B Y T TRNG I HC DC H NI NGUYN XUN HI BC U NGHIN CU QUI TRNH TNG HP MOXIFLOXACIN KHA LUN TT NGHIP DC S H NI 2013 B Y T TRNG I HC DC H NI NGUYN XUN HI BC U NGHIN CU QUI TRNH TNG HP MOXIFLOXACIN KHA LUN TT NGHIP DC S Ngi hng dn: 1.TS. Vn Th M Hu 2.TS. L Nguyn Thnh Ni thc hin: 1.VinHaSinhBin-VinHnlm Khoa hc v cng ngh Vit Nam. 2.B mn Ha Hu c Trng H Dc H Ni. H NI - 2013 LI CM N cthhonthnhkhalunttnghipngthihn,tc nhng mc tiu ra, trong ba thng va qua, em nhn c s gip tn tm t cc thy c, bn b trong v ngoi trng i hc Dc H Ni. Nhn dp ny, em xin by t lng bit n ti: TS.VnThMHu,cthngxuynngvin,gip,tomi iu kin cho em thc hin ti ny.TS.L Nguyn Thnh, Trung tm Nghin cu v Pht trin thuc Vin Ha Sinh BinVin Hn lm Khoa hc v Cng ngh Vit Nam, thy lun theo di v gip em trong qu trnh lm kha lun. CcthycgiotrongBmnHaHuctruyntkinthc qubutrong sutthi gianemhctp trong trngtonntng gipem thc hin tt nhim v ca kha lun tt nghip. CccnbTrungtmNghincuvPhttrinthucgipem trongqutrnhthcnghim,phngNghincucutrcVinHahc VinHnlmKhoahcvCngnghVitNamgipemophIR, 1H-NMR, 13C-NMR v MS ca cc hp cht iu ch c. Cui cng, em xin by t lng bit n su sc ti gia nh, bn b quan tm, gip , to iu kin em c th tp trung hon thnh kha lun tt nghip ng hn, thu c kt qu mong mun. H Ni, ngy21 thng 05 nm 2013 Sinh vin Nguyn Xun Hi MC LC DANH MC CC K HIU, CC CH CI VIT TT DANH MC CC BNG DANH MC CC HNH V, S T VN ....................................................................................... 1 CHNG 1: TNG QUAN ............................................................... 3 1.1 Tng quan v moxifloxacin ....................................................................... 3 1.1.1 Cng thc cu to v tnh cht ............................................................ 3 1.2.2 C ch tc dng, ch nh, chng ch nh v liu dng. .................. 4 1.2 Phng php tng hp moxifloxacin hydroclorid .................................. 5 1.2.1 Tng hp hp cht ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylat. ....................................................... 6 1.2.2 Tng hp mch nhnh C7 (S,S)-2,8-diazabicyclo[4.3.0]nonan. ....... 7 1.2.3 Tng hp moxifloxacin dng mui hydroclorid ................................. 8 CHNG 2: NGUYN LIU, THIT B, NI DUNG V PHNG PHP NGHIN CU .................................................... 12 2.1 Nguyn vt liu, thit b ........................................................................... 12 2.1.1 Nguyn vt liu ................................................................................... 12 2.1.2 Thit b th nghim ............................................................................. 13 2.2 Ni dung nghin cu ................................................................................ 14 2.3 Phng php nghin cu......................................................................... 14 CHNG 3: THC NGHIM, KT QU V BN LUN ...... 16 3.1 Tng hp ha hc ..................................................................................... 16 3.1.1 Tng hp moxifloxacin hydroclorid thng qua to phc bis(acyloxy-O) borat .................................................................................... 17 3.1.1.1 Tng hp 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic-O3,O4)bis(acyloxy-O) borat .................... 17 3.1.1.2. Tng hp 1-cyclopropyl-7-(2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic-O3,O4)bis(acyloxy-O) borat. ..................................................................... 18 3.1.1.3. Tng hp moxifloxacin hydroclorid ............................................ 18 3.1.2 Tng hp moxifloxacin thng qua to phc boron difluorid .......... 20 3.1.2.1. Tng hp 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic-O3,O4)difluoro borat. .............................. 20 3.1.2.2. Tng hp 1-cyclopropyl-7-(2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic-O3,O4)difluoro borat. ................................................................................ 20 3.1.2.3. Tng hp moxifloxacin hydroclorid ............................................ 21 3.2. Kim tra tinh khit v xc nh cu trc ca cc cht tng hp. . 22 3.2.1 Kim tra tinh khit ........................................................................ 22 3.2.2 Khng nh cu trc .......................................................................... 23 3.2.2.1 Ph hng ngoi IR. ....................................................................... 23 3.2.2.2Ph proton (1H-NMR). ................................................................. 25 3.2.2.3Ph cng hng t carbon (13C-NMR) v MS ............................ 27 3.3 Bn lun .................................................................................................... 28 3.3.1 Phn ng to phc trung gian borat ................................................ 28 3.3.2 Phn ng gn amin vo nhn quinolin ............................................ 30 3.3.3 Qu trnh to mui moxifloxacin hydroclorid .................................. 31 KT LUN V KIN NGH .......................................................... 33 4.1. Kt lun .................................................................................................... 33 4.2. Kin ngh .................................................................................................. 33 TI LIU THAM KHO PH LC DANH MC CC K HIU, CC CH CI VIT TT Ac: Acetyl BnNH2 : Benzylamin CDCl3: Cloroform-D CTCT: Cng thc cu to CTPT: Cng thc phn t DMF : Dimethylformamid DMSO:Dimethyl sulfoxidD2O: Deuterium oxid VC : n v carbon EA: Ethyl acetat Equiv: Tng ng EtOH : Ethanol HPLC: Sc k lng hiu nng cao KLPT: Khi lng phn t IR : Ph hng ngoi Me: Methyl MeI: Iodomethan Moxi : Moxifloxacin Moxi.HCl: Moxifloxacin hydroclorid MS: Ph khi lng ppm : Phn triu QT1: Qui trnh 1 QT2: Qui trnh 2 TEA: Triethylamin TLC: Sc k lp mng Tert-BuOK: Kali tert-butylat THF: Tetrahydrofuran 1H- NMR: Ph cng hng t proton 13C- NMR: Ph cng hng t carbon DANH MC CC BNG Bng 1: Danh mc cc nguyn liu, ha cht, dung mi s dng12 Bng 2:Gi tr Rf v nhit nng chy cc cht tng hp c22 Bng 3: S liu phn tch ph IR ca cc cht tng hp c24 Bng 4: S liu phn tch ph cng hng t proton 1H-NMR 25 Bng 5: S liu phn tch ph cng hng t carbon13C-NMR27 Bng 6: So snh phn ng to phc borat gia hai qui trnh29 Bng 7: So snh phn ng gn amin gia hai qui trnh 30 Bng 8: So snh phn ng to mui gia hai qui trnh 31 DANH MC CC HNH V, S HNH V Hnh 1: Moxifloxacin hydroclorid3 Hnh 2: Gatifloxacin v balofloxacin 4 Hnh3:Acid1-cyclopropyl-6-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-7-fluoro-8-methoxy-4-oxo- quinolin-3-carboxylic 9 S S1:Quy trnh tng hp ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylat (Grohe-Heitzer)6 S 2:Quy trnh tng hp cht (11) ca Cecchetti7 S 3: Quy trnh tng hp amin mch nhnh(19) 8 S 4: Phn ng tng hp moxifloxacin hydroclorid ca Petersen8 S5:Tnghpmoxifloxacinhydrocloridquahpchttrunggian bis(acyloxy-O)borat 9 S 6: Tng hp moxifloxacin hydroclorid qua hp cht trung gian difluoro borat 10 S 7: Tm ttcc qui trnh tng hp moxifloxacin hydroclorid11 S 8: Qui trnh tng hp moxifloxacin hydroclorid16 S 9: Phn ng tng hpphc(21)17 S 10: Phn ng tng hp cht (22) 18 S 11: Phn ng thy phn v to mui moxifloxacin hydroclorid t phc bis(acyloxy-O) borat 18 S 12:Phn ng tng hp cht (23)20 S 13: Phn ng tng hp cht (24) 21 S 14: Phn ng thy phn v to mui moxifloxacin hydroclorid t phc difluoroborat21 S 15: Cch phn ng to phc borat 28 S 16: C ch phn ng gn amin301 T VN Trong vi chcnmtr liy,ccquinolonphttrin thnh mt h khng sinh mnh. Ngun gc ca cc khng sinh ny bt u khi Lesher pht hin ra acid nalidixic vo nm1962.ylmt tc nhn khng khun yu, ch c tc dng ln cc vi khun Gram (-) ng tit niu. Tuy nhin cc th h quinolon tip theo c ph tc dng m rng ln c Gram (+), Gram (-) v vi khun k kh, c bit l cc khng sinh fluoroquinolon[5]. Ngy nay, cc khng sinh quinolon c s dng iu tr cho cc nhim khun ng h hp trn v di, nhim khun ng tiu ha, cc bnh nhim trng ly lan quang sinh dc, nhim khunng niu, vim mng no[3][24]. Ti Vit Nam, nhm khng sinh fluoroquinolon l mt trong4 nhm khng sinh c s dng hng u ti cc bnh vin cng vi cc nhm cephalosporin, penicillin, macrolid v chim 6.5% v doanh thu. Trongnng. Moxifloxacin c thi gian bn thi di (12h), t to phn ng mt sloikhngsinhthucnhmfluoroquinolonhaycsdngl levofloxacin, moxifloxacin, ciprofloxacin[1] Trongsny,moxifloxacinctcdngcbitttviccbnhnhim khun ng h hp, do vy n c dng iu tr vim phi mc phi ti cngng, vim ph qun cp tnh, nhim trng xoang khng thuc ca vi khun[6][9][13]. Tuy nhin, y l loi thuc m tng hp ha hc kh phc tp, cho n nay nc ta cha c cng trnh no cng b v vic nghin cu tng hp moxifloxacin, trongkhigithnhnhp moxifloxacin canc ngoi l kh cao[2]. Nh vy, vic nghin cu sn xut nguyn liu moxifloxacin ti Vit Nam ngi bnhcchic s dng moxifloxacin generic t nguyn liu trong nc vi gi thnh hp l l rt cn thit. Do , nghin cu tng hp moxifloxacin c ngha thit thc trong vic ch ng to ngun nguyn liu 2 trong nc. Vi mong mun chn c qui trnh tng hp moxifloxacin thch hp, cho hiusutcao,cthpdngtrongnc,tiNghincutnghp Moxifloxacinc tin hnh vi cc mc tiu: 1. Nghin cu tng hp moxifloxacin hydroclorid t hp cht ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylat qui m phng th nghim theo mt s qui trnh. 2.So snh cc qui trnh tng hp t tm ra qui trnh hiu qu hn. 3 CHNG 1: TNG QUAN 1.1 Tng quan v moxifloxacin Moxifloxacinl khng sinh thuc nhm fluoroquinolon th h th 4 c ph khng khun rng,c pht trin bicngtydc phm Bayer AG. Moxifloxacin (dng mui hydroclorid) c bo ch thnh thuc ung, tim v phn phi vi tn bitdc l Avelox, Avalox v Avelon. Moxifloxacin cn c dng dng dung dch nh mt (bit dc Vigamox) iu tr vim kt mc[15]. y l thuc khng sinh ph bin trn th trng, c tiu th mnh. Doanh s hng nm ca thuc Avelox vo khong 500 triu USD.[29] 1.1.1 Cng thc cu to v tnh cht Cng thc cu to: OMeNFNCOOHOHHHN.HCl(1)12345678 Hnh 1: Moxifloxacin hydroclorid Tnkhoahc:Acid1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-quinolin -3-carboxylic hydroclorid. Cng thc phn t: C21H24FN3O4.HCl Trng lng phn t: 437.9 g/mol. Tnh cht vt l:Moxifloxacin hydroclorid c dng bt kt tinh mu vng n vng nht[28]. dng base moxifloxacin tan km trongnc.Tuynhin,dngmuintantttrongnc (24mg/ml 25oC)[7]. Moxifloxacin bn vi nhit v nh sng v tbthyphntrongdungdch.Nhitnngchyca 4 moxifloxacin hydroclorid t 238-242oC[13]. Gc quay cc ring l -256o 25oC (C=0.5 mol/L trong nc)[28]. 1.2.2C ch tc dng, ch nh, chng ch nh v liu dng. Moxifloxacin thuc nhm tng hp 8-methoxy fluoroquinolon c cu trc nhn ging vi gatifloxacin(2) v balofloxacin(3). (Hnh 2).N NOMe OMeNFOCOOH FNOCOOHHNHNGatifloxacinBalofloxacin(2) (3) Hnh 2: Gatifloxacin v balofloxacin N l kt qu ca nhngthayi v cu trc phn t acid nalidixic, dn n tng c tnh khng khun v ci thin tnh cht dc ng hc, trong khi cc tc dng ph c gim xung. Nhm cacbonyl (C =O) ti cc v tr 3 v 4 trong cu trc nhn l cn thit cho hotng khng khun ca moxifloxacin, l v tr lin kt vi cc ADN gyrase ca vi khun. Nguyn t flo ti v tr 6, gip tngcng hiu qu chng li vi khun Gram m v mrngphkhngkhunGramdng.Vng(S,S)-2,8-diazabicyclo[4.3.0]nonan v tr 7 tng thm hot tnh khng khun, c bit l i vi cc vi khunPseudomonas sp.. S hin din ca acid cacboxylic v nhiu nhm chc amin, lm chomoxifloxacin c tnh chtlng tnh, iu ny gip cho moxifloxacin c kh nngha tan trong cht bo v tng cng kh nng thm nhp cc m, m v cc t chc vim nhim.[16][17] -Cchtcdng:Moxifloxacincanthipvoqutrnhchuynha ADN ca vi khun bng cch c ch ca hai enzym topoisomerase II (ADNgyrase)vtopoisomeraseIV.Trong vikhungrammADN 5 gyraselchtcdngchnh,trongkhi vi khunGramdng topoisomerase IV chu nh hng nhiu nht.[4][12] -Dcnghc: Sinh kh dng dng vin nn l 91%, thuc phn b tt vo cc t chctrongcth, chuyn ha qua gan v thi tr qua thn.[4] -Chnh:Dng iu tr nhim khun ng h hp, vim da v t chc di da, nhim trng bng.[4] -Chng ch nh:[4] oMn cm vi bt c thnh phn no ca thuc hoc cc quinolon khc. oPh n c thai v cho con b. oTr em thiu nin ang trong giai on pht trin. -Liu lng v cch dng:[4] oLiu lng: 400mg moxifloxacin 1 ln/ngy. oCch dng:Ung nguyn c vin thuc vi mtlngnc va, nn ung thuc ngoi ba n. Truyn thuc theong tnhmch vi thi gian trn 60 pht, cc dung dch c th tim truynl:nc ct, dung dch glucose 40%, NaCl 0.9%. 1.2 Phng php tng hp moxifloxacin hydroclorid Qui trnh tng hp moxifloxacin c th chia thnh 3 giai on [12]: -Tng hp hp cht ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylat. -Tng hp mch nhnh C7(S,S)-2,8-diazabicyclo[4.3.0]nonan. -Tnghpmoxifloxacinbngphnnggiahpchtethyl1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-6 quinolincarboxylatviaminmchnhnh,sautomui moxifloxacin hydroclorid. 1.2.1 Tng hp hp cht ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylat. Hpchtethyl1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylat c tng hp theo phng php Grohe-Hetzer s 1.ylmt trong nhngphngphpph bin tng hp nhn khng sinh quinolon.OMeFFFCOOMeOMeFFFCOClKO OEtO OTEA, MgCl2OMeFFFOEtO OAc2O, CH(OEt)3OMeFFFOEtO OOEtNH2EtOHOMeFFFOEtO ONHOMeFFNOEtO O(4)(5)(6)(9)(10)(11)OHFFFCOOHNaH, MeIDMFNaOH 10%MeOHOMeFFFCOOHSOCl2Acetonitrile(7)(8)K2CO3DMFy. 97%y. 68%y. 93%y. 83%y. 83%S 1.Quy trnh tng hpethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylat (Grohe-Heitzer) Acid(6)ctnghptnguynliubanuacid(4).Nhmacid carboxylic (6) c hot ha bng phn ng vi thionyl chlorid to thnh acyl clorid, cht ny s phn ng vi mui kali ca acid malonic monoethyl ester trong iu kin c mt ca triethylamin to thnh hp cht (8) di dng hn hp ceton/enol, phn ng din ra nhit thng.un nng (8)vi triethyl orthoformat trong iu kin hi lu vi dung mi anhydrid acetic cho hp cht (9). Khng cn tinh ch, cht ny phn ng vi cyclopropylamin 7 to thnh hp cht (10). Nhn quinolon(11)ca moxifloxacin c iu ch bng phn ng vi K2CO3 trong dung mi DMF.[2] Bn cnhphngphptng hp nhn moxifloxacin Grohe-Heitzer cp,gnyCechettivngnghipcsdnghochtethyl3-dimethylamino acrylat thay th cho mui malonat, phn ng ca hp cht (7),snphm(12)tothnhphnngvicyclopropylaminchohpcht (10).Nhvy, so vi quy trnh Grohe-Heitzer, quy trnh phn ng ny rt gn c mt phn ng v iu kin n gin hn (S 2).[25] OMeFFFCOCltoluen, 90oCOMeFFFOEtO ONH2EtOHOMeFFFOEtO ONHOMeFFNOEtO O(10)(11)Acetonitril(7)(12)K2CO3DMFy. 79%y. 82%y. 83%N-CH=CH-COOEtNMe2 S 2.Quy trnh tng hp cht (11)ca Cecchetti 1.2.2 Tng hp mch nhnh C7 (S,S)-2,8-diazabicyclo[4.3.0]nonan. Btu t pyridin-2,3-dicarboxylic(13), phn ng vi anhydrid acetic s cho sn phm anhydrid(14). Sau khi loi b anhydrid acetic, sn phm th phn ng vibenzylamin to thnh hp cht(15).Nhnpyridinc kh ha bng hydro, tip theo l kh ha nhm chc amid bng LiAlH4 thu c hn hp racemic(17). T hn hp racemic, phn lpng phn quang hc c thc hin bng cch s dng acid L-(+) v D-(-)-tartaric. u tin, sn phm khng mong mun (R,R)c loi b do to kt tinh vi acid L-(+)-tartaric. Dung dch cn li c kim ha, sn phm (S,S) c phn lp bngkttinhviacidD-(-)-tartaric.Aminmchnhnh(19)(S,S)-2,8-8 diazabicyclo[4.3.0]nonan thu c bng phn ng loi b nhm benzyl trong iu kin hydro ha xc tc Pd/C (S 3).[12][26] N COOHCOOHAc2ONOOOBnNH2y. 84%NNOOHNNOOHNNHNNHNNHBnBn BnHH HHH2,Pd/CMeOHy. 93%LiAlH4THF1. Acid L-(+)-tartaric2. Kt tinh3. Lc4. D-(-)-tartaric5. Kt tinh6. NaOHH2,Pd/CMeOHy. 95%(13) (14) (15) (16)(17) (18) (19)Bn S 3.Quy trnh tng hp amin mch nhnh 1.2.3 Tng hp moxifloxacin dng mui hydroclorid Nm1990,Petersencngbphnng tnghpmoxifloxacin bng phnngamin(S,S)-2,8-diazabicyclo[4.3.0]nonanvi(11).Moxifloxacin dng base tip tc phn ng viacidclohydricthuc moxifloxacin dng mui hydroclorid.[19] OMeFFNOEtO OOMeNFNCOOHOHNHHNHHNHH2. HCl1.(11)(19)(1).HCl S 4.Phn ng tng hp moxifloxacin hydroclorid ca Petersen uimcaphngphpnylqutrnhphnngngin,dtin hnh,tuynhinnhcimchnhlsdngmtlng(S,S)-2,8-diazabicyclo[4,3,0]nonan (19) ln (githnhcao),ng thi phn ng km chn lc to ra mtlng ln sn phm ph l acid 1-cyclopropyl-6-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-7-fluoro-8-methoxy-4-oxo-quinolin-3-carboxylic (20).[14][20] 9 OMeNNCOOHOFNH(20)HH Hnh 3: Acid 1-cyclopropyl-6-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-7-fluoro-8-methoxy-4-oxo- quinolin-3-carboxylic loi b sn phm ph trn phi s dng sc k HPLC, iu ny lm gimhiusutcaqutrnhtnghpdnnlmtnggithnhsn phm[14][18].Mtsnhmnghincutinhnhnghincu,citinphnngny nhm t c hiu sut cao, loi b c sn phm ph.Nm2005,Chavavcng s cngb qui trnh tng hp moxifloxacin hydroclorid it chtu l ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylat(11)vihiusutkhcao(S 5).[9] OMeFFNOEtO OH3BO3Ac2O, 100-105oCOMeNFNO OOBOAc AcOHNNHHHTEA,MeCNOMeNFNCOOHOHNHHHClMeOHy. 95% y. 72%y. 90%OMeFFNO OOBOAc AcO.HCl(11) (21)(19)(22) (1)HNHH S 5. Tng hp moxifloxacin hydroclorid qua hp cht trung gian bis(acyloxy-O)borat Cht(11) phn ng vi acid boric v anhydrid acetic to phc bis(acyloxy-O) borat (21).Tip theo phc (21) phn ng vi amin (19) thu c moxifloxacin 10 bis(acyloxy-O) borat (22). Phcmoxifloxacin bis(acyloxy-O) borat(22)sphn ng tip vi acid clohydric to mui moxifloxacin hydroclorid (1).[9] Nm2006, Dandala v cng s pht trin mtphngphptng hp miqua hp cht trung gian difluoro borat (S 6). Hp cht (11) phn ng vi HBF4/H2O to hp cht difluoro borat (23) trung gian.Phc (23) phn ngtipviamin(19)trongmitrngbasechomoxifloxacindifluoro borat(24).Thy phn moxifloxacin difluoro borat(24) trong mi trng base thu c moxifloxacin dng base. Cui cng, moxifloxacin base to mui vi acid hydrocloric cho moxifloxacin hydroclorid. [8][11] OMeFFNOEtO OHBF4 50%OMeFFNO OOBF FHNNHHHTEA,MeCNOMeNFNCOOHOHNHHy. 71%OMeNFNO OOBF FHN(23) (24)(11)(25)HHy=84%baseHClOMeNFNCOOHOHNHH(1).HCl S 6.Tng hp moxifloxacinhydroclorid qua hp cht trung gian difluoro borat C phngphpcaChavavDandalau ch s dng mtlng nh (S,S)-2,8-diazabicyclo[4,3,0]nonan (19),ng thi phn ng gia amin (19) vi cc phc trung giantrong mi trng base cho sn phm th chn lc v tr C-7, bi vy sn phm moxifloxacin hydrocloridto ra khng ln sn phmphisomer(20),iunykhcphccnhcimlnnht trong qui trnh ca Petersen.[14] Ngoi nhng phngphpk trn, moxifloxacin hydrocloridcng c th ctnghpbngmtsphngphpkhctccdncht carboxamid,nitrilhayacid1-cyclopropyl-7-[(1S,6S)-2,8-11 diazabicyclo[4.3.0]non-8-yl]-6,8-difluoro-4-oxo-quinolin-3-carboxylic hydroclorid.[9][11][16][23]. Cc qui trnh tng hp moxifloxacin hydroclorid c tm tt bng s sau: OMeNFNCOOHOHNHHOMeNFNCOOHOHNHH.HClOMeNFNO OOBFFOMeNFNO OOBOAcAcOOMeFFNCOOEtOOMeNFNCNOOMeNFNCOOMeFFNCNOOMeFFNCOONR1R2ONR2R1HNHNHNHNHNNHHNNHHNNHHCl(26)(27)(28)(29)NFNCOOHOHNFtert-BuOKTHF/MeOH(30)(22)(24)(25)(1)HHHHHHHHHHHHHHHH(11) S 7: Tm tt cc qui trnh tng hp moxifloxacin hydroclorid Trncs cc cng trnh nghin cu trn, ti tin hnh nghin cu tng hp moxifloxacin hydroclorid t ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylattheo hai phngphpca Chava v Dandala qui m phng th nghim. Sau , so snh hai phng php trn tm ra phng php tng hp moxifloxacin hydroclorid hiu qu hn. 12 CHNG 2: NGUYN LIU, THIT B, NI DUNG V PHNG PHP NGHIN CU 2.1 Nguyn vt liu, thit b 2.1.1 Nguyn vt liu Bng 1: Danh mc cc nguyn liu, ha cht, dung mi s dng. STTTn nguyn liuNgun gcHm lng 1 Ethyl1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylat Tng hp 2 (S,S)-2,8-diazabicyclo [4,3,0]nonan Tng hp 3 Acid boric Sigma-Aldrich99.9% 4 Acid fluoroboric Acros50% 5 Anhydrid acetic Schalau Chemie 99% 6 Triethylamin Merck 99% 7 Acetonitril Burdick & J ackson 99.9% 8 HCl Trung Quc36.5% 9 NH3 Trung Quc25-28% 10Aceton Trung Quc99% 11Ethanol Trung Quc99% 12Ethylacetat Trung Quc99% 13Methanol Trung Quc99% 14n-hexan Trung Quc99% 13 STTTn nguyn liuNgun gcHm lng 15 DiclomethanTrung Quc99% 16 Methanolic HCl 3MAldrich3M 2.1.2 Thit b th nghim -Bn mng sc k silica gel nhm Art 5562 DC Alurolle Kieselgel 60F254 (Merck). -Dng c thy tinh nh bnh cu, ng ong, bnh nn, a khuy, pipet, cc c m -Gi kim loi, du silicon. -H thng phu lc chn khng, phu lc, bnh chit, giy lc, my khuy t gia nhit, h thng sinh hn xon, cn phn tch, cn k thut.