Nghiên cứu một số phương pháp tô ̉ ng hợp pregnan và một số dẫn xuất của chúng từ 9α hydroxy androstendion

BỘ GIÁO DỤC VÀ ĐÀO TẠO VIỆN HÀN LÂM KHOA HỌC VÀ CÔNG NGHỆ VIỆT NAM HỌC VIỆN KHOA HỌC VÀ CÔNG NGHỆ - NGUYỄN THỊ DIỆP NGHIÊN CỨU MỘT SỐ PHƯƠNG PHÁP TỔNG HỢP PREGNAN VÀ MỘT SỐ DẪN XUẤT CỦA CHÚNG TỪ 9α-HYDROXY ANDROSTENDION LUẬN ÁN TIẾN SỸ HÓA HỌC HÀ NỘI – 2017 BỘ GIÁO DỤC VÀ ĐÀO TẠO VIỆN HÀN LÂM KHOA HỌC VÀ CÔNG NGHỆ VIỆT NAM HỌC VIỆN KHOA HỌC VÀ CÔNG NGHỆ - NGUYỄN THỊ DIỆP NGHIÊN CỨU MỘT SỐ PHƯƠNG PHÁP TỔNG HỢP PREGNAN VÀ MỘT SỐ DẪN XUẤT CỦA CHÚNG TỪ 9α-HYDROXY ANDROSTENDION Chuyên ngành: Hóa Hữu Mã số: 62.44.01.14 LUẬN ÁN TIẾN SỸ HÓA HỌC NGƯỜI HƯỚNG DẪN KHOA HỌC: PGS.TS Lưu Đức Huy Hà Nội – 2017 LỜI CAM ĐOAN Tôi xin cam đoan tất kết nghiên cứu khoa học trình bày Luận án nhóm nghiên cứu PGS TS Lưu Đức Huy-Viện Hóa họcViện Hàn lâm Khoa học Cơng nghệ Việt Nam-thực hiện; hồn tồn khơng sử dụng kết nghiên cứu nhà Khoa học khác Tôi xin hồn tồn chịu trách nhiệm trước pháp luật tính trung thực kết nghiên cứu Tác giả luận án NCS Nguyễn Thị Diệp LỜI CẢM ƠN Với lịng biết ơn sâu sắc, tơi xin chân thành cảm ơn PGS.TS Lưu Đức Huy giao đề tài, hướng dẫn nhiệt tình, truyền cảm hứng tạo điều kiện thuận lợi để tơi hồn thành Luận án này Luận án hồn thành Phịng Hóa học Steroid Alkaloid-Viện Hóa học-Viện Hàn Lâm Khoa học Công nghệ Việt Nam Tôi xin cảm ơn đồng nghiệp Phịng thí nghiệm giúp đỡ tơi công tác, học tập nghiên cứu Tôi xin gửi lời cám ơn chân thành đến Lãnh đạo nhân viên Phòng Đào tạo Sau Đại học Viện Hóa học Học viện Khoa học Cơng nghệ đồng nghiệp Viện Hóa học động viên, giúp đỡ suốt trình thực đề tài bảo vệ Luận án Acknowledgement This Thesis is funded by Vietnam National foundation for Science and Technology Development (Grant No.104.01-2012.20) and National Pharm.-Chem Program 2007-2020 (Grant No.CNHD.ĐT.059/15-17) Hà nội, ngày tháng năm 2017 Nghiên cứu sinh Nguyễn Thị Diệp MỤC LỤC MỞ ĐẦU…………………………………………………… …………………………………1 CHƯƠNG TỔNG QUAN…………………………………… ………………………….4 1.1 Phương pháp tổng hợp mạch bên pregnane 1.1.1 Phương pháp cyanohydrin tổng hợp mạch bên pregnane 1.1.2 Phương pháp acetylene tổng hợp mạch bên pregnane 1.2 Phương pháp bảo vệ nhóm 3- 20-ketosteroid 11 1.3 Đưa nối đôi vào vị trí 1(2), 9(11) 16(17) phân tử steroid 14 1.3.1 Tạo lập nối đôi ∆9(11) ∆16(17) 14 1.3.2 ∆1(2) -dehydro hóa 17 1.3.2.1 ∆1(2) -dehydro hóa phương pháp vi sinh 17 1.3.2.2 ∆1(2)-dehydro hóa phương pháp hóa học 19 1.4 Tổ ng hơ ̣p ma ̣ch bên corticoid 22 1.4.1 Chuyển hố nhóm 17-ethynyl đến mạch bên corticoid 22 1.4.2 Chuyển hóa 20-ketopregnane đến mạch bên corticoid 25 1.5 Tổng hợp 16β-methyl-17α-hydroxypregnane 28 1.5.1 Gắn mảnh 16β-methyl-17α-hydroxy vào 20-ketopregnane 28 1.5.2 Gắn nhóm methyl vào vị trí 16β- phân tử corticosteroid 29 CHƯƠNG THỰC NGHIỆM……………………………….……………………… …32 2.1 Phương pháp dehydrat hóa 9α-OH AD tổng hợp androsta-4,9(11)-diene- 3,17-dione (Δ9-AD) (2) 32 2.2 Phương pháp cô ̣ng hơ ̣p nitrile vào hơ ̣p chấ t 17-ketosteroid (phương pháp cyanohydrin) 32 Sử dụng KCN 33 2.2.1 2.2.1.1 Phương pháp chung 33 2.2.1.2 Tổng hợp 17α-hydroxy-17β-cyanoandrosta-4,9(11)-diene-3-one (3) 33 2.2.2 Sử dụng acetone cyanohydrin 33 2.2.2.1 Phương pháp chung 33 2.2.2.2 Tổng hợp 17α-hydroxy-17β-cyanoandrosta-4,9(11)-diene-3-one (3) 33 2.3 2.3.1 Phương pháp bảo vệ nhóm carbonyl 33 Phương pháp bảo vệ nhóm carbonyl sử dụng neopentyl glycol 34 2.3.1.1 Phương pháp chung 34 2.3.1.2 Tổng hợp 17α-hydroxy-3,3-(2,2-dimethyl propylenedioxy)-17β-cyano androsta-5,9(11)-diene (4a)…………… 34 2.3.1.3 Tổng hợp 3,20-bis-(2,2-dimethyl propylenedioxy)-16α,17α-epoxy pregna-5,9(11)-diene (10a) 34 Phương pháp chung bảo vệ chức 3-keto-∆4 phân tử steroid sử dụng 2.3.2 ethylene glycol 35 2.3.2.1 Tổng hợp 3,3-(1,2-ethyleneketal)-17β-cyanoandrosta-5,9(11)-diene- 17α-ol (4b)…………… 35 2.3.2.2 Tổng hợp 3,3-(1,2-ethyleneketal)-17α,21-dihydroxypregna-5,9(11)- diene-20-one-21-acetate (4c)…………… 35 Phương pháp chung bảo vệ chức 20-keto phân tử steroid sử dụng 2.3.3 ethylene glycol 35 2.3.3.1 Tổng hợp 3,20-bis-(1,2-ethyleneketal)-16α,17α-epoxypregna-5,9(11)- diene (10b)…… 36 2.3.4 Tổng hợp 3,17-bis-(1,2-ethyleneketal)-androsta-5-en-9α-ol (10c)………… 36 2.3.5 Tổng hợp 9α-hydroxy-3-methoxyandrosta-3,5-diene-17-one (4d)……… 36 Dehydrat hóa 17α-hydroxysteroid đến dẫn xuất ∆16(17) tương ứng 36 2.4 2.4.1 Phương pháp chung 36 2.4.2 Tổng hợp 3,3-(2,2-dimethyl propylenedioxy)-17-cyanoandrosta- 5,9(11),16(17)-triene (5) 37 2.5 Phương pháp cộng hợp acetylene vào hợp chất 17-ketosteroid (phương pháp acetylene) 37 2.5.1 Tổng hợp 9α,17β-dihydroxy-17α-ethynylandrosta-4-en-3-one 37 2.5.2 Tổng hợp 17α-ethynyl-17β-hydroxyandrosta-4,9(11)-diene-3-one (7) 37 2.6 Phương pháp epimer hóa gián tiếp trung tâm C-17 hợp chất steroid thông qua ester 17-ONO2 38 2.6.1 Tổng hợp 17α-ethynyl-17β-nitrooxyandrosta-4,9(11)-diene-3-one (7’) 38 2.6.2 Tổng hợp 17β-ethynyl-17α-hydroxyandrosta-4,9(11)-diene-3-one (8) 38 2.7 Phương pháp tổng hợp 20-ketosteroid (mạch bên pregnane) 38 2.7.1 2.7.1.1 Theo phương pháp cyanohydrin, sử dụng hợp chất Mg 38 Phương pháp chung 38 2.7.1.2 Tổng hợp 3,3-(2,2-dimethyl propylenedioxy)-pregna-5,9(11),16(17)- triene-20-one (6a)…… 39 Theo phương pháp cyanohydrin, sử dụng hợp chất Li 39 2.7.2 2.7.2.1 Phương pháp chung 39 2.7.2.2 Tổng hợp pregna-4,9(11)-diene-17α-ol-3,20-dione (6b) 40 Theo phương pháp acetylene, hydrat hóa nhóm ethynyl tổng hợp 2.7.3 pregna-4,9(11)-diene-17α-ol-3,20-dione (6b) 40 2.8 Phương pháp tổng hợp dẫn xuất epoxy 40 Theo phương pháp oxy hóa nối đơi C=C liên hợp 40 2.8.1 2.8.1.1 Tổng hợp 3,3-(2,2-dimethyl propylenedioxy)-16α,17α-epoxypregna- 5,9(11)-diene-20-one (9) 40 2.8.1.2 Tổng hợp 16α,17α-epoxypregna-5-en-3β-ol-20-one (23)….………… 41 Theo phương pháp dehalohydrin 41 2.8.2 2.8.2.1 Phương pháp chung 41 2.8.2.2 Tổng hợp 9β,11β-epoxy-16β-methyl-17α,21-dihydroxypregna-4-en- 3,20-dione (19a)…… 41 2.8.2.3 Tổng hợp 9β,11β-epoxy-16β-methyl-17α,21-dihydroxypregna-1,4- diene-3,20-dione (19b) 41 2.9 Phương pháp tổng hợp 16β-methyl-17α-hydroxypregnane 42 2.9.1 Phương pháp chung 42 2.9.2 Tổng hợp 3,20-bis-(2,2-dimethyl propylenedioxy)-16β-methylpregna- 5,9(11)-diene-17α-ol (11a) 42 2.9.3 Tổng hợp 3,20-bis-(1,2-ethyleneketal)-16β-methylpregna-5,9(11)-diene- 17α-ol (11b)… 42 2.10 Phương pháp giải phóng nhóm bảo vệ 42 2.10.1 Phương pháp chung 43 2.10.2 Tổng hợp 16β-methy-17α-hydroxypregna-4,9(11)-diene -3,20-dione (12)43 2.11 Phương pháp tạo lập nối đôi ∆1(2) 43 2.11.1 Phương pháp chung 43 2.11.2 Tổng hợp 16β-methyl-17α-hydroxypregna-1,4,9(11)-triene-3,20-dione (13a)…… 43 2.11.3 Tổng hợp pregna-1,4,9(11)-triene-17α,21-diol-3,20-dione-21-acetate (13b)…………………………………………………………………………………43 2.12 Phương pháp tổng hợp mạch bên corticoid 44 2.12.1 Phương pháp tổng hợp mạch bên corticoid sử dụng hợp chất siêu hóa trị iod PhI(OAc)2 44 2.12.1.1 Phương pháp chung 44 2.12.1.2 Tổng hợp 16α,17α-epoxypregna-4,9(11)-diene-21-ol-3,20-dione (15) 44 2.12.1.3 Tổng hợp 16α,17α-epoxypregna-5-en-3β,21-diol-20-one (25) 45 2.12.2 Phương pháp tổng hợp mạch bên corticoid sử dụng I2 môi trường kiềm…… 45 2.12.2.1 Phương pháp chung tổng hợp mạch bên corticoid qua hợp chất trung gian 21,21-diiodide ………………………………………………………………45 2.12.2.2 Tổng hợp 21-acetoxy-16β-methylpregna-4,9(11)-diene-17α,21-diol- 3,20-dione (16a)…… 46 2.12.2.3 Tổng hợp 21-acetoxy-16β-methylpregna-1,4,9(11)-triene-17α,21-diol- 3,20-dione (16b)…… 46 2.12.2.4 Phương pháp chung tổng hợp mạch bên corticoid qua dẫn xuất 21- monoiodide…… 46 2.12.2.5 Tổng hợp 21-acetoxypregna-4,9(11)-diene-17α,21-diol-3,20-dione (17)…………… ……………………………………………47 2.12.2.6 Tổng hợp 16β-chloro-17α-hydroxy-21-iodopregna-4-en-3,20-dione (22) …………………………………………………………………………………………… 47 2.13 Phương pháp đưa halogen vào phân tử steroid 47 2.13.1 Phương pháp halohydrin 47 2.13.1.1 Phương pháp chung 47 2.13.1.2 Tổng hợp 9α-bromo-16β-methyl-11β,17α,21-trihydroxypregna-4-en- 3,20-dione-21-acetate (18a)…………… 47 2.13.1.3 Tổng hợp 9α-bromo-16β-methyl-11β,17α,21-trihydroxypregna-1,4- diene-3,20-dione-21-acetate (18b)………… 48 2.13.1.4 Tổng hợp 9α-bromo-11β,17α,21-trihydroxypregna-1,4-diene-3,20- dione-21-acetate (18c) 48 2.13.2 Phương pháp cộng mở vòng epoxy ……………………………………… 48 2.13.2.1 Tổng hợp 16β-chloro-17α-hydroxypregna-4-en-3,20-dione (21’’)……….…………………………………………………………………………48 2.13.2.2 Tổng hợp 16β-chloropregna-5-en-3β,17α-diol-20-one (24a)…………………… ……………………………………………………………48 2.13.2.3 Tổng hợp 16β-bromopregna-5-en-3β,17α-diol-20-one (24b)…………….………………………………………………………………… 49 2.14 Phương pháp khử halogen (dehalogen hóa) tổng hợp prednisolone acetate (20)………… 49 CHƯƠNG KẾT QUẢ VÀ THẢO LUẬN……………………………………… 50 3.1 Dehydrat hóa 9α-OH AD tổng hợp androsta-4,9(11)-diene-3,17-dione (Δ9- AD) 53 3.2 Tổng hợp mạch bên pregnane 54 3.2.1 Phương pháp cyanohydrin 54 3.2.2 Phương pháp acetylene 66 3.3 Phương pháp tổng hợp 16β-methyl-17α-hydroxypregnane 71 3.4 Phương pháp tạo lập nối đôi ∆1(2) 81 3.5 Phương pháp tổng hợp mạch bên corticoid 83 3.5.1 Phương pháp tổng hợp mạch bên corticoid sử dụng hợp chất siêu hóa trị iod PhI(OAc)2 83 3.5.2 Phương pháp tổng hợp mạch bên corticoid sử dụng I2 môi trường kiềm… 85 3.5.2.1 Phương pháp tổng hợp mạch bên corticoid qua hợp chất trung gian 21,21-diiodide…… 85 3.5.2.2 Phương pháp tổng hợp mạch bên corticoid qua hợp chất trung gian 21-monoiodide…… 87 3.5.3 So sánh hai phương pháp tổng hợp mạch bên corticoid………………………90 3.6 Phương pháp đưa halogen vào phân tử steroid 90 3.6.1 Theo phương pháp halohydrin 90 3.6.2 Theo phương pháp cộng mở vòng epoxy 91 3.7 Tổng hợp dẫn xuất epoxy theo phương pháp dehalohydrin 93 3.8 Phương pháp khử halogen (dehalogen hóa) 95 C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 3.9 Đề xuất hai sơ đồ tổng hợp số dược phẩm steroid dựa phương pháp nghiên cứu 96 3.9.1 Sơ đồ tổng hợp hydrocortisone acetate pednisolone từ 9α-OH AD 96 3.9.2 Sơ đồ tổng hợp betamethasone beclomethasone từ 9α-OH AD 99 KẾT LUẬN……………………………………………………………… 116 NHỮNG ĐÓNG GÓP MỚI CỦA LUẬN ÁN……………………………………118 DANH MỤC CÁC CƠNG TRÌNH ĐÃ CÔNG BỐ…………………………… 119 TÀI LIỆU THAM KHẢO…………………………………………………………120 PHỤ LỤC………………………………………………………………………… 131 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 122 25 J N M Batist, A F M Slobbe, A F 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66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 130 Pimelobacter simplex, and Rhodococcus erythropolis, Appl Microbiol Biotechnol (RU.), 2011, 47 (3), 270-273 125 N V Carpova-Rodina, V A Andryushina, Luu Duc Huy et al., Transformation of Δ4-3-ketosteroids by free and Immobilized cells of Rhodococcus erythropolis Actinobacterium, Appl Microbiol Biotechnol (RU.), 2011, 47 (4), 386-392 126 L D Huy, N T Diep et al., Transformation of androstenedione into 17αhydroxy-16β-methylpregna-4-en-3,20-dione, Indian J Chem., Sect B, 2016, 55B (July), 888-891 127 L D Huy, N T Diep, and L T K Nhung, Alternative road for synthesis of 16α,17α-epoxypregn-4,9(11)-diene-21-ol-3,20-dione from 9α-hydroxy androstenedione, Pharm Chem J (RU), 2012, 46 (6), 356-359 128 Luu D Huy and Nguyen T Diep, Synthesis of 16β-methylpregn-4,9(11)-diene17α-ol-3,20-dione from 9α-hydroxyandrostenedione, Pharm Chem J (RU), 2015, 49 (7), 486-489 129 Lưu Thị Kim Nhung, Góp phần nghiên cứu vài phương pháp ứng dụng tổng hợp pregnan từ phytosterol thông qua androstendion, Luận văn Thạc sĩ Khoa học Hóa học, 2012, Viện Hóa học-Viện Hàn lâm KHCNVN, Hà nội 130 Nguyễn Văn Đại, Nghiên cứu số phương pháp tổng hợp corticosteroid từ androstendion hợp chất tương tự, Luận văn Thạc sĩ Khoa học Hóa học, 2015, Viện Hóa học-Viện Hàn lâm KHCNVN, Hà nội Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 131 PHỤ LỤC Trang Phổ IR 9α-hydroxyandrostenedione (9α-OH AD) (1) P-1 Phổ 1H-NMR 9α-hydroxyandrostenedione (9α-OH AD) (1) P-1;2 Phổ 13C-NMR 9α-hydroxyandrostenedione (9α-OH AD) (1) P-2;3 Phổ DEPT 9α-hydroxyandrostenedione (9α-OH AD) (1) P-3 Phổ EI-MS 9α-hydroxyandrostenedione (9α-OH AD) (1) P-4 Phổ 1H-NMR androsta-4,9-diene-3,17-dione (∆9-AD) (2) P-4;5 Phổ IR 17α-hydroxy-17β-cyanoandrosta-4,9(11)-diene-3-one (3) P-5 Phổ 1H-NMR 17α-hydroxy-17β-cyanoandrosta-4,9(11)-diene-3- P-6 one (3) Phổ ESI-MS 17α-hydroxy-17β-cyanoandrosta-4,9(11)-diene-3-one P-6 (3) 10 Phổ IR 17α-hydroxy-3,3-(2,2-dimethyl propylenedioxy)-17β- P-7 cyanoandrosta-5,9(11)-diene (4a) 11 Phổ 1H-NMR 17α-hydroxy-3,3-(2,2-dimethyl propylenedioxy)- P-7;8 17β-cyanoandrosta-5,9(11)-diene (4a) 12 Phổ 1H-NMR 3,3-(1,2-ethyleneketal)-17β-cyanoandrosta-5,9(11)- P-8;9 diene-17α-ol (4b) 13 Phổ 13 C-NMR 3,3-(1,2-ethyleneketal)-17β-cyanoandrosta- P-9 14 Phổ IR 3,3-(1,2-ethyleneketal)-17α,21-dihydroxypregna-5,9(11)- P-10 5,9(11)-diene-17α-ol (4b) diene-20-one-21-acetate (4c) 15 Phổ 1H-NMR 3,3-(1,2-ethyleneketal)-17α,21-dihydroxy P-10;11 pregna-5,9(11)-diene-20-one-21-acetate (4c) 16 Phổ IR 9α-hydroxy-3-methoxyandrosta-3,5-diene-17-one (4d) P-11 17 Phổ IR 3,3-(2,2-dimethyl propylenedioxy)-17-cyanoandrosta- P-12 5,9(11),16(17)-triene (5) 18 Phổ H-NMR 3,3-(2,2-dimethyl propylenedioxy)-17- Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn P-12;13 C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 132 cyanoandrosta-5,9(11),16(17)-triene (5) 19 Phổ IR 3,3-(2,2-dimethyl propylenedioxy)-pregna- P-13 3,3-(2,2-dimethyl propylenedioxy)-pregna- P-14 5,9(11),16(17)-triene-20-one (6a) 20 Phổ H-NMR 5,9(11),16(17)-triene-20-one (6a) 21 Phổ IR pregna-4,9(11)-diene-17α-ol-3,20-dione (6b) 22 Phổ 1H-NMR pregna-4,9(11)-diene-17α-ol-3,20-dione (6b) P-15 P-15;16 23 Phổ IR 17α-ethynyl-17β-hydroxyandrosta-4,9(11)-diene-3-one (7) P-16 24 Phổ 1H-NMR 17α-ethynyl-17β-hydroxyandrosta-4,9(11)-diene-3- P-17 one (7) 25 Phổ IR 17α-ethynyl-17β-nitrooxyandrosta-4,9(11)-diene-3-one P-18 (7’) 26 Phổ IR 17β-ethynyl-17α-hydroxyandrosta-4,9(11)-diene-3-one (8) P-18 27 Phổ 1H-NMR 17β-ethynyl-17α-hydroxyandrosta-4,9(11)-diene-3- P-19 one (8) 28 Phổ IR 3,3-(2,2-dimethyl propylenedioxy)-16α,17α-epoxypregna- P-20 5,9(11)-diene-20-one (9) 29 Phổ H-NMR 3,3-(2,2-dimethyl propylenedioxy)-16α,17α- P-20;21 propylenedioxy)-16α,17α- P-21 31 Phổ 1H-NMR 3,20-bis-(2,2-dimethyl propylenedioxy)-16α,17α- P-22 epoxypregna-5,9(11)-diene-20-one (9) 30 Phổ IR 3,20-bis-(2,2-dimethyl epoxypregna-5,9(11)-diene (10a) epoxypregna-5,9(11)-diene (10a) 32 Phổ IR 3,20-bis-(1,2-ethyleneketal)-16α,17α-epoxypregna- P-23 5,9(11)-diene (10b) 33 Phổ 1H-NMR 3,20-bis-(1,2-ethyleneketal)-16α,17α-epoxypregna- P-23;24 5,9(11)-diene (10b) 34 Phổ ESI-MS 3,20-bis-(1,2-ethyleneketal)-16α,17α-epoxypregna- P-24 5,9(11)-diene (10b) 35 Phổ IR 3,17-bis-(1,2-ethyleneketal)-androsta-5-en-9α-ol (10c) P-25 36 Phổ P-25 IR 3,20-bis-(2,2-dimethyl propylenedioxy)-16β- Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 133 methylpregna-5,9(11)-diene-17α-ol (11a) 37 Phổ 1H-NMR (CDCl3) 3,20-bis-(2,2-dimethyl propylenedioxy)- P-26 16β-methylpregna-5,9(11)-diene-17α-ol (11a) 38 Phổ H-NMR (DMSO-d6) 3,20-bis-(2,2-dimethyl P-27 propylenedioxy)-16β-methyl pregna-5,9(11)-diene-17α-ol (11a) 39 Phổ ESI-MS 3,20-bis-(2,2-dimethyl propylenedioxy)-16β- P-28 40 Phổ IR 3,20-bis-(1,2-ethyleneketal)-16β-methylpregna-5,9(11)- P-28 methylpregna-5,9(11)-diene-17α-ol (11a) diene-17α-ol (11b) 41 Phổ H-NMR 3,20-bis-(1,2-ethyleneketal)-16β-methylpregna- P-29 5,9(11)-diene-17α-ol (11b) 42 Phổ IR 16β-methyl-17α-hydroxypregna-4,9(11)-diene-3,20-dione P-30 (12) 43 Phổ H-NMR 16β-methyl-17α-hydroxypregna-4,9(11)-diene- P-30;31 3,20-dione (12) 44 Phổ 13 C-NMR 16β-methyl-17α-hydroxypregna-4,9(11)-diene - P-31 3,20-dione (12) 45 Phổ DEPT 16β-methyl-17α-hydroxypregna-4,9(11)-diene-3,20- P-32 dione (12) 46 Phổ NOESY 16β-methyl-17α-hydroxylpregn-4,9(11)-diene-3,20- P-32;33 dione (12) 47 Phổ 1H-NMR 16β-methyl-17α-hydroxypregna-1,4,9(11)-triene- P-33;34 3,20-dione (13a) 48 Phổ 13 C-NMR 16β-methyl-17α-hydroxypregna-1,4,9(11)-triene- P-34 3,20-dione (13a) 49 Phổ ESI-MS 16β-methyl-17α-hydroxypregna-1,4,9(11)-triene- P-35 3,20-dione (13a) 50 Phổ 1H-NMR pregna-1,4,9(11)-triene-17α,21-diol-3,20-dione-21- P-35;36 acetate (13b) 51 Phổ 13C-NMR pregna-1,4,9(11)-triene-17α,21-diol-3,20-dione-21acetate (13b) Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn P-36;37 C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 134 52 Phổ DEPT pregna-1,4,9(11)-triene-17α,21-diol-3,20-dione-21- P-37 acetate (13b) 53 Phổ ESI-MS pregna-1,4,9(11)-triene-17α,21-diol-3,20-dione-21- P-38 acetate (13b) 54 Phổ IR 3,3-(2,2-dimethyl propylenedioxy)-16α,17α-epoxy-20,20- P-38 dimethoxypregna-5,9(11)-diene-21-ol (14) 55 Phổ 1H-NMR 3,3-(2,2-dimethyl propylenedioxy)-16α,17α-epoxy- P-39 20,20-dimethoxypregna-5,9(11)-diene-21-ol (14) 56 Phổ IR 16α,17α-epoxypregna-4,9(11)-diene-21-ol-3,20-dione (15) 57 Phổ H-NMR 16α,17α-epoxypregna-4,9(11)-diene-21-ol-3,20- P-40 P-40;41 dione (15) 58 Phổ H-NMR 21-acetoxy-16β-methylpregna-4,9(11)-diene- P-41;42 17α,21-diol-3,20-dione (16a) 13 59 Phổ C-NMR 21-acetoxy-16β-methylpregna-4,9(11)-diene- P-42 17α,21-diol-3,20-dione (16a) 60 Phổ H-NMR 21-acetoxy-16β-methylpregna-1,4,9(11)-triene- P-43 17α,21-diol-3,20-dione (16b) 61 Phổ 13 C-NMR 21-acetoxy-16β-methylpregna-1,4,9(11)-triene- P-44 17α,21-diol-3,20-dione (16b) 62 Phổ ESI-MS 21-acetoxy-16β-methylpregna-1,4,9(11)-triene- P-44 17α,21-diol-3,20-dione (16b) 63 Phổ IR 21-acetoxypregna-4,9(11)-diene-17α,21-diol-3,20-dione P-45 (17) 64 Phổ 1H-NMR 21-acetoxypregna-4,9(11)-diene-17α,21-diol-3,20- P-45 dione (17) 65 Phổ 13 C-NMR 21-acetoxypregna-4,9(11)-diene-17α,21-diol-3,20- P-46 dione (17) 66 Phổ ESI-MS 21-acetoxypregna-4,9(11)-diene-17α,21-diol-3,20- P-46;47 dione (17) 67 Phổ H-NMR 9α-bromo-16β-methyl-11β,17α,21- trihydroxypregna-4-en-3,20-dione-21-acetate (18a) Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn P-47;48 C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an 135 68 Phổ 13 C-NMR 9α-bromo-16β-methyl-11β,17α,21-trihydroxy P-48 pregna-4-en-3,20-dione-21-acetate (18a) 69 Phổ H-NMR 9α-bromo-16β-methyl-11β,17α,21- P-49 trihydroxypregna-1,4-diene-3,20-dione-21-acetate (18b) 13 70 Phổ C-NMR 9α-bromo-16β-methyl-11β,17α,21- P-50 trihydroxypregna-1,4-diene-3,20-dione-21-acetate (18b) 71 Phổ ESI-MS 9α-bromo-16β-methyl-11β,17α,21- P-50 trihydroxypregna-1,4-diene-3,20-dione-21-acetate (18b) 72 Phổ 1H-NMR 9α-bromo-11β,17α,21-trihydroxypregna-1,4-diene- P-51 3,20-dione-21-acetate (18c) 73 Phổ 13C-NMR 9α-bromo-11β,17α,21-trihydroxypregna-1,4-diene- P-52 3,20-dione-21-acetate (18c) 74 Phổ DEPT 9α-bromo-11β,17α,21-trihydroxypregna-1,4-diene- P-52 3,20-dione-21-acetate (18c) 75 Phổ IR 9β,11β-epoxy-16β-methyl-17α,21-dihydroxypregna-4-en- P-53 3,20-dione (19a) 76 Phổ 1H-NMR 9β,11β-epoxy-16β-methyl-17α,21-dihydroxy P-53;54 pregna-4-en-3,20-dione (19a) 77 Phổ 13C-NMR 9β,11β-epoxy-16β-methyl-17α,21-dihydroxy P-54;55 pregna-4-en-3,20-dione (19a) 78 Phổ H-NMR 9β,11β-epoxy-16β-methyl-17α,21-dihydroxy P-55;56 pregna-1,4-diene-3,20-dione (19b) 79 Phổ 13 C-NMR 9β,11β-epoxy-16β-methyl-17α,21-dihydroxy P-56;57 pregna-1,4-diene-3,20-dione (19b) 80 Phổ DEPT 9β,11β-epoxy-16β-methyl-17α,21-dihydroxypregna- P-57 1,4-dien-3,20-dione (19b) 81 Phổ ESI-MS 9β,11β-epoxy-16β-methyl-17α,21-dihydroxypregna- P-58 1,4-diene-3,20-dione (19b) 82 Phổ IR prednisolone acetate (20) P-58 83 Phổ 1H-NMR prednisolone acetate (20) P-59 84 Phổ 13C-NMR prednisolone acetate (20) P-60 Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn C.33.44.55.54.78.65.5.43.22.2.4 22.Tai lieu Luan 66.55.77.99 van Luan an.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.C.33.44.55.54.78.655.43.22.2.4.55.22 Do an.Tai lieu Luan van Luan an Do an.Tai lieu Luan van Luan an Do an Stt.010.Mssv.BKD002ac.email.ninhd 77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77.77.99.44.45.67.22.55.77.C.37.99.44.45.67.22.55.77t@edu.gmail.com.vn.bkc19134.hmu.edu.vn.Stt.010.Mssv.BKD002ac.email.ninhddtt@edu.gmail.com.vn.bkc19134.hmu.edu.vn

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