2-(Trifluoromethyl)pyrimidine-5-carboxylic acid

White to pale yellow solid

To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (56.8 g, 252.8 mmol) dissolved in THF (500 mL) was added 1M aq. LiCH (380 mL, 379.3 mmol). The reaction mixture was stirred at RT for 16 h, concentrated under vacuum toremove the organic solvent and the remaining aqueous acidified to pH 1 with conc.HCI. The resultant precipitate was collected by vacuum filtration to afford 44.4(91 percent yield) of the title compound as off-white powder.1H NMR (500 MHz, DMSO-d6): 6 [ppm] 9.44 (5, 2H).LCMS (Analytical Method A) Rt = 0.81 mm, MS (ESineg): m/z = 190.9 (M)-.To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (56.8 g, 252.8 mmol) dissolved in THF (500 mL) was added 1M aq. LiCH (380 mL, 379.3 mmol). The reaction mixture was stirred at RT for 16 h, concentrated under vacuum toremove the organic solvent and the remaining aqueous acidified to pH 1 with conc.HCI. The resultant precipitate was collected by vacuum filtration to afford 44.4(91 % yield) of the title compound as off-white powder.1H NMR (500 MHz, DMSO-d6): 6 [ppm] 9.44 (5, 2H).LCMS (Analytical Method A) Rt = 0.81 mm, MS (ESineg): m/z = 190.9 (M)-.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.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.2-(Trifluoromethyl)pyrimidine-5-carboxylic acid (44.39 g, 231 .1 mmol), methoxymethanine hydrochloride (33.8 g, 346.6 mmol) and DIPEA (119.5 mL, 924.3 mmol) were combined in DCM (750 mL) then HATU (105.4 g, 277.3 mmol) was added and the mixture stirred at RT for 2 h. The reaction mixture was washed with water (3 x 300 mL), the organic phase collected, dried (over Mg504), filtered andconcentrated in vacuo to give a viscous yellow oil. The crude material was purified by dry flash chromatography (eluting with 0 - 40 % EtOAc in heptane) to give 54.2 g (95% yield) of the title compound as a free flowing pale yellow oil.1H NMR (500 MHz, Chloroform-d): 6 [ppm] 9.22 (5, 2H), 3.61 (5, 3H), 3.43 (5, 3H). LCMS (Analytical Method A) Rt = 1 .03 mm, MS (ESipos): m/z = 235.9 (M+H).Intermediate II (1 g, 5.2 mmo[), ammonium chloride (0.56, 10.4 mmol) andtriethylamine (1.45 mL, 10.4 mmol) were suspended in 1, 4-dioxane. T3P (50 % inEtOAc, 7.3 mL, 12.5 mmol) was added and the reaction stirred at 100 C for 24 h.The reaction was re-treated with T3P (50 % in EtOAc, 3.65 mL, 6.25 mmol) andheated for a further 6 h. The reaction was re-treated with ammonium chloride(0.56, 10.4 mmol) and triethylamine (1.45 mL, 10.4 mmol) and stirred at 100 C for18 h. The reaction mixture was diluted with water (20 mL) and extracted withEtOAc (3 x 20 mL). The combined organics were dried over MgSO4, filtered andconcentrated under reduced pressure. The crude material was purified by BiotageIsolera chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 1:1) toafford 642 mg (71% yield) of the title compound as a colourless oil. 1H NMR (250 MHz, Chloroform-d): 6 [ppm] 9.19 (5, 2H). LCMS (Analytical Method A) Rt = 0.96 mm.

Molecular Weight:192.10
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:1
Exact Mass:192.01466183
Monoisotopic Mass:192.01466183
Topological Polar Surface Area:63.1
Heavy Atom Count:13
Complexity:199
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes