Download Diapositiva 1

MICROWAVE SYNTHESIS OF ATORVASTATIN CALCIUM SALT
Juan Hernando, M. Paz Matía, J. Luis. Novella, Julio Alvarez-Builla*
Planta Piloto de Química Fina. Universidad de Alcalá. Ctra. Madrid-Barcelona Km. 33,600. 28871
Alcalá de Henares. Madrid. España.
Introduction
Atorvastatin, usually marketed under the trade name Lipitor, is a member of the drug class known as statins,
used to lower cholesterol synthesis[1]. Atorvastatin inhibits the rate-determining step of the enzyme located in hepatic
tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and related derivatives. This
lowers the amount of cholesterol produced, which in turn lowers the total amount of cholesterol. Atorvastatin,
commercially available as calcium salt [2], is normally prepared via sodium salt and subsequent reaction with CaCl2 [3,4] .
We have proposed an alternative route, using microwave irradiation in all steps, for the synthesis of Atorvastatin
calcium salt, obtained directly from diol tert-butyl ester (4) by reaction with Ca(OH)2 following the synthetic method
indicated in the scheme.
H3C
CH3
O
CH3
O
O
H3C
H3C
CH3
H3C
NH2
O
H3C
CH3
O
O
O
O
1
CH3
AcOH
+
N
O
N
H
O
H3C
O
H3C
H
N
CH3
CH3
3
F
O
F
2
HCl
H3C
CH3
OH
Ca2+
OH
O
H3C
OH
OH
O
O
CO2
N
CH3
N
Ca(OH)2
O
N
H
N
H
4
H3C
CH3
CH3
F
F
2
5
The procedure was optimized in a CEM Explorer apparatus –performing batch experiments- and was scaled up using the
CEM Voyager flow system, using the best conditions obtained in the batch method. The synthesis of the calcium salt 5
was not implemented to flow method, due to the poor solubility of Ca(OH)2 in methanol.
Product
Solvent
Power
(W)
3ª
AcOH
250
150
10
61
0,12
3b
AcOH
250
150
10
61
4,8
3c
AcOH
250
150
10
57
38,4
4ª
MeOH
60
60
1
89
0.076
4b
MeOH
60
60
1
85
1.064
5a
MeOH
50
60
2
95
0.076
a CEM
Explorer
b CEM
T (ºC) t (min)
Voyager (1 cycle)
c CEM
REFERENCES (PON LAS REFERENCIAS COMPLETAS)
[1] B. D, Rorh et al. J. Med, Chem. 1991, 34, 357.
[2] WO 02 057 229
[3] K. L. Baumann et al. Tetrahedron Lett. 1992, 17, 2283.
[4] WO 06 097 909
Yield
(%)
Scale (mmol)
Voyager (8 cycles)