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5-(3-methyl-1,2,4-oxadiazol-5-yl)-2,4(1H,3H)-pyrimidinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a suspension of Sodium hydride (120 mg, 3.00 mmol) in THF (15 mL) activated molecular sieves (0.3 nm, beads about 2 mm) were added. Then, N- hydroxyethanimidamide (commercially available from ABCR, 222 mg, 3.00 mmol) dissolved in THF (8 mL) was added.After 15 min. Methyl 2,4-bis(methyloxy)-5-pyrimidinecarboxylate (Prep32, 540 mg, 2.72 mmol) dissolved in THF (12 mL) was added. After 10 min. N,N-Dimethylformamide (DMF) (7.00 mL) was added and the reaction mixture was stirred at 60 0C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a red oil (195mg).The residue was dissolved in HCI 4M in dioxane (15mL, psiOmmol) and heated at 9OC for2h. Solvents were evaporated under vaccum to obtain 170mg of the title compound as brown solid. MS (ES) (mlz): 196.12 [M+H]+.
Example 26A tert-Butyl {(3-methyl-1,2,4-oxadiazol-5-yl)[3-(trifluoromethyl)phenyl]methyl}carbamate (Racemate) A quantity of 319 mg of <strong>[146621-92-3](DL)-[(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid</strong> (1.0 mmol) in 2 ml of DMF and 6 ml of dichloromethane was admixed with 162 mg (1.2 mmol) of HOBt, 230 mg (1.2 mmol) of EDC, 89 mg (1.2 mmol) of N-hydroxyacetamidine and 261 mul of N,N-diisopropylethylamine and the reaction mixture was stirred at RT overnight. The dichloromethane was removed on a rotary evaporator and the remaining mixture was diluted with ethyl acetate. This organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator to remove the solvent. The residue was heated to reflux in 4 ml of pyridine for 30 minutes, then cooled to RT. The pyridine was removed on a rotary evaporator and the residue was purified by preparative HPLC (Method 10). This gave 237 mg (66% of theory) of the title compound. LC-MS [Method 1]: Rt=0.95 min; MS [ESneg]: m/z=356 (M-H)- 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.40 (s, 9H), 2.26-2.35 (m, 3H), 6.29 (d, 1H), 7.60-7.67 (m, 1H), 7.76 (dd, 2H), 7.89 (s, 1H), 8.43 (d, 1H).
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20 - 27℃;
Triethylamine (2.1 mE, 15.0 mmol) and HATU (2.09 g, 5.5 mmol) were added to a solution of (1S,3R)-3- [(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (1.13 g, 5.0 mmol) and N-hydroxyethanimidamide (0.37 g, 5.0 mmol) in DCM (25 mE) and the resulting mixture was stirred at RT overnight. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (x3). The combined organic phases were passed through a phase separator cartridge and concentrated in-vacuo to give the crude uncyclised product, which was immediately dissolved in THF (50 mE), treated with Cs2CO3 (3.26 g, 10 mmol) and heated at reflux at 70 C. overnight. The reaction mixture was concentrated to remove the THF and the residue was partitioned between sat. aq. NaHCO3 and EtOAc. The phases were separated and the aqueous phase was extracted thrther with EtOAc (x2). The combined organic phases were passed through a phase separator cartridge and concentrated. The crude residue was purified by flash chromatography (normal silica, mesh size: 60-120, 0% to 10% MeOH inDCM) to give tert-butyl [(1R,35)-3-(3-methyl-1 ,2,4-oxadi- azol-5-yl)cyclopentyl]carbamate (1.15 g, 87%).
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