4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carbaldehyde → (S)-4-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

温度

25 °C

In a 5 ml-reaction tube a solution of (S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.4) (22 mg, 0.1 mmol) in methanol (0.3 ml) was treated at room temperature at under an inert atmosphere with 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (19.9 mg, 110 μmol). The tube was closed and the reaction mixture was stirred at 25° C. for 60 minutes. Then decaborane (24.4 mg, 200 μmol) was added in one portion, the tube was closed, and the mixture was warmed to 45° C. for 15 hours. For the workup, the reaction solution was quenched with a solution of sodium carbonate (10%). Methanol was removed at reduced pressure, then the residue was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduce pressure. The crude product was purified by basic preparative HPLC and after evaporation triturated with a mixture of ether and heptane. The (S)-4-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (8 mg, 20% yield) was obtained as a colorless oil. MS (ISP): m/z=388.2 [M+H]+.

1. customThe tube was closed
2. customthe tube was closed
3. temperaturethe mixture was warmed to 45° C. for 15 hours
4. customFor the workup, the reaction solution was quenched with a solution of sodium carbonate (10%)
5. customMethanol was removed at reduced pressure
6. extractionthe residue was extracted three times with ethyl acetate
7. dry with materialThe combined organic layers were dried over sodium sulphate
8. customevaporated
9. customThe crude product was purified by basic preparative HPLC
10. customafter evaporation
11. customtriturated with a mixture of ether and heptane

ORDレコード

ord-55a7d1cdd09f4a4e887a9329108d3847

出典データセット

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08785436B2