TAP CHI HOA HQC T. 50(6) 772-776 THANG 12 NAM 2012
NGHIEN CU'U T 6 N G HaP MOT QUINOLIN QUINON MO'I:
7-(CACBOXYMETOXY)-3-SUNFOQUINOLIN-5,6-DION
Nguyen HQ-u Dinh', VQ Thj Len, Biii Thj Yen Hdng Khoa Hda hgc, TrudngDgi hgc Suphgm Hd Ndi
Din T6a soan 16-10-2012
Abstract
Reaction of (6-hydroxy-3-sulfoquinolin-7-yloxy)acetic, (5-chloro-6-hydroxy-3-suIfoquinolin-7-yIoxy)acetic, (5- bromo-6-hydroxy-3-sulfoquinolin-7-yloxy)acetic acids with nitric acid afforded a new quinoline quinone, 7- (carboxymethoxy)-3-sulfoquinoline-5,6-dione, which is readily reduced by H2N-OH, H2N-NH2, H2NNH-Ph and ElOH to give 7-(carboxymethoxy)-3-sulfoquinoline-5,6-dio!. The structure of the obtained compounds was determined by elemental analysis, !R, ESI MS, ID NMR and 2D NMR spectroscopy methods.
Keywords: Quinoline, quinone, quinol, heterocyclic quinone.
1. MO DAU
Cac hgp chat chira nhan quinon c6 vai tro quan Irpng Irong cac he sinh hpc. Noi bat nhat la coenzim Q, Viet gpn la CoQ, co Iam hoat dpng la nhan 1,4- benzoquinon gan vdi mach nhanh gom 10 dan vi isoprenyl. Quinon coenzim nay co mat d hau het cac te bao sinh vat nen con dugc gpi la ubiquinon, no la mpt mat xich Irong chuoi ho hap hay chuoi van chuyen electron nham oxi hoa ca chat cung cap tdi 95% nang luong cho co the [I, 2].
cac quinolin quinon (quinon co khung quinolin) hien dang dugc chii y nghien cuu nhieu vi vai tro va hoat tinh sinh hpc ciia chiing. PyrroloquinoMne quinone (PQQ) la mpt coenzim gan kel vdi quinoprotein dehydrogenase giir chiic nang xuc lac Irong chuoi chuyen electron-nang lugng d vi khuan Gr- [3, 4]. Mpt so quinolin quinon co hogt tinh sinh hpc cao [5, 6], co nhiJng chat da dugc su dyng iam thuoc chira Irj ung thu streptonigrin, pixantron [7].
Quinolin quinon con la chat dau thfch hgp cho vigc ting hgp nhieu logi hgp chat da dj vong co hogt tinh sinh hpc phong phii nhu cac aza- anthraquinon, aza- phenantroquinon [6, 7]. Tuy nhien da so cac hgp chat quinolin quinon dugc chiet tach tu nim, s6 lugng cac quinolin quinon long hgp con rit it va thudng thugc Ioai paraquinon [8, 9].
Mdi day [10], chiing toi dg tim ra phuong phap mdi tao vong quinolin tir eugenol va thu dugc axit (6-hydroxy-3-sunfoquinoIin-7-yloxy)axetic. 6 day chiing toi trinh bay ket qua chuyin hoa chat nay thanh hgp chat logi orthoquinon khung quinolin.
2. THl/C NGHIEM
2.1. Tim dieu kien dieu che hop chat orthoquinon khung quinolin
Cac hgp chat quinolin dau dugc dieu che theo phuang phap mo ta d tai ligu [9], do la axit (6- hydroxy-3-sunfoquinolin-7-yloxy)axetic (1), axit (5- clo-6-hydroxy-3-sunfoquinolin-7-yloxy)axetic (2), axit (5-brom-6-hydroxy-3-sunfoquinolin-7- yloxy)axetic (3), HNO3 68% ciia Merck, HNO3 95%
dugc dieu che tu KNO3 va H2S0:]. Cach tien hanh phan ling nhu sau:
Cho 1 mmol hgp chat quinolin vao binh cau 100ml, them 10ml axit axetic bang. Khuay dlu va cho tilp 1ml H2SO4 hogc 1,5 ml AC2O dl hoa tan hit chat dau, sau dd cho rat tu tu chat oxi hoa roi tiep tuc khuay hon hgp trong 5h. Do hon hpp san pham vao 80ml etyl axetat va Ipc lay chat ran mau vang tuai, rua nhilu lan bing etyl axetat, sly trong tu sly chan khong d 40''C, ki higu la Qq. Cac Ihi nghiem dugc trinh bay d bang 1.
