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Synlett 2011(2): 203-206  
DOI: 10.1055/s-0030-1259283
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

First Synthesis of Methyl 2-Amino-6-Methoxynicotinate Using a Combination of Microwave and Flow Reaction Technologies

Gyorgy Jegesa, Tamas Meszarosa, Tamas Szommera, Jozsef Kovacsa, Tamas Nagya,, Dmytro Tymoshenko*b, Nader Fotouhic, Paul Gillespiec, Agnieszka Kowalczykc, Robert A. Goodnow Jr.c
a AMRI Hungary, Zahony u. 7, 1031 Budapest, Hungary
b AMRI, 26 Corporate Circle, Albany, NY 12203, USA
c Roche Research Center, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 0711, USA
e-Mail: dmytro.tymoshenko@amriglobal.com;
Further Information

Publication History

Received 30 August 2010
Publication Date:
23 December 2010 (online)

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Abstract

The synthesis of methyl 2-amino-6-methoxynicotinate, a valuable building block for the preparation of fused 2-pyridones, is reported. The optimized synthesis includes sequential microwave-induced regioselective 6-methoxylation, esterification, followed by microwave-induced reaction with p-methoxybenzylamine, and final deprotection under flow reaction hydrogenation conditions. Two key steps in the reported synthesis are a microwave-induced methoxylation and a microfluidic hydrogenation that afford improved regioselectivity and purity profile of the reaction products.

Key words

2-pyridone - microwave - microfluidic reaction - cyclization - hydrogenation

    References and Notes

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1

Current address: EGIS Gyógyszergyár Nyrt., Keresztúri út 30-38, 1106 Budapest, Hungary

21

Experimental Procedures for the Preparation of Methyl 2-Amino-6-methoxynicotinate (4) and Fused Pyrimidines 14 and 15
Procedures and analytical data for 2-chloro-6-methoxynicotinic acid (6) and methyl 2-chloro-6-methoxynicotinate (9), as well as methyl 2-[3-(ethoxycarbonyl)thioureido]-6-methoxynicotinate (14) and 7-methoxy-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4 (1H)-one (15) can be found in the Supporting Information. Methyl 6-Methoxy-2-(benzylamino)nicotinates 13a,b A 100 mL Milestone microwave reaction vessel was charged with crude methyl 2-chloro-6-methoxynicotinate (9, 6.50 g, 32.2 mmol), 1,4-dioxane (128 mL), and benzylamine or 4-methoxybenzylamine (0.32 mol, 10 equiv). The vessel was capped and the reaction mixture was microwave irradiated at 170 ˚C for 2 h using a Milestone MicroSYNTH T640 Microwave instrument. The vessel was cooled to r.t. and the reaction mixture concentrated to dryness under reduced pressure. The residue obtained was purified by column chromatography on silica with hexanes-EtOAc eluent by gradient method from 4:1 to 1:1. The fractions were concentrated under reduced pressure and the residue was triturated with diethyl ether to afford compounds 13a,b.
Methyl 6-Methoxy-2-(benzylamino)nicotinate (13a)
Yield 45%. ¹H NMR (400 MHz, CDCl3): δ = 8.51 (br s, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.23 (t, J = 7.5 Hz, 1 H), 5.95 (d, J = 8.5 Hz, 1 H), 4.73 (d, J = 5.8 Hz, 2 H), 3.85 (s, 3 H), 3.81 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 168.0, 166.5, 158.8, 142.3, 139.9, 128.4, 127.4, 126.9, 98.0, 97.8, 53.4, 51.3, 44.8. ESI-HRMS: m/z calcd for C15H16N2O3 [M + H]+: 273.1234; found: 273.1234. Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C, 66.40; H, 5.98; N, 10.14.
Methyl 6-Methoxy-2-(4-methoxybenzylamino)-nicotinates (13b)
Yield 67%. ¹H NMR (300 MHz, CDCl3): δ = 8.43 (br s, 1 H), 7.98 (d, J = 8.5 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 5.95 (d, J = 8.5 Hz, 1 H), 4.66 (d, J = 5.7 Hz, 2 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.79 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 168.0, 166.5, 158.7, 158.6, 142.3, 131.9, 128.7, 113.9, 97.9, 97.7, 55.3, 53.4, 51.3, 44.3. ESI-HRMS: m/z calcd for C16H18N2O4 [M + H]+: 303.1340; found: 303.1339. Anal. Calcd for C16H18N2O4: C, 63.57; H, 6.00; N, 9.27. Found: C, 63.85; H, 6.02; N, 9.37.
Methyl 2-Amino-6-methoxynicotinate (4) A solution of methyl 6-methoxy-2-(4-methoxybenzylamino) nicotinate (4.0 g, 13.23 mmol) in EtOH (25 mL) was hydrogenated in an H-Cube instrument over a 70 mm 10% Pd/C CatCart column under full hydrogenation mode (ref. 18) and column temperature 70 ˚C. The solvent was removed under reduced pressure to afford 2.3 g (95%) of the title compound. ¹H NMR (300 MHz, DMSO-d 6): δ = 7.93 (d, J = 8.5 Hz, 1 H), 7.27 (br s, 2 H), 6.01 (d, J = 8.5 Hz, 1 H), 3.82 (s, 3 H), 3.76 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d 6): δ = 167.6, 166.6, 159.7, 142.2, 99.7, 98.3, 53.5, 51.4. ESI-HRMS: m/z calcd for C8H10N2O3 [M + H]+: 183.0764; found: 183.0764.