tert-butyl N-(2-amino-2-oxoethyl)carbamate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of N-(t-butoxycarbonyl)glycine (3.01 g, 17.2 mmol) in anhydrous methylene chloride (150 ml) were added 1-hydroxybenzotriazole (4.63 g, 34.3 mmol), WSC (6.60 g, 34.4 mmol) and 4-dimethylaminopyridine (210 mg, 1.72 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen overnight. After checking the completion of the reaction, 28% aqueous ammonia solution was added thereto and resulting mixture was stirred for 15 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford (carbamoylmethyl)carbamic acid t-butyl ester (717.7 mg, yield 24%) as a colorless and transparent syrup. was added resulting mixture was stirred for 15 minutes the completion of the reaction the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on a silica gel column

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

Procedure: To a solution of tert-butyl 4-(2-(2-chloropyridin-4-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (160 mg, 0.36 mmol) in THF (5 ml) are added Boc-gly-NH2 (124 mg, 0.72 mmol), XantPhos (124 mg, 0.14 mmol), Pd(OAc)2 (24 mg, 0.07 mmol) and K2CO3 (197 mg, 1.44 mmol). The microwave tube is purged with nitrogen for 1 min then sealed. The mixture is microwaved at 90° C. for 2 h. After cooling to room temperature, EtOAc (30 ml) and water (30 ml) are added. The organic layer is separated, washed with brine and dried over sodium sulfate. After the removal of organic solvent in vacuo, the residue is purified through Biotage column chromatography (MeOH/DCM=1/100 to 5/20) to give the desired product (188 mg, 90%). The microwave tube is purged with nitrogen for 1 min then sealed The mixture is microwaved at 90° C. for 2 h EtOAc (30 ml) and water (30 ml) are added The organic layer is separated washed with brine dried over sodium sulfate After the removal of organic solvent in vacuo the residue is purified through Biotage column chromatography (MeOH/DCM=1/100 to 5/20)

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

Procedure: To a solution of tert-butyl 4-(2-(2-chloropyridin-4-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (160 mg, 0.36 mmol) in THF (5 ml) are added Boc-gly-NH2 (124 mg, 0.72 mmol), XantPhos (124 mg, 0.14 mmol), Pd(OAc)2 (24 mg, 0.07 mmol) and K2CO3 (197 mg, 1.44 mmol). The microwave tube is purged with nitrogen for 1 min then sealed. The mixture is microwaved at 90° C. for 2 h. After cooling to room temperature, EtOAc (30 ml) and water (30 ml) are added. The organic layer is separated, washed with brine and dried over sodium sulfate. After the removal of organic solvent in vacuo, the residue is purified through Biotage column chromatography (MeOH/DCM=1/100 to 5/20) to give the desired product (188 mg, 90%). The microwave tube is purged with nitrogen for 1 min then sealed The mixture is microwaved at 90° C. for 2 h EtOAc (30 ml) and water (30 ml) are added The organic layer is separated washed with brine dried over sodium sulfate After the removal of organic solvent in vacuo the residue is purified through Biotage column chromatography (MeOH/DCM=1/100 to 5/20)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Carbamoylmethyl-carbamic acid tert-butyl ester (8a; 0.84 g, 4.8 mmol) was dissolved in dichloromethane (10 mL), and added with triethylamine (1.0 mL, 7.2 mmol) and benzyl chloroformate (0.85 g, 0.75 mL, 5.0 mmol) at 0° C. After stirring for 5 min, 4-dimethylaminopyridine (DMAP; 0.32 g, 2.6 mmol) was added slowly with continuous stirring at 0° C. for 1 h. After the reaction is completed, dichloromethane (10 mL) and saturated Na2CO3 solution (10 mL) were added. The organic phase was washed by H2O (10 mL), 1N HCl (20 mL), H2O (20 mL) and saturated NaCl solution (20 mL) separately, and dried over MgSO4 and concentrated under reduced pressure to remove dichloromethane to obtain white solid product 12 (1.15 g; 95%). 1H-NMR (200 MHz) (CDCl3) δ: 7.30˜7.38 (m, 5H, ArH), 5.17 (s, 2H, CO2CH2Ph), 5.02 (br, s, 1H, NHBOC), 3.94 (d, 2H, Gly-H), 1.43 [s, 9H, CO2C(CH3)3] with continuous stirring at 0° C. for 1 h The organic phase was washed by H2O (10 mL), 1N HCl (20 mL), H2O (20 mL) and saturated NaCl solution (20 mL) separately dried over MgSO4 concentrated under reduced pressure to remove dichloromethane

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

Procedure: Deprotection of 500 mg of Boc-Gly-NH2 was performed similarly to that in Example 28 (Process 3), and the obtained product was dissolved in dichloromethane, and 0.39 ml of tri-ethylamine, 0.67 g of Boc-Thz-OH, 0.47 g of HOBt and 0.64 g of EDC hydrochloride were added under ice cooling and the mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 139 (Process 2) to give 0.54 g of the title compound as oil. The reaction mixture was treated similarly to that in Example 139 (Process 2)

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

Procedure: Deprotection of 500 mg of Boc-Gly-NH2 was performed similarly to that in Example 28 (Process 3), and the obtained product was dissolved in dichloromethane, and 0.39 ml of tri-ethylamine, 0.67 g of Boc-Thz-OH, 0.47 g of HOBt and 0.64 g of EDC hydrochloride were added under ice cooling and the mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 139 (Process 2) to give 0.54 g of the title compound as oil. The reaction mixture was treated similarly to that in Example 139 (Process 2)

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

Procedure: Deprotection of 500 mg of Boc-Gly-NH2 was performed similarly to that in Example 28 (Process 3), and the obtained product was dissolved in dichloromethane, and 0.39 ml of tri-ethylamine, 0.67 g of Boc-Thz-OH, 0.47 g of HOBt and 0.64 g of EDC hydrochloride were added under ice cooling and the mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 139 (Process 2) to give 0.54 g of the title compound as oil. The reaction mixture was treated similarly to that in Example 139 (Process 2)

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

Procedure: Benzyl-2-aminoacetate, TFA salt (13; 1.72 g, 5.12 mmol) and carbamoylmethyl-carbamic acid tert-butyl ester (8a; 1.13 g, 6.19 mmol) were dissolved in 40 mL dichloromethane with stirring at 0° C., followed by addition of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC; 1.33 g, 7.0 mmol) and triethylamine (1.0 mL, 7.2 mmol), and the reaction was replaced under room temperature with continuous stirring for 6 h. After the reaction was completed, dichloromethane was removed by concentration under reduced pressure. The obtained solid was dissolved in ethyl acetate (50 mL), and then the organic phase was washed by H2O, 5% citric acid, H2O, saturated NaHCO3 and saturated NaCl solution separately, and dried over MgSO4 and concentrated under reduced pressure to remove ethyl acetate to obtain colorless oil-like 14 (1.15 g; 72.6%). 1H-NMR (200 MHz) (CDCl3) δ: 7.28-7.33 (m, 5H, ArH), 6.89 (br, s, 1H, CONHCH2), 5.36 (br, s, 1H, NHBOC), 5.13 (s, 2H, CO2CH2Ph), 4.04 (d, 2H, CH2CO2CH2Ph), 3.81 (d, 2H, CH2NHBOC), 1.40 [s, 9H, CO2C(CH3)3]. was replaced under room temperature with continuous stirring for 6 h dichloromethane was removed by concentration under reduced pressure The obtained solid was dissolved in ethyl acetate (50 mL) the organic phase was washed by H2O, 5% citric acid, H2O, saturated NaHCO3 and saturated NaCl solution separately dried over MgSO4 concentrated under reduced pressure to remove ethyl acetate

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

Procedure: To a solution of N-(t-butoxycarbonyl)glycine (3.01 g, 17.2 mmol) in anhydrous methylene chloride (150 ml) were added 1-hydroxybenzotriazole (4.63 g, 34.3 mmol), WSC (6.60 g, 34.4 mmol) and 4-dimethylaminopyridine (210 mg, 1.72 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen overnight. After checking the completion of the reaction, 28% aqueous ammonia solution was added thereto and resulting mixture was stirred for 15 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford (carbamoylmethyl)carbamic acid t-butyl ester (717.7 mg, yield 24%) as a colorless and transparent syrup. was added resulting mixture was stirred for 15 minutes the completion of the reaction the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was purified by chromatography on a silica gel column

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

Procedure: To a solution of tert-butyl 4-(2-(2-chloropyridin-4-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (160 mg, 0.36 mmol) in THF (5 ml) are added Boc-gly-NH2 (124 mg, 0.72 mmol), XantPhos (124 mg, 0.14 mmol), Pd(OAc)2 (24 mg, 0.07 mmol) and K2CO3 (197 mg, 1.44 mmol). The microwave tube is purged with nitrogen for 1 min then sealed. The mixture is microwaved at 90° C. for 2 h. After cooling to room temperature, EtOAc (30 ml) and water (30 ml) are added. The organic layer is separated, washed with brine and dried over sodium sulfate. After the removal of organic solvent in vacuo, the residue is purified through Biotage column chromatography (MeOH/DCM=1/100 to 5/20) to give the desired product (188 mg, 90%). The microwave tube is purged with nitrogen for 1 min then sealed The mixture is microwaved at 90° C. for 2 h EtOAc (30 ml) and water (30 ml) are added The organic layer is separated washed with brine dried over sodium sulfate After the removal of organic solvent in vacuo the residue is purified through Biotage column chromatography (MeOH/DCM=1/100 to 5/20)