A green chemistry approach to ibuprofen piconol

Article abstract of DOI:10.1081/SCC-200048418

Ibuprofen piconol synthesis has been described. The use of solid catalyst has demonstrated green chemistry approach with promoted atom economy of 94% compared to the reported 68%.

Full text of DOI:10.1081/SCC-200048418

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A Green Chemistry Approach to
Ibuprofen Piconol
C. M. Haricharan Raju a , P. Naga Lakshmi a , Ch.
Srinivas a , G. Om. Reddy a & Palle V. R. Acharyulu a
a Technology Development Centre, Custom
Pharmaceutical Services, Dr. Reddy's Laboratories ,
Bollaram Road, Miyapur, Hyderabad, 500 050, India
Published online: 28 Jul 2007.
To cite this article: C. M. Haricharan Raju , P. Naga Lakshmi , Ch. Srinivas ,
G. Om. Reddy & Palle V. R. Acharyulu (2005) A Green Chemistry Approach to
Ibuprofen Piconol, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:2, 209-212, DOI: 10.1081/
SCC-200048418
To link to this article: http://dx.doi.org/10.1081/SCC-200048418
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Synthetic Communicationsw, 35: 209–212, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048418
A Green Chemistry Approach to
Ibuprofen Piconol†
C. M. Haricharan Raju, P. Naga Lakshmi, Ch. Srinivas,
G. Om. Reddy, and Palle V. R. Acharyulu
Technology Development Centre, Custom Pharmaceutical Services,
Dr. Reddy’s Laboratories, Miyapur, Hyderabad, India
Abstract: Ibuprofen piconol synthesis has been described. The use of solid catalyst has
demonstrated green chemistry approach with promoted atom economy of 94%
compared to the reported 68%.
Keywords: Atom economy, clay, green chemistry, ibuprofen, ibuprofen piconol,
NSAID
INTRODUCTION
Green chemistry, or environmentally benign chemistry, mainly focuses on the
chemical processes that reduce generation of waste or eliminate the use of
hazardous substances.[1]
Arylpropionic acid derivatives such as ibuprofen (1) and flurbiprofen (2)
belong to the class of anti-inflammatory and analgesic agents (Chart 1).
Although ibuprofen is the most sought agent as a nonsteroidal anti-inflam-
matory drug (NSAID), its piconol derivative (3) has found application as
topical anti-inflammatory agent in acne treatment.[2–5]
†DRL Publication No: 430.
Received in India November 5, 2004
Address correspondence to Palle V. R. Acharyulu, Technology Development
Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories, Bollaram Road,
Miyapur, Hyderabad 500 050, India. E-mail: raghupv@drreddys.com

210
C. M. H. Raju et al.
Chart 1.
The synthesis of ibuprofen piconol has been well documented in litera-
ture.[6] The synthetic approach involves preparation of acid chloride 4,
using thionyl chloride followed by treatment with pyridine 2-methanol to
furnish ibuprofen piconol (Scheme 1).
The atom economy for this approach was calculated to be 68%. Herein,
we report a simple, one-step procedure for the synthesis of ibuprofen
piconol using environmentally benign catalysts such as montmorillonite
K-10 and resins.
The condensation reaction between ibuprofen and piconol was initially
attempted with acid resin catalysts (Scheme 2). Although the product
formation (Table 1) was observed by using resins such as Indian 130,
Amberlyst-15, Indian 140, the reaction did not proceed to completion with
toluene or xylene as solvents.
Reaction of ibuprofen mixing with piconol in the presence of montmor-
illonite K-10 clay in refluxing toluene gave 3 in good yield. The reaction
was also carried out in xylene under reflux; however, toluene was preferred
Scheme 1.

A Green Chemistry Approach to Ibuprofen Piconol
211
Scheme 2.
because of better reaction profile. Addition of catalytic quantities of p-tolue-
nesulfonic acid improved the recovery of the product in xylene as solvent,
Table 1.
Ibuprofen piconol: Ibuprofen (4.1 g, 20 mmol), piconol (2.4 g, 22 mmol)
and Montmorillonite clay K-10 (20% w/w with respect to ibuprofen) in
toluene was heated under reflux for 18 hr. The progress of the reaction was
monitored by using thin-layer chromatography. It was filtered, and the
filtrate was washed with sodium bicarbonate solution and oxalic acid
solution. The organic layer was concentrated under reduced pressure to
isolate the crude product, which was purified by distillation (5.7 g, 97% yield).
1H NMR (200 MHz, CDCl3). d 0.9–1.0 (d, H), 1.4–1.5 (d, 3H), 1.7–2.0
(septet, 1H), 2.4–2.5 (d, 2H), 3.7–4.0 (q, 1H), 5.2 (s, 2H), 6.9–7.2
(d, 2H), 7.2–7.4 (dd, 4H), 7.5–7.7 (t, 1H), 8.4–8.6 (d, 1H).
13CNMR(50 MHz, CDCl3) d: 173.8, 155.8, 148.9, 140.3, 137.2, 136.2, 129.1,
127.0, 122.3, 120.7, 66.4, 44.8, 44.7, 29.9, 22.1, 18.1
CHN: C, 76.64; H, 8.68; N, 4.47; O, 10.21.
HPLC condition: Column: Hichrom C8 (250 ꢀ 4.6 mm), 5 micron, Mobile
phase: 0.01 M KH2PO4:CH3CN (30:70), Flow: 1.0 mL/min, UV 254 nm.
Table 1. Ibuprofen piconol synthesis using different catalysts and solvents
S. No.
Catalyst
Solvent
Yield
1
2
3
4
5
6
7
Indian130
Amberlyst-15
Indian140
Toluene
Toluene
Toluene
20%
29%
48%
Montmorillonite K10
Montmorillonite K10
Montmorillonite K10
Montmorillonite
K10 þ PTSA
Dichloromethane
Toluene
Xylene
No reaction
97%
70%
Xylene
97%

212
C. M. H. Raju et al.
ACKNOWLEDGMENTS
We thank the management of Custom Pharmaceutical Services, Dr. Reddy’s
Laboratories for permission to publish this work. Cooperation extended by
all the colleagues of analytical research and development is highly
appreciated.
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