Nghiên cứu tổng hợp chọn lọc 10B-Azidoartemisinin

TAP CHI HOA HOC

DOL 10.15625/0866-7144.2015-0084

T.53(1) 35-40 THANG 2 NAM 2015

NGHIEN CLPU T6N G HOP CHON LOC 10j8-AZIDOARTEMISININ

Le Huy Binh, Nguyen Thanh Binh, Nguyen Thi Thiiy Van, Tran Khic VG*

Bd mdn Cdng nghe Hda dugc vd Bdo v | Thuc vgt, Vien Ky thugt Hda hgc,

Trudng Dgi hgc Bdch khoa Hd Ngi

Din Tda soan 7-7-2014; Chip nhan dang 4-12-2014

Abstract

This paper presents a simple method for selective synthesis of the key compound, 10/?-azidoartemisinin. The

compound lOyS-azidoartemisinin was selectively synthesized by the reaction of dihydroartemisinin (2) with NaN], KI

using ZnCl2 as a catalyst at 0-5 °C. The strucmre of 10^-azidoartemisinin was elucidated based on 'H, '^CNMR

spectmm and known documents.

Keywords. Artemisinin, dihydroartemisinin, artemether, arteether, sodium azide.

l.DATVANDE

Artemisinin (1) li mgt sesquitecpen lacton chiet

xuat tir cay thanh hao hoa vang (Artemisia annua L.)

dugc sii dyng lam nguyen lieu dau quan trgng eho

eac nghien ciru kham phi thude sdt ret [1]. Mdt sd

hgp chat ban tdng hgp cd hogt tinh khing sdt ret

nhu: artemether (3a), arteether (3b) va artesunat (3c)

(hinh 1) dugc ban tong hgp tir dihydroartemisinin

(2) hi?n dang dugc su dyng trong dilu fri lim sang

sdt ret [2-5]. Gan day, cac thii ngjiiem lim sang edn

cho thay nhieu dan xuit ciia artemisinin the hien mot

sd hoat tinh sinh hgc khac nhu: boat tinh khang u,

khang virus, khang nam va lic che mien dich [6].

Trong sd cac din xuit cua artemisinin dugc tdng

hgp gin day dang chii y la cac din xuit chira nhan

triazole the d vi fri C-10 cua khung artemisinin. Cac

dan xuit nay dugc tdng hgp qua phan iing cdng

ddng vdng 1,3 giira hgp chat frung gian 10-

azidoartemisinin vdi cac ankyn. Mdt sd dan xuat

kilu nay the hien hogt tinh irc chi tl bao ung thu vii

mgnh hgn ca Taxol [7].

Cac dan xuat cua artemisinin chira nito d vi fri

C-10 dugc Haynes va cgng sy [8, 9] dieu che lan

dau tien qua phin iing cua dihydroartemisinin (2)

vdi trimethylsilyl chloride va sodium bromide trong

dung mdi toluene d 0 °C cho san pham trung gian

lO^-bromodeoxoartemisinin. Chit nay sau dd phan

ling ngay vdi cac amine bgc 1 hoac bac 2 dl cho san

pham la cac 10-aminoartemisinin. Tren co sd

phugng phap nay, Sungsik Cho va cdng su da dieu

chi hgp chat lO-azidoartemisinin qua phan irng cua

dihydroartemisinin (2) vdi frimethylsiiyi bromide va

sodium azide frong dung mdi diclometan d nhiet do

phdng frong 12 gid. San phim thu dugc la hdn hgp

ciia 10^-azidoartemisinin (4), 10«-azidoartemisinin

(5) va san pham 9a,10^-azidoartemisinin (6) vdi

hieu suit lin lugt la 17 %, 21 % va 49 % [7]. Dl

nang eao hieu suit cua sin phim, Lijun va cdng si^

dS cai tien quy trinh bang each sir dyng

trimethylsilyl bromide va sodium azide vdi su cd

mat Clia mgt lugng nhd KI (2,5 % moi) trong dung

mdi diclometan d nhiet dd phdng trong 28 gid thu

dugc san pham 10^-azidoartemisinin (4) vdi hieu

suit 47% va mdt lugng nhd san pham lOa￾azidoartemisinin (5%) [10]. Theo hiiu biit ciia

chiing tdi, hien chua cd bao cao ve viec dieu che cic

lO-azidoartemisinin sir dung kem clorua lam chit

xiic tie. Trong qua trinh nghien ciiu tdng hgp cac

din xuat mdi cua artemisinin va sang Igc hogt tinh

khang ung thu, chiing tdi phai su dyng chit chia

khda lO^-azidoartemisinin. Vi vay, bai nay chiing

tdi frinh bay tdng hgp chgn Igc hgp chit

lO^-azidoartemisinin sir dung kem clorua lam chit

xiic tac.

2. THl/C NGHIEM

Dihydroartemisinin mua tir cdng ty Dugc khoa,

Trudng Dgi hgc Dugc Ha Ngi. Cic tac nhin va dung

mdi phan iing mua ciia hang Merck va Aldrich.

Diem ehay dugc do fren may Electrothermal IA

9200 Shimadzu. Phd ' H NMR va '^C NMR dugc do

tren may Bruker AVANCE 500 MHz tgi Vien Hda

hgc, sii dyng dung mdi do CDCI3. Do chuyln dich

hda hgc (5) tinh bing ppm so vdi chit chuin (TMS).

Hing so tuong tic (J) dugc bilu diln bing Hz. Tiln

trinh phan iing dugc theo ddi bdi sic ky Idp mdng