* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
5-bromo-6-methoxypicolinic acid: A suspension of 5-bromo-6-chloropicolinic acid (15.0 g, 63.4 mmol, 1.0 equiv.) in MeOH (130 mL) at ambient temperature was treated with a 4.37 M sodium methoxide solution in MeOH (58.0 mL, 253 mmol, 4.0 equiv.). The resultant mixture was heated at 80 °C for 18 hours, resulting in a thick mixture. The reaction was diluted with MeOH (100 mL) and stirred at 80 °C for 24 hours. The reaction mixture was cooled to ambient temperature, acidified to pH=3 with concentrated aqueous HC1, diluted with water and extracted with EtOAc (three times). The combined organic layers were dried over MgSO4, filtered and concentrated to afford a residue that was co-evaporated with DCM/hexanes (1:1 mixture, 200 mL, three times) to afford 5-bromo-6-methoxypicolinic acid (13.9 g, 94percent) as a white solid. ‘H NMR (500 MHz, CDC13) 5 10.22 (br s, 1H), 8.06 (d, I = 7.7 Hz, 1H), 7.73 (d, I = 7.7 Hz, 1H), 4.10 (s, 3H). LCMS (ES-) [M-Hj+: 229.9/23 1.9.
With sodium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 16 h;
To a solution of 5-bromo-6-methoxypicolinic acid (1) (1.0 g, 0.00431 mol) in DMF (10 mL, 10 vol), cooled to 0 °C was added Na2CO3 (456 mg, 0.00431 mol) and MeI (0.536 mL, 0.0086 mol) the mixture was stirred for16 h at room temperature. Water was added, extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (9:1-8:2) to give pure compound (2): Off white solid; yield: 94 percent, 1H NMR (500MHz, CDCl3) δ: 3.98 (s, 3H), 4.08 (s, 3H), 7.58 (d, 1H, Ar-H),7.98 (d, 1H, Ar-H): MS: m/z (percent) 247.6 [M+2], HPLC purity(99.52 percent).
Reference：
[1] Asian Journal of Chemistry, 2015, vol. 27, # 12, p. 4579 - 4582
[2] Letters in Organic Chemistry, 2016, vol. 13, # 4, p. 249 - 254
Step 3. Synthesis of ethyl 5-bromo-6-methoxypyridine-2-carboxylate (C16). para-Toluenesulfonic acid hydrate (roughly 0.3 g) was added to a solution of 5- bromo-6-methoxypyridine-2-carboxylic acid (C15) (12.2 g, 52.6 mmol) in ethanol (300 mL). The reaction mixture was heated at reflux for 48 hours, then concentrated in vacuo to provide the title product. Yield: 13.5 g, 51 .9 mmol, 99%.
97%
With chloro-trimethyl-silane; at 20℃; for 2h;
To a solution of <strong>[1214334-70-9]5-bromo-6-methoxypicolinic acid</strong> (1.03 g, 4.42 mmol) in ethanol (25 mL) trimethylsilyl chloride (3.84 g, 35.3 mmol) was added. The mixture was stirred at rt for 2 h before it was concentrated. The remaining residue was taken up in sat. aq. NaHCO3 solution and extracted three times with EA. The combined organic extracts were dried over MgSO4, filtered and concentrated and dried to give ethyl 5-bromo-6-methoxypicolinate 42 (1.12 g, 97%) as a white solid
With potassium permanganate; tert-butyl alcohol; In water; at 70℃; for 20h;
[0416] To a stirred solution of 3-bromo-2-methoxy-6-methylpyridine (11 g, 54 mmol) in tBuOH: water (1: 2, 900 mL) was added KMnO4 (8.6 g, 54 mmol) at room temperature. Thereaction mixture was stirred at 70 C for 2 h. Then another 1 eq of KMnO4 (8.6 g, 54 mmol) was added and stirred at 70 C for 2 h. Again 1 eq of KMnO4 (8.6 g, 54 mmol) was added and stirred at 70 C for 16 h. After consumption of starting material (by TLC), the reaction was diluted with 1 M HC1 solution (150 mL) and stirred for 30 mm, filtered and washed withEtOAc (2 x 200 mL). The filtrate was extracted with EtOAc (2 x 100 mL) and the combined organic extracts were basified with 0.5 N sodium hydroxide solution (2 x 200 mL). The organic layer was separated, aqeous layer was acidified with concentrated hydrochloric acid to pH 2 and extracted with CH2C12 (2 x 200 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 5-bromo-6-methoxypicolinic acid (6.4 g, 51%) as a white solid.
15%
With selenium(IV) oxide; In diphenyl ether-biphenyl eutectic; at 200℃; for 3h;
Step 2. Synthesis of 5-bromo-6-methoxypyridine-2-carboxylic acid (C15). Selenium dioxide (72.3 g, 0.696 mol) was added to a solution of 3-bromo-2- methoxy-6-methylpyridine (C14) (70.3 g, 0.348 mol) in Dowtherm (300 mL). The reaction mixture was heated at 200 C for 3 hours; after cooling to room temperature, the mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was extracted twice with a cold solution of aqueous potassium carbonate. The combined aqueous layers were acidified to pH 5, and the resulting precipitate was isolated by filtration to provide the title product. Yield: 12.2 g, 0.0526 mol, 15%.
N-(1H-benzo[d]imidazol-2-yl)-5-bromo-6-methoxypicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a solution of compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL), cooled to 0 C, was added compound 3 (255 mg, 0.0011 mol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,Ndiisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and the mixture was stirred for 16 h at ambient temperature. Water was added and extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (8:2-5:5) to give compound 4.
