TAP CHI H 6 A H O C T. 50(3)357-361 T H A N G 6 N A M 2 0 I 2
T6NG Hap MOT s6
2-ARYL^-(2'-HYDROXIPHENYL)-2.3-DIHIDRO-1H-1,5-BENZOOIAZEPIN
DuoTig Ngpc Toan'', Nguyen Minh Thdo^
Khoa Hda hgc, Trir&ng Dgi hgc Suphgm Thdi Nguyen
^Khoa Hod hgc. Tru&ng Dgi hgc Khoa hgc Ty nhien - DHQG Hd Ngi Din Tda sogn 22-02-2012
Abstract
Ei^t new compounds of type 2-aryl-4-(2'-hydroxyphenyl)-2,3-dihydro-l//-I,5-benzodiazepines have been synthesized fixim a;/J-unsaluraled ketones of 2-acetyl-l-hydroxybenzene by reaction of corresponding (a;j5-unsalurated ketones with o-phenylenediamine. The structure of synthesized compounds has been confirmed and biological activities of these compounds have been investigated.
Keywords: Benzodiazepines, hydroxyphenyl. phenylenediamine.
1. MO DAU
Benzodiazepin vd din xuat cua nd tgo thdnh mpt ldp quan gpng ciia cac hgp chat di vdng bdi nd cd mpt loat cac tinh chatgi lipu va dugc Iy [I]. Cdc dan xuat ciia benzodiazepin dugc su dyng rpng rai nhu thudc chdng co gigt, thudc chong Io au, gidm dau, an than, tram cdm va thudc gay me [2], Trong nhung thap ky gan day, hoat tinh cua dan xudt 1,5- benzodiazepin da dugc nghien ciru tdc dung chii'a mpt sd benh nhu ung thu, nhiem sieu vi vd cdc roi loan lim mgch [3, 4]. Ben cgnh dd, dan xuat benzodiazepin cung cd tdm quan trgng trong thuang mai va dugc sir dung lam thuoc nhupm cho sgi acrylic trong nhiep anh [5].
Tiep theo vipc tdng hcrp vd nghien ciru tinh chat cua cac xeton a,/3-kb6ng no di tir 2-axetyI-l-
hidroxibenzen [6], bdi nay trinh bay ket qua ve chuyen hda cdc xeton a,/?-khdng no d tren thdnh cac hgp chat 2-aryI-4-(2'-hidroxiphenyI)-2,3-dihidro- 7//-l,5-benzodiazepin.
2. THl/C NGHIEM
Cdc xeton ct,/3-kh6ng no dugc tdng hgp theo tdi lipu [6]. Cdc chdt chua di vdng benzodiazepin dugc tong hgp theo phuang phap sau: Dun hoi luu 30-40 gid hon hgp gom 10'^ mol xeton a;^khdng no vdi IO""' mol o-phenylendiamin gong dung mdi etanol tuypt ddi va xuc tdc Id 5-7 gipt axit axetic bdng. San pham tach ra dugc Ipc hiit va ket tinh lgi gong dung mdi thich hgp din khi fren ban mdng silicagel chi cho mpt vit ggn vd trdn.
Sa do phdn ung:
Ar.
^^^ ^COCH=CHAr
r Y 0-H2NC6H4NH2
a
C0CH3OH ^ ^ U . ,
Trong do Ar la: CsH,, 4-CIC6H4, S-ClCsH,, 4-BrC6a,, 4-CH)C6H4, S-O^NCsH,, 4-02NC«H,, 4-CH3OC6H4.
Ph6 hong ngoai do duoi dang vien nen vcri KBr 3 KET QUA VA T H A O LUAN tren may FTS-6060; Ph6 cpng hirong tir hat nhan
(NMR) duijc do trong dung moi DMSO tren may Sau khi kit tinh Iji, cac san pham thu dircyc deu 6 BRUKER XL-500 t?i Vien Hoa hpc, Vien Khoa hpc dang tinh the CO mau tir vang nhat d6n vang dam.
»4 Cong ngh? Vi?t Nam. Pho khoi lupng cua eac Cac chat da dirpc kiem tra dp tinh khiet bang each hW chat nghien cijru dupe ghi trSn may AutoSpec do nhift dp nong chiy, sic ky ban mong v6i h | dung Prem'. ,r ., . moi n-hexan-etyl axetat vai ti le 5:1 (theo the tich)
357
TCHH, T. 50(3), 2012
vd nhd cdc phuang phdp phA. Kit qud cho thfiy cdc hgp chAt thu dugc cd d^ tinh khilt cao vd c6 nhiJng ddc dilm khdc hdn vdi cdc xeton a ^ k h d n g no ban diu. MOt s6 d& ki§n vl dilu chi, tinh chit v|it II, phA h6ng ngogi (IR), ph6 kh6i lugng (MS) cua cdc benzodiazepin dugc ghi d bdng 1.
TrSn ph6 IR ciia cdc benzodiazepin chung tdi t6ng hgp dugc cd cdc bdng sdng hAp thy d 1590- 1601 cm' d$c trung cho dao d$ng hda trj ciia li€n kit C=C cOng nhu C^N trong vdng benzodiazepin.
Dilm khdc bipt dl nh§n th4y nh4t giOa ph6 IR ciia cdc benzodiazepin vdi xeton a;^khdng no dd Id sg r.iSt di bdng sdng hip th^ d$c tnmg cho dao d$ng hda trj ciia lien kit C=0 xeton lien hgp vdi C=C d t4n s6 I635-I685 c m ' . Trfin ph6 IR cua cdc benzodiazepin khdng cdn cdc bdng sdng d tan s6 990-960 cm"' Id tin hi^u dftc trung cho dao dpng biln dgng cua nhdm /ram-vinyl khi tham gia lien hgp vdi
DttomgNggc Todn vdc^ngsy nhdm C = 0 vd xuk hi§n bang sdng hip thu cd cudng dO mgnh d 3378-3341 cm'' ddc tiarng cho dao dpng hda tri ciia Ii6n kit N-H trong vdng benzodiazepin.
Ngodi ra, g£n ph6 IR cua cdc benzodiazepin vin cdn cdc bdng sdng hip th\i d$c tnmg cho dao dgng hda trj cua cdc nhdm chirc trong hgp phin 2-hidroxiaxetophenon vd hg^) phan andehit ban dau, chdng hgn dao d^ng nhdm -OH d 3398-3305 cm'', C-H no if 2924-2880 cm'', C-H thorn d 3119-3029 cm"'....
TrSn phd kh6i lugng cua cdc chat khdo sdt cd pic ion phdn tur p.'iii hgp vdi kit qud tinh theo cdng thiic dg kiln vd tudn thco "quy tdc niter" vd c6 cdc pic ion phdn mdnh ddc trimg phii hgp vdi quy lugt phdn mdnh.
c i u tnic cua cdc sdn phim tong hgp dugc dd dugc xdc nhdn nhd kit qud phdn tich phd ' H NMR vd '^C NMR, HSQC vd HMBC.
Bdng I: S6 2-aryI-4-{2'
lipu ve t6ng hgp vd pho IR, MS ciia cdc hgp chat hidroxiphcnyl)-2,3-dihidro-///-l,5-benzodiazepin H<;^
chat I II III IV
V VI VII VIII
Ar CjH,
4-CIC6H,
3-CIC6H,
4-BrC6H,
4-03NC6Hj
3-02NC6H4
4-CHjC6H4
4-CHjOC6H4
°C 245- 246 257-
258 277-
278 282-
283 265-
266 271-
272 263-
264 280-
281 R't 0,67
0,78
0,63
0,72
0,75
0,69
0,65
0,72 II.
%
78 85 82 85 75 74 76 81
Pho IR (u c m ' ) tJoH. U N H
3341
3362
3355
3348
3352
3378
3352
3365 3064;
2923 3064;
2894 3055;
2883 3048;
2890 3074;
2903 3081;
2862 3024;
2853 3015;
2830 Uc-N.C-C
1603
1599
1598
1600
1601
1605
1596
1604 tJN()2
1506 1341 1518;
1343
Pho M S M 314 348,5
348.5
393 359 359 328 344
M-, %
348(70,2) 350(27,1) 348(100) 350(3 K 8 ) 394(36,8)
359(37)
359(38,8)
328(39,3)
'He dung moi n-hexan.etyl axetat 5:1 theo thi tfch.
Tren phd H NMR cua cdc benzodiazepin deu thdy mat di tin hipu mpt cap ddi doublet dudi dgng hieu irng mdi nhd ddc trung cho chuyin djch hda hgc cua nhdm trans vinyl trong cdc xeton a;j5-khdng no, trong khi dd xuat hipn cdc tin hipu dgc trung cho chuyen djch hda hpc cua 3 proton no trong vdng benzodiazepin, hai proton H^; Hb cgng hudng d
(3,15-3.47 ppm), proton H^ (5,16-5,50 ppm). Tren phd ' H NMR ciia hgp chat VII xuat hipn tin hipu singlet ddc trung cho chuyen djch hda hpc cua proton nhdm NH (6,10 ppm). Tren pho 'HNMRcua cdc hgp chit cdn lgi proton NH ndy xuat hipn tin hipu dudi dgng doublet do tuang tdc vdi He (J: 2,5- 3,5 Hz). Cdc hgp chit I-VI tin hieu ciia Ha, Hb diu ^ xudt hipn dudi dgng doublet of doublets do cac proton ndy tucmg tac vdi nhau va vdi He. Dac bipt, tren pho ' H NMR ciia hgp chat VII, VIU do dO chuyen djch hda hgc cua Ha, Hb Id tuang doi g ^ nhau nen tin hieu ciia chung Ian vdo nhau dudi dgng doublet hodc multiplet vdi cudng dg 2H. DU kien phd ' H NMR cua cdc benzodiazepin dugc ghi d J i bdn_ 7. .,
358
TCHH, T. 50(3), 2012 Tong h(jp m0t so 2-aryl-4-.
Bdng 2: Dd kif n pho 'H NMR ciia cAc benzodiazepin (dung moi DMSO - dg) Phs'H
H„ H,, H, Hj, H4, Hj, Hj
H NMR: 5 ppm (JH ) H„Hio,
H„,H„ H v6ng Ar
"O-
3,l8(IH,dd,Ha, J: 14,0 v4 3,5);
3,25(IH,d(l,Hb, J: 14,0 vi. 7,5);
5,28(lH,m,Hc, J: 7,5 v i 3,5)
6,70(lH,t,H5, J: 8,0 v4 1,0);
6,S4(lH,(ld,H, V:8,0v41,0);
7 , 2 2 ( l H , t , H „ y:8,0);7,38(lH,
d d , H , , J : 8 , 0 v a 1.0)
15,37
(0
6,15(lH,d, J:2,5)
6,89(1H, Id, H|„
./:8,0v41,5);
7,05(lH,dd,H,j, J: 8,0 v4 1,5);
7,09 (lH,td, HIO, J: 8,0 v4 1,5);
7,17(IH,dd,H,, y:8,0v41,5)
7,29(3H, m, H „ i , i , , J : 7 , 5 v 4 1,5); 7,41 (2H,d, H|5,„J:7,5)
. V / \N
3,15ClH,dd,Ha, J: 14,5 v4 3,5);
3,31(lH,dd,Hb, ./: 14,5 v4 7,0);
5,28(1H, m. He, .; 7,0 v4 3,5)
6,70(1H,1, H5, J: 8,0 v4 1,0);
6,83(IH,dd, H, J; 8,0 v4 1,0);
7,27(1H, Id, H„
y : 8 , 0 v 4 l , 0 ) ; 7,38(1H, dd, H„
J: 8,0 v4 1,0) 15,32
(s) 6,18(IH,d,
J:3,0)
6,89(lH,td,H,|.
y:8,0v41,5);
7 , 0 4 ( l H , d d , H i ! ./:8,0v4l,5);
7 , 1 0 ( l H , l d , H „ ,/:8,Ov4 1,5);
7,16(lH,dd,H„
y:8,Ov4 1,5)
7,34 (2H, d, H,>,„,J:8,5);
7,42 (2H, d, H,M.,J;8,5)
3,16(1H, dd. Ha, J: 14,0 v4 3,5);
3,33(1H. dd, Hb.
J: 14v4 7,0);
5,28(1H, m. He, J: 7,0 v4 3,5)
6,71(1H, Id. H„
J: 7,5 v4 1,0);
6,83(lH,dd, H, y:7,5v4 1,0);
7,26(1H, td,H„
J: 7,5 v4 1,0);
7,37(lH,d,H„
J: 7.5) 15,27
(s) 6,19(lH,d,
1:2,5)
6,90(1H, td, HI,, 7: 8,0 v4 1,5);
7 , 0 4 ( l H , d d , H , „ J: 8,0 v4 1,5);
7,11 (lH,td, HIO, J: 8,0 v4 1.5);
7,16(1H, dd, H „ 7: 8,0 va 1,5)
7,30 (2H, m, H „ , I „ 7 : 8,0);
7,42(1H, d, H„, J: 8,0);
7,46(1H,S, H,s, J: 8,0)
3 , 1 5 ( l H , d d . H a , J: 14,0 v4 3,5);
3,30(1H, dd, Hb, J: 14,0 v4 7,0);
5 , 2 5 ( l H , m , H c , J: 7,0 v4 3,5) 3,18(1H, dd, Ha,
J: 14,0 v4 3,5);
3,43(1H, dd, Hb, J: 14,0 v4 7,0);
5,47(lH,m,Hc, J: 7,0 v4 3,5) 3,18(1H, dd. Ha,
J' 14,0v4 3,5);
3,45(IH, dd, Hb, J. 14,0 v4 6,5);
5,49(1H, m, He, J: 6,5 v4 3,5)
3,19(2H,ni,Ha,b);
5 , 1 6 ( l H , s , H c )
3,18(2H,d,Ha,b);
5,16(1H. m. He)
6,71(lH,td, H„
7: 8,0 v4 1,0);
6 , 8 4 ( l H , d d , H , 7: 8,0 vi 1,0);
7,27(lH,td, H„
7: 8,0 v4 1,5);
7,38(1H, d, H„
7: 8,0) 15,32
(s) (lH,d,7:
3,0)
6,66 (IH, 7:7,5);6,81(1H,
d, H„ 7: 8,0);
7,24 (IH, I, H., 7 8,0 v4 7,5);
7,32(1H, d, H„
J: 7,5) 6,65(1H, Id, Hi,
7: 8,0 v4 1,0);
6,80(IH, dd, H, J: 8,0 v4 1,0);
7 , 2 4 ( l H , t d , H „ J: 8,0 v i 1,5);
7,37(1H, dd, H„
,0v4 1,5) 6,73(lH,t,H5, J-7,0); 6,85 (IH,
d,H,7:7,5);
7 , 2 8 ( l H , t , H . , 7 7,5); 7,42 (IH,
d, H., 7. 7.5) 6 , 7 3 ( l H , t d , H „ J: 8,0 v4 1,0);
6,85(1H, dd, H, 7: 8,0 vi 1,0);
7,28(lH,td, H<, 7: 8,0 v i 1,5);
7,42(lH,dd,H5 '•8,0v41,5)
6,89(lH,td, H||, 7: 8,0 v i 1,0);
7,04 (IH, dd, H|„
7: 8,0 v i 1,5);
7,10(lH,Id,Hi„, 7: 8,0 v i 1,5);
7,16(1H, dd, H,, 7: 8,0 v i 1,0)
7,37(2H, d, H|i „ 7: 8,5);
7,47 (2H, d, H,«i„7:8,5)
15,22 (s)
15,19 (s)
15,40 (s)
15,42 (s)
6,30 (lH,d, 1:3,0)
6,31 (lH,d,7:
3,5)
6,10 (IH, s)
6,07 (lH,d, 7: 2,0)
6,91(lH,t, H||, /: 8,0); 7,06 (IH, d, H I I , 7: 8,0);
7,13(lH,t,H|o, 7. 8,0); 7,16 (IH, d , H „ 7 : 8 , 0 ) 6,92(lH,td,Hii,
7: 8,0 v i 1,5;) 7,06(lH,dd,Hi„
J: 8,0 v i 1,5);
7,14(1H, td. Hi„, 7 8,0 v i 1,5);
7,17(1H, dd. Ho, 7: 8,0 v i 1,5) 6,87(1H, t, HII, 7 8,0): 7,05 (IH,
d, H„, 7; 8,0);
7,10(lH,t,H,o, 7: 8,0); 7,15 (IH,
d. Ho. 7: 8,0) 6,88(1H, td, HII,
7: 8,0 vi 1,5);
7,06(1H, d , H | „ 7: 8,0 va 1,5);
7,09(lH,td, H„, 7: 8,0 v i 1,5);
7 , 1 6 ( l H , d d , H „ 7: 8.0 v i 1,5)
7,70 (2H, d.
H I , 10,7: 8,5);
8,14 (2H,d, Hit 11,7:8,5)
7,57 (IH, t, H„, 7: 8,0); 7,87 (IH,
d,H„,7:8,0);
8,05 (IH, dd, H|„
7:8,0 v i 1,5);
8,28(1H, t. His, 7: 1,5) 7,11 (2H, d, Hi,i„7:8,0);
7,28 (2H, d.
H I , ,0,7: 8,0)
6,86 (2H, d.
H I , „, 7: 8,5);
7,28 (2H, d, Hii i„ 7: 8,5)
TCHH, T. 50(3), 2012
Tir bing 2 cho IhSy, lln hi?u cOng hirdng ciia proton nh6m OH c6 dp chuyen djch h6a hpc ldn (15,19-15,42 ppm), di^u niy c6 th^ giii thich nhir sau: proton ctia nh6m OH gSn nguydn tit N Irong v6ng benzodiazepin nfin t^o dupe Ii6n ket hidro vdi nguydn tir nita niy, do vjy tin hi|u c^ng hudng cila proton niy djch chuydn ve phia tru-dng ydu. Nhttng dit ki^n trin chimg td vdng benzodiazepin di dirpc hlnh thinh.
Tren ph6 "C NMR ciia mOt s6 hpp chSt t6ng hpp dirpc thiy diy dii tin hidu cdng hirdng ciia cAc nguydn tir cacbon khong tuong duang trong phfin tir
Duang Ngpc Todn vd dngsi/
d nhttng viing thich hpp (xem bang 3). Tuy nhidn nhidu tin hi^u rlt gin nhau vi do phan tOr cic hpp chit niy cd nhilu nguydn tit cacbon b$c 4 (6-7 nguydn tii) cho Ifn hifu yiu ndn vi|c ^uy ket g5p nhidu khd khin. VI vSy, dl cd the quy ket chinh xac cic tin hifu trdn phA C NMR, chung tdi di ghi pho HMBC vi HSCJC ciia chat IV vi chat VIII. Ket qui quy kit cho thiy tin hidu.cfng hudng ciia cic nguydn lit cacbon thudc vdng benzodiazepin; C^i, d (35,3-36,7 ppm), C.d (66,6-66,9 ppm), C7d(170,6- 170,9 ppm). Tin hipu ciia cic nguyen tir cacbon dupe trinh biy d bing 3.
Vi tri C 1 2 3 4 5 6 7 a,b c 8 9 10 11 12 13 14 15 16 17 18 19 Khic
Bdng 3. Dtt kien ph6 "C NMR ciia m^t s benzodiazepin (,5: ppm. DMSO) Ph6 "C NMR:.! ppm
II 119,0 161,5 117,3 132,5 117,8 128,7 170,7 36,0 66,6 140,7 128,2 127,3 119.5 120.3 132,9 128,9 127,9 128,0 143,4 128,0 127,9
MI 119,0 161.5 117.3 132,6 117,8 128,8 170,7 35,9 66,7 140,6 128,2 127,4 119,6 120,3 133,0 130,0 132,8 146,8 127,1 126,1 124,7
IV 119,0 161,5 117,3 132,5 117,8 128,7 170,7 35,9 66,6 140,7 128,2 127,4 119,5 120,3 132,9 120,1 128,3 131,0 143.8 131.0 128.3
V 118,9 161,4 117,3 132,6 117,7 128,6 170,6 35,3 66,9 140,5 128,2 127,4 119,7 120,3 133,1
VI 118,9 161,4 117,3 132.6 117,7 128,7 170,8 35,4 66,8 140,5
VIII 119,0 161,6 117,4 132,5 117,8 128,7 170,9 36,7 66,8 140,8 I2S.2 , 128,1 127.4
119.8 120.3 133.2 146.5 j 146.5 123.2 1 132.9 127.5
151,8 127,5 123,2
-
147.5 129,7 122,0 120,9
-
127,3 119,3 120,4 132,9 136,7 127,1 113,6 158,5 113,6 127,1 55,0 OCHj Cdc du kipn vl phd IR, 'H NMR, '^C NMR,
HSQC, HMBC cimg cdc dii kipn vgt li xac djnh d tren da xac nhdn cau tgo cua cac hgp chat chua di vdng benzodiazepin long hgp dugc.
De djnh hudng ung dyng cua cac hgp chat tdng hgp dugc, chung tdi dd tien hanh thu nghiem hogt tinh khang khudn va chdng nam cua mgt so dan xuat benzodiazepin tgi Phdng nghien ciru vi sinh, Benh vipn 19-8 Bp Cdng an:
Ndng dp chat thu nghipm. 2 mg/5 ml DMf^
(Dimelylfomamii).
Chung logi khuan: Trgc khuan Gr(-): Klebsiella preumoniae ( K.p). Cdu khuan Gr(+): Staphylococas | epidermidis (S.e). Nam men: Candida Albicans ( C a ) . _ _ ^•
Nhd dung dich thu nghiem vdo cdc Id dye tren nin thgch da dugc cay vi khudn vdi cdc muc 100 pi va 150 p-l. Hogt tinh khdng vi sinh vgt dugc danh gid theo dp ldn ciia dudng kinh vdng trdn vd khuan (theo mm). Ket qua dugc gidi thieu d bang 4.
360
TCHH, T. 50(3), 2012 Tdng hgp mgt so 2-aryl~4
Hpp chat I II III IV V VI VIII
Bdng 4: io9t tinh khing khuan vi chong nam ciia cic benzodiazepin S. e. fGr +)
100 Ml 15 0 20 0 0 0 0
150nl 20
0 25 0 0 0 0
K.p.(Gr-) 100 Ml
10 10 18 15 10 15 15
150 Ml 20 20 18 20 20 15 17
C. a. (Nam men) 100 Ml
20 20 20 20 20 20 20
150 Ml 20 20 20 20 20 20 20 4. KET LUAN
Bdng phdn ung ciia cdc xeton a./?-khdng no (di tir 2-axetyI-I-hidroxibenzen) vdi o-phenylendiamin da tong hgp dugc 08 hgp chat chira vdng benzodiazepin. Cau tgo ciia cac san pham dd dugc xac nhgn bdng cdc phuang phdp pho IR, NMR vd MS. Hogt tinh khdng khuan vd chong nam ciia cdc hgp chat long hgp dugc dd dugc thu nghipm.
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