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Example 16 N4-[(trans-4-aminocyclohexyl)methyl]-5-fluoro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine Phosphorous pentachloride (8.0 g, 38.4 mmol) was added to a mixture of 5-fluorouracil (10.0 g, 76.9 mmol) and phosphorous oxychloride (30 mL). The reaction mixture was heated at reflux, for 14 h, under N2. The reaction mixture was cooled to room temperature and then poured into ice. The remaining residue from the flask was dissolved in saturated Na2CO3 and poured into the ice mixture. The mixture was extracted with EtOAc (*3) and the organic phase was dried over anhydrous Na2SO4. The solution was concentrated in vacuo to yield 9.1 g (71percent) of 5-fluoro-2,4-dichloropyridine as a pale yellow oil.
With phosphorus pentachloride; trichlorophosphate; for 14.0h;Heating / reflux;
Example 16 N4-[(trans-4-aminocyclohexyl)methyl]-5-fluoro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine Phosphorous pentachloride (8.0 g, 38.4 mmol) was added to a mixture of 5-fluorouracil (10.0 g, 76.9 mmol) and phosphorous oxychloride (30 mL). The reaction mixture was heated at reflux, for 14 h, under N2. The reaction mixture was cooled to room temperature and then poured into ice. The remaining residue from the flask was dissolved in saturated Na2CO3 and poured into the ice mixture. The mixture was extracted with EtOAc (*3) and the organic phase was dried over anhydrous Na2SO4. The solution was concentrated in vacuo to yield 9.1 g (71%) of 5-fluoro-2,4-dichloropyridine as a pale yellow oil.
With N-ethyl-N,N-diisopropylamine; In ethanol; at 40℃; for 1h;
To a solution of the above 5-fluoro-2,4-dichloropyridine (67 mg, 0.4 mol) in EtOH (2 mL) were added tert-butyl trans-4-aminomethylcyclohexylcarbamate (100 mg, 0.44 mmol) and DIPEA (77 muL, 0.44 mmol). The reaction mixture was heated at 40 C. for 1 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc and washed with brine. The aqueous layer was re-extracted with EtOAc (*2). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield 127 mg (89%) of {4-[(2-chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester.
With triethylamine; In acetonitrile;Cooling with ice;
To 2,4 dichloro-5-fluoropyridine (1g, 6mmol) dissolved in CH3CN (8ml) cooled in an ice bath was added Et3N (1.16ml, 8.4mmol) and cyclopropylamine (0.29ml, 8.4mmol) in CH3CN (2ml). Reaction stirred O0C for 2 hours, evaporated water added and reaction extracted with EtOAc (x3). The organic fractions were combined washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (0.92 g). MS: [M+H]+ = 188
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 20.0℃; for 18.0h;
A solution of 2.2 g 2,4-chloro-5-fluoropyridine, 2.28 g 4-chlorophenylboronic acid and 0.6 g tetrakistriphenylphosphinpalladium in 30 niL tetrahydrofuran was added 30 niL of a 10% a solution of potassium carbonate in water and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed water, 10% aqueous citric acid, 10% aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of heptane : dichloromethane = 9 : 1 to 1 : 1 (only starting spot was removed) The product fractions were collected and evaporated. The residue was subjected to kugelrohr distillation at 0.03 mBar and 110C to yield 1.72 g of the title compound as colorless oil which solidified into white crystals, MS 241 and 243 (M+H)+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 20.0℃; for 18.0h;
Example 10d6-Chloro-2-(4-chloro-phenyl)-3-fluoro-pyridine A solution of 2.2 g 2,4-chloro-5-fluoropyridine, 2.28 g 4-chlorophenylboronic acid and 0.6 g tetrakistriphenylphosphine palladium in 30 ml tetrahydrofuran was added 30 ml of a 10% a solution of potassium carbonate in water and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed water, 10% aqueous citric acid, 10% aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of heptane:dichloromethane=9:1 to 1:1 (only startspot was removed) The product fractions were collected and evaporated. The residue was subjected to Kugelrohr distillation at 0.03 mbar and 110 C. to yield 1.72 g of the title compound as colorless oil which solidified into white crystals. MS (EI) (M+H): 241 and 243:
tert-butyl N-[(8-endo)-3-(2-chloro-5-fluoro-4-pyridyl)-3-azabicyclo[3.2.1]octan-8-yl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.7%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 150.0℃;Inert atmosphere;
To a solution of tert-butyl N-[(8-endo)-3-azabicyclo[3.2.1]octan-8-yl]carbamate (200 mg, 884 muetaiotaomicron) in NMP (3.33 ml) (CAS Registry Number: 1330763-51-3) was added DIPEA (228 mg, 309 mu, 1.77 mmol) followed by <strong>[189281-48-9]2,4-dichloro-5-fluoropyridine</strong> (176 mg, 1.06 mmol). The reaction mixture was degassed with argon for 2 minutes. The vial was closed under argon and the dark red reaction mixture was stirred over night at 150 C. TLC showed reaction was complete. The reaction mixture was added to H20 (20 ml) and extracted with EtOAc (3 x 50 ml). The organic phase was washed with brine and dried with MgS04. The crude material was purified by flash chromatography (silica gel, 12 g, 0 % to 60 % EtOAc in heptane) to afford the title compound as an off-white powder (253.8 mg, 713 muiotaetaomicron, 80.7 % yield). MS ES+ (m/z): 356.2 [(M+H)+]
2-chloro-5-fluoro-N-methylpyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
In tetrahydrofuran; at 80.0℃; for 18.0h;
Into a 20-mL vial, was placed tetrahydrofuran (8 mL), <strong>[189281-48-9]2,4-dichloro-5-fluoropyridine</strong> (300 mg, 1.81 mmol, 1 equiv), a solution of methanamine (113 mg, 3.64 mmol, 2.01 equiv) in tetrahydrofuran (1.82 mL). The resulting solution was stirred for 18 h at 80 C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 200 mg (69%) of as a white solid. Analytical Data: LC-MS: (ES, m/z): RT = 0.469 min, LCMS 32: m/z = 161 [M+l].
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