Nghiên cứu tổng hợp và tính chất của một số glucopyranosyl thioure có chứa dị vòng pyrimidin

MỤC LỤC MỞ ĐẦU CHƯƠNG TỔNG QUAN 1.2 TỔNG QUAN VỀ THIOURE 1.2.1 Cấu trúc liên kết phân tử [46,55] .2 1.2.2 Tính chất thioure 1.2.3 Ứng dụng thioure 1.2.4 Phương pháp điều chế dẫn xuất thioure 1.3 TỔNG QUAN VỀ GLUCOSYL ISOTHIOXYANAT 13 1.3.1 Giới thiệu glucosyl isothioxyanat 13 1.3.2 Tính chất hố học glycosyl isothioxyanat[70,71,83,84] 13 1.3.3 Phương pháp tổng hợp glycosyl isoxyanat glucosyl isothioxyanat [83,101] 15 1.3 TỔNG QUAN VỀ DỊ VÒNG PYRIMIDIN 17 1.3.1 Tổng hợp vòng pyrimidin 17 1.3.2 Tính chất pyrimidin [7,9,86,96] 20 1.4 ỨNG DỤNG LỊ VI SĨNG TRONG HOÁ HỌC CACBOHYDRAT [14,56,75,88] 22 1.5 MỐI LIÊN QUAN GIỮA CẤU TRÚC HÓA HỌCVÀTÁC DỤNG SINH HỌC 25 CHƯƠNG THỰC NGHIỆM 30 2.1 TỔNG HỢP MỘT SỐ XETON α,β-KHÔNG NO 32 1,3-Diphenylprop-2-en-1-on (hay benzylidenaxetophenon) (3a1) 33 3-(4’-Fluorophenyl)-1-phenylprop-2-en-1-on [hay (4’-fluorobenzyliden)-axetophenon] (3b1) 33 3-(4’-Clorophenyl)-1-phenylprop-2-en-1-on [hay (4’-clorobenzyliden)-axetophenon] (3c1) .33 3-(3’-Clorophenyl)-1-phenylprop-2-en-1-on [hay (3’-clorobenzyliden)-axetophenon] (3d1) 33 3-(4’-Bromophenyl)-1-phenylprop-2-en-1-on [hay (4’-bromobenzyliden)-axetophenon] (3f1) 33 3-(4’-Metylphenyl)-1-phenylprop-2-en-1-on [hay (4-metylbenzyliden)-axetophenon] (3g1) 33 3-(3’-Metoxyphenyl)-1-phenylprop-2-en-1-on [hay (3’-metoxybenzyl-iden)axetophenon] (3j1) 34 3-(3’,4’-Dioxymetylenphenyl)-1-phenylprop-2-en-1-on [hay (3’,4’-dioxymetylenbenzyliden)axetophenon] (3l1) 34 10 3-(4’-Hydroxyphenyl)-1-phenylprop-2-en-1-on [hay (4’-hydroxy-benzyliden)axetophenon] (3m1)34 11 3-(3’-Hydroxyphenyl)-1-phenylprop-2-en-1-on [hay (3’-hydroxy-benzyliden)axetophenon] (3n1)34 12 3-(2’-Hydroxyphenyl)-1-phenylprop-2-en-1-on [hay (2’-hydroxy-benzyliden)axetophenon] (3o1)34 13 3-[4’-(Dimetylamino)phenyl]-1-phenylprop-2-en-1-on [hay (4’-dimetyl- aminobenzyliden)axetophenon] (3p1) 34 15 3-(4’-Clorophenyl)-1-(4-metoxyphenyl)prop-2-en-1-on [hay (4’-cloro-benzyliden)-4metoxyaxetophenon] (3c2) 35 i 16 3-(3’-Clorophenyl)-1-(4”-metoxyphenyl)prop-2-en-1-on [hay (3’-cloro-benzyliden)-4metoxyaxetophenon] (3d2) 35 17 3-(2’-Clorophenyl)-1-(4”-metoxyphenyl)prop-2-en-1-on [hay (2’-cloro-benzyliden)-4metoxyaxetophenon] (3e2) 35 18 3-(4’-Bromophenyl)-1-(4”-metoxyphenyl)prop-2-en-1-on [hay (4’-brom-obenzyliden)-4metoxyaxetophenon] (3f2) 35 19 1-(4’-Metoxyphenyl)-3-(4”-metylphenyl)prop-2-en-1-on [hay (4’-metylbenzyliden)-4metoxyaxetophenon] (3g2) 35 20 1-(4’-Metoxyphenyl)-3- [4”-(propan-2-yl)phenyl]prop-2-en-1-on [hay (4’-isopropylbenzyliden)-4metoxyaxetophenon] (3h2) 35 22 3-(3’-Metoxyphenyl)-1-(4”-metoxyphenyl)prop-2-en-1-on [hay (3’-metoxybenzyliden)-4metoxyaxetophenon] (3j2) 36 23 3- [4’-(Dimetylamino)phenyl]-1-(4”-metoxyphenyl)prop-2-en-1-on [hay (4’dimetylaminobenzyliden)-4-metoxyaxetophenon] (3p2) 36 24 1-(4’-Bromophenyl)-3-(4”-fluorophenyl)prop-2-en-1-on [hay (4’-fluorobenzyliden)-4bromoaxetophenon] (3b3) 36 25 1-(4’-Bromophenyl)-3-(4”-clorophenyl)prop-2-en-1-on [hay (4’-clorobenzyliden)-4bromoaxetophenon] (3c3) 36 26 1-(4’-Bromophenyl)-3-(3”-clorophenyl)prop-2-en-1-on [hay (3’-clorobenzyliden)-4bromoaxetophenon] (3d3) 36 27 1-(4’-Bromophenyl)-3-(2”-clorophenyl)prop-2-en-1-on [hay (2’-clorobenzyliden)-4bromoaxetophenon] (3e3) 36 29 1-(4’-Bromophenyl)-3-(4”-metylphenyl)prop-2-en-1-on [hay (4-metylbenzyliden)4bromoaxetophenon] (3g3) 37 30 1-(4’-Bromophenyl)-3- [4”-(propan-2-yl)phenyl]prop-2-en-1-on [hay (4’-isopropylbenzyliden)-4bromoaxetophenon] (3h3) 37 31 1-(4’-Bromophenyl)-3-(4”-metoxyphenyl)prop-2-en-1-on [hay (4’-metoxybenzyliden)-4bromoaxetophenon] (3i3) 37 32 1-(4’-Bromophenyl)-3-(3”-metoxyphenyl)prop-2-en-1-on [hay (3’-metoxybenzyliden)-4bromoaxetophenon] (3j3) 37 33 1-(4’-Bromophenyl)-3-(2”-metoxyphenyl)prop-2-en-1-on [hay (2’-metoxybenzyliden)-4bromoaxetophenon] (3k3) 37 34 1-(4’-Bromophenyl)-3- [4”-(dimetylamino)phenyl]prop-2-en-1-on [hay (4’dimetylaminobenzyliden)-4-bromoaxetophenon] (3p3) 37 A-Phương pháp đun hồi lưu truyền thống (QTA1) 37 B-Phương pháp sử dụng lị vi sóng (QTA2) 38 2-Amino-4,6-diphenylpyrimidin (4a1) 39 2-Amino-4-phenyl-6-(4”-fluorophenyl)pyrimidin (4b1) 39 ii 2-Amino-4-phenyl-6-(4”-clorophenyl)pyrimidin (4c1) 2-Amino-4-phenyl-6-(3”-clorophenyl)pyrimidin (4d1) 2-Amino-4-phenyl-6-(4”-bromophenyl)pyrimidin (4f1) 2-Amino-4-phenyl-6-(4”-metoxyphenyl)pyrimidin (4i1) 2-Amino-4-phenyl-6-(3”-metoxyphenyl)pyrimidin (4j1) 2-Amino-4-phenyl-6-(3”,4”-dioxymetylenphenyl)pyrimidin (4l1) 10 2-Amino-4-phenyl-6-(4”-hydroxyphenyl)pyrimidin (4m1) 11 2-Amino-4-phenyl-6-(3”-hydroxyphenyl)pyrimidin (4n1) 13 2-Amino-4-phenyl-6-(4”-dimetylaminophenyl)pyrimidin (4p1) 14 2-Amino-4-(4’-metoxyphenyl)-6-(4”- fluorophenyl)-pyrimidin (4b2) 15 2-Amino-4-(4’-metoxyphenyl)-6-(4”-clorophenyl)pyrimidin (4c2) 16 2-Amino-4-(4’-metoxyphenyl)-6-(3”-clorophenyl)-pyrimidin (4d2) 17 2-Amino-4-(4’-metoxyphenyl)-6-(2”-clorophenyl)-pyrimidin (4e2) 19 2-Amino-4-(4’-metoxyphenyl)-6-(4”-metylphenyl)-pyrimidin (4g2) 20 2-Amino-4-(4’-metoxyphenyl)-6-(4”- isopropylphenyl)-pyrimidin (4h2) 21 2-Amino-4,6-bis(4’-metoxyphenyl)pyrimidin (4i2) 22 2-Amino-4-(4’-metoxyphenyl)-6-(3”-metoxyphenyl)-pyrimidin (4j2) 23 2-Amino-4-(4’-metoxyphenyl)-6-(4”-dimetylaminophenyl)pyrimidin (4p2) 24 2-Amino-4-(4’-bromophenyl)-6-(4”-fluorophenyl)pyrimidin (4b3) 26 2-Amino-4-(4’-bromophenyl)-6-(3”-clorophenyl)pyrimidin (4d3) 27 2-Amino-4-(4’-bromophenyl)-6-(2”-clorophenyl)pyrimidin (4e3) 28 2-Amino-4,6-bis(4’-bromophenyl)pyrimidin (4f3) 29 2-Amino-4-(4’-bromophenyl)-6-(4”-metylphenyl)-pyrimidin (4g3) 30 2-Amino-4-(4’-bromophenyl)-6-(4”-isopropylphenyl)-pyrimidin (4h3) 31 2-Amino-4-(4’-bromophenyl)-6-(4”-metoxyphenyl)-pyrimidin (4i3) 33 2-Amino-4-(4’-bromophenyl)-6-(2”-metoxyphenyl)-pyrimidin (4k3) 34 2-Amino-4-(4’-bromophenyl)-6-(4”-dimetylaminophenyl)-pyrimidin (4p3) 35 2-Amino-4-(4’-isopropylphenyl)-6-phenylpyrimidin (Phản ứng ‘one-pot’ từ cấu tử) (4h1) 2.3 TỔNG HỢP N-(2,3,4,6-TETRA-O-AXETYL-β-D-GLUCO-PYRANOSYL)-N’-(4’,6’DIARYLPYRIMIDIN-2’-YL)THIOURE A-Phương pháp đun hồi lưu B-Phương pháp khơng dung mơi lị vi sóng N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-(4’,6’-diphenylpyrimidin-2’-yl)thioure (6a1) N-(2,3,4,6-tetra-O-axetyl--D-glucopyranosyl-N’-[4’-phenyl-6’-(4”’-flurophenyl)pyrimidin-2’- yl]thioure (6b1) N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(4”’-clorophenyl)pyrimidin-2’- yl]thioure (6c1) iii N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(3”’-clorophenyl) pyrimidin-2’yl]thioure (6d1) 45 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(4”’-bromophenyl)pyrimidin-2’yl]thioure(6f1) 45 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(4”’-metylphenyl)pyrimidin-2’yl]thioure (6g1) 45 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(4”’-isopropylphenyl)pyrimidin-2’yl]thioure (6h1) 46 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(-4”’-metoxyphenyl) pyrimidin-2’yl]thioure (6i1) 46 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(3”’- metoxyphenyl)pyrimidin-2’yl]thioure (6j1) 46 10 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-phenyl-6’-(2”’-hydroxyphenyl)pyrimidin2’-yl]thioure (6o1) 46 11 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-metoxyphenyl) - 6’-(4”’fluorophenyl)pyrimidin-2’-yl]thioure (6b2) 46 12 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-metoxyphenyl)- 6’-(4’”clorophenyl)pyrimidin-2’-yl]thioure (6c2) 46 13 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-metoxyphenyl)- 6’-(3’”clorophenyl)pyrimidin-2’-yl]thioure (6d2) 47 14 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-(4”-metoxyphenyl)- 6’-(2’”clorophenyl)pyrimidin-2’-yl]thioure (6e2) 47 15 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-metoxyphenyl) -6’-(4’”bromophenyl)pyrimidin-2’-yl]thioure (6f2) 47 16 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-metoxyphenyl)- 6’-(4’”metyphenyl)pyrimidin-2’-yl]thioure (6g2) 47 17 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-(4”-metoxyphenyl)-6’-(4’”-isopropylphenyl)pyrimidin-2’-yl]thioure (6h2) 47 18 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’,6’-bis(4”-metoxy-phenyl)pyrimidin-2’yl]thioure (6i2) 47 20 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-(4”-metoxyphenyl) 6’-(4’”-dimetylaminophenyl)pyrimidin-2’-yl]thioure (6p2) 48 21 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-(4”-bromophenyl)-6’-(4’”fluorophenyl)pyrimidin-2’-yl]thioure (6b3) 48 22 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-bromophenyl)-6’-(4’”clorophenyl)pyrimidin-2’-yl]thioure (6c3) 48 iv 23 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-bromophenyl) -6’-(3’”clorophenyl)pyrimidin-2’-yl]thioure (6d3) 48 25 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’,6’-bis(4”-bromo-phenyl)pyrimidin-2’yl]thioure (6f3) 49 26 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-bromophenyl) -6’-(4’”metylphenyl)pyrimidin-2’-yl]thioure (6g3) 49 27 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-bromophenyl) -6’-(4’”isopropylphenyl)pyrimidin-2’-yl]thioure (6h3) 49 29 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4”-bromophenyl) -6’-(3’”metoxyphenyl)pyrimidin-2’-yl]thioure (6j3) 49 2.4 DEAXETYL HÓA CÁC DẪN XUẤT N-(2,3,4,6-TETRA-O-AXETYL-β-D-GLUOPYRANOSYL)N’-(4’,6’-DIARYLPYRIMIDIN-2’-YL)THIOURE 50 2.4.1 Hoạt hoá nhựa trao đổi ion Wofatit KPS 50 2.4.2 Deaxetyl hoá số dẫn xuất N-(2,3,4,6-tetra-O-axetyl- -D-glucoyranosyl)-N’-(4’,6’diarylpyrimidin-2’-yl)thioure 50 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-(4’,6’-diphenyl-pyrimidin-2’-yl)thioure (7a1) 50 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(3”-clorophenyl)-6’phenylpyrimidin-2’- yl]thioure (7d1) 51 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(4-bromophenyl)-6’-phenylpyrimidin-2’yl]thioure (7f1) 51 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’- [4’-(-4”-metoxyphenyl) -6’-phenylpyrimidin-2’yl]thioure (7i1) 51 2.5 TỔNG HỢP 2-IMINOTHIAZOLIDIN-4-ON 51 (Z)-2- [4”- phenyl-6’’-(4’”-Fluorophenyl)pyrimidin]-2”-ylimino)-3-(2’,3’,4’, 6’-tetra-O-axetyl-β-Dglucopyranosyl)thiazolidin-4-on (8b1) (Z)-3- [4”-(4’”-fluorophenyl)-6”-phenylpyrimidin]-2”-yl)-2- (2’,3’,4’,6’-tetra-O-axetyl-β-D-glucopyranosyl-1’-imino)thiazolidin-4-on (8b1 8’b1) 51 (Z)-2-[4”-phenyl-6”-(2’”’-Hydroxyphenyl)pyrimidin]-2”-ylimino)-3-(2’,3’, 4’,6’-tetra-O-axetyl-βD-gluco-pyranosyl)thiazolidin-4-on (Z)-3-[4”-(2’”-hydroxyphenyl)-6”-phenylpyrimidin]-2”-yl)-3(2’,3’,4’,6’-tetra-O-axetyl-β-D-gluco-pyranosyl-1’-imino)thiazolidin-4-on (8o1 8’o1) 52 (Z)-2-[4”-(4’”- bromophenyl)-6”-(4””-Dimetylaminophenyl) 53 pyrimidin]-2”-ylimino)-3-(2’,3’,4’,6’-tetra-O-axetyl-β-D-gluco-pyranosyl)thiazolidin-4-on (Z)-3- [4”(4’”-dimetylaminophenyl)-6”-(4””-bromophenyl)pyrimidin]-2”-ylimino)-3-(2’,3’,4’,6’-tetra-O-axetyl-βD-gluco-pyranosyl)thiazolidin-4-on (8p3 8’p3) 53 2.6 HOẠT TÍNH SINH HỌC CỦA DẪN XUẤT 2-AMINO-4,6-DIARYLPYRIMIDIN VÀ CÁC HỢP CHẤT THIOURE TƯƠNG ỨNG 53 2.6.1 Các chủng khuẩn nấm dùng thử nghiệm 53 2.6.3 Phương pháp thử 54 Nguyên tắc 54 v Chương KẾT QUẢ VÀ THẢO LUẬN 55 3.1 TỔNG HỢP CÁC XETON α,β-KHÔNG NO 55 3.2 TỔNG HỢP CÁC 2-AMINO-4,6-DIARYLPYRIMIDIN………………………………………… 58 3.2.2 Phổ IR 71 3.2.3 Phổ 1H-NMR 71 3.2.3 Phổ MS 75 3.3 TỔNG HỢP CÁC N-(2,3,4,6-TETRA-O-AXETYL- -D-GLUCOPYRANOSYL)-N’-(4’,6’DIARYLPYRIMIDIN-2’-YL)THIOURE 77 3.3.1 Tổng hợp N-(2,3,4,6-tetra-O-axetyl--D-glucopyranosyl)-N’-(4’,6’-diarylpyrimidin-2’yl)thioure 77 3.3.2 Phổ IR 78 3.3.3 Phổ NMR 83 3.3.4 Phổ MS 105 3.4 VỀ PHẢN ỨNG DEAXETYL HÓA MỘT SỐ HỢP CHẤT N-(2,3,4,6-TETRA-O-β-DGLUCOPYRANOSYL)-N’-(4’,6’-DIARYLPYRIMIDIN-2’-YL)THIOURE 110 3.5 VỀ TỔNG HỢP MỘT SỐ DẪN XUẤT 2-IMINOTHIAZOLIDIN-4-ON 112 3.6 HOẠT TÍNH SINH HỌC CỦA DẪN XUẤT 2-AMINO-4,6-DIARYLPYRIMIDIN VÀ CÁC HỢP CHẤT THIOURE TƯƠNG ỨNG 132 KẾT LUẬN……………………………………………………………………………………………… 139 DANH MỤC CÁC CƠNG TRÌNH LIÊN QUAN ĐẾN LUẬN ÁN…………………………………….140 TÀI LIỆU THAM KHẢO 142 vi MỤC LỤC BẢNG Bảng 3.1 Các xeton  , -không no tổng hợp Bảng 3.2 Kết tổng hợp hợp chất 2-amino-4,6-diarypyrimidin (4) 61 Bảng 3.3 (Tiếp theo) ………………………………………………………………………………61 Bảng 3.4 Mối tương quan độ chuyển dịch hoá học NH2 số nhóm Hammett (σ) hợp chất 2-amino-4,6-diarylpyrimidin Bảng 3.5 Một số thông số phân tử số 2-amino-4,6-diarylpyrimidin Bảng 3.6 Kết tổng hợp N-(2,3,4,6-tetra-O-axetyl-β-D-glucopyranosyl)-N’-4’,6’diarylpyrimidin-2’-yl)thioure (6) Bảng 3.7 Phổ IR hợp chất thioure Bảng 3.8 Phổ 1H-NMR N-(2,3,4,6-tetra-O-axetyl--D-glucopyranosyl)-N’(4’,6’diphenylpyrimidin-2’-yl)thioure