* 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.
General procedure: The compounds in examples 255-275 were synthesized using the general procedure outlined in Example 134. In these cases in the final step, the appropriate Boc protected aniline ( 1 eq) was reacted with the chloropyrimidine intermediate (1 eq) in DMSO and stirred at 100- 120 C for 16 h. This crude mixture was directly purified by preparative HPLC to afford pure Boc protected compounds. After isolation, the Boc protected piperidines were deprotected using acidic conditions to afford the final compounds after evaporation to dryness. In some cases the compounds were washed with basic solutions to afford the free base.
With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃;
A solution of tert-butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-l- carboxylate (5.7 g, 17.68 mmol) in Ethyl acetate (150 mL) was degassed with N2 for 15 minutes. 10% Palladium on carbon (2.0 g, 17.68 mmol) was added to the reaction mixture and stirred under H2 balloon pressure for 14 h. After completion, the reaction mixture was filtered through celite and concentrated under reduced pressure to get tert-butyl 4-(4-amino-2-fluoro-phenyl)piperidine- 1-carboxylate (4.6 g, 13.60 mmol, 76.88% yield) as brown solid. LCMS (ESI+): 239.5 [M+H- 56]+.
8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile[ No CAS ]
[ 188975-15-7 ]
tert-butyl 4-(4-((6-cyano-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) amino)-2-fluorophenyl) piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene; at 100℃; for 3h;
To a stirred solution of 8-cyclopentyl-2-(methylsulfinyl)-7-oxo-7, 8-dihydropyrido [2, 3-d] pyrimidine-6-carbonitrile (150 mg, 0.49 mmol, 1 equiv) in toluene (5 mL), was added tert-butyl 4-(4-amino-2-fluorophenyl) piperidine-1-carboxylate (160 mg, 0.54 mmol, 1.1 equiv). The resultant reaction mixture was allowed to stir at 100 C for 3h. Progress of the reaction was monitored by LCMS. After completion of the reaction, solid observed was filtered and dried under vacuum to obtain desired product. LCMS: 533 [M+H] +
4-[4-(2,6-dioxopiperidin-3-ylamino)-2-fluorophenyl]piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;
To the <strong>[188975-15-7]tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate</strong> (4.5 g, 15.29 mmol) dissolved in DMF (45 mL) was added NaHCO3 (7.7 g, 91.72 mmol) and 3-bromopiperidine-2,6- dione (17.61 g, 91.72 mmol) at rt. The resulting reaction mixture was stirred at 70C for 16h. After completion of reaction (monitored by TLC), the reaction mixture was cooled to rt, diluted with water and extracted with ethyl acetate (2 × 500 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated under in vacuo. The crude residue was purified by using flash column chromatography (Silica gel 230-400 mesh; gradient 0-100% EtOAc in pet ether) to afford the desired tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidine-1-carboxylate (4.3 g, 9.54 mmol, 62.44% yield, 68% purity) LC-MS (ES- ): m/z 404.23 [M - H]-
4-(4-amino-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester[ No CAS ]
[ 188975-15-7 ]
Yield
Reaction Conditions
Operation in experiment
With palladium on activated charcoal; hydrogen; In ethyl acetate; at 20℃; for 16h;
To the tert-butyl 4-(4-amino-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.6 g, 15.73 mmol) dissolved in EtOAc (48 mL) was added Pd/C (2.40 g, 22.51 mmol). The reaction flask was evacuated and back filled with hydrogen by using hydrogen bladder and the reaction was stirred under hydrogen atmosphere at rt for 16h. The progress of reaction was monitored by LCMS. Reaction mixture was filtered through Celite bed and washed with ethyl acetate (2 x 30 mL). Filtrate was concentrated to yield the crude product which was purified by column chromatography using silica (230-400 mesh size) and 0-100% EtOAc/Pet.Ehter as eluent to afford tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate (4.5 g, 14.22 mmol, 90.36% yield, 93% purity) as yellow LC-MS (ES+): m/z 239.28 [M + H]+
tert-butyl 4-(4-bromo-2-fluorophenyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.7%
With copper(ll) bromide; In acetonitrile; at 20℃;
To a cooled solution of tert-butyl nitrite (2.10 g, 20.38 mmol, 2.42 mL), copper dibromide (4.55 g, 20.38 mmol, 966.59 μL) in Acetonitrile (10 mL) at 0 C was added a solution of tert-butyl 4-(4-amino-2-fluoro-phenyl)piperidine-l-carboxylate (4.0 g, 13.59 mmol) in Acetonitrile (20 mL) and allow to stir the reaction mixture at room temperature for 2 h. After completion, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (100 mL). The organic layer was washed with NaHCO3 solution (40 mL), brine (40 mL), dried over sodium sulphate and concentrated under reduced pressure to get crude which was purified by column chromatography on silica gel eluted with 10 % ethyl acetate in petroleum ether to afford tert-butyl 4-(4-bromo-2-fluoro-phenyl)piperidine-l-carboxylate (1.7 g, 3.08 mmol, 22.70% yield) as a light brown sticky solid. LCMS (ESI+): 302.0 [M+H-56]+.