s o BO NGHIEN CtfU TONG
HOP DAN XUAT DIMER PHENYLBUTENOID
Trucmg Ngoc Tuyen*, Nguyen Thi Tliu Thuang*
T O M TAT
Muc Heu: Tir nliimg nguyen lieu re tien vd cdc phdn img thong dung tim hdnh tong hgp dimer phenylbuterwid-mot chai dugc chiii tie cdc cdy hg gimg md gan day dd dugc thie nghiem tien te'bao ung thu vd CO tdc dung doc v&i tebdo.
Phuangphap nghien cdu: cho deh nay chua cd tdi lieu ndo ve tohg hgp cdc ddn chai ndy,dua tien cdc phdn img plio bieh va de thuc hien nhu Witiig, Diels-Ander, benzyl hoa..., chung toi dd thiB kemot quy trinh tohg hap gom 2 buac tohg hap nguyen lieu ddu vd 6 bu&c detong liap dan xu^ trung gian dau tien ciia dimei' plienylbutawid. Sdn phdm tong hap dugc xdc dinh cdu true hdng cdc phuang phdp vqt ly hien dqi nhu quang pholidng ngoqi, plio cgng huang tir hqt nhdn, pho khoi.
Kei qud: Dd tohg lurp dugc ddn xuat ddu tien cua dimer phenylbutanoid vd dd duac xdc dinh do tinh khiB vd chdng minh cmi true bdng cdc phucmg phdp vqt ly hien dqi.
Kei luam Tie ket qud tren, co the irng dung quy trinh ndy detiep tuc dieu che'cdc ddn xuai cua dimer phenylbutenoid
Tit khoa: Hg gung, ung thu, dimer phenylbutenoid, Diels-Ander, Wittig ABSTRACT
STUDY OF PREPARATION OF PHENYLBUTENOID DIMER
Truong Ngoc Tuyen, Nguyen Thi Thu Thuong
* Y Hoc TP. Ho Chi Minh * Vol. 14 - Supplement of No 1 - 2010:100 -104 Objectives: based on simple starting materials and well-known reaction, we design and synthesis a derivative ofplienylbutenoid dimer- a compound has potential in cancer tieatment.
Method: until now, there has been any researdi about synthesis of derivatives of phenylbutenoid dimer, in order to get phenylbutenoid dimei- we design a scheme consisting of 8 steps (induding 2 steps for preparing starting materials). Produd were detamined the purity and structure by modem physical methods such as infra- red, nuclear magnetic resonance and mass spectiophotometiy.
Result: as a result, from the scheme was designed, we synthesized the first derivative of phenylbutenoid dimer through 8 steps.
Conclusion: from the result, we can apply the scheme to prepare derivatives of phenylbutenoid dimer.
Keywords: Zingiberaceae, cancer, phenylbutenoid dimer, Diels-Ander, Wittig
DAT V A N DE ^"^ ^^ P^^* *^'^" ^ " ^ S ^^ ^ ^ * "^^ *^^ dung tiong dieu tii la m6t nhu cau cap bach, het sue Ngay nay, ung thu la mgt tiong nhimg - /L--^ > ^
® -^ ^ ° , , * - . , ? - can thiet va quan hong.
nguyen nhan gay tu vong hang dau tien the
gioi. Cimg voi ti le benh tang cao, su xuat hien Gan day, cac nha khoa hoc da chung minh cua tinh hang khang thuoc dang lam cho ung rang cac dimer phenylbutenoid dugc tim thay thu ngay cang \td nen nguy hiem. Do vay, viec trong cac cay hp Gimg co kha nang gay dgc te
* • Khoa Duac - Dai hpc Y Duoc Tp. Ho Chi Mmh
Dia chl lien lac: TS. Tnrong Ngoc TuySn DT- 0903330604 Email [email protected]
bao''', mo ra mgt huong nghien cuu moi voi hi vpng tim ra thuoc khang ung thu. Da co nhieu nghien cuu ve cac dimer phenylbutenoid nhung chu yeu la phuong phap chiet tach va thii tac dung dugc ly ma chua di sau vao phuong phap tong hpp hoa hgc, mac du ham lupng cua cac dimer phenylbutenoid trong tu nhien rat thap va qui trinh chiet tach, tinh che rat phuc tap<".
Chinh vi vay, chiing toi thuc hien nghien cuu nay nham tim ra mgt phuong phap tong hgp cac dan xuat dimer phenylbutenoid de co the cung cap mgt Iupng mau lon va phong phli hon cho nghien cuu.
'yr- n
S^oc
:yr^^
Hinh 1: Cdu tqo hoa hoc dm mot so'dimer phenylbutenoi^^^"'
DOI TUlQNGJWUt^NG PHAP NGHIEN CUlJ Nghien cuu nay dupc thuc hi^n nham tong hgp dan xuat dimer phenylbutenoid tir cac hgp chat hoa hgc don gian dua tren nhimg phan ling th6ng dung.
Phucmg phap tong hap hoa hgc*^*
Hoa diat sir dung la nhiing chat don gian va re tien nhu; 3,4-dimethoxybenzaldehyd, 4- hydroxy-3-methoxybenzaldehyd (vanilin), benzyl bromid, triphenylphosphin, allyl bromid, glycerol,.... Phan iing dugc chpn la nhiing phan ling pho bien, hieu suat cao va co tiie hen hanh tiong dieu kien phong thi nghiem 6 Viet Nam nhu: phan iing bao ve nhom -OH bang goc benzyl, phan iing Wittig, Diels-Ander,...
Qui trinh tong hpp dupc thie't ke cu the nhu sau:
OCH3
H j C O ' S ^ ' H3CO'
- ^ HjCCrV ^ ^ H.CO'V
O C H a - - •
••^ ---'rx) H-YJO "-^2C ^o
Dieu kien: (i): PPhs, toluen, 0-25 "C; (ii): KHSO., K2SO4,190-200 »C; (iii): NaBHj, MeOH, 0-25 °C;
(iv): PhsP.HBr, 100 -C; (v): Benzyl bromid, IGCO3, DMF, 100 "C; (vi): A, ii-BuLi, E « 3 , 0-25 "C;
(vU): B, 100 "C; (viii): n-BuLi, EbO, 0-25 "C.
Uinh 2: Sado tong hop ddn chiit dimer phmylhutenoid
Phuomg phap thuc hien lam nguyen lieu cho phan iing long hop muoi Giai doan 1: dieu che 3,4KUmethoxyben2yl triphenylphosphonium.
alcol bing phan ung khir hoa 3,4- Giai doan 2: sau khi bao ve nhom-OH bing dimelhoxybenzaldehyd voi natri borohydrid de S * benzyl, tiep tuc gan them vong hexen vao
phan tir vanilin bang phan ung Wittig va Diels- Alder de tao hgp chat cydohex-3- encarbaldehyd.
Giai doan 3: thuc hien phan iing Wittig giiia muoi triphenylphosphonium va hgp chat cydohex-3-encarbaldehyd de dfeu die din xuat dimer phenylbutenoid.
Trong thuc nghiem:
Theo doi phan iing bang sac ky lop mong (SKLM). So bg toi uu hoa doi voi cac phan ling CO hieu suat thap.
Tinh che san pham bang sic ky cgt (SKC) va ke't tinh lai.
Kiem tra dp tinh khiet cua san pham bSng nhiet do nong chay, sac ky lop mdng Xac dinh c a u t n i c b a n g p h o IR, ^H- N M R v a M S .
KETQUA
Tong hpp allyltriphenylphosphoniiiTn bromid (1)
Them allyl bromid vao binh cau chiia tiiphenylphosphin trong toluen khan 6 0°C . Khuay trong 24 gio 6 nhiet dp thudng. Lpc lay hia, say a 60°C. San ph&n la chat ran ke't tinh vo dinh hmh, mau tiang (H = 92,7%.). Nhiet dp nong chay: 223°C. Pho IR (v, cm-\ KBr): 1486 (UC-H); 788, 759 {6c-H(aryi)); 3047 (i'c-H{aryi)); 719, 694
(65C-Hkfciii).
Tong hgp acrolein'" (2)
Cho niia lugng glycerol, kaH hydrosulfat, kali sulfat vao binh cau 2 co. Mgt co cua binh cau gan voi cgt Vigreux co gan nhiet ke. Nhanh con lai cua cgt Vigreux gan voi sinh han thang noi voi erlen hiing qua simg bo. Dim each dau 6 200
°C. Khi hon hpp phan iing bit dau chay long, tiep tuc them timg gipt glycerol cho den het.
Hiing san phaim cho den khi nhiet ke chi 100 <!
thi ngung. Dimg cpt Vigreux chung cat san phain tho. Hung san pham 6 phan doan 51±1 <:.
San pham la chat long tiong suo't, khong mau, co miu kho chiu, kich iing manh mat, miii, gay rat da. Hieu suat 25,44%. Nhiet do s6i: 52 "C. NMR PMSO-500MHz) 6: 9,54 {IH, d, J=7,5Hz, CHO); 6,59-6,57 (IH, m, =CH-); 6,47-6,43 (IH, m,
=CH2); 6,35-6,28 (IH, m, ^Hi).
Tong hgp 3,4-dimethoxybenzyI alcol (3) Them nahi borohydrid vao binh cau chiia dung dich 3,4-dimethoxybenzaldehyd hong methanol 6 0 "C. Khuay a nhiet dp thuong trong 60 phiit. Trung hoa bang acid hydroclorid 10% 6 0 °C. C6 quay loai dung m6i, chiet tai bang dicloromethan. Co quay thu hoi dung moi, tie'n hanh SKC voi he dung m6i hexan:aceton (10:1). San pham thu dupc co dang dau sanh, mau vang nhat, khong miii.
Hieu suat: 91,1%. 'H-NMR (DMSO-500MHz)
&: 6,93 (IH, d, J = IHz, H^-Ar); 6,90-6,88 (IH, m, He-Ar), 6,84 (IH, d, J=8Hz, Hs-Ar); 4,61 (2H, s,-CH2-); 3,89 (3H,s,-OCH3); 3,87 (3H,s, -OCHs);
1,66 (lH,s,-OH). ESI-MS m/z: 151,00 [M-OH]-.
Tong hgp [{3,4-dimethoxyphenyl)methyl]
triphenylphosphonium bromid (4) Cho 3,4-dimethoxybenzyl alcol (3) vao hon dich triphenylphosphin hydrobromid trong acetonitiil khan, dun hoi luu 6 85 "C trong 3 gio. Co quay toi can, ket tinh lai tiong h6n hgp tehahydrohiran va diethyl ether San pham la chat ran ket tinh khong mau, toi xop. Hieu sua't: 95,5%. Nhiet do nong chay: 235 "C. Pho IR (v cm-i, KBr): 1255 (uc-o(aryi)); 1226 ( uc-o{aikyi));
746 (&5C-H ke cin); 867 (62C-H ke can). ESI-MS m/z:
413,196 [M-Br]^
Tong h g p 4-benzyloxy- 3 methoxybenzaldehyd''(5)
Cho benzyl bromid vao binh cau chiia dung dich 4-hydroxy-3-methoxy benzaldehyd trong DMF, khuay deu. Them kali carbonat vao h6n hgp phan ung. Dun hoi luu 6 100 °C
trong 3 gio. Gan lay dich, them nuoc cat de san phaim ket tinh. Lgc lay tiia, say 6 khoang 40-50
"C. San phaim la chat ket tinh mau hang, khong mui. Hieu suat: 98%. Nhiet do nong chay = 62 C Pho IR (v, cm-i, KBr): 3012 (uc<);
1676 (uAryi-cHo); 1261,1031 (6c-o); 813 (62c-Hked,n).
ESI-MS m/z: 265,08 [M+Na]\
Tong hgfp l-(4-benzyloxy-3- methoxyphenyl)but-l,3-dien (6)
Them ii-BuLi vao binh cau chua allyl triphenylphosphonium bromid (1) trong diethyl ether khan 6 0°C. Khuay tiong 2 gio 6 nhiet dp phong. Them dung dich 4-benzyloxy- 3-methoxy benzaldehyd tiong diethyl ether khan vao b'lnh phan ung 6 0°C. Sau phan iing, trung hoa bang dung dich amoni clorid bao hoa (6 0°C) de'n pH hung tinh. Chiet lay lop dung moi hiiu co, lam khan bang nahi sulfat Co quay loai dung moi. SKC vol he dung moi hexan:aceton (30:1). San pham la chat long dang dau, set, khong mau, co miii kho chiu.
Hieu suat: 57%. 'H-NMR (DMSO-500MHz) 6:
7,44-7,42 (2H, m, H2-.6"); 7,39-7,36 (2H, m, H3-.S-); 7,33-7,30 (IH, m, H4-); 7,02 (IH, d, H5);
6,9 (IH, d, H2); 6,87-6,86 (IH, m, Hs); 6,86-6,83 (IH, m. Hi); 6,38 (IH, d, Hz); 6,19-6,15 (IH, m, H3); 5,40-5,36 (IH, m, H4a); 5,24 (IH, m, Hib);
5,07 {2H, s, -CH2-); 3,81 (3H, s, -OCH3).
Tong hgp 2-[(4-benzyloxy)-3- methoxy phenyl] cyclohex-3-en carbaldehyd"*' (7)
Cho vao binh cau l-(4-ben2yloxy-3- methoxyphenyl)but-l,3-dien (6), acrolein (2).
Khuay va dun hoi luu 6 100°C tiong 8 gio. Tien hanh SKC voi he dung moi hexan: aceton (30:1).
San pham la chat long dang dau tiong suot 6 nhiet dp thuong, ket tinh khi de lanh, co mau nhat, mili kho chju. Hieu suat 42,3%. 'H-NMR (DMSO-SOOMHz) 6: 9,62 (IH, s, -CHO); 7,44-7,42 (2H, m, H2~.6"); 7,39-7,36 (2H, m, H3-.5"); 7,33-7,32 (IH, m, H.-); 6,96-6,94 (IH, m, Hs-Ar); 6,83 (IH, m, H2-Ar); 6,71-6,69 (IH, m, Hs-Ar) 5,83-5,82
(IH, m, H..); 5,61-5,58 (IH, m, H3), 5,03 (2H, s, - CH2-); 3,75 3H, s, -OCH3); 3,73-3,70 (IH, m, H2);
2,59-2,58 (IH, m. Hi); 2,13-2,07 (2H, m, Ih^ H&,);
1,81-1,78 (IH, m, R=t.); 1,70-1,67 (IH, m, Hsb). ESI- MS m/z: 345,17 [M+Na]-.
Tong hgfp (±)-traHS-3-(4-benzyloxy-3- methoxyphenyI)-4-[(E)-3,4-
dimethoxystyryl] cyclohex-1-en (A) Cho n-BuLi vao binh cau chiia [(3,4- dimethoxyphenyl)methyl]triphenyl
phosphonium bromid (4) tiong diethyl ether khan 6 0 °C. Khuay 6 nhiet do phong trong 2 gio.
Them dung dich 2-[(4-benzylox)')-3- methoxyphenyl]cyclohex-3-encarbaldehyd (7) tiong diethyl ether khan vao binh phan iing 6 O'C. Sau phan ung, tnmg hoa bang dung dich amoni dorid bao hoa (6 0°C) deh pH trung tinh.
Chiet lay lop dung m6i huu co, lam khan bang natri sulfat. Co quay lo^ dung moi. Tien hanh SKC vdi h? dung m6i hexan:aceton (30:1). San phain la chat ran ket tinh mau tiang, co miii nhe.
Hieu suat: 41,3%.. Nhi|t do nong chay: 119°C.
Pho IR (v, cm-', KBr): 2835 (6c-o (m«hyi)); 91257, 1244, 1080 (uc-o); 1309, 966 (6c<:); 748 (&C.H). ' H - NMR {DMSO-5aOMHz); 7,43-7,26 (5H, m, Ar- benzyl); 6,80-6,65 (6H, m, 2 vong Ar); 6,09 (IH, d, H2-); 6,03-5,98 (IH, m, H2); 5,89-5,86 (IH, m, Hr);
5,68-5,65 (IH, m. Hi); 5,1 (2H, s,-CH2-); 3,86 (3H, s,-OCH3); 3,85 (3H, s,-OCH3); 3,82 (3H, s, -OCH3);
3,18-3,15 (IH, m, lh); 2,38-2,32 (IH, m, H4); 2,20 (2H, m, Hsa, Hfi.); 1,93-1,90 (IH, m, Hsb); 1,7-1,64 (IH, m, Hsb). ESI-MS m/z: 479,20 [M+Na]\
BAN LUAN
Trong nghien ciiu nay, chung toi da so bp khao sat dugc mgt so phan iing don gian tiong qui tiinh, dieu die dugc cac san pham hung gian tinh khiet, xay dung dugc co so dii lieu ve nhiet do nong chay, pho IR, pho 'H-MMR, pho MS ciia san pham tong hgp dupc.
Thuc hien so do tien, chung t6i da tong hgp thanh c6ng (±)-fra«s-3-(4-benzyloxy-3- methoxyphenyl)-4-[(£)-3,4-dimethoxystyryl]
cyclohex-1-en (A) voi hieu suat toan qui trinh
la 20,53"o Tir diphenylbutenoid na\, chiing ta dang tiep tuc thuc hien phan iing thuy phan de dieu che (±)-h-flns-3-(4-hydroxy-3- mefhoxyphenyl)-4-[(£)-3,4-dimethox>'styr\'l]
cydohex-1-en (B) la mgt diphenylbutenoid trong tu nhien co tac dung gay dgc te bao rat tot va dong thoi co the tao them mgt so ether tien nhom - O H phenol nay de tao ra cac dan xuat khac ciia diphenylbutenoid lam nguyen lieu cho cac nghien ciiu tiep theo nhu thir hoat tinh dpc te bao(^' va cac hoat tinh sinh hgc khac nhu giam dau, khang viem'-*'^"'.
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Han Ah-Reum, Min Hye-Young, Tn Windono, Jeohn Gwang- Ho. Jang Dae Sik. Lee Sang Kook, Seo Eun-Kyoung (20Oi), "A new cj-totoMc phenylbutenoid dimer from the Rhizomes of Z i n ^ cassumunar", Planta Med. 70.1095-1097 6 Holmes H L (1948), The Diels-Alder reaction ethylemc and
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