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Synthetic Communications
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New Synthesis of Simvastatin
Radha Krishna Singamsetty a; Satish Kumar Vujjini a; Nagaraju Manne a; Brahmeshwara Rao Mandava
Venkata Naga a; Vurimidi Himabindu b; Apurba Battacharya a; Mahesh Reddy Ghanta a; Rakeshwar
Bandichhor a
a Innovation Plaza, Dr. Reddy's Laboratories Ltd., Bachupally, Qutubullapur, India b Department of Chemistry,
Institute of Science and Technology, J. N. T. University, Kukatpally, Hyderabad, India
Online Publication Date: 01 January 2008
To cite this Article Singamsetty, Radha Krishna, Vujjini, Satish Kumar, Manne, Nagaraju, Venkata Naga, Brahmeshwara Rao
Mandava, Himabindu, Vurimidi, Battacharya, Apurba, Ghanta, Mahesh Reddy and Bandichhor, Rakeshwar(2008)'New Synthesis of
Simvastatin',Synthetic Communications,38:24,4452 — 4459
To link to this Article: DOI: 10.1080/00397910802369570
URL: http://dx.doi.org/10.1080/00397910802369570
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New Synthesis of Simvastatin
Radha Krishna Singamsetty,
1
Satish Kumar Vujjini,
1
Nagaraju Manne,
1
Brahmeshwara Rao Mandava Venkata Naga,
1
Vurimidi Himabindu,
2
Apurba Battacharya,
1
Mahesh Reddy
Ghanta,
1
and Rakeshwar Bandichhor
1
1
Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally,
Qutubullapur, India
2
Department of Chemistry, Institute of Science and Technology,
J. N. T. University, Kukatpally, Hyderabad, India
Abstract: A noninfringing synthesis of simvastatin 1, starting from lovastatin 2,is
presented. This synthesis features the protection of the free hydroxyl group of the
lovastatin with 3,4-dihydro-2H-pyran (DHP) and opening of the lactone ring with
n-BuNH
2
to afford amide 4as a key intermediate.
Keywords: 3,4-Dihydro-2H-pyran, low-density lipoprotein, methylation,
simvastatin
INTRODUCTION
Simvastatin
[1]
1is a semisynthetic version of a fermentation product 2of
Aspergillus terreus. Orally active simvastatin 1(Fig. 1), a prodrug that
gets hydrolyzed in vivo to the corresponding hydroxy acid, which is
responsible for eliciting pharmacological effects.
[2]
Simvastatin 1targets
a specific enzyme that is responsible for catalyzing the conversion of 3-
hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate.
Received April 15, 2008.
DRL-IPD Communication Number IPDO-IPM-00085.
Address correspondence to Rakeshwar Bandichhor, Innovation Plaza, IPD,
R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, & 54, Bachupally,
Qutubullapur, R. R. Dist. 500073, A. P., India. E-mail: rakeshwarb@drreddys.com
Synthetic Communications
1
, 38: 4452–4459, 2008
Copyright #Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369570
4452
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The mode of action involves the inhibition of (HMG-CoA) reductase and
eventually lowers the low-density lipoprotein (LDL) level.
[2]
The discovery of lovastatin 2
[3]
led to the development of a more
potent LDL lowering agent, simvastatin (synvinolin) 1, way back in
1991 by Merck. Syntheses of lovastatin 2and simvastatin 1have been
extensively explored.
[4]
However, most of the developed syntheses except
a few appear to be industrially incompatible. Askin et al.
[1]
reported an
elegant synthesis of 1, although it involves expensive bis-silyloxy protec-
tions of naked hydroxy groups. Thaper et al.
[5]
published a relatively
better large-scale preparation method that incorporates four steps, how-
ever, the use of more expensive amine (cyclopropyl amine) for amidation
appears to be less attractive. Herein we report a cost-effective and
noninfringing semisynthetic route for 1on a large scale.
