Synthesis
The general procedure for the synthesis of 4-methyl-1,3-oxazole-5-carboxylic acid from the compound (CAS:77287-34-4) and ethyl 2-chloroacetoacetate is as follows:
1. ethyl 2-chloroacetoacetate (1 wt., 1 eq., 1000 g) was mixed with formamide (0.68 v/v, ca. 2.8 eq.), and the resulting solution was heated to 120° C. The reaction was carried out as follows.
2. After 5 hours of reaction, the mixture was cooled to room temperature and allowed to stand overnight under nitrogen protection.
3. the mixture was treated with 3M NaOH aqueous solution (6 vol.), the reaction was moderately exothermic and stirred for 4 hours at room temperature.
4. Add ethyl acetate (6 v/v) and separate the two phases. The organic layer was discarded and the aqueous phase was adjusted to pH 2 with 32% aqueous HCl (about 2.0 vol. portions required), at which point a precipitate began to form.
5. The suspension was treated with ethyl acetate (8 v/v) with vigorous stirring until most of the precipitate was dissolved.
6. The aqueous phase was further extracted twice with ethyl acetate (6 vol. parts each), the organic layers were combined and distilled to a small volume (the suspension was observed to reappear).
7. Fresh ethyl acetate (8 vol. parts) was added and the mixture was evaporated to dryness.
8. The collected solid was dried under reduced pressure at 40 °C overnight to afford 4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5% yield).
References
[1] Patent: WO2005/80382, 2005, A1. Location in patent: Page/Page column 47-48
[2] Patent: WO2007/22933, 2007, A1. Location in patent: Page/Page column 31-32
[3] Patent: WO2007/22980, 2007, A1. Location in patent: Page/Page column 35; 36
[4] Patent: WO2005/123717, 2005, A1. Location in patent: Page/Page column 21-22
[5] Patent: WO2006/108700, 2006, A1. Location in patent: Page/Page column 34-35
