TAP CHi HOA HOC T. 50(3) 323-326 T H A N G 6 N A M 2 0 1 2
NGHIEN CLTU QUY TRJNH T O N G HgP NHAN K H A N G SINH FLUOROQUINOLON ETYL 1-CYCL0PR0PYL-6,7-DIFLU0R0-1,4-
DIHYDRO-8-METOXY-4-OXO-3-QU1NOL1NECACBOXYLAT
Le Nguyen Thanh*, Tran Hiru Gidp, NguySn Th} Minh Hdng, Nguyin Vdn Hdng, ChSu Vdn Minh Vi?n Hda sinh bien, Vi?n Khoa hgc vd Cdng ngh4 Vi^l Nam
Din Tda sogn 30-11-2011 Abstract
Fluoroquinolone is an important class of antibiotic with a broad spectrum of activity against Gram-positive, Gram- negative and mycobacterial organisms as well as anaerobes. Particularly, moxifloxacin and gatifloxacin, fluoroquinolone antibiotics in the fourth generation, are under clinical phase for the treatment of multidrug resistant tuberculosis MDR-TB In this paper, we reported the synthesis of fluoroquinolone core, the key intermediate in the synthesis of moxifloxacin and gatifloxacin.
Keywords' Fluoroquinolone, antibiotic, moxifloxacin. gatifloxacin.
1. MO DAU
Quinolon la mgt hg khang sinh quan trpng, cd phd tdc dung rpng vdi cac vi khudn Gram (-), Gram (+), mycobacteria va vi khuan yem khi. Cde khdng sinh nay cd hieu qua dilu trj tot, dac bi?t td doi vdi cac vi khuan da khdng vdi cdc hp khang sinh khde.
Cac khdng sinh quinolon dugc su dung de dieu trj cho cac nhiem khuan dudng hd hdp tren va dudi, nhiem khudn dudng tieu hda, cde b?nh nhiem triing lay Ian qua dudng sinh dye, nhiem khuan dudng nieu, viem mang nao [I]. Ci Vi?t Nam, khdng sinh quinolon dupe chu y trong chuang trinh qudc gia, hien tai cd 2 khang sinh ciprofloxacin thi h? 2 va levofloxacin thi he 3 da dugc nghien cuu long hgp [2]. Hien nay, cac thudc khdng sinh thi h? 4 dugc chii y nhilu do cd dpc tinh thdp, sinh khd dyng cao va cd tac dyng khang khuan tdt vdi nhieu chiing vi khuan, kl ca cac vi khuan da khdng cac thuoc khang sinh quinolon the he trudc.
H 1 J . J
Hinh I: Cdu true hda hgc ciia moxifloxacin va gatifloxacin
Ddc bi?t, gatifloxacin vd moxifloxacin (hinh 1) la hai . nghien
cuu tren lam sdng dl su dyng cho dilu trj lao da khdng thuoc [3]. Nhdn etyl l-cyclopropyI-6,7- difluoro-l,4-dihydro-8-metoxy-4-oxo-3-quinoline- cacboxylat Id hgp chat trung gian quan trpng de long hgp hai khdng sinh nay [4, 5]. Trong khudn kho bdi bao nay, chiing tdi thdng bao ket qud nghien cuu quy trinh tong hgp nhan etyl I-cycIopropyI-6,7-difluoro- l,4-dihydro-8-metoxy-4-oxo-3-quinoIinecacboxyIat su dyng phucmg phap Grohe-Heitzer.
2. THI/C NGHIEM 2.1. Thiet bi, boa chat
Sdc ki ldp mdng thuc hien tren ban mdng silica gel 6OF254 (Merck) va quan sdt dudi den UV, budc sdng 254 nm. Sdc ki cgt su dyng Merck silica gel 40 (mesh 70-230). Pho egng hudng tir hgt nhan dugc ghi tren mdy Bruker Avance 500 MHz vdi TMS lam chat npi chudn, dp dich chuyin hda hpe dugc bao cao theo so li?u ppm. Hda chat va dung mdi dupe mua tir nhung nhd cung cap nhu cdng ty hda chat Merck hay Aldrich vd sd dyng khdng qua tinh che.
Dich hiru ca dugc lam khd bdng natri sulfat khan vd cat cd chdn khdng sir dyng mdy eat quay chdn khong Buchi.
2.2. Thirc nghiem
Metyl 3-metoxy-2,4,5-trifluorobenzoat (2):
Ldm Ignh dung djch phan ting gom axit 3-hydroxy- 2,4,5-trifluorobenzoic (9,6 g, 50 mmol) vd
TCHH, T. 50(3), 2012
iodometan (28,2 g, 200 mmol) trong DMF (100 mL) den 0°C. Timg phka nhi ch& NaH (3,6 g, 150 mmol) (da rira qua v6i 10 mL n-hexan) ducyc cho vio dung djch phin rnig trong v6ng 30 phiit. Khu^y h6n hqrp phin ling i nhiet dO 0-5°C trong v6ng 18 gi6, sau d6 cSt lo?i dung m6i dvrdi ip sufe giim. 116a tan phAn cSn trong hSn hiyp nuAc-etyl axetat vi di6u chinh pH tdi 7 bing axit axetic. Rita djch httu co bing dung djch NaOH 0,5 N, vi mrdc, sau d6 lim kho vi cat lo?! dung mdi dudi ip suat giim d^ thu du(;-c sin phSm cSn thi^t 2 dudri d?ng diu. lli?u suit 95! 4.
'H NMR (500 MHz, CDCIj) S: 3,93 (s, 311, ester CHj), 4,05 (s, 3H, ete CHj), 7,47 (m, 1H).
Axil 3-nieto\y-2,4,5-trinuorobenTOic (3):
Khuay h6n hc;rp phin ling gom chat 2 (10 g, 45 mmol) vi 30 mL dung djch NaOH 1 N trong 50 mL metanol 6 nhi?t dO thirfifng trong vdng 3 gid. Sau d6, cat loai MeOH dudi ip suit giim vi rCra phin djch nudc bing n-hexan ( 2 x 1 0 mL) roi axit hda tdi pH
= 2,0 bing dung djch HCl 6 N. Lcjc liy ket tiia tao thanh roi rira bing nudc vi lim kho dudi chan khong de thu dugrc axit 3 dudi d ^ g chat rin miu tring (7 g, 76%). Diem ndng chay 14 116-118°C.
'H NMR (500 MHz, CDClj) S: 4,07 (s, 3H), 7,55 (m, IH).
3-Metoxy-2,4,5-trifluorobenzoyl clorid (4).
Dun hoi tuu dung djch phan Omg cua axit 3 (6,18 g, 30 mmol) vi thionyl clorid du trong vong 3 gid.
Luong thionyl clorid thira dugc loai bd bing chung cat d ap suit giim, thu dugc sin pham 4 Chat nay dugc sir dyng d phan ung ti6p theo khong cin qua tinh che.
Etyl (3-metoxy-2,4,5-trifluorobenzoyl)axctat (5): Lim mat dung djch phin irng gom kali etyl malonat (10,2 g, 60 mmol) trong axetonitril khan (60 mL) den nhiet dg 10-15°C. Them trietylamin (6,06 g, 60 mmol) vao dung dich phin img, ticp theo la cho magnesium clorid (7,14 g, 75 mmol) roi khuay dung djch d nhiet dg 20-25°C trong vdng 3 gid. Lim lanh dung djch phan irng xuong 0°C roi them tir tir 3-metoxy-2,4,5-trifluorobenzoyl clorid (4) (30 mmol), sau dd cho them 1 lugng trietylamin (0,6 g, 6 mmol) vao. H6n hgp phin img dugc khuay d nhi?t dg phdng trong vdng 18 gid roi co cat chan khdng de loai axetonitril. Cho toluen (50 mL) vao hon hgp va cat quay chan khdng. Cho them 1 lugng toluen (30 mL) vao hdn hgp va giir d nhiet dg 10-15°C. Cho dung djch HCl (13%, 75 mL) vio dung djch phin ling vi giu nhi|t dg khong vugt qua 25°C. Hon hgp phin irng lag pha. Tach lay pha hiiu co vi rira bang dung djch HCl 12%, sau dd rua bang nudc rdi cat
Le Nguyin Thinh vd c(iBg J lo(ii dung mdi dudi ip suit giim. C}n cdn 1^1 dirjc ket tinh trong etyl axclat de thu dugc sin phim 5 li hSn hgp kcto/enol cd tl H 3/1 (7,45 g, 90%).
'IINMR (500 MHz, C O a j ) :
diing cnol S: 1,33 (l, J = 7,0 Hz, 3H), 4,03 (s, 311), 4,26 (q, J - 7,0 Hz, 2H), 5,80 (s, IH), 7,40 (m.lll), 12,68 (5, IH),
dang xcto 5: 1,26 (t, 7 - 7,0 I Iz, 3H), 3,93 (d, J
= 4,0 11/, 211), 4,02 (s, 3H), 4,21 (q, J = 7,0 H2, 211), 7,47 (m, 111).
