Ethyl4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate

Intermediate B2-Ethyl 2-trifluoromethyl-4-chloropyrimidine-5-carboxylate To a solution of diethyl (ethoxy methylene) malonate (10 g, 46.24 mmol) and trifluoroacetamidine (6.2 g, 55.48 mmol) in anhydrous EtOH (60 mL) was added sodium ethoxide (3.15 g, 46.24 mmol). Then the reaction mixture was refluxed at 80C for 8h under NIntermediate B3-Ethyl 2-trifluorormethylpyrimidine-5-carboxylate A mixture of Step A: Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate A mixture of 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 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 Intermediate B3-Ethyl 2-trifluorormethylpyrimidine-5-carboxylate A mixture of Step A: Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate A mixture of 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 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 To a solution of diethyl (ethoxy methylene) malonate (10 g, 46.24 mmol) and trifluoroacetamidine (6.2 g, 55.48 mmol) in anhydrous EtOH (60 mL) was added sodium ethoxide (3.15 g, 46.24 mmol). Then the reaction mixture was refluxed at 80C for 8h under N2 atmosphere. TLC confirmed the completion of the reaction. Then the reaction mixture was cooled to room temperature and evaporated the excess ethanol by rotavapor and poured into ice water to get solid. The solid was filtered and washed with DI water and hexane, dried under vacuum to give the ethyl 2-(trifluoromethyl)-1, 6-dihydro-6-oxopyrimidine-5-carboxylate as a pale yellow solid (5g, 60%), which was used without further purification for next step. The intermediate (2.4 g) was slowly added to phosphoryl (V) oxychloride (25 ml) and the reaction mixture was heated to 100C for 3h. After cooling the reaction mixture to room temperature, slowly poured into crushed ice. Slowly stirred to get the solid, then filtered the solid and purified by column chromatography on silica gel (EtOAc 5% in Hexane) to afford intermediate as an off-white solid. Yield: 2.5g, 95%. 1H NMR (DMSO-d6, 400MHz): 9.41(1H, s), 4.41(2H, q), 1.36(3H, t). ESIMS: 255 (M+1).Intermediate B2-Ethyl 2-trifluoromethyl-4-chloropyrimidine-5-carboxylate To a solution of ethyl 4-hydroxy-2-trifluorormethylpyrimidine-5-carboxylate (51.8 g) in dichloromethane (600 ml) cooled in an ice bath was added oxalyl chloride (57.4 ml) followed by dimethylformamide (0.2 ml).The mixture was stir at room temperature for 16 h and then evaporated.toluene was added and evaporated.The residue was dissolved in dichloromethane, washed with water, dried (MgSO4) and evaporated to give the title compound as an orange oil (55.7 g, 100%).1H-NMR (CDCl3) delta 9.25 (1H, s), 4.51 (2H, q), 1.46 (3H, t); 13C-NMR (CDCl3) delta 126.0 (2C), 161.1, 158.1 (q, J=39 Hz), 127.0, 118.9 (q, J=276 Hz), 63.5, 14.4.ETHYL 4-HYDRAZINO-2-TRIFLUOROMETHYLPYRIMIDINE-5-CARBOXYLATE A solution of To a solution of

Molecular Weight:254.59
XLogP3:2.3
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:3
Exact Mass:254.0069896
Monoisotopic Mass:254.0069896
Topological Polar Surface Area:52.1
Heavy Atom Count:16
Complexity:262
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes