B GIO DC V O TO

B Y T

TRNG I HC DC H NI

NGUYN TH HUYN

TNG HP V TH HOT TNH KHNG T

BO UNG TH CA MT S DN CHT
2- ARYL-4-QUINAZOLINON

LUN VN THC S DC HC

H NI 2014

B GIO DC V O TO

B Y T

TRNG I HC DC H NI

NGUYN TH HUYN

TNG HP V TH HOT TNH KHNG T

BO UNG TH CA MT S DN CHT
2- ARYL-4-QUINAZOLINON

LUN VN THC S DC HC

CHUYN NGNH: CNG NGH DC PHM

V BO CH THUC
M S: 60720402

Ngi hng dn khoa hc: TS. Vn Th M Hu

TS. L Nguyn Thnh

H NI 2014

LI CM N
hon thnh kha lun ny, em xin t lng bit n su sc n: TS. Vn Th
M Hu v TS. L Nguyn Thnh l nhng ngi c, ngi thy tn tnh hng
dn, to mi iu kin thun li v ng vin em trong sut qu trnh thc hin lun
vn ny.
Em cng xin cm n s gip nhit tnh ca: TS. Nguyn Minh Hng, TS.
Cao Bch Hu, ThS. o nh Cng, c nhn Trn Hu Gip, c nhn Nguyn Anh
Dng, c nhn H Th Thoa, c nhn Nguyn Th T Oanh (Trung tm nghin cu v
pht trin thuc - Vin ha sinh bin - Vin Hn lm Khoa hc v Cng ngh Vit
Nam), cc thy c gio B mn Ha hu c cng cc thy c gio trong cc B mn,
phng ban, th vin - Trng i hc Dc H Ni.
Mc d c nhiu c gng nhng do hn ch v thi gian, kin thc cng nh
ti liu tham kho nn lun vn ca em khng th trnh khi nhng sai st trong ni
dung v hnh thc, em rt mong nhn c s gp ca cc thy c lun vn ca
em c hon thin hn.
Cui cng, con xin cm n b m, em cm n anh ch, bn b lun ng
vin, gip con/ em trong sut qu trnh hc tp v nghin cu va qua.
H Ni, ngy

thng

nm 2014

Hc vin

Nguyn Th Huyn

MC LC
T VN

CHNG 1: TNG QUAN

1.1.
2-ARYL-4-QUINAZOLINON: DN CHT TNG NG SINH
HC CA 3-ARYLISOQUINOLINON

1.2.

1.1.1.

3-Arylisoquinolinon

1.1.2.

Pht trin khung 3-arylisoquinolinon thnh 2-aryl-4-quinazolinon

1.1.3.

Mt s tc dng sinh hc ca dn cht 2-aryl-4-quinazolinon

1.1.3.1.

Tc dng chng ung th

1.1.3.2.

Mt s tc dng khc

PHNG PHP TNG HP

10

1.2.1.

Phn ng Niementowski V. v phn ng Niementowski V. m rng.

11

1.2.2.

Phn ng ca Shishoo C. J.

12

1.2.3.

Phn ng ngng t anthanilamid v benzoyl clorid

12

1.2.4. Phn ng ngng t anthranilamid v aldehyd

CHNG 2: NGUYN VT LIU, TRANG THIT B V PHNG PHP
NGHIN CU

13
15

2.1.

NGUYN VT LIU, HA CHT, DUNG MI

15

2.2.

THIT B TH NGHIM

16

2.3.

PHNG PHP NGHIN CU

16

2.3.1.

Phng php tng hp 2- aryl-4-quinazolinon

16

2.3.2.

Phng php tinh ch v xc nh cu trc

16

2.3.3.

Phng php xc nh hot tnh khng t bo ung th

17

CHNG 3: KT QU NGHIN CU
3.1.

3.2.

3.3.

TNG HP HA HC

19
19

3.1.1.

Tng hp dn cht trung gian 2-amino benzamid

21

3.1.2.

Tng hp dn cht trung gian aldehyd thm

24

3.1.3.

Tng hp dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c)

25

KIM TRA TINH KHIT, KHNG NH CU TRC

35

3.2.1. Kim tra tinh khit

35

3.2.2. Khng nh cu trc

37

TH HOT TNH GY C T BO UNG TH

CHNG 4: BN LUN

44
46

4.1.

4.2.

V TNG HP HA HC
4.1.1.
trc

Tng hp dn cht trung gian 2-amino benzamid v khng nh cu

46

4.1.2.

Tng hp dn cht trung gian aldehyd thm v khng nh cu trc 48

4.1.3.

Tng hp dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c)

V XC NH CU TRC
4.2.1.
4.2.2.

4.3.

46

48
50

Ph hng ngoi( IR)

50
1

Ph cng hng t ht nhn proton ( H-NMR)

13

13

51

4.2.3.

Ph cng hng t ht nhn C ( C-NMR)

53

4.2.4.

Ph khi lng (MS)

55

V HOT TNH KHNG T BO UNG TH

KT LUN V KIN NGH

57
61

KT LUN

61

KIN NGH

61

TI LIU THAM KHO

64

DANH MC CC K HIU, CH VIT TT

ATCC

Tiu chun M (the American Type Culture Collection )

13

Ph cng hng t ht nhn

C-NMR

H-NMR

Ph cng hng t ht nhn proton

CTCT

Cng thc cu to

CTPT

Cng thc phn t

ppm

dch chuyn ha hc (phn triu)

DCM

Dicloromethan

DMAC

N,N-dimethylacetamid

DMEM

Mi trng nui cy t bo (Dulbecco's Modified Eagle Medium)

DMF

Dimethylformamid

DMSO

Dimethylsulfoxid

DMSO-d6

Dimethylsulfoxid deutri ha

EC50

Nng 50% c tc dng ti a

ESI

Ion ha phun in (Electron Spray Ionization)

EtOAc

Ethylacetat

Hep-G2

Hepatocellular carcinoma - t bo ung th gan

IC50

Nng c ch 50% t bo ung th th nghim

IR

Ph hng ngoi (Infrared Spectrometry)

Hng s tng tc (Hz)

KB

Human epidemic carcinoma - t bo ung th da

LU

Human lung carcinoma - t bo ung th phi

MCF-7

Human breast carcinoma - t bo ung th v

MIC

Nng c ch ti thiu

MOM

Methoxy methyl

MS

Ph khi lng (Mass Spectrometry)

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromid

PMB

p-Methoxylbenzyl

SKLM

Sc k lp mng

TLC

Sc k bn mng (Thin Layer Chromatography)

Tnc

Nhit nng chy

DANH MC CC BNG, BIU

Tn bng

TT

Trang

Bng 3.1

Kt qu tng hp cc dn cht 14a-k v 15a-c

35

Bng 3.2

Gi tr Rf v Tnc ca cc dn cht 14a-k v 15a-c

36

Bng 3.3

Kt qu phn tch ph khi lng (LC-MS) ca cc dn

38

cht 14a-k v 15a-c

4

Bng 3.4

S liu ph IR ca cc dn cht 14a-k v 15a-c

39

Bng 3.5

S liu ph 1H-NMR ca cc dn cht 14a-k v 15a-c

40

Bng 3.6

S liu ph 13C-NMR ca cc dn cht 14a-k v 15a-c

42

Bng 3.7

Kt qu th hot tnh gy c t bo ca 14a-k v 15a-c

45, 57

trn 4 dng t bo ung th ngi.

8

Bng 4.1

Ph 1H-NMR ca cc dn cht trung gian 4, 6, 11

48

DANH MC CC HNH V, S
HNH V
TT
1

Tn hnh
Hnh 1.1

Cu trc hp cht 7,8-dimethoxy-2-methyl-3-(4,5-

Trang
2

methylendioxy-2-vinylphenyl) isoquinolin-1(2H)-on.
2

Hnh 1.2

Cu trc dy hp cht 3-arylisoquinolinon trong nghin

cu ca Cho v cng s
3

Hnh 1.3

Cu trc cc hp cht 3-arylisoquinazolinon trong nghin

cu ca Cho v cng s
4

Hnh 1.4

Cu trc mt s dn cht 3-arylisoquinolinon c hot

tnh chng ung th cao

5

Hnh 1.5

Cu trc nhm hp cht HCT 116

Hnh 1.6

Cu trc nhm hp cht 6-alkylamino- v 2,3-dihydro-

3-methoxy-2-phenyl-4-quinazolinon
7

Hnh 1.7

Cu trc nhm hp cht 6-pyrrolidinyl-2-(2-subtituted

phenyl)-4-quinazolinon
8

Hnh 1.8

Cu trc hp cht 2- (naphtalen-1-yl)-6-pyrrolidinyl-4quinazolinon

Hnh 1.9

Cu trc hp cht 2- aryl-6-substituted quinazolinon

10

Hnh 1.10

Cu trc ca dn cht Ratitrexed

11

Hnh 1.11

Cu trc ca hp cht Methaqualon

12

Hnh 4.1

Ph hng ngoi ca cht 15c

51

13

Hnh 4.2

a)Ph 1H-NMR; b) Ph 1H-NMR gin rng ca cht 15c

14

Hnh 4.3

a)Ph

13

C-NMR; b) Ph

13

C-NMR gin rng ca cht

52, 53
54, 55

15c
15

Hnh 4.4

Ph khi lng (MS) ca cht 15c

56

S
Tn s

TT
1

S 1.1

Thit k cc dn cht 2-aryl-4-quinazolinon da trn

Trang
6

phng php nhm th ng cu sinh hc

2

S 1.2

Phn ng tng hp Niementowski V.

11

S 1.3

Phn ng tng hp Niementowski V ci tin

11

S 1.4

Phn ng tng hp ca Patel V.S v Patel S.R

11

S 1.5

Phn ng tng hp ca Shishoo C.J v cng s

12

S 1.6

Phn ng tng hp ca Hour M. J. v cng s

12

S 1.7

Phn ng ngng t anthranilamid v benzoyl clorid ci

13

tin
8

S 1.8

Phn ng tng hp ca Hour M. J. v cng s

13

S 1.9

Phn ng tng hp ca Na Yeun Kim v Cheol-Hong

14

Cheon
10

S 3.1

Tng hp cc dn cht trung gian 2-amino benzamid

19

11

S 3.2

Tng hp dn cht trung gian 2-(dimethylamino)

19

benzaldehyd

12

S 3.3

Tng hp cc dn cht 2-aryl-4-quinazolinon

13

S 3.4

Tng hp 2-amino-5-methyl benzamid

21

14

S 3.5

Tng hp 2-amino-4-methyl benzamid

22

15

S 3.6

Tng hp 2-amino-5-(dimethylamino) benzamid

23

16

S 3.7

Tng hp 2-(dimethylamino)benzaldehyd

24

17

S 4.1

C ch tng hp cc cht 2-aryl-4-quinazolinon

49

20,25

T VN
Hin nay t l mc cc bnh ung th c xu hng gia tng hu ht cc quc
gia trn th gii, ng th hai sau bnh tim mch cc nc pht trin [4]. Theo t
chc Y t Th gii c tnh trn ton cu c khong 20 triu ngi ang mc ung th,
trong c khong 6 triu ngi cht hng nm. T l cht do ung th chim 12%
trong cc nguyn nhn gy t vong ngi. Cng xu hng trn th gii th ti Vit
Nam theo c tnh c n 150.000 ca mi mc v khong 75.000 ngi cht v ung
th hng nm [3].
Trong qu trnh tm kim cc thuc chng ung th mi, nhiu nghin cu hin
nay tp trung vo vic tm kim cc cht c hot tnh khng t bo ung th [24]. Mt
trong nhng dy hp cht c hot tnh gy c t bo c ch hin nay l dy hp
cht 3-arylisoquinolinon c pht hin vo nhng nm cui th k 19 [9]. Da trn
pht hin ny nhiu nghin cu pht trin cu trc ca 3-arylisoquinolinon nhm tm
kim cc hp cht mi c tc dng khng t bo ung th c nhiu nh khoa hc
quan tm v nghin cu [6-10]. Mt trong nhng hng pht trin cu trc l thay i
cc nhm chc, nhm th tng ng sinh hc ca 3-arylisoquinolinon to nn
dy hp cht 2-aryl-4-quinazolinon. Kt qu ca mt s nghin cu cho thy cc dn
cht ny th hin hot tnh khng t bo ung th tt [6-11;15-19].
Hi nhp vi xu hng nghin cu ca th gii trong vic tm kim cc dn
cht 2-aryl-4-quinazolinon c hot tnh khng t bo ung th tt, lun vn: Tng hp
v th hot tnh khng t bo ung th ca mt s dn cht 2-aryl-4quinazolinon c tin hnh vi hai mc tiu :
1- Tng hp c mt s dn cht ca 2-aryl-4-quinazolinon.
2- Th hot tnh ca cc dn cht tng hp c trn mt s dng t bo ung th.

CHNG 1: TNG QUAN

1.1.

2-ARYL-4-QUINAZOLINON: DN CHT TNG NG SINH HC

CA 3-ARYLISOQUINOLINON

1.1.1. 3-Arylisoquinolinon
Dy hp cht 3-arylisoquinolinon c gio s Cho v cng s pht trin trong
qu trnh nghin cu tng hp cc hp cht t nhin benzo[c]phenanthridin fagaronin
vo nm 1998. Dy hp cht ny c tc dng khng t bo ung th tt da trn s c
ch enzym topoisomerase I trong qu trnh sao chp ADN. Mt trong nhng hp cht
c tc dng khng t bo ung th rt tt nng nanomol l 7,8-dimethoxy-2methyl-3-(4,5-methylendioxy-2-vinylphenyl)-isoquinolin-1(2H)-on (Hnh 1.1) [10].

