A new method for the synthesis of antihypercholesterolemic agent simvastatin

Article abstract of DOI:10.1002/hlca.200390066

A new synthetic method for the preparation of the cholesterol-lowering drug simvastatin from the naturally occurring lovastatin is reported. The synthesis employs first the protection of the OH group of lovastatin (1) and then the protection of the lactone C=O group to prevent enolization via conversion to the orthoesters 4a and 4b. Alkylation of the 2-methylbutyrate side chain is then successfully achieved. Removal of the protecting groups affords antihypercholesterolemic agent simvastatin (2).

Full text of DOI:10.1002/hlca.200390066

Helvetica Chimica Acta Vol. 86 (2003)
673
A New Method for the Synthesis of Antihypercholesterolemic Agent
Simvastatin
by Kadir Dabak* and Mustafa Adiyaman
Department of Research and Development, Eczacibasi ÷zg¸n Kimya, Organize Sanayi Bolgesi, Fatih Cad. 12,
Cerkezkoy 59500, TR-Tekirdag
(phone: 90-282-7581771; fax: 90-282-7581770; e-mail: kadird@eczacibasi.com.tr)
A new synthetic method for the preparation of the cholesterol-lowering drug simvastatin from the naturally
occurring lovastatin is reported. The synthesis employs first the protection of the OH group of lovastatin (1) and
then the protection of the lactone CˆO group to prevent enolization via conversion to the orthoesters 4a and 4b.
Alkylation of the 2-methylbutyrate side chain is then successfully achieved. Removal of the protecting groups
affords antihypercholesterolemic agent simvastatin (2).
Introduction.
Simvastatin (2), like other statins (lovastatin (1), pravastatin,
mevastatin, atorvastatin, fluvastatin, cervastatin, etc., derivatives and analogs thereof)
is a (hydroxymethyl)glutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor
and is used as an antihypercholesterolemic agent [1 5].
Simvastatin (2) is prepared from a fermentation product, lovastatin (1). It has been
reported [6] that 1 cannot be converted directly to simvastatin (2) by an alkylation
reaction. Because of higher acidity of the lactone a-H atoms compared with the a-H
atoms of the ester side chain, alkylation occurs preferentially in the a-position of the
lactone. In general, there are two known routes to introduce the additional a-Me group
to the 8-acyl side chain of 1. One involves a deacylation/reacylation procedure,
comprised of de-esterification of 2-methylbutanoyloxy side chain of 1 and re-
esterification with 2,2-dialkylbutyric acid [7][8]. The other one involves protection
reactions and an alkylation of the methylbutanoyloxy side chain with methylhalide/
metal alkylamide, and deprotection reactions. In many of the synthetic procedures
described in the literature, the latter methodology is used to prepare 2 from 1 [9 15].
All synthetic approaches to prepare simvastatin (2) suffer from severe disadvan-
tages, such as an excessive number steps, including those involving the ring opening of

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the lactone group of 1, the insertion and removal of protecting groups and necessity for
lactonization, and/or use of expensive reagents.
We report here a less-expensive, safe, and reliable method to synthesize simvastatin
(2) from lovastatin (1). Both the protection and the removal of the protecting groups
and methylation reactions are easy to handle, and 2 is obtained in only four steps with
inexpensive reagents.
Results and Discussion.
In this study, we decided to methylate the (S)-2-
methylbutanoyloxy side chain of 1 in order to avoid the problematic deacylation/
reacylation reactions. To achieve our goal, we needed to protect the lactone CˆO
group to prevent an alkylation at the a-position of the lactone ring. Although the
protection of the CˆO group of a lactone [16][17] as an orthoformate derivative with
ethyleneglycol has been reported, no such method has been used in the preparation of
2.
Our synthesis started with the conversion of 1 to its benzoate derivative 3a with
PhCOCl and pyridine in CH2Cl2 in 95% yield. Then, 3a treated with ethane-1,2-diol,
(EtO)3CH, and a catalytic amount of H2SO4 in THF gave the desired orthoformate 4a
in 51% yield (Scheme). The methylation of the (S)-2-methylbutanoyloxy side chain of
4a was conducted with BuLi, pyrrolidine, and MeI in THF, followed by aqueous
workup to give simvastatin b-hydroxyorthoformate derivative 5 in 85% yield. It has to
be emphasised that simultaneous removal of the OH protecting group in 4a occurred
during the aqueous workup due to generation of the basic medium in each case. Finally,
we have successfully obtained the cholesterol-lowering agent simvastatin (2) in 92%
yield by removing the CˆO protecting group of compound 5 by treatment with dilute
HCl in THF.
Scheme. Synthesis of Simvastatin (2)

