Duong NghTa Bang vd Dtg Tap chi KHOA HOC & CONG NGHE 128(14): 61 -64
NGfflEN CUtJ TONG HOfP MOT SO DAN XUAT QUINOLIN TIT 3-CLO-2-METYL ANILIN
Duong Nghfa Bang' , IVguyln f)ang Due', Hoang Lam', Vu. A. Sayapin^ V. N. Komissarov^, V.N. Minkin^
Trudng Dai hoc Khoa hoc - DH Thai Nguyen.
• Vien nghien ciru Vgl ly vd Hoa hgc hint ca thuQC trudng Dgi hoc Southern Federal TOM TAT
Tren thj trudng hi?n nay dang luu hanh nhi6u loai thuoc co thanh phtin chinh chiia hf quinolin.
Trong s6 do c6 nhii'ng loai thuoc rat quan trpng nhu Saquinavir la mpt trong nhung chit trc che virut HIV hieu qua nhat hien nay, Chinh vi vay, viec nghien ciiu tong hgp cac hup chat co chira he quinolin dugc cdc nha khoa hgc trong va ngoai nude tap trung nghien cuu manh me trong thdi gian gan day. Npi dung bai bao sir dyng phuong phap Conrad-Limpach de t6ng hop mpt s6 din xuat quinolin mdi tir 3-clo-2-metylanilin, Bai bao the hien ro phuong phap thuc hi6n phan iing tong hgp, phucmg phap tinh ch6 san phlm va dSc biet la phuang phap xac djnh tinh chit vat ly cua san pham nhu nhiet d6 nong chay. Cau Uiic ciia cac chat san pham dugc tac gia chiing minh bang phuong phap ph6 hi6n dai 1^ 'H-NMR.
Tu' kh6a: Quinolin. 3-chloro-2-methylanllin. qulnolon, qulnin, sopcaln, plasmocin, saquinavir.
Conrad-Limpach. . MO DAU
Nhiing hgp chat hiJu co cd chua he quinolin, thudng the hien cd hoat tinh sinh hgc da dang.
Nhieu hgp chat da dugc sir dung lam thanh phan chinh trang mgt sd loai thudc luu hanh tren thi tru'diig. Quinin (thudc chdng sdt ret), Sopcain (thuoc gay me), plasmocin va acrikhin (thudc chdng sdt ret)[l], Saquinavir la mgt trong nhifng chat ire che virut HIV hieu qua nhat hien nay [2]. Chinh vi vay trong nhii'ng nam gan day nhieu nha khoa hgc trong nude cung nhu iren the gidi lap trung manh me vao viec tdng hgp cung nhu nghien ciiu cau true va hoat tinh sinh hgc cua chiing.
Trong bai bao nay chiing tdi thong bao \h qua trinh tdng hgp mgt sd dan xuat mdi ciia quinolin tir 3-clo-2-metyianilin.
E-mail [email protected]
THUC NGHIEM
Cdc dan xudt m&i cua quinolin duac tong h(>p
Quy trinh tong hap 7-clo-2,8-dimetylquinolin- 4(}H)-on
Cho 22 ml (0, lmal)3-clo-2-metylanilin vao binh ndn dung tich 200ml. them 50 ml elylaxetoaxetatat va vai gigt HCI dac lam xuc tac. Sau khoang 30 phiit khi thay nhiJng gigt hoi nude ngung tu tren thanh binh chung ta cha them khoang 15 g Na2S04 de hut nude.
Hdn hop giil d nhiet do phdng khoang 12 gid, sau dd dugc chuyen sang binh cau 3 cd. Do them vao binh khoang 60 ml PPA ( Poli Axil Photphonc). Lap them sinh han, nhiet ke va may khuay. Dun ndng lir lir Idi khi hdn hgp d nhiet do 140° C thi bat dSu linh gid. Giu nhiet do ciia hdn hgp trong khoang 140-150 "C 61
Duong NghTa Bang vd Dig Tap chi KHOA HOC & CONG NGHE 128(14), 61 trong thdi gian 2h. Hdn hgp de ngudi va rot
sang cdc thuy linh dung tich 1 lit cd chiia san 0,5 kg H2O da. Trung hoa hdn hgp bang dung djch NaOH 40% cho 3%n mdi trudng trung tinh. Lgc ket tiia, rua bang nude ndng, say khd, ket tinh lai bang ancol isopropylic thu duoc 37,1 g (H=83,8%) tinh thg mau vang nhaltne = 22rC-223°C
Quy trinh long hop 4,7-diclo- 2,8- dlmetylquinolin
Diing pheu nhd gigt them tirng phan nhd 120 ml POCl.1 vao binh ciu 2 cd dung lich 250ml chua 37,1 g quinolon 5 cho tdi khi quinolon 5 tan het. Lap sinh ban hdi luu va dun sdi nhe trong vdng 2h. Hdn hgp dugc lam ngudi, chuyen til' tir sang cdc thuy linh dung tich 1 cd chiia s5n 0,5 kg H2O da. Trung hoa hdn hgp bang NaOH 40% den mdi trudng trung tinh, Lgc lay ket tiia, say khd, tinh che qua cot sac ki chua Silica gel bang dung mdi CHCh. Thu duoc 30,5 g (H = 82,2%) tinh the mau trSng vditn.=102-104''C
Quy trinh tong hgp S-nitro - 4,7-diclo-2,8- dimetylquinolin
Hda tan 33,1 Ig (0,03mol) quinolin 6 vao 25ml HjSO^d nhiet do tir 10-15°C Dung djch dirge lam lanh tdi -5°C va them tirng gigt hdn hop gdm 9ml H3SO4 (dac) va 9ml HNO3 (dac). Giii' nhiet dp trong thdi gian phan ung khong qua -S°C Thu bd he lam lanh, khuay deu dung djch d nhiet dd 20-25''C trong thdi gian 3h. Dung djch dugc trung hda bang NaOH 40% . Lgc lay ket tiia rua bang nude am, lam khd, tinh che bang phuo'ng phap sac ky col (CHCls/silica gel), K6l linh lai bang ancol isopropylic thu duo'c 20,74 g (H-62,6%)) tinh the mau vang nhat vdi tnc - 109-111 "C.
Pho NMR - IH thu'c hien tren may "Bruker- Advance 500 MHz" tai Vien Hda hgc, Vien Han lam Khoa hgc va Cdng nghe Viel Nam.
Nhiet dp ndng chay thuc hien trong 6ng capila do trong glixerol.
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KET QUA VA THAO LUAN
Cd rat nhigu phuang phap tdng hop quinolm, nhung trong dk lai nay chiing loi chon phuang phap tdng hgp Conrad-Limpach (tuong tu phuang phap Combes) la di tii' dan xuat 3- clo-2-melyl anilin do phan ung xay ra trong digu kien don gian, phii hgp vdi dieu kien phdng Ihi nghiem.
Dau tien dan xuat 3-clo-2-melylanilin phan li'ng vdi elylaxetoaxetatat trong dieu kien xiic tac axit d nhiet do phdng ta thu duoc san pham cua phan ung ngung tu theo so do 2 [4,5], Soda 2:
C'HjOH, ^U C CH,COCHjC0OC;H., — ~
Lugng nude thoat ra sau phan ung la rat Idn, chiing la cd the nhin thSy cac gigt nude ngung tu tren thanh binh. Luong nude nay se can trd lien do phan img va cd kha nang lam giam hieu xuat phan u'ng. Chinh vi vay, tac gia da sir dung Na2S04 de hiit nude, lam khd hdn hgp.
San pham ciia phan ung ngung tu dugc vdng hoa trong axit polipholphoric (PPA) trong dieu kien dun ndng d nhiet do khoang 140° C.
Kel qua phan irng thu dugc 7-clo-8- metylquinolin-4(l/:/)-on theo so do 3.
