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6-chloro-4-(trifluoromethyl)pyridine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.6%
To a solution of butyl magnesium chloride (27.8mL, 47.2mmol, 0.7eq, 1.7 M in THF) in THF was added butyl lithium (30.0mL, 74.3mmol, l. leq, 2.5M in hexane) at 0C and the reaction mixture was stirred for 10 min, then diluted with THF (80mL) and cooled to -78C. Then, <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (17.5g, 67.5mmol, leqm procedure described in Example 93) in THF (30mL) was added and the reaction mixture was stirred for lh at same temperature, before being poured onto crushed dry ice then slowly allowed to warm to RT for 16h. TLC indicated polar spot and the reaction mixture was concentrated and acidified with 2N HC1 (80mL) and extracted with EtOAc (2X 500mL). The organic layer was separated, dried with sodium sulfate and concentrated under reduced pressure to give crude residue. The crude compound was recrystallized from n-pentane (30mL) and dried using high vacuum to give 6-chloro-4-(trifluoromethyl)nicotinic acid (lOg, 66.6%) as an off white solid compound. LCMS: [M+H]+ 224.05.
53.8%
A stirred solution of 20% n-butyl magnesium chloride (63 mL, 127.2 mmol, 1.1 eq) in THF (50 mL) was cooled to 0 C and n-butyl lithium (48 mL, 115.8 mmol, le q, 2.5M in hexane) was added. The resulting reaction mixture was stirred for 10 mm, then diluted with THF (100 mL), cooled to -78 C and a solution of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (30 g, 115.8 mmol, 1 eq) in THF (50 mL) was added. The reaction mixture was stirred for lh at -78 C. The mixture was quenched with crushed dry ice and allowed to warm to RT and stirred for 16 h. TLC analysis indicated the formation of a polar spot. The reaction mixture was concentrated, acidified with 2N HC1 (80 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude compound which was recrystallized from n-pentane (30 mL) and dried on high vacuum to give 6-chloro-4-(trifluoromethyl)nicotinic acid (14 g, 53.8% yield) as off white solid. LCMS: [M+Hj 226.29.
With acetyl chloride; sodium iodide; In acetonitrile; at 40℃; for 1.5h;
[006521 Prepared using General Procedure 17. To a stirred a solution of 5-bromo-2- chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mrnol). The reaction mixture was heated to 40C and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40C for 90 mm. Once cooled, the reaction was quenched with NaHCO3 (5 mL) and extracted with EA (3 x 5 mL). The combined organics were washed with brine (10 mL), dried over MgSO4and concentrated to give 80.0 mg (40%) of 5-brorno-2-iodo-4- (trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (rnIz) calculated for C6H2BrFLN: 351.9; found 352.5 [M+H], tR = 3.91 mm. (Method 1).
With acetyl chloride; sodium iodide; In acetonitrile; at 40℃; for 1.5h;
Prepared using General Procedure 17: To a stirred a solution of 5- bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol) in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol). The reaction mixture was heated to 40C and acetyl chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was stirred at 40C for 90 min. Once cooled, the reaction was quenched with NaHC03 (5 mL) and extracted with EA (3 x 5 mL). The combined organics were washed with brine (10 mL), dried over MgS04 and concentrated to give 80.0 mg (40%) of 5-bromo- 2-iodo-4-(trifluoromethyl)pyridine as a white crystalline solid which was used in the subsequent step without purification. LCMS-ESI (m/z) calculated for C6H2BrF3IN: 351.9; found 352.5 [M+H]+, tR = 3.91 min. (Method 1).
5-bromo-2-methylsulfanyl-4-trifluoromethylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
In 1,4-dioxane; for 14h;Reflux;
Step 1 : A mixture of <strong>[823221-93-8]5-bromo-2-chloro-4-trifluoromethyl-pyridine</strong> (1.0 g, 3.8 mmol) and sodium thio- methoxide (400 mg, 5.79 mmol) in dioxane (15 mL) was heated at reflux for 14 h. The RM was concentrated under reduced pressure and diluted with EtOAc and subsequently washed with water and brine (60 mL). The organic layer was dried and concentrated under reduced pressure to give the crude product which was purified by CC (Si02, EtOAc Hex) to yield the desired compound (800 mg, 77%).
N-[6-chloro-4-(trifluoromethyl)-3-pyridyl]-2,2-dimethyl-propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With methanesulfonic acid(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); potassium carbonate; In 1,4-dioxane; at 90 - 110℃; for 2.5h;
Procedure for synthesis of N-[6-chloro-4-(trifluoromethyl)-3-pyridyl]-2,2-dimethyl- propanamide (Step 1) A mixture of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (commercially available) (75 mg, 0.288 mmol), 2,2-dimethylpropanamide (32 mg, 0.317 mmol), XantPhos Pd G3 precatalyst (13 mg, - - 0.014 mmol), K2C03 (79 mg, 0.57 mmol) in 1 ,4-Dioxane (0.5 ml.) was heated at 90C for 0.5h and then 1 10C for 2h. Purification by reverse phase HPLC delivered product (14 mg, 15%). LC-MS: (positive ES MH+ 281 ).
15%
With XantPhos Pd G3 precatalyst; potassium carbonate; In 1,4-dioxane; at 90 - 110℃; for 2.5h;
A mixture of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (commercially available) (75 mg, 0.288mmol), 2,2-dimethylpropanamide (32 mg, 0.317 mmol), XantPhos Pd G3 precatalyst (13 mg,0.0 14 mmol), K2C03 (79 mg, 0.57 mmol) in 1 ,4-Dioxane (0.5 mL) was heated at 90C for 0.5hand then 110C for 2h. Purification by reverse phase HPLC delivered product (14 mg, 15%). LC-MS: (positive ES MH+ 281).
To a solution of <strong>[823221-93-8]5-bromo-2-chloro-4-trifluoromethyl-pyridine</strong> (2.54 g, 9.80 mmol) in MeOH (25 mL) was added 25% NaOMe in MeOH (3.2 ml, 14.70 mmol) and heated at reflux for 2 h. The RM was diluted with water and extracted with hexane. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure to give 5-bromo-2-methoxy-4-trifluoromethyl-pyridine(1.7 g, 68%).
63.47%
In methanol; at 70℃; for 6h;
To a solution of <strong>[823221-93-8]5-bromo-2-chloro-4-(trifluoromethyl)pyridine</strong> (24.0 g, 93.02 mmol, 1.0 eq) in methanol (200 mL), was added 30% NaOMe (33.08 mL, 186.04 mmol, 2.0 eq). Then, the reaction mixture was heated at 70C for 6 h. TLC analysis indicated formation of a non-polar spot. The reaction mixture was diluted with water and extracted with EtOAc (3 X 200mL). The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure at 30C. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 5% EtOAc in pet ether as an eluent to give 5-bromo-2-methoxy-4-(trifluoromethyl)pyridine (15g, 63.47%) as an off white solid. TLC: 5% EtOAc in pet ether; Rf: 0.8.
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