Etyl 2-( 2,4,5-trinuoro-3-mctoiybeiiioyl>3- cloxy acrylat (d) Dung djch phin iing bao gom chii 5 (7 g, 25 mmol) v i trictyl ortoformat (5,55 g, 37,i mmol) trong axetic anhydrid 40 mL dugc dun hoi luu trong vdng 22 gid. Sau dd, cit lo?i dung moi roi cho thfim mgt lugng toluene, r^i I9I cit loai diroi chin khdng dc thu dugc chat 6 dudi djng sin pham thd 7,9 g. Sin phim niy dugc sir dgng d phin irng ticp theo khdng cin qua tinh che.
Etyl 2-(3-nictoxy-2,4,5-trinuort>beiizoyl)-3- (cyclopropylamino) acn, lat (7): Hda tan sin phan 6 (7,9 g) trong 40 mL ElOH, lim l?nh xuong 5"C, roi nhd tir tir cyclopropylamin (2,13 g, 37,5 mmol) vio dung djch phan ung trong vdng 1 gid. Sau khi ket thiic, phin umg dugc khuay d nhi?t dg phong trong vdng 18 gid. Dung djch phan iing dugc chiet phan bo vdi nudc va etyl axetat. Tach liy pha hiiu CO va lim khd bing Na2S04, sau dd cat loai dung mdi dudi ip suit giam. Phan c§n cdn !?i dugc tinh che qua sic ki cgt thu dugc sin pham 7 (6,4 g, 75%) mp 57-59°C.
' H NMR (500 MHz, CDCI3) S: 0,85 (m, 2H), 0,93 (m, 211). 1,08 (t. J =1,0 Hz, 3H), 2,98 (m, 111). 4.01 (s, 3H),4,06(q,J=7,0Hz,2H),6,85(ni, 111), 8,20 (d, V = 14,0 Hz, 1H), 10,87 (b, 1H).
' H NMR (500 MHz. CDClj) S: 0,86 (m, 2H), 0,93 (m, 2H), 0,95 (t../ = 7,0 Hz, 3H), 2,97 (m, IH),
•1,01 (s, 3H), 4,06 ( q , y = 7,0 Hz, 2H), 6,99 (m,lH), 8,17 (d, IH), 8,21 (d, J = 14,5 Hz, IH), 9,47 (b, IH).
Etyl l-cyclopropyl-6,7-dinuoro-l,4-dibydn>- 8-mctoxy-4-oxo-3-quinoIinecacboxyIat (8), Dung djch phan irng gom chat 7 (6 g, 17,5 mmol) va KiCO] (9,65 g, 70 mmol) trong DMF (40 mL) dirijc dun ndng d 100°C trong 3 gid. Sau khi lim ngugi, phin irng dugc dd vao hdn hgp nudc di. Ket tinh 190 thanh dugc lgc, rira vdi nudc, lam khd de thu diii;":
chat 8 (4,3 g, 77%). Nhiet do ndng chiy d 183' 184°C.
'H NMR (500 MHz, CDCI3) <5: 1,04 (m, 2H), 1,19 (m,2H), 1,39 (t, 7 = 7.0 Hz. 3H), 3,97 (m, IH), 4,07 (s, 3H), 4,37 (q, J= 7,0 Hz. 2H), 8,03 (dd, J=
10,0 Hz; 8,8 Hz, IH), 8,59 (s, IH).
324
TCHH, T. 50(3), 2012
^COOH
Nghiin ciru quy trinh tdng hgp...
Sa do I: Quy trinh tong hgp nhan khdng sinh theo phuang phdp Grohe-Heitzer 3. KET QUA VA THAO LUAN
Nhan khang sinh fluoroquinolon cd the dugc tong hgp theo nhieu con dudng khdc nhau bang cdch su dyng cac phucmg phap Gould-Jacobs, Grohe- Heitzer, Gesner-Hayakawa vd Chu-Mitscher [6].
Chung tdi da lua chgn phuong phdp Grohe-Heitzer de nghien cihi quy trinh tdng hgp nhan etyl I-cyclopropyl-6,7-difluoro-l,4-dihydro-8-metoxy-4- 0X0-3-quinolinecarboxylat (sa do I).
