Description
Pitavastatin, launched for the treatment of hypercholesterolemia, belongs to
the family of second-generation statins, also referred to as superstatins due to their
improved efficacy as cholesterol lowering agents. Like other statins, pitavastatin
reduces plasma cholesterol levels by competitively inhibiting HMG-CoA reductase,
the rate-limiting enzyme of cholesterol biosynthesis in the liver. It is a more potent
inhibitor of HMG-CoA reductase than the previously marketed statins and has the
potential benefit of not undergoing significant metabolism by CYP3A4. Pitavastatin
is synthesized in a multi-step sequence, including the key step of introducing the
dihydroxyheptenoate side chain by cross-coupling of a 3-iodoquinoline intermediate
with an alkenylborane reagent. Unlike rosuvastatin, pitavastatin has a high oral bioavailability (～80%). Plasma protein binding is
also high for pitavastatin (＞95%), and regardless of the dosing, the highest tissue
levels are found in the liver, its target organ. After oral administration, the peak
plasma concentration is reached at ,0.8 h and the mean elimination half-life is
～11 h. Pitavastatin is only minimally metabolized, mainly by CYP2C8 and
CYP2C9, and the predominant route of elimination of the parent drug and its
metabolites is by means of bile excretion followed by elimination in the feces. In clinical studies, oral doses of 2–4 mg/day of pitavastatin produced dose-dependent
reduction in LDL-cholesterol levels by 40–48% from baseline in patients with
heterozygous familial hypercholesterolemia. In a 12-week double-blind comparative
study, pitavastatin (2 mg/day) was more effective than pravastatin (10 mg/day) in
reducing LDL-cholesterol levels (38 and 18%, respectively); however, both agents produced similar increases in HDL-cholesterol (～9%). The drug was well tolerated
and the adverse reactions were mild and transient.
Synthesis
The convergent synthesis was
achieved by cross-coupling of aryl halide 149 with (E)-
alkenyl borane 155 which was derived from terminal
acetylene 154 by via hydroboration. Anthranilic acid
(143) was treated with TsCl and sodium carbonate in hot
water to give N-tosylated intermediate in 78% yield, which
was converted to the corresponding acid chloride 144 with
PCl5 in o-dichlorobenzene at 85??C. Intermediate 144,
without isolation, was reacted with fluorobenzene in the
presence of AlCl3 at 80??C to give the Friedel-Crafts product
which was then hydrolyzed in hot water to give
fluorobenzophenone free aniline 145 in 64% yield from the
N-tosyl anthranilic acid. Acetyl cyclopropane (146) was
reacted with diethyl carbonate to give the corresponding
ethyl ester 147. The quinoline core structure was obtained by
condensing fluorobenzophenone 145 with 147 under acidic
conditions with a Dean-Stark trap to give quinoline-3-
carboxylic ethyl ester 148 in 90% yield. Ester 148 was
hydrolyzed with potassium hydroxide, and the free
carboxylic acid thus obtained was subsequently photoiododecarboxylated
with iodine and PhI(OAc)2 to give aryl iodide 149 in 74% yield. 3-Trimethylsilylpropynal (150)
was used as the starting material to prepare the chiral side
chain. Compound 150 was reacted with di-anion 151 in
THF at low temperature to give the corresponding diol ester
which was first reacted with Et2BOMe and then reduced to
acetylene with sodium borohydride. The free diol was
protected as ketal with 2,2-dimethoxypropane in the presence
of TsOH to give dimethylketal acetylene 152 in 99% yield.
The ester functionality was hydrolyzed with sodium
hydroxide to give the acid in 92% yield. The racemic free
acid was resolved with (R)-(1-naphthyl)ethylamine to give
the pure diastereomeric salt 153 which crystallized out in
31% yield and 97% e.e. Esterification of the free carboxylic
acid liberated from the crystalline salt with ethyl iodide gave
optically pure acetylene 154 in 70% yield. Hydroboration of
acetylene 154 with disiamylborane gave (E)-alkenyldisiamylborane
155 and the excess borane reagent was
quenched with sodium ethoxide in ethanol. After
evaporation of all volatile material, the residue was directly
subjected to the cross-coupling reaction. Palladium (II)
chloride and aryl iodide 149 were mixed in acetonitrile to
give coupling product 156 in 99% yield. After the ketal in
156 was hydrolyzed under acid conditions and the ester was
hydrolyzed with sodium hydroxide, the resulting carboxylic
sodium salt was reacted with calcium chloride to yield
pitavastatin calcium (XIX) with 99% e.e.