san phim thu dugc tu cac thi nghigm 4-11 deu nhu nhau: la chat ran mau vang tuoi nhung bi6n mau khi bao quan, khong n6ng chay ma phan buy d tren 280''C, it tan trong nudc, trong dung moi huu ca thong thudng, tan trong DMSO, tan va ddi mau Irong dung djch kiem manh va trong axit mgnh.
d thi nghi|m 1 va 2 h6n hgp phan iing bj hoa den, chat hihi eg mau vang tuoi chi tgo ra vdi lugn^
khong dang kl. 0 thi nghi8m 3 khdng thu dugc chat mau vang tuoi ma thu dugc chit mau vang nhat la
TCHH, T. 50(6), 2012
sAn pham thi nhdm NO2 vao vj tri 5 tire la axit (6- hydroxy-5-nitro-3-sunfoquinolin-7-yloxy)axetic (ki hi^u la Qn) vdi higu suit 50%.
Khi ket tlnh lgi Qq trong etanol-nudc 1:1 da Ihu dug^ chat kit tinh hinh kim mau vang nhat phan hiiy
Nguyen Hiru Dinh vd cgng su d 285°C, ki hl^u la Qh. Khi cho Qq phan ung vdi H2N-OH, HiN-NHz, HjNNH-Ph thi dlu thu dugc san phim la Qh. Axyl hda Qh bang anhydrit axetic xuc tac H2SO4 thi thu dugc chat ket tinh mau vang nhgt phan hiiy d SOO^C, ki higu la Qa.
Bdng 1: Tim dilu kign tdng hgp orthoquinon khung quinolin
Chat dau HO3S
1
HO3S
HO3S
?
"5 1
^NCl
^ (2)
•"^•''^OCHjCOOH Br
'^-''^OCHzCOOH Thi nghiam
1 2 3 4 5 6 7 8 9 10 11
Tac nhan KjCrjOj+HiSO, KiCriC+AcOH HNOj 68% + HjSO, HNOj 95% + HiSO, UNO, 68% + HiSO, HNO) 95% + H2S04 HNO, 95% + AC2O H N O J 68% + HiSO,
HNO] 95% + H2SO4 H N O J 95% + AC2O H N O J 68% + HiSO,
Dieu ki^n ph^n iing t° ph6ng, 5 h t" ph6ng, 5 h t" phong, 12 h f phdng,5 h t° 40-50°C, 5 h
t° phong, 5h t" phong, 5h t° 40-50°C, 5h
t" phong, 5h t" phong, 5h t° 40-50°C, 5h
Hieu suat 0%
vet 0%
30%
25%
80%
60%
65%
80%
65%
70%
2.2. Nghien cuii cau true
Pho hing ngoai do tren may IMPACT 410 Nicolet d dgng vien nen vdi KBr; pho khdi lugng ghi tren may 1100 Series LC/MSD-Trap-SL, pho NMR dugc ghi Irong dung moi DMSO Iren may Bmker XL-500, tgi Vign Hoa hpc, phi XRD ghi Iren may Hitachi S-4800 tgi Vign Vat lieu; dlu thupc Vien Khoa hgc va Cong nghg Viet Nam.
3. KET QUA VA THAO LUAN
D I chuyin khung benzen thanh khung quinon, thdng thudng ngudi ta oxi hoa cac hgp chat logi diphenol, aminophenol, phenol, amin thom, hoac bromphenol. Dii vdi cac chat dl bi oxi hoa, ngudi ta dung FeCls, Ag20 hoac Mn02. Dii vdi cac chit kho bj oxi hoa, ngudi ta dimg HNOj hogc K2Cr207. cac quinolin 1, 2, 3 la nhihig chit khong d l bi oxi hoa vi vgy chung toi sir dyng HNO3 hoac K2Cr207 trong moi tnrong axit nhu ghi d bang 1. Kit qui cho thiy hgp chit 2 va 3 cho higu suit cao han hgp chit 1. Vi 2 va 3 deu dugc dilu chi tir 1 nhung higu suat phan img dilu chi 3 cao hon [10], nen chung tdi cho ring diing chit diu la 3 vdi dieu kign nhu md ta d thi nghigm 9 va 11 la thich hgp nhit cho vigc tao thanh hgp chit mong dgi.
Vi$c thir mau nggn lua cua Qq tren day dong cho kit qua am. Phd EDX cho thiy Qq co chira C, N, O,
S (% khii lugng lin lugt la 34, 17, 36, 10) va khong chua Cl va Br nhu d 2 va 3.
Khac biet ro ret giua phi IR cua Qq va ciia cac chat diu la d viing hap thy ciia nhom cacbonyl. 0 viing nay mli chat 1, 2 va 3 chi cho mpt van hap thu manh lin lugt d 1680, 1740 va 1713 cm"' trong khi do Qq cho 3 van hip thy mgnh d 1775, 1709 va 1629 cm"'. M6i chit Qh va Qn cho I van hip thy cua nhom cacbonyl d 1670 va 1730 cm"', trong khi do d phi cua Qa co 3 van d 1787, 1749 va 1653 cm"'.
Tren phi +MS ciia Qq co pic ion gia phan td [M-l-H]"^ d m/z = 314 au, den phi -MS ciia Qh co pic ion gia phan td [M-H]" d m/z = 314 au, cac gia trj dd phii hgp vdi cong thiic d so do 1. Tren pho +MS ciia Qn c6 pic [M-l-H]* d m/z = 345 au, tren pho -MS ciia no c6 pic [M-H]" d m/z = 343 au (gia trj tinh theo cong Ihuc la 344 au).
cac dir kign thyc nghigm tren cho phep dy doan cong thuc ciia Qq, Qh, Qa nhu d so dl 1.
Vigc quy kit cac tin higu tren phi 'H NMR, C NMR ciia cac chit noi tren dugc hi trg bdi pho 2D NMR. Vi dy, phi HSQC va HMBC trinh bay d hinh 1, 2 cho phep quy kit cac tin hieu cpng hudng cua proton va cacbon d Qq. Phi NOESY cua Qa khong nhihig cho phep phan bigl tin higu proton ctia hai nhom axetyl (HI3 cd van giao vdi HI 1 con H14 thi khong) ma con cho thiy chung d gin nhau (HI 3 va H14 cd van giao vdi nhau) va d xa H2 (khong co
773
TCHH, T. 50(6), 2012 Nghien am tong hpp mpt...
van giao vdi H2) tire l i a Q a khong c6 nhbm axetyl tich pho N M R cua cSo hiyp ch& nghiSn ctiu duqre li?t nao dinh vJo nghuyen tOr N quinolin. KSt quS phan ke 4 b i n g 2 v4 3.
101 101 ,
|01 ,
, O BOH/H,0. , 9 H O C O C H 3 " , 3
= ^ 3 Y ^ W ° " ' ^ i ^ H03S,A^oJ4,OH ;^^o H03S,^A,^OCOCH3
^ |6 — " 6 — - I 1 6
X -iK^K H,N-NH, A J-^.A, "2SO4 A A A
^ ^ V t ? .a " ^ P h ^ ^ V : ? ,2 ' N - ^ 0 „
"CH2COOH - ^ "CH2COOH "CH2COOH (Qq, M = 313au) (Qh,M = 315au) (Qa, M = •'°° =">
So 66 I. %\f tao thinh v i phan iing cua Q q
= 399 au)
2 4 8 1 1
1 1 1
"1 »
i ' 1
0
W
1 i
1
0 w 12
O C H J C O O H
, — • • ! 1 i 1 — e s t
fl 1
»
. 1
°T 1
*
KcP 7 OCHiCOOH
'•
9 B 7 E 5 Hinh 2 Phd HMBC ciia Qq /fin/j/: Pho HSQC ciia Qq
Bdng 2 Tin hieu ' H N M R ciia cac chat nghien cuu, (5 (ppm), J (Hz) Kihigu
Qq Qn Qh Qa
H2 8,80 d, J 2
9,08 s 9,11 s 9,09 d, J 2
H4 8,16 d, J 2
8,27 s 9,06 s 8,33 d, J2
H8 6,62 s 7,62 s 7,08 s 7,49 s
Hll 4,75 s 5,12s 5,01 s 4,95 s
Hkhac
- -
HO: 10,05 tii; 10,60 til H13:2,51 s;H14: 2,37 s
Qq Qh Qn
C2 150,29 145,45 144,79
Bang 3: Tin hieu '^C NMR eiia cac chit nghien ciru, S (ppm) C3
141,89 137,87 137,28
C4 132,04 125,83 126,16
C5 176,13 138,72 131,22
C6 173,74 133,18 135,65
C7 154,13 151,55 453,41
C8 114,07 101,21 106,98
C9 153,20 142,23 142,33
CIO 124,74 115,29 114,12
CU 64,95 66,36 74,66
C12 168,82 170,40 173,13
TCHH, T. 50(6), 2012
Sy giam mgnh dg chuyan djch hda hgc cua H8 d Qq so vdi d 1, 2, 3 (7,23; 7,42; 7,47 ppm [10]) va so vdi d cac hgp chit khac trong bang 2 la do nd khdng phai la proton thom ma dS trd thanh proton anken cua quinon Qq. DO chuygn djch hda hgc cua C5 va C6dQq la 176,13 va 173,74 ppm (bang 3) chimg t6 chOng la nhihig nguyen tu cacbon cacbonyl.