-My ct quay chn khng Buchi-R210. -My ht kh -T sy -n t ngoi bc sng 254 nm. -My o nhit nng chy EZ- Melt ca hng SRS-USA ti b mn Ha Hu c- Trng H Dc H Ni. -Ph hng ngoi IR ghi trn my FTIR Impact-410 bngphngphp nn vin KBr, ti Vin Ha hc - Vin Hn lm Khoa hc & Cng ngh Vit Nam. -Ph khi lng MS c ghi trn my Agilent 1120 ti Vin Ha hc - Vin Hn lm Khoa hc & Cng ngh Vit Nam. -Ph cng hng t ht nhn (1H- NMR, 13C- NMR) c o trn my Bruker AM 500 FT-NMR Spectrometer, Vin Ha hc Vin Hn lm Khoa hc v Cng ngh Vit Nam vi TMS l cht chun ni.14 2.2 Ni dung nghin cu -Tnghpmoxifloxacinhydrocloridtethyl1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylatquaphctrunggian1-cyclopropyl-7-[(S.S)-2,8-diazabicyclo[4,3,0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylicacid-O3,O4)bis(acyloxy-O)borat. -Tng hp moxifloxacin t ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylatquaphctrunggian1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4,3,0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic difluoro borat. -Kim tra tinh khit v xc nh cu trc cc cht tng hp c. -So snh, nh gi hiu qu 2 qui trnh trn. 2.3 Phng php nghin cu -Tng hp ha hc oS dngccphngphptng hp ha hcthngthng tng hp cc cht d kin. oTheo di qu trnh phn ng bng sc k lp mng (TLC). -Kim tra tinh khit oKim tra s b tinh khit ca sn phm bng TLC v o nhit nng chy. TLCctinhnhtrnbnmngsilicagelKieselgel 60F254 (Merck). Cc cht c ha tan trong ethyl acetat , tin hnh chy sckvsoidint ngoi bc sng 254 nm. onhit nng chy:S dngmyonhit nng chy EZ- Melt ca hng SRS-USA. -Khng nh cu trc 15 oCc cht tng hp c khng nh cu trc bng phng php ph: ph hng ngoi (IR), ph khi (MS), ph cng hng t ht nhn proton 1H-NMR v ph cng hng t ht nhncarbon 13C- NMR. 16 CHNG 3: THC NGHIM, KT QU V BN LUN 3.1 Tng hp ha hc Moxifloxacin hydroclorid c tng hp theo 2 qui trnh di y: OMeNFNCOOHOHNHHOMeFNCOOEtOOMeFFNOOMeFNCOOEtOOMeFFNOMeNFNOHNHHOMeNFNOHNHH(CH3CO)2OH3BO3+HNNHTEAAcetonitril MeOHHClFHBF4 50% AcetonitrilHNNHTEA1)TEA/ MeOH2) HCl.HClOOBOAcO OOBFOOOOBOAcBFAcOAcOFFFHHHH.(11)(21)(22)(1)(11)(23)(24) S 8: Qui trnh tng hp moxifloxacin hydroclorid Quitrnh1:Tnghpmoxifloxacinhydroclorid thng qua to phc bis(acyloxy-O)borat. Qui trnh 2: Tng hp moxifloxacin hydroclorid thng qua to phc difluoro borat. 17 3.1.1Tnghpmoxifloxacinhydrocloridthngquatophcbis(acyloxy-O) borat 3.1.1.1Tnghp1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic-O3,O4)bis(acyloxy-O)borat Phng trnh phn ng N FFOCOOEtOMe+BOAcAcO OAcH3BO3+(CH3CO)2OOMeFFNO OOBOAcAcO(11) (21) S 9: Phn ng tng hp phc(21) Tin hnh Ly (3 g; 48.5 mmol) acid boric v anhydrid acetic (16.2 ml; 171.7 mmol) vo trong mt bnh cu 50ml. Ton b hn hp c un hi lu, khuy u. Sau 1.5h thm cht (11)(10,01 g, 30.9 mmol) vo hn hp, tip tc khuy u v t nhit phn ng 100oC. Theo di phn ng bng TLC vi h dung mi trin khai l n-hexan: EA=1:1. Phn ng kt thc sau 2h. ngui hn hp v nhit phng, thm 100ml nc lnh vo hn hp ri duy tr nhit 0-5oC trong 2h. Sau em sn phm ra lc, sn phm thu c emra bng nc ctcho ti khi pHncra =7. Sy kh sn phm nhit 55-60oC ti khi lng khng i.Sn phm thu c l cht rn c mu trng hi vng. Khi lng 12.420 g. Hiu sut 95.2 %. 18 3.1.1.2.Tnghp1-cyclopropyl-7-(2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylic-O3,O4)bis(acyloxy-O)borat. Phng trnh phn ng OMeNFNOHNHHOOBOAc AcOOMeFNO OOBOAc AcOFHNNH+ TEA(21) (19)(22)HHAcetonitril S 10: Phn ng tng hp cht (22) Tin hnh Ha tan phc (21) (8.0053 g; 19.40 mmol) trong 40 ml acetonitril. Sau thm (S,S)-2,8-diazabicyclo[4,3,0]nonan (19) (2.8g; 22.24 mmol; 1.17equiv) v triethylamin (4 ml; 29.12 mmol). Khuy trn hn hp phn ng nhit phng,theodiphnngbngTLCvihdungmikhaitrinl EA:MeOH=3:1, phn ng kt thc sau 2.5h. Loi b dungmidi p sut gim, ri thm 20ml n-hexan nhit phng trong 1h. em lc hn hp thu ly chtrn sau ra libng n-hexan. Sn phm thu c c dng cht do mu nu. 3.1.1.3. Tng hp moxifloxacin hydroclorid Phng trnh phn ng OMeFNO OOBOAc AcOOMeNFNCOOHOHNHH+HClMeOH.HClNHNHH(22)(1) 19 S 11: Phn ng thy phn v to mui moxifloxacin hydroclorid t phc bis(acyloxy-O) borat Tin hnh Phn ng ny c tin hnh qua 2 giai on: Giai on 1: Ph phc v to mui moxifloxacin hydroclorid emtonbsnphm(22)thuctrnhatanhontontrong methanol (50ml).Saunh tng git acid clohydric 36.5% vo hn hp, khuyu v dng ch th anngkim tra pH ca dung dch, chon khi pHdd=1 th ngng phn ng. Tip tc khuyu hn hp trong 2h. Ri lm lnh hn hp phn ng nhit 0-5oC trong 16h, thy xut hin kt ta mu vng. em lc thu ly ta. Giai on 2: Tinh ch moxifloxacin hydroclorid Tathucemha tan trong khong 150mlnc ct. Ri trung ha dung dch trn bng dung dch NH325-28%.Sauchit ly moxifloxacin dng base bng diclomethan. Pha hu c c lm kh bng Na2SO4khan ri loi dung mi di p sut gim thu c bt moxifloxacin dng base mu vngm.Btnysaucha tantrongcn tuytiri nh tng gitacid hydrocloridmethanolic 3M, kim tra pH phn ng cho ti khi pHdd=1 th ngng phn ng. hn hp nhit 0-5oC trong 16h thy xut hin kt ta moxifloxacin dng mui. Lc dung dch, sy ta thu c nhit 50-55oC ti khilngkhngi. Moxifloxacinhydrocloridthuc c mu vng nht. Nhit nng chy 240-244oC Khi lng 6.808g. Hiu sut:78.8 % 20 3.1.2 Tng hp moxifloxacin thng qua to phc boron difluorid 3.1.2.1. Tng hp 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic-O3,O4)difluoroborat. S phn ng OMeFFNCOOEtOOMeFFNO OOBF F+HBF4100oC(11) (23) S 12:Phn ng tng hp cht (23) Tin hnh Ly dung dch HBF4 50% (4ml; 31.4mmol, 10 equiv) cho vo mt bnh cu nh 10ml, thm cht (11) (1,00g; 3.1mmol) vo trong bnh cu. un nng hiluckhuy trn phn ng nhit 100oC, theo di phn ng bng TLC h dung mi n-hexan: EA=1:3. Sau 10h phn ng kt thc. Thm 10ml nc ct vo trong hn hp, ri lm lnh phn ng v 0-5oC, sau 2h emlc thu ly kt ta v ra ta bngnc ct cho ti khi pHnc ra=7. Sn phm em sy kh 40-50oC ti khi lng khng i. Sn phm thu c c dng bt kt tinh mu trng. Khi lng 960 mg. Nhit nng chy: 270-272oC. Hiu sut phn ng l 90.3%. 3.1.2.2.Tnghp1-cyclopropyl-7-(2,8-diazabicyclo[4,3,0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylic-O3,O4)difluoro borat. Phng trnh phn ng 21 OMeNFNOHNHHOOBF FOMeFNO OOBFFFHNNH+TEA(23) (19) (24)HHAcetonitril S 13: Phn ng tng hp cht (24) Tin hnh Ha tan phc difluoro borat (24) (960 mg; 2.79 mmol) trong acetonitril (5 ml).Sauthm(S,S)-2,8-diazabicyclo[4,3,0]nonan(19)(424mg;3.35 mmol,1,2equiv) vtriethylamin(1ml;7.17mmol).Khuytrn hn hp phnngnhitphng,theodiphnngbngTLChdungmi EA:MeOH=3:1.Sau 5h phn ng kt thc. Hn hp sau phn ng em lc v loi b ta, ra hn hp bng dung mi acetonitril, bc hi ton b dung mi p sut thp cho n khi thu c bt mu vng nht. 3.1.2.3. Tng hp moxifloxacin hydroclorid Phng trnh phn ng OMeNFNOHNHHOOBF F(24)OMeNFNCOOHOHNHH(1)1. TEA/ MeOH2. HCl S 14: Phn ng thy phn v to mui moxifloxacin hydroclorid t phc difluoro borat Tin hnh emtonbsnphm(24)thuctrnhatanhontontrong methanol(5ml),sauthmtriethylamin(0.26ml;1.86mmol)vohn 22 hp,unnnghiluckhuy trn phn ng. Theo di phn ng kt thc bng TLC vi h dung mi EA: MeOH=1:3. Sau 5h, phn ng kt thc. Bchidungmidi p sut gimchonkhithuc bt kh. Ha tanhontonlng bt trn trong methanol, trung ha bng NH3 25-28%, sauthmacidhydrocloridmethanolicvodungdchtrnpHdd=1. Khuy trn hn hp phn ng trong 1h. Sau lm lnh v 0-5oC trong 16h. Cui cng em lc v ramoxifloxacin hydroclorid bng methanol lnh.Sy sn phm nhit 40-50oCn khilngkhngi. Sn phm c dng bt kt tinh mu vng. Khi lng 796mg. Nhit nng chy: 239-244oC Hiu sut: 58.8%.3.2. Kim tra tinh khit v xc nh cu trc ca cc cht tng hp. 3.2.1 Kim tra tinh khit Kimtrasbtinhkhitcaccchttrunggianvsnphm moxifloxacin tng hpc bngTLCvonhit nng chy.Kt qu c th hin bng 2. Bng 2:Gi tr Rf v nhit nng chy ca cc cht tng hp c ChtH dung mi khai trinRf Tonc (oC) (21)EA: MeOH (3:1)0.75113-114 (22)EA: MeOH (1:3)0.25 Nhit phng (23)EA: MeOH (3: 1) 0.78 270-272 (24)EA: MeOH (1:3) 0.27 132-134 Moxi base Qui trnh 1 MeOH0204-208 23 Moxi base Qui trnh 2 MeOH0204-207 Moxi.HCl Qui trnh 1 MeOH0241-244 Moxi.HCl Qui trnh 2 MeOH0240-244 Nhn xt: Vi cc h dung mi khai trincc cht u cho mt vt gn, r, khng c vt ph. Nhit nng chy ca cc cht xcnh,trongnhit nng chy moxifloxacin dng base v dng muiu nm trong khong nhit m cc ti liu tham kho a ra. T c th s b thy rng cc cht tng hp c l tinh khit.[28][13] 3.2.2 Khng nh cu trc khngnh cu trc ca cc cht tng hpc th ph hng ngoi (IR) v phcng hng t ht nhn 1H- NMR ca cc cht tng hp c tin hnh phn tch, bn cnhcchp cht moxifloxacin dngbasecng c phn tch thm ph MS, 13C-NMR vmoxifloxacinhydrocloridc phn tch ph 13C-NMR. Kt qu phn tch ph c trnh by c th phn phn tch ph v ph lc. 3.2.2.1 Ph hng ngoi IR. Cc cht tng hpcoph hng ngoi trn my FTIR Impact-410 ti Vin hn lm Khoa Hc v Cng Ngh Vit Nam. Ph c ghi trong vng 4000- 600 cm-1, bng phng php nn vin KBr (ph lc 1-5). Kt qu phn tch ph IR ca cc cht (21), (23), moxifloxacin base (qui trnh 1) v moxifloxacin hydroclorid (qui trnh 1, qui trnh 2) c trnh by bng 3 v ph lc 1-5. 