Nghiên cứu tổng hợp Levofloxacin, thuốc kháng sinh nhóm fluoroquinolon thế hệ thứ ba

Tiiu ban: cdc clidt co hogi linh sinh hqc /55,V.- 978-604-913-012-0<br /> <br /> <br /> <br /> NGHIEN ClTU TONG HOP LEVOFLOXACIN, THUOC KHANG SINH<br /> NHOM FLUOROQUINOLON THE HE THlT BA*<br /> SYNTHESIS OF LEVOFLOXACIN, THE THIRD GENERATION OF<br /> FLUOROQUINOLON ANTIBIOTIC<br /> <br /> Nguyen Qudc VuQTig, Nguyen Le Tuan, Tran Thi Cam Hien, Dao Due Thien,<br /> Pham Van Ly, Tran Van Sung<br /> Vien Hda hoc<br /> 18 - Hoang Qudc Viet, Cau Giay, Ha Ndi<br /> Email: nguyenvh62@gmail.com<br /> Tom tat:<br /> Levofloxacin, thudc khdng sinh nhdm fluoroquinolon thi hi thu ba da dugc<br /> tdng hgp qua 8 bu&c, su dung tdc nhdn quang hogt methyl D-lactate. Qui trinh<br /> tdng hgp bao gdm; bu&c 1 Id phdn ung hogt hda tdc nhdn methyl D-lactale; bu&c<br /> 2 Id phdn ung the luong phdn tu v&l sir ddo cdu hinh cho sdn phdm quang hogt 2.<br /> Cdc bu&c 3, 4 la qud trinh khu vd ddng vdng cho sdn phdm (-) 3(S)-<br /> methylbenzoxacin 3. Cdc bu&c 5, 6, 7 Id phdn irng Gould-Jacobs v&l phdn ung<br /> cdng logi sau dd axyl hda ddng vdng cho sdn phdm hi nhdn 3 vdng<br /> pyridobenzoxacin 6 vd tiip theo Id thiiy phdn cho hgp chdt 7. Cudi cimg Id phdn<br /> ung the nhdn thom & C-10 cua nhdm 10-F bdng methyl plperzazine cho sdn phdm<br /> levofloxacin 8.<br /> Abstract:<br /> Levofloxacine, the third generalion of fluoroquinolon antibiotic, was<br /> synthesized in 8 steps using chiral reagent methyl D-lactate. The synthetic<br /> strategy consist of; step 1 is the activation of chiral reagent methyl D-lactate; step<br /> 2 Is Ihe bimolecular nucleophilic substitution with a configuration inversion to<br /> give (-)-(S)-enanliomer 2; steps 3, 4 are the reduction and cyclization to afford (-<br /> )3(S)-methylbenzoxacin 3; steps 5, 6, 7 are the Gould-Jacobs reaction with<br /> addUion-elimination sequence followed by cycloacylation to give a tricyclic core<br /> product of pyridobenzoxacine 6, then followed by hydrolysis to give compound 7.<br /> The final step is nuclear aromatic substitution at C-10 of 10-F group by methyl<br /> piperazine to give levofloxacin 8.<br /> <br /> <br /> I. Gioi thieu ve thuoc khang sinh levofloxacin<br /> Levofloxacin la thudc khang sinh nhdm fluoroquinolon thi he thii ba cd ten khoa hoc<br /> la(-)-(5)-9-fluoro-2,3 -dihydro-3 -methyl-10(-4-methyI-1 -yl-1 -piperazinyl)-7-oxo-7//-<br /> pyrido[I,2,3-c/e]-l,4-benzoxazine-6-carboxyIic acid, la ddng phan quang hoc (-)3(5) ciia<br /> racemic (R, S)-ofloxacin.<br /> Levofloxacin cd boat tinh khang vi khuan rdng bao gdm ca vdi vi khudn gram am va<br /> vi khuan gram duong, dugc dimg dieu tri nhilm triing xoang, viem phi quan cdp va man tinh,<br /> da, phdi, tai, dudng hd hap, xuang va khdp, nhiem triing dudng tiet nieu, phu khoa ciing nhu<br /> viem tuyen tien liet,.. .Dugc dung dieu tri vdi ca loai vi khuan da khang cac thudc khang sinh<br /> kbac. Levofloxacin dieu tri bieu qua tieu chay nhiem triing do E. coll, Campylobacter jejuni,<br /> ly true triing, va cdn dugc chi dinh dilu tri lam sang trong viern phdi cdng ddng. Levofloxacin<br /> la 1 trong nhirng thudc tieu thu manh nhdt tren thi trudng thudc the gidi, chi rieng trong nam<br /> 188<br />  Hoi nghi Khoa hqc ky niem 35 ndm Vien Khoa hqc vd Cong nghe Viet Nam - Hd Noi 10/2010<br /> <br /> <br /> 2008 doanh sd ban ra eiia levofloxacin dat ban 1,4 ti dd la My. Levofloxacin hien dang dugc<br /> su dung d Viet Nam theo con dudng nhap khau thudc do dd khdn^ the chii ddng dugc ngudn<br /> thuoc, ban nira, nude ta d viing nhiet ddi ndng am nen de mac nhieu benh nhiem vi khuan va<br /> kha nang bimg phat dich benh rat ldn. Do dd viec nghien cuu tdng hgp levofloxacin la het siic<br /> cap thiet lam tien de cho viec nghien cim quy trinh cdng nghe tdng hgp thudc khang sinh<br /> levofloxacin quy md lugng Idn sau nay.<br /> Do boat tinh khang vi khuan va hieu qua sir dung cao, ldp chat fluoroquinolon da dugc<br /> tap trung nghien cim cao do tren toan thi gidi. Trong khoang 20 nam (1985-2005) da cd hon<br /> 2000 cdng trinh khoa hoc va khoang 10.000 ddn xudt fluoroquinolon dugc tdng hgp dk nghien<br /> cuu sir lien quan cau tnic va boat tinh (SAR). Hang tram cac cdng trinh va patent dugc cdng<br /> bd, cho den nay da cd bon 20 loai thudc khang sinh nhdm nay dugc dua ra sir dung lam sang<br /> [1-6]. Cac ket qua nghien cim da xac dinh nhiing vi tri thich hgp ciia cac nhdm chirc nang vdi<br /> he vdng va cd khoang each thuan lgi vdi cac thanh vien kbac [7-13]. Levofloxacin dugc tdng<br /> hgp theo 2 hudng chinh: mot la sir dung cac phuang phap tdng hgp hon hgp racemic sau dd<br /> tach hon hgp racemic ciia cac chdt trung gian[10, 14, 16-18]; hai la sir dung tac nhan phan<br /> img la chdt cd boat tinh quang boat [9-12, 18]. Cac phuang phap tach ddng phan quang hoc<br /> dugc sir dung nhu sdc ky cdt sir dung chdt nhdi la chdt bdp phu bdt ddi ximg (phuong phap<br /> hda ly), tao thanh cae ddng phan lap thi khdng ddi quang (phuang phap boa hoe) hoae sir<br /> dung enzym (phuang phap hda sinh). Trong bai bao nay chiing tdi tiln banh nghien eim tdng<br /> hgp levofloxacin d qui md phdng thi nghiem.<br /> II. Ket qua va thao luan<br /> Levofloacin dugc nghien ciiu tdng hgp theo so do sau:<br /> <br /> <br /> <br /> r^os-ci' II<br /> NH,<br /> HO II<br /> <br /> COOCH3<br /> o F ^ NH<br /> COOCH-, "<br /> EtaN/MesN. HCI COOCH3<br /> 1 ^ EtsN/Toluene<br /> /CH2CI2; 97% hoi luu 5 ngay, 65%<br /> <br /> NaBH4<br /> 90%<br /> COOC2H5<br /> COOC2H5 KOt-Bu F<br /> ||—COOC2H5 /DMF<br /> C2H5O<br /> COOC2H5<br /> ^ N ^ NH F" ^ "NH<br /> KONBu, 88% F .. L .OH<br /> 65%<br /> <br /> 50-60° C (CH3CO)20<br /> /CH3COOH<br /> 73%<br /> + H2SO4<br /> O COOH<br /> COOC2H5 p<br /> COOH<br /> HCI/AcOH -N NH<br /> fr-<br /> h6i luu, 92% DMSO, 100° C<br /> 67%<br /> <br /> <br /> <br /> Hinh 1: So dd tdng hgp levofloxacin<br /> d bude 1 tac nhan quang boat methyl D-Iactate dugc boat hda bdng phan img vdi p-<br /> tosyl chloride de thu dugc tosylate 1 cd nhdm rdi tdt thuan lgi cho phan img thi nucleophin<br /> ludng phan tir tiep theo. Khi tien banh theo phuang phap tdng hgp tosylate thdng thudng vdi<br /> <br /> 189<br /> Tiiu ban: cdc chdt co hogt tinh sinh hqc jsBN: 978-604-913-012-0<br /> <br /> <br /> xuc tac DMAP trong pyridine/CH2Cl2 chi thu dugc tosylate 1 d hieu sudt khoang 50%. Vi vay<br /> chiing tdi da nghien cuu va ap dung tdng hgp tosylate 1 theo phuang phap mdi sir dung he<br /> xue tac EtsN/MesN.HCI trong CH2CI2. Kit qua thu dugc that tuyet vdi, bieu sudt phan img<br /> gdn nhu toan Iugng va khdng cd san pham phu. Cac dii lieu phd khdng dinh cau tnic ciia san<br /> phdm. Sir cd mat cua he vdng thom tosyl da dugc chi ra bdi cac dai dao ddng d 1452,<br /> 1599cm"' tren phd IR va cac tin bieu d viing thorn 5H 7,8l(d, 2H); 7,34(d, 2H) tren phd ' H -<br /> NMR. Sir cd mat ciia mach propionate dugc the hien bdi dai dao ddng d 1757 cm" cua nhdm<br /> este COOCH3 va cac tin hieu d 6H 4,95 (q, IH ciia 2-CH), d 5H 3,66(s, 3H ciia 3-OCH3), d 6H<br /> 1,50 (d, 3H ciia 3-CH3). Bude tilp theo la phan iing tbi ai nhan ludng phan tir vdi sir tdn<br /> cdng eiia tac nhan ai nhan 2,3,4- trifluoroaniline vao tosylate 1 cho san phdm amine este 2 vdi<br /> sir dao cdu hinh cho gia tri [a]D am nguge vdi[a]z) duong ciia tac nhan methyl D-lactate. Phan<br /> img diln ra khi dun hdi luu hon hgp dung dich ciia 2,3,4- trifluoroaniline va tosylate 1 trong<br /> toluene vdi xuc tac trietbyl amine (EtsN) trong vdng 5 ngay cho hieu xuat khoang 65%. Cac<br /> tin hieu tren phd ' H - N M R d 5H tir 6,87-6,76 (m, IH) va 5H tir 6,30-6,25 (m, IH) la sir hien<br /> dien ciia he vdng thom va dublet d 5H 4,26 la tin hieu ciia proton amine NH. Sir cd mat ciia<br /> mach nhanh isopropanoate dugc thi hien qua cac tin bieu 5H tir 4,13-4,07(m, IH) la ciia nhdm<br /> 2'-CH, 5H 3,75(S, 3 H ) cua nhdm O-CH3 va 5Hl,5I(d, 3H) la cua nhdm 3'-CH3. Tin hieu da<br /> vach d 6cl44,42-139,20 ciia 4-CF, 5-CF va 6-CF do tuong tac cua flo vdi nguyen tir cac bon<br /> (khdng bi khir trong ky thuat phd proton) chiing minh sir hien dien cua cac nhdm lien ket nay.<br /> Phan ling khir nhdm methyl este eiia 2 diln ra thuan lgi trong n-hexane vdi sir cd mat ciia<br /> MeOH cho hieu sudt tren 90%. Tren phd 'H-NMR ciia san phdm nay tin bieu ciia nhdm O-<br /> CH3 da biin mdt va xudt bien tin hieu singulet tii d 5H 2,96 ciia nhdm OH; cdn tren phd '^C-<br /> NMR xudt bien them tin hieu d 5c 65,89 ciia nhdm r-CH20H, phd khdi ESI-MS cho pic ion<br /> gia phan tir [M-^H]"^ d m/z 206. Phan iing ddng vdng ndi phan tir ciia ancol 3 xay ra trong mdi<br /> trudng kilm d 65° C vdi sir du thira ciia kalium tert-butoxide trong dung mdi phan cue phi<br /> proton dimethylformamide cho benzoxacine 4 vdi hieu suat 65%. Sir tach cac tin hieu ciia cac<br /> proton Ha d 5H 4,27(dd, 3, 10,5 Hz) va proton Hb d 5H 3,37(dd, 8, 10,5Hz) ciia nhdm 2-CH2<br /> da khang dinh nhdm nay khdng cdn dugc quay tu do nira ma da bi cd dinh do hinh thanh vdng<br /> 6 ciia phan tir 1,4-benzoxacin. Tren phd C-NMR tin hieu da vach ciia tuong tac C-F da thay<br /> ddi cho thay rd tuong tac ciia cac nhdm 7-CF va 8-CF la cac cap dublet d 5cI45,39-139,56.<br /> Cac bude tiep theo la phan iing Gould Jacobs bao gdm qua trinh cdng loai ciia diethyl<br /> ethoxymethylenemalonate vdi benzoxacine 4 trong mdi tmdng kiem ciia kalium tert-butoxide<br /> d nhiet do phdng. Hdn hgp phan img sau khi xir ly va dugc tinh che cho san pham 5 vdi bieu<br /> suat khoang 88%. Tren phd NMR ciia san pham cdng loai 5 xuat hien nhiing tin hieu mdi d 5H<br /> 7,75(s, IH ciia nhdm N-CH=) va d 5H 4,30-4,04 (m, 7H) ciia 3 nhdm O-CH2 (1 nhdm CH2 cua<br /> vdng 1,4-benzoxacine; 2 nhdm CH2 cua cac nhdm ethyl este) va nhdm 3-CH da ehiing minh<br /> chat 5 la san pham cdng loai. Qua trinh axyl hda ddng vdng tiep theo dugc tiln hanh trong<br /> hdn hgp ciia acetic anhydride va H2SO4 d khoang 50-60° C eho hgp chdt ba vdng<br /> pyridobenzoxacine 6. Cau tnic hda hoc ciia hgp chat nay dugc the hien rd net qua cac dir lieu<br /> phd. Tin hieu ciia proton 5-CH bi anh hudng lien hgp manh vdi cac nhdm 7-CO va 6-<br /> COOCH3 nen nam d tmdng thdp 5H 8,42 (s, IH). d viing thom chi cdn tin hieu ciia 1 proton<br /> ciia 8-CH d 5H 7,79-7,75(m, IH). Qua trinh axyl hda ddng vdng da loai bd mot nhdm ethyl<br /> este nen chi cdn tin hieu ciia 1 nhdm ethyl este d 6H 4,36(q, 2H) va d 5H l,40(t, 3H); tin hieu<br /> ciia cac proton khae it thay ddi. Phd '^C-NMR cho cac tin bieu mdi d 5c 173,03 ciia nhdm<br /> xeton 7-CO; 165,23 cua nhdm este 6-COO; 145,95 cua nhdm C-5; De tranh phan img trao ddi<br /> este-arnit d bude tiep theo nhdm etyl este cua chdt 6 da dugc thiiy phan. Bude thiiy phan<br /> dugc tien banh don gian khi dun bdi luu chat 6 trong hdn hgp acid HCl/AcOH cho san phdm<br /> 7. Sir mat di tin hieu ciia nhdm ethyl este tren phd IR va NMR chiing minh phan iing da xay<br /> ra hoan toan. Phan iing tbi nhan thom d C-10 ciia nhdm 10-F dugc tien banh trong<br /> <br /> 190<br />  Lldi nghi Khoa hqc ky niem 35 ndm Vien Khoa hqc vd Cong nghe Viet Nam - Hd Noil0/2010<br /> <br /> <br /> dimethylsulfoxide (DMSO) d 100° C, su dung Iugng du thira ciia methyl piperzazine vira la<br /> tac nhan vira la xiic tac phan iing, cho san phdm levofloxacin 8 vdi bieu xudt khoang 67%.<br /> Cac tin hieu tren phd NMR da chi ra sir cd mat cua nhdm thi methyl piperazine d 5H 3,45-<br /> 3,36(m, 4H) va 2,56-2,55(m, 4H) ciia 4xCH2, 2,37(s, 3H) cua nhdm 2-CH3. Tren phd '^C-<br /> NMR chi cdn mot cap dublet d 5c 156,97(154,99)(9-CF) va xudt hien them cac tin hieu ciia<br /> vdng piperazine d 6c 55,50 ciia 4 nhdm N-CH2 va 46,33 cua N-CH3; Phd khdi ESI-MS cho<br /> pig ion gia phan tir [M+H]^ d m/z 362. Nang sudt quay cue [ajo = - 67° (c= 0,655; NaOH) phii<br /> hgp vdi levofloxacin.<br /> <br /> III. Phan thuc nghiem<br /> Hoa chat va thiet bi: Cac tac nhan 2,3,4-trifluoroaniline, methyl D-Iactate, p-toluene<br /> sulfonyl chloride... dugc mua tir hang Sigma Aldrich va Merck. Cac san phdmphan iing dugc<br /> tinh che qua silicagel 60 (Merck). Phd hdng ngoai dugc do tren may Impact-410 Nicolet. Phd<br /> NMR dugc ghi tren may Bmker Avance 500 vdi TMS lam chdt ndi chudn cho ' H va tin hieu<br /> dung mdi cho cho '^C NMR. Phd khdi ESI-MS dugc do tren may Agilent 6310 ion trap, [ajo<br /> dugc do tren may phan cue kl P0LAX-2L.<br /> Phan thuc nghiem duuc tien hanh dua theo cac qui trinh trong cac tai lieu 16,10,<br /> 15,17].<br /> Cac san phdm phan iing thu dugc cho cac dir lieu phd nhu sau:<br /> (2R)-2-(tosyloxy)propionaie 1: chdt dang ddu trong sudt.<br /> IR (film): 3008, 2966, 1757, 1599, 1452, 1368, 1183, 1087 cm"'; ' H NMR (CDCI3)<br /> 7,81(d, 2H); 7,34(d, 2H); 4,95(q, IH); 3,66(s, 3H); 2,44(s, 3H); l,50(d, 3H).