4-chloro-N,N-diethylbutanamide

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

Procedure: To a well-stirred suspension of pentane-washed sodium hydride (0.52 g of 60%, 3 mmole) in 3 ml dry DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12 mmoles) (prepared as in Example 53). To this was added 10 ml of DMF and the mixture was stirred at ambient temperature for 45 minutes then warmed to about 50° C. for 15 minutes whereupon 4-chloro-N,N-diethylbutyramide (1.92 g, 11 mmoles) was added. The mixture Was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days and then at 60°-70° C. for a further 4 hours. After cooling, the mixture was poured into 400 ml of brine and extracted with methylene chloride (4×100 ml). After combining, the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75 g). This was purified by flash chromatography on silica gel to give 1.64 g of the title compound as an oil. was added The mixture Was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days at 60°-70° C. for a further 4 hours After cooling extracted with methylene chloride (4×100 ml) the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a well-stirred suspension of pentane-washed sodium hydride (0.52 g of 60%, 3 mmole) in 3 ml dry DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12 mmoles) (prepared as Example 53). To this was added 10 ml of DMF and the mixture was stirred at ambient temperature for 45 minutes then warmed to about 50° C. for 15 minutes whereupon 4-chloro-N,N-diethylbutyramide (1.92 g, 11 mmoles) was added. The mixture was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days and then at 60°-70° C. for a further 4 hours. After cooling, the mixture was poured into 400 ml of brine and extracted with methylene chloride (4×100 ml). After combining, the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75 g). This was purified by flash chromatography on silica gel to give 1.64 g of the title compound as an oil. was added The mixture was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days at 60°-70° C. for a further 4 hours After cooling extracted with methylene chloride (4×100 ml) the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine dried over sodium sulfate filtered concentrated in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-N,N-diethylbutanamide (2.16 g), 4-amino-5-chloro-2-methoxy-N-(2-morpholinylmethyl)benzenamide (3 g), prepared following the procedure as described in EP-A-0,243,959, and sodium carbonate (1.58 g) in N,N-dimethyl-formamide (90 ml) was stirred for 48 hours at 70° C. The solvent was evaporated and water was added to the residue. This mixture was extracted twice with dichloromethane and the combined extracts were washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /CH3OH 95/5). The first fraction was collected and the solvent was evaporated. The residue was converted into the hydrochloric salt in 2-propanol and diisopropyl ether. The salt was filtered off and crystallized from acetonitrile. The precipitate was filtered off and dried, yielding 1.43 g (30.4%) of (±)-2-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]-N,N-diethyl4-morpholine-butanamide monohydrochloride. hemihydrate (compound 1; mp. 122.2° C.). prepared The solvent was evaporated water was added to the residue This mixture was extracted twice with dichloromethane the combined extracts were washed with water dried filtered the solvent evaporated The residue was purified by column chromatography over silica gel (eluent: CHCl3 /CH3OH 95/5) The first fraction was collected the solvent was evaporated The salt was filtered off crystallized from acetonitrile The precipitate was filtered off dried

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

Procedure: To a well-stirred suspension of pentane-washed sodium hydride (0.52 g of 60%, 3 mmole) in 3 ml dry DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12 mmoles) (prepared as in Example 53). To this was added 10 ml of DMF and the mixture was stirred at ambient temperature for 45 minutes then warmed to about 50° C. for 15 minutes whereupon 4-chloro-N,N-diethylbutyramide (1.92 g, 11 mmoles) was added. The mixture was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days and then at 60-70° C. for a further 4 hours. After cooling, the mixture was poured into 400 ml of brine and extracted with methylene chloride (4×100 ml). After combining, the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75 g). This was purified by flash chromatography on silica gel to give 1.64 g of the title compound as an oil. was added The mixture was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days at 60-70° C. for a further 4 hours After cooling extracted with methylene chloride (4×100 ml) the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a well-stirred suspension of pentane-washed sodium hydride (0.52 g of 60%, 3 mmole) in 3 ml dry DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12 mmoles) (prepared as in Example 53). To this was added 10 ml of DMF and the mixture was stirred at ambient temperature for 45 minutes then warmed to about 50° C. for 15 minutes whereupon 4-chloro-N,N-diethylbutyramide (1.92 g, 11 mmoles) was added. The mixture Was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days and then at 60°-70° C. for a further 4 hours. After cooling, the mixture was poured into 400 ml of brine and extracted with methylene chloride (4×100 ml). After combining, the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75 g). This was purified by flash chromatography on silica gel to give 1.64 g of the title compound as an oil. was added The mixture Was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days at 60°-70° C. for a further 4 hours After cooling extracted with methylene chloride (4×100 ml) the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a well-stirred suspension of pentane-washed sodium hydride (0.52 g of 60%, 3 mmole) in 3 ml dry DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12 mmoles) (prepared as Example 53). To this was added 10 ml of DMF and the mixture was stirred at ambient temperature for 45 minutes then warmed to about 50° C. for 15 minutes whereupon 4-chloro-N,N-diethylbutyramide (1.92 g, 11 mmoles) was added. The mixture was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days and then at 60°-70° C. for a further 4 hours. After cooling, the mixture was poured into 400 ml of brine and extracted with methylene chloride (4×100 ml). After combining, the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75 g). This was purified by flash chromatography on silica gel to give 1.64 g of the title compound as an oil. was added The mixture was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days at 60°-70° C. for a further 4 hours After cooling extracted with methylene chloride (4×100 ml) the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine dried over sodium sulfate filtered concentrated in vacuo