B Y T

TRNG I HC DC H NI

NG VN THNG

NGHIN CU THM D TNG HP

PROPACETAMOL HYDROCLORID
KHA LUN TT NGHIP DC S

H NI 2013

B Y T
TRNG I HC DC H NI

NG VN THNG

NGHIN CU THM D TNG HP

PROPACETAMOL HYDROCLORID
KHA LUN TT NGHIP DC S

Ngi hng dn:

DS. Nguyn Vn Giang
Ni thc hin:
B mn Cng nghip Dc
Trng i hc Dc H Ni

H NI 2013

LI CM N
Vi tt c lng knh trng, u tin ti xin by t lng cm n chn thnh v
su sc nht ti DS. Nguyn Vn Giang cng vi PGS.TS. Nguyn nh Luyn
ch nhim b mn Cng nghip Dc Trng i hc Dc H Ni, tn tnh
hng dn gip ti trong sut thi gian qua.
Cm n DS. Phm Th Hin, CN. Phan Tin Thnh cng cc bn ang lm
thc nghim ti Phng Tng hp Ha dc gip ti tm ti liu, ch dn thao
tc thc nghim gip ti trong sut qu trnh lm ti ti B mn.
Ti cng xin cm n cc thy c b mn Cng nghip Dc cng cc thy
c trong Trng i hc Dc H Ni du dt ti trong 5 nm va qua.
Cui cng ti xin cm n gia nh v bn b lun gip , khch l ti
trong thi gian qua.
H Ni, ngy 21 thng 05 nm 2013.
Sinh vin

Ng Vn Thng

MC LC
Trang

T VN .................................................................................................. 1
CHNG 1: TNG QUAN........................................................................... 2
1.1. Tng quan v propacetamol hydroclorid ............................................. 2
1.1.1. Cng thc cu to, cng thc phn t.................................................... 2
1.1.2. Tnh cht l ha ...................................................................................... 2
1.1.3. Cc phng php nh tnh, nh lng theo BP 2010 .......................... 3
1.1.4. Dc ng hc, c ch tc dng, tc dng v cng dng ..................... 3
1.1.5. u v nhc im khi s dng propacetamol........................................ 5
1.2. i nt v tin thuc (prodrug).............................................................. 5
1.2.1. Khi nim................................................................................................ 6
1.2.2. Mc ch ca tin thuc.......................................................................... 6
1.2.2.1. Tin thuc ci thin thm qua mng/kh nng vn chuyn qua
mng .................................................................................................... 6
1.2.2.2. Tin thuc ko di tc dng ................................................................. 7
1.2.2.3. Tin thuc lm thay i tan trong nc.......................................... 8
1.2.2.4. Tin thuc lm tng bn ha hc, gim chuyn ha ...................... 9
1.2.2.5. Tin thuc a thuc n ch tc dng ....................................... 10
1.2.2.6. Tin thuc lm gim c tnh v tc dng ph ................................. 10
1.2.2.7. Tin thuc ci thin mi v ................................................................ 10
1.3. Phng php tng hp propacetamol hydroclorid t paracetamol 11
1.3.1. Tng hp tc nhn acyl ha monocloroacetyl clorid .......................... 11
1.3.2. Cc phng php tng hp propacetamol hydroclorid vi tc nhn acyl
ha-monocloroacetyl clorid. ............................................................... 11
CHNG 2: I TNG, NI DUNG V PHNG PHP NGHIN
CU........................................................................................ 16

2.1. Dng c, ha cht v phng php nghin cu ................................. 16

2.1.1. Dng c, ha cht ................................................................................. 16
2.1.2. Ni dung nghin cu ............................................................................ 17
2.1.3. Phng php nghin cu...................................................................... 18
2.1.3.1. Tng hp ha hc v kim tra tinh khit ..................................... 18
2.1.3.2. Xc nh cu trc .............................................................................. 18
CHNG 3: THC NGHIM, KT QU V BN LUN ................. 20
3.1. Kt qu v thc nghim........................................................................ 20
3.1.1. Giai on 1 ........................................................................................... 20
3.1.2. Giai on 2 ........................................................................................... 20
3.1.3. Giai on 3 ........................................................................................... 26
3.1.4. Giai on 4 ........................................................................................... 27
3.2. Kim tra tinh khit........................................................................... 30
3.3. Xc nh cu trc cc cht tng hp ....................................................... 30
3.3.1. Kt qu phn tch ph ca PAPC ......................................................... 30
3.3.2. Kt qu phn tch ph ca propacetamol ............................................. 33
3.4. Bn lun ................................................................................................. 35
KT LUN V XUT .......................................................................... 38
TI LIU THAM KHO
PH LC

DANH MC CH VIT TT
BP 2010

: British Pharmacopoeia 2010

DEA

: Diethylamin

DMSO

: Dimethyl sunfoxid

Gly

: Glycin

IR

: Ph hng ngoi (Infrared spectroscopy)

MP

: Methylpresnisolon

MS

: Ph khi lng (Mass spectroscopy)

PAPC

: p-acetamidophenyl monocloroacetat

Rf

: H s lu gi (retension factor)

tonc

: Nhit nng chy

TEA

: Triethylamin

THF

: Tetrahydrofuran

TLC

: Sc k lp mng (Thin layer chromatography)

: Ph cng hng t ht nhn proton (1H nuclear

H-NMR

magnetic resonance)

DANH MC CC BNG
Trang
Bng 2.1

Dng c c s dng trong kha lun

16

Bng 2.2

Nguyn liu dung mi c s dng trong kha lun

17

Bng 3.1

Kho st t l mol gia PAPC: monocloroacetic n hiu sut

22

Bng 3.2

Kho st t l mol gia PAPC: DEA n hiu sut phn ng

26

Bng 3.3

Rf v tonc ca paracetamol v cc cht tng hp c

30

Bng 3.4

Kt qu phn tch ph hng ngoi ca PAPC

31

Bng 3.5

Kt qu phn tch ph khi lng ca PAPC

31

Bng 3.6

Kt qu phn tch ph cng hng t ht nhn proton ca

PAPC

Bng 3.7

32

Kt qu phn tch ph hng ngoi ca propacetamol

hydroclorid

33

Bng 3.8

Kt qu phn tch ph khi lng ca propacetamol base

33

Bng 3.9

Kt qu phn tch ph cng hng t ht nhn proton ca

propacetamol hydroclorid

34

DANH MC CC HNH V
Trang
Hnh 1.1

Tin thuc ester ca enalaprilat

Hnh 1.2

C ch tc dng ca levodopa

Hnh 1.3

Tin thuc to tc dng ko di ca ampicillin

Hnh 1.4

Tin thuc ca 6-mercaptopurin

Hnh 1.5

Tin thuc ca albendazol

Hnh 1.6

Tin thuc ca carbamazepin

Hnh 1.7

Tin thuc ca dexamethason

Hnh 1.8

Tin thuc ca paracetamol

Hnh 1.9

Tin thuc hectacillin ca ampicillin

Hnh 1.10

Mepredex, tin thuc gn dextran ca methylprednisolon

10

Hnh 1.11

Carbecitabin tin thuc ca 5-fluorouracil

10

Hnh 1.12

Tin thuc ca chloramphenicol

11

Hnh 3.1

Sc k lp mng paracetamol (tri) v PAPC (phi)

21

Hnh 3.2

Biu kho st t l mol pracetamol/monocloroacetic

22

Hnh 3.4

Biu kho st t l mol PAPC/DEA

27

Hnh 3.3

Sc k lp mng sn phm paracetamol (tri), PAPC

(gia), propacetamol hydroclorid (phi)