Helvetica Chimica Acta Vol. 86 (2003)
675
We have also obtained simvastatin (2) via protection of the OH group of 1 with
pivaloyl chloride in a manner similar to the benzoate protection (Scheme).
The main feature of the new synthesis is in the use of the above-described CˆO
group protection of the lactone as the orthoester derivatives 4a and 4b. This synthesis of
2 involves four simple synthetic steps and overcomes also the formation of a dimer of 2,
as the lactone ring is not opened in contrast to the methods involving lactone opening
and closing.
Experimental Part
General. All reactions were carried out under an inert atmosphere of N2 and with glassware dried in oven
(1508) unless otherwise noted. The following solvents and reagents were dried over molecular sieves prior to
use: THF, pyrrolidine, DMF, toluene. TLC: EM Science (E. Merck) plates precoated with silica gel 60 F254 (0.25-
mm thickness). Spots were visualized by any of the following methods: UV, I2, phosphomolybdic acid (PMA),
anisaldehyde, or KMnO4. Flash column chromatography (FC): with the solvents specified. M.p.: Electrothermal
Thomas-Hoover cap. melting-point apparatus; uncorrected. IR (KBr for the solids and film for the oil; cmÀ1):
Jasco FT-IR, model 5300. 1H-NMR (d [ppm], CDCl3): 300-MHz Varian instrument; TMS as internal standard;
the coupling constants Jare given in Hz. 13C-NMR: at 75 MHz. MS: VG-Zabspec double-focusing spectrometer;
EI-MS at 70 eV.
(2R,4R)-2-[2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-Hexahydro-2,6-dimethyl-8-{[(S)-2-methylbutanoyl]oxy}-
naphthalen-1-yl)ethyl]-3,4,5,6-tetrahydro-6-oxo-2H-pyran-4-yl Benzoate (3a). To a soln. of lovastatin (1; 20 g,
49.63 mmol) in toluene (250 ml) were added pyridine (8.64 g, 109.17 mmol) and then slowly PhCOCl (13.95 g,
99.26 mmol) at r.t. The mixture was stirred at r.t. for 18 h and then diluted with toluene (25 ml). The resulting
soln. was washed with 1n HCl soln. (2 Â 25 ml), 10% NaHCO3 (30 ml), and H2O (30 ml). The org. phase was
separated and dried (Na2SO4). Na2SO4 was filtered off, and the filtrate was concentrated in vacuo. The product
precipitated upon addition of hexane (150 ml), and the filtration afforded 3a (20.3 g, 91%). White crystalline
1
product. M.p. 114 1178. IR: 2962, 2931, 2877, 1724, 1449, 1265, 1109, 704. H-NMR: 0.82 (t, J ˆ 7.2, Me); 1.04
(d, J ˆ 6.7, Me); 1.07 (d, J ˆ 6.6, Me); 1.24 1.76 (m, 4 C H, CH, Me); 1.81 2.02 (m, 3 CH, CH2); 2.23 2.44
2
(m, CH); 2.88 (d, J ˆ 4.7, CH2); 4.59 (m, CH); 5.37 (m, CH); 5.53 (m, 2 CH); 5.78 (d, J ˆ 9.4, CH); 5.98 (d, J ˆ
9.4, CH); 7.46 (t, J ˆ 7.6, 2 CH); 7.65 (t, J ˆ 7.1, CH); 8.03 (d, J ˆ 3.5, 2 CH). 13C-NMR: 11.8; 14.2; 16.5; 23.0;
