid (67a).
Chất dầu, 35%, IR (film, cm-1): 3261 (OH), 3055 (NH), 2927, 2865 (CH, CH2), 1650, 1629 (C=O). 1H NMR (500 MHz, DMSO-d6, δ (ppm)): 8,61 (d, J = 9,0 Hz, 1H, NH); 5,40 (s, 1H, H-12); 5,06 (t, J = 10,0 Hz, H-10); 2,42–2,39 (t, J = 7,0 Hz, 2H); 2,30–2,36 (m, 1H); 2,20–2,14 (td, J = 3,5 Hz, 14,0 Hz, 1H); 1,98 (m, 3H); 1,81–1,78 (m, 1H); 1,63–1,60 (m, 1H); 1,52–1,39 (m, 3H); 1,38–1,29 (m, 1H); 1,27 (s, 3H, H-14); 0,99–0,94 (m, 1H); 0,88 (d, J = 6,5 Hz, 1H, H-15); 0,71 (d, J = 7,0 Hz, 3H, H-16). 13C NMR (125 MHz, DMSO-d6, δ (ppm)): 172,7; 171,2; 104,3; 91,6; 80,4; 76,0; 51,7; 45,6; 37,3; 36,3; 34,0; 32,8; 31,2; 29,4; 26,0; 24,6; 22,7; 20,2; 12,9. ESI-HRMS tìm thấy: 399.21311; lý thuyết: C19H31N2O7 [M+H]+: 399.21258.
N1-hydroxy-N5-((3R, 6R, 9R, 10S, 12R, 12Ar)-3,6,9- trimethyldecahydro-3H-3,12- epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)glutaramide (67b).
Chất dầu, 45%, IR (film, cm-1): 3267 (OH), 3059 (NH), 2921, 2876 (CH, CH2), 1670, 1639 (C=O). 1H NMR (500 MHz, DMSO-d6, δ (ppm)): 8,54 (d, J = 9,0 Hz, 1H, NH); 5,41 (s, 1H, H-12); 5,08 (t, J = 10,0 Hz, H-10); 2,30–2,35 (m, 3H); 2,19– 2,11 (m, 3H); 2,0–1,97 (m, 1H); 1,82–1,67 (m, 4H); 1,63–1,57 (m, 1H); 1,52–
1,44 (m, 4H); 1,27–1,23 (m, 4H); 0,89 (d, J = 6,5 Hz, 3H, H-15); 0,85–0,82 (m, 1H); 0,73 (d, J = 7,0 Hz, 3H, H-16). 13C NMR (125 MHz, DMSO-d6, δ(ppm)): 172,7; 171,1; 104,3; 91,7; 80,4; 76,0; 51,7; 45,6; 37,3; 36,2; 34,1; 32,8; 31,2; 29,3; 26,0; 24,6; 23,6; 21,6; 20,2; 12,9. ESI-HRMS tìm thấy: 413.22876; lý thuyết: C20H33N2O7 [M+H]+: 413.22823.
N1-hydroxy-3,3-dimethyl-N5-((3R, 6R, 9R, 10S, 12R, 12Ar)- 3,6,9- trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10- yl)pentanediamide (67c).
Chất dầu, 45%, IR (film, cm-1): 3227 (OH), 3046 (NH), 2929, 2879 (CH, CH2), 1679, 1628 (C=O). 1H NMR (500 MHz, DMSO-d6, δ (ppm)): 10,41 (s, 1H, NH); 8,73 (s, 1H, OH); 8,63 (d, J = 9,0 Hz, 1H, NH); 5,39 (s, 1H, H-12); 5,08 (t, J = 10,0 Hz, 1H, H-10); 2,29–2,27 (m, 1H); 2,20–2,12 (m, 3H); 2,04–1,97 (m, 3H); 1,82–1,78 (m, 1H); 1,62–1,60 (m, 2H); 1,52–1,37 (m, 3H); 1,36–1,30 (m, 1H); 1,26 (s, 3H, H-14); 1,18–1,12 (m, 1H); 0,99 (m, 6H, 2CH3); 0,90 (d, J = 6,5 Hz, 3H, H- 15); 0,83–0,76 (m, 1H); 0,73 (d, J = 7,0 Hz, 3H, H-16). 13C NMR (125 MHz, DMSO-d6, δ (ppm)): 171,0; 167,7; 103,3; 90,6; 80,1; 75,0; 51,4; 46,9; 45,2; 43,6; 36,2; 36,0; 33,7; 32,9; 31,2; 30,6; 25,6; 24,3; 23,6; 20,8; 13,0. ESI-HRMS tìm thấy: 441.26006; lý thuyết: C22H37N2O7 [M+H]+: 441.25953. 77
N1-hydroxy-N4-((3R, 6R, 9R, 10S, 12R, 12Ar)-3,6,9-trimethyldecahydro-3H- 3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)maleamide (67d).
