Efficient Synthesis of the Nucleus of Atorvastatin Calcium

Article abstract of DOI:10.1080/00397911.2015.1111382

An efficient synthetic route for the parent nucleus of atorvastatin calcium was successfully established through the modification of the related reactions. Under the optimized conditions, compound 1 was obtained in 61.2% yield (lit. 51.4%) from methyl isopropyl ketone via five steps. Two impurities generated by the aldol condensation of methyl isopropyl ketone were identified by gas chromatography-mass spectrometry and their generation can be inhibited by reducing the mixing time of methyl isopropyl ketone and NaH. One oxybromination protocol with hydrogen peroxide was employed to make the best of bromine. A debromination by-product was isolated and confirmed by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry and its generation mechanism was discussed. The impurity can be inhibited by protecting the reaction from light and easily removed by recrystallization.

Full text of DOI:10.1080/00397911.2015.1111382

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient Synthesis of the Nucleus of Atorvastatin
Calcium
Yuzhi Xing, Shipeng Chen, Yingtao Zhou, Na Liu, Ligong Chen & Yang Li
To cite this article: Yuzhi Xing, Shipeng Chen, Yingtao Zhou, Na Liu, Ligong Chen & Yang Li
(2015) Efficient Synthesis of the Nucleus of Atorvastatin Calcium, Synthetic Communications,
45:24, 2832-2840, DOI: 10.1080/00397911.2015.1111382
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1111382
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Date: 18 December 2015, At: 05:45

1
Synthetic Communications , 45: 2832–2840, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1111382
EFFICIENT SYNTHESIS OF THE NUCLEUS OF
ATORVASTATIN CALCIUM
1
,2
1,2
1,2
1,2
Yuzhi Xing, Shipeng Chen, Yingtao Zhou, Na Liu,
1
,2
1,2
Ligong Chen, and Yang Li
School of Chemical Engineering and Technology, Tianjin University,
1
Tianjin, China
2
Collaborative Innovation Center of Chemical Science and Engineering
(
Tianjin), Tianjin, China
GRAPHICAL ABSTRACT
Abstract An efficient synthetic route for the parent nucleus of atorvastatin calcium was
successfully established through the modification of the related reactions. Under the
optimized conditions, compound 1 was obtained in 61.2% yield (lit. 51.4%) from methyl
isopropyl ketone via five steps. Two impurities generated by the aldol condensation of
methyl isopropyl ketone were identified by gas chromatography–mass spectrometry and
their generation can be inhibited by reducing the mixing time of methyl isopropyl ketone
and NaH. One oxybromination protocol with hydrogen peroxide was employed to make
1
the best of bromine. A debromination by-product was isolated and confirmed by
H
13
NMR, C NMR, and high-resolution mass spectrometry and its generation mechanism
was discussed. The impurity can be inhibited by protecting the reaction from light and
easily removed by recrystallization.
Received August 20, 2015.
Address correspondence to Yang Li, School of Chemical Engineering and Technology, Tianjin
University, Tianjin 300072, P. R. China. E-mail: liyang777@tju.edu.cn
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2
832

SYNTHESIS OF THE NUCLEUS OF ATORVASTATIN
2833
Keywords Atorvastatin calcium; parent nucleus; reaction mechanism; synthesis
INTRODUCTION
Atorvastatin calcium (tradename Lipitor; Fig. 1) is a synthetic HMG-CoA
reductase inhibitor, which was discovered and developed by Warner-Lambert
(now merged with Pfizer). It lowers plasma cholesterol level by inhibiting endogen-
ous cholesterol synthesis and also reduces low density lipoprotein (LDL) cholesterol,
[
1]
apolipoprotein B, and triglyceride levels. It is an efficient hypolipidemic reducing
the rate of mortality in coronary patients. 4-Fluoro-a-[2-methyl-1-oxopropyl]-
c-oxo-N,b-diphenylbenzene butyramide (1, Fig. 1) is known as the nucleus of
atorvastatin calcium. Hence, the synthesis of compound 1 has been intensively
studied.
As reported, compound 1 was normally synthesized from N-phenyl- 4-methyl-
3
-oxo-pentanamide as a key intermediate, which was conventionally obtained from
[
2]
malonic acid and acetone in four steps. Later, the tedious and inefficient synthetic
route mentioned previously was improved through the condensation of aniline and
isobutyryl Meldrum's acid in refluxing toluene to yield the key intermediate, but the
[
3]
[
4]
total yield was still poor. In 2006, an alternative synthetic route was reported
Scheme 1).
Although this route was feasible for large-scale production, the use of
(
unfriendly thiazolidine derivatives and expensive 4-fluorobenzaldehyde made it
industrially unattractive. Therefore, it remains a challenge to develop an efficient
synthetic methodology for compound 1.
Based on this work, herein we present a more efficient and higher-yielding
[
5]
synthetic route to compound 1 with an overall yield of 61.2% (Scheme 2).
RESULTS AND DISCUSSION
Initially, the condensation reaction between methyl isopropyl ketone and
dimethyl carbonate was examined, and the obtained results are summarized in
Table 1.
Figure 1. Structures of atorvastatin calcium and compound 1.

