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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)
1H-NMR : Ph cng hng t ht nhn proton (1H nuclear
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 32
Bng 3.7 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 6
Hnh 1.2 C ch tc dng ca levodopa 7
Hnh 1.3 Tin thuc to tc dng ko di ca ampicillin 8
Hnh 1.4 Tin thuc ca 6-mercaptopurin 8
Hnh 1.5 Tin thuc ca albendazol 9
Hnh 1.6 Tin thuc ca carbamazepin 9
Hnh 1.7 Tin thuc ca dexamethason 9
Hnh 1.8 Tin thuc ca paracetamol 9
Hnh 1.9 Tin thuc hectacillin ca ampicillin 9
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 3
S 1.2 S thy phn ca propacetamol bi esterase 4
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
1
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.
2
CHNG 1: TNG QUAN
1.1. Tng quan v propacetamol hydroclorid
1.1.1. Cng thc cu to, cng thc phn t
CTPT: C14 H21ClN2O3 KLPT: 300,8 vC
- 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].
3
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
Phc mu hng
4
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].
5
Chng ch nh
Tuyt i
- Mn cm vi propacetamol v cc thnh phn ca thuc, c bit l N,N-
diethylglycin 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)
6
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
7
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 L-
aminoacid thm decarboxylase.
- Levodopa c vn chuyn qua hng ro mu no nh h vn chuyn tch cc L-
aminoacid. 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.
H vn chuyn tch cc (Hng ro mu no)
L-aminoacid
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.
Ngoi vi
No L-aminoacid thm
decarboxylase no
L-aminoacid thm
decarboxylase ngoi vi
8
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
9
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 0-
5oC. 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 100-
106oC [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
1 B lc ht chn khng Buchner Buchi Thy S
2 Cn k thut XB 320 Precisa Thy S
4 n soi UV sc k CN6 Vilber Lourmart c
5 My ct quay chn khng Buchi CH 9230
Model: R-210; No 0700012009
Buchi Thy S
6 My o pH Eutech Instrusments pH 510 Eutech M
7 My khuy t gia nhit Wisd Wise stir MSH
20A
Daihansci Hn Quc
8 My to kh N2 Nitrox UHP N0751
Model UHP N0751E SIN 9900774
Domnick Hunter Ltd- Anh
9 T hotte Unilab
Model TH 1300
Jinan Unilab Instrusments.
Co. Ltd Trung Quc
10 T sy Wisd Wiseven Serial No:
0409300124T002
Daihansci Hn Quc
11 Bnh cu, bnh sc k, bnh 2 c, bnh 3 c,
bnh nh mc 25 ml,pipet, cc c m, ng
nghim, a thy tinh.
Lenz c
17
- Ph hng ngoi IR c ghi trn my Impact-410 Micolet ti Vin Ha hc-
Vin 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
paracetamol: monocloroacetic 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%
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.
0%
10%
20%
30%
40%
50%
60%
1/2 1/2,5 1/3 1/3,5
Hi
u s
ut
T l mol
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:
S 3.5. Quy trnh tng hp PAPC
Tinh ch Ethanol 96%
PAPC
Ra ta Ethanol 96% Nc ra
Hi lu 138-140oC
3-4h
Khuy 4-5h
Rt t t
vo nc
Lc Nc ci
Anhydrid acetic
Acid monocloroacetat
Ha tan
Lm lnh
0-5oC
Ct loi
acid acetic Acyl ha
Pyridin
THF
Paracetamol
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
T l mol PAPC: DEA 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%
27
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.
56%
58%
60%
62%
64%
66%
68%
70%
1/2 1/2,5 1/3 1/3,5
Hi
u s
ut
T l mol
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
S 3.8. Quy trnh tng hp propacetamol hydroclorid
Ha tan 40oC
PAPC
Aceton
K2CO3
KI
Khuy u
30 pht
Nh t t DEA
Khuy u 2-3h
Ct loi dung mi
Propacetamol
dng base
Ha tan
trong aceton
HCl/aceton Acid ha to
mui
Lc, ra ta
Tinh ch Methanol
Sn phm
DEA
Aceton
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 to
nc ca paracetamol v cc cht tng hp c
Cht Rf tonc (
oC)
Paracetamol 0,1 167-169oC
PAPC 0,56 183-185oC
Propaceamol
hydroclorid 0,22 223-225
oC
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 max(cm-1
) Nhm
PAPC
3272 v 3215
3060
2961
2812
1765
1665
1554 v 1517
1208
717
N-H (-CONH-)
C=C (vng thm)
C-H (-CH3)
C-H (-CH2-)
C=O (-COO-)
C=O (-CONH-)
C-H (vng thm)
C-O-C (ester)
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 Cng thc cu to m/z
PAPC
M=227,64
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
PAPC
1H-NMR (DMSO): (ppm)
2,04 (3H; s; CH3-CO-);
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
(cm-1
) Nhm
Propacetamol
hydroclorid
3235
3130
2947
2576
1767
1682
1503
1196
N-H (-CONH-)
C-H (vng thm)
C-H (-CH3)
C-H (-CH2-)
C=O (-COO-)
C=O (-CONH-)
C=C (vng thm)
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
M=264,34
263 [M-H]-
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
Propacetamol
hydroclorid
1H-NMR (DMSO): (ppm)
1,26 (6H; t; J= 7; 2CH3-CH2-);
2,05 (3H; s; CH3CO-);
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:
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
Amin bc 3
Mui amoni
bc 4
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.
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xut bn Y hc, H Ni, tr. 50,107.
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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.
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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.
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pharmacokinetics of propacetamol, a paracetamol formulation for
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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",
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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
China, China.
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20. McNicol E. D., Tzortzopoulou A., Cepeda M. S., et al. (2011), "Single-
dose intravenous paracetamol or propacetamol for prevention or
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macromolecular and other prodrugs of Doxorubicin", The Open Drug
Deliv J, 2, pp. 77-85.
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basic action to clinical utilization, Annales francaises d'anesthesie et de
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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
Ph lc 2: Ph khi lng MS ca PAPC
M=227,64
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
M= 264,34
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)