A novel and efficient route for the preparation of atorvastatin

Article abstract of DOI:10.1016/j.cclet.2011.04.016

A novel and efficient synthetic method of atorvastatin was described. The key step of the synthesis was the construction of the olefin linkage between the chiral side chain and skeleton via a Horner-Wadsworth-Emmons reaction, resulting in the advanced intermediate of atorvastatin under hydrogenation of the olefin over Pd/C. This novel method is more useful for the practical synthesis of atorvastatin than its document reported methods.

Full text of DOI:10.1016/j.cclet.2011.04.016

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1159–1162
www.elsevier.com/locate/cclet
A novel and efficient route for the preparation of atorvastatin
Jian Gao a, Yang Hui Guo b, Ya Ping Wang b, Xiang Jing Wang a, Wen Sheng Xiang a,
*
a Department of Biochemical Engineering, Northeast Agricultural University, Harbin 150030, China
b Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou 318000, China
Received 17 January 2011
Available online 18 July 2011
Abstract
A novel and efficient synthetic method of atorvastatin was described. The key step of the synthesis was the construction of the
olefin linkage between the chiral side chain and skeleton via a Horner–Wadsworth–Emmons reaction, resulting in the advanced
intermediate of atorvastatin under hydrogenation of the olefin over Pd/C. This novel method is more useful for the practical
synthesis of atorvastatin than its document reported methods.
# 2011 Wen Sheng Xiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Atorvastatin; Horner–Wadsworth–Emmons reaction; Synthesis; Intermediate
Atorvastatin (1, Lipitor1) is the first totally synthesized HMG-CoA reductase inhibitor developed and marketed as
a single enantiomer. It becomes the standard of care for treatment of hypercholesterolemia and ranked as one of the
most successful drugs of this decade because of its efficacy, safety and long-term benefits [1–3]. Hence, there has been
considerable interest in the synthesis of atorvastatin 1. A number of different routes to this drug have been reported,
mostly based on the convergent synthesis using 2 as the advanced intermediate [4–10]. The routine for syntheses of 2
involved a Paal–Knorr condensation of diketoamide 3 with chiral ester 4 as outlined in Scheme 1. However, all of the
published methods for the preparation of the atorvastatin side-chain involve several drawbacks such as (a) low overall
yields; (b) lengthy and tedious processing steps; and (c) the use of several expensive reagents. Therefore, the
development of practical, concise and high yield approaches for the key intermediate 2 of atorvastatin is requisite and
significant. Herein we describe a new more convenient and efficient method for the synthesis of the compound 2 as
shown in Scheme 2.
Our synthesis of fragment 8 as a key pyrrole precursor was outlined in Scheme 3. We used phthalimide 9 as the
starting material which is readily available and inexpensive. The phthalimide 9 was converted to the key precursor
diethyl (aminomethyl) phosphonate 8 through four step reactions according to the literature [11,12].
With the phosphonate 8 in hand, we studied its cyclization reaction with diketone 3 and optimized the reaction
conditions as shown in Table 1. We found that the reaction conditions under a catalytic amount of acetic acid in
anhydrous toluene (Table 1, entries 5 and 6) resulted in good conversion to the desired pyrrole 6. Comparison of entries
5 and 6 revealed that an excess of diketone 3 (entry 6) afforded slightly improved yields relative to equivalent amount
(entry 5).
* Corresponding author.
E-mail address: xiangwensheng@yahoo.com.cn (W.S. Xiang).
1001-8417/$ – see front matter # 2011 Wen Sheng Xiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.04.016