Chất dầu, 50%, IR (film, cm-1): 3278 (OH),3049 (NH), 2922, 2878 (CH, CH2), 1669, 1637 (C=O), 1579 (C=C). 1H NMR (500 MHz, DMSO-d6, δ (ppm)): 6,95 (d, J = 15,5 Hz, 1H); 6,85(d, J = 15,5 Hz, 1H); 6,53 (d, J = 9,5 Hz, 1H, NH); 5,45–5,41 (m, 2H, H-12, H-10); 2,45–2,42 (m, 1H); 2,37–2,33 (m, 1H); 2,05–2,01 (m, 1H); 1,92–1,88 (m, 1H); 1,80–1,73 (m, 1H); 1,66–1,60 (m, 1H); 1,54–1,46 (m, 4H); 1,41 (s, 3H, H-14); 1,29–1,26 (m, 1H); 1,06–1,02 (m, 1H); 0,98 (d, J = 6,5 Hz, 3H, H-15); 0,86 (d, J = 7,0 Hz, 3H, H-16). 13C NMR (125 MHz, DMSO-d6, δ (ppm)): 165,4; 163,3; 135,9; 131,4; 104,4; 91,7; 80,4; 76,3; 51,7; 45,6; 37,3; 36,3; 34,0; 32,8; 25,9; 24,6; 23,7; 20,2; 12,9. ESI-HRMS tìm thấy: 397.19746; lý thuyết: C19H29N2O7 [M+H]+: 347.19693. N1-hydroxy-N2-((3R, 6R, 9R, 10S, 12R, 12Ar)-3,6,9-trimethyldecahydro-3H- 3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)phthalamide (67e). Chất rắn, 44%, đnc 173oC; IR (KBr, cm-1): 3264 (OH), 3039 (NH), 2931, 2877 (CH, CH2), 1676, 1629 (C=O), 1549 (C=C). 1H NMR (500 MHz, DMSO-d6, δ (ppm)): 7,96–7,88 (m, 4H, H-Ar); 5,59 (s, 1H, H-12); 5,37 (d, J = 11,0 Hz, 1H, H-
1,84–1,80 (m, 1H); 1,67–1,61 (m, 3H); 1,50–1,46 (m, 1H); 1,36–1,29 (m, 2H); 1,24–1,18 (m, 4H); 1,02–0,97 (m, 1H); 0,91 (d, J = 6,5 Hz, 3H, H-15); 0,72 (d, J = 7,0 Hz, 3H, H-16). 13C NMR (125 MHz, DMSO-d6, δ (ppm)): 167,9; 166,7; 134,3; 134,0; 132,2; 131,4; 123,5; 104,5; 92,3; 79,9; 76,8; 51,6; 45,7; 37,3; 36,3; 34,1; 30,9; 25,9; 24,7; 20,9; 20,2; 12,7. ESI-HRMS tìm thấy: 447.21311; lý thuyết: C23H31N2O7 [M+H]+: 447.21258.
N1-hydroxy-N6-((3R, 6R, 9R, 10S, 12R, 12Ar)-3,6,9-trimethyldecahydro-3H- 3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)adipamide (67f).
Chất dầu, 45%; IR (film, cm-1): 3230 (OH), 3029 (NH), 2922, 2869 (CH, CH2), 1681, 1635 (C=O). 1H NMR (500 MHz, DMSO-d6, δ (ppm)): 9,80 (s, 1H, NH); 8,6 (s, 1H, NH); 7,0 (s, 1H, OH); 5,40 (s, 1H, H-12); 5,35 (t, J = 9,5 Hz, 1H, H-10); 2,25–2,22 (m, 4H); 2,21–2,0 (m, 1H); 2,10 (m, 2H); 1,95–1,85 (m, 1H); 1,70–1,60 (m, 5H); 1,58–1,48 (m, 1H); 1,43 (s, 3H, H-14); 1,42–1,32(m, 4H); 1,10– 1,00 (m, 1H); 0,99 (d, J = 6,5 Hz, 3H, H-15); 0,97–0,92 (m, 1H); 0,87 (d, J = 7,50 Hz, 3H, H-16). 13C NMR (125 MHz, DMSO-d6, δ (ppm)): 174,0; 171,0; 106,0; 91,9; 80,7; 76,3; 51,7; 45,6; 37,3; 36,3; 35,7; 34,9; 32,2; 32,1; 26,1; 24,6; 24,1; 21,7; 20,3; 13,2. ESI-HRMS Tìm thấy: 427.24441; lý thuyết: C21H35N2O7 [M+H]+: 427.24388.
N1-hydroxy-N8-((3R, 6R, 9R, 10S, 12R, 12Ar)-3,6,9-trimethyldecahydro-3H- 3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)octanediamide (67g).
Chất dầu, 60%, IR (film, cm-1): 3278 (OH), 3029 (NH), 2931, 2856 (CH, CH2), 1675, 1645 (C=O). 1H NMR (500 MHz, DMSO-d6, δ (ppm)): 9,80 (s, 1H, NH); 8,6 (s, 1H, NH); 7,02 (s, 1H, OH); 5,45 (s, 1H, H-12); 5,35 (t, J = 9,5 Hz, 1H, H-10); 2,50– 2,11 (m, 6H); 2,10–2,0 (m, 1H); 1,92–1,84 (m, 1H); 1,80–1,76 (m, 2H); 1,75–1,58 (m, 5H); 1,50–1,42 (m, 2H); 1,40 (s, 3H, H-14); 1,39–1,20 (m, 7H); 1,12–1,10 (m, 1H); 0,98 (d, J = 6,5 Hz, 3H, H-15); 0,84 (d, J = 7,5 Hz, 3H, H-16). 13C NMR (125 MHz, DMSO-d6, δ(ppm)): 174,0; 171,3; 104,5; 91,9; 80,7; 75,9; 51,7; 45,6; 37,3; 36,3; 35,9; 32,4; 32,2; 28,4; 28,0; 27,9; 26,1; 24,8; 24,6; 24,5; 21,6; 20,3; 13,2. ESI-HRMS tìm thấy: 455.27571; lý thuyết: C23H39N2O7 [M+H]+: 455.27518.
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