2-Pyrimidinecarboxylic acid, methyl ester

Step A: Step A: Methyl pyrimidine-2-carboxylate: HCl gas was bubbled through 700 ml MeOH as 0° C. to give a saturated solution. Pyrimidine-2-carbonitrile (21.585 g, 205.38 mmol)was added and the reaction was stirred at ambient temperature for 16 hours at, then heated at 40-50° C. for 3 hours. The solvent was evaporated under vacuum, leaving an off-white semi-solid, which was dissolved water and the pH adjusted 7.0 using NaHCO[00119] Preparation 3, Step 1: A solution of 2-cyanopyrimidine, (26 g, 24.8 mmol) in anhydrous MeOH (150 mL) was placed in a 250 ml pressure bottle and cooled to 0 [00119] Preparation 3, Step 1: A solution of 2-cyanopyrimidine, (26 g, 24.8 mmol) in anhydrous MeOH (150 mL) was placed in a 250 ml pressure bottle and cooled to 0 Methyl pyrimidine-2-carboxylate (11):A stirred solution of cyano 10 (1.01 g, 9.52 mmol) in methanolic HC1 (20 mL, 4N solution) was refluxed for 16 h and concentrated under reduced pressure; the residue was diluted with water and neutralized with sodium bicarbonate solution. The aqueous layer was extracted with 20percent IPA/CHPreparation of pyrimidine-2-carboxylic Acid Methyl Ester: [0303] Pyrimidine-2-carbaldehyde was prepared as described for COMPOUND 68 using Step A: Preparation of methylpyrimidine-2-carboxylate: HCl gas was bubbled through methanol (MeOH, 700 mL) at a temperature of 0 C. for 30 minutes to give a saturated solution. Pyrimidine-2-carbonitrile (21.585 g, 205.38 mmol) was added to this solution, and the mixture was stirred at room temperature for 16 hours and then at a temperature ranging from about 40 to about 50 C. for 3 hours. The reaction mixture was concentrated, and the residue was dissolved in water. The pH was adjusted to about 7.0 using solid NaHCO3. The aqueous layer was extracted with 20% isopropyl alcohol (iPrOH)/dichloromethane (DCM) (3*). The combined organics were dried over sodium sulfate, filtered and concentrated under vacuum to give the desired product as white solids (23.0 g, 81%). 1H NMR (400 MHz, CDCl3) delta 8.97-8.96 (d, J=4.7 Hz, 2H), 7.53-7.50 (t, J=4.7 Hz, 1H), 4.09 (s, 3H).Step A: Methyl pyrimidine-2-carboxylate: HCl gas was bubbled through 700 ml MeOH as 0 C. to give a saturated solution. Pyrimidine-2-carbonitrile (21.585 g, 205.38 mmol)was added and the reaction was stirred at ambient temperature for 16 hours at, then heated at 40-50 C. for 3 hours. The solvent was evaporated under vacuum, leaving an off-white semi-solid, which was dissolved water and the pH adjusted 7.0 using NaHCO3. The mixture was extracted with 20% iPrOH/CH2Cl2, dried over sodium sulfate and concentrated under vacuum to white residue (23.0 g, 81%).Step A: Preparation of methylpyrimidine-2-carboxlate: To a cold (0 C.) solution of saturated HCl in MeOH (60 mL) was added a solution of pyrimidine-2-carbonitrile (1.4 g, 13 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature overnight. Methanol was removed and the resulting white solids were triturated with ether (200 mL). The solids were dissolved in water (20 mL) and the pH was adjusted to 4 with saturated NaHCO3 The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organics were dried, filtered and concentrated to give a white solid (0.8 g), which was used in the next step without purification.[00119] Preparation 3, Step 1: A solution of 2-cyanopyrimidine, (26 g, 24.8 mmol) in anhydrous MeOH (150 mL) was placed in a 250 ml pressure bottle and cooled to 0 0C. Anhydrous HCl was bubbled through the solution for 10 min. The reaction vessel was capped and heated at 55 0C for 14 h. The mixture was cooled and concentrated in vacuo. The resultant residue was treated with CHCI3 / isopropyl Methyl pyrimidine-2-carboxylate (11):A stirred solution of cyano 10 (1.01 g, 9.52 mmol) in methanolic HC1 (20 mL, 4N solution) was refluxed for 16 h and concentrated under reduced pressure; the residue was diluted with water and neutralized with sodium bicarbonate solution. The aqueous layer was extracted with 20% IPA/CH2CI2, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford ester 11 (0.43 g, 32.5%) as liquid.TLC: 100% EtOAc (Rf: 0.1)1H NMR (500MHz, CDC13): delta 8.96 (d, J = 5.0 Hz, 2H), 7.50 (t, J = 5.0 Hz, 1H), 4.08 (s, 3H). Mass (ESI): 139 (M++l).Methyl pyrimidine-2-carboxylate. To a solution of pyrimidine-2-carbonitrile (0.5 g, 4.76 mmol) and water (4.76 mmol) in methanol (15 mL) was bubbled HCl gas until the solution was saturated. Once saturation was completed the solution was refluxed for 2 hours. The reaction was cooled in dry ice to-induce crystallization of a white powder which was discarded. The resultant solvate was concentrated and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The sodium bicarbonate layer was extracted two more times with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated to afford title ester as a white solid powder. 1H NMR (300 MHz, CDCl3) delta 8.96-8.94 (d, j=4.9 Hz, 2 H), 7.26-7.52 (t, j=4.9 Hz, 1 H, ), 4.07 (s, 1H).Step A: Preparation of methylpyrimidine-2-carboxlate: To a cold (0 C.) solution of saturated HCl in MeOH (60 mL) was added a solution of pyrimidine-2-carbonitrile (1.4 g, 13 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature overnight. Methanol was removed and the resulting white solids were triturated with ether (200 mL). The solids were dissolved in water (20 mL) and the pH was adjusted to 4 with saturated NaHCO3 The aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organics were dried, filtered and concentrated to give a white solid (0.8 g), which was used in the next step without purification.Synthesis of [0505] Synthesis of General procedure: To a mixture of 1H-pyrrole-3-carboxylic acid (1.0 g, 9.00 mmol) and cesium carbonate (1.58 mL, 19.80 mmol) in ACN (20 mL) colled in an ice bath, was added iodomethane (1.68 mL, 27.0 mmol). The resulting mixture was stirred at RT. The mixture was then filtered, and the solid was washed with EtOAc. The filtrate was concentrated and dried under reduced pressure to give methyl 1-methyl-1H-pyrrole-3-carboxylate (577 mg). LCMS- ESI (pos.): 140.1 (M+H)+.Thionyl chloride (1.49 mL, 20.0 mmol) was slowly added to methanol (20.0 mL) at 0 C under nitrogen and stirred for 30 min. Pyrimidine-2-carboxylic acid 3 (0.25 g, 2.0 mmol) was added and the mixture was stirred at room temperature for 24 h, concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous solution of sodium bicarbonate [28]. The layers were separated and the aqueous phase was extracted with dichloromethane (3 x 15 mL). The organic phases were combined, dried with anhydrous magnesium sulfate and then concentrated under vacuum to yield 4 in 62%. The crude product was used in the next step without further purification. To a solution of

Molecular Weight:138.12
XLogP3:-0.7
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:138.042927438
Monoisotopic Mass:138.042927438
Topological Polar Surface Area:52.1
Heavy Atom Count:10
Complexity:121
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes