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

ĐẠI HỌC QUỐC GIA HÀ NỘI TRƯỜNG ĐẠI HỌC KHOA HỌC TỰ NHIÊN  NGUYỄN THỊ THANH MAI NGHIÊN CỨU TỔNG HỢP VÀ TÍNH CHẤT CỦA MỘT SỐ GLUCOPYRANOSYL THIOURE CĨ CHỨA DỊ VỊNG PYRIMIDIN LUẬN ÁN TIẾN SĨ HĨA HỌC HÀ NỘI – 2010 ĐẠI HỌC QUỐC GIA HÀ NỘI TRƯỜNG ĐẠI HỌC KHOA HỌC TỰ NHIÊN  NGUYỄN THỊ THANH MAI NGHIÊN CỨU TỔNG HỢP VÀ TÍNH CHẤT CỦA MỘT SỐ GLUCOPYRANOSYL THIOURE CĨ CHỨA DỊ VỊNG PYRIMIDIN Chuyên ngành: Hóa Hữu Mã số: 62.44.27.01 LUẬN ÁN TIẾN SĨ HÓA HỌC NGƯỜI HƯỚNG DẪN KHOA HỌC: PGS TS.NGUYỄN ĐÌNH THÀNH HÀ NỘI – 2010 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’-dimetylaminobenzyliden)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 2-Amino-4-phenyl-6-(4”-clorophenyl)pyrimidin (4c1) 39 2-Amino-4-phenyl-6-(3”-clorophenyl)pyrimidin (4d1) 39 2-Amino-4-phenyl-6-(4”-bromophenyl)pyrimidin (4f1) 39 2-Amino-4-phenyl-6-(4”-metoxyphenyl)pyrimidin (4i1) .40 2-Amino-4-phenyl-6-(3”-metoxyphenyl)pyrimidin (4j1) .40 2-Amino-4-phenyl-6-(3”,4”-dioxymetylenphenyl)pyrimidin (4l1) 40 10 2-Amino-4-phenyl-6-(4”-hydroxyphenyl)pyrimidin (4m1) 40 11 2-Amino-4-phenyl-6-(3”-hydroxyphenyl)pyrimidin (4n1) 40 13 2-Amino-4-phenyl-6-(4”-dimetylaminophenyl)pyrimidin (4p1) 41 14 2-Amino-4-(4’-metoxyphenyl)-6-(4”- fluorophenyl)-pyrimidin (4b2) 41 15 2-Amino-4-(4’-metoxyphenyl)-6-(4”-clorophenyl)pyrimidin (4c2) 41 16 2-Amino-4-(4’-metoxyphenyl)-6-(3”-clorophenyl)-pyrimidin (4d2) 41 17 2-Amino-4-(4’-metoxyphenyl)-6-(2”-clorophenyl)-pyrimidin (4e2) 41 19 2-Amino-4-(4’-metoxyphenyl)-6-(4”-metylphenyl)-pyrimidin (4g2) 42 20 2-Amino-4-(4’-metoxyphenyl)-6-(4”- isopropylphenyl)-pyrimidin (4h2) 42 21 2-Amino-4,6-bis(4’-metoxyphenyl)pyrimidin (4i2) 42 22 2-Amino-4-(4’-metoxyphenyl)-6-(3”-metoxyphenyl)-pyrimidin (4j2) 42 23 2-Amino-4-(4’-metoxyphenyl)-6-(4”-dimetylaminophenyl)pyrimidin (4p2) 42 24 2-Amino-4-(4’-bromophenyl)-6-(4”-fluorophenyl)pyrimidin (4b3) 42 26 2-Amino-4-(4’-bromophenyl)-6-(3”-clorophenyl)pyrimidin (4d3) .43 27 2-Amino-4-(4’-bromophenyl)-6-(2”-clorophenyl)pyrimidin (4e3) .43 28 2-Amino-4,6-bis(4’-bromophenyl)pyrimidin (4f3) 43 29 2-Amino-4-(4’-bromophenyl)-6-(4”-metylphenyl)-pyrimidin (4g3) .43 30 2-Amino-4-(4’-bromophenyl)-6-(4”-isopropylphenyl)-pyrimidin (4h3) .43 31 2-Amino-4-(4’-bromophenyl)-6-(4”-metoxyphenyl)-pyrimidin (4i3) 43 33 2-Amino-4-(4’-bromophenyl)-6-(2”-metoxyphenyl)-pyrimidin (4k3) 44 34 2-Amino-4-(4’-bromophenyl)-6-(4”-dimetylaminophenyl)-pyrimidin (4p3) 44 35 2-Amino-4-(4’-isopropylphenyl)-6-phenylpyrimidin (Phản ứng ‘one-pot’ từ cấu tử) (4h1) .44 2.3 TỔNG HỢP N-(2,3,4,6-TETRA-O-AXETYL-β-D-GLUCO-PYRANOSYL)-N’-(4’,6’DIARYLPYRIMIDIN-2’-YL)THIOURE 44 A-Phương pháp đun hồi lưu 44 B-Phương pháp khơng dung mơi lị vi sóng 44 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-(4’,6’-diphenylpyrimidin-2’-yl)thioure (6a1) 45 N-(2,3,4,6-tetra-O-axetyl--D-glucopyranosyl-N’-[4’-phenyl-6’-(4”’-flurophenyl)pyrimidin-2’yl]thioure (6b1) 45 N-(2,3,4,6-Tetra-O-axetyl--D-glucopyranosyl)-N’-[4’-phenyl-6’-(4”’-clorophenyl)pyrimidin-2’yl]thioure (6c1) 45 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 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 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 ... HỌC TỰ NHIÊN  NGUYỄN THỊ THANH MAI NGHIÊN CỨU TỔNG HỢP VÀ TÍNH CHẤT CỦA MỘT SỐ GLUCOPYRANOSYL THIOURE CĨ CHỨA DỊ VỊNG PYRIMIDIN Chun ngành: Hóa Hữu Mã số: 62.44.27.01 LUẬN ÁN TIẾN SĨ HÓA HỌC... 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. .. 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