HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 12, 2011, pp. 2851-2856
Received, 21st August, 2011, Accepted, 6th October, 2011, Published online, 11th October, 2011.
DOI: 10.3987/COM-11-12343

■ Synthesis of N-(3-Cyano-7-ethoxy-1,4-dihydro-4-oxoquinolin-6-yl)acetamide

Qiang Zhang, Yongjun Mao, Zheng Liu, Kai Xie, Yi Zhu, Yabing Wei, Xiangrui Jiang,* and Jingshan Shen

Chinese Academy of Sciences, Shanghai Institute of Materia Medica, 555 Zuchongzhi Rd., Zhangjiang Hi-Tech Park, Shanghai, 201203, China

Abstract

New route for the preparation of N-(3-cyano-7-ethoxy-1,4- dihydro-4-oxoquinolin-6-yl)acetamide (1), a key intermediate for the synthesis of selective EGFR kinase inhibitors, was described.

4(1H)-Quinolones are a series of important intermediates for the synthesis of anticancer,1 antimalarial,2 antidiabetic,3 antiviral4 agents and reversible (H+/K+) ATPase inhibitors.5 N-(3-Cyano-7-ethoxy-1,4-dihydro-4-oxoquinolin-6-yl)acetamide (1, Figure 1) was a key intermediate for either EKB-569 (2) or neratinib (3) , both of which were developed as dual irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (EGFR-2) protein tyrosine kinases.6
In the previous reports, 1 was prepared using 2-amino-5-nitrophenol (4) as starting material.7 5 was synthesized by acelytion, ethylation and reduction of 4 (Scheme 1), and then reacted with ethyl (E)-2-cyano-3-ethoxypropenoate to furnish 6. In the following thermal cyclization, the reaction mixture was heated at 260 °C for 20 h to give 1 with 35% yield.

An efficient and mild synthesis for 1 is needed in the process for 2 and 3. To address this issue, we conceived an alternative strategy using compound 7 as starting material. Herein, we wish to report this approach as a new mild promising method for the preparation of compound 1.
We noted that Atkins8 and Tois9 had reported the preparation of 3,8-disubstatuted 4-hydroxyquinolines and 6,7-disubstitued 4-hydroxyquinolines, respectively, by condensation of N,N-dimethylformamide dimethyl acetal (DMF-DMA) with the corresponding substituted o-nitrophenylethanones to afford nitroenamine intermediates. Intermediates were in turn subjected to hydrogenation conditions over palladium-on-carbon to give the corresponding substituted 4(1H)-quinolones. These convenient routes possessed the advantage of avoiding thermal cyclization at high temperature. Enlightened by the noticeable merit of this approach in the preparation of 4-hydroxyquinolines, we wondered if this strategy could be applied in the synthesis of compound 1. Therefore, a new synthetic route using reductive cyclization method was designed and examined (Scheme 2).

The key intermediate 12 can be readily prepared from 3-amino-4-hydroxybenzoic acid according to the well-established chemistry.11 Esterfication of 7 followed by acetylation gave 9 in 87% yield. Ethylation of 9 followed by hydrolysis afforded the substituted benzoic acid 11, whose treatment with fuming nitric acid produced compound 12. By treating 12 with SOCl2 and following reaction with ethyl cyanoacetate, the synthesis of compound 13 was achieved in excellent yield (90%) by two steps. Treatment of 13 in DMSO/H2O provided the compound 14 in 84% yield. Condensation of 14 with DMF-DMA gave compound 15. The next reductive cyclization of 15 was achieved with zinc-acetic acid-ethanol system to give 1 in good yield. Because the sodium salt form of 1 can dissolve in the mixture of ethanol and water, it is ready to give 1 in satisfying HPLC purity (99.20%) by simple alkalization, acidification and filtration. Finally, the overall yield of this reductive cyclization process was about 31% (from 7) over ten steps.

EXPERIMENTAL
All commercially available materials and solvents were used as received products without 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 spectrometer at 400 MHz using TMS as an internal standard. Infrared spectra were recorded using a Thermo-Nicolet MAGNA-IR 750. The mass spectra were (LRMS and HRMS) obtained from a Finnigan MAT-95/711 spectrometer. All MS experiments were performed using electrospray ionization (ESI) in positive or negative ion mode. Melting points were measured on a Buchi-510 melting point apparatus, which are uncorrected. Elemental analyses were carried out in the Analytical Laboratories of Shanghai Institute of Meteria Medica.
Methyl 3-amino-4-hydroxybenzoate (8)
To a solution of 7 (3.1 kg, 20 mol) in MeOH (25 L) was added SOCl2 (1.5 L, 21 mol) at 5 oC with stirring and allowed to reflux at 65 oC for 8 h. Excess MeOH and SOCl2 were distilled off, and the crude products were dissolved in EtOAc (8 L). The organic layer was washed with 5% aqueous NaHCO3 solution, water, brine and dried. Filtration followed by evaporation of the solvent in vacuo afforded 3.2 kg of 8 as a pale solid, yield 95%, mp 110 oC. 1H NMR (300MHz, DMSO-d6): δ 3.75 (s, 3H), 4.78 (br s, 2H), 6.72 (d, J = 8.2 Hz, 1H), 7.10 (dd, J = 2.1, 8.2 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 11.70 (br s, 1H). ESI-MS (m/z) 168 [M + H]+.
Methyl 3-acetamido-4-hydroxybenzoate (9)
To a stirred solution of 8 (3 kg, 18 mol) in AcOH (15 L) was added acetic anhydride (2.6 L, 27 mol) at 60 oC, and the mixture was stirred at this temperature for 3 h. The mixture was poured to chilled water (35 L) over 1h. The resulting white solid was filtered, washed with water and dried to give 3.5 kg of pure product 9 as a white powder, yield 92%, mp 181-183 °C. 1H NMR (300 MHZ, DMSO-d6): δ 2.10 (s, 3H), 3.78 (s, 3H), 6.91 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 2.0, 8.4 Hz, 1H), 8.45 (s, 1H), 9.35 (s, 1H), 10.82 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 23.7, 51.5, 114.9, 120.0, 123.3, 126.5, 126.6, 152.3, 166.0, 169.2. ESI-MS (m/z) 210 [M + H]+.
Methyl 3-acetamido-4-ethoxybenzoate (10)
To a stirred suspension of 9 (3.5 kg, 16.7 mol) and K2CO3 (3.5 kg, 25 mol) in DMF (25 L) was added bromoethane (1.9 L, 25 mol) at 60 oC, and the mixture was stirred at this temperature for 6 h. The mixture was poured to chilled water (40 L). The resulting white solid was filtered, washed with water and dried to provide 3.8 kg of 10 as a white powder, yield 96%, mp 153-155 oC. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J = 6.9 Hz, 3H), 2.20 (s, 3H), 3.90 (s, 3H), 4.25 (q, J = 6.9 Hz, 2H), 6.95 (d, J = 8.4 Hz, 1H), 7.75 (br s, 1H), 7.80 (dd, J = 2.0, 8.4 Hz, 1H), 9.05 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 14.7, 24.8, 51.8, 64.3, 109.8, 120.7, 122.6, 126.0, 127.1, 150.8, 166.6, 168.1. ESI-MS (m/z) 238 [M + H]+.
3-Acetamido-4-ethoxybenzoic acid (11)
To a stirred solution of 10 (3.8 kg, 16 mol) in MeOH (30 L) was added aqueous NaOH solution (1 M, 16 L, 16 mol) at room temperature, and the resulting solution was stirred at this temperature for 5 h. Excess MeOH was distilled off, and the residue was dissolved in water, acidified with conc. HCl (1.3 L) to pH 2-3 at room temperature. The resulting precipitate was collected by suction filtration, washed with water, dried under reduced pressure to yield 3.4 kg of 11 as a white powder, yield 96%, mp 188-190 °C. 1H NMR (300 MHz, DMSO-d6): δ 1.50 (t, J = 7.3 Hz, 3H), 2.15 (s, 3H), 4.20 (q, J = 7.3 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 7.65 (dd, J = 1.4, 8.5 Hz, 1H), 8.55 (s, 1H), 9.10 (s, 1H), 12.65 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 14.4, 23.8, 64.2, 111.6, 122.4, 123.0, 126.0, 127.1, 152.2, 166.9, 168.4. ESI-MS (m/z) 222 [M - H]-.
5-Acetamido-4-ethoxy-2-nitrobenzoic acid (12)
To a stirred solution of 11 (3.3 kg, 15 mol) in AcOH (18 L) was added fuming nitric acid (1.8 L, 39 mol) at 25-35 °C. The resulting solution was stirred at this temperature for 6 h and diluted with chilled water (45 L). The resulting precipitate was collected by suction filtration, washed with water, dried under reduced pressure to provide 3.4 kg of 12 as a slightly brown solid, yield 85%, mp 234-236 °C. 1H NMR (300 MHz, DMSO-d6): δ 1.40 (t, J = 6.9 Hz, 3H), 2.15 (s, 3H), 4.25 (q, J = 6.9 Hz, 2H), 7.60 (s, 1H), 8.55 (s, 1H), 9.40 (s, 1H), 13.25 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 14.1, 24.1, 65.3, 107.4, 119.0, 120.9, 131.1, 144.2, 149.6, 165.6, 169.5. ESI-MS (m/z) 267 [M - H]-. Anal. Calcd for C11H12N2O6: C, 49.26; H, 4.51; N, 10.44. Found: C, 49.25; H, 4.58; N, 10.54.
