tert-butyl (2R)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate

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

Procedure: Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added to a solution of (R)-N-Boc-pyrrolidine-2-methanol (125.3 mg, 0.62 mmol) and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane at 0° C. under argon. After stirring for 1 h, the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL). The organic layer was sequentially washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (R)-N-Boc-pyrrolidine-2-methanol methanesulfonate, which was used crude. the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL) The organic layer was sequentially washed with water (15 mL) and brine (15 mL) dried over anhydrous sodium sulfate the solvent was removed in vacuo

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

Procedure: A mixture of tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g, 26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213.), 3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate (10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at 100° C. for 6 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) to give 3.62 g (45%) of the title compound as a colorless oil. After cooling to room temperature the aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried over magnesium sulfate concentrated in vacuo The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1)

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

Procedure: Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added to a solution of (R)-N-Boc-pyrrolidine-2-methanol (125.3 mg, 0.62 mmol) and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane at 0° C. under argon. After stirring for 1 h, the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL). The organic layer was sequentially washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (R)-N-Boc-pyrrolidine-2-methanol methanesulfonate, which was used crude. the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL) The organic layer was sequentially washed with water (15 mL) and brine (15 mL) dried over anhydrous sodium sulfate the solvent was removed in vacuo

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

Procedure: (R)-tert-butyl 2-(((S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrrolidine-1-carboxylate (94 mg, 50%) was prepared by the procedure described in Example 38, Step 1, using (S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one and (R)-tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate.

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

Procedure: Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added to a solution of (R)-N-Boc-pyrrolidine-2-methanol (125.3 mg, 0.62 mmol) and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane at 0° C. under argon. After stirring for 1 h, the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL). The organic layer was sequentially washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (R)-N-Boc-pyrrolidine-2-methanol methanesulfonate, which was used crude. the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL) The organic layer was sequentially washed with water (15 mL) and brine (15 mL) dried over anhydrous sodium sulfate the solvent was removed in vacuo

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

Procedure: Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added to a solution of (R)-N-Boc-pyrrolidine-2-methanol (125.3 mg, 0.62 mmol) and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane at 0° C. under argon. After stirring for 1 h, the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL). The organic layer was sequentially washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (R)-N-Boc-pyrrolidine-2-methanol methanesulfonate, which was used crude. the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL) The organic layer was sequentially washed with water (15 mL) and brine (15 mL) dried over anhydrous sodium sulfate the solvent was removed in vacuo

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

Procedure: A mixture of tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g, 26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213), 3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate (10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at 100° C. for 6 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) to give 3.62 g (45%) of the title compound as a colorless oil. After cooling to room temperature the aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried over magnesium sulfate concentrated in vacuo The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1)

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

Procedure: A mixture of tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g, 26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213), 3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate (10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at 100° C. for 6 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) to give 3.62 g (45%) of the title compound as a colorless oil. After cooling to room temperature the aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried over magnesium sulfate concentrated in vacuo The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1)

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

Procedure: A mixture of tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g, 26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213.), 3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate (10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at 100° C. for 6 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) to give 3.62 g (45%) of the title compound as a colorless oil. After cooling to room temperature the aqueous layer was extracted with ethyl acetate twice The combined organic layers were dried over magnesium sulfate concentrated in vacuo The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1)

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

Procedure: (R)-tert-butyl 2-(((S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrrolidine-1-carboxylate (94 mg, 50%) was prepared by the procedure described in Example 38, Step 1, using (S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one and (R)-tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate.