tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate

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

Procedure: 2-{Hydroxy-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methyl}-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 72 (15), 5608-5617, 2007) following the general procedures described in these Examples.

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

Procedure: To a solution of (rac)-2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 1 eq) and 2-chloro-benzylamine (1.2 eq) in DCE (20 mL) was added acetic acid (0.8 eq) and allowed to stir for 20 minutes followed by the addition of sodium triacetoxyborohydride (2 eq). The reaction mixture was stirred for 12 h. After completion of reaction on TLC, the reaction was quenched with water and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated using rotary evaporator to give sticky crude product, which was then purified with column chromatography (2-5% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—3.0 cm, Height of silica—approx. 4 inch) to afford the desired (rac)-2-[(2-chloro-benzylamino)-methyl]-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a sticky solid (40-70%). The reaction mixture was stirred for 12 h After completion of reaction on TLC the reaction was quenched with water extracted with DCM (3×50 mL) The organic layer was dried over anhydrous Na2SO4 concentrated evaporator to give sticky crude product, which was then purified with column chromatography (2-5% Methanol:DCM, Mesh Size-100-200 silica, Diameter of column—3.0 cm, Height of silica—approx. 4 inch)

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

Procedure: Dess Martin Periodinane (7.8 g, 0.0186 mol) was added in one portion to the solution of (rac)-2-hydroxymethyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 0.0093 mol) in DCM (50 mL) under an inert atmosphere. The reaction was stirred until completion (about 2 h) then quenched with saturated solution of sodium thiosulphate, extracted with DCM (3×100 mL) washed with brine (50 mL), dried over anhydrous sodium sulphate, and concentrated using a rotary evaporator to afford 1.6 g (84%) of (rac)-2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown colored oil. then quenched with saturated solution of sodium thiosulphate extracted with DCM (3×100 mL) washed with brine (50 mL) dried over anhydrous sodium sulphate concentrated a rotary evaporator

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (3.5 g, 14.3 mmol) in toluene at −78° C. was added DIBAL-H (17.6 mL, 30 mmol, 1.7 M) dropwise, while maintaining the reaction temperature below −65° C. The reaction was stirred at −78° C. for 2 hr and then quenched with methanol (10 mL). The mixture was then diluted with ethyl acetate (50 mL), saturated NH4Cl was added and the mixture was stirred vigorously for 20 min at room temperature. The two phases were then separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organics were then washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography to give 3 g of the desired product. while maintaining the reaction temperature below −65° C quenched with methanol (10 mL) The mixture was then diluted with ethyl acetate (50 mL), saturated NH4Cl was added the mixture was stirred vigorously for 20 min at room temperature The two phases were then separated the aqueous layer was extracted with DCM (3×50 mL) The combined organics were then washed with brine dried over Na2SO4 concentrated in vacuo purified by column chromatography