2834
Y. XING ET AL.
Scheme 1. Synthetic route of compound 1 reported by Lai et al..
Scheme 2. New synthetic route to compound 1.
Table 1. Optimization of the condensation reaction
a
Entry
Solvent
Base (equiv)
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
1,4-Dioxane
Methanol
1,4-Dioxane
THF
CaH
2
(2.0)
30
30
30
30
30
30
30
30
30
30
10
50
70
18
18
18
6
16
18
6
6
6
6
Trace
19
38
89
41
43
88
78
55
90
54
92
90
CH ONa (2.0)
3
Potassium t-butoxide (2.0)
NaH (2.0)
Toluene
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (1.5)
NaH (1.1)
NaH (2.2)
NaH (2.0)
NaH (2.0)
Cyclohexane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1
1
1
1
18
3.5
3.5
NaH (2.0)
a
Yields determined by GC.

SYNTHESIS OF THE NUCLEUS OF ATORVASTATIN
2835
As shown in Table 1, sodium methoxide, potassium t-butoxide, CaH , and
2
NaH were employed in the reaction, only with NaH as a base, compound 2 was
obtained in 88% yield (Table 1, entries 1–4). This indicated that NaH is a strong
enough base to complete the deprotonation of methyl isopropyl ketone, leading
to undergo efficient condensation reaction. Subsequently, several solvents were
evaluated for this reaction (Table 1, entries 4–7). Obviously, the solvent polarity
is quite important to the reaction, and thus the reaction proceeds smoothly in
tetrahydrofuran (THF) or 1,4-dioxane. Because it is hard to isolate and recycle
THF from the reaction mixture due to the formation of methanol during the pro-
cess of reaction, 1,4-dioxane was chosen as the solvent for further optimization.
Then, after screening NaH loading and temperature (Table 1, entries 7–13), the
optimum conditions of the condensation reaction are 2.0 equiv. of NaH in
1
,4-dioxane solvent at 50 °C.
Unexpectedly, two by-products (10% of the total) were detected and confirmed
by gas chromatography–mass spectrometry (GC-MS) as compounds 6 and 7.
By-products 6 and 7 were generated via the aldol condensation of methyl isopropyl
ketone (Scheme 3). NaH, as a strong base, extracts the proton alpha to the carbonyl
of methyl isopropyl ketone to form the carbon anion, which, in turn, leads to
nucleophilic addition to another methyl isopropyl ketone and then intramolecular
dehydration to 6 and 7. Obviously, it is difficult to prevent the formation of these
two by-products in this reaction. Fortunately, the side reaction can be inhibited by
reducing the mixing time of methyl isopropyl ketone and NaH. After the examin-
ation of the mixing period, it was found that 10 min of stirring is appropriate after
addition of methyl isopropyl ketone into a suspension of NaH, and only 2% of
by-products were detected.
As described in Scheme 1, compound 3 was prepared by N-acylation of aniline
[
4b]
with ester 2 as an acylating agent in the presence of ethylene diamine. In addition,
a solution of ester 2 with 2 equiv. of aniline was stirred at 110 °C in a sealed tube for
2
0 h, and 4% of compound 2 was still remained by high-performance liquid chroma-
[6,7]
tography (HPLC). As reported,
acetylketene 8 is a plausible intermediate
(Scheme 4) for this reaction, and an equilibrium exists between ester 2 and acetylk-
etene 8, so removal of the formed methanol during the reaction is a prerequisite for
obtaining a good yield of compound 3. Thus, in this study, in order to avoid the
side reaction induced by ethylene diamine, compound 3 was obtained in 91.9% yield
[4b]
(
lit. 80%) in the presence of trimethylamine by removal of methanol in about 6 h.
Compound 4 was synthesized by Friedel–Crafts acylation of fluorobenzene
[
8]
with phenylacetyl chloride in the presence of aluminum chloride. By employing
dichloromethane as solvent, the acylation undergoes slowly to present compound
4
9
with 61% yield in 3 h, while it proceeds effectively to afford compound 4 with
0% yield in 1 h without solvent but with excess of fluorobenzene. Considering that
Scheme 3. Generation of by-products 6 and 7.

