HETEROCYCLES

Short Paper | Regular issue | Vol. 89, No. 5, 2014, pp. 1203-1209
Received, 5th September, 2013, Accepted, 25th March, 2014, Published online, 27th March, 2014.
DOI: 10.3987/COM-13-12830

■ New Synthesis of N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide

Yongjun Mao, Yang He, Fuqiang Zhu, Weiming Chen, Jingshan Shen, and Jianfeng Li*

Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, 501 Haike Rd, Shanghai 201203, China

Abstract

New synthetic route of N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (1) is described on a hectogram scale. The key steps include the intramolecular cyclization of 3-amino-2-(2-chlorobenzoyl)acrylonitrile 22 to give the 3-cyano-4-quinolone 7, which was chlorinated by POCl3 to give the final product 1 in 36.9% yield over 9 steps and 98.9% purity (HPLC). Purification methods of 7 and 1 were also given.

4-Chloroquinolines are the key synthetic precursors for anticancer,1 anti-malarial,2 antidiabetic,3 antiviral4 agents and reversible (H+/K+) ATPase inhibitors.5 N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (1, Figure 1) was developed as an important intermediate for the preparation of pelitinib (2) and neratinib (3), which were developed as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2) kinases.6

In the previous reports,7 1 was prepared based on Gould-Jacobs methodology using 2-amino-5- nitrophenol (4) as starting material (Scheme 1). 5 was then reacted with ethyl (E)-2-cyano-3- ethoxypropenoate to afford the corresponding ethyl cyanopropenoate 6. 3-Cyano-4-quinolone 7 was obtained with ~ 40% yield through thermal cyclization at 260 ºC for 20 h in Dowtherm A. After chlorination with POCl3 in diglyme, 1 was produced with 65% yield. This route was straightforward, while the high temperature required for cyclization of 6 to 7 on a kilogram scale was proved to be disadvantageous and so the overall yield is not good.

Recent years we developed a couple of new routes for synthesis of 7,8 as shown in Schemes 2 and 3. The key step in the first route is the basic cyclization of o-[(2-cyanovinyl)amino]benzoate (11) in t-BuONa/t-BuOH system to give the final product at kg scale. In the second, a reductive cyclization method was adopted, 3-(dimethylamino)-2-(2-nitrobenzoyl)acrylonitrile 15 was converted to 7, while the overall yield is not attractive.

Here, we report a new synthetic method for compound 1 (Scheme 4). The cheap and easily available material 2-amino-5-chlorophenol (16) was converted to 17 through simple reactions with high yield.6
Through a Friedel-Crafts acylation, compound 18 was obtained in 95% yield,9 which was then treated with 1 eq. of Br2 in CH2Cl2 to give 19,10 and followed by 1.1 eq. of NaCN in EtOH/DMSO at room temperature to afford 20 in 78% yield over two steps.11 20 was then condensed with CH(OEt)3 and Ac2O, substituted by NH3 in EtOH to give the 3-amino-2-(2-chlorobenzoyl)acrylonitrile 22 in 84% yield.12 The intramolecular cyclization of 22 was carried out in K2CO3/DMF condition to afford the 3-cyano-4-quinolone 7,13 which was purified by heating and stirring in 50% EtOH/EtOAc to give the compound with 73% overall yield and > 99% purity (HPLC). At the last step, 4-chloro-3-cyanoquinoline 1 was obtained by reaction with POCl3 in EtOAc, catalyzed by 5 mol % DMAP. Purification of 1 was carried out by triturating and stirring in DMF at rt with 88% isolated yield and 98.9% purity (HPLC).

In summary, we have developed a new synthetic route for 4-chloro-3-cyanoquinoline 1 on a hectogram scale. Starting from the easily available material 2-amino-5-chlorophenol (16), through the Friedel-Crafts acylation, substitution by -Br and -CN respectively, and the key intramolecular cyclization of 3-amino-2- (2-chlorobenzoyl)acrylonitrile 22 to give the 3-cyano-4-hydroxyquinoline 7, which was chlorinated by POCl3 in EtOAc to give the final product 1 in 36.9% yield over 9 steps and 98.9% purity (HPLC). Purification methods of 7 and 1 were also given.

