Nghiên cứu tổng hợp, hoạt tính sinh học (kháng khuẩn chống viêm, chống ung thư) và khả năng ứng dụng của một số xetôn α, β không no có chứa nhân dị vòng indol, furan, cumarin, q

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 HpC (KHANG
K H U A N , CHONG VIEM, CHONG UNG THU) VA KHA NANG
iTNG DVNG CUA MpT SO XETON a,P - KHONG NO CO C H I T A
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


- 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 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


BAO 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 moi, 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; 8axetyl-7-hidroxi-4-metylcumarin;

6-axetyl-5

(hoac

7)

-hidroxi-4-

metylcumarin; cac dan xuSt 3-axetylcumarin, 6-axetyl-7-hidroxi-4metylquinolin-2-on; 3-axetyl-4-hidroxi-N-phenylquinolin-2-on (11 hcrp

chat).


- Bang phan ung ngung tu theo Claisen-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.


- 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 Hlfu TRLfONG

RS.TS.

JACITI

^/^


SUMMARY
1. Title: ''Study on synthesis, biological activities (antibacterial, anti
inflammatory and anti cancer) and practical application of some a,fiunsaturated ketones containing heterocyclic nuclei: indole, furan, coumarin,
quinoline^\
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


quinolin-2-one;
3-acetyl-4-hydroxy-N-phenyl
compounds) were synthesized as precursors.

quinolin-2-one

(11

- A series of some a,P-unsaturated ketones containing heterocyclic nuclei
(indole, fiiran, coumarin and quinoline) were synthesized via ClaisenSchmidt 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-lphenylquinoline-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.


BANG VIET TAT
PMB: para-MetylbenzylTMS: TrimetylsilylTIPS: Tri-iso-propylsilyl
Ph: Phenyl
Et: Etyl
Ar: Aryl
DMF: Dimetylfomamit
DMSO: Dimetylsunfoxit
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


MUC 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
vong cumarin

42


3.5.2. 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


M 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).

0

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]:
RCH2P>h3Cr + CH3COCHO

NaHC03

H-

(-HCI) '

COCH.

•Ph3P=0
-^
^ R-CH=CH-C0-CH3

•0

Ph3

Quang dong phan hoa 4-benzanamino-3-metyl-5-stiryl isoxazolin [2]
^3^^

.a

_^ N=CHPh

^™\Q/

,

CH=CHPh

.,

^COCH=CHPh

f w

<

N
I
H

CH:

Phan hiiy cac P-aminoxeton [3,4]:

COCH3
x^^/N=CH-

+

Q..^

N

0^'

r^^^^z-'^.NH-CH
"CH-,CO~
W

,/^.NH.

o-

R'

•Q-CO-CH=CH-Q;
N

Chung cat hoi luu diaxetoancol de tach phan tii nuac va tao thanh xeton
a,p-khong no [5]:
2 CH3-CO-CH

Ba(0H)2 CH3
^
CH.

OH
C-CH2-CO-CH3

•H2O

CH3

\ C=CH-C-CH3
n-

CH: /

II
O

Tucmg tu cung co the cong hgp axewlcloma vao mot olefin r6i tiip theo
nhiet phan san pham cioxeton:


CH;
I

H3C-C=CH2 +CH3COCI

O
il

CH3-C-CH2-C-CH3
I
Cl

CH3

-HCI

CH3

o

I

II

CH3-C=CH-C-CH3

- Phan ung ciia axit cacboxylic vai ankylvinyl liti [6]:
COOH
RCH=CHLi

O

CH=CHR
OLi

/^\^C0OLi
RCH=CHLi

OLi

II

•CH=CHR

H2O

Oxi boa theo Saegusa [7,8]:

wTMS-OCOCH

o

OH
R

• OTMS

R

r^R

TMS-CI

OTMS

A Pd'U 0

Pd(OCOCH3)2

R
^ >

Pd'

o

o

R
N ^ Pd + H-

Thi du:

O T I P S LiTMP, TMS-Cl

TMSC

OTIPS '*^*'**'^*;' '^^*^'3 ^^*''' '"^'^ ^
diaJiyI cacbonat. CH3CN
PMBO

THF. -7rc

PMBO

Phuong phap selen oxi hoa [9] xeton:
o

bazcT

-O
PhSeBr

o

o

[O]

»SePh

Ph-Se=0

Thi du:
Ph'

1. LDA. TKF.-T8^C
2. PhSeBr

"

Ph-

SePh

H^O^. Pirdin

Ph: 5 X , 30Phut

r66%j


Tuy 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:
\

\

?

/

I

^ 2 0 ^ - ^ ^

^ _C-CH-C-0
OH
'

C = 0 + -CH2-C=0

c-c = o

Chinh bang phan ung ngung tu Claisen-Schmidt, nhom chiing toi da tong hgp
dugc hang loat day xeton a,P - khong no co chiia cac nhan di vong trong phan
tii. [13,20]

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
H

C6H5-CH = CH-CO-CH3

C6H5-CH2CH2-CO-CH3

(Zn/CH3C0OH)

CH, = C H - C O - C H ,

CH2-CH-CO-CH3

+ Br,

I

I

Br

Br

Base

0

CH.

b CH3

CH3

^COCH,
CH
CH'

(-H.0)

/


) Cong 1,2: Chu yeu vai hgp chat ca magie
.1
R^

^^^

R2'

r,
O

R^

OH

1.RMaX

^R.

1/R
R'

2.H^

"R3

+) Cong 1,4: Day la phan iing dac trung nhat ciia xeton a,P - khong no.
OH
CH,'2 -= CH,
'-"2 - C

\

CH,
'2 -- 'CH,
-^'2 - C

CH,
'2 -- •CH,
-i»2 = C

HBr

\

'CH-

CH3

Br
R^

0
RMgX

R^

OMgX

I

I

r

R2'

-

CH-

Br

R^

OH

1

I

R^

0

R2'

Cdc phdn ung cong hop ddng vdng dehidrat hda de tao ra cdc hcrp chat
di vong:

+) Cong hgp dong vong voi phenyl hidrazin hay hidroxylamin de tao thanh
vong pizarolin [21]. Thi du:
CH2 = C H - C - C H 3
11
O

+ Ph-NHNH,

n-CH3

.H,0
^-

N

I
Ph
CH. = CH - C - CH3

CH

H,0
+ H2N-OH

O

\ ^ / N
O'

+) Phan ling ngi phan tu dong vong thanh cac hgp chat kieu flavon [22-27]
Thi du:
< ^ / ^ _ Ar

COCH-CH-Ar
— OH

S/Xilen

O

+) Phan ling vai guanidin de tao vong pirimidin [28], thf du:

c'

HN

Ar - CO-CH = CH-Ar' -

\\

C-NH^

HoN

rr'N
N

Nn2


L3. 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].


IL 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:
OH

COCH,
HO
ZnClOH

COCH3

'
(
)!
^ V ^
OH

HQ^
_

_ _ _ _
K:C03 - Axeton

(
)!
^^^:r^
OCH;


2-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:
pH

OCOCH3
(CH,0>.0 ^
7^ *"

'

rf^
lv J]

AICI3
;;

1

OH

OH

f^"

ff^-COCH;
*" V ) \

i.
KXO. - Axeton

f^ ^ '

"-^^

ncu

1
OCOCH3

^^^"^

OH

^^^'

• 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:
pH
^"

CH3
LH3

CH3
yM3
(CHjOsO

HO

HO'^^'^'^O^'^0

r^:^^^>^^

cH^

I

AICI3

cH^coo^^-^'^^o^'^o

Hcr"'^=^^-^^o^''^o

• 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):
CH,CO

(I4)

pH
/CPCH3

+ CH3COCH2COOEt

••* 3-Axetvl cumarin dugc tong hgp bang phan iing dong vong ciia andehit
salixylic vai etyl axetoaxetat trong moi truang kiem yeu:

t

/OH

^-\
CFi-COO^Ja

^ClIO

^

/ ^
^

/COCH^

"^V/^^^^--

-^

*-s)


• 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:

COCH

/

OH
CHiCOONa

CH3C0CH,C00Et

(I7)
CH3O

OCH1

7

COCH3
' ./OH

CH30.^i^

41^

CHiCOONa

3^COCH3

^:

+ CH.COCHoCOOEt -^=^

(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:
pH

CH,

CH.

