• Nghien CIFU - Ky thuat
(atom and atom type) molecular quadratic indices, significance interpretation, comparison to other molecular descnptors, and QSPR/QSAR applications", Bmorg. Med. Chem., 12(24): p. 6351-69.
13. Marrero-Ponce Y., etai. (2005), "Non-stochastic and stochastic linear indices of the "molecular pseudograph's atom adjacency matrix": application to 'in silico' studies for the rational discovery of new antimalarial compounds", Bioorg. Med Chem., 13(4), p. 1293-1304.
14. Man-ero-Ponce Y and F. Torrens (2008), "Novel 20 TOMOCOMD-CARDD Descriptors: Atom-based (Ngdy nhan bii: 13/08/2015
stochastic and non-stochastic bilinear indices and their QSPR applications', J. Math. Chem., 44(3), p. 650- 673.
15. Jeliazkova N. N. (2006), "AMBIT: Building blocks for a future (Q)SAR decision support system", http://ambit.acad.bg.
16. Alvarez-Ginarte Y M., et al. (2008),
"Chemometric and chemolnformatic analyses of anabolic and androgenic activities of testosterone and dihydrotestosterone analogues", Bioorg. Med. Chem., 16(12). p. 6448-6459.
- Ngay duyjt dang: 01/10/2015)
^Nghien cmi dieu che bisoprolol.
Phan 1: Toi mi hoa qui trinh dieu che 2-isopropoxyethanol va alcol p-hydroxybenzylic
Truong Phuong*, Biii Thi Hdng Phuc
Dgi hgc Y - Dugc- TP. Ho Chi Minh 'E-mail: [email protected]Summary
2-isopropoxyethanol and p-hydroxybenzyi alcohol were synthetized from ready-available, simple matenats for use as substantial materials in synthesis of the antihypertensive drug bisoprolol. The pmcess was optimized by Software MODDE 5.0 for stability, simplicity and suitability for domestic preparation.
Keywords: 2-lsopropoxyethanol, Isopropyl bromid, p-hydroxybenzylic, Bisoprolol, Antihypertensive.
Dat van d§
Bisoprolol Id t h u l c uc c h l beta t h i hd ll, fie c h l chgn lgc tren beta I, d u g c s u dyng n h i l u , ngodi fac dyng Iren bdnh nhan tang h u y l t dp bisoprolol con chung minh duge kha nang giam tu vong (30%) tren benh nhdn suy tim nang'^'. Tgi Vidt Nam, nhu d u sfi dyng bisoprolol cung kha cao. Vdi cde biet d u g c da dgng tren thi trudng nhu: Concor (Merck KgaA), Detensiel (Merck Cleaculevenot), Monocor (Am, Cyanamid), Soprol (Lederie), Zebeta (Lederie), Ihuoc nay cung da duge dua vao Dugc dien nhilu n u d c (BP2013, USP34)P-^i.
Tren t h i gidi cd mdt s l phuang phdp d i l u c h l
bisoprolol '•'•^. T i t cd cac phuang phdp deu di l u hai nguyen lieu d i u Id 2-isopropoxyelhanol va alcol p-hydroxybenzylic, hai nguydn lieu nay khdng cd d Viet Nam, n l u d n phdi hoan loan nhgp ngogi vdi gia cao. Nganh hda d u g c trong nudc khdng t h i phat trien khi ehi dga vao hda e h l l nhgp ngogi. Chinh vi vgy, nghien cuu lgo ra nhung nguyen lieu dau Id mgt vide lam hodn loan t h i l l thgc nham fao co s d cho vigc phdi trien edng nghiep hda dugc. Trong qua trinh nghien euu, Chung tdi nhan Ihay r i n g vide long hgp hai c h i t nay ddu ed the thgc hidn d u g c trong nudc l u nhung nguyen ligu re, d l k i l m . Bdi bao nay la kel qua nghien cfiu dieu c h l 2 nguyen lieu tren.
TvU» CHI DirpC H p c - 10/2015 (SO 474 NAM 55)
Nghien CCFU - Ky thuat
Ooi tu'O'ng, nguyen iieu va phu'O'ng phap nghien cii'u
Doi tugng
H O -
HgC CH3
,OH
Nguyen lieu
Acid acetic, alcol Isopropylic, n-hexan, natri borohydrid, dicloromethan, ethylen glycol, methanol, natri hydroxid, aceton tinh khilt hda hgc (Trung Quoc), natri hydnd Sigma-Aldrich, p-hydroxybenzaldehyd Acres, alcol p-hydroxybenzylic chuan Merck, isopropoxyefhanol chuan Acres.
Cac hg dung moi sac ky
Hd 1: dicloromefan - aceton (9:1). Hd 2: ethylacefat - n-hexan (2:1). Hd 3: clorofomn - aceton (4:1).
Trang thilt bj
May Idm lanh Eyela PFR-1000, may lam dd EverMed, may c6 quay Stuart, bep cdch Ihuy Memmert, may k h u i y l u Stuart SB162, buing soi UV Vilber Lourmat, mdy do d i l m chay Stuart, may do pho IR FTIR 8101 Shimadzu MPC- 2200, mdy do p h l MS Quattro micro ™API va MierOTOF-Q 10187, mdy do pho NMR Brucker.
T i l n hanh nghien cuu tai bd mdn Hod dugc, khoa Dugc - Dai hgc Y Dugc TP. Hd Chi Minh vd xdc djnh d u true b i n g cac pho NMR vd MS tai Vign hoa hgc Viet Nam - Vidn khoa hge Viet Nam.
Phuo>ng phap nghien cii'u Tong hap isopropoxyethanol
H3C, H3C'
' ) ^ O H
nH NaH
H O ' ^ ~ " • ' " > H O ^ ^ ^ Tong ha'p alcol p-hydroxybenzylic
^ H3C H3C
isopropyl bromid
HO CHO
I . N a O H 2. CH3COOH
+ NaBHi ^^~\ /r + BH3 + CH3CO
4-hydroxybenzaldehyd natri borohydrid 4-hydroxybenzyl alcol
Tot wu hoa b i n g p h i n m i m MODDE 5.0.
Ket qua va ban iuan D i l u che isopropyl bromid Tien hinh phan img
Trong binh d u 100 ml cd cd l u , eho vdo 3 ml (0,039 moi) alcol isopropylic va 36 ml (0,32 moi) acid hydrobromie. Lap vao hd t h i n g chung d t Dun trong 2 gid d nhigt dp 59-61 "C. Qua trinh phan ung fao isopropyl bromid va qua trinh chung d t isopropyl bromid xay ra dong thdi vdi nhau Tgi nhidt do 59 - 61 °C isopropyl bromid vua tao Ihanh se bay hai va ngung tu ngay sang binh hung san pham.
San p h i m thu dufgc Irong blnh hung dugc rua 3 l i n vdi n u d c bdng blnh lang gan d l logi di phan alcol isopropylic va aeid hydrobromie ed the bi Idi cuon sang khi chung c i t Sau do lam khan b i n g Na^SO^. Hieu s u i t phan ung d u g e tinh dua tren ti Id eCia isopropyl bromid thu d u g c sau khi tinh e h l va luong isopropyl bromid Iheo so moi ly I h u y l l .
Hieu s u i t dat 86,74% da kha cao, luy nhien eac phan fing ester hda Ihudng cho hidu s u i t tren 90%. Do do tien hdnh Ihay doi cac thdng s l de khdo sdt tdc ddng cua tfing Ihdng so va lim ra thdng sd foi u u .
T . ^ c m D i r p c H p c - 10/2015 (SO 474 NAM 551
• Nghien CIFU - Ky thuat
Khao sit cac yiu td anh huwig din phan iing
Nhiit do phan ung
Dieu kien phan fing: alcol isopropylic 3 ml (0,039 moi) vd acid hydrobromie 36 ml (0.32 moi).
Thdl gian 2 gid. Thay doi nhiel do 50, 60, 70 "C.
Nhgn xel: Kel qua eho Ihdy lgi nhiet do s6i cua isopropyl bromid 60 °C, hieu suai phan fing cao nhat (86,51%).
77 1$ moi 2 nguyin liiu acid hydrobromie - alcol isopropylic
Dieu kien phan ung: isopropyl alcol 3 ml (0,039 moi) thdi gian 2 gid, nhiet dp 60 °C. Theo tai ligu Iham khdo, so moi HBr dung d u so vdi alcol isopropylic 8 l l n . T i l n hanh khao sal ede tt Iesau: (1:1), (2:1). (3:1). (4:1). (5:1). (6:1), (7:1).
(8:1) tuong ung vdi ede gid trj cua HBr Id 4,5; 9;
13,5; 18, 22,5; 27; 31,5; 36 ml.
Nhdn xdt: tgi nhidt do 60 °C, thdi gian 2 gid, ti le HBr - alcol isopropylic = 3:1, hieu s u i l phan ling dieu c h l isopropyl bromid cao nhat (96,73%).
Thai gian phan irng
D i l u kidn phan fing: alcol Isopropylic 3 ml (0,039 moi) va acid hydrobromie 13,5 ml (0,12 moi), thdl gian 2 gid, nhiet dp 60 °C Thay doi thai gian: 1 , 2 , 3 , 4 , 5, 6. 7 gid. L i y djeh phan ung thu dLfoe d cdc moc Ihdi gian khdc nhau, tinh che va so sanh the tieh thu d u g c
Nhdn xet: Hieu s u i t phdn fing tang d i n theo thdi gian, tuy nhien sau thdi d i l m 3 gid, hidu suit khdng thay doi dang ke. Nhu vay sau 3 gid, lugng isopropyl bromid sinh ra da h i t , chgn 3 gid la thdi gian ngan nhdt phdn ung dgt higu s u i t cao nhlt (96,73%). Phan ung nay khdng d n t h i l t ke toi uu hoa vi higu s u i t phan ung da dat trdn 90%.
Xic dinh tinh chat vat ly vi do tinh khiet Phwang phip vit /y
Tinh fan: san pham lhu d u g c tdch ldp vdl nguyen lieu gdm alcol isopropylic va acid hydrobromie. Nhu vgy, san p h i m ed linh chat khae vdi nguyen lieu.
Tien hanh do nhiet do sdi theo DDVN IV. San pham ed nhiel dp sdi 59 "C khae vdi nhidt dd sdi cOa nguyen lieu isopropyl alcol 82.6 °C, acid hydrobromie 122 °C.
Phwang phip hda hgc
V6 eo hda san pham thu d u g c bang KOH 20%.
K i t qua: d n eho k i t lua vang, nhu vay sdn pham fhu d u g c cd nhdm (-Br).
Pho khoi MS cho k h l i lugng phdn l u 122.99 phil hgp vdi d u trUe d g dodn Id CjH^Br.
Kiim tra do tinh khiit
T i l n hanh kiem tra dp tinh k h i l t cGa sdn pham bang phuong phap chung d t phan dogn djch san p h i m de kiem tra xem ed s g x u l l hign eCia nguydn lidu hay cac tgp c h i t khde eo nhiel dp sdi khdc vdi nhiel do sdi eua isopropyl bromid khdng.
K i t qud: sau khi chung cat phdn dogn, san pham thu d u g c hau h i t d khoang nhigt do 59-61
°C. d cdc nhigt do khac, lugng djch sdn p h i m lhu d u g c la khdng ddng ke. Dieu dd chung td sdn pham lhu d u g c tuong doi tinh khilt va dii dieu kign de thue hign edc budc tiep theo.
T o n g h g p 2-isopropoxyethanol Tien hinh phan U'ng Gdm 2 giai dogn:
Giai doan 1: Diiu chi monoethylenglycolat natri.
Trong binh d u 100 ml eo ca t u , eho 12,5 ml (0,22 moi) ethylen glycol; 0,9 g (0,04 moi) NaH va 100 ml THF. Phan ung thuc hien d 0 °C, thdi gian 2 gid. NaH la fac nhan base mgnh d l hut am, dd tdc dung vdi nudc Irong khdng khf tgo thdnh NaOH. Do do dung cy tiln hdnh phai that khd.
Giai doan 2; Diiu chi 2-isopropoxyethanol.
Trong binh c i u 100 ml, monoethylenglycolat natri lgo thdnh eho phdn ung ngay vdi 3,8 ml (0.04 moi) Isopropyl bromid. Hdn hgp d u g c khuay trgn d nhiet dd 59 °C, trong 10 gid. Dun hoi luu vdi he t h i n g sinh han d u g c ldm lanh. San pham lhu dugc dem chung d t sa bg d khoang nhidt dp 120-141 °C l i y djch, tinh higu s u i t phan ung.
Luu y' Tuy chia thanh 2 gial doan nhung thgc le 2 phdn fing xay ra eung mdt liic.
Tinh che, tinh hieu suit
Chung cat phan dogn d khoang nhiel dp 139- 141 °C lhu djeh 2-isopropoxyethanol tinh khilt.
Nhdn xet: vdi cdc thdng so d trdn, hieu s u i t phan ung chl dat 48,03%. Do vdy, c i n phai ttln hdnh khao sal s g dnh hudng cua cdc thdng s l
TAP CHI Dirpc H p c -10/2015 (S6 474 NAM 55) 65
Nghien CIFU - Ky thuat
den higu s u i t phdn ung, t f i dd tim ra dieu kien toi u u .
Khao sat cac yeu td inh hu-ong Nguyen tic tiin hanh
c l dinh cdc thdng so giai dogn 2 nhu tren.
Tien hanh khao sat giai dogn 1 bdng each thay doi Ihdng s6 d giai doan 1 de lim d i l u kign Ihich hgp n h l t C o s d d l ddnh gia la higu s u i t ether thu d u g c d giai dogn 2.
Khao sit giai do^n 1 - Dung mdi tham gia phan fing
T i l n hanh khao sat vide diing hay khdng dilng dung mdi THF trong giai doan 1.
Nhan xet: k i t qud eho thiy, dung moi THF khdng lam thay doi hieu s u i t phdn ung dang ke.
THF Id khdng d n t h i l l . - Tl Id ethylenglyeol - NaH
Dieu kien phan ung: 0,9 g (0,04 moi) NaH, phdn ung thuc hidn trong thdi gian 2 gid, nhigt do 30 °C (giai doan 1). 3,8 ml (0,04 moi) isopropyl bromid, nhigt dp 59 "C, trong 10 gid {Giai doan 2).
