Tng hp khng sinh cefixime

2011

MC LC
Li m u....................................................................................................................... 2 Chng I: TNG QUAN V KHNG SINH V PHN NHM CEPHALOSPORIN 1.1. Gii thiu chung v khng sinh ........................................................................... 3 1.2. Tng quan v phn nhm cepholosporin ............................................................. 3 1.2.1. Cu trc chung ca cephalosporin ........................................................... 3 1.2.2. Tnh cht vt l v ha hc ca cephalosporin ........................................ 4 1.2.3. C ch tc dng ca cephalosporin .......................................................... 5 1.2.4. nh lng cephalosporin ........................................................................ 5 1.2.5. Phn loi cephalosporin............................................................................ 5 1.3. Cefixime ............................................................................................................... 6 1.3.1. Gii thiu v cefixime .............................................................................. 6 1.3.2. Hot tnh ca cefixime ............................................................................. 7 1.3.3. Cng dng ca cefixime ........................................................................... 7 1.3.4. Dc ng hc ......................................................................................... 7 1.3.5. Thn trng v nhng triu chng khi s dng thuc ............................... 7 Chng II: TNG HP CEFIXIME .............................................................................. 7 2.1. Quy trnh tng hp cefixime c bn i t (7-AVCA).......................................... 8 2.1.1. Quy trnh tng qut................................................................................... 8 2.1.2. Quy trnh thc nghim ........................................................................... 10 2.2. Quy trnh tng hp cefixime thng qua mui alkil hoc aril-sulfonat cefixime 10 2.2.1. Quy trnh tng qut................................................................................. 10 2.2.2. Quy trnh thc nghim ........................................................................... 14 2.3. Quy trnh tng hp cefixime thng qua mui tert-octilamin cefixime .............. 14 2.3.1. Quy trnh tng qut................................................................................. 14 2.3.2. Quy trnh thc nghim ........................................................................... 15 2.4. Phng php phn tch cefixime ........................................................................ 17 Kt lun.......................................................................................................................... 17 Ti liu tham kho ......................................................................................................... 18

GVHD: TS. on Ngc Nhun

Tng hp khng sinh cefixime

2011

Li m u
rong sut cuc i, ngi no cng c t nhiu t b nhim khun d nng hay nh v mi ln nh vy c th phi dng mt loi khng sinh no . Khng sinh l mt v kh quan trng chng li cc vi sinh vt gy bnh [2]. Trong nhiu nm qua, vic s dng v dng sai mc ch cc loi thuc khng khun lm tng s lng v cc loi sinh vt khng thuc [9]. Cc loi thuc khng sinh ang mt dn tc dng. Do vy, rt nhiu loi bnh vim nhim c th s mt kim sot vo mt ngy no . Vi tc du lch v thng mi ton cu ngy cng tng, tnh trng khng khun s ly lan khp th gii ch khng b hp trong bt c mt khu vc hay quc gia no. ng trc thc trng cc mi e da t khng thuc ngy cng tng ny, tnh trng nhim trng lan rng hn v nhiu bnh khng cn d dng c cha khi, dn n iu tr ko di, tn km v nguy c t vong cao cho bnh nhn, WHO ku gi th gii c nhng hnh ng khn cp v phi hp lm chm s ly lan ca khng thuc, hn ch tc ng ca n ngy hm nay v bo tn cc tin b y t cho cc th h tng lai [9]. Chnh v nhng l do , chng ta cn tm hiu v nguyn cu nhiu hn v cch thc s dng hp l cc loi khng sinh, bo ch ra nhiu loi khng sinh mi tt hn chng li qu trnh khng khng sinh ca vi khun. Vi mc tiu ny, em chn ti: tm hiu v nguyn cu v qu trnh tng hp khng sinh cefixime.

GVHD: TS. on Ngc Nhun

Tng hp khng sinh cefixime

2011

Chng I: TNG QUAN V KHNG SINH V PHN NHM CEPHALOSPORIN

1.1. Gii thiu chung v khng sinh[1]
Khng sinh l nhng hp cht c ngun gc vi sinh vt, bn tng hp hay tng hp. Khng sinh c tc dng km hm hoc tiu dit cc vi sinh vt gy bnh nng thp. Mt s khng sinh c tc dng ngn cn s pht trin ca cc t bo ung th. Cn c vo tc dng tr bnh, c th chia khng sinh thnh 3 nhm chnh: Khng sinh khng khun Khng sinh tr nm Khng sinh chng ung th Trong 3 nhm khng sinh trn, khng sinh khng khun c s dng rng ri vi s lng rt nhiu so vi cc nhm khng sinh khc v cc thuc khc [10]. Nhm beta-lactam thuc nhm khng sinh khng khun gm 2 phn nhm: penicillin v cephalosporin.

1.2. Tng quan v phn nhm cephalosporin

Nm 1948 ln u tin ngi ta trch c cephalosporin C t mi trng nui cy. Cephalosporin C c hiu qu trn nhng loi vi khun khng vi penicilin, nhng hiu qu ny yu khng th s dng trn lm sn, nn ngi ta phi thay i cu trc nhm thay i hot tnh ca phn t c th ng dng c trong iu tr [10]. Nhng bin i v mt cu trc mong dn n m rng ph khng khun sang vi khun gram m, c bit nhng vi khun nguy him trong mi trng bnh vin, gia tng s khng ca phn t i vi beta-lactam v ci thin v mt dc ng hc [1].

1.2.1. Cu trc chung ca cephalosporin[1]

H R v R3 thay i O R7 H R7 = H hoc OCH3 X N R X = S hoc O N R7 = H: cephalosporin R3 O R7 = OCH3: cephamycin COOH Nhng cephalosporin bn tng hp s dng trong iu tr c nhng nhm th rt khc nhau trn C3 v chui acilamino v tr 7. Nhm COOH c th dng mui, acid hay este.

GVHD: TS. on Ngc Nhun

Tng hp khng sinh cefixime

2011

Phn t c 2C bt i: C6(R) v C7(R) mi c hot tnh sinh hc. Nhm R lm bin i t tnh khng khun v tnh bn ca phn t. S khng vi betalactam c th c c bng s la chn hp l R, R7 v X. S thay i trn R3 lm thay i t tnh dc ng hc ca phn t (iu ny c th lm tng hot tnh khng khun).

1.2.2. Tnh cht vt l v ha hc ca cephalosporin[1]

a) Tnh cht vt l Cc cephalosporin thng dng tinh th trng hoc c mu nh, khng mi hoc c mi thong nh. Trong dung dch nc cephalosporin l nhng cht quay cc phi do c s hin din ca 2 cacbon bt i (6,7). Ta c th da vo nng sut quay cc nh tnh hoc kim tinh khit. Ph UV: cu trc cephem cho 2 hp thu khong 260nm v 220nm. Ph IR: nh trng hp penicillin vng 1600-1800cm-1 l vng c trng nht. b) Tnh cht ha hc Tnh khng bn ca vng beta-lactam S tn cng ca cc tc nhn thn in t (An): cc baz m vng azetidin-2on, to ra nhng dn xut ca acid cephalosporic khng c hot tnh sinh hc. V d: cc baz (NaOH, KOH) m c to mui ca acid cephalosporic.
O R N O NuR3 COOH H N H H S O AN R O Nu N H N H H O S H R3 COOH
+

H N

H H

S R3 COOH

R N O Nu H

Cc cephalosporin bn trong mi trng acid. Tnh acid Do cha nhm COOH nhm C4, cc cephalosporin th hin nh cc acid , bt bo ha kh mnh, c th: - To mui: thng l mui Na, c s dng di dng thuc tim hoc dung dch ung v tan c trong nc. - To cc este l tin cht cho mt s khng sinh cephalosporin bn tng hp.

GVHD: TS. on Ngc Nhun

Tng hp khng sinh cefixime

2011

Phn ng ca nhm th R3 S thay i nhm th R3 to ra nhiu cephalosporin bn tng hp khc nhau. V vy, phn ng ti cc nhm th ny rt quan trng. Phn ng chui acilamino Bn cht ca chui acilamino 7- xc nh tnh bn ca cephalosporin. Mt s cn tr khng gian to ra gn vng -lactam th khng thun li cho tc dng ca -lactam v v vy c tc dng bo v.

1.2.3. C ch tc dng ca cephalosporin[1]

Cc cephalosporin c tc dng c ch qu trnh sinh tng hp thnh t bo vi khun tng t nh cc Penicilin. c ch tng hp thnh t bo vi khun bng cch lm gin on tng hp peptidoglycan, dn n gim s n nh mng t bo vi khun v ly gii t bo vi khun.

1.2.4. nh lng cephalosporin[1]

Phng php Iod: acid cephalosporin c c sau khi thy phn cephalosporin bng kim s c oxy ha nh lng bng I2 trong mi trng acid acetic, lng d ca I2 s c nh lng bng Na2S2O3 vi ch th h tinh bt. Phng php mi trng khan: sau khi ha tan trong DMF, nhm COOH v tr 4 s c nh lng bng dung dch chun metilat natri, im tng ng xc nh bng o th hoc bng ch th mu. Phng php ha l: nh lng bng ph UV vi mu chun i chiu hoc bng HPLC.

1.2.5. Phn loi cephalosporin[2]

Da vo kh nng khng betalactam v kh khng khun, c th chia cc cephalosporin lm 4 th h: Cephalosporin th h 1: Ph khng khun : cu khun Gram(+), Gram(-), mt s trc khun Gram(-), mt s t cu khun. Cephalosporin th h I khng th hin u im no hn so vi phenicillin. V d: cephalothin, cephalexin, cephaloridin Cephalosporin th h 2: Ph khng khun: cu khun Gram(+) nh th h 1, tc dng mnh hn vi cc cu khun Gram(-) v vi khun ym kh. Kh nng khng beta-lactam tt. V d: cephamandol, cefuroxim, cefoxitin Cephalosporin th h 3: Ph khng khun: Li im ca cephalosporin III ch hot tnh mnh trn vi khun Gam(-), kh nng khng beta-lactam tt, trn GVHD: TS. on Ngc Nhun 5

Tng hp khng sinh cefixime

2011

chng Gam(+) v him kh c hot tnh ging cc th h trc. V d: cefoperazon, cefotiam, cefixime Cephalosporin th h 4 : c ph khng khun rng hn th h 3, nht l tc dng mnh vi chng Gram(-) nn hiu qu iu tr cao hn so vi cc th h trc. Kh nng khng beta-lactam tt. V d: cefepim..

1.3. Cefixime 1.3.1. Gii thiu v cefixime[4]

Cefixime l khng sinh cephalosporin th h III, dng ung hoc tim. Hot tnh mnh trn vi khun Gam(-). Cefixime tn ti cc dng mui khc nhau, thng l mui trihidrat. N ln u tin c cng b ti Hoa K. Pat. S 4.409.214 ca tng cng ty Fujisawa, Nht Bn. Cng thc ha hc: acid 7-[2-(2-amino-4-thiazolil)-2-(carboximetoxiimino) acetamido]-3-vinil-3-cephem-4-carboxilic. Cu trc phn t:
S H2N N N O N H O COOH COOH O H H N S CH2

Cng thc phn t: C16H15N5O7S2 Khi lng phn t: 453.45 g/mol Nhit si: 218-225 C ha tan trong nc: 55.11 mg/L Dng tn ti: dng bt, rn, trng hoc mu vng nht. [3] Tn thng mi : SUPRAX.

GVHD: TS. on Ngc Nhun

Tng hp khng sinh cefixime

2011

1.3.2. Hot tnh ca cefixime Hot tnh dit khun ca cefixime l kt qu ca s c ch tng hp vch t bo. Cefixime n nh cao vi beta-lactam v kt qu l nhiu vi khun khng vi penicillin v mt s cephalosporin do s hin din ca beta-lactam c th nhy vi cefixime. Tuy nhin trn vi khun Gram(+) th tc dng km hn penicillin v cephalosporin th h I. 1.3.3. Cng dng ca cefixime Cefixime c s dng iu tr nhim khun nh vim ph qun, vim amian, vim tai, nhim trng da, bnh lu, v nhim trng ng tit niu, nhim trng mi, vim tai gia, vim xoang, nhim trng thn, tit niu v nhim trng ng mt cp tnh,... 1.3.4. Dc ng hc[3] Ch c khong 4050% liu dng c hp th qua ng tiu ho. S hp thu cefixime khng b thay i ng k khi c thc n. Cefixime dng dung dch c hp thu tt hn dng vin. Thi gian bn thi l 0,82 gi. Khong 20% liu dng (tng ng khong 50% liu hp thu) c o thi di dng khng i trong nc tiu trong vng 24 gi. 1.3.5. Thn trng v triu chng khi s dng thuc[3] Thn trng khi s dng cefixime nhng bnh nhn b suy thn nng, nhng ngi qu mn cm vi cc thuc cephalosporin khc, nhy cm vi penicillin, bnh nhn c tin s bnh ng tiu ha c bit l vim i trng. Khng dng cho tr di 6 thng tui, khng nn s dng thuc i vi ph n c thai v cho con b. Cc ri lon ng tiu ha : tiu chy, bun nn, au bng, i ma v to bn, vim i trng mng gi. Phi ngng s dng nu xy ra tiu chy trm trng. H thn kinh trung ng: nhc u, chong vng. Phn ng qu mn: cc d ng bao gm ni mn, nga, m ay, st, au khp. Cc phn ng ny thng gim i khi ngng iu tr. Huyt hc v ha hc lm sng : Gim tiu cu, gim bch cu v tng bch cu i toan. Cc triu chng ny t xy ra v t hi phc. Cc tc dng ngoi khc : cc phn ng c th c khc bao gm nga vng sinh dc v vim m o.
[3]

[3]

GVHD: TS. on Ngc Nhun

Tng hp khng sinh cefixime

2011

Chng II: TNG HP CEFIXIME

2.1. Quy trnh tng hp cefixime c bn i t (7-AVCA)[4]
2.1.1. Quy trnh tng qut
Bandi Parthasaradhi v cng s a ra quy trnh tng hp trihidrat cefixime qua 2 bc c bn, n gin, thu c trihidrat cefixime c tinh khit cao (99,9%), cc ha cht s dng trong tng hp khng mang tnh c hi. Hiu sut qu trnh tng hp: 62-64%. Sng ch ny s dng NaOH bc thy phn mui este ci thin c mu sc, lm cho tan ca cefixime thu c t qu trnh ny cng c nng cao. Thi gian thc hin thy phn phi t hn 30 pht, tt nht l t 5-20 pht, v khi thc hin qu lu mu sc ca cefixime khi hnh thnh b nh hng v c s hnh thnh cc tp cht khng mong mun. Quy trnh tng hp cefixime chia lm 2 bc: Bc 1: Acid 7-amino-3-vinil-3-cephem-4-carboxilic (7-AVCA) (I) c phn ng vi 2-mercapto-1,3-benzothiazolil-(Z)2-(2-aminothiazol4-yl)2-(metoxi carbonil)-metoxiimino acetat mt dn xut acid thiazolil acetic (II) trong dung mi hu (nh tetrahidrofuran, aceton, dimetilsulfoxid (DMSO), v mt s dung mi khc, tt nht l tetrahidrofuran) v nc 0-15C trong s hin din ca 1 baz nh trimetilamin, trietilamin hoc tributilamin. Bc 2: Cho acetat etil hoc diclorometan (acetat etil tt hn) vo khi sn phm tch lp, tin hnh chit thu lp nc, gi nhit khong 0-15C, tt hn khi duy tr ti 0-10oC. Nu c cht khng ha tan trong hn hp thu c, cn lc loi b. sau , acid 7-[2-(2-Amino-4-thiazolil)-2-(metoxicarbonilmetoxiimino)acetamido] -3-vinil-3-cephem-4-carboxilic (III) dng mui vi trietilamin hin din trong lp nc, c thy phn bng cch s dng mt hidroxid kim loi kim nh NaOH, KOH (NaOH tt hn). Nhit thc hin thy phn khong 0-15C, tt nht l 010C, thc hin thy gii t hn 30 pht, tt nht l t 5-20 pht. Thm mt axit ngay sau khi hon thnh phn ng thy phn iu chnh pH khong 4,5-8,0 (tt hn 4,5-6,0) ti 30-35oC. u tin s dng acid clohidric hoc acid sulfuric. Cefixime kt tinh bng cch iu chnh pH ca dung dch xung khong 2,0-3,5 vi acid v lm lnh thu c cefixime di dng trihidrat.

GVHD: TS. on Ngc Nhun

Tng hp khng sinh cefixime

2011

H H H2N N O

S CH2 COOH
+

S H2N N

O S N O

N S

Tetrahidrofuran (THF) + H2 O toC= 0-10oC

(I)

(II)

COOR1

S H2N N N
(III)

O N H O O

H H N

S CH2 R2 NH+ R3 R4
baz: N

R2 R3 R4

COOR1 O

+ Acetat etil Hn hp tch lp, chit thu lp nc + than hot tnh, lc. + NaOH, < 30 pht, toC= 0-15oC +HCl, pH=4.5-8.0, toC=30-35oC Lc b b rn, + HCl: pH=2.0-3.5 Khuy, lm lnh, lc thu sp
(IV)

S H2N N N

O N H O O

H H N

S CH2 COOH .3 H2O

COOH

Trong : R1: alkil ngn (C1-C4). u tin: R 1: metil hoc etil. R2, R3 v R4 c lp vi nhau i din cho hidro, alkil (C1-C4), cicloalkil (C5-C6), aril (C6-C12) tt l phenil. Nm 2004, Pandurang Balwant Deshpande v cng s cng a ra quy trnh tng hp cefixime ci thin hn v mu sc v ha tan ca cefixime. Quy trnh ny ging nh quy trnh ca Bandi Parthasaradhi (nm 2008) c trnh by GVHD: TS. on Ngc Nhun 9

Tng hp khng sinh cefixime

2011

trn, ch khc l s dng thm NaHSO3 giai on tch chit hp cht este acid 7-[2(2-Amino-4-thiazolil)-2-(metoxicarbonilmetoxiimino)acetamido]-3-vinil-3-cephem-4carboxilic (III), sau khi thy gii bng NaOH xong acid ha bng HCl thm aceton vo qu trnh tch lp d dng hn [5]. Hiu sut thu c bc 2 l 90.5%.

2.1.2. Quy trnh thc nghim

Tetrahidrofuran (340ml) c cho vo (350ml) nc v lm lnh n 4oC. (25g) Acid 7-amino-3-vinil-3-cephem-4-carboxilic (7-AVCA) v (55g) 2-mercapto1,3-benzothiazolil-(Z)-2-(2-aminothiazol-4-il)-2-(metoxicarbonil)-metoxiimino acetat c thm vo 4oC. Sau , thm t t vo khi phn ng hn hp ca (12g) trietilamin v (350ml) tetrahidrofuran trong 2h 4oC. Tip tc khuy trong 4h v duy tr nhit ny. Thm vo (250ml) acetat etil, thc hin lc v ra li bng (100ml) acetat etil. Lp nc tch ra, thc hin chit thu lp nc. S dng (350ml) acetat etil ra sch lp nc thu c 14oC. Lp hu c c chit bng (100ml) nc. (2.5g) than hot tnh c cho vo phn nc mi chit c 25oC, khuy trong 30 pht. Tin hnh lc v ra phu lc bng (300ml) nc lnh 0oC. Phn nc ny c cha 7-[2-(2-amino-4-thiazolil)-2- (carboximetoxiimino)acetamido]-3-vinil-3-cephem-4carboxilictrietil amin. Thy phn mui este thu c sau lc bng (13,5g) NaOH trong (75ml) nc, khuy trong 15 pht 0-8oC. Sau , thm vo (30ml) acid HCl (1:1) iu chnh pH n 4.8-5.2. Thm (5g) than hot tnh vo 15-20oC, khuy trong 15 pht. Lc v ra sch bng (166ml) nc. Sau , acid etilendiamintetraacetic, (EDTA, 0.25g) c thm vo 20-25oC. Nhit c nng ln 35oC, pH c iu chnh ln 2.5 bng HCl (1:1), khuy trong 30 pht 35oC. Sau h nhit xung 30oC. Tip tc khuy trong 3h 30-32oC. Sau lm lnh n 2oC. Khuy trong 1h 2-5oC. Cht rn kt tinh c lc, ra sch 3 ln vi nc lnh (mi ln 110ml) sy kh, thu c trihidrat cefixime (40g) tinh th trng. Lng nc chim 11.1%, tinh khit HPLC: 99.9%. Chy sc k kh (GC) khng pht hin tetrahidrofuran v acetat etil.

2.2. Quy trnh tng hp cefixime thng qua mui alkil hoc aril-sulfonat cefixime[7]
2.2.1. Quy trnh tng qut
Theo Walter Cabri v cng s cho rng: dn xut ca cefixime c cng thc (III) l cht rn v nh hnh, ha tan cao trong dung mi hu c. Nn n phi c c lp chit bng cch s dng dung mi vd: ete. Tuy nhin iu ny thc y s kt tinh ca cc sn phm ph khng mong mun. GVHD: TS. on Ngc Nhun 10

Tng hp khng sinh cefixime

2011

R3 N H

S N N
(III)

H H H S N N O COOR2 COOR4 CH2

Vic s dng acid sulfuric (WO 98/31685) trong qu trnh loi b nhm bo v gn trn gc acid ca dn xut cefixime trong cc quy trnh tng hp trc s lm kt ta mt lng mui sulfat cefixime ( ha tan km) lm cho trihidrat cefixime thu c c tinh khit khng cao. Mc khc, khi s dng acid sulfuric c kh nng acid s ht mt phn nc ca dung dch phn ng lm gim tc phn ng, ngn chn s chuyn i hon ton thnh cefixime. ng dng iu ny, sng ch ny s dng acid sulfuric kt tinh ht dn xut (III) thnh sulfonat cefixime (IV) vi tinh khit cao, sau chuyn i thnh trihidrat cefixime (V) vi hiu sut cao hn v khng cn chit tch hp cht (III) ra khi dung mi tng hp n. V vy, sng ch ny d p dng trong quy m cng nghip. Walter Cabri tin hnh nhiu th nghim khc nhau trn nhng dung mi khc nhau, thay i khi lng cc cht phn ng. Kt qu thu c cefixime c tinh khit cao. Hiu sut khong 74-76%. Acid alkilsulfonic:acid metansulfonic, etansulfonic, trifluorometansulfonic, s dng tt nht l acid metansulfonic. Trong : R l 1 alkil mch ngn (C1-C6). Acid arilsulfonic: acid benzensulfonic, p-toluensulfonic, mesitilen sulfonic. Trong : R l 1 nhm c cha vng benzen hoc naphthalen. C acid alkil hoc arilsulfonic c th cha cc nhm halogen (F,Cl, Br), hidroxi, carboxi, nitro, sulfo, metil. Quy trnh tng hp trihidrat cefixime gm 3 bc: Bc 1: Bt u t mt dn xut acid 7-amino-3-vinil-3-cephem-4carboxilic (7-AVCA) cng thc (I) phn ng vi dn xut ca acid 2-(aminothiazol-4il)-2-(carboximetoxiimino)acetic cng thc (II). To thnh acid 7-[2-(aminothiazol-4il)-2-(carboximetoxiimino)acetamido]-3-vinil-3-cephem-4-cacboxilic dn xut ca cng thc (III).

GVHD: TS. on Ngc Nhun

11

Tng hp khng sinh cefixime

2011

Bc 2: Sau , acid 7-[2-(aminothiazol-4 -il)-2-(carboximetoxiimino)acetamido]-3-vinil-3-cephem-4-carboxilic (III) c phn ng vi RSO3H l mt acid akil hoc aril-sulfonic trong dung mi hu c v d nh mt este (acetat etil, acetat metil, format etil hoc carbonat dimetil), mt xeton (aceton, metil etil ceton hay metil isobutil ceton), mt nitril (acetonitril hoc propionitril), mt ete (tetrahidrofuran), hoc cc dung mi khc (diclorometan hoc hn hp ca chng), nu mun c s hin din ca mt ng dung mi v d axit hu c (chng hn nh acid formic, acid acetic hoc propionic). Nhit phn ng c th nm trong khong t -20C-50C, tt nht l t 0C n 40C to thnh tinh th mui alkil hoc aril-sulfonat ca cefixime (IV). Metansulfonat cefixime thu c c hm lng nc l 0,5% hoc thp hn sau khi sy. Mui ny trong iu kin m bnh thng, c xu hng ti hidrat ha cho n khi n nh hm lng nc tng ng. Thng dng monohidrat metansulfonat cefixime. Bc 3: Cc hp cht (IV) c lc hoc ly tm thu tinh th ri chuyn thnh cefixime (I) bng cch phn ng vi mt amin, amoniac, kim (v d natri hoc kali) cacbonat, bicarbonat, hydroxit, photphat. Sau , loi b cc nhm bo v theo acid chng hn nh benzhidril hoc tert-butil bng cch s dng acid trifluoroacetic hoc nhm triclorua anisole, acid clohidric hoc acid metansulfonic hoc acid p-toluensulfonic. Dung mi c s dng c th l nc, hoc hn hp nc v ru (nh metanol, etanol, propanol, butanol), ceton (chng hn nh aceton hoc metil etil ceton), hoc cc dung mi khc (nh tetrahidrofuran hoc acetonitril).

GVHD: TS. on Ngc Nhun

12

Tng hp khng sinh cefixime

2011

R3 N H

S N N
(II)

O z O COOR4
+

R1 N H O

H H N

S CH2 COOR2

(I)

R3 N H

S N
(III)

H H H S N N O COOR2 COOR4 CH2

Dung mi hu c nh acetat etil, THF + H2O. Lm lnh 2oC, Khuy

+ H2SO4, pH= 2.1 + dung mi hu c, 0-40oC. Tch, chit thu lp hu c. + dd NaOH long. Tch, chit thu lp nc.

+ dd H2SO4 dm hu c pH=2.1. tch chit thu lp hu c. 30-35oC. Lm lnh 2oC, kt tinh

O N H O O

H2N N N
(IV)

H H N

x RSO3H.nH2O

CH2 COOH

COOH

Amin, amoniac, carbonat natri

S H 2N N N O N H O COOH COOH O H H N S CH2 * 3 H2O

Acid + dm hu c

GVHD: TS. on Ngc Nhun

13

Tng hp khng sinh cefixime

2011

Trong : R1: -H hoc 1 nhm trimetilsilil R2: -H, trimetilsilil; tert-butil; p-metoxibenzil; p-metoxibenzil; 3,4-dimetoxibenzil R3: tritil; tert-butoxicarbonil; p-metoxibenziloxicarbonil. R4: tert-butil, p-metoxibenzil, 3,4-dimetoxibenzil Z l: -Cl, -S-mercaptobenzothiazolil, -O-P+(Ph)3Cl, -O-P(S)(OET)2, -O-P(O)( OET)2, OSO2Me, -O-SO2Ph-O-SO2-pTol, -O-COtBu, -O-C(O)OEt, -O-CHN+(CH3)2Clhoc-benzotriazol-1-il-3-oxid.

2.2.2. Quy trnh thc nghim tng hp metansulfonat cefixime

(11,25g) Acid 7-amino-3-vinil-3-cephem-4-carboxilic, acid 2-(aminothiazol -4-il)2-(tert-butoxicarbonilmetoxiimino)acetic S-mercaptobenzothiazol este (24, 18g) trong (400ml) EtOAc v (13,5ml) nc, TEA (13,5ml) c thm vo trong 15 pht, gi cho hn hp nhit t 20- 22C, khuy trn mnh cho n khi acid 7-amino3-vinil-3-cephem-4-carboxilic ht (HPLC phn tch). Sau khi hon thnh phn ng, nc c thm vo v pH c iu chnh ln 2,1 vi acid sulfuric pha long. Hn hp phn ng tch lp v lp nc c chit vi EtOAc. Nc c thm vo pha hu c chit c v pH c iu chnh n 7.0 vi dung dch NaOH. Lp hu c c tch ra v li c chit xut bng nc. Cc cht chit c t pha nc c thu gom li v thm vo EtOAc (150ml) v pH c iu chnh ti 2.1 vi acid sulfuric. Cc lp c tch ra, sau lp nc c chit vi EtOAc. Cc cht chit thu c t lp hu c c tp trung li v cho CH3CN (153ml) v HCOOH (5,5ml), MeSO3H (13,1ml) vo hn hp, gi nhit t 30C- 35C. Sau khi phn ng trong 1 gi (HPLC phn tch), hn hp c lm lnh ti 2C, sn phm c lc, ra sch bng acetonitril, sau sy kh thu c (23,11g) monohidrat metansulfonat cefixime.

2.3. Quy trnh tng hp cefixime thng qua mui tertoctilamin cefixime[6]
2.3.1. Quy trnh tng qut
Nm 2003, Martin Decristoforo v cng s a ra quy trnh tng hp cefixime mi l, thng qua mui tert-octilamin cefixime (IV). Qu trnh tng hp khng cn chit cch ly hp cht c cng thc (III) ra khi dung mi nn d thc hin trn quy m cng nghip. Martin Decristoforo thc hin nhiu quy trnh thc GVHD: TS. on Ngc Nhun 14

Tng hp khng sinh cefixime

2011

nghim vi khi lng ca cc cht phn ng khc nhau, thay th mt s dung mi trong bc chuyn tinh th mui tert-octilamin cefixime thnh trihidrat cefixime, thay th hp cht c cng thc (II) dn xut ca acid thiazolil acetic bng cc dn xut khc. Kt qu u cho thy tinh khit ca trihidrat cefixime thu c khong 96% hoc cao hn. Hiu sut ca qu trnh iu ch tert-octilamin cefixime khong 80%.
S

H H H2N N O

S CH2 COOH
+

H2N N

O S N O

N S

COOR1

+Tetrahidrofuran (THF) + H2O

(I)

(II)

S H 2N N N
(III)

O N H O O

H N

S CH 2

toC= 0-10oC
R2 R3 R4

baz: N

COOR 1 O

R2 NH+ R3 R4

+ Tertoctilamin trong dung mi hu c Sy kh thu sn phm H2N

S N N O O N H O COOH COOR1

H H N

S CH2 * H2N

CH3 CH2 CH3

(IV)

CH3 CH3 CH3

+ H2O Lm lnh 0oC

S H 2N N N
cefixime

+ dd NaOH long
O N H O O COOH COOH H H N S CH 2 .3 H2O

+ dd HCl long pH= 3.0

Trong , R1 l alkil mch ngn (C1-C4) GVHD: TS. on Ngc Nhun 15

Tng hp khng sinh cefixime

2011

2-mercapto-1,3-benzothiazolil-(Z)2-(2-aminothiazol4-il)2-(metoxi carbonil)-metoxiimino acetat mt dn xut thiazolil acetic acid (II) c th c tng hp bng phn ng ca acid 2-(2-amino-4-thiazolil)-(Z)-2-((aril-or-alkil)-oxicarbonil metoxiimino)acetic vi 2,2-benzothiazolil disulphid trong mt dung mi hu c, nh diclorometan trong s hin din ca mt phosphin, triphenilphosphin hoc mt phosphit v d nh trietil phosphit, c thc hin ti nhit phng. Hp cht (II) c th c thay th bng hp cht c cng thc:
S H2N N N O COOR1 R O

Trong : R: OP30 (Ph)3Cl31 , OP(S)(OR4)2 , Obenztriazol-1-il, S (2-metil-thiadiazol-5-il), SOCHN+(CH3)2Cl31 or -benztriazol-1-il-3-oxid.

2.3.2. Quy trnh thc nghim

Bc 1: Ly (32,3g) acid 2-(2-amino-4-thiazolil)-(Z)2-(metoxicarbonil metoxiimino) acetic, (1250ml) diclorometan, (39,5g) triphenilphosphin v (50g) 2,2'benzothiazolil disulphid c thm vo v hn hp c khuy 5 pht 20C. Sau , thm vo khi phn ng (25g) trietilamin. Bc 2: Thm vo hn hp thu c trong bc 1 (22g) acid 7-amino-3vinil-ceph-3-em-4-carboxilic, (12,5ml) nc v (10g) trietilamin. Khuy trn hn hp trong 2 gi 30-35C. Sau khi hon thnh phn ng (HPLC xc nh), thm vo hn hp thu c (25g) tert-octilamin trong (50ml) diclorometan. Thu sn phm kt tinh: acid 7-{2-[(2-aminothiazol)-4-il]-2-[(Z)(metoxi-cacbonil)metoxiimino]acetamido}-3vinil-ceph-3-em-4-cacboxilic trong hnh thc mt mui vi tert-octilamin. Sy kh sn phm. Hiu sut: 98,6%. Bc 3: Ly (5g) acid 7-2-[(2-aminothiazol)-4-il]-2-[(Z)(metoxicarbonil) metoxiimino]acetamido}-3-vinil-ceph-3-em-4-carboxilic di hnh thc mt mui vi tert-octilamin c ha tan trong (100ml) nc v lm lnh n 0C. Thm (7,7ml) NaOH 5M. Sau , thm vo (0.08g) acid HCl v (1.75g) than hot tnh. Khuy u. Tin hnh lc. Cho (50ml) nc v (100ml) etanol vo dung dch thu c sau lc, pH c iu chnh n 3.0 bng axit HCl 6N. Lm lnh trong 1 gi, acid 7-{-2-[(2aminothiazol)-4-il]-2-[(Z)(metoxicarbonil)metoxiimino]acetamido}-3-vinil-ceph-3GVHD: TS. on Ngc Nhun 16

Tng hp khng sinh cefixime

2011

em-4-carboxlic kt tinh di hnh thc trihidrat, sy kh thu sn phm (3,59g) dng bt tinh th mu trng. Hiu sut: 98,2%. tinh khit: (HPLC): 98,9%.

2.4. Phng php phn tch cefixime[11]

Nng Cefixime c xc nh bng sc k lng hiu nng cao (HPLC) s dng pha o vi u d tia cc tm. Ct l mt C18 Ultrabase (5-mm, 4.6 3150 mm). Pha ng l mt hn hp ca acetonitril v nc (13:100 v / v) c cha 1% acid percloric v 1% trietilamine. T l dng chy l 1,7 ml / pht. Cc bc sng pht hin 280nm (Shimatzu SPD6A,Touzart etMatignon, Php).

Kt lun
Cc phng php tng hp cefixime hin nay vi tiu ch: nhm to cefixime c cht lng tt hn v mu sc v ha tan. Trnh s dng cc ha cht c hi, qu trnh tng hp t hiu sut tt v n gin d thc hin. Cefixime c tinh kit cao. D thc hin trn quy m cng nghip. Khi tin hnh tng hp cefixime ta nn chn quy trnh tng hp thng qua mui tert-octilamin cefixime hoc thng qua mui alkil hay aril-sulfonat cefixime thu c hiu sut tt hn.

GVHD: TS. on Ngc Nhun

17

Tng hp khng sinh cefixime

2011

TI LIU THAM KHO

[1] DSCK1. Nguyn Huy Cng; Ha dc- Dc l; NXB Y HC; H Ni-2006; 220-224, 229-231. [2] PGS.TS. Hong Th Kim Huyn; Ha dc Dc l III; NXB Y HC; H Ni2007; 120-113. [3] Sanofi-aventis Canada Inc. 2150 St. Elzear Blvd. West Laval, Quebec H7L 4A8; Product Monograph SUPRAX; No. 142028; (25/11/2010). [4] Bandi Parthasaradhi, Kura Rathnakar v cng s; United States Patent Application Publication Process for the preparation of cefixime; US2008/0242858A1; (02/11/2008). [5] Pandurang Balwant Deshpande v cng s; United States Patent Application Publication Process for the preparation of cefixime; No: US 2004/0082560A1; (29/04/2004) [6] Martin Decristoforo, Johannes Ludescher v cng s; United States Patent Allication Publication Process for purification of cephalosporin derivative; US 2003/0208065A1; (06/11/2003) [7] Theo Walter Cabri, Marco Alpegiani v cng s; United States Patent Application Publication Process for the preparation of cefixime via alkyl or aryl-sulfonates; US 2005/0032771 A1; (10/02/2005). [8] Om Dutt Tyagi, Dnyandeo Rayho Rane v cng s; United States Patent Application Publication Process for the preparation of cefixime; No. US 2009/0227787A1, (10/09/2009) [9] Bi K Chu; tp ch Dc Hc S dng thuc khng sinh Thy in; S 41987. [10] Nguyn Khnh Thnh; Tp ch dc hc Tm hiu v khng sinh cephalosporin; S 4-1987. [11] Randal Lee Schapaugh v cng s; United States Patent Application Publication; Methods of measuring the dissolution rate of an analyte in a non- aqueous liquid composition; US 2004/0115837 A1; (17/06/2004).

GVHD: TS. on Ngc Nhun

18