ACKNOWLEDGEMENT
This work was supported by grants from the National Science and Technology Major Project (No. 2012ZX09301001-001) and the Key Project of Science and Technology of Shanghai (No. 10431902800).

EXPERIMENTAL
All commercially available materials and solvents were used as received without any further purification. 1H NMR spectra were recorded on a Varian Gemini 300 spectrometer and 13C NMR spectra were obtained from a Bruker AMX 400/600 at 400 MHz using TMS as an internal standard. Infrared spectra were recorded using a Thermo-Nicolet MAGNA-IR 750. Mass spectra were obtained from a Finnigan MAT-95/711 spectrometer. Melting points were measured on a Buchi-510 melting point apparatus, which are uncorrected. The HPLC results were generated using a Waters 2487 UV/Visible Detector and Waters 515 Binary HPLC Pump.

N-(4-Chloro-2-ethoxyphenyl)acetamide (17). To a stirred solution of 2-amino-5-chlorophenol 16 (300 g, 2.09 mol) in AcOH (1.5 kg) at 60 ºC was added Ac2O (260 g, 2.55 mol) over 1 h, and the mixture was stirred at this temperature for 1 h. The mixture was poured into ice water (5 kg) over 20 min and stirred. The resulting tan solid was filtered, washed with water (500 g × 2) and dried at 50 ºC to give N-(4-chloro- 2-hydroxyphenyl)acetamide (372 g, 95.8%) as a tan powder. 1H NMR (300 MHz, DMSO-d6): δ 2.06 (s, 3H), 6.78 (dd, J = 1.8, 6.9 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H), 9.23 (s, 1H), 10.24 (s, 1H).
To a stirred suspension N-(4-chloro-2-hydroxyphenyl)acetamide (372 g, 2.01 mol) and K2CO3 (410 g, 2.96 mol) in DMF (1.9 kg) at 60 ºC was added EtBr (261 g, 2.4 mol) over 1 h, and the mixture was stirred at this temperature for 1 h. The mixture was poured into ice water (7 kg) and stirred for 30 min. The resulting grey solid was filtered, washed with water (500 g × 2) and dried at 50 ºC to provide 17 (410 g, 95.7%) as a grey powder. 1H NMR (300 MHz, CDCl3): δ 1.46 (t, J = 5.4 Hz, 3H), 2.20 (s, 3H), 4.08 (q, J = 5.4 Hz, 2H), 6.83 (d, J = 1.8 Hz, 1H), 6.92 (dd, J = 1.8, 6.6 Hz, 1H), 7.68 (br s, 1H), 8.30 (d, J = 6.6 Hz, 1H).

N-(5-Acetyl-4-chloro-2-ethoxyphenyl)acetamide (18). Anhydrous AlCl3 (500 g, 3.74 mol) was suspended in CH2Cl2 (3 kg) under nitrogen and cooled to 0−5 ºC. AcCl (196 g, 2.5 mol) was added dropwise to the mixture over 1 h and stirred at 0−5 ºC for another 1 h. A solution of 17 (400 g, 1.87 mol) and AcCl (95 g, 1.2 mol) in CH2Cl2 (1.8 kg) was added dropwise to the previous AlCl3 solution over 2 h and keep the reaction temperature below 20 ºC. A dark blue solution was obtained and stirred at rt for another 20 h. The reaction solution was then poured into chilled 10% hydrochloric acid (4 kg) and stirred for 1 h. The organic layer was separated and washed with water (2 kg × 3), dried over anhydrous Na2SO4. The solvent was recovered to give the 18 (454 g, 95.0%) as a tan solid. 1H NMR (300 MHz, CDCl3): δ 1.46 (t, J = 5.1 Hz, 3H), 2.19 (s, 3H), 2.57 (s, 3H), 4.11 (q, J = 5.1 Hz, 2H), 6.82 (s, 1H), 7.69 (br s, 1H), 8.72 (s, 1H). ESI-MS (m/z) 254.0 (M – H), 255.9 (M + H).

N-(5-(2-Bromoacetyl)-4-chloro-2-ethoxyphenyl)acetamide (19). Br2 (32 g, 0.2 mol) was added to a stirred solution of 18 (440 g, 1.72 mol) in CH2Cl2 (5 kg). The reaction mixture was stirred at 20–25 ºC for 1 h. Another portion of Br2 (243 g, 1.52 mol) was added and the reaction solution was stirred at 20–25 ºC for 12 h that the solution turned from red to faint yellow. The solvent was removed and 19 (580 g) was obtained as a faint red oil, which was used at the next step without purification. 1H NMR (300 MHz, CDCl3): δ 1.49 (t, J = 7.5 Hz, 3H), 2.22 (s, 3H), 4.16 (q, J = 7.5 Hz, 2H), 4.48 (s, 2H), 6.88 (s, 1H), 7.68 (br s, 1H), 8.78 (s, 1H). ESI-MS (m/z) 333.9 (M – H), 335.9 (M + H).

N-(4-Chloro-5-(2-cyanoacetyl)-2-ethoxyphenyl)acetamide (20). A solution of 19 (580 g, 1.72 mol) in DMSO (1 kg) and EtOH (2 kg) was cooled in an ice-water bath, then treated dropwise with NaCN (92.7 g, 1.89 mol) in H2O (0.8 kg) over 1 h. The mixture was stirred for another 4 h at 20–25 ºC. The resulting solution was diluted with H2O (5 kg), filtered, and the filtrate was acidified with 2 M HCl to pH = 4–5. The resulting solid was collected via suction filtration, washed with water (500 g × 2), and dried under reduced pressure to give 20 (376 g, 78%) as a pale solid. 1H NMR (300 MHz, CDCl3): δ 1.52 (t, J = 7.5 Hz, 3H), 2.23 (s, 3H), 4.09 (s, 2H), 4.18 (q, J = 7.5 Hz, 2H), 6.92 (s, 1H), 7.67 (br s, 1H), 8.82 (s, 1H).

N-(5-(3-Amino-2-cyanoacryloyl)-4-chloro-2-ethoxyphenyl)acetamide (22). A mixture of 20 (300 g, 1.07 mol), CH(OEt)3 (311g, 2.1 mol) and Ac2O (1.5 kg) was heated at 120 ºC for 2 h. The solvent was removed to give the N-(4-chloro-5-(2-cyano-3-ethoxyacryloyl)-2-ethoxyphenyl)acetamide 21 (370 g) as a red oil, which was used at the next step without purification.
21 (370 g, 1.07 mol) was dissolved in EtOH (2.5 kg) and cooled to ~10 ºC. NH3 was then babbled to the solution till to saturated, and the reaction solution was stirred at 20 ºC for another 2 h. The resulting solid was collected by suction filtration, washed with 50% EtOH/H2O, and dried under reduced pressure to give 22 (276 g, 84%) as a pale solid. 1H NMR (300 MHz, CDCl3): δ 1.38 (t, J = 7.5 Hz, 3H), 2.10 (s, 3H), 4.16 (q, J = 7.5 Hz, 2H), 7.14 (s, 1H), 7.59 (br s, 2H), 7.95 (m, 1H), 9.18 (s, 1H). ESI-MS (m/z) 306.0 (M – H), 308.0 (M + H).