Xuat phdt tir nguyen Ii?u ban ddu la axit 3- hydroxy-2,4,5-trifluorobenzoic (1), nhdm hydroxyl phenol vd acid ciia chdt 1 dugc metyl hda bang phan ling vdi metyl iod su dung baza NaH trong mdi trudng DMF. Lugmg Me! dugc sii dyng khoang 4 Ian ducmg lugng moi so vdi axit 1. Hieu suat phan ling la 95%. DU li?u phd NMR khdng djnh cdu true cua san pham khi xudt hien hai pic cua nhdm metyl este va metoxy vdng benzen d vj tri 3,93 va 4,05.
Tiep do nhdm este dugc thiiy phdn bang kiem trong mdi trudng metanol, sau do axit hda de giai phdng trd lai nhdm cacboxylic. Tren phd NMR tin hi?u nhdm metyl este d vj tri 3,93 khdng cdn xudt hi?n.
Nhdm cacboxylic cua hgp chat 3 dugc hogt hda bang phan iing vdi thionyl clorid tao thanh axyl clorid 4, chdt nay dugc sd dung d phdn irng tiep theo md khong cdn tinh che. Axyl clorid phdn iing vdi muoi kali malonat este trong dieu kien cd mdt cua MgCl2 vd trietylamin de tao thdnh hgp chat 5 dudi dang hdn hgp xeto/enol ti I? 3:1 vdi hieu suat cao.
Tren dii lieu phd proton NMR, tin hi^u cua 2 hidro ciia dgng xeto xuat hi$n d vj tri 3,93 ppm, trong khi do d dgng enol, tin hipu proton xuat hien d vi tri 5,80 va 12,68 ppm. Viec su dyng mudi kali malonate este d nhi$t dd thudne rdt thuan lai cho viec tdng hgp d khoi h_,',. ., ,, - UI • .'.--'- .•.-,'. ' ! ; f d y n g
muoi liti ciia axit malonat nhimg phdn umg can dien ra d nhi?t dg thap (-78"C den -SCC), khdng phii hgp vdi vi?c san xuat, dieu chi d lugng ldn [7]. Dun ndng 5 vdi trietyl ortoformat trong dieu kien hdi luu vdi dung mdi axetic anhydrid cho hgp chat 6. Sau khi cat logi bd dung mdi axetic anhydrid, can cdn lai dugc sir dung d phdn ung tiep theo ma khdng can tinh che. Can 6 dugc phdn ung vdi cyclopropyl amin trong mdi trudng etanol dl tgo thdnh hgp chdt 7 vdi hieu suat cao 75% qua 2 budc. O giai doan nay san pham 7 thu dugc la hdn hgp ddng phan E/Z vdi ti 1?
3/1. Nhan quinolone 8 cCia moxifloxacin dugc dieu chi bdng phan iing ciia hdn hgp E/Z 7 vdi K2CO3 trong dung mdi DMF, dun ndng trong vdng 3 gid d nhi|t dp lOO^C. Hi^u suat cua phan iing la 77%. 0 phdn ling nay, chiing tdi da sit dyng baza K2CO3 Id hda chat re tien de thay the cho NaH nhu trong quy trinh ma Sanchez vd cpng su dd bdo cao. Nhu vay chung tdi thu dupe san pham 8 tu nguyen li^u ban dau vdi hi?u suat khoang 38%.
4. KET LUAN
Da tdng hgp thanh cdng nhdn khan^ sinh fluoroquinolon qua 6 budc vdi hi?u sudt tdng Id 38%. Vi?c nghien ciru cdi tien quy trinh de nang hieu suat hay tong hgp nhdn khdng sinh theo phucmg phdp khdc dang dugc nghien ciiu. Them vao dd, quy trinh tong hgp khang sinh moxifloxacin vd gatifloxacin tii nhdn fluoroquinolon nay se dugc chiing tdi cong bd trong nhitng bao cao tiep theo.
Ldi cam ffn: Cong trinh ndy dugc thyc hi?n trong khudn khd de tdi cdp ca sa Vi^n Hoa sinh bien, Vi^n Khoa hgc vd cong nghe Viet Nam ndm 2011 vd di tdi "Nghien cuu qui trinh cong ngh^ long hap thuoc
TCHH.T. 50(3),2012
khdng sinh fluoroquinolon the he mii Moxifloxacin "
thu0c chitang trinh "Nghien cieu khoa hoc cdng nghe trong diitn quoc gia phdt trien cdng nghiep hoa ditcfc den ndm 2020 " do B^ cdng Ihuang cap kinhphi, md so de Idi CNHD.DT. 038/12-14.
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