24.5; 27.0; 27.7; 30.9; 33.5; 33.6; 35.7; 36.9; 37.4; 41.6; 42.7; 66.3; 68.1; 76.8; 128.6; 128.8; 129.5; 129.89; 129.97;
.
‡
131.8; 133.2; 133.8; 166; 168.2; 176.8. EI-MS: 508.6 (M ).
(2R,4R)-2,2-(Ethylenedioxy)-6-[2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl-8-{[(S)-2-meth-
ylbutanoyl]oxy}naphthalen-1-yl)ethyl]-3,4,5,6-tetrahydro-2H-pyran-4-yl Benzoate (4a). To a soln. of 3a (11.4 g,
20 mmol) in dry THF (150 ml) was added ethane-1,2-diol (10.2 g, 200 mmol), (EtO)3CH (8.9 g, 60 mmol), and 3
drops of H2SO4. The mixture was stirred for 48 h at r.t. Then, 150 ml of sat. NaHCO3 soln. was added, and THF
was removed under reduced pressure. The aq. phase was extracted with AcOEt (2 Â 150 ml). The org. phase was
separated and dried (Na2SO4). Na2SO4 was filtered off, and the filtrate was concentrated under reduced
pressure. The residue was purified by FCwith hexane/AcOEt 3 :1 to give 4a (6.05 g, 51% yield). White solid.
M.p. 113 1158. IR: 2939, 2924, 1719, 1705, 1460, 1274, 1186, 1111, 703. 1H-NMR: 0.75 (t, J ˆ 7.62, Me); 0.86
(d, J ˆ 7, Me); 1.03 (d, J ˆ 4.1, Me); 1.06 (d, J ˆ 3.5, Me); 1.25 1.42 (m, C H, CH); 1.48 1.74 (m, C H, C H);
2
2
1.76 2.10 (m, C H, CH); 2.16 (d, J ˆ 3.52, CH2); 2.23 2.42 (m, 2 C H, 2 CH); 3.93 (m, CH); 4.02 4.16
2
2
(m, C H, 2 CH); 5.31 (m, CH); 5.47 (m, 2 CH); 5.68 (d, J ˆ 9.4, CH); 5.94 (d, J ˆ 9.4, CH); 7.46 (t, J ˆ 7.6,
2
2 CH); 7.53 (t, J ˆ 7.03, CH); 8.14 (d, J ˆ 7.03, CH). 13C-NMR: 11.7; 14.1; 16.4; 22.9; 24.9; 27.06; 27.7; 30.9; 32.6;
32.9; 34.8; 35.1; 37.3; 37.4; 41.5; 64.2; 64.2; 64.2; 68.2; 70.4; 118.6; 128.4; 128.5; 129.6; 129.9; 130.8; 132.1; 133.1;
.
‡
133.7; 166.1; 176.9. EI-MS: 552.7 (M ).
(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-6,6-(Ethylenedioxy)-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-yl]ethyl}-
1,2,3,7,8,8a-hexahydro-3,7-dimethyl-naphthalen-1-yl 2,2-Dimethylbutanoate (5) from 4a. To a stirred soln. of
pyrrolidine (3.56 g, 50 mmol) in anh. THF (100 ml) was added BuLi (3.2 g, 50 mmol; 2.5m in hexane) at À 208.
The resulting mixture was stirred at À 208 for 30 min and then transferred via cannula under N2 pressure to a
stirred soln. of 4a (5.53 g, 10 mmol) in THF (100 ml) cooled to À 308 to À 358 at such a rate that the temp. was
kept below À 308. After completion of the addition, the mixture was stirred at À 308 for 2 h, and then MeI
(7.1 g, 50 mmol) was added while keeping the temp. at À 308. The mixture was stirred for additional 1.5 h,
allowed to warm to À 108, and kept at this temp. for 1 h. The reaction was quenched by careful addition of H2O

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Helvetica Chimica Acta Vol. 86 (2003)
(200 ml). The resulting slurry was stirred for 20 min. at 08, THF was removed under reduced pressure, and the
aq. phase was extracted with AcOEt (2 Â 150 ml). The combined org. extracts were washed with H2O (2 Â
150 ml) and dried (Na2SO4). Na2SO4 was filtered off and the filtrate was concentrated under reduced pressure to
give 5 (2.27 g, 85%) as an oily product, which was used directly in the next step. IR: 2963, 1720, 1461, 1372, 1250,
948, 861, 777. 1H-NMR: 0.78 (t, J ˆ 7.6, Me); 1.03 (d, J ˆ 7, Me); 1.05 (s, 2 Me); 1.22 1.43 (m, C H, C H); 1.44
2
1.75 (m, 6 H); 1.82 2.03 (m, 4 H); 2.04 (dd, J ˆ 9.6, CH); 2.21 (d, J ˆ 3.5, CH2); 2.23 2.41 (m, 2 C H); 3.82
2
4.01 (m, 2 CH); 4.02 4.22 (m, 2 C H); 5.77 (m, CH); 5.98 (d, J ˆ 9.2, CH). 13C-NMR: 9.5; 14.3; 23.3; 24.9; 27.5;
2
30.6; 32.9; 33.2; 37.3; 37.5; 42.4; 37.9; 64.1; 65.4; 68.3; 70.1; 118.9; 128.5; 129.8; 131.9; 133.4; 177.9. EI-MS: 462.6
.
‡
(M ).
(2R,4R)-2-[2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-Hexahydro-2,6-dimethyl-8-{[(S)-2-methylbutanoyl]oxy}-
naphthalen-1-yl)ethyl]-3,4,5,6-tetrahydro-6-oxo-2H-pyran-4- yl 2,2-Dimethylpropanoate (3b). The reaction was
conducted in a manner similar to the preparation of 3a, with 1 (10 g, 24.8 mmol) as the starting material. The
corresponding ester 3b was obtained as an off-white solid (11.2 g, 92%). M.p. 95 968. IR: 2968, 2870, 1728, 1708,
1461, 1245, 1154, 1075, 872. 1H-NMR: 0.84 (t, J ˆ 7.6, Me); 0.95 (d, J ˆ 7.9, Me); 1.03 (d, J ˆ 7.8, Me); 1.11 (d, J ˆ
7.0, Me); 1.24 (s, 3 Me); 1.31 1.50 (m, C H); 1.51 2.03 (m, 4 C H); 2.22 2.43 (m, 4 CH); 2.75 (m, C H); 2.86
2
2
2
(d, J ˆ 18.2, CH); 4.45 (m, CH); 5.23 (m, CH); 5.35 (m, CH); 5.54 (m, CH); 5.77 (m, CH); 5.95 (d, J ˆ 9.4,
CH). 13C-NMR: 11.8; 14.1; 16.5; 23.0; 24.5; 27.0; 27.2; 27.7; 30.9; 32.7; 33.4; 33.5; 35.5; 36.9; 37.4; 39.0; 41.6; 65.4;
.
‡
68.0; 76.8; 128.6; 129.9; 131.8; 133.2; 169.0; 176.8; 177.7. EI-MS: 488.1 (M ).
(2R,4R)-2,2-(Ethylenedioxy)-6-[2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl-8-{[(S)-2-meth-
ylbutanoyl]oxy}naphthalen-1-yl)ethyl]-3,4,5,6-tetrahydro-2H-pyran-4-yl 2,2-Dimethylpropanoate (4b). The re-
action was conducted in a manner similar to the preparation of 4a, with 3b (9.77 g, 20 mmol) as the starting
1
material. Yield: 5.11 g (48%). IR: 2958, 2873, 1723, 1461, 1286, 1161, 1039, 950, 733. H-NMR: 0.84 (t, J ˆ 7.6,
Me); 0.86 (d, J ˆ 7.9, Me); 1.02 (d, J ˆ 7.8, Me); 1.11 (d, J ˆ 7.0, Me); 1.23 (s, 3 Me); 1.24 1.76 (m, 3 C H); 1.91
2
2.04 (m, 2 C H); 2.06 2.51 (m, 3 CH); 3.85 4.22 (m, 2 C H, 2 CH); 4.31 (m, CH); 5.05 (m, CH); 5.24
2
2
(m, CH); 5.43 (m, CH); 5.85 (m, CH); 5.92 (d, J ˆ 9.3, CH). 13C-NMR: 11.8; 14.1; 16.4; 23.0; 24.9; 27.1; 27.2;
27.7; 29.9; 30.8; 32.6; 32.9; 34.8; 37.3; 37.4; 39.0; 41.6; 64.0; 64.1; 67.4; 68.2; 70.3; 118.5; 128.4; 129.6; 132.1; 133.7;
.
‡
176.9; 178.1. EI-MS: 532.2 (M ).
Compound 5 from 4b. The reaction was conducted in a manner similar to the preparation of 5 from 4a.
Compound 5 was obtained in 84% yield (2.76 g), which was used directly in the next step. Spectroscopic data
were identical with those of compound 5 obtained from 4a.
(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-{2-[(2R,4R)-3,4,5,6-tetrahydro-4-hydroxy-6-oxo-
2H-pyran-2-yl]ethyl}naphthalen-1-yl 2,2-Dimethylbutanoate (ˆ Simvastatin; 2). To a soln. of 5 (4.63 g, 10 mmol)
in THF (50 ml) was added 1n HCl (10%, 10 ml) at r.t. The mixture was stirred at r.t. for 3 h. THF was removed
under reduced pressure, and the aq. phase extracted with AcOEt (2 Â 50 ml). The combined org. extracts were
washed with sat. NaHCO3 (2 Â 25 ml) and dried (Na2SO4). Na2SO4 was filtered off, and the filtrate was
concentrated under reduced pressure. The residue was crystallized from toluene/hexane to give 2 (3.85 g, 92%).
1
White solid. M.p. 132 1348. IR: 2945, 2930, 1701, 1389, 1255, 1162, 1076,1056. H-NMR: 0.83 (t, J ˆ 7.3, Me);
1.04 (d, J ˆ 7.1, Me); 1.10 (s, 2 Me); 1.20 1.73 (m, Me, 4 C H); 1.83 2.03 (m, C H, CH); 2.24 2.44 (m, C H ,
2
2
2
CH); 2.65 2.81 (m, 2 CH); 4.32 (m, CH); 4.63 (m, CH); 5.33 (m, CH); 5.43 (m, CH); 5.84 (m, CH); 5.98
(d, J ˆ 9.4, CH). 13C-NMR: 9.6; 14.1; 23.3; 24.5; 24.9; 25.0; 27.5; 30.8; 33.1; 33.2; 36.3; 36.8; 37.6; 38.8; 43.2; 62.7;
.
‡
68.3; 76.7; 128.6; 129.9; 131.7; 133.1; 170.8; 178.3. EI-MS: 418.2 (M ).
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Received October 3, 2002