2-acetyloxyacetic acid

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

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbonyl diimidazole (CDI) (2.3 g, 14.24 mmol) was added to a stirred solution of 2-acetoxyacetic acid (1.68 g, 14.24 mmol) in NMP (10 mL). After 30 minutes, 6-bromo-N-(5-(N-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (50f) (1.38 g, 3.56 mmol) was added in one portion and the resulting solution was stirred for 30 minutes before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (897 mg, 21.36 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford 6-bromo-N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (142). 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.64 (d, J=1.2 Hz, 1H), 8.60 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.79 (dd, J=0.8, 9.6 Hz, 1H), 7.67 (dd, J=2.0, 9.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.81 (s, 2H), 2.37 (s, 3H). MS m/z 427.9, 429.9 (M+1)+. to afford a residue which After removal of all solvents 2M NaHCO3 (10 mL) was added The precipitate was filtered dried in air

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbonyl diimidazole (CDI) (324 mg, 2.0 mmol) was added to a stirred solution of 2-acetoxyacetic acid (236 mg, 2.0 mmol) in NMP. After 20 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (310 mg, 1.0 mmol) was added in one portion and the resulting solution was stirred for 1 hour before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (252 mg, 6.0 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (43). 1H NMR (400 MHz, d6-DMSO) δ 10.02 (s, 1H), 9.46 (d, J=6.8 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.82 (m, 2H), 7.53 (m, 2H), 7.18 (m, 1H), 6.08 (m, 1H), 4.80 (d, J=6.0 Hz, 2H), 2.37 (s, 3H). MS m/z 350.1 (M+1)+. to afford a residue which After removal of all solvents 2M NaHCO3 (10 mL) was added The precipitate was filtered dried in air

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

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

Procedure: According to the procedure described in example 13 step 13a acetoxyacetic acid (0.667 g) and 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 0.81 g) gave 2-((3-chloropyrazin-2-yl)methylamino)-2-oxoethyl acetate (0.99 g) after purification by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/ethyl acetate 1/1).

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

Procedure: According to the procedure described in example 13 step 13a acetoxyacetic acid (0.667 g) and 2-aminomethyl-3-chloropyrazine hydrochloride (content 77%; 0.81 g) gave 2-((3-chloropyrazin-2-yl)methylamino)-2-oxoethyl acetate (0.99 g) after purification by column chromatography (silica gel; gradient of dichloromethane to dichloromethane/ethyl acetate 1/1).

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbonyl diimidazole (CDI) (2.3 g, 14.24 mmol) was added to a stirred solution of 2-acetoxyacetic acid (1.68 g, 14.24 mmol) in NMP (10 mL). After 30 minutes, 6-bromo-N-(5-(N-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (50f) (1.38 g, 3.56 mmol) was added in one portion and the resulting solution was stirred for 30 minutes before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (897 mg, 21.36 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford 6-bromo-N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (142). 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.64 (d, J=1.2 Hz, 1H), 8.60 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.79 (dd, J=0.8, 9.6 Hz, 1H), 7.67 (dd, J=2.0, 9.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.81 (s, 2H), 2.37 (s, 3H). MS m/z 427.9, 429.9 (M+1)+. to afford a residue which After removal of all solvents 2M NaHCO3 (10 mL) was added The precipitate was filtered dried in air

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbonyl diimidazole (CDI) (324 mg, 2.0 mmol) was added to a stirred solution of 2-acetoxyacetic acid (236 mg, 2.0 mmol) in NMP. After 20 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (310 mg, 1.0 mmol) was added in one portion and the resulting solution was stirred for 1 hour before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (252 mg, 6.0 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (43). 1H NMR (400 MHz, d6-DMSO) δ 10.02 (s, 1H), 9.46 (d, J=6.8 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.82 (m, 2H), 7.53 (m, 2H), 7.18 (m, 1H), 6.08 (m, 1H), 4.80 (d, J=6.0 Hz, 2H), 2.37 (s, 3H). MS m/z 350.1 (M+1)+. to afford a residue which After removal of all solvents 2M NaHCO3 (10 mL) was added The precipitate was filtered dried in air

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

Procedure: To a solution of acetoxyacetic acid (0.13 g, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (3/1) yielded 0.15 g (29%) acetic acid 3-(4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-[1,2,4]oxadiazol-5-ylmethyl ester as white solid, MS: m/e (%)=533.0 (MH+, 100). heated to 40° C. for a few minutes cooled to room temperature the mixture was stirred at 100° C. for 5 hours Filtration and chromatography on silicagel with ethylacetate/heptane (3/1)

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

Procedure: Process A: Methyl (2S,4S)-4-fluoropyrrolidine-2-carboxylate hydrochloride (18.4 g) was suspended in dehydrated acetonitrile (370 mL). While the suspension was cooled in an ice bath, diisopropylethylamine (18.3 mL) was added dropwise and the mixture was stirred for 15 minutes. Subsequently, 1-hydroxybenzotriazole (4.59 g), glycolic acid (8.37 g) and 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 g) were added and the reaction mixture was stirred at room temperature for 6 hours and left overnight. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1). The eluted yellow oil was dissolved in dehydrated methanol (50 mL). While being cooled in an ice bath, the solution was added to methanol (250 mL) saturated with ammonia. The mixture was stirred at room temperature for 3 hours. The resulting crystal was collected by filtration, washed with methanol, and dried under reduced pressure to give (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide as a white crystal (15.6 g, 82% yield). Process B: Methyl (2S,4S)-4-fluoropyrrolidine-2-carboxylate hydrochloride (1.84 g) was suspended in dehydrated acetonitrile (37 mL). While the suspension was cooled in an ice bath, diisopropylethylamine (1.83 mL) was added dropwise and the mixture was stirred for 15 minutes. Subsequently, 1-hydroxybenzotriazole (0.46 g), acetoxyacetic acid (1.30 g) and 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g) were added and the mixture was stirred at room temperature for 4 hours and left overnight. The reaction mixture was then concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL). The solution was washed successively with water (20 mL), a saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL). The washes were combined and sodium chloride was added to saturation. The resulting mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (30 mL) saturated with ammonia and the solution was stirred at room temperature for 4 hours. The resulting crystal was collected by filtration, washed with methanol, and dried under reduced pressure to give (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide as a white crystal (1.50 g, 79% yield). Process C: Methyl (2S,4S)-4-fluoropyrrolidine-2-carboxylate hydrochloride (1.84 g) was suspended in dehydrated acetonitrile (30 mL). While the suspension was cooled in an ice bath, triethylamine (3.10 mL) was added dropwise and the mixture was stirred for 30 minutes. To the reaction mixture, acetoxyacetyl chloride (1.13 mL) was added dropwise at the same temperature and the mixture was further stirred for 1 hour. The insoluble material in the reaction mixture was collected by filtration and washed with acetonitrile. The filtrate and the wash were combined and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL) and the solution was washed successively with water (20 mL) and saturated brine (2×20 mL). The washes were combined and sodium chloride was added to saturation. The resulting mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (30 mL) saturated with ammonia and the solution was stirred at room temperature for 2.5 hours. The resulting crystal was collected by filtration, washed with methanol, and dried under reduced pressure to give (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide as a white crystal (1.42 g, 76% yield). While the suspension was cooled in an ice bath the mixture was stirred at room temperature for 4 hours left overnight The reaction mixture was then concentrated under reduced pressure the resulting residue was dissolved in ethyl acetate (150 mL) The solution was washed successively with water (20 mL) sodium chloride was added to saturation The resulting mixture was extracted with ethyl acetate (100 mL×2) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was dissolved in methanol (30 mL) saturated with ammonia the solution was stirred at room temperature for 4 hours The resulting crystal was collected by filtration washed with methanol dried under reduced pressure

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbonyl diimidazole (CDI) (2.3 g, 14.24 mmol) was added to a stirred solution of 2-acetoxyacetic acid (1.68 g, 14.24 mmol) in NMP (10 mL). After 30 minutes, 6-bromo-N-(5-(N-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (50f) (1.38 g, 3.56 mmol) was added in one portion and the resulting solution was stirred for 30 minutes before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (897 mg, 21.36 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford 6-bromo-N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (142). 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 9.64 (d, J=1.2 Hz, 1H), 8.60 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.79 (dd, J=0.8, 9.6 Hz, 1H), 7.67 (dd, J=2.0, 9.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.81 (s, 2H), 2.37 (s, 3H). MS m/z 427.9, 429.9 (M+1)+. to afford a residue which After removal of all solvents 2M NaHCO3 (10 mL) was added The precipitate was filtered dried in air

Conditions: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Carbonyl diimidazole (CDI) (324 mg, 2.0 mmol) was added to a stirred solution of 2-acetoxyacetic acid (236 mg, 2.0 mmol) in NMP. After 20 minutes, N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (310 mg, 1.0 mmol) was added in one portion and the resulting solution was stirred for 1 hour before it was heated at 125° C. for 15 minutes in a microwave reactor. The reaction solution was subjected to standard aqueous work up to afford a residue which was hydrolyzed by lithium hydroxide monohydrate (252 mg, 6.0 mmol) in THF/MeOH/H2O (3:2:1). After removal of all solvents 2M NaHCO3 (10 mL) was added. The precipitate was filtered and dried in air to afford N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (43). 1H NMR (400 MHz, d6-DMSO) δ 10.02 (s, 1 H), 9.46 (d, J=6.8 Hz, 1 H), 8.59 (s, 1 H), 8.11 (s, 1 H), 7.82 (m, 2 H), 7.53 (m, 2 H), 7.18 (m, 1 H), 6.08 (m, 1 H), 4.80 (d, J=6.0 Hz, 2 H), 2.37 (s, 3 H). MS m/z 350.1 (M+1)+. to afford a residue which After removal of all solvents 2M NaHCO3 (10 mL) was added The precipitate was filtered dried in air