RESULTS AND DISCUSSION
Methylation at the 2-position in lovastatin 2to obtain simvastatin 1,
without a protecting hydroxy group and using excess lithium pyrrolidide
and methyl iodide, also allows the formation of side products that make
the synthesis cumbersome. However, in the prior process, different pro-
tecting groups
[1]
such as tert-butyldimethylsilyl (TBDMS) (expensive), tri-
methylsilyl (TMS), and dimethoxy propane were successfully employed.
In our efforts to develop a robust and scaleable route for simvastatin
1as shown in Scheme 1, we chose lovastatin 2, a commercially available
starting material. Use of 3,4-dihydro-2H-pyran (DHP), one of the suita-
ble protecting groups in hydroxyl protection, was found to be cost-effec-
tive, nonhazardous, and easy to handle, and overall the transformation
was high yielding.
Parallel to the development of the synthesis of 1, we also prepared all
the reported impurities 7–10 (Fig. 2) in significant quantities. The spec-
troscopic data of these impurities are in complete agreement with the
related known values.
Figure 1. Structure of simvastatin 1.
New Synthesis of Simvastatin 4453
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Tetrahydro pyran (THP) protection in the first step was found to be
concentration dependent. The reaction time in this step was less at lower
dilution, and the transformation was also efficient.
It was also observed that 2.2 eq. of DHP with respect to 3was
more than sufficient to achieve better yield and purity. Optimization
studies of hydroxy protection stage revealed that the 1.4 to 1.8 eq. of
DHP was not enough to effect the optimal conversion. Eventually 2.0
eq. of the same was found to be ideal for this transformation as shown
in Table 1 (entry 4).
Scheme 1. Synthesis of simvastatin 1.
4454 R. K. Singamsetty et al.
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The number of equivalence of n-butyl amine was also investigated.
An amount of 1.4 eq. of n-butyl amine was optimal for the preparation
of amide 4. Optimization results are summarized in Table 2 (see entry 2).
In further transformation, a solution of 4.0 eq. n-BuLi and pyrroli-
dine each was added to a solution of 4in THF. After stirring for 1 h,
methyl iodide was added slowly to the reaction mass and subsequently
quenched upon completion of reaction. The pyrrolidine hydrochloride
salt was removed by extraction, and the organic layer was concentrated
Figure 2. Structure of reported impurities 7–10.
Table 1. Quantification of DHP in the conversion of 2to 3
Purity by HPLC
(%)
Entry Input 2(g) H
2
SO
4
(eq.) DHP (eq.) 32
1 5.0 0.05 1.4 71.27 27.82
2 5.0 0.05 1.6 94.48 4.34
3 5.0 0.05 1.8 96.98 2.72
4 5.0 0.05 2.0 98.93 0.46
5 10.0 0.05 2.2 97.46 0.09
New Synthesis of Simvastatin 4455
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to afford amide 5as syrup with excellent yield (>99%) and purity (high
pressure liquid chromatography [HPLC]). Optimization results regarding
number of equivalence of bases, alkylating agent, and solvent are sum-
marized in Table 3 (entry 6; best result at 100-g scale).
Deprotection, hydrolysis, and ammonium salt formation to obtain 6
were accomplished in one pot with an overall yield of 86%, and the opti-
mization results are summarized in Table 4. Optimization of number of
equivalents of HCl involved in the deprotection was essential to effect
transformation efficiently. An amount of 1.3 eq. of HCl was optimal
for the preparation of 6(see Table 4, entry 7).
Finally, p-TsOH-catalyzed lactonization of 6in toluene and acetoni-
trile afforded 1, with 93% yield and 99% purity.
EXPERIMENTAL
The
1
H and
13
C NMR spectra were recorded in DMSO-d6 at 400 MHz,
on a Varian Gemini NMR spectrometer. The chemical shifts are reported
in dppm relative to TMS. The mass spectrum (70 eV) was recorded on
HP-5989a LC-MS spectrometer. The solvents and reagents were used
without any purification.
