New and improved synthesis of Montelukast, an anti-asthmatic drug

Article abstract of DOI:10.1080/00397910601055032

A new industrially viable synthesis of Montelukast, an anti-asthmatic drug, is described. Copyright Taylor & Francis Group, LLC.

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New and Improved Synthesis of Montelukast,
an Anti‐asthmatic Drug
Bollikonda Satyanarayana a & Padi Pratap Reddy a
a Research and Development Centre, Dr. Reddy's Laboratories Limited,
Hyderabad, India
Published online: 06 Mar 2007.
To cite this article: Bollikonda Satyanarayana & Padi Pratap Reddy (2007) New and Improved Synthesis
of Montelukast, an Anti‐asthmatic Drug, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:4, 545-549, DOI: 10.1080/00397910601055032
To link to this article: http://dx.doi.org/10.1080/00397910601055032
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Synthetic Communicationsw, 37: 545–549, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601055032
New and Improved Synthesis
of Montelukast, an Anti-asthmatic Drug
Bollikonda Satyanarayana and Padi Pratap Reddy
Research and Development Centre, Dr. Reddy’s Laboratories Limited,
Hyderabad, India
Abstract: A new industrially viable synthesis of Montelukast, an anti-asthmatic drug,
is described.
Keywords: anti-asthmatic, inflammation, leukotriene antagonist, Montelukast
INTRODUCTION
Montelukast,[1] used in the treatment of asthma and seasonal allergic rhinitis
(hay fever), is an oral leukotriene receptor antagonist.[2] Leukotrienes are a
group of naturally occurring chemicals in the body that promote inflammation
in asthma and seasonal allergic rhinitis and in certain other diseases as allergy.
Montelukast effectively works by binding to some of these leukotrienes.
Therefore, it is used as an anti-asthmatic, anti-allergic, anti-inflammatory,
and cytoprotective agent.
Our present work reports a new and industrially scalable process for
the preparation of (1-f1-f3(R)-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenylg-
3-[2-(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethylg-cyclopropyl)-
acetic acid, commonly known as Montelukast.
DRL Pub. No. IPDO-IPM 00026.
Address correspondence to Padi Pratap Reddy, Research and Development Centre,
Dr. Reddy’s Laboratories Limited, Bulk Actives Unit 1V, IDA, Jeedimetla, Hyderabad,
AP, India. E-mail: reddyppou@yahoo.co.in
545

546
B. Satyanarayana and P. P. Reddy
DISCUSSION
An earlier reported synthetic approach involves the reaction of 2-(2-(2-
(3(R)-(3-(2-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-(methanesulfonyloxy)
propyl)-phenyl)-2-propoxy) tetrahydro pyran[3] with methyl 1-(acetylthio-
methyl) cyclopropane acetate in the presence of hydrazine and caesium
carbonate in acetonitrile as solvent to yield methyl ester of Montelukast in
pyran-protected form. The protected compound is further reacted with pyridi-
nium, p-toluene sulfonate, to yield Montelukast 4. Thus, the process involved
multiple steps with a series of protection and deprotection of the diol intermedi-
ate; use of hazardous, costly raw materials; and typical reaction conditions at
cryogenic conditions (2258C). Tedious workup procedures practised for the
isolation of the required product resulted in excessive time cycles, rendering
the process more costly and less ecofriendly, in turn proving the process to be
less amenable for commercial scaling.
Therefore, to overcome these difficulties, a new alternate process was
developed for the preparation of Montelukast wherein 2-(3(R)-f3-[2-(7-
chloro-quinolin-2-yl)-vinyl]-phenylg-3-hydroxy-propyl)-benzoic acid methyl
ester[4] 1 was subjected to mesylation with methane sulfonyl chloride,
followed by condensation with (1-mercaptomethyl-cyclopropyl)-acetic
acid[5] 2 to give 2-(3(R)-(1-carboxymethyl-cyclopropyl methyl sulfanyl)-3-
f3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenylg-propyl)-benzoic acid methyl
ester, which was isolated as its dicyclohexyl-amine salt 3 in pure form.
Ester function in 3 was elaborated into tertiary alcohol by reacting with
methyl magnesium chloride to furnish Montelukast 4 in 70% yield
(Scheme 1). Structure of 4 was confirmed by comparison with an authentic
sample of Montelukast.
Interestingly, in the conversion of mesylated derivative of dicyclohexyla-
mine salt 3, there is complete retention of configuration at the chiral centre as
evidenced by optical purity (vide chiral high performance liquid chromato-
graphy (HPLC)) of Montelukast 4, derived from 3. 2-Carbomethoxy phenyl
alkyl moiety could be blocking the b face at the chiral center of the
mesylated compound, compelling the nucleophilic attack of the mercapto
compound from the other face and resulting in retention of configuration.
Thus, a new industrially scalable process has been described for the prep-
aration of Montelukast.
EXPERIMENTAL SECTION
1H and 13C NMR spectra were measured on a Varian Mercury Plus FT NMR
spectrometer at 400 MHz and 100 MHz, respectively, and the chemical shifts
were reported as d values in parts per million relative to TMS as an internal
standard. The IR spectra were recorded in the solid state as KBr dispersion
using a Perkin-Elmer FT-IR spectrophotometer. Mass spectra were recorded on

Synthesis of Montelukast
547
Scheme 1.
Shimadzu LCMS-QP 8000, LC-MS and AB-4000 Q-trap LC-MS/MS. Melting
points were determined in open capillaries and are uncorrected.
2-(3(R)-(1-Carboxymethyl-cyclopropylmethylsulfanyl)-3-f3-[2-
(7-chloro-quinolin-2-yl)-vinyl]-phenylg-propyl)-benzoic Acid
Methyl Ester Dicyclohexyl-amine Salt (3)
A mixture of 2-(3(R)-f3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenylg-3-
hydroxy-propyl)-benzoic acid methyl ester (1, 100.0 g, 0.218 mol) and
toluene (500.0 mL) was azeotroped for the removal of water. Toluene was

548
B. Satyanarayana and P. P. Reddy
distilled off under reduced pressure to obtain a residue, which was dissolved in
dichloromethane (1000 mL) and was cooled to 0–58C. Diisopropyl ethyl-
amine (36.7 g, 0.284 mol) was added to the reaction mass at 0–58C and
stirred for 15–30 mins. To it, methane sulfonyl chloride (27.5 g, 0.240 mol)
was added slowly at 0–58C, and the reaction mass was maintained at 25–
358C until reaction completion. The reaction mass was washed with water
(600 mL), and the organic layer was concentrated under reduced pressure to
obtain a syrupy product. This product was added to a mixture of sodium
methoxide (44.0 g, 0.817), 1-mercapto methyl cyclopropane acetic acid (2,
47.5 g, 0.327 mol), dichloromethane (450.0 mL), and dimethyl formamide
(450.0 mL) and refluxed for reaction completion. The reaction mass was
washed with water (450.0 mL) followed by washing with a vacuum salt
solution, and the organic layer was concentrated under reduced pressure to
obtain a residue. The residue was further dissolved in acetone (200.0 mL),
and dicyclohexyl amine (79.1 g, 0.437 mol) was added to it and stirred at
25–358C for solid separation. The separated solid was filtered, washed with
acetone (50.0 mL), and dried at 45–508C to yield 3.
Yield: 75%; mp: 130–1358C; [a]2D5 ¼ þ70 (conc.: 1% w/v in methanol),
1
IR (cm21): 3428 (N-H), 1721 (C55O). H NMR (CDCl3): 0.2–0.5 (m, 4H,
CH2), 1.0–1.3 (m, 10H, CH2), 1.5–1.55 (d, 2H, CH2) 1.6–1.9 (m, 8H,
CH2), 2.1–2.6 (m, 8H, CH2), 2.8–3.0 (m, 2H, CH2), 3.80 (s, 3H, CH3),
3.9–4.0 (m, 1H, CH3), 7.3–7.9 (m, 12H, ArH), 8.0–8.1 (d, 2H, ArH), 8.3–
8.4 (d, 1H, ArH). Mass: 586 (M þ H)þ, 1171 (2M þ H)þ (where M is free
acid of 4). Anal. calcd. for C46H55ClN2O4S (766.5): C, 71.99; H, 7.22; N,
3.65. Found: C, 71.90; H, 7.30; N, 3.57. 13C NMR (DMSO, d ppm): 173.9,
167.3, 156.7, 147.9, 143.4, 142.2, 136.4, 136.0, 134.9, 134.2, 131.9, 130.7,
129.9, 129.6, 129.3, 128.8, 128.3, 128.2, 127.1, 126.6, 126.5, 126.1, 125.8,
125.5, 120.2, 51.9, 51.8, 51.8, 48.9, 41.3, 39.0, 38.1, 31.9, 31.9, 31.9, 31.9,
31.4, 25.4, 25.4, 24.3, 24.3, 24.3, 24.3, 17.2, 12.1, 11.8.
(1-f1-f3(R)-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenylg-3-[2-
(1-hydroxy-1-methyl-ethyl)-phenyl]-propylsulfanylmethylg-
cyclopropyl)-acetic Acid (4)
A mixture of 3 (100.0 g, 0.129 mol), toluene (1000.0 mL), acetic acid
(15.0 mL), and water (500.0 mL) was stirred for a few minutes. The organic
layer was washed with water (100.0 mL) and dried over sodium sulphate.
The solvent was removed under reduced pressure to obtain a residue. The
residue was dissolved in a mixture of toluene (760.0 mL) and tetrahydrofuran
(760.0 mL) and was cooled to 08C. Methyl magnesium chloride (3 M,
261.0 mL) was added to the above solution at 0–58C and was maintained
for reaction completion. The reaction mass was quenched with a mixture of
acetic acid (90.0 mL) and water (750.0 mL), followed by washing with
aqueous sodium bicarbonate solution (1000.0 mL) and water (500.0 mL).

Synthesis of Montelukast
549
The organic layer was dried over sodium sulphate and was concentrated under
reduced pressure to obtain a residue, which was dissolved in toluene
(100.0 mL) and stirred for solid separation. The separated solid was filtered,
washed with toluene (30.0 mL), and recrystallized successively in toluene
and methanol to yield 4.
Yield: 70%; mp: 145–1488C; [a]2D5 ¼ þ102 (conc.: 1% w/v in
methanol). IR (cm21): 3574 (OH), 3439 (H), 1714 (C ¼ O). 1H NMR
(CDCl3): 0.3–0.5 (m, 4H, CH2), 1.3–1.5 (s, 6H, CH3), 2.0–2.2 (m, 2H,
CH2) 2.3–2.4 (s, 2H, CH2), 2.5–2.6 (quart, 2H, CH2), 2.7–3.1 (m, 2H,
CH2), 3.9–4.1 (m, 1H, CH), 4.9–5.0 (s, 1H, OH), 7.0–7.2 (m, 3H, Ar-H),
7.4–8.0 (m, 11H, Ar-H), 8.4 (d, 1H, Ar-H), 11.9–12.1 (s, IH, OH). Mass:
586 (M)þ. Anal. calcd. for C35H36NO3ClS (585.5): C, 71.71; H, 6.19; N,
2.39. Found: C, 71.35; H, 6.67; N, 2.42.13C NMR (DMSO, d ppm): 175.9,
156.8, 148.0, 146.7, 144.1, 139.9, 136.5, 135.9, 135.1, 134.2, 131.0, 129.7,
128.8, 128.3, 128.2, 127.2, 126.8, 126.6, 126.3, 125.6, 125.5, 125.3, 125.1,
120.3, 71.6, 49.4, 43.9, 39.5, 39.3, 311.7, 31.7, 31.6, 18.0, 12.4, 12.0.
ACKNOWLEDGMENT
The authors thank the management of Dr. Reddy’s Laboratories Ltd., Bulk
Actives Unit 1V, for supporting this work.
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