Tổng hợp một số hợp chất hữu cơ có hoạt tính sinh học

DAI HOC QUOC GIA HA NOI TRlrtTNG DAI HOC KHOA HOC TITNHIEN • • • • Ten de tai " TONG HOP MOT SO HOP CHnt HUU CO CO HOflT TINH SINH HOC MA SO: ft QT-05- 19 OAl HOC QUOC GIA HA MOl Oi I 5fib CHU TRI D £ TAI: Th.S THAN THI THANH VAN CAN BO THAM GIA: Cac sinh vien phong THHC HA NOI- 2006 l.BAOCAOTOMTAT: a Ten de tai: "Tong hop mot so hop chat huru ca c6 boat tinh sinh hoc" Ma so: QT-05-19 b Cbu tri de tai: Th.S Trdn Thi Thanh Van c Can bo tham gia: Cac sinh vien phong THHC d Muc tieu va no! dung nghien cufu: - Muc tieu: Tie'n hanh t6ng hop, nghien cuu ca'u tao va thu hoat tinh sinh hoc ctia m6t so dan xu^t ciia axit arylacrylic Trong quan tarn han ca la t6ng hgp m6t s6' hidrazit cua axit arylacrylic va chuy^n hoa hidrazon chiia nhan 5-nitrofuranyl c6 hoat tinh sinh hoc cao - Not dung: Tien hanh phan vtng t6ng hgp cac ch^t huu ca, xac dinh c^u tao san pham nha cac phuong phap ph6 IR, UV-VIS, MS, 'H-NMR, thu hoat tinh khang khu&,khang na'm cua mOt s6' chat tdng hgp dugc e Ket qua dat dugc: • Da tong hgp m6t s6 metyl va etyl este cua axit arylacrylic, tir t6ng hgp cac hidrazit va ih cac hidrazit tong hgp cac hidrazon ciia axit arylacrylic • C^u true cua cac hgp cha't mod nh^n dugc da dugc xac nh^n nhcy cac phuong phap phd h6ng ngoai, ph6 c6ng hucmg ttf hat nhan va ph6 kh6'i lugng • Hoat tinh sinh hoc cua mot so san phSm dugc thir tren mOt s6 chung n&i va vi khu^n • V6i ke't qua da va se cong bo cac c6ng trinh sau day: Tong hap, xac dinh cdu tao va thi hoat tinh sinh hoc cua mot so dan xud't cua axit arylacrylic, bai giri tap chi Hoa hoc va umg dung, se dang nam 2006 Dua tren de tai da gop phin dao tao dugc: -\- Da gop phin h6 trg 01 hoc vien cao hoc bao ve c6ng luan van cao hoc: • f Tinh binh sii dung kinb phi: Tong kinh phi dugc ca'p cho viec thuc hien d6 tai la 10 trieu d6ng chu yeu dugc dung de mua hoa chat nghiem Mot phSn chu yeu khac dugc diing d^ thue mucm chuyen mon va lao dong Hd not, ngayi^ thdng ^ nam 2006 CHU NHllM Dfi TAI KHOA HOA HOC "uPGS TS Tran Thi Nhu Mai , S j:>t4ln ThS Tran Thj Thanh Van i^y!n/u' SUMMARY: a Reaserching Project: activity" "Synthesis of some organic compounds have biological Code: QT 05-19 b Director: Tran Thi Thanh Van, M.S c Members: Some students in Organic Synthesis Group U d Researching Attitudes and Contents: - Researching Attitudes: synthesis of, study on structure and test biological activity of some derivatives of arylacrylic acid - Researching Contents: Perfoming synthetic reactions of the organic compounds, determining the constitutions of the products by spectroscopies as IR, UV-VIS, MS, 'H-NMR, test of some biological activity of some compounds e Results: • Several of methyl, ethyl este hidrazides and hidrazones of arylacryhc acid have been synthesized • The constitutions of the products have been determined by using IR-, UV-VIS, MSand 'H-NMR- spectroscopies • The bioactivity of some compounds have been tested • One reaserching paper has been published and submitted • The reaserching project has contributed to the graduations of one master PHAN N O I D U N G C H I N H MUC LUC Trang A Ldl Md DAU B N O I D U N G CHINH Tdng hgp cac metyl va etyl este ciia axit arylacrylic T6ng hgp cac hidrazit cua axit arylacrylic T6ng hgp cac hidrazon cua axit arylacrylic Thir hoat tinh sinh hoc cua mot s6' cha't tdng hgp dugc 10 Thuc nghiem 11 Ket luan 12 C