S o d d 3 . CjHiOH,, .J.O
^^ PPA Ho-no'c
Quinolon dugc d o hoa bang POCI3, phan irng xay ra khi dun sdi hdn hgp trong vdng 2 gid thu dugc san pham cudi ciing la 4,7-diclo- 2,8-dimetylquinolin. D6 phan irng dat hieu suat cao thi quinolon phai kho, vi POCI3 bi thiiy phan manh lam giam hieu suat phan irng chinh.
So do 4:
Duong NghTa Bang va Dtg Tap chi KHOA HOC & CONG NGHE 128(14): 61 -64 Sau phan ung, san pham duoc tinh che bang
phuong phap sac ki cgt va dugc xac djnh cau triic bang phd cdng hudng tir hat nhan ' H NMR (ket qua theo bang I).
Bang I: Tin hieu 'H-NMR (5, ppm vdJ. Hz) ciia cdc dan xudt quinolin thu duac Hop
ch^t 4 5
2- C H , 2,71 2,76
8- C H , 2,85 2.91
3-H 7,35 7,48
5-H 7,95 (J-8,5)
6-H 7.52 (J=8,5)
7,70 Phd cdng hudng 'H NMR cho thay: 2,71 (s, 3H, S'-CH.,) la dac trung ciia -CH.i; 2,85 (s, 3H, 2-CH.,) la dac trung ciia -CH,; 7,35(s, 1H,3-H) la dac trung ciia -CH nhan thom;
7,51 (d, IH, 6-H, J=8,5) la dac trung cua nhdm -CH nhan thom the octo-oclo ; 7,95 (d, IH, 5-H, J=8,5) la dac trung nhdm -CH the octo-oclo. Til' nhii'ng dir kien ve cac phd ghi dugc chiing tdi xac djnh dugc cau tao ciia chat tdng hgp dugc la diing nhu cong thii'c cCiaS da du kien.
Tir quinolin 5 tiep tuc thuc hien phan ung nitro hda. Theo tai lieu [3], sir phan bd mat do electron tren he quinolin (theo hinh 1):
Hinh 1: Mat do electron tren he quinolin Dua vao mat dp electron ta dl dang du doan phan ling nitro hda xay ra d cac vj tri sd 5 va 8. Tuy nhien, vi tri sd 8 da cd nhdm metyl chiem chd nen phan irng nitro hda quinolin xay ra chii y6u d vj tri 5 (Iheo sa dd 5).
Sodd5:
Phd cdng hudng IH NMR cho thay: 2,76 (s, 3H, 8'-CH3) la dac trung ciia nhdm -CH3;
2,93 (s, 3H, 2-CH3) la dac trung cua nhdm - CH3; 7,48 (s, IH, 3-H,) la dac trung cua nhdm -CH nhan thom; 7,70 (s, IH, 6-H) la dac trung ciia -CH nhan thorn. Dac biet la su bien mat ciia vach pho ciia Hidro d vj tri so 5
so vdi chat 4 chung td nd da dugc thay the bang nhdm nitro. Tii' nhirng dtr kien do chiing tdi xac dinh dugc cau tao ciia chat tdng hgp dupe la diing nhu cong thirc ciia 7 da du kien.
Cac quinolin 4 va 5 la nhfhig hgp chat cd trien vgng rat Idn trong viec sir dung lam chat dau trang tdng hgp hiru co theo nhiing hudng sau:
- Chat 4 va 5 deu cd nhdm CH.i d vi tri sd 2, day la nhdm metyl boat dgng hda nen cd the sir dung vao cac phan irng ngung tu vdi nhdm cacbonyl de tao ra nhirng hop chat mdi.
- Chat 4 va 5 deu cd nguyen tir CI d vj tri sd 4 va sd 7, O vj tri cua CI chiing ta cd the thay the nd bang nhimg nhdm khac nhau, dac biet viec thay the nguyen lu d o bang cac nhdm amin cd y nghTa rat Idn trong tdng hgp hii'u co, - Nhdm Nitro d chat 5 cd the de dang bj khu thanh nhdm NH3. Nd md ra mgt hudng rat quan trgng trong viec phat trien tdng hgp cac hgp chat mdi tii' hgp chat nay.
