B GIO DC V O TO

I HC NNG

MAI VN T

NGHIN CU BN TNG HP CHT TRUNG GIAN

TRONG QUY TRNH TNG HP THUC UNG TH

Cng trnh c hon thnh ti

I HC NNG

Ngi hng dn khoa hc: GS.TSKH. TRN VN SUNG

Phn bin 1 : PGS.TS. L T Hi

Phn bin 2 : PGS.TS. Nguyn Phi Hng

VINBLASTIN T CATHARATHIN V VINDOLIN CHIT

TCH T CY DA CN (CATHARANTHUR ROSEUS)

Chuyn ngnh: Ha hu c
M s: 60 44 27

Lun vn c bo v trc hi ng chm Lun

vn tt nghip Thc s Khoa hc hp ti i hc Nng
vo ngy 13 thng 11 nm 2012.

TM TT LUN VN THC S KHOA HC

Nng - 2012

C th tm hiu lun vn ti:

- Trung tm Thng tin Hc liu, i hc Nng
- Th vin trng i hc S phm, i hc Nn

1
M U
1. T VN
S thay i kh hu ton cu dn ti s khc nghit ca thi

2
Trong ti ny chng ti t ra mc tiu: nghin cu bn
tng hp cht trung gian trong quy trnh tng hp thuc chng
ung th vinblastin t catharathin v vindolin chit tch t cy

tit, mi trng b nhim l iu kin sng thay i v thi

da cn.

quen sinh hot ca con ngi c nhiu bt li cho sc khe,...

2. MC TIU NGHIN CU

Nhng yu t ny tc ng n sc khe con ngi, lm gia

2.1. Thu thp ti liu, thng tin

tng nguy c mc bnh, m trong c nguy c cc t bo b bin

2.2. Tin hnh thc nghim

i. y l mt trong nhng nguyn nhn lm cho s ca mc bnh

ung th ngy cng tng. V th, mt trong nhng nhim v hng

Tng hp mt s cht trung gian trong quy trnh tng hp

vinblastin (S 1)

u ca cc nh khoa hc l nghin cu, ci tin cc bin php

cha tr ung th nng cao cht lng sng cho ngi bnh.
Vinblastin l mt loi thuc c s dng iu tr bnh ung
th thng qua phng php ha tr liu. y l hp cht c ngun
gc t nhin, c tch ra t l da cn. Hot cht ny c kh
nng chng phn bo c s dng kt hp vi mt s loi thuc
khc iu tr nhiu loi ung th nh ung th bch cu, ung th
bng quang, ung th tinh hon, cc u bch huyt , Tuy nhin,
vinblastin li c hm lng rt thp ch chim khong 0,01%
trong l da cn kh v qu trnh phn lp hp cht ny rt tn
km, y kh khn v hiu sut thp [15], [16]. Chnh v nhng
yu t ny nn vinblastin lun l i tng quan tm ca cc nh
khoa hc. Phng php bn tng hp tn dng 2 alkaloid ph
trong qu trnh phn lp vinblastin t da cn l catharanthin v
vindolin c quan tm nhiu nht. y l 2 alkaloid c hm
lng cao hn vinblastin (trong 1 tn nguyn liu thc vt kh
tch c 400 g catharanthin v 800 g vindolin [15] v c kh
nng ghp i to thnh vinblastin. Do vic nghin cu bn
tng hp vinblastin t vindolin v catharanthin l rt cn thit.

S 1. S tng cc cht trung gian tng hp vinblastin

3. I TNG V PHM VI NGHIN CU
- Nghin cu quy trnh tng hp bn cht trung gian 56, 57,

58 v cht 59 trong qu trnh tng hp thuc chng ung th

th nh ung th bch cu, ung th bng quang, ung th tinh

vinblastin t catharathin v vindolin, chit tch t cy da cn.

hon, cc u bch huyt,

- Cc cht tng hp c kim tra tinh khit bng sc k

Tuy nhin, vinblastin li c hm lng rt thp ch chim

lp mng (SKLM), sc k lng hiu nng cao ( HPLC), sc k

khong 0,01% trong l da cn kh v qu trnh phn lp hp

lng gn vi khi ph (LC/ MS)

cht ny rt tn km, y kh khn v hiu sut thp lm cho gi

4. PHNG PHP NGHIN CU

thnh ca sn phm rt cao.

5. B CC CA LUN VN
Ngoi phn m u, kt lun, cc danh mc ti liu tham

T cc kt qu kho st s b ca Vin Ha hc cng nghip,

kt hp so snh v tham kho cc ti liu nc ngoi, chng ti

kho v ph lc, ni dung lun vn chia lm 4 chng

nhn thy rng vi cng ngh chit sut hin i hiu sut thu hi

Chng 1 trnh by tng quan ca ti liu.

khong 40%, trn ging da cn tt nht (c hm lng vinblastin

Chng 2 nu nguyn liu ho cht v phng php nghin cu.

0,014% tnh theo khi lng l kh tng ng vi

Chng 3 trnh by phn thc nghim ca ti.

Madagasca), chi ph ti thiu phn lp 1 gam vinblastin vn cn

Chng 4 trnh by kt qu nghin cu v tho lun ca ti.

ln hn 200 USD, trong khi gi xut xng ca Eli Lilly,

6. TNG QUAN TI LIU NGHIN CU

Geoden Richer v ca Cipla ch dao ng trong khong 120 135

Cy da cn cn c tn l bng da, hi ng. Tn khoa hc l

USD/1 gam vinblastin sunfat. Nh vy nu thun ty ch da vo

Catharanthus roseus (L.) G. Don [Apocynaceae] l loi cy c cao

chit tch, cc thuc chng ung th t l v hoa da cn ca Vit

khong 40 60 cm.Thn mm t nhiu cnh nn cy thng nghing

Nam s khng cnh tranh c ngay th trng trong nc.

v mt pha. Hoa c 5 cnh mu pht hng hoc mu trng. Cy c

ti nghin cu bn tng hp cht trung gian trong quy

ngun gc Madagasca (chu Phi), c ngi Php a vo trng

trnh tng hp vinblastin t vindolin v catharathin chit tch t

Vit Nam lm cy cnh. Cy d trng, pht trin nhanh nn t

cy da cn lm thuc chng ung th ca chng trnh ha dc

lu sau n lan ra nhiu a phng, nht l cc tnh ng bng

thc hin thnh cng s to ra cng ngh bn tng hp vinblastin

v ven bin nc ta. Dng cy p, mm mi, l xanh mt, hoa rc

ph hp vi Vit Nam, tn dng c hiu qu cc hot cht chit

sng

sut t l da cn v lm gim gi thnh ca thuc, mang li

cuc sng tt p hn cho mi ngi.

Vinblastin l hp cht c ngun gc t nhin, c tch ra t

l da cn. Hot cht ny c kh nng chng phn bo c s
dng kt hp vi mt s loi thuc khc iu tr nhiu loi ung

CHNG 1

sau: acid pyrocatechic, sc t flavonoid (glucosid ca quercetin

TNG QUAN TI LIU

v kampferol) v anthocyanin t thn v l da cn hoa .

1.1. TNG QUAN V CY DA CN

Ngoi ra t l chit c acid ursolic, t r chit c cholin.

Cy da cn cn c tn l bng da, hi ng. Tn khoa hc

Nm 1952, khi nghin cu tc dng ca cc alkaloid t l

l Catharanthus roseus (L.) G. Don [Apocynaceae] l loi cy

da cn ln chut , R. Noble v C. Noble pht hin ra cc hp

c cao khong 40 60 cm. Thn mm t nhiu cnh nn cy

cht ny c kh nng lm gim s lng bch cu trong mu

thng nghing v mt pha. Hoa c 5 cnh mu pht hng

chut. T , theo nh hng nghin cu cc cht gy c t

hoc mu trng. Cy c ngun gc Madagasca (chu Phi),

bo hoc gy c ch phn bo bch cu c tnh, cc vinca

c ngi Php a vo trng Vit Nam lm cy cnh.

alkaloid c hot tnh nh vinblastin, vincristin, vindesin v

Cy d trng, pht trin nhanh nn t lu sau n lan ra

vinorelbin c phn lp hoc bn tng hp ng dng

nhiu a phng, nht l cc tnh ng bng v ven bin

trong iu tr ung th, c bit l cc bnh Hodgkin v cc bnh

nc ta. Dng cy p, mm mi, l xanh mt, hoa rc sng,

ung th mu.

y l nhng nt c trng to c s hp dn ca loi cy

ny.

Nm 1958, ln u tin Noble v Beer phn lp c

vinblastin 1 cn gi l vincaleukoblastin t l cy da cn

Theo ng y, da cn c tc dng lm sn, chng vim, h p,

Trong cc nm 1959 n 1962, Johnson v Svoboda tm ra

c s dng iu tr mt s bnh: vim i trng, bnh tr, kh h

vincristin - mt alkaloid c hm lng thp trong cy da cn.

bch i, tng huyt p, vim nhim phn ph, kinh b, zona, phong

Hp cht mui sunfat ca vinblastin v vincristin c p

nga, i tho ng, vng da. L v phn ngn ca cy c dng

dng rng ri trong cc tr liu ha hc cha ung th mu, ung

lm thuc. C th ti gi p, phi kh sc ung hoc ch bin

th m bo bch huyt, ung th tinh hon v ung th v [32].

thnh dng tr.

Vinblastin 1 c FDA ph chun vo nm 1965 l thuc

Hot cht ca da cn l alkaloid c nhn indol trong tt c

iu tr nhiu loi ung th nh: bch cu, bng quang, tinh hon,

cc b phn ca cy, nhiu nht trong l v r. Da cn Vit

cc u bch huyt, v c bn trn th trng hn 40 nm.

Nam c t l alkaloid ton phn l 0,1 - 0,2%. R cha hot cht

Vinblastin 1 tr thnh mt dc phm quan trng, tuy nhin li

(0,7 - 2,4%) nhiu hn trong thn (0,46%) v l (0,37 - 1,15%).

c hm lng rt nh trong thc vt (chim 0,01% trong l da

Cc cht ch yu l: vinblastin, vincristin tetrahydroalstonin,

cn kh v vic tch hp cht ny t thc vt rt mt thi gian,

prinin, vindolin, catharanthin, ajmalicin, alstonine, leurocin,

tn km, hiu sut thp v y kh khn [15], [16]. Do

vincaleucoblastin, vincosid (1 glucoalkaloid tin thn sinh tng

vinblastin l i tng lun c cc nh khoa hc quan tm.

hp cc alkaloid). T da cn, ngi ta cn chit c cc cht

Nhiu phng php tng hp vinblastin c nghin cu bao

gm: nui cy t bo [15], cng ngh chuyn ha [31] , bn tng

a. Bn tng hp vinblastin t catharanthin v vindolin

hp v tng hp ton phn. Trong phng php bn tng hp

b. Bn tng hp vinblastin t vindolin

tn dng 2 alkaloid ph trong qu trnh tch vinblastin 1 t

da cn l vindolin 4 v catharanthin 3 c hm lng ln hn
nhiu (trong 1 tn nguyn liu thc vt kh tch c 400 g
catharanthin v 800 g vindolin , ng thi cng l cc monome
c th ghp i to thnh vinblastin 1 cng c quan tm rt
ln.
Cho n nay, vinblastin v cc dn xut s dng lm thuc
chng ung th trn th gii c sn xut ch yu theo hai
con ng [23]:
- Chit xut t l da cn;
- Bn tng hp t vindolin v catharanthin.
Vinblastin v cc dn xut l cc alkaloid dimeric c hm
lng thp (~ 0,01 % trong l da cn kh), trong khi alkaloid
ch yu ca da cn l vindolin - mt trong hai phn monomer
cu thnh vinblastin - c hm lng trong l da cn ln hn 4
n 5 ln so vi vinblastin. Trong qu trnh phn tch alkaloid
tng s ca da cn bng sc k hp ph, thng thng
vindolin v catharanthin c ra gii ra trc so vi vinblastin.
h gi thnh thuc, tn dng ph phm vindolin,
catharanthin cng nh cc vinca alkaloid khc, cc nghin cu
bn tng hp vinblastin v cc dn xut t vindolin v
catharanthin c pht trin mnh m v a vo p dng
trn th gii t cui nhng nm 1970 [13], [23].
1.2. CC PHNG PHP TNG HP VINBLASTIN
1.2.1. Gii thiu v vinblastin
1.2.2. Phng php bn tng hp

10

9
CHNG 2

3.2.1. Tng hp cht 56

NGUYN LIU V PHNG PHP NGHIN CU

2.1. NGUYN LIU
2.2. DUNG MI V HA CHT NGHIN CU
2.3. CC PHNG PHP CHUYN HA HA HC
2.4. PHNG PHP XC NH CU TRC HA HC CA
CC CHT
CHNG 3
THC NGHIM
3.1. THIT B V HACHT
3.2. NGHIN CU TNG HP CC CHT TRUNG GIAN
TRONG QUY TRNH TNG HP VINBLASTIN
Tng hp cc cht 56, 57, 58, 59 theo s hnh 3.1

Quy trnh tng hp

2,92 g (20 mmol) cht 54, 1,28 g (40 mmol) MeOH khan, 0,344
g (2 mmol) p-toluensunfonic acid v 50 ml CHCl3 c cho vo bnh
cu 100 ml hai c c b loi nc, sinh hn hi lu. Hn hp phn
ng c un hi lu 10h, ngui sau c ra vi nc, trung
ha bng NaHCO3 n pH = 5 v cui cng ra vi H2O. Dch chit
c lm khan vi Na2SO4. ct loi dung mi, thu c 3,03 g sn
phm dimethyl-2-oxoglutarat 56 ( HS: 87%).
Ph hng ngoi IR (KBr) (cm-1): 3461,55 ; 2972,70; 1732,86;
1626,39; 1435,34; 1254,48; 1202,24; 1084,02; 979,55; 611,14;
514,91 cm-1.
Ph 1H-NMR (500MHz, CDCl3) (ppm): 3,86 (3H, s, OCH3);
3,66 (3H, s, OCH3); 3,14 (2H, t, J = 6,5 Hz, H-3); 2,66 (2H, t, J = 6,5
Hz, H-4).
Ph 13C-NMR (125MHz, CDCl3) (ppm): 192,18 (C-2); 172,36
(C-5); 160,84 (C-1); 52,96; 51,90 (2xOCH3); 34,10 (C-3); 27,3 (C-4).
3.2.2. Tng hp hp cht 57

Hnh 3.1. S tng hp cc hp cht trung gian trong quy trnh

tng hp ton phn vinblastin

12

11
3.2.3. Tng hp cht 58 v 59

Quy trnh tng hp

2,04 g (10mmol) L-tryptophan c ha trong 50 ml THF (0,756
g, 10,5mmol). 100ml benzene c cho vo v quay ct ht dung
mi p sut gim, thu c mui khan. Cn mui c ha trong
50ml THF khan, cho 2,2g (12,6 mmol) dimethyl-2-oxoglutarate vo.
Hn hp phn ng c un hi lu 15 h, ct loi dung mi. Cn
c ha trong 100ml CH2Cl2 v ra vi 50ml nc, lm khan bng
Na2SO4. ct loi dung mi. Tch trn ct silicagel vi h dung mi
ra gii EtOAc/CH2Cl2 = 10 : 90, CH2Cl2/MeOH/ HOAc = 90/10/5.

Quy trnh tng hp

Thu c 1,39 g (42%) sn phm 57.

637 mg (1,9 mmol) cht 57 c ha trong 15 ml THF. Nh t t

Ph hng ngoi IR (KBr) (cm ): 3341,71; 1731,15; 1654,05;

-1

1404,23; 1185,25; 1068,05 cm-1

292 mg (2,1 mmol) isobutyl chloroformate v 196 mg (1,9 mmol) Nmethylmorpholine, khuy thm 10 pht, cho 247 mg (1,9 mmol) N-

Ph 1H-NMR (500MHz, CDCl3) (ppm): 8,48 (1H, s); 7,48 (1H,

hydroxy-2-thiopyridone v 233 mg (2,3 mmol) triethylamine vo hn

d, J = 8 Hz) ; 7,36 (1H, d, J = 8,0 Hz) ; 7,20 (1H, t, J = 7,5 Hz); 7,11

hp phn ng khuy thm 30 pht nhit phng sau lm lnh

(1H, t, J = 7,5 Hz); 5,45 (1H, d, J = 7,0 Hz); 3,71 (3H, s, OCH3); 3,34

xung -15oC bng mui v nh 1750 mg t-butylthiol, dung dch

(1H, d, J = 15,5 Hz); 3,10 (1H, dd, J = 15,5 v 7,5 Hz); 2,84 2,89

phn ng c tng t t ln 20oC bng cch chiu bng in 250W

(1H, m); 2,63 2,68 (1H, m); 2,47 2,52 (1H, m); 2,18 2,22 (1H,

trong 30 pht. Quay ct ht dung mi p sut gim, thu c cn.

m).

Cn c ha trong 100ml CH2Cl2 v ra vi HCl long v cui

Ph 13C-NMR (125MHz, CDCl3) (ppm): 175,36 (C-16); 173,72

cng vi 50ml nc, lm khan bng Na2SO4. Ct loi dung mi.

(C-19); 172,56 (C-17); 136,96 (C-6); 130,56 (C-8); 126,06 (C-1);

Tch trn ct silicagel vi h dung mi ra gii l EtOAc thu c

122,87 (C-2); 119,93 (C-3); 118,72 (C-4); 111,42 (C-5); 106,27 (C-

654 mg (81%) sn phm 58

9); 63,98 (C-11); 52,90 (C-18); 49,53 (C-13); 34,24 (C-14); 30,73
(C-15); 24,03 (C-10).

425 mg (1 mmol) cht 58 c ha trong 12 ml THF. cho t t

528 mg (1 mmol) Belleaureagent, hn hp phn ng khuy thm 2
gi nhit phng sau c quay ct dung mi ht dung mi
p sut gim, thu c cn.Tch trn ct silicagel vi h dung mi
ra gii l EtOAc thu c 227 mg (80%) sn phm 59.

13

14

Ph hng ngoi IR (KBr) (cm-1): 3382,09; 2927,53; 2856,51;

CHNG 4

-1

1667,97; 1465,26; 1419,58; 1165,48; 1076,97 cm .

Ph H-NMR (500MHz, CDCl3) (ppm): 8,35 (1H, s); 7,50 (1H,
1

KT QU V THO LUN
4.1. TNG HP HP CHT 56: dimethyl - 2-oxoglutarat

d, J = 7,5 Hz); 7,31 (1H, d, J = 7,5 Hz); 7,18 (1H, t, J = 7,0 Hz); 7,12
(1H, d, J = 7,0 Hz); 5,36 (1H, d, J = 7,0 Hz); 5,20 (1H, d, J = 7,0 Hz);
3,65 (3H, s); 3,41 (1H, m); 3,10 3,15 (1H, m); 2,49 2,72 (3H, m);
1,88 1,94 (1H, m)
Ph C-NMR (125MHz, CDCl3) (ppm): 173,75 (C-16); 171,17
13

(C-17); 136,38 (C-6); 132,45 (C-8); 126,64 (C-1); 122,35 (C-2);

119,87 (C-3); 118,43 (C-4); 111,06 (C-5); 105,54 (C-9); 52,53 (C11); 52,23 (C-18); 49,35 (C-13); 31,51 (C-14); 26,32 (C-15); 23,60
(C-10).

Dimethyl-2-oxoglutarat

to

thnh

khi

cho

2-

oxopentanedioic acid phn ng vi MeOH khan (1:2 theo t l mol),

xc tc l p-toluensunfonic acid cho hiu sut cao (87%).
Ph hng ngoi: (Hnh 4.1) cho nh hp th c trng ca nhm
carbonyl 1732,86 cm-1 (C=O).
Ph 1H-NMR (Hnh 4.2 v 4.3) c hai tn hiu triplet vng
trng cao vi H = 3,14 (2H, t, J = 6,5 Hz, H-3); 2,66 (2H, t, J = 6,5
Hz, H-4). c bit xut hin hai tn hiu singlet ti H = 3,86, 3,66
(2x3H, s, 2 x OCH3) c trng cho nhm methyl este.
Ph 13C-NMR ca hp cht dimethyl -2-oxoglutarat 56 (Hnh 4.4
v 4.5) c mt ca 7 cacbon trong c 2 nhm cacbon bc 2 (CH2);
2 nhm cacbon bc 1 (OCH3) v 3 nhm cacbon bc 4 (C). Ph 13CNMR c tn hiu ca 3 nhm methyl este = 173,72 (C-19) ;
172,56 (C-17), nhm xton = 175,36 (C-16) v c tn hiu ca 2
nhm OCH3 = 52,96 v 51,90 ppm.
T cc s liu ph hng ngoi, ph khi, 1H -NMR v 13C-NMR
ca cht 56
oxoglutarat.

cho thy n hon ton ph hp vi dimethyl -2-

15

16

Hnh 4.3. Ph cng hng t ht nhn 1H-NMR ca cht 56

Hnh 4.1. Ph hng ngoi ca cht 56

Hnh 4.2. Ph cng hng t ht nhn 1H-NMR ca cht 56

Hnh 4.4. Ph cng hng t ht nhn 13C-NMR ca cht 56

18

17

Bng 4.1. S liu ph 1H- v 13C-NMR ca cht 57

4.2. TNG HP HP CHT 57

(3-Oxo-5-carboxy-9-methoxycarbonylindolizino[8,7-b]indole)

STT

Cht 57
H (J=Hz)

Ti liu [28]
C

H (J=Hz)

126,06

122,87

7,36 (d, J = 8,0 Hz)

7,26 (d, J = 7,2 Hz)

119,93

7,20 (t, J = 7,5 Hz)

7,12 (m)

118,72

7,11 (t, J = 7,5 Hz)

7,05 (m)

111,42

7,48 (d, J = 8,0 Hz)

7,42 (d, J = 7,2 Hz)

vi H = 7,48 (1H, d, J = 8,0 Hz, H-2); 7,36 (1H, d, J = 8,0 Hz, H-5)

136,96

v hai tn hiu triplet vi H = 7,20 (1H, t, J = 7,5 Hz, H-3); 7,11

(1H, t, J = 7,5 Hz, H-4). C mt tn hiu duplet H = 5,45 (1H, d, J

130,56

= 7,0 Hz) c trng cho H-11. c bit xut hin tn hiu singulet

106,27

=3,71(3H, s, OCH3) c trng cho nhm OCH3

10

24,03

3,34 (1H, d, J = 15,5

3,30 (1H, d, J = 15

Hz)

Hz)

5,45 (d, J = 7,0 Hz)

5,38 (d, J = 7,5 Hz)

3,10 (2H, dd, J=15,5

3,00 (dd, J=15,6 v

v 7,5)

7,5)

2,84 2,89 (2H, m)

2,72 2,84 (2H, m)

3,71 (3H, s)

3,55 (3H, s)

Ph hng ngoi: (Hnh 4.6) cho nh hp th c trng ca

nhm OH 3341,71 cm-1 v keton 1731,15 cm-1 .
Ph 1H-NMR (Hnh 4.7; 4.8 v 4.9) c hai tn hiu dublet

Ph

13

C-NMR (Hnh 4.10 v 4.11) c mt ca 17 cacbon

trong c 3 nhm CH2 cacbon bc 2; 1 nhm OCH3 cacbon bc 1;

11

63,98

NMR xut hin tn hiu =172,56 c trng cho nhm COOH (C-

12

17); = 173,72 c trng cho nhm keton (C-16) v = 173,72 ppm

13

49,53

c trng cho nhm este (C-18).

14

34,24

5 nhm cacbon bc 3 v 8 nhm cacbon bc 4 (C). c bit ph 13C-

Ph khi ESI-MS cho pic c m/z= 327 l pic ca ion gi nh

-

[M-1] ph hp vi cng thc phn t C17H16O5N2 (Hnh 4.12)

1

13

T cc s liu ph hng ngoi, ph khi, H -NMR v CNMR ca cht 57 hon ton ph hp vi d liu ph trong ti liu 28
(xem bng 4.1).

15

30,73

16

175,36

17

172,56

18

173,72

19

52,09

19

20

Hnh 4.10. Ph cng hng t ht nhn 13C-NMR ca cht 57

Hnh 4.5. Ph hng ngoi ca cht 57

Hnh 4.6. Ph cng hng t ht nhn 1H-NMR ca cht 57

Hnh 4.11. Ph khi ESI-MS ca cht 57

22

21

Bng 4.2. S liu ph 1H- v 13C-NMR ca cht 59

4.3. TNG HP CHT 58 v 59

STT

Cht 59
H (J=Hz)

Ti liu [28]
C

H (J=Hz)

126,64

122,35

119,87

7,31 (1H, d , J=7,5

Hz)
7,12 (1H, t, J=7,0 Hz)

118,43

7,18 (1H, t, J=7,0 Hz)

111,06

7,50 (1H, d, J=7,5 Hz)

Ph 1H-NMR (Hnh 4.14; 4.15 v 4.16) c hai tn hiu dublet

136,38

vi H = 7,50 (1H, d, J = 7,5 Hz, H-5); 7,31 (1H, d, J = 7,5 Hz, H-2)

v hai tn hiu triplet vi H = 7,18 (1H, t, J = 7,0 Hz, H-4); 7,12

132,45

(1H, t, J = 7,0 Hz, H-3). c bit xut hin tn hiu singulet =3,65

105,54

(3H, s, OCH3) c trng cho nhm OCH3

10

23,60

3,15 3,45 (2H, m)

3,05 3,30 (2H, m)

11

52,53

5,20 5,36 (2H)

4,58 (2H, m)

nhm cacbon bc 3 v 7 nhm cacbon bc 4 (C). c bit ph 13C-

12

NMR xut hin tn hiu = 173,75 c trng cho nhm keton (C-16)

13

49,35

v = 171,17 ppm c trng cho nhm este (C-17).

14

31,51

2,49 2,78 (2H, m)

2,49 2,82 (2H, m)

15

26,32

2,65 (2H, m)

2,54 (2H, m)

16

173,75

17

171,17

18

52,23

3,65 (3H, s)

3,79 (3H, s)

Cht 58: Cht 58 l cht trung gian, khng bn, v vy chng ti

chuyn ha lun thnh cht 59 v xc nh cu trc ca cht 59
Cht 59:(3-Oxo-9-methoxycarbonylindolizino[8,7-b]indole)
Ph hng ngoi: (Hnh 4.13) cho nh hp th c trng ca
nhm keton 1731,15 cm-1 .

Ph 13C-NMR (Hnh 4.17 v 4.18) c mt ca 16 cacbon trong

c 4 nhm CH2 cacbon bc 2; 1 nhm OCH3 cacbon bc 1; 4

Ph khi ESI-MS cho pic c m/z= 285 l pic ca ion gi nh

+

[M+1] ph hp vi cng thc phn t C16H16O3N2 (Hnh 4.18)

T cc s liu ph hng ngoi, ph khi, 1H -NMR v 13C-NMR
ca cht 59 hon ton ph hp vi ti liu 28 (xem bng 4.2)

7,38 (1H, d , J=8,7

Hz)
7,23 (1H, t , J=7,8
Hz)
7,13 (1H, t, J=7,8
Hz)
7,51(1H, d, J=7,8
Hz)

23

Hnh 4.12. Ph hng ngoi ca cht 59

24

Hnh 4.16. Ph cng hng t ht nhn 13C-NMR ca cht 59

Hnh 4.13. Ph cng hng t ht nhn 1H-NMR ca cht 59

Hnh 4.18. Ph khi ESI-MS ca cht 59

25
KT LUN V KIN NGH
Kt lun
- Chng ti tng c cc hp cht trung gian 56, 57, 58,
59 trong quy trnh tng hp ton phn vinblastin lm thuc chng
ung th vi hiu sut cao, quy trnh khng phc tp.
- Cc sn phm thu c c xc nh cu trc ha hc
bng vic kt hp cc phng phng php ph hin i nh: Ph
hng ngoi (FTIR); ph khi phn gii cao (HR-ESI-MS); ph cng
hng t ht nhn 1H-NMR, 13C-NMR. Cc s liu ph cho thy s
ph hp hon ton ca cc cht tng hp c vi cc cu trc d
on.
Kin ngh
Tip tc nghin cu tng hp cc hp cht tip theo
trong quy trnh bn tng hp cht trung gian trong quy trnh
tng hp ton phn thuc chng ung th vinblastin t cc ha
cht c bn.