Ethyl 4-methyloxazole-5-carboxylate

Preparation of 4-methyloxazole-5-formic acid ethyl ester (OXE) A 500 mL-stirred reaction vessel with a 30 mm 4-Methyl-oxazole-5-carboxylic acid A solution of 40.0 grams (0.243 mol, 1.0 eq) of 2-Chloro-3-oxo-butyric acid ethyl ester in 240 mL formic acid (99%) was stirred at room temperature in a 500 mL round bottom flask equipped with a H2O condenser. To this solution was added 80.0 grams (1.27 mmol, 5.2 eq) of ammonium formate. The solution was then heated to reflux for five hours. After cooling to room temperature, the solution was diluted with water (1 L) and neutralized with Na2CO3. The aqueous solution was then extracted three times with Et2O and the combined organic fractions were dried over MgSO4. After concentration, vacuum distillation (10 mmHg, b.p. 53 C.-61 C.) gave a mixture of starting material and 4-Methyl-oxazole-5-carboxylic acid ethyl ester as a colorless oil (21.7 grams). This mixture was dissolved in 100 mL of aqueous sodium hydroxide (2 N) and refluxed for 1 minute. The reaction was then poured onto ice and acidified with concentrated HCl and the known (Sen & Sengupta (1985) Ind. J. Chem. Section B: Org. Chem. Including Med. Chem. 24B(5):535-8) free acid precipitated as a white solid (6.04 grams, 20% overall yield) Mp: 241.4-242.6 C.Preparation 2: 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1 , 3-oxazol-5-yl)-4H- 1.2.4-triazole; Ethyl 4-methyl-1, 3-oxazole-5-carboxylate (7.0 g) was stirred at 25 C with a solution of sodium hydroxide (8.0 g) in water (70 ml) for 2 h. The resulting solution was cooled in an ice bath and conc. aqueous HCI was slowly added with vigorous stirring until pH 2 had been reached. Filtration, washing with a small volume of cold water and drying resulted in an off-white solid (3.5 g). This material (5.4 g) was allowed to react in DMF (60 ml) with 4-methyl-3- thiosemicarbazide (4.6 g), 1H-1, 2, 3-benzotriazo)-1-ol (1.1 g), N-[2-(dimethylamino)ethyl]- N-ethylcarbodiimide hydrochloride (8.6 g), and triethylamine (6.2 ml) for 14 h at 25 C. The solvent was evaporated under reduced pressure and the residue heated wit NaOH (8.5 g) in water (150 ml) at 70 C for 3.5 h. The resulting solution was cooled in an ice bath and conc. aqueous HCI (17.7 ml) was slowly added with vigorous stirring. Filtration, washing with a small volume of cold water and drying resulted in a yellow powder (5.3 g). To this material (4.8 g) in EtOH (60 ml) containing 1-bromo-3-chloropropane (3.7 ml) was carefully added with stirring sodium hydride (1.1 g, 60% in mineral oil). The mixture was heated at 60 C for 1.5 h. Acetic acid (0.15 ml) was added, volatiles evaporated under reduced pressure and the residue submitted to column chromatography (EtOAc - acetone gradient). The material thus obtained was triturated with cyclohexane to provide the title compound as a faint yellow solid (6.1 g). NMR (¹H, CDC13): 8 7.90 (s, 1 H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H).

Molecular Weight:155.15
XLogP3:1.3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:155.058243149
Monoisotopic Mass:155.058243149
Topological Polar Surface Area:52.3
Heavy Atom Count:11
Complexity:149
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes