ETHYL 2-(TRIFLUOROMETHYL)PYRIMIDINE-5-CARBOXYLATE

Intermediate B3-Ethyl 2-trifluorormethylpyrimidine-5-carboxylate Step A: To a solution of ethyl. 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (37.5 g, 142.9 mmol) in ethanol (750 mL) was added DIPEA (68 mL, 392.3 mmol), 10 percent Pd/C(50 percent wet, 3 g) and the reaction mixture stirred under an atmosphere of hydrogenfor 1 h. The reaction mixture was filtered through glass fibre filter paper and thefiltrate concentrated under reduced pressure to give a yellow solid. The solid wastaken up in EtOAc (500 mL), washed with water (500 mL), 1M aq HCI (500 mL), saturated aq. NaHCO3 (500 mL), dried (over MgSO4), filtered and concentrated under reduced pressure. The pale yellow solid was triturated with heptane and the solid collected by filtration. The filtrate was concentrated and trituration repeated with heptane. The mother liquers from both batches were combined and purifiedby Biotage IsoleraTM chromatography (eluting with 1 - 30 percent EtOAc in heptane on a bOg KP-Si02 column). The product containg fractions were concentrated and the residue triturated with heptane. All the solids were combined to give 56.8 g (90 percent yield) of the title compound as yellow solid.1H NMR (250 MHz, Chloroform-d): 6 [ppm] 9.43 (5, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H).LCMS (Analytical Method A) Rt = 1 .24 mm, MS (ESipos): m/z = 220.9 (M+H).4-chloro-2- (trifluoromethyl) pyrimidine-5-carboxylate (1.99g, 7.82mmol) solution of ethanol (30 mL) added diisopropyl ethyl amine (2.43g, 18.8mmol), 10percent palladium - carbon (200mg), under hydrogen atmosphere, stirred at room temperature for 3.5 hours. Thereafter, the reaction mixture was diatomaceous earth filtration, concentrated under reduced pressure. Utilizing silica column chromatography (hexane / ethyl acetate) The residue obtained was purified, thereby obtaining the title compound (1.36g79percent)Step A: Intermediate B4-2-Trifluoromethyl-5-formylpyrimidine To a solution of At -78 deg.] C in was added 1mol / L toluene solution of diisobutylaluminum hydride to the compound of Reference Example 77 (50.0mg, 0.227mmol) of toluene (0.8 mL of) solution (0.25mL, 0.25 mmol), for 15 minutes stirring. Thereafter, the reaction solution was added saturated Rocher ear saline solution, stirred for 1 hour. The mixture was extracted with ethyl acetate for use organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Utilizing silica column chromatography (hexane / ethyl acetate) The residue obtained was purified, thereby obtaining the title compound (30.0mg, 75%).2-Trifluoromethyl-pyrimidine-5-carbaldehyde To a solution of To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxy.ate (25.5 g, 1 16.0 mmol) in dichloromelhane (580 mL) at -78 0C was slowly added DEBAL-H (1.0 M; 130.0 mL, 130.0 mmol). The mixture was stirred at -78 0C. After 2 h, the mixture was quenched via slow addition of HCl (2.0 M in water). The mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (3x). The combined organic extracts was dried over Na2SO4, filtered and concentrated to give the title compound (28.2 g).To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5~carboxylate (25.5 g, 116.0 mmol) in dichloromethane (580 mL) at -78 0C was slowly added DIBAL-H (1.0 M; 130.0 mL, 130.0 mmol). The mixture was stirred at -78 0C. After 2 h, the mixture was quenched via slow addition of HCl (2.0 M in water). The mixture was allowed to warm to ambient temperature. The mixture was extracted with diethyl ether (3x). The combined organic extracts was dried over Na2SO4, filtered and concentrated to give the title compound (28.2 g).To a solution of Step B: 2-(Trifluoromethyl)pyrimidine-5-carbaldehyde To a solution of Intermediate B3-Ethyl 2-trifluorormethylpyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-trifluoromethylpyrimidine-5-carboxylate (55.7 g), 10% palladium on carbon (0.3 g), ethanol (1000 ml) and N, N-diisopropylethylamine (90 ml) was shaken under hydrogen pressure maintained at 1 atmosphere for 2 h.The catalyst was then filtered off and the solvents evaporated.The residue was dissolved in dichloromethane, washed with ammonium chloride solution, then water, dried (MgSO4) and evaporated to give the title compound as a buff solid (48 g, 100%).1H-NMR (CDCl3) delta 9.42 (2H, s), 4.51 (2H, q), 1.45 (3H, t); 13C-NMR (CDCl3) delta 162.7, 159.4 (2C), 159.3 (q, J=37 Hz), 126.3, 119.6 (q, J=275 Hz), 62.9, 14.4.Step A: Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (2.51 g, 9.86 mmol, Matrix) and 10% Pd/C (0.105 g, 0.099 mmol) was evacuated and purged with N2 (3*) and EtOH (49 mL) was added followed by DIEA (4.2 mL, 24.0 mmol). The reaction was placed under a hydrogen atmosphere (via balloon) and left stirring at ambient temperature for about 4 h. The reaction was filtered through a pad of Celite, washing with EtOH and the filtrate was concentrated under reduced pressure. The crude material was taken up in DCM (25 mL) and washed with saturated aqueous NH4Cl (2*20 mL). The organics were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give ethyl 2-(trifluoromethyl)pyrimidine-3-carboxylate (2.00 g, 92%) as a yellow solid; 1H NMR (400 MHz, CDCl3) delta 9.43 (s, 2H), 4.51 (q, 2H), 1.46 (t, 3H).To a solution of ethyl. 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (37.5 g, 142.9 mmol) in ethanol (750 mL) was added DIPEA (68 mL, 392.3 mmol), 10 % Pd/C(50 % wet, 3 g) and the reaction mixture stirred under an atmosphere of hydrogenfor 1 h. The reaction mixture was filtered through glass fibre filter paper and thefiltrate concentrated under reduced pressure to give a yellow solid. The solid wastaken up in EtOAc (500 mL), washed with water (500 mL), 1M aq HCI (500 mL), saturated aq. NaHCO3 (500 mL), dried (over MgSO4), filtered and concentrated under reduced pressure. The pale yellow solid was triturated with heptane and the solid collected by filtration. The filtrate was concentrated and trituration repeated with heptane. The mother liquers from both batches were combined and purifiedby Biotage IsoleraTM chromatography (eluting with 1 - 30 % EtOAc in heptane on a bOg KP-Si02 column). The product containg fractions were concentrated and the residue triturated with heptane. All the solids were combined to give 56.8 g (90 % yield) of the title compound as yellow solid.1H NMR (250 MHz, Chloroform-d): 6 [ppm] 9.43 (5, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H).LCMS (Analytical Method A) Rt = 1 .24 mm, MS (ESipos): m/z = 220.9 (M+H).4-chloro-2- (trifluoromethyl) pyrimidine-5-carboxylate (1.99g, 7.82mmol) solution of ethanol (30 mL) added diisopropyl ethyl amine (2.43g, 18.8mmol), 10% palladium - carbon (200mg), under hydrogen atmosphere, stirred at room temperature for 3.5 hours. Thereafter, the reaction mixture was diatomaceous earth filtration, concentrated under reduced pressure. Utilizing silica column chromatography (hexane / ethyl acetate) The residue obtained was purified, thereby obtaining the title compound (1.36g79%)To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate(30.2 g, 1 19.0 mmol) in ethanol (594 mL) under nitrogen were added palladium (10% on carbon, 50% water wet; 2.58g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred68 under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with sat. NaHCO3 (2x), brine, dried over Na2SO4, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+l ).To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5- carboxylate (30.2 g, 119.0 mmol) in ethanol (594 mL) under nitrogen were added palladium(10% on carbon, 50% water wet; 2.58g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with sat. NaHCO3 (2x), brine, dried over Na2SO4, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+l).Step A: Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (30.2 g, 119.0 mmol) in ethanol (594 mL) under nitrogen were added palladium (10% on carbon, 50% water wet; 2.58g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with saturated aqueous sodium bicarbonate (2x), saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+1).Intermediate B3-Ethyl 2-trifluorormethylpyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-trifluoromethylpyrimidine-5-carboxylate (55.7 g), 10% palladium on carbon (0.3 g), ethanol (1000 ml) and N, N-diisopropylethylamine (90 ml) was shaken under hydrogen pressure maintained at 1 atmosphere for 2 h.The catalyst was then filtered off and the solvents evaporated.The residue was dissolved in dichloromethane, washed with ammonium chloride solution, then water, dried (MgSO4) and evaporated to give the title compound as a buff solid (48 g, 100%).1H-NMR (CDCl3) delta 9.42 (2H, s), 4.51 (2H, q), 1.45 (3H, t); 13C-NMR (CDCl3) delta 162.7, 159.4 (2C), 159.3 (q, J=37 Hz), 126.3, 119.6 (q, J=275 Hz), 62.9, 14.4.Step A: Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (2.51 g, 9.86 mmol, Matrix) and 10% Pd/C (0.105 g, 0.099 mmol) was evacuated and purged with N2 (3*) and EtOH (49 mL) was added followed by DIEA (4.2 mL, 24.0 mmol). The reaction was placed under a hydrogen atmosphere (via balloon) and left stirring at ambient temperature for about 4 h. The reaction was filtered through a pad of Celite, washing with EtOH and the filtrate was concentrated under reduced pressure. The crude material was taken up in DCM (25 mL) and washed with saturated aqueous NH4Cl (2*20 mL). The organics were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give ethyl 2-(trifluoromethyl)pyrimidine-3-carboxylate (2.00 g, 92%) as a yellow solid; 1H NMR (400 MHz, CDCl3) delta 9.43 (s, 2H), 4.51 (q, 2H), 1.46 (t, 3H).To a solution of ethyl. 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (37.5 g, 142.9 mmol) in ethanol (750 mL) was added DIPEA (68 mL, 392.3 mmol), 10 % Pd/C(50 % wet, 3 g) and the reaction mixture stirred under an atmosphere of hydrogenfor 1 h. The reaction mixture was filtered through glass fibre filter paper and thefiltrate concentrated under reduced pressure to give a yellow solid. The solid wastaken up in EtOAc (500 mL), washed with water (500 mL), 1M aq HCI (500 mL), saturated aq. NaHCO3 (500 mL), dried (over MgSO4), filtered and concentrated under reduced pressure. The pale yellow solid was triturated with heptane and the solid collected by filtration. The filtrate was concentrated and trituration repeated with heptane. The mother liquers from both batches were combined and purifiedby Biotage IsoleraTM chromatography (eluting with 1 - 30 % EtOAc in heptane on a bOg KP-Si02 column). The product containg fractions were concentrated and the residue triturated with heptane. All the solids were combined to give 56.8 g (90 % yield) of the title compound as yellow solid.1H NMR (250 MHz, Chloroform-d): 6 [ppm] 9.43 (5, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H).LCMS (Analytical Method A) Rt = 1 .24 mm, MS (ESipos): m/z = 220.9 (M+H).4-chloro-2- (trifluoromethyl) pyrimidine-5-carboxylate (1.99g, 7.82mmol) solution of ethanol (30 mL) added diisopropyl ethyl amine (2.43g, 18.8mmol), 10% palladium - carbon (200mg), under hydrogen atmosphere, stirred at room temperature for 3.5 hours. Thereafter, the reaction mixture was diatomaceous earth filtration, concentrated under reduced pressure. Utilizing silica column chromatography (hexane / ethyl acetate) The residue obtained was purified, thereby obtaining the title compound (1.36g79%)To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate(30.2 g, 1 19.0 mmol) in ethanol (594 mL) under nitrogen were added palladium (10% on carbon, 50% water wet; 2.58g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred68 under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with sat. NaHCO3 (2x), brine, dried over Na2SO4, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+l ).To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5- carboxylate (30.2 g, 119.0 mmol) in ethanol (594 mL) under nitrogen were added palladium(10% on carbon, 50% water wet; 2.58g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with sat. NaHCO3 (2x), brine, dried over Na2SO4, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+l).Step A: Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (30.2 g, 119.0 mmol) in ethanol (594 mL) under nitrogen were added palladium (10% on carbon, 50% water wet; 2.58g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with saturated aqueous sodium bicarbonate (2x), saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+1).To a solution of Ethyl 2-(trifluoromethyl)-5-pyrimidinecarboxylate [e.g. available from J. Med. Chem., (2000), 43 (21), 3995] (49 mg) in ethanol (0.63 ml) was treated with 2N sodium hydroxide (0.443 ml) and the solution stirred at room temperature for 24 h. 2M Hydrochloric acid (0.31 ml) was added and the mixture blown down to dryness. The residue was suspended in dry dichloromethane (0.5 ml) and treated at room temperature with oxalyl chloride (0.019 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and then added dropwise to a solution of Intermediate 15 (53 mg) in acetonitrile (1 ml). DIPEA (0.039 ml) was added and the mixture was stirred at room temperature for 18 h. The mixture was blown down to dryness and the residue was purified by mass directed autoprep HPLC followed by SPE cartridge (1 g, aminopropyl) eluting with methanol. The eluent was blown down to dryness to give Example 340 as a beige solid (9 mg). LCMS showed MH+=464; TRET=2.42 min.Example 340 W-{[1 -ethyl-6-methyl-4-(tetrahydro-2H-pyran-4-ylamino)-1 H- pyrazolo[3, 4-b]pyridin-5-yl]methyl}-2-(trifluoromethyl)-5-pyrimidine carboxamideEthyl 2-(trifluoromethyl)-5-pyrimidinecarboxylate [e.g. available from J. Med. Chem., (2000), 43 (21), 3995 (49mg) in ethanol (0.63ml) was treated with 2N sodium hydroxide (0.443ml) and the solution stirred at room temperature for 24h. 2M Hydrochloric acid (0.31ml) was added and the mixture blown down to dryness. The residue was suspended in dry dichloromethane (0.5ml) and treated at room temperature with oxalyl chloride (0.019ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and then added dropwise to a solution of Intermediate 15 (53mg) in acetonitrile (1ml). DIPEA (0.039ml) was added and the mixture was stirred at room temperature for 18h. The mixture was blown down to dryness and the residue was purified by mass directed autoprep HPLC followed by SPE cartridge (1g, aminopropyl) eluting with methanol. The eluent was blown down to dryness to give Example 340 as a beige solid (9mg). LCMS showed MH+ = 464; TRET = 2.42min.

Molecular Weight:220.15
XLogP3:1.4
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:3
Exact Mass:220.04596196
Monoisotopic Mass:220.04596196
Topological Polar Surface Area:52.1
Heavy Atom Count:15
Complexity:224
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes