Organic Process Research & Development 2009, 13, 67–72
An Improved and Scalable Process for Zafirlukast: An Asthma Drug†
Gilla Goverdhan, Anumula Raghupathi Reddy, Aalla Sampath, Kurella Srinivas, Vurimidi Himabindu,‡ and
Ghanta Mahesh Reddy*,§
Research and DeVelopment, Integrated Product DeVelopment, Dr. Reddy’s Laboratories Ltd., SurVey No.’s 42, 45, 46, and 54,
Bachupally, Qutubullapur, Ranga Reddy District - 500 072, Andhra Pradesh, India, Institute of Science and Technology, Center
for EnVironmental Science, J.N.T. UniVersity, Kukatpally, Hyderabad - 500 072, Andhra Pradesh, India, and Research and
DeVelopment, Inogent Laboratories PriVate Limited (A GVK BIO Company), 28A, IDA, Nacharam,
Hyderabad - 500 076, India
Abstract:
large-scale production.6 The problems include the following:
(i) use of chloroform solvent for brominating 2 with DBDMH/
AIBN led to poor-quality product and formation of a dibromo
impurity 9a beyond acceptable limits; (ii) removal of chloro-
form, a class-2 solvent,7 from the reaction mixture reduced the
yield of 3 drastically; and (iii) Friedel-Crafts alkylation of 4
with 3 in the presence of zinc bromide in 1,4-dioxane yielded
polysubstituted indole derivatives as impurities.
An improved and scalable process for the large-scale production
of zafirlukast (Accolate), an important drug for asthma, is
discussed along with impurity and scale-up-related issues.
Hence, we reviewed the earlier synthesis, modified the
reaction conditions, and developed a process that obviates the
above problems. This improved method, whose details are
presented in this paper, is suitable for large-scale production of
the drug in pure form and conforms to all the regulatory
requirements.
Introduction
Zafirlukast 1, is a potential drug used for the treatment of
pulmonary disorders such as asthma. It acts by antagonizing
one or more of the arachidonic acid metabolites, such as
leukotriene, which inhibits the activity of cytochrome isozymes
CYP 3A4 and CYP 2C9. The CYP 3A4 isozyme is also
responsible for the metabolism of many other drugs.1
Results and Discussion
In the present approach (Scheme 2), commercially available
3-methoxy-4-methylbenzoic acid (2) was first converted to the
ester 8 in 98.0% yield and 99.0% purity, by treating with thionyl
chloride in methanol. Alkyl bromination of 8 was achieved
using cyclohexane as solvent instead of chloroform, and by
adding the brominating agent (DBDMH) lot-wise. The benzyl
bromide 9 was obtained in 84.0% yield with 99.0% purity.
HPLC examination revealed the presence of the dibromo
impurity 9a in less than 1.0%.
In the literature several synthetic methods were reported for
the preparation of zafirlukast 1.2-5 We have earlier reported a
laboratory synthesis of zafirlukast 1 (Scheme 1),4 which
presented several problems during the process development for
(6) In the literature several synthetic methods (refs 2-5) were reported
for the preparation of zafirlukast 1. We have taken up one of the
synthetic methods reported by us for process development for large-
scale production (Scheme 1).4 With this processes we have faced many
problems during the laboratory development to achieve the quality of
the final product 1, and we discuss some of the issues/points as follows.
Friedel-Crafts alkylation of 4 with 3 in the presence of zinc bromide
in 1,4-dioxane medium afforded the product 5 with poor yield and
quality. Indoles 4 have two active positions, i.e. 2 and 3; during the
Friedel-Crafts reaction alkylations may occur at positions 2 and 3,
which lead to the formation of impurities. These impurities also
participate in the subsequent reactions. Attempts were made to remove
the polysubstituted impurities corresponding to derivatives of 6 in
different solvents, but this was not successful. Related polysubstituted
impurities of 7 were converted into hydrochloride salt, and attempts
were made to remove the impurities of 7 in different solvents, but
this was not successful. Thus, to meet the regulatory requirements,
quality was impacted on preparation of 1 in Scheme 1. Hence, Scheme
1 is not suitable for commercial production of 1, and meeting the drug
substance with regulatory requirements is very tough using Scheme
1. Finally, we selected Scheme 2 for process development in the
laboratory; we achieved the regulatory requirements, and it was
implemented in commercial scale also.
† Dr. Reddy’s Communication #: IPDO-IPM-00122.
* Author for correspondence. E-mail: reddyghanta@yahoo.com.
‡ Institute of Science and Technology, Center for Environmental Science,
J.N.T. University.
§ Research and Development, Inogent Laboratories Private Limited (A GVK
BIO Company).
(1) Phipatanakul, W.; Eggleston, P. A.; Conover-Walker, M. K.; Kesa-
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2000, 105 (4), 704.
(2) Bernstein, P. R.; Brown, F. J.; Matassa, V. G.; Yee, Y. K. U.S. Patent
4,859,692, 1989.
(3) Gutman, A.; Nisenevich, G.; Zaltzman, I.; Ponomarev, V.; Sotrihin,
M. WO 02/46153 A2, 2002.
(4) Srinivas, K.; Srinivasan, N.; Krishna, M. R.; Reddy, C. R.; Arunagiri,
M.; Lalitha, R.; Reddy, K. S. R.; Reddy, B. S.; Reddy, G. M.; Reddy,
P. P.; Kumar, M. K.; Reddy, M. S. Org. Process Res. DeV. 2004, 8,
952–954.
(7) International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH). Q3C(R3):
Impurities: Guideline for Residual Solvents. 1997.
(5) Ansell, C. L.; Derrick, I.; Moseley, J. D.; Stott, J. A. Org. Process
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10.1021/op800137b CCC: $40.75
Published on Web 12/19/2008
2009 American Chemical Society
Vol. 13, No. 1, 2009 / Organic Process Research & Development
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