N-(3-Cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (7). 22 (250 g, 0.81 mol) and K2CO3 (134.0 g, 0.97 mol) were suspended in DMF (1.8 kg) under nitrogen. The reaction mixture was stirred and heated to 120 ºC for 3 h. Around 0.8 kg DMF was removed and the residue was poured into chilled water (3 kg), the resulting mixture was stirred at rt for 3 h. The resulting solid was filtered, washed with water, and dried to give the crude product 7 (175 g), which was suspended in 50% EtOH/EtOAc (700 g), stirred and heated to 70 ºC for 1 h. After cooled to rt, the resulting solid was collected by suction filtration, washed by 50% EtOH/EtOAc (80 g × 2), dried at 50 ºC to give the pure product 7 (160 g, 73%) as a pale solid, mp > 300 ºC. 1H NMR (DMSO-d6, δ): 1.45 (t, 3H, J = 6.6 Hz), 2.14 (s, 3H), 4.20 (q, 2H, J = 6.6 Hz), 7.05 (s, 1H), 8.59 (d, 1H, J = 6.3 Hz), 8.70 (s, 1H), 9.18 (s, 1H), 12.52 (d, 1H, J = 6.3 Hz). 13C NMR (DMSO-d6, δ): 14.1, 23.9, 64.6, 93.0, 99.7, 116.3, 117.0, 118.7, 126.5, 136.5, 145.4, 152.9, 168.7, 173.5. ESI-MS (m/z): 270.2 (M – H), 272.2 (M + H). HPLC Conditions: Column: Phenomenex Prodigy ODS3, 150 mm × 4.6 mm × 5 µm; Detection: 230 nm; Flow rate: 1.0 mL/min; Temperature: 30 ºC; Injection load: 5 μL; Solvent: DMF; Concentration: 0.5 mg/mL; Run time: 60 min; Mobile phase A: water (0.1% H3PO4); Mobile phase B: acetonitrile; Gradient program: time (min): 0, 5, 45, 50, 52, 60; % of mobile phase A: 95, 95, 5, 5, 95, 95; % of mobile phase B: 5, 5, 95, 95, 5, 5, tR: 15.546 min, purity: 99.1%.

N-(4-Chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (1). Compound 7 (140 g, 0.51 mol), DMAP (3.0 g, 0.025 mol) were suspended in EtOAc (1.2 kg) and stirred at rt. POCl3 (230 g, 1.5 mol) was added slowly to the mixture over 1 h, then heated to reflux for another 2 h to give a clear solution. After cooled to rt, the reaction solution was poured slowly into ice-water (2 kg) and stirred for 1 h. The resulting solid was filtered, washed with water (200 g × 2), and dried to give the crude product 1 (140 g), which was suspended in DMF (400 g), stirred at rt for 1 h. The solid was filtered, washed with EtOAc (80 g × 3), and dried at 50 ºC to give the pure product 1 (130 g, 88%) as a faint brown solid, mp 255 – 258 ºC. 1H NMR (DMSO-d6, δ): 1.50 (t, 3H, J = 6.3 Hz), 2.25 (s, 3H), 4.40 (q, 2H, J = 6.3 Hz), 7.60 (s, 1H), 9.01 (s, 1H), 9.17 (s, 1H), 9.54 (s, 1H). ESI-MS (m/z): 290.1 (M+H). Anal. Calcd for C14H12ClN3O2: C, 58.04; H, 4.17; N, 14.50. Found: C, 57.81; H, 4.07; N, 14.18. IR (KBr): 3334.4, 2993.0, 2235.1, 1689.4, 1618.0, 1521.6, 1427.1, 1348.0, 1259.3, 1161.0, 1037.5, 694.3. HPLC Conditions: Column: Phenomenex Prodigy ODS3, 150 mm × 4.6 mm × 5 µm; Detection: 230 nm; Flow rate: 1.0 mL/min; Temperature: 30 ºC; Injection load: 5 μL; Solvent: DMF; Concentration: 0.5 mg/mL; Run time: 60 min; Mobile phase A: water/acetonitrile/H3PO4 = 950/50/0.5; Mobile phase B: water/acetonitrile/H3PO4 = 50/950/0.5; Gradient program: time (min): 0, 5, 45, 50, 52, 60; % of mobile phase A: 100, 100, 0, 0, 100, 100; % of mobile phase B: 0, 0, 100, 100, 0, 0, tR: 26.018 min, purity: 98.9%.

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