New synthesis of simvastatin

Article abstract of DOI:10.1080/00397910802369570

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-BuNH2 to afford amide 4 as a key intermediate. Copyright Taylor & Francis Group, LLC.

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New Synthesis of Simvastatin
a
Radha Krishna Singamsetty , Satish Kumar Vujjini
a
a
,
Nagaraju Manne , Brahmeshwara Rao Mandava
a
b
Venkata Naga , Vurimidi Himabindu , Apurba
a
a
Battacharya , Mahesh Reddy Ghanta & Rakeshwar
a
Bandichhor
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
Available online: 07 Nov 2008
To cite this article: Radha Krishna Singamsetty, Satish Kumar Vujjini, Nagaraju
Manne, Brahmeshwara Rao Mandava Venkata Naga, Vurimidi Himabindu, Apurba
Battacharya, Mahesh Reddy Ghanta & Rakeshwar Bandichhor (2008): New Synthesis
of Simvastatin, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:24, 4452-4459
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1
Synthetic Communications , 38: 4452–4459, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802369570
New Synthesis of Simvastatin
1
Radha Krishna Singamsetty, Satish Kumar Vujjini,
1
1
Nagaraju Manne, Brahmeshwara Rao Mandava Venkata Naga,
1
2
Vurimidi Himabindu, Apurba Battacharya, Mahesh Reddy
1
1
Ghanta, 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
2
n-BuNH to afford amide 4 as a key intermediate.
Keywords: 3,4-Dihydro-2H-pyran,
simvastatin
low-density
lipoprotein,
methylation,
INTRODUCTION
[
1]
Simvastatin 1 is a semisynthetic version of a fermentation product 2 of
Aspergillus terreus. Orally active simvastatin 1 (Fig. 1), a prodrug that
gets hydrolyzed in vivo to the corresponding hydroxy acid, which is
[
2]
responsible for eliciting pharmacological effects. Simvastatin 1 targets
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
4
452

New Synthesis of Simvastatin
4453
Figure 1. Structure of simvastatin 1.
The mode of action involves the inhibition of (HMG-CoA) reductase and
[
2]
eventually lowers the low-density lipoprotein (LDL) level.
[3]
The discovery of lovastatin 2 led to the development of a more
potent LDL lowering agent, simvastatin (synvinolin) 1, way back in
1
extensively explored. However, most of the developed syntheses except
991 by Merck. Syntheses of lovastatin 2 and simvastatin 1 have been
[4]
[
1]
a few appear to be industrially incompatible. Askin et al. reported an
elegant synthesis of 1, although it involves expensive bis-silyloxy protec-
[5]
tions of naked hydroxy groups. Thaper et al. 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 1 on a large scale.
RESULTS AND DISCUSSION
Methylation at the 2-position in lovastatin 2 to 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-
[
1]
tecting groups 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
1
as 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.

4454
R. K. Singamsetty et al.
Scheme 1. Synthesis of simvastatin 1.
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 3 was
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).

New Synthesis of Simvastatin
4455
Figure 2. Structure of reported impurities 7–10.
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 4 in 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
Table 1. Quantification of DHP in the conversion of 2 to 3
Purity by HPLC
(
%)
Entry
Input 2 (g)
H
2
SO
4
(eq.)
DHP (eq.)
3
2
1
2
3
4
5
5.0
5.0
5.0
5.0
0.05
0.05
0.05
0.05
0.05
1.4
1.6
1.8
2.0
2.2
71.27
94.48
96.98
98.93
97.46
27.82
4.34
2.72
0.46
0.09
10.0

4456
R. K. Singamsetty et al.
Table 2. Optimization of n-butyl amine quantity in the conversion of 3 to 4
Purity by
HPLC (%)
Entry
Input 2 (g)
Residue (g)
n-Butyl amine (eq.)
4
3
1
2
5.0
5.0
7.1
7.8
1.2
1.4
93.33
97.72
3.18
0.21
to afford amide 5 as 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 6 in toluene and acetoni-
trile afforded 1, with 93% yield and 99% purity.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded in DMSO-d6 at 400 MHz,
on a Varian Gemini NMR spectrometer. The chemical shifts are reported
in d ppm 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 3. Quantification of reagents and solvent
THF
Residue n-Buli Pyrrolidine MeI (volumes with Conversion
Entry Input 4 (g)
(g)
(eq.)
(eq.)
(eq.) respect to 4)
of 5 (%)
1
2
3
4
5
6
10.0
10.0
10.0
10.0
10.0
100.0
11.0
11.5
11.4
11.1
11.0
115.0
7.5
7.5
4.5
4.0
3.5
4.0
8.8
7.5
5.8
5.3
4.8
4.0
7.16
7.16
7.16
7.16
5.0
13.0
13.0
10.0
10.0
6.0
99.67
99.67
99.57
99.32
98.90
99.60
4.0
6.0

New Synthesis of Simvastatin
4457
Table 4. Optimization of acid=base on THP deprotection and amide hydrolysis
Entry 5 (g) Quantity=yield HCl (eq.) NaOH (eq.) HPLC purity (%)
1
2
3
4
5
6
7
5.0
5.0
5.0
5.0
5.0
5.0
50.0
1.7=49
0.4=11
1.9=54
2.7=77
1.2=34
2.8=80
30.5=87
4.0
4.0
4.0
4.0
4.0
3.6
4.0
4.0
94.97
94.97
93.16
95.37
97.58
98.11
98.09
0.53
0.45
1.0
1.0
1.3
1.3
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
ꢁ
3
for 4 h at 49 C, the reaction mixture was concentrated under reduced
6 C, n-BuNH (0.32 mol, 34 mL) was added. After additional stirring
ꢁ
2
pressure to afford crude material 4 as brown syrup. Crude yield:
1
1
48.3 g (>100%); purity by HPLC: 98%; H NMR (400 MHz, DMSO-
d6): d 7.77 and 7.69 (t, J ¼ 6.4 Hz, 1H), 5.94 (d, J ¼ 9.6 Hz, 1H), 5.78
(
dd, J ¼ 9.6, 6.0 Hz, 1H), 5.48 (s, 1H), 5.24–5.18 (m, 1H), 4.63–4.59 (m,
1
1
2
H), 4.36 (d, J ¼ 6.0 Hz, 1H), 4.26 (d, J ¼ 5.6 Hz, 1H), 4.12–4.00 (m,
H), 3.82–3.70 (m, 1H), 3.10–2.94 (m, 2H), 2.50 (t, J ¼ 4.0 Hz, 1H),
.44–2.20 (m, 4H), 1.98–1.22 (m, 22H), 1.03–1.00 (m, 6H), 0.88–0.80
þ
(
m, 9H); MS: m=e ¼ 584.4 (M þ Na ).
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, 82 mL) in THF (278 mL), 1.6 M n-
ꢁ
BuLi (1 mol, 622 mL) was added at ꢂ25 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 ꢂ45 C, methyl
iodide (1 mol, 63 mL) was added to the reaction mixture and stirred for
.5 h. The reaction mixture was quenched with 1 N aq. HCl (915 mL),
and the organic layer was separated, concentrated, and dried under
1

4458
R. K. Singamsetty et al.
reduced pressure to afford crude material 5 as a thick brown syrup.
1
Crude yield: 154 g (>100%); H NMR (400 MHz, DMSO-d6): d 7.77
and 7.69 (t, J ¼ 6.4 Hz, 1H), 5.94 (d, J ¼ 9.6 Hz, 1H), 5.77 (dd, J ¼ 9.6,
6
.0 Hz, 1H), 5.48 (s, 1H), 5.20–5.18 (m, 1H), 4.63–4.59 (m, 1H), 4.36
(
3
4
d, J ¼ 6.0 Hz, 1H), 4.27 (d, J ¼ 5.6 Hz, 1H), 4.10–4.02 (m, 1H), 3.79–
.71 (m, 1H), 3.04–2.95 (m, 2H), 2.50 (t, J ¼ 4.0 Hz, 1H), 2.39–2.23 (m,
H), 1.99–1.20 (m, 21H), 1.26–1.00 (m, 9H), 0.88–0.75 (m, 9H); MS:
þ
m=e ¼ 598.4 (M þ Na ).
(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-
[5]
noicacidammonium Salt 6
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, 30 mL) 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 6 as a light-brown-
1
colored solid in 87% isolated yield (39.5 g) and 98% purity (HPLC). H
NMR was found to be satisfactory as per literature.
2
,2-Dimethylbutanoicacid(1S,2R,7S,8S,8aR)1,2,3,7,8a-hexahydro-
,7,dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-
3
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
reaction mixture was cooled to 43 C and filtered. The solvent was com-
h at 83 C, water, a by-product, was azeotropically distilled out. The
ꢁ
ꢁ
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

New Synthesis of Simvastatin
4459
methanol=water (1:1). The wet material was dried over a period of 2 h at
5
was found to be satisfactory as per literature.
ꢁ
1
4 C to afford 1 (21.5 g) in 93% yield and 99% purity (HPLC). H NMR
ACKNOWLEDGMENTS
We acknowledge Dr. Reddy’s Laboratories for financial and analytical
support.
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1
2
3
. Askin, D.; Verhoeven, T. R.; Liu, T. M.-H.; Shinkai, I. Synthesis of synvino-
lin: Extremely high conversion alkylation of an ester enolate. J. Org. Chem.
1
991, 56, 4929–4932.
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disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug
Metab. Dispos. 1989, 51, 138–145.
. (a) Kysika, R.; Kren, V. Determination of lovastatin (mevinolin) and mevino-
linic acid in fermentation liquids. J. Chromatogr. 1993, 630, 415–417. (b)
Moore, R. N.; Bigam, G.; Chan, J. K.; Hogg, A. M.; Thomas, T.; Verderas,
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terreus: Determination of the origin of carbon, hydrogen, and oxygen atoms
by carbon-13 NMR and mass spectrometry. J. Am. Chem. Soc. 1985, 107,
3694–3701. (c) Rosen, T.; Heathcock, C. H. The synthesis of mevinic acids.
Tetrahedron 1986, 42, 4909–4951.
4
5
. Hoffman, W. F.; Alberts, A. W.; Anderson, P. S.; Chem, J. S.; Smith, R.L.;
Willward, A. K. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibi-
tors, 4: Side-chain ester derivatives of mevinolin. J. Med. Chem. 1986, 29,
8
49–852. Also see Ref. 1.
. Thaper, R. K.; Kumar, Y.; Kumar, S. M. D.; Misra, S.; Khanna, J. M. A cost-
efficient synthesis of simvastatin via high-conversion methylation of an alkox-
ide ester enolate. Org. Process Res. Dev. 1999, 3, 476–479.