Table 2. Optimization of n-butyl amine quantity in the conversion of 3to 4
Purity by
HPLC (%)
Entry Input 2(g) Residue (g) n-Butyl amine (eq.) 43
1 5.0 7.1 1.2 93.33 3.18
2 5.0 7.8 1.4 97.72 0.21
Table 3. Quantification of reagents and solvent
Entry Input 4(g)
Residue
(g)
n-Buli
(eq.)
Pyrrolidine
(eq.)
MeI
(eq.)
THF
(volumes with
respect to 4)
Conversion
of 5(%)
1 10.0 11.0 7.5 8.8 7.16 13.0 99.67
2 10.0 11.5 7.5 7.5 7.16 13.0 99.67
3 10.0 11.4 4.5 5.8 7.16 10.0 99.57
4 10.0 11.1 4.0 5.3 7.16 10.0 99.32
5 10.0 11.0 3.5 4.8 5.0 6.0 98.90
6 100.0 115.0 4.0 4.0 4.0 6.0 99.60
4456 R. K. Singamsetty et al.
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2-Methyl-butyricacid-8-[6-butylcarbamoyl-3-hydroxy-5-(tetrahydro-
pyran-2-yloxy)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-
naphthalen-1-yl Ester 4
A solution of sulphuric acid (0.06 mL) in THF (10 mL) was added to a
solution of 3,4-dihydro-2H-pyran (0.54 mol 49.4 mL) in THF (40 mL).
After the addition over a period of 10 min and stirring for 5 min, lovas-
tatin 2(0.25 mol, 100 g) was added at 28 C. After stirring for 45 min at
36 C, n-BuNH
2
(0.32 mol, 34 mL) was added. After additional stirring
for 4 h at 49 C, the reaction mixture was concentrated under reduced
pressure to afford crude material 4as brown syrup. Crude yield:
148.3 g (>100%); purity by HPLC: 98%;
1
H NMR (400 MHz, DMSO-
d6): d7.77 and 7.69 (t, J¼6.4 Hz, 1H), 5.94 (d, J¼9.6 Hz, 1H), 5.78
(dd, J¼9.6, 6.0 Hz, 1H), 5.48 (s, 1H), 5.24–5.18 (m, 1H), 4.63–4.59 (m,
1H), 4.36 (d, J¼6.0 Hz, 1H), 4.26 (d, J¼5.6 Hz, 1H), 4.12–4.00 (m,
1H), 3.82–3.70 (m, 1H), 3.10–2.94 (m, 2H), 2.50 (t, J¼4.0 Hz, 1H),
2.44–2.20 (m, 4H), 1.98–1.22 (m, 22H), 1.03–1.00 (m, 6H), 0.88–0.80
(m, 9H); MS: m=e¼584.4 (M þNa
þ
).
2,2-Dimethyl-butyricacid-8-[6-butylcarbamoyl-3-hydroxy-5-
(tetrahydro-pyran-2-yloxy)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-
hexahydro-naphthalen-1-yl Ester 5
To a solution of pyrrolidine (1 mol, 82mL) in THF (278 mL), 1.6 M n-
BuLi (1 mol, 622 mL) was added at 25 C. After the addition over a per-
iod of 1 h and stirring for 25 min, a solution of 4(0.25 mol, 139 g) in THF
(556 mL) was added. After stirring for additional 1 h at 45 C, methyl
iodide (1 mol, 63mL) was added to the reaction mixture and stirred for
1.5 h. The reaction mixture was quenched with 1N aq. HCl (915 mL),
and the organic layer was separated, concentrated, and dried under
Table 4. Optimization of acid=base on THP deprotection and amide hydrolysis
Entry 5 (g) Quantity=yield HCl (eq.) NaOH (eq.) HPLC purity (%)
1 5.0 1.7=49 4.0 4.0 94.97
2 5.0 0.4=11 0.53 4.0 94.97
3 5.0 1.9=54 0.45 4.0 93.16
4 5.0 2.7=77 1.0 4.0 95.37
5 5.0 1.2=34 1.0 3.6 97.58
6 5.0 2.8=80 1.3 4.0 98.11
7 50.0 30.5=87 1.3 4.0 98.09
New Synthesis of Simvastatin 4457
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reduced pressure to afford crude material 5as a thick brown syrup.
Crude yield: 154 g (>100%);
1
H NMR (400 MHz, DMSO-d6): d7.77
and 7.69 (t, J¼6.4 Hz, 1H), 5.94 (d, J¼9.6 Hz, 1H), 5.77 (dd, J¼9.6,
6.0 Hz, 1H), 5.48 (s, 1H), 5.20–5.18 (m, 1H), 4.63–4.59 (m, 1H), 4.36
(d, J¼6.0 Hz, 1H), 4.27 (d, J¼5.6 Hz, 1H), 4.10–4.02 (m, 1H), 3.79–
3.71 (m, 1H), 3.04–2.95 (m, 2H), 2.50 (t, J¼4.0 Hz, 1H), 2.39–2.23 (m,
4H), 1.99–1.20 (m, 21H), 1.26–1.00 (m, 9H), 0.88–0.75 (m, 9H); MS:
m=e¼598.4 (M þNa
þ
).
(3R,5R)-7-[(1S,2S,6R,8S,8aR)-8-[(2,2-Dimethylbutanoyl]oxy]-2,6-
dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyhepta-
noicacidammonium Salt 6
[5]
HCl (0.15 mol, 15 mL) was added to a solution of 5(0.12 mol, 67.6 g) in
methanol (149 mL) at 2 C. After stirring for 4 C at 45 min to afford in
situ amide intermediate, 10% aq. NaOH (0.5 mol, 188 mL) was added
to the reaction mixture. After additional stirring for 4 h at 77 C, the reac-
tion mixture was cooled to 33 C and water (135 mL) was added. After
adjusting the pH to 4.7 (by adding 10% HCl) at 15 C, the reaction mix-
ture was extracted with EtOAc (338 mL), and 28% ammonium hydroxide
solution (0.24 mol, 30mL) in methanol (30 mL) was added to the organic
layer. After stirring for 30 min at 28 C, the reaction mixture was cooled
to 3 C and stirred additionally for 1 h to afford 6as a light-brown-
colored solid in 87% isolated yield (39.5 g) and 98% purity (HPLC).
1
H
NMR was found to be satisfactory as per literature.
2,2-Dimethylbutanoicacid(1S,2R,7S,8S,8aR)1,2,3,7,8a-hexahydro-
3,7,dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-
yl]ethyl]-1-naphthalenyl Ester 1
[5]
A solution of p-TsOH (0.003 mol, 0.5 g) in toluene (421 mL) was added to
a solution of 6(0.055 mol, 25 g) in acetonitrile (173 mL) after stirring for
8 h at 83 C, water, a by-product, was azeotropically distilled out. The
reaction mixture was cooled to 43 C and filtered. The solvent was com-
pletely distilled from the filtrate at 60 C under vacuum, and methanol
(300 mL) was added to the residue at 45 C. After stirring for 20 min,
activated carbon (2.5 g) was added and stirred for an additional period
of 0.5 h. The reaction mixture was filtered, washed with methanol
(50 mL), and heated to 38 C. Water (350 mL) was added to the filtrate
and cooled to 13 C over a period of 2 h. The obtained solid mass was
filtered, followed by washing with a precooled mixture (110 mL) of
4458 R. K. Singamsetty et al.
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methanol=water (1:1). The wet material was dried over a period of 2 h at
54 C to afford 1(21.5 g) in 93% yield and 99% purity (HPLC).
1
HNMR
was found to be satisfactory as per literature.
ACKNOWLEDGMENTS
We acknowledge Dr. Reddy’s Laboratories for financial and analytical
support.
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New Synthesis of Simvastatin 4459
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