3,3,3-trifluoropropyl methanesulfonate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3,3,3-Trifluoropropyl methanesulfonate was prepared by reaction of 3,3,3-trifluoropropanol with methanesulfonyl chloride by an analogous procedure to that used for Example 52 step 1.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 1.06 mmol, intermediate 12, step 2) in DMF (6 mL) was added 3,3,3-trifluoropropyl methanesulfonate (305 mg, 1.59 mmol) followed by potassium carbonate (439 mg, 3.17 mmol). The reaction was stirred at 60° C. overnight. The mixture was diluted with ethyl acetate and extracted with brine. The organic phase was dried and concentrated to give 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1-(3,3,3-trifluoropropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (510 mg, 84.6% yield) as yellow syrup. LCMS retention time 2.275 min; LCMS MH+ 569. extracted with brine The organic phase was dried concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,3,3-trifluoropropan-1-ol (500 mg, 4.38 mmol) in DCM (10 mL) was added TEA (1.22 mL, 8.77 mmol) followed by dropwise addition of methanesulfonyl chloride (0.51 mL, 6.58 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with DCM and the organic phase washed with brine, dried and concentrated to give crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1) to give 3,3,3-trifluoropropyl methanesulfonate (490 mg, 58.2% yield) as light yellow oil. TLC (petroleum ether/ethyl acetate=3:1), Rf=0.6. the organic phase washed with brine dried concentrated to give crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (5:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of 3-hydroxy-4-methoxy-benzoic acid ethyl ester (1.75 g, 8.92 mmol), methanesulfonic acid 3,3,3-trifluoro-propyl ester (2.06 g, 10.7 mmol) and anhydrous K2CO3 (2.49 g, 17.8 mmol) in acetone (20 mL) is heated with stirring at reflux temperature overnight. After cooling, the mixture is diluted with AcOEt followed by washing of the organic phase with 2N aqueous NaOH and brine. The organic layer is dried over Na2SO4 and evaporated, and the crude product is purified by silica gel chromatography (eluent: hexane/AcOEt 5:1) to give the title compound as oil. TLC, Rf (hexane/AcOEt 1:1)=0.59. MS: 293.0 [M+H]+. 1H-NMR (CDCl3): δ 1.42 (t, 3H), 2.74 (m, 2H), 3.96 (s, 3H), 4.33 (m, 2H), 4.40 (m, 2H), 6.94 (m, 1H), 7.59 (s, 1H), 7.77 (m, 1H) ppm. is heated at reflux temperature overnight After cooling by washing of the organic phase with 2N aqueous NaOH and brine The organic layer is dried over Na2SO4 evaporated the crude product is purified by silica gel chromatography (eluent: hexane/AcOEt 5:1)