KET LUAN
Bang phan irng Conrad-Limpach, phan irng d o hda, phan ling nitro hda, chung tdi da thu dugc 02 dan xuat rat quan trgng ciia quinolin.
Day la 02 quinolin hoan loan mdi, chua dugc cong bd Iren bat ki tap chi nao ke ca trong nude va tren the gidi. Tir 02 quinolin nay chiing ta cd the phat trien nghien ciiu theo nhieu hudng khac nhau de tao ra nhieu san pham cd y nghTa khac. Cau triic cua 02 quinolin da dupe xac djnh bang phd cdng hudng tu hat nhan 'H NMR.
TAI LIEU THAM KHAO 1. D6 Dinh Rang (chii biSn), Dang Dinh Bach, Le Thi Anh Dao, Nguyen Manh Ha, Nguyln Thi Thanh Phong, Hoa hoc hiru ca 3, Nxb GD 2005.
2. Nguyen Van Tuyin (chii bien), Ngo Qu6c Anh, Dang Thj Tuyet Anh, Pham Thj Tham, Pham ThS Chinh, Giao trinh hoa dugc. Nxb KH & KT 2014 3. The chemistry of aniline - Part I- WILEY-2007.
4. Jean-Cristophe Brouet, Shen Gu, Norton P.
Peel, and John D. Williams A Survey of Solvents for the Conrad-Limpach Synthesis of 4- Hydroxyqulnolones. Synth Commun. Jan I, 2009;
39(9): 5193-5196.
5. Jie Jack Li. Name Reactions. Springer 2009, pp 133-134.
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Duong NghTa Bang vd Dig Tap chi KHOA HOC & CONG NGHE 128(! ' ' ' "'^
"Cong Uinh dugc hoan thanh vdi su tai trg ciia Quy phdt triln khoa hpc va cong ngh^ qu6c £• "^^ ^ ^ "
(NAFOSTED, ma sd 104.01-2011.37). Chuong trinh (No 8) cua vien han lam Khoa hgc N - '^^'y '^S' danh cho nghien cuu co ban (ma s6 No 14-03-00672)".
"This work was financially supported by the Vietnam National Fund for Development of Scieii-^ .md Technology NAFOSTED (Grant No.104.01-2011.37), Programs (No 8) of Russian Academy of Sciences, Russian Foundation of Basic Research (grant Jfs 14-03-00672)"
S U M M A R Y
S Y N T H E S I S O F S O M E D E R I V A T I V E S O F Q U I N O L I N E F R O M 2 - C H L O R O - 2 - M E T H Y L A N I H N E
Duong Nghia Bang'', Nguyen Dang Due', Hoang Lam', Yu. A. SayapinS V. N. KomissarovS V.N. Minkin^
'College of Science - TNU.
'Research Insliiute of Physical and Organic Chemistiy at the Southern Federal University.
The organic compounds containing quinoline system are often diverse biological activities. Many of these compounds have been used as the main ingredient in a number of drugs in circulation in the market, Ouinine(malaria medicine), Sopcain(anesthetic), plasmoxin and acrikhin(antimalarial drugs), Saquinavir is the most efficient inhibitor for the HIV virus today. Therefore, the study of synthetic compounds containing quinoline system is attracted many scientists inside and outside the country strong research focus in recent times. This paper is uses method Conrad-Limpach for the synthesis of some new quinoline derivatives from 3-chloro-2-methylaniline. The paper made clear implementation methodology fiision, product refinement methods and especially methods of determining the physical properties of the product as the melting temperature. The molecular structure of the latter was established by ' H - N M R spectroscopy.
Key words: Quinoline. 3-ch!oro-2-methylaniline, quinotone, quinine, sovcam, plasmocin, saquinavir, Conrad-Limpach. .
Ngdy nhan bdi. 30/7/2014; Ngdy phdn blen:07/8/2014; Ngdy duyet ddng 25/11/2014 Phan bien klioa hoc: TS Lanh Thi Ngqc - Trudng Dgi hgc Nong LJ-"i - DHTN
E-mail duongbang2009'a^mail com 64