O
O
N

H 3CO
OCH 3O

(IC50 = 0,2 nM, SKMEL-2)

Hnh 1.1: Cu trc hp cht 7,8-dimethoxy-2-methyl-3-(4,5-methylendioxy-2vinylphenyl)isoquinolin-1(2H)-on.

Trong qu trnh tm kim cht chng ung th mi, Cho v cng s s dng
hp cht 7,8-dimethoxy-2-methyl-3-(4,5-methylendioxy-2-vinylphenyl)-isoquinolin1(2H)-on lm cht dn ng tng hp cc dn cht 3-arylisoquinolinon. Trong
nghin cu ny, Cho v cng s tng hp c 12 dn cht 3-arylisoquinolinon,
trong c 6 hp cht c tc dng sinh hc trn c 5 dng t bo ung th th nghim
gm: ung th phi, ung th bung trng, khi u c tnh, ung th i trng, khi u thn
kinh trung ng [10].(Hnh 1.2)

R2
R1

NH

R1 = H; 6-CH3; 5-N(CH3)2
R2 = H; 3,4-OCH2O; 4-CF3; 4-CH3;
2-CH3; 4-Cl; 4-Br; 4-OCH3

Hnh 1.2: Cu trc dy hp cht 3-arylisoquinolinon trong nghin cu ca

Cho v cng s
Cng cng xu hng nghin cu trn nm 2009, Cho v cng s tip tc tng
hp c 9 dn cht 3-arylisoquinolinon (Hnh 1.3) v th nghim hot tnh sinh hc
trn 3 dng t bo ung th gm: ung th phi, ung th i trng, v ung th bung
trng. Trong , hp cht c nhm th R1 = CH3; R2 = R3 = R4 = H; R5 = PMB (pmethylbenzyl); v hp cht c nhm th R2 = CH3; R1 = R3 = R4 = H; R5 = PMB l 2
hp cht c hot tnh khng t bo ung th cao trn c 3 dng t bo ung th vi IC50
t 2,37g/ml n 13,27g/ml [8].
R4
R3
R1
NH

R2

OR5

R1 = H; CH3
R2 = H; CH3
R3 = H; OCH3
R4 = H; OCH3
R5 = PMB; MOM

Hnh 1.3: Cu trc cc hp cht 3-arylisoquinolinon trong nghin cu ca

Cho v cng s
Trn th gii cng c rt nhiu nghin cu tng hp v th hot tnh khng t
bo ung th ca cc dn cht 3-arylisoquinolinon. Trong mt th nghim in vitro trn
5 dng t bo ung th ngi (phi, bung trng, khi u c tnh, i trng v thn kinh
trung ng), cc dn cht 3-arylisoquinolinon c tc dng khng t bo ung th tt
[10, 11]. Mt trong nhng dn cht ca 3-arylisoquinolinon c hot tnh sinh hc cao
l dn cht 3-napthalenylisoquinolinon [6]. Mt s dn xut 3-arylisoquinolinon c
tc dng chng khi u rt tt tng t nh cc thuc chng li s tng sinh ca khi u

c tnh [17,18]. Bn cnh dn cht cha vng thm v tr s 3 ca vng quinazolinon

cc d vng khc c c tnh thm nh: thiophen, pyridin, furan cng c hot tnh
khng t bo ung th [18].(Hnh 1.4)
R4
R5

R1
R2

R3

Y1
NH

R3

NH

Y2
R4

Y1

R2
R1

Ar
NH

Y2
O

Y1,2 = H, N(CH3) 2
R 1-5 = H, OCH3, Cl, Br, OC2H5, ...

Ar: Thiophenyl;
pyridinyl; f uranyl

Hnh 1.4: Cu trc mt s dn cht 3-arylisoquinolinon c hot tnh chng ung

th cao
c bit tc gi Kazuo Hatturi v cng s cng ty dc phm Chugai, Nht
Bn cng tng hp v ng k bn quyn v dy hp cht 3-arylisoquinolinon vi
hot tnh chng ung th. Nhm hp cht tng hp c th tc dng sinh hc trn t
bo ung th trc trng v th hin tc dng rt cao nng IC50 khong 1 nanomol
(Hnh 1.5) [15,16].

H3CO
OCH3
NH

(H3C) 2N

N(CH 3)2

NH

(H 3C) 2N

HCT 116
IC50 = 1,1 nM

NH

(H3C)2N

HCT 116
IC50 = 8,9 nM

OCF 3

HCT 116
IC50 = 3,5 nM

Hnh 1.5: Cu trc nhm hp cht 3-arylisoquinolinon c tc dng trn

dng t bo ung th trc trng HCT 116
Nh vy, dy cc hp cht 3-arylisoquinolinon v ang c nhiu nh khoa
hc trn th gii quan tm v nghin cu nhm tm ra cc hp cht c hot tnh khng
t bo ung th mi ng dng trong iu tr.

1.1.2. Pht trin khung 3-arylisoquinolinon thnh 2-aryl-4-quinazolinon

Vi mc tiu tm kim cc cht c hot tnh chng ung th, lun vn s dng
phng php nhm th ng cu sinh hc trong thit k thuc pht trin cu trc
ha hc ca dn cht 3-arylisoquinolinon. Phng php nhm th ng cu sinh hc l
mt phng php tip cn thay i cht dn ng, hoc thay i trong qu trnh
chuyn ha thuc m khng lm thay i nhiu v mt cu trc ha hc [2,20]. Trong
lnh vc nghin cu v pht trin thuc, nhm th ng cu sinh hc tr thnh mt
trong cc cng c c ng dng rt c hiu qu thit k cu trc. S d nh vy l
v s thay th bng cc nhm ng cu sinh hc thng em li cc cht c hot tnh
sinh hc kh tng t nhau nhng li c s khc nhau r rt v cc tnh cht l ha hc
khc nh phn cc, bn ha hc, v.v Cho n nay nhm ng cu sinh hc
thng c coi l nhng nhm hoc cht c tnh cht l ha hc tng t nhau v c
mt loi hot tnh sinh hc tng t nhau [2].
Hin nay c 6 kiu thay th hay c p dng trong phng php s dng
nhm ng cu sinh hc cho thit k cu trc, bao gm: thay th nguyn t hoc nhm
c ha tr 1, thay th nguyn t hoc nhm c ha tr 2, thay th nguyn t hoc nhm
c ha tr 3, thay th bng cc vng tng ng, thay th bng cc nhm c phn
cc tng t nhau, v thay th bng cc nhm chc c cu trc o ngc [2].
Phng php thay th bng vng tng ng c coi l cc nhm ng cu
sinh hc ca nhau (cc vng ng cu sinh hc), l mt trong cc k thut thit k cu
trc c s dng ph bin nht c bit hiu qu. C th tm thy rt nhiu nghin
cu khoa hc s dng k thut thay th bng cc vng ng cu sinh hc c cng
b. c bit, s thay th -CH= bng N= trong cc vng thm l trng hp hay gp
v hiu qu nht trong s cc nhm ng cu sinh hc kinh in [2].
Nh vy, dn cht 2-aryl-4-quinazolinon l hp cht tng ng sinh hc vi
dn cht 3-arylisoquinolinon, vn c bit n l c tc dng khng t bo ung th
tt. Trong lun vn ny, mt s dn cht 2-aryl-4-quinazolinon vi cc nhm th
tng t khung d vng cng nh ti vng phenyl c thit k vi mong mun tm
ra cc hp cht c hot tnh khng t bo ung th trin vng. (S 1.1)

R3

R1

R1

NH

R2

NH

R2

R3

3-arylisoquinolinon

2-aryl-4-quinazolinon

S 1.1: Thit k cc dn cht 2-aryl-4-quinazolinon da trn phng php

nhm th ng cu sinh hc
1.1.3. Mt s tc dng sinh hc ca dn cht 2-aryl-4-quinazolinon
Trn th gii c nhiu cng trnh nghin cu tng hp v th hot tnh sinh
hc cho thy cc dn cht c tng hp t quinazolinon c nhm th v tr s 2 c
tc dng sinh hc phong ph nh: chng ung th, an thn, khng khun, khng nm,
v.v c bit, cc dn cht c nhm th v tr s 6 hay v tr s 7 vng
quinazolinon v cc nhm th (CH3, OCH3, OCF3, ) v tri 2,3, ca vng thm
v tr s 2 ca vng quianzolinon cho thy hot tnh sinh hc ca cc dn cht tng ln
ng k.
1.1.3.1.

Tc dng chng ung th

V tc dng chng ung th, trn th gii c mt s cng trnh nghin cu

khoa hc ca cc dn cht 2- aryl - 4- quinazolinon.
Tc gi Mann-Jen Hour v cc cng s cng b kt qu v tng hp v th
tc dng gy c t bo ca 6-alkylamino- v 2,3-dihydro-3-methoxy-2-phenyl-4quinazolinon v cc hp cht lin quan. Da trn cu trc khung cc tc gi tng
hp c 18 dn cht. Trong cc hp cht c R6 l cc nhm th d vng cha N;
R7 = R2' = R4' = R5' = H; v R3' = -OCH3 c hot tnh khng t bo ung th rt tt c
9 dng t bo ung th th nghim vi gi tr EC50 < 1,0g/mL [23].

R5'
R4'
R7

R3'
NH

R6

R2'

R6 = H; OCH3; OCH2O; N(CH 3)2; N

; N

; N

CH3 ; N

R7 = R2' = R4' = R5' = H; OCH 3

R3' = OCH 3

Hnh 1.6: Cu trc nhm hp cht 6-alkylamino- v 2,3-dihydro-3methoxy-2-phenyl-4-quinazolinon

Nm 2007, tc gi Mann-Jen Hour v cc cng s tip tc nghin cu v dn
cht 6-pyrrolidinyl-2-(2-subtituted phenyl)-4-quinazolinon. Nhm hp cht tng hp
c cho tc dng tt i vi vic c ch s pht trin ca t bo ung th mu ngi
v chut th nghim vi gi tr EC50 t 0,30

10,10M. Trong , nhm th R l -

F, -Cl v -N(CH3)2 cho hot tnh khng t bo ung th cao nht [22].
N
NH

R = F,Cl, OCF3, OH, OCH3, OC2H5, N(CH3) 2

Hnh 1.7: Cu trc nhm hp cht 6-pyrrolidinyl-2-(2-subtituted phenyl)4-quinazolinon

Nm 2011, tc gi Yang C. Wu v cng s tin hnh th hot tnh chng khi u
ca 2- (naphtalen-1-yl)-6-pyrrolidinyl-4-quinazolinon trn cc dng t bo ung th
ngi. Kt qu cho thy hp cht ny c hot tnh sinh hc cao trn 3 dng t bo ung
th vi cc gi tr IC50 nh sau: t bo ung th phi (IC50 = 0,053 0,006 M), t bo
ung th vm hng (IC50 = 0,041 0,003 M), t bo ung th biu b (IC50 = 0,083
0,01 M) [33].

N
NH

N
O

Hnh 1.8: Cu trc hp cht 2- (naphtalen-1-yl)-6-pyrolidinyl-4-quinazolinon

Gn y nht nm 2013, tc gi Mann-Jen Hour v cc cng s tip tc cng b
kt qu th tc dng sinh hc trn 5 dng t bo ung th ngi: khi u c tnh, ung th
phi, ung th biu m khng nh phi, ung th gan v ung th vm hng ca 15 dn
cht 2- aryl-6-substituted quinazolinon tng hp c. Kt qu cho thy c 6 dn cht
c tc dng gy c t bo mnh nng IC50 t 0,07 M n 8,89 M trn c 5
dng t bo ung th. Trong hp cht c nhm th R6 l pyrrolidinyl v R2 l vng
napthalenyl cho tc dng gy c t bo mnh nht nng IC50 t 0,03-1,35 M
trn 5 dng t bo ung th th nghim [21].
R6 = N
N

R2

R2 =

R6 = N

NH

R6
O

R2 =
N

R6 = N

R6 = N

R2 =
S

R6 = OCH 3
R6 = N(CH 3)2

Hnh 1.9: Cu trc nhm hp cht 2- aryl-6-substituted quinazolinon

Trong nhng nm gn y mt s dn cht 4(3H)-quinazolinon c nhm th
v tr s 2 c s dng lm tc nhn chng ung th. Ratitrexed (ZD 1694) c
tan tt trong nc, l tc nhn c ch thymidalat synthase. Cht ny tng t acid folic
c vn chuyn mt cch c hiu qu vo t bo ca ng vt c v qua tc nhn vn
chuyn folat. Hp cht ny c a vo iu tr bnh ung th kt trng tin trin
di tn bit dc Tomudex ( Astra Zeneca) [19].

CH3
O
HOOC(H2 C) 2

NH

CH 3
NH

HOOC

Hnh 1.10: Cu trc ca hp cht Ratitrexed

Nh vy, tc dng chng ung th hay hot tnh c t bo trn t bo ung th
ca cc dn cht quinazolinon l tc dng sinh hc c cc nh khoa hc quan tm
nht. V vy, trong nghin cu ny chng ti tp trung nghin cu hot tnh khng cc
t bo ung th. Ngoi ra, dn cht 2-aryl-4-quinazolinon cn nhiu tc dng sinh hc
phong ph khc nh: an thn, gy ng, khng khun, khng nm

1.1.3.2.

Mt s tc dng khc

Tc dng an thn, gy ng
Methaqualon l thuc an thn c nh khoa hc ngi n Gujiral M.L.
pht minh vo nm 1955 trong chng trnh nghin cu thuc phng chng st rt v
c a ra th trng nh l mt thuc an thn khng gy nghin vo nm 1966 di
tn bit dc: Renonal, Melsed, hay Mandrax [30].
Mc d, Methaqualon c nhiu tc dng ph, nhng vn c nhiu nghin cu
tip theo tm kim thuc c tc dng an thn, gy ng tng t nh Methaqualon
nhng c tnh thp hn, ch yu l cc nghin cu tng hp v th sng lc tc dng
an thn, gy ng ca cc hp cht 2-alkyl-3-aryl-4-quinazolinon [12].

