Tổng hợp và chuyển hoá một số dẫn xuất của (an pha) d GLUCOZƠ và (an pha) d GLUCOZAMIN

DAI HOC QUOC GIA HA NOI
TRUONG DAI HOC KHOA HOC TU NHIEN

DE TAI NGHIEN CWU KHOA HOC

TONG HQP VA CHUYEN HOA
•

MOT SO DAN XUAT CUA
a-D-GLUCOZa VA a-D-GLUCOZAMIN
Mas6: QT-05-16

CHU TRI DE TAI: PGS.TS. NGUYEN DINH THANH
CAN BO THAM GIA: 1. Th.S. Pham H6ng Lan
2. Cac sinh vien phong THHC-l

OAI HOC Q U O C GIA HA NO*
TRUNG TAr.^ THOr.'G TIN THU VIEN

pr/^t ^9
Ha Noi - 2005


1. BAO CAO TOM TAT
a. Ten de tai:
TONG HOP VA CHUYEN HOA MOT SO DAN XUAT CUA
a-D-GLUCOZO VA a-D-GLUCOZAMIN
Ma so:
b. Chu nhiem de tai:

QT-05-16

PGS. TS. Nguyln Dinh Thanh

c. Cdn bp tliam gia: 1. Th.S. Pham Hong Lan
2. Cac sinh vien phong THHC-l
d. Muc tieu vd noi dung ngliien citu
+ Muc tieu:
\. Tong hgp mot so hcrp chat glycozylamin co chua nhan di vong 1,3-thiazol va
benzo-l,3-thiazol tren ca so a-D-glucozamin clohidrat va D-glucoza.
2. Tong hop mot so dan xuat tu glycozyl isothioxianat va cac aminouraxin,
aminothiouraxin khac nhau.
3. Nghien cuu pho (HN, CHTN-^H va '^C cua cac hgp chat tong hop dugc.
4. Khao sat hoat tinh sinh hoc (hoat tinh khuan, khang nam) cua cac hgp chat tong
hgp dugc.
5. Nghien cuu moi quan he cau true-tinh chat hay cau true-hoat tinh bang viec su
dung cac phuong phap hoa lugng tu {ab initio, AMI, PM3,...).
+ Ngi dung:
1. Nghien cuu thuc hien phan ung cua D-glucozamin clohidrat va D-glucoza ciang
nhu mot so dan xuat cua chung vai mot so 2-amino-l,3-thiazol va 2-aminobenzo-l,3thiazol.
2. Nghien cuu thuc hien cac phan ung chuyen hoa tren ca sa cac hgp chat nhan
dugc a tren.
3. Nghien cuu moi quan he cau truc-tinh chat hay cau truc-hoat tinh bing cac tinh
toan hoa lugng tu(aZ? initio, AMI, PM3,...)hay ca hoc phan tu (MM+, AMBER,...).
4. Cau true cua cac hgp chat nhan dugc se dugc xac nhan bing cac phucmg phap
vat ly hien dai (pho hong ngoai, pho cong huang tu hat nhan proton va cacbon-13 va ph6
khoi lugng).
5. Cac tinh chat sinh hgc cua cac chat tren se dugc khao sat bang cac phuang phap
chuyen mon.
2. Ket qua dat du'oc
+ Ket qud /clioa iipc:
I. Da tong hgp dugc 5 hgp chat 2-axetamido-2-deoxi-P-D-glucopiranoz}'lamin tiJ

N-axetyl-P-D-glucozamin va mot so 2-amino-l,3-thiazol hay 2-aminobenzo-l,3-thiazol


the khac nhau.
2. Da tong hgp dugc 6 hgp chat 4,6-0-etyliden-p-D-glucopiranoz>'lamin tu 4.6etyliden-P-D-glucopiranoza va mot so 2-amino-l,3-thiazol hay 2-aminobenzo-l,3-thiazol
the khac nhau.
3. Da tong hgp dugc 8 hgp chat 3-(tetra-0-axetyl-a-D-glucopiranozylamino)isothiazolo[3,4-d]pirimidin-4,6-dion khac nhau tir cac aminouraxin, aminothiouraxin voi
glucozyl isothioxianat.
4. Da nghien cuu be mat nang lugng quay doi vai nhom hidroximet\i ngoai vong
ciia a-D-2-amino-2-deoxyglucopyranoza va P-D-2-amino-2-deoxyglucopyranoza da
dugc mo ta bang each sir dung phuang phap ab initio 6 cac mirc li thuyet cao 6-31G(d)
va 6-3 lG(2d, Ip).), va nhan thay rang su chuyen doi qua lai de dang nhat trong pha khi la
giua cac cau dang TG va GT (trong ca hai truang hgp anome a va P).
5. Da nghien ciru anh huang cau hinh cua nhom 2-axetamit den cau dang ben cua
phan tir N-axetyl-D-glucozamin bang phuang phap toi im hoa hinh hoc theo phuang
phap ca hoc phan tir AMBER va theo phuang phap ca hgc lugng tu AMI, va da nhan
thay rang a phan tir N-axetyl-D-glucozamin, anome P ben han anome a ve mat nang
lugng (khi khong co anh huang cua dung moi) va doi vai cac anome thi cau hinh ben
nhat la cau hinh (E)-syn.
6. Cau true ciia cac hgp chat da tong hgp dugc xac nhan bang cac phuang phap vat
ly hien dai (pho hong ngoai, pho cong huang tir hat nhan proton va cacbon-13 va pho
khoi lugng).
7. Da thir hoat tinh khang khuan va khang nam cua cac hgp chat da tong hgp dugc.
+ Ket qua dao tao:

04 cir nhan hoa hoc

+ Ket qua cong bo:

02 bai bao va 03 bao cao khoa hoc

1. Nguyln Dinh Thanh, Dang Nhu Tai, Pham Hong Lan, Phan img
cuaglucopiranozyl isothioxianat voi mot so 6-aminouraxin va 6-amino-2-thiouraxin, Tap
chi Hod hoc va (fug dung, N.9 (45) (2005), tr. 24-27.
2. Nguyen Dinh Thanh, Study on the molecular conformations of a-D-2-amino-2deoxyglucopyranose using ab initio method, Tap chi Hod hoc vd lfng dung, NIC (46)
(2005), tr. 37-41.
3. Nguyln Dmh Thanh, Dang Nhu Tai, Mai Thi Thoa, Contribution to study on
synthesis of someglucopyranozylamines containing thiazole and benzothiazole rings
from 4,6-0-ethylidene-D-glucopyranose, Tuyen tap cdc cong trinh Hoi nghi Khoa hoc vd
Cong nghe Hod Hiru ca todn quoc lan thu 3, Ha noi 11/2005, tr. 150-153.
4. Nguyln Dinh Thanh, Dang Nhu Tai, Biii Ngoc Linh, Gop phin tdng hgp mot s6
din xuat chira dj vong tham thiazol va benzothiazol ciia 2-axetyl-D-glucozamin, Tuyin
tap cdc cong trinh Hoi nghi Khoa hoc vd Cong nghe Hod Huu ca todn qudc Idn thu 3, Ha
noi 11/2005, tr. 154-158.
5. Nguyen Dinh Thanh, Dang Nhu Tai, Pham Nhat Quang, Gop phin nghien ciru
anh huang cau dang cua nhom axetyl den cau dang ben cua phan tir N-axetyl-Dglucozamin, Tuyen tap cdc cong trinh Hoi nghi Khoa hoc vd Cong nghe Hod Hiru ca
todn quoc Idn thic 3, Ha noi 11/2005, tr. 227-230.
ii


3. TINH HINH SLT DUNG KINH PHI
T6ng kinh phi dugc cip: 15.000.000 V'ND
Phan bo kinh phi: nhu da ghi trong HDNCKH thuc hien de tai cap Dai hoc Quoc gia Ha
Noi nam 2005, ma s6 QT-05-16.
KHOA HOA HOC

CHU TRI DE TAI

Ih

PGS.TS. Trdn

PGS.TS. Nguyin Din/t Titt

TliiNlmMai

TRUTOfNG DAI HOC KHOA HOC TU' NTHEN
PHOHlEu TfiUONG

PBS.lS.UOAU/^juw^am^

111


2. SUMMARY
a. Reaserching project:
SYNTHESIS .AND TRANSFOR]\L\TIONS OF SOME DERFV ATIVES OF
a-D-GLUCOSE AND a-D-GLUCOSAAHNE
Code Number:
b. Principal Researcher:

QT-05-16
Assoc. Prof. Dr. Nguyen Dinh Thanh

c. Cooperating Institution(s): 1. MA. Pham Hong Lan
2. Some students in Organic Synthesis I Lab
Hanoi University of Science, VNU, Hanoi
d. Objectives and contents
+ Objectives
1. Synthesize some derivatives of glycosylamines of a-D-glucosamine hydrochloride and

a-D-glucose by reactions of the ones with some 2-amino-l,3-thiazoles or 2aminobenzo-1,3-thiazoles.
2. Synthesize some derivatives from glycosyl isothioxianates and some different
aminouracils and aminothiouracils.
3. Study on spectroscopies (IR-, ' H - and ^^C-NMR and MS) of synthesized compounds.
4. Investigate the biological activities of synthesized compounds (for example, antiviral,
antifungal, ...).
5. Study on quantitative structure-activity relationship (QSAR) or quantitative structureproperty relationship correlations (QSPR) for these derivatives using the quantum
chemical methods {ab initio, AMI, PM3,...).
+ Contents
1. Study on performance of reactions of D-glucosamine hydrochloride and a-D-glucose
with some with some 2-amino-l,3-thiazoles or 2-aminobenzo-l,3-thiazoles.
2. Study on performance of reactions of transformation of the synthesized above
compounds.
3. Study on quantitative structure-activity relationship (QSAR) and quantitative structureproperty relationship correlations (QSPR) for these derivatives using the quantum
chemical methods {ab initio, AMI, PM3,...) or molecular mechanics (MM+,
AMBER, ...).
4. Structure of synthesized compounds will be confirmed by using modem physic
methods (IR-, ' H - and ^^C-NMR, mass spectroscopies).
5. Investigate the biological activities of synthesized compounds by using the
professional procedures.
e. Results obtained
+ Results in science:
1. Five compounds of 2-acetamido-2-deoxi-P-D-gIucopyranosylamines from Niv


acetyl-P-D-glucosamine and some different substituted 2-aminobenzo-l,3-thiazoles or 2amino-l,3-thiazoles.
2. Six compounds of 4,6-0-ethylidene-P-D-glucop}Tanosylamines from 4,6-0ethylidene-P-D-glucopyranos and some different substituted 2-aminobenzo-l,3-thiazoIes
or 2-amino-l,3-thiazoles.
3.
Eight

compounds
of
3-(tetra-0-acetyl-a-D-glucop>Tanosylamino)isothiazolo[3,4-d]pyrimidine-4,6-diones from different 6-aminouracils, aminothiouracils
and glucopyranosyl isothiocyanate.
4. The rotational energy surface have
been dscribed for the exocyclic
hydroxymethyl group of a-D-2-amino-2-deoxyglucopyranose and of P-D-2-amino-2deoxygluco-pyranose using high-level ab initio methods. These data definitively establish
the potential energy surface along this coordinate in the gas phase.
5. Using geometry minimum by molecular mechanics (AMBER) and quantum
mechanics (AMI), it showed that in N-acetyl-D-glucozamine, anomer P was more stable
than anomer a in energy (when the influence of the solvent wasn't included in these
calculations), and for both anomers the most stable configurations were the (E)-syn ones.
6. The structures of synthesized compounds have been confirmed using modem
physical methods (IR-, ' H - and 'C-NMR and mass spectroscopies).
7. Examination of anti-microorganism.
+ Results in education: 04 bachelors of science
+ Publication: Five rearching articles have been reported:
1. Nguyen Dinh Thanli, Dang Nhu Tai, Pham Hong Lan, 2005, Reaction of
glucopyranosyl isothiocyanate with some 6-aminouracils and 6-amino-2-thiouracils,
Journal of Chemistry and Application, N.9 (45), tr. 24-27.
2. Nguyen Dinh Thanh, Dang Nhu Tai, Mai Thi Thoa, 2005, Contribution to study on
synthesis of some glucopyranozyl-amines containing thiazole and benzothiazole rings
from 4,6'O'ethylidene-glucopyranose, Proceedings of the Third National Conference
of Science and Technology in Organic Chemistry, Hanoi, 11/2005, pp. 150-153.
3. Nguyen Dinh Thanh, Dang Nhu Tai, Bui Ngoc Linh, 2005, Contribution to synthesis
of some compounds contaning aromatic heterocycles thiazole and benzothiazole oflacetylglucosamine, Proceedings of the Third National Conference of Science and
Technology in Organic Chemistry, Hanoi, 11/2005, pp. 154-158.
4. Nguyen Dinh Thanh, Dang Nhu Tai, 2005, Contribution to study on anomerism and
tautomerism in glucosylhydrazine using quantum chemical methods AMI and PM3,
Proceedings of the Third National Conference of Science and Technology in Organic

Chemistry, Hanoi, 11/2005, pp. 222-226.
5. Nguyen Dinh Thanh, Dang Nhu Tai, Pham Nhat Quang, 2005, Contribution to study
on the influence of conformation of acetyl group to stable confofmation of N-acetylD'glucosamine molecule. Proceedings of the Third National Conference of Science
and Technology in Organic Chemistry, Hanoi, 11/2005, pp. 227-230.


MUC LUC
Trang
1 M6DAU
i
+ Muc tieu:
1
+ Noi dung:
1
2 NQI DUNG CHINH
2
A. Tong quan
2
2.1 Tong quan ve glycozylamin
2
2.1.1 Danh phap
2
2.1.2 Tac dung sinh hoc cua glycozylamin
2
2.1.3 Phucmg phap tong hgp glucozylamin
2
2.1.4 Mot so tinh chat cua glucozylamin
2
2.2 Tong quan ve glycozyl isothioxianat
5

2.2.1 Giai thieu ve glucozyl isothioxianat
5
2.2.2 Phuang phap tong hgp glucozyl isoxianat/isothioxianat
5
2.3.3 Tinh chat hoa hoc ciia glucozyl isoxinat/isothioxianat
7
B Phan thuc nghiem
9
2.3 Tong hgp cac 2-axetamido-2-deoxi-D-glucopiranozylamin (GlcNAcamin)) tir N-axetylp-D-glucozamin
9
2.3 Tong hgp 4,6-0-etyliden-D-glucopiranozylamin tij 4,6-0-etyliden-D-gIucoza
(EtGIcamin)
12
2.4 Tong hgp 3-glucozylaminoisothiazolo[3,4-d]pirimidin (GAIP) tir glucoza
14
C Ket qua va ban luan
18
2.5 Tong hgp cac glucopiranozylamin (GlcNAcamin) tirN-axetyl-P-D-glucozamin
18
2.6 Tong hgp 4,6-O-etyliden-D-glucopiranozylamin (EtGIcamin) tir 4,6-0-etyliden-Dglucoza
19
2.7 Tong hgp cac hgp chat ciia 3-glucozylamino- isothiazolo[3,4-d] pirimidin
19
2.8 Phin tinh toan li thuylt
22
* Theo phuang phap AMBER:
24
* Theo phuang phap AMI
24
3. KET LUAN

25
4. TAI LIEU THAM KHAO
26
TOM T A T C A C CONG TRINH NCKH CUA CA NHAN
29
GIAI T H i C H CAC KY H I E U VA CHU* VIET T A T
Me
Metyl
Et
Etyl
Bu-n
n-Butyl
Ac
Axetyl
EtGlc
4,6-0-Etyliden-D-glucoza
ADGLCNAc
N-axetyl-a-D-glucozamin
BDGLCNAc
N-axetyl-P-D-glucozamin
GlcNAcamin
2-Axetamido-2-deoxi-D-glucopiranozylamin
EtGIcamin
4,6-0-Etyliden-D-glucopiranozylamin
Galamin
Galactopyranosylamin
GAIPl
2,3,4,6-tetra-0-axetylglucopiranozylaminoisothiazolo[3,4-d]pirimidin

1 MODAU
Nhu da biet, cacbohidrat thamgia vao thanh phin ciia rat nhieu loai hgp chat hoa
hoc trong thien nhien, tir cac duang dan co mat trong nhieu loai hoa qua nhu fructoza,
cac disaccarit nhu saccaroza (duong mia)... den cac polysaccarit nhu xenlulo, tinh
bot,...[l]. Chinh vi the loai hgp chat nay da dugc nghien cim tir lau. Mat khac, cac hgp
chat tren ca sa cac monosaccarit co nhieu hoat tinh sinh hgc dang chu y [2,3,4], nhat la
cac N-glucozit voi cac amin di vong (indol, quinolin, quinazolin, pyrimidin, imidazol,
flavon) va da dugc quan tam nghien cuu ca ve mat ly thuyet ciing nhu thuc nghiem. Cac
monosaccarit thamgia thanh phan cua nhieu hgp chat c6 hoat tinh sinh hgc, chang han, Ldaunozamin la hgp phan cua cac thuoc daunomycine va adriamycine, la hai loai thuoc
manh dugc sir dung trong viec dieu tri cho benh nhan ung thu; L-vancozamin la hgp phan
cua thuoc khang sinh vancomycine; sinigrin la mot S-glycozit va co donggop vao miii
dac trung cua mil tat va tucmg hat cai; loai thuoc dugc sir dung rong rai nhat trong dieu tri
benh nhan AIDS la zidovudine, cung dugc biet duoi ten ggi azidothymine, hay AZT (co
ten hoa hpc la 3'-azido-2',3*-dideoxythimidin), va loai thuoc co hieu qua cao han hien
nay la J^J (co ten hoa hgc la 2',3'-dideoxy-2',3'-didehidrothimidin), deu la cac Nglycozit ciia amin di vong chua nita la pirimidin va monosaccarit la dan xuat azit ciia
ribofuranoza [6-11].
Nhin chung, hoa hoc cacbohidrat chua dugc nhieu nha khoa hpc trong nuac
nghien cim. Trong mpt vai nam gan day da xuat hien mpt so cong trinh nghien cim trong
ITnh vuc nay ciia cac tac gia Viet nam (xem tai lieu dan ra a duoi), song hau het la a ITnh
vuc oligosaccarit hay polisaccarit, ma chii yeu la chi a mirc dp bien tinh cac polime nay.
Vi vay de tai ciia chiing toi co muc tieu va npi dung nhu sau:
+ Muc tieu:
1. Tong hgp mpt so hgp chat glycozylamin c6 chira nhan di vong 1,3-thiazol va
benzo-l,3-thiazol tren ca sa a-D-glucozamin clohidrat va D-glucoza .
2. Tong hgp mpt so dan xuat tir glycozyl isothioxianat va cac aminouraxin,
aminothiouraxin khac nhau.
3. Nghien cim pho (HN, CHTN-^H va '^C cua cac hgp chat tong hgp dugc.
4. Khao sat hoat tinh sinh hpc (hoat tinh khuan, khang nam) cua cac hgp chit t6ng
hgp dugc.
5. Nghien cim moi quan he cau truc-tinh chat hay cau truc-hoat tinh bing viec sir

dung cac phuang phap hoa lugng tir {ab initio, AMI, PM3,...).+ Noi dung:
1. Nghien cim thuc hien phan ung cua D-glucozamin clohidrat va D-glucoza ciang
nhu mpt so dan xuat ciia chiing vai mpt so 2-amino-1,3-thiazol va 2-aminobenzo-1,3thiazol.
2. Nghien ciai thuc hien cac phan img chuyen hoa tren ca sa cac hgp chit nhan
dugc a tren.
3. Nghien cim moi quan he cau triic-tinh chat hay cau triic-hoat tinh bing cac tinh


toan hoa lugng tir (aft initio, AMI, PM3,...)hay ca hpc phan tir (MM+, AMBER,...).
4. Cau true cua cac hgp chat nhan dugc se dugc xac nhan bang cac phuang phap
vat ly hien dai (pho hong ngoai, pho cong huang tir hat nhan proton va cacbon-13 va pho
kh6i lugng).
5. Cac tinh chat sinh hpc cua cac chat tren se dugc khao sat bang cac phucmg phap
chuyen mon.
2 NOl DUNG CHINH
A. Tong quan
2.1 Tong quan ve glycozylaniin

2.L1

Danhphdp

Cac N-glycozyl dugc gpi ten la cac glycozylamin. Trong truang hgp cac amin di
vong phirc tap, nhu cac nucleozit, each gpi tuang tu dugc sir dung.
Vidu:
^^

Ten goi day dii: N-phenyl-P-D-glucopiranozylamin,
Ten rut gon: N-phenyl-D-glucozylamin.

NH-

OH

\

2.L2 Tdc dung sinh hgc cda

/

(khong goi Id anilin

^D-glucopiranozit.

glycozylamin

Co mpt so rat 1cm cac hgp chat cacbonhydrat co chira nita. Trong do co nhi6u hgp
chat CO nhieu cong dung dac biet. Chung c6 nhieu hoat tinh sinh hpc quan trpng va
glucozylamin cung la mpt trong cacbohidrat c6 chira nita co nhieu hoat tinh sinh hpc
quan trpng.

2.1.3 Phitomgphdp tong hpp glucozylamin
Phuang phap thuong hay sir dung de dieu che glucozylamin la sir dung phan img
ngung tu giira amin va duong khir trong dung moi metanol hoac etanol soi, c6 chira 10%
lugng H2O va co mpt lugng nho axit lam xiic tac. San pham tach ra duai dang tinh th6
sau khi cho bay hoi dung moi va lam lanh.
2.1.4 Mot so tinh chdt cua

glucozylamin

Monosaccarit va dan xuat co cac cau true dang vong (furanozo, piranozo,
septanozo) va dang khong vong. Bang phuang phap nghien cim ciu true ciia cac
andozylamin da chi ra rang trong dung dich, cac andozylamin ciing ton tai mpt can bing
nhu tren tuong tu nhu 6 cac monosaccarit. Vi vay cac andozylamin c6 thi phan img tao
ra cac dan xuat co the duai cac dang mach ha, hoac vong piran va fliran.
Su CO mat ciia nhom amin trong phan tir cua monosaccarit lam thay doi co ban
tinh chat hoa hpc ciia no. Khi xem xet cac tinh chat ciia glucoz\-lamin cin phan biet cac
tinh chat von co ciia chung nhu tinh amin. tinh chat dac trung ciia duong va nhijns tinh
chat dac thii gay nen boi su tuong tac giua cac nhom hidroxi, amin, cac nhom thi....


1. Su ddo quay
Sir dao quay cua cac glucozylamin co dugc la do ton tai mot can bang trong do
xay ra su chuyen dich cac anome thong qua cac hgp chat trung gian khong vong bazo
Schiff:
CgHsNH

CH

H

__^

HC—NHCgHs

CgHgN^CH

C—OH

H

H

C—OH

C—OH

Doi vai cac glucozylamin khong con nguyen tir hidro dinh voi nguyen tir nita thi
CO the dugc giai thich la do su hinh thanh ion imonium khong vong do viec tach mpt
proton ra khoi ion amonium the:
_(C6H5CH2)2N==CH

(C6H5CH2)2NH—CH
H

H

C—OH

HC—N(C6H5CH2)2
H

C—OH

C—OH

2. Su ddo quay trong moi truang axit
Co che xay ra nhu sau:

I

HCNH2

HCNH2

HCNH'

H2NCH

+ HA
HCO

HA
HCOHA'

HCO

HCO —I

I

Su chuyen mpt cap electron tir nguyen tir nito ciia nhom amoni dan den su hinh
thanh ion imonium. Tir do dan den su chuyen tir dang vong den dang khong vong va
ngugc lai. Giira chiing co mpt can bang dugc hinh thanh.
3. Sir ddo quay trong moi trudng baza
Co che xav ra nhu sau:
HCNi-^

HCNH.

HG=NH

+ B

+

BH.NCH
HB ^

HjNCH

-i-B

^

HCO
HCO

HC0-

I

HCO

HCO
I

(1)

Thuc chat bazo co it anh huong den tinh quay quang ciia cac glucoz>1amin vi nita

it CO xu huong nhuang proton nen khong co sp (1) hoac co rat it can bang lech ve phia
ben trai.


4. Phdn uns thuy phdn glucozylamin
Sir thuy phan cua glucozylamin xay ra theo co che sau:
I
HC—NHj

H
+ I
HO^G

-HOr^ V

HC=NH2

C-t—NH2

HA
"OH

COH

COHA

CO

+ A

I

SP

+
— C-

I

•OH

Nguoi ta thay rang toe dp thuy phan glucozylamin phu thupc vao pH cua dung
dich va chung dat cue dai trong moi truang axit yeu. Do la do qua trinh thuy phan can ca
xuc tac axit va xuc tac bazo.
5. Axetyl hod glucozylamin
Phuong phap hay dugc sir dung de axetyl hoa glucozylamin la cho glucozylamin
phan img voi lugng du anhidrit axetic trong piridin a O^C trong thoi gian tir 2 gio den hai
ngay. Dung dich sau phan ung dugc rot vao trong nuoc da. Sau vai gio chat ran dugc
gom lai va ket tinh lai bang etanol.
Duoi dieu kien khac nghiet hon thi nguyen tir hidro ciia nito ciing bi thay the. San
pham thu dugc la dan xuat N-axetyl-tetra-0-axetyl:
.OH

OAc

,NH^
OH

(Ac)20
C6H4CH3-P CH3C00Na ;120°

'"'AC'^^^^IJ^^NH
'oAc

C6H4CH3-P

6. Metyl hoa glucozylamin
Phuong phap chu yeu de metyl hoa glucozylamin la: sir dung metyl iotdua voi xuc
tac Ag20. Cac phuong phap khac sir ly nhe nhang hon, vi du phan img voi (CH3)2S04 voi
NaOH thi hieu suat thap hon.
Co nhieu bang chung chirng minh rang trong phan img metyl hoa,cac
glucozylamin trong trang thai cau true dang vong khong tham gia vao phan ung.
7. Chuyen vi Amadori
Cac hgp chat glucozylamin c6 mpt phan img rat quan trpng la chuyen vi Amadori.
Do la phan img bien doi dan xuat N-andosylaminthanhf dan xuat N-l-amino-deoxy-2ketozo.
Co nhieu co che de xuat cho chuyen vi Amadori nhung nguoi ta chu y nhit din co
che xuc tac bang axit.


R—NH-R'
H--NRR'
HHO- ^•H^ O^
H- •OH
HCH2OH

+H

HHHOHH-

OH

•H

HC-NRR'

i

HHOHH-

OH
CH2OH

HC=N-R

H

HCOH
R'

H2C
HOH
H-

OH
OH
CH2OH

H

H"
R—N

O
-H
-OH
OH
CH2OH

^OH
HO
H
H—OH
H-(-OH
CH2OH

-H

HC-NH-R

HC=NH-R
H

HCOH

OH
•H

HC-NRR*

HC-NH-R
H

CHON

R—NH-R'
I
H2C
HO
HO
H-hOH
H
CH20H

. H2C-NH-R
H

H

C=OH
I
•NH-R'

H*

C^O

I

H2C
HOHO- - H
H- - O H

H - -OH
H-CO

Nguyen tir nito cua dan xuat glucozylamin (I, R' =H hoac la mot goc) nhan mpt
proton tir xuc tac axit tao ra amonium (II) va giira cation va bazo Schiff (HI) c6 mpt can
bang. Su chuyen dich electron den nguyen tir nito mang dien tich duong lam cho Ci
mang dien tich duong trong thai gian ngan. Tiep do lam dich chuyen electron tir C2 den
Cl lam cho lien ket C-H kem ben de dang tach proton chuyen thanh dang enol cua dan
xuat xeton (IV). Su tautome hoa tir dang xeton (V) thanh dang vong on dinh (VI) hoac
(VII).
2.2 Tong quan ve glycozyl isothioxianat
2.2.1 Gi&i thieu ve glucozyl isothioxianat
Isothioxianat va glycozyl isothioxianat dugc thu hut sir chu y tong hgp trong
nhung nam gan day do kha nang phan img cao, chimg de dang chuyen hoa thanh cac hgp
chat di vong (nucleozit va glycozylamin chira nhan di vong), glycozylthioure,
glycozylguanidin va cac hgp chat ciia P-xiclodextrin co cac tinh chat dugc ly cao [42, 44,
45]. Cac isothioxianat de dang tham gia cac phan ung cong hgp va cong hgp-dong vong,
cac phan img voi cac nucleophinl khac nhau chi ra 'dac trung electrophin manh cua
nhom -NCS. Su day electron manh cua nguyen tir cacbon trong nhom -NCS dong vai tro
quan trong trong nhimg phan img nay.
R

N = C ^ S

Cac nucleophin gan voi nguyen tir hidro de tach ra va co kha nang proton hoa
nguyen tir nito deu co the phan img voi isothioxianat, trong khi do phan am dien se lien
ket voi nguyen tir cacbon ciia nhom -NCS:
R

N ^ C = S

+ HX

^

R

NH-C

X

:S:

2.2.2 Phuorng phap tong hprp glucozyl isoxianat/isothioxianat
Lan dau tien Fischer da tong hgp dan xuat isothioxianat ciia monosaccarit bans


each xu li axetylglycozyl halogenua voi thioxianat vo co trong dung moi phan cue. Phu
thupc vao kha nang phan ung cua halogenua va dilu kien phan ung, nhan dugc hoac
thioxianat hoac isothioxianat:
R-SCN
R-X +

SCN'
-X

R-NCS

Glucozyl thioxianat c6 the dong phan hoa 6 muc dp nao do thanh isothioxianat
tuong ung. Phan umg giira axetylglycozyl halogenua voi thioxianat vo co co the chay

theo CO che SNI hay SN2. Co che SNI tao dieu kien cho su tao thanh thioxianat, hgp chit
nay co the bi dong phan hoa thanh isothioxianat. Chang han, 2,3,4,6-tetra-O-axetyl-P-Dglucopiranozyl isothioxianat dugc dieu che bang each cho 2,3,4,6-tetra-O-axetyl-a-Dglucopuanozyl bromua phan ung voi bac thioxianat trong xilen khan hoac bang each
dong phan hoa nhiet hgp chat thioxianat tuong ung nhan dugc tir 2,3,4,6-tetra-O-axetyla-D-glucopiranozyl bromua va kali thioxianat trong axeton:

N=c=s

•S-C=N
H

OAc,
^""H

Dang chu y la 1,3,4,6-tetra-0-axetyl-2-amino-2-deoxy-a-D-glucopiranoza
hidrobromua phan img voi bac thioxianat cho 2-axetamido-3,4,6-tri-0-axetyl-2-deoxy-PD-glucopiranozyl isothioxianat, trong phan img nay xay ra su di chuyen 0-axetyl->Naxetyl:
H

^^^'

H

OAc

H

N=C=X
H
NHAc

^OAc

AgXCNAcO-VVir^
AcoOynV^H
H

\

Cl
NHAc

Mpt phuong phap khac de tong hgp glycozyl isothioxianat la bang each chuy§n vi
allylic cac hgp chat thioxianat khong no:
,OMs

.OMs

\
H

Ciing CO the xuat phat tir 23,4-tri-0-axyl(benzoyl)-6-0-trityl-N-(2,2dietoxicacbonylvinyl)-P-D-glucopiranozylamin. Giai doan dau phan img vai brom (R =
Ac) hoac clo (R = Bz). sau do xir li voi photgen^thiophotgen trong moi truong bazo, vai
su CO mat ciia CaCOi trong CH2CI2.


H2OH
NH-CH=C(0Ei)2 RO

NHsBr

^

0
NCX

Br. (CI2)
CH2CI2

•

CXQz/ OH"^
-

—

I

RO

Khi sir dung muoi kim loai kiem nguoi ta thuong diing cac xuc tac chuyen pha n6u
khong, san pham cua phan ung chi la cac dan xuat xianat hay thioxianat thong thuong. 6
day, xuc tac chuyen pha c6 vai tro trong viec dong phan hoa dan xuat xianat hay
thioxianat thanh dan xuat isoxianat va isothioxianat. Cac xuc tac chuyen pha thudng dimg
la diankyl ete cua polietilen glycol, cac ete vong, cac muoi tetraankyl halogenua bac 4.
Cac muoi kim loai kiem thuong dugc sir dung la natri thioxianat, kali thioxianat va amoni
thioxianat. Hieu suat phan ung kha cao, tir 70-80%.
•OAc

OAc

N=C=X

2.3.3 Tinh chdt hod hpc cda glucozyl isoxinat/isothioxianat
1. Phdn irng vai amoniac vd amin. Su tao thanh cdc ddn xuat ureit vd thioureit
Tuong tu nhu cac aryl isoxianat va thioisoxianat, cac glucozyl isoxianat va
isothioxianat khi tac dung voi cac amin bac 1 (amin beo, tham hay di vong...) trong cac
dung moi tro (nhu xilen, toluen, benzen, clorofom,...) hay amoniac trong ancol dan den
su tao thanh cac ure va thioure N,N'-thQ, phan img nay xay ra de dang, khong can sir
dung xuc tac:
OAc
OAc
R-NH
N=C=S
NHR

2. Phdn irng vai aminoaxit
D-glucozylure/thioure protein c6 the tong hgp tuong tu bang phan img tetra-O-axetyl-aD-glucopiranozyl isoxianat^'isothio xianat vai D,L-alanin metyleste hidroclorua:
CH2OAC
Q

Ac
Ac

CH3-CH

CX
Aci

COOMe Benzen khan

NHs^.a'

»-

Ac

NH-C-NH-CH
II
\
X
COOMe

3. Phdn irns amit
l-(2,3,4-Tri-(9-axyl-y^-D-glucopiranozyl)-3-phenaxyl-ure/thioure ciing dugc di^u
ch^ til phenaxylamin hidroclorua trong moi truong khi tro:


NCX +Ph-CONH2.HCl

dung dich NaHCOj R
*-

>fH-C-NH-COPh
11
X

khucfy 6 dki

4. Phdn tens vai aminoaxeton hidroclorua
Phan ung dugc tien hanh trong moi truang khi tro voi dan xuat cua glucopiranozyl
isothioxianat:
=C=S

+ CH3COCH2NH2.HCI

5. Phdn ung vai 2-cloetylamin hidroclorua
Phan img dugc tien hanh trong dung dich hon hgp nuoc - dietyl ete, tuy theo ty le
CO the cho ta hai loai san pham:

Bz'
-^-^ + CICH2CH2NH2.HCI

f^nuoc-ele^'v^

BzO 1

S'

2(-2.3.4-Tribenzoyl
ghtcopiranozyl)
. aminothiazol

r^

I,3-Di(2,3,4-tribenzoyl
glucopiranozyljthioureylen

6. Phdn imo vdi diamin vd diazometan
Cac diamin nhu o-phenylendiamin, 2,3-diaminopiridin de dang phan ung voi cac
isothioxianat cho cac thioure tuong ung. Su vong hoa kem theo desunfua hoa cua cac
thioure nay bing each diing metyl iodua trong THE cho cac glycozylaminobenzimidazol

va N-glycozyl-3-deazapurin tuong img:

8


HjN^

N

N

^NH2

N

N
H

"^NHR

R=
2,3,4,6-tetra-O-axetyl-p-D-glucopiranozyi

B Phan thyc nghiem
- Diem nong chay dugc do tren may HMK 70/3159. Pho hong ngoai dugcghi tren
may FTIR Magna 760 (NICOLET, My) tai Trung tam Hoa hpc Dau mo (Khoa Hoa,
Truong DHKHTN) bang phuang phap do phan xa tren mau bpt KBr. Pho khoi lugng
(EI-MS) dugcghi tren may HP 5989B MS, pho NMR dugc do tren may Bruker Avance
500 MHz voi TMS la chat npi chuan (tai Phong phan tich Cau true, Vien Hoa hpc, Vien
Khoa hpc va Cong nghe Viet nam); . Sac ki lop mong dugc thuc hien tren ban mong

trang san DC 60 F254 (Merck).

2.3 Tong hpp cdc 2-axetamido-2-deoxi-D-glucopiranozylamin (GlcNAcamin) ) tirNaxetyl-P-D'glucozamin
2.3.1 Tong hap 2-axetamidO'2-deoxi-l3'D'glucopiranoza (N-axetyl-P-D-glucozamin)[13]
Them timg mau nho natri kim loai (1 l,50g, 500 mmol) vao trong 500 ml metanol
khan trong binh Erlenmeyer dung tich 1 lit. Khi tat ca lugng natri hoa tan het,giir dung
dich a -25°C va them vao do 1 lOg (510 mmol) 2-amino-2-deoxi-a-D-glucoza clohidrat.
Khuiy cin than h5n hgp trong 4-5 phut va Ipc qua pheu Ipc Buchner haygiay Ipcgap. Neu
cac dilu kien tren dugc dap img thi khong quan sat thay tinh the ciiaglucozamin tu do.
N8u khong loc ngay hon hgp phan img ngay sau khi ket thuc phan img thi c6 the bat dau
sir kit tinh din din su bit kin pheu Ipc (xem sa do 1),
Rira pheu Ipc bang metanol (2x100 ml). Dich Ipc da hgp nhat lai la dung
dichglucozamin qua bao hoa, dugc che hoa ngay voi 60 ml (630 mmol) anhidrit axetic
(lugng anhidrit axetic dugc them vao phai bang 1,2-1,5 duong lugng, su N-axetyl hoa
xay ra mpt each chpn ipc va phan img nhanh chong ket thiic, bai vay lugng du cua tac
nhan axyl hoa phan img khong anh huong. Trong qua trinh ket tinh san pham, lugng du
anhidrit axetic se phan img cham voi dung moi). Day binh cau bang niit va ngay lap tire
nhiine vao nuoc da de lam cham lai phan img da bat dau. Qua vai phiit, ket thuc viec lam


lanh va giu dung dich trong khoang 12gia 6 -25°C va mot vai gio o 0°C. Nghien nho can
than ket tiia tinh the tao thanh bang thia, Ipc tren phlu Ipc Buchner va rira bang 100 ml
metanol. De kho san phim tren phlu Ipc ngoai khong khi, sau do trong binh hut am chan
khong tren P2O5. Hieu suit san phim dat 88,25g (78,3%), Dnc 204-205°C, [a]D^'
+75->+42° (c 2, nuoc). Theo tai lieu tham khao [13]: Dnc203-205°C, [a]D^'+75^+42° (c
2, nuoc).
N-axetyl-p-D-glucozamin dieu che dugc du tinh khiet de sir dung chogiai doan
tong hgp tiep theo va cho da so muc dich khac. D I tinh chi, nguoi ta hoa tan san phin
vao trong mpt lugng toi thieu nuoc nong, roi pha loang bang 7-8 phin etanol va them ete
vao cho den khi xuat hien due. Khi de yen 6 nhiet dp phong thi tinh the tach ra.

OH
(CHaCOJzO

CHgONa
CH3OH

nw^-^

mm^ .^^

HO
OH

HO
NHAc

HCt.HzN

Sa do 1. Tong hap 2-axetamido-2-deoxi-fl-D-glucopiranoza (N-axetyl-P-D-gluco-zamin)
2.3.2 Tong hop cdc 2-axetamido-2-deoxi-D-glucopiranozylamin (GlcNAcamin) tir Naxetyl-p-D'glucozam in

A

OH +
NH-

NHGlcNAc

NHAc
R=H (I), CH3 (II). COOMe (III). COOEt (IV)

NHGlcNAc

Sado 2. Tdng hap 2-axetamido-2-deoxi-D-glucopiranozylamin (GlcNAcamin) tu Naxetyl-p-D-glucozamin.
Qui trinh tong hap chung: Cho (0,005mol) 2-aminobenzo-1,3-thiazol hay 2amino-1,3-thiazol the khac nhau va l,12g (0,005mol) N-a.xetyUP-D-glucozamin vao
trong 25ml etanol 96'' trong binh day tron dung tich 50ml. Them vao do 0,3ml axit
CH3COOH bang. Hon hgp dugc dun hoi luu tren noi each thuy soi. Sau 30-40gid hiu
nhu toan bp chat phan img hoa tan hoan toan. Cat loai VA lugng dung moi, sau do lam
lanh dung dich thi san pham tach ra duoi dang tinh the. San pham dugc Ipc va rira bang
nhirns lucms nho etanol va lam kho ngoai khong khi. Viec tinh che duoc thuc hien bins
each hoa tan san pham trong lugng con toi thieu. Lpc nong va thu dich loc. Lam bay hoi
10


dung moi, san phim se kit tinh. Sau day la cac truang hgp cu thi (xem Sa do 2 vd Bdng
Bdng 1. Cdc hap chdt N-(4'phenylthiazol-2-yl)-2-axetamido-2-deoxi-/3-Dglucopiranozylamin vdN-(benzothiazol-2-yl)-2'axetamido-2-deoxi-/3-Dglucopiranozylamin (GlcNAcamin)
86 TT
1
2
3
4
5

Hgp chat
GlcNAcamin-1,
R=H
GlcNAcamin-2,
R=CH3
GlcNAcamin-3,
R=COOMe

GIcNAcamin-4,
R=COOEt
GlcNAcamin-5

Hieu
suat,%

VOH

Pho hong ngoai, cm''
vc=o
VNH
SNH

228-230

50

3455

3326

1628

1549

-

186-188

49

3459

3385

1628

1550

-

220-222

67

3447

3362

1647

1562

1698

236-238

58

3365

3299

1650

1562

1699

218-220

62

3459

3327

1628

1549

-

Dnc, T

Vc=0(este)

/) Tong: hap N-(benzo-l,3-thiazol-2-yl)-2-axetamido-2-deoxi-a-D-glucopiranozylamin
(GlcNAcamin-1)

Tir 0,75g (0,005mol) 2-aminobenzo-1,3-thiazol va 1,12g (0,005mol) N-axetyl-PD-glucozamin. Hieu suat 0,83g (50%). San pham ket tinh dang tinh the hinh kim, mau
trang, nhiet dp nong chay 228°C. Pho hong ngoai: VoH=3455cm'\ VNH=3326cm'',
vc=o= 1628cm"', 5NH= 1549cm*'.
2) Tong hap N-(6-met\dbenzo-L3-thiazol-2-yl)-2'axetamido-2-deoxi-B-D-glucopiranozylamin (GlcNAcamin-2)
Tir 0,82g (0,005mol) 2-amino-6-metylbenzo-l,3-thiazol va l,12g (0,005mol) Naxetyl-P-D-glucozamin. Hieu suit 0,9g (52%). San pham ket tinh dang tinh the hinh kim,
miu tring, nhiet dp nong chay 186-188°C. Pho hong ngoai: VoH=3459cm"', VNH=3385
cm"', Vc=o=1628cm"', 6NH=1550cm"'.
3) Tdng hap N-(6-cacbometoxibenzo-L3-thiazol-2-yl)-2-axetamido-2-deoxi-B-D-glucopiranozylamin (GlcNAcamin-3)
Tir l,04g (0.005mol) metyl 2-aminobenzo-l,3-thiazol-6-cacboxylat va 1,12g
(0,005mol) N-axetyl-P-D-glucozamin. Hieu suat l,3g (67%). San pham ket tinh dang tinh
thi hinh kim, miu vang, nhiet dp nong chay 220-222°C. Pho hong ngoai: VoH=3447cm'',
VNH=3362cm"', Vc=o= 1647cm'', 5NHl562cm'', Vc=0(este) 1698cm''.
4) T6n2 hap N-(6-cacboetoxibenzo-L3-thiazol-2-vl)-2-axetamido-2-deoxi-B-D-glucopiranozylamin (GlcNAcamin-4)
Tir 1,11 g (0,005mol) etyl 2-aminobenzo-1,3-thiazol-6-cacboxylat va 1.12g
11


(0,005mol) N-axetyl-P-D-glucozamin. Hieu suit l,08g (58%). San phim kit tinh dang
tinh the hmh kim, mau vang, nhiet dp nong chay 236-238°C. Ph5 hdng ngoai:
VoH=3365cm'', VNH=3299cm'', Vc=o=1650cm"', 5NH=1562, Vc=o(este)= 1699cm''.
5) Tong hap

N-f4-(p-clophenyl)-l,3-thiazol-2-yl]-2-axetamido-2-deoxi-a-D-gluco-

piranozylamin (GlcNAcamin-5)
Til l,05g (0,005mol) 2-amino-4-(p-clophenyl)-l,3-thiazol va l,12g (0,005mol) Naxetyl-P-D-glucozamin. Hieu suit l,2g (62%). San phim kit tinh dang tinh thi hmh kim,
miu vang, nhiet dp nong chay 218-220°C. Ph6 h6ng ngoai: 3459cm"', voH=3327cm"',
VNH=1628cm'', Vc=o= 1549cm"'.
2.3 Tong hpp 4,6-O-etyliden-D-glucopiranozylamin tit 4,6-0-etyliden-D-glucozo^
(EtGIcamin)

2.3.1 Tong hap 4,6-O-etyliden-D-glucoza (Sa do 3)
Cho tir tir 0,2ml axit sunfuric dac vao 27ml parandehit, roi rot hon hgp nay vao
binh cau chua 36g D-glucozo. Sau do lac manh trong khoang 30 phut de hon hgp tro
thanh trang thai nira ran, de 6 nhiet dp phong trong 3 ngay. Khuay hon hgp trong 120ml
etanol tuyet doi, dieu chinh pH dung dich 6,5-7,0 bang dung dich Na2C03. Dun nong cho
tan het chat ran (co the diing than hoat tinh de hap phu chat ban). Dung dich de qua dem
tao tinh thi. Hieu suit 14-16g (70-80%). Nhiet dp nong chay 179°C-18rC. Theo tai lieu
[14,15]: 179°C-18rC.
OH
HO^r

V

parandehit/HCI

^2^

H0\^.,.^ A
^%H

Sado 3. Tong hap 4,6-0-etyliden-a-D-glucoza (EtGlc) tic D-glucoza.
2.3.2 Tdng hap 4.6-0-etvliden-D-glucopiranozylamin tu 4,6-0-etvliden-a-D-glucoza
Qui trinh tong hpp chung: Hoa tan (0,005mol) 2-aminobenzo-1,3-thiazol hay 2amino-1,3-thiazol thi khac nhau vao 20ml etanol tuyet doi chira trong binh cau 100ml,
them tilp l,03g (0,005mol) 4,6-O-etyliden-a-D-glucoza vao, lac d^u. Them tilp 0,1ml
axit axetic bang va hon hgp dugc dun soi hoi luu each thuy trong 6-8gid. De hon hgp
phan img 6 nhiet dp phong, san pham se dugc tach ra. Lpc hut, say kho. Tien hanh ket
tinh lai san phim trong etanol 96°. Sau day la cac trucmg hgp cu the (xem Sa dd 4 vd
Bdng 2).
I) Tdn2 hap 4.6-O-etvliden-N-(4-phenvl-l,3-thiazol-2-vl}-0~D-slucopvzanoz\'lamin
(EtGIcamin-1}

Tir 0,82g 4-phenyl-2-amino-1,3-thiazol va l,03g (0,005mol) 4,6-O-etyliden-D12


glucoza Hieu suit 30%. Nhiet dp nong chay 180-182°C. Ph6 hdng ngoai
cm"', visjH=3220cm'*.

VOH=

3365

2) Tons hap 4,6-O-etyliden-Nf4-(p-metvlphenyl)-l,3-thiazol-2-ylJ-0-D-slucopyzanozylamin (EtGlcamin-2)
Tir 0,85g 2-amino-4-(p-metylphenyl)-1,3-thiazol va l,03g (0,005mol) 4,6-0etyliden-D-glucozo. Hieu suit 28%». Nhiet dp nong chay 136-138°C. Ph6 h6ng ngoai
voH=3308cm'', VNH=3114cm"'.

H^C

KT^
OH

OH

Sado 4. Tong hap 4,6-0-etyliden-D-glucopiranozylamin tir 4,6-0'etyliden-D-glucoza
(EtGIcamin).
Bdng 2. Cdc hap chdt N-(4-phenylthiazol-2-yl)-4,6-0-etyliden-p-D-glucopyranozylamin
vd N-(benzothiazol-2-yl)-4,6-0-etyliden-p-D-glucopyranozylamin
SoTT
1
2
3
4

5
6

Hgp chat
EtGlcamin-1,
R,=H
EtGlcamin-2,
Ri=CH3
EtGlcamin-3,
R]=C1
EtGlcamin-4,
R2=H
EtGlcamin-5,
R2=CH3
EtGlcamin-6,
R2=C00Et

Hieu
suat,%

VOH

VNH

Vc=0(este)

180-182

30

3365

3220

-

136-138

28

3308

3114

-

170-172

35

3365

3220

-

193-194

38

3466

3275

-

239-240

40

3460

3284

-

228-230

38

3365

3299

1699

Dnc, °C

13

Pho hong ngoai, cm"'


3) Tons hap 4,6-O-etyliden-N-f(4-(p-clovhenyl)-l,3-thiazol-2-yll-0-D-glucopyzanozvlamin (EtGlcamin-3)
Tir l,06g 2-amino-4-(p-clophenyl)-l,3-thiazol va l,03g (0,005mol) 4,6-0etyliden-D-glucozo. Hieu suit 35%. Nhiet dp nong chay 170-172°C. Ph6 hdng ngoai
voH=3365cm"', VNH=3220cm*'.
4) Tong hap 4,6-O-etyliden-N-(benzo-1.3-thiazol-2-yl)-0-D-glucopyranozylamin
(EtGlcamin-4)
Tir 0,75g 2-aminobenzo-1,3-thiazol va l,03g (0,005mol) 4,6-0-etyliden-Dglucozo. Hieu suat 38%. Nhiet dp nong chay 193-194°C. Pho hong ngoai VOH=3460
cm'', VNH=3275cm"'.
5) Tdrig hap 4.6-0-etyliden-N-(6-metylbenzo-L3-thiazol-2-yl)-p-D-glucopiranozvlamin
(EtGlcamin-5)
Tir 0,82g 6-metyl-2-aminobenzo-1,3-thiazol va l,03g (0,005mol) 4,6-0-etyIidenD-glucozo. Hieu suat 40%. Nhiet dp nong chay 238-240°C. Pho hong ngoai
voH=3460cm"', VNH=3284cm''.
6) Tdng hap 4,6-0-etyliden-N-(6-cacboetoxibenzo-1.3-thiazol-2-yl)-p-D-glucopiranozylamin (EtGlcamin-6)
Tir l,04g 6-cacbetoxi-2-aminobenzo-1,3-thiazol va l,03g (0,005mol) 4,6-0etyliden-D-glucozo. Hieu suat 38%. Nhiet dp nong chay 228-230°C. Pho hong ngoai
voH=3365cm"', VNH=3299cm"',vc=o=1699 cm"'.

2.4 Tdng hap 3'glucozylaminoisothiazolo[3y4-d]pirimidin (GAIP) tieglucozff
2.4.1 Tong hap 2,3.4,6-tetra-O-axetyl-0-D-glucopiranozvl isothioxianat (Sa do 5)
1) Tdng hap 2.3,4,6-tetra-O-axetyl-a-D-glucopiranozyl bromua [16,17]
Nho timg gipt 2,4ml axit pecloric 54% vao 40ml anhidrh axetic trong binh cau 3
c6 250ml CO lip may khuay, pheu nho gipt, nhiet ke va dugc lam lanh bang nuoc da. Sau
do dung dich dugc lam am den nhiet dp phong, lOg a-D-glucozo monohidrat dugc them
tir tir vao hon hgp dang khuay voi toe dp sao cho nhiet dp phan img nam trong khoang 30
- 40*^C trong 30 phut. Photpho do (3g) dugc them vao sau khi lam lanh hon hgp phan img
xudng 20°C va nhd gipt 18g (5,8ml) brom vao vdi tdc dp sao cho phan img khdng vugt
qua 20°C. Sau khi hit brom 3,6ml nuoc dugc nhd gipt vao binh phan img dang khuiy va
lam lanh trong vdng nira gid de tranh nhiet dp khdng vugt qua 20°C. Hdn hgp phan img
dugc giir 2 gid d nhiet dp phdng.

14


OH
HO--^^—-V
.
^

OAc
^O^
^O

OAc

I.ACaO.HCIO^AcO-^^—=^---0^
i.Ac20.HCI04AcO-^r-^-—O

H 0 \ . . - ^
OH^H

2 3,^p

•

A c O - \ . ^ ^

Pb(SCN)2
—

^

j^^
^^^X

Aco ^^

\

.N=C=S

OA,

5a do 5. Tdng hgp 2,3,4,6-tetra-O-axetyl-p-D-glucopiranozyl isothioxianat tir Dglucoza.
Clorofom (30ml) dugc them vao, hdn hgp dugc lpc qua phlu lpc xdp. Binh phan
ung va pheu lpc dugc rira bang 10ml clorofom. Dich lpc dugc rot vao 80ml nude da dugc
chiira trong pheu chiet 250ml. Sau khi rua, ldp clorofom dugc chiet tiep vao pheu chiet
250ml khac cd chua 30ml nude lanh. Qua trinh dugc lap lai bang each them lOmI
clorofom vao dung dich nuoc ban dau va hgp nhat cac dich chiet clorofom lai. Sau khi
lac manh, ldp clorofom dugc rot vao 75ml natri hidrocacbonat bao hoa trong cdc 500ml
va khuay manh. Hdn hgp dugc chuyen vao pheu chiet 250ml, rdi them mpt it clorofom va
lac manh. Chiet lay ldp clorofom dugc khuay vdi 5g silic dioxit mdi nung. Hdn hgp dugc
lpc, dem cd dudi ap suat thap de loai bd hoan toan dung mdi, thu dugc khdi ran tinh the.
Nghien chat ran trong cdc vdi 30ml hdn hgp ete dau hoa va ete (2:1 v/v) thu dugc cac
tinh the min mau trang xdp, lpc tinh the va rira chat ran bang mdt lugng ete lanh, tetra-0axetyl-a-D-glucopiranozylbromua dugc lam khd dudi ap suat thap tren NaOH ran. Hieu
suit 14g (58%), nhiet do ndng chay 88°C, theo tai lieu [16,17 ] la 88 - 89°C.
2) Tdng hap 2,3,4,6-tetra-O-axetyl-P-D-glucopiranozyl isothioxianat [18]
Hdn hgp cua 5g tetra-0-axetyl-a-D-glucopiranozylbromua trong 30ml xilen va 4g
chi thioxianat dugc dun hdi luu trong 3 gid. Sau dd hdn hgp dugc lam lanh va lpc loai
mudi chi, xir li dung dich bang each khuay manh vdi 70ml ete dau hoa. Tetra-O-axetyljS-D-glucopiranozyl isothioxianat mau trang dugc tach ra, lpc, lam khd dugc 3,5g (H =
73%), kit tinh lai trong C2H5OH, nhiet do ndng chay 112°C, theo tai lieu [18] la 112114°C. Phd hdng ngoai: vc=o(este) 1748cm"^; vc.o-c(este) 1232cm"'; VN^=S 2095 cm"'.

2.4.2 Tdng hap 3-glucozvlaminoisothiazolo[3.4-d]pirimidin (GAIP)
Phuang phdp chung tong hap cdc hap chdt
cua 3'glucozylaminoisothiazolo[3,4-d]pirimidin: Hdn hgp ciia 0,39g (0,001 moi) 2,3,4,6-tetra-O-axetyl-P-Dglucopiranozyl isothioxianat va 0,001 moi 6-aminouraxin (hoac 6-amino-2-thiouraxin)
trong 10ml xilen khan dugc dun hdi luu each dau trong thdi gian 14 gid, sau dd lam bay
hoi dung mdi phan img d nhiet dp phdng hay d dudi ap suat giam. Phan can dugc lpc va
kit tinh lai trong dung mdi toluen. Sau day la cac trudng hgp cu the (xem Sa do 6 vd
Bdng 3a vd 3b).

15


N=C=S

+

>r

-N"'"'

^Aco\^

Jl

i.

^

\

OAC

H
'^N^N-^X

I

Sado 6. Tdng hap 3-glucozylaminoisothiazolo[3,4'd]pirimidin tir 2,3,4,6-tetra-O-axetylp-D-glucopiranozyI isothioxianat.
1) Tons hap 3-glucozylaminoisothiazolo[3,4-d]pirimidin-4,6-dion (GAIP-1)
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-O-axetyl-a-D-glucopiranozyl isothioxianat va
0,13g (0,001mol) 6-aminouracil thu dugc 0,22g tinh thi 3-glucozylaminoisothiazolo[3,4d]pirimidin-4,6-dion, hieu suit 43%, kit tinh lai trong toluen, nhiet dp ndng chay 84^C.
Phd hdng ngoai: Vc=o(este) =1742cm"'; Vc-o-C(esie)= 1226cm*' va V^.H =3463cm"'.
2) Tdng hap 3-glucozylaminoisothiazolo[3.4-dlpirimidin -7-phenyl-4,6-dion (GAIP-2)
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-O-axetyl-a-D-glucopiranozyl isothioxianat va
0,2g 6-amino-l-phenyluracil thu dugc 0,25g tinh thi 3-glucozylaminoisothiazolo[3,4d]pirimidin-7-phenyl-4,6-dion, hieu suit 42%, kit tinh lai trong toluen, nhiet dp ndng
chay 87''C. Phd hong ngoai: Vc=o (este) =1743cm"'; Vc-o-c (este) =1225cm"' va V^.H = 3493
cm''
Bdng 3a. Cdc ddn xudt cua 3-glucozylaminoisothiazolo[3,4-d]pirimidin
Ki hieu

Nhdm the

Dnc CC)

GAIPl
GAIP2
GAIP3
GAIP4
GALP5
GAIP6
GAIP7

GAIP8

R:=H; X=0; R2=H
Ri=H; X - 0 ; Rz^CeHs
Ri=H; X=0; R2=o-CH3C6H4
Ri=H; X=0; R2=p-C2H50C6H4
Ri=H; X=0; R2=p-BrC6H4
Ri=H; X-S; R2=H
Ri=H;X=S;R2=C6H5
Ri= C6H5; X=S; R2=C6H5

84
87
100
106
108
88
96
108

Hieu sua
(%)

43
42
46
54
52
43
53

56

3) Tdns hap 3-2lucozylaminoisothiazolo[3,4-dlpirimidin-7-(o~metylphenyl}-.4,6-dion
(GAlP-3)
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-O-axetyl-a-D-glucopiranozyl isothioxianat va
0,22g (0,001mol) 6-amino-l-o-metyl-phenyluracil thu dugc 0,28g tinh the 3glucozylaminoisothiazolo[3,4-d]pirimidin-7-(o-metylphenyl)-4,6-dion, hieu suit 46%,
kit tinh lai trong toluen. nhiet dp ndng chay 100°C. Phd hdng ngoai: vc=o (este, =1743cm-1
16


Vc-o-c (esicr 1245cm"'; VN-H =3305 va 3494cm''.
4) Tdng hap 3-2lucozylaminoisothiazolo[3.4-dl pirimidin -7-(p-etoxiphenyl)-4,6-dion
{GAIP-4)
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-O-axetyl-a-D-glucopiranozyl isothioxianat va
0,28g (0,001mol) 6-aniino-l-p-brom-phenyluracil thu dugc 0,35g tinh thi 3glucozylaminoisothiazoIo[3,4-d]pirimidin-7-(p-etoxiphenyI)-4,6-dion, hieu suit 52%, kit
tinh lai trong toluen, nhiet dp ndng chay 108°C. Pho hong ngoai: Vc=o (este) =1744cm*';
Vc-o-c(este)= 1238cm"' va V^.H^ 3458cm"'.
Bdng 3b. Phd hdng ngoai cua cdc ddn xudt
3-glucozylaminoisothiazolo
[3,4-d]pirimidin
'.aminoisoiniazoLO[D,^-ajpirimiain
Ki hieu

GAIPl
GAIP2
GAIP3
GAIP4
GAIP5
GAIP6
GAIP7

GAIP8

Cac bang sdng hap thu dac trung (cm"')
v^_^ 1744-v^^^,„..^
Vv. „ 3450
"^4^0
Vc=o
1744; vco-c (este) 19481248; VN-H
Vc=o 1743; vco-c (este) 1225; VN.H 3494
Vc=o
N.H3499
vc=o 1753;
A/-'-J, Vc^.c(este)
vc^.c(este) 1245;
i^^^, Vv^-H-J^^^

v c o 1744; Vc.o-c(este) 1240; V^.H 3458
Vc=o 1742;
t / ^ ^ ; Vc-0<:(este)
^ ^ ^ ; VN-H
420
vc=o
Vco<:(este) 11239;
VN-H 33420

Vc=o
1742; Vc=s
1226;
V^.H
Vc=o 1742;

Vc=s 1038;
1038;Vc-o-c(esie)
Vc-o-c(esie)
1226;
V^.H3463
vc=ol742;vc=s 1040; vc-o-c (este) 1229; V^.H 3459
Vc=o 1744; vc=s 1040; vco-c (este) 1240; VN-H 3487

5) Tdng hap 3-glucozylaminoisothiazolo[3A-d]pirimidin -7-(p-bromphenyl)-4,6-dion
(GAIP-5)
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-(9-axetyl-a-D-glucopiranozyl isothioxianat va
0,25g (0,001 moi) 6-amino-l-/?-etoxiphenyluracil thu dugc 0,34g tinh the 3glucozylaminoisothiazolo[3,4-d]pirimidin-7-(p-bromphenyl)-4,6-dion, hieu suat 54%, kit
tinh lai trong toluen, nhiet dp ndng chay 106°C. Phd hdng ngoai: vc=o (este)= 1744cm"';
Vc-o-c (este)^ 1248cm"' va V^-.H =3490cm''.
6) Tdng hap 3-glucozvlaminoisothiazolo[3.4-d]pirimidin-4-on-6-thion (GAIP-6)
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-O-axetyl-a-D-glucopiranozyl isothioxianat va
Tiln hanh theo phuong phap tren tir 0,15g 6-aminothiouracil thu dugc 0,23g tinh thi 3glucozylaminoisothiazolo[3,4-d]pirimidin-4-on-6-thion, hieu suat 43%, ket tinh lai trong
toluen, nhiet dp ndng chay 88°C. Phd hdng ngoai: Vc=o (este) =1744cm"';
Vc-o-c(este)= 1248cm"'; vc=s =1038cm"' va VN-H =3490cm''.
7) Tdn2 hap 3-2lucozylaminoisothiazolo[3,4-dlpirimidin-7-phenyl-4-on-6-thion (GAIP-

71
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-(9-axet>'l-a-D-glucopiranozyl isothioxianat va
17

DAI HOC Q U O C GlA HA rjOl
TRUNG TAT/ THONG TIN THU VlEhJ

pr/.0C'7

0,21g (0,001mol) 6-amino-l-phenyl-2-thiouracil thu dugc 0,32g tinh thi 3glucozylaminoisothiazolo[3,4-d]pirimidin-7-phenyl-4-on-6-thion, hieu suit 55%), kit tinh
lai trong toluen, nhiet do ndng chay96°C. Phd hdng ngoai: v c o (este) 1742cm"';
Vc-o-c (este) 1229cm''; Vc=s 1032cm'' va VN.H 3460cm"'.
8) Tdn2 hap 3-slucozylaminoisothiazolo[3,4-d]pirimidin-5,7-diphenyl-4-on-6-thion
rGAIP-8)
Tir 0,39g (0,001 moi) 2,3,4,6-tetra-O-axetyl-a-D-glucopiranozyl isothioxianat va
0,3g (0,001mol) 6-amino-l,3-diphenylthiouracil thu dugc 0,38g tinh thi 3glucozylaminoisothiazolo[3,4-d]pirimidin-5,7-diphenyl-4-on-6-thion, hieu suit 56%), kit
tinh lai trong toluen, nhiet dp ndng chay 108°C. Phd hdng ngoai: vc=o (este) =1744cm"';
Vc-o-c (cste)='1241cm''; vc=s=1038cm"' va VN.H=3487cm"'.

C Ket qua va ban luan
2.5 Tong hop cac glucopiranozylamin (GlcNAcamin) tir N-axetyl-P-D-glucozamin
Bang each cho dan xuat 2-aminothiazoI va 2-aminobenzothiazol vdi N-axetyl-PD-glucozamin trong etanol 96%, thdi gian phan ung trung binh tir 30-50h se thu dugc
cac san pham glucozylamin vdi hieu suat tucmg ddi cao (50 - 60%) (xem Bdng 1).
Phan ung nay la loai phan img tach nude, nen thdng thudng thi phan ung dugc
tien hanh trong dung mdi khan. Nhung do N-axetyl-a-D-glucozamin la chat it tan trong
etanol nen neu tien hanh trong dung mdi etanol khan thi phan img xay ra d dang di the rat
khd khan, chinh vi vay phan img dugc tien hanh trong dung mdi etanol 96° vira tao dieu
kien cho phan img xay ra de dang vi hgp chat nay nam trong dung dich, ddng thdi vdi
ndng dp 96% khdng anh hudng den can bang loai nude cua phan img. Phan img can xiic
tac axit, thdng thudng la axit axetic bang.
Cau true cua cac N-axetylglucozylamin dugc xac nhan bang each ghi phd hdng
ngoai va phd ' H - C H T N . Trong phd hdng ngoai cua cac N-(benzothiazol-2-yl)-2axetamido-2-deoxi-P-D-glucopiranozylamui va N-(4-phenylthiazol-2-yl)-2-axetamido-2deoxi-P-D-glucopiranozyl-amin cd cac bang sdng hap thu dac tnmg cho cac nhdm the cd
mat trong phan tir: nhdm OH d 3459-3365 cm"'( VQH Hen hgp); nhdm NH d 3385-3299
cm"'; nhdm chuc amit cd cac hap thu Vc=o (amit) d 1650-1628 cm"' (vach amit I) va
5NH d 1562-1549 cm"'. Ngoai ra trong phd cdn xuat hien mdt sd bang sdng hap thu dac
tnmg cho dao ddng hoa tri cua lien ket C=C trong nhan di vdng thom d vimg 1549-1528
va 1465-1464 cm'' (xem bdng 1).
Trong phd ' H - C H T N ciia cac glucozylamin ndi tren, cd hai vimg tin hieu cdng

hudng, tuang img vdi hai loai proton trong phan tir: cac proton trong nhan thom benzen
va nhan dj vdng thiazol cd cac tin hieu cdng hudng nam trong viing 7,112-8,543 ppm;
cac proton cua hgp phan cacbohidrat cd tin hieu cdng hudng d viing <5 ppm: cac nhdm
OH vdi dp chuyen dich hod hpc d 4,546-5,347 ppm, cac proton no trong vdng piranozo
cd dp chuyen dich hoa hpc nam trong viing 3,224-4,975 ppm. Proton ciia lien ket amit
(trong nhdm N-axetyl ciia NTI-CO-CH3) cd dp chuyen dich hoa hpc nam trong viing
18