24 Bng 3: Kt qu o IR ca cc cht tng hp c ChtCTCT Ph IR (KBr), cm-1 vOHvNHvCHvC=OvC=CvC-NvC-FvC-O (8) OMeFNO OOBOAc AcOF 2998; 2857 1688; 1645; 1614 1571 132614661249;1166 (12) OMeFNO OOBF FF 3017; 2975; 2869 1716; 1626 1553126714721164;1040 Moxi base OMeNFNCOOHOHNHH Overlaped 344729361725; 1621 1500132014451175;1038 Moxi .HCl (QT1) OMeNFNCOOHOHNHH.HCl Overlaped 353129641714; 1624 1516132214571188 1042 Moxi.HCl (QT2) OMeNFNCOOHOHNHH.HCl Overlaped 347829421709; 1623 1512131814541186 Nhn xt: Cc chtu c s sng ng viccdaong ca cc nhm lin kt, ph hp vi ti liu tham kho [8,11,20]25 3.2.2.2Ph proton(1H-NMR). Ph 1H- NMR ca cc chtcotrnmyBruker AM 500 FT-NMR Spectrometer, Vin Ha hc Vin Hn lm Khoa hc v Cng ngh Vit Nam vi TMS l cht chun ni. Kt qu phn tch ph 1H-NMR ca cc cht c th hin bng 4 v ph lc 6-10.Bng 4: S liu phn tch ph cng hng t proton 1H-NMR ChtCng thc cu to dch chuyn ha hc (21) OMeFFNO OOBOAcAcO 1H-NMR(500MHz,CDCl3,ppm) :9.19(s, 1H-C2); 8.09-8.05(m,1H-C5); 4.40-4.36(m,1H-C1);4.19(d, J =2.5Hz,3H,OCH3);2.01(s,6H-2CH3CO);1.43-1.39(m,2H-cyclopropyl);1.32-1.30(m,2H-cyclopropyl). (23) OMeFFNO OOBFF 1H- NMR (500MHz, CDCl3&DMSO, ppm):9.04(s,1H-C2);7.98(m,1H-C5); 4.36-4.33(m, 1H- C1); 4,10(s,3H- OCH3);1.29-1.27(m,2H-cyclopropyl);1.21(m,2H-cyclopropyl). Moxi base (QT1) OMeNFNCOOHOHNHH 1H-NMR(500MHz,DMSO,ppm) :8.62(s, 1H); 7.60(d, J =14.5Hz, 1H); 4.12-4.10(m,1H);3.99-3.94(m,1H); 3.89-3.87(m, 1H); 3.54(m, 3H); 3.37-3.23(m,4H);2.87(m,1H);2.51(m, 1H); 2.24(m, 1H); 1.73- 1.59(m, 3H); 26 1,.41(m, 1H); 1.21-1.17(m, 1H); 1.13-1.08(m, 1H); 1.02-0.96(m, 1H); 0.89-0.84(m, 1H). Moxi.HCl (QT 1) OMeNFNCOOHOHNHH.HCl 1H-NMR(500MHz,D2O,ppm) :8.57(s,1H);6.85(d,J =13.5,1H); 4.04(m,2H);3.94(m,1H);3.76(m, 2H);3.67(m,1H);3.52(m,3H); 3.35(d,J =12.5,1H);3.08-3.04(m, 1H);2.78(m,1H);1.85(m,4H); 1.23(m,1H);1.10(m,1H);0.91(m, 1H). Moxi.HCl (QT 2) OMeNFNCOOHOHNHH.HCl 1H-NMR(500MHz,D2O,ppm) :8.58(s,1H);6.86(d,J =13.5Hz, 1H); 4.09-4.08 (m, 2H); 3.94 (m, 1H); 3.80-3.71 (m, 2H); 3.66 (m, 1H); 3.53 (s, 3H); 3.35 (d, J =12.5Hz, 1H); 3.06 (t, J =10Hz, 1H); 2.78 (m, 1H); 1.89-1.80(m,4H);1.24-1.20(m,1H); 1.13-1.08(m,1H);1.02-1.01(m,1H); 0.91(m,1H). Nhn xt: Da vo kt qu phn tch ph bng 4 v cn c vo ph (ph lc 6-10) chng ti nhn thy s lng, dch chuyn, bi ca cc tn hiu l ph hp vi cng thc cu to ca cc cht tng hp c.[20][22] 27 3.2.2.3Ph cng hng t carbon (13C-NMR) v MS khngnh thm v cu trc, moxifloxacin dng base co thm phkhi(MS),phcnghngtcarbon(13C-NMR)vmoxifloxacin hydroclorid co thm phph cng hng t carbon (13C-NMR). - Ph MS: Khi ph cho pic ion phn t [M-H]- m/z=400 ph hp vi khilng phn t ca sn phm ng vi cng thc phn t C21H24FN3O4 (ph lc 11). - Ph 13C-NMR kt qu c th hin bng 5 v ph lc 12, 13. Bng 5: S liu phn tch ph 13C-NMR ChtCng thc cu to dch chuyn ha hc Moxi base (QT1) OMeNFNCOOHOHNHH (125MHz,DMSO,ppm): 175.85(C=O,ceton);165.83(C=O, acid);149.98(C-F);140.21;137.26; 137.18;134.53;116.41;106.35; 106.18;61.16(OCH3);58.40;55.93; 52.12;52.07;44.30;36.18;22.80; 21.28; 9.64; 8.13. Moxi.HCl (QT1) OMeNFNCOOHOHNHH.HCl (125MHz, D2O, ppm): 175.31(C=O, ceton);169.3(C=O;acid);154.6(C-F); 152.6; 141.4; 137.3; 134.6; 116.9; 106.2;106.0;67.1(OCH3);55.2; 54.0;51.7;42.7;41.3;34.4;20.5; 17.5; 9.4; 8.34. 28 Moxi.HCl (QT2) OMeNFNCOOHOHNHH.HCl (125MHz,D2O,ppm):175.0(C=O, ceton);169.1(C=O,acid);152.4(C-F); 150.1; 141.2; 137.2; 134.5; 116.7; 105.9;104.9;61.7(OCH3);55.4; 53.8;51.9;42.6;41.3;43.4;20.6; 17.6; 9.5; 8.4. Nhn xt: Da vo kt qu phn tch ph bng 5 v cn c vo ph (ph lc 12, 13 v 14) chng ti nhn thy s lng, dch chuyn, bi ca tn hiu l ph hp vi cng thc cu to ca cc cht tng hp c.[21] Nh vy kt hp cc kt qu phn tch ph IR, MS, 1H-NMR v 13C-NMR c th khng nh cc cht tng hp c c cu trc ng nh d kin. 3.3 Bn lun Xut pht t nguyn liubanu l ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylat,chaiquitrnhutri qua 3 bc to ra moxifloxacin dng mui hydroclorid. 3.3.1 Phn ng to phc trung gian borat Vic to phc borat s lmthayi li s phn b in t trong vng quinolin, dn n lm tng kh nng i in t ti v tr C7, to iu kin cho phn ng gn amin sau ny tr nn d dng hn. C ch ca phn phc tng hp phc borat c th hin s 15: 29 N FFOOMeBXX XOOEtXN FFOOMeB XXOOOMeFFNO OOBXX(31) (11)Et(32)X=F, AcON FFOOMeBXX XOOEt(33)S 15: C ch phn ng to phc borat Trong phn t BX3, nguyn t Bo cn 1 orbital trngv c kh nng nhn thm 2 in t electron t oxy trong nhm C=O to lin kt phi tr OB hnh thnh cht trung gian (31), cht trung gian ny khng bn mau chng tch loi mt phn t EtX to cht (32). Lc ny nguyn t Bo li xut hin 1 orbital trng, orbital trng ny nhn thm 2 in t electron t gc COO- to phc borat (33). S khc bit trong phng php tng hp phc borat qui trnh 1 v qui trnh 2 c th hin trong bng 6: Bng 6: So snh phn ng to phc borat gia hai qui trnh Qui trnh 1 Qui trnh 2 Tc nhn s dng S dng 2 tc nhn vi lnglacidboric(1.5equiv)v anhydrid acetic (4.5equiv) SdngtcnhnlHBF4 vi lng ln 10equiv. Thi gian, iu kin tin hnh phn ng Tin hnh 100oC trong 3.5 gi. Tin hnh 100oC trong 10 gi. Hiu sut95.2%90.3% Khc Sn phm ln nhiu tp acid aceticsauphnng.Do tacnphirabngnc Phnngtoramtsn phm ph l HF. HF c tnh nmncao,dnnph 30 lnh ti khi loi b hon ton acid. hydngcthitbphn ng bng thytinh. loi b HF trong sn phm, ta borat c ra nhiu ln vi nc ct cho ti khi pHnc ra trung tnh. 3.3.2 Phn ng gn amin vo nhn quinolin ylbc quan trng trong qu trnhphn ng, quytnh hiu sut tng hp ca c qui trnh ng thi y cng l giai on hnh thnh nhiu tp v sn phm ph.C ch phn ng c th c gii thch theo s sau: OMeNFNOHNHHOOBX XHNNHOMeFFNO OOBX XOMeFNO OOBX XHNNFHHHHHOMeFNO OOBX XHNNF HHHHF(34)(35) (36)(33)X=OAc, F S 16: C ch phn ng gn amin y l phn ng th i nhn (SN)vonhnthmvi tc nhn i nhn l (S,S)-2,8-diazabicyclo[4,3,0]nonan.