Bảng 3.8 (tiếp theo) Bảng 3.8 (tiếp theo) Bảng 3.9 Phổ 13C-NMR N-(2,3,4,6-tetra-O-axetyl--D-glucopyranosyl)-N’(4’,6’diphenylpyrimidin-2’-yl)thioure Bảng 3.10 Phổ MS số hợp chất N-(2,3,4,6-tetra-O-axetyl--D-glucopyranosyl)-N’(4’,6’-diarylpyrimidin-2’-yl)thioure Bảng 3.11 Một số hợp chất N-(-D-glucopyranosyl)-N’-(4’,6’-diarylpyrimidin-2’-yl)thioure Bảng 3.12 Phổ 1H-NMR hợp chất N-(-D-glucopyranosyl)-N’-(4’,6’-diphenylpyrimidin-2’yl)thioure 7a1 Bảng 3.13 Kết tổng hợp số dẫn xuất 2-iminothiazolidin-4-on Bảng 3.14 Số liệu phổ 1H-NMR 2-iminothiazolidin-4-on 8/8’ 118 Bảng 3.15 Số liệu phổ 13C-NMR 2-iminothiazolidin-4-on 8/8’ Bảng 3.16 Hoạt tính sinh học hợp chất 2-amino-4,6-diarylpyrimidin Bảng 3.17 Các đóng góp nhóm vào hoạt tính sinh học hợp chất 2-amino-4,6diarylpyrimidin Bảng 3.18 Các giá trị thông số phân tử nghiên cứu QSAR theo mơ hình Hanhsch số 2-amino-4,6-diarylpyrimidin vii Bảng 3.19 Hoạt tính sinh học hợp chất N-(2,3,4,6-tetra-O-axetyl- -D-glucopyranosyl)N’-(4’,6’-diarylpyrimidin-2’-yl)thioure 135 Bảng 3.20 Các đóng góp nhóm vào hoạt tính sinh học hợp chất N-(2,3,4,6 -tetra-Oaxetyl--D-glucopyranosyl)-N’-(4’,6’-diarylpyrimidin-2’-yl)thioure 135 Bảng 3.21 Các giá trị thông số phân tử nghiên cứu QSAR theo mô hình Hanhsch số hợp chất N-(2,3,4,6-tetra-O-axetyl--D-glucopyranosyl)-N’-(4’,6’-diarylpyrimidin-2’yl)thioure 136 Bảng 3.22 Các giá trị thông số phân tử nghiên cứu QSAR số N-( -Dglucopyranosyl)-N’- [(4’,6’-diaryl)pyrimidin-2’-yl]thioure .137 Bảng 3.23 Các đóng góp nhóm vào hoạt tính sinh học hợp chất N- -D-glucopyranosyl)-N’[(4’,6’-diaryl)pyrimidin-2’-yl]thioure 137 Bảng 3.24 Các giá trị thông số phân tử nghiên cứu QSAR theo mơ hình Hanhsch số hợp chất N-(-D-glucopyranosyl)-N’- [(4’,6’-diaryl)pyrimidin-2’-yl]thioure 138 viii KẾT LUẬN Đã tổng hợp 35 hợp chất 2-amino-4,6-diarylpyrimidin từ xeton α,β không no với guadinin hydroclorua, phương pháp khác có phương pháp áp dụng phương pháp tổng hợp hữu lị vi sóng: Phương pháp đun sơi hồi lưu truyền thống dung môi etanol 96%; Phương pháp hồi lưu lị vi sóng; Phương pháp có dung mơi khơng hồi lưu lị vi sóng; Phương pháp khơng dung mơi lị vi sóng (áp dụng cho dãy hợp chất thứ với R =H); Phương pháp ‘one-pot’ lị vi sóng (áp dụng cho việc tổng hợp 2-amino-4-(4’isopropyl)-6-phenylpyrimidin) Các phương pháp tổng hợp lị vi sóng phần lớn cho hiệu suất phản ứng cao, thời gian phản ứng nhanh phương pháp đun hồi lưu cổ điển Đã tổng hợp 31 hợp chất glucosyl thioure chứa dị vòng pyrimidin từ per-Oaxetyl-β-D-glucopyranosyl isothioxianat 2-amino-4,6-diarylpyrimidin theo hai phương pháp: Phương pháp đun hồi lưu dung môi dioxan khan với hiệu suất từ 56-77% phương pháp không dung mơi lị vi sóng với hiệu suất cao (67-80%), tiết kiệm thời gian, lượng dung môi, giảm thiểu ô nhiễm môi trường Cấu trúc sản phẩm tổng hợp theo hai phương pháp đồng Đã Deaxetyl hóa hợp chất thioure với hiệu suất từ 62-65% Đã tổng hợp hợp chất 2-iminothiazolidin-4-on từ N-(2,3,4,6-tetraO-axetyl-D-glucopyranosyl)-N’(4’,6’- diarylpyrimidin-2’-yl)thioure với etyl bromoaxetat với hiệu suất từ 54-68%, sản phẩm thu hỗn hợp đồng phân Cấu trúc chất tổng hợp xác nhận phương pháp phổ IR, H13 NMR, C-NMR, kết hợp kỹ thuật phổ hai chiều HMBC, HSQC, COSY phổ khối lượng phân giải cao Đã nhận thấy hợp chất 2-amino-4,6-diarylpyrimidin hợp chất glucosyl thioure tương ứng tổng hợp thể khả kháng trực khuẩn Gram(–) Enterobacter, cầu khuẩn Gram(+) S Epidermidis, diệt nấm Candida albicans (Calbicans) Đã bước đầu tính tốn số đóng góp nhóm vào hoạt tính sinh học khung phân tử theo phương pháp Free - Wilson đưa phương trình hồi qui đa biến mơ tả thay đổi hoạt tính sinh học theo mơ hình Hansch 139 DANH MỤC CÁC CƠNG TRÌNH KHOA HỌC CỦA TÁC GIẢ LIÊN QUAN ĐẾN LUẬN ÁN [1] Nguyễn Đình Thành, Nguyễn Thị Thanh Mai, Đặng Như Tại, Phạm Hồng Lân, Góp phần tổng hợp số 2-amino-4,6-diarylpirimidin, Tuyển tập cơng trình khoa học “Kỷ niệm 50 năm thành lập khoa Hoá học, trường ĐHTH Hà Nội 19562006”, Hà Nội 10/2006, tr 104-108 [2] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, High-resolution mass spectra of some 1-(2’,3’,4’,6’-tetra-O-acetyl--D-glucopyranosyl)-3-(4”,6”-diarylpyrimidine-2”yl)thioureas, Tạp chí Khoa học Cơng nghệ, T 45, N 1B, pp 202-209 (2007) [3] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Synthesis of some derivatives of 1(2’,3’,4’,6’-tetra-O-acetyl--D-glucopyranosyl)-3-(4”,6”-diarylpyrimidine-2”yl)thioureas using microwave oven, Tuyển tập cơng trình Hội nghị Khoa học Cơng nghệ, Hóa học Hữu tồn quốc thứ tư, Hà Nội 10/2007, tr 206-210 [4] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, 1-(2’,3’,4’,6’-tetra-O-acetyl-Dglucopyranosyl)-3-(4”,6”-diarylpyrimidine-2”-yl)thioureas, 11th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-11), 1-30 November 2007 (MDPI), A030 [5] Nguyễn Đình Thành, Nguyễn Thị Thanh Mai, Hoạt tính sinh học số dẫn xuất 2-amino-4,6-diarylpyrimidin hợp chất thioure tương ứng, Tuyển tập báo cáo Hội nghị tồn quốc “Khoa học Cơng nghệ Hố Dược”, lần thứ nhất, Hà Nội 12/2008, tr 160-168 [6] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Syntheis of some derivatives of 1(2’,3’,4’,6’-tetra-O-acetyl--D-glucopyranosyl)-3-(4”,6”-diarylpyrimidine-2”-yl)thioureas, Tạp chí Hố học, T.46, N.1, pp 102-107 (2008) [7] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, NMR spectra of some N-(tetra-Oacetyl--D-glucopyranosyl)-N’-(4’,6’-diarylpyrimidine-2’-yl)thioureas, Tạp chí Phân tích Hố Lý Sinh học, T 14, 165-170 (2009) [8] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Tran Thi Ha Thu, Synthesis of some N-(2,3,4,6-tetra-O-acetyl--D-glucopyranosyl)-N’- [4’-(p-bromophenyl)-6’- arylpyrimidine-2’-yl]thioureas, Tạp chí Hố học, T.47, N.4A, tr.217-222 (2009) 140 [9] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Synthesis of N-tetra-O-acetyl--Dglucopyranosyl-N’-(4’,6’-diarylpyrimidine-2’-yl)thioureas, Carbohydr Res., Vol 344 , 2399-2405 (2009) [10] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Synthesis of 2iminothiazolidin-4ones from N-(per-O-acetyl-β-D-glucopyranosyl)-N’-(4’,6’-diarylpyrimidine-2’- yl)thioureas, Tạp chí Khoa học, Khoa học tự nhiên Công nghệ (Đại học Quốc gia Hà Nội) T25 No 25 p273-280 (2009) [11] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Synthesis of some 2-amino-4,6diarylpyrimidine derivatives using microwave-assisted method, Tạp chí Hố học T47 (5) p 628-632 (2009) [12] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Analysis of NMR spectra of N(per-O-acetyl--D-glucopyranosyl)-N’- [4’-(p-bromophenyl)-6’-arylpyrimidine-2’yl]thioureas, Tạp chí Phân tích Hố Lý Sinh học T15 (2009) [13] Nguyễn Đình Thành, Nguyễn Thị Thanh Mai, Microwave-Assisted synthesis of N-Tetra-O-Acetyl-β-D-glucopyranosyl)-N’-(4’,6’-diarylpyrimidine-2’yl)thioureas.13rd international Electronic Conference on Synthetic Organic Chemistry (ECSOC-13), 1-30 November 2009 [14] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Synthesis of some N-(2,3,4,6tetra-O-acetyl--D-glucopyranosyl)-N’-4’- [(p-methoxyphenyl)-6’-arylpyrimidine-2’yl]thioureas, Tạp chí Hố học, (2009) (đã nhận đăng) [15] Nguyen Dinh Thanh, Nguyen Thi Thanh Mai, Bui Thi Thu Trang, Analysis of NMR spectra of N-(per-O-acetyl--D-glucopyranosyl)-N’- [4’-(p-methoxyphenyl)-6’arylpyrimidine-2’-yl]thioureas, Tạp chí Phân tích Hố 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DỊ VỊNG PYRIMIDIN 1.3.1 Tổng hợp vịng pyrimidin Pyrimidin ba đồng phân diazin, dị vòng cạnh chứa hai dị tố nitơ vòng, bền vững tan nước, có nhiệt độ nóng chảy