Practical synthesis of methyl (E)-2-(3-(3-(2-(7-chloro-2-quinolinyl) ethenyl)phenyl)-3-oxopropyl)benzoate, a key intermediate of Montelukast

Article abstract of DOI:10.1016/j.cclet.2012.03.023

A novel and practical synthetic route is presented for the preparation of methyl-(E)-2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropyl) benzoate, the key intermediate of Montelukast, a leukotriene antagonist. The main diarylpropane framework was prepared via a polarity conversation reaction resulting in an acyl anion equivalent followed by a nucleophilic substitution reaction. The overall yield of this approach was 61%. This method is simple for operation and suitable for industrial production.

Full text of DOI:10.1016/j.cclet.2012.03.023

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 518–520
www.elsevier.com/locate/cclet
Practical synthesis of methyl (E)-2-(3-(3-(2-(7-chloro-2-
quinolinyl)ethenyl)phenyl)-3-oxopropyl)benzoate, a key
intermediate of Montelukast
Liang He a, Yang Hui Guo b, Ya Ping Wang b, Xiang Jing Wang a,
Ji Zhang a, Wen Sheng Xiang a,
*
a Department of Biochemical Engineering, Northeast Agricultural University, Harbin 150030, China
b Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou 318000, China
Received 22 December 2011
Available online 18 April 2012
Abstract
A novel and practical synthetic route is presented for the preparation of methyl-(E)-2-(3-(3-(2-(7-chloro-2-quinolinyl)ethe-
nyl)phenyl)-3-oxopropyl)benzoate, the key intermediate of Montelukast, a leukotriene antagonist. The main diarylpropane
framework was prepared via a polarity conversation reaction resulting in an acyl anion equivalent followed by a nucleophilic
substitution reaction. The overall yield of this approach was 61%. This method is simple for operation and suitable for industrial
production.
# 2012 Wen Sheng Xiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Montelukast; Synthesis; Intermediate; Polarity conversion
Since the discovery that leukotrienes play a significant role in asthma and associated inflammatory diseases, the
search for specific antagonists or inhibitors of the aracadonic acid cascade has been intensive [1–4]. Montelukast
sodium is a selective and orally active leukotriene antagonist that effectively inhibits the biosynthesis of the
leukotrienes. It has been found to be useful in the treatment of asthma as well as other conditions mediated by the
leukotrienes, such as inflammation and allergies [3]. As a key intermediate of Montelukast, methyl-(E)-2-(3-(3-(2-(7-
chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropyl)benzoate 1 has attracted considerable attention from the academic
community. The synthesis of intermediate 1 has been described in a plethora of literature [5–11] and two procedures
were selected for the industrial production of 1 (Scheme 1): (1) King et al. developed a method that utilized a Grignard
reaction followed by a Pd-catalyzed Heck reaction to form compound 1 [9,10]; (2) Suri et al. prepared the key
diarylpropane framework by employing both an alkylation of b-ketoesters and the decarboxylation reaction [11]. The
high overall yield and the minimum number of steps render the first approach attractive. However, the expensive
reagent and rigorous reaction conditions are its impediments. The limitations of the second approach are its long
synthetic route and the low overall yield. Thus, the development of practical syntheses of 1 is still in demand. Here, we
* Corresponding author.
E-mail address: xiangwensheng@yahoo.com.cn (W.S. Xiang).
1001-8417/$ – see front matter # 2012 Wen Sheng Xiang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.03.023

L. He et al. / Chinese Chemical Letters 23 (2012) 518–520
519
Scheme 1. Document reported the main synthetic routes for compound 1.
report a more convenient and efficient route to synthesis of the target compound 1 for constructing Montelukast
(Scheme 2). Although the raw material we used is the same as that in the literature, we developed the reaction of
methyl 2-(2-bromoethyl)benzoate with 1,3-di(1,3-dithian-2-yl)benzene 2 to form the desired diarylpropane
framework, which performed in a convenient manner suitable for industrial use.
In our synthetic strategy, compound 2 was prepared by the reaction of isophthalaldehyde with 1,3-propanedithiol-
catalyzed by a Lewis acid with a yield of 99%. The dipole reversal of compound 2 was achieved by the reaction of
BuLi at À20 8C and to which a solution of methyl 2-(2-bromoethyl)benzoate in dry THF was added dropwise at
À20 8C to give compound 3 in 71% yield according to the reaction conditions reported in the literature [12–15].
Methyl 2-(2-bromoethyl)benzoate was prepared in 95% yield according to the literature [16]. Afterwards we focused
our attention on deprotection of compound 3. Several different reagents listed in Table 1 were employed to evaluate
their optimality. We found that NBS was the best reagent for the deprotection of compound 3 to afford 4 with a yield of
94%. Moreover, the number of equivalents of NBS and the reaction temperature are very important for this reaction in
order to avoid undesirable potential byproducts. Finally, the condensation of compound 4 with 7-chloroquinaldine was
carried out in acetic anhydride at 140 8C for 8 h to give the anticipated product 1 with a yield of 93%. The structures of
1
prepared compounds were identified by MS, HRMS, H NMR, 13C NMR and 2D NMR and gave the satisfactory
analytic data [17]. There are certain obvious advantages in our strategy over the previous routes: (i) the condensation
reaction between compound 4 and 7-chloro-2-methylquinoline was completed in a higher yield and with more simple
post-processing method than the reaction between isophthaldialdehyde and 7-chloro-2-methylquinoline. (ii) Low cost
reagent and easy procedure was used to afford the primary diarylpropane framework. (iii) Our strategy gave an overall
yield of 61%, which is higher than the highest overall yield reported in documents. Moreover, all of intermediates can
be purified by simple recrystallization that makes it more suitable for industrial production.
Scheme 2. Our strategy for the intermediate 1. Regents and conditions: (a) 1,3-propanedithiol, BF3–Et2O, CH2Cl2, 0 8C, 1 h; (b) methyl 2-(2-
bromoethyl)benzoate, BuLi, THF, À20 8C; (c) NBS, CH3CN/H2O (95/5), À20 8C to À10 8C and (d) 7-chloroquinaldine, Ac2O, 140 8C.

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L. He et al. / Chinese Chemical Letters 23 (2012) 518–520
Table 1
The cleavage of 1,3-dithiane based on oxidation.
Entry
Ratio of 4/oxidant
Oxidant
Solvent
Time (h)
Temp (8C)
Yield (%)
1
2
3
1: 2.2
1: 6
NBS
CH3CN/H2O
THF
0.5
5
À20
À10–0
0–20
94
89
85
H5IO6
1: 4
Dess–Martin
CH2Cl2
12
In summary, we have developed a practical and efficient approach for the preparation of the target compound 1 from
readily available low cost materials. Additionally, this economic strategy would be a good alternative to the industrial
production of the intermediate 1.
Acknowledgments
This study was supported by the National Key Project for Basic Research (No. 2010CB1126102) and the
Outstanding Youth Foundation of Heilongjiang Province (No. JC200706).
References
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[17] Representative data of compounds. Compound 1: light yellow solid, mp 121–123 8C. 1H NMR (400 MHz, CDCl3): d 8.25 (s, 1H), 8.04–8.09
(m, 2H), 7.91–7.93 (m, 2H), 7.77 (d, 1H, J = 7.6 Hz), 7.73 (d, 1H, J = 16 Hz), 7.68 (d, 1H, J = 8.8 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.40–7.47 (m,
2H), 7.40 (d, 1H, J = 16 Hz), 7.35–7.39 (m, 2H), 7.26–7.31 (m, 1H), 3.90 (s, 3H), 3.39 (s, 4H); 13C NMR (100 MHz, CDCl3): d 199.2, 167.8,
156.4, 148.5, 143.3, 137.4, 136.8, 136.3, 135.7, 134.1, 132.3, 131.6, 131.5, 130.9, 129.5, 129.4, 129.1, 128.7, 128.3, 128.2, 127.3, 126.9, 126.4,
125.8, 119.7, 52.1, 40.9, 29.6; ESI-MS m/z: 456.1 [M+H]+; HR-MS 456.1346 ([M+H]+, calcd. for C28H23ClNO3: 456.1361); Compound 2:
ivory solid, mp 123–125 8C. 1H NMR (400 MHz, CDCl3): d 7.57 (s, 1H), 7.41 (d, 2H, J = 8.0 Hz), 7.30 (t, 1H, J = 8.0 Hz), 5.15 (s, 2H), 3.01
(m, 4H), 2.86 (m, 4H), 2.12 (m, 2H), 1.88 (m, 2H); 13C NMR (100 MHz, CDCl3): d 139.55, 129.06, 127.74, 127.40, 51.11, 31.94, 25.00; ESI-
MS m/z: 315.1 [M+H]+; HR-MS 337.0158 ([M+Na]+, calcd. for C14H18NaS4: 337.0184); Compound 3: white solid, mp 100–103 8C. 1H NMR
(400 MHz, CDCl3): d 8.11 (s, 1H), 7.92 (m, 1H), 7.79 (d, 1H, J = 7.6 Hz), 7.42–7.37 (m, 2H), 7.32 (t, 1H, J = 7.6 Hz), 7.17 (t, 1H, J = 7.6 Hz),
7.07 (d, 1H, J = 7.6 Hz), 5.23 (s, 1H), 3.77 (s, 3H), 3.04 (m, 2H), 2.86–2.89 (m, 4H), 2.70 (m, 4H), 2.30–2.25 (m, 2H), 2.12 (m, 1H), 1.90–1.95
(m, 3H); 13C NMR (100 MHz, CDCl3): d 167.83, 142.60, 142.42, 139.53, 131.90, 131.12, 130.59, 129.64, 128.92, 128.83, 128.44, 126.27,
125.95, 58.74, 51.92, 51,48, 46.70, 32.00, 29.49, 27.57, 25.05, 24.95; ESI-MS m/z: 477.1 [M+H]+; HR-MS 499.0837 ([M+Na]+, calcd. for
C24H28NaO2S4: 499.0864); Compound 4: white solid, mp 55–57 8C. 1H NMR (400 MHz, CDCl3): d 10.03 (s, 1H), 8.44 (s, 1H), 8.21 (d, 1H,
J = 7.6 Hz), 8.02 (d, 1H, J = 7.6 Hz), 7.91 (d, 1H, J = 7.6 Hz), 7.60 (t, 1H, J = 7.6 Hz), 7.43 (m, 1H), 7.34 (m, 1H), 7.26 (t, 1H, J = 7.6 Hz), 3.87
(s, 3H), 3.35–3.41 (m, 4H); 13C NMR (100 MHz, CDCl3): d 198.3, 191.5, 167.7, 143.1, 137.6, 136.6, 133.6, 133.2, 132.4, 131.5, 131.0, 129.7,
129.4, 129.3, 126.5, 52.0, 40.8, 29.4; ESI-MS m/z: 297.1 [M+H]+; HR-MS 319.0915.([M+Na]+, calcd. for C18H16NaO4: 319.0941).