Morpholine → HCID 59395807, compound

Temperature

60 °C

5-[(4-Fluorophenyl)methyl]-1H-tetrazole (75 mg, 0.4 mmol) was treated with potassium carbonate (100 mg, 0.7 mmol) and DMF (3 ml). The mixture was treated with a solution of 3-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (100 mg, 0.2 mmol) in DMF (0.5 ml). The mixture was stirred and heated at 60° C. 3 hours then cooled and evaporated. The residue was partitioned between chloroform (4 ml) and water (2 cm3). 1 cm3 of saturated aqueous sodium bicarbonate (3 ml) was added to each. The mixture was separated and the organic phase evaporated. The residue was dissolved in anhydrous THF (3 ml) and the mixture degassed by the cautious successive application of vacuum and nitrogen pressure to the mixture. The mixture was treated with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol) and morpholine (0.2 ml, 2.3 mmol) and then stirred in a nitrogen atmosphere for 2 h. The mixture was evaporated and partitioned between chloroform (4 ml) and saturated aqueous ammonium chloride (3 ml). The mixture was separated, and the aqueous phase re-extracted with chloroform. The organic phase was evaporated and the residue dissolved in MeOH (3 ml). The solution was added to the top of a 2 g aminopropyl SPE and washed with MeOH (15 ml). The desired product was eluted from the cartridge with a 3% v/v solution of AcOH in MeOH (20 ml). Product containing fractions were combined and evaporated and the residue subjected to purification by flash column chromatography (gradient elution from 10:1 cyclohexane/EtOAc to EtOAc). Product-containing fractions were combined and evaporated to yield the product as a colourless oil. Trituration in minimal diethyl ether caused the product to solidify and this was thoroughly dried to yield the title compound as a white solid (18.7 mg, 18%).

1. temperature3 hours then cooled
2. customevaporated
3. customThe residue was partitioned between chloroform (4 ml) and water (2 cm3)
4. addition1 cm3 of saturated aqueous sodium bicarbonate (3 ml) was added to each
5. customThe mixture was separated
6. customthe organic phase evaporated
7. dissolutionThe residue was dissolved in anhydrous THF (3 ml)
8. customthe mixture degassed by the cautious successive application of vacuum and nitrogen pressure to the mixture
9. stirringstirred in a nitrogen atmosphere for 2 h
10. customThe mixture was evaporated
11. custompartitioned between chloroform (4 ml) and saturated aqueous ammonium chloride (3 ml)
12. customThe mixture was separated
13. extractionthe aqueous phase re-extracted with chloroform
14. customThe organic phase was evaporated
15. dissolutionthe residue dissolved in MeOH (3 ml)
16. additionThe solution was added to the top of a 2 g aminopropyl SPE
17. washwashed with MeOH (15 ml)
18. washThe desired product was eluted from the cartridge with a 3% v/v solution of AcOH in MeOH (20 ml)
19. additionProduct containing fractions
20. customevaporated
21. customthe residue subjected to purification by flash column chromatography (gradient elution from 10:1 cyclohexane/EtOAc to EtOAc)
22. customevaporated

ORD record

ord-362b96db44a64f1298337694fe02e887

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08143264B2