An efficient synthesis of N3,4-diphenyl-5-(4-fluorophenyl)-2-isopropyl-1H- 3-pyrrolecarboxamide, a key intermediate for atorvastatin synthesis

Article abstract of DOI:10.1016/j.bmcl.2003.10.019

An efficient synthesis of N3,4-diphenyl-5-(4-fluorophenyl)-2-isopropyl-1H- 3-pyrrolecarboxamide, a key intermediate for the synthesis of an effective HMG-CoA reductase inhibitor atorvastatin, is described. The synthesis is based on the 1,3-dipolar cycload

Full text of DOI:10.1016/j.bmcl.2003.10.019

Bioorganic & Medicinal Chemistry Letters 14 (2004) 129–131
An efficient synthesis of N3,4-diphenyl-5-(4-fluorophenyl)-2-
isopropyl-1H-3-pyrrolecarboxamide, a key intermediate for
atorvastatin synthesis
Pramod. S. Pandey* and T. Srinivasa Rao
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi-110016, India
Received 30 August 2003; accepted 2 October 2003
Abstract—An efficient synthesis ofN3,4-diphenyl-5-(4-fluorophenyl)-2-isopropyl-1 H-3-pyrrolecarboxamide, a key intermediate for
the synthesis ofan effective HMG-CoA reductase inhibitor atorvastatin, is described. The synthesis is based on the 1,3-dipolar
cycloaddition reaction ofmesoionic munchnone (1,3-oxazolium-5-olate) with N1,3-diphenyl-2-propynamide leading to N-benzyl
pyrrole, and N-debenzylation using sodium in liquid ammonia as key steps.
# 2003 Elsevier Ltd. All rights reserved.
Atorvastatin (1, Lipitor1, Sortis1) is an HMG-CoA
reductase inhibitor, which inhibits the action ofHMG-
CoA reductase and thereby decreases endogenous cho-
lesterol synthesis, leading to a decrease in circulating
low-density lipoprotein cholesterol,1 ofgreat medicinal
and commercial importance.2 Hence, there has been
considerable interest in the recent past in the synthesis
ofatorvastatin 1.3,4 Roth and co-workers have synthe-
sized atorvastatin 1 in lactone form using N3,4-diphenyl
-1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-iso-
propyl-1H-3-pyrrolecarboxamide 2 as an intermediate.5
They have used 1,3-dipolar cycloaddition reaction of
mesoionic munchnone (1,3-oxazolium-5-olate) 3 with
N1,3-diphenyl-2-propynamide for the synthesis of 2.
But the synthesis of 2 is not economical as the starting
material, ethyl 2-bromo-2-(4-fluorophenyl)acetate, is not
readily accessible and some ofthe reagents used are very
expensive.
1,3-Dipolar cycloaddition reactions ofmesoionic
munchnones (1,3-oxazolium-5-olates) derived from
cyclodehydration ofsecondary N-acylamino acids with
acetylenic dipolarophiles give rise to a mixture ofpyr-
role regioisomers.6 The product distribution ofregioi-
Keywords: Atorvastatin; Munchnone; 1,3-Dipolar cycloaddition;
somers is highly dependent on substituents.7 As part of
1,3-Oxazolium-5-olate; N-Debenzylation.
our study on the effect ofsubstituents on the regioselec-
tivity ofthese reactions, we have studied the 1,3-dipolar
* Corresponding author. Tel.: +91-11-2659-1506; fax: +91-11-2658-
2037; e-mail: pramod@netearth.iitd.ac.in
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.10.019

130
P.. S. Pandey, T. Srinivasa Rao / Bioorg. Med. Chem. Lett. 14 (2004) 129–131
cycloaddition reactions ofmesoionic munchnone 7 with
ethyl phenylpropiolate and N1,3-diphenyl-2-propyna-
mide.8 The reaction of 7 with ethyl phenylpropiolate
(Scheme 1) is regioselective giving 1:9 ratio ofregioi-
somers 8a and 8b (8a being the desired isomer). How-
ever, we have found that the reaction of 7 with N1,3-
diphenyl-2-propynamide is not regioselective giving 1:1
ratio ofregioisomers 9a and 9b (Scheme 2), thus
increasing the yield of 9a, which is precursor for 10.
Interestingly, the regioisomer 9a is easily separated from
9b by crystallization. Hence, this result has led us to
synthesize the pyrrole 10 in a convenient and efficient
manner (Scheme 2). We also used natural amino acid l-
valine which is readily available and inexpensive as the
starting material.
Et3N, followed by hydrolysis with NaOH in methanol–
water (4:1) gave 6 in 95% yield. 1,3-Dipolar cycloaddi-
tion reaction9 ofmesoionic munchnone (1,3-oxazolium-
5-olate) 7, derived from cyclodehydration of 6 by using
DCC in toluene, with N1,3-diphenyl-2-propynamide
gave two pyrrole regioisomers 9a and 9b in 1:1 ratio
1
(80% mixture yield). The ratio was determined by H
NMR signals of(CH 3)2CH– proton appearing at d
3.27 ppm in 9a and d 2.92 ppm in 9b. The regioisomers
9a and 9b were easily separated by crystallization from
their mixture using benzene–hexane (1:1) solvent mix-
ture. The resultant 9a was easily debenzylated10 to
afford 10 in 83% yield by using sodium in liquid
ammonia and t-BuOH at À78 ꢀC for 10 min.
In conclusion, we have developed an efficient and eco-
nomical route for the synthesis of 10, a key intermediate
for atorvastatin synthesis, by using 1,3-dipolar cycload-
dition reaction ofmesoionic munchnone (1,3-oxazo-
lium-5-olate) 7 with N1,3-diphenyl-2-propynamide and
N-debenzylation using sodium in liquid ammonia in the
presence of t-BuOH at À78 ꢀC, as key steps. Now our
efforts are towards the synthesis ofatorvastatin 1 via the
intermediate 2.
Treatment of l-valine 4 with dry HCl gas in MeOH
gave valine methyl ester hydrochloride, which on wash-
ing with liquor ammonia solution gave valine methyl
ester. This was treated with benzyl bromide and K2CO3
in chloroform at room temperature to afford N-benzyl-
valine methyl ester 5 in 83% overall yield. The reaction
of 5 with 4-fluorobenzoyl chloride in the presence of
Acknowledgements
T.S.R. thanks the Council ofScientific and Industrial
Research, New Delhi, for providing a Senior Research
Fellowship.
References and notes
1. Chong, P. H.; Seeger, J. D. Pharmacotherapy 1997, 17,
1157.
2. Graul, A.; Castaner, J. Drugs Future 1997, 22, 956.
3. (a) Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.;
Millar, A.; Nanninga, T. N.; Roth, B. D. Tetrahedron
Lett. 1992, 33, 2279. (b) Baumann, K. L.; Butler, D. E.;
Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga,
T. N.; Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992,
33, 2283.
4. Radl, S.; Stach, J.; Hajicek, J. Tetrahedron Lett. 2002, 43,
2087.
5. Roth, B. D.; Blankley, C. J.; Chucholowski, A. W.; Fer-
guson, E.; Hoefle, M. L.; Ortwine, D. F.; Newton, R. S.;
Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.; Wilson,
M. J. Med. Chem. 1991, 34, 357.
Scheme 1. Reagents and conditions: (i) dry HCl gas, CH3OH, reflux,
4 h; (ii) liquor ammonia solution; (iii) benzyl bromide (1.1 equiv),
K2CO3 (2 equiv), CHCl3, rt, 12 h; (iv) 4-fluorobenzoyl chloride
(1.1 equiv), Et3N (2 equiv), CH2Cl2, 0ꢀC to rt, 12 h; (v) NaOH,
MeOH–H2O (4:1), reflux, 3 h; (vi) DCC (1.2 equiv), toluene; (vii) ethyl
phenylpropiolate (1 equiv), reflux, 7 h.
6. Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M.
J. Org. Chem. 1982, 47, 786.
7. (a) Coppola, B. P.; Noe, M. C.; Abdon, R. G.; Konsler,
R. L. J. Org. Chem. 1993, 58, 7324. (b) Coppola, B. P.;
Noe, M. C.; Schwartz, D. J.; Abdon, R. L., II; Trost,
B. M. Tetrahedron 1994, 50, 93. (c) Coppola, B. P.; Noe,
M. C.; Hong, S. S. Tetrahedron Lett. 1997, 38, 7159.
8. N1,3-diphenyl-2-propynamide was prepared from phe-
nylpropiolic acid and aniline by using DCC and catalytic
amount ofDMAP in dichloromethane at room temper-
ature in 85% yield.
9. Procedure for 1,3-dipolar cycloaddition: A solution of
amido acid 6 (300 mg, 0.914 mmol) and N1,3-diphenyl-2-
propynamide (223 mg, 1.0 mmol) in toluene (10 mL) was
treated with DCC (226 mg, 1.09 mmol) in toluene (6 mL).
The resulting yellow mixture was refluxed under nitrogen
Scheme 2. Reagents and conditions: (i) N1,3-diphenyl-2-propynamide
(1 equiv), reflux, 7 h; (ii) Na (4 equiv), liquid NH3, t-BuOH (2 equiv),
THF, À78 ꢀC, 10 min.

P.. S. Pandey, T. Srinivasa Rao / Bioorg. Med. Chem. Lett. 14 (2004) 129–131
131
for 7 h. After cooling, crystalline dicyclohexyl urea was
removed by filtration. The filtrate was poured into
saturated aqueous NaHCO3 (15 mL), and the mixture
extracted with chloroform (25 mL). The organic layer was
dried over Na2SO4, and evaporated. Complete removal of
dicyclohexyl urea by passing it through a small column of
silica gel, benzene as eluent, yielded 355 mg (80%) of
mixture of 9a and 9b in 1:1 ratio. From the mixture
168 mg (48%) of 9a was separated out as a white solid by
crystallization using benzene–hexane (1:1) solvent mix-
ture. Physical and spectroscopic data for 9a: mp 218–
220 ꢀC; IR (KBr) 3403, 3060–2931, 1664, 1595, 1563,
1527, 1495, 1436, 1309, 1242, 1218, 1154, 845, 753, 737,
(0.8 mmol) ofrfeshly cut sodium metal and 25 mL ofliq
ammonia. Blue colour started appearing slowly and in
5 min the reaction mixture became blue in colour. 29 mg
(0.4 mmol) of t-BuOH in 2 mL ofTHF was added ofl-
lowed by 100 mg (0.2 mmol) of 9a in 5 mL ofTHF. The
reaction mixture was stirred at À78 ꢀC till the entire blue
colour had disappeared. The cooling bath was removed
and ammonia was evaporated by using a waterbath. The
reaction mixture was then quenched with a minimum
amount ofaqueous NH 4Cl and extracted with EtOAc.
The organic layer was then dried over Na2SO4, con-
centrated and purified by column chromatography (silica
gel) to give 68 mg of 2 as a white solid in 83% yield. Phy-
sical and spectroscopic data for 10: mp 208–210 ꢀC; IR
(KBr) 3404, 3291, 3059–2870, 1642, 1528, 1438, 1313,
1253, 1192, 752, 692 cmÀ1. 1H NMR (300 MHz, CDCl3) d
8.34 (bs, 1H), 7.43–6.96 (m, 15H), 4.11 (septet, J=6.9 Hz,
1H), 1.41 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.67, 165.73, 163.52, 145.3, 144.6, 137.9, 132.19,
131.29, 129.20, 128.64, 127.87, 126.70, 124.65, 123.20,
121.29, 119.13, 118.52, 116.50, 25.95, 22.27.
696 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.36–6.81 (m,
;
20H), 5.08 (s, 2H), 3.27 (septet, J=7 Hz, 1H), 1.40 (d,
J=7 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 166, 164,
161, 143, 138.33, 134.55, 132.93, 130.54, 128.72, 128.39,
127.31, 126.61, 125.48, 123.57, 119.61, 115.31, 115.03,
48.03, 26.65, 21.38.
10. Procedure for N-debenzylation: A 50 mL three necked
flask cooled to À78 ꢀC, was charged with 18 mg