<br /> Methyl (2S)-2-(2,3,4-trifluoroanilino)propionate 2: chdt dang ddu mau vang cam.<br /> IR (KBr): 3405, 3080, 2994, 2965, 1743, 1642, 1519 cm"'; ' H NMR (CDCI3) 6,82-<br /> 6,76(m, IH); 6,30-6,25 (m, IH); 4,26 (d, IH cua NH); 4,13-4,07 (m, IH); 3,75 (s, 3H); 1,51<br /> (d, 3H); '^C NMR (CDCI3) 175,55(000); 146,15-140,60 (4-CF, 5-CF, 6-CF);<br /> 134,26(134,17); 112,59-112,42; 107,11-106,94; 53,69; 53,40; 20. [ajo = -37 ° (c= 0,112;<br /> CH3OH).<br /> (2S)-2-(2,3,4-trifluoroanilinno)-l-propanol 3: Chdt dang ddu mau vang chanh.<br /> IR (KBr): 3406, 2982, 2897, 1644, 1611, 1517, 1044 cm"'; ' H NMR (CDCI3) 6,83-<br /> 6,75(m, IH); 6,44-6,30 (m, IH); 3,82(brs, IH ciiaNH); 3,69-3,67(m, IH); 3,57-3,53 (m, 2H);<br /> 2,96(brs, IH ciia OH ); 1,23 (d, 3H); '^C NMR (CDCI3) 144,20-139,07 (4-CF, 5-CF, 6-CF);<br /> 133,60-133,51(10); 111,10-110,93 (IC); 106,21-106,10(10); 65,89; 50,96; 17,01; ESI-MS,<br /> m/z 206 [M+H]^; [a]z)= -35 ° (c= 0,112; CH3OH).<br /> (3S)-(-)-7,8-difluoro-3,4-dihydro-3-metltyl-2H-[l,4]benzoxazine 4: Chat dang ddu<br /> mau vang nhat.<br /> IR (KBr): 3395, 2973, 2931, 2889, 1609, 1505 cm"'; ' H NMR (CDCI3) 6,54 (ddd,<br /> IH); 6,25 (ddd, IH), 4,27 (dd, j=3, j=10,5; IH), 3,78 (dd, j=8 j=10,5; IH); 3,50 (dqd, IH);<br /> 1,19 (d, 3H); X NMR (CDCI3) 145,39-139,56(7-CF, 8-CF); 133,32-133,21; 131,07; 108,54-<br /> 107,79; 107,79; 70,97; 44,89; 17,39; [a]z)= -42° (c= 0,112; CH3OH)<br /> Diethyl[(3S)-7,8-difloro-3-metliyl-2,3-diltydro-4H-[l,4]benzoxazin-4-<br /> yljmethylenemalonate 5. Chat dang ddu mau vang.<br /> <br /> <br /> <br /> 191<br /> Tiiu ban: cdc chdt co hogi tinh sinh hqc ISBN: 978-604-913-012-0<br /> <br /> <br /> ' H NMR (CDCI3) 7,75(s, IH); 6,79-6,76(m, 2H); 4,3-4,04(m, 7H ciia 3xCH2 va 3-<br /> CH); 1,38-1,26 (m, 9H ciia 3XCH3).<br /> (3S)-(-)-9,10-Difloro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-<br /> deJ[l,4Jbenzoxazine-6-carboxylic acid ethyl ester 6: Tinh the mau trdng.<br /> IR (KBr): 3427, 3034, 2998, 2919, 1721, 1677, 1601, 1563, 1481, 1353, 1256, 1180,<br /> 1072 805, 645, 425 cm"'; ' H NMR (CDCI3) 8,42(s, IH cua 5-CH); 7,79-7,75 (m, IH); 4,51-<br /> 4,45 (m, 3H ciia 2-CH2, 3-CH); 4,36(q, 2H ciia OCH2-); I,61(d, 3H ciia 3-CH3); l,40(t, 3H<br /> ciia nhdm ethyl); '^C NMR (CDCI3) 173,03 (7-CO); 165,23(6-000); 150,43(148,43)(10-CF);<br /> 145,95; I43,45-14I,22(9-CF); 135,02; 124,26 (2xC); 110,74; 105,89(105,73); 69,00; 61,25;<br /> 55,03; 18,06; 14,36; [a]D= -52° (c= 0,250; acetic acid)<br /> (3S)-(-)-9,10-Difloro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-<br /> d,e][l,4]benzoxazine-6-carboxylic acid 7. Tinh the mau trdng.<br /> ' H NMR (CDCI3): 14,80 (s, IH ciia 6-COOH); 9,08 (s, IH ciia 5-CH); 7,82(dt, IH ciia<br /> 8-CH); 5,02(dt, IH cua 3-CH); 4,69(dd, IHa cua 2-CH2); 4,50(dd, IHb cua 2-CH2); l,48(d,<br /> 3H ciia 3-CH3); '^C NMR (CDCI3) 176,46(7-00); 165,59(6-COOH); 149,89(148,00)(10-CF);<br /> 147,07; 142,58(I40,70)(9-CF); 135,96(135,87); 125,30; 121,35; 107,72; 103,63(103,48);<br /> 68,90; 55,03; 17,77; [a]z)= -59° (c= 0,985; DMSO).<br /> (3S)-(-)-9-fluoro-3-methyl-l 0-(4-metltyl-l-piperazinyl)- 7-oxo-2,3-diliydro- 7H-<br /> pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylic acid 8 (levofloxacin). Tinh the mau trang.<br /> IR(KBr), cm"' : 3429, 3272, 3079, 2943, 2858, 2808, 1721, 1621, 1521, 1450; ' H -<br /> NMR (CDCI3) 8,62 (s, IH); 7,70 (d, IH,), 4,53-4,35(m, 3H,), 3,45- 3,36(m, 4H), 2,56-<br /> 2,55(m, 4H), 2,37 (s, 3H), 1,61 (d, 3H); '^C NMR (CDCI3) 177,05(7-00); 167,18(6-COOH);<br /> 156,97(154,99)(9-CF); 144,75; 139,38; 133,16; 124,71; 120,22; 107,63; 105,14(104,95);<br /> 68,16; 55,62 va 55,50 (4x0); 50,56; 46,33; 18,31; ESI-MS, m/z: 362[M+1]^; [a]D= - 67° (c=<br /> 0,655; NaOH(0,05mol/I)<br /> IV. Ket luan:<br /> Day la lan dau tien d Viet Nam thudc khang sinh nhdm fluoroquinolon the he thii ba,<br /> levofloxacin, da dugc nghien ciiu tdng hgp thanh cdng. Con dudng tdng hgp qua 8 bude sir<br /> dung tac nhan quang boat methyl D-lactate. Cau tnic cac san pham phan ung dugc khang dinh<br /> bang cac phuang phap phd, cac sd lieu phd phii hgp vdi cac tai lieu da cdng bd. Hieu suat cao<br /> ciia cac bude phan iing cho phep cac nghien cim trien khai tiep viec tdng hgp hgp chat nay d<br /> qui md ldn ban.<br /> <br /> Di tdi dugc thvrc hien tai phong tong hgp hiru co-Vien Hda hgc Vien KH vd<br /> CNVN vd dugc tdi trg b&i chuong trinh "Nghien ciru khoa hpc cong nghe trgng diem quoc<br /> gia phdt trien cdng nghiep hod dirge den ndm 2020".<br /> <br /> <br /> TAI LIEU THAM KHAO<br /> 1. Mitscher L. A., Chem. Rev. 105(2), 559-592 (2005).<br /> 2. De Souza et al., US Pat. 6,964,966 B2.<br /> 3. P.L. Henrling, Basel and A. Matter, Basel, Prog. Drug Res., 38, 57-106 (1992).<br /> 4. D. T. Chu and P. B. Fernandes, Antimicrob. Agents Chemother., 33(2), 131-135<br /> (1989).<br /> 5. P.L. Herrling, Basel and A. Matter, Basel, Prog Drug Res., 21,9 (1977).<br /> <br /> 192<br />  Hgi nghi Khoa hqc ky niem 35 ndm Vien Khoa hqc vd Cong nghe Viet Nam - Hd Noil 0/2010<br /> <br /> <br /> 6. 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