2836
Y. XING ET AL.
Scheme 4. Proposed mechanism of N-acylation of aniline.
fluorobenzene can be easily recycled by distillation, employment of excess fluoroben-
zene for this acylation would be the best choice.
2
-Bromo-1-(4-fluorophenyl)-2-phenylethanone 5 was obtained by bromination
of compound 4 with a suitable brominating agent. Bromine is normally used for bro-
[
9]
mination reactions by virtue of extensive sources and low favorable E-factors. Only
0% of the available bromine was utilized with the formation of HBr as a by-
5
product. Thus, we developed one oxybromination protocol, which was based on
the oxidation of HBr to bromine with hydrogen peroxide. This bromination method
allows complete utilization of bromine atoms and therefore the atom economy is
much greater. Moreover, this method also has the advantage of low cost, high atom
efficiency, and environmental friendliness.
The last step was a nucleophilic substitution of compound 3 with compound 5
in the presence of a base. Initially, the effects of base were examined and summarized
in Table 2, and it was found that potassium carbonate, as a base, presented better
results than other bases. This indicated that potassium carbonate is the appropriate
base to extract the acidic proton alpha to the carbonyl of compound 3, which, in
turn, leads to induce the nucleophilic substitution. Weaker or stronger bases would
cause undesired side reactions, resulting in poor yield of compound 1.
During the workup of this nucleophilic substitution to get compound 1, a
1
13
by-product (4.5% of the total) was isolated and confirmed by H NMR,
C
NMR, and HRMS as compound 4. When compound 5 and potassium carbonate
were mixed in acetone, the compound 4 was not detected by HPLC. With the
consideration of the instability of C-Br bond, a plausible debromination mechanism
[
12]
for compound 5 was proposed
(Scheme 5). The debromination reaction begins
with homolysis of the C-Br bond induced by light or heat to produce radical 9
and bromine radical. Then radical 9 captures a hydrogen from the medium to form
the compound 4. Based on this debromination mechanism, protection of the reaction
mixture from light could inhibit this side reaction. Indeed, when the reaction of
compounds 3 and 5 proceeded in a sealed flask covered with aluminum foil, the
amount of compound 4 in the mixture was reduced to less than 1.0%. Furthermore,
Table 2. Effects of base for the synthesis of compound 1
a
Entry
Base
Time (h)
Yield (%)
1
2
3
4
5
Na
2
CO
CO
3
10
5
5
5
5
50
80
42
56
60
K
2
3
NaOH
KOH
Triethylamine
a
Isolated yields of products.

SYNTHESIS OF THE NUCLEUS OF ATORVASTATIN
2837
Scheme 5. Proposed mechanism for the formation of compound 4.
compound 4 was easily removed through recrystallization in isopropyl alcohol. Thus,
compound 1 with 99.8% purity was efficiently obtained in this way.
CONCLUSION
In conclusion, a cost-effective and high-yielding synthetic method for the
nucleus of atorvastatin calcium 1 was established, and the involving reactions were
systematically investigated. Two impurities generated by the aldol condensation of
methyl isopropyl ketone were detected and confirmed by GC-MS. One oxybromina-
tion protocol was employed to make the best use of bromine. A debromination by-
1
13
product generated in the last step was isolated and confirmed by H NMR,
C
NMR, and HRMS, its formation mechanism was proposed, and it could be easily
removed by recrystallization in isopropyl alcohol. Finally, compound 1 was obtained
in 61.2% total yield and 99.8% purity.
EXPERIMENTAL
Reagents and solvents were obtained from commercial suppliers. The reaction
of methyl isopropyl ketone and dimethyl carbonate was monitored by GC with a SE-
5
4 (30 m) capillary column (Chromatographic Technology R&D Center, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences) and flame ionization
detector (FID). The composition of the reaction mixture was identified by GC-MS
equipped with HP-5 capillary column (30 m × 0.25 mm, 0.2 µm film thickness) and
an ion trap MS detector. The other reactions were monitored by thin-layer chroma-
tography (TLC) using commercial silica-gel plates. The purity of products was
detected by high-performance liquid chromatography (HPLC) on Agilent 1,100
series instrument. Melting points were observed on YRT-3 melting-point tester.
1
13
H NMR and C NMR spectra were recorded on Bruker Avance III 600-MHz
instrument. HRMS was measured on a MicrOTOF-Q II instrument.
[4b]
Preparation of Methyl 4-Methyl-3-oxopentanoate (2)
Methyl isopropyl ketone (10.00 g, 116.10 mmol) was added slowly to a suspen-
sion of sodium hydride (60% in mineral oil, 9.29 g, 232.25 mmol) in 1,4-dioxane
(70 mL). The mixture was stirred at room temperature for 10 min. Dimethyl carbon-
ate (15.70 g, 174.31 mmol) was added and the mixture was stirred at 50 °C for 3 h.

2838
Y. XING ET AL.
The mixture was cooled to room temperature, and acetic acid (14 mL) was slowly
added. The precipitate was filtered and washed with 1,4-dioxane (20 mL). The filtrate
was concentrated under vacuum. Compound 2 was collected at 80–85 °C under
1
vacuum (∼10 mbar) as colorless liquid (14.73 g, yield 88%). H NMR (600 MHz,
1
3
CDCl ) d: 3.69 (s, 3H), 3.48 (s, 2H), 2.68 (m, 1H), 1.01 (d, J ¼ 7.2 Hz, 6H).
C
3
NMR (150 MHz, CDCl ) d: 205.95, 167.38, 51.44, 46.23, 40.44, 17.26.
3
[4b]
Preparation of N-Phenyl-4-methyl-3-oxo-pentanamide
(3)
A mixture of compound 2 (5.00 g, 34.69 mmol), triethylamine (0.88 g,
8
.70 mmol), and aniline (3.88 g, 41.62 mmol) in toluene (30 mL) was heated to 70 °
C. The reaction mixture was stirred at 70 °C for 1 h and then gradually heated to
10–120 °C. The methanol formed during the reaction was distilled off together with
1
some toluene for 5 h. After cooling to room temperature, the mixture was washed
with 5% hydrochloric acid (30 mL) and water (2 × 30 mL). The organic phases were
dried over anhydrous magnesium sulfate and then concentrated to give a red oil 3
1
(
5
6.55 g, 91.9% yield). H NMR (600 MHz, CDCl ) d: 9.23 (s, 1H), 7.09–7.55 (m,
3
1
3
H), 3.59 (s, 2H), 2.73 (m, 1H), 1.17 (d, J ¼ 6.6 Hz, 6H). C NMR (150 MHz,
CDCl ) d: 210.4, 164.5, 137.6, 128.8, 124.5, 120.1, 47.7, 41.5, 17.6.
3
[
10]
Preparation of 1-(4-Fluorophenyl)-2-phenylethanone
(4)
Powdered aluminum chloride (10.36 g, 77.89 mmol) was added to fluoroben-
zene (40 mL) cooled by an ice bath. Phenyl acetyl chloride (10.00 g, 64.93 mmol)
was added dropwise and the mixture was stirred for 1 h at less than 10 °C. The mix-
ture was poured slowly into a mixture of ice (30 g), water (20 mL), and 2 N hydro-
chloric acid (40 mL), and the obtained aqueous phase was extracted with
dichloromethane (2 × 30 mL). The organic phases were combined, washed with 5%
NaHCO solution (30 mL), and concentrated to give the crude product. Then, the
3
solid was dissolved in petroleum ether (30 mL) and heated to 80–85 °C for a while
and then cooled to room temperature. White crystal appeared, and the crystal was
filtered and dried to give 4 (12.51 g, 90% yield). Mp 81.8–82.5 °C (lit. mp 80–82 °
1
C). H NMR (600 MHz, CDCl ) d: 8.06–8.02 (m, 2H), 7.35–7.25 (m, 5H), 7.12 (t,
3
1
3
J ¼ 8.4 Hz, 2H), 4.26 (s, 2H). C NMR (150 MHz, CDCl ) d: 196.05, 167.03,
3
1
4
64.49, 134.51, 133.05, 131.35, 131.26, 129.45, 128.77, 127.02, 115.87, 115.66,
þ
5.49. HRMS (ESI), calcd.: C H FO [MþNa] m=z: 237.0794; found: 237.0687.
1
4
11
[11]
Preparation of 2-Bromo-1-(4-fluorophenyl)-2-phenylethanone
(5)
Compound 4 (5.00 g, 23.34 mmol) was suspended in water (15 mL) in a flask
covered with aluminum foil. Five drops of 40% aqueous solution of HBr was added.
The mixture was stirred at room temperature for 5 min, Br (2.05 g, 12.84 mmol) was
2
added dropwise. The reaction mixture was stirred at room temperature for 5 h, and
3
0% aqueous solution of H O (6.5 mL, 25.70 mmol) was slowly added. After 12 h,
2 2
dichloromethane (30 mL) was added and the organic layer was washed with 5%
aqueous sodium sulfite (10 mL) and 5% aqueous sodium chloride (2 × 20 mL) and
then dried over anhydrous magnesium sulfate. The organic mixture was

SYNTHESIS OF THE NUCLEUS OF ATORVASTATIN
2839
1
concentrated to give a light yellow oil 5 (5.82 g, 85% yield). H NMR (600 MHz,
CDCl ) d: 8.01–7.98 (m, 2H), 7.49 (d, J ¼ 7.2 Hz, 2H), 7.36–7.30 (m, 3H), 7.07 (t, J
3
1
3
¼
8.6 Hz, 2H), 6.32 (s, 1H). C NMR (150 MHz, CDCl ) d: 189.33, 166.29, 164.59,
3
1
35.52, 131.69, 131.63, 130.04, 128.89, 128.74, 115.71, 115.57, 51.07.
Preparation of 4-Fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-
diphenylbenzene Butyramide (1)
To a mixture of compound 3 (3.50 g, 17.06 mmol) and potassium carbonate
(3.54 g, 25.61 mmol) in acetone (20 mL), a solution of compound 5 (5.00 g,
1
7.06 mmol) in acetone (5 mL) was added dropwise, and then the mixture was stirred
at room temperature for 5 h. During the whole process, the flask was covered with
aluminum foil. The mixture was filtered and the filter cake was washed with acetone
(
20 mL). The combined filtrate was evaporated to give the crude product. Isopropyl
alcohol (30 mL) was added and the mixture was heated to 85–90 °C. After cooling to
–5 °C, the resulting suspension was filtered, washed with isopropyl alcohol (5 mL),
0
and dried in vacuum oven at 50 °C to afford 1 (5.70 g, 80% yield) as white solid with
1
a purity of 99.8%. Mp 203–205 °C (lit. 206–209 °C). H NMR (600 MHz, DMSO-d )
6
d: 10.20 (s, 1H), 8.13 (t, J ¼ 7.2 Hz, 2H), 7.36–7.01 (m, 12H), 5.42 (d, J ¼ 11.4 Hz,
1
H), 4.87 (d, J ¼ 11.4 Hz, 1H), 2.90 (m, 1H), 1.16 (d, J ¼ 7.2 Hz, 3H), 0.93 (d, J ¼ 3.6
13
Hz, 3H). C NMR (150 MHz, DMSO-d ) d: 208.08, 196.42, 165.82, 165.01, 164.14,
6
1
1
38.11, 135.09, 132.15, 131.75, 131.69, 128.83, 128.67, 128.61, 127.52, 123.91, 119.63,
15.83, 115.69, 63.02, 51.75, 39.42, 18.80, 17.86. HRMS (ESI), calcd.: C H FNO
3
2
6
24
ꢀ
[
M-H] m=z: 416.1740; found: 416.1716.
SUPPLEMENTAL MATERIAL
1
13
Full experimental details, H and C NMR spectra, and HPLC traces can be
accessed on the publisher's website.
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