M U Methadone l mt opioid tng hp, c s dng y t nh l mt thuc gim au v bo dng chng gy nghin s dng trong cc bnh nhn ph thuc opioid. N c pht trin c vo nm 1937.Mc d ha hc khng ging nh morphine hoc heroin, methadone hot ng trn cc th th opioid ging nh cc loi thuc ny, v do c nhiu tc dng tng t. Methadone cng c s dng trong qun l au mn tnh nghim trng, do thi gian di hot ng ca n, cc hiu ng cc k mnh m, v chi ph rt thp. Methadone c gii thiu vo Hoa K vo nm 1947 bi Eli Lilly v Cng ty. Methadone l hu ch trong vic iu tr ph thuc opioid. N c khoan dung vi cc opioid khc bao gm c heroin v morphine, cung cp hiu ng rt ging nhau v thi gian di hiu lc. Liu ung methadone c th n nh bnh nhn hi chng rt lui opioid gim nh. Liu cao hn ca methadone c th chn cc hiu ng phn khch ca heroin, morphine, v cc loi thuc tng t. Kt qu l, bnh nhn iu tr bng methadone ng liu c th gim bt hoc ngng hon ton vic s dng cc cht ny. Methadone c chp thun cho ch khc nhau cc quc gia khc nhau. Ph bin l thng qua nh l mt thuc gim au v ph duyt iu tr ph thuc opioid. N khng phi l gim vic s dng cc loi thuc khng gy nghin nh methamphetamine, hoc ru. Sau y chng ta s tm hiu v vic xy dng quy trnh cng ngh tng hp methadone.

Phn 1: TNG QUAN

1.1. Tn, tnh cht l, ha, tc dng dc l ca methadone. 1.1.1. Tn: Methadone c cng thc cu to:

Cng thc phn t : C21H27NO Khi lng phn t: 309.445gam/mol (RS)-6-(Dimethylamino)-4,4 diphenylheptan-3-one 3-Heptanone, 6-(dimethylamino)-4,4-diphenyl-, hydrochloride. 6-(Dimethylamino)-4,4-diphenyl-3--heptanone hydrochloride Methadone (cn c gi l Symoron, Dolophine, Amidone, Methadose, Physeptone, Heptadon, Phy v nhiu tn khc) l mt opioid tng hp, c s dng y t nh l mt thuc gim au v bo dng chng gy nghin s dng trong cc bnh nhn ph thuc opioid.

1.1.2.

Tnh cht vt l: Sinh kh dng: 40-90%( bng ming) Thi gian bn hy l 15-60h Dng mui: C21H27NO.HCl

Dng tinh th mu trng,c nhit nng chy l 235oC. Khi lng phn t: 345,91 gam/mol 20oC, trong nc c PKa l 8,25

1.1.3. Tnh cht ha hc

1.1.4. Tc dng dc l Cc tc dng ca Methadone bao gm: gim au, m du, c ch h hp v ph sng. Mc ph sng khi s dng Methadone bng ng ung t hn so vi tim chch Heroin. Cc tc dng khc bao gm: h huyt p, co ng t (thu hp ng t), gim ho v gii phng Histamin gy nga da. Cc tc ng ln h tiu ha bao gm: gim co bp d dy, gim nhu ng rut, tng co tht c trn mn v, tng co tht c Oddi, c th gy co tht ng mt. Tc ng trn h ni tit bao gm lm gim Hormon kch thch nang trng (FSH) v gim hormone kch thch hong th (LH), tng Prolactin, gim hormone kch thch thng thn (ACTH), gim testosterone, tng Hormon chng li niu (ADH). Cc chc nng ni tit c th tr li bnh thng sau 2-10 thng s dng Methadone. Cc tc dng ngoi ca iu tr Methadone ng ung bao gm: ri lon gic ng, nn v bun nn, to bn, kh ming, tng tit m hi, gin mch v nga, ri lon kinh nguyt ph n, chng v to nam gii, suy gim tnh dc bao c gm lit dng, gi nc v tng cn. Hu ht ngi s dng Heroin u xut hin mt s tc dng ngoi khi s dng methadone. Khi iu tr liu n nh, dung np tng dn cho n khi khi k nng nhn thc v kh nng ch khng cn b nh hng. Triu chng to bn, suy gim tnh dc, v i khi tng tit m hi c th vn tip tc gy kh chu cho bnh nhn trong sut qu trnh iu tr duy tr bng Methadone. Methadone c th tan trong m v gn vo cc m trong c th bao gm phi, gan, thn, lch, do , nng Methadone ti cc m ny cao hn hn nng Methadone trong mu. V vy, Methadone sau c vn chuyn chm t cc c quan ny vo trong mu. V Methadone s dng ng ung c sinh kh dng cao v thi gian bn hy di, c th s dng liu ung hng ngy iu tr. Methadone c chuyn ha ch yu ti gan qua h thng men Cytochrome P450. Khong 10% liu Methadone ung c o thi ra khi c th di dng khng i. Phn cn li c chuyn ha v cc sn phm chuyn ha (hu ht khng c tc ng) c thi tr qua nc tiu v phn. Methadone cng c bi tit qua m hi v nc bt. 1.1.5. Tiu chun dc in: Theo dc in Anh_ BP

Tng qut cng thc cu to v cng thc phn t :

Tc dng : gim au trn opioid. Tn quc t (IUPAC) :o (6R)-6-(Dimethylamino)-4,4-diphenylheptan-3-one hydrochloride. o C th tinh ch n 90-100% trng lung kh.

o

c tnho B ngoi : l dng tinh th trng hoc gn nh trng. o Tnh tan : tan trong nc v d tan trong cn.

Nhn bit :o o o o o o Th nht nhn bit A,C,D Th 2 nhn bit A,B,D C tnh cht xoay quang hc ( xem phn kim tra ). Nhit nng chy : 239-242 oC (2.2.14). Ph hng ngoi (2.2.24). Pha long 1 ml dung dch S ( xem phn kim tra ) n 5 ml vi nc R v thm 1 ml dung dch amoniac long. o R1. Trn u , cho php ng trong 5 pht v lc . Lc cho phn ng ( a) ca clorua (2.3.1).

Kim trao Dung dch S

o o

o o

Ho tan 2,50g trong nuc carbon dioxide R ( carbon dioxidefree water R) v pha long ti 50,0 ml vi cng mt loi dung mi. Hin tng xut hin Ho tan ht (2.2.1) v dung dch khng mu.(2.2.2,Method II). Tnh axit hoc kim Pha long 10ml dung dch S ti 25ml vi nuc carbon dioxideR ( carbon dioxide-free water R ). Mi 10ml dung dch trn cho thm 0.2 ml cht ch th metyl v 0.2 ml NaOH 0.01M. Dung dch chuyn sang mu vng. Thm 0.4 ml HCl 0,01M , dung dch chuyn sang mu . Tnh cht xoay quang ( 2.2.7) -125 n -135 ( cht kh ), xc nh dung dch S Lin quan ti vt cht ( Related substances ) Sc k lng (2.2.29) Dung dch th nghim : ho tan 25.0g cht kim tra vo pha ng v pha long ti 100 ml Dung dch chun (a) : pha long 1.0 ml dung dch th nghim ti 50 ml vi pha ng. Pha long 1.0 ml dung dch ti 10 ml vi pha ng. Dung dch chun (b) : ho tan 12.0 mg imipramine hyrochloride CRS vo pha ng v pha long n 10 ml.vi 1 ml dung dch cho thm 5 ml dung dch th nghim v pha long ti 10 ml vi pha ng. Ct : -kch c : di 0.125m, ng knh 4,6 mm; -pha tnh : octadecylsilyl silicagel for chromatography R (5m), -nhit : 25oC Pha pha ng : trn 35% th tch axetonitril P vi 65% th tch ca axit photphoric R ( c nng dung dch 11.5 g/l ), iu chnh pH n 3,6 vi dung dch tetraethylammonium hydroxide R. iu chnh tc chy 1.0 ml/pht.

o ph t ngoi ti 210nm. t c cn bng trong 30 pht. ( injection 10l ). Thi gian chy ct 7 ln nhiu hn so vi s lu gi ca levomethadone. Thi gian lu gi ca levomethadone khong 5 pht. (Run time 7 times the retention time of levomethadone Retention time Levomethadone = about 5 min. ) H thng ph hp vi dung dch chun (b) : - phn gii : ti thiu 2.5 gia 2 im ch th ca imipramine v levomethadone. Gii hn : -vi bt k tp cht no : khng nhiu hn mt na din tch nh cao chnh trong sc k thu c vi dung dch chun (a) (0.1%). -tng s : khng nhiu hn 2.5 ln din tch nh cao chnh trong sc k thu c vi dung dch chun (a) (0.5%). -b qua cc gii hn : 0.25 ln din tch nh cao chnh trong sc k thu c vi dung dch chun (a) ( 0.05%). Dextromethadone Sc k lng ( 2.2.29) Dung dch kim tra : ho tan 40.0 mg cht kim tra vo pha ng v pha long ti 100 ml . Dung dch chun : pha long 1.0 ml dung dch kim tra ti 10 ml vi pha ng. pha long 1.0 ml dung dch ti 20 ml vi pha ng. Ct chy : -kch thc : cao 0.25m, ng knh 4.6 mm; -pha tnh : 2-hydroxypropylbetadex for chromatography R (5 m); -nhit : 10oC

Pha ng : trn 1% th tch ca triethylamine R iu chnh pH 4.0 vi axit photphoric R, 15% th tch ca acetonitrieR v 85% th tch ca dung dch potassium ihdrogen photphat R ( nng 13.6 g/l). Tc chy : 0.7ml/pht. o ph t ngoi ti 210nm. Thi gian cn bng 30 pht. (Injection 10 l ). Thi gian lu : levomethadone : dextromethadone = khong 1:4 H thng ph hp vi dung dch kim tra : -s lng a l thuyt : ti thiu 2000, tnh ton vi nh cao chnh ca levomethadone. -yu t tailing : ti a 3 nh so vi levomethadone. Gii hn : -dextromethadone : khng qu din tch nh cao chnh trong sc k thu uc vi dung dch chun ( 0.5 %). Sy (2.2.32) ti a 0.5%, xc nh trn 1.000 g khi sy trong t sy ti 105oC Tro sunfat (2.4.14) ti a 0.1 % , xc nh trn 1.0 g.

Kho nghimo Ho tan 0.300 g trong hn hp ca 40ml nc R v 5ml axit axetic R. Chun vi bc nitrat 0.1M, xc nh im tng ng bng in cc bc. 1ml dung dch AgNO3 0.1M tng ng vi 34.59mk C21H28ClNO

D tr, bo qun :o Trnh nh sng

Tp cht :o Cc tp cht c bit A,B,C,D,E,F.

o R = H, R = CH3: (6S)-6-(dimethylamino)-4,4-diphenylheptan-3-one, D. R = CH3, R = H: (5RS)-6-(dimethylamino)-5-methyl-4,4diphenylhexan-3-one,

R = H, R = CH3: (4RS)-4-(dimethylamino)-2,2-diphenylpentanenitrile, C. R = CH3, R = H: (3RS)-4-(dimethylamino)-3-methyl-2,2-diphenylbutanenitrile 1.1.6. ng dng: Thuc thung uc s dng thay th cho cc cht dng thuc phin, dung trong iu tr cai nghin ma tu, ch nh cho cc bnh nhn l thuc cht dng thuc phin v nhng ngi s dng cc cht dng thuc phin thng xuyn v ko di. Tc dng khng mong mun ca thuc: Thuc c cc tc dng khng mong mun nh : h huyt p, co ng t, gy nga. cc tc dng ln ung tiu ho nh : gim co bp d dy, gim nhu ng rut, tng co tht c trn mn v Bn cnh c cc tc dng ph khc

nh : ri lon gic ng, bun nn v nn, to bn, kh ming, tng tit m hi,gin mch, nga, ri lon kinh nguyt ph n, chng v to nam gii, suy gim tnh dc ( bao gm c lit dung ), gi nuc v tng cn. Chng ch nh : khng dung cho nhng bnh nhn c tn thng chc nng gan, suy gan,cc bnh nhn suy h hp nng, hen cp tnh, ng c ru cp tnh, tn thng u, vin lot i trng, co tht ng mt cc bnh nhn mn cm vi bt c thnh phn no ca thuc .

1.1.7. Cc loi ph: Ph khi lng :

Ph IR:

Ph 1H-NRM - ph 13C-NRM

1.1.8. Gi thnh:

Unit description Methadone HCl 10mg/ml vial Methadone HCl powder Metadol 25mg Tablet Metadol 10mg Tablet Methadone intensol 10mg/ml Metadol 5mg Tablet Methadone HCl 10mg tablet Metadol Concentrate 10mg/ml liquid Methadone HCl 5mg tablet Dolophine HCl 10mg tablet Metadol 1mg Tablet Methadose 5mg tablet

Cost(USD) 7.48 5.91 1.69 0.9 0.85 0.56 0.37 0.37 0.34 0.21 0.17 0.16

Unit ml g Tablet Tablet ml Tablet Tablet ml Tablet Tablet Tablet Tablet

Methadose 10mg tablet Dolophine HCl 5mg tablet Metadol 1mg/ml solution http://www.drugbank.ca/drugs/DB00333

0.14 0.13 0.1

Tablet Tablet ml

1.2. Cc phng php tng hp methadone: 1.3. Quy trnh thc nghim tng hp methadone: 1.3.1. Thc nghim 1: 1 dung dch cha 3,77g 1-dimethyl amino-2-propanol (CH3CHOHCH2N(CH3)2 ) v 10ml CCl4 c lm lnh v khuy trn 0oC. 1 dung dch th 2 cha 5,72 g thionyl chloride ( SOCl2 ) v 2ml CCl4. Phn ng trn ln 2 dung dch trn c tin hnh nhit phng trong 30 pht v sau nhit phn ng c tng ln nh nc nng tun hon.Nhng cht khng tan th kt ta ra, 1-dimethyl amino-2-chloropanehydrochloride bt u kt tinh nhit si ca dung dch. Sn phm phn ng c lm lnh, dung mi ether dng lc v chit. sn phm thu c l 1-dimethyl amino-2chloropanehydrochloride c khi lng l 5,5g. sau tip tc cho kt tinh li th ta s thu c 1-dimethyl amino-2-chloropanehydrochloride tinh khit nng chy 192-193oC. Ly 2/10 g 1-dimethyl amino-2-chloropanehydrochloride ha tan vi 1,5ml dung dch NaOH 20%, lc u. 1-dimethyl amino-2chloropanehydrochloride tinh khit khng tan trong NaOH c tch ra. Ta em sn phm tch ra i lc v chit bng ether, sau sy kh loi ether ta thu c 0,8 g 1-dimethyl amino-2-chloropanehydrochloride. Nghin mn 1,36g NaOH rn v ha tan trong 10ml DMF, thm vo 6g phenylacetonitrile c ha tan trong 8ml DMF. Sau khi khuy trn 15 pht nhit phng th ngi ta cho 4,1 g 1-dimethyl amino-2chloropanehydrochloride. Tin hnh phn ng 50oC trong vng 1,5h. sau hn hp c lm lnh, tip theo l c pha long bng nc. Hn hp c cha 2,2 diphenyl-4- dimethyl aminovaleronitrile v 2,2 diphenyl-3methyl-4-dimethyl aminobutylroniytole c hnh hnh thnh phn ng trn. em chit 350ml hn hp trn bng ether sau loi b dung mi ta thu c 7,83g hn hp sn phm. Cho chy sc k ta xc nh c hn

hp gm c 58,4% l 2,2 diphenyl-4- dimethyl aminovaleronitrile v 29,3% l ca 2,2 diphenyl-3-methyl-4-dimethyl aminobutylroniytole, 10,8% l ca diphenyl acetonitrile. T l methadone v iso methadone c trnh by theo phng php trn l 66,5 : 33,5. Tc nhn phn ng C2H5MgBr, sau c thy phn trong mi trng axit 1.3.2. Thc nghim 2: 1.3.3. Thc nghim 3:

Phn 2: QUY TRNH CNG NGH2.1. S phn ng:

2.2. S khi :

CH3CHOHCH2N(CH3)2+CCl4 Thit b phn ng

SOCl2+CCl4

ete NaOH20% lm schChit

Loi nc Loi ete

NaOHr+(CH5)2CHCN 6 sp kt tinh DMF Thit b phn ng

c c

lm lnh Loi nc

ete

Chit

C 2 H 5 MgBr H 2 O/H+

c c

Lai ete

Thit b phn ng

HCl

axit ha

Kt tinh

Lc ly tm

Sy thu sp Methadone2.4. S quy trnh cng ngh:

2.42.Quy trnh tng hp Methadonehoi th? NaOHr

hoi th?

9

(C 6H 5) 2 CHCN

C 2 H 5 MgBr + H 2 O/H+

SOCl

2 +CCl 4DMF

nu?c r?a

nu?c r?a

lo?i b?

2hoi hoi

6

nng

2ete

nng

6

4Nu?c ngung Nu?c ngungkh ra hoi nng Nu?c ngung kh vo

3

lo?i hoi nng Nu?c

3

7hoi th?

ngung

10

nu?c

5nu?c l?nh

nng

ete

4nu?c nng nu?c l?nh

lo?i ete hoi nng nu?c ngung ete

5 4nu?c nng nu?c l?nh

NaOH 20%

hoi nng nu?c ngung ete

lo?i

1

5

HCl

hoi nng

1 8

nu?c ngung

5

Chung don gi?n Thi?t b? chi?t Thi?t b? k?t tinh Thi?t b? ph?n ?ng 1 v? Thng ch?a Tn thi?t b? Nhm 3Th.s Nguy?n Th? Thy M?

2 3 2 2 6

10 9 8 7 6

Thi?t b? s?y L?c ly tm Thi?t b? axit ha Thi?t b? lm l?nh Thi?t b? ph?n ?ng 2 v? Tn thi?t b? QUY TRNH T?NG H?P METHADONEB?N V? SO ? DY CHUY?N T?NG H?P METHADONE

1 1 1 1 2 S?.lg

CH 3 CHOHCH +CCl

2 N(CH 3 ) 2 4

4 3

1 1

1 1

2 1 STT SVTH GVHDB? mn

S?.lg STT

Cng ngh? h?u co Ha

T? l?Hon thnh

du?c v Ha ch?t b?o v? th?c v?t