Diisopropylethylamine → N-[(4aR,7aR)-6-[5-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyrimidin-2-yl]-7a-isothiazol-5-yl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide

온도

110 °C

2-(2-Chloro-5-fluoro-6-methyl-pyrimidin-4-yl)propan-2-ol (104 mg, 0.51 mmol) is dissolved in 1,4-dioxane (3 mL). N-[(4aR,7aR)-7a-Isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (125 mg, 0.36 mmol) is added followed by diisopropylethylamine (158 μL, 0.91 mmol). The reaction is heated via microwave irradiation in a sealed microwave vessel to 110° C. for 1 hr. The reaction is concentrated to give the crude product. The crude product is purified via HPLC using a Waters XBridge 5 μm C18 OBD 30×75 mm column and eluted with a gradient of: 36% B isocratic for 3 min followed by 36-51% B over 5 min where solvent A is 10 mM ammonium bicarbonate in water with 5% MeOH and solvent B is acetonitrile. The desired fractions are combined and diluted with saturated NaHCO3 (aq, 100 mL). The mixture is extracted with 4:1 CHCl3:isopropanol (3×100 mL). The organic layers are combined, washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to give the title compound (33 mg, 0.064 mmol): EZ/MS (m/z): 513 (M+H).

1. concentrationThe reaction is concentrated
2. customto give the crude product
3. customThe crude product is purified via HPLC
4. washeluted with a gradient of: 36% B
5. waitfollowed by 36-51% B over 5 min
6. additiondiluted with saturated NaHCO3 (aq, 100 mL)
7. extractionThe mixture is extracted with 4:1 CHCl3
8. washwashed with brine (1×50 mL)
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated

ORD 기록

ord-061b87ecb2bb46b68ef206d8991ec4cd

출처 데이터셋

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08772282B2