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J. Gao et al. / Chinese Chemical Letters 22 (2011) 1159–1162
F
F
O
O
NHPh
NH2
O
O
O
O
O
O
Ph
O
+
OH OH
O
Ph
O
Ph
O
O
N
O
F
Ca2+
PhHN
N
O
PhHN
3
4
2
2
1
Scheme 1. Document reported synthetic route for atorvastatin 1.
F
F
O
O
O
O
O
O
O
Ph
O
Ph
O
N
O
N
PhHN
PhHN
F
2
5
O
O
NHPh
Ph
O
Ph
O
F
O
O
O
3
N
PO(OEt)
+
2
PhHN
+
O
O
H N
2
PO(OEt)
2
8
7
6
Scheme 2. Our retrosynthetic strategy for the intermediate 2 of atorvastatin.
O
O
O
O
b
a
c
d
N
N
N
NH
H2N
PO(OEt)2
OH
PO(OEt)2
Br
O
O
O
O
11
12
10
8
9
Scheme 3. Synthesis of precursor 8. Reagents and conditions: (a) formaldehyde solution (36%), 105 8C, 2 h, 94%; (b) HBr (40%), H2SO4, 80 8C,
1 h, 90%; (c) triethylphosphite, 90 8C, 1 h, 99%; (d) hydrazine hydrate, EtOH, 25 8C, 1 d.
And then, we focused our attention on the connection of the phosphonate ester 6 to the aldehyde 7 which was the
same raw material in the synthesis of rosuvastatin and fluvastatin [13–16] (Scheme 4). A variety of conditions of
the Horner–Wadsworth–Emmons reaction were evaluated to prepare olefin 5. Initial experiment with 6 revealed that
the use of several base such as t-BuOK, NaH, and LDA failed to afford the desired olefination product. However, BuLi
was found to be the right reagent provided compound 5 as a mixture of cis/trans isomers in a 1/3 proportion as
determined by 1H NMR (integration for vinylic protons). Compounds 5a and 5b could be separated from each other by
the flash chromatography on silica gel (petroleum ether/ethyl acetate, 10:1). The structures of 5a and 5b were
identified by MS, HRMS, 1H NMR, 13C NMR and 2D NMR. Finally, hydrogenation of the mixture of 5a and 5b over
10% Pd/C afforded the key intermediate 2 of atorvastatin in 95% of yield. The compound 2 gave the same analytic data

J. Gao et al. / Chinese Chemical Letters 22 (2011) 1159–1162
1161
Table 1
Preparation of phosphonate ester 6 as ylide precursor.
F
O
O
Ph
O
NHPh
+
N
PO(OEt)
H N
PO(OEt)
2
2
2
PhHN
Ph
O
F
8
3
6
.
Entry
Ratio of 3/8
Addition
Solvent
Temp (8C)
Yield (%)
1
2
3
4
5
6
7
1:1
TiCl4
ZnCl4
TsOH
CH2Cl2
DMSO
Toluene
Toluene
Toluene
Toluene
AcOH
30
90
90
90
90
90
90
0
0
1:1
1:1
33
46
68
76
0
1:1
BF3(Et2O)
AcOH
AcOH
–
1:1
1.4:1
1.4:1
F
F
F
O
O
O
H
O
O
O
Ph
O
O
O
O
O
+
a
b
Ph
O
O
Ph
O
N
O
N
PhHN
H
PhHN
O
N
PO(OEt)2
PhHN
7
)
5b (cis/trans
5a/
2
6
Scheme 4. Synthesis of the advanced intermediate 2. Reagents and conditions: (a) BuLi, THF, À78 to 70 8C, 3 h, 68%; (b) 10% Pd/C, H2, 97%.
as reported in the literature [7,10]. The protective intermediate 2 could easily be translated to the atorvastatin
according to the literature [17]. At last, the prepared compounds gave satisfactory analytical data [18].
In conclusion, we developed a convenient, efficient and economical synthetic approach for compound 2 from
available low cost raw material and reagents with good total yields of 42.0%. Furthermore, our strategy should change
the way of atorvastatin producing in industry.
Acknowledgments
We are grateful for the financial supports from the National Key Project for Basic Research (No. 2010CB11261 02)
and the Outstanding Youth Foundation of Heilongjiang Province (No. JC200706).
References
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[15] A.S. Prasad, R. Shanmughasamy, J. Jibin, et al. WO 2010023678 A1 (2010).
[16] S. Manne, T. Srinivasan, S.R. Maramreddy, et al. WO 2007125547 A2 (2007).
[17] B.C. Chen, J.E. Sundeen, P. Guo, et al. J. Labelled Compd. Radiopharm. 43 (2000) 261.
[18] Representative data of 2: [a]D25 + 4.9 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3): d 1.07 (m, 1H), 1.32 (s, 3H), 1.38 (s, 3H), 1.45 (s, 9H), 1.55
(d, 3H, J = 7.2 Hz), 1.55 (d, 3H, J = 7.2 Hz), 1.68 (m, 2H), 2.26 (dd, 1H, J = 15.2 Hz, 6.4 Hz), 2.40 (dd, 1H, J = 15.2 Hz, 7.2 Hz), 3.59 (sept,
1H, J = 7.2 Hz), 3.71 (m, 1H), 3.84 (m, 1H), 4.09 (m, 1H), 4.17 (m, 1H), 6.88 (s, 1H), 6.99–7.03 (m, 3H), 7.08 (d, 2H, J = 8.0 Hz), 7.18–7.28
(m, 9H); 13C NMR (100 MHz, CDCl3): d 170.1, 164.8, 163.5, 161.0, 141.5, 138.4, 134.7, 133.2, 133.1, 130.5, 128.8, 128.7, 128.3, 128.2, 126.5,
123.5, 121.8, 119.6, 115.4, 115.3, 115.2, 98.7, 80.7, 66.4, 65.9, 42.5, 40.9, 38.1, 36.0, 29.9, 28.1, 26.1, 21.7, 21.5, 19.6; ESI-MS m/z: 655.4
[M+H]+; HR-MS 655.3575 ([M+H]+, C40H47FN2O5; calcd. 655.3547);
Compound 5a(cis): 1H NMR (400 MHz, CDCl3): d 0.85–0.91 (m, 1H), 1.26 (s, 3H), 1.38 (s, 3H), 1.44 (s, 9H), 1.46 (d, 3H, J = 6.4 Hz), 1.46 (d,
3H, J = 6.4 Hz), 1.47 (m, 2H), 2.39 (dd, 1H, J = 15.2 Hz, 6.4 Hz), 2.43 (dd, 1H, J = 15.2 Hz, 7.2 Hz), 3.63 (sept, 1H, J = 7.2 Hz), 4.22 (m, 1H),
4.35 (m, 1H), 5.57 (t, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 7.6 Hz), 6.88–6.93 (m, 3H), 6.96–7.00 (m, 1H), 7.04–7.08 (m, 4H), 7.16–7.25 (m, 6H);
13C NMR (100 MHz, CDCl3): d 169.9, 164.1, 163.0, 160.6, 138.5, 138.3, 134.4, 132.7, 132.6, 131.3, 130.9, 129.3, 129.1, 128.7, 127.9, 127.5,
127.4, 127.2, 123.6, 123.3, 121.6, 119.9, 115.8, 115.7, 115.5, 115.1, 98.9, 80.7, 65.5, 42.4, 34.5, 32.0, 29.5, 28.1, 26.8, 26.0, 22.7, 22.4, 21.1,
19.6; ESI-MS m/z: 653.1 [M+H]+; HR-MS 653.3367 ([M+H]+, C40H45FN2O5; calcd. 653.3391);
Compound 5b(trans): 1H NMR (400 MHz, CDCl3): d 0.87 (m, 1H), 1.26 (s, 3H), 1.38 (s, 3H), 1.44 (s, 9H), 1.46 (d, 3H, J = 6.4 Hz), 1.46 (d, 3H,
J = 6.4 Hz), 1.47 (m, 2H), 2.39 (dd, 1H, J = 15.2 Hz, 6.4 Hz), 2.43 (dd, 1H, J = 15.2 Hz, 7.2 Hz), 3.82 (sept, 1H, J = 7.2 Hz), 4.22 (m, 1H), 4.35
(m, 1H), 5.19 (dd, 1H, J = 14.0 Hz, 5.6 Hz), 6.77 (d, 1H, J = 14.0 Hz), 6.88–6.93 (m, 3H), 6.96–7.00 (m, 1H), 7.04 À 7.08 (m, 4 Hz), 7.16–7.25
(m, 6H); 13C NMR (100 MHz, CDCl3): d 169.0, 163.2, 162.1, 159.6, 141.6, 137.3, 133.4, 132.3, 132.2, 131.1, 129.7, 127.9, 127.8, 127.7, 127.4,
127.0, 126.9, 126.0, 123.8, 122.6, 121.1, 118.5, 114.8, 114.0, 113.8, 97.9, 79.7, 66.2, 64.8, 41.4, 35.3, 30.9, 28.9, 28.7, 27.1, 25.1, 21.7, 20.4,
20.3, 18.7; ESI-MS m/z: 653.1 [M+H]+; HR-MS 653.3367 ([M+H]+, C40H45FN2O5; calcd. 653.3391);
Compound 6: 1H NMR (400 MHz, CDCl3): d 1.27 (t, 3H, J = 7.2 Hz), 1.27 (t, 3H, J = 7.2 Hz), 1.55 (d, 6H, J = 7.2 Hz), 3.46 (sept, 1H,
J = 7.2 Hz), 3.95–4.07 (m, 4H), 4.25 (d, 2H, J = 10.8 Hz), 6.90 (s, 1H), 6.97–7.01 (m, 3H), 7.07–7.10 (d, 2H, J = 8 Hz), 7.16 À 7.20 (m, 7H),
7.31–7.34 (m, 2H); 13C NMR (100 MHz, CDCl3): d 164.7, 163.7, 161.3, 141.7, 138.3, 134.4, 134.0, 133.9, 130.3, 129.2, 128.7, 128.4, 127.7,
127.6, 126.7, 123.7, 122.6, 119.8, 116.4, 115.4, 115.1, 62.7, 62.6, 42.3, 40.7, 26.6, 21.4, 16.4, 16.3; ESI-MS m/z: 549.1 [M+H]+; HR-MS
548.2295 ([M]+, C31H34FNO4P; calcd. 548.2240).