2-(ethylamino)acetic acid;hydrochloride

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

Procedure: To a suspension of ethyl glycine·HCl 2 (38.4 g, 275 mmol) in 1,2-dichloroethane (360 mL) was added triethylamine (77.0 mL, 550 mmol) at room temperature. After stirring for 30 minutes the heterogenous mixture was cooled to 0° C. and ethyl oxalyl chloride 1 (30.3 mL, 275 mol) was added dropwise over the course of 1 h. Upon completion of the addition, the cooling bath was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with water (250 mL) and the layers separated. The aqueous layer was backwashed with 2 portions of dichloromethane (250 mL). The combined organic layers were washed with water (250 mL), followed by brine (250 mL), dried over MgSO4 and concentrated to give an oil 3 that was taken directly onto the next step. Upon completion of the addition the cooling bath was removed the reaction was stirred at room temperature overnight The reaction was diluted with water (250 mL) the layers separated The combined organic layers were washed with water (250 mL) dried over MgSO4 concentrated

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

Procedure: To a suspension of ethyl glycine·HCl 2 (38.4 g, 275 mmol) in 1,2-dichloroethane (360 mL) was added triethylamine (77.0 mL, 550 mmol) at room temperature. After stirring for 30 minutes the heterogenous mixture was cooled to 0° C. and ethyl oxalyl chloride 1 (30.3 mL, 275 mol) was added dropwise over the course of 1 h. Upon completion of the addition, the cooling bath was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with water (250 mL) and the layers separated. The aqueous layer was backwashed with 2 portions of dichloromethane (250 mL). The combined organic layers were washed with water (250 mL), followed by brine (250 mL), dried over MgSO4 and concentrated to give an oil 3 that was taken directly onto the next step. Upon completion of the addition the cooling bath was removed the reaction was stirred at room temperature overnight The reaction was diluted with water (250 mL) the layers separated The combined organic layers were washed with water (250 mL) dried over MgSO4 concentrated

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

Procedure: To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.22 mmol) in NMP (1.5 ml) under argon was added triethyl amine (0.113 g, 1.118 mmol) and ethyl glycine hydrochloride (0.096 g, 0.68 mmol). The reaction mixture was heated at 100° C. for 16 hours. To the reaction mixture ethyl acetate was added and it was washed with water and brine. Ethyl acetate layer was dried over sodium sulphate, filtered and concentrated under reduced pressure and residue obtained was purified by column chromatography to obtain {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-acetic acid ethyl ester (0.080 g, 69%) as an off white solid. it was washed with water and brine Ethyl acetate layer was dried over sodium sulphate filtered concentrated under reduced pressure and residue obtained was purified by column chromatography

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

Procedure: To a stirred mixture of 58.9 parts of potassium acetate, 100.5 parts of ethyl glycine monohydrochloride and 790 parts of ethanol, there were added 100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (prepared following the procedure described in Example 9 or Example 14. After stirring for 1/2 hour, there were added portionwise 9.4 parts of sodium cyanotrihydroborate. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1). The eluent of the desired fraction was evaporated, yielding 71 parts (56.2%) of ethyl N-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66). prepared Stirring was continued for 1/2 hour at room temperature The reaction mixture was evaporated the residue was partitioned between water and dichloromethane The organic layer was separated washed with water dried filtered evaporated The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1) The eluent of the desired fraction was evaporated

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

Procedure: To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.22 mmol) in NMP (1.5 ml) under argon was added triethyl amine (0.113 g, 1.118 mmol) and ethyl glycine hydrochloride (0.096 g, 0.68 mmol). The reaction mixture was heated at 100° C. for 16 hours. To the reaction mixture ethyl acetate was added and it was washed with water and brine. Ethyl acetate layer was dried over sodium sulphate, filtered and concentrated under reduced pressure and residue obtained was purified by column chromatography to obtain {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-acetic acid ethyl ester (0.080 g, 69%) as an off white solid. it was washed with water and brine Ethyl acetate layer was dried over sodium sulphate filtered concentrated under reduced pressure and residue obtained was purified by column chromatography

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

Procedure: To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.22 mmol) in NMP (1.5 ml) under argon was added triethyl amine (0.113 g, 1.118 mmol) and ethyl glycine hydrochloride (0.096 g, 0.68 mmol). The reaction mixture was heated at 100° C. for 16 hours. To the reaction mixture ethyl acetate was added and it was washed with water and brine. Ethyl acetate layer was dried over sodium sulphate, filtered and concentrated under reduced pressure and residue obtained was purified by column chromatography to obtain {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-acetic acid ethyl ester (0.080 g, 69%) as an off white solid. it was washed with water and brine Ethyl acetate layer was dried over sodium sulphate filtered concentrated under reduced pressure and residue obtained was purified by column chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.90 g (69.6 mmol) ethylglycinate hydrochloride are suspended under argon in 100 mL of dry DMA. 24.3 mL (139 mmol) diisopropylethylamine and 10.21 g (46.4 mmol) of 2-bromo-6-fluoronitrobenzene are then added at RT. The orange solution is then heated to 80° C. for 16 h. After cooling, the reaction mixture is poured onto iced-cold water and the suspension is collected by filtration to afford, after drying in HV at 50° C., the title compound as a dark orange solid, which is used in the next step without further purification. After cooling the suspension is collected by filtration to afford after drying in HV at 50° C. the title compound as a dark orange solid, which is used in the next step without further purification

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.90 g (69.6 mmol) ethylglycinate hydrochloride are suspended under argon in 100 mL of dry DMA. 24.3 mL (139 mmol) diisopropylethylamine and 10.21 g (46.4 mmol) of 2-bromo-6-fluoronitrobenzene are then added at RT. The orange solution is then heated to 80° C. for 16 h. After cooling, the reaction mixture is poured onto iced-cold water and the suspension is collected by filtration to afford, after drying in HV at 50° C., the title compound as a dark orange solid, which is used in the next step without further purification. After cooling the suspension is collected by filtration to afford after drying in HV at 50° C. the title compound as a dark orange solid, which is used in the next step without further purification

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

Procedure: To a stirred mixture of 58.9 parts of potassium acetate, 100.5 parts of ethyl glycine monohydrochloride and 790 parts of ethanol, there were added 100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (prepared following the procedure described in Example 9 or Example 14. After stirring for 1/2 hour, there were added portionwise 9.4 parts of sodium cyanotrihydroborate. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1). The eluent of the desired fraction was evaporated, yielding 71 parts (56.2%) of ethyl N-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66). prepared Stirring was continued for 1/2 hour at room temperature The reaction mixture was evaporated the residue was partitioned between water and dichloromethane The organic layer was separated washed with water dried filtered evaporated The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1) The eluent of the desired fraction was evaporated

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

Procedure: To a stirred mixture of 58.9 parts of potassium acetate, 100.5 parts of ethyl glycine monohydrochloride and 790 parts of ethanol, there were added 100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (prepared following the procedure described in Example 9 or Example 14. After stirring for 1/2 hour, there were added portionwise 9.4 parts of sodium cyanotrihydroborate. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1). The eluent of the desired fraction was evaporated, yielding 71 parts (56.2%) of ethyl N-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66). prepared Stirring was continued for 1/2 hour at room temperature The reaction mixture was evaporated the residue was partitioned between water and dichloromethane The organic layer was separated washed with water dried filtered evaporated The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1) The eluent of the desired fraction was evaporated

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

Procedure: To a stirred mixture of 58.9 parts of potassium acetate, 100.5 parts of ethyl glycine monohydrochloride and 790 parts of ethanol, there were added 100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (prepared following the procedure described in Example 9 or Example 14. After stirring for 1/2 hour, there were added portionwise 9.4 parts of sodium cyanotrihydroborate. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1). The eluent of the desired fraction was evaporated, yielding 71 parts (56.2%) of ethyl N-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66). prepared Stirring was continued for 1/2 hour at room temperature The reaction mixture was evaporated the residue was partitioned between water and dichloromethane The organic layer was separated washed with water dried filtered evaporated The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1) The eluent of the desired fraction was evaporated

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

Procedure: To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added triethylamine (80 μl, 0.566 mmol), 4-dimethylaminopyridine (14 mg, 0.118 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.283 mmol) and ethyl glycine hydrochloride (40 mg, 0.283 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated under reduced pressure to give the title compound (95 mg, 0.187 mmol, 79%) as a colorless amorphous substance. The diluted mixture was washed sequentially with water The organic layer thus obtained was dried over magnesium sulfate concentrated under reduced pressure The residue thus obtained ethyl acetate=2:1 eluate was concentrated under reduced pressure