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

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.

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

References and Notes

1

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

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For recent examples of cyclization based on 2-amino-nicotinic acid, see:

10a 1,8-Naphthyridin-4(1H)-ones: Bilokin MD. Yushchenko DA. Pivovarenko OV. Pivovarenko VG. Ukr. Bioorg. Acta  2008,  6:  13 

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10c 4-Chloropyrido[2,3-d]pyrimidine: Echeverria M. Mendivil B. Cordeu L. Cubedo E. Garcia-Foncillas J. Font M. Sanmartin C. Palop JA. Arch. Pharm. (Weinheim, Ger.)  2006,  339:  182 

10d 3-Benzimidazolo-2-pyridinamine and 1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine: Bamford MJ. Alberti MJ. Bailey N. Davies S. Dean DK. Gaiba A. Garland S. Harling JD. Jung DK. Panchal TA. Parr CA. Steadman JG. Takle AK. Townsend JT. Wilson DM. Witherington J. Bioorg. Med. Chem. Lett.  2005,  15:  3402 

10e 1H-Pyrido[2,3-b]azepine-5,8-dione: Kunick C. Lauenroth K. Wieking K. Xie X. Schultz C. Gussio R. Zaharevitz D. Leost M. Meijer L. Weber A. Jorgensen FS. Lemcke T. J. Med. Chem.  2004,  47:  22 

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11a Nakamoto K, Matsukura M, and Tanaka K. inventors; EP  1782811. Direct copper-catalyzed amination of 2,6-dichloro-nicotinic acid results in 4.5% of 2-amino-6-chloroderivative. Its further alcoholysis gives corresponding 6-ethoxy- and 6-isopropoxy-2-aminonicotinic acids:

11b Chen Q, Feng Y, Wang Z, Yue B, and Zhuang W. inventors; CN  1701031. Synthetic applications of the title compound were described recently without preparative details:

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Optimization experiments were performed using 0.05 M solutions of 13a,b in EtOH using a 30 mm 10% Pd/C CatCart^® cartridge. Two modes have been tested at the given temperatures:

18a

controlled mode, 30 bar, liquid flow rate 1 mL/min, hydrogen flow rate 2 N mL/min

18b

full hydro-genation mode, atmospheric pressure, liquid flow rate 1 mL/min, hydrogen flow rate 30 N mL/min.

Biological activities and medicinal applications have been reported for 2-mercaptopyrido[2,3-d]pyrimidin-4 (3H)-ones:

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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.