New and practical synthesis of montelukast sodium, an antiasthmatic drug

Article abstract of DOI:10.1080/00397911.2012.684755

A new and practical synthesis of montelukast sodium, an antiasthmatic drug, is described. The key steps are the synthesis of nitrile derivative 4 by chiral reduction of keto ester 9 using (-)-DIP-Cl, synthesis of vinylquinoline framework 16 by Wittig reaction, and Heck coupling of nitrile 4 with vinylquinoline 16. The method is operationally simple and suitable for the industrial production of the drug substance. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.684755

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A New and Practical Synthesis of Montelukast Sodium,
an Antiasthmatic Drug
M. Saravanan a c , B. Satyanarayana b & P. Pratap Reddy b
a Research and Development, Dr. Reddy's Laboratories Ltd., Bachupalli, Hyderabad, Andhra
Pradesh, India
b Research and Development, Macleods Pharmaceuticals Ltd., Andheri(E), Mumbai, India
c Department of Chemistry, Institute of Science and Technology, J. N. T. University,
Hyderabad, Andhra Pradesh, India
Accepted author version posted online: 10 Jan 2013.
To cite this article: M. Saravanan , B. Satyanarayana & P. Pratap Reddy (2013): A New and Practical Synthesis of Montelukast
Sodium, an Antiasthmatic Drug, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, DOI:10.1080/00397911.2012.684755
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A New and Practical Synthesis of Montelukast Sodium, an Antiasthmatic Drug
M. Saravanan1,3, B. Satyanarayana2, P. Pratap Reddy2,
1Research and Development, Dr. Reddy’s Laboratories Ltd., Bachupalli, Hyderabad,
Andhra Pradesh, India 2Research and Development, Macleods Pharmaceuticals Ltd.,
Andheri(E), Mumbai, India 3Department of Chemistry, Institute of Science and
Technology, J. N. T. University, Hyderabad, Andhra Pradesh, India
, Tel.: +91 9000770751; Fax: +91 40 44346285 E-mail: saravananm@drreddys.com;
saravanan_jaishu@yahoo.com
Abstract
A new and practical synthesis of montelukast sodium, an anti-asthmatic drug is
described. The key steps are the synthesis of nitrile derivative 4 by chiral reduction of
keto ester 9 using (-)-DIP-Cl, synthesis of vinylquinoline framework 16 by Wittig
reaction and Heck coupling of nitrile 4 with vinylquinoline 16. The method is
operationally simple and suitable for the industrial production of the drug substance.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: Montelukast; anti-asthmatic; leukotriene; Heck coupling; chiral reduction
INTRODUCTION
Montelukast sodium (1),[1-4] sodium 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)
phenyl)-3-(2-(2-hydroxy propan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl)acetate,
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is a selective and orally active leukotriene receptor antagonist[5] that inhibits the cysteinyl
leukotriene CysLT1 receptor and has been shown to be effective in the treatment of
chronic asthma.[6] This drug is developed by Merck & Company and is currently being
marketed under the brand name of Singulair. In recent years, extensive efforts have been
made towards the convenient and efficient synthesis of montelukast sodium (1) [7-9] and
most of these methods involved linear synthetic methodology.
Herein, we report a new and efficient synthesis of montelukast sodium (1) through a
convergent synthetic approach. From a retrosynthetic analysis (Scheme 1),
vinylquinoline 16 and nitrile 4 were identified as key frameworks. Our synthetic
sequence surmounts many shortcomings associated with the previous reports and is
suitable for a large scale synthesis.
RESULTS AND DISCUSSION
Synthesis of the target compound 1 was accomplished following the synthetic pathway
described in Scheme 4. Key intermediates 4 and 16 were prepared through new route.
The only reported synthesis of keto ester 9, which is the key starting material of 4 was
carried out in five steps.[10] Ortho-carboxylation of benzaldehyde followed by coupling of
the resulted hydroxypthalide[11] with 3’-bromoacetophenone gave keto lactone. Ring
opening of keto lactone with sodium hydroxide followed by hydrogenation[12] and
subsequent acid catalyzed esterification of the resulted keto acid yielded keto ester 9.
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In our approach to 4 as shown in Scheme 2, Grignard reaction of 3-bromobenzaldehyde
(5) with vinylmagnesium bromide in toluene at 0 oC provided 1-(3-bromo-phenyl)-prop-
2en-1-ol (7)[13] in 95% yield. Recently, a number of new applications of the Heck
coupling have been reported in the literature.[14, 15] Now we have utilized Heck coupling
reaction, an extremely efficient method for mixed coupling of aryl and alkenyl carbon
bonds in the preparation of keto ester 9. Palladium-catalyzed coupling of 7 with 2-
iodomethyl benzoate (8) in toluene at 100 oC using 20 mol % of palladium (II) acetate, 20
mol % of triphenylphosphine, and 3 mol equiv of triethylamine served as a single step
preparation of keto ester 9 with 75% isolated yield.
Chiral reduction[16] of keto ester 9 to the desired (S)-hydroxy ester 10[8, 17] was
quantitatively achieved in DCM medium using (-)-DIP chloride. To achieve the optimal
reaction completion and high enantioselectivity, 1.3 equiv of the reagent was required.
The reduction of 9 with (-)-DIP chloride at 25 oC followed by isolation of the product
from hexane gave the hydroxy ester 10 in 76% yield with >98.7% ee. (+)-DIP chloride
provided the corresponding (R)-enantiomer. The hydroxy ester 10 was further reacted
with methylmagnesium chloride in toluene at 5 oC to provide the bromo biarylpropanol
11[8, 17a] in 72% yield.
The activation of hydroxy group in 11 for the nucleophilic displacement by the
mercaptan 13 was best accomplished with methanesulfonyl chloride and
diisopropylethylamine in dichloromethane at – 15 o C. Usage of other solvents, such as
toluene, THF and acetonitrile led to incomplete conversion to the mesylate product 12.
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Different salts (Li, Cs, Na, K) of the mercaptan 13 were screened for displacement of the
mesylate 12; the lithium salt was proved to be the most effective. The lithio salt is then
prepared by addition of n-BuLi to a solution of 13 in THF at - 15 o C. In view of unstable
nature of 12, its solution was as such added to lithio salt of 13 at - 15 o C and then the
mixture was aged at 5 oC for 5 h followed by conventional work up and purification to
afford 4 in 52% yield. Thus, nitrile 4 was successfully obtained in 20.3% overall yield in
6 steps starting from commercially available 3-bromobenzaldehyde.
A new synthetic methodology was also provided to the desired vinylquinoline framework
16. The only reported synthesis of 16[18] was carried out by Mannich reaction of 14 with
formalin and diethylamine hydrochloride and the resulted product amine was converted
into quaternary salt by reacting with methyliodide followed by Hofmann elimination. As
presented in Scheme 3, we have synthesized 16 in 2 steps. Oxidation of 14 wih SeO2 in
THF at 25 oC for 6 h gave 2-formylquinoline 15[19] with 78% isolated yield. Wittig
reaction of 15 with methyltriphenylphosphonium bromide in THF and DCM at 0 - 15 oC
for 4 h furnished 16 with 71% yield. Thus, vinylquinoline framework 16 was obtained in
55.3% overall yield in 2 steps starting from 7-chloro-2-methylquinoline (14).
The synthesis of 1 required a carbon-carbon bond formation between 4 and 16. Heck
coupling methodology has been investigated and there is no report for the preparation of
3 via Heck coupling. Palladium-catalyzed coupling of 16 with 4 was conducted in DMF
at 110 oC using palladium (II) acetate and triphenylphosphine in the presence of
triethylamine as base. The reaction was completed in 6 - 8 h, providing crude compound
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3
[20] in 58% yield. Hydrolysis of 3 using caustic lye at elevated temperature followed by
conventional work up yielded montelukast 2[2, 20] with 65% yield. Different bases (KOH,
NaOH and LiOH) were screened for hydrolysis in different solvents at moderate and
elevated temperature; usage of caustic lye (40% solution) as reactant as well as medium
proved to be the most effective. Finally, treatment of acid 2 with mol equiv of sodium
hydroxide followed by evaporation furnished montelukast sodium (1) in 96% yield.
