You are on page 1of 118

i hc Bch Khoa H Ni MC LC

n tt nghip 2009

MT S K HIU VIT TT.....................................................................3 ng dng ca thalidomide.......................................................................13 Tc dng dc l ca thalidomide [18]....................................................13 Mi quan h gia c tnh gy qui thai v cc ng phn R,S ca thalidomide................................................................................................18 2.GI HOT CHT V THNH PHM THALIDOMIDE....................21 Gi hot cht thalidomide [25].................................................................21 2.1.Gi thnh phm thalidomide (vin nang)............................................23 Gi thnh phm thalidomide (vin nang) trn th trng th gii............23 2.2.2. Gi thnh phm thalidomide (vin nang) c bn trn th trng Vit Nam 24 CC PHNG PHP TNG HP THALIDOMIDE..............................25 Tng hp racemic thalidomide................................................................25 Phng php tng hp lp th S-(-)thalidomide [36]...............................29 QUY TRNH CNG NGH........................................................................30 Tng hp racemic.....................................................................................30 Tng hp lp th [36]................................................................................35 QUY TRNH LA CHN..........................................................................37 S phn ng........................................................................................38 38 5.2. Tm tt quy trnh ...............................................................................38 Tnh cht cc nguyn liu ch yu s dng trong quy trnh....................38 Phng php khc iu ch hp cht trung gian N-phthaloyl-DL-glutamic anhydride (2) [42] ....................................................................................47 L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

PHN 2. THC NGHIM V KT QU.................................................49 NGUYN VT LIU V DNG C........................................................49 Nguyn vt liu.........................................................................................49 Dng c.....................................................................................................49 Dung mi chy sc k...............................................................................50 TNG HP THALIDOMIDE.....................................................................50 iu ch N-phthaloyl-DL-glutamic anhydride (2) [26]............................50 iu ch thalidomide................................................................................53 KT QU V BN LUN..........................................................................69 V TNG HP HA HC........................................................................69 V iu ch N-phthaloyl-DL-glutamic anhydride (2)...............................69 V iu ch thalidomide 1.......................................................................73 V XC NH CU TRC CA CC CHT TNG HP [44], [45], [46], [47], [48]..............................................................................................76 V ph hng ngoi IR [44], [45], [46], [47]............................................76 V ph khi MS [47], [48].......................................................................78 V ph cng hng t ht nhn 1H-NMR [44], [46]...............................80 V ph cng hng t ht nhn 13C-NMR v DEPT [44], [46].............81 KT LUN....................................................................................................83 TI LIU THAM KHO............................................................................84 PH LC.......................................................................................................85

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni LI CM N

n tt nghip 2009

c th hon thnh n tt nghip ng thi hn, t c nhng mc tiu ra, trong ba thng va qua, em nhn c s gip tn tm t cc thy c, bn b trong v ngoi trng i hc Bch Khoa H Ni. Nhn dp ny, em xin by t lng bit n ti: GS.TSKH Phan nh Chu, ngi thy thng xuyn ng vin, to mi iu kin cho em thc hin ti ny. Thy tn tnh hng dn em c v mt l thuyt ln k thut thc nghim. Cc thy c gio trong B mn Cng ngh Ha Dc & Ha cht bo v thc vt Khoa Cng ngh Ha hc Trng i hc Bch Khoa H Ni truyn t kin thc qu bu trong sut thi gian em hc tp trong trng. Nhng kin thc m em hc c t cc thy c l yu t quan trng gip em thc hin tt nhim v ca n tt nghip. Cc cn b phng Nghin cu cu trc Vin Ha hc Vin Khoa hc v Cng ngh Vit Nam gip em o ph 1H-NMR, 13C-NMR, DEPT v MS ca cc hp cht iu ch c. ThS.DS. V Bnh Dng GTrung tm Nghin cu, sn xut, ng dng thuc th nghim Hc vin Qun Y v cc cn b Phng Dc hc v cc hp cht t nhin Trung tm nghin cu ng dng Sinh Y Dc hc Hc vin Qun Y gip em o ph IR ca cc hp cht iu ch c. DS. o Vn n - Phng Dc hc v cc hp cht t nhin Trung tm nghin cu ng dng Sinh Y Dc hc Hc vin Qun Y tn tnh hng dn v h tr ti liu cho em tm hiu s dng phn mm MODDE v INForm trong ti u ha v quy hoch thc nghim. Cui cng, em xin by t lng bit n su sc ti gia nh, bn b quan tm, gip , to iu kin em c th tp trung hon thnh n ng hn, thu c kt qu mong mun. H Ni, thng 6 nm 2009 Sinh vin L S Tng

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni T VN

n tt nghip 2009

Thalidomide nguyn th l mt thuc an thn gy ng c hng dc phm Chemie Grunenthal ca c tm ra, v a vo s dng trong nm 1957. Trong vng 4 nm t 1957 n 1961 tung ra th trng vi gn 70 bit dc khc nhau trong c cc bit dc ni ting nh Contergan, Neurosedyn, Pantosediv T nm 1958 n 1961 thalidomide l mt trong nhng thuc an thn gy ng bn chy nht hi by gi, do thuc c cng hiu cao li c c tnh rt thp so vi cc thuc an thn gy ng khc lc . Nhng vo nm 1961 ti Khoa nhi bnh vin Hamburg, hai nh dc l Lenz v Taussig pht hin ra hin tng pht trin chn tay khng bnh thng tr s sinh, m trong thi k mang thai cc b m c s dng thalidomide. Ngay lp tc sau pht hin , tt c cc bit dc c cha thalidomide b cm s dng tt c cc nc. Sau s c tai ting ny, thalidomide tng chng b qun lng, th nhng k t nhiu cng trnh nghin cu v hot cht ny vn khng ngng c tip tc, nhiu tc dng cha bnh mi cng nh nghi vn v c tnh ca thalidomide ln lt c nghin cu v khm ph. Sau gn 30 nm dy cng nghin cu k t khi b cm, ngi ta pht hin ra nhiu tc dng cha bnh v cng qu bu khc ca hp cht y tai ting ny trong vic iu tr mt s bnh him ngho, v a thalidomide vo s dng lm sng. C th ni rng thalidomide l mt trong nhng hp cht tai ting nht cho ngnh ho dc t trc n nay, nhng cng l mt trong nhng hp cht c s cng trnh nghin cu nhiu nht (theo thng k nm 2006 th t nm 1957 n 2006 c trn 7000 cng trnh khoa hc cng b lin quan n hp cht ny, ring nm 2005 v 2006 mi nm cng b trn 700 cng trnh). Mt s cc ch nh s dng thalidomide, nh vic iu tr cc bnh ri lon min dch, l tc nhn thch ng min dch, s dng trong cc bnh do nhim HIV/AIDS , trong vic iu tr a khp dng cp, trong iu tr ban nt do phong (ENL), hay iu tr ri lon thn kinh v nhn thc, kim sot nng TNF- khng bnh thng trong m ngi, iu tr cc khi u c tnh, ung th a ty xngThalidomide c T chc qun l Thuc v Thc phm L S Tng Lp CN Ha Dc v HC BVTV K49 1

i hc Bch Khoa H Ni

n tt nghip 2009

M (FDA) cho php lu hnh vi bit dc Thalomid (Celgene). nc ta nhu cu v thuc thalidomide trong iu tr bnh l kh ln, rt nhiu bnh nhn rt cn thuc ny nhng Vit Nam cha sn xut c nn bnh nhn c nhu cu iu tr phi t gi mua t nc ngoi (M, Canada, i Loan) vi gi thnh kh t. Gn y, cng ty dc phm Nanopharm ti H Ni bt u cho bn thalidomide dng vin nn (nhp khu t i Loan) nhng gi thnh vn cn kh t so vi thu nhp ca ngi dn Vit Nam. Chnh v vy trong phm vi n tt nghip em c giao nhim v Nghin cu quy trnh tng hp thalidomide. n ca em gm 3 phn chnh: Phn 1:Tng quan Thu thp cc thng tin v thalidomide, tnh cht l ho hc, tc dng dc l ca thalidomide, cc phng php tng hp thalidomide c cng b v nhng thng tin khc v thalidomide. Phn 2: Thc nghim v kt qu. Tng hp N-phthaloyl-DL-glutamic anhydride lm nguyn liu iu ch thalidomide. Tng hp thalidomide. Ti u ha v quy hoch thc nghim quy trnh tng hp thalidomide vi s gip ca cc phn mm MODDE 5.0 v INForm 3.1. Phn 3: Kt qu v bn lun. V cui cng l kt lun.

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

MT S K HIU VIT TT

Ac BOC CDI DCM 4-DMAP DMF EDC ENL Et Me HOBT Ph TFA THF TNF- TLC

Acetyl Tert-butoxycarbonyl Carbonyl diimidazole Dichloro methane CH2Cl2 4-dimethylamino pyridine Dimethylformamide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Erythema Nodosum Leprosum (ban nt do phong Ethyl Methyl Hydroxybenzotriazole Pheynyl Acid trifloroacetic Tetrahydrofuran Tumor necrosis factor- (nhn t hoi t u bu) Thin layer chromatography (sc k lp mng)

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

PHN 1. TNG QUAN V THALIDOMIDE


1. 1.1. -

TN, TNH CHT L HA V TC DNG DC L Tn, cng thc [1] Tn ring: thalidomide.

Tn khoa hc (theo danh php IUPAC): (2,6-Dioxo-3piperidinyl)-1H-isoindole-1,3(2H)-dione (1). Tn gi khc: N-(2,6-dioxo-3-piperidyl)phthalimide; phthalimidoglutarimide; 3-phthalimidoglutarimide; 2,6-dioxo-3phthalimidopiperidine; N-phthalylglutamic acid imide; Nphthaloylglutamimide.
-

Cng thc phn t: C13H10N2O4. Khi lng phn t: 258.23 g/mol.

Thnh phn phn trm cc nguyn t: C 60.47%, H 3.90%, N 10.85%, O 24.78%. Cng thc cu to:
O

N NH O O

Thalidomide (1) (-(2,6-Dioxo-3-piperidinyl)-1H-isoindole1,3(2H)-dione)


-

Cc bit dc [2]
t nc lu hnh Ba Lan, Thy S, Ty c Italy Angola, c, Ghana, Anh, Guinea, New Zealand, Ty Phi Nht Bn

STT Tn bit dc 1 Algosediv 2 Asmadion 3 Asmaval 4 Bonbrain

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni
Calmorex Contergan Contergan Forte Contergan Saft Contergan9 Suppositorium 10 Corona-Robetinf 11 Distaval 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Distaval Forte Ectiluran Enterosediv Gastrinide Glutanon Grippex Imida-Lab Imidan Imidene Imidene ipnotico Isomin Kevadon Lulanin NeoNibrol (New Nibrol) Neosedyn Nerufatin Neurosedyn Nevrodyn Noctimid Noctosediv Noxodyn Noxosedyn Ondasil Pantosediv Peracon Peracon-Expectorans Poli-Gripan Prednisediv Proban-M 5 6 7 8 Italy Ba Lan, Ty c Ty c Ty c Ty c

n tt nghip 2009

Italy Angola, c, Ghana, Anh, Guinea, New Zealand, Ba Lan, Ty Phi Anh Brazil B, Phn Lan, Ireland, H Lan, Ba Lan, Thy S Italy Nht Bn Ty c Ba Lan Ty Ban Nha Italy Italy Nht Bn Canada, Ba Lan, M Denmark Nht Bn Denmark Nht Bn Na Uy, Thy in Na Uy B Phn Lan, Ireland, H Lan, Ba Lan, Thy S Thy in Thy in Brazil Ty c Phn Lan Ty c Hong Kong, Ireland, Malaysia, Pakistan Phn Lan, Ireland, Ty c Nht Bn

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni
41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 Profarmil Quetimid Quietoplex Sanodormin Sedalis Sedi-Lab Sedimide Sedin Sediserpil Sedoval K-17 Shin-Naito-S Shin Nibrol Sleepan Slip Softenil

n tt nghip 2009

56 Softenon 57 58 59 60 61 62 63 64 65 66 67 68
1.2.

Softenon Forte Talargan Talimol Tensival Thalin Thalinette Theophyl-Choline Ulcerfen Valgis Valgraine Valip Verdil

Italy Italy Italy Nht Bn Brazil Ba Lan Italy Brazil Italy Italy Nht Bn Nht Bn Nht Bn Brazil Argentina, Peru Austria, B, Cyprus, Phn Lan, Ireland, Malta, H Lan, Ba Lan, Ty Ban Nha, Thy S, Ty c Ty c Mexico Canada Angola, c, Ghana, Anh, Guinea, New Zealand, Ty Phi Israel Israel Italy Italy Angola, c, Ghana. Anh, Guinea, New Zealand, Ty Phi c, Ghana, Anh, Guinea, New Zealand, Ty Phi Italy Brazil

Tnh cht vt l [1]

- Tinh th hnh kim, c mu trng hay trng xm, khng mi.


-

Nhit nng chy: 269-2710C.

- Hp th UV cc i ti cc bc sng: 220 nm, 300 nm. tan: Tan t trong nc: ~2.10-4 mol/L; 45-60 mg/L. Tan t trong methanol, ethanol, acetone, ethyl acetate, butyl acetate, axit acetic bng. Tan
-

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

tt trong dioxane, DMF, pyridine. Khng tan trong ether, chloroform, benzene.
1.3.

Nhit nng chy: 269-271C. Cc d liu ph [3] Ph IR (KBr): 3194 (N H); 1778, 1707 (C = O imide) cm-1.

Ph 1H NMR (300 MHz, DMSO-d6): = 11,00 (s, 1H, NH); 8,037,78 (br s, 4H, Ar, 2H); 5,15 (dd, J= 12,8; 5,4 Hz, 1H, CHCO); 2,89-2,72 (m, 1HA, CH2CO), 2,69-2,47 (m, 2H, CH2CH2), 2,13-2,01 (m, 1HB, CH2CO). Ph 13C NMR (DMSO-d6): 4 nguyn t carbon ca 4 nhm carbonyl ti cc v tr c =173,2; 170,2; 167,6; su nguyn t carbon ca vng benzene c = 135,3; 131,7; 123,8; ba nguyn t carbon cn li ca vng piperidinedione cng hng ti 49,5 (C-1); 31,4 (C-5); v 22,5 (C-6). Ph khi (MS): m/z 259 (M++1, 50), 154 (100), 136 (75), 120 (16), v 107 (27).
1.4.

Cc ph thalidomide

- Ph khi MS [4]:
1 0 0 7 6 1 0 4 1 1 1 5 0 5 0 6 6 3 9 6 37 0 8 3 1 3 0 1 4 8 1 6 9 O 1 6 0 1 8 6 2 0 2 2 1 3 O 2 3 0 2 5 8 1 7 3 O

N NH

2 8 0 ( m 1 4

9 0

1 1 7

1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 1 1 1 2 1 3 0 4 1 5 0 6 1 7 0 8 0 9 2 0 2 1 2 2 0 3 2 4 2 5 0 6 0 7 0 0 0 0 1 0 1 0 1 1 0 0 0 2 0 0 2 2 a in lib ) T h a lid o m id e

- Ph cng hng t ht nhn 1H-NMR [5]

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

10

PPM

- Ph cng hng t ht nhn 13C-NMR [6]

180

160

140

120

100 PPM

80

60

40

20

Ph hng ngoi IR [7]:

Trng thi: rn (vin KBr) My o: PERKIN-ELMER 21 (GRATING)

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

1.5.

Tiu chun dc in [8]

Cng thc phn t: C13H10N2O4 Phn t lng: 258.23 Thalidomide cha t nht 98.0% v ti a 101.5% C13H10N2O4 tnh ton da trn sn phm lm khan. ng gi v bo qun: Bo qun trong l kn, trnh nh sng, nhit phng. Thalidomide chun <11>: USP thalidomide RS. Nhn bit <197K>: Hp th hng ngoi. Gii hn vi khun <61>: t tiu chun cho php. Hm lng nc, theo phng php Ic <921>: Khng qu 0,5%. Dung mi: DMSO (dimethyl sulfoxide) khan nc. Kim loi nng, xc nh theo phng php II <231>: 0.002%. tinh khit trn sc k: H dung mi A: Nc : acetonitrile : phosphoric acid = 95 : 5 : 0.1 (cc dung mi c lc v kh kh tp). H dung mi B: Nc : acetonitrile : phosphoric acid = 85 : 15 : 0.1 (cc dung mi c lc v kh kh tp). L S Tng Lp CN Ha Dc v HC BVTV K49 9

i hc Bch Khoa H Ni

n tt nghip 2009

H dung mi pha long: Nc : acetonitrile : phosphoric acid = 50 : 50 : 0.1. Pha ng: S dng hn hp h dung mi A, B theo cc t l khc nhau. iu chnh nu cn thit (xem System Suitability trong Chromatography <621>). Dung dch phthalic acid d tr (Phthalic acid stock solution): Cho 100 mg phthalic acid vo bnh nh mc dung tch 100 ml, sau ha tan bng h dung mi acetonitrile: nc (85:5), thm acetonitrile ti vch nh mc. Trn v ha tan nh lng vi acetonitrile thu c dung dch c nng 0.1 mg/ml (ha tan tng bc nu cn thit). Dung dch chun d tr (Standard stock solution): Ha tan nh lng USP thalidomide RS trong acetonitrile vi my siu m, thu c dung dch c nng 1 mg/ml. Dung dch chun: Dng pipet ly 2.0 ml dung dch chun d tr v 2.0 ml dung dch phthalic acid d tr, cho v bnh nh mc dung tch 100 ml, sau thm h dung mi pha long ti vch nh mc. Dng pipet ly 10.0 ml dung dch va pha cho vo bnh nh mc dung tch 100 ml, thm 10.0 ml dung dch phosphoric acid 1%, cho nc ti vch nh mc v lc u. H sc k (xem Chromatography <621>): Sc k lng thc hin trn ct kch thc 3.9 mm x 15 cm, s dng loi ht L1 kch thc 4 m, detector 218 nm. Tc pha ng l 2 ml/pht. Thc hin sc k nh sau: Chy sc k i vi dung dch chun v ghi li cc peak theo trnh t: thi gian lu tng i l 0.35 i vi phthalic acid v khong 1.0 i vi thalidomide; thi gian khng lu (tailing factor) i vi cc phthalic acid v thalidomide khng qu 2.0; sai s chun tng i c xc nh theo peak ca phthalic acid vi cc ln lp li khng qu 2.0%. Thi gian (pht) 0 0 15 H dung mi A (%) 100 100 50 H dung mi B (%) 0 0 50 Phng php ra gii Cn bng Gradien tuyn 10

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009 tnh

15 20 20 30

50 100 100

50 0 0

Gradien tuyn tnh ng thnh phn

Trnh t: Ln lt chy h sc k vi mt lng khng i dung dch chun v dung dch th (khong 200 l), ghi li sc k v o din tch cc peak. Tnh phn trm ca tp cht trong thalidomide theo cng thc: 50 000(Cp/W) (ri/rp) Trong , Cp l nng (mg/ml) ca ca phthalic acid trong dung dch chun; W l lng thalidomide trong dung dch th; ri l phn peak tng ng vi lng tp cht trong dung dch th; v rp l phn peak tng ng ca phthalic acid trong dung dch chun: hm lng mi tp cht khng qu 0.1% v tng hm lng cc tp khng qu 0.3%. Tp cht thng thng <466>: Dung dch th: Ha tan chnh xc mt lng thalidomide trong acetonitrile thu c dung dch c nng khong 2 mg/ml. Dung dch chun: Ha tan chnh xc mt lng glutamine trong h dung mi acetonitrile : nc (1:1) thu c dung dch c nng khong 0.1 mg/ml. Cht ra gii: h dung mi methylene chloride (CH2Cl2) : methanol : acetic acid (75:25:0.05). Th tch p dng: 2 l (dung dch chun) v 100 l (dung dch th). trc quan (visualization): 4. Gii hn: 0.1%. Tp cht hu c d bay hi, phng php I <467>: t cc tiu chun cho php. (theo quy nh c hiu lc ti 1/7/2007) Th nghim: L S Tng Lp CN Ha Dc v HC BVTV K49 11

i hc Bch Khoa H Ni

n tt nghip 2009

Pha ng: H dung mi nc : acetonitrile : phosphoric acid (85:15:0.1), iu chnh nu cn thit (xem System Suitability trong Chromatography <621>). Dung dch ni chun: Ha tan chnh xc 150 mg phenacetin trong 80 ml acetonitrile trong bnh nh mc dung lng 100 ml, thm acetonitrile ti vch nh mc v lc u. Dung dch chun: Ha tan chnh xc mt lng USP thalidomide RS trong acetonitrile vi s h tr ca my siu m, thu c dung dch c nng 1 mg/ml. Ly 10.0 ml dung dch va pha, cng vi 5.0 ml ca dung dch ni chun vo bnh nh mc dung tch 100 ml, sau thm 10.0 ml phosphoric acid 1%. Thm nc ti vch nh mc v lc u. Dung dch chun b th nghim: Ha tan chnh xc 100 mg thalidomide trong 80 ml acetonitrile bng my siu m. Thm acetonitrile ti vch nh mc v lc u. Dng pipet ly 10.0 ml dung dch va pha, 5.0 ml dung dch ni chun vo bnh nh mc 100 ml, thm 10.0 ml phosphoric acide 1%, sau thm nc ti vch nh mc v lc u. H sc k (xem Chromatography <621>): sc k lng c trang b detector 237 nm, s dng ct c kch thc 3.9 nm x 15 cm, s dng loi ht L1 c kch thc 4 m. Tc ra gii khong 1.0 ml/pht. Chy sc k vi dung mi chun, ghi li cc peak tng ng theo Trnh t: phn tch R gia thalidomide v phenacetin t nht l 3.0; hiu qu phn tch c xc nh bng cc peak ca thalidomide v phenacetin ln lt khng c t hn 7000 v 9000 a l thuyt; thi gian khng lu khng qu 2.0; sai s chun tng i qua cc ln lp li khng qu 1.0%. Trnh t: mi ln chy sc k vi 20 l khng i dung mi chun v dung mi chun b th nghim, ghi li sc k , tnh din tch peak chnh. Tnh lng C13H10N2O4 trong thalidomide theo cng thc sau: 1000C(Ru/Rs)

L S Tng Lp CN Ha Dc v HC BVTV K49 12

i hc Bch Khoa H Ni

n tt nghip 2009

Trong , C l nng (mg/ml) ca USP thalidomide RS trong dung dch chun; Ru v Rs l t l din tch cc peak thu c tng ng vi dung dch chun b th nghim v dung dch chun. ng dng ca thalidomide L nguyn liu lm thuc an thn gy ng v iu tr cc bnh nh ban nt do phong (ENL)[9]; hi chng Behcets[10]; cc bnh ower bnh nhn nhim HIV/AIDS [11], [12] nh: suy mn, Kaposis Sarcoma, bnh Crohns, tiu chy, lot; bnh u a ty [13]; u sc t [14]; vim khp dng thp [15], [16]; cc bnh ung th lin quan n to mch [17]. Tc dng dc l ca thalidomide [18] Tc dng: n nay c ch tc dng c thalidomide vn cha c lm sng t. Thalidomide c nhng tnh cht iu chnh min dch, chng vim, ngn cn s to mch. Cc nghin cu trong ng nghim v th nghim lm sng cho thy tc ng min dch ca hp cht ny khc nhau di cc iu kin khc nhau, nhng c th lin quan ti phong b cht chn lc tin vim cytokine TNF- hoc lm gim kh nng thch ng ca cc phn t kt dnh b mt t bo chn lc lin quan ti s di c bch cu. Vic s dng thalidomide c ghi nhn lm gim nng tun hon ca TNF- cc bnh nhn mc bnh hng bannuts do phong (ENL), tuy nhin, n cng lm tng nng TNF cc bnh nhn nhim HIV dng tnh. Cc tnh cht chng vim, min dch ca thalidomide gm ngn chn s tham gia ca i thc bo n vic tng hp prostaglandin, v s thay i lng interleukin-10, interleukin-12 to thnh bi cc t bo n nhn ngoi vi. Thalidomide iu tr bnh a u ty nh vic tng s lng cc t bo tiu dit tun hon t nhin, v tng nng interleukin-2, interferon-gamma (mt cytokine t t bo T c hot tnh gy c t bo). Thalidomide c ch s L S Tng Lp CN Ha Dc v HC BVTV K49 13

i hc Bch Khoa H Ni

n tt nghip 2009

to mch khi nui cy rn ng mch ngi trong ng nghim. Cc qu trnh t bo b mch c ch bi thalidomide gm c s ny n cc t bo ni m.

Chuyn ha: Hin nay ngi ta vn cha xc nh c con ng chuyn

ha ca thuc trong c th ngi. Thalidomide khng chuyn ha gan m n thy phn khng cn enzyme huyt thanh to thnh rt nhiu sn phm. Trong mt nghin cu c lp li vi cng liu cho thy, c 10 ph n khe mnh s dng 200 mg thalidomide trong 18 ngy th dc ng hc ca thalidomide ngy u v cui tng t nhau, iu chng t thalidomide khng to ra hay c ch qu trnh chuyn ha ca n. Cc sn phm chuyn ha t thalidomide [19] (Hnh 2) Ngoi ra cc ng phn lp th ca thalidomide cn b hydroxyl ho vng phthaloyl hoc dioxopiperidine [20] (xem Hnh 1)
O HO N NH O O O O

N NH

O O O

OH

T halidomide
N NH O O O

Hnh 1. S hydroxyl ha ca thalidomide

Ch nh: Thalidomide c ch nh iu tr cp tnh vi biu hin da bnh thng cho n nghim trng i vi bnh hng ban nt do phong (ENL) nhng khng phi l liu php duy nht iu tr

L S Tng Lp CN Ha Dc v HC BVTV K49 14

i hc Bch Khoa H Ni

n tt nghip 2009

ENL i km vi vim dy thn kinh. N c ch nh l liu php duy tr ngn chn v trit vi biu hin da ca bnh ENL. Thalidomide c ch nh iu tr bnh u a ty c hoc khng kt hp vi Dexamethasone.

Chng ch nh: Thalidomide c chng ch nh i vi ph n mang thai, hoc ph n c kh nng mang thai; i vi nhng bnh nhn qu mn cm vi thuc hoc cc thnh phn ca thuc. Tc dng khng mong mun: Nu s dng thalidomide trong thi k mang thai, c th gy ra hin tng qui thai hoc lm cht non thai nhi.

Khi s dng thalidomide thng i km vi cc triu chng: ng g, ng gt, pht ban, bnh thn kinh ngoi bin (ph hy cc t bo thn kinh ngoi bin), chng mt do gim huyt p, gim bch cu trung tnh.

L S Tng Lp CN Ha Dc v HC BVTV K49 15

i hc Bch Khoa H Ni
O

n tt nghip 2009

N NH O O

Thali domi de

HN COOH O NH

O C O

N COOH

CONH2

HN COOH CONH2

COOH

-(2-carboxyl benzamido)glutarimide

Phthaloyl glutamine

Phthaloyl isoglutamine

HN COOH COOH

CONH2

HN COOH CONH2

COOH

N-(2-carboxylbenzoyl)glutamine

N-(2-carboxylbenzoyl)isoglutamine
O

H2 N NH O

N COOH O

COOH

-aminoglutarimide

Phtaloylglutamic acid

HN COOH COOH

COOH

H2 N COOH

CONH 2

H2 N CONH2

COOH

N-(2-carboxylbenzoyl)glutamic acid

Glutamine

Isoglutamine

COOH H2 N COOH COOH COOH

Phthalic acid

Glutamic acid

Hnh 2. Cc sn phm chuyn ha ca thalidomide L S Tng Lp CN Ha Dc v HC BVTV K49 16

i hc Bch Khoa H Ni

n tt nghip 2009

Tng tc thuc:

Thuc trnh thai hormone: ung thalidomide v thuc trnh thai cha ethinyl estradiol v norethindrone khng nh hng n ng hc ca cc hormone. Thalidomide tng cng tc dng an thn ca mt s thuc nh barbiturate, chlorpromazine, reserpine v c kh nng gy ng gt khi ung ru. Do tc dng hip ng, nhng thuc lin quan n thn kinh ngoi bin cn c s dng cn thn cho bnh nhn dng thalidomide. Cch dng v liu dng: Cch dng: Nu s dng mt liu hng ngy, nh sn xut khuyn co bnh nhn ung vi nc trc lc i ng ( hn ch tc dng gy ng ca thuc), hoc t nht 1 gi sau khi n ti. Nu chia thnh liu cao (khong 400 mg/ngy) th nn ung mt ln trc khi i ng hoc chia thnh nhiu ln ung vi nc cch 1 gi sau cc ba n. Liu dng: o Bnh hng ban nt do phong (ENL): i vi bnh nhn mc bnh ENL da, giai on mc nh, liu dng thalidomide t 100 n 300 mg/ngy, ung mt ln trc lc i ng hoc 1 gi sau khi n ti. Bnh nhn c trng lng nh hn 50 kg nn ung vi liu di 100 mg/ngy. i vi bnh nhn mc bnh ENL da, giai on nghim trng do phn ng ENL hoc nhng ngi trc cn mt liu cao kim sot phn

L S Tng Lp CN Ha Dc v HC BVTV K49 17

i hc Bch Khoa H Ni

n tt nghip 2009

ng ENL liu dng thalidomide l 400 mg/ngy, c th ung mt ln trc khi i ng hoc chia thnh nhiu ln ung, t nht 1 gi sau mi ba n. i vi nhng bnh nhn vim dy thn kinh km vi phn ng ENL, cho bnh nhn dng corticosteroids kt hp vi thalidomide. S dng lng steroid gim dn v ngng hn khi bnh vim dy thn kinh thuyn gim. Liu dng thalidomide phi c tip tc cho ti khi du hiu v cc triu chng ca phn ng gim. Thng khong thi gian ny t nht l 2 tun. Sau 2 n 4 tun, bnh nhn nn gim liu khong 50 mg. o Bnh u a ty (Multiple myeloma) Thalidomide c ung kt hp vi Dexamethasone trong mt chu k iu tr 28 ngy. Liu thalidomide l 200 mg/ngy c ung trc lc i ng hoc 1 gi sau khi n ti. Liu Dexamethasone l 40 mg/ngy c ung vo cc ngy 1-4, 9-12, 17-20 trong mi chu k 28 ngy. i vi bnh nhn xut hin tc dng ph nh to bn, bnh thn kinh ngoi bin th cn ngng s dng ngay, hoc s dng vi liu thp. Khi cc tc dng ph gim i, th c th bt u dng li liu thp hay liu trc , ty vo nh gi lm sng. Dng thuc. Thuc ung: vin nang 50 mg, 100 mg, 200 mg. Mi quan h gia c tnh gy qui thai v cc ng phn R,S ca thalidomide Vic s dng li thalidomide thi gian gn y trong iu tr lm sang kch thch mt cuc nghin cu v c ch tc dng phn t gy ra c tnh qui thai ca thalidomide. Thalidomide c s dng dng hn hp racemic, nn ngi ta cho rng ch c mt ng phn tc dng an thn v ng phn cn li gy ra tc dng qui thai. Hai mi nm sau thm ha thalidomide, ch c (S)-thalidomide c chng minh l cc tc dng gy qui thai i vi chut [21], ngi ta i n kt lun, thm ha khng xy ra nu ch dung dng phn (R)-thalidomide. Tuy nhin, qua thc nghim cho thy c 2 ng L S Tng Lp CN Ha Dc v HC BVTV K49 18

i hc Bch Khoa H Ni

n tt nghip 2009

phn v c hn hp racemic ca thalidomide u gy ra tc dng qui thai i vi cc con th New Zealand [22]. n nay, ngi ta vn cha bit r rng c ch tc dng ca thalidomide khi s dng cc ng phn tinh khit. Bi v thy c mt s chuyn ha ln nhau gia cc ng phn sau khi vo c th, cc ng phn ny trong mi trng nc di tc dng ca abumin huyt thanh s chuyn ha qua li ln nhau. Nguyn t H c tnh acid mnh ti trung tm bt i ca thalidomide epime ha nhanh chng di iu kin sinh l (xem Hnh 3), lm cho vic nh gi s khc nhau v hot tnh sinh hc gia cc ng phn lp th R,S l rt kh [23] Tuy nhin, ngi ta pht hin ra s c ch qu trnh gii phng TNF- mang tnh chn lc lp th ca thalidomide trong c th ngi [24]. Nghin cu s chuyn ha ca cc ng phn lp th thalidomide [20] cho thy rng, trong khi ng phn S ch yu chuyn ha bng cch hydroxyl ha vng phthaloyl (Hnh 4), trong lc th ng phn R tri qua qu trnh hydroxyl ha vng dioxopiperidine (Hnh 5)
O

N NH O HO

O H N NH O O O

O H N NH O O O

S(- )- Thalidomid e

R( +)- T halidomide

Hnh 3. S chuyn ha qua li gia hai ng phn (R) v (S) ca thalidomide L S Tng Lp CN Ha Dc v HC BVTV K49 19

i hc Bch Khoa H Ni

n tt nghip 2009

Mc d n nay vn khng th xc nh c mi quan h gia s chuyn ha cc ng phn thalidomide v c tnh gy qui thai, tuy nhin cc nh nghin cu c th a ra nhng gi thuyt sau:
O HO N O H N H O

(S)
O O

NH

(S)
NH

(S)-5-hydroxylthalidomide
O H N H OH

(S)-thalidomide

(S)
O

(R)
O O

NH

(3'R,5'S)-5'-hydroxylthalidomide

Hnh 4: Cc sn phm hydroxyl ho ca S(-)-thalidomide


O HO N O H N H O

(R)
O O

NH

(R)
NH

(R)-5-hydroxylthalidomide
O H N H OH

(R)-thalidomide

(R)
O

(S)
O O

NH

(3'S,5'R)-5'-hydroxylthalidomide

Hnh 5: Cc sn phm hydroxyl ho ca R(+)-thalidomide L S Tng Lp CN Ha Dc v HC BVTV K49 20

i hc Bch Khoa H Ni 2. GI HOT CHT V THNH PHM THALIDOMIDE

n tt nghip 2009

Gi hot cht thalidomide [25] Thalidomide hin nay ang c nhiu nc sn xut. Sau y l bng gi thnh ca mt s hng sn xut :

Tn

Tn catalogue TRC Biomedical Research Chemicals Wako Pure Chemicals Product List Wako Pure Chemicals Product List SinoChemex per Product

Tn cng ty Toronto Research Chemicals Inc. Wako Chemicals GmbH Wako Pure Chemical Industries, Ltd. SinoChemex per Company

a ch 2 Brisbane Rd. Nissanstrasse 2 1-2, Doshomachi 3-Chome 669 Pingxinguan

Thnh ph

Nc

Lin h Phone: (416) 665-9696 Phone: 1-800-727-9240 Fax: (416) 665-4439 Email: info@trccanada.com Phone: 49-2131-3 11-0 Fax: 49-2131-31 11 00 Phone: +81-6-6203-3741 Fax: +81-6-6201-5964 Phone: 86-21-64582533 Fax: 86-21-34511207

S lng 5g

Gi

Thalidomide

North York

Canada

$560

(+/-)Thalidomide (+/-)Thalidomide (a)Thalidomide

Neuss

c Nht Bn Trung Quc

10 g

72000 YEN

Chuo-ku Shanghai

10 g 500mg

72000 YEN $189.00

L S Tng Lp CN Ha Dc v HC BVTV K49 21

i hc Bch Khoa H Ni
List APAC Pharmaceutic al Product List Hangzhou APAC PharmaTech Rd 1#, Room 402 28 Xiangyuan Road Gongshu Trung Quc

n tt nghip 2009
Email: sales.sinochemexper@gm ail.com Phone: +86 (571) 8195 6956 Fax: +86 (571) 8885 7587 Email: sales@apacpharma.com Phone: 86-27-82261049 Fax: 86-27-82629206 Email: Sales@atomole.com Phone: +44(0)870 486 8629 Fax: +44(0)870 486 8627 Fax: +44(0)870 288 9672 Email: sales@carbonesci.com Phone: (650) 938-4849 Fax: (650) 938-4850 Email: sales@aksci.com Phone: 1 847 403-7044 Fax: 1 847 298-5008 Email: info@ocheminc.com Phone: +1(410) 997 5552 Fax: +1(410) 309 5955 Email:

Thalidomide

1kg

$1,650

Thalidomide

Thalidomide

()Thalidomide Thalidomide

150 Zhongjia Atomole Atomole Village, Suite Scientific Scientific 104 Product List Co., Ltd Hanyang District SUITE LG01, Carbone Carbone CHANCERY Scientific Scientific HOUSE Product List Co., Ltd. CHANCERY LANE AK Scientific 897-4G AK Product Independence Scientific, Inc Catalog Ave. OChem Product List APAC Pharmaceutic al Product OChem Incorporation APAC Pharmaceutic al, LLC 9044 Buckingham Park Drive 6851 Oak Hall Lane Suite 101

Wuhan

Trung Quc

50g

$680

LONDON

ANH

25g

$430

Mountain View Des Plaines

2.5g

$195.00

250g

Lin h

Thalidomide

Columbia

1kg

$1,650

L S Tng Lp CN Ha Dc v HC BVTV K49 22

i hc Bch Khoa H Ni
List New Brunswick Technology Center 100 Jersey Avenue, Box D-12 Building D, 3rd Floor sales@apacpharma.com

n tt nghip 2009

Thalidomide

Bosche Scientific Product List

Bosche Scientific, LLC

New Brunswick

Phone: (732)-565-9988 Fax: (732)-875-0899 Email: sales@BoscheSci.com

50g

$690

2.1.

Gi thnh phm thalidomide (vin nang)

Gi thnh phm thalidomide (vin nang) trn th trng th gii


Tn thng mi Thalidomide Celgene Celgene Thalidomide Celgene ONCOTHAL Cadila Pharmaceuticals Ltd M n 59572-0220-16 N/A 28 10 200 100 $ 6080,71 750 rupee $ 217,17 N/A M M 59572-0210-15 59572-0215-13 28 28 100 150 $ 5340,85 $ 5710,66 $ 190,74 $ 203,95 Cng ty sn xut Celgene Nc M S hiu sn phm 59572-0205-14 S vin/1 gi 28 Hm lng hot cht (mg) 50 Gi thnh/1 gi $ 3290,24 Gi thnh/1 vin $ 117,51

L S Tng Lp CN Ha Dc v HC BVTV K49 23

i hc Bch Khoa H Ni
TALIMYDE THYCAD THALODA Shantha Biotech Cadila Pharmaceuticals Limited (Vibra) Alkem Laboratories Ltd. (Cytomed) n n n N/A N/A N/A 10 10 THAANGIO Dr. Reddy's Laboratories Ltd n N/A 30 100 100 10 10 10 100 50 50

n tt nghip 2009
990 rupee 350 rupee 333 rupee N/A 585 rupee 810 rupee N/A 2430 rupee N/A N/A

2.2.2. Gi thnh phm thalidomide (vin nang) c bn trn th trng Vit Nam Trn th trng Vit Nam hin nay ch c duy nht cng ty Nanopharm ti H Ni c nhp v bn thalidomide dng vin nang.
Tn THADO Tn cng ty Nanopharm a ch 223A- Ng 22Khng HThanh Xun Thnh ph H Ni Nc Vit Nam Lin h in thoi : 04. 5570025 - Fax : 04. 5681500 Hm lng/vin 50 mg Gi/vin 700.000 VN

Ch thch: - N/A: Khng c thng tin. (*) Cc bo gi chi tit khc xin xem phn ph lc

L S Tng Lp CN Ha Dc v HC BVTV K49 24

i hc Bch Khoa H Ni

n tt nghip 2009

CC PHNG PHP TNG HP THALIDOMIDE C rt nhiu phng php tng hp racemic thalidomide cng nh cc ng phn quang hc ca (S), (R)-thalidomide c cng b, sau y xin lit k mt vi phng php trong s . Tng hp racemic thalidomide
2.1.1.

Phng php 1 [26], [27], [28] un hi lu anhydride phthalic (5) vi L-glutamic acid (4) trong pyridine thu c acid N-phthaloyl glutamic (3), sau un si hp cht (3) trong anhydride acetic ng vng thnh N-phthaloyl glutamic anhydride (2) vi hiu sut 74%. Tip tc cho hp cht (2) un nng chy vi urea, amoniac hoc thiourea 170-180C trong 20 pht to thnh thalidomide (1) vi hiu sut 70%.
O O OH O + H 2N OH O O O OH N

Pyridine

(CH 3CO)2O 74%


OH

5
O

3
urea 170 - 180 oC
O O

N O O O

20' 70%

N NH O O

2
2.1.2.

Phng php 2 [29] Trong phng php ny, L-glutamine (7) v anhydride phthalic (5) phn ng vi nhau trong pyridine 80-850C to thnh N-phthaloyl-glutamine (6), ri cho tc dng lun vi tc nhn ngng t to thnh thalidomide (1) vi hiu sut 45%. Tc nhn ngng t c th l CDI, SOCl2.

L S Tng Lp CN Ha Dc v HC BVTV K49

25

i hc Bch Khoa H Ni
O O OH O

n tt nghip 2009
O O OH N H

Pyridine, 80 - 85 C

H 2N

O O

NH2

O O O O NH N O

NH2

7 CDI, SOCl2 45%

2.1.3.

Phng php 3 [30] Trong phng php ny, ngi ta un si N-phthaloyl-DL-glutamine (6) trong acetic anhydride ng vng, sau 5 pht to thnh thalidomide (1) vi hiu sut 33%.
O O OH N O O NH N O

Ac2O 5' 30%

O O

NH2

6
2.1.4.

Phng php 4 [31]


O O N O O O NH2 O OH O O OH N

H2N

1. Na2CO3 2. HCl 67%

O O

NH2

7 CDI, 4-DMAP

O NH

THF 90%

Trong phng php ny, cc phn ng c thc hin di bu kh nitrogen. Cho N-carbethoxyphthalimide (8) tc dng vi L-glutamine (7) L S Tng Lp CN Ha Dc v HC BVTV K49 26

i hc Bch Khoa H Ni

n tt nghip 2009

trong dung dch Na2CO3, sau thc hin qu tnh acid ha to thnh Nphthaloyl-L-glutamine (6) vi hiu sut 67%. Sau cho N-phthaloyl-Lglutamine x l vi carbonyl diimidazole CDI, c mt ca xc tc 4-DMAP trong THF to thnh thalidomide (1) vi hiu sut 91%.
2.1.5.

Phng php 5 [32]


O O OH N S O O NH N H2N O O OH NH2 O

L vi sng 15' 85%

Phng php ny s dng l vi sng thc hin phn ng vi u im l thi gian phn ng xy ra rt ngn, v hiu sut kh cao. Hn hp Nphthaloyl-L-glutamic acid (3) v thioure (9) phn ng trong l vi song, sau 15 pht to thnh thalidomide (1) vi hiu sut 85%.
2.1.6.

Phng php 6 [33]

O BOC H N O OH BOC HN NH O

CDI, 4-DMAP THF 24h

TFA/DCM (1:1) 220C, 1h

NH2

10
O NH F3CCOOH 3N O + O O

11
O O NH N O

THF, Et 3N 24h, 800C 55%

12

un hi lu N-(tert-butoxycarbonyl)-L-glutamine (10) vi CDI v 4DMAP trong THF sau 24 gi thu c vng N-BOC glutarimide (11). Cho 11 tc dng vi acid trifloro acetic (TFA) trong dichlormethane (DCM) 220C L S Tng Lp CN Ha Dc v HC BVTV K49 27

i hc Bch Khoa H Ni

n tt nghip 2009

trong 1 gi thu c mui TFA ca vng glutarimide (12). Cho mui ny tc dng vi phthalic anhydride (5) trong THF vi xc tc l Et3N 800C, sau 24 gi thu c thalidomide (1) vi hiu sut 55%.
2.1.7.

Phng php 7 [34]


O

O H 2N

O NH

5
N H O

Pyridine, 1h 69%

13

un hi lu -aminoglutarimide (13) vi phthalic anhydride (5) trong pyridine thu c thalidomide (1) vi hiu sut 69%.
2.1.8.

Phng php 8 [35] Piperidine-2,6-dione (14) tc dng vi Br2 1500C trong CHCl3 trong 2 gi to thnh -bromoglutarimide (15) sau cho tc dng vi Potassium phthalimide (16) trong DMF to thnh thalidomide (1) vi hiu sut 30%.
O

NK O O NH N O

Br2
O N H O

Br

16
N H O

14

CHCl 3, 150 C, 2h 64%

15

DMF, to, 10h 30%

2.1.9.

Phng php 9 [3] Axit L-glutamic acid (4) tc dng vi SOCl2 trong MeOH to thnh dimethyl ester (17) vi hiu sut 95%.

L S Tng Lp CN Ha Dc v HC BVTV K49

28

i hc Bch Khoa H Ni
NH2 HOOC COOH

n tt nghip 2009
MeOH, SOCl2 95%
MeOOC NH2 COOMe

4
NHBOC

17 Na/NH3(L) Fe(NO3)3, THF, -330C 68%

NHBOC O NH O

(BOC)2O, DMAP Dioxane/H2O 88%

MeOOC

COOMe

18 TFA/DCM
F3CCOOH3N

O NH O

11 5/Acetic acid 55%

O NH

12

Bo v nhm amino bng cch cho ester tc dng vi di-tert-butyl dicarbonate (BOC)2O trong hn hp dung mi Dioxane/H2O vi xc tc DMAP to thnh tert-butoxycarbonyl L-glutamic acid dimethyl ester (18) vi hiu sut 88%. Cho ester ny tc dng vi Na/NH3 lng trong THF -330C, vi xc tc Fe(NO3)3 ng vng to thnh glutarimide (11) vi hiu sut 68%. Cho glutarimide (11) ny tc dng vi TFA trong DCM to thnh amino glutarimide trifloroacetate (12), ri tip tc tc dng vi anhydride phthalic (5) trong acid acetic bng to thnh thalidomide (1) vi hiu sut 55%. Phng php tng hp lp th S-(-)thalidomide [36] Ngng t benzyloxyamin (BnONH2) vi BOC-glutamic -phenyl ester (20) to thnh vng glutarimide (21) di iu kin nh nhng. Acid phn nhm bo v BOC, ri phthaloyl ha vi phthalic anhydride, to thnh N-benzyloxythalidomide (22). Hydro phn vi xc tc Pd-C to thnh Nhydroxythalidomide (23), loi nhm hydroxy bng cch tc dng vi bromoacetophenon, xc tc 4-DMAP, to thnh S-(-)thalidomide (1).

L S Tng Lp CN Ha Dc v HC BVTV K49

29

i hc Bch Khoa H Ni
OH BOCHN

n tt nghip 2009
OPh BOCHN

1. PhOH, DCC, pyridine EtOAc, t0 phng 2. H2, Pd-C, MeOH

OBn O

OH O

R,S 19 BnONH2, EDC, HOBT, Et3N CH2Cl 2, 3 ngy, t0 phng


BOCHN

R,S 20

90%

1. Kh HCl, CH2Cl2 t 0 phng, 5h


N OBn O O

R,S 21

71%

2.

Et 3N, THF, ry 4 A0
O O

H2, Pd-C

O N

MeOH,

t0

O N

phng, 2h
O O

OBn

OH

R,S 22

70%

R,S 23
O

89%

BrCH2COPh Et3N, CH3CN, xc tc DMAP MeCN, t0 phng, 2h

O N

S-(-) T halidomide 1 80%

QUY TRNH CNG NGH Tng hp racemic


2.1.10. -

Cng ngh 1

Bc 1: iu ch N-phthaloyl-DL-glutamic anhydride (2) [26] un hi lu trong 2 gi hn hp L-glutamic acid (4) (32,6 g; 0,22 mol) v

phthalic anhydride (5) (32,6g; 0,22 mol) trong 120 ml pyridine. Sau khi lm L S Tng Lp CN Ha Dc v HC BVTV K49 30

i hc Bch Khoa H Ni

n tt nghip 2009

bay hi dung dch di p sut gim, thm vo cn cn li 90 ml anhydride acetic, ri un si hn hp trong 2-3 pht. Trong qu trnh ct loi bt dung mi th sn phm kt tinh c sinh ra v qu trnh to thnh tinh th c hon thin khi va lm lnh xung v thn trong cho thm ete khan vo. Ra sn phm kt tinh bng ete, ri sy kh thu c N-phthaloyl-DLglutamic anhydride (2) (41g, hiu sut 74%), c nhit nng chy l 1951960C. Sn phm khng thay i khi kt tinh li t ethyl acetate, l tinh th chc, khng mu hnh lng knh.
i.

Bc 2: iu ch thalidomide (1) Cch 1 [27]: Nung chy cch du 26 g (0,1 mol) N-phthaloyl-DL-glutamic anhydride

vi 12 g (0,2 mol) urea nhit d 170-1800C, cho n khi phn ng kt thc, khong 20 pht. Trong qu trnh phn ng, kh CO2 v NH3 thot ra mnh lit. Sau khi lm lanh, sn phm c kt tinh phn on bng cn 95%, phn u c th cha dn xut ca acid phthalic. Sn phm thu c 3phthalimido-2,6-dioxopiperidine (thalidomide) (1) c nhit nng chy 2692710C, hiu sut 65-70%. Sn phm ny tan trong cn nng, dimethyl formamide (DMF), v tan trong dung dch kim mnh, thu c dung dch c mu hi vng.
ii.

Cch 2 [28]: Nung chy cch du 1 mol N-phthaloyl-DL-glutamic anhydride (2) vi

2 mol urea 170-1800C trong 45 pht. Sau khi lm lnh, ha tan thalidomide (1) th trong 60 ml ethanol 95%, un nng ti 60 0C, ri li lm lnh. Qu trnh kt tinh c lp li thm 3 ln. thalidomide thu c l bt mu trng, c nhit nng chy l 2750C, vi hiu sut 70-75%.
2.1.11.

Cng ngh 2 [29]

L S Tng Lp CN Ha Dc v HC BVTV K49

31

i hc Bch Khoa H Ni

n tt nghip 2009

Trn 5 g (34,21 mmol) L-glutamine (7) vo 25 ml pyridine trong bnh cu y trn 5 c, c dung tch 100 ml, nhit phng. Thm 5 g (33,80 mmol) phthalic anhydride (5) vo, ri ung nng hn hp ti 80-850C. Sau 6 gi, chng ct mt phn hn hp phn ng di chn khng, ri lm lnh hn hp ti 400C. Cho 3,1 g (45,5 mmol) imidazole vo bnh cu, lm lnh bnh cu n 5-100C, ri cn thn nh vo 1,6 ml (22 mmol) SOCl 2. Khuy hn hp phn ng nhit phng trong 1 gi, ri ung nng n 85 0C v khuy trong 3 gi nhit ny. Sau chng ct ti 1/5 th tch ban u. Lm lnh hn hp ti 250C ri thm vo 100 ml hn hp H2O:C2H5OH (4:1), 50C. Axit ha hn hp bng HCl 37% ti pH=7-0,5 0C ri tip tc khuy trong 4 gi nhit d phng, lc cht rn kt ta, ri ra 2 ln vi 25 ml H 2O. Cht rn thu c cho sy kh di chn khng 400C qua m thu c 3,9 g sn phm 1 l tinh th mu trng (hiu sut 45%).
2.1.12.

Cng ngh 3 [30] ung si 1 g N-phthaloyl-DL-glutamine (6) trong 5 ml acetic anhydride trong 5 pht, ri lm bay hi dung mi di p sut thp. Cht gm trong thu c cho ha tan trong dung dch cn, iu chnh pH ti 9 vi dung dch Na2CO3 ri thc hin qu trnh kt tinh thu c 0,31 g thalidomide (hiu sut 33%), nhit nng chy c th tng t 270-2720C nu qu trnh kt tinh li thay dung dch cn bng dung dch dioxane. Nc ci cho ra mt cht du kh kim sot. Hiu sut phn ng khng thay i ng k khi thi gian phn ng tng ln gp i.

2.1.13.

Cng ngh 4 [31]


-

Bc 1: iu ch N-phthaloyl-L-glutamine Khuy hn hp dung dch gm L-glutamine (7) (43,8 g; 300 mmol) v

Na2CO3 (33,4 g; 315 mmol) trong 750 ml H2O, ri thm nhanh cht rn Ncarbethoxyphthaimide (8) (65,8 g; 300 mmol). Sau 1 gi, lc v loi b Ncarbethoxyphthaimide khng phn ng. iu chnh pH ca dch lc ti 3-4 bng HCl 6 N. Khuy huyn ph thu c trong 1 gi. Lc phn huyn ph L S Tng Lp CN Ha Dc v HC BVTV K49 32

i hc Bch Khoa H Ni

n tt nghip 2009

ny ri ra vi mt lng nc ln, lm kh trong khng kh, ri sy trong chn khng (600C, < 1 mmHg) qua m, thu c 51,8 g bt trng 6 (hiu sut 67%) c nhit nng chy l 169-1710C.
-

Bc 2: iu ch thalidomide un hi lu hn hp gm N-phthaloyl-L-glutamine (6) (125 g, 452

mmol), CDI (76,1 g, mmol), v 4-DMAP (0,20 g; 1,6 mmol) trong dung mi THF (750 ml) trong 16 gi. Lc hn hp huyn ph sau phn ng, ra phn rn thu c vi DCM (200 ml), sy kh trong khng kh, v sy kh trong chn khng (600C, < 1 mmHg) thu c 106 g (hiu sut 91%) sn phm l bt trng 1 c nhit nng chy 274-2760C.
2.1.14.

Cng ngh 5 [32] Trn acid N-phthaloyl-L-glutamic (3) (3 g, 10,8 mmol) vi thiourea (0,882 g; 11,6 mmol) trong ng nghim Pyrex. Cho hn hp vo l vi sng gia nh (cng sut 1000 W, iu chnh mc pht sng 70%) trong 15 pht. Ha tan sn phm th trong THF v tinh ch bng sc k ct cha silica gel (THF: hexane = 1:1) thu c thalidomide (1) (2,375 g, hiu sut 85%), nhit nng chy l 269-271%.

2.1.15.

Cng ngh 6 [34] un si dung dch gm 1,3 g -aminoglutarimide (13) v 1,5 g phthalic anhydride (5) trong 10 ml pyridine trong 1 gi. C c dung dch di chn khng, ra cn vi EtOH, ri kt tinh li bng dioxane thu c 1,8 g thalidomide (1), nhit nng chy l 2700C.

2.1.16.

Cng ngh 7 [35] un nng hn hp 11 g glutarimide (14), 16 g Br2 trong 20 ml CHCl 3 trong mt bnh kn 120-1500C trong 2 gi to thnh 12 g bromoglutarimide, c nhit nng chy l 1070C.

L S Tng Lp CN Ha Dc v HC BVTV K49

33

i hc Bch Khoa H Ni

n tt nghip 2009

Ha tan -bromoglutarimide (5 g) trong 50 ml DMF, va khuy va un nng nh nhng hn hp vi 6 g potassium phthalimide (16) trong 10 gi, lm bay hi di p sut chn khng, phn cn ra vi nc v EtOH, ri kt tinh li trong dioxane hay pyridine cho ra 2 g thalidomide (1), c nhit nng chy 2700C.
2.1.17.

Cng ngh 8 [3]


-

Bc 1: iu ch L-1,5-dimethyl-2-aminopentandiate (17)

Dng phu chit nh git SOCl 2 (40,16 g; 326 mmol) vo dung dch Lglutamic acid (14) (12 g; 81,6 mmol) trong MeOH khan (250 ml) trong 30 pht 00C. Khuy mnh hn hp phn ng trong 12 gi nhit phng. Lm bay hi dung mi di p sut thp, pha long bng dung dch NaHCO 3, ri chit vi CH2Cl2 (5x200 ml). Ra lp hu c vi H2O v mui, ri lm khan bng Na2SO4. Lm bay hi dung mi thu c diester (17) (12,86g; 73,47 mmol; hiu sut 95%) c mu vng nht. Bc 2: iu ch L-1,5-dimethyl-2-[(tert-butoxycarbonyl)] amino pentandiate (18)
-

Lm nng dung dch diester (17) (12 g; 68,6 mmol) v (BOC)2O trong hn hp dioxane : H2O (1:1) vi xc tc DMAP ti nhit phng, ri tip tc khuy trong 12 gi. Sau khi lm bay hi dung mi, cho dung dch NaHCO3 pha long phn cn, ri chit vi CH2Cl2 (5x100ml). Dng nc (3x100 ml) ra lp hu c, ri lm khan nc bng Na2SO4 khan. Cho dung mi bay hi c 16,6 g; 60,31 mmol sn phm 18 (hiu sut 88%). Bc 3: iu ch L-tert-butyl N-(2,6-dioxohexahydro-3-pyridine) carbamate (11)
-

Khuy dung dch sodium amide NaNH2 [65,46 mmol; c iu ch t Na (1,5 g) tc dng vi NH3, xc tc Fe(NO3)3 trong NH3 lng (250 ml)], ng thi thm vo (6 g, 21,82 mmol) dung dch diester 18 trong THF khan (150 ml) nhit -330C. Khuy trong 2 gi, ri thm 10 g NH 4Cl, cho php NH3 bay hi. Thm 200 ml H2O, ri chit hn hp bng chloroform (3x200 ml). Lm khan dch chit vi Na2SO4, c c, ri phn tch bng sc k ct L S Tng Lp CN Ha Dc v HC BVTV K49 34

i hc Bch Khoa H Ni

n tt nghip 2009

silica gel (CHCl3 : acetone = 9 : 1) thu c (3,38g; 13,11 mmol; hiu sut 68%) tinh th 11 c nhit nng chy 212-2140C.
-

Bc 4: iu ch amino glutarimide trifloroacetate (12)

T t thm TFA (20 ml) vo dung dch ca 11 trong CH2Cl2 (200 ml) 0 C. Khuy mnh dung dch trong 3,5 gi nhit phng. Sau khi phn ng kt thc (nhn bit bng TLC), ct quay dung mi thu c 2,62 g cht rn aminoglutarimide trifloroacetate (12).
0

Bc 5: iu ch thalidomide (1)

Cho phthalic anhydride (5) (1,02 g; 7 mmol) v Et3N (2,43 ml) vo (2g; 8,26 mmol) amino glutarimide trifloroacetate (12). un hi lu hn hp trn 2 gi trong 75 ml acid acetic bng. Sau khi phn ng kt thc (theo di bng TLC), cho hn hp vo . Lc chn khng bng phu Burner thu c bt, kt tinh bt ny t ethyl acetate c thalidomide (1) (1,15 g; 4,48 mmol; hiu sut 65%). Tng hp lp th [36] Bc 1: iu ch N-tertbutyloxycarbonyl glutamic acid -phenyl ester (20)
-

Khuy dung dch gm (1 g; 2,9 mmol) BOC-Glu(Obn)-OH (19), phenol (278 mg; 2,9 mmol), dicyclohexylcarbodiimide (DCC) (609 mg; 2,9 mmol) v pyridine (250 l; 2,9 mmol) trong 15 ml ethyl acetate nhit phng qua m. Lc kt ta dicyclohexylurea. Theo th t ra dch lc vi dung dch NaHCO3 bo ha, acid citric 10%, nc. Sau lp hu c c lm khan bi Na2SO4. Ct dung mi di p sut thp. S dng sc k (SiO2, ether du ha : ethyl acetate = 2 : 1) tinh ch thu c 1,1 g (hiu sut 94%) BOCGlu(Obn)-Oph, c nhit nng chy 840C. Ha tan n trong 20 ml MeOH, ri hydro ha trn xc tc Pd-C (115 mg) trong 2 gi. Lc tch xc tc, ri ct dung mi di p sut thp. Tch bng sc k (SiO2, ether du ha : ethyl acetate = 3 : 1) c 852 mg (99%) hp cht (20) c nhit nng chy 750C.

L S Tng Lp CN Ha Dc v HC BVTV K49

35

i hc Bch Khoa H Ni
-

n tt nghip 2009 iu ch (S)-1-benzyloxy-3-tert-

Bc

2:

butyloxycarbonylaminopiperidine-2,6-dione (21) Cho 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (498 mg; 2,6 mmol) vo dung dch gm hp cht 20 (568 mg; 1,7 mmol), 1hydroxybenzotriazole (HOBT) (279 mg; 2 mmol), triethylamine (Et3N) (1,2 ml; 8,7 mmol) v benzyloxyamine (BnONH2) (264 l; 2 mmol) trong 25 ml CH2Cl2. Khuy hn hp trong 3 ngy nhit phng. Theo th t ra dch lc vi dung dch NaHCO3 bo ha, acid citric 10%, nc. Sau lp hu c c lm khan bng Na2SO4. Cho dung mi bay hi di p sut thp. Tch bng sc k ct (SiO2, cyclohexane : diethyl ether = 1 : 2) c 403 mg 21 (hiu sut 71%) c nhit nng chy 146-1500C.
-

Bc 3: iu ch (S)-1-benzyloxy-3-phthalimidopiperidine-2,6-dione (22)

Ha tan 21 (1,3 g; 3,9 mmol) trong 20 ml CH2Cl2. Sc kh HCl vo dung dch trong 10 pht ri khuy trong 30 pht. Cho CH2Cl2 bay hi di p sut thp ri ha tan dn xut mui chlorohydride trong 50 ml THF. Cho vo Et 3N (3,3 ml; 23,4 mmol), phthalic anhydride (5) (692 mg; 4,7 mmol) v ry phn t loi 4 . Sau khi un nng 2 gi, lc hn hp v loi b dung mi di p sut thp. Dng sc k (SiO2, cyclohexane : diethyl ether = 1 : 1) thu c 993 mg 22 vi hiu sut 70%, c nhit nng chy 1290C.
-

Bc 4: iu ch (S)-1-hydroxy-3-phthalimidopiperidine-2,6-dione (23)

Ha tan hp cht 22 (327 mg; 0,9 mmol) trong 30 ml MeOH, v thm vo 10% Pd-C (35 mg). Khuy hn hp di bu kh hydrogen trong 2 gi, ri lc. ct dung mi di p sut thp. Phn tch bng sc k (SiO2, ether du ha : ethyl acetate = 1 : 1) c 219 mg (hiu sut 89%) hp cht 23, c nhit nng chy 224,80C.
-

Bc 5: iu ch thalidomide (1)

L S Tng Lp CN Ha Dc v HC BVTV K49

36

i hc Bch Khoa H Ni

n tt nghip 2009

Khuy dung dch gm hp cht 23 (164 mg; 0,6 mmol), Et3N (83 l; 0,6 mmol), bromoacetophenone (BrCH2COPh) (120 mg; 0,6 mmol) v xc tc DMAP (7 mg; 0,06 mmol) trong 30 ml CH3CN nhit phng trong 2 gi (c th tch cht trung gian phenaxylete khi phn ng c 30 pht). Ct dung mi di p sut thp. Tch bng sc k (SiO2, cyclohexane : diethylether = 1:1) thu c 124 mg (hiu sut 80%) S-(-)thalidomide, c nhit nng chy 2690C. QUY TRNH LA CHN T cc quy trnh trn, em chn quy trnh tng hp trn c s cc ti liu [26], [27], [28] lm phng n tin hnh thc nghim iu ch thalidomide v n c cc u im sau: - Th nht l cc nguyn liu chnh (phthalic acid, glutamic acid, urea) c gi thnh thp hn nu so snh vi gi nguyn liu ca cc phng php khc. - Th hai l hiu sut ca phn ng tng i cao, gm 2 giai on,mi giai on hiu sut trn di 70%.
-

Th ba l cc bc phn ng n gin, ph hp vi iu kin sn xut

ca ta. Sau y l s cc phn ng :

L S Tng Lp CN Ha Dc v HC BVTV K49

37

i hc Bch Khoa H Ni S phn ng


O O OH O + H 2N OH O O

n tt nghip 2009

O OH

Pyridine
N

(CH3CO)2O 74%
OH

5
O

3
urea 170 - 180 oC
O O

N O O O

20' 70%

N NH O O

5.2. Tm tt quy trnh un hi lu anhydride phthalic (5) vi L-glutamic acid (4) trong pyridine thu c acid N-phthaloyl glutamic (3), sau un si hp cht (3) trong anhydride acetic ng vng thnh N-phthaloyl glutamic anhydride (2) vi hiu sut 74%. Tip tc cho hp cht (2) un nng chy vi urea, amoniac hoc thiourea 170-180C trong 20 pht to thnh thalidomide (1) vi hiu sut 70%. Tnh cht cc nguyn liu ch yu s dng trong quy trnh 5.3.1. Phthalic anhydride

Tnh cht vt l [1] Tn: 1,2-benzenedicarboxylic anhydride Isobenzofuran-1,3-dione

Cng thc phn t: C8H4O3 Cng thc cu to:


O

L S Tng Lp CN Ha Dc v HC BVTV K49

38

i hc Bch Khoa H Ni
-

n tt nghip 2009

L tinh th trng, t trng 1,53 g/cm3, tan trong nc 0,62 g/100 g nc, tan nhiu trong nc nng nhng d chuyn ha thnh phthalic acid, tan trong pyridine 80 g/ 100 g, tan trong cn, benzene, t tan trong ether. - Khi lng phn t: M = 148.12
-

Nhit nng chy 130,80C Tnh cht ha hc [37] Tc dng vi ru to thnh hn hp ester: C6H4(CO)2O + ROH C6H4(CO2H)CO2R

Ester ha nhm tip theo i hi phi loi nc C6H4(CO2H)CO2R + ROH C6H4(CO2R)2 + H2O

Diester quan trng nht l di(2-ethylhexyl) phthalate ("DEHP"), c s dng sn xut polyvinyl chloride (PVC). Phthalic anhydride tc dng vi ammonia to thnh phthalic monoamide, phthalimide, phthalonitrile
O O O NH 2 OH O

NH3

-H2O

NH

+NH3 -2H2O

CN

CN

Phthalic anhydride tham gia phn ng Friedel-Craft vi benzene, ri ng vng to thnh anthraquinone, l nguyn liu sn xut thuc nhum, hay lm xc tc trong cng nghip giy.
O O O

FeCl3
COOH

H2SO4

iu ch [37]

Ngi ta iu ch phthalic anhydride bng cch oxy ha o-xylene hoc naphthalene trong khng kh nng: L S Tng Lp CN Ha Dc v HC BVTV K49 39

i hc Bch Khoa H Ni
CH3

n tt nghip 2009
O

3O2 360-3900C
O

H2O

CH3

4,5O2 xc tc, 360-3900C

3 H2O +

2 CO2

5.3.2. Glutamic acid

Tnh cht vt l [1]


-

Tn: L-glutamic acid, (S)-2-aminopentandioic acid; -amino glutaric Vit tt: Glu Cng thc phn t: C5H9NO4 Cng thc cu to:
O O

acid. -

HO NH2

OH

L tinh th t phng (orthorrhombic), t trng 1,538 g/cm3, tan trong nc 8,64 g/l (250C); 21,86 g/l (500C); 55,32 g/l (750C); 140 g/l (1000C), t tan trong methanol, ethanol, ether, acetone v cc dung mi trung tnh.
-

- Khi lng phn t: M = 147,13

Nhit nng chy : 1600C Nhit thng hoa: 2000C quay cc []D22,4= +31,40 (HCl 6N) Tnh cht ha hc [38] 40

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni
-

n tt nghip 2009

Glutamic acid l mt amino acid nn tnh cht ha hc ca n chnh l tnh cht ca cc nhm amino (-NH2) v acid carboxylic (-COOH). Trong mi trng acid, n ch yu tn ti dng cation, cn trong mi trng base n ch yu tn ti dng anion. Mui natri ca glutamic acid dng trong thc phm gi l m chnh.
-

pKa: pk1 = 2,19; pk2 = 4,25; pk3 = 9,67

- Phn ng N-axyl ha
CH2 CH 2COOH H3 N H CH2 CH 2COOH H3 N H COO COO CH2 CH 2COOH

RCOCl

RCOHN H

COOH

CH2 CH 2COOH

(CH 3CO)2O

H3 CCOHN H

COOH

CH 3COOH

Phn ng N-alkyl ha
CH2 CH 2COOH H3 N H COO CH2 CH 2COOH

RCH2Cl

RH2 CHN H

COOH

Phn ng vi aldehyde
CH2 CH 2COOH CH2 CH 2COOH

H3 N H

COO

RCHO

RHC

N H

COOH

Phn ng ester ha
CH2 CH 2COOH H3 N H COO CH2 CH 2COOH

ROH

HCl
ClH3 N H COOR

iu ch [38]

L S Tng Lp CN Ha Dc v HC BVTV K49

41

i hc Bch Khoa H Ni

n tt nghip 2009

Phng php iu ch glutamic acid trong cng nghip ch yu l phng php ln men t mt ng (sucrose), tinh bt (glucose), ammonium sulfate vi cc xc tc enzyme. 5.3.3. Urea

Tnh cht vt l [1] Tn: carbamide, carbonyldiamide Cng thc phn t: CO(NH2)2
-

L tinh th trng, khng mi, t trng d418 = 1,3 g/cm3, tan trong nc, methanol, glycerol. Khng tan trong chloroform, ether. - Khi lng phn t: M = 60,06
-

Nhit nng chy: 132,70C Nhit si: 2950C. Tnh cht ha hc [39] Urea b phn hy thnh ammonia v isocyanic acid nhit cao
CO(NH2)2 NH4NCO NH3 + HNCO

- Urea tc dng vi aldehyde formic di iu kin acid to thnh methylene urea, hoc tip tc phn ng vi aldehyde formic to thnh dimethylene urea
H2N C O NH2

HCHO - H2O

H2N C O

N=CH 2

HCHO - H2O

H 2 C=N C O

N=CH 2

Urea tc dng vi aldehyde formic di iu kin base to thnh methylol urea


H2 N C O NH2

HCHO/OH-

H2 N C O

NHCH 2OH

HCHO/OH-

HOH2CHN C O

NHCH 2OH

- Urea tc dng vi ru to thnh carbamide acid ester, cn gi l urethane L S Tng Lp CN Ha Dc v HC BVTV K49 42

i hc Bch Khoa H Ni
NH 2CONH 2 + ROH

n tt nghip 2009
NH 2COOR + NH3

Urea tc dng vi acid malonic to thnh barbituric acid


O O C

+
NH2

HOC O

COH O

- 2 H2O
O

HN

NH

H2 N

urea

malonic acid

bacbituric acid

iu ch [39]

Urea c sn xut t NH3 lng v kh CO2 nhit v p sut cao. C 2 cht phn ng u l sn phm nh my tng hp NH3. S to thnh carbamate ammonium, ri tch nc thnh urea xy ra ng thi
t 0 cao, p cao 2 NH3 + CO2 NH2COONH4 ammonium carbamate

NH2COONH4

NH2CONH2 urea

H2O

5.3.4. Pyridine

Tnh cht vt l [1] Tn: Pyridine Cng thc phn t: C5H5N Cng thc cu to:
N

L cht lng khng mu, c mi c trng, d chy, t trng d420 = 0,9827; khc x nD20 = 1,50920; to hn hp ng ph vi nc theo t l 1:3 nhit si l 92-930C; Tan trong cn, nc, ether, du ha. L dung
-

L S Tng Lp CN Ha Dc v HC BVTV K49

43

i hc Bch Khoa H Ni

n tt nghip 2009

mi tt cho cc hp cht hu c, v c. Tnh base yu, to mui vi cc acid mnh pKA = 5,19. - Khi lng phn t: M = 79,10

Nhit nng chy: -41,60C Nhit si: 115,20C

Tnh cht ha hc [40]


-

Tnh thm ca pyridine km benzene khi th hin phn ng th electrophyl v c chng minh bng cch nitro ha quinoline th nhm NO2+ vo nhn benzene ch khng vo nhn pyridine
NO2 lanh + N NO2 N

+ N

HNO3

Pyridine c th tham gia phn ng th nucleophyl, chng hn un pyridine vi NaOH 4000C s c nhm OH- th vo v tr .
-

- V pyridine l base bc 3 nn n c th d dng kt hp vi cc ankyl halogenua hay sulfate v cc tc nhn ankyl khc. Mui pyridine bc 4 kt tinh tt
N + NaOH 4000C N OH

N + NaNH2

130-1500C

NH2 + NaH

CH3 N + CH3I N I

L S Tng Lp CN Ha Dc v HC BVTV K49

44

i hc Bch Khoa H Ni

n tt nghip 2009

Do c kh nng ha tan rt tt cc mui v c v cc cht hu c nn pyridine c dng lm dung mi rt tt, cht gi HX trong cc phn ng axyl ha.

iu ch [40]
CH2O + NH 3 350-5500C Al2O 3, SiO 3 N + CH3 N N

CH3CHO +

CH 3CHO + CH 2=CH-CH=O +

NH3

2 H 2O

H2

5.3.5. Acetic anhydride

Tnh cht vt l [1]

- Tn: acetic anhydride


-

Cng thc phn t: C4H6O3

- Cng thc cu to:


O

H 3C H3C

O O

L cht lng, nng mi acetic, t trng d 420 = 1,080; khc x nD20 = 1,3904; tan trong nc to thnh acid acetic, trong cn to thnh ethyl acetate
-

Khi lng phn t: M = 102,09 Nhit nng chy: -730C Nhit si: 1390C Tnh cht ha hc [41] Tham gia phn ng O-acetyl ha (c bit l cc phn ng ester ha)

L S Tng Lp CN Ha Dc v HC BVTV K49

45

i hc Bch Khoa H Ni
COOH OH

n tt nghip 2009
COOH OCOCH 3

(CH3CO)2O

CH3COOH

Salicylic acid

Aspirin

Tham gia phn ng N-acetyl ha


NH2 NHCOCH3

(CH3CO)2O

+ Acetanilide

CH3COOH

Anilin

Tham gia phn ng C-acetyl ha


O

(CH3CO)2O

CH3

+ acetophenone

CH3COOH

iu ch [41] Cho sodium acetate tc dng vi cc mui v c chloride


CH3COONa CH3COONa + + X-Cl CH3COCl X = SOCl2, SO2Cl, POCl2 CH3COCl (CH3CO)2O + + XONa NaCl

- Trong cng nghip acetic anhydride c sn xut bng cch nhit phn acid acetic
CH3COOH CH3COOH + t0 CH2=C=O CH2=C=O + H2O

(CH3CO)2O

Hoc oxy ha aldehyde acetic

L S Tng Lp CN Ha Dc v HC BVTV K49

46

i hc Bch Khoa H Ni
CH 3CHO + O 2 CH3CO3H CH 3CHO

n tt nghip 2009
(CH3CO) 2O + H2O

Phng php khc iu ch hp cht trung gian N-phthaloyl-DLglutamic anhydride (2) [42]
H 3C O Cl Cl O O Cl P O O O CH3

P(OCH2CH3) 3

500C

24
NH 2 HO OH

25
O H OH

+
O

Na2CO3/H2O

O O

OH

O H O O

(CH3CO)2O/H2SO4 98%
N

Bc 1: iu ch (1-chloro-1,3-dihydro-3-oxo-1-isobenzofuranyl)phosphonic acid diethyl ester (25) Cho 28 g phthaloyl chloride (138 mmol) vo bnh cu dung tch 250 ml c trang b khuy t v phu nh git. ung nng dung dch ti 500C v cho t t 22,9 g triethylphosphite (138 mmol) trong 0,5 gi bng phu nh git. Sau tip tc duy tr khuy nhit ny trong 0,5 gi tip theo. Trong 2 gi sau, khuy hn hp phn ng nhit phng ti khi ngng thot kh. Trong sut qu trnh phn ng, bm chn khng c duy tr loi b lng kh sinh ra. Sau phn ng, thu c 41,7 g (1-chloro-1,3-dihydro-3-oxo-1L S Tng Lp CN Ha Dc v HC BVTV K49 47

i hc Bch Khoa H Ni

n tt nghip 2009

isobenzofuranyl)-phosphonic acid diethyl ester (25) t tinh khit 99% (xc nh bng sc k lp mng TLC) v c s dng ngay cho giai on sau khng cn qua tinh ch. Bc 2: iu ch N-phthaloyl-L-glutamic acid Cho 36,5 g Na2CO3 (0,17 mol) vo 170 ml nc, khuy u trong bnh cu dung tch 500 ml. Ha tan 25 g L-glutamic acid (0,17 mol) vo dung dch trn, khuy nhit phng. Sau 15 pht, cho 51,8 g (25) (0,17 mol) (thu c bc 1) vo v khuy trong 5 gi nhit phng. Hn hp sau phn ng c lc loi kt ta. pH ca dung dch duy tr 1-2 bng HCl 6N. Hn hp phn ng tip tc c duy tr khuy trong 2 gi tip theo. Lc, thu phn rn, ra vi nc v sy trong chn khng v kt tinh li trong ethyl acetate/hexane (nu cn). Sn phm (N-phthaloyl-L-glutamic acid) thu c 32,6 g, hiu sut 70%, c im chy 159-1610C. nh gi tinh khit bng sc k lp mng TLC (Silica gel), h dung mi Butan-1-ol:nc:acetic acid = 3:1:1. Bc 3: iu ch N-phthaloyl-L-glutamic anhydride Cho 10 g (2) (36,1 mol) thu c bc 2 vo 40 ml acetic anhydride trong bnh cu dung tch 250 ml c trang b khuy t v ng CaCl2 lm kh. Dung dch c un nng ti 650C trong 15 pht. Thm nhanh mt lng nh acid sulfuric c (300 l) vo hn hp. Khuy u hn hp phn ng trong 2 gi nhit phng. Phn kt ta mu trng c lm lnh v lc. Cht rn thu c ra vi diethyl ether loi acetic acid/acetic anhydride d. Cui cng, thu c 7,1 g N-phthaloyl-L-glutamic anhydride (hiu sut 76%), c im chy 196-1980C.

L S Tng Lp CN Ha Dc v HC BVTV K49

48

i hc Bch Khoa H Ni

n tt nghip 2009

PHN 2. THC NGHIM V KT QU NGUYN VT LIU V DNG C Nguyn vt liu


Phthalic anhydride loi P. ca Trung Quc. L-glutamic acid loi P. ca Hungary. Urea loi P. ca Trung Quc. Acetic anhydride loi P. ca c.

Dung mi pyridine, acetone, diethyl ether, formic acid, isopropanol, chloroform, methanol tt c c ct li trc khi s dng. Dng c Bn mng sc k silica gel nhm Art 5562 DC Alurolle Kieselgel 60 F254 (Merck).

Bnh cu 1 c dung tch 100 ml, bnh cu 3 c dung tch 100 ml, bnh cu 200 ml, nhit k, cc thy tinh, ng ong, h thng phu lc, my khuy t gia nhit, h thng sinh hn xon, cn in t chnh xc 1%. n t ngoi bc sng 254 nm, n hng ngoi. My o im chy BOETIUS-MK (c) ti Phng th nghim b mn CN Ha Dc & Ha cht BVTV Khoa Cng ngh Ha hc Trng i hc Bch Khoa H Ni.

Ph 1H-NMR ,13C-NMR v DEPT o trn my Brucker AC 500 (500MHz, DMSO) ti Vin Ha hc Vin Khoa hc t nhin v Cng ngh Vit Nam.

Ph IR o trn my FT-IR 1000 ca hng Varian (M) ti phng Dc hc v cc hp cht t nhin - Trung tm Nghin cu ng dng Sinh - Y Dc hc Hc vin Qun Y.

Ph MS o trn my ph khi 5989 B MS thuc Vin Ha hc Vin Khoa hc t nhin v Cng ngh Vit Nam.

L S Tng Lp CN Ha Dc v HC BVTV K49

49

i hc Bch Khoa H Ni Dung mi chy sc k Chloroform : isopropanol : formic acid = 75 : 20 : 5 TNG HP THALIDOMIDE iu ch N-phthaloyl-DL-glutamic anhydride (2) [26] Phng trnh phn ng:
O O OH O + H 2N OH O

n tt nghip 2009

O OH

Pyridine
N

OH

5
(CH 3CO)2O

3
O

N O O O

Cch tin hnh: un hi lu trong 2 gi hn hp L-glutamic acid (4) (8,2 g; 0,055 mol) v phthalic anhydride (5) (8,2 g; 0,055 mol) trong 30 ml pyridine. Sau khi ct kit pyridine (1 gi) di p sut chn khng, thu c phn dch c, mu vng sm. ngui dch ny ti nhit phng, sau thm vo 23 ml acetic anhydride. Trong qu trnh un nng hn hp, ti thi im bt u hi lu, xy ra s si mnh lit. Sau khong 1 pht hin tng ny dng, tip tc un hi lu hn hp trong 30 pht. Sau tin hnh ct loi 12 ml dung mi Ac2O (1/2(*) lng dung mi s dng ban u, qu trnh ct loi din ra trong 40 pht, di iu kin p sut chn khng). Phn dch cn li c kt tinh nhit phng, qua m. X l, tch loi: Lc ht kit dch, thu c tinh th mu trng. Ngm tinh th ny vi 20 ml ether khan (diethyl ether Et2O) trong 15 pht loi acetic acid/acetic anhydride v pyridine cn d. Sn phm cui cng c lc, ra vi ether khan, sy kh ti khi lng khng i. L S Tng Lp CN Ha Dc v HC BVTV K49 50

i hc Bch Khoa H Ni Kt qu:

n tt nghip 2009

Thu c 10,93 g, hiu sut 76,16%.

Tinh th mu trng tinh.


Nhit nng chy: (190 192) (196 197).

Rf = 0,2 vi h dung mi chy sc k chloroform : isopropanol : formic acid = 75 : 20 : 5. Thc hin mt s m phn ng khc lm nguyn liu cho giai on iu ch thalidomide: (5) TT (g) 1 2 3 4 5 16,3 32,6 32,6 32,6 32,6 (mol) 0,11 0,22 0,22 0,22 0,22 (g) 16,3 32,6 32,6 32,6 32,6 (mol) 0,11 0,22 0,22 0,22 0,22 (4) VP. (ml) 60 120 120 120 120 VA. (ml) 45 90 90 90 90 VE. (ml) 40 50 50 50 40 Sn phm (g) 21,6 44,02 44,04 42,92 38,68 Hiu sut (%) 75.8 77,2 77,2 75,3 67,7

Ch thch: - VP. : Th tch dung mi pyridine s dng. - VA. : Th tch dung mi acetic anhydride s dng. - VE. : Th tch diethyl ether s dng. Tinh ch: Nghin nh, mn 10 g N-phthaloyl-DL-glutamic anhydride (2) th, cho vo bnh cu 1 c dung tch 100 ml c cha 40 ml dung mi acetone. un si, hi lu trong thi gian 30 pht di iu kin khuy trn (my khuy t). Sau gn b cn, thu ly dch. Dch ny c kt tinh t nhin nhit phng. Sau khi bay hi t nhin 10 ml (trong qu trnh kt tinh), lm lnh hn hp L S Tng Lp CN Ha Dc v HC BVTV K49 51

i hc Bch Khoa H Ni

n tt nghip 2009

bng nc trong 15 pht ri lc, ra. Tinh th hnh kim thu c c mu trng tinh, nhit nng chy (195 196) (200 201). Hiu sut 85% (khi lng: 8,5 g). Tin hnh kt tinh li tng t vi lng N-phthaloyl-DL-glutamic anhydride trn, hiu sut trung bnh 78%. Lu : (*): Lng dung mi Ac2O ct ra c nh hng ti hiu sut phn ng. Nu ct t qu, hiu sut s thp do sn phm ha tan mt lng trong phn dch cn li. Nu ct nhiu qu, dch cn li c nht cao, gy kh khn cho qu trnh tch sn phm (v cc tp cht nng cao cng kt tinh cng vi sn phm), lm gim hiu sut. Cu trc ca hp cht N-phthaloyl-DL-glutamic anhydride iu ch ra c xc nh qua cc d liu ph IR, 1H-NMR, 13C-NMR v MS:

IR max (KBr, cm-1): 3469,20 (ip(C=O)2 + op(C=O)2); 3067,52 v 2924,06 (C-H no (CH v CH2), dao ng ha tr (stretching vibration); 1817,21 (C=O anhydride vng no (symmetric)); 1775,97 v 1715, 70 (phthalimide (symmetric v asymmetric)); 1474,60 (C-H no (CH v CH2), dao ng bin dng (bending vibration)); 1230,34 v 973,38 (C-O vng anhydride); 719,59 (C-H thm).
10 O 8 7 9 1 2 N 13 4 5 O 11 O 18 3 14 12 17 16 O 15 O 19

H-NMR (DMSO) (ppm): 7,855 7,907 (m, 4H, H-5,6,7,8); 4,794 4,823 (m, 1H, H-13); 2,339 2,313 (m, 4H, H-17 v H-12).

C-NMR (DMSO) (ppm): 173,666 (C-16); 170,283 (C-14); 167,470 (C1 v C-3); 134,776 (C-6 v C-7); 131,288 (C-4 v C-9); 123,366 (C-5 v C8); 51,142 (C-13); 30,428 (C-17); 23,746 (C-12).

13

MS: m/z = 259(M+, 37), 214(15), 186(100), 173(88), 148(14), 130(34), 104(58), 76(67).

L S Tng Lp CN Ha Dc v HC BVTV K49

52

i hc Bch Khoa H Ni iu ch thalidomide 1.1.1. Phng trnh phn ng


O

n tt nghip 2009

urea
N O O O O O O N NH O

1.1.2. Cch tin hnh


1.1.2.1. Quy

hoch thc nghim [43]

Tin hnh quy hoch thc nghim vi s tr gip ca phn mm MODDE 5.0 (Umetrics Inc.). Qu trnh thao tc trn MODDE 5.0 c m t bng hnh v bn di: Khi ng chng trnh MODDE 5.0: M mt trnh lm vic mi bng vic chn Menu File New Chn tn trnh lm vic mi l Thalidomide

L S Tng Lp CN Ha Dc v HC BVTV K49

53

i hc Bch Khoa H Ni Khai bo bin u vo

n tt nghip 2009

Thc hin khai bo cc bin u vo l cc thng s cn kho st ca giai on 2 quy trnh tng hp thalidomide:

1. Bin nhit :
a.

Tn bin: Temperature (vit tt l temp).

b. n v o: C (oC). Thuc tnh ca bin: L bin c th kim sot thng s (controlled), bin nh lng nhiu mc (Quantitative multilevel): 165, 175, 185.
c.

2. Bin thi gian: a. Tn bin: Time (vit tt l time). b. n v o: pht (minute).

L S Tng Lp CN Ha Dc v HC BVTV K49

54

i hc Bch Khoa H Ni
c.

n tt nghip 2009

Thuc tnh ca bin: c th kim sot thng s (controlled), bin nh lng nhiu mc (Quantitative multilevel): 15, 20, 25.

3. Bin t l mol: Tn bin: Ratio (U/A) (vit tt l ratio). nh ngha: l t l mol gia urea v N-phthaloyl-DL-glutamic anhydride tham gia phn ng.
a.

Thuc tnh ca bin: c th kim sot thng s (controlled), bin nh lng nhiu mc (Quantitative multilevel): 1:1; 2:1; 3:1.
b.

Kt qu khai bo 3 bin u vo c hin th nh sau:

L S Tng Lp CN Ha Dc v HC BVTV K49

55

i hc Bch Khoa H Ni

n tt nghip 2009

Khai bo bin u ra i vi trng hp quy hoch thc nghim cho giai on iu ch thalidomide, ch c mt bin u ra duy nht l hiu sut (Field) a. Tn bin: Field (field). b. n v: %.

Chn m hnh quy hoch thc nghim

L S Tng Lp CN Ha Dc v HC BVTV K49

56

i hc Bch Khoa H Ni

n tt nghip 2009

La chn m hnh Screening (pht hin cc nhn t quan trng ti giai on u ca phng php, s dng m hnh ng m hnh bc 2, v m hnh tng tc bn trong). Chn Screening Ojective khi : Chng ta bt u xem xt v bit c mt t nhng nh hng qua li ca mt vi bin u vo trn bin u ra, hoc bit v nhng hot ng ca bin u ra trong mt gii hn thc nghim hay bit v kch thc thc t ca vng thc nghim . Mc ch ca chng ta l lm gim s lng nhng factor (yu t), ch gi li nhng yu t c nh hng ln nht trong bin u ra. La chn ny ph hp cho tt c cc loi factor.

Trong trng hp c th quy hoch thc nghim cho giai on tng hp thalidomide, chng ta chn m hnh Screening Objective l hon ton ph hp Chn m hnh bc 2 L9 ba mc (3 mc cho mi yu t, s thc nghim phi tin hnh l 9). Cui cng, ta thu c bng s liu nh hng thc nghim vi yu cu: s lng thc nghim l nh nht nhng thu c lng thng tin ln nht..

L S Tng Lp CN Ha Dc v HC BVTV K49

57

i hc Bch Khoa H Ni

n tt nghip 2009

1.1.2.2. Tin hnh thc nghim Thc hin phn ng: Nghin nh, trn u x (g) N-phthaloyl-DL-glutamic anhydride vi y (g) urea. Gia nhit cch ct trn bp khuy t gia nhit. Hn hp phn ng nng chy > 1000C. Duy tr nhit hn hp phn ng ti T0C trong thi gian t (pht) (trong sut thi gian phn ng, NH3 v CO2 thot ra mnh lit, kh thot ra lm xanh giy qu). X l, tch loi v tinh ch: Sau khi dng phn ng, ngui hn hp phn ng ti 90 0C th cho 25 ml EtOH 95% vo, un si, khuy ti khi phn rn tan hon ton th dng. hn hp kt tinh t nhin nhit phng. Sau 15 pht, lm lnh hn hp bng nc trong 15 pht, sau gn b dch, tip tc cho 25 ml EtOH

L S Tng Lp CN Ha Dc v HC BVTV K49

58

i hc Bch Khoa H Ni

n tt nghip 2009

25% vo lp li qu trnh kt tinh 2 ln. Di y l bng kt qu thc nghim: T l t T (oC) mol (pht) (U/A) 165 165 165 175 175 175 185 185 185 15 20 25 15 20 25 15 20 25 1 2 3 2 3 1 3 1 2 Tnc hn hp (0C) 140 115 100 115 100 140 100 140 115 Hiu sut (%) 17.05 38.76 40.31 48.06 68.22 21.71 24.81 35.66 65.12

STT

y (g)

x (g) 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5 6.5

(1) (g) 1.1 2.5 2.6 3.1 4.4 1.4 1.6 2.3 4.2

1* 2 3 4 5 6 7 8 9 Kt qu:

1.5 3 4.5 3 4.5 1.5 4.5 1.5 3

Tinh th thu c l tinh th hnh kim mu trng. Dung mi kt tinh acetone. Nhit nng chy: 269 2710C. (1*: Sn phm ny c im chy l 263 2640C).

Rf = 0,6 vi h dung mi chy sc k chloroform : isopropanol : formic acid = 75 : 20 : 5.

Cu trc ca thalidomide iu ch ra c xc nh bng cc d liu ph IR, 1H-NMR, 13C-NMR, DEPT90, DEPT135 v MS:

L S Tng Lp CN Ha Dc v HC BVTV K49

59

i hc Bch Khoa H Ni

n tt nghip 2009

IR max (KBr, cm-1): 3477,66 (ip(C=O)2 + op(C=O)2); 3112,74 v 2919,55 (C-H no (CH v CH2), dao ng ha tr (stretching vibration); 3198,61 (N-H); 1778,12 v 1703,66 (phthalimide (symmetric v asymmetric)); 1474,32 (C-H no (CH v CH2), dao ng bin dng (bending vibration)); 729,71 (C-H thm).
10 O 8 7 9 1 2 N 13 4 5 O 11 O 18 3 Ha 12 16 14 NH 15 O 19 Hb 17

H-NMR (DMSO) (ppm): 11,073 (s, 1H, H-15); 7,882 7,934 (m, 4H, H-5,6,7,8); 5,132 5,168 (dd, 1H, H-13, J = 13,0 Hz v J = 5,5 Hz); 2,863 2,935 (m, 1H, Ha -12); 2,497 2,633 (m, 2H, H-17), 2,052 2,1 (m, 1H, Hb -12).
13

C-NMR (DMSO) (ppm): 172,563 (C-16); 169,658 (C-14); 167,054 (C-1 v C-3); 134,772 (C-6, C-7); 131,167 (C-4, C-9); 123,303 (C-5, C-8); 48,970 (C-13); 30,856 (C-17); 21,922 (C-12). DEPT90 (DMSO) (ppm) CH: 134,772 (C-4, C-7); 123,303(C-5, C8); 48,970 (C-13).

DEPT135 (DMSO) (ppm)


o

CH&CH3 : 134,772 (C-4, C-7); 123,303(C-5, C-8); 48,970 (C13). CH2: 30,856 (C-17); 21,922 (C-12).

MS: m/z = 258 (M+, 26), 230(18), 202(19), 173(87), 148(50), 130(29), 111(53), 104(67), 76(100).
1.1.2.3. Ti

u ha quy trnh [43]

Da trn s liu thc nghim thu c, tin hnh xc nh cc iu kin ti u sao cho hiu sut qu trnh thu c l ln nht. Cng vic c thc hin vi s tr gip ca phn mm INForm 3.1. Di y l cc hnh nh m L S Tng Lp CN Ha Dc v HC BVTV K49 60

i hc Bch Khoa H Ni

n tt nghip 2009

t qu trnh x l s liu, xc nh iu kin ti u bng phn mm INForm 3.1: M trnh lm vic mi v nhp s liu thc nghim:

Sau khi hon thnh thao tc nhp s liu thc nghim (bng vic sao chp Ctrl + C v dn Ctrl + V), click OK chuyn sang khai bo cc thuc tnh ca bin Khai bo cc thuc tnh ca bin

Temperature (0C): l bin iu kin nhit ca quy trnh, chn Processing Condition.
a.

Time (min.): bin thi gian thc hin quy trnh, l bin iu kin, chn Processing Condition.
b.

Ratio (U/A): L t l mol gia urea v N-phthaloyl-DL-glutamic anhydride tham gia phn ng, c thuc tnh l bin thnh phn, chn Ingredient.
c. d.

Field (%): L bin u ra, bin hiu sut ca qu trnh, chn Property. 61

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

Sau khi hon thnh khai bo thuc tnh ca cc bin u vo, u ra, chn OK, trn mn hnh s hin th bng kt qu thc nghim khai bo thuc tnh ca bin:

Chn d liu kim tra: Tip tc click OK chuyn sang chn d liu kim tra qu trnh luyn mng.

Click Set Test Data la chn d liu kim tra cho qu trnh luyn mng.

L S Tng Lp CN Ha Dc v HC BVTV K49

62

i hc Bch Khoa H Ni

n tt nghip 2009

Click vo Options thit t la chn d liu kim tra:

Chn thit t Smart selection (la chn thng minh): vi thit t ny, trong qu trnh luyn mng, INForm s t la chn d liu no t tin cy cao nht. Ly gi tr 15% tng cu trc d liu. Gi tr ny c th thay i ty chn theo quy m ca d liu thc nghim. Click OK hon tt thit t. Hnh di cho thy INForm la chn d liu 2 lm d liu kim tra. Click OK tin hnh luyn mng.

L S Tng Lp CN Ha Dc v HC BVTV K49

63

i hc Bch Khoa H Ni

n tt nghip 2009

n nh thng s luyn mng Chn Seperately tin hnh luyn ring l cho mi tnh cht (mi bin c thuc tnh Property). Interactive mode c la chn thit t thng s ty theo tng m hnh.

Click Parameters n nh cc thng s luyn mng.

L S Tng Lp CN Ha Dc v HC BVTV K49

64

i hc Bch Khoa H Ni

n tt nghip 2009

La chn thut ton lan truyn ngc (back-propagationn algorithms): 1. Type; 2. Standard Incremental; Cc thng s cu trc mng ln lt nh sau:
1. 2.

S lp n (Number of Hidden Layers): 1 S nt trong lp n (Number of Nodes): 3.

3. 4. 5. 6. 7.

Yu t momen (momentum): 0,8 Tc luyn (Learning rate): 0,7. S vng lp ti a (Target Epochs): 1000. Sai s luyn (Target MS Error): 0,0001. Mm ngu nhin (Random seed): 10.000

8. S vng lp ti thiu: 20 9. T trng sai s th : 0,1. 10. S vng lp ti hn: 200

L S Tng Lp CN Ha Dc v HC BVTV K49

65

i hc Bch Khoa H Ni

n tt nghip 2009

Click OK hon tt thit t thng s luyn mng. Tin hnh luyn mng vi cc thng s mng thit t:

Kt qu : L S Tng Lp CN Ha Dc v HC BVTV K49 66

i hc Bch Khoa H Ni R2 luyn: 99,68. R2 th : 100.

n tt nghip 2009

Chn View Results xem kt qu luyn mng, sau Close chuyn sang phn ti u ha. Ti u ha iu kin:

Rng buc (Constraints): khng c.

Trng s: Mc nh (1). Hm mc tiu: Field (%) = Up.

Sau khi hon tt la chn iu kin ti u ha, click Optimize ti u ha. Kt qu cho thy:

L S Tng Lp CN Ha Dc v HC BVTV K49

67

i hc Bch Khoa H Ni Cc thng s ti u:


n tt nghip 2009

Temperature (0C): 1730C Time (minutes): 19,06 pht

Ratio (U/A): 2,51. Hiu sut tng hp d on: 80,68%

Tin hnh thc nghim kim tra kt qu ti u ha trn INForm vi cc thng s ti u:

Nhit (0C)

Thi gian (pht ) 19,06

A. T l mol (mol) 0,025 (g) 6,5 (mol)

U. (g) 3,77

Sn ph m (g) 4,68

Hiu sut (%) 72,6

170 - 175 Vi:

2,51

0,06275

A.: N-phthaloyl-DL-glutamic anhydride.

U.: Urea. Kt lun: Vi cc iu kin trn, phn ng iu ch thalidomide t Nphthaloyl-DL-glutamic anhydride t hiu sut ti u l 72,6%.

L S Tng Lp CN Ha Dc v HC BVTV K49

68

i hc Bch Khoa H Ni KT QU V BN LUN V TNG HP HA HC V iu ch N-phthaloyl-DL-glutamic anhydride (2)

n tt nghip 2009

Xut pht t phng php ca tc gi King F.E. [26], chng ti d nh chia quy trnh iu ch hp cht N-phthaloyl-DL-glutamic anhydride (2) thnh hai giai on c lp d kim sot, nh gi tin trnh phn ng v ti u ha tng giai on:

Giai on 1: iu ch N-phthaloyl-DL-glutamic acid (3)


O O OH O + H 2N OH O O O OH N

Pyridine - H 2O

OH

Giai on 2: T 3 iu ch N-phthaloyl-DL-glutamic anhydride (2)


O O OH N O

(CH3CO)2O
OH

N O

1.1.1. Giai on 1 Bng nhiu phng php khc nhau, chng ti n lc tch hp cht 3 ra khi hn hp sau phn ng ca giai on 1: nh gi cc hp cht 3, 4, 5 l cc hp cht khng tan trong nc, chng ti a nc vo hn hp sau phn ng vi hy vng cc cht ny s kt ta ra. Kt ta ny s c lc, tch sau kt tinh li thu c tinh th hp cht 3. Tuy nhin, tri vi mong mun, chng ti khng quan st thy xut hin kt ta khi cho H2O vo hn hp sau phn ng. Chng ti cho rng Pyridine + H2O l mt h dung mi l tng ha tan ton b cc hp cht 3, 4, 5 t l ln.

L S Tng Lp CN Ha Dc v HC BVTV K49

69

i hc Bch Khoa H Ni

n tt nghip 2009

l gii cho s vng mt kt ta ni trn, chng ti cng a ra gi thuyt: gia hp cht 3, 4 v dung mi pyridine c s to mui (acid + base hu c) v mui ny tan trong nc. Tng t nh vy, hp cht 5 d sau phn ng b thy phn (do s c mt ca H2O l sn phm, to thnh phthalic acid c kh nng to mui tan vi pyridine. Trn c s , chng ti s dng HCl v H2SO4 y pyridine ra khi cc mui, to thnh cc acid mong i: 3, 4 v phthalic acid. Tuy nhin ngay c khi pHdung dch 7, vn khng c kt ta no to ra. Chng ti cho rng cc cht 3, 4, 5 khng ch to mui vi pyridine m chng cn kt hp vi nhau to thnh 1 hn hp tan v tan c trong nc nn khng th kt ta ra Chng ti tin hnh th nghim v gim lng dung mi s dng. Kt qu cho thy cc trng hp s dng lng t dung mi pyridine hn cho hiu sut sn phm thp hn. Chng ti cho rng: nu lng dung mi pyridine khng to hn hp ng ph vi ton b lng H2O sinh ra (t l mol to hn hp ng ph l pyridine:nc=1:3), lng nc cn li s tc dng vi tc nhn Ac2O giai on sau, lm gim lng tc nhn, t gy gim hiu sut sn phm.

Chng ti tin hnh thay i dung mi pyridine bi cc dung mi khc c si gn tng ng: 1,4-dioxane, DMF (dimethyl formamide) nhm trnh vic to lin kt bn gia dung mi cht tan. Tuy nhin khi theo di tin trnh phn ng trn sc k bn mng th khng nhn thy du hiu chng t phn ng xy ra. Chng ti cng xc nh im chy ca phn rn thu c trong hn hp sau phn ng th nhn thy khng phi hp cht mong i. Trong trng hp ny, chng ti cho rng 1,4-dioxane v DMF khng p ng y vai tr ca dung mi pyridine trong phn ng: dung mi Nacyl ha. Chng ti s dng 4-DMAP kt hp vi hai dung mi trn xc tc cho qu trnh N-acyl ha. Tuy nhin, vt hn c s mong i, 4DMAP xc tc tt c cc hng acyl ha, kt qu cho thy trn sc k bn mng: xut hin nhiu vt st nhau, lin tip ko di. Khi xc nh im chy ca cn rn sau phn ng nhn thy khng phi hp cht 3 nh mong i.

C ch phn ng:

L S Tng Lp CN Ha Dc v HC BVTV K49

70

i hc Bch Khoa H Ni
O

n tt nghip 2009
O

Pyridine
O + H 2N COOH COOH

- H 2O

N + COOH O

COOH

4
2O

HN COOH COOH

COOH

3'

Vi tt c nhng tht bi trn chng ti suy ngh, phn tch c ch phn ng to thnh hp cht 3 nh trn v c mt s gi thuyt nh sau: Ti thi im kt thc phn ng, s thu c hn hp gia cht trung gian 3 nh trn v hp cht 3 trng thi cn bng. C 2 hp cht ny to lin kt bn vi pyridine v lin kt ny khng th ph c bng vic a acid v c (HCl, H2SO4) vo nh lm. Lin kt bn ny lm tn ti dng cht tan tt trong pyridine v nc.

Trong qu trnh ct dung mi pyridine, ti thi im ban u, H2O (to thnh sau phn ng) s to hn hp ng ph vi pyridine v b ct ra, gy chuyn dch cn bng, to ra 3 nhiu hn. V vy, trong thi gian ct pyridine, phn ng vn tip tc din ra.

Trn c s gi thuyt , chng ti quyt nh khng tch 3 m tin hnh ct pyridine sau cho Ac2O vo thc hin ng vng to anhydride. Chng ti cho rng khi ct pyridine phi m bo ct kit H2O v lng H2O d s tc dng vi Ac2O, lm gim lng tc nhn Ac2O trong giai on 2. 1.1.2. Giai on 2 Khi thc hin giai on 2 (loi nc ng vng to anhydride), c mt s vn cn lu :

L S Tng Lp CN Ha Dc v HC BVTV K49

-H

Py rid i ne

71

i hc Bch Khoa H Ni

n tt nghip 2009

Ti thi im ban u ca phn ng, thng xut hin s si mnh lit din ra trong khong 1 pht sau dng. C th l gii rng s si ny gy ra bi nhit to thnh t hai phn ng sau:
1. 2.

3 2 + H2O + Q1 H2O + Ac2O 2AcOH + Q2

Ti thi im ban u ca phn ng, do nng cc cht tham gia phn ng cao nn tc hai phn ng ny din ra nhanh, dn ti s ta nhit nhanh. Lng nhit ny lm si mnh dung dch. Sau khong 1 pht, tc phn ng gim, lng nhit ta ra khng nhanh v mnh nh ban u nn khng cn hin tng si mnh lit na.

Chng ti cng tin hnh th nghim gim lng dung mi Ac2O s dng nhng kt qu cho thy hiu sut sn phm thu c gim i. V lng Ac2O s dng bao gm: lng cho phn ng loi nc + lng phn ng vi nc to AcOH. Nu ly t i, lng dnh cho phn ng loi nc to anhydride khng , lm hiu sut phn ng gim r rt. Sau phn ng, tin hnh ct lng dung mi. Nu ct t hn th khng m bo qu bo ha sn phm kt tinh ra ton lng. Nu ct qu nhiu dung mi, s thu c mt hn hp c, qunh, nn hp cht 2 khng th kt tinh ra (do sn phm chnh v tp cht u nng qu bo ha). Dung mi diethyl ether (Et2O) c s dng tinh ch sn phm. Dung mi ny c ha tan thp i vi sn phm 2, tan ln vi AcOH/Ac2O v pyridine nn c th dng ra 2. Mt khc, do Et2O d bay hi nn lm cho sn phm sau ra c ti, xp cao, d lc, t b mt mt (do bm vo cc dng c). Chng ti cng th s dng H2O ngm ra sn phm nhm loi AcOH/Ac2O v pyridine, tuy nhin H2O c kh nng ha tan 2 li gy thy phn cho cht ny. ng thi 2 ra vi H2O khng c c ti xp nh i vi Et2O. Chnh v vy, chng ti chn Et2O lm dung mi tinh ch ln 1 cho hp cht 2. Kt tinh li: Da trn ti liu [26], chng ti thc hin kt tinh li vi dung mi ethyl acetate. Tuy nhin, kh nng ha tan ca dung mi ny vi 2 thp (ngay c nhit si), do cho hiu sut kt tinh 72

L S Tng Lp CN Ha Dc v HC BVTV K49

i hc Bch Khoa H Ni

n tt nghip 2009

khng cao. Mt khc, kt tinh bng dung mi ethyl acetate cho tinh th nh, vn, khng ti xp. Chng ti th nghim vi dung mi acetone v nhn thy:
o

Kh nng ha tan 2 tt hn dung mi ethyl acetate.

o Tinh th thu c khi kt tinh vi acetone l tinh th mu trng, hnh kim, c ti, xp cao. Tuy nhin dung mi acetone c nhc im l d bay hi ngay c nhit thng do khng ph hp cho vic lc nng. Chng ti khc phc nhc im ny bng cch gn ly dch. Dch ny c lm lnh kt tinh nhit phng, sau tip tc c lm lnh bng nc . Tinh th thu c trng hn v loi b c pyridine d (gy mu vng cho 2 trc kt tinh li).

Hp cht 2 khi xc nh im chy, quan st thy hai khong im chy khc nhau trn v di 2000C. Tham kho trong cc ti liu cng b v chy ca hp cht ny, chng ti thy rng c ti liu ch cng b 1 khong im chy trn hoc di 200 0C, c ti liu cng b ng thi hai khong im chy ny. Theo chng ti, c th l do 2 tn ti hai dng cu trc tinh th khc nhau hoc tinh th ca 2 tn ti dng khan v dng ngm nc. Trong qu trnh o im chy, chng ti quan st thy hai dng tinh th khc nhau ny.

V iu ch thalidomide 1
O

ureanc
O O

N NH O O

Phn ng iu ch thalidomide 1 thc hin iu kin hn hp cc cht tham gia phn ng u nng chy, do phi m bo yu cu khuy trn v iu nhit. Nu qu nhit, cc cht trong hn hp phn ng s b chy, b phn hy. Gi thuyt v c ch phn ng: L S Tng Lp CN Ha Dc v HC BVTV K49 73

i hc Bch Khoa H Ni phn ng:


Bc

n tt nghip 2009

Chng ti cho rng y l mt qu trnh lin hp nhiu bc vi nhiu

1: Urea nng chy sau phn hy thnh NH3 v isocyanic acid:


NH 4NCO NH 3 + HNCO

CO(NH 2)2
Bc

2: NH3 phn ng vi (2) to amide


O

N O O O

2NH3

N CONH2 O

CONH2

21

Hoc
O O

N O O O

NH3

N COOH O

CONH2

22

Sau
O O

N COOH O

CONH 2

+ NH = C = O

CONH 2 OCONH2

O O

2''
Bc

23

3: Amide ng vng to thalidomide 1

L S Tng Lp CN Ha Dc v HC BVTV K49

74

i hc Bch Khoa H Ni
O

n tt nghip 2009
O

- NH3
N CONH2 O O O CONH2 N NH O

2'

Hoc
O O

CONH 2 OCONH2

- (NH3 + CO2)
N NH O O O

O O

23

Trong qu trnh thc hin phn ng iu ch thalidomide 1, chng ti nhn thy:

T l cc cht tham gia phn ng nh hng ti nhit nng chy ca

hn hp phn ng. T l urea cng cao cng lm nhit nng chy gim. Hn hp u phi c nghin nh, trn u m bo tnh ng nht khi nng chy. iu ny nh hng ln ti hiu sut ca phn ng.

Da trn s liu thu c t thc nghim, c th nhn thy t l U/A = 2

3; thi gian 20 pht, nhit 1750C th cho hiu sut cao hn.

V ti u ha v quy hoch thc nghim: Vi s tr gip ca phn mm

MODDE 5.0 v INForm 3.1, chng ti thc hin thnh cng quy hoch thc nghim vi s th nghim nh nht 9. Thay v s dng phng php kho st thc nghim truyn thng: ch thay i mt yu t, cc yu t khc khng i, chng ti s dng phng php hin i nh hng thc nghim. Vi phng php ny, chng ti va c th gim s th nghim phi L S Tng Lp CN Ha Dc v HC BVTV K49 75

i hc Bch Khoa H Ni

n tt nghip 2009

thc hin ng thi c th kho st c s tng tc gia cc yu t (iu m trong m hnh thc nghim truyn thng cha lm c). V XC NH CU TRC CA CC CHT TNG HP [44], [45], [46], [47], [48]. Ph l phng php vt l hu hiu nht hin nay c ng dng trong ha hc hu c xc nh cu trc ca cc hp cht. Cc d liu v ph IR,
1

H-NMR, 13C-NMR, DEPT v MS cho thy cc cht 2 v 1 c cu trc ph

hp vi hng d on. V ph hng ngoi IR [44], [45], [46], [47] Ph hng ngoi IR cho php ta xc nh cc nhm chc ca phn t v mi lin kt ha hc c c trng bi mt tn s nhm (). Di y l mt s nhn nh chung v cc d liu ph hng ngoi IR ca cc hp cht 2 v 1:
-

Hp cht 2: Trn ph hng ngoi IR ca hp cht 2 nhn thy 1 pic yu ti 3469 cm-1

l cng dao ng ha tr c trng ca hai nhm carbonyl in-phase v outphase (ip(C=O)2 + op(C=O)2). Cng dao ng ha tr loi ny thng xut hin trong khu vc (3470 3570) cm-1 [46]. Trong vng (3100 2900) cm-1 c trng cho dao ng ha tr ca cc nhm CH v CH2, thy xut hin cc pic yu ti 3067,52 cm-1 v 2924,06 cm-1. Cc dn xut ca phthalimide thng c 2 pic t 1800 1700 cm -1 do s khc nhau v tng tc gia hai nhm carbonyl [45]:

L S Tng Lp CN Ha Dc v HC BVTV K49

76

i hc Bch Khoa H Ni

n tt nghip 2009

C O N X

C O O

C N X

C O

Dao ng ha tr i xng (symmetric) (1800 1750) cm-1

Dao ng ha tr bt i xng (asymmetric) (1750 1700) cm-1

i vi hp cht 2, nhn thy s c mt ca cc pic: 1775,97 v 1715,70 cm-1 vi cng rt mnh, th hin dao ng ha tr i xng v bt i xng ca C=O trong khung phthalimide. i vi anhydride vng 6 cnh no, ngi ta thng quan st thy cc tn hiu c trng cho dao ng ha tr i xng v bt i xng ln lt ti (1830 1820) cm-1 v (1790 1782) cm-1 [46]. Trn ph IR ca 2, ta quan st thy 1 pic c cng mnh ti 1817,21 cm-1 nm trong vng dao ng ha tr i xng ca C=O anhydride. Tuy nhin trong khu vc (1790 1782) cm -1 tng ng vi dao ng ha tr bt i xng ca C=O anhydride, khng quan st thy tn hiu no c cng ln. C th l gii rng tn hiu ny b cc tn hiu khc che khut. Ta cng c th quan st thy r cc tn hiu c trng ca C-O trn vng no anhydride trong vng (952 909) v (1299 1176) cm -1: l hai pic ti 973.38 v 1230,34 cm-1. Ti vng (900 675) cm-1 l vng c trng cho CH ca vng thm, c 1 tn hiu mnh ti 719,59 cm-1. Ngoi ra cn quan st thy tn hiu trung bnh ti 1474,60 cm-1 nm trong vng dao ng bin dng ca CH v CH 2. Tn hiu ny dch chuyn gim tn s dao ng do nh hng ca nhm carbonyl C=O ng cnh.

L S Tng Lp CN Ha Dc v HC BVTV K49

77

i hc Bch Khoa H Ni - Hp cht 1

n tt nghip 2009

Quan st ph hng ngoi IR ca hp cht 1, nhn thy c kh nhiu im tng t: s c mt ca 1 pic c trng cho dao ng bin dng CH vng thm (729,71 cm-1); C=O phthalimide cng dao ng ha tr (3477,66 cm-1); CH v CH2 vng no (3112,74 v 2919,55 cm-1); dao ng bin dng CH v CH2 no (1474,32 cm-1); dao ng ha tr i xng v bt i xng ca C=O phthalimide (1778,12 v 1703,66 cm-1). Tuy nhin, c th nhn thy s vng mt ca cc pic c trng cho lin kt C-O ca vng no anhydride trong vng (952 909) v (1299 1176) cm-1 nh trong hp cht 2; ng thi thy s xut hin ca mt pic yu ti vng (3250 3150) cm-1 vng c trng cho lin kt N H amide: 3198,61 cm-1. T c th kt lun rng lin kt CO khng tn ti trong cu trc hp cht 1, nhng li xut hin lin kt mi NH. Nhng d liu ny chng t phn ng xy ra v hp cht thu c rt ph hp vi nh hng iu ch hp cht 1. V ph khi MS [47], [48] Ph MS cho bit thng tin v khi lng phn t v cc mnh v tng ng ca hp cht kim tra. Vic phn tch cc phn mnh ca cc hp cht cng nhm khng nh thm cu trc c xc nh thng qua cc ph IR, NMR trc . Trn ph MS ca hp cht 1 thy pic ion phn t [M]+=258; cn hp cht 2 li c pic ion phn t [M]+=259. Trn ph ca hai hp cht ny, c th quan st thy cc phn mnh ging nhau: 173, 148, 132, 130, 104 v 76. Sau y l s phn mnh d on ca hp cht 1 (theo phn mm NIST MS Interpreter): (xem trang bn)

L S Tng Lp CN Ha Dc v HC BVTV K49

78

i hc Bch Khoa H Ni
O N NH O O O

n tt nghip 2009

m/z 258
O N NH O O O NH O HC N CH CH2 O

m/z 230
- CO

m/z 111
- CO

m/z 186
O N H

O N NH O O O CH2 N CH

m/z 83

m/z 202

m/z 173
O

m/z 76
- CO

-H
C C

N O

m/z 169
- CN
OH
N

m/z 104

NH O O

m/z 148

m/z 130

Hnh 6. S phn mnh ca hp cht 1 L S Tng Lp CN Ha Dc v HC BVTV K49 79

i hc Bch Khoa H Ni V ph cng hng t ht nhn 1H-NMR [44], [46]

n tt nghip 2009

Ph cng hng t ht nhn 1H-NMR cho php nhn dng v xc nh s v loi proton trong cu trc ca mt hp cht ha hc. i lng c trng cho mi nhm proton cc phn t khc nhau l chuyn dch ha hc , hng s tng tc J v cng pic. Di y l mt s nhn nh chung v cc d liu ph cng hng t ht nhn 1H-NMR ca cc hp cht 2 v 1:
-

Hp cht 2

Trn cng hng t ht nhn 1H-NMR ca hp cht 2, ti v tr 7,855 7,907 ppm, thy xut hin 1 multiplet l tn hiu c trng cho 4 nguyn t H ti C-5,6,7,8 trn vng thm. Bn cnh cng c th quan st thy 1 multiplet ti 4,794 4,823 ppm, cho thy s c mt ca 1 proton CH trn C13. Proton ny chu nh hng ht in t t nguyn t N v hiu ng lin hp ca nhm carbonyl C14 nn c s chuyn dch mnh v pha trng yu. Cc tn hiu multiplet ti 2,339 2,381 ppm v 2,247 2,313 ppm ln lt c trng cho 2 proton CH2 ca C-17 v C-12. Proton CH2 ca C17 gn nhm carbonyl C16 hn nn chu nh hng ca hiu ng lin hp, chuyn dch v pha trng yu nhiu hn proton CH2 ca C12 (xa nhm C19=O).
10 O 8 7 9 1 2 N 13 4 5 O 11 O 18 3 14 12 17 16 O 15 O 19

Hp cht 1

Trn ph 1H-NMR ca hp cht 1, quan st thy: 1 singlet ti 11,073 ppm, c trng cho proton N-H. 1 multiplet ti 7,882 7,934 ppm c trng cho 4 proton ca vng thm ti C-5,6,7,8. Ti v tr 5,132 5,168 ppm xut hin 1 double-doublet l tn hiu c trng ca 1 proton C-H tng ng vi C-13. S chuyn dch mnh v pha trng yu nh vy c th gii thch bi L S Tng Lp CN Ha Dc v HC BVTV K49 80

i hc Bch Khoa H Ni

n tt nghip 2009

tng tc phng ca nguyn t N-2 v nhm carbonyl C 14=O v tng tc khng gian ca H-15 ln proton H-13. Multiplet ti 2,863 2,935 ppm v 2,052 2,1 ppm cho thy s c mt ca 2 proton CH2 ca C-17 (Ha v Hb). 2 proton ny nm hai pha khc nhau nn chu tng tc khc nhau t H-15, do c chuyn dch ha hc tng ng khc nhau (hai proton khng tng ng v t). Tn hiu multiplet ti 2,497 2,633 ppm cho thy s c mt ca 2 proton CH2 ca C-12 (hai proton tng ng v t).
10 O 8 7 9 1 2 N 13 4 5 O 11 O 18 3 14 12 17 16 NH 15 Ha Hb O 19

V ph cng hng t ht nhn 13C-NMR v DEPT [44], [46] Ph 13C-NMR cho ta bit v s lng nguyn t carbon trong cc v tr khc nhau ca phn t. i lng c trng cho mi carbon mi nhm khc nhau l chuyn dch ha hc . Ph DEPT90 cho tn hiu ca C trong CH, ph DEPT135 cho tn hiu ca carbon trong CH&CH 3 (pha trn) v tn hiu ca carbon CH2 (pha di). Di y l mt s nhn nh chung v cc d liu ph cng hng t ht nhn 13C-NMR, DEPT ca cc hp cht 2 v 1:
-

Hp cht 2:
10 O 8 7 9 1 2 N 13 4 5 O 11 O 18 3 14 12 17 16 O 15 O 19

Trn ph 13C-NMR ca hp cht 2, quan st thy 3 pic c trng nm trong vng carbonyl: 173,666; 170,283 v 167,470 ppm, ln lt th hin C16=O, C14=O v 2 nhm carbonyl ti C1, 3=O. 2 nhm carbonyl ti C-1,3 lin L S Tng Lp CN Ha Dc v HC BVTV K49 81

i hc Bch Khoa H Ni

n tt nghip 2009

kt trc tip vo vng thm, chu nh hng ht in t ca vng ny nn b chuyn dch mnh v pha trng mnh. C14 chu tng tc xa ca N-2 nn cng chuyn dch v pha trng mnh nhng t hn C-1,3. Ti cc v tr 134,776; 131,288; 123,366 ln lt l cc tn hiu ca carbon vng thm C6,7; C4,9; C5,8. Cc carbon ny nm v tr khc nhau so vi C1,3=O nn chu nh hng khc nhau do c chuyn dch ha hc khc nhau. Ngoi ra, c th quan st thy cc tn hiu c trng cho carbon ca cyclo alkane ti C13 (51,142 ppm); C17 (30,428 ppm); C12 (23,746 ppm). Do c s tng tc ca N5 v 2 nhm carbonyl C14,16=O m cc nguyn t carbon cyclo alkane s c chuyn dch ha hc khc nhau. C13 va gn N-5 v C=O s chuyn dch mnh v pha trng yu. C17 ch gn C=O s chuyn dch v trng yu t hn C13.
-

Hp cht 1

T ph DEPT90 v DEPT135, nhn thy trong cng thc cu to ca 1 khng cha nhm methyl CH3, c 3 tn hiu CH ti CH: 134,772 ppm (C4,7 thm); 123,303 ppm (C5,8 thm); 48,970 ppm (C13 cyclo alkane); c 2 tn hiu CH2 ti 30,856 ppm (C17 cyclo alkane); 21,922 ppm (C12 cyclo alkane).
10 O 8 7 9 1 2 N 13 4 5 O 11 O 18 3 14 12 17 16 NH 15 O 19

T ph 13C-NMR ca hp cht 1, chng ta tip tc nhn thy cc pic c trng ca C=O: 172,563 ppm (C16=O); 169,658 ppm (C14=O) v 167,054 ppm (C1, 3=O). Tt c cc v tr ny hon ton tng t vi ph 13C-NMR ca hp cht (2). T , ta c th kt lun rng, hp cht 1 v 2 c b khung carbon hon ton ging ht nhau v so snh vi cc d liu ph cng b [3] cho thy sn phm thalidomide iu ch ra c cu trc hon ton ph hp nh cng thc biu din.

L S Tng Lp CN Ha Dc v HC BVTV K49

82

i hc Bch Khoa H Ni KT LUN

n tt nghip 2009

Sau thi gian gn ba thng thc hin ti, vi s hng dn tn tnh, chu o ca cc thy c v s n lc ca bn thn, em hon thnh c nhim v m n tt nghip t ra. C th, l nhng cng vic sau: tng quan v: tnh cht vt l, tc dng dc ca thalidomide. Lit k c h thng cc phng php tng hp thalidomide v cht trung gian Nphthaloyl-DL-glutamic anhydride. La chn phng php ti u, ph hp vi iu kin sn xut Vit Nam.
1.

Kho st phng php v thng s iu ch hp cht trung gian Nphthaloyl-DL-glutamic anhydride lm nguyn liu iu ch thalidomide. Thay i dung mi kt tinh cht ny thu c hiu sut cao hn v cht lng tinh th tt hn.
2.

Kho st phng php v thng s iu ch thalidomide. ng dng hai phn mm MODDE 5.0 v INForm 3.1 quy hoch thc nghim v ti u ha quy trnh iu ch thalidomide.
3.

4. Tm c h dung mi chy sc k theo di tin trnh phn ng v s b nh gi sn phm thu c. Cu trc ca cc hp cht tng hp ra (1) v (2) c nhn dng, xc nh bng cc hng s vt l (Rf, tnc) v cc loi ph IR, MS, 1H-NMR, 13CNMR, DEPT90, DEPT135.
5.

L S Tng Lp CN Ha Dc v HC BVTV K49

83

i hc Bch Khoa H Ni TI LIU THAM KHO

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

84

i hc Bch Khoa H Ni PH LC PH LC 1. GI HOT CHT THALIDOMIDE PH LC 2. CC PH Hnh 7. Ph IR ca hp cht 2 Hnh 8. Ph IR ca hp cht 1 Hnh 9. Ph MS ca hp cht 2 Hnh 10. Ph MS ca hp cht 1 Hnh 11. Ph 1H-NMR ca hp cht 2 Hnh 12. Ph 1H-NMR (2) ca hp cht 2 Hnh 13. Ph 13C-NMR ca hp cht 2 Hnh 14. Ph 1H-NMR ca hp cht 1 Hnh 15. Ph 1H-NMR (2) ca hp cht 1 Hnh 16. Ph 13C-NMR ca hp cht 1 Hnh 17. Ph 13C-NMR v DEPT ca hp cht 1

n tt nghip 2009

90 109 109 110 111 112 113 114 115 116 117 118 119

L S Tng Lp CN Ha Dc v HC BVTV K49

85

i hc Bch Khoa H Ni PH LC 1. GI HOT CHT THALIDOMIDE

n tt nghip 2009

Tn 1H-Isoindole1,3(2H)-dione, 2(2,6-dioxo-3piperidinyl)-

Tn catalogue Aurora Screening Library TRC Biomedical Research Chemicals TRC Biomedical Research Chemicals ChemPur Product List ChemPur Product List

Tn cng ty Aurora Fine Chemicals Ltd Toronto Research Chemicals Inc. Toronto Research Chemicals Inc. ChemPur GmbH ChemPur GmbH

a ch

Thnh ph

Nc

Lin h Email: aurora@aurorafinechemicals.c om Phone: (416) 665-9696 Phone: 1-800-727-9240 Fax: (416) 665-4439 Email: info@trc-canada.com Phone: (416) 665-9696 Phone: 1-800-727-9240 Fax: (416) 665-4439 Email: info@trc-canada.com Phone: +49 721 9338140 Fax: +49 721 472001 Email: info@ChemPur.de Phone: +49 721 9338140 Fax: +49 721 472001 Email: info@ChemPur.de

S lng

Gi

Reininghausstr asse 49

Graz

mg

Lin h

Thalidomide

2 Brisbane Rd.

North York

Canada

500mg

$70

Thalidomide

2 Brisbane Rd.

North York

Canada

5g

$560

(+/-)-Thalidomide

Rueppurrer Str. 92 Rueppurrer Str. 92

Karlsruhe

100 mg

Lin h

(+/-)-Thalidomide

Karlsruhe

500 mg

Lin h

L S Tng Lp CN Ha Dc v HC BVTV K49

86

i hc Bch Khoa H Ni
Thalidomide Harteg Product List Wako Pure Chemicals Product List Wako Pure Chemicals Product List Wako Pure Chemicals Product List Advanced Technology Product List Advanced Technology Product List Harteg GmbH Wako Chemicals GmbH Wako Chemicals GmbH Wako Chemicals GmbH Advanced Technology & Industrial Co., Ltd Advanced Technology & Industrial Co., Ltd Barensteiner Str. 13 Dresden c

n tt nghip 2009
Phone: +49 (0) 351 6465219 Fax: +49 (0) 351 6465219 Email: info@harteg.com Phone: 49-2131-3 11-0 Fax: 49-2131-31 11 00 Phone: 49-2131-3 11-0 Fax: 49-2131-31 11 00 Phone: 49-2131-3 11-0 Fax: 49-2131-31 11 00 Phone: (852) 2390 2293 Phone: (852) 2394 5546 Fax: (852) 2789 8314 Email: cas@advtechind.com Phone: (852) 2390 2293 Phone: (852) 2394 5546 Fax: (852) 2789 8314 Email: cas@advtechind.com Phone: 0091-8532-235006 Phone: 0091-8532-236328 Fax: 0091-8532-235876 Email: vbshilpa@sancharnet.in Email: vbshilpa789@yahoo.co.in N/A Lin h

(+/-)-Thalidomide

Nissanstrasse 2

Neuss

10 g

72000YE N 2300YE N 12000YE N

(+/-)-Thalidomide

Nissanstrasse 2

Neuss

100 mg

(+/-)-Thalidomide

Nissanstrasse 2 Unit B, 1/F., Cheong Shing Building 17 Walnut St. Unit B, 1/F., Cheong Shing Building 17 Walnut St.

Neuss

1g

THALIDOMIDE

Tai Kok Tsui

Hong Kong

N/A

Lin h

THALIDOMIDE

Tai Kok Tsui

Hong Kong

N/A

Lin h

Thalidomide

Shilpa Medicare Product List

Shilpa Medicare Ltd.

10/80, Rajendra Raichur Gunj

N/A

Lin h

L S Tng Lp CN Ha Dc v HC BVTV K49

87

i hc Bch Khoa H Ni
Kanto Product List Kanto Chemical Co., Inc. Kanto Chemical Co., Inc. International Business Department Wako Pure Chemical Industries, Ltd. Wako Pure Chemical Industries, Ltd. Wako Pure Chemical Industries, Ltd. 11-5, Nihonbashi Honcho 3chome, Chuoku Marusan bldg. 11-5, Nihonbashi Honcho 3chome, Chuoku 1-2, Doshomachi 3Chome 1-2, Doshomachi 3Chome 1-2, Doshomachi 3Chome Phone: +81-3-3663-7631 Fax: +81-3-3667-8277 Email: reaginfo@gms.kanto.co.jp

n tt nghip 2009
19700 YEN

(+-)-Thalidomide

Tokyo

Nht Bn

100 mg

(+-)-Thalidomide

Kanto Product List

Tokyo

Nht Bn

Phone: +81-3-3667-6991 Fax: +81-3-3639-9435 Email: kanto61@gms.kanto.co.jp

100 mg

19700 YEN

(+/-)-Thalidomide

Wako Pure Chemicals Product List Wako Pure Chemicals Product List Wako Pure Chemicals Product List

Chuo-ku

Nht Bn

Phone: +81-6-6203-3741 Fax: +81-6-6201-5964

10 g

72000YE N

(+/-)-Thalidomide

Chuo-ku

Nht Bn

Phone: +81-6-6203-3741 Fax: +81-6-6201-5964 Phone: +81-6-6203-3741 Fax: +81-6-6201-5964

100 mg

2300YE N 12000YE N

(+/-)-Thalidomide

Chuo-ku

Nht Bn

1g

L S Tng Lp CN Ha Dc v HC BVTV K49

88

i hc Bch Khoa H Ni
Thalidomide; N(2,6-Dioxo-3Piperidyl)Phthalimi de;2-(2,6-Dioxo-3Piperidinyl)-1HIsoindole-1,3(2H)Dione; Imida-Lab; Imidan (Peyta); Imidene; Isomin; K 17; Kedavon; Kevadon

n tt nghip 2009

Shanghai Specbiochem Product List

Unit A101-2, Shanghai No.326, Edison Specbiochem Rd Co., Ltd. Zhangjiang High-tech Park

Shanghai

Trung Quc

Phone: (86)21-51320052 Fax: (86)21-51320053 N/A Email: info@specbiochem.com

Lin h

SinoChemex Thalidomide (+ And per Product -) List

SinoChemex per Company

669 Pingxinguan Rd 1#, Room 402 669 Pingxinguan Rd 1#, Room 402 669 Pingxinguan Rd 1#, Room 402

Shanghai

Trung Quc

Phone: 86-21-64582533 Fax: 86-21-34511207 Email: N/A sales.sinochemexper@gmail.co m Phone: 86-21-64582533 Fax: 86-21-34511207 Email: 100mg sales.sinochemexper@gmail.co m Phone: 86-21-64582533 Fax: 86-21-34511207 500mg Email: sales.sinochemexper@gmail.co m

Lin h

(a)-Thalidomide

SinoChemex per Product List

SinoChemex per Company

Shanghai

Trung Quc

$50.40

(a)-Thalidomide

SinoChemex per Product List

SinoChemex per Company

Shanghai

Trung Quc

$189.00

L S Tng Lp CN Ha Dc v HC BVTV K49

89

i hc Bch Khoa H Ni

n tt nghip 2009

thalidomide

Shanghai Chemhere Product List

Shanghai Chemhere Co., Ltd.

Unit 602, No.14, Ziwei Rd Zhangjiang High-tech Park

Shanghai

Trung Quc

Phone: 86-21-26607989 Fax: 86-21-50790120 Email: sales@chemhere.com

N/A

Lin h

Thalidomide

Finechemie & Pharma Product List

Finechemie & Pharma Co., Ltd.

6-23-3, Sunway New Conception Mansion Chongqing No. 30 Longshan Road Jiangbei Zone 6-23-3, Sunway New Conception Mansion Chongqing No. 30 Longshan Road Jiangbei Zone

Trung Quc

Phone: +86-23-99186710 Fax: +86-23-99186729 Email: sale@finechemie.com

N/A

Lin h

Thalidomide

Finechemie & Pharma Product List

Finechemie & Pharma Co., Ltd.

Trung Quc

Phone: +86-23-99186710 Fax: +86-23-99186729 Email: sale@finechemie.com

N/A

Lin h

L S Tng Lp CN Ha Dc v HC BVTV K49

90

i hc Bch Khoa H Ni
China Hallochem Pharma Co., Ltd Product List 17F, Venus Science Incubate Center No.60 Chongqing Xingguang Road, New North Zone 17F, Venus Science Incubate Center No.60 Chongqing Xingguang Road, New North Zone

n tt nghip 2009
Phone: 86-23-67030786 Phone: 86-23-67030787 Phone: 86-23-67030788 Fax: +86-23-67030809 Fax: +86-23-67030818 Email: info@hallochem.com Note: Please send your inquiry letter to related E-mail. Phone: 86-23-67030786 Phone: 86-23-67030787 Phone: 86-23-67030788 Fax: +86-23-67030809 Fax: +86-23-67030818 Email: info@hallochem.com Note: Please send your inquiry letter to related E-mail. Phone: 86-311-87895969 Fax: 86-311-87039608 Email: china.cspc@gmail.com

Thalidomide

China Hallochem Pharma Co., Ltd.

Trung Quc

N/A

Lin h

Thalidomide

China Hallochem Pharma Co., Ltd Product List

China Hallochem Pharma Co., Ltd.

Trung Quc

N/A

Lin h

Thalidomide

China CSPC Pharmaceutic al Group Product List APAC Pharmaceutic al Product List APAC Pharmaceutic al Product List

China CSPC Pharmaceuti cal Group Hangzhou APAC PharmaTech Hangzhou APAC PharmaTech

47th Fengshou Rd

Shijiazhuang

Trung Quc

N/A

Lin h

Thalidomide

28 Xiangyuan Road

Gongshu

Trung Quc

Phone: +86 (571) 8195 6956 Fax: +86 (571) 8885 7587 25g Email: sales@apacpharma.com Phone: +86 (571) 8195 6956 Fax: +86 (571) 8885 7587 100g Email: sales@apacpharma.com

$380

Thalidomide

28 Xiangyuan Road

Gongshu

Trung Quc

$965

L S Tng Lp CN Ha Dc v HC BVTV K49

91

i hc Bch Khoa H Ni
Thalidomide APAC Pharmaceutic al Product List Atomole Scientific Product List Shanghai FWD Chemicals Product List Shanghai FWD Chemicals Product List Shanghai FWD Chemicals Product List Conier Chem & Pharma Product List BIOTREND Chemicals Hangzhou APAC PharmaTech 28 Xiangyuan Road 150 Zhongjia Village, Suite 104 Hanyang District Meilong Rd 428, Suite 1501, Lingyun Apartment Meilong Rd 428, Suite 1501, Lingyun Apartment Meilong Rd 428, Suite 1501, Lingyun Apartment Gongshu Trung Quc

n tt nghip 2009
Phone: +86 (571) 8195 6956 Fax: +86 (571) 8885 7587 1kg Email: sales@apacpharma.com $1,650

Thalidomide

Atomole Scientific Co., Ltd Shanghai FWD Chemicals Limited Shanghai FWD Chemicals Limited Shanghai FWD Chemicals Limited

Wuhan

Trung Quc

Phone: 86-27-82261049 Fax: 86-27-82629206 Email: Sales@atomole.com

50g

$680

Thalidomide

Xuhui District

Trung Quc

Phone: +86-21- 54294019 Fax: +86-21- 54293447 Email: sales@fwdchem.com Phone: +86-21- 54294019 Fax: +86-21- 54293447 Email: sales@fwdchem.com Phone: +86-21- 54294019 Fax: +86-21- 54293447 Email: sales@fwdchem.com Phone: +86-28-84552617 Fax: +86-28-84559521 Email: sales@conier.com Phone: +41 44 805 76 76 Fax: +41 44 805 76 77

25g

$285

Thalidomide

Xuhui District

Trung Quc

100g

$712.50

Thalidomide

Xuhui District

Trung Quc

250g

$1068.75

thalidomide

Conier Chem & Pharma Yihuan Road Co., Ltd BIOTREND Chemicals Unterdorfstr. 21b

Chengdu Wangen/Zur ich

Trung Quc Switzerla nd

N/A

Lin h

Thalidomide

100mg

Lin h

L S Tng Lp CN Ha Dc v HC BVTV K49

92

i hc Bch Khoa H Ni
Product List AG SUITE LG01, CHANCERY HOUSE CHANCERY LANE Tocris House, IO Centre Moorend Farm Avenue, Avonmouth Unit 68 Gazelle Road Weston Industrial Estate Unit 68 Gazelle Road Weston Industrial Estate Unit 68 Gazelle Road Weston Industrial Estate Email: info@biotrend.ch

n tt nghip 2009

Thalidomide

Carbone Scientific Product List

Carbone Scientific Co., Ltd.

LONDON

ANH

Phone: +44(0)870 486 8629 Fax: +44(0)870 486 8627 Fax: +44(0)870 288 9672 Email: sales@carbonesci.com Phone: +44 (0)117 916 3333 Fax: +44 (0)117 916 3344 Email: customerservice@tocris.co.uk Phone: +44 (0)1934 624 695 Fax: +44 (0)2030 700 369 Email: customerservice@ascentscienti fic.co.uk Phone: +44 (0)1934 624 695 Fax: +44 (0)2030 700 369 Email: customerservice@ascentscienti fic.co.uk Phone: +44 (0)1934 624 695 Fax: +44 (0)2030 700 369 Email: customerservice@ascentscienti fic.co.uk

25g

$430

Thalidomide

Tocris Bioscience Product List

Tocris Bioscience

Bristol

Anh

N/A

Lin h

(+/-)-Thalidomide

Ascent Scientific Product List

Ascent Scientific

WestonSuper-Mare

Anh

100mg

18

(+/-)-Thalidomide

Ascent Scientific Product List

Ascent Scientific

WestonSuper-Mare

Anh

100mg

$26

(+/-)-Thalidomide

Ascent Scientific Product List

Ascent Scientific

WestonSuper-Mare

Anh

100mg

36 EUR

L S Tng Lp CN Ha Dc v HC BVTV K49

93

i hc Bch Khoa H Ni
Fluorochem Fluorochem Microbiology Ltd. Product List

n tt nghip 2009
Phone: (01457) 868921 Fax: (01457) 869360 Fax: (01457) 860927 Email: enquiries@fluorochem.co.uk Phone: (01457) 868921 Fax: (01457) 869360 Fax: (01457) 860927 Email: enquiries@fluorochem.co.uk Phone: (650) 938-4849 Fax: (650) 938-4850 Email: sales@aksci.com Phone: (650) 938-4849 Fax: (650) 938-4850 Email: sales@aksci.com Phone: (650) 938-4849 Fax: (650) 938-4850 Email: sales@aksci.com Phone: 858-201-6118 Fax: 858-451-8607 Email: sales@acccorporation.com Phone: 858-201-6118 Fax: 858-451-8607 Email:

(+/-)-Thalidomide

Wesley Street

Old Glossop

Anh

100 mg

25.00

(+/-)-Thalidomide

Fluorochem Fluorochem Microbiology Ltd. Product List AK Scientific AK Product Scientific, Catalog Inc AK Scientific AK Product Scientific, Catalog Inc AK Scientific AK Product Scientific, Catalog Inc ACC Corp Product List American Custom Chemicals Corp. American Custom Chemicals

Wesley Street

Old Glossop

Anh

500 mg

110.00

()-Thalidomide

897-4G Independence Ave. 897-4G Independence Ave. 897-4G Independence Ave. P O Box 910574

Mountain View Mountain View Mountain View

500mg

$39.00

()-Thalidomide

2.5g

$195.00

()-Thalidomide

10g

Lin h

Thalidomide

San Diego

N/A

Lin h

Thalidomide

ACC Corp Product List

P O Box 910574

San Diego

N/A

Lin h

L S Tng Lp CN Ha Dc v HC BVTV K49

94

i hc Bch Khoa H Ni
Corp. American Custom Chemicals Corp. Aurora Fine Chemicals LLC sales@acccorporation.com Phone: 858-201-6118 Fax: 858-451-8607 Email: sales@acccorporation.com

n tt nghip 2009

Thalidomide

ACC Corp Product List

P O Box 910574

San Diego

100 mg

Lin h

1H-Isoindole1,3(2H)-dione, 2(2,6-dioxo-3piperidinyl)-

Aurora Screening Library

7929 Silverton Ave. Suite 609

San Diego

Phone: +1 858 549 4700 Fax: +1 858 549 4701 Email: aurora@aurorafinechemicals.c om Phone: 858-452-9925 1-877-452-9925 Fax: 858-452-9926 Email: support@agscientific.com Phone: 858-452-9925 1-877-452-9925 Fax: 858-452-9926 Email: support@agscientific.com Phone: 310-516-8000 Phone: 800-813-1514 Fax: 310-516-7512 Fax: 800-525-2299 E-Mail: sales@spectrumchemical.com

mg

Lin h

(+/-)-Thalidomide

A. G. AG Scientific Scientific, Product List Inc.

6450 Lusk Blvd. Suite E102

San Diego

100 mg

$70.00

(+/-)-Thalidomide

A. G. AG Scientific Scientific, Product List Inc. Spectrum Chemicals and Laboratory Products, Inc.

6450 Lusk Blvd. Suite E102

San Diego

500 mg

$260.00

Thalidomide

Spectrum Chemicals Product List

14422 South San Pedro St.

Gardena

N/A

Lin h

L S Tng Lp CN Ha Dc v HC BVTV K49

95

i hc Bch Khoa H Ni

n tt nghip 2009
Phone: 858 450 9600 Phone: 800 854 3417 Fax: 858 453 3552 Fax: 800 776 0999 Fax: 866 642 0301 Email: customer.service@emdbioscie nces.com Phone: 1-877-786-1922 Phone: (203)786-5436 Fax: (203)786-5437 Email: sales@betapharma.com Phone: 800-248-2436 Phone: 203-932-2489 Fax: 203-937-8400 Email: sales@citychemical.com Phone: 800-248-2436 Phone: 203-932-2489 Fax: 203-937-8400 Email: sales@citychemical.com Phone: 800-248-2436 Phone: 203-932-2489 Fax: 203-937-8400 Email: sales@citychemical.com

(+/-)-Thalidomide

CALBIOCH EM

EMD Biosciences, Inc.

10394 Pacific Center Court

San Diego

100 MG

$92

Thalidomide

Beta Pharma Catalog

91 Shelton Beta Pharma, Avenue, Suite: Inc. 211

New Haven

N/A

Lin h

(+/-)-Thalidomide

City Chemical Products Catalogue City Chemical Products Catalogue City Chemical Products Catalogue

City Chemical LLC

139 Allings Crossing Road

West Haven

1 gm

120.00

Thalidomide

City Chemical LLC

139 Allings Crossing Road

West Haven

10 gm

720.00

(+/-)-Thalidomide

City Chemical LLC

139 Allings Crossing Road

West Haven

100 mg

23.00

L S Tng Lp CN Ha Dc v HC BVTV K49

96

i hc Bch Khoa H Ni
THALIDOMIDE MicroSource Product List 3B Scientific Corporation Product List OChem Product List OChem Product List OChem Product List OChem Product List Waterstone Technology Product List APAC Pharmaceutic al Product MicroSource 21 George Discovery Washington Systems, Inc. Plaza 3B Scientific Corporation OChem Incorporatio n OChem Incorporatio n OChem Incorporatio n OChem Incorporatio n Waterstone Technology APAC Pharmaceuti cal, LLC 1840 Industrial Drive, Suite 160 9044 Buckingham Park Drive 9044 Buckingham Park Drive 9044 Buckingham Park Drive 9044 Buckingham Park Drive 12202 Hancock Street 6851 Oak Hall Lane Suite 101 Gaylordsvill e M

n tt nghip 2009
Phone: (860) 350-8078 Fax: (860) 354-5300 Email: compounds@msdiscovery.com Phone: 847-281-9822 Fax: 847-281-9855 Email: sales@3bsc.com Phone: 1 847 403-7044 Fax: 1 847 298-5008 Email: info@ocheminc.com Phone: 1 847 403-7044 Fax: 1 847 298-5008 Email: info@ocheminc.com Phone: 1 847 403-7044 Fax: 1 847 298-5008 Email: info@ocheminc.com Phone: 1 847 403-7044 Fax: 1 847 298-5008 Email: info@ocheminc.com Phone: 1-317-644-0862 Fax: 1-317-569-8068 Email: sales@waterstonetech.com N/A Lin h

Thalidomide

Libertyville

25g

$380

Thalidomide

Des Plaines

5g

Lin h

Thalidomide

Des Plaines

25g

Lin h

Thalidomide

Des Plaines

100g

Lin h

Thalidomide

Des Plaines

250g

Lin h

Thalidomide

Carmel

N/A

Lin h

Thalidomide

Columbia

Phone: +1(410) 997 5552 25g Fax: +1(410) 309 5955 Email: sales@apacpharma.com

$380

L S Tng Lp CN Ha Dc v HC BVTV K49

97

i hc Bch Khoa H Ni
List APAC Pharmaceutic al Product List APAC Pharmaceutic al Product List ChemPacific Product List APAC Pharmaceuti cal, LLC APAC Pharmaceuti cal, LLC ChemPacific Corp 6851 Oak Hall Lane Suite 101 6851 Oak Hall Lane Suite 101 6200 Freeport Center

n tt nghip 2009

Thalidomide

Columbia

Phone: +1(410) 997 5552 Fax: +1(410) 309 5955 100g Email: sales@apacpharma.com Phone: +1(410) 997 5552 Fax: +1(410) 309 5955 1kg Email: sales@apacpharma.com Phone: +001 410-633-5771 Fax: +001 410-633-5808 N/A Email: sales@chempacific.com Phone: 301-317-5072 Fax: 301-317-5073 Email: allichemchemical@yahoo.com Phone: 301-317-5072 Fax: 301-317-5073 Email: allichemchemical@yahoo.com

$965

Thalidomide

Columbia

$1,650

Thalidomide

Baltimore

Lin h

Thalidomide

Allichem Product List

Allichem LLC

8510 Corridor Road Ste A

Savage

1g

$280

Thalidomide

Allichem Product List

Allichem LLC

8510 Corridor Road Ste A

Savage

5g

$780

Thalidomide

ChemPacific Product List

ChemPacific Corp

6200 Freeport Center

Baltimore

Phone: +001 410-633-5771 Fax: +001 410-633-5808 1g Email: sales@chempacific.com

$280.00

L S Tng Lp CN Ha Dc v HC BVTV K49

98

i hc Bch Khoa H Ni
Thalidomide ChemPacific Product List LKT Laboratories Product List ChemPacific Corp 6200 Freeport Center Baltimore M

n tt nghip 2009
Phone: +001 410-633-5771 Fax: +001 410-633-5808 5g Email: sales@chempacific.com Phone: 1-888-LKT-LABS Phone: 1-888-558-5227 Fax: 651-644-8357 Email: info@lktlabs.com Phone: (800) 421-3701 Phone: (636) 207-7651 Fax: (800) 483-1993 Fax: (636) 207-7683 Email: customerservice@tocrisusa.co m Phone: 1-800-325-3010 Phone: 1-314-771-5765 Phone: 1-314-771-5750 (Call Collect) Fax: 1-800-325-5052 Fax: 1-314-771-5757 Phone: 1-800-325-3010 Phone: 1-314-771-5765 Phone: 1-314-771-5750 (Call Collect) Fax: 1-800-325-5052 Fax: 1-314-771-5757 Please see website for additional locations around the $780.00

Thalidomide

LKT 2233 Laboratories, University Inc. Avenue West

St. Paul

N/A

Lin h

Thalidomide

Tocris Bioscience Product List

Tocris Bioscience Ltd.

16144 Westwoods Business Park

Ellisville

N/A

Lin h

(+/-)-Thalidomide

SIGMA

SigmaAldrich

P O Box 14508

St. Louis

N/A

Lin h

(+)-Thalidomide

SIGMA

SigmaAldrich

P O Box 14508

St. Louis

N/A

Lin h

L S Tng Lp CN Ha Dc v HC BVTV K49

99

i hc Bch Khoa H Ni

n tt nghip 2009

world.

(-)-Thalidomide

SIGMA

SigmaAldrich

P O Box 14508

St. Louis

Phone: 1-800-325-3010 Phone: 1-314-771-5765 Phone: 1-314-771-5750 (Call Collect) Fax: 1-800-325-5052 Fax: 1-314-771-5757 Please see website for additional locations around the world. Phone: 732-603-9577 Fax: 732-906-1522 Email: info@tecoland.com Phone: 732-906-7666 Fax: 732-906-1522 Email: info@haoruiM.com

N/A

Lin h

Thalidomide

Tecoland Product List Haorui PharmaChem Product List

Tecoland Corporation Haorui PharmaChem Inc.

100 Menlo Park Drive, Suite 316 100 Menlo Park, Suite 316 New Brunswick Technology Center 100 Jersey Avenue, Box

Edison

mg to kg

Lin h

Thalidomide

Edison

mg to kg

Lin h

Thalidomide

Bosche Scientific Product List

Bosche Scientific, LLC

New Brunswick

Phone: (732)-565-9988 Fax: (732)-875-0899 Email: sales@BoscheSci.com

50g

$690

L S Tng Lp CN Ha Dc v HC BVTV K49

100

i hc Bch Khoa H Ni
D-12 Building D, 3rd Floor Changzhou Synasia Pharmaceutic al and Chemical Product List SST Product List

n tt nghip 2009

Thalidomide

Synasia Fine Chemical, Inc.

240 Amboy Ave.

Metuchen

Phone: 732-205-9880 Fax: 732-205-1788 Email: info@synasia.com

N/A

Lin h

Thalidomide

SST Corporation

635 Brighton Road

Clifton

Phone: (800) 222-0921 Phone: (973) 473-4300 Fax: (973) 473-4326 Email: info@sst-corp.com Phone: 201-796-4288 Fax: 201-796-3291 Email: info@skechem.com Phone: (800) 942-0430 Phone: (610) 941-0430 Fax: (610) 941-9252 E-Mail:info@biomol.com Phone: (800) 942-0430 Phone: (610) 941-0430 Fax: (610) 941-9252 E-Mail:info@biomol.com

N/A

Lin h

Thalidomide

SK Energy SK Energy and and Chemical Chemical, Product List Inc. BIOMOL Product List BIOMOL International

22-10 Route 208 South

Fair Lawn

N/A

Lin h

Thalidomide

5100 Campus Drive

Plymouth Meeting

500 mg

$283

Thalidomide

BIOMOL Product List

BIOMOL International

5100 Campus Drive

Plymouth Meeting

100 mg

$72

L S Tng Lp CN Ha Dc v HC BVTV K49

101

i hc Bch Khoa H Ni
Thalidomide AmplaChem Product List AmplaChem, 100 Fifth Ave, Inc. Suite 300 Pittsburgh M Phone: 412-455-5567 Fax: 317-815-3759 Email: info@amplacheminc.com

n tt nghip 2009
N/A Lin h

Thalidomide

AvaChem Scientific Product List AvaChem Scientific Product List Texas Biochemicals Product List Texas Biochemicals Product List Amfinecom Product List Wako Pure Chemicals Product List

AvaChem Scientific LLC AvaChem Scientific LLC Texas Biochemical s Inc. Texas Biochemical s Inc. Amfinecom Inc. Wako Chemicals M, Inc.

P O Box 780442

San Antonio

Phone: (210)-667-3815 Fax: (210)-764-2240 Email: ChemSupply@avachem.com Phone: (210)-667-3815 Fax: (210)-764-2240 Email: ChemSupply@avachem.com Phone: 979-696-7070 Fax: 979-696-7171 Email: info@texasbiochemicals.com Phone: 979-696-7070 Fax: 979-696-7171 Email: info@texasbiochemicals.com Phone: 804 861 0001 Fax: 804 861 0015 Email: sales@amfinecom.com Phone: 804-271-7677 Fax: 804-271-7791 Email:

50mg

$49

Thalidomide

P O Box 780442

San Antonio

10g

Lin h

THALIDOMIDE

2151 Harvey College Mitchell Pkwy Station South, Ste# 225 2151 Harvey College Mitchell Pkwy Station South, Ste# 225 824 Bollingbrook Street 1600 Bellwood Road St. Petersburg

5g

$559.00

()-Thalidomide

500 mg

$219.5

Thalidomide

25g

$365

(+/-)-Thalidomide

Richmond

10 g

72000YE N

L S Tng Lp CN Ha Dc v HC BVTV K49

102

i hc Bch Khoa H Ni
Information@wakousa.com Wako Pure Chemicals Product List Wako Pure Chemicals Product List Wako Chemicals M, Inc. Wako Chemicals M, Inc. Phone: 804-271-7677 Fax: 804-271-7791 Email: Information@wakousa.com Phone: 804-271-7677 Fax: 804-271-7791 Email: Information@wakousa.com

n tt nghip 2009

(+/-)-Thalidomide

1600 Bellwood Road

Richmond

100 mg

2300YE N

(+/-)-Thalidomide

1600 Bellwood Road

Richmond

1g

12000YE N

L S Tng Lp CN Ha Dc v HC BVTV K49

103

i hc Bch Khoa H Ni PH LC 2. CC PH

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

104

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

105

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

106

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

107

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

108

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

109

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

110

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

111

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

112

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

113

i hc Bch Khoa H Ni

n tt nghip 2009

L S Tng Lp CN Ha Dc v HC BVTV K49

114

You might also like