cac thi nghigm d bang 1 cho thay khi tang nong d$ axit nitric ho^c tang nhigt dg phan img thi higu suit Qq tang, khi thay HNO3 95% bing HNO3 68%
va khong dun ndng thi khdng thu dugc Qq ma thu dugc san pham cua phan irng nitro h6a (Qn). Tren
Nguyen HOu Dinh vd cgng su CO sd d6 chung tdi giai thich sy tgo thanh Qq nhu sau.
Nhu da biit, khi dun n6ng hoac chieu sang HNO3 bj phan huy tgo thanh NO2, O2 va H2O, axit cang dac cang de phan hiiy: 4HNO3 —> 4NO2 + O2 + 2H2O.
Chic chin la nhigt va anh sang da gay ra su phan cit dong li lien ket 0-N Igo glc ra 'NO2 vk HO' (ki higu chung la G'): HO-NO2 — HO' + 1^102.
Chiing toi cho ring phan ung oxi hoa 1 xay ra theo CO che goc dugc khoi ma bdi "NO2 va HO' nhu de nghj d s a d o 2.
C o HO3S- ^ ^ ^ v ^ ,0H
11 T *^^ T T T
N V ^ ^ O R N ^ ^ OR ,. H03S.
. H03S, GH
HO H
\ ^
G'l-GH OH
l ^ V r
\IJ
'P
"OR
-P
"OR
So 36 2: Giai thich su tao thanh Qq tir 1
Sir tao thanh din xuat o-quinon tir 2 vi 3 co le cung xay ra theo co chi goc nhu de nghj o so do 3.
X X H 0 3 S . , „ , ^ ^ , A ^ 0 ^. H O j S ^ ^ j s ^ ^ ^ A ^ O H ^ HO3S
0» ^ O . 0 ^ H 0 3 S ^ 1 ^ 0 ^ H 0 3 S ,
^ N ^ - ^ O R - ° " % ^ ^ 0 R •="
(Qq)
Sadd 3: Giii thich S(l tao thanh Qq tir 2 (X = Cl) va 3 (X = Br)
TCHH, T. 50(6), 2012
Hgp chat Qq thugc logi o-quinon nen k^m ben va CO lyc oxi hda mgnh, vi (hi khi g^p cac chat khu nhu mgnh H2N-OH, HjNjNHi, HzNNH-Ph va khi dun hii luu trong EtOH dl kit tinh Igi n6 da bj khu thanh hgp chat logi dihydroxy Qh.
CJ phan ung axyl h6a Qq, nguyen tir N quinolin b) proton h6a bdi proton ciia nhdm SO3H va ciia H2SO4 them vao, do d6 nd da khdng bj axyl hda.
4. KET LUAN
Oxi h6a cac axit (6-hydroxy-3-sunfoquinolin-7- yIoxy)axetic, (5-clo-6-hydroxy-3-sunfoquinolin-7- yloxy)axetic, (5-brom-6-hydroxy-3-sunfoquinolin-7- yloxy)axetic bing axil nitric deu Igo thanh mpt quinolin quinon mdi la 7-(cacboxymetoxy)-3- sunfoquinoIin-5,6-dion chat nay de bj khit bdi H2N- OH, H3N-NH2, HjNNH-Ph ya EtOH din din hgp chat dihydroxy tuang iing. Cau igo ciia cac hgp chai nghien ciru da dugc xdc djnh nhd phan tich djnh tinh nguyen to, phan tich pho ESI MS, pho IR, pho ID NMR va 2D NMR.
Ldi cam ffn; Cdng trinh ndy dugc hodn thdnh vdi sg tdi Ira ciia Quy phdt tnen khoa hgc vd cdng nghi qudc gia Viet Nam - NAFOSTED.
Nghien ciru tong hgp mgt...
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1 2.
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Lien he: Nguyen Huu DTnh
Khoa H6a hgc, Trudng Dgi hpc Su pham Ha Npi 136 Xuan Thiiy, Cau Giay, HaNpi
Dien ihoai: 04 37560196, Email: [email protected].
