HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 8, 2014, pp. 1885-1891
Received, 11th May, 2014, Accepted, 16th June, 2014, Published online, 20th June, 2014.
DOI: 10.3987/COM-14-13023

■ A New and Practical Synthesis of 7-(3-Chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile

Yongjun Mao, Jianfeng Qin, Haijun He, Gang Liu, Bingyi Gao, and Han Wang*

Department of Medicinal Chemistry, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

New and improved synthetic route of bosutinib intermediate 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (3) is described on a hectogram scale. An intramolecular cyclization of 3-(2-aminophenyl)-3-oxopropanenitrile 11 with DMF-DMA to form the 4-oxo-1,4-dihydroquinoline-3-carbonitrile ring is adopted as the key step. Product 3 is obtained with 29.8% yield over eight steps and 98.6% purity (HPLC), which make it as a process of cost effective, environmental friendly and feasible for scale-up operation.

Bosutinib (1, SKI-606, marketed as Bosulif ®, Figure 1) is a tyrosine kinase inhibitor undergoing research for use in the treatment of cancer.1 Bosulif ® was originally developed by Wyeth Pharmaceuticals (merged to Pfizer in 2009) and received the US FDA and EU European Medicines Agency approval on September 4, 2012 and March 27, 2013 respectively for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.2

A couple of synthetic route of 1 were developed on a multi-grams scale, while a practical synthetic process is needed. The earlier and common work to prepare 1 was based on the Gould-Jacobs methodology through a thermal cyclization at 250 ºC for 4 h in Dowtherm A to synthesize the key intermediate 7-fluoro-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (2, Figure 1).3 The main problem was that the high reaction temperature leaded to a messy and tedious operation and too many materials were destroyed in the reaction as tar or resin, which resulted in difficulties for purification and thus the overall yield was reduced dramatically (~ 40%). Withbroe et al.4 developed a streamlined process for the synthesis and isolation of bosutinib monohydrate. Yin et al.5 also reported a new synthesis of 1 that 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (3, Scheme 1) was adopted as the key intermediate. Vanillic acid (4) was used as the starting material, followed by esterification, alkylation, nitration, reduction, cyclization and so on.

In order to develop a practical and commercial process of preparing compound 1, a new and practical synthetic route was obtained, which adopted an intramolecular cyclization of 3-(2-aminophenyl)- 3-oxopropanenitrile 16 with dimethylformamide dimethyl acetal (DMF-DMA) to form the key intermediate 3, as shown in Scheme 2. Methyl vanillate (5) was used as the starting material, which was reacted with 1-bromo-3-chloropropane at K2CO3/DMF condition to give compound 6 in 91% isolated yield, based on the reported method.5a The benzoic acid 11 was obtained from 6 in 92% yield through the basic ester hydrolysis. The next nitration was carried out by HNO3 in AcOH, compound 12 was obtained in 85% yield after recrystallization from MeOH. By treating 12 with oxalyl chloride and following reaction with ethyl cyanoacetate and NaOEt, compound 14 was achieved, which was purified by recrystallization from hexane/EtOAc in good yield (79%, two steps). Treatment of 14 with 90% DMSO in H2O solution provided the compound 15 in 82% yield after recrystallization from hexane/EtOAc. The aniline 16 was obtained through catalytic hydrogenation of 15 under H2/Raney Ni/THF condition at room temperature. The crude 16 was purified by stirring in THF/MeOH, giving 91% overall yield and 96.9% purity (HPLC). The final cyclization of 16 was carried out in THF at room temperature by condensation with DMF-DMA to give the title compound 3, most likely through the enaminoketonitrile intermediated 17 which could not be isolated by us so far. The crude 3 was purified by heating and stirring in 50% EtOH/EtOAc to give the compound with 71% overall yield. During the synthetic process research of ivacaftor6 as well as the N-(3-cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide as the key intermediate of neratinib,7 the similar reductive cyclization method was developed by us.

In summary, we have developed a new and practical synthetic route of bosutinib intermediate 3 on a hectogram scale. Adopting the easily commercially available methyl vanillate (5) as the starting material, through the simple and traditional steps including alkylation, ester hydrolysis, nitration, decarboxylation, reduction, and cyclization to give the final product 3 in 29.8% yield over eight steps and 98.6% purity (HPLC). Purification methods of the intermediates involved in the route were also given.

ACKNOWLEDGMENT
This work was supported by the Special Scientific Foundation for Outstanding Young Teachers in Shanghai Higher Education Institutions (No. ZZGJD13017), the Scientific Research Foundation of Shanghai University of Engineering and Technology (SUES) (No. 2012-24), and the Undergraduate Innovative Training Project of SUES (No. cx1404020).

EXPERIMENTAL
All commercially available materials and solvents were used as received without any further purification. 1H NMR and 13C NMR spectra were recorded on a Bruker UltraShield 400 Plus spectrometer using TMS as an internal standard. Mass spectra were obtained from a Finnigan MAT-95/711 spectrometer. The HPLC results were generated using a Waters 2487 UV/Visible Detector and Waters 515 Binary HPLC Pump.
Methyl 4-(3-chloropropoxy)-3-methoxybenzoate (6). 1-Bromo-3-chloropropane (404 g, 2.57 mol) was added dropwise to a stirred mixture of methyl vanillate (5, 360 g, 1.98 mol) and potassium carbonate (415 g, 3.0 mol) in DMF (1.8 kg) at 60 ºC. The reaction mixture was stirred at this temperature for another 1 h then cooled to room temperature, and poured slowly into ice-water (8 kg) while stirring constantly. The solid formed was filtered off and washed with cold water (0.8 kg × 2), dried at 60 ºC for 4 h. The white product was stirred and heated with 2:1 hexane/EtOAc (1 kg) at 60 ºC for 2 h then cooled to room temperature, the resulting solid was filtered off and washed with 2:1 hexane/EtOAc (300 g × 2), dried at 50 ºC for 4 h to afford 6 (466 g, 91%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.32 (m, J = 6.4 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 4.23 (t, J = 6.0 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H). ESI-MS (m/z) 281.0 [M+Na]+.
4-(3-Chloropropoxy)-3-methoxybenzoic acid (11). A mixture of 6 (400 g, 1.55 mol), NaOH (80 g, 2.0 mol) in MeOH (2 kg) and H2O (2 kg) was stirred and heated at 50–60 ºC for 12 h to form a clear solution. Until it was cooled to room temperature, H2SO4 was added slowly into the reaction solution to acidify to pH 2–3. The white suspension was stirred at the ambient temperature for 1 h. The resulting solid was filtered off and washed with H2O (0.5 kg × 3) and MeOH (0.3 kg × 1), dried at 50 ºC for 5 h to give 11 (349 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.19 (m, J = 6.0 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 3.81 (s, 3H), 4.15 (t, J = 6.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.55 (dd, J = 2.0, 8.4 Hz, 1H), 12.68 (s, 1H). ESI-MS (m/z) 267.0 [M+Na]+.
4-(3-Chloropropoxy)-5-methoxy-2-nitrobenzoic acid (12). A stirred suspension of 11 (300 g, 1.23 mol), 65% HNO3 (179 g, 1.85 mol) and AcOH (1.5 kg) was stirred at 40–50 ºC for 6 h to form a white solution. The mixture was poured slowly into ice water (5 kg) over 20 min and stirred. The resulting white solid was filtered, washed with H2O (300 g × 3) and dried at 60 ºC for 5 h. The crude product was recrystallized from MeOH (0.7 kg) to afford 12 (303 g, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.21 (m, J = 6.0 Hz, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 4.23 (t, J = 6.0 Hz, 2H), 7.30 (s, 1H), 7.62 (s, 1H), 13.52 (br s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 31.88, 42.17, 56.96, 66.59, 108.77, 111.97, 121.93, 141.89, 149.62, 152.43, 166.61. ESI-MS (m/z) 312.0 [M+Na]+.
Ethyl 3-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)-2-cyano-3-oxopropanoate (14). (COCl)2 (190 g, 1.5 mol) and DMF (7.3 g, 0.1 mol) were added respectively to a mixture of 12 (290 g, 1.0 mol) in CH2Cl2 (2 kg) at room temperature and the mixture was stirred for 4 h to form a homogeneous solution. The solvent was removed to give 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoyl chloride (13) as a light-brown oil.
A suspension of NaOEt (95 g, 1.4 mol) in anhydrous EtOH ( 0.8 kg) was stirred at 40–50 ºC for 1 h to get a solution firstly, and CNCH2CO2Et (170 g, 1.5 mol) was added. The resulting white suspension was heated to reflux for another 0.5 h and then cooled to –5 ºC in an ice-salt bath and treated dropwise with 13 (1.0 mol) in THF (0.8 kg) over 2 h, keeping the reaction temperature below 0 ºC. The reaction mixture was then added to chilled water (6 kg), stirred and acidified to pH 2–3 with H2SO4. The resulting solid was collected by suction filtration, washed with H2O (400 g × 3), and dried at 50 ºC for 5 h to give crude 14, which was recrystallized from 3:1 hexane/EtOAc (1 kg) to afford 14 (304 g, 79%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 0.99 (t, J = 7.0 Hz, 3H), 2.23 (m, J = 6.0 Hz, 2H), 3.80 (t, J = 6.4 Hz, 2H), 3.87 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 4.26 (t, J = 6.0 Hz, 2H), 7.09 (s, 1H), 7.78 (s, 1H), 10.35 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 14.32, 31.96, 42.20, 57.17, 60.00, 66.49, 80.85, 108.70, 111.86, 117.23, 127.75, 138.58, 148.34, 154.24, 164.17, 181.77. ESI-MS (m/z) 407.1 [M+Na]+.