N
N
O

Hnh 1.11: Cu trc ca hp cht Methaqualon

Ngoi ra cn c mt s hot cht pht trin v sau ny nh mecloqualon,
ethaqualon c tc dng an thn gy ng nhng u c vn v dung np thuc v s
l thuc thuc nn cc hot cht ny u b kim sot cht ch [12].

Tc dng khng khun, khng nm

V tc dng khng khun, khng nm ca cc dn cht 2-aryl-4-quinazolinon,
trn th gii c nhiu cng trnh khoa hc nghin cu v tc dng ny.
Nm 2007, hai nh khoa hc ngi Ai Cp l Awwad A. Radwan v Salah G.
Ali tin hnh nghin cu ti tng hp cc dn cht 4(3H)- quinazolinon mi c
hot lc khng khun, khng nm. Trong nghin cu ny mt lot cc dn cht 4(3H)quinazolinon c tng hp c hot tnh khng khun tt [5].
Gn y nht nm 2012, G.Khodarahmi v Hassanzadeh cng cc cng s tip
tc nghin cu hot tnh khng khun, khng nm v hot tnh gy c t bo ca mt
s dn cht Quinazolinon mi tng hp. Kt qu th nghim cho thy cc dn xut
tng hp c hiu lc vi c vi khun Gram dng v Gram m c bit trn hai chng
Staphylococcus aureus v Pseudomonas aeruginosa c hiu lc cao nng mg/ml
[13].
Ngoi ra, dn cht 2-aryl-4-quinazolinon cn nhiu tc dng sinh hc phong
ph khc nh: tc dng chng ng kinh, tc dng lm mm c, tc dng li tiu,
v.v
Ti Vit Nam, hin nay cha c nghin cu no v dn cht 2-aryl-4quinazolinon. Nh vy, trong lun vn ny s dng phng php thay th vng ng
cu sinh hc trong thit k cu trc cc dn cht 2-aryl-4-quinazolinon t dn cht 3arylisoquinolinon, vn c bit n l dn cht c tc dng khng t bo ung th tt,
vi mong mun tm kim sng lc nhng hp cht c hot tnh khng ung th c trin
vng.

1.2.

PHNG PHP TNG HP

Hin nay nhiu dn cht ca quinazolinon ngoi vic c ng dng lm thuc

cn c s dng lm nguyn liu trong tng hp ha hc, trong ha phn tch v

nhiu ng dng khc. Do tim nng ng dng a dng ca cc dn cht quinazolinon,
nn t cui th k 19 n nay c nhiu phng php tng hp quinazolinon v dn
cht c cng b trong nhiu ti liu khc nhau.

10

1.2.1. Phn ng Niementowski V. v phn ng Niementowski V. m rng.

Phng php tng hp dn cht quinazolin-4-on ph bin nht l phn ng ln
u tin c Niementowski V. m t nm 1885 v ngy nay phn ng mang tn ng
[28]. Khi un nng acid anthranilic vi mt lng d formamid 120oC, nc c
gii phng v hu nh acid anthranilic c chuyn hon ton thnh quinazolin-4-on.
C nhiu ci tin i vi phn ng Niementowski V., phn ng c th tin hnh vi
cc dn cht ca acid anthranilic th cho cc dn cht 2-aryl-4-quinazolinon. Tuy
nhin, theo quy lut cn tin hnh phn ng nhit cao hn v thi gian phn ng
ko di hn.
H
N
R1

N
R1

HCONH2

O
COOH

R
NH

S 1.2: Phn ng tng hp ca Niementowski V.

Phn ng cng c th thc hin c vi cc amid mch thng to thnh cc
dn cht th alkyl v tr s 2 [7]. Ni chung phi tin hnh phn ng nhit cao
hn v hiu sut gim i khi khi lng phn t amid tng ln.
Phn ng Niementowski V. cng c th tin hnh bng cch ngng t gia
amid ca acid anthranilic vi ethyl orthoformat [25] .
Cl

NH 2
CONH2

CH2(OC2H 5)2

Cl

N
NH

O(CH 2CH2OH)2
O

S 1.3: Phn ng tng hp Niementowski V ci tin.

Patel V.S v Patel S.R. ci tin phn ng Niementowski V. bng phn ng
ng vng gia cc acid N-acylantharanilic th vi formamid nhit t 100oC n
180oC trong khong 3 gi thu c dn cht 2-aryl-4-quinazolinon vi hiu sut t
60% n 83% [29].
H
N
R1

O
COOH

N
HCONH 2

R1

R
NH

S 1.4: Phn ng tng hp ca Patel V.S v Patel S.R .

11

1.2.2. Phn ng ca Shishoo C. J.

Theo Shishoo C.J. v cng s, cc dn cht quinazolin-4-on th v tr s 2 c
th tng hp d dng bng phn ng gia ester methyl anthranilat vi cc nitril vi s
c mt ca kh hydroclorid khan trong dioxan [32]. (S 1.5)
NH2

R C NH X

OR'

R
NH

S 1.5: Phn ng tng hp ca Shishoo C.J. v cng s.

Phn ng ny c nhc im l kh hydroclorid bay hi trong qu trnh phn
ng d n mn dng c v thit b th nghim nn t c s dng.
1.2.3. Phn ng ngng t anthanilamid v benzoylclorid
Phn ng ngng t anthranilamid v benzoylclorid l phn ng hay c s
dng trong tng hp cc dn cht 2-aryl-4-quinazolinon.
Hour M. J. v cng s c rt nhiu nghin cu v hp cht 2-aryl-4quinazolinon. Trong nghin cu tng hp v th hot tnh sinh hc ca nhm dn cht
6-pyrrolidinyl-2-(2-substited phenyl)-4-quinazolinon, ng v cng s tng hp
c hp cht 2-(2-dimethylaminophenyl)-6-pyrrolidinyl-4-quinazolinon bng cch s
dng NaHSO3 lm xc tc trong mi trng N,N-dimethylacetamid (DMAC). Phn
ng c un hi lu 150oC trong khong 2 gi, sau hn hp phn ng vo
nc (S 1.6). Hiu sut phn ng l 25,0% [23].

O
NH 2
NH2

Cl

NaHSO3 , DMAC

(H 3C) 2N

150 oC

N
NH

N(CH 3)2

S 1.6: Phn ng ngng t anthranilamid v benzoylclorid

Phn ng cho hiu sut thp c th do hp cht benzoylclorid km bn d b
thy phn v kh bo qun.

12

Nm 2013, hai nh khoa hc Monireh Shakiba Nahad v Ghodsi Mohammadi

Ziarani nng cao hiu sut phn ng ngng t anthranilamid v benzoylclorid bng
cch s dng cht xc tc SBA-Pr-SO3H, mt acid c cu trc nano, trong dung mi
ethanol hoc dimethylformamid (DMF), hn hp phn ng c un nng 130oC.
Hiu sut phn ng l 52 - 91% [26]. (S 1.7)
O
NH 2

Cl

NH2

SBA-Pr-SO3H

NH

C2H5OH/DMF, 130 oC
O

R = 3-Cl; 4-Cl; 2,4-(Cl)2; 2-CH3

S 1.7: Phn ng ngng t anthranilamid v benzoyl clorid ci tin

1.2.4. Phn ng ngng t anthranilamid v aldehyd
Cng theo Hour M. J. v cng s th cc dn cht 2-aryl-4(3H)-quinazolinon
c tng hp bng cch ngng t dn cht ca anthranilamid v benzaldehyd. Tng
t phn ng ngng t anthranilamid v benzoyl clorid, phn ng ny s dng NaHSO3
lm cht xc tc phn ng ngng t v DMAC lm dung mi phn ng. Phn ng
c un hi lu trong 2 gi nhit 150oC. Hiu sut phn ng l 75 - 95%.
NH2

NaHSO 3 , DMAC

R'

R
NH 2

R'

NH

150 oC

S 1.8: Phn ng tng hp ca Hour M. J. v cng s

Phng php ca Hour M. J. c s dng tng hp nhiu dn cht th C2,
C6, C7 ca vng quinazolinon. Nm 2013, Hour M. J. v cng s tng hp c 16
dn cht 2-aryl-4-quinazolinon.
c bit gn y nht nm 2014, Na Yeun Kim v Cheol-Hong Cheon pht
trin phng php tng hp cc hp cht quinazolion bng phn ng ngng t
anthranilamid v cc aldehyd trong iu kin oxy ha chn khng trong dung mi

13

dimethyl sulfoxid (DMSO), phn ng c un nhit 100oC trong 12-36 gi, v

cho hiu sut phn ng 38 - 98% [27].
NH2
NH 2

O
H

DMSO, 100 oC
R

NH

12-36h
O

S 1.9: Phn ng tng hp ca Na Yeun Kim v Cheol-Hong Cheon

14

CHNG 2: NGUYN VT LIU, TRANG THIT B V PHNG

PHP NGHIN CU
2.1.

NGUYN VT LIU, HA CHT, DUNG MI

Cc ha cht, dung mi dng trong qu trnh tng hp c xut x t cc cng ty

nh: Merk, Sigma-Aldrich, Trung Quc,v.v Cc ha cht ny c s dng trc

tip khng qua tinh ch thm. Cc ha cht c trnh by bng di y:
TT

Nguyn liu

2- Methylbenzaldehyd

Xut x

TT

Nguyn liu

Merk

16

Ethylacetat

Xut x
Trung
Quc

3- Methylbenzaldehyd

Merk

17

Nc ct

2-Trifloromethylbenzaldehyd

Merk

18

CDCl3

Merk

3-Trifloromethylbenzaldehyd

Arcros

19

DMSO-d6

Merk

2-

Arcros

20

Dimethylformamid

Merck

Arcros

21

Kh H2

VN

Trifloromethoxybenzaldehyd
6

3Trifloromethoxybenzaldehyd

Vit
Nam

2- Florobenzaldehyd

Merk

22

Acid 5-cloro-2-nitrobenzoic

Merk

3- Florobenzaldehyd

Merk

23

2-amino-4-methylbenzonitril

Merk

Naphthalen-1-carbaldehyd

Merk

24

Acid5-methyl-2-nitrobenzoic

Merk

10

Methanol

Merk

25

Ammonia Water

Trung
Quc

11

Ethanol

Trung

26

NaHSO3

Quc
12

Diclomethan

13

n-N-hexan

14

Aceton

Trung
Quc

Merck

27

N,N-dimethylacetamid

Merk

Malaysia

28

Dimethylamin 40%

Trung

29

Thionylclorid

Merk

30

10% Pd/C

Merk

Fischer

Quc
15

KOH

Trung
Quc

15

2.2.

THIT B TH NGHIM

Dng c thy tinh: bnh cu 2 c dung tch 100ml, bnh cu 100ml, 50ml, sinh hn,
phu, cc thy tinh cc loi, bnh lc ht, phu Buchner, bnh nn, bnh chit
Cn k thut in t Shimadzu (Nht Bn).
Bm ht chn khng DIVAC.1.21 (M).
My ct quay Buchi R 210 (Thy S).
T sy Memmert (c).
Ph cng hng t ht nhn (1H-NMR,

13

C-NMR) c ghi trn my ph

AVANCE Spectrometer AV500 (BRUKER, c), Vin ha hc - Vin Hn lm

Khoa hc v Cng ngh Vit Nam.
My o ph khi khi lng LC-MSD-Trap-SL - Vin Ha hc cc hp cht thin
nhin Vin Hn lm Khoa hc v Cng ngh Vit Nam
My o ph hng ngoi c ghi trn my Perkin Elmer ti Vin Ha hc - Vin
Hn lm Khoa hc v Cng ngh Vit Nam
My o nhit nng chy nhit in Electrothermal digital.
My khuy t gia nhit IKA-RTC (c).

2.3.

PHNG PHP NGHIN CU

2.3.1. Phng php tng hp 2- aryl-4-quinazolinon

S dng cc phng php tng hp hu c kinh in v hin i tng hp cc
dn cht d kin.
Theo di tin trnh phn ng v s b nh gi tinh khit cc cht bng sc k
lp mng (SKLM).
2.3.2. Phng php tinh ch v xc nh cu trc
S dng phng php sc k nh: sc k ct, sc k lp mng (SKLM) v phng
php kt tinh tinh ch cc hp cht tng hp c.
S dng cc phng php ph hin i xc nh cu trc ha hc ca cc hp
cht tng hp c nh: ph hng ngoi (IR), ph cng hng t ht nhn (1HNMR v 13C-NMR), ph khi lng (LC_MS).

16

2.3.3. Phng php xc nh hot tnh khng t bo ung th

Th hot tnh khng t bo ung th ca cc dn cht tng hp c theo
phng php MTT l php th c t bo chun nhm sng lc, pht hin cc cht
c kh nng km hm s pht trin hoc dit t bo ung th iu kin in vitro [14,
31].

2.3.3.1.

Nguyn tc:

y l phng php th nghim in vitro o s tng sinh v sng st ca t

bo ung th c nui cy trong a 96 ging.
Hp cht MTT c tn khoa hc l 3-(4,5-dimethyl-2-thiazolyl)-2,5diphenyltetrazolium bormid, c mu vng c thm vo mi ging v t bo c
37oC, 5% CO2. Mu vng bin i thnh formazan tm trong ty th ca t bo sng.
Kh nng hp th ca dung dch c mu ny c th c nh lng bng my quang
ph k bc sng 540 600nm. S bin i mu ch xy ra khi enzym reductase
trong ty th hot ng, v nh vy s chuyn i lin quan trc tip n s lng t
bo sng st. Nhm nghin cu s dng phng php ny nghin cu c tnh ca
cc dn cht tng hp c trn bn dng t bo ung th ngi: t bo ung th biu
m - KB, t bo ung th gan - Hep G2, t bo ung th phi - LU, t bo ung th v MCE 7. Phng php ny hin ang c p dng ti Vin nghin cu ung th quc
gia M (NCI).

2.3.3.2.

Dng t bo th nghim:

Cc dng t bo ung th ngi c cung cp bi ATCC gm:

-

KB (Human epidemic carcinoma) t bo ung th biu m.

Hep G2 (Hepatocellular carcinoma) t bo ung th gan.

LU (Human lung carcinoma) t bo ung th phi.

MCF - 7 (Human breast carcinoma) t bo ung th v.

2.3.3.3.

Cht chun dng tnh: Ellipticin ca hng Sigma - Aldrich.

17

2.3.3.4.

Tin hnh:

a. Chun b t bo.
Cc dng t bo ung th nghin cu c nui cy trong cc mi trng nui cy
ph hp c b sung thm 10% huyt thanh bo thai b (FBS) v cc thnh phn cn
thit khc iu kin tiu chun (5% CO2; 37oC; m 98%; v trng tuyt i).
Ty thuc vo cc c tnh ca tng dng t bo khc nhau, thi gian cy chuyn
cng khc nhau.
T bo pht trin pha log s c s dng th c tnh.
b. Quy trnh xc nh hot tnh khng t bo ung th.
-

Pha 200 l dung dch t bo pha log nng 3 x 104 t bo/ml vo mi ging (a
96 ging) trong mi trng DMEM cho cc dng t bo HepG2, MCF7, KB, LU.

Mu th c pha long sao cho t n nng cui cng l 128 g/ml; 32 g/ml;
8 g/ml; 2 g/ml; 0,5 g/ml. 37oC, 5% trong 3 ngy.

Ging iu khin (i chng dng) ch gm 200 l dung dch t bo 3 x 104 t

bo/ml.

Sau 3 ngy nui cy; tip vi MTT 0,2mg/ml 37oC trong 4 gi.

Loi b mi trng, thm 100 l DMSO lc u formazan c th ha tan hon

ton.

c mt quang bc sng 540 nm trn my Spectrophotometter Genios

TECAN. Mt quang phn nh s lng t bo cn sng st.

c. Tnh kt qu:
Phn trm km hm s pht trin ca t bo (Growth inhibition) c tnh ton
da trn s liu o mt quang hc OD trn my quang ph TECAN theo cng thc
sau:

OD control (-) - OD control (+)

IC(%) =

100

OD mu th - OD control (+)

Gi tr IC50 c tnh da trn kt qu s liu phn trm km hm s pht trin

ca t bo bng phn mm my tnh tablet curve.

18

CHNG 3: KT QU NGHIN CU
3.1.

TNG HP HA HC
Dn cht 2-aryl-4-quinazolinon c tng hp theo cc bc sau:

Tng hp cc dn cht trung gian 2-aminobenzamid.

NO 2
H3C

SOCl2
H 3C

COOH
1

NO2

NO2

NH 4OH

COCl

Dicloromethan

H 3C

CONH2
3

2
NH2

H 2, 10% Pd/C
CH3OH

CH3

CONH 2
4

H3C

NH 2

KOH

CN

C2H5OH

H 3C

CONH 2

6
NO2

Cl

NH 2

SOCl2
Cl

COOH
7

NO2

NO2

NH 4OH

COCl

Dicloromethan

Cl

8
NO 2

NH(CH3) 2
(H 3C)2N

DMF, 110 oC

CONH2
9
NH 2

H2, 10% Pd/C

CONH 2

CH3OH

(H 3C)2N

10

CONH 2
11

S 3.1: Tng hp cc dn cht trung gian 2-aminobenzamid

Tng hp dn cht trung gian 2-(dimethylamino)benzaldehyd.

NH(CH3) 2
K 2CO3, DMF, 110oC

OHC
F

OHC
H3C

CH 3

13

12

S 3.2: Tng hp dn cht trung gian 2-(dimethylamino)benzaldehyd

19

Tng hp cc dn cht 2-aryl-4-quinazolinon bng phn ng ngng t cc dn cht

2-aminobenzamid vi cc aldehyd thm theo s phn ng sau: (S 3.3)
5'

NH2

OHC

NaHSO3
R2

R1
CONH 2

N,N-dimethylacetamid

4'

1'

R2

12
4 3 NH

R1
6

150 oC

6'

14a-k
CHO
NaHSO3

NH2
R1

N,N-dimethylacetamid

CONH 2

150 oC

8
7

N
12
4 3 NH

R1
6

15a-c

14a: R1 = 6-CH3; R2 = 2-CH3

15a: R1 = 6-CH3

14b: R1 = 6-CH3; R2 = 3-CH3

15b: R1 = 7-CH3

14c:

R1 = 6-CH3; R2 = 2-CF3

15c: R1 = 6-N(CH3)2

14d: R1 = 6-CH3; R2 = 3-CF3

14e:

R1 = 6-CH3; R2 = 2-OCF3

14f:

R1 = 6-CH3; R2 = 3-OCF3

14g: R1 = 6-CH3; R2 = 2-F

14h: R1 = 6-CH3; R2 = 3F
14i:

R1 = 6-CH3; R2 = 2-N(CH3)2

14j:

R1 = 7-CH3; R2 = 2-N(CH3)2

14k: R1 = 7-CH3; R2 = 2-OCF3

S 3.3: Tng hp cc dn cht 2-aryl-4-quinazolinon.

20

2'

3'

3.1.1. Tng hp dn cht trung gian 2-aminobenzamid

3.1.1.1.

Tng hp 2-amino-5-methylbenzamid

Cng thc:
3

2 NH2

H 3C 5

CONH 2

CTPT: C8H10N2O; KLPT: 150,18

S :
NO 2
H3C

SOCl2
H 3C

COOH
1

NO2

NH 4OH

COCl

Dicloromethan

NO2
H 3C

CONH2
3

NH2

H 2, 10% Pd/C
CH3OH

CH3

CONH 2
4

S 3.4: Tng hp 2-amino-5-methylbenzamid.

Gm 2 giai on:
-

Tng hp 5-methyl-2-nitrobenzamid (3).

Tng hp 2-amino-5-methylbenzamid (4).

Tin hnh:
Tng hp 5-methyl-2-nitrobenzamid (3).
Nh t t thionyl clorid (7ml; 90mmol) vo bnh cu cha 5,43g (30mmol) acid
5-methyl-2-nitrobenzoic 1. Hn hp ny c un hi lu 50oC trong 4 gi, sau
loi thionyl clorid bng ht chn khng. Sn phm 2 c ha tan trong 30ml DCM,
sau nh t t 25ml dung dch NH4OH 0oC, tip tc khuy nhit phng
khong 4h. Kt thc phn ng ct loi dung mi di p sut gim. Lc ra ta bng
nc, sy kh thu c 5-methyl-2-nitrobenzamid 3 (4.418g dng bt mu trng).
Hiu sut 82%.

21

Tng hp 2-amino-5-methylbenzamid (4).

Thm 200ml dung dch methanol vo bnh cu cha 4,418g (24,5mmol) 5methyl-2-nitrobenzamid 3 trn. Sau thm t t 250mg 10%Pd/C vo bnh phn
ng. Hn hp phn ng c hydro ha nhit phng. Sau 8h kt thc phn ng
lm lnh, lc loi b xc tc, ct loi dung mi thu c 2-amino-5-methylbenzamid 4
(3,458g cht bt mu trng). Hiu sut 94%.
3.1.1.2.

Tng hp 2-amino-4-methylbenzamid (6)

Cng thc:
H 3C

3
4
5

2 NH2
1

CONH 2

CTPT: C8H10N2O; KLPT: 150,18

S :
H3C

NH 2

KOH

CN

C2H5OH

H 3C

NH 2
CONH 2
6

S 3.5: Tng hp 2-amino-4-methylbenzamid.

Tin hnh:
Ly 1,32g(10mmol) 2-amino-4-methylbenzonitril 5 cho vo bnh cu 100ml.
Thm t t 24ml EtOH vo khuy n khi tan hon ton, sau thm 2,8g (50mmol)
KOH vo hn hp trn. Hn hp c un hi lu 90oC trong mi trng kh N2 v
theo di phn ng bng SKLM vi h dung mi trin khai n-hexan-ethylacetat (1:1).
Sau 24h kt thc phn ng, thm nc vo v chit hn hp phn ng bng
ethylacetat. Dch ethylacetat c lm kh qua natri sulfat, cui cng c ct loi dung
mi. Cn c tinh ch bng sc k ct thu c 2-amino-4-methylbenzamid 6 l
cht bt mu trng ng.
Khi lng sn phm: 1,10g. Hiu sut phn ng: 73%.

22

3.1.1.3.

Tng hp 2-amino-5-(dimethylamino)benzamid

Cng thc:
NH 2
(H 3C)2N

CONH2

CTPT: C9H13N3O; KLPT: 179,22

S :
NO 2
Cl

SOCl2
Cl

COOH
7

NO 2

NO 2

NH4OH

COCl

Dicloromethan

Cl

8
NO 2

NH(CH3) 2
(H3C) 2N

DMF, 1100C

CONH2
9
NH 2

H 2, 10% Pd/C

CONH 2

CH 3OH

(H3C) 2N

10

CONH 2
11

S 3.6: Tng hp 2-amino-5-(dimethylamino)benzamid.

Gm 3 giai on:
-

Tng hp 5-cloro-2-nitrobenzamid(9).

Tng hp 5-(dimethylamin)- 2-nitrobenzamid(10).

Tng hp 2-amino-5-(dimethylamin)benzamid(11).

Tin hnh:
Tng hp 5-cloro-2-nitrobenzamid(9).
Cc bc tin hnh tng hp cht 9 tng t cht 3. Cht trung gian 5-cloro-2nitrobenzamid 9 c tng hp t (0,6ml; 10mmol) thionylclorid v 500mg (2,5mmol)
acid 5-cloro-2-nitrobenzoic 7.
Khi lng sn phm: 480mg cht bt mu trng. Hiu sut 96%.
Tng hp 5-(dimethylamin)- 2-nitrobenzamid(10).
Cho t t 1,5ml (11,5mmol) dimethylamin 33% vo bnh kn c cha 480mg
(2,4mmol) 5-cloro-2-nitrobenzamid 9 trn, thm 3ml DMF. Tin hnh un hi lu
110oC. Sau 16h kt thc phn ng, hn hp phn ng vo nc , lc ra ta thu
c 5-(dimethylamin)- 2-nitrobenzamid 9 (480mg cht bt mu trng). Hiu sut
96%.

23

Tng hp 2-amino-5-(dimethylamin)benzamid(11).
Cc bc tin hnh tng hp cht 11 tng t cht 4. Cht trung gian 2-amino5-(dimethylamin)benzamid 11 c tng hp t 480mg (2,3mmol) 5-(dimethylamin)2-nitrobenzamid 10 trn v 30mg 10%Pd/C trong 20ml dung dch methanol. Sn
phm thu c 2-amino-5-(dimethylamin)benzamid 11 (300mg cht bt mu trng).
Hiu sut 72%.
3.1.2. Tng hp dn cht trung gian aldehyd thm
a s cc hp cht trung gian aldehyd thm c s dng l cc hp cht c
sn s dng trc tip. Ngoi ra, c mt dn cht trung gian l 2(dimethylamino)benzaldehyd 13 c tng hp thm.
Cng thc:

OHC
H 3C

CH3

CTPT: C9H11NO; KLPT: 149,19

S :
NH(CH 3)2
K 2CO 3, DMF, 110 0C

OHC
F

OHC
H3C

CH 3

13

12

S 3.7: Tng hp 2-(dimethylamino)benzaldehyd.

Tin hnh:
Ly 1ml (1,178g, 9,5mmol) 2-fluorobenzaldehyd 12 vo bnh cu 50ml. Thm
1,3g (9,5mmol) K2CO3 v 5ml dung mi DMF vo bnh cu. Sau cho thm 6,4ml
(dung dch 33%, 47,5mmol) dimethylamin vo bnh phn ng. Hn hp phn ng
c un 110oC. Sau phn ng 8h kim tra phn ng bng SKLM vi h dung mi
n-hexan : ethylacetat = 95:05, phn ng xy ra hon ton. Thm nc vo v chit
hn hp phn ng bng ethylacetat. Dch ethylacetat c lm kh qua natri sulfat,

24

cui cng c ct loi dung mi. Cn c tinh ch bng sc k ct thu c 2(dimethylamino)benzaldehyd 13 l cht du mu trng ng.
Khi lng sn phm: 1,3g. Hiu sut phn ng : 92%.
3.1.3. Tng hp dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c)
5'

NH2

OHC

NaHSO3
R2

R1
CONH 2

N,N-dimethylacetamid

4'

1'

R2

12
4 3 NH

R1
6

150 oC

6'
2'

3'

14a-k
CHO

NaHSO3

NH2
R1

N,N-dimethylacetamid

CONH 2

12
4 3 NH

R1
6

150 oC

15a-c

S 3.3: Tng hp cc dn cht 2-aryl-4-quinazolinon.

Quy trnh tng hp chung:
Cho vo bnh cu 2mmol (4 hoc 6 hoc 11), tng ng 2 mmol aldehyd thm,
208mg NaHSO3 v 2ml DMAC. Khuy u cho hn hp tan hon ton v un hi lu
nhit 150oC trong 2 gi. Theo di phn ng bng SKLM vi h dung mi trin
khai n-hexan/ ethylacetat. Sau khi kt thc phn ng ngui bnh phn ng, hn
hp phn ng vo nc , thy c kt ta to thnh th tin hnh lc ht kit, ra ta
nhiu ln bng nc ct. Ra tip vi ln bng dung mi thch hp (EtOH lnh,
methanol, etylacetat). Sy kh ta thu c trong chn khng. Sau y l kt qu c
th:
6-Methyl-2-o-tolyl quinazolin-4(3H)-on (14a)
Cng thc:
N
NH

H 3C

CH3

CTPT: C16H14N2O; KLPT: 250,30

25

Tin hnh:
Hp cht 14a c tng hp t (2mmol) cht 4; 0,23ml(2mmol) 2methylbenzaldehyd; 208mg (2mmol) NaHSO3; trong 2ml DMAC.
Sn phm thu c l 386mg cht bt mu trng ng. Hiu sut 77%.(bng 3.1)
Nhit nng chy: 215-216oC. (bng 3.2)
Rf = 0,75 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 2.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 2.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 2.3, bng 3.5.

(ppm): xem ph lc 2.4, bng 3.6.

6-Methyl-2-m-tolyl quinazolin-4(3H)-(14b)
Cng thc:
N

CH 3
NH

H 3C
O

CTPT: C16H14N2O; KLPT: 250,30

Tin hnh:
Cc bc tin hnh tng hp cht 14b tng t cht 14a, t 300mg (2mmol)
cht 4; 0,24ml(2mmol) 3-methylbenzaldehyd; 208mg (2mmol) NaHSO3; trong 2ml
DMAC.
Sn phm thu c l 450mg cht bt mu trng ng. Hiu sut 90%.(bng 3.1)
Nhit nng chy: 235-236oC. (bng 3.2)
Rf = 0,68 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 3.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 3.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 3.3, bng 3.5.

(ppm): xem ph lc 3.4, bng 3.6.

26

6-Methyl-2-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-on (14c)
Cng thc:
N
NH

H3C

CF 3

CTPT: C16H11F3N2O; KLPT: 304,27

Tin hnh:
Cc bc tin hnh tng hp cht 14c tng t cht 14a, t 300mg (2mmol)
cht 4; 0,26ml(2mmol) 2-trifluoromethylbenzaldehyd; 208mg (2mmol) NaHSO3 trong
2ml DMAC.
Sn phm thu c l 290mg cht bt mu vng nht. Hiu sut 48%.(bng 3.1)
Nhit nng chy: 195-196oC. (bng 3.2)
Rf = 0,58 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (1:1))(bng 3.2)
ESI_MS: xem ph lc 4.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 4.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 4.3, bng 3.5.

(ppm): xem ph lc 4.4, bng 3.6.

6-Methyl-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-on (14d)
Cng thc:
N

CF3
NH

H 3C
O

CTPT: C16H11F3N2O; KLPT: 304,27

Tin hnh:
Cc bc tin hnh tng hp cht 14d tng t cht 14a, t 300mg (2mmol)
cht 4; 0,27ml(2mmol) 3-(trifluoromethyl)benzaldehyd; 208mg (2mmol) NaHSO3
trong 2ml DMAC.

27

Sn phm thu c l 500mg cht bt mu vng nht. Hiu sut 82%. (bng
3.1)
Nhit nng chy: 299-300oC. (bng 3.2)
Rf = 0,58 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 5.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 5.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 5.3, bng 3.5.

(ppm): xem ph lc 5.4, bng 3.6.

6-Methyl-2-(2-(trifluoromethoxy)phenyl)quinazolin-4(3H)-on (14e)
Cng thc:
N
NH

H3C

OCF3

CTPT: C16H11F3N2O2; KLPT: 320,27

Tin hnh:
Cc bc tin hnh tng hp cht 14e tng t cht 14a, t 300mg (2mmol)
cht 4; 0,29ml(2mmol) 2-(trifluoromethoxy)benzaldehyd; 208mg (2mmol) NaHSO3
trong 2ml DMAC.
Sn phm thu c l 530mg cht bt mu vng nht. Hiu sut 98%. (bng
3.1)
Nhit nng chy: 201-202oC. (bng 3.2)
Rf = 0,61 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (1:1))(bng 3.2)
ESI_MS: xem ph lc 6.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 6.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 6.3, bng 3.5.

(ppm): xem ph lc 6.4, bng 3.6.

28

6-Methyl-2-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-on (14f)
Cng thc:
N

OCF 3
NH

H 3C
O

CTPT: C16H11F3N2O2; KLPT: 320,27

Tin hnh:
Cc bc tin hnh tng hp cht 14f tng t cht 14a, t 300mg (2mmol)
cht 4; 0,29ml(2mmol) 3-(trifluoromethoxy)benzaldehyd; 208mg (2mmol) NaHSO3
trong 2ml DMAC.
Sn phm thu c l 520mg cht bt mu vng nht. Hiu sut 96%. (bng
3.1)
Nhit nng chy: 245-246oC. (bng 3.2)
Rf = 0,63 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (1:1))(bng 3.2)
ESI_MS: xem ph lc 7.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 7.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

(ppm): xem ph lc 7.3, bng 3.5.

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 7.4, bng 3.6.

2-(2-Fluorophenyl)-6-methyl quinazolin-4(3H)-on (14g)

Cng thc:
N
NH

H 3C

CTPT: C15H11FN2O; KLPT: 254,26

Tin hnh:
Cc bc tin hnh tng hp cht 14g tng t cht 14a, t 300mg (2mmol)
cht 4; 0,21ml(2mmol,) 2-fluorobenzaldehyd; 208mg (2mmol) NaHSO3 trong 2ml
DMAC.

29

Sn phm thu c l 353mg cht bt mu vng. Hiu sut 70%. (bng 3.1)
Nhit nng chy: 228-229oC. (bng 3.2)
Rf = 0,75 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (1:1))(bng 3.2)
ESI_MS: xem ph lc 8.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 8.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 8.3, bng 3.5.

(ppm): xem ph lc 8.4, bng 3.6.

2-(3-Fluorophenyl)-6-methyl quinazolin-4(3H)-on (14h)

Cng thc:
N

F
NH

H 3C
O

CTPT: C15H11FN2O; KLPT: 254,26

Tin hnh:
Cc bc tin hnh tng hp cht 14h tng t cht 14a, t 300mg (2mmol)
cht 4; 0,21ml(2mmol) 3-fluorobenzaldehyd; 208mg (2mmol) NaHSO3 trong 2ml
DMAC.
Sn phm thu c l 455mg cht bt mu vng. Hiu sut 90%. (bng 3.1)
Nhit nng chy: 308-309oC. (bng 3.2)
Rf = 0,70 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (1:1))(bng 3.2)
ESI_MS: xem ph lc 9.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 9.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 9.3, bng 3.5.

(ppm): xem ph lc 9.4, bng 3.6.

30

2-(2-(Dimethylamino)phenyl)-6-methyl quinazolin-4(3H)-on (14i)

Cng thc:
N
NH

H 3C

N(CH 3)2

CTPT: C17H17N3O; KLPT: 279,34

Tin hnh:
Cc bc tin hnh tng hp cht 14i tng t cht 14a, t 300mg (2mmol)
cht 4; 300mg (2mmol) cht 13; 208mg (2mmol) NaHSO3 trong 2ml DMAC.
Sn phm thu c l 432mg cht bt mu trng ng. Hiu sut 77%. (bng
3.1)
Nhit nng chy: 204-205oC. (bng 3.2)
Rf = 0,54 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 10.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 10.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 10.3, bng 3.5.

(ppm): xem ph lc 10.4, bng 3.6.

2-(2-(Dimethylamino)phenyl)-7-methyl quinazolin-4(3H)-on (14j)

Cng thc:
H 3C

N
NH

N(CH 3)2

CTPT: C17H17N3O; KLPT: 279,34

Tin hnh:
Cc bc tin hnh tng hp cht 14j tng t cht 14a, t 300mg (2mmol)
cht 6; 300mg (2mmol) cht 13; 208mg (2mmol) NaHSO3 trong 2ml DMAC.

31

Sn phm thu c l 340mg cht bt mu trng ng. Hiu sut 61%. (bng
3.1)
Nhit nng chy: 214-215oC. (bng 3.2)
Rf = 0,72 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 11.1, bng 3.3
IR(KBr,
1

max

(cm-1)): xem ph lc 11.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 11.3, bng 3.5.

(ppm): xem ph lc 11.4, bng 3.6.

7-Methyl-2-(2-(trifluoromethoxy)phenyl)quinazolin-4(3H)-on (14k)
Cng thc:
H3C

N
NH

OCF3

CTPT: C16H11F3N2O2; KLPT: 320,27

Tin hnh:
Cc bc tin hnh tng hp cht 14k tng t cht 14a, t 300mg (2mmol)
cht 6; 0,29ml(2mmol) 2-(trifluoromethoxy)benzaldehyd; 208mg (2mmol) NaHSO3
trong 2ml DMAC.
Sn phm thu c l 440mg cht bt mu vng nht. Hiu sut 69%. (bng
3.1)
Nhit nng chy: 204-205oC. (bng 3.2)
Rf = 0,63 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (1:1))(bng 3.2)
ESI_MS: xem ph lc 12.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 12.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 12.3, bng 3.5.

(ppm): xem ph lc 12.4, bng 3.6.

32

6-Methyl-2-(naphthalen-1-yl)quinazolin-4(3H)-on (15a)
Cng thc:
N
NH

H 3C
O

CTPT: C19H14N2O; KLPT: 286,33

Tin hnh:
Cc bc tin hnh tng hp cht 15a tng t cht 14a, t 300mg (2mmol)
cht 4; 0,27ml (2mmol) 1-naphthaldehyd; 208mg (2mmol) NaHSO3 trong 5ml
DMAC. Lc ra ta vi ethanol lnh.
Sn phm thu c l 438mg cht bt mu vng m. Hiu sut 76%. (bng
3.1)
Nhit nng chy: 264-265oC. (bng 3.2)
Rf = 0,65 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 13.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 13.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 13.3, bng 3.5.

(ppm): xem ph lc 13.4, bng 3.6.

7-Methyl-2-(naphthalen-1-yl)quinazolin-4(3H)-on (15b)
Cng thc:
H 3C

N
NH
O

CTPT: C19H14N2O; KLPT: 286,33

Tin hnh:
Cc bc tin hnh tng hp cht 15b tng t cht 14a, t 200mg (1,33mmol)
cht 6; 0,18ml (0,133mmol) 1-naphthaldehyd; 140mg (1,4mmol) NaHSO3 trong 3ml
DMAC. Lc ra ta vi ethanol lnh.

33

Sn phm thu c l 266mg cht bt mu vng m. Hiu sut 70%. (bng

3.1)
Nhit nng chy: 293-294oC. (bng 3.2)
Rf = 0,65 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 14.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 14.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 14.3, bng 3.5.

(ppm): xem ph lc 14.4, bng 3.6.

6-(Dimethylamino)-2-(naphthalen-1-yl)quinazolin-4(3H)-on (15c)
Cng thc:
N
NH

(H 3C)2N
O

CTPT: C20H17N3O; KLPT: 315,37

Tin hnh:
Cc bc tin hnh tng hp cht 15c tng t cht 14a, t 300mg (1,68mmol)
cht 11; 0,2ml (1,68mmol) 1-naphthaldehyd; 281mg (1,68mmol) NaHSO3 trong 3ml
DMAC. Lc ra ta vi nc, ethanol v ethylacetat.
Sn phm thu c l 317 mg cht bt mu vng m. Hiu sut 60%. (bng
3.1)
Nhit nng chy: 251-252oC. (bng 3.2)
Rf = 0,72 (TLC, Silicagel 60 F254, h dung mi n-hexan: EtOAc (2:1))(bng 3.2)
ESI_MS: xem ph lc 15.1, bng 3.3.
IR(KBr,
1

max

(cm-1)): xem ph lc 15.2, bng 3.4.

H-NMR (500MHz, DMSO-d6),

13

C-NMR (125MHz, DMSO-d6),

(ppm): xem ph lc 15.3, bng 3.5.

(ppm): xem ph lc 15.4, bng 3.6.

34

Bng 3.1: Kt qu tng hp cc dn cht 14a-k v 15a-c.

M

Hiu

(.v.c)

sut (%)

2- CH3

250,30

77

cht bt, mu trng ng

6-CH3

3- CH3

250,30

90

cht bt, mu trng ng

14c

6-CH3

2-CF3

304,27

48

cht bt, mu vng nht

14d

6-CH3

3-CF3

304,27

82

cht bt, mu vng nht

14e

6-CH3

2-OCF3

320,27

98

cht bt, mu vng nht

14f

6-CH3

3-OCF3

320,27

96

cht bt, mu vng nht

14g

6-CH3

2-F

254,26

70

cht bt, mu vng

14h

6-CH3

3-F

254,26

90

cht bt, mu vng

14i

6-CH3

2-N(CH3)2

279,34

77

cht bt, mu trng ng

10

14j

7-CH3

2-N(CH3)2

279,34

61

cht bt, mu trng ng

11

14k

7-CH3

2-OCF3

320,27

69

cht bt, mu vng nht

12

15a

6-CH3

286,33

76

cht bt, mu vng m

13

15b

7-CH3

286,33

70

cht bt, mu vng m

14

15c

6-N(CH3)2

315,37

60

cht bt, mu vng m

R1

R2

14a

6-CH3

14b

TT

hiu

3.2.

