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With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.666667 h;
Step C methyl 5-bromo-3-methylpyridine-2-carboxylate To a solution 5-bromo-3-methylpyridine-2-carboxylic acid (2.6 g, 12 mmol) in N,N-dimethylformamide (20.0 mL) was added potassium carbonate (4.99 g, 36.1 mmol) and methyl iodide (1.50 mL, 24.1 mmol) and the reaction was stirred 80° C. for 40 min. The reaction mixture was partitioned with EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.3 g (83percent yield) of the desired product as a yellow solid.
82%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 0.666667 h;
Example 11.1: methyl S-bromo-S-metliylpyridine-Z-carboxylateO; To a solution of 5-bromo-3-methylpyridine-2-carboxylic acid (450 mg, 2.08 mmol) in dimethylformamide (2 mL) was added potassium carbonate (862 mg, 6.24 mmol) and iodomethane (739 mg, 5.21 mmol) and the reaction was stirred at 80 0C for 40 min. The reaction mixture was partitioned with ethyl acetate and water and the organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to afford the product as a yellow solid (380 mg, 82percent). 1H NMR (300 MHz, CDCl3): δ 8.91 (s, IH), 7.86 (s, IH), 3.98 (s, 3H), 2.60 (s, 3H).
To a mixture of 5-bromo-3-methylpicolinic acid (600 mg, 2.8 mmol) in MeOH (10 mL) was added 50C12 (397 mg, 3.3 mmol). The mixture was stirred at reflux temperature for 6 hours. LCMS showed the reaction was complete. The reaction mixture was evaporated in vacuo to afford methyl 5-bromo-3-methylpicolinate (640 mg, 99percent yield), m/z = 229.76(M+H), as an off-white solid.
With water; sodium hydroxide In ethanol at 80℃; for 1.5 h;
Step B 5-bromo-3-methylpyridine-2-carboxylic acid To a solution of 5-bromo-3-methylpyridine-2-carbonitrile (3.9 g, 20 mmol) in ethanol (30 mL) was added 6.0 M sodium hydroxide in water (15 mL), and the reaction was stirred at 80° C. for 1.5 h. The reaction mixture was concentrated, diluted with water and partitioned in EtOAc. The aqueous phase was acidified to pH 2-3. The product then was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated to give 4.2 g (98percent yield) of the desired product as a yellow solid.
98%
Stage #1: at 80℃; for 1.5 h; Stage #2: Acidic aqueous solution
Example 10.1: 5-bromo-3-methylpyridine-2-carboxylic acid; To a suspension of 5-bromo-3-methylpyridine-2-carbonitrile (1.22 g, 7.21 mmol) in ethanol (10 mL) was added 6N sodium hydroxide (5 mL) and the reaction was stirred at 80 <n="35"/>0C for 1.5 h. The organic was concentrated and the reaction mixture was dilute with water and partitioned in ethyl acetate. The aqueous phase was acidified to pH 2-3. The product was extracted with ethyl acetate, washed with brine, dried over sodium sulphate, filtered and concentrated to afford the product as a yellow solid (185 mg, 98percent). 5H NMR (300 MHz, CDCl3): δ 8.54 (bs, IH), 7.90 (s, IH), 2.76 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.666667h;
Step C methyl 5-bromo-3-methylpyridine-2-carboxylate To a solution 5-bromo-3-methylpyridine-2-carboxylic acid (2.6 g, 12 mmol) in N,N-dimethylformamide (20.0 mL) was added potassium carbonate (4.99 g, 36.1 mmol) and methyl iodide (1.50 mL, 24.1 mmol) and the reaction was stirred 80 C. for 40 min. The reaction mixture was partitioned with EtOAc and water. The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 2.3 g (83% yield) of the desired product as a yellow solid.
82%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.666667h;
Example 11.1: methyl S-bromo-S-metliylpyridine-Z-carboxylateO; To a solution of 5-bromo-3-methylpyridine-2-carboxylic acid (450 mg, 2.08 mmol) in dimethylformamide (2 mL) was added potassium carbonate (862 mg, 6.24 mmol) and iodomethane (739 mg, 5.21 mmol) and the reaction was stirred at 80 0C for 40 min. The reaction mixture was partitioned with ethyl acetate and water and the organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated to afford the product as a yellow solid (380 mg, 82%). 1H NMR (300 MHz, CDCl3): delta 8.91 (s, IH), 7.86 (s, IH), 3.98 (s, 3H), 2.60 (s, 3H).
(i) Methyl 5-bromo-3-methylpicolinateSulfuric acid (0.025 mL) was added to 5-bromo-3-methylpicolinic acid (1 g) in methanol (20 mL) at 20C under an atmosphere of nitrogen. The resulting solution was stirred at reflux for 19 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The combined organic phases was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (1.019 g).1H NMR (500 MHz, DMSO) delta 8.62 (s, 1H), 8.16 (s, 1H), 3.86 (s, 3H), 2.46 (s, 3H). m/e (APCI+) 232 [M+H]+
With thionyl chloride; at 20 - 90℃; for 4h;
Methyl 5-bromo-3-methylpicolinate (B35.1) (0467) To a solution of 5-bromo-3-methylpicolinic acid (500 mg, 2.31 mmol) in MeOH (10 mL) was added SOCl2 (275 mg, 23.1 mmol) at rt. Then the reaction mixture was stirred at 90 C. for 4 h. The solvent was removed to give the title compound (500 mg, 94%) as a off white solid. The crude product was used in the next step without further purification. LC-MS: [M+H]+=232.0.
With thionyl chloride; at 90℃; for 4h;
To a solution of 5-bromo-3- methylpicolinic acid (500 mg, 2.31 mmol) in MeOH (10 mL) was added SOd2 (275 mg, 23.1 mmol) at rt. Then the reaction mixture was stirred at 90 C for 4 h. The solvent was removed to give the title compound (500 mg, 94%) as a off white solid. The crude product was used in the next step without further purification. LC-MS: [M+H] = 232.0.
O.144.b b)
b) 5-Bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl ester To a stirred pale yellow solution of 5-bromo-3-methylpyridine-2-carboxylic acid (20 g, 92.6 mmol), DMAP (0.57 g, 4.6 mmol) in DMF (120 mL) was added Boc anhydride (20.2 g, 92.6 mmol) at ambient temperature. The reaction mixture was stirred at 35~40° C. for 2 h before addition of another portion of Boc anhydride (20.2 g, 92.6 mmol). The reaction was stirred at 35~40° C. for another 16 h to achieve full conversion to the title compound, which was used directly in the following step without further purification. ESIMS: 272 [(M+H)+].
With dmap In N,N-dimethyl-formamide
O.144.m m)
m) 5-Bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl ester To the stirred pale yellow solution of 5-bromo-3-methylpyridine-2-carboxylic acid (20 g, 92.6 mmol), DMAP (0.57 g, 4.6 mmol) in DMF (120 mL) was added Boc anhydride (20.2 g, 92.6 mmol) at ambient temperature. The reaction mixture was stirred at 35~40° C. for 2 h before addition of another portion of Boc anhydride (20.2 g, 92.6 mmol). The reaction was stirred at 35~40° C. for another 16 h to achieve full conversion to the title compound, which was used directly in the following step without further purification. ESIMS: 272 [(M+H)+].
37.1 Synthesis of tert-butyl 5-bromo-3-methylpicolinate
To a 50-mL round-bottomed flask were added 5-bromo-3-methylpicolinic acid (7.95 g, 36.8 mmol) and di-tert-butyl dicarbonate (16.6 g, 73.6 mmol) in THF (73 ml) followed by addition of 4-(dimethylamino)pyridine (0.450 g, 3.68 mmol). It was stirred at RT for 3 h. It was quenched with sat. NaHCO3 and extracted with EtOAc (3×80 ml). The organic phase was then washed with sat. NaHCO3 again, and washed with brine and dried over MgSO4. The solution was filtered and concentrated in to give the crude material as a yellow oil. The crude material was purified by silica gel chromatography eluting with a gradient of 10% to 20% to 30% (40% EtOAc in Heptane) in Heptane, to provide tert-butyl 5-bromo-3-methylpicolinate (9.81 g, 36.0 mmol, 98% yield) as clear colorless oil. MS m/z=294.0/296.1 (M+Na)
With dmap In tetrahydrofuran at 20℃; for 2h;
13.a
Acid 13: 5-cyano-3-methyl-pyridine-2-carboxylic acid; a) 5-Bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl ester; To a solution of 10.20 g (47.2 mmol) 5-bromo-3-methyl-pyridine-2-carboxylic acid and 20.61 g (94 mmol) di-tert-butyldicarbonate in 100 ml THF were added 0.577 g DMAP. Evolution of C02 started immediately and the mixture was stirred for 2 h at RT. TBME and sat aqNaHC03 were added. The layers were separated and the organic layer washed with sat aq NaHC03 and brine, and dried with MgS04.H20. Chromatography on silica gel (hexanes/ EtOAc 1-7%) provided the title compound as a yellow liquid.HPLC: RtH3= 3.018 min; ESIMS [M+H]+ = 272, 274 (1 Br); 1 H-NMR (360 MHz, CDCI3): δ 8.59 s, 1 H), 7.77 (s, 1 H), 2.52 (s, 3H), 1.65 (s, 9H).
With dmap In tetrahydrofuran at 20℃; for 2h;
1.a
a) 5-Bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl esterTo a solution of 5-bromo-3-methyl-pyridine-2-carboxylic acid (10.20 g, 47.2 mmol) and di-tert-butyldicarbonate (20.61 g, 94 mmol) in 100 ml THF were added DMAP (0.577 g). Evolution of CO2 started immediately and the mixture was stirred for 2 h at rt. TBME and sat aq NaHCO3 were added. The layers were separated and the organic layer washed with sat aq NaHCO3 and brine, and dried with MgSO4.H2O. Chromatography on silica gel (hexanes/EtOAc 1-7%) provided the title compound as a yellow liquid.HPLC: RtH3=3.018 min; ESIMS [M+H]+=272, 274 (1 Br); 1H-NMR (360 MHz, CDCl3): δ 8.59 s, 1H), 7.77 (s, 1H), 2.52 (s, 3H), 1.65 (s, 9H).
With thionyl chloride; In methanol; for 6h;Reflux;
To a mixture of 5-bromo-3-methylpicolinic acid (600 mg, 2.8 mmol) in MeOH (10 mL) was added 50C12 (397 mg, 3.3 mmol). The mixture was stirred at reflux temperature for 6 hours. LCMS showed the reaction was complete. The reaction mixture was evaporated in vacuo to afford methyl 5-bromo-3-methylpicolinate (640 mg, 99% yield), m/z = 229.76(M+H), as an off-white solid.
To a solution of compound 7 (4.9 g, 22.68 mmol) in C2H5OH(20 mL) was added H2SO4 (2.2 g, 22.68 mmol) at room temperature.The mixture was heated at 80 C for 8 h. Solvent was concentrated invacuo and EtOAc (200 mL) was added. After washed with water(100 mL×3), the organic phase was dried over Na2SO4, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, petroleum ether/EtOAc=20/1) to affordethyl 5-bromo-3-methylpicolinate (8, 4.6 g, 83%) as colorless liquid. 1HNMR (300 MHz, DMSO-d6) delta (ppm): 8.62 (s, 1H), 8.14 (s, 1H), 4.34 (q,J=7.1 Hz, 2H), 2.45 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
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