An Improved and Scalable Process for Zafirlukast: An Asthma Drug
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
Org. Process Res. Dev., 2009, 13 (1), pp 67–72
DOI: 10.1021/op800137b
Melting range: 142−145 °C; MS (m/z): 576 (M+ + H); IR (KBr, cm−1): 3326 (NH), 1679 (−C═O), 1H NMR (CDCl3) δ 7.0−8.0 (m, 11H), 3.7 (s, 3H), 4.0 (s, 2H), 3.9 (s, 3H), 2.6 (s, 3H), 1.45−1.8 (s, 9H).
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US 20040186300 A1
zafirlukast ethanolate as white powder with mp 132-133° C. (dec.) and 99.8% purity by HPLC. 1H NMR (CDCl3, δ, ppm): 1.22 (t, J 7.05 Hz, 3H), 1.45-1.87 (m, 8H), 2.66 (s, 3H), 3.67 (s, 3H), 3.73 (q, J 7.05 Hz, 4H), 3.79 (s, 3H), 3.98 (s, 2H), 5.08-5.23 (m, 1H), 6.58 (s, 1H), 6.73 (s, 1H), 7.01-7.51 (m, 9H), 8.23 (d, J 7.52 Hz, 1H), 9.67 (s, 1H).
Zafirlukast, cyclopentyl 3 - [2-methoxy-4- [(o-tolylsulfonyl)carbamoyl]- benzyl]-l-methyIindole-5-carbamate, having the formula:
is a first anti-asthmatic leukotriene antagonist (Matassa, V.G. et al, J. Med. Chem., v. 33, 1781 '(1990); U. S. Patent No. 4,859,692 and The Merck Index, 12th Edition, 10241). Methods for the preparation of Zafirlukast are described in J. Med. Chem., v. 33, 1781 (1990), U. S. Patent 4,859,692 and U.S. Patent 5,993,859 starting from methyl 3-methoxy-4-(l-methyl-5-nitroindol-3-ylmethyl)benzoate [la]
Alkyl (l-alkylindol-3-ylmethyl)benzoates of formula [lb] are useful as chemical intermediates in the pharmaceutical industry.
These compounds may be obtained by a process described in J. Med. Chem., v. 33, 1781 (1990) and U. S. Patent 4,859,692. This process comprises the steps of:
(a) reacting an alkyl (halomethyl)benzoate of formula [2] with an equivalent amount of an indole of formula [3]
in the presence of an equivalent quantity of silver(I) oxide,
(b) isolating the alkyl (indol-3-ylmethyl)benzoates of formula [4] from the reaction mixture obtained in step (a) above,
(c) reacting the compound [4] with an alkylating agent of formula [6],
The above process has serious disadvantages in the isolation of the product [4] in step (b) which is due to the fact that alkylation of indole, that is unsubstituted at positions 1-, 2- and 3-, at the 3-position, is accompanied by the undesired process of poly alkylation, to form polysubstituted indoles of formula [7] and/or formula [8] :
while at the same time some quantity of the starting unreacted indole remains in the reaction mixture. Most common methods for the separation of alkyl (indol-3-ylmethyl)benzoate of formula [4] from by-products of polyalkylation and starting unreacted indole, which are all covalent compounds with similar physical properties, include column chromatography that is an unpractical method for industrial scale applications.
updated info
PRODUCT PATENT ROUTE
Allylic bromination of methyl ester 54 using bromine in presence
of CCl4 resulted bromo compound 55, which was reacted with 5-nitro
indole 124 using silver oxide as catalyst to obtain condensed compound
125. N-methylation of 125 utilizing methyl iodide in presence of NaH
afforded N-methyl indole derivative 57. Thus obtained 57 was subjected
to reduction using palladium carbon (Pd/C) in methanol followed by
reacted with cyclopentyl chloroformate to obtain compound 59.
Hydrolysis of 59 using LiOH.H2O subsequently reaction with o-toluene
sulfonamide (OTSA) in presence of 1-[3-(dimethylamino)propyl]-3-ethyl
carbodiimide hydrochloride (DMAPEC) and DMAP furnished zafirlukast
4. Matassa et al3 also reported similar procedure for the synthesis of
Zafirlukast 4.
of CCl4 resulted bromo compound 55, which was reacted with 5-nitro
indole 124 using silver oxide as catalyst to obtain condensed compound
125. N-methylation of 125 utilizing methyl iodide in presence of NaH
afforded N-methyl indole derivative 57. Thus obtained 57 was subjected
to reduction using palladium carbon (Pd/C) in methanol followed by
reacted with cyclopentyl chloroformate to obtain compound 59.
Hydrolysis of 59 using LiOH.H2O subsequently reaction with o-toluene
sulfonamide (OTSA) in presence of 1-[3-(dimethylamino)propyl]-3-ethyl
carbodiimide hydrochloride (DMAPEC) and DMAP furnished zafirlukast
4. Matassa et al3 also reported similar procedure for the synthesis of
Zafirlukast 4.
zafirlukast…….{3-[2-Methoxy-4-(toluene-2-sulfonylaminocarbonyl)
benzyl]-1-methyl-1H-indol-5-yl} acetic acid cyclopentyl ester……………………………….Arie, G.; Genndy, N.; Igor, Z.; Victor, P.; Maxim, S. WO 02/46153
benzyl]-1-methyl-1H-indol-5-yl} acetic acid cyclopentyl ester……………………………….Arie, G.; Genndy, N.; Igor, Z.; Victor, P.; Maxim, S. WO 02/46153
A2, 2002.
