Concise and alternative synthesis of zafirlukast, an anti-asthma drug

Article abstract of DOI:10.1080/00397911.2011.603875

Concise and alternative synthesis of zafirlukast (1) is described. The synthesis features fewer steps, convergent synthesis, and novel intermediates.

Full text of DOI:10.1080/00397911.2011.603875

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Concise and Alternative Synthesis of
Zafirlukast, an Anti-Asthma Drug
Gilla Goverdhan a b , Anumula Raghupathi Reddy a , Vurimidi
Himabindu b & Ghanta Mahesh Reddy c
a Research and Development, Dr. Reddy's Laboratories Ltd.,
Integrated Product Development, Qutubullapur, Andhra Pradesh,
India
b Institute of Science and Technology, Center for Environmental
Science, J.N.T. University, Hyderabad, Andhra Pradesh, India
c Research and Development, Macleods Pharmaceuticals Ltd.,
Mumbai, Maharashtra, India
Accepted author version posted online: 13 Feb 2012.Version of
record first published: 08 Nov 2012.
To cite this article: Gilla Goverdhan, Anumula Raghupathi Reddy, Vurimidi Himabindu & Ghanta
Mahesh Reddy (2013): Concise and Alternative Synthesis of Zafirlukast, an Anti-Asthma Drug,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:4, 498-504
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Synthetic Communications1, 43: 498–504, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.603875
CONCISE AND ALTERNATIVE SYNTHESIS OF
ZAFIRLUKAST, AN ANTI-ASTHMA DRUG
Gilla Goverdhan,1,2 Anumula Raghupathi Reddy,1
Vurimidi Himabindu,2 and Ghanta Mahesh Reddy3
1Research and Development, Dr. Reddy’s Laboratories Ltd.,
Integrated Product Development, Qutubullapur, Andhra Pradesh, India
2Institute of Science and Technology, Center for Environmental Science,
J.N.T. University, Hyderabad, Andhra Pradesh, India
3Research and Development, Macleods Pharmaceuticals Ltd.,
Mumbai, Maharashtra, India
GRAPHICAL ABSTRACT
Abstract Concise and alternative synthesis of zafirlukast (1) is described. The synthesis
features fewer steps, convergent synthesis, and novel intermediates.
Keywords Alternate synthesis; novel intermediates; selective bromination; zafirlukast
INTRODUCTION
Zafirlukast is a selective and competitive receptor antagonist of the cysteinyl
leukotrienes D-4 and E-4, which is indicated for the prophylaxis and treatment
of mild to moderate persistent and chronic asthma.[1] Leukotrienes are a class of
Received March 29, 2011.
Dr. Reddy’s Communication No. IPDO-IPM-0000238.
Address correspondence to Ghanta Mahesh Reddy, Research and Development, Macleods
Pharmaceuticals Ltd., Andheri East, Mumbai 400093, Maharashtra, India. E-mail: reddyghanta@
yahoo.com
498

ALTERNATIVE SYNTHESIS OF ZAFIRLUKAST
499
Figure 1. Structure of zafirlukast (1).
compounds that have been identified as responsible for the contraction of human
airway and lung vascular smooth muscle. A chemical agent that is effective in block-
ing the induced constricting actions of leukotriene could be used to treat inflamma-
tory processes in the pulmonary system. Zafirlukast works by directly blocking
substances called leukotrienes, which are molecules that contribute to inflammation
and narrowing in the airways, a process that leads to symptoms such as difficulty in
breathing in patients with asthma.
The action of zafirlukast (trade name: Accolate) reduces inflammation and
thus helps to control the symptoms of asthma and improve lung function.
Zafirlukast is a potent, selective CysLT1 receptor antagonist sold for the treatment
of asthma as well as for the symptoms associated with allergic rhinitis. It binds to
the human CysLT1 and CysLT2 receptors with IC50 values of approximately 5
and 7,400 nM, respectively.
In the literature several synthetic methods were available for the preparation of
zafirlukast 1 including one route reported by our group.[2–8] Most of the reported
syntheses of zafirlukast involved either linear or poor-yielding processes or excessive
number of stages. In continuation of earlier work, herein we describe a convergent
strategy for the synthesis of zafirlukast. The easily available 5-nitroindole derivative
(5) and acid derivative (2) were effectively transformed to the target compound
involving very straightforward reactions. Compounds 3 and 4 are novel and reported
for the first time here, including synthesis and charcerization with spectral data.
Compound 7 has been disclosed in the literature, and synthesis and characterization
are not reported here.[9]
RESULTS AND DISCUSSION
In formulating the synthetic plan for zafirlukast, we envisioned a coupling
between the sulfonamide 4 and carbamate 8, allowing the synthesis of target com-
pound 1 (Scheme 1). Indole derivative 8 could be obtained from reduction of nitro
indole and subsequent carbamate formation. The other fragment could be syn-
thesized via sulfamidation followed by selective bromination. Synthesis of these frag-
ments started with inexpensive and readily available starting materials 5-nitroindole
derivative (5) and benzoic acid derivative (2).
The chemical route for the synthesis of zafirlukast (1) is shown in Scheme 2.
Synthesis of intermediate 4 commenced from benzoic acid 2, and coupling of acid
2 with sulfonamide under peptide coupling conditions [N, N0-dicyclohexylacarbodii-
mide (DCC–dimethylaminopyridine DMAP)] furnished compound 3 in 95% yield.

500
G. GOVERDHAN ET AL.
Figure 2. Retrosynthesis of zafirlukast.
Mass spectrum of compound 3 showed a m=z 318 [M-H] peak in the negative mode.
Infrared (IR) spectrum displayed characteristic absorptions at 1700 cmꢀ1 and 1336
and 1156 corresponding to carbonyl and sulfonyl stretching respectively. The proton
NMR spectrum showed a singlet at d 9.61 corresponding to the NH proton and three
singlets at d 3.77, 2.72, and 2.22 corresponding to OCH3 and two aromatic methyl
groups (adjacent to sulfonyl and methoxy groups). Aromatic protons appeared as
double doublets at d 8.27, a doublet at d 7.16, and a multiplet at d 7.60–7.24,
confirming the structure of sulfonamide 3.
The aim of selective bromination of sulfonamide 3 was achieved with 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) and azobisisobutyronitrile (AIBN) in
chloroform to yield the monobromo compound 4 with 86% yield and 96.0% purity.
Mass spectrum showed protonated molecular ion peak at m=z 398 and sodium
adduct at m=z 420.1H NMR spectrum of compound 4 is characterized by the pres-
ence of a multiplet at d 7.61–7.27 and a double doublet at d 8.28 corresponding to
aromatic protons. The methoxy adjacent aromatic methyl group was deshielded
Scheme 1. Concise and alternative synthesis of zafirlukast.

ALTERNATIVE SYNTHESIS OF ZAFIRLUKAST
501
and appeared as a singlet for two protons. Other methyl protons were unchanged,
and the IR spectrum displayed characteristic absorptions at 1703 and 1336 and
1165 cmꢀ1, corresponding to carbamate carbonyl and sulfonyl stretching respect-
ively, further confirming the assigned structure.
The other intermediate 7 was prepared by a two-step sequence starting from
nitroindole derivative 5. To get the carbamate functionality in the final molecule,
the nitro group in 5 was reduced to amine 6 under catalytic hydrogenation con-
ditions followed by carbamate ester 7 formations.
The nitro group in compound 5 was reduced to amine in the presence of Pd=C
under a hydrogen atmosphere to give compound 6, which was coupled with cyclo-
pentyl chloroformate using N-methylmorpholine to afford compound 7. Carbamate
7 was characterized by 1H NMR, mass and IR spectral data. In the 1H NMR, three
singlets due to O-methyl, N-methyl, and aromatic methyl groups displayed at d 3.89,
3.65, and 2.64, respectively. Aromatic protons appeared as a multiplet at d 7.60–7.12,
two doublets at d 8.05 and 7.86, and a singlet at 6.65. A singlet at d 3.75 corresponds
to NCH3 protons and multiplets at d 5.25–5.19, 1.94–1.85, and 1.83–1.70 correspond
to cyclopentyl group protons. IR spectrum showed disappearance of nitro group
bands, amine absorptions at 1689 cmꢀ1 for carbonyl group and mass spectrum show-
ing the protonated molecular ion appeared at m=z 259, and the sodium adduct
appeared at m=z 281, further supporting the structure of compound 7.
Finally alkylation of compound 7 with compound 4 under silver oxide con-
ditions provided zafirlukast in 40% yield. IR spectra showed bands at 1690, &
3331 and 1340, and 1161 cmꢀ1 for carbamate, amide carbonyl, and sulfonyl groups
1
respectively. The H NMR spectra revealed four singlets at d 4.00, 3.82, 3.68, and
2.68 corresponding to benzylic, O-methyl, N-methy, and aromatic methyl respect-
ively. Cyclopentyl group protons appeared in the alicyclic region as two multiplets
at d 1.90–1.53 and d 5.10–5.04. All the aromatic protons displayed between d 7.0
and 8.25 and account for zafirlukast. In the mass spectrum, the protonated molecu-
lar ion appeared at m=z 576, which is consistent with the assigned structure of
zafirlukast.
CONCLUSION
In conclusion, we have successfully prepared zafrilukast in an alternative con-
cise and convergent synthesis of zafirlukast (1) from 5-nitroindole derivative (5) and
acid derivative (2). Three novel intermediates (3, 4, and 7) were synthesized, charac-
terized, and confirmed by spectral data. These novel derivatives will be used as an
intermediates to prepare for 1.
EXPERIMENTAL
The 1H and 13C spectra were measured in CDCl3 and dimethylsulfoxide
(DMSO-d6) at 50, 100, 200, and 400 MHz on Varian Gemini (200 MHz) and
Mercury Plus (Varian 400 MHz) Fourier transform (FT)–NMR spectrometers,
and the chemical shifts were reported in d ppm. The FT-IR spectra were recorded
in solid state as KBr dispersion using a Perkin-Elmer 1650 FT-IR spectrophot-
ometer. The mass spectrum (70 eV) was recorded on a HP–5989A LC=MS

502
G. GOVERDHAN ET AL.
spectrometer. Melting points were determined by using the capillary method on a
Polmon (model MP-96) melting-point apparatus. The solvents and reagents were
used without further purification.
3-Methoxy-4-methyl-N-(o-tolylsulfonyl) Benzamide (3)
A mixture of 3-methoxy-4-methyl benzoic acid 2 (100 g, 0.602 mol), 4-
(dimethylamino)pyridine (90.3 g, 0.722 mol), 1,3-dicyclohexyl carbodiimide
(149.0 g, 0.723 mol), and o-toluene sulfonamide (123.5 g, 0.722 mol) in dichloro-
methane (1000 mL) was stirred at 25–35 ꢁC for 4–6 h. After completion of reaction,
the unwanted solid by-product (dicyclohexylurea, DCU) was filtered and washed
with dichloromethane (200 mL). Diluted HCl (200 mL) was added to the filtrate;
the organic layer was separated and washed with water (500 mL). The filtrate was
distilled completely under vacuum below 45 ꢁC and cooled to 25 ꢁC. Dichloro-
methane (100 mL) was charged to reaction mass and stirred for 15 min at
25–35 ꢁC. Cyclohexane (1000 mL) was added to the compound, heated to
50–55 ꢁC, and the reaction mass was stirred for about 40 min at that temperature.
The reaction mass was cooled to 30 ꢁC and then stirred for about 50 min. The sepa-
rated solid was filtered and washed with cyclohexane (100 mL). The wet compound
was dried under vacuum at 70–75 ꢁC to furnish 3 (182.0 g, 94.7%). HPLC purity
95.2%; mp 145–150 ꢁC; MS (m=z): 318 [M-H]; IR (KBr, nmax, cmꢀ1): 3260, 2939,
1
1700, 1577, 1418, 1336, 1266, 1156, 1061, 881, 753; H NMR (200 MHz, CDCl3):
d 9.61 (s, 1H), 8.27 (dd, J ¼ 1.4, 7.8 Hz, 1H), 7.60–7.24 (m, 5H), 7.16 (d, J ¼ 7.6 Hz,
Hz, 1H), 3.77 (s, 3H), 2.72 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, DMSO-d6): dC
164.8, 157.1, 137.5, 136.8, 133.5, 132.3, 131.8, 130.4, 130.3, 130.0, 126.2, 120.6, 109.6,
55.4, 19.5, 16.1. Anal. calcd. for C16H17NO4S: C, 60.17; H, 5.37; N, 4.39. Found: C,
60.12; H, 5.34; N, 4.41.
N-(4-Bromomethyl-3-methoxybenzoyl)-2-methylbenzene
Sulfonamide (4)
DBDMH (56.5 g, 0.63 moles) and AIBN (0.31 g, 0.006 mol) were added at
room temperature to a stirred solution of 3-methoxy-4-methyl-N-(o-tolylsulfonyl)
benzamide 3 (100 g, 0.313 mol) in chloroform (500 mL). The resulting reaction mass
was heated to reflux (60–65 ꢁC) and maintained for 6–8 h. After completion of reac-
tion (monitored by thin-layer chromatography, TLC), the reaction mixture was
quenched with 30% sodium carbonate solution (300 mL) and washed with water
(200 mL). The organic layer was separated and dried over sodium sulfhate, and
the solvent was removed under vacuum below 65 ꢁC. Cyclohexane (1000 mL) was
added to the residue, heated to 80 ꢁC, and stirred for about 40 min at that tempera-
ture. The reaction mass was cooled to to 30 ꢁC and stirred for about 50 min. The
separated solid was filtered and washed with cyclohexane (100 mL). The wet com-
pound was dried under vacuum at 60–65 ꢁC to furnish 4 (107.0 g, 86.3%). HPLC
purity 96.4%; mp 150–154 ꢁC; MS (m=z): 398 [MþþH]; IR (KBr, nmax, cmꢀ1):
3251, 2984, 1703, 1577, 1417, 1405, 1336, 1272, 1165, 880, 754; 1H NMR
(200 MHz, CDCl3): d 9.61 (s, 1H), 8.28 (dd, J ¼ 1.4, 7.8 Hz, 1H), 7.61–7.27 (m,
6H), 4.49 (s, 2H), 3.85 (s, 3H), 2.72 (s, 3H). Anal. calcd. for C16H16 NO4SBr: C,

ALTERNATIVE SYNTHESIS OF ZAFIRLUKAST
503
48.25; H, 4.05; N, 3.52. Found: C, 48.20; H, 4.01; N, 3.51; 13C NMR (100 MHz,
CDCl3): dC 163.7, 157.6, 137.6, 136.2, 134.2, 132.5, 132.2, 131.9, 131.5, 131.1,
126.5, 119.7, 110.4, 55.9, 27.1, 20.4.
Cyclopentyl 1-Methyl-1H-Indol-5-ylcarbamate (7)
A suspension of N-methyl-5-nitro indole 5 (100 g, 0.568 mol) and 10% Pd-C
(15.0 g) in ethyl acetate (800 mL) was hydrogenated in a autoclave under hydrogen
pressure (3.0–3.5 kg=cm2) at 25–35 ꢁC. The reaction mass was maintained at
25–35 ꢁC for 3–4 h. After completion of the reaction (monitored by TLC), reaction
mass was filtered through hyflow and washed with ethyl acetate (100 mL). The fil-
trate was washed with 10% sodium hydroxide solution (200 mL) and followed by
saturated sodium chloride solution (200 mL). N-Methylmorpholine (63.1 g,
0.625 mol) was slowly added to the separated organic layer and followed by cyclo-
pentyl chloroformate (93 g, 0.626 mol) at 25–35 ꢁC. The resulting reaction mass
was maintained at room temperature for 45–60 min. After completion of the reaction
(monitored by TLC), the reaction mixture was washed with 10% sodium hydroxide
solution (200 mL) and followed by saturated sodium chloride solution (200 mL). The
solvent was distilled up to 80% of the reaction mass, cooled to 0–5 ꢁC, and stirred for
1–2 h for complete solid precipitation. The separated solid was filtered and washed
with ethyl acetate (50 mL). The wet compound was dried under vacuum at
50–55 ꢁC to afford the title compþound 7 (130 g, 73.6%). HPLC purity 99.2%; mp
104–108 ꢁC; MS (m=z): 259.2 [M þ H], 281.3 [Mþ þ Na]; IR (KBr, nmax, cmꢀ1):
1
3284, 2953, 1689, 1541, 1496, 1291, 1245, 1162, 1039, 716; H NMR (400 MHz,
CDCl3): d 7.64 (s, 1H), 7.25 (s, 0.5 H), 7.20 (s, 0.5 H), 7.15 (d, J ¼ 8.8 Hz, 1H),
7.01 (d, J ¼ 3.2 Hz, 1H), 6.53 (s, 1H), 6.41 (d, J ¼ 3.2 Hz, 1H), 5.25–5.19 (m, 1H),
3.75 (s, 3H), 1.94–1.85 (m, 2H), 1.83–1.70 (m, 4H), 1.68–1.55 (m, 2H); 13C NMR
(100 MHz, CDCl3): dC 154.1, 133.8, 130.2, 129.5, 128.5, 114.9, 111.3, 109.2, 100.7,
32.8, 32.7, 23.6. Anal. calcd. for C15H18 N2O2: C, 69.74; H, 7.02; N, 10.84. Found:
C, 69.88; H, 7.06; N, 10.80.
[3-[[2-Methoxy-4-[[[(2-methyl phenyl)sulfonyl]amino]carbonyl]-
phenyl]methyl]-1-methyl-1H-indole-5-yl] Carbamic Acid Cyclopentyl
Ester (1)
Silver oxide (6.25 g, 0.0271 mol) was added to a solution of compound 7 (10.0 g,
0.0387 mol) and compound 4 (22.5 g, 0.0541 mol) in 1,4-dioxane (70.0 mL) at room
temperature. The reaction mixture was heated to 95–100 ꢁC and stirred for
12–15 h. The reaction mixture was filtered through hyflow and washed with acetone
(90.0 mL). The filtrate was concentrated, and methanol (90.0 mL) and ethyl acetate
(10.0 mL) were added. Subsequently, the mixture was heated to reflux, maintained
for 60 min, cooled to 25–35 ꢁC, and stirred for 1 h. The obtained solid was filtered
and dried at 50–55 ꢁC to provide 20.0 g (90%) of crude compound with 61.7% purity.
The crude compound was purified by using column chromatography (dichloro-
methane–methanol 9:1) to afford the title compound 1 (8.9 g, 40.0%). HPLC purity
98.6%; mp: 205–209 ꢁC; MS (m=z): 576 [Mþ þ H]; IR (KBr, nmax, cmꢀ1): 3370, 2960,
1
1690, 1581, 1455, 1340, 1226, 1161, 1034, 868, 758; H NMR (400 MHz, CDCl3): d

504
G. GOVERDHAN ET AL.
9.35 (br, 1H), 8.24 (d, J ¼ 7.8 Hz, 1H), 7.49 (t, J ¼ 7.6 Hz, 2H), 7.38 (t, J ¼ 7.6 Hz,
1H), 7.30 (s, 1H), 7.27 (d, J ¼ 7.6 Hz, 1H), 7.26 (s, 2H), 7.18 (d, J ¼ 8.8 Hz, 1H),
7.10 (d, J ¼ 7.6 Hz, 1H), 7.06 (d, J ¼ 7.6 Hz, 1H), 6.74 (s, 1H), 6.54 (s, 1H),
5.22–5.18 (m, 1H), 4.00 (s, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 2.68 (s, 3H), 1.90–1.53
(m, 8H); 13C NMR (100 MHz, CDCl3): dC 164.8, 157.1, 154.3, 137.4, 136.7, 136.0,
134.0, 133.5, 132.1, 131.1, 129.7, 129.4, 128.0, 127.7, 127.7, 126.0, 119.8, 115.2,
111.7, 109.7, 109.4, 109.1, 77.5, 55.2, 32.5, 32.5 32.3, 24.8, 23.4, 23.4, 20.0.
ACKNOWLEDGMENTS
The authors are thankful to the management of Dr. Reddy’s Laboratories
Ltd., IPDO Bachupally, for supporting this work. Cooperation from colleagues
at Dr. Reddy’s Laboratories Ltd., IPDO, Bachupally, in analytical research and
development is appreciated.
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