CH3CO

.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,

CHi-CO-CH
C

+ CH3C0CH,C00Et

\

NH

CH3C00k^
(CH3CQ)20

/ "^O

AlCl-

^ 120-130*^0

^

N"^O

CH:

?

HO
^

^

^

l

^

'

1

^

(I.

H

H,N

**• 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


OH

COOEt

NH

2

•OH

CH.
COOEt

1) NaOH

t"C

2) HCI

r'^
-

COCH3

2,2.2. Phuang phdp chung tong hpp cdc xeton a,p- khdng no
A^r-C0CH3 + A^r-CHO
I
II

^^^"^ - A ^ r - C O C H - C H - A^r
H.O

III

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.


IIL KET QUA VA THAO 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)
COCHj

+) Ph6 hdng ngoai (cm"^): 3303(V.OH) , 1606(v.co), 1143 (v.

OH

coc)
+) Ph6 ^H-NMR (5pp^): 2,51 (3H, -COCH3); 3,82 (3H, OCH.

OCH3); 6,30; 6,47 va 7,84 (C3-H, C5-H va Cg-H cila vong

benzen); 12,63 (IH,-OH).

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:

OH

+) Hieu suat 62%, giai doan metyl hoa
COCH3

+) San pham co t ^ 48-50^C (theo tai lieu [32], t^^c 48-50V)
+) Ph6 h6ng ngoai (cm"'):

OCH.

3243(V.OH)

, 1615(v_co), 1150 (v_

coc)-

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

-)San pham co t^nc ! 6 ; - 1 6 2 ' t (theo tai lieu [33]. t'
CHj

161-162T)
+) Pho hong ngoai (cm"'): 1736(v.co lacton) ,

>X^n-^4
- ^
-Q
0

HO ^

M

1632(v.co xeton), 3437 (V.OH)
+) Ph6 'H-NMR (5ppJ: 2,39 (CH3); 2,60 (COCH3);

CH-,C = 0

6,1(C3-H);

6,9 (C5-H); 7,70 (C6-H) 11,61 (OH).

+) Ph6 kh6i lugng (m/z): 218 (M'')(Phan tu khdi cua hgp chAt 218); 203
(M^-CH3); 190(M"-COCH3); ...

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
OH

I

CH.CO.

CH3

165-166^0)

4I

-f-) Pho hong ngoai (cm"'): 3236 (V.QH), 1743(v.co
2

lacton), 1606(v.co xeton).
X

1-

+) Pho 'H-NMR (5ppJ: 2,59 (3H, d, C4- CH3); 2,69 (3H, s, -COCH3);
6,27(1H, C3-H); 6,93 (IH, d, Cg-H, Jo=9Hz); 8,16 (IH, d, C7-H, Jo=9Hz);
14,19 (lH,s,C5-0H).
+) 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)...
+) Hieu suit: 4 1 %

3.1.5. 6-Axetyl-7-hidroxi-4-Tnetylcumarin

(!$):

Dugc tong hop ciing bang phan iing dong vong ciia 2,4-dihidrcxi
axetophenon vai etyl axetoaxetat nhung sir dung POCI3 lam xiic tac.
+) Hieu suat: 32%
+)San pham co ^',, 2i2''C ':heo :ai heu [J5]. t".


CH3

212"C)

CH3C0xi^^^^i^ 3

+) Pho hong ngoai (cm"'): 3240 (V.QH), 1728(v.co

HO "7"^^-^ ^ 0 ^ 2 ^ 0
8

lacton), 165 1(V.CO xeton).

1

+) Pho ^H-NMR (5ppJ: 2,50 (3H, -CH3); 2,71 (3H, -COCH3); 6,28(1H, C3H);6,90(s, 1H,C5-H); 8,17 (s, IH, Cg-H); 12,33 (s, IH,-OH).
+) 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):
^^
+) Hieu suit: 40%

r

+)Sanphimc6tV: 130-13l"C

If
'

J
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).

S.1.7. 3-Axetyl-7-metoxi-4-metyl

cumarin (17)

Dugc tong hgp tuong tu Ig nhung di tu 2-hidroxi-4-metoxi-axetophenon ( dong
vong voi etyl axetoaxetat):
+) Hieu suit: 35%

+)San pham co t V : 145-146^
+) Pho hong ngoai (cm"'): 1720(v.co lacton) ,
1654(v.co xeton).
) Pho5 1'H-NMR (5pp„): 2,44 (s, 3H, -CH3); 2,58(s, 3H, -COCH3); 3,89 (s, 3H,
CH3O-); 6,90 (d, I a Q-H); 6,82 ; J, !H. C-H); 7.62 (d. IH, C.-Hj.
+) Ph6 kh6i lugng (m.'z); 232 (M"") !C,:H,:04 .M. 232).

I",


3,1.8. 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:
^"3^^^V^.^cocH3

+) Hieu suit: 30%
^ ^ ^ ^ p ^ , ^ ^^ ^0^^ ^ 134-135V
+) Pho hong ngoai (cm''): 1711(v.co lacton) ,
I690(v.coxeton).

+) Ph6 'H-NMR (5ppJ: 2,39 (s, 3H, -CH3); 2,48(s, 3H, -COCH3); 3,86 (s, 3H,
CH3O-); 7,30 (q, IH, C7-H); 7,32 (d, IH, C5-H); 7,41 (d, IH, Cg-H).
+) Ph6 khoi lugng (m/z): 232 (M^) (Ci3H,204 .M. 232).

3.1.9. 6-Axetyl-7'hidroxi-4-metylquinolin-2-on (I9):
Dugc tong hgp bang phan iing dong vong cua m-aminophenon vai etyl
axetoaxetat roi este hoa nhom hidroxi a vi tri 7 bai anhidrit axetic va chuyen
vi Fries este tiep theo (tuong tu I3):
+) Hieu suit: 45%
+)Sanphim co t^e: 291-293^0

Kl "

- 0

I '

H

-r

\

1

+) Pho hong ngoai (cm'): 1666(v.co lactam) , 1645(v.co
xeton); 3000 (V.OH); 3154 (V.NH)-

+) Ph6 'H-NMR (6ppn,): 2,44 (3H, -CH3); 2,69(3H, -COCH3); 6,26 (IH, C3-H);
6,71 (1H,C8-H);8,15(1H,A-H); 11,67 (IH, OH); 12,24 (IH, NH).
+) 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:


/,0
^n^6/&
L

-h) Hieu suat: 44% (Giai doan chuyen vi Fries)

>^!^'

JI

.L
'H

+)Sanphimc6tV:163-165'C

+) Ph6 h6ng ngoai (cm''): 1665(v.co lactam) , 1642(v.c
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
CT
'

J

jli- ' °

'O"

+) Hieu suit: 90% (Giai doan cu6i)
+)San pham co t\, : 237-238°C (Theo tai lieu [36
tV : 237-239°C)

io^^^C^'2
M

+) Ph6 'H-NMR (5ppJ: 2,69 (3H, -COCH3); 6,49 (q, IH, C5-H, Jo=8,5H2

Jm=lHz); 7,32 (m, 3H, C,o-H, Cn-H va C^-H, Jo=8Hz); 7,58 (m, 2H, C6-F

va C7-H); 7,62 (q, 2H, C9-H va C,3-H, Jo=8Hz, Jm=l,5Hz); 8,16 (q, IH, Cs

H, Jo=8Hz, Jm=l,0Hz). Rieng proton cua OH xuat hien vai tin hieu rat nho <
7,95 ppm, CO le do tao lien ket hidro vai nhom CO axetyl ben canh.

Nhu vay tat ca cac hgp chat metyl xeton khai dau (Ii-In) deu dugc tong hg]

bang cac phan iing huu ca da biet nhung da co su cai tien va van dung sang ta<

vao dieu kien cu the ciia tung truang hgp rieng biet, Cau tao ciia cac hgp cha

nay deu dugc xac dinh chinh xac nha cac phuang phap pho hong ngoai, con:
hucmg tu proton va pho khoi lugng.

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