TAI LIEU THAM K H A O 12 A L61 MO DAU Nham gop phSn tim nhung chat c6 hoat tinh sinh hoc cao phuc vu cho muc dfch tim nhung loai thu6'c m6i ch6'ng lai nhung can benh the ki, chung toi da thuc hien de tai "tdng hgp m6t so hgp ch^t hOu ca c6 hoat tinh sinh hoc" vcd mong muon gop mot phin nho cho muc dich tren Trong d6 tai chung t6i quan tam han ca den viec tdng hgp mot s6 dan xuit cia axit arylacrylic nhu cac este, hidrazit, hidrazon chiia nhan 5-nitro furanyl da dugc bie't la c6 hoat tinh sinh hoc cao Cac cha't tdng hgp dugc da dugc xac dinh ca'u tao bang cac phuong phap vat ly hien dai va m5t s6' ch^t da dugc thu hoat tinh sinh hoc tren mot s6' chung vi khuan va na'm B PHAN N O I D U N G CHINH Tdng hgp cac metyl va etyl este cua axit arylacrylic Metyl va etyl este cua axit arylacrylic dugc tdng hgp true tiep tir phan ung cua cac ancol va axit arylacrylic su c6 mat cua H2SO4 lam xuc tac De tang hieu suat phan ung chung t6i da dung du ancol va dun nong nhe h6n hgp phan vtng Cac meiyi va etyl este thu dugc a dang tinh th^ hay dang long a dieu kien thucmg, c6 diem nong chay hoac diem spi xac dinh.^ Ca^u true cua san phim dugc xac dinh bang cac phuang phap phd hong ngoai, tu ngoai, phd cdng huong tu nhan proton va phd kh6'i lugng Sa dd phan utig: R-CH=CH-COOH + R'-OH ^ " R - C H = C H - C O O R ' + H2O R: C^H^-, P-CH3O-C6H4-, m-N02-C6H4-, m-Cl-C6H4R ' C2H5-, CH3Bdng 1: Ket qua tdng hop va xac dinh cdu tao cac este cua axit arylacrylic TT R R' * nc cnai) Hieu suat Vc=o Phd hong ngoai (cm"^ Vc=C -QH3 (271) 79,4 1711 1638 -CH3 93-94 74,6 1711 1639 -CH3 125-126 74,1 1708 1638 m-Cl-QH4- -CH3 53-54 81,9 1732 1715 2-C4H4O- -CH3 (146-147) 72,6 1717 1641 NO2C4H,0- 91-92 1706 1640 C6H3- P-CH3OCfiH4m-NOjCfiH4- -QH3 63,8 Vri 1313 1270 1206 1173 1323 1524 1295 1355 1318 793 1258 677 1017 1211 1282 1512 1213 1349 ^c-o-c V N Pho tu ngoai (A,^3„ nm) 277,5 216,5 260,3 203,0 272,4 220,8 303,0 Tren phd hdng ngoai cua cac metyl va etyl este ciia axit arylacrylic cho tha'y cue dai ha'p thu cua nhom -OH axit c6 chan rong (tir 2313-2512 cm') da m^t han, thay vao la sir xua't hien cac cue dai hap thu ciia lien ke't C-O-C este a khoang 1200-1300 cm"' (xem hinh va 2) Tdng hgp cac hidrazit cua axit arylacrylic Cac hidrazit dugc tdng hgp true tie'p tiJ phan ung cua cac etyl va metyl este cua axit acrylic vdi hidrazin hidrat dung m6i etanol hoac metanol Cac phan ung thuc hien tuang dO'i de nhung then gian phan utig thuang keo dai (khoang 12 gid) Cac san pham thu dugc a dang long hoac tinh the c6 nhiet d6 s6i hoac nhiet nong chay xac dinh Ca'u triic ciia cac san ph^m dugc xac dinh bang phuang phap phd hdng ngoai, tu ngoai va phd cong huong tijf hat nhan proton Ke't qua tdng hgp cac hidrazit dugc cho a bang San ph^m hidrazit tao c6 phd hdng ngoai khac vdi cac este ban dau Tren phd hdng ngoai xua't hien cac cue dai ha'p thu cua lien ket NH a vung tir 3230-3416 cm"', cue dai h^p thu cua lien ket C=0 a 1664-1716 cm', nhung cac cue dai hap thu thuang tu, khOng sac net c6 hien tugng tao lien ke't hidro giua nhom C=0 cacbonyl va NH2 Bang 2: Ket qua tong hap vd xac dinh cdu tao cac hidrazit TT R QH5- P-CH3O- Pho hong ngoai (cm') Hieu suat Vc=0 Vc=C Vc-N 24-25 55,5 1714 1636 1279 1202 85-86 58,5 1716 1639 1174 *• nc VNOI Vci 71,4 1644 1664 CftH4- m-Ci-C5H4- 23-24 50,0 1692 1640 NO2C4H,0- 120121 62,1 1705 1642 m-N02- 1207 1211 1175 1284 1242 Phottf ngoai (X^,„ nm) 275,4 216,4 309,8 C6H4- 103105 R-CH=CH-C0-NH-NH2 1532 1344 786 210,8 260,8 206,4 269.2 214,0 1511 1315 1# Hinh 1: Pho hong ngoai cua este metyl m-cloxinamat Tren phd c5ng huong tir hat nhan proton, ngoai cac tin hieu cua cac proton nhan thom thi tin hieu cua proton nhom -CH=CH- cung xua't hien rat ro net va dac biet la cac pic c6 cucmg ye'u chuyen dich hoa hoc 8,0 va 2,lppm dac trung cho proton cua nhom -NH-NH- (xem bang 5) Dai hoc Ouoc gia turyi acrylalTTiRfyr -^-r-r n H-r.,., Hinh 2: Pho hong ngoai cua metyl 3-furyl acrylat 96 94 92 90 m B6 64 82 ! ill 80 'ij 78 76 ^I 74 !^ 72 70 ! S ! i '!' i 68 66 l! ;l 64 62 60 58 56 Hinh 3: Phd cong hong ngoai cua 2-(5-nitrofuryl-2) acryloyl hidrazit Tong hgp cac hidrazon cua axit arylacrylic Thuc hien phan iJng ngung tu cac hidrazit vcd furan-2 andehit the thu dugc cac hidrazon khac Tren phd hong ngoai cua hidrazon khOng tha'y xua't hien dao dong hoa tri ciia lien ke't N-H cua nhom NH2 khoang 3416-3230 c m ' ma thay vao la lien ke't C-H cua vong furan khoang 3199-3016 c m ' va C-O-C a 1348-1184 cm' va dac biet d viing 1684-1600 cm"' xua't hien them nhieu dinh dan xen nhau, dieu cho tha'y lien ke't C=N da dugc hinh (xem bang 3) Bang 3: Ket qua tong hgp vd xac dinh cdu tao cac hidrazon Ar-CH=CH-C-NH-N=CH-^ J^—X O' -yO TT Ar X '• nc Hieu suat Phd hong ngoai (cm'^) Vc=0 Vc=c Vc=N "^c-o-c 1623 1662 1345 1207 1316 1294 QH,- H 224225 QH,- NO2- 198200 65,0 1678 1623 1678 64,0 1642 1603 1642 — 1639 1295 1096 1675 1254 1087 67,2 1648 P-CH30-QH4- H 228230 m-NOj-QH^- NO2- 232234 65,5 1684 P-CI-C6H4 H 228230 64,0 1675 1644 1348 1258 Pho ttr ngoai (>^„, nm) 326.6 277,0 221,8 376,6 281,0 214,8 324,0 228,0 204,0 380,8 323,4 316,8 260,4 Phd kh6'i lugng cua cac hidrazon cho cac ion phan tu dung vcd du kien Lien ket 0=C-NH- ciia cac hidrazon kh6ng ben, de bi cat dut va nhung hidrazon chiia Cio nguyen tir c6 xua't hien ion dong vi (xem so phan manh) o II CI^O^CH= CH-C-NH-N=CH M"" 319/321 'I W NO- O' o NH-N=CH O m/e 139 NO2 C1-^Q^CH=CH-Cm/e 165/167 - C H = C H - C - N H - N = C H - ^ )>— NOl U"*"+ ^319/321 iomi O M O te-N=CH- '' ^ NO2 m/e 139 O o C1^^^CH=CH-Cm/e 165/167 NO < ^ C H E C H m/e 125 ^ m/e 103 So dd phan manh cua 5-nitro fufuryliden p-clo xinamoyl hidrazon ^ang 4: Pho cong huong tic hat nhdn proton cua mot so chat tong hop duoc Chat 0,N n CH=CH-COOC.H 2J^5 O OoN n O ' ^ •CH=CH-C-NH-NH- (ppm) 6,66(d, J=16Hz, IH, H ' ) ; 7,33(d, J=3,5Hz, IH, H*); 6,75(d, J = H Z , IH, H^); 7,4(d, J=I6Hz, IH, H^); l,34(t,3H, -CH,); 4,28(q, 2H, -CH,) 6,8(d, J=15,5Hz, IH, H'); 7,81(d, J=4Hz IH, H^); 7,5(d, J=2Hz, IH, H^); 7,55(d, J=15,5Hz, IH, H^); 8,0(q,J-l,0Hz, IH, H^)6 £ ( d J = , H z , H , H') Thu hoat tinh sinh hoc cua mot so chat tong hgp dugc Tien hanh thur hoat tinh khang khua'n, khang na'm cua mot so este hidrazit va hidrazon Ket qua cho th^y miu T2, T4, T7, T8 cd tac dung ddi vai chung S A SB P A Cac mau Tl de'n T5 d^u cd tac dung v6i nam men Dac biel mfiu T4 cd t^c dm.^ r A Chung tren Ke't qua thit hoat tinh sinh hoc thi hien d bdng " ' ^ ^° ^^^ '^'^"g ^oi ca S P A •• ^*"P^/°'^°'^"^ A"'-^"^ (Tu c^u vang thugc cSu khu& gam (+)) Chung RA: Pseudomonas Aeraginosa (Mu xanh thuoc true khua'n gam ( Chung B.A: Bacillus Subtilis (Thuoc gam (+)) ' ' '^'"'"^ Sam (-)) Nam men: Candida albicans Bdng 5: Ket qud thi hoat Unh sinh hoc cua mot so ddn xudt cua axit arylacryhc Miu (50(il) Cong thirc Duong kinh von? vo khnap (mm) S.A P.A B.A Nam mpn Tl