3-(4-(3-Chloropropoxy)-5-methoxy-2-nitrophenyl)-3-oxopropanenitrile (15). A mixture of 14 (300 g, 0.78 mol), DMSO (1.2 kg) and H2O (100 g) was heated at 100–110 ºC for 30 min. Then the brown solution was cooled to around 50 ºC, poured into chilled water (4 kg), and stirred for 1 h. The resulting precipitate was collected by suction filtration, washed with H2O (300 g × 3) and 50% EtOH/H2O (200 g × 1), dried at 60 ºC for 4 h to give a brown solid, which was recrystallized from 1:1 hexane/EtOAc (0.8 kg) to afford 15 (200 g, 82%) as light-tan solid. 1H NMR (400 MHz, DMSO-d6): δ 2.22 (m, J = 6.4 Hz, 2H), 3.79 (t, J = 6.8 Hz, 2H), 3.94 (s, 3H), 4.27 (t, J = 6.0 Hz, 2H), 4.52 (s, 2H), 7.32 (s, 1H), 7.76 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 31.75, 33.02, 42.06, 57.18, 66.57, 108.71, 110.67, 115.47, 128.97, 138.73, 149.41, 154.21, 191.71. ESI-MS (m/z) 335.0 [M+Na]+.
3-(2-Amino-4-(3-chloropropoxy)-5-methoxyphenyl)-3-oxopropanenitrile (16). Compound 15 (180 g, 0.57 mol) and Raney Ni (wet, 30 g) were added to THF (3 kg), and stirred for 6 h at room temperature under H2 atmosphere to form a clear brown solution. The reaction mixture was then filtered through a celite pad, the filter cake was washed by THF (250 g × 2). The combined filtrate was concentrated to give the product as a light-brown solid, which was stirred with 1:1 THF/MeOH (400 g) at room temperature for 2 h. The resulting precipitate was collected by suction filtration, washed with MeOH (150 g × 2), dried at 50 ºC for 2 h to afford 16 (147 g, 91%) as light-tan solid. 1H NMR (400 MHz, DMSO-d6): δ 2.21 (m, J = 5.6 Hz, 2H), 3.71 (s, 3H), 3.79 (t, J = 5.6 Hz, 2H), 4.08 (t, J = 5.6 Hz, 2H), 4.54 (s, 2H), 6.40 (s, 1H), 6.98 (s, 1H), 7.17 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 30.31, 31.74, 42.33, 56.97, 65.33, 100.00, 107.27, 114.22, 116.88, 139.79, 149.94, 155.81, 187.77. ESI-MS (m/z) 305.1 [M+H]+. HPLC Conditions: Column: Acclaim C18 (150 mm × 2.1 mm × 5 µm); Detection: 280 nm; Flow rate: 0.8 mL/min; Temperature: rt; Injection load: 2 μL; Solvent: MeCN; Run time: 5 min; Mobile phase: MeCN /water = 80/20, tR: 0.563 min, purity: 96.9%.
7-(3-Chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (3). To a stirred suspension of 16 (120 g, 0.42 mol) in THF (0.5 kg) was added DMF-DMA (65.7 g, 0.55 mol). The mixture was stirred at room temperature for 2 h to give a light-yellow suspension. H2O (1.2 kg) was added to the reaction solution and stirred at room temperature for 1 h, the resulting solid was collected by suction filtration, washed with 50% EtOH/H2O (100 g × 2), and dried at 60 ºC to give a grey solid. The product was stirred and heated with 1:1 EtOH/EtOAc (190 g) at 60 ºC for 2 h then cooled to room temperature, the resulting solid was filtered off and washed with 1:1 EtOH/EtOAc (50 g × 2), dried at 60 ºC for 4 h to afford 3 (87 g, 71%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.27 (m, J = 3.2 Hz, 2H), 3.82 (t, J = 3.2 Hz, 2H), 3.88 (s, 3H), 4.19 (t, J = 3.6 Hz, 2H), 7.07 (s, 1H), 7.45 (s, 1H), 8.58 (s, 1H), 12.50 (br s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 31.77, 42.23, 56.27, 65.89, 93.21, 101.54, 104.93, 117.62, 119.73, 135.18, 145.33, 148.54, 153.17, 173.77. ESI-MS (m/z) 315.1 [M+Na]+. HPLC Conditions: Column: Acclaim C18 (150 mm × 2.1 mm × 5 µm); Detection: 280 nm; Flow rate: 0.8 mL/min; Temperature: rt; Injection load: 2 μL; Solvent: acetonitrile; Run time: 5 min; Mobile phase: acetonitrile/water = 80/20, tR: 0.490 min, purity: 98.6%.

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