DAI HOC QUOC GIA HA N p i TRU'OfNG DAI HOC KHOA HOC TU'NHIEN KET QUA THUC HIEN DE TAI NGHIEN CtTU KHOA HOC TRONG DIEM CAP DAI HOC QUOC GIA HA NOI "NGHIEN Ciru TONG HOP, HOAT TINH SINH
Trang 1DAI HOC QUOC GIA HA N p i TRU'OfNG DAI HOC KHOA HOC TU'NHIEN
KET QUA THUC HIEN DE TAI NGHIEN CtTU KHOA HOC
TRONG DIEM CAP DAI HOC QUOC GIA HA NOI
"NGHIEN Ciru TONG HOP, HOAT TINH SINH H p C (KHANG
K H U A N , CHONG VIEM, CHONG UNG THU) VA KHA NANG
NHAN DI VONG: INDOL, FURAN, CUMARIN, QUINOLIN"
Ma so: QGTD-05-03
Chu nhiem dl tai: GS.TSKH NGUYEN MINH THAO
Cac can bo tham gia:
+ PGS.TS Nguyen Dinh Thanh + PGS.TS Tran Cong Yen + TS Lull Van Chinh + ThS Pham Van Phong + ThS Nguyen Thj Minh Thir + ThS Tran Van Tinh » + KTV Le Thj Minh Nguyet + Mot so NCS, HVCH va sinh vien
DAI HOC QUOC G\A HA NOI
TRUNG TAM THONG TIN THU VIEN
o:}C(,cccoc^
Ha Noi - 2007
Trang 2- Qtkdnt ide glA thjUe^ kiin djt tiki nd^ jeut ehdjt thdnh ednt iUt (Biut ^idnt d£^ ^an Xtufa h^ od ©dng, nqht,
^dit fJtdnQ, ad ^hdnjg, ^di oa,, ^ai twe QJUM QJH JCd
MI dd ghuy dt tdi od tac- ntol tDlst ltli§t ihttan Hht gidp,
dS ehung tdi hodn thdnh ahltnt OVL
- &fdng tdi edng, xin ehdn thdnh edm dn (Ban^ ^Idnt hltUf ^hong, JChoa, hne od ©ong, ttghe^ ^radng ^ql hoe Xho4L hoe Q^U nhiin ~ ^'JCQ/Q, "JCd Qtdl dd ddng olin, dng ho od gluft dd ehdng tdi hodn thdnh de tdi ndg,
- &uing idl edng xin ednt tUt ^ttdng nghien edu eau true - ^len 'Xod ttoe; ^hong Q'ku' nghiem Itoal linh tinh hoe - ^len JCod tioe ede ho^ ehdi thien nhien eun
^len JChou hoe od ©ong nghe ^lel Qtant; ^Itong Qtghlen edu <Vl unh odt - (Benh olen 19-8 - ^o ©ong an; ^ttdng Qlghlen ed'u te ffdo od mo fthol — Xhou Sinh hoe; (Ban ©hu nhlent Xhoa JCod hoe; ^t^ung tdm 'Xod n)axL od (Bo 0nSn Xod iioe XuCu e& — 3Chou JCod ttoe - ^94j^ng ^ql hoe 3Choa hoe QCu nhien - ^XQ/^
Xa (mi,
NHOM NGHIEN CLTU THUC HI$N D ^ TAI QGTD^5-03
Trang 3BAO CAO TOM TAT
1 Ten de tai: ''Nghien cuu tdng hap, hoat tinh sinh hgc (khdng khudn, chong viem vd chong ung thu) vd kha ndng ung dung cua mot so xeton a, fi-khong
no CO chua nhan di vong: indol,furan, cumarin, quinolin^'
Ma so: QGTD-05'03
2 Chu nhiem de tai: GS.TSKH Nguyin Minh Thdo
3 Cac can bo tham gia:
- PGS.TS Nguyin Dinh Thanh - Khoa Hoa hpc - Truang DHKHTN-DHQG Ha Npi
- PGS.TS Trin Cong Yen - Khoa Sinh hpc - Truang DHKHTN-DHQG Ha Npi
- TS Luu Van Chinh - Vien Khoa hpc va Cong nghe Viet Nam
- ThS Pham Van Phong - Khoa Hoa hpc - Truang DHKHTN-DHQG Ha Npi
- ThS Nguyen Thi Minh Thu - Khoa Hoa hpc - Truang DHKHTN-DHQG Ha Npi
- ThS Tran Van Tinh - Benh vien 19-8 - Bp Cong an
- KTV Le Thj Minh Nguyet - Khoa Hoa hpc - Truang DHKHTN-DHQG Ha Npi
- Mpt s6 NCS, HVCH va sinh vien
4 Muc tieu va noi dung nghien cihi
+ Muc tieu: Tong hgp mpt so xeton a, P-khong no m o i , co kha nang co hoat tinh sinh hoc (khang khuan, chong viem va chong ung thu)
+ Noi dung: Tong hgp cac hgp chat xeton a, p-khong no moi co chua cac nhan
dj vong indol, furan, cumarin va quinolin Xac dinh cau tao cua chung nha cac phucmg phap ph6 hong ngoai, cong huang tir hat nhan, pho kh6i lugng cung nhu cac phuang phap Hoa lugng tu Kiem tra hoat tinh sinh hgc (khang khuSn, chong nam, chong viem nhiem va chong ung thu) ciia cac hgp chAt tdng hop dugc de xac dinh kha nang ung dung cua chiing
5 Cac ket qua dat duo^c
* Ket qud ve khoa hpc vd ky thuat:
- Da tong hgp cac chat dau thugc loai Hidroximetoxiaxetophenon; axetyl-7-hidroxi-4-metylcumarin; 6-axetyl-5 (hoac 7) -hidroxi-4- metylcumarin; cac dan xuSt 3-axetylcumarin, 6-axetyl-7-hidroxi-4- metylquinolin-2-on; 3-axetyl-4-hidroxi-N-phenylquinolin-2-on (11 hcrp chat)
Trang 48 Bang phan ung ngung tu theo Claisen8 Schmidt giua cac chat dau loai metylxeton 6 tren voi cac andehit tham da tong hgp dugc cac day xeton
a, P-khong no co chua cac nhan di vong indol, furan, cumarin, quinolin (84 chat)
- Da xac dinh cau tao ciia cac hgp chat tong hgp dugc nha pho hong ngoai, pho cong huang tu hat nhan va pho khoi lugng
- Cac xeton a, P-khong no tong hgp dugc deu co hoat tinh khang khuan, chong nam va dac biet co mot hgp chat trong do c6 kha nang chong ung thu gan va phoi rat dang chii y
- Ngoai ra trong qua trinh nghien ciiu da tong hgp dugc mot so hgp chat khong binh thuang khac va da gop phan lam ro co ch^ phan ung tao thanh chiing
*Ket qud irng dung thuc te:
- Hau het cac chat tong hgp dugc deu co hoat tinh khang khuan, chong nam, chong viem nhiem, trong do co mot hgp chat [(4-hidroxi-N-phenyl quinolin-2-on-3-yl)(p-nitrophenyl)xeton] co kha nang chdng ung thu ph6i
va ung thu gan ca In Vitro va In Vivo Ket qua nay ma ra kha nang ung
dung rat lan
^Ket qud ddo tao:
- Dang gop phan dao tao 1 nghien cuu sinh (NCS Via Minh Tan)
- Da dao tao 4 thac sT (Dao Thi Thao, Do Tiin Diing, Nguyen Xuan Tii va D6 Duy Thang), gop phan dao tao mot s6 thac si khac va co 3 hgcvien cao hgc se bao ve vao cuoi nam 2007
- Da dao tao 13 cii nhan hoa hgc
*Ket qud cong bo:
- Da cong bo 8 cong trinh tren cac tap chi hoac bao cao a cac Hgi nghi khoa hgc
6 Tinh hinh kinh phi ciia de tai:
- Kinh phi dugc cSp cho de tai trong 2 nam la 300 trieu ddng, trong do chii ylu dh
mua hoa chat va dung cu (khoang 40%); thi nghiem va thue khoan chuyen mon (40%)
- Kinh phi cap cho nam 2005 la 150 trieu Da quylt toan xong
Trang 5- Kinh phi cap cho nam 2006 la 150 trieu Da quyet toan khoang 125 trieu Con lai khoang 25 trieu (kl ca phan tai vu chua tam ung) dung de chi hgp dong thii nghiem hoat tinh chong ung thu tren chugt (khoang 18 trieu) va chi nghiem thu 2 cap (cap CO so va cap DHQG Ha Ngi)
KHOA QUAN LY
P.Chu nhiem Khoa Hoa hoc
Chu nhiem de tai
PGS.TS Tran Thi Nhu Mai GS.TSKH Nguyen Minh Thao
TRUdNG DAI HOC KHOA HOC TU^ NHIEN a •
OHO H l f u TRLfONG
RS.TS. JACITI ^/<t,\4^
^
Trang 6SUMMARY
1 Title: ''Study on synthesis, biological activities (antibacterial, anti
inflammatory and anti cancer) and practical application of some unsaturated ketones containing heterocyclic nuclei: indole, furan, coumarin, quinoline^\
a,fi-Code: QGTD-05-03
2 Director: ProfDr.Sc Nguyen Minh Thao
3 Menbers:
- Assoc.Prof.Dr Nguyen Dinh Thanh
- Assoc.Prof.Dr Tran Cong Yen
- Dr.Luu Van Chinh
- Master Pham Van Phong
- Master Nguyen Thi Minh Thu
- Master Tran Van Tinh
- Technician Le Thi Minh Nguyet
- Some Ph.D., Masters and students
4 Researching Attitudes and Contents
- Researching Attitudes: Synthesizing a new^ series of a,P-unsaturated
ketones expected to have remarkable bioactivities (antibacterial, anti inflammatory and anti cancer)
- Reseaching contents: Synthesizing a new series of a,P-unsaturated ketones
which contain heterocyclic nuclei such as indole, furan, coumarin, quinoline Structures of these compounds were determined by using IR, NMR, MS data and some quantum chemistry calculations Bioactivities (antibacterial, anti inflammatory and anti cancer) of these compounds have been tested to evaluate the practical application
5 Main result:
*Result in science and technology:
- Some hydroxymethoxyacetophenones such as 8-acetyl-7-hydroxy-4-methyl
coumarin; 6-acetyl-5 (or 7)-hydroxy-4-methyl coumarin; some 3-acetyl coumarin and some quinolin-2-one derivatives: 6-acetyl-7-hydroxy-4-methyl
Trang 7quinolin-2-one; 3-acetyl-4-hydroxy-N-phenyl quinolin-2-one (11 compounds) were synthesized as precursors
- A series of some a,P-unsaturated ketones containing heterocyclic nuclei (indole, fiiran, coumarin and quinoline) were synthesized via Claisen-Schmidt condensed reaction of the methyl ketone precursors with aromatic aldehydes (84 compounds)
- Structures of these compounds were elucidated by using IR, NMR and MS data
- All synthesized a,P-unsaturated ketones have antibacterial, anti fungi activities and especially, there is a compound which has a remarkble anti cancer activity to lung and lirer cancer cells
- Furthermore, some intermediates and unexpected compounds found in the experimental processes were used as eridences (to support) for proposal mechanism reactions
"^Result in practical application
- Almostall synthesized compounds have antibacterial, anti fungi, anti inflammatory activities Especially, there is a copound: (4-hydroxy-l-phenylquinoline-2-one-3-yl)(p-nitrophenyl)vinyl ketone which has anti
cancer activity to lung and liver cancer cells in vitro and in vivo This result
leads to a huge promised practical application
^Result in training:
- These is a Ph.D student researching in this project (The project's director is
a co-supervisor for the Ph.D student Vu Minh Tan)
- There ware four graduated MS and there are three more M.S students who will graduate at the end 2007
- Thirteen chemistry B.S were trained from this project
*Publicaions:
- Eight research papers have been published
Trang 8BANG VIET TAT
IR: Pho hong ngoai
^H-NMR: Pho cong huang tu proton
MS: Pho khoi lugng
S.epidermidis: Staphylococcus epidermidis
C.albicans: Candida albicans
P aureus: Pseudomonas aureus
E coli: Eschirichia coli
B.s: Bacillus subtilis
Hep-2: Dong ung thu gan
LU: Dong ung thu phoi
DCUT: Doi chiing ung thu
TBUT: Te bao ung thu
UT: ung thu
Trang 9MUC LUC
• •
Trang
MO DAU 1 LTONG QUAN: Ve cac xeton a,p-kh6ng no 2
1.1 Cac phuang phap tong hgp xeton a,p-kh6ng no 2
1.2 Tinh chdt hoa hgc ciia cac xeton a,p-kh6ng no 4
1.3 Hoat tinh sinh hgc va kha nang iing dung ciia cac xeton a,P-kh6ng no 6
II PHU^ONG PHAP NGHIEN ClTU VA THU^C NGHIEM 7
2.1 Phuang phap nghien ciiu 7
2.2.Thuc nghiem 7
2.2.1 Tong hgp cac chat dau thugc loai metylxeton 7
2.2.2 Phuang phap chung tong hgp cac xeton a,P-kh6ng no 10
in KET QUA VA THAO LUAN 11
3.1 Tong hgp cac hgp chat metylxeton khai dau 11
3.2.Phuang phap tong hgp cac xeton a,p-kh6ng no 15
3.3.Xac dinh cau tao cac xeton a,P-kh6ng no 25
3.4.Hoat tinh sinh hgc ciia cac xeton a,P-kh6ng no 35
3.4.1 Tham do sa bg hoat tinh khang khuan va chong nam ciia cac xeton 35
a,P-kh6ng no
3.4.2.Thii nghiem hoat tinh khang vi sinh vat kiem dinh ciia mot so xeton 38
a,p-kh6ng no
3.4.3.Thii nghiem hoat tinh chong ung thu cua mot so xeton a,P-kh6ng no 40
3.5.Cac san pham khong binh thuang khac tong hgp dugc ngoai xeton 42
a,P-kh6ng no
3.5.1 Cac san pham ngung tu a ca hai nhom 3-axetyI- va 4-metyl- ciia 42
vong cumarin
Trang 103.5.2 Cac san pham ciia phan iing cong hgp vao nhom xeton a,P-kh6ng 43
no theo kieu Michael
3.5.3 Mot so san pham khac 44
IV.KET QUA DAO TAO VA SAN PHAM KHOA HOC KHAC 50
V.TINH HINH KINH PHI CUA DE TAI 51
KET LUAN 52 TAI LIEU THAM KHAO 53
PHU LUC 57
Trang 11M O DAU Cac xeton a,p-kh6ng no la mot lap chat hiju ca rgng lan ma trong phan tii ciia chiing co chiia he lien hgp giiia noi doi vinyl vai nhom cacbonyl xeton Chinh
vi vay ma chiing co thi tham gia vao nhieu phan iing de chuyen thanh nhieu loai hgp chat huu ca khac nhau nhu cac phan ung dong vong pirazolin, isoxazolin, pirimidin va dac biet la tao thanh cac hgp chat tuang tu flavon
Mat khac, nhiiu xeton a,P- khong no va nhieu hgp chat dugc chuyen hoa tu chung CO nhiing hoat tinh sinh hgc dang chii y nhu khang khuan, chong nam, ch6ng lao, diet co dai va tru sau, Dac biet nhung nam gan day, nhieu hgp chat flavonoit da thi hien ca hoat tinh chong ung thu va chong HTV Chiing toi nghT rang nlu tong hgp cac xeton a,P- khong no ma trong phan tu ciia chiing co chiia nhieu hgp phan rieng biet (nhat la cac di vong) deu co hoat tinh sinh hgc thi co the
se tao cac hgp chat co hoat tinh sinh hgc ly thii va da dang han, dac biet khi chuyen hoa cac hgp chat xeton a,P- khong no do thanh cac hgp chat loai flavonoit
Vi vay nhiem vu ciia de tai ma chiing toi thuc hien la tong hgp cac xeton a,P-kh6ng no co chiia cac nhan di vong indol, furan, cumarin, quinolin, va co the CO hoat tinh sinh hgc (khang khuan, chong nam, khang viem va chong ung thu)
Trang 120
TONG QUAN TAI LIEU VE CAC XETON a,p - KHONG NO
l.l.Cac phuoTig phap tong hop xeton a,p - khong no
Co nhieu phuang phap tong hgp cac xeton a,P - khong no, chang han:
- Ngung tu cac ankyl triphenylphotpho clorua vai andehit piruvic (kieu phan ung Vittig) [1]:
n-O
Tucmg tu cung co the cong hgp axewlcloma vao mot olefin r6i tiip theo
nhiet phan san pham cioxeton:
Trang 13TMSC PMBO
OTIPS '*^*'**'^*;' '^^*^'3 ^^*''' '"^'^ ^
diaJiyI cacbonat CH3CN PMBO
Phuong phap selen oxi hoa [9] xeton:
Trang 14Tuy nhien, phuang phap pho bien va thuan tien hon ca de tong hgp xeton a,P - khong no la thuc hien phan iing ngung tu Claisen-Schmidt, nghla la thuc hien phan iing giira mot andehit tham vai mot metylxeton trong dieu kien xiic tac axit (it ph6 biin) [10] hoac mot baza (pho bien han) [11] hay
CO truang hgp dung ca AI2O3 lam xiic tac [12] Co che chung nhu sau:
1.2.Tinh chat hoa hoc cua cac xeton a,P - khong no:
Do trong phan tii ciia cac xeton a,P - khong no co chiia he lien hgp giiia noi doi anken vai nhom cacbonyl nen chiing c6 kha nang tham gia vao nhieu phan iing khac nhau de tao ra nhieu loai hgp chat hiiu ca khac nhau:
- Cdc phdn ung cong hgp 1,2; 1,4 hay 3,4:
-r) Cong 3,4: Chii yeu la khu hoa, halogen hoa va cong hgp dong vong
CH CH'
/
Trang 15) Cong 1,2: Chu yeu vai hgp chat ca magie
+) Cong hgp dong vong voi phenyl hidrazin hay hidroxylamin de tao thanh
vong pizarolin [21] Thi du:
n - C H 3 CH2 = C H - C - C H 3 H , 0
Trang 16L3 Hoat tinh sinh hoc va kha nang frng dung cua cac xeton a,P - khong
no
Nhieu cong trinh [29,30] khi nghien ciiu ve hoat tinh sinh hgc ciia cac xeton a,P - khong no deu da khang dinh chiing hau het co hoat tinh khang khuan
doi vai cac chiing loai g/"^ va ca cac chung loai g/^\ ciing nhu kha nang
chong nam men Ngoai ra con co nhung hgp chat the hien kha nang diet co dai [30]
Trang 17IL PHirONG PHAP NGHIEN CUU VA THUC NGHIEM
2.1 Phu-OTig phap nghien ciru:
- Tong hgp cac chat diu va cac xeton a,p - khong no dugc thuc hien theo cac
phuang phap va cac phan iing tong hgp hiiu co da biet, vai sir cai tien va van
dung sang tao vao dieu kien cu the ciia cac day chat trong ngi dung nghien ciiu
cua de tai
- Cau tao cua cac hgp chat tong hgp dugc xac dinh bai cac phuang phap pho
hong ngoai, cong huang tu hat nhan, pho khoi lugng Chieu huomg va ca che
phan ling dugc xac dinh bang phucmg phap Hoa lugng tii (Phuang phap tinh
gan diing)
- Hoat tinh khang khuan va chong nam dugc xac djnh theo phuang phap da ghi
trong Dugc dien (danh gia theo do lan duang kinh vong vo khuan) dugc thuc
hien a benh vien 19.8 Bg Cong an Hoat tinh chong vi sinh vat kiem dinh va
hoat tinh chong ung thu (In vitro) dugc thuc hien a Phong nghien ciiu Thu
nghiem hoat tinh sinh hgc- Vien hoa hgc cac hgp chat thien nhien- Vien Khoa
hgc va cong nghe Viet nam Hoat tinh chong ung thu tren chugt (In vivo) dugc
thuc hien a Phong thi nghiem Mo phoi va te bao Khoa Sinh hgc - Truang
DHKHTN - DHQG Ha Ngi
2.2 Thirc nghiem tong hop hiru co
2.7.7 Tong hop cdc chdt dau thupc loai metylxeton:
*•* 2-Hidroxi-4-metoxi axetophenon dugc tong hgp bang phan iing axetyl hoa
true tiep resoxinol roi tiep theo metyl hoa mot nhom hidroxi a vi tri 4 bai
dimetylsunphat trong moi truang kiem yeu:
Trang 182-Hidroxi-5-metoxi axetophenon dugc tong hgp bang each este hoa
hidroquinon, roi chuyen vi Fries va cuoi ciing metyl hoa mot nhom hidroxi a
vi tri 5 bai dimetylsunphat trong moi truang kiem yeu:
• 8-Axetvl-7-hidroxi-4-metvl cumarin dugc tong hgp bang phan iing ciia
resoxinol vai etyl axetoaxetat dl tao thanh vong cumarin roi este hoa nhom
hidroxi a vi tri 7 va chuyen vi Fries tiep theo:
• 6-Axetyl-5(hoac 7)-hidroxi-4-metvl cumarin dugc tong hgp bang phan iing
dong vong giua 2,4-dihidroxi axetophenon vai etyl axetoaxetat trong dieu
kien xiic tac khac nhau (AICI3 va POCI3):
••* 3-Axetvl cumarin dugc tong hgp bang phan iing dong vong ciia andehit
salixylic vai etyl axetoaxetat trong moi truang kiem yeu:
^ C l I O " ^ V / ^ ^ ^ ^ - - *-s)
-^
Trang 19• 3-Axetvl-7(hoac 6)-metoxi-4-metvl cumarin dugc tong hgp bang phan iing
dong vong ciia 2-hidroxi-4(hoac 5)-metoxi-axetophenon voi et>! axetoaxetat
trong moi truong kiem yeu:
(I7)
C H 3 0 ^ i ^ 41^ 3 ^ C O C H 3
+ CH.COCHoCOOEt -^=^ CHiCOONa ^ : (Ig)
"l* 6-Axetvl-7-hidroxi-4-metvl quinolin-2-on dugc tong hgp bang phan ung
dong vong m-aminophenon vai etyl axetoaxetat roi este hoa nhom hidroxi a
vi tri 7 va chuyen vi Fries tiep theo a nhiet do cao:
.cH3cocH,cooEt—rr"i £ M 2 h ^ ^ ^ -^2i^ r X ^1 ^^^^
H2N Hd 'r ° CH3CC/ ^ ^ N O HO I ""
^ H H
•• 5-AxetyI-6-hidroxi-4-metvl quinolin-2-on dugc tong hgp bang phan iing
dong vong p-aminophenol roi este hoa nhom hidroxi a vi tri 6 roi chuyen vi
Fries tiep theo:
pH
HO, C H i - C O - C H + CH3C0CH,C00Et
**• 3-Axet\'l-4-hidroxi-N-phenvl quinoiin-2-on dugc tong hgp bing phan iing
dong vong cua diphenylamin vai diety! malonat roi tiep theo phan hiiy san
pham tao thanh bang dung dich kiem
Trang 202,2.2 Phuang phdp chung tong hpp cdc xeton a,p- khdng no
A^r-C0CH3 + A^r-CHO ^^^"^ - A ^ r - C O C H - C H - A^r
Dun soi hoi luu hon hgp ciia metyl xeton (Ii-n) vai cac andehit tham hoac di vong tham (IIi.) theo ti le moi 1:1 trong clorofom vai vai gigt piperidin lam xiic tac (hoac trong etanol vai dung dich NaOH lam xiic tac) trong thai gian thich hgp (tu 8-30 gia, tuy theo phan iing cu the) San pham tach ra a dang ket tiia dugc igc hiit, nia sach, de kho ngoai khong khi va c6 the ket tinh lai tii etanol hoac etanol-nuac hay etanol-dimetylfomamit,
Cac xeton a,P - khong no tong hgp dugc dugc giai thieu a cac bang 1-8
Trang 21IIL KET QUA VA T H A O LUAN 3.L T6ng hgp cac hop chat metyl xeton kho-i dau (Ii-u):
3.LL 2-Hidroxi'4-metoxi axetophenon (Ij): Dugc tong hgp tii resoxinol qua
hai giai doan (axetyl hoa true tiip resoxinol bang axit axetic bang vai xiic tac la kem clorua khan r6i metyl hoa nhom hidroxi a vi tri so 4 bang dimetylsunphat trong moi truang kiem yeu hoac bang each diaxetat hoa resoxinol roi chuyen vi Fries tiip theo a nhiet do 145^C Hieu suat: 65% (giai doan cuoi)
+) San phim co t^nc 52-53^C (theo tai lieu [31], t^^c 52-53^C) +) Ph6 hdng ngoai (cm"^): 3303(V.OH) , 1606(v.co), 1143 (v coc)
+) Ph6 ^HNMR (5pp^): 2,51 (3H, COCH3); 3,82 (3H, OCH3); 6,30; 6,47 va 7,84 (C3-H, C5-H va Cg-H cila vong benzen); 12,63 (IH,-OH)
-OH
COCHj
OCH
3.1.2 2-Hidroxi'5-metoxi axetophenon (I2): Dugc tong hgp bang each diaxetat
hoa hidroquinon, chuyen vi Fries tiep theo roi metyl h6a nhom hidroxi a vi tri 5 trong moi truang kiem yeu (K2CO3) bai tac nhan dimetylsunphat:
3J.3.8'Axetyl-7-hidroxi'4'metyl cumarin (Is): Dugc tong hgp bang phan iing
ciia resoxinol vai etyl axetoaxetat roi axetat hoa nhom hidroxi va chuyen vi Fries tiep theo
Trang 22CHj
-)San pham co t^nc ! 6 ; - 1 6 2 ' t (theo tai lieu [33] t'
>X^n-^4 0
161-162T) +) Pho hong ngoai (cm"'): 1736(v.co lacton) , 1632(v.co xeton), 3437 (V.OH)
3.L4 6-Axetyl'5-hidroxi-4-metyl cumarin (I4):
Dugc tong hgp bang phan iing dong vong cua 2,4-dihidroxi axetophenon vai etylaxetoaxetat trong su co mat ciia tac nhan nhom clorua lam xiic tac
+) San phim co t^^ 165-166^C (theo tai lieu [34], t^e 165-166^0)
-f-) Pho hong ngoai (cm"'): 3236 (V.QH), 1743(v.co lacton), 1606(v.co xeton)
+) Ph6 kh6i lucmg (ra/z): 218 (lvr)(C,2H,o04, M=218); 203 (M^-CHj); 190(M^-COCH3); 175 (203-CO hoac I9O-CH3), 147 (175-CO)
Trang 23C3-+) PhSkhm lugng (m/z): 218 (M^), 203, 190, 175, 147,
3.1.6 3-Axetyl cumarin (I^
Dugc tong hgp bang phan iing dong vong ciia andehit salixylic vai etyl axetoaxetat trong moi truang kiem yeu (CH3C00Na):
^^<A^^QOQ\{^ +) Hieu suit: 40%
r If J + ) S a n p h i m c 6 t V : 1 3 0 - 1 3 l " C
' 1 +) Pho hong ngoai (cm"'): 1725(v,co lacton) , 1635(v
CO xeton)
+) Pho 'H-NMR (5ppJ: 2,59 (s, 3H, -COCH3); 7,42 (m, IH, Cg-H); 7,45 (d,
IH, Cg-H); 7,75 (m, IH, C7-H); 7,96 (d, IH, C5-H); 8,65 (s, IH, C4-H)
+) Ph6 khoi lugng (m/z): 188 (M^) (CuHsOj M 188)
+) Ph6 kh6i lugng (m.'z); 232 (M"") !C,:H,:04 M 232)
I",
5 1
Trang 243,1.8 3-Axetyl-6-metoxi'4-metyl cumarin (Is)
Dugc t6ng hgp tuang tu le va I7 nhung di tu 2-hidroxi-5-metoxi-axetophenon
vai etyl axetoaxetat:
+) Ph6 khoi lugng (m/z): 232 (M^) (Ci3H,204 M 232)
+) Ph6 khoi lugng (m/z): 217 (M^), 202 (100%) (M^-CH3),
3.1.10 5-Axetyl-6-hidroxi-4-metylquinolin-2-on (Ijo):
Dugc tong hgp bang phan ung dong vong p-aminophenol vofi et\'I axetoaxetat, este hoa tiep theo roi chuyen vi Fries este nhan dugc:
Trang 25/,0 -h) Hieu suat: 44% (Giai doan chuyen vi Fries)
^n^6/& >^!^' +)Sanphimc6tV:163-165'C
L J I L +) Ph6 h6ng ngoai (cm''): 1665(v.co lactam) , 1642(v.c
' H xeton); 3252 (V.OH); 3059 (V.NH) • +) Ph6 'H-NMR (5ppJ: 2,03 (3H, -CH3); 2,60 (3H, -COCH3); 6,92 (IH, C3-H) 7,68 (d, IH, Cg-H); 8,08 (d, IH, C7-H); 9,91 (IH, OH); 11,58 (IH, NH)
3.1.11 3-Axetyl-4-hidroxi-N-phenylquinolin-2-on (Iji):
Dugc tong hgp b^ng phan ung dong vong cua diphenylamin vai dietyl malona r6i tiep theo phan hiiy san pham tao thanh bang dung dich kiem
OH +) Hieu suit: 90% (Giai doan cu6i)
CT J +)San pham co t\, : 237-238°C (Theo tai lieu [36
3.2 Phucng phap tong hop cac xeton a,P - khong no
Cac xeton a.p - khong no dugc to g HOT bang phan img n2Lmg tu cua hop che meryi xeton fli.:-! 6' iren vai cac an^eh:: :ham hoac andehr di vonii thG':n tron
Trang 26moi truang kiem, nghla la thuc hien theo dieu kien ciia phan iing Schmidt:
Claisen-Ar-C0CH3 + Ar'-CHO ^^^^ » Ar - CO - CH - CH - Ar'
(I) (II) ^'^'^^ m
Vai tro ciia kiem a day la lam xiic tac cho phan iing ngung tu, ma thuc chat la
dk keo proton tach khoi nhom -CH3 axetyl va chuyen no thanh cacbanion, tu do
tao lien ket vai C-electrophin ciia nhom cacbonyl andehit Moi truong baza a day thuang la dung dich KOH (hoac NaOH) trong etanol Tuy nhien trong cac truang hgp sii dung dan xuat axetyl ciia vong cumarin thi lai dung piperidin (baza huu co) trong clorofom lam xiic tac (vi trong moi truang kiem manh vong cumarin thuang bi pha va lien ket 1-2)
Thai gian phan iing tuy thugc vao cac metyl xeton va cac andehit, co the tu 5-8 gia den 25-30 gia Liic dau khi dun soi hoi luu, hon hgp phan iing tan het, nhung sau do, san pham dugc tao thanh tach ra a dang ket tiia ngay khi dang dun soi
Cac xeton a,p - khong no ma chiing toi tong hgp dugc deu a dang tinh the, thuang dugc tinh che bang each ket tinh lai trong etanol hoac hon hgp etanol- nuac (theo the tich) hay hon hgp etanol:dimetylfomamit Do tinh khiet cua cac xeton a,P - khong no dugc kiem tra bang sac ki ban mong (cho mot vet ggn vai
tn so Rf khac vai cac chat dau) tien hanh tren ban mong silicagen trong he dung moi clorofom: etyl axetat = 4:1 (theo the tich)
Ket qua tong hgp cac xeton a,|3 - khong no dugc giai thieu a cac bang 1-8
Bdng 1: Cdc xeton a,/3- khong no ddy
2-hidroxi-4-(kodc 5-) metoxi axetophenon
OH
-CO CV - Cn - Ar
• ^
C H Q - 4 - '! f-^l-S'
Trang 273,4 phenyl
Nitropheny)- -fiiryI-2 IndolyI-3
5-(p- Metylindolyl- -3
N- Dioximetilen-
3,4 phenyl
Nitropheny)- -furyl-2 Indolyl-3
5-(p- Metylindolyl- -3
* Bdng mong silicagel He dung moi Clorofom: Etylaxetat=' 10:1 (doi vai
cdc Xeton X3 vd X5,6,7,8) He dung moi Clorofom: n-Hexan= 10:1 (doi vai xeton X2 vd X4) vd 1:1 (ddi vai Xeton XI)
DAI HOC QUOC GIA HA NGI TRUNG TAM THONG TIN THU VlEN
OCO^COOC04-i>
Trang 28Bdng 2: Cdc Xeton a,^- khong no ddy 8'axetyl-7-hidroxi'4-metyl cumarin
238 237-
239
168-170 243-
1520,1337
(NO2) 1525,1342 (N02)
(NH indoO
(NR indol)
(NH indol)
}
Trang 29270 144-
*Bdng mong silicagel: He dung moi Clorofom: Etyl axetat~4:l
Bdng 3: C3c Xeton a,fi- khong no ddy 6-axetyl-5-(hodc 7-) hidroxi
-4-metylcumarin
CH3
A r - C H ^ C H - C O ^ f e : ; ; ^ ' ^ ^ ^ 3
/ / -or^o
p-Dimetyl-o-Hidroxiphenyl
Dioximetilenphenyl
1530,1353 0<O2)
1139
(C-O-C)
4 1 3 3
-1
Trang 30*Bdng mong silicagel: He dung moi Clorofom: Etyl axetat=4:l
Bdng 3: C3c Xeton a,fi- khong no ddy 6'axetyl-5'(hoac 7-) hidroxi
-4-metylcumarin
CH3 Ar-CH = C H - C O ^ ^ ; j ? = ^ \ / ^ 3
/ / • o r ^ o
p-Dimetyl-o-Hidroxiphenyl
Dioximetilenphenyl
3,4-
5-(p-Nitrophenyr>-i^jrv-1-2 -
t**
"c
219-220 264-
344-Hieu suat
1530,1353 (N02)
Trang 313,4-Indolyl-3
2-MetylindoIyl-3
298-299 279-
280 301-
302 300-
301 309-
1194 (C-O-C) 1545,1333
(N02)
3106 (NHindoI)
3195 (NHindoI)
Bdng 4: Cdc Xeton oc,P- khong no ddy 3-axetyl cumarin
Mi-
248-250 198-
200 194-
195 216-
217 o-Hidrcxiphenyl 132-
1S3
Hieu suat
Trang 321212 (COC vong)
I
1
1
Hieu suat
1703
; 704
V c o xeton
—
1525
134:-(NO:)
Trang 333,4-m-Nitrophenyl
p-Nitrophenyl
p-Dimetyl aminophenyl 3,4-
Dioximetilen phenyl
234-235
177-178
179-180 194-195
807 (C-Cl) 1526-
1355 iN02)
1529,
1359 (NO2)
1257,
1198 (COC)
Bdng 6: Cdc Xeton oc,P- khong no ddy 5-axetyl-
1
1
1
Trang 341548 (NO2)
* Bdn mong silicagen He Clorophom: Etyl axetat = 4:1 (Theo the tich)
Bdng 7: Cdc Xeton a,fi- khong no ddy
ilir/1-2 j 344
5-(^' \ itrophen y\ )- -1 ~> V
730
Hieu suat
Trang 353211 (NHindoI)
3185 (NHindoI)
r
3.3 Xac djnh cau tao cua cac xeton a,P - khong no
Cac xeton a,P - khong no dugc chiing toi tong hop deu la cac chat ran ket
tinh, dugc tinh che can than bang ket tinh lai, co nhiet do nong chay va gia tri Rf
tren sac ki ban mong khac vai cac chat dau
Cau tao cua chung dugc xac dinh bang pho hong ngoai, pho cong huong tu hat
nhan va pho khoi lugng
*Tren pho hong ngoai cua cac xeton a,P - khong no deu co vach a khoang 940 - 990 cm", dac trung cho dao dgng bien dang khong phang cua nhom vinyl vai cau hinh trans Cac xeton a,p - khong no di tu dan xuSt cua
vong cumarin thi tren pho hong ngoai deu co vach dao dgng hoa tri ciia nhom
CO lacton trong vung 1700 -1750 cm"^ va vach dac trung cho dao dgnghoa tri
ciia nhom CO xeton lien hgp o vung 1600 - 1640 cm'\ Ph6 h6ng" ngoai ctia
xeton a,p - khong no chua vong quinolon -2 ciing deu co vach dac trung cho
dao donghoa tri ciia nhom CO lactam trong vung 1650 - 1670 cm"^ va c6 nhom
CO xeton a vung 1600 - 1640 cm'^ Ngoai ra tren pho hong ngoai ctia cac xeton
a,p - khong no ciing deu co cac vach dao dong dac trung cho cac nhom Lhac co
mat trong phan tu nhu OH, NO2, NH,
C'.ic dir kien pho hong ngoai dugc ghi a bang 1-8
*Ph6 cong hucmg tu proton ciia cac ?ce:on a.3 - kliong n-j dcu cho ::n :ieu
;nv)t doi vach doi (dciiplet) dirai dang h;e\: ^ 2 ina: nha trons khoam 6.?1- 8.0?
Trang 36@
va 7,15 - 8,62 ppm va hang so tuang tac spin - spin J^ 15 - 16,5 Hz, dac trung
cho chuyen dich hoa hgc ciia nhom vinyl a cau hinh trans Ngoai ra tren pho
cung xuat hien cac tin hieu dac trung cho chuyen dich hoa hgc ciia cac proton khac trong phan tu
Cac du kien pho cong huang tu proton ciia cac xeton a,p - khong no dugc ghi a bang 9
Bdng 9: Pho ^H-NMR ciia cdc xeton oc^fi- khong no
Xeton Cong thirc 'ppm (J Hz)
CH=CH- Cac proton khac
3,85 (s, 3H'); 6,5(d, IH", J=2,5); 6,56 (q, l H \ j m = 2 , 5 , Jo=9); 7,25(m, 2H, H ' % a H " , Jm=2,5, Jo=9); 7,50 (q, 1H^ Jm=2,0 Jo=9);8,12(q, 1 H ' ^ Jm=3,0, Jo=6,5); 8,22 (d, I H ^ J-9), ll,98(s, IH'); 13,05 (s,
IH'O-7,69 va 8,17 (J =15,5)
3,82 (s, 3H0; 6,96 (c, IH, H \ J=3); 7,22 (q, 1 H \ Jm=3, Jo=6); 7,34 (d, 1H% J-4); 7,56 (d, I H ^ J=3);7,53(d, l H ^ J = 4 ) ; 8 , 1 9 ( d , 2H, H ' % a H ' \ j = 9 ) , 8 , 3 3 ( d ,
2 H , H " v a H " , J = 9 ) ; l l , 7 7 ( s ,
I H ' )
7,73 va 8,17
Trang 37l H ^ J = 7 , 5 ) ; 8 , 2 2 ( s , l H ^ ) ; 12,46 (s, IH')
X9
/N(CH3)2
4'
6,90 va 7,23 (J = 1 6 )
2,49(3H, CH3); 2,98(6H, N(CH3)2); 6,17(1H, C3-H); 6,70 (2H, C2-H va C6- -H); 6,94 (IH, C5-H); 7,51 (2H, C3-H va Cs H);7,69(1H,C6-H);11,0(1H, OH)
(J=16)
2,41(3H, CH3); 6,09 (2H, );6,17(1H,C3-H);6,93(1H,C5- H);6,95(1H,C5-H);7,17(1H, C6-H);7,43(1H,C2 H);7,70 (IH, C6-H);8,30(IH,OH)
7,66
(J = 1 6 )
2,42 (s, 3H, -CH3); 6,20 (IH, H); 6,97 (1H,C5-H); 7,73 (IH, C6-H); 7,48 (1H,C4-H), 7,95 (1H,C7'-H);7,22(2H,C5-Hva C6-H); 7,99(C2-H); 11,30 (OH); 11,93 (NH)
H v a C 6 - H ) ; 8 , 2 ! ( C 7 - H ) ; 8 , 3 3 (C:-H); 1! ,30 (OH)
Trang 382,45 (3H,-CH3); 5.49 (-CH2-, 2H); 6,19 (C3-H); 6,96 (C5-H); 7,72(C6-H); 7,56 (C4-H), 7,96 (C7-H);8,15(C2'-H); 7 , 2 0 - 7 , 3 5
7,83 va 7,93 (J = 1 5 )
2,64(s,3H,-CH3);3,05(s, 6H, N(CH3)2); 6,28 (IH, C3-H); 6,78 (d,2H,Cu-HvaC,3-H;J=9,5); 6,95 (d, IH, C7-H, J=9); 7,82 (d,
2 H , C I O - H ; C H - H ; J = 9 , 5 ) ; 8 , 5 9 (d,lH; Cg-H; J-9); 13,76(OH)
2,64 (s, 3H, -CH3); 6,28 (IH, H);6,91 (m, IH, C , 4 - H } ; 6 , 9 7 (m, 2H,C,2-HvaCi3-H);7,33 (m, IH, C n - H ) ; 7,97 (d,lH, C7-
C3-H ; J = 9 ) ; 8 , 5 3 ( d , l C3-H ; C 8 - C3-H ; J = 9 ) ;
9 , 9 5 ( S , I H , C,o-H); 10,42(s, IH, C5-OH)
2,68(s, 3H,CH3);6,13(s, 2H, CH2-); 6,26 (s, IH, C3-H1;6,95
-(m, 1 H , C , 4 - H ) ; 7 , 0 3 ( d , IH,
C7-H);7,41 (d,lH,Ci3-H);7,75 ( d , l H ; C r H ) ; 8 , 6 I ( d m , C,o-
b - C H
Trang 392.65(s 3H,-CH3); 6.26(1 H,
C;-H ) : 7 , 2 8 ( m 2 C;-H , C,3-C;-HvaC,4- Hl;7,52(m, IH C,2-H);8,17
C,3HvaC,4(m IH, C l 5 H ) ; 8 , 2 6 ( l H , C l o H);8,57(d,lH;C8-H;J=9);7,13 ( d , l H , C 7 - H ; J - 9 ) ; 1 2 , 1 3 ( l H ; NH); 13,85(s, IH, O H )
7,91 (J =15,5)
CH2-); 6,28 (1H,C3-H1; 6,90 ( 1H,C5-H);7,03(d, IH, C14-H); 7,40Jd,lH,C,3-H);7,68(IH; Cio-H); 8,38 (IH,C8-H); 9,81 (s,
2,54(3H,-CH3);6,15(2H,-IH, O H )
7,80 va 8,20 (J =15,5)
2,51 H); 6,89 (1H,C5-H); 7,27 (m, 2H, C,3-HvaCi4-H};7,52(lH, C,2-H); 8,09 ( I H , C , 5 - H ) ; 8,23 ( l H , C r H ) ; 8 , 3 2 ( l H ; C 9 - H ) ; 9,95 (1H,NH); 12,08 (IH, OH)
7 , 5 I ( l H , C r H ) ; 7 , 5 4 ( 2 H , C , o - H
va Cu-H); 7,79 (2H, Cn-H va C13-H); 7,45 (1H,C6-H); 7,78 (1H;C7-H);7,96(1H;C5-H); 8,73(1H, C4-H)
7,24(1H,
C.rH);7,26(iH,C13- H);7.5inH.C,5-HK",74(lH, C-
H):'?43(lH,Co-Hi;7^i9(lH.C3-H );7.95 (IH):'?43(lH,Co-Hi;7^i9(lH.C3-H;C5-H):'?43(lH,Co-Hi;7^i9(lH.C3-H):^.06(1H):'?43(lH,Co-Hi;7^i9(lH.C3-H;
, Ci,rH);S.'^5(lH C.^Hi
Trang 40n
CH3O ^ 5
6,91 va 7,35
(J = 1 6 )
2,50 (s,3H.-CH3); 3,84 (s,3H, CH3O-); 6,08 (s, 2H, -CH2-); 6,95(1H, C5-H; J=8);-^,08(IH, C6-H;Jo=8;Jm= 1,5); 7,31 (IH, C7-H,Jo=9;Jin=3);7,37(lH, C5-H;J=3);7,43(iH;C8-H; J=9);7,50(1H,C2-H;J=1,5)
2,50 (s,3H,-CH3); 3,89 (s,3H, CH3O-);7,01 (d, IH, C6-H; Jo=9; Jm=2,5); 7,09 (d,IH, Cg-
H ; J = 2 , 5 } ; 7 , 4 I ( m , l H , C 4 - I J ; Jo=7,5); 7,45 (m,2H, C3-H, Cs- H,Jo=7,5); 7,68 (m,2H, C2-H; C6-H; J=7,5); 7,88 (d, 1H;C5- H; J-9)
J m = 2 , 5 ] ; 7 , 0 5 ( d , I H , C r H ; Jm=2,5); 7,50 (m,2H, C3-H, C5- H; Jo-9); 7,92 (d,IH, C5-H; Jo
l H , C 5 - H ; J o = 9 ) ; 7 , 4 5 ( d , l H , C^-H; J m = ! 5 )