28

DANH MC CC S
Trang
S 1.1

Tnh cht ha hc ca propacetamol

S 1.2

S thy phn ca propacetamol bi esterase

S 1.3

Tng hp monocloroacetyl clorid

11

S 1.4

Tng hp propacetamol hydroclorid

12

S 1.5

Tng hp propacetamol hydroclorid

13

S 1.6

Tng hp monocloroacetyl clorid theo nghin cu trong

nc

14

S 1.7

Tng hp p-acetamidophenyl monocloroacetat

14

S 1.8

Tng hp propacetamol hydroclorid

14

S 1.9

Tng hp tc nhn anhydrid acid hn tp

15

S 3.1

Tng hp tc nhn acyl ha anhydrid acid hn tp

20

S 3.2

Tng hp p-acetamidophenyl monocloroacetat

20

S 3.3

Quy trnh tng hp PAPC trong K2CO3/aceton

23

S 3.4

Quy trnh tng hp PAPC trong NaOH 10%

23

S 3.5

Quy trnh tng hp PAPC

25

S 3.6

Tng hp propacetamol base

26

S 3.7

Quy trnh tng hp propacetamol hydroclorid

27

S 3.8

Quy trnh tng hp propacetamol hydroclorid

29

S 3.9

C ch phn ng acyl ha

35

S 3.10 Phn ng N-acyl ha

36

S 3.11 C ch xc tc ca KI

36

T VN
Cng vi s pht trin ca x hi hin nay th m hnh bnh tt cng ngy
cng tr nn phc tp. Khi m ngi dn ang ngy cng s dng thuc nhiu hn
th i cng vi n l nguy c v tc dng ph v c tnh ca thuc ngy cng tng
cao.
Thit k tin thuc ang l mt trong lnh vc thu ht c nhiu s quan
tm ca cc nh tng hp ha dc trong v ngoi nc. Vic thay i cc thng s
vt l, ha l s gip tng hiu qu iu tr ng thi gim tc dng ph v c tnh
ca thuc.
Trn th gii hin nay, paracetamol l thuc gim au, h st ang c
dng rt ph bin do thuc an ton, hiu qu v dung np tt [20]. Trong nhng
trng hp cp tnh, bnh nhn hn m, chn thng nng hoc phu thutthuc
tim paracetamol s l la chn cho cc bc s gim nhanh chng cc triu chng
trn. Nhng do t tan v d b thy phn trong nc nn paracetamol gp rt nhiu
hn ch trong vic bo ch di dng thuc tim.
Chnh v nhng nhc im nh vy, tin thuc propacetamol hydrochlorid
c iu ch v a vo s dng rt rng ri di dng bt pha tim p ng
nhu cu s dng ngy cng a dng ca x hi.
Vi vai tr to ln ca propacetamol hydroclorid trong thc t iu tr do
chng ti thc hin ti Nghin cu thm d tng hp propacetamol
hydroclorid vi mc tiu sau:
Nghin cu xy dng, tng hp propacetamol hydroclorid quy m phng
th nghim.

CHNG 1: TNG QUAN

1.1. Tng quan v propacetamol hydroclorid
1.1.1. Cng thc cu to, cng thc phn t

KLPT: 300,8 vC

CTPT: C14 H21ClN2O3

- Tn khoa hc:

4-(Acetylamino)phenyl (diethylamino)acetat hydroclorid.

- Tn gi khc:
+ N, N-diethylglycin 4-(acetylamino)phenyl ester hydroclorid.
+ Propacetamol hydroclorid.
- Thnh phn
C: 55,91%

H: 6,99%

Cl: 11,81%

N: 9,32%

O: 15.97%

1.1.2. Tnh cht l ha

Tnh cht l hc:
Bt kt tinh mu trng hoc gn nh trng.
Tan t do trong nc, t tan trong ethanol, thc t khng tan trong aceton.
Tnh cht ha hc
Ha tnh ca propacetamol l do c nhm ester ni vi nhn thm, nhm chc
acetamid, N bc 3 v nhn thm.
- D b thy phn to paracetamol.
- N bc ba to ta vng vi acid picric.
- Cho kt ta trng vi Ag+ ca ion Cl-.
- Nhn thm hp th nh sng t ngoi c th dng nh tnh v nh lng.
- Thy phn trong mi trng HCl to 4-aminophenol, sn phm thy phn tc
dng vi FeCl3 cho phc mu hng v to ta mu tm vi thuc th
kalibicromat [2,12].

Phc mu hng

S 1.1. Tnh cht ha hc ca propacetamol

1.1.3. Cc phng php nh tnh, nh lng theo BP 2010
nh tnh
a. Ph hng ngoi ca ch phm phi ph hp vi ph hng ngoi ca
propacetamol chun.
b. Cho phn ng ca ion clorid.
nh lng: Phng php nh lng trong mi trng khan.
Chun bng acid percloric trong mi trng acid acetic khan v anhydrid
acetic, pht hin im tng ng bng ch th o th.
1ml acid pecloric 0,1M tng ng vi 30,08 mg propacetamol hydroclorid.
Hm lng t t 98,0% -102,0% tnh theo ch phm khan [12].
1.1.4. Dc ng hc, c ch tc dng, tc dng v cng dng
Dc ng hc
Propacetamol l mt tin cht ca paracetamol. Khi vo mu cht ny c thy
phn nhanh chng bi cc enzym esterase trong huyt tng v gii phng ra
paracetamol [20].
Paracetamol chuyn ha ch yu qua gan v thi tr qua thn. Thi tr qua thn
ch yu dng lin hp vi acid glucuronic v sulfat, di 5% dng khng i.
Chuyn ha cytocrom P450 ti gan to N-acetyl benzoquinonimin l cht trung
gian, cht ny tip tc lin hp vi nhm sulfydrid ca glutathion to ra cht
khng cn hot tnh. Nu dung liu cao s to ra nhiu N-acetyl benzoquinonimin
lm cn kit glutathion gan khi N-acetyl benzoquinonimin s phn ng vi nhm
sulfydrid ca protein gan gy tn thng gan, hoi t gan khng hi phc [9,19].
Tc dng v c ch

S 1.2. S thy phn ca propacetamol bi esterase

Tc dng dc l ca propacetamol cng chnh l tc dng dc l ca
paracetamol.
Paracetamol c tc dng h st, gim au khng c tc dng chng vim. H
st khi c th b st do bt k nguyn nhn no, thuc khng gy h nhit ngi
bnh thng, khng lm thay i cn bng acid-base, khng gy kch ng tiu ha,
khng chng kt tp tiu cu [9]. liu iu tr sau khi tim thuc propacetamol
hydroclorid c th gy au ti ch tim, lm h huyt p 15 pht u [10,14]. Khi
dng liu cao c th gy bun nn, nn, chn n, au bng [8].
Ch nh
- Gim au trong cc trng hp: ung th, c bit trong giai on hu phu.
- iu tr triu chng st trong cc bnh nhim trng, bnh c tnh, khi cc ng
dng khc (nht l ng ung) khng thch hp.
- Cn c thay th ngay khi c th dng paracetamol bng ng ung [8,20].
Liu lng
1g propacetamol sau khi thy phn bi esterase gii phng ra 0,5g paracetamol.
Tim bp hoc tim tnh mch trc tip dung dch propacetamol trong 1-2 pht
hoc tim truyn tnh mch 125ml dung dch ng trng glucose 5% hoc NaCl
0,9% trong 15pht. Khong cch cc ln dng phi cc nhau t nht 4h [25].
Ch nh cho ngi ln v tr em 17kg.
Tr em: 20-30mg/kg/1ln, khng vt qu liu ti a l 120mg/kg/ngy tng
ng 60mg/kg/ngy paracetamol [19].
Ngi ln: 1-2g, 2 n 4 ln/ngy, khng dng qu 6g/ngy, ngoi l c trng
hp ln n 8g/ngy.
i vi nhng ngi suy thn nng ( thanh thi creatinin di 10ml/pht)
khong cch gia hai ln dng ti thiu l 8h [8,19].

Chng ch nh
Tuyt i
- Mn cm vi propacetamol v cc thnh phn ca thuc, c bit l N,Ndiethylglycin do thuc gii phng [11].
- Nghi ng c d ng vi propacetamol, nht l nhng nhn vin y t tip xc vi
thuc c xut hin d ng [10].
- Suy t bo gan.
Tng i
- C thai 3 thng u [7, 8].
Ch phng v thn trng
- c bo co xut hin eczema cc nhn vin y t sau khi pha ch thuc tim
ny, do vy cn phi eo gng tay khi pha thuc hoc s dng h thng bm ht
thuc.
- Khng ngi c tin s eczema thao tc pha thuc, tip xc vi thuc [10].
1.1.5. u v nhc im khi s dng propacetamol
u im:
- Tc dng nhanh mnh, kim sot c nng trong mu hn so vi cc ng
dng khc, thun tin cho bc s khi cn gim au nhanh.
- n nh v mt ha hc, khng b nh hng bi cc t dc so vi thuc tim
paracetamol.
Nhc im:
Ngoi cc tc dng khng mong mun ca paracetamol, cn c thm mt s
nhc im khc ca thuc nh:
- Gy d ng cc nhn vin y t khi pha ch thuc tim tip xc vi
propacetamol [10].
- Tc dng ph khc: chng mt, au bng, bun nn, tng huyt p 15 pht ngay
sau khi tim, au ti ch tim [20,8,16].
1.2. i nt v tin thuc (prodrug)

Vo nm 1958, khi nim v tin thuc (prodrug) c Adrien Alberlt a ra.

ng xut cc phng php tip cn c th c s dng thay i mt s
thuc tnh nht nh hay lm gim c tnh ca thuc. Nhng mi n cui nm
1970 cc nghin cu v tin thuc mi thc s bt u pht trin. Trong nhng nm
2001-2002, 14% thuc mi c ph duyt trn ton th gii l tin thuc. n
ngy nay tin thuc ang l mt trong nhng lnh vc m cc nh nghin cu v
pht trin thuc mi quan tm [17,21,23].
1.2.1. Khi nim
Tin thuc (prodrug) l nhng hp cht m bn thn khng c tc dng dc
l hoc c tc dng rt yu in vitro nhng vo trong c th n chuyn thnh cht c
hot tnh [5,23].
1.2.2. Mc ch ca tin thuc
1.2.2.1. Tin thuc ci thin thm qua mng/kh nng vn chuyn qua mng
a. Chuyn thuc thnh dng ester v amid
i vi nhng nhm thuc c cc nhm chc phn cc hoc d b ion ha nh
nhm hydroxyl, nhm amin, nhm carboxylic thng c thm qua mng km.
V vy chuyn tm thi cc nhm chc ny sang dng ester hoc amid l nhng gii
php hiu qu ci thin thm ca thuc qua mng sau s b thy phn bng
cc enzym esterase hoc amidase khng c hiu to ra thuc c tc dng. VD:
enalapril v enalaprilat; cefuroxim v cefuroxim acetil; beclomethason v
beclomethason dipropionat.

Enalaprilat

Enalapril

Hnh 1.1. Tin thuc ester ca enalaprilat

b. Thit k tin thuc ci thin s vn chuyn thuc qua mng

Mt v d kinh in ca loi tin thuc ny l levodopa (tin thuc ca dopamin)

dng iu tr Parkinson. Do bn cht qu phn cc ca dopamin nn thuc khng
hp thu qua c ng tiu ha, cng nh khi dng ng tim thm qua c
hng ro mu no.
- Levodopa khi vo mu b decarboxyl ha to thnh dopamin nh enzym Laminoacid thm decarboxylase.
- Levodopa c vn chuyn qua hng ro mu no nh h vn chuyn tch cc Laminoacid. Tuy nhin, hn ch s phn hy sm ca levodopa ngoi vi, mt
trong hai thuc c ch enzym ny l carbidopa v benserazid lun c s dng
ng thi vi levodopa.
No

L-aminoacid thm
decarboxylase no

H vn chuyn tch cc

(Hng ro mu no)

L-aminoacid
Ngoi vi

L-aminoacid thm
decarboxylase ngoi vi

Hnh 1.2. C ch tc dng ca Levodopa

1.2.2.2. Tin thuc ko di tc dng
Cc loi tin thuc ny gip gim c tn s s dng, gim c tc dng
ph v c tnh. Phng php hay dng nht l to cc ester hoc amid c mch
alkyl di t 3 n 10 carbon v vy thuc phi c cc nhm chc nh OH, NH2 hay
COOH. VD: Bacampicillin, Testosterol propionat, tolmentin glycin, haloperidol
decanoat l mt trong rt nhiu tin thuc thuc loi ny.

Bacampicillin

Ampicillin

Hnh 1.3. Tin thuc to tc dng ko di ca Ampicillin

Tuy nhin cng c nhng tin thuc ko di tc dng khng thuc dng ester
hay amid, c th gn thm nhm CH3 hoc to cu ni -S-
VD: Azathioprin l tin thuc ko di tc dng ca 6-mecaptopurin

Azathioprin

6-mercaptopurin

Hnh 1.4. Tin thuc ca 6-mercaptopurin

1.2.2.3. Tin thuc lm thay i tan trong nc
Cc tin thuc thng c bo ch thun li cho vic bo ch thuc
tim, thuc nh mt. Cc nhm chc hay c s dng to tin thuc lm tng
tan vn l cc nhm -OH, -NH2 v -COOH. Vi nhm -OH chc ny c th to
dng ester vi acid amin, dng mui phosphat hay dn cht succinat [3]. Hoc c
th to mt s nhm chc c bit lm tng tan nh: =S=O, to lin kt vi
amin to mui tan vi HCl, HBr..
VD: Metronidazol v metronidazol N,N-dimethylglycinat, albendazol v
albendazol sulfoxid, carbamazepin v N-gly-carbamazepin, paracetamol v
propacetamol hydroclorid. [24].

Albendazol

Albendazol sunfoxid

Hnh 1.5. Tin thuc ca albendazol

Carbamazepin

N-gly-carbamazepin

Hnh 1.6. Tin thuc ca carbamazepin

Dexamethason

Dexamethason phosphate dinatri

Hnh 1.7. Tin thuc ca dexamethason

Paracetamol

Propacetamol hydroclorid

Hnh 1.8. Tin thuc ca paracetamol

1.2.2.4. Tin thuc lm tng bn ha hc, gim chuyn ha
VD:

Ampicillin

Hectacillin

Hnh 1.9. Tin thuc hectacillin ca ampicillin

10

Trong hetacillin nhm amin c kha ngn cn s tn cng vo vng lactam dn n m vng ny v lm mt hot tnh ca ampicillin. Vo c th
hetacillin phn hy dn dn gii phng ampicillin v aceton.
1.2.2.5. Tin thuc a thuc n ch tc dng
Tin thuc loi ny thng c thit k bng cch to phc hp vi mt cht
mang ph hp. Cht mang c hp thu chn lc bi t bo hay vi sinh vt gy
bnh.
VD: Mepredex l mt tin thuc ca methylprenisolon c thit k a
thuc chn lc n i trng dng iu tr vim i trng mn tnh.

Hnh 1.10. Mepredex, tin thuc gn dextran ca methylprednisolon

1.2.2.6. Tin thuc lm gim c tnh v tc dng ph
Cc loi tin thuc lm tng thm qua mng, a thuc chn lc n ch
tc dng, tin thuc c tc dng ko di, tin thuc lm tng bn ca thuc u
c vai tr lm gim c tnh v tc dng ph ca thuc [5].
Carbecitabin l mt tin thuc ca 5-fluorouracil dng iu tr ung th.
Carbetabin c c tnh trn ng tiu ha thp hn so vi 5-fluorouracil [22].

Carbecitabin

5-fluorouracil

Hnh 1.11. Carbecitabin tin thuc ca 5-fluorouracil

1.2.2.7. Tin thuc ci thin mi v
Mt s thuc c mi v kh chu gy ra nhng kh khn khi s dng v lm
gim hiu qu. VD:

11

Cloramphenicol (v ng)

Cloramphenicol palmitat (Khng ng)

Hnh 1.12. Tin thuc ca chloramphenicol

1.3.

Phng php tng hp propacetamol hydroclorid t paracetamol

1.3.1. Tng hp tc nhn acyl ha monocloroacetyl clorid

Monocloroacetyl clorid c tng hp trc tip t thionyl clorid hay
phosphor clorid v acid monocloroacetic khan.

S 1.3. Tng hp monocloroacetyl clorid

Tng hp bng phng php (1) thu c sn phm tinh khit hn do to
thnh SO2 v HCl c loi i d dng trng thi kh [1].
1.3.2. Cc phng php tng hp propacetamol hydroclorid vi tc nhn acyl
ha-monocloroacetyl clorid.
a. Phng php 1: Theo Tang Linh v cng s tng hp nm 1990.
-

S :

12

S 1.4. Tng hp propacetamol hydroclorid

- Quy trnh:
Paracetamol c ha tan trong aceton, thm K2CO3, lm lnh hn hp xung 05oC. Sau nh t t monocloroacetyl clorid vo hn hp phn ng, kt hp khuy
trong 2h. Theo di tin trnh phn ng bng TLC cloroform-toluen-aceton (13:5:2).
Khi kt thc phn ng, tip tc lp sinh hn, tng nhit ln 40oC, thm mt
lng nh KI, sau nh t t DEA vo hn hp phn ng, un hi lu trong 2h.
Phn ng xong, hn hp c ngui, lc loi b ta, ct quay thu hi dung mi
di p sut gim thu c sn phm dng du mu nu . Ha tan du ny trong
ethanol sau thm t t acid hydrocloric trong ethanol n khi pH=2. Lc thu ly
ta, ra ta 2 ln bng aceton, sy 50oC thu c propacetamol hydroclorid th,
hiu sut 78,2%. Nhit nng chy 225-227oC [26].
Nhn xt: quy trnh trn dng tc nhn l cloroacetyl clorid, iu ch kh
khn v t tin.
b. Phng php 2: Theo Lei Miao.
- S :

13

S 1.5. Tng hp propacetamol hydroclorid

- Quy trnh:
Phn ng qua 2 giai on:
Giai on 1: Paracetamol c ha tan trong THF v pyridin, lm lnh 0-5oC
sau c acyl ha bi monocloroacetyl clorid, tip tc khuy trong 2h, kt thc
phn ng cho hn hp vo nc, lc ta kt tinh li trong ethanol 96% thu c
PAPC. Hiu sut t 80%.
Giai on 2: PAPC c cho t t vo TEA 45oC khuy trong 2h 45 pht, sau
lm ngui, cho hn hp phn ng vo nc , sau chit bng ether, lm
khan dch chit bng MgSO4, ct quay thu hi ether di p sut gim thu c
propacetamol base dng du, sau sn phm c to mui vi HCl trong
aceton. Lc, ra ly ta thu c sn phm propacetamol hydroclorid. Hiu sut t
41% [18].
Theo J.C. Cognacq: giai on 2, PAPC c cho t t vo lng d DEA
hoc DEA/TEA un hi lu 45oC trong 2h. Sau hn hp c ha tan vo
nc lnh, chit bng ether, dch chit c lm khan bng MgSO4, ct quay di
p xut gim, tip acid ha bng HCl. Lc, ra ta bng aceton, sy kh thu
c propacetamol hydroclorid, nhit nng chy tonc: 228oC [13].
Nhn xt: gian on 2 ca c hai quy trnh trn phn ng tin hnh kh khn
(cho t t PAPC vo hn hp DEA/TEA), nhiu cng on, phc tp (chit, lm
khan, ct di p sut gim), s dng dung mi ether gy c hi, c hai quy trnh
u cho hiu sut thp.

14

c. Phng php 3: Theo mt s nghin cu trong nc.

- Giai on 1: Tng hp monocloroacetyl clorid bng SOCl2 v acid
monocloroacetic.

S 1.6. Tng hp monocloroacetyl clorid theo nghin cu trong nc

Quy trnh: un hi lu acid monocloroacetic vi SOCl2 t l mol (1:1,4), nhit
70-80oC trong 4h. Kt thc phn ng, chng ct ly sn phm nhit 100106oC [6].
- Giai on 2: Tng hp p-acetamidophenyl monocloroacetat.

S 1.7. Tng hp p-acetamidophenyl monocloroacetat

Quy trnh: Acyl ha paracetamol bng monocloroacetyl clorid (t l mol
paracetamol: monocloroacetyl clorid= 1: 1,5) trong dung dch NaOH 10% (t l
mol paracetamol: NaOH= 1: 1,4), kim sot pH khong 7-8 bng dung dch NaOH
10%, nhit phn ng 5-10oC, thi gian phn ng 10-15 pht. Lc ra ta bng
nc lnh n pH trung tnh, sy kh, tinh ch sn phm bng ethanol 96%.
Giai on 3: Tng hp propacetamol hydroclorid.

S 1.8. Tng hp propacetamol hydroclorid

Quy trnh: PAPC c ha tan trong aceton sau nh t t vo bnh cu
cha sn DEA vi t l mol PAPC:DEA l 1:3,5, duy tr nhit 40-50oC, lin
tc khuy trong 4h. Ct quay hn hp phn ng 50oC di p sut gim loi
aceton v DEA. Sau sn phm c ha tan trong ether, lm lnh, lc loi ta.

15

Dch ether c ct quay di p sut gim thu c propacetamol base dng du

mu nu .
Ha tan du ny bng aceton, dng h thng bnh Kipp to kh HCl t hn
hp NaCl v H2SO4 c. Sc kh vo dung dch propacetamol/aceton n pH t 1-2.
yn 1h, lc ra ta bng aceton n pH trung tnh. Sy kh 45-50oC. Tinh ch
bng ethanol 96%. Tc gi khng cng b hiu sut [6].
Nhn xt:
-

SOCl2 l ha cht c hi, phn hy mnh khi gp nc gy kh khn trong

thc hin phn ng, hiu sut thu c thp. Quy trnh tng hp phc tp.

Gi thnh t.
Qua vic tham kho cc ti liu trn chng ti thy c nhng nhc

im khi dng tc nhn acyl ha cloroacetyl clorid nn a ra tng dng mt

tc nhn mi l anhydrid acid hn tp lm tc nhn acyl ha [4].
- S :

S 1.9. Tng hp tc nhn anhydrid acd hn tp

- Quy trnh:
un hi lu hn hp acid monocloroacetic v anhydrid acetic (t l mol ln lt
l 1: 1,2) 138-140oC trong 3-4h. Sau khi phn ng xong ct quay 80oC loi
acid acetic, thu c dung dch mu vng nht .
u im:
- Quy trnh iu ch n gin.
- Tc nhn d iu ch, t gy c hi, gi thnh r.

16

CHNG 2: I TNG, NI DUNG V PHNG PHP

NGHIN CU
2.1. Dng c, ha cht v phng php nghin cu
2.1.1. Dng c, ha cht
Thc hin kha lun ny chng ti s dng mt s ha cht, dung mi v
thit b ca phng th nghim Tng hp ha dc B mn Cng nghip Dc.
Dng c:
Bng 2.1. Dng c c s dng trong kha lun
Stt

Tn thit b/ dng c

Xut s

B lc ht chn khng Buchner

Buchi Thy S

Cn k thut XB 320

Precisa Thy S

n soi UV sc k CN6

Vilber Lourmart c

My ct quay chn khng Buchi CH 9230

Buchi Thy S

Model: R-210; No 0700012009

6

My o pH Eutech Instrusments pH 510

Eutech M

My khuy t gia nhit Wisd Wise stir MSH Daihansci Hn Quc

20A

My to kh N2 Nitrox UHP N0751

Domnick Hunter Ltd- Anh

Model UHP N0751E SIN 9900774

9

T hotte Unilab
Model TH 1300

Jinan Unilab Instrusments.

Co. Ltd Trung Quc
Daihansci Hn Quc

10

T sy Wisd Wiseven Serial No:

0409300124T002

11

Bnh cu, bnh sc k, bnh 2 c, bnh 3 c, Lenz c

bnh nh mc 25 ml,pipet, cc c m, ng
nghim, a thy tinh.

17

Ph hng ngoi IR c ghi trn my Impact-410 Micolet ti Vin Ha hcVin Hn lm v Khoa hc Cng ngh vit Nam.

My o khi ph HP-5989-MS (ti Vin Ha hc- Vin Hn lm v Khoa hc

Cng ngh Vit Nam)

My o ph cng hng t Bruker 500MHz (ti Vin Ha hc- Vin Hn lm

v Khoa hc Cng ngh Vit Nam)

Ha cht:
Bng 2.2. Nguyn liu dung mi c s dng trong kha lun
Tn ha cht v thuc th

Ngun gc

Aceton

Trung Quc

Acid sulfuric c

Trung Quc

Anhydrid acetic

Merck- c

Diclomethan

Trung Quc

Diethylamin

Trung Quc

Ethanol 96%

Vit Nam

Kali carbonat

Trung Quc

Methanol

Trung Quc

Monocloro acetylclorid

Trung quc

Natri clorid

Trung Quc

Nc ct

Vit Nam

Paracetamol

Vit Nam

Tetrahydrofuran

Trung Quc

Triethylamin

Merck- c

2.1.2. Ni dung nghin cu

- Tng hp propacetamol theo cc giai on sau:
Giai on 1: Tng hp tc nhn acyl ha anhydrid acetic hn tp.

18

Giai on 2: Tng hp p-acetamidophenyl monocloroacetat (PAPC).

Giai on 3: Tng hp propacetamol base.

Giai on 4: Acid ha propacetamol base to mui v tinh ch sn phm.

- Kim tra tinh khit v xc nh cu trc cc cht tng hp c.

2.1.3. Phng php nghin cu
2.1.3.1. Tng hp ha hc v kim tra tinh khit
- S dng phng php tng hp ha hc, da trn cc phn ng:
Phn ng acyl ha to sn phm trung gian PAPC.
Phn ng alkyl ha to propacetamol dng base.
Acid ha to mui propacetamol hydroclorid.
- Dng TLC theo di tin trin ca phn ng.
- Kim tra tinh khit ca sn phm bng TLC v nhit nng chy.
2.1.3.2. Xc nh cu trc
- Cc cht tng hp c xc nh cu trc bng cc ph: Ph hng ngoi (IR),
ph khi (MS), ph cng hng t ht nhn proton (1H-NMR).
Ph hng ngoi (IR): c ghi ti Vin Ha hc- Vin Hn lm v Khoa hc
Cng ngh Vit Nam, trn my Impact- 410 Micolet vi k thut nn KBr trong
vng 4000- 400cm-1. Cc mu rn c phn tn trong KBr sy kh vi t l
khong 1: 2000 ri p di dng film mng di p lc cao c ht chn khng
lo b hi m.

19

Ph khi lng (MS): Ph khi lng ca cc cht c gh trn my o khi

ph 1100 series LC/MSD Trap Agilent ti Vin Ha hc- Vin Hn lm v Khoa
hc Cng ngh Vit Nam vi ch o LC-MS.
Ph cng hng t proton (1H-NMR): c ghi trn my o ph cng hng t
Bruker AV- 500MHz ti Vin Ha hc- Vin Hn lm v Khoa hc Cng ngh
Vit Nam dng DMSO lm dung mi, vi cht i chiu trimethylsilan (TMS)
[3].

20

CHNG 3: THC NGHIM, KT QU V BN LUN

3.1. Kt qu v thc nghim
3.1.1. Giai on 1
Tng hp tc nhn acyl ha: anhydrid acid hn tp.
-

S :

S 3.1. Tng hp tc nhn acyl ha anhydrid acid hn tp

-

Tin hnh:
un hi lu hn hp gm 10,0g acid monocloroacetic (0,11mol) v 12,0ml

anhydrid acetic (0,13mol) t l mol acid monoloroacetic: anhydrid acetic= 1:1,2

138-140oC trong 3-4h. Sau khi phn ng xong ngui v ct hn hp 80oC di
p sut gim cho ti khi th tch cn khong 20ml.
Kt qu:
- Thu c dung dch mu vng nht ca acetic monocloroacetic anhydrid.
3.1.2. Giai on 2
Tng hp p-acetamidophenyl monocloroacetat v kho st vi xc tc, dung
mi khc nhau.
-

Phng trnh phn ng.

S 3.2. Tng hp p-acetamidophenyl monocloroacetat

-

Tin hnh:
Ha tan 6,0g paracetamol (0,04mol) trong 10ml THF, thm 4,8ml pyridin (0,06

mol), khuy cho hn hp tan hon ton. Sau nh t t 20ml acetic

21

monocloroacetic anhydrid iu ch trn vo dung dch, ng thi lm lnh

0-5oC, kt hp khuy trong 4-5h. Hn hp khi phn ng xong c ct 80oC
loi bt THF, sau rt t t hn hp vo nc. Lc ta to thnh, ra ta bng
ethanol 96%. Sy 40-50oC.
Kt qu:
-

Thu c 5,0g PAPC.

Cm quan: Mu trng, ta bng, xp.

tonc: 183-185oC.

Hiu sut: 55,3%.

Rf = 0,56 (H dung mi khai trin diclomethan: methanol= 20: 1).

Hnh 3.1. Sc k lp mng paracetamol (tri) v PAPC (phi)

Nhn xt:
-

PAPC thu c sch, vt nh gn khng xut hin vt ca paracetamol, chng

t phn ng xy ra hon ton.

Sn phm gn nh khng cn tp ester ca acid acetic.

22

* Kho st nh hng ca t l s mol gia paracetamol v monocloroacetic.

Bng 3.1: Kho st t l mol gia paracetamol: acid monocloroacetic n hiu
sut
T l mol

Nhit

Hiu sut

1:2

0-5oC

40,20%

1:2,5

0-5oC

55,34%

1:3

0-5oC

55,06%

1:3,5

0-5oC

54,87%

paracetamol: monocloroacetic

60%

Hiu sut

50%
40%
30%
20%
10%
0%
1/2

1/2,5

1/3

1/3,5

T l mol

Hnh 3.2. Biu kho st t l mol pracetamol/acid monocloroacetic

Nhn xt:
Da vo biu ta nhn thy khi tng t l mol paracetamol/acid
monocloroacetic ln 1/2,5 th hiu sut tng ln r rt nhng khi tng ln 1/3 v
1/3,5 th hiu sut khng tng na thm ch cn gim. V vy l mol paracetamol:
acid monocloroacetic =1: 2,5 cho hiu sut thu c cao nht.

23

* Tin hnh kho st tng hp PAPC vi xc tc l K2CO3 v dung mi aceton

-

Phng trnh phn ng.

S 3.3. Quy trnh tng hp PAPC trong K2CO3/aceton

-

Tin hnh:
Ha tan hon ton 6,0g paracetamol (0,04mol) trong 60ml aceton sau thm

18g K2CO3, cho t t 20ml acetic monocloroacetic anhydrid iu ch trn vo

hn hp, lm lnh 0-5oC, khuy trong 4-5h. Kt thc phn ng, chm sc k
khng cn vt paracetamol, sau cho hn hp vo nc khuy u n khi K2CO3
tan ht, lc ra ta v tinh ch bng ethanol 96%.
Kt qu:
-

Thu c 3,18g PAPC th. Kt tinh li trong ethanol 96%.

tonc= 183-185oC.

Hiu sut: 35,2%.

Rf = 0,56.
Nhn xt: Vi xc tc K2CO3/aceton quy trnh phn ng d dng hn nhng thu

c hiu sut thp, to nhiu tp ester ca acid acetic.

* Tin hnh kho st tng hp PAPC vi xc tc dung dch NaOH 10%
-

Phng trnh phn ng.

S 3.4. Quy trnh tng hp PAPC trong NaOH 10%

-

Tin hnh:

24

Ha tan 6,0g paracetamol (0,04mol) bng dung dch 16ml NaOH 10%, lm lnh
5-10oC, sau nh t t 20ml acetic monocloroacetic anhydrid iu ch trn
vo hn hp, khuy u lun duy tr iu kin lnh. Dng dung dch NaOH 10%
iu chnh pH t 7-8, khuy lin tc trong 4-5h. Lc, ra ta bng nc lnh n
pH trung tnh, sy kh, tinh ch bng ethanol 96%.
Kt qu:
-

Thu c 2,11g PAPC th,

tonc= 183-185oC.

Hiu sut: 23,3%.

Rf = 0,56.
Nhn xt:
Phn ng thu c vi hiu sut thp c th do:

Paracetamol thy phn mt phn to ra 4-aminophenol.

Mi trng kim lm anhydrid b thy phn nhanh chng gy tn tc nhn v

phn ng khng hon ton.

25

Quy trnh tng hp PAPC c s ha nh sau:

Ha tan

Pyridin
THF
Paracetamol

Lm lnh
0-5oC

Ct loi
acid acetic

Acyl ha

Khuy 4-5h
Hi lu 138-140oC
3-4h
Rt t t
vo nc
Anhydrid acetic
Acid monocloroacetat
Nc ci

Lc

Nc ra

Ra ta

Ethanol 96%

Tinh ch

Ethanol 96%

PAPC

S 3.5. Quy trnh tng hp PAPC

26

3.1.3. Giai on 3
Tng hp propacetamol base.
Phng trnh phn ng

S 3.6. Tng hp propacetamol base

-

Tin hnh:
Ha tan 10,0g PAPC (0,044mol) vo 100ml aceton un hi lu nhit 45-

50oC, sau thm 15,1g K2CO3 khuy lin tc K2CO3 phn tn u, thm tip
0,5g KI, khuy trong 30 pht. Sau nh t t 11,75ml DEA (0,11mol) t l
PAPC: DEA= 1: 2,5 vo hn hp, sau khi nh xong tip tc khuy thm 2h nhit
50oC. Khi kt thc phn ng, ngui, lc thu ly dch, sau ct quay dch
60oC n kit loi aceton v DEA d, thu c propacetamol dng du mu nu
.
Kt qu:
-

Thu c 7,83g propacetamol th dng du.

Hiu sut: 67,5% (theo lng PAPC).

* Kho st nh hng ca t l s mol gia PAPC v DEA.

Bng 3.2. Kho st t l mol gia PAPC: DEA n hiu sut phn ng
Nhit

Hiu sut

1:2

45-50oC

60,20%

1:2,5

40-50oC

67,5%

1:3

45-50oC

67,34%

1:3,5

45-50oC

67,1%

T l mol PAPC: DEA

27

70%
68%

Hiu sut

66%
64%
62%
60%
58%
56%
1/2

1/2,5

1/3

1/3,5

T l mol

Hnh 3.3. Biu kho st t l mol PAPC/DEA

Nhn xt:
Da vo biu ta nhn thy khi tng t l mol PAPC/DEA ln 1/2,5 th
hiu sut tng ln r rt nhng khi tng ln 1/3 v 1/3,5 th hiu sut khng tng na
thm ch cn gim. V vy l mol PAPC: DEA =1: 2,5 cho hiu sut thu c cao
nht.
3.1.4. Giai on 4
Chuyn thnh dng mui propacetamol hydroclorid.
-

S :

S 3.7. Tng hp paracetamol hydroclorid

-

Bc mt: To HCl kh bng NaCl khan v H2SO4 c sau dn kh HCl ha

tan trong aceton lnh.
2NaCl(rn)

H2SO4(c)

Na2SO4

2HCl

Quy trnh: Nh t t 26,5ml H2SO4 (0,5mol) c vo 58,5g NaCl (1mol), kh

HCl sinh ra c dn vo mt bnh cu cha khong 150ml aceton c lm lnh.
-

Bc hai: To mui propacetamol hydroclorid.

28

Tin hnh: Hon tan hon ton 10g propacetamol base ( c tng hp giai
on 3) trong aceton, thm t t HCl/aceton vo khuy lin tc n khi pH=2 th
dng li tip tc khuy trong 30 pht cho phn ng hon ton, ra ta bng aceton,
sy kh 45-50oC.
Kt qu:
-

Thu c 8,26g propacetamol hydroclorid.

Cm quan: Mu vng nht.

tonc: 223-225oC,

Hiu sut: 72,4% (theo lng propacetamol base).

Rf= 0,22 (H dung mi khai trin diclomethan: methanol= 20:1).

Hnh 3.4. Sc k lp mng sn phm paracetamol (tri), PAPC (gia),

propacetamol hydroclorid (phi)

Quy trnh tng hp propacetamol hydroclorid t PAPC c s ha nh

sau:

29

Ha tan 40 C

PAPC
Aceton
K2CO3
KI

Khuy u
30 pht
Nh t t

DEA

Khuy u 2-3h
DEA
Aceton

Ct loi dung mi

Propacetamol
dng base

Ha tan
trong aceton

Acid ha to
mui

HCl/aceton

Lc, ra ta

Tinh ch

Methanol

Sn phm
S 3.8. Quy trnh tng hp propacetamol hydroclorid

30

3.2. Kim tra tinh khit

Chng ti kim tra tinh khit ca cc cht tng hp c bng sc k lp
mng v nhit nng chy nh sau:
-

TLC c tin hnh trn bn mng trng sn silicagel GF254 70-230 mesh, quan
st di n t ngoi bc sng 254nm.

Dung mi ha tan: ethanol 96%.

H dung mi khai trin: diclomethan: methanol (20: 1).

o nhit nng chy bng my o nhit nng chy EZ-Melt.

Gi tr Rf v nhit nng chy (tonc) ca cc cht c tm tt trong bng sau:
Bng 3.3. Rf v tonc ca paracetamol v cc cht tng hp c
Cht

Rf

tonc (oC)

Paracetamol

0,1

167-169oC

PAPC

0,56

183-185oC

0,22

223-225oC

Propaceamol
hydroclorid

Nhn xt:
-

Kt qu TLC trn c 2 h dung mi thu c 1 vt sn phm, gn, r di nh

sng n t ngoi bc sng 254nm, khng c vt l. Ring propacetamol l
tin cht nn khi ha tan trong dung mi ethanol 96% b thy phn mt phn
to propacetamol nn sc k c xut hin vt ca paracetamol.

Nhit nng chy ca cc cht dao ng khong hp t 2-4oC.

S b kt lun cc cht tng hp c l tinh khit.
Tin hnh o ph xc nh cu trc cc cht tng hp c.

3.3. Xc nh cu trc cc cht tng hp

3.3.1. Kt qu phn tch ph ca PAPC
a. Ph hng ngoi IR
Phn tch ph ca cc cht tng hp c, cho php chng ti nhn bit cc
di hp th c trng ca dao ng ha tr, dao ng bin dng ca cc nhm chc

31

v cc lin kt in hnh c trong cu trc phn t cc cht m chng ti tng hp

c nh: -CONH-; >CO; -CCl[3].
Bng 3.4. Kt qu phn tch ph hng ngoi ca PAPC
Cht

Cng thc

PAPC

max(cm-1)

Nhm

3272 v 3215

N-H (-CONH-)

3060

C=C (vng thm)

2961

C-H (-CH3)

2812

C-H (-CH2-)

1765

C=O (-COO-)

1665

C=O (-CONH-)

1554 v 1517

C-H (vng thm)

1208

C-O-C (ester)

717

C-Cl

Nhn xt: T kt qu trn cho thy s sng ph hp vi cc dao ng ca

cc nhm lin kt. Trong dao ng ca nhm NH l dao ng mnh.
b. Ph khi lng (MS)
Bng 3.5. Kt qu phn tch ph khi lng ca PAPC
Cht
PAPC
M=227,64

Cng thc cu to

m/z
225,9 [M-H]-

Nhn xt: T cc d liu liu phn tch ph bng trn v ph (ph lc 2)

u thy trong ph c pic phn t vi s khi ng bng khi lng phn t d
kin.

32

c. Ph cng hng t ht nhn (1H-NMR)

Bng 3.6. Kt qu phn tch ph cng hng t ht nhn ca PAPC
Cht

Cng thc cu to

S liu phn tch 1H-NMR

1

H-NMR (DMSO): (ppm)

2,04 (3H; s; CH3-CO-);

PAPC

4,66 (2H; s; -CH2CO-);

7,1 (2H; d; J=9; H2; H6);
7,66 (2H; d; J=9; H3; H5);
10,02 (1H; s; -NHCO-)

Ghi ch: : dch chuyn ha hc (ppm), s: singlet, d: doudlet, t: triplet, m:

multiplet, J: hng s tng tc spin- spin.
Nhn xt: Da vo kt qu phn tch ph bng 3.6 v cn c vo ph
(ph lc 1-4) chng ti nhn thy:
-

S lng proton, dch chuyn, bi ca tn hiu l ph hp vi cng thc

cu to ca PAPC.

Kt hp vi kt qu ph IR, ph MS c th khng nh cht chng ti tng hp

c c cng thc cu to nh d kin.

33

3.3.2. Kt qu phn tch ph ca propacetamol

a. Ph hng ngoi IR
Bng 3.7. Kt qu phn tch ph hng ngoi ca propacetamol hydroclorid
Cht

Cng thc cu to

max

Nhm

-1

(cm )
3235

N-H (-CONH-)

3130

C-H (vng thm)

2947

C-H (-CH3)

Propacetamol

2576

C-H (-CH2-)

hydroclorid

1767

C=O (-COO-)

1682

C=O (-CONH-)

1503

C=C (vng thm)

1196

C-O-C (ester)

Nhn xt: Da vo cc d liu liu phn tch ph bng trn v ph (ph

lc 5) s sng ng vi cc dao ng ca c nhm lin kt l ph hp.
b. Ph khi lng (MS) ca propacetamol base
Bng 3.8. Kt qu phn tch ph khi lng ca propacetamol base
Cht

Cng thc cu to

m/z

Propacetamol
base

263 [M-H]-

M=264,34
Nhn xt: T d liu bng trn c th nhn thy ph c pic phn t vi s
khi ng bng khi lng phn t tnh theo cng thc d kin.

34

Bng 3.9. Kt qu phn tch ph cng hng t ht nhn proton ca propacetamol

hydroclorid
Cht

Cng thc cu to

S liu phn tch 1H-NMR

1

H-NMR (DMSO): (ppm)

1,26 (6H; t; J= 7; 2CH3-CH2-);

2,05 (3H; s; CH3CO-);
Propacetamol
hydroclorid

3,26 (4H; m; J=5; 2-CH2-CH3);

4,45 (2H; s; -CH2-CO-);
7,16 (2H; d; J=9; H3; H5);
7,66 (2H; d; J=9; H2; H6);
10,2 (1H; s; -NH);
10,35 (1H; s; -NH+-);

Ghi ch: : dch chuyn ha hc (ppm), s: singlet, d: doudlet, t: triplet, m:

multiplet, J: hng s tng tc spin- spin.
Nhn xt: Da vo kt qu phn tch ph bng 3.9 v cn c vo ph
(ph lc 5-8) chng ti nhn thy:
S lng proton, dch chuyn, bi ca tn hiu l ph hp vi cng thc
cu to ca propacetamol hydroclorid. Trong do Cl- ca PAPC b th bng
diethylamin v to mui vi HCl nn ph xut hin thm pic: 1,26 (6H; t; J= 7;
2CH3-CH2-); 3,26 (4H; m; J=5; 2-CH2-CH3) v 10,35 (1H; s; -NH+-).
- Kt hp vi kt qu ph IR, ph MS c th khng nh cht chng ti tng hp
c c cng thc cu to nh d kin.

35

3.4. Bn lun
- Phn ng acyl ha to PAPC vi tc nhn anhydrid acid hn tp
Vi tc nhn l anhydrid hn tp th nhm acyl no hot ha mnh hn s th
vo phn t cn acyl ha.
Phn ng gia anhydrid acid hn tp v paracetamol, c ch phn ng xy ra nh
sau:

S 3.9. C ch phn ng acyl ha

Phn ng acyl ha xy ra thng theo c ch i in t. Nguyn t C ca nhm
acyl mang in tch dng nn l tc nhn i in t.
L hn hp ca anhydrid acetic v acid monocloroacetic nn phn ng s to ra
c tp ester ca acid acetic vi paracetamol v vy phn ng cho hiu sut tt v
to t tp nht th qua thc nghim chng ti nhn thy t l monocloroacetic:
anhydrid acetic l 1: 1,2 l tt nht.
Mt s yu t nh hng n hiu sut:
Xc tc cho phn ng acyl ha thng l cc base yu hoc c th l acid, qua
kho st chng ti nhn thy xc tc bng pyridin cho hiu sut tt. Nu dng
cc base mnh qu c th lm thy phn tc nhn acyl ha, nu dng tc nhn
base yu qu th phn ng xy ra c th s chm hiu sut khng c cao.
Qu trnh acyl ha bng tc nhn anhydrid acid yu hn so vi tc nhn
halogenid acid v vy khi nh xong tc nhn ta cn phi un nng nh, khuy
trong 4-5h cho paracetamol phn ng ht.

36

Cn phi ha tan ht paracetamol trong THF v pyridin th s thu c hiu sut

cao hn.
Sn phm thng c ln tp ester ca acid acetic qua th nghim chng ti nhn
thy tinh ch bng ethanol 96% s loi c tp ny.
Hn hp sau phn ng xut hin kt ta th c th lc ta sau tinh ch li
trong ethanol 96%, cn dch sau khi lc c th ct di p sut gim loi bt
THF sau rt t t vo nc, lc ta v tinh ch.
- Phn ng alkyl ha to propacetamol dng base
-

S phn ng:
Amin bc 3
Mui amoni
bc 4

S 3.10. Cc phn ng N-alkyl ha

Mt s yu t nh hng n hiu sut:
Xc tc bng K2CO3 v KI trong aceton qua kho st cho cho hiu sut cao, cn
dng t DEA v qu trnh thc hin phn ng n gin.
C ch ca xc tc KI nh sau:

S 3.11. C ch xc tc ca KI
Vi dung mi l aceton th cn phi ha tan ha ton PAPC 40-45oC do PAPC
t tan v trnh thy phn PAPC, sau mi cho thm K2CO3 v KI vo, khuy 30
pht KI hot ha cho phn ng.
Nhit phn ng khong: 45-50oC trnh thy phn PAPC.
Thi gian hi lu khong 2h l phn ng ht vi PAPC.
Sau phn ng cn ct quay dch di p sut gim loi ht aceton v DEA khi
acid ha khng c c tp mui clorid ca DEA.
- Qu trnh acid ha to propacetamol

37

Cn ha tan propacetamol trong aceton v dng HCl kh trong aceton lm

phn ng nh vy mi gim c s thy phn ca propacetamol trong HCl.
Qua trnh thc hin cn nh rt t t HCl kh/aceton vo dung dch propacetamol
gim s thy phn. Khi nh n pH=2 th dng v tip tc khuy trong 30
pht phn ng hon ton.
Qua qu trnh kho st chng ti nhn thy tinh ch bng methanol s loi c
bt tp paracetamol v 4-aminophenol.

38

KT LUN V XUT
- Kt lun
Trong qu trnh thc hin kha lun ny chng ti thu c mt s kt qu
nh sau:
1. Tng hp thnh cng propacetamol hydroclorid t paracetamol
Khng nh c cu trc ca cc cht trung gian v sn phm tng hp
bng phng php phn tch ph IR, MS, 1H-MNR.
nh gi s b tinh khit ca propacetamol bng TLC v o nhit
nng chy.
2. Kho st nh hng ca cc xc tc n hiu sut qu trnh phn ng.
Kho st nh hng ca K2CO3/aceton; dung dch NaOH 10% n hiu sut
tng hp PAPC.
Kho st nh hng ca t l mol n hiu sut tng hp ca PAPC v
propacetamol.
- xut
1. Nghin cu kho st thm cc yu t, ti u ha quy trnh lm tng hiu sut ca
qu trnh tng hp propacetamol.
2. Kim nghim propacetamol t BP 2010 v trin khai tng hp quy m pilot.

TI LIU THAM KHO

Ting Vit.

1.

Trn Mnh Bnh, Nguyn Quang t (2007), Ha hu c tp II, Nh

xut bn Y hc, H Ni, tr. 50,107.

2.

Trn c Hu (2007), Ha dc tp I, Nh xut bn y hc, H Ni, tr.

101-103.

3.

Nguyn Hu nh, Trn Th (1999), ng dng mt s phng php

ph nghin cu cu trc phn t, Nh xut bn gio dc, H Ni, tr.
27-351.

4.

T Minh Kong (2007), K thut sn xut dc phm tp I, Nh xut

bn Y hc, H Ni, tr. 49-62.

5.

Nguyn Hi Nam (2010), Nghin cu v pht trin thuc mi, Trng

i hc Dc H Ni-B mn ha Dc, H Ni, tr. 143-170.

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Trng Phng, Hunh Th Hi Vn, Trnh M Hong (2009),

"Nghin cu iu ch mt s dn cht ca paracetamol", Tp ch dc
hc - 9/2009, S 401, tr. 50-55.

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B Y T (2001), Vidal 2001, tr. 461-462.

8.

Phm Thip, V Ngc Thy (2004), Thuc bit dc & cch s dng,
Nh xut bn Y Hc, H Ni, tr. 783.

9.

Mai Tt T, V Th Trm (2007), Dc l hc tp II, Nh xut bn Y

Hc, H Ni, tr. 264-276.

Ting Anh.
10.

Barbaud A., Trechot P., Bertrand O., et al. (1995), "Occupational

allergy to propacetamol", Lancet, 346(8979), pp. 902.

11.

Berl V., Barbaud A., Lepoittevin J. P. (1998), "Mechanism of allergic

contact dermatitis from propacetamol: sensitization to activated N, Ndiethylglycine", Contact dermatitis, 38(4), pp. 185-188.

12.

British Pharmacopoeia (2009), British Pharmacopoeia volume II, pp.

1779.

13.

Cognacq J. C., P-acetamidophenyl diethylaminoacetate. 1978, United

States Patent US 4127671.

14.

Depr M., Hecken A., Verbesselt R., et al. (1992), "Tolerance and
pharmacokinetics of propacetamol, a paracetamol formulation for
intravenous use", Fundamental & clinical pharmacology, 6(6), pp. 259262.

15.

Friedel H. A., Langtry H. D., Buckley M. M. (1993), "Nabumetone",

Drugs, 45(1), pp. 131-156.

16.

Hersch M., Raveh D., Izbicki G. (2008), "Effect of intravenous

propacetamol on blood pressure in febrile critically ill patients",
Pharmacotherapy: The Journal of Human Pharmacology and Drug
Therapy, 28(10), pp. 1205-1210.

17.

Huttunen K. M., Rautio J. (2011), "Prodrugs-an efficient way to breach

delivery and targeting barriers", Current Topics in Medicinal
Chemistry, 11(18), pp. 2265-2287.

18.

Lei M. (2009), Synthesis of Amphibian Alkaloids and Development of

Acetaminophen Analogue, University of Science & Technology of
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19.

Martindale (2005), Matindale volume I, pp. 85.

20.

McNicol E. D., Tzortzopoulou A., Cepeda M. S., et al. (2011), "Singledose intravenous paracetamol or propacetamol for prevention or
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21.

Rollas S., Kkgzel Gniz (2008), "Hydrazone, amide, carbamate,

macromolecular and other prodrugs of Doxorubicin", The Open Drug
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22.

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amines", Molecules, 13(3), pp. 519-547.

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poor water solubility", Advanced drug delivery reviews, 59(7), pp. 677694.

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basic action to clinical utilization, Annales francaises d'anesthesie et de
reanimation,pp. 332.

Ting Trung.
26.

, , (2007), "",
pp. 75-76.

PH LC
Ph lc 1: Ph hng ngoi IR ca PAPC
Ph lc 2: Ph khi lng MS ca PAPC
Ph lc 3: Ph cng hng t proton 1H-NMR ca PAPC
Ph lc 4: Ph cng hng t proton 1H-NMR ca PAPC (m rng)
Ph lc 5: Ph hng ngoi IR ca propacetamol hydroclorid
Ph lc 6: Ph khi lng MS ca propacetamol base
Ph lc 7: Ph cng hng t proton 1H-NMR ca propacetamol hydroclorid
Ph lc 8: Ph cng hng t proton 1H-NMR ca propacetamol hydroclorid (m
rng)

Ph lc 1: Ph hng ngoi IR ca PAPC

M=227,64

Ph lc 2: Ph khi lng MS ca PAPC

Ph lc 3: Ph cng hng t proton 1H-NMR ca PAPC

Ph lc 4: Ph cng hng t proton 1H-NMR ca PAPC (m rng)

Ph lc 5: Ph hng ngoi IR ca propacetamol hydroclorid

M= 264,34

Ph lc 6: Ph khi lng MS ca propacetamol base

Ph lc 7: Ph cng hng t proton 1H-NMR ca propacetamol hydroclorid

Ph lc 8: Ph cng hng t proton 1H-NMR ca propacetamol hydroclorid (ph m rng)