Preparation of ethyl 2,2′-bipyridyl-5-carboxylate_Industrial additives

Preparation background and overview of ethyl 2,2′-bipyridine-5-carboxylate

Ethyl 2,2′-bipyridine-5-carboxylate is an organic intermediate that can be prepared through a four-step reaction using 2-acetylpyridine as the starting material.

Preparation of ethyl 2,2′-bipyridine-5-carboxylate

Preparation of ethyl 2,2′-bipyridine-5-carboxylate Step 1, 1-[2-oxo-2-(2-pyridyl)ethyl]pyridinium iodide (4) Preparation

Prepare a solution of iodine (7.1g, 28.0mmol) and 2-acetylpyridine (2.8mL, 25.0mmol) in pyridine (30mL) in a reaction flask equipped with a condenser and drying tube, and place the reaction mixture Stir at 90°C for 6h. At this point, the resulting suspension was filtered and the residue was refluxed in EtOH (300 mL) with activated carbon (3.0 g) for 4 h. The suspension was then filtered while hot, and the filtrate was concentrated under reduced pressure to obtain crude product 4. The crude product was recrystallized from saturated EtOH solution to purify 4 as a yellow solid (6.3 g, 65%). ¹HNMR (DMSO, MHz): δ6.50 (2H, s), 7.82-7.85 (1H, m), 8.08 (1H, d, J=7.7Hz), 8.14 (1H, td , J=7.5, 1.7Hz)), 8.27 (2H, t, J=6.2Hz), 8.73 (1H, t, J=7.8Hz), 8.87 (1H, d, J=3.7Hz), 9.00 (2H, d, J=5.5Hz). ¹³CNMR (DMSO, 75MHz): δ67.57, 122.96, 128.63, 130.05, 139.07, 147.22, 147.26, 150.48, 151.37, 192.38.

Preparation of 2,2′-bipyridyl-5-carboxylic acid ethyl ester, step 2, preparation of 5-methyl-2,2′-bipyridine (5)

Methacrolein (1.8mL, 22.0mmol) and NH₄OAc (9.3g, 120.0mmol) were added successively to a solution of 4 (6.5g, 20mmol) in formamide (200mL) middle. The mixture was stirred at 80°C for 16 hours. At this point, the crude mixture was cooled and extracted with diethyl ether (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (5% MeOH in CH₂Cl₂) to afford 5 (3.7 g, 98%) as a brown oil. ¹HNMR (CDCl₃, 300MHz): δ2.31 (3H, s), 7.26-7.30 (1H, m), 7.63 (1H, dd, J=8.1 , 2.0Hz), 7.80 (1H, td, J=8.1, 1.7Hz), 8.28 (1H, d, J=8.1Hz), 8.36 (1H, d, J=8.4Hz), 8.51 (1H, s), 8.67 (1H, d, J=4.7Hz). ¹³CNMR (CDCl₃, 75MHz): δ18.17, 120.46, 120.65, 123.22, 133.26, 136.69, 137.29, 148.95, 149.48, 153.48, 156.14. HREI-MS calculated for C11H10N2: 170.0844. The measured value is 170.0839.

Preparation of ethyl 2,2′-bipyridyl-5-carboxylate Step 3, preparation of 2,2′-bipyridyl-5-carboxylic acid (6)

Potassium permanganate (12.3g, 78mmol) was added to a solution of 5 (3.4g, 20mmol) in water (200mL) in 7 portions every 1 hour. The mixture was heated at 70°C for 3 hours and then at 90°C for a further 4 hours. The brown mixture was then filtered through Celite while hot and washed with hot water (2 × 25 mL). The filtrate was concentrated under reduced pressure to approximately 10 mL, then 1 M HCl was slowly added until a pH of 4 was obtained. The residue was then filtered and dried to obtain pure product 6 as a white solid (3.2 g, 80%). ¹HNMR (DMSO, 300MHz): δ7.48-7.53 (1H, m), 7.99 (1H, t, J=7.7Hz), 8.38-8.51 (3H, m), 8.73 (1H , d, J=4.3Hz)), 9.16 (1H, d, J=1.2Hz). ¹³CNMR (DMSO, 75MHz): δ119.64, 120.70, 124.36, 126.63, 136.97, 137.63, 149.01, 149.61, 153.76, 157.64, 165≅ Calculated value of HREI-MSC11H8N2O2: 200.058 6. Actual measurement: 200.0583.

Preparation of 2,2′-bipyridyl-5-carboxylic acid ethyl ester Step 4, preparation of 2,2′-bipyridyl-5-carboxylic acid ethyl ester (7)

P-Toluenesulfonic acid (11.4g, 60mmol) was added to a solution of 6 (2.4g, 12mmol) in ethanol (50mL). The reaction mixture was stirred at ambient temperature for 18 hours. At this time, the mixture was concentrated under reduced pressure, and NaHCO₃ solution was added to the mixture until a solution having a pH of di-tert-butylpyridine 8 was obtained. The crude product was then extracted with ethyl acetate (3 x 100 mL) and the combined organic portions were washed with brine (150 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. Column chromatography of the crude product (5% MeOH in CHCl) afforded 7 as a white solid (2.3 g, 84%). ¹HNMR (CDCl₃, 300MHz): δ1.44 (3H, t, J=7.1Hz), 4.44 (2H, q, J=7.1Hz), 7.35 -7.38 (1H, m), 7.86 (1H, td, J=7.7, 1.8Hz), 8.41 (1H, dd, J=8.3, 2.1Hz), 8.49 (2H, t, J=8.1Hz), 8.71- 8.72 (1H, m), 9.28 (1H, dd, J=2.1, 0.8Hz). ¹³CNMR (CDCl₃, 75MHz): delta boric acid 14.31, 61.42, 120.49, 121.90, 124.45, 125.98, 137.06, 137.97, 149.39, 150.53, 155.18, 159.41, 165.38 . HREI-MS calculated for C13H12N2O2: 228.0899. Actual measurement: 228.0898.

References

[1]From Journal of Combinatorial Chemistry,9(1),115-120;2007