for reproducibly optimum methylation conversion of >99.5%
and 87% yield. Lithium pyrrolidide was prepared by treat-
ment of n-butyllithium with pyrrolidine in THF at -20 °C
and methylation reaction carried out at -35 to -40 °C. Later,
n-butyllithium was replaced by hexyllithium. Use of n-
hexyllithium on large scale has advantages over n-butyl-
lithium in terms of greater stability and safety. It does not
emit inflammable butane gas as a byproduct, otherwise
released by n-butyllithium, requiring special scrubbing
systems for handling on industrial scale.
Amide hydrolysis of 4a and 4b without purification with
methanolic sodium hydroxide followed by treatment of the
resulting dihydroxy carboxylate with ammonium hydroxide
afforded ammonium salt 5 as a crystalline solid in a single-
pot process. Finally, the lactonization of 5 by acid-catalyzed
reaction or by refluxing in toluene gave simvastatin, 2, in
(bt, J ) 3.0 Hz, 1H), 5.7 (dd, J ) 6.1, 9.5 Hz, 1H), δ 5.9 (d,
J ) 9.6 Hz, 1H) 6.2 (bt, J ) 5.3 Hz, 1H); IR (CHCl ) 3500-
3
-
1
3000, 3000, 1740, 1660, 1530, 1450, 1210, 860, 760 cm .
From Mevinolinic Acid Ammonium Salt (Method II).
1b (40 g) suspended in toluene (1280 mL) was refluxed at
107 °C under a sweep of nitrogen for 5 h. The clear solution
thus obtained was cooled to 60 °C and concentrated by
distilling off 1000 mL of toluene in a vacuum. Cyclopro-
pylamine (40 mL, 0.57 mol) was added at 30 °C and the
solution heated at 40-42 °C for 12 h. Removal of solvent
at reduced pressure afforded the title compound in quantita-
tive yield in gum-like form which was taken to the next step.
HPLC purity ) 99.6%.
N-Cyclopropyl-7-[1,2,6,7,8,8a (R)-hexahydro-2(S),6(R)-
dimethyl-8(S)-[[2,2-dimethyl- butanoyl]oxy-1(S)-naphthyl]-
3
(R), 5(R)-dihydroxyheptanoic Acid Amide (4a) and (4b).
THF (343 mL, m.c. 0.02% w/w) and pyrrolidine (54.86 g,
.77 mol, m.c. 0.2% w/w) were cooled to -30 °C, and
98% yield. The overall yield of this four-step process (1a
0
f 2) was 87%.
n-butyllithium (464 mL, 1.6 M solution in hexane) was added
via a cannula, maintaining temperature of -20 °C. The
reddish clear solution was stirred for 30 min at -20 °C.
Amide 3 in THF (262 mL) was added at -45 to -40 °C,
and the mixture was stirred for 1 h at the same temperature.
Methyl iodide (24.6 mL, 0.392 mol) was syringed in,
maintaining the temperature below -30 °C. The cloudy
solution thus obtained was stirred for 1 h at -35 to -30 °C.
Reaction was quenched by addition of water (350 mL). The
mixture was stirred for 5 min, and the lower aqueous layer
was separated. The organic layer was washed with 2 N HCl
It is worthwhile to note that the rate of methylation of
the alkoxide ester enolate is highly dependent on the
concentration as well as the hexane/THF ratio that influences
the solubility of alkoxide ester enolate. After extensive
studies, it became evident that both the concentration of 3
and the hexane/THF ratio influenced the methylation process.
The optimum concentration of 4% of 3 in a hexane/THF
ratio of 1.3 gave the highest (>99.5%) methylation conver-
sion.
In conclusion, a highly efficient and economical process
for the commercial preparation of simvastatin, 2, starting
from lovastatin, 1a, or its precursor 1b has been developed.
This process involves the use of a new intermediate, amide
(150 mL, chilled). To the combined aqueous layers and acid
wash was added NH Cl (100 g) and the mixture was
4
extracted with hexane (200 mL). The combined organic
phases were concentrated under vacuum to give an oil. It
3, and eliminates the need for protection and deprotection
of the dihydroxy system of the open pyranone.
contains the titled compound 4a along with some traces of
6
4
b.
Experimental Section
6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dim-
General. Lovastatin, 1a, and mevinolinic acid, 1b, were
obtained from an in-house source. HPLC analysis were
performed on a Waters LC Module-I with detection at 238
nm in acetonitrile/THF/water and orthophosphoric acid (85%
w/w HPLC grade). H-spectra were obtained at 300 MHz
using TMS as an internal standard. All operations were done
under an inert atmosphere of nitrogen. Cyclopropylamine
ethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-naphthyl]ethyl-4(R)-
hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Simvastatin)
(2). To the concentrated solution from the previous step
containing amides 4a and 4b was added NaOH solution (2
N, 400 mL) and MeOH (700 mL). The mixture was refluxed
at 75-78 °C for 3 h, cooled to 50 °C, and MeOH (about
500 mL) was removed by rotary evaporation. The concentrate
was diluted with water (300 mL) followed by acidification
with 2 N HCl to pH 4 at 10-15 °C. Material was extracted
with EtOAc (500 mL). To the ethyl acetate extract a solution
1
(CPA) and THF were used as such, pyrrolidine and MeI were
dried prior to use. n-Butyllithium and hexyllithium were
purchased from Chemetall GmBH.
N-Cyclopropyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(s),6(R)-
dimethyl-8(s)-[[2(S)-methyl- butanoyl]-oxy]-1(S)-naphthyl]-
of NH OH and methanol (1:1, 40 mL) was slowly added at
22-25 °C. The precipitates were stirred at 25 °C for 1.5 h
4
3(R), 5(R)-dihydroxyheptanoic Acid Amide (3). From
and then cooled to 5 °C. Filtration, followed by washing
with EtOAc and drying in a vacuum at 35 °C afforded the
ammonium salt 5 (39 g, 97.6% HPLC purity).
Lovastatin (Method I). 1a (40 g, 0.098 mol) and CPA (40
mL, 0.57 mol, m.c. 0.3% w/w) were heated at 40-42 °C
for 8 h. The excess CPA was distilled off, THF (20 mL,
m.c. 0.04% w/w) was added and removed at reduced pressure
1
H NMR (MeOH-d + D O, 300 MHz) δ 0.831 (m, 6H,
3
2
2-Me gps), 1.075 (m, 9H, 3-Me gps), 1.53 (m, 6H), 1.97
(m, 2H), 2.27 (m, 5H), 3.68 (m, 1H), 4.07 (m, 1H), 5.52
(m, 1H), 5.50 (bt, J ) 3.0 Hz, 1H), 5.77(dd, J ) 6.1, 9.5
Hz, 1H), 5.96 (d, J ) 9.6 Hz, 1H); IR (KBr): δ 3380, 2995,
to give amide 3 as a gum in quantitative yield and 99.8%
1
purity by HPLC; H NMR (CDCl
3
, 300 MHz) δ 0.495 (m,
2H), 0.50 (m, 2H), 0.86 (m, 6H), 1.08 (m, 6H), 2.3 (d, 2H)
-
1
δ 2.6 (m, 1H), 3.7 (m, 1H), 4.18 (m, 1H), 5.4 (m, 1H), 5.5
1720, 1560, 1450, 1150, 1100, 870, 860 cm
478
•
Vol. 3, No. 6, 1999 / Organic Process Research & Development