CONCLUSION
In summary, we have presented a new and practical method for the total synthesis of
montelukast sodium (1) in good yields using readily accessible raw materials.
Furthermore, the two key intermediates, nitrile derivative 4 and vinylquinoline
framework 16 were synthesised through a new approach.
EXPERIMENTAL SECTION
The 1H NMR spectra were recorded on a Varian Mercury plus 400 MHz FT-NMR
spectrometer, chemical shift values were reported on δ ppm relative to TMS. The 13C
NMR spectra were recorded on a Varian Mercury plus 200 MHz FT-NMR spectrometer,
the chemical shift values were reported on δ ppm relative to CDCl3 and DMSO-d6. The
IR spectra recorded in the solid state as KBr dispersion using Perkin Elmer FT-IR
spectrophotometer. The mass spectra were recorded on Shimadzu LCMS-QP8000 and
Micro-mass LCT Premier XE mass spectrometer. Elemental analysis for CHN was
performed on Perkin Elmer model 2400 CHN/O analyzer.
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Sodium 2-(1-((((R)-1-(3-((E)-2-(7-Chloroquinolin-2-Yl)Vinyl)Phenyl)-3-(2-(2-
Hydroxy Propan-2-Yl)Phenyl)Propyl)Sulfanyl)Methyl)Cyclopropyl)Acetate (1)
To a heterogeneous mixture of 2 (1.0 g, 0.0017 mol) in methanol (10 mL), was added
sodium hydroxide (0.067 g, 0.00167 mol) and stirred at 25 oC for 1 h. The resulted clear
solution was treated with animal charcoal and then distilled off under reduced pressure at
55 oC to afford 0.99 g of 1 (96.0% yield) as a white solid. Mass: 586.3 (M+ + 1); IR cm-
1
1: 3600 - 3100 (OH), 1715 (C=O); H NMR (DMSO-d6): δ 8.42 (d, J = 8.2 Hz, 1H), 8.03
(d, J = 1.8 Hz, 1H), 8.0 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 16.8 Hz,
1H), 7.58 (dd, J = 1.8, 8.8 Hz, 1H), 7.50 (d, J = 16.8 Hz, 1H), 7.42 - 7.30 (m, 4H), 7.15 -
7.03 (m, 4H), 5.15 (br, 1H), 4.02 (t, J = 7.2 Hz, 1H), 3.11 - 3.05 (m, 1H), 2.75 (dd, 4.0,
12.0 Hz, 1H), 2.69 (d, J = 12.6 Hz, 1H), 2.54 (d, J = 12.6 Hz, 1H), 2.21 (m, 1H), 2.12 (d,
J = 14.6 Hz, 1H), 2.10 (m, 1H), 2.00 (d, J = 14.6 Hz, 1H), 0.45 - 0.35 (m, 2H), 0.25 -
0.16 (m, 2H); 13C NMR (DMSO-d6): δ 176.0, 156.8, 148.0, 146.7, 144.1, 139.9, 136.5,
136.0, 135.1, 134.2, 131.0, 129.7, 128.8, 128.4, 128.3, 127.2, 126.8, 126.6, 126.3, 125.7,
125.5, 125.3, 125.1, 120.3, 71.6, 49.4, 43.7, 40.1, 38.8, 31.9, 31.7, 31.6, 18.0, 12.4, 12.0.
Anal. Calcd for C35H35ClNNaO3S: C, 69.12; H, 5.80; N, 2.30. Found: C, 69.17; H, 5.74;
N, 2.33.
Complete experimental and spectral details are available online in the Supplementary
Information.
ACKNOWLEDGMENTS
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The authors are thankful to the management of Dr. Reddy’s Laboratories Limited and the
colleagues of Research and Development for their constant encouragement and excellent
cooperation.
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Scheme 1 Retro-synthetic analysis of montelukast (2).
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Scheme 2 New synthesis of nitrile derivative 4
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Scheme 3 Alternate approach to the synthesis of vinylquinoline framework 16
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Scheme 4 New approach to the synthesis of montelukast sodium (1)
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