ethyl 2-pyrrolidin-1-ylacetate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.5 g (6.5 mM) 2-anilinonicotinic acid, methylester, in dry xylenes at room temperature is added 0.69 g (14.54 M) of sodium hydride (NaH) (50 percent (%) oil emulsion) followed by addition of a small amount of N,N-dimethylformamide (DMF). The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade (°C.) and 1.05 milliliters (mL) (6.5 mM) of ethyl-1-pyrrolidineacetate in xylene is slowly added over a period of 10 minutes. The reaction mixture is heated for 1 to 3 hours prior to the addition of aliquots of 0.32 g NaH followed by 1.05 mL of ethyl-1-pyrrolidineacetate as described above (total 3 aliquots). Following addition of the aliquots, the reaction mixture is cooled to 0° C., quenched with a slow addition of glacial acetic acid, and then water is added. The product is filtered and washed with water, acetone, methylene chloride, and acetone. The solid then obtained is dried in vacuo to give 1.20 g (60% yield) of title compound, a white solid. The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade is slowly added over a period of 10 minutes The reaction mixture is heated for 1 to 3 hours addition of the aliquots quenched with a slow addition of glacial acetic acid water is added The product is filtered washed with water, acetone, methylene chloride, and acetone The solid then obtained is dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.5 g (6.5 mM) 2-anilinonicotinic acid, methylester, in dry xylenes at room temperature is added 0.69 g (14.54 M) of sodium hydride (NaH) (50 percent (%) oil emulsion) followed by addition of a small amount of N,N-dimethylformamide (DMF). The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade (° C.) and 1.05 milliliters (mL) (6.5 mM) of ethyl-1-pyrrolidineacetate in xylene is slowly added over a period of 10 minutes. The reaction mixture is heated for 1 to 3 hours prior to the addition of aliquots of 0.32 g NaH followed by 1.05 mL of ethyl-1-pyrrolidineacetate as described above (total 3 aliquots). Following addition of the aliquots, the reaction mixture is cooled to 0° C., quenched with a slow addition of glacial acetic acid, and then water is added. The product is filtered and washed with water, acetone, methylene chloride, and acetone. The solid then obtained is dried in vacuo to give 1.20 g (60% yield) of title compound, a white solid. The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade is slowly added over a period of 10 minutes The reaction mixture is heated for 1 to 3 hours addition of the aliquots quenched with a slow addition of glacial acetic acid water is added The product is filtered washed with water, acetone, methylene chloride, and acetone The solid then obtained is dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.5 g (6.5 mM) 2-anilinonicotinic acid, methylester, in dry xylenes at room temperature is added 0.69 g (14.54 M) of sodium hydride (NaH) (50 percent (%) oil emulsion) followed by addition of a small amount of N,N-dimethylformamide (DMF). The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade (° C.) and 1.05 milliliters (mL) (6.5 mM) of ethyl-1-pyrrolidineacetate in xylene is slowly added over a period of 10 minutes. The reaction mixture is heated for 1 to 3 hours prior to the addition of aliquots of 0.32 g NaH followed by 1.05 mL of ethyl-1-pyrrolidineacetate as described above (total 3 aliquots). Following addition of the aliquots, the reaction mixture is cooled to 0° C., quenched with a slow addition of glacial acetic acid, and then water is added. The product is filtered and washed with water, acetone, methylene chloride, and acetone. The solid then obtained is dried in vacuo to give 1.20 g (60% yield) of title compound, a white solid. The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade is slowly added over a period of 10 minutes The reaction mixture is heated for 1 to 3 hours addition of the aliquots quenched with a slow addition of glacial acetic acid water is added The product is filtered washed with water, acetone, methylene chloride, and acetone The solid then obtained is dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.5 g (6.5 mM) 2-anilinonicotinic acid, methylester, in dry xylenes at room temperature is added 0.69 g (14.54 M) of sodium hydride (NaH) (50 percent (%) oil emulsion) followed by addition of a small amount of N,N-dimethylformamide (DMF). The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade (°C.) and 1.05 milliliters (mL) (6.5 mM) of ethyl-1-pyrrolidineacetate in xylene is slowly added over a period of 10 minutes. The reaction mixture is heated for 1 to 3 hours prior to the addition of aliquots of 0.32 g NaH followed by 1.05 mL of ethyl-1-pyrrolidineacetate as described above (total 3 aliquots). Following addition of the aliquots, the reaction mixture is cooled to 0° C., quenched with a slow addition of glacial acetic acid, and then water is added. The product is filtered and washed with water, acetone, methylene chloride, and acetone. The solid then obtained is dried in vacuo to give 1.20 g (60% yield) of title compound, a white solid. The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade is slowly added over a period of 10 minutes The reaction mixture is heated for 1 to 3 hours addition of the aliquots quenched with a slow addition of glacial acetic acid water is added The product is filtered washed with water, acetone, methylene chloride, and acetone The solid then obtained is dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.5 g (6.5 mM) 2-anilinonicotinic acid, methylester, in dry xylenes at room temperature is added 0.69 g (14.54 M) of sodium hydride (NaH) (50 percent (%) oil emulsion) followed by addition of a small amount of N,N-dimethylformamide (DMF). The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade (°C.) and 1.05 milliliters (mL) (6.5 mM) of ethyl-1-pyrrolidineacetate in xylene is slowly added over a period of 10 minutes. The reaction mixture is heated for 1 to 3 hours prior to the addition of aliquots of 0.32 g NaH followed by 1.05 mL of ethyl-1-pyrrolidineacetate as described above (total 3 aliquots). Following addition of the aliquots, the reaction mixture is cooled to 0° C., quenched with a slow addition of glacial acetic acid, and then water is added. The product is filtered and washed with water, acetone, methylene chloride, and acetone. The solid then obtained is dried in vacuo to give 1.20 g (60% yield) of title compound, a white solid. The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade is slowly added over a period of 10 minutes The reaction mixture is heated for 1 to 3 hours addition of the aliquots quenched with a slow addition of glacial acetic acid water is added The product is filtered washed with water, acetone, methylene chloride, and acetone The solid then obtained is dried in vacuo

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

Procedure: The solution of ethyl 2-(pyrrolidin-1-yl)acetate (1.8 g, 11.95 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated on vacuum pump and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 54% yield (1.4 g). LC-MS (ESI): Calculated mass: 129.1; Observed mass 130.1 [M+H]+ (rt: 0.26 min). The mixture was concentrated on vacuum pump quenched extracted as in Intermediate Example 15(b) The solvent was distilled off to afford the product in 54% yield (1.4 g) Observed mass 130.1 [M+H]+ (rt: 0.26 min)

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

Procedure: The solution of ethyl 2-(pyrrolidin-1-yl)acetate (2 g, 12.7 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 91% yield (1.5 g). LC-MS (ESI): Calculated mass: 129.1; Observed mass 130.1 [M+H+] (rt: 0.26 min). The mixture was concentrated quenched extracted as in Intermediate Example 15(b) The solvent was distilled off to afford the product in 91% yield (1.5 g) Observed mass 130.1 [M+H+] (rt: 0.26 min)

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

Procedure: To a solution of pyrrolidine (1.2 g, 16.3 mmol, 1.0 eq) in DMF were added K2CO3 (5.63 g, 40.7 mmol, 2.5 eq.) and ethyl 2-bromoacetate (1.73 g, 24.4 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 80% yield (2 g). LC-MS (ESI): Calculated mass: 157.2; Observed mass 158.1 [M+H]+ (rt: 0.2 min). quenched extracted as in Intermediate Example 5(a) The solvent was distilled off to afford the product in 80% yield (2 g) Observed mass 158.1 [M+H]+ (rt: 0.2 min)

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

Procedure: Using the method of Example 5, ethyl 1-pyrrolidineacetate was reacted with 2-(N,N-diethylamino)ethanol to provide 2-(N,N-diethylamino)ethyl 1-pyrrolidineacetate, b.p. 92° C. at 250 μmHg.

Conditions: temp:225.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1.3 g of sodium hydride (in the form of a 60% by weight suspension in mineral oil) and 100 g (0.64 mol) of ethyl 1-pyrrolidineacetate was added 91 g of 2-(1-pyrrolidinyl)ethanol. The mixture was heated slowly to about 225° C., and the ethanol by-product was collected in a Dean-Stark trap. The reaction mixture was cooled to about 25° C., then 12 g of 1-bromopropane was added to react any alkoxide present. The sodium bromide by-product was removed by filtration. The desired product 2-(1-pyrrolidinyl)ethyl 1-pyrrolidineacetate was purified by distillation at 95° C. at a pressure of 250 μmHg. The structural assignment was confirmed by mass spectral analysis. the ethanol by-product was collected in a Dean-Stark trap The reaction mixture was cooled to about 25° C. 12 g of 1-bromopropane was added to react any alkoxide present The sodium bromide by-product was removed by filtration The desired product 2-(1-pyrrolidinyl)ethyl 1-pyrrolidineacetate was purified by distillation at 95° C. at a pressure of 250 μmHg

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 80 g (0.51 mol) of ethyl 1-pyrrolidineacetate and 0.5 g of sodium hydride (in the form of a 60% by weight suspension in mineral oil) was added 48 g (0.54 mol) of 2-(N,N-dimethylamino)ethanol. The mixture was purged with nitrogen gas, heated gradually and then maintained at about 150° C. while collecting the ethanol by-product in a Dean-Stark trap. The liquid reaction product was distilled at 85° C. at a pressure of 100 μmHg to provide 2-(N,N-dimethylamino)-ethyl 1-pyrrolidineacetate. The structure of the product was confirmed by nuclear magnetic resonance and infrared spectral analysis. The mixture was purged with nitrogen gas heated gradually while collecting the ethanol by-product in a Dean-Stark trap The liquid reaction product was distilled at 85° C. at a pressure of 100 μmHg

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

Procedure: To an ice bath-cooled solution of 213.4 g (3 mol) of pyrrolidine in 450 mL of tetrahydrofuran was added dropwise over about 2 hours 250.5 g (1.5 mol) of ethyl bromoacetate, maintaining the temperature below 30° C. To this solution was added 150 mL of toluene to precipitate pyrrolidinium bromide, which was separated by filtration. The filtrate was evaporated under vacuum to provide a residue of about 241 g of ethyl 1-pyrrolinidineacetate. maintaining the temperature below 30° C to precipitate pyrrolidinium bromide, which was separated by filtration The filtrate was evaporated under vacuum to provide a residue of about 241 g of ethyl 1-pyrrolinidineacetate