反应详情

温度

0 °C

A solution of 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM) (74 mg, 0.25 mmol) in methanol (5 ml) was cooled to 0° C. and treated with 5-(but-2-ynyloxy)pyrazine-2-carboxylic acid (CAS[1221447-98-8]) (40.8 mg, 0.21 mmol). The suspension was stirred at 0° C. for 30 minutes, then a solution of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) (50 mg, 0.19 mmol) in methanol (1 ml) was added dropwise. The resulting yellow solution was stirred at 0° C. for 4 hours. For the workup, the reaction mixture was evaporated at reduced pressure and the residue treated with a saturated solution of sodium carbonate (10 ml). Extraction with ethyl acetate, combination of the organic layers, drying over sodium sulphate, and evaporation at reduced pressure yielded the crude product. After chromatography on a silica-NH2 phase using ethyl acetate as the eluent, the product was obtained as a yellowish oil which, after trituration in isopropyl ether, yielded the 5-but-2-ynyloxy-pyrazine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide (52 mg, 63% yield) as a white solid. MS (ISP): m/z=434.2 [M+H]+.

1. stirringThe resulting yellow solution was stirred at 0° C. for 4 hours
2. customFor the workup, the reaction mixture was evaporated at reduced pressure
3. additionthe residue treated with a saturated solution of sodium carbonate (10 ml)
4. extractionExtraction with ethyl acetate, combination of the organic layers
5. dry with materialdrying over sodium sulphate, and evaporation at reduced pressure
6. customyielded the crude product
7. customthe product was obtained as a yellowish oil which