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Example 5 3-((5-chloro-2-(trifluoromethyl)phenyl)ethvnyl)-5-(l-(piperidin-4-yl)-lH-pyrazol-4- yl)-lH-pyrrolor2,3-b1pyridine Step 1) 2-bromo-4-chloro-l-(trifluoromethyl)benzene To a stirred solution of 40percent HBr (2.20 mL, 15.34 mmol) in 0 (2 mL) was added 2-amino-4- chlorobenzotrifluoride (0.50 g, 2.56 mmol) at 0 °C. Then a solution of sodium nitrite (0.21 g, 3.07 mmol) in H20 (2 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for a further 0.5 hours, a solution of cuprous bromide (0.63 g, 4.35 mmol) in 40percent HBr (2.20 mL, 15.34 mmol) and H20 (3 mL) was added. The mixture was stirred at 75 °C for 3 hours, then cooled to rt, and extracted with EtOAc (40 mL x 4). The combined organic phases were washed with brine (80 mL x 2), dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a yellow liquid (0.76 g, 100percent). GC -MS: 257.9.
100%
40percent HBr (2.20 mL, 15.34 mmol) was dissolved in H2O (2 mL), then at 0 ° C,2-Amino-4-chlorobenzotrifluoride (0.50 g, 2.56 mmol) was added to the reaction mixture, followed by 0 ° C,An aqueous solution of sodium nitrite (sodium nitrite (0.21 g, 3.07 mmol) dissolved in 2 mL of water) was added dropwise to the reaction mixture.After the reaction solution was stirred at 0 ° C for half an hour, additional cuprous bromide (0.63 g, 4.35 mmol) of 40percent HBr (2.20 mL, 15.34 mmol) andA mixed solution of H2O (3 mL).The reaction solution was stirred at 75 ° C for 3 hours, and then cooled to room temperature.It was then extracted with ethyl acetate (40 mL x 4).The combined organic phases were washed with brine (80 mL x 2).Dry with anhydrous Na2SO4,The title compound was obtained as a yellow liquid after concentration under reduced pressure.(0.76g, 100percent).
5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-methoxypyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium dihydrogenphosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In tetrahydrofuran; water; at 60℃;Inert atmosphere; Sonication;
General procedure: [0550] In a flask which had been dried by heating andflushed with argon, 1.0 eq. of the appropriate boronic acids,1.0 eq. of the aryl bromide or aryl iodide and 0.05 eq. ofXPhos precatalyst [(2'-aminobiphenyl-2-yl)( chloro )palladium/dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphane(1:1)], J. Am. Chern. Soc. 2010, 132, 14073-14075]were initially charged. The flask was then evacuated threetimes and in each case vented with argon. THF (about 12ml/mmol) which had been degassed in an ultrasonic bath and3.0 eq. of aqueous potassium phosphate solution (0.5 molar)were added, and the reaction mixture was stirred at 60 C.Water and ethyl acetate were then added to the reaction mixture.After phase separation, the aqueous phase was extractedonce with ethyl acetate. The combined organic phases weredried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified eitherby flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanolmixtures) or by preparative HPLC (Reprosil CIS, water/acetonitrilegradient or water/methanol gradient).
193 mg
With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; water; at 60℃;Inert atmosphere; Sonication;
General procedure: General Method 2B: Suzuki coupling In a flask whichhad been dried by heating and flushed with argon, 1.0 eq. of the appropriateboronic acids, 1.0 eq. of the aryl bromide or aryl iodide and 0.05 eq. of XPhosprecatalyst[(2'-aminobipheny1-2-y1)(chloro)palladium/dicyclohexyl(2',4',61-triisopropylbipheny1-2-yl)phosphane(1:1)], J. Am. Chem. Soc. 2010, 132, 14073-14075] were initially charged. Theflask was then evacuated three times and in each case vented with argon. THF(about 12 ml/mmol) which had been degassed in an ultrasonic bath and 3.0 eq. ofaqueous potassium phosphate solution (0.5 molar) were added, and the reactionmixture was stirred at 60 C. Water and ethyl acetate were then I uiu fore=countries added to the reaction mixture. After phase separation, the aqueousphase was extracted once with ethyl acetate. The combined organic phases weredried (sodium sulphate), filtered and concentrated = under reduced pressure.The crude product was then purified either by flash chromatography (silica gel60, mobile phase: cyclohexane/ethyl acetate mixtures ordichloromethane/methanol mixtures) or by preparative HPLC (Reprosil C18,water/acetonitrile gradient or water/methanol gradient).443 mg (2.20 mmol) of5-chloro-2-methoxypyridin-4-ylboronic acid and 571 mg (2.20 mmol) of2-bromo-4-chloro-1-(trifluoromethyl)benzene in the presence of XPhosprecatalyst were reacted according to General Method 2B.Yield: 193 mg (purity 93%, 25% of theory)
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