5-bromo-N-(5-fluoro-1H-benzo[d]imidazol-2-yl)-6-methoxypicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a solution of compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL), cooled to 0 C, was added compound 3 (255 mg, 0.0011 mol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,Ndiisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and the mixture was stirred for 16 h at ambient temperature. Water was added and extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (8:2-5:5) to give compound 4.
5-bromo-N-(4-fluorobenzo[d]thiazol-2-yl)-6-methoxypicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 16.0h;
General procedure: To a solution of compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL), cooled to 0 C, was added compound 3 (255 mg, 0.0011 mol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,Ndiisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and the mixture was stirred for 16 h at ambient temperature. Water was added and extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (8:2-5:5) to give compound 4.
5-bromo-N-(6-fluorobenzo[d]thiazol-2-yl)-6-methoxypicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a solution of compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL), cooled to 0 C, was added compound 3 (255 mg, 0.0011 mol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,Ndiisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and the mixture was stirred for 16 h at ambient temperature. Water was added and extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (8:2-5:5) to give compound 4.
5-bromo-N-(6-methoxybenzo[d]thiazol-2-yl)-6-methoxypicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a solution of compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL), cooled to 0 C, was added compound 3 (255 mg, 0.0011 mol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,Ndiisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and the mixture was stirred for 16 h at ambient temperature. Water was added and extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (8:2-5:5) to give compound 4.
N-(benzo[d]thiazol-2-yl)-5-bromo-6-methoxypicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a solution of compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL), cooled to 0 C, was added compound 3 (255 mg, 0.0011 mol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,Ndiisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and the mixture was stirred for 16 h at ambient temperature. Water was added and extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (8:2-5:5) to give compound 4.
With sodium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.0h;
To a solution of 5-bromo-6-methoxypicolinic acid (1) (1.0 g, 0.00431 mol) in DMF (10 mL, 10 vol), cooled to 0 C was added Na2CO3 (456 mg, 0.00431 mol) and MeI (0.536 mL, 0.0086 mol) the mixture was stirred for16 h at room temperature. Water was added, extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (9:1-8:2) to give pure compound (2): Off white solid; yield: 94 %, 1H NMR (500MHz, CDCl3) delta: 3.98 (s, 3H), 4.08 (s, 3H), 7.58 (d, 1H, Ar-H),7.98 (d, 1H, Ar-H): MS: m/z (%) 247.6 [M+2], HPLC purity(99.52 %).
With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16.0h;
To a solution of 5-bromo-6-methoxy picolinicacid1 (1.5 g, 0.00646 mol) in DMF (15mL, 10 vol), cooledto 0oC Na2CO3 (685 mg, 0.00646 mol) and MeI (0.834 mL,0.0129 mol) were added and the mixture was stirred for 16hat room temperature. Water was added, extracted with ethylacetate, concentrated under reduced pressure to obtain 5-bromo-6-methoxy-pyridine-2-carboxylic acid methyl ester(1.5 g, 0.00609 mol) in EtOH (15mL), NH2NH2.H2O (1.21 g,0.0243 mol) was added and the mixture was stirred for 3h at70oC, cooled to room temperature, solvents were evaporated,water (15mL) was added, filtered the reaction mass, to givepure compound 2.
5-bromo-6-methoxypicolinic acid: A suspension of 5-bromo-6-chloropicolinic acid (15.0 g, 63.4 mmol, 1.0 equiv.) in MeOH (130 mL) at ambient temperature was treated with a 4.37 M sodium methoxide solution in MeOH (58.0 mL, 253 mmol, 4.0 equiv.). The resultant mixture was heated at 80 C for 18 hours, resulting in a thick mixture. The reaction was diluted with MeOH (100 mL) and stirred at 80 C for 24 hours. The reaction mixture was cooled to ambient temperature, acidified to pH=3 with concentrated aqueous HC1, diluted with water and extracted with EtOAc (three times). The combined organic layers were dried over MgSO4, filtered and concentrated to afford a residue that was co-evaporated with DCM/hexanes (1:1 mixture, 200 mL, three times) to afford 5-bromo-6-methoxypicolinic acid (13.9 g, 94%) as a white solid. ?H NMR (500 MHz, CDC13) 5 10.22 (br s, 1H), 8.06 (d, I = 7.7 Hz, 1H), 7.73 (d, I = 7.7 Hz, 1H), 4.10 (s, 3H). LCMS (ES-) [M-Hj+: 229.9/23 1.9.
5-bromo-6-methoxypyridine-2-carbonyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
To a stirred solution of <strong>[1214334-70-9]5-bromo-6-methoxypicolinic acid</strong> (440 mg, 2 mmol) in CH2C12 (10 mL) at 0 C under an argon atmosphere were added oxalyl chloride (722 mg, 6 mmol) and DMF (catalytic amount). The reaction mixture was warmed to room temperature and stirred for 2 h. After consumption of acid (monitored by TLC), the volatiles were evaporated in vacuo to afford 5-bromo-6-methoxypicolinoyl chloride.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
[0436] To a stirred solution of <strong>[1214334-70-9]5-bromo-6-methoxypicolinic acid</strong> (350 mg, 1 mmol) in CH2C12 (2 mL) under an argon atmosphere were added oxalyl chloride (347 mg, 2 mmol) and DMF (catalytic amount) at 0 C. The reaction mixture was stirred at room temperature for 2 h. After consumption of acid (by TLC), the volatiles were evaporated in vacuo to give 5- bromo-6-methoxypicolinoyl chloride.
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