Tnh cht

KIM TRA TINH KHIT, KHNG NH CU TRC

3.2.1. Kim tra tinh khit

Sau khi tng hp cc dn cht 14a-k v 15a-c c kim tra tinh khit
bng sc k lp mng v o nhit nng chy (Tnc) ca chng.
Sc k lp mng (SKLM)
SKLM c tin hnh trn bn nhm trng sn Silicagel 60 F254. Cc cht 14ak v 15a-c c ha tan trong dung mi ethylacetat, chy sc k lp mng vi h
dung mi n-hexan : ethylacetat (1:1

2:1). Sau khi chy sc k, em soi bn mng

35

di n t ngoi c bc sng 254nm th thy cc cht em th u cho 1 vt gn.

Gi tr Rf ca cc cht 14a-k v 15a-c khi trin khai vi hai h dung mi c tm tt
bng 3.2.
o nhit nng chy
Cc cht 14a-k v 15a-c c kim tra tinh khit bng SKLM ng thi
c tin hnh o nhit nng chy. Kt qu o nhit nng chy cho thy: cc
dn cht tng hp c u c im chy r rng, khong chnh lch hp. Kt qu c
th c tm tt bng 3.2.
Bng 3.2: Gi tr Rf v Tnc ca cc dn cht 14a-k v 15a-c

TT

K
hiu

Nhit
R1

R2

nng chy

H dung mi SK
Rf

(n-hexan:EtOAc)

(T C)

14a

6-CH3

2- CH3

215-216

0,75

2:1

14b

6-CH3

3- CH3

235-236

0,68

2:1

14c

6-CH3

2-CF3

195-196

0,58

1:1

14d

6-CH3

3-CF3

299-300

0,58

2:1

14e

6-CH3

2-OCF3

201-202

0,61

1:1

14f

6-CH3

3-OCF3

245-246

0,63

1:1

14g

6-CH3

2-F

228-229

0,75

1:1

14h

6-CH3

3-F

308-309

0,70

1:1

14i

6-CH3

2-N(CH3)2

204-205

0,54

2:1

10

14j

7-CH3

2-N(CH3)2

214-215

0,72

2:1

11

14k

7-CH3

2-OCF3

204-205

0,63

1:1

12

15a

6-CH3

264-265

0,65

2:1

13

15b

7-CH3

293-294

0,65

2:1

14

15c

6-N(CH3)2

251-252

0,72

2:1

36

Thng qua sc k khi chy SKLM v nhit nng chy ca cc dn cht

c th khng nh cc cht ny l tinh khit, iu kin o ph v th hot tnh
sinh hc.
3.2.2. Khng nh cu trc
Ph khi lng (LC-MS)

3.2.2.1.

Cc dn cht tng hp c ghi ph khi lng theo phng php phun m

in t (ESI-MS) trn my LC-MSD-Trap-SL ti Vin Ha hc cc hp cht thin
nhin Vin Hn lm Khoa hc v Cng ngh Vit Nam. 14 ph c ghi cc
ph lc 2.1

15.1, bng 3.3.

5'
8
7

6'

4'

1'

R2

2
4 3 NH

R1
6
5

8
7

3'

2
4 3 NH

R1

2'

15a-c

14a-k

37

Bng 3.3: Kt qu phn tch ph khi lng ca cc dn cht 14a-k v 15a-c

K

M (.v.c)

m/z (ESI-MS)

2- CH3

250,30

251,1 [M+H]+

6-CH3

3- CH3

250,30

249,0 [M-H]-

14c

6-CH3

2-CF3

304,27

305,0 [M+H]+

14d

6-CH3

3-CF3

304,27

305,0 [M+H]+

14e

6-CH3

2-OCF3

320,27

319,0 [M-H]-

14f

6-CH3

3-OCF3

320,27

319,0 [M-H]-

14g

6-CH3

2-F

254,26

255,1 [M+H]+

14h

6-CH3

3-F

254,26

255,1 [M+H]+

14i

6-CH3

2-N(CH3)2

279,34

280,1 [M+H]+

10

14j

7-CH3

2-N(CH3)2

279,34

280,1 [M+H]+

11

14k

7-CH3

2-OCF3

320,27

319,0 [M-H]-

12

15a

6-CH3

286,33

287,1 [M+H]+

13

15b

7-CH3

286,33

287,1 [M+H]+

14

15c

6-N(CH3)2

315,37

314,1 [M-H]-

R1

R2

14a

6-CH3

14b

TT

hiu

Ph hng ngoi (IR)

Ph hng ngoi c ghi trn my Perkin Elmer ti Vin Ha hc - Vin Hn
lm Khoa hc v Cng ngh Vit Nam. 14 ph c ghi li cc ph lc 2.2
15.2 . Kt qu phn tch s liu ph hng ngoi c ghi bng 3.4.

38

5'
8
7

6'

4'

1'

R2

2
4 3 NH

R1
6
5

8
7

3'

2
4 3 NH

R1

2'

15a-c

14a-k

Bng 3.4: S liu ph IR ca cc dn cht 14a-k v 15a-c

T
T

Ph IR (KBr), cm-1

K
hi

R1

R2

NH

(amid)

CH

(aryl)

C=C
C=O

(aryl)

14a

6-CH3

2- CH3

3055-2928

1682

1453

14b

6-CH3

3- CH3

3041-2928

1682

1484

14c

6-CH3

2-CF3

3414

3036-2872

1648

1490 -1151

14d

6-CH3

3-CF3

3414

3036-2951

1648

1490 -1151

14e

6-CH3

2-OCF3

3071-2958

1661

1494 -1577

14f

6-CH3

3-OCF3

3086-2958

1661

1494

14g

6-CH3

2-F

3019-2877

1680

1443 -1495

14h

6-CH3

3-F

3024 2883

1680

1495

14i

6-CH3

2-N(CH3)2 3513

2921-2970

1585-1621 1484

10 14j

7-CH3

2-N(CH3)2

3069-2934

1596-1664 1449

11 14k

7-CH3

2-OCF3

3022-2880

1612-1676 1453

12 15a

6-CH3

3041-2914

1677

13 15b

7-CH3

3142-2972

1617-1659 1499-1577

3159-2924

1633

14 15c 6-N(CH3)2

3421

3430

39

1484-1585

1509

Ph cng hng t ht nhn (NMR)

Ph cng hng t ht nhn proton v

13

C c ghi trn my ph AVANCE

Spectrometer AV500 (BRUKER, c) trong dung mi DMSO d6 ti Vin Ha hc

Vin Hn lm Khoa hc v Cng ngh Vit Nam. 18 ph cng hng t ht nhn v
14 ph 13C c ghi cc ph lc 1.1 15.3; 2.4
cng hng t ht nhn proton v

13

15.4 . Kt qu phn tch s liu ph

C ca 14 dn cht c ghi bng 3.4 v bng

3.5.
5'
8
7

6'

4'

1'

R2

2
4 3 NH

R1
6
5

8
7

3'

2
4 3 NH

R1

2'

15a-c

14a-k

Bng 3.5: S liu ph 1H-NMR ca cc dn cht 14a-k v 15a-c

TT

K
hiu

14a

14b

14c

R1

6-CH3

6-CH3

6-CH3

R2

H-NMR (DMSO); (ppm), J(Hz))

2- CH3

12,36 (s, 1H, NH); 7,96 (s, 1H, H5); 7,66 (dd,
1H, H6, J1=8,25, J2=2,0); 7,59 (d, 1H, H7,
J=8,5); 7,49 (d, 1H, H8, J=2,5); 7,43 (m, 1H,
H5); 7,35 (m, 2H, H3, H4); 2,46 (s, 3H, C2CH3); 2,37 (s, 3H, C6-CH3)

3- CH3

12,35 (s, 1H, NH); 8,00 (m, 3H, H5, H2, H6);
7,66 (m, 2H, H7, H5); 7,43 (m, 2H, H8, H4);
2,45 (s, 3H, C6-CH3); 2,40 (s, 3H, C3-CH3)

2-CF3

12,69 (s, 1H, NH); 7,98 (s, 1H, H6); 7,90 (d,
1H, H5, J=7,5); 7,83 (t, 1H, H3, J=7,0); 7,78
(m, 2H, H5, H7); 7,68 (dd, 1H, H8, J=8,5);
7,59 (d, 1H, H4, J=8,5); 2,47 (s, 3H, C6-CH3)

14d

6-CH3

3-CF3

12,68 (s, 1H, NH); 8,53 (s, 1H, H2); 8,46 (d,
1H, H6, J=7,5); 7,97 (s, 1H, H5); 7,96 (d, 1H,
H4, J=7,5); 7,81 (t, 1H, H7, J=9); 7,71 (m,
2H, H8, H5); 2,48 (s, 3H, C6-CH3)

14e

6-CH3

2-OCF3

12,57 (s, 1H, NH); 7,97 (s, 1H, H6); 7,81 (dd,

40

1H, H5, J1=2,5; J2=2,0); 7,71 (m, 2H, H4, H7);

7,63 (s, 1H, H8, J=8,5); 7,58 (m, 2H, H3, H5);
2,468 (s, 3H, C6-CH3)
6

10

11

12

13

14f

14g

14h

14i

14j

14k

15a

15b

6-CH3

6-CH3

6-CH3

6-CH3

7-CH3

7-CH3

3-OCF3

12,64 (s, 1H, NH); 8,24 (d, 1H, H5, J=8,0);

8,16 (s, 1H, H2); 7,97 (s, 1H, H7); 7,713 (m,
3H, H8, H5, H6); 7,61 (d, 1H, H4, J=8); 2,472
(s, 3H, C6-CH3)

2-F

12,48 (s, 1H, NH); 7,97 (m, 1H, H5); 7,97 (d,
1H, H6, J=1,0); 7,79 (dt, 1H, H4, J1=8,5;
J2=2,0); 7,64 (m, 2H, H7, H8); 7,40 (m, 2H,
H3, H5); 2,47 (s, 3H, C6-CH3)

3-F

12,51 (s, 1H, NH); 8,06 (d, 1H, H2, J=8);

8,01 (d, 1H, H5, J=10); 7,96 (s, 1H, H5); 7,67
(m, 2H, H6, H7); 7,62 (m, 1H, H8); 7,46 (m,
1H, H4); 2,469 (s, 3H, C6-CH3)

2-N(CH3)2

12,74 (s, 1H, NH); 7,94 (s, 1H, H5); 7,85 (dd,
1H, H6, J=8); 7,66 (m, 2H, H7, H8); 7,49 (m,
1H, H4); 7,26 (d, 1H, H5, J=8); 7,15 (m, 1H,
H3); 2,67 (m, 6H, -N(CH3)2); 2,45 (s, 3H, C6CH3)

2-N(CH3)2

12,92 (s, 1H, NH); 8,46 (d, 1H, H5, J=8); 8,21
(d, 1H, H6, J=8); 7,60 (s, 1H, H6); 7,51 (m,
1H, H8); 7,31 (m, 2H, H4, H5); 7,28 (m, 1H,
H3); 2,93 (m, 6H, -N(CH3)2)

2-OCF3

10,31 (s, 1H, NH); 8,18 (d, 1H, H6, J=8); 8,12
(dd, 1H, H5, J=8); 7,61 (m, 2H, H4, H6); 7,51
(t, 1H, H8, J=7,5); 7,42 (d, 1H, H3, J=8); 7,35
(d, 1H, H5, J=8); 2,53 (s, 3H, C7-CH3)

6-CH3

12,58 (s, 1H, NH); 8,17 (m, 1H, H2); 8,12 (d,
1H, H4, J=8,5); 8,05 (m, 2H, H5, H8); 7,79
(m, 1H, H3); 7,69 (dd, 1H, H5, J=8,5); 7,66
(m, 2H, H3, H7); 7,60 (m, 2H, H7, H8); 2,50 (s,
3H, C6-CH3)

7-CH3

12,58 (s, 1H, NH); 8,19 (m, 4H, H2, H4, H5,
H8); 7,79 (d, 1H, H5, J=7); 7,66 (m, 4H, H3,
H6, H7, H6); 7,41 (d, 1H, H8, J=3,5); 2,50 (m,
3H, C7-CH3)

41

12,38 (s, 1H, NH); 8,19 (m, 1H, H2); 8,09 (d,
1H, H4, J=8,5); 8,04 (m, 1H, H5); 7,76(d, 1H,
14

15c

6-N(CH3)2

H8, J=6,5); 7,64 (m, 4H, H3, H6, H7, H8);

7,38 (dd, 1H, H5, J1=3; J2=3,0); 7,29 (d, 1H,
H7, J=3,0); 3,05 (m, 6H, 2 (-CH3))

Bng 3.6: S liu ph 13C-NMR ca cc dn cht 14a-k v 15a-c

TT

K
hiu

14a

14b

14c

14d

14e

14f

R1

6-CH3

6-CH3

6-CH3

6-CH3

6-CH3

6-CH3

13

R2

C-NMR, (DMSO); (ppm)

2- CH3

161,66
(C4);
153,47
(C2);
146,72;
136,29;136,06; 135,67; 134,28; 130,47;
129,76; 129,06; 127,20; 125,64; 125,10;
120,69; 20,80 (CH3(C3)); 19,51 (CH3(C2))

3- CH3

162,12 (C4), 151,57 (C2); 146,72 (C9); 137,88;

136,23; 135,84; 132,70; 131,82; 128,46;
128,14; 127,32; 125,21; 124,74; 120,68 (C10);
20,94 (CH3(C3)); 20,82 (CH3(C6))

2-CF3

161,25 (C4); 151,49 (C2); 146,38 (C8a); 136,87;

135,89; 133,11; 132,39; 130,72; 130,40;
127,30; 126,90; 125,20; 124,87; 122,69;
120,92; 20,85 (-CH3)

3-CF3

162,04 (C4); 150,12 (C2); 146,43 (C8a); 136,81;

135,97; 133,75; 131,62; 129,83; 129,53;
127,63; 127,53; 125,27; 124,35; 120,91;
20,86(-CH3)

2-OCF3

161,38 (C4); 149,5 1(C2); 146,60 (C2); 145,68

(C8a); 136,91; 135,59; 132,18; 131,36; 128,21;
127,62; 125,20; 121,55; 120,98; 120,80;
118,93; 20,83 (-CH3)

3-OCF3

148,48 (C4); 136,80; 135,97; 135,02; 130,74;

127,51; 126,72; 125,27; 123,72; 120,89;
120,14; 109,52; 20,86 (-CH3)

42

10

11

12

13

14

14g

14h

14i

14j

14k

15a

15b

15c

6-CH3

6-CH3

6-CH3

7-CH3

7-CH3

2-F

161,38 (C4); 160,54; 158,55; 149,055;

146,675; 136,76; 135,82; 132,73; 130,96;
127,34; 125,19; 122,36; 120,82; 116,21;
20,83(-CH3)

3-F

136,69; 135,95; 135,03; 130,74; 130,68;

127,47; 125,26; 123,77; 120,84; 118,16;
117,99; 114,48; 114,29; 20,85(-CH3)

2-N(CH3)2

161,17 (C4); 152,88 (C2); 151,86 (C2); 147,26

(C8a); 136,22; 135,69; 131,61; 130,59; 127,36;
125,23; 122,17; 120,88; 119,18; 43,70 (N(CH3)2); 20,83 (-CH3)

2-N(CH3)2

162,01 (C4); 152,35 (C2); 145,29 (C8a); 132,32;

131,29; 128,010; 127,56; 126,29; 124,93;
124,79; 120,17; 119,26; 45,08 (-N(CH3)2);
21,92 (-CH3)

2-OCF3

161,95 (C4); 149,26; 149,09; 146,49; 145,96;

132,58; 131,85; 128,97; 127,84; 127,64;
126,76; 126,35; 121,46; 121,31; 118,68; 21,97
(-CH3)

6-CH3

161,797 (C4); 152,77 (C2); 146,67 (C8a);

136,44 (C6); 135,70; 133,10; 131,73; 130,24;
128,28; 127,58; 127,24; 126,98; 126,28;
125,17; 125,14; 125,01; 120,91; 20,81 (-CH3)

7-CH3

161,75 (C4); 153,63 (C2); 148,81 (C8a); 144,98

(C7); 133,12; 131,70; 130,32; 130,23; 128,29;
128,15; 127,60; 127,08; 126,99; 126,30;
125,68; 125,17; 125,06; 118,78(C4a); 21,31 (CH3)

6-N(CH3)2

161,95 (C4); 149,08; 149,03; 139,69; 133,18;

131,95; 130,41; 129,92; 128,34; 128,27;
127,52; 126,86; 126,21; 125,27; 125,05;
121,87; 120,50; 104,67; 40,15 (-CH3)

43

3.3.

TH HOT TNH GY C T BO UNG TH

Th hot tnh gy c t bo trn mt s dng t bo ung th ngi c tin

hnh ti Phng Ha sinh ng dng Vin Ha hc Vin Hn lm Khoa hc v Cng

ngh Vit Nam.
Ti phng Ha sinh ng dng (Vin Ha hc), 14 dn cht do nhm nghin cu
tng hp c 14a-k v 15a-c c th hot tnh gy c t bo trn cc dng t
bo ung th ngi theo phng php MTT. Cc dng t bo ung th c s dng l:
KB (Human epidemic carcinoma) ung th biu m; Hep G2 (Hepatocellular
carcinoma) ung th gan; LU (Human lung carcinoma) ung th phi v MCF-7
(Human breast carcinoma) ung th v.
Kt qu th hot tnh gy c t bo ca 14 dn cht tng hp c trnh
by bng 3.6.
Kt qu cho thy dn cht 14c, 14e, 14g, 14h, 14i, 14k, 15a-c c hot tnh c
ch trn c bn dng t bo ung th ngi, ring cht 14i khng c hot tnh trn t
bo ung th phi.
Trong ng lu l dn cht 15c c hot tnh tt trn c bn dng t bo ung
th nng IC50 = 0,051 0,5 g/ml.

44

Bng 3.7: Kt qu th hot tnh gy c t bo ca 14a-k v 15a-c trn 4 dng t

bo ung th ngi

TT

K hiu
cht

Gi tr IC50 (g/ml)
R1

R2
KB

Hep-G2

LU

MCF7

14a

6-CH3

2- CH3

>128

nt

nt

nt

14b

6-CH3

3- CH3

>128

nt

nt

nt

14c

6-CH3

2-CF3

4,48

5,81

62

74

14d

6-CH3

3-CF3

>128

Nt

nt

nt

14e

6-CH3

2-OCF3

1,18

1,36

25,33

14f

6-CH3

3-OCF3

>128

nt

nt

nt

14g

6-CH3

2-F

29,17

24,8

104

29,25

14h

6-CH3

3-F

0,32

0,5

7,21

21,11

14i

6-CH3

0,84

5,27

>128

10

14j

7-CH3

>128

nt

nt

nt

11

14k

7-CH3

70,4

32

104

>128

12

15a

6-CH3

3,92

5,8

11,69

16,64

13

15b

7-CH3

14,85

20,75

30

30,62

14

15c

6-N(CH3)2

0,051

0,096

0,125

0,5

0,31

0,35

0,45

0,53

2N(CH3)2
2N(CH3)2
2-OCF3

Ellipticin

45

CHNG 4: BN LUN
4.1.

V TNG HP HA HC

4.1.1. Tng hp dn cht trung gian 2-aminobenzamid v khng nh cu trc

Tng hp 2-amino-5-methylbenzamid 4
NO 2
H3C

NO2

SOCl2

COOH

H 3C

COCl

NO2

NH 4OH
Diclomethan

H 3C

CONH2
3

2
NH2

H 2, 10% Pd/C
CH3OH

CH3

CONH 2
4

Tng hp 2-amino-5-methylbenzamid 4 t acid 5-methyl-2-nitrobenzoic 1 qua

3 bc. u tin acid 1 c hot ha bng tc nhn thionylclorid v un hi lu
50oC trong 4h thu c sn phm l benzoylclorid 2. Sau hp cht 2 tip tc phn
ng vi dung dung dch NH4OH nhit 0oC trong dung mi DCM thu c hp
cht 3 (hiu sut 82%). Cui cng hydro ha nhm NO2 ca 3 vi xc tc 10%Pd/C
nhit phng thu c hp cht 2-amino-5-methylbenzamid 4, phn ng c hiu
sut cao 94%.
Sn phm 4 c khng nh cu trc bng ph cng hng t ht nhn proton
1

H-NMR. Trn ph 1H-NMR ca hp cht 4 thy: pic rng ca nhm amid v tr

7,65-7,34 ppm; cc H ca vng thm xut hin v tr 6,96-6,59 ppm; proton ca

nhm amin NH2 xut hin v tr 6,30 ppm; v pic nhm CH3 xut hin v tr 2,13
ppm. D liu ph 1H-NMR ca hp cht 4 ph hp vi ti liu tham kho c [22,
23]. (bng 4.1, ph lc 1.1)
Tng hp 2-amino-4-methylbenzamid 6
H3C

NH 2

KOH

CN

C2H5OH

H 3C

NH 2
CONH 2
6

46

 tng hp 2-amino-4-methylbenzamid 6, tin hnh thy phn 2-amino-4methylbenzonitril trong mi trng kim KOH/ EtOH, phn ng c un hi lu
90oC, cho hiu sut 73 %.
Sn phm 6 c khng nh bng ph cng hng t ht nhn proton 1HNMR. Trn ph 1H-NMR ca hp cht 6 cng cho thy: proton ca vng thm xut
hin v tr 7,26-6,47 ppm; proton ca nhm CH3 xut hin v tr 2,26 ppm. D
liu ph 1H-NMR ca hp cht 6 ph hp vi ti liu tham kho c [22,23].(bng
4.1, ph lc 1.2)
Tng hp 2-amino-5-(dimethyl amino)benzamid
NO 2
Cl

SOCl2
Cl

COOH
7

NH4OH

COCl

Dicloromethan

Cl

8
NO 2

NH(CH3) 2
DMF, 1100C

NO 2

NO 2

(H3C) 2N

CONH2
9
NH 2

H 2, 10% Pd/C

CONH 2

CH 3OH

10

(H3C) 2N

CONH 2
11

Qa trnh tng hp 2-amino-5-(dimethyl amino)benzamid 11 gm 4 bc. Phn

ng hot ha acid 7 v amin ha 8 tng t khi tng hp 2, 3 thu c hp cht 9.
Tip tc tin hnh phn ng th a nhm dimethylamin vo hp cht 9 trong dung
mi DMF, phn ng c tin hnh trong bnh kn. Phn hn hp phn ng c un
nng 110oC, thu c hp cht 10. Hiu sut phn ng cao 96%. Sau kh ha
nhm NO2 ca hp cht 10 bng phn ng hydro ha vi xc tc 10%Pd/C nhit
phng thu c 2-amino-5-(dimethyl amino)benzamid 11. Hiu sut phn ng 72%.
Sn phm thu c 11 khng nh bng ph cng hng t ht nhn proton 1HNMR. Trn ph 1H-NMR ca hp cht 11 cng cho thy: pic rng ca nhm amid v
tr 7,72-7,00ppm proton ca vng thm xut hin v tr 6,91-6,61ppm; proton ca
nhm amin NH2 xut hin v tr 5,87 ppm; v pic nhm CH3 xut hin v tr
2,75ppm. D liu ph 1H-NMR ca hp cht 11 ph hp vi ti liu tham kho c
[22,23].(bng 4.1, ph lc 1.3)

47

Bng 4.1: Ph 1H-NMR ca cc dn cht trung gian 4, 6, 11

TT Cht
1

CTCT

H-NMR (DMSO; (ppm), J(Hz))

7,65-7,34 (2H, -CONH2); 6,96 (dd, 2H, H4,6,

NH2

J=3,0); 6,59 (d, 1H, H3, J=8,5); 6,30 (s, 2H, C2-

CH3

CONH 2

H 3C

NH 2

7,26 (m, 1H, H6, J=3,5); 6,49 (s, 1H, H5); 6,47

CONH 2

(d, 1H, H3, J=8,0); 2,26 (s, 3H, C4-CH3).

NH2); 2,13 (m, 3H, C5-CH3).

7,72-7,00 (s, 2H, -CONH2); 6,91 (d, 1H, H6,

11

(H 3C)2N

NH 2

J=2,5); 6,81 (dd, 1H, H4, J=9); 6,61 (d, 1H, H3,

CONH2

J=3,5) 5,87 (s, 2H, C2-NH2); 2,75 (m, 6H, N(CH3)2).

4.1.2. Tng hp dn cht trung gian aldehyd thm v khng nh cu trc

NH(CH 3)2
K 2CO 3, DMF, 110 0C

OHC

OHC

H3C

CH 3

13

12

Hu ht cc aldehyd thm trong lun vn ny u c s dng trc tip khng

qua x l g thm. Tng hp thm dn cht 2-(dimethylamin)benzaldehyd bng phn
ng th nhm dimethylamino vo o-flourobenzaldehyd vi cht xc tc kim K2CO3
trong mi trng DMF 1100C. Phn ng cho hiu sut 92%.
Sn phm thu c 12 khng nh bng ph cng hng t ht nhn proton 1HNMR. Trn ph 1H-NMR ca hp cht 11 cng cho thy: proton ca nhm CHO
xut hin v tr 10,21ppm; cc proton ca vng thm xut hin v tr 7,76-7,04; v
proton ca 2 nhm CH3 xut hin v tr thp nht 2,95ppm. D liu ph 1H-NMR
ca hp cht 13 ph hp vi ti liu tham kho c [8,9,10].( ph lc 1.4)
4.1.3. Tng hp dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c)
Cc dn cht 2-aryl-4-quinazolinon c th tng hp theo nhiu phng php
khc nhau, trong lun vn ny cc dn cht 2-aryl-4-quinazolinon c tng hp theo
phng php ca Hour M. J. v cng s. Cc dn cht u c tng hp theo c ch

48

chung l phn ng ngng t cc dn cht 2-aminobenzamid v cc aldehyd thm c

un nng 150oC trong mi trng N,N-dimethylamin sau c tinh ch thu sn
phm. Phng php ny c la chn v:
-

Nguyn liu v cc hp cht aldehyd thm ban u sn c, a dng.

Phn ng tin hnh d dng, hiu sut phn ng cao.

Sn phm thu c hu ht l cc cht kt tinh trong nc, ch cn lc ra,

d tinh ch.

C ch phn ng xy ra theo s 4.1 di y:

NH2

DMAC
R1

R1

NH 2

16

NH2

-H2O

H
N

R
R1

R
NH

17

18
NaHSO3

N
R1

R
NH

19

S 4.1: C ch tng hp cc cht 2-aryl-4-quinazolinon

u tin phn ng cng hp i nhn vo nhm carbonyl ca hp cht aldehyd,
tip theo c s loi nc to thnh cht 17.
Sau , cht 17 ng vng to vng 6 cnh bn to thnh cht 18 trong dung
mi N,N-dimethylacetamid, cui cng di tc dng oxy ha ca NaHSO3 18 dehydro
ha tch hydro to thnh vng quinazolinon bn 19 [1,22,23,27].
Tng hp cc dn cht 2-aryl-4-quinazolinon theo phng php ca Hour M. J.
v cng s khc phc c nhc im cc phng php tng hp trc l phi s
dng hp cht benzoyl clorid km bn trong iu kin nng m nc ta, phn ng
to ra acid v c HCl gy hao mn thit b th. Hn na, phng php ny d thc
hin, hiu sut phn ng tng i cao 48-98%, tinh ch sn phm d dng.

49

4.2.

V XC NH CU TRC

4.2.1. Ph hng ngoi( IR)

tin hnh o ph hng ngoi ca 14 dn cht tng hp c. Qua nghin
cu ph ca cc cht, chng ti nhn bit c cc di hp th c trng ca cc
nhm chc v lin kt ca cc cht tng hp c. Kt qu bin gii ph c trnh
by bng 3.4. Sau y l mt s nhn xt chung:
Ph hng ngoi ca 14 cht 14a-k v 15a-c u c xut hin di hp th
mnh tng ng vi dao ng nhm NH amid nm trong vng t 3513-3414
cm-1 ph hp vi dao ng ha tr ca nhm amin bc 2 b nh hng bi
nhm carbonyl. Tuy nhin trn ph hng ngoi ca mt s cht khng xut
hin di hp th mnh ny iu ny c th gii thch nh sau, do pic ca nhm
amid c tnh cht t v thp nn c th do trong qu trnh o ph b b qua.
Trn ph hng ngoi cng xut hin di ph c trng ca nhm -CH c
trng c trnh by bng 3.4 v ph lc 2.2 15.2.
Trn ph hng ngoi ca 14 dn cht tng hp c u xut hin di hp
th ca nhm C=O amid 1680-1585 cm-1.
Trn 14 ph ca 14 dn cht 14a-k v 15a-c tng hp c u xut hin
di hp th c trng ca cc nhm CH thuc vng thm 2880-3159 cm-1.
Nh vy, qua vic xc nh s c mt ca cc nhm th c trng, s b c
th nhn thy phn ng tng hp xy ra. Tuy nhin, khng nh chc chn cu
trc ca cc cht th cn thm d liu ca ph khi lng v ph cng hng t ht
nhn.
Di y l hnh nh minh ha ph hng ngoi ca cht 15c.

50

C=O

NH

CH
CH

Hnh 4.1: Ph hng ngoi ca cht 15c

4.2.2. Ph cng hng t ht nhn proton (1H-NMR)
Ph 1H-NMR cho thy cc tn hiu c trng ca cc proton v s lng proton
tng dng ca 14 dn cht tng hp c ghi qua s liu v dch chuyn ha hc ,
bi, hng s ghp cp J, v cng ca cc pic c trnh by bng 3.5. Sau
y l bin gii v mi quan h cu trc phn t v ph 1H-NMR ca cc cht tng
hp c. Ph 1H-NMR cho thy tn hiu ca proton H-N3 ( tn hiu t, cng yu)
xut hin trong vng 10,31 12,92 ppm (xem bng 3.5).
S tn hiu proton xut hin trong ph 1H-NMR tng ng vi s nguyn t hydro
c mt trong cng thc ha hc d kin.
Trn ph 1H-NMR ca cc cht cn xut hin cc tn hiu c trng ca proton
nhn thm (bng 3.5, ph lc 2.3 15.3).
Trn ph 1H-NMR ca 14a-k v 15a-c xut hin cc tn hiu c trng ca
proton ca cc nhm CH3 xut hin vng thp nht 2,37-3,05 ppm.

51

Sau y l ph cng hng t ht nhn 1H-NMR minh ha ca hp cht 15c.

a)

-N(CH3)2

-NH

52

b)

H3,6, 7,8
H7
H4

H8
H5

H5

H2

Hnh 4.2: a)Ph 1H-NMR; b) Ph 1H-NMR dn rng ca cht 15c

4.2.3. Ph cng hng t ht nhn 13C (13C-NMR)
14 dn cht tng hp (I-XIV) c ghi ph 13C-NMR. Kt qu phn tch
ph c trnh by bng 3.6 cho thy cc cht c ghi ph c s carbon v dich
chuyn ha hc

ca cc v tr carbon trong cng thc phn t ph hp vi cng thc

d kin.
Nguyn t carbon nhm C=O (amid) l C4 c tn hiu cng hng trong vng
136,87 162,12 ppm.
Nguyn t carbon C2 c tn hiu cng hng t trong vng 136,79 160,54 ppm.
Nguyn t carbon cc nhm th CH3 c tn hiu ph cng hng trong vng
20,82 - 40,15 ppm.
Ph 13C-NMR ca cc cht cn cho thy s lng nguyn t carbon v dch
chuyn ha hc c trng ca carbon nhn thm c trnh by r bng 3.6 v
ph lc 2.4 15.4.

53

Sau y l ph 13C-NMR minh ha ca hp cht 15c.

a)

-CH3

54

b)

C4

C5

Hnh 4.3: a)Ph 13C-NMR; b) Ph 13C-NMR dn rng ca cht 15c

4.2.4. Ph khi lng (MS)
khng nh thm v cu trc ca 14 dn cht 14a-k v 15a-c chng ti
tin hnh ghi ph MS (LC_MS) ca cc dn cht ny.
Sau y l v d phn tch ph khi lng xc nh s ph hp gia CTPT
d kin v CTPT ca cht 15c tng hp c. Cht 15c c CTPT d kin l
C20H17N3O tng ng vi s khi l 315,37. Trn ph xut hin pic [M-H]- cng
ln nht c s khi 314 (Hnh 4.4). Nh vy, s b cho thy cht 15c c s khi
ng nh s khi d kin

55

[M-H]-

[M]

Hnh 4.4: Ph khi lng (MS) ca cht 15c

T cc kt qu ghi ph thu c c th nhn thy 14 cht tng hp c u
xut hin pic phn t c cng phn t ln, khi lng ion phn t ph hp vi
khi lng phn t d on ca cht d kin.
Tm li d liu ph thc nghim cho php khng nh cu trc cc hp cht
tng hp dy 14a-k v 15a-c ng nh d kin v l sn phm tinh khit. T , cc
dn cht 2-aryl-4-quinazolinon ny s c tin hnh th hot tnh sinh hc.

56

4.3.

V HOT TNH KHNG T BO UNG TH

Da trn kt qu th hot tnh khng t bo ung th bng 3.7 c th nhn thy

mt s mi lin quan gia cu trc v tc dng gy c trn bn dng t bo ung th

th nghim nh sau:
Bng 3.7: Kt qu th hot tnh gy c t bo ca 14 dn cht trn 4 dng t
bo ung th ngi.

TT

Gi tr IC50 (g/ml)

K hiu
cht

CTCT

14a

NH

H 3C

CH 3

KB

Hep-G2

LU

MCF7

>128

nt

nt

nt

>128

nt

nt

nt

4,48

5,81

62

74

>128

nt

nt

nt

1,18

1,36

25,33

>128

nt

nt

nt

29,17

24,8

104

29,25

0,32

0,5

7,21

21,11

14b

CH3
NH

H 3C
O

14c

NH

H 3C

CF 3

14d

CF3
NH

H 3C
O

14e

NH

H 3C

OCF 3

14f

OCF3
NH

H 3C
O

14g

NH

H 3C

14h

F
NH

H 3C
O

57

14i
H 3C

NH

NMe2

NH

NMe2

NH

OCF 3

0,84

5,27

>128

>128

nt

nt

nt

70,4

32

104

>128

3,92

5,8

11,69

16,64

14,85

20,75

30

30,62

0,051

0,096

0,125

0,5

0,31

0,35

0,45

0,53

10

14j

H 3C

11

14k

H 3C

12

15a

NH

H 3C
O

13

15b

H 3C

N
NH
O

14

15c

NH

Me2 N
O

Ellipticin

Cc dn cht c hot tnh th u c tc dng trn c 4 dng t bo ung th c

bit c p ng tt nht trn dng t bo ung th biu m KB trong c dn
cht 15c c hot tnh mnh nht vi IC50 = 0,051g/ml.
Hu ht cc dn cht c cha nhm th F trn vng phenyl th v tr C2 ca
vng quinazolinon nh: -F, -OCF3, -CF3 u c hot tnh gy c trn c bn
dng t bo ung th. Tuy nhin nhm th -CH3 c hai v tr C2 v C3 u
khng c hot tnh trn c bn dng t bo ung th ngi.
Dn cht 14c c nhm th -CF3 v tr C2 trn vng phenyl c hot tnh tt trn
c 4 dng t bo ung th c bit l trn t bo ung th biu m, ngc li dn
cht 14d cng cha nhm th -CF3 trn vng phenyl nhng v tr C3li hon
ton khng c hot tnh c ch trn c bn dng t bo ung th.

58

Tng t nh vy, dn cht 14e v 14f cho thy nhm th -OCF3 v tr C2 c

hot tnh sinh hc cao IC50 = 1,18 g/ml; 1,36 g/ml; 2,00 g/ml; 25,33 g/ml
tng ng vi bn dng t bo ung th biu m, ung th gan, ung th phi, ung
th v, cn v tr C3 li khng c hot tnh sinh hc. Khi so snh vi ti liu
tham kho [22] nhm th -OCF3 v tr C2 c hot tnh khng t bo ung th
da trn chut v trn ngi cao nng IC50= 0,35 v 0,47 M.
Ngc li dn cht 14h nhm th -F v tr th C3 li c hot tnh cao hn
trn c bn dng t bo ung th so vi dn cht 14g c nhm th -F v tr C2.
So snh vi ti liu tham kho [22] dn cht 6-pyrolidinyl-2(2-substituted
phenyl)-4-quinazolinon c nhm th -F v tr 2 cng c hot tnh trn 2 dng
t bo ung th da ngi v chut trn tng s 6 dng ung th th nghim
nng IC50= 0,51 v 0,75 M.
Cc dn cht 15a-c c nhm th naphthalen v tr C2 ca vng quinazolinon
u c hot tnh sinh hc cao trn c bn dng t bo ung th ngi. Tng t
khi so snh vi ti liu tham kho [33] cho thy dn cht 2-(napthalen-1-yl)-6pyrolidinyl-quinazolinon cng c tc dng rt tt trn 6 dng t bo ung th:
ung th da, ung th phi, ung th gan, ung th vm hng, khi u c tnh vi
nng IC50= 0,033-1,350 M.
T 3 cp dn cht 14c v 14k, 14i v 14j, 15a v 15b cho thy nhm th -CH3
v tr C6 c tc dng gy c t bo ung th tt hn so vi v tr C7 ca vng
quinazolinon
Dn cht 15c c nhm th dimethylamin v tr C6 c hot tnh sinh hc rt
cao cao IC50 = 0,051 g/ml; 0,096 g/ml; 0,125 g/ml; 0,5 g/ml tng ng vi
bn dng t bo ung th biu m, ung th gan, ung th phi, ung th v. Tng
t khi so snh vi ti liu tham kho [23] dn cht 6-alkylamino v 2,3dihydro-3-methoxy-2-phenyl-4-quinazolinon cng c nhm th dimethylamin
v tr C6 cng c hot tnh khng t bo ung th cao IC50= 3,5 0,3 M.

59

Nh vy, kt qu th hot tnh gy c t bo ung th ca cc dn cht 14a-k

v 15a-c cng vi vic so snh vi cc dn cht c cng b trong cc ti liu
tham kho c, c th cho thy:
Nhm th v tr C6 cho hot tnh ca dn cht tng hp c cao hn v tr
C7.
Nhm th naphthalen v tr C2 ca vng quinazolinon cho hot tnh gy c
cc t bo ung th cao.
Dn cht c nhm th dimethylamin v tr C6 c hot tnh sinh hc cao.
Hu ht cc hp cht tng hp c c tnh chn lc trn dng t bo ung th
KB t bo ung th biu m, t bo hay c s dng trong cc nghin cu
th hot tnh sinh hc.
V tr nhm th 2 v 3 trn vng 2-phenyl khng c tnh quyt nh n hot
tnh gy c t bo ung th ca cc hp cht tng hp c.

60

KT LUN V KIN NGH

KT LUN
T nhng kt qu nghin cu trnh by trn, c th rt ra mt s kt lun
nh sau:
1.

tng hp c 14 dn cht 2-aryl-4-quinazolinon (14a-k; 15a-c). Trong

c 13 cht 14b-k v 15a-c l cc cht mi, cha thy cng b trong cc ti liu tham
kho c. Tt c cc cht tng hp c u c kim tra tinh khit bng sc k
lp mng v o nhit nng chy. Cu trc cc dn cht tng hp c xc nh
bng cc php o ph hng ngoi IR, ph cng hng t ht nhn (1H-NMR,

13

C-

NMR), ph khi lng (MS). Kt qu thu c cho php kt lun cc cht tng hp
c c cu trc ng nh d kin.
2.

th hot tnh gy c t bo ung th ca 14 dn cht tng hp c vi 4

dng t bo ung th ngi l t bo ung th biu m KB, t bo ung th gan Hep

G2, t bo ung th phi LU, t bo ung th v MCE 7. Kt qu cho thy c 9 dn
cht trong 14 dn cht tng hp c c hot tnh sinh hc trn c 4 dng t bo ung
th ngi. c bit hp cht 15c c hot tnh khng t bo ung th rt tt nng
IC50 = 0,051 g/ml trn t bo ung th da, IC50 = 0,096 g/ml trn t bo ung th gan,
IC50 = 0,125 g/ml trn t bo ung th phi, IC50 = 0,5 g/ml trn t bo ung th v.

KIN NGH
T cc kt qu nghin cu trn nhm nghin cu xin c mt s xut nh
sau:
Tip tc th sng lc hot tnh gy c t bo ca cc dn cht tng hp c
trn cc dng t bo ung th khc nhau: ung th i trng, ung th d dy
Tip tc tng hp v sng lc hot tnh gy c t bo ung th ca cc dn cht
2-aryl-4-quinazolinon khc nhm tm kim cc cht c trin vng trong dy dn cht
ny.

61

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