ethyl (2S)-pyrrolidine-2-carboxylate

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

Procedure: The ethyl ester product from part (e) (1.75 g., 2.63 mmole) is dissolved in methanol (75 ml.) at room temperature under argon. The solution is hydrogenated with 20% palladium hydroxide on carbon catalyst (300 mg.) at room temperature and atmospheric pressure for 3 hours. The reaction is filtered through Celite to remove the catalyst, and the volatiles are evaporated to give 1.7 g. of 1-(S)-6-[(Trifluoroacetyl)amino]-2-[[[(1-amino)pentyl]methoxyphosphinyl]oxy]-1-oxohexyl]-L-proline, ethyl ester. The reaction is filtered through Celite to remove the catalyst the volatiles are evaporated to give 1.7 g

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

Procedure: Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and ethyl (S )-pyrrolidine-2-carboxylate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-bromo-2-chloro-3-nitropyridine (5.94 g, 25 mmol) and (S)-ethyl pyrrolidine-2-carboxylate (7.52 g, 52.5 mmol) were combined and stirred at 90° C. for 10 min in a closed vial. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes to afford (S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.43 g, 24.49 mmol, 98% yield) as a yellow viscous oil. [M+H] calc'd for C12H14BrN3O4, 344. found, 344. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-bromo-2-chloro-3-nitropyridine (5.94 g, 25 mmol) and (S)-ethyl pyrrolidine-2-carboxylate (7.52 g, 52.5 mmol) were combined and stirred at 90° C. for 10 min in a closed vial. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes to afford (S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.43 g, 24.49 mmol, 98% yield) as a yellow viscous oil. [M+H] calc'd for C12H14BrN3O4, 344. found, 344. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes

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

Procedure: To 30 ml of tetrahydrofuran, 1.4 g of proline ethyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and recrystallized from methanol-ethyl ether, whereby 2.1 g (yield: 76%) of 1-(1,3-dithiol-2-ylidene)-2-ethoxycarbonylpyrrolidinium perchlorate (Compound No. 41) was obtained as crystals having a melting point of from 113° to 114° C. The mixture was stirred at room temperature for 1 hour the precipitated crystals were collected by filtration recrystallized from methanol-ethyl ether

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

Procedure: To 30 ml of tetrahydrofuran, 1.4 g of proline ethyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration and recrystallized from methanol-ethyl ether, whereby 2.1 g (yield: 76%) of 1-(1,3-dithiol-2-ylidene)-2-ethoxycarbonylpyrrolidinium perchlorate (Compound No. 41) was obtained as crystals having a melting point of from 113° to 114° C. The mixture was stirred at room temperature for 1 hour the precipitated crystals were collected by filtration recrystallized from methanol-ethyl ether

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

Procedure: The ethyl ester product from part (e) (1.75 g., 2.63 mmole) is dissolved in methanol (75 ml.) at room temperature under argon. The solution is hydrogenated with 20% palladium hydroxide on carbon catalyst (300 mg.) at room temperature and atmospheric pressure for 3 hours. The reaction is filtered through Celite to remove the catalyst, and the volatiles are evaporated to give 1.7 g. of 1-(S)-6-[(Trifluoroacetyl)amino]-2-[[[(1-amino)pentyl]methoxyphosphinyl]oxy]-1-oxohexyl]-L-proline, ethyl ester. The reaction is filtered through Celite to remove the catalyst the volatiles are evaporated to give 1.7 g

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 60 mmoles of pyruvic acid plus 60 mmoles of L-proline ethyl ester in redistilled chloroform is cooled to -50° C. in an acetone-dry ice bath. To this solution is added 60 mmoles of a precooled solution of dicyclohexylcarbodiimide (DCC) in cloroform and the mixture is stirred at -5° C. for 1 hour. The reaction mixture is slowly warmed to room temperature and stirred for an additional 2 hours and then stirred at 4° C. overnight. The mixture is filtered to remove dicyclohexylurea, then cooled in an ice bath. The organic phase is washed with cold water, cold 1N NaHCO3 and finally with cold saturated NaCl. The organic phase is dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator yielding N-pyruvoyl-L-proline ethyl ester. The reaction mixture is slowly warmed to room temperature stirred for an additional 2 hours stirred at 4° C. overnight The mixture is filtered to remove dicyclohexylurea cooled in an ice bath The organic phase is washed with cold water, cold 1N NaHCO3 and finally with cold saturated NaCl The organic phase is dried over anhydrous MgSO4 filtered The solvent is removed with a rotary evaporator

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

Procedure: Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-(ethoxycarbonyl)-pyrrolidine in DMSO at ambient temperature.

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 60 mmoles of pyruvic acid plus 60 mmoles of L-proline ethyl ester in redistilled chloroform is cooled to -50° C. in an acetone-dry ice bath. To this solution is added 60 mmoles of a precooled solution of dicyclohexylcarbodiimide (DCC) in cloroform and the mixture is stirred at -5° C. for 1 hour. The reaction mixture is slowly warmed to room temperature and stirred for an additional 2 hours and then stirred at 4° C. overnight. The mixture is filtered to remove dicyclohexylurea, then cooled in an ice bath. The organic phase is washed with cold water, cold 1N NaHCO3 and finally with cold saturated NaCl. The organic phase is dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator yielding N-pyruvoyl-L-proline ethyl ester. The reaction mixture is slowly warmed to room temperature stirred for an additional 2 hours stirred at 4° C. overnight The mixture is filtered to remove dicyclohexylurea cooled in an ice bath The organic phase is washed with cold water, cold 1N NaHCO3 and finally with cold saturated NaCl The organic phase is dried over anhydrous MgSO4 filtered The solvent is removed with a rotary evaporator

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

Procedure: Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-(ethoxycarbonyl)-pyrrolidine in DMSO at ambient temperature.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-bromo-2-chloro-3-nitropyridine (5.94 g, 25 mmol) and (S)-ethyl pyrrolidine-2-carboxylate (7.52 g, 52.5 mmol) were combined and stirred at 90° C. for 10 min in a closed vial. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes to afford (S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.43 g, 24.49 mmol, 98% yield) as a yellow viscous oil. [M+H] calc'd for C12H14BrN3O4, 344; found, 344. The crude material was purified by flash column chromatography (20-30% EtOAc in hexanes