Theo tai lidu tham khao, s l moi ethylen glycol diing d u so vdi natri hydrid 5.5 l i n . Tien hanh khao sat Igi eac tile sau: 1,5:1,2,5:1,3,5:1,4,51, 5,5:1.
Nhgn xel: Tgi ti Id 3,5:1 hieu s u i t phan ung cao n h l t vdi lugng ethylenglyeol fl nhdt Ti Id 4,5.1; 5,5:1 higu s u i t khdng thay doi n h i l u , nhung lugng ethylen glycol s u dung lgi d u n h i l u , khdng c i n Ihiel. d eac ttie 2,5:1,1,5:1 hieu s u i l gidm x u i n g . D i l u nay cd the giai Ihich nhu sau:
do NaH d u phdn ung vdi isopropyl bromid d giai dogn 2 fao thanh isopropyl alcol va NaOH lam giam higu s u i t phan ung. Do dd, chgn ti Id 3,5:1.
- Nhief do phdn ung
Dieu kidn phdn ung; ethylen glycol 8,7 g (0,14 moi), NaH 0,96 g (0,04 moi), phan ung thuc hign tnDng thdi gian 2 gid (giai dogn 1). 3,8 ml (0,04 moi) isopropyl bromid, nhigt do 59 °C, trong 10 gid (G/a; doan 2).
Thay d l i nhiet do giai doan 1: C C , 30 "C, 50 "C, 80 "C.
Nhdn xdt: d khoang nhiel dp l u 0-50 "C, hidu s u i t phan ung khdng chenh leeh ddng k l , d 80
"C hieu s u i t dd giam xudng, Nhu vay chgn 30 "C
Id nhiet dp phong cho phdn ung d u g c t i l n hdnh thugn lgi.
- Thdi gian phdn fing
Dieu kien phan fing: ethylen glycol 8.7 g (0,14 moi); NaH 0,9 g (0,04 moi), phan ung Ihuc hign nhigt dg 30 "C (giai dogn 1). 3,8 mi (0,04 moi) isopropyl bromid, nhidt dp 59 °C, Irong 10 gid (Giai do^n 2). Thay d l i thdi gian phdn ung: 0,5, 1,2, 3, 4, 5 gid.
Lay djch phan ung thu d u g c d cde m i c thdi gian khdc nhau, tinh e h l vd so sdnh the tfch lhu d u g c
Nhan xel: kel qud cho thay, fai thdi diem 0,5 gid, phan fing chua xdy ra hodn lodn, hieu s u i t thap, higu suat phdn ung tdng dan d i n khi dgt t l i da d Ihdl diem 2 gid. Sau do higu s u i t bdt dau giam. N h u vdy. chgn thdi gian 2 gid theo nhu patent tham khdo.
Nhu vgy dieu kien thfch hgp phdn fing la elhylen glycol 8,7 g (0.14 moi); NaH 0,9 g (0,04 moi), nhidt dd 30 °C, thdi gian 2 gid.
Khao sat cac yiu td anh hwdng din phin Ong tao 2-isopropoxyethanol
- Nhiet dp phan ung
D i l u kign phan ung: elhylen glycol 8,7 g (0,14 moi), NaH 0,9 g (0,04 moi), nhigt dg 30 *C, thdi gian 2 gid (giai doan 1), 3,8 ml (0,04 moi) isopropyl bromid, thdi gian 10 gid.
Khdo sal cdc nhiet do sau: 60 °C, 80 °C. 100 "C, 120 °C.
Nhgn xel: k i t qud cho thay, nhiet dd cd dnh hudng r i t Idn den higu s u i t phan fing. Cl 70 °C phdn fing chua xay ra hoan toan, d 120 "C higu s u i t phdn ung gidm. Do dd chgn 100 °C.
Tf le moi ciia isopropyl bromid vd monoethylenglycolat natri
D i l u kien phdn ung: ethylen glycol 8,7 g (0,14 moi); NaH 0,9 g (0,04 moi), nhigt dg 30 °C, thdi gian 2 gid (giai doan 1), 3.8 ml (0.04 moi) isopropyl bromid, nhiet do 100 °C thdi gian 10 gid.
Theo phuang trinh phdn fing, tt Id so moi cila isopropyl bromid va monoethylenglycolat nalri (dua vdo lugng NaH) la 1:1. T i l n hanh khao sdt lai cdc fi lg 1:1; 1,5:1; 2 : 1 , tinh c h l san pham va linh higu s u i t thu dugc.
66 p r-wf n l rrrr- n o r - . i nntti« /«*S d
• Nghien CIFU - Ky thuat
Nhan xdt: tt l^ giua 2 thdnh p h i n trdn cd anh hudng Idn d i n higu s u i t phan ung. chgn 1,5:1 Id ti le t l i u u .
- Thdi gian phan fing
D i l u kign phdn ung: ethylen glycol 8,7 g (0,14 moi); NaH 0,9 g (0,04 moi), nhigt dg 30 °C, thdi gian 2 gid (giai dogn 1), isopropyl bromid : elhylenglycolat nalri 1,5:1, nhiet do 100 °C. thdi gian thay d l i : 8, 9 , 1 0 , 1 1 , 1 2 g i d . Lay djch phan fing thu dwgc d cdc moc thdi gian do, tinh c h l vd so sdnh hidu s u a t
Nhdn xel: kel qua cho thay, tgi thdi diem 10 gid, phan ung eho hidu s u i t eao nhat N h u vdy, chgn 10 gid Id Ihdi gian t l i u u .
Tdi IFU hoa quy trinh tong hgp 2-isopropoxyethanol
Chon yiu td anh hwdng din hieu suit phan Ong di khao sit
T u thgc nghigm thdm dd, l i l n hanh b l trf lhi nghiem bgc 2 Iheo md hinh Box-Behnken vdi 3 y l u t l sau:
Y l u t l X,: Ihdi gian phan fing dieu c h l 2-isopropoxyethanol.
Y l u t l X^: nhidt do phdn ung tgo ether.
Y l u t l X3: tt lg moi isopropyl bromid va monoethylenglycolat natri.
Trong dd:
X., nhan cac gid trj (1;2;3); X^ nhgn ede gia trj (80;100;120); X3 nhgn cac gid trj (1;1,5;2).
Mi hda cic yeu td khao sat
Bang 1 : Ma hda cic yiu td khao sat phin img dieu chi 2-isopropoxyethanol Yeu to
X, X.
X.
Miicdimi-t 1 80 1
Cac mirc M i i c CO s a O
2 120 1,5
Mile fren +1 3 120
2 B6 tri ma trin thwc nghiem theo md hinh Box- Behnken vdi phin mim Modde 5.0
Bang 2: Ma tran thwc nghiem vi kit qui tdi wu hda cac phan img IWatfif Vleettiyten Ntmtdg Tife;sopropyf Hiiu suit nghian giyco/-WaH (gidj bromid va NaH (%)
113 N4 N5 N6 N7 N8 N9 NIO N11 N12 N13 N14 N15
1 3 1 3 1 3 2 2 2 2 2 2 2
120 120 too too too 100 80 120 80 120 too 100 100
1,5 1,5 1 1 2 2 1 1 2 2 1,5 1,5 1,5
63,4 66.28 51.87 54,76 64,84 69,16 50,43 54,75 61,96 72,05 79,25 80.69 8213 Phuong trinh b l mgt dap ung d l i vdi hi§u s u i t d u g c t h i l l lap nhu sau:
Y(%) = 80,69 + 1,8025 X, + 3,4225 X^ + 7,025 X3 - 9.36625 X,^ - 9,72624 X^^ - 11,1662X3^+1,4425X3X3 K i t qud phan tfch cac he sd eua phuong trinh h l i quy fhuc nghigm. S u tuong quan giua hidu s u i t vd cdc y l u to khao sat chat che, t h i hidn qua hg s l tuang quan R2 = 0,999 vdi muc dd tin d y 95 % (p < 0,05). 3 y l u to khao sat d i u dnh hudng cd y nghTa d i n hieu s u i l phan fing.
S f i dyng chuc nang d g dodn cua MODDE 5.0 hidu s u i t i l l uu dgt dwgc eiia phdn ung Id :
83,27% tgl edc Ihdng so d i l u kien: X I = 2 , 1 ; X 2 = 104; X3 = 1,67.
Thuc hign 3 l i n cac phan ung, s u dyng ede thdng so l l i u u Iheo d g dodn thu d u o c k i t qud fa 82.13%.
Nhgn xel: Md hlnh ddp ung l i t cdc gid tri chgn de khao sat t l i uu. VCing gid tri cgc dai deu nhin Ihay duge trdn cdc dudng dong muc, gid In higu s u i t lhu d u o c sau khi t i l n hdnh bdng thgc nghigm dga Irdn md hlnh cd gid In g i n b i n g gia lri d g dodn.
Xac djnh dp tinh khiet vi cau true Tinh chit vat ly
Nhiet dp sdi cOa 2-isopropoxyelhanol: 139- 141 °C phil hgp vdi tdi lieu 131-141 '^C va chat c h u i n (140-141°C).
3V
C H H3CA
'fl 2Q'-y^
1.5 1.5
56,19 60,52
T ^ C H l DU'OC H O C - 10/2015 (SO 474 NAIM 55)
• Nghien CLPU - Ky thuat
Bang 3: Phd cua 2-isopropoxyethanol
IR(cm-1) 'H-NMR
8 ppm (lo^i dinh, so H, nhdm)
''C-NMR Sppm (nhom)
PtiD IR cua san ptiam fioan tc phu hop vol ptio ctiuan
3,604 - 3,650 (m,1H,-CH<) 3,519 - 3,537 (t, 2,5Hz, 2H, -CH,-) 3,660-3,700(1,2,5 Hz,2H,-CHj-) 1,181-1,186(d, 2,5Hz. 3H.-CH,)
72.581 (C,,) 60.776 (C,) 68.630 (C,) 21.068(C^.C,)
104.14
1.169-1.174(d. 2.5Hz 3H.-CH,)
Nhgn x e t Dga vao k i t qua cua cac phuong phap xdc djnh d u tnJc, dp tinh k h i l t cho t h i y san pham phu hgp vdi d u triic d g dodn. San p h i m 2-isopropoxyethanol tinh khilt va ed the s u dyng lam nguyen lidu cho phan ung l i l p sau.
T i n g hgp alcol p-hydroxybenzylic Tien hinh phan img
Trong 1 d e cd md 150 ml cho vdo 2,5 g (0,02 moi) p-hydroxybenzaldehyd. Hda lan mdt h i n hgp g i m 0,9 g (0,02 moi) NaOH r i n va nudc, cho t i l p vao d c cd md Irdn. Dat d c cd md Iren b i p k h u i y l u , k h u i y cho hdn hgp tan hodn lodn Ihanh djch dong n h l t vd trong. Hoa tan mgi hon hgp gom 0,3 g NaBH^ va nudc, cho lung gigt h i n hgp Iren vao coc cd md. Phan ung dugc Ihuc hidn trong 30 phUt nhiel dd 15-20 "C. Tinh che sdn pham, tinh hieu s u i t
Tinh chi sin phim; Sau khi phdn fing k i t thOc, sdn p h i m d dang m u l i natri hda lan trong nudc, do dd can phdi acid hda de thu san pham dgng k i t tua. Cdc budc tmh c h l thu alcol p-hydroxybenzylic nhu sau: S l y khd ran, hda tan ran trong 20 ml CHCI3 dun ndng, de ngupi t f i t f i vd Idm lanh cho k i t tinh lai. Sau do Igc thu alcol p-hydroxybenzylic tinh k h i l t K i l m Ira dg ttnh khiel bdng s i c ki Idp mdng vdi he 1, 2, 3.
Nhin xet: vdi cae thdng so dugc d dinh d tren. k i t qua eho I h l y hieu s u i t phan ung chua dwgc cao, chf dat 68,41%. Do vdy, can phai tien hanh khdo sat s g anh hudng ciJa cac thdng s l d i n hieu s u i t phan fing, t u do lim ra d i l u kidn toi uu.
Khio sit cic yiu td inh hwang den phan Ong dieu che alcol p-hydroxybenzyfic
Nhiet dd phin wng
T i l n hanh Iheo cac dieu kign p-hydroxybenzaldehyd 2,5 g (0.02 moi) 0,9 g (0,02 moi) NaOH. 0,378 g NaBH4(0,01 moi) thdi gian 30 phtit nhigl dp 15-20 °C. Khao sat l h u nghigm lgi cdc nhidt dg 0 , 1 5 , 30 °C.
Nhdn xdt hidu s u i t phdn fing xdy ra d 15 vd 30
°C chenh lech nhau khdng dang ke. Do dd, chgn 30
"C de tiln hanh phdn fing vi dd Id nhigt do phdng.
77/# p-hydroxybezaldehyd - NaBH_, T i l n hanh Iheo cde d i l u kien p-hydroxybenzaldehyd 2,2 g (0,02 moi). NaOH 0,9 g (0.02 moi), thdi gian 30 phut, nhidt dd 30
°C. Thay doi ti Id eiia p-hydroxybezaldehyd vd NaBHJan lugt Id: 1,5:1; 2:1; 2,5:1; 3:10; 3,5:1.
Nhdn xet: hidu s u i t dgi cao n h l t khi tt Id p-hydroxybezaldehyd va NaBH^ la 2,5:1. Cf fi Id 3.5:1, lugng NaBH^ khdng dCi d l phdn ung h i t vdi p-hydroxybenzaldehyd d i n d i n djeh san pham cdn nguyen lieu, khd tinh c h l , higu s u i t phan ung giam. T7 le 1,5:1, lugng NaBH^ s u dung tai nhilu vua khong d n thiet lgi lam lugng muoi sinh ra sau qua Irinh aeid hda nhieu len, do dd d n Ihem nudc d l hda tan m u l l , luong nudc nhilu eung lam tan mdt phan san p h i m gdy glam hidu s u i t Do dd, chgn fi Id 2,5:1 cho hidu s u i t cao n h l t
7710 p-hydroxybezaldehyd - NaOH T i l n hanh theo cac d i l u kign p-hydroxybenzaldehyd 2,5 g (0,02 moi), NaBH^
0,3g (0,008 moi), Ihdi gian 30 phOl. nhiel d6 30
"C. Thay doi ti Id cOa p-hydroxybezaldehyd vd NaOH lan lugt la: 1:0.5; 1:1; 1:1,5 d l khdo sdt s u dnh hudng cua NaOH len hieu s u i t phan ung Nhgn x e t k i t qua cho Ihay, d ti Id 1:0,5, lugng NaOH chua du de hda tan p-hydroxybenzaldehyd.
68 TAP CH'
• Nghien CIFU - Ky thuat
djch sdn p h i m van con nguyen lieu, ldm higu suat phan fing thap. Vdi 2 tt le cdn tgi. higu s u i t khdng chenh lech n h i l u . Do dd, chgn tf l^ 1:1 la ti Id cho higu s u i t cao nhat vd ton fl nguydn lieu nhai d the.
Thdi gian phan ung
T i l n hanh theo cdc dieu kign p-hydroxybenzaldehyd 2,5 g (0,02 moi) NaBH^
0.3g (0,008 moi), NaOH 0,9 g (0,02 moi) nhidt do 30 °C va l i y djeh phdn ung c h i m tgl ede thdi d i l m 15 phiit, 30 phut. 45 phut. 60 p h i i t 75 phut. 90 phut t r i l n khai SKLM vdi hd dung mdi dielorometan - aceton (9:1). Mau d l i c h i l u Id p-hydroxybenzaldehyd chuan.
Nhan x e t hieu s u i t tang ddn theo thdi gian phan fing va dgt cao n h l t lai Ihdi d i l m 60 phiit, sau dd hi#u s u i t cd xu hudng gidm. Do dd, chpn 60 phut la thdi gian khdo sdt de thgc hidn b u d c toi uu hda.
Chon acid vi pH dich phan img T i l n hanh aeid hda djch phan ung b i n g 3 logi acid: HCl. H^SO^, CH3COOH. K i t qud cho hidu s u i l khdng ehenh lech ddng k l , do dd lua chgn acid acetic theo nhu tdi lieu tham khao. Khao sal pH d 3 gia In 6, 7, 8, tinh e h l , linh khoi lugng va so sanh higu s u i t phan fing.
Nhgn xet k i t qua eho thiy, hieu s u i l phan ung dgt cao nhat d gia trj pH 7. & pH 8 djeh san p h i m cdn lfnh kiem, sdn p h i m khdng ben trong mdi trudng kiem, do do hieu s u i t thap, d pH 6 lugng acid cho vao d u n h i l u , higu s u i t lgi giam d\. Do dd chgn gid trj pH 7 d l thgc hign bude toi uu hda.
Toi uv hoa quy trinh tong hgp alcol p-hydroxybenzylic
Chgn yiu td anh hwang din hieu suit phan ung di khio sit
T u Ihge nghidm tham dd, tiln hanh b l tri thi nghidm bdc 2 theo md hlnh Box-Behnken vdi 3 y l u to sau:
Yeu to X,: thdi gian phdn fing (phut).
Y l u t l X^: tt Id p-hydroxybezaldehyd va NaBH^.
Y l u lo X3: pH djeh phdn ung.
Trong dd:
- X, nhin cac gia trj (30; 60; 90).
- XJ nh$n cac gia trj (1,5; 2,5; 3,5).
- X, nh$n cac gia trj (6; 7; 8).
Ma hoa cic yiu td khao sat
Bang 4: Ma hda cic yiu td khao sit phan wng diiu chi alcol p-hydroxybenzylic
Yillt6
X, X, X,
M&c duui-1 30 1.5 6
Cac muc MuccasaO
60 2.5 7
Muc tren +1 90 3,5 8 Bo Irf ma trgn thue nghiem theo md hinh Box- Behnken vdi phan mem Modde 5.0.
Bang 5: Ma trin thwc nghiim vi kit qua tdi wu hda
tfli ngliiem Ttiai gian p-hydroxybezaldehyd - HaBH,
1,5 1.5 3,5 3,5 2,5 2,5
pH 7 7 7 7 6 6
Hieu sui
54,44 49,6 42,34 45,16 66,53 62,5
N12 N13 N14 N15
8 65.73 8 52.02 7 85.89 7 85.08 7 85.48 Phu'ang trinh be mat dap irng d6i vai hidu su^t du'gc t h i l t lap nhu* sau:
Y(%) = 85.4833 - S.2925 X , - 3,02375 X , - 19,0029 X,2 - 18,5954 X / - 4,58791 X,=
Trong do:
-X,; thai gian phan irng (phut); X,' ti le p-hydroxybezaldehyd va HaBH. X^- pH;
Y: hieu suStphSn img {%)
Ket qua phan tich cac he so cua phirang trinh h6i quy thyc nghidm du'gc the hien ty hinh 1. S y t y a n g quan giya hieu suat va cac yeu to Ichao sSt chat che, the hign qua he so t y a n g quan R^ = 0.996 val m y c do tin egy 95 % (p < 0.05).
T.^P CHi Diroc HOC - 10/2015 (SO 474 NAIM 55) 69
• Nghien CIFU - Ky thuat
Sw tic dgng cua cic yiu td khao sat len hi$u suit phan Ong
Hinh 1: Thir tw tic dong cOa cic yiu td lin hiiu suit phin img Hinh 1 the hien s g tac dgng cua cde y l u l l
khao sdt ldn higu s u i t phan fing. Yeu to X^ (ti le p-hydroxybezaldehyd : NaBH^), vd y l u lo Xg (pH aeid hda djch sau phdn fing) d l u a n g quan Ihudn, trong do y l u td X^ d dnh hudng Idn n h i t Khi blnh phuong gid trj cde yeu to nay thi xay ra tuang quan nghjch Idm gidm mgnh hieu s u i t
S u dung ehuc nang d g dodn ciia MODDE 5.0 higu s u i t l l i uu dgt d u g c eua phdn ung Id:
86,34% lgi cdc thong so d i l u kidn: X, = 59; X^
= 2 , 3 7 ; X 3 = 7 .
Thuc hidn phan ung sfi dyng eac Ihdng so loi uu theo d u dodn d u g c k i t qud 86,29%.
So vdi phuong trinh hoi quy thgc nghiem, hidu s u i t ndy cao hon. ed t h i san p h i m lhu d u g c chua d u g c s i y khd hodn todn edn ldn nude. Tuy nhidn s u chdnh Idch ndy Id khdng dang k l .
Bang 6: Phd cOa alcol p-hydroxybenzylic Nhin xit
Md hinh dap ung lot, cde gia tn chgn de khdo sdt toi u u . Viing gid trj cgc dgi d i u nhin thay dugc tren cdc dudng dong mfic, gia tn higu s u i t thu duge sau khi l i l n hanh bang thgc nghidm dga frdn md hinh ed gid trj g i n bang gla tri d g doan.
Xac djnh dd tinh khiet va cau tnic K i t qua do d i l m chay; 124. N h u vdy k i t qua phu hgp vdi fai lidu tham khdo (118-125 °C) vd c h i t chuan (123 °C).
Sac kf Idp mong: san pham sau tinh c h l cho 1 vet khdc vet p-hydroxybenzaldehyd va cho v i t ngang vdi ehuan.
^ 1 ^ HO'^
UV(nm} IR(cnr') 'H-NMR Sppm (I09I dJnh, so H, nhom) "C-NMR Sppm ( nhom)
• Pho IR cua san pham ho^n toan phil hgp vd'i ph6 chuin
4.3a(s.2H.-CH,-) 4.98(S,1H, OH alcol) 6,720 - 6,737(d, 8,5Hz, 2H, H, vS H.
7,114-7,130 (d,8Hz,2H,H,vaHJ
62,98(-CH,-OH) 114,97 c, vac.) 128,24(C,»SC,) 132,89 (CJ 9,24,(s,1H, OH phenol) 156,34(=C-OH) Nhin xit
Dua vdo k i t qua cua cac phuang phdp xdc dinh c i u Iriic, do tinh k h i l t cho t h i y san pham phil hgp vdi d u Iriic d u dodn. Sdn p h i m alcol p-hydroxybenzylic tinh khiet va co t h i s u dyng Idm nguydn lidu cho phan fing l i l p sau.
K e t l u a n
T u nhfing nguyen lieu don gian, d l k i l m d Viet Nam. chiing tdi da xay dung dugc quy trinh l i n g hgp 2-isopropoxyelhanol va alcol p-hydroxybenzylic nguydn lieu d n t h i l t cho tong hgp thuoc chong tdng huyet dp bisoprolol. Qui
(Ngay nhan bii: 09/08/2013
trinh d u g c t l i u u hda bang phan m i m MODDE 5.0. Quy trinh dan gian. phii hgp vdi ^ l u kign d Viet Nam, d linh ung dyng eao.
T a i i i e u t h a m I t h a o 1. Lechat P. et al (1999), "The cardiac bisopmlol study tt (CIBIS ll): a randomized tnal", Lancet, 353 (9146), p. 9 -13.
2. British Pharmacopoeia 2009.
3. United States Pharmacopoeia (2013), CD-room 4. Ruchi A., Ramaknshnan A , Ajay D. C , Rajesh H. P. ( 2005), "A novel process for the synthesis of bisoprolol and its intermediate", WO2007069266.
5. Zongli Zhang (2010), "Synthesis technology of bisoprolol", CN101B98972.
• Ngiy duyit ding; 01/10/2015)
