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.

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

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.

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

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

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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

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Ting Anh.

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pharmacokinetics of propacetamol, a paracetamol formulation for

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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)