benzyl N-[(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate

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

Procedure: To a solution of tert-butyl (3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-fluoropyrrolidine-1-carboxylate (380 mg, 1.2 mmol) in DCM (20 mL) was added TFA (0.34 mL, 3.4 mmol, 3 mol eq). The resulting reaction was stirred at ambient temperature for 2 hr. More TFA (0.34 mL, 3.4 mmol, 3 mol eq) was added and stirring at ambient temperature continued for another 2 hr. The volatiles were removed to give a colorless residue. DCM (30 mL) and aqueous K2CO3 (1 M, 5 mL) were added. The organic layer was separated, extracted with more DCM (30 mL), dried over Na2SO4 and evaporated to give the title compound as a colorless gum (246 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.29-7.43 (m, 5 H) 4.80-5.21 (m, 4 H) 4.07-4.28 (m, 1 H) 3.46 (br. s., 1 H) 2.96-3.30 (m, 2 H) 2.74 (br. s., 1 H). 19F NMR (376 MHz, chloroform-d) δ ppm −72.38 (s, 1F). m/z (APCI+) for C12H15FN2O2 239.2 (M+H)+. Chiral purity was determined as below (using the racemic sample to compare): The resulting reaction stirring at ambient temperature continued for another 2 hr The volatiles were removed to give a colorless residue The organic layer was separated extracted with more DCM (30 mL) dried over Na2SO4 evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the above solution of crude 2-fluoro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine was added benzyl [(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate (238 mg, 1 mmol). The resulting solution was heated at 100° C. (block temperature) and stirred for 14 hr. After cooling, the volatiles were removed and the residue was purified via flash chromatography (eluting with a gradient of 100% heptane to 100% ethyl acetate and then to 10% ammonia (7 N in methanol-90% ethyl acetate) to give the title compound as a light yellow solid (402 mg, 82% yield (over 2 steps)). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1 H) 7.98 (s, 1 H) 7.91 (s, 1 H) 7.80 (d, J=5.75 Hz, 1 H) 7.71 (s, 1 H) 7.27-7.41 (m, 5 H) 4.98-5.30 (m, 3 H) 4.55-4.68 (m, 1 H) 4.16-4.34 (m, 1 H) 3.76-3.96 (m, 6 H) 3.64-3.71 (m, 1 H) 1.50 (d, J=6.72 Hz, 6 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −178.93 (br. s., 1F). m/z (APCI+) for C24H28FN9O2 494.2 (M+H)+. Chiral purity was determined as below (using racemic sample to compare): After cooling the volatiles were removed the residue was purified via flash chromatography ( eluting with a gradient of 100% heptane to 100% ethyl acetate

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

Procedure: To a solution of tert-butyl (3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-fluoropyrrolidine-1-carboxylate (380 mg, 1.2 mmol) in DCM (20 mL) was added TFA (0.34 mL, 3.4 mmol, 3 mol eq). The resulting reaction was stirred at ambient temperature for 2 hr. More TFA (0.34 mL, 3.4 mmol, 3 mol eq) was added and stirring at ambient temperature continued for another 2 hr. The volatiles were removed to give a colorless residue. DCM (30 mL) and aqueous K2CO3 (1 M, 5 mL) were added. The organic layer was separated, extracted with more DCM (30 mL), dried over Na2SO4 and evaporated to give the title compound as a colorless gum (246 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.29-7.43 (m, 5 H) 4.80-5.21 (m, 4 H) 4.07-4.28 (m, 1 H) 3.46 (br. s., 1 H) 2.96-3.30 (m, 2 H) 2.74 (br. s., 1 H). 19F NMR (376 MHz, chloroform-d) δ ppm −72.38 (s, 1F). m/z (APCI+) for C12H15FN2O2 239.2 (M+H)+. Chiral purity was determined as below (using the racemic sample to compare): The resulting reaction stirring at ambient temperature continued for another 2 hr The volatiles were removed to give a colorless residue The organic layer was separated extracted with more DCM (30 mL) dried over Na2SO4 evaporated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the above solution of crude 2-fluoro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine was added benzyl [(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate (238 mg, 1 mmol). The resulting solution was heated at 100° C. (block temperature) and stirred for 14 hr. After cooling, the volatiles were removed and the residue was purified via flash chromatography (eluting with a gradient of 100% heptane to 100% ethyl acetate and then to 10% ammonia (7 N in methanol-90% ethyl acetate) to give the title compound as a light yellow solid (402 mg, 82% yield (over 2 steps)). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1 H) 7.98 (s, 1 H) 7.91 (s, 1 H) 7.80 (d, J=5.75 Hz, 1 H) 7.71 (s, 1 H) 7.27-7.41 (m, 5 H) 4.98-5.30 (m, 3 H) 4.55-4.68 (m, 1 H) 4.16-4.34 (m, 1 H) 3.76-3.96 (m, 6 H) 3.64-3.71 (m, 1 H) 1.50 (d, J=6.72 Hz, 6 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −178.93 (br. s., 1F). m/z (APCI+) for C24H28FN9O2 494.2 (M+H)+. Chiral purity was determined as below (using racemic sample to compare): After cooling the volatiles were removed the residue was purified via flash chromatography ( eluting with a gradient of 100% heptane to 100% ethyl acetate