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An im proved syn thetic m ethod o f saqu inav ir, an H IV protease inhib itor, is descr ibed. In com parison w ith the
m e thods in the repo rted w orks, the im proved procedures had seve ra l adv antages, such as less expensive agen ts, shor
ter reac tion tim e, and a sm aller am ount of the solven t needed. T o m easure the optica l pu rities o f the products, the in
termed iates we re de term ined by m eans o f chira lH PLC. Som e of the interm ed iates can a lso be used fo r the preparation
of new pro tease inhib itors.
K eywo rds H IV; Protease inh ibito r; Saqu inav ir; Synthesis
A rticle ID 1005 9040( 2006) 01 051 05
In troduction
The hum an im munodeficiency virus( H IV ) is the
causat iv e agen t of acquired imm unodef iciency syndrom e
( A ID S). S in ce H IV pro tease is essen tial for the repli
ca tio n and m atu ra tio n o f H IV, the in act iv ation of H IV
pro tease by eith er m utation or chem ical inh ib it io n leads
to the product ion o f imm ature, noninfectious viral parti
[ 1]
cles . Saqu in av ir( com pound 1) , anH IV protease in
h ib ito r, w as f irst approved by the FDA in 1995. Sa
quinav ir inhibitsH IV protease w ith aK i va lu e of 0 12
[ 2]
nm o l/L and show s a specificity for the enzym e . Be
52
V o.l 22
60 ! , 3 h, 93% ; c. phthalic anhydride, tolu ene, reflux, 94% ; d. triphosgen e, 70 80 ! , 10 h; e. H 2, 10% Pd /C, 40 50 ! ,
H 2 O, 93% ; p. triphosgene, 60
70 ! , 3 h; q.
t BuNH 2 , r. t. , 14 h, 82% ; r. 3039 8 kPa H 2, 5% R u /C, 100 ! , 16 h, 65% ; s. N a2 CO 3, 4 methyl 2 p entanon e, reflux, 15 h, 95% ; t.
N aHCO3 , H 2 O; u. N aOH, ethanol and H 2 O, reflux, 5 h, 89% ; v. 2, HOO B t, D CC, TH F - 10 ! , 2 h, r. t. , 16 h, 93% .
( A ) syn th es is of fragm en t 2; ( B) synthesis of fragm ent 3; ( C ) syn th es is of fragm en t 4; ( D ) assem b ly.
N o. 1
53
[ 9]
Conclusion
In conclu sio n, w e have com pleted an im proved
syn th etic m ethod of saqu in av ir, wh ich is lik ely m ore
favourable in the sca le up preparation. In com parison
w ith the reported works, several steps have been im
proved. For exam ple, the expensive agents can be re
placed by cheaper ones; the reactio n t im e can be
m arked ly shortened; and a w ater separator w as adopted
to save th e solvent during azeotropic dehydration. T he
optica l purity o f the in term ed ia tes can be determ in ed
w ith ch ira l HPLC. Som e interm ediates can be also
used for the preparation of new protease in hib ito rs,
wh ich is underway in our labora tory.
Experim ental
1
54
V o.l 22
N o. 1
55
H z, 1H ) , 2 70 2 60 ( m, 4H ) , 2 22 2 16 ( m,
2H ) , 2 06 2 00( m, 1H ) , 1 95 1 89( m, 1H ),
1 76 1 60( m, 3H ) , 1 54 1 46 ( m, 3H ), 1 28
( s, 9H ) , 1 16 1 37( m, 4H ) .
Re fe rences
[ 1]
[ 2]
2001, 15,
[ 3]
G hosh A. K. , B ilcer G. ,
2203
[ 4]
[ 5]
[ 6]
[ 7]
Burger C. ,
et al. ,
US Pa ten t
[ 8]
[ 9]
[ 10]
[ 11]
[ 12]
[ 13]
1961,