(S,S)-2,8-diazabicyclo[4,3,0]nonanc kh nngtn cng chn lc vo v tr C-7 trong phn t(33) to hp cht trung gian (35), phc ny khng bn s mau chng tch loi HF to thnh phc (36). 31 Khi so snh qui trnh 1 v qui trnh 2 ta thy c nhng im khc bit sau (Bng 7): Bng 7: So snh phn ng gn amin gia hai qui trnh Qui trnh 1Qui trnh 2 Chtthamgia phn ng. (S,S)-2,8-diazabicyclo [4,3,0]nonan: 1.17 equiv. Et3N: 1.5 equiv (S,S)-2,8-diazabicyclo [4,3,0]nonan: 1.2 equiv Et3N: 1.5 equiv Thigian,iu kin phn ng 2.5h ti 25oC c khuy trn5h ti 25oC c khuy trn 3.3.3 Qu trnh to mui moxifloxacin hydroclorid S khc bit trong phn ng to mui giahaiquitrnhc th hin trong bng 8:Bng 8: So snh phn ng to mui gia hai qui trnh Qui trnh 1Qui trnh 2 Phnngthy phn phc borat S dng acid hydrocloric trong thi gian 2h nhit thng. Sdngtriethylamin,un nng hiluckhuy trn trong 5h. Phnngto mui hydroclorid S dng tc nhn l acid hydroclorid methanolic. Hiusutton phn. 77.8%58.8% C hai qui trnh u cho hiu sut tng hp tt, hn ch cc sn phm phcbitlisomer(20),vgimclngamin(S,S)-2,8-diazabicyclo [4,3,0]nonan xung mc thp (~1.2 equiv). Tuy nhin khi tin hnh 2 phng php ny, thi gian tin hnh phn ng 32 qui trnh 2 di hn qui trnh 1. Ngoi ra qui trnh 2, phi s dng 1 lng ln HBF4 (10 equiv) cht tham gia phn ng lm gi thnh sn phm tng ln cao. Thm vo , phn ng gia (11) vi HBF4 sinh ra HF cht ny c th to ra hintng demethyl ha nhm OCH3, lm ph hy cc thit b phn ng bng thytinh,toratakhtanlntrong sn phmlmgimcht lng sn phm. Do vy qui trnh 1l la chn tt hn so vi qui trnh 2khi tin hnh tng hp tng hp moxifloxacin hydroclorid. 33 KT LUN V KIN NGH 4.1. Kt lun T nhng kt qu nghin cu trnh by trn ti rt ra mt s kt lun sau: 1 tng hp thnh cng moxifloxacin theo c hai qui trnh: oQuitrnhtnghpmoxifloxacinhydrocloridtethyl1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylat quaphc trung gian 1-cyclopropyl-7-[(S.S)-2,8-diazabicyclo[4,3,0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylicacid-O3,O4)bis(acyloxy-O) borat.Hiu sut: 77.8% oQuitrnhtnghpmoxifloxacintethyl1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolincarboxylat quaphctrunggian1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4,3,0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylic difluoro borat. Hiu sut:58.8%. 2Quitrnhtnghpmoxifloxacinhydrocloridtheohngtophc bis(acyloxy-O) borat cho hiu sut cao hn, thi gian tin hnh ngn v n gin hn so vi qui trnh tng hp moxifloxacin hydroclorid theo hng to phc difluoro borat. 4.2. Kin ngh T nhng kt qu thc nghimthuc trn, chng ti c mt s xut nh sau: -Tip tc nghin cu hon thin qui trnh tng hp t hiu sut cao v n nh hn na. -Tip tc nghin cu m rng qui m ca qui trnh. TI LIU THAM KHO A. Ting Vit [1] B y t (2009), Bocosdngkhngsinhvkhngkhngsinhti15 bnh vin Vit Nam nm 2008-2009. [2] L Nguyn Thnh v cng s (2012), Nghin cu qui trnh tng hp nhn khngsinhfluoroquinolonEthyl1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolin carboxylat, Tp ch ha hc, 50(3), 323-325. [3] Mai Tt T (2007), Dc l hc, tp 2, Nh xut bn Y hc, tr. 172-174. [4] Vidal Vit Nam 2011-2012, Nh xut bn CMPMedica Asia Pte Ltd, tr. 77-82. B. Ting Anh [5]AndressonM.I.,MacgownA.P.(2003),Developmentofquinolones, Journal of antimicrobial chemotherapy, pp. 1-11. 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[27]Zhi-XianWang,et al(2007),Processfor the preparation of the boron difluoridechelatofquinolone-3-carboxylicacid,UnitedStatesPatent,US 20070208174 A1 [28]http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=152946.[29]http://www.annualreport2011.bayer.com/en/healthcare.aspx. PH LC Ph lc 1: Ph IR ca cht (21) Ph lc 2: Ph IR ca cht (23) Ph lc 3: Ph IR ca moxifloxacin base (qui trnh 1) Ph lc 4: Ph IR ca moxifloxacin hydroclorid (qui trnh 1) Ph lc 5: Ph IR ca moxifloxacin hydroclorid (qui trnh 2) Ph lc 6: Ph 1H-NMR ca cht (21) Ph lc 7: Ph 1H-NMR ca cht (23) Ph lc 8: Ph 1H-NMR ca moxifloxacin base (qui trnh 1) Ph lc 9: Ph 1H-NMR ca moxifloxacin hydroclorid (qui trnh 1) Ph lc 10: Ph 1H-NMR ca moxifloxacin hydroclorid (qui trnh 2) Ph lc 11: Ph MS ca moxifloxacin base (qui trnh 1) Ph lc 12: Ph 13C-NMR ca moxifloxacin base (qui trnh 1) Ph lc 13: Ph 13C-NMR ca moxifloxacin hydroclorid (qui trnh 1) Ph lc 14: Ph 13C-NMR ca moxifloxacin hydroclorid (qui trnh 2)