* 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.
Reference：
[1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 24, p. 3537 - 3541
[2] Patent: WO2012/24615, 2012, A1, . Location in patent: Page/Page column 56
2
[ 14432-12-3 ]
[ 20265-39-8 ]
Yield
Reaction Conditions
Operation in experiment
14%
With sodium methylate In tetrahydrofuran; methanol at 140℃; for 16 h; Sealed tube
4-Amino-2-chloropyridine (15 g, 117 mmol, 1.0 equiv) was dissolved in 100 mL of THF. A solution of sodium methoxide in methanol (1.0 M, 234 mL, 234 mmol, 2.0 equiv) was added and the resulting solution was refiuxed in a sealed tube for 16 hours at 14O0C. The reaction mixture was poured into 50OmL of a rapidly stirring saturated sodium bicarbonate solution. 50OmL of ethyl acetate was added and the layers were separated. The organic layer was dried over sodium sulfate, decanted, and concentrated in vacuo. Chromatography on SiO2 (30percent ethyl acetate in hexanes) provided 29b as a yellow solid (2.1 g, 14percent).
With N-Bromosuccinimide In dichloromethane at 0 - 30℃; for 0.5 h;
Synthesis of 3-bromo-2-methoxypyridin-4-amine (2) To a solution of 2-methoxypyridin-4-amine (1, 20.0 g, 161.2 mmol) in dichloromethane (200 mL) at 0° C., N-bromo succinimide (26.6 g, 161.2 mmol) was added and the reaction mixture was stirred at 30° C. for 30 min. After completion, the mixture was quenched with ice cold water (100 mL) and the reaction mass was extracted with dichloromethane (300 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was triturated with n-pentane and diethyl ether to afford 3-bromo-2-methoxypyridin-4-amine (2) as yellow solid. Yield: 30.0 g, 92percent; MS (ESI) m/z 203.09[M+1]+.
89%
With N-Bromosuccinimide In dichloromethane at 0 - 20℃; for 2 h;
3-bromo-2-methoxypyridin-4-amine (i42): To a stirred solution of 2-methoxypyridin-4-amine (2 g, 16 mmol) in DCM (1 14 mL), NBS (2.87 g, 16 mmol) was slowly added at 0°C and the reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC. After completion , the solvent was concentrated under reduced pressure. The crude product was purified by silica gel (100:200 mesh) column chromatography using 15percent ethyl acetate in n-hexanes as eluent to afford 3- bromo-2-methoxypyridin-4-amine (i42) (2.9 g, Yield 89percent). 1H NMR (400 MHz, Chloroform-d) δ 3.97 (s, 3H), 4.58 (s, 2H), 6.29 (d, J = 5.7 Hz, 1 H), 7.73 (d, J = 5.6 Hz, 1 H). MS (ESI) m/e (M+1 )+: 203
81%
With N-Bromosuccinimide In acetonitrile at 20℃; for 1 h; Cooling with ice
2-Methoxy-4-aminopyridine (3.81 g, 27.5 mmol)And NBS (5 g, 28 mmol) were dissolved in 25 ml and 40 ml of acetonitrile, respectively,Then, NBS dissolved in acetonitrile was added dropwise to the reaction solution under ice-cooling,Followed by reaction at room temperature for 1 h.After completion of the reaction, the reaction solvent was removed and extracted with ethyl acetate. After completion of the extraction, the solvent was removed and recrystallized from acetone to give Compound 34a (895 mg, 81percent).
77%
With N-Bromosuccinimide In acetonitrile at 0 - 20℃;
2-methoxy-4-aminopyridine (5 g, 40.3 mmol) was dissolved in MeCN and NBS (7.18 g, 40.3 mmol) was added therein in portions at 0° C. The mixture was slowly raised to room temperature and was allowed to react with stirring and the reaction was monitored by TLC. After the reaction was completed, the resultant was diluted with EA, washed with saturated NH4Cl solution, sodium hydrosulfite and saturated NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound, yield 77percent. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, 1H), 6.36 (d, 1H), 6.20 (s, 2H), 3.7 (s, 3H).
With N-Bromosuccinimide; In dichloromethane; at 25℃; for 4h;
To a solution of 2-methoxypyridin-4-amine (5.0 g, 40.28 mmol) in DCM (10 mL) was added NBS (7.17 g, 40.28 mmol) at 0C. Then the reaction mixture was stirred at 25C for 4 hrs. The solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc=5/1 to 2/1) to give the title compound (7.9 g, 38.91 mmol, 96.60% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) d = 7.67 (d, J = 5.6 Hz, 1H), 6.26 (d, J = 5.6 Hz, 1H), 3.90 (s, 3H).
92%
With N-Bromosuccinimide; In dichloromethane; at 0 - 30℃; for 0.5h;
Synthesis of 3-bromo-2-methoxypyridin-4-amine (2) To a solution of 2-methoxypyridin-4-amine (1, 20.0 g, 161.2 mmol) in dichloromethane (200 mL) at 0 C., N-bromo succinimide (26.6 g, 161.2 mmol) was added and the reaction mixture was stirred at 30 C. for 30 min. After completion, the mixture was quenched with ice cold water (100 mL) and the reaction mass was extracted with dichloromethane (300 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was triturated with n-pentane and diethyl ether to afford 3-bromo-2-methoxypyridin-4-amine (2) as yellow solid. Yield: 30.0 g, 92%; MS (ESI) m/z 203.09[M+1]+.
90%
With N-Bromosuccinimide; In dichloromethane; at 5℃; for 0.5h;
A solution of bromosuccimide (2.15 g, 12.083 mmol) in DCM (25 mL) was added dropwise to a solution of 2-methoxy-pyridin-4-ylamine (1.5 g, 12.083 mmol) in DCM (85 mL) maintaining the temperature below 5 C. The reaction was continued for 30 minutes and then concentrated dry. The residue was taken in EA (50 mL) and washed with water (40 mL) and brine (20 mL). Drying over MgSO4, filtering, and solvent removal afforded the crude product that further purified by chromatography over silica gel (gradient of EA in heptane from 0 to 30%) to a pure oil (2.23 g, 90%). 1H NMR (300 MHz, Chloroform-d) δ 3.96 (s, 3H), 4.59 (s, 2H), 6.28 (d, J=5.6 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H). MS m/z 203 (MH+).
89%
With N-Bromosuccinimide; In dichloromethane; at 0 - 20℃; for 2h;
3-bromo-2-methoxypyridin-4-amine (i42): To a stirred solution of 2-methoxypyridin-4-amine (2 g, 16 mmol) in DCM (1 14 mL), NBS (2.87 g, 16 mmol) was slowly added at 0C and the reaction was stirred at room temperature for 2h. The progress of the reaction was monitored by TLC. After completion , the solvent was concentrated under reduced pressure. The crude product was purified by silica gel (100:200 mesh) column chromatography using 15% ethyl acetate in n-hexanes as eluent to afford 3- bromo-2-methoxypyridin-4-amine (i42) (2.9 g, Yield 89%). 1H NMR (400 MHz, Chloroform-d) δ 3.97 (s, 3H), 4.58 (s, 2H), 6.29 (d, J = 5.7 Hz, 1 H), 7.73 (d, J = 5.6 Hz, 1 H). MS (ESI) m/e (M+1 )+: 203
81%
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 1h;Cooling with ice;
2-Methoxy-4-aminopyridine (3.81 g, 27.5 mmol)And NBS (5 g, 28 mmol) were dissolved in 25 ml and 40 ml of acetonitrile, respectively,Then, NBS dissolved in acetonitrile was added dropwise to the reaction solution under ice-cooling,Followed by reaction at room temperature for 1 h.After completion of the reaction, the reaction solvent was removed and extracted with ethyl acetate. After completion of the extraction, the solvent was removed and recrystallized from acetone to give Compound 34a (895 mg, 81%).
77%
With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;
2-methoxy-4-aminopyridine (5 g, 40.3 mmol) was dissolved in MeCN and NBS (7.18 g, 40.3 mmol) was added therein in portions at 0 C. The mixture was slowly raised to room temperature and was allowed to react with stirring and the reaction was monitored by TLC. After the reaction was completed, the resultant was diluted with EA, washed with saturated NH4Cl solution, sodium hydrosulfite and saturated NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure, and the residue was purified by column chromatography to give the title compound, yield 77%. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, 1H), 6.36 (d, 1H), 6.20 (s, 2H), 3.7 (s, 3H).
With N-Bromosuccinimide; In acetonitrile; at 10℃;
The 2-[2-methoxy-4-(7-methoxy-l,6-naphthyridin-4-yloxy)phenyl]acetic acid used as a starting material was prepared as follows :-; A solution of iV-bromosuccinimide (9.8 g) in acetonitrile (80 ml) was added dropwise to a stirred solution of 2-methoxypyridine-4-amine CHeIv. Chim. Acta, 1964, 363-376; 6.82 g) in acetonitrile (40 ml) that had been cooled to 10C. The mixture was concentrated by evaporation. The oily residue was triturated under a mixture of diethyl ether and petroleum ether (b.p. 40-60C). There was thus obtained 3-bromo-2-methoxypyridine-4-amine as a solid (11 g); 1R NMR Spectrum: (DMSOd6) 3.8 (s, 3H), 6.21 (br s, 2H), 6.35 (d, IH), 7.59 (d, IH); Mass Spectrum: M+H4" 203 and 205.
With N-Bromosuccinimide In acetic acid at 10 - 35℃; for 3h;
28.1 (1) Synthesis of 3,5-dibromo-2-methoxypyridin-4-amine
(1) Synthesis of 3,5-dibromo-2-methoxypyridin-4-amine A mixture of 2-methoxy-pyridin-4-ylamine (15 g) and NBS (47.3 g) was stirred in an acetic acid solvent (150 mL) at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and a 5 M aqueous sodium hydroxide solution (200 mL) was added to the residue at 0° C., followed by extraction with diethyl ether. The organic layer was directly purified by a silica gel pad (ethyl acetate/n-heptane, 10%) to give the title compound (32.4 g). ESI-MS m/z 283 [M+H]+
32.4 g
With N-Bromosuccinimide; acetic acid at 20℃; for 3h;
2.7 (7) Synthesis of 3,5-dibromo-2-methoxypyridin-4-amine
A mixture of 2-methoxy-pyridin-4-ylamine (15 g) and NBS (47.3 g) was stirred in an acetic acid solvent (150 mL) at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and a 5 N aqueous sodium hydroxide solution (200 mL) was added to the residue at 0° C., followed by extraction with diethyl ether. The organic layer was directly purified by a silica gel pad (ethyl acetate/n-heptane, 10%) to give the title compound (32.4 g). (0211) ESI-MS m/z 283 [M+H]+
A mixture of 6,8-dihydro-5/-/-imidazo[2,1-c][1 ,4]oxazine-2-carbaldehyde (0.156 g; 1.025 mmol) and 4-amino-2-methoxypyridine (0.130 g; 1.047 mmol) in ethanol (1 ml_) was stirred at 65C for 2.5 days. The solvent was evaporated and the residue was dried under reduced pressure to give quantitatively /V-((6,8-dihydro-5/-/-imidazo[2,1-c][1 ,4]oxazin-2-yl)methylene)-2- methoxypyridin-4-amine which was used without further purification.
A mixture of <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (0.1 15 g; 1.016 mmol) and 4-amino-2- methoxypyridine (0.126 g; 1.016 mmol) in ethanol (1 mL) was stirred at 65°C for 16 h. The solvent was evaporated and the residue was dried under reduced pressure to give quantitatively 2-methoxy-/V-(thiazol-4-ylmethylene)pyridin-4-amine which was used without further purification. ESI/APCI (+): 220 (M+H).
General procedure: To a mixture of an aldehyde (1.0 eq) and magnesium sulfate (1.3 eq) in ethanol was added an amine (1.0 eq). The mixture was heated overnight at 80 C and filtered. The filtrate was concentrated under reduced pressure to give quantitatively the imine which was used without further purification in the next step.
63.1.A General procedure H:
General procedure: To a mixture of an aldehyde (1.0 eq) and magnesium sulfate (1.3 eq) in ethanol was added an amine (1.0 eq). The mixture was heated overnight at 80 °C and filtered. The filtrate was concentrated under reduced pressure to give quantitatively the imine which was used without further purification in the next step.
With triethylamine; HATU; In dichloromethane; at 20℃;
Example 5 Preparation of 5-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide A solution of <strong>[164149-28-4]4-cyano-2-fluoro-benzoic acid</strong> (6.7 g, 40.58 mmol), HATU (15.4 g, 40.58 mmol), 2-methoxypyridin-4-amine (5.0 g, 40.58 mmol) and Et3N (22.62 mL, 162.3 mmol) in dichloromethane (60.3 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography sing a gradient of ethyl acetate in hexanes (0-50%) to yield 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 66%) as a white solid. ESI-MS m/z calc. 271.07, found 272.1 (M+1)+; Retention time: 1.17 minutes (3 minutes run).
1 Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide
Example 1 Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexane, the hexane was decanted and the product was dried under reduced pressure to yield 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g, 74%) as a cream solid. ESI-MS m/z calc. 314.07, found 315.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.
74%
With pyridine In dichloromethane at 0 - 20℃;
4
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexane, the hexane was decanted and the product was dried under reduced pressure to yield 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g, 74%) as a cream solid. ESI-MS m/z calc. 314.07, found 315.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.
28.3 g
With N-ethyl-N,N-diisopropylamine In 2-methyltetrahydrofuran; toluene
Specific Example:
To a vessel containing 2-fluoro-4-(trifluoromethyl)benzoic acid (1) (25.0 g, 116.5 mmol, 1.00 equivs), toluene (200 mL), and a small amount of dimethylformamide (0.17 g, 2.33 mmol, 0.2 mL, 0.02 equivs) was added oxalyl chloride (17.75 g, 139.8 mmol, 1.20 equivs) as a solution in toluene (50 mL). The mixture was heated at 40 - 50 °C and stirred until the reaction to the acid chloride was complete and a distillation was performed to remove volatiles. The concentrated solution of acid chloride (2) in toluene was charged to a mixture of 2- methoxypyridin-4-amine (3) (15.19 g, 122.4 mmol, 1.05 equivs) and Hunig’s base (33.13 g, 44.7 mL, 256.4 mmol, 2.20 equivs) in 2-methyltetrahydrofuran (200 mL). The combined mixture was stirred until the reaction was complete. The reaction was quenched with 1 N aqueous hydrochloric acid solution (40 mL) and the phases were split. The organic solution with the product was washed with 2N aqueous sodium hydroxide solution and again the phases were split. The resulting organic solution of the product 2-fluoro-N-(2-methoxypyridin-4-yl)-4- (trifluoromethyl)benzamide (4) in 2-methyltetrahydrofuran was distilled and diluted with cyclohexane so that the product could be crystallized from cyclohexane and isolated by filtration. The white to off-white crystalline product was dried with heat (45 - 55 °C) and under vacuum to afford 28.3 g (77.3% yield).
Example 2 Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide A solution of <strong>[207981-46-2]2-fluoro-5-(trifluoromethyl)benzoyl chloride</strong> (25 g, 110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8 mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0 C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (33.6 g, 97.00%) as an off-white solid. ESI-MS m/z calc. 314.07, found 315.2 (M+1)+; Retention time: 1.44 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.12-8.07 (m, 2H), 8.07-7.98 (m, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.24-7.19 (m, 2H), 3.85 (s, 3H) ppm.
With triethylamine; HATU; In dichloromethane; at 20℃;
Example 4 Preparation of 5-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide A solution of <strong>[394-30-9]5-chloro-2-fluoro-benzoic acid</strong> (5.0 g, 28.64 mmol), HATU (10.89 g, 28.64 mmol), 2-methoxypyridin-4-amine (3.6 g, 28.64 mmol) and Et3N (15.98 mL, 114.60 mmol) in dichloromethane (45.0 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 47%) as a white solid. ESI-MS m/z calc. 280.04, found 281.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run). To 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 13.50 mmol) in acetonitrile (126.3 mL) was added TMSI (7.7 mL, 54.00 mmol). The reaction was stirred at 50 C. overnight. The acetonitrile was evaporated and the crude re-dissolved in ethyl acetate. The organics were washed with water, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography using a gradient of ethyl acetate in hexanes (0-100%) and then methanol in dichloromethane (0-20%) yielded 5-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (950 mg, 26%) as a white solid. ESI-MS m/z calc. 266.03, found 267.1 (M+1)+; Retention time: 1.24 minutes (3 minutes run).
Example 7 Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide A solution of <strong>[151982-51-3]4-bromo-2-fluoro-benzoyl chloride</strong> (2 g, 8.42 mmol) in dichloromethane (10.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (1.0 g, 8.42 mmol), pyridine (2.0 mL, 25.27 mmol) and dichloromethane (40.0 mL) at 0 C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as an off-white solid. ESI-MS m/z calc. 323.99, found 325.1 (M+1)+; Retention time: 1.37 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) delta 10.80 (s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m, 1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H), 3.84 (s, 3H) ppm.
44%
With pyridine; In dichloromethane; at 0 - 20℃;
A solution of <strong>[151982-51-3]4-bromo-2-fluoro-benzoyl chloride</strong> (2 g, 8.42 mmol) in dichloromethane (10.0 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (1.0 g, 8.42 mmol), pyridine (2.0 mL, 25.27 mmol) and dichloromethane (40.0 mL) at 0 C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as an off-white solid. ESI-MS m/z calc. 323.99, found 325.1 (M+1)+; Retention time: 1.37 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) delta 10.80 (s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m, 1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H), 3.84 (s, 3H) ppm.
8 Example 8
Example 8 Preparation of 2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide A solution of 2,5-difluorobenzoyl chloride (2.0 mL, 16.14 mmol) and dichloromethane (14.25 mL) was added drop-wise to a mixture of 2-methoxypyridin-4-amine (2.0 g, 16.14 mmol), pyridine (3.9 mL, 48.42 mmol) and dichloromethane (57.0 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid.ESI-MS m/z calc. 264.07, found 265.3 (M+1)+; Retention time: 1.22 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.12-8.05 (m, 1H), 7.58 (ddd, J=8.3, 5.4, 2.9 Hz, 1H), 7.52-7.41 (m, 2H), 7.25-7.19 (m, 2H), 3.84 (s, 3H) ppm.
Example 9 Preparation of 4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide A solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol), <strong>[289039-49-2]4,5-dichloro-2-fluoro-benzoic acid</strong> (285.1 mg, 1.36 mmol), HATU (622.4 mg, 1.64 mmol) and n-methylmorpholine (299.9 muL, 2.73 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3*). The organics were combined, washed with water (3*), brine and dried over Na2SO4, filtered through a short plug of silica and evaporated to dryness. The material was taken up in HBr (in acetic acid) (6.689 mL of 33% w/v, 27.28 mmol) and stirred at 95 C. for 16 h. The solution was cooled to room temperature, filtered and solid product washed with water (2*) and then ether (2*) and dried under vacuum to give 4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (250 mg, 61%) as an off white solid. ESI-MS m/z calc. 299.99, found 301.3 (M+1)+; Retention time: 1.16 minutes (3 minutes run).
61%
A solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol), <strong>[289039-49-2]4,5-dichloro-2-fluoro-benzoic acid</strong> (285.1 mg, 1.36 mmol), HATU (622.4 mg, 1.64 mmol) and N-methylmorpholine (299.9 muL, 2.73 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water (3×), brine and dried over Na2SO4, filtered through a short plug of silica and evaporated to dryness. The material was taken up in HBr (in acetic acid) (6.689 mL of 33% w/v, 27.28 mmol) and stirred at 95 C. for 16 h. The solution was cooled to room temperature, filtered and solid product washed with water (2×) and then ether (2×) and dried under vacuum to give 4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (250 mg, 61%) as an off white solid. ESI-MS m/z calc. 299.99, found 301.3 (M+1)+; Retention time: 1.16 minutes (3 minutes run).
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In 2-methyltetrahydrofuran; at 35 - 40℃;Large scale;
Example 15A Preparation of 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide A 50 liter jacketed glass reactor was fitted with an N2 inlet, a mechanical stirrer, and a condenser. With the stirrer set to 150 rpm and the jacket temperature set at 40 C., 2-Me-THF (6.000 L, 3.0 vol), <strong>[115029-24-8]2-fluoro-4-(trifluoromethyl)benzoic acid</strong> (2000 g, 9.610 mol), 2-methoxypyridin-4-amine (1.278 kg, 10.09 mol), and TEA (2.917 kg, 4.018 L, 28.83 mol) were added to the reactor, which resulted in a slightly hazy, light amber solution. The reactor was switched to reaction control and heated to 35 C. To the solution was added T3P in 2-Me-THF (9.176 kg, 9.176 L of 50% w/w, 14.42 mol) over 30-45 min, which resulted in a light amber solution. After 2 hours, the reaction was judged to be complete by HPLC analysis (<2% of 1 remaining). The reaction was quenched with water (1.000 L, 0.5 vol), which was added via addition funnel over a period of 10 minutes in order to control the exothermic quenching reaction. The mixture was then diluted with 2-Me-THF (8.000 L, 4.0 vol) and water (8.000 L, 4.0 vol) and stirred for 30 minutes at 30-40 C. After stirring was stopped, the layers were allowed to separate, and the aqueous layer was removed. The organic layer was washed with 10% aqueous NaOH (6.000 L, 3.0 vol), stirring resulted in an emulsion. Brine (500.0 mL, 0.25 vol) was added, and the mixture was stirred for about 5 minutes. The layers were separated, and the aqueous layer removed. The organic layer was washed again with brine (10.00 L, 5.0 vol), and the aqueous layer was drained. The organic layer was dried over Na2SO4, and filtered through diatomaceous earth (Celite). The filter cake was washed with 2-Me-THF (4.000 L, 2.0 vol) and pulled dry. The filtrate was transferred to a rotovap, and partial distillation of solvent was begun at a bath temperature of 40 C. and a pressure of 150 mbar, resulting in the formation of solids in the mixture. Cyclohexane (10.00 L, 5.0 vol) was added portionwise during the partial distillation. Distillation was stopped, the reaction mixture (?8 liter) was slurried on the rotovap, and the bath temperature was reduced to room temperature. The mixture was filtered, and the filter cake was washed with cyclohexane (2.000 L, 1.0 vol) and pulled dry under a nitrogen blanket to afford a light yellow solid. The solid was scooped out of the funnel and dried in vacuo (40 C., <30 mbar, rotovap) to afford 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (2,501 g, 7.959 mol, 83%) as a fine, off-white solid.
7.1 g
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In 2-methyltetrahydrofuran; ethyl acetate; at 40℃; for 16h;
A solution of 2-fluoro-4-(tnfluoromethyl)benzoic acid (4) (5.0 g, 24 mmol) in 2-methyltetrahydrofuran (30 mL) at 40 C was treated with T3P solution (23 mL of 50 % w/v in ethyl acetate, 36 mmol) followed by pyndine (5.7 g, 5.8 mL, 72 mmol), triethylamine (7.3 g, 10 mL, 72 mmol) and 2-methoxypyndin-4-amine (3.3 g, 26 mmol). The reaction was heated at 40 C for 16 hours. Water (50 mL) was added and the mixture stirred. The resulting layers were separated, and the organic layer was washed with 50 mL 0.1 N HC1, 50 mL 10% KOH and 50 mL brine. The solution was dried over sodium sulfate, filtered and evaporated to provide 2-fluoro-N-(2-methoxy-4-pyndyl)-4- (trifluoromethyl)benzamide (5) (7.1 g, 94%). ESI-MS m/z calc. 314.07, found 315.2 (M+1)+. LC/MS retention time (Method B): 1.21 minutes (3 minute run). ?H NIVIR (400 MHz, DMSO-d6) 10.96 (s, 1H), 8.14 -8.07 (m, 1H), 7.96-7.88 (m, 2H), 7.76 (dd, J = 8.1, 1.6 Hz, 1H), 7.22 (d, J = 4.7 Hz, 2H), 3.85 (s, 3H) ppm.
6-chloro-N-(2-methoxypyridin-4-yl)-2-morpholinopyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃;Inert atmosphere;
[000189j A mixture of 4-(4,6-dichloropyrimidin-2-yl)morpholino 1 (0.3 g, 1 eq), 2- methoxy 4-amino pyridine 2 (0.168 g, 1 eq), cesium carbonate (0.437 g, 1.5 eq) in 1,4-dioxane (20 mL) was taken and purged with argon for 10 mm, followed by the addition of BNAP (0.099 g, 0.2 eq) and purged argon for additional 5 mm. Palladium acetate (0.04 g, 0.2 eq) was added and stirred at 100 C for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was taken in ethyl acetate (50 mL), washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 30% EtOAc-hexane to afford the desired product 3. LCMS (mlz): 322.20 (M + 1).
1-(4-bromo-2-nitrophenyl)-N-(2-methoxypyridin-4-yl)methanimine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid In 1,2-dichloro-ethane at 90℃; for 15h;
33-a (Example 33-a) 6-Bromo-2- (2-methoxypyridin-4-yl) -2H- indazole
4-Bromo-2-nitrobenzaldehyde (1.00 g, 4.35 mmol), 4- amino-2-methoxypyridine (593 mg, 4.78 mmcl), and acetic acid (1.24 mL, 21.7 mmcl) were dissolved in 1,2-dichloroethane (15 ml) and then stirred at 90°C for 15 h. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction solution, followed by partition operation using ethyl acetate. The organic phase waswashed with brine, then dried over magnesium sulfate, and filtered. Then, the solvent was distilled off under reduced pressure to give the crude compound. The residue was purified by silica gel column chromatography (silica gel, ethyl acetate:hexane = 0:100 to 25:75) to give 1-(4-bromo-2-nitrophenyl)-N-(2-methoxypyridin-4-yl)methanimine(468 mg, <32%) as a crude product.
Stage #1: 4-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Inert atmosphere;
Stage #2: 4-amino-2-methoxypyridine With triethylamine In dichloromethane at 20℃; for 12h; Inert atmosphere;
4.
Compound 4a (100mg, 0.44mmol)Dissolve in dichloromethane (10mL),Then add oxalyl chloride (113mg, 0.88mmol)And a catalytic amount of N,N-dimethylformamide.Replace with nitrogen three times and stir at room temperature for 2 hours,Concentrate under reduced pressure to obtain a residue,The residue was then dissolved in dichloromethane (20 mL),Add triethylamine (133mg, 1.32mmol)And compound 3d (82mg, 0.66mmol),After replacing with nitrogen three times, stirring at room temperature for 12 hours,Add water (20mL) and dichloromethane (30mL) to separate the liquids,The aqueous phase was extracted with dichloromethane (30mL x 3),After the organic phase is combined,Dry with anhydrous sodium sulfate,Filter and concentrate under reduced pressure to obtain a residue,The residue is purified by column chromatography(Ethyl acetate: petroleum ether=0-100%)Obtain 4b (90 mg), yield: 62%.
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