Ethyl 3-(5-acetamido-4-ethoxy-2-nitrophenyl)-2-cyano-3-oxopropanoate (13)
A mixture of 12 (3.5 kg, 13.0 mol) and SOCl2 (15 L) was stirred and heated at around 50 oC for 1 h to form a homogeneous solution. The solvent was recovered and the residue was azeotroped once with 5 L CH2Cl2 to provide 5-acetamido-4-ethoxy-2-nitrobenzoyl chloride. A suspension of NaOMe (0.75 kg, 11.0 mol) in MeOH (20 L) was stirred at 40–50 oC for 1 h to get a solution firstly, and ethyl cyanoacetate (1.4 L, 13.1 mol) was added dropwise over 1 h. The resulting white suspension was cooled below 0oC in an ice-salt bath and treated with 5-acetamido-4-ethoxy-2-nitrobenzoyl chloride (2.8 kg, 10.4mol) in THF (12 L) over 2 h, keeping the reaction temperature below 8 oC. To the mixture was then added chilled water (80 L), acidified to pH 2–3 with conc. HCl. The resulting solid was collected by suction filtration, washed with water, and dried under reduced pressure to give 3.2 kg of 13 as pale powders, yield 89% (from 12), mp 169–171 oC. 1H NMR (300 MHZ, DMSO-d6): δ 0.98 (t, J = 6.9 Hz, 3H), 1.44 (t, J = 6.9 Hz, 3H), 2.19 (s, 3H), 3.85 (q, J = 6.9 Hz, 2H), 4.30 (q, J = 6.9 Hz, 2H), 7.77 (s, 1H), 8.15 (s, 1H), 9.50 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 13.9, 14.2, 24.3, 59.7, 65.2, 80.1, 107.2, 116.7, 118.9, 125.7, 133.5, 140.1, 147.8, 163.5, 169.8, 181.6. ESI-MS (m/z) 362 [M – H]-. Anal. Calcd for C16H17N3O7: C, 52.89; H, 4.72; N, 11.57. Found: C, 52.86; H, 4.74; N, 11.73.
N-[5-(2-Cyanoacetyl)-2-ethoxy-4-nitrophenyl]acetamide (14)
A mixture of 13 (3.0 kg, 8.2 mol), DMSO (15 L) and water (0.3 L) was heated at 100–110 °C for 30 min. Then the solution was cooled to around 50 °C and diluted with chilled water (60 L). The resulting precipitate was collected by suction filtration, washed with EtOAc, dried under reduced pressure to provide 1.9 kg of 14 as a pale yellow solid, yield 84%, mp 171–175 °C (dec.). IR: 3320, 2273, 1720, 1500 cm-1. 1H NMR (300 MHz, CDCl3): δ 1.56 (t, J = 5.4 Hz, 3H), 2.28 (s, 3H), 3.86 (s, 2H), 4.28 (q, J = 5.4 Hz, 2H), 7.88 (s, 1H), 8.01 (br s, 1H), 8.58 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 14.1, 24.2, 32.3, 65.4, 107.4, 115.3, 118.5, 126.9, 133.4, 140.5, 149.2, 169.7, 191.3. ESI-MS (m/z) 290 [M – H]-. HRMS (ESI): Calcd for C13H13N3O5Na: 314.0753. Found: 314.0773. Anal. Calcd for C13H13N3O5: C, 53.61; H, 4.50; N, 14.43. Found: C, 53.35; H, 4.52; N, 14.20.
N-{5-[2-Cyano-3-(N,N-dimethylamino)acryloyl]-2-ethoxy-4-nitrophenyl}acetamide (15)
To a stirred suspension of 14 (0.7 kg, 2.0 mol) in DME (6 L) was added DMF-DMA (0.4 L, 3.0 mol). The mixture was stirred at room temperature for 1 h. The resulting solid was collected by suction filtration, washed with EtOAc, and dried under reduced pressure to give 0.63 kg of 15 as a bright-yellow powder, yield 91%, mp 258–260 °C. 1H NMR (300 MHz, DMSO-d6): δ 1.43 (t, J = 6.9 Hz, 3H), 2.19 (s, 3H), 3.28 (br s, 3H), 3.32 (s, 3H), 4.29 (q, J = 6.9 Hz, 2H), 7.73 (s, 1H), 7.88 (br s, 1H), 8.26 (s, 1H), 9.51 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 14.2, 24.3, 38.7, 47.5, 65.1, 107.3, 118.3, 133.4, 140.2, 147.6, 157.8, 169.8. ESI-MS (m/z): 345 [M – H]-. Anal. Calcd for C16H18N4O5: C, 55.49; H, 5.24; N, 16.18. Found: C, 55.20; H, 5.12; N, 15.93.
N-(3-Cyano-7-ethoxy-4-oxo-1,4-dihydroquinolin-6-yl)acetamide (1)
To a mixture of 15 (0.52 kg, 1.5 mol) and zinc powder (0.6 kg, 9.0 mol) in water (5 L) and EtOH (5 L) was added AcOH (0.13 L, 2.3 mol). The suspension was refluxed with stirring for 12 h. The mixture was cooled to about 40 °C, then NaOH (0.18 kg, 4.5mol) was added and the solution was stirred at 40–50 °C for another 30 min. The resulting solution was filtered, and the filtrate was acidified with conc. HCl to pH 2–3 at 40–50 °C. The resulting precipitate was collected by suction filtration, washed with EtOH, dried under reduced pressure to give 0.35 kg of 1 as a pale solid, yield 85%, mp > 300 °C. 1H NMR (300 MHz, DMSO-d6): δ 1.45 (t, J = 6.6 Hz, 3H), 2.14 (s, 3H), 4.20 (q, J = 6.6 Hz, 2H), 7.05 (s, 1H), 8.59 (d, J = 6.3 Hz, 1H), 8.70 (s, 1H), 9.18 (s, 1H), 12.52 (d, J = 6.3 Hz, 1H). ESI-MS (m/z) 270 [M – H]-.

References

1. S. Kamath and J. K. Buolamwini, Med. Res. Rev., 2006, 26, 569. CrossRef
2. M. Foley and L. Tilley, Pharmacol. Ther., 1998, 79, 55. CrossRef
3. L. A. Mitscher, Chem. Rev., 2005, 105, 559. CrossRef
4. M. Llinas-Brunet, M. D. Bailey, E. Ghiro, V. Gorys, T. Halmos, M. Poirier, J. Rancourt, and N. Goudreau, J. Med. Chem., 2004, 47, 6584. CrossRef
5. C. A. Leach, T. H. Brown, R. J. Ife, D. J. Keeling, M. E. Parsons, C. J. Theobald, and K. J. Wiggald, J. Med. Chem., 1995, 38, 2748. CrossRef
6. (a) A. Wissner, E. Overbeek, M. F. Reich, M. B. Floyd, B. D. Johnson, N. Mamuya, E. C. Rosfjord, C. Discafani, R. Davis, X. Shi, S. K. Rabindran, B. C. Gruber, F. Ye, W. A. Hallett, R. Nilakantan, R. Shen, Y. F. Wang, L. M. Greenberger, and H. R. Tsou, J. Med. Chem., 2003, 46, 49; CrossRef (b) H. R. Tsou, E. G. Overbeek-Klumpers, W. A. Hallett, M. F. Reich, M. B. Floyd, B. D. Johnson, R. S. Michalak, R. Nilakantan, C. Discafani, J. Golas, S. K. Rabindran, R. Shen, X. Shi, Y. F. Wang, J. Upeslacis, and A. Wissner, J. Med. Chem., 2005, 48, 1107; CrossRef (c) D. H. Boschelli, B. Wu, F. Ye, Y. Wang, J. M. Golas, J. Lucas, and F. Boschelli, J. Med. Chem., 2006, 49, 7868. CrossRef
7. (a) A. Wissner, S. K. Rabindran, and H. R. Tsou, PCT Int. Appl. Patent 2005, WO 034955 (Chem. Abstr., 2005, 142, 411245); (b) W. Chew, G. K. Cheal, and J. F. Lunetta, PCT Int. Appl. Patent 2006, WO 127207 (Chem. Abstr., 2006, 146, 27735); (c) R. G. Gould and W. A. Jacobs, J. Am. Chem. Soc., 1939, 61, 2890. CrossRef
8. R. J. Atkins, G. F. Breen, L. P. Crawford, T. J. Grinter, M. A. Harris, J. F. Hayes, C. J. Moores, R. N. Saunders, A. C. Share, T. C. Walsgrove, and C. Wicks, Org. Process Res. Dev., 1997, 1, 185. CrossRef
9. J. Tois, M. Vahermo, and A. Koskinen, Tetrahedron Lett., 2005, 46, 735. CrossRef
10. Y. Mao, J. Li, Kai Xie, H. Li, R. Zhang, H. Duan, H. Guo, and J. Shen, PCT Int. Appl. Patent 2009, WO 149622 (Chem. Abstr., 2009, 152, 74720).
11. A. Wissner, H. R. Tsou, M. B. Floyd, B. D. Johnson, and E. G. Overbeek-Klumpers, PCT Int. Appl. Patent 2003, WO 050090 (Chem. Abstr., 2003, 139, 36453); (b) H. O. Bayer, C. Swithenbank, and R. Y. Yih, U.S. Pat. Appl. Publ. 1977, US 4046798 (Chem. Abstr., 1977, 87, 201082).