Background and overview[1]
2-Methyl-4-oxazolemethanol is an organic intermediate that can be prepared from serine methyl ester hydrochloride as the starting material.
Preparation method[1]
Step 1
Add sodium methoxide (25% w/w in methanol, 1.65 mL, 7.20 mmol) to a solution of methanol (50 mL) in dichloromethane (450 mL) at 0-5°C. After 5 minutes, chloroacetonitrile (50 mL, 790 mmol) was added and the solution was stirred at 0-5°C for 1.5 hours. Serine methyl ester hydrochloride (99.0 g, 636 mmol) was added at 0-5°C and the resulting slurry was warmed to room temperature and stirred for 18 hours. Water (200 mL) was added and the mixture was stirred for 10 minutes to ensure all solids had dissolved, then the aqueous and organic layers were separated. The organic layer was washed with water (200 mL) and concentrated by distillation at atmospheric pressure to obtain a residual volume of 150 mL. Add fresh methylene chloride (500 mL) and warm the solution to 30°C. 1,8-diazabicyclo[5.4.0]undec-7-ene (95 mL, 635 mmol) was added over 2 hours while maintaining the internal temperature of the reaction at 30 °C. After the addition was complete, the reaction mixture was cooled to room temperature and HCl (200 mL; 2M; aqueous) was added. The organic layer was then washed with water (200 mL).
Concentrate the organic layer by distillation at atmospheric pressure, leaving a residual volume of 300 mL. Heptane (mL) was added and the solution was concentrated by distillation at atmospheric pressure, leaving a residual volume of 300 mL. Heptane (100 mL) was added, the solution was cooled to 45 °C, and seeds of methyl ester 2 were added to induce crystallization. The resulting slurry was cooled to 0-5°C and aged for 2 hours. The slurry was filtered, and the filter cake was washed with cold heptane and then dried to obtain methyl ester 2, which is 2-methyloxazole-4-carboxylic acid methyl ester, with a yield of 69%. Mp = 48°C; 1 H NMR (MHz, CDCl3) δ8.16 (s, 1H), 3.91 (s, 3H), 2.52 (s, 3H); 13C NMR (100MHz , CDCl3) δ162.2,161.6,143.7,133.1,51.9,13.7; IR (neat cm-1) 1732,1585; LRMS (CI + ve) m/z 142(M++H).
Step 2
Preparation of 2-methyl-4-oxazolemethanol. Methyl ester 2 (500 g, 3.55 mol) was suspended in diethyl ether (7.7 L) and cooled to -5°C. Add lithium aluminum hydride solution (1.0M in tetrahydrofuran, 2.13L, 2 rubber additives.13mol) while maintaining the temperature at -5°C. After 1 hour, water (81 mL) was added, followed by NaOH (81 mL; 15% w/v; aqueous solution) and additional water (242 mL). Sodium sulfate (1.02kg) was added and the resulting suspension was warmed to room temperature. The slurry was filtered and the filter cake was washed with dichloromethane (3×2.5L). The filtrate and washing liquid were combined, and then concentrated to dryness to obtain 2-methyloxazole-4-methanol as an off-white solid (280g). If desired, the alcohol can be recrystallized from heptane. Yield 70%, 1H NMR (MHz, CDCl3) δ7.48 (s, 1H), 5.00 (br s, 1H ), 4.53 (s, 2H), 2.43 (s, 3 H); 13C NMR (100MHz, CDCl3) δ162.2,140.3,134.9,55.8,13.7; IR (neat cm-1) 3212,1578; LRMS (CI + ve) m/z 114 (M + + H).
Main reference materials
[1] Benoit G E , Carey J S , Chapman A M , et al. Large-Scale Preparation of 2-Methyloxazole-4-carboxaldehyde[J]. ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2008, 12(1):88-95 .
