O-propan-2-ylhydroxylamine;hydrochloride

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

Procedure: A mixture of phenylglyoxylic acid (3.0 g.), isopropoxyamine hydrochloride (2.5 g.), ethanol (100 ml) and water (50 ml) was stirred and adjusted to pH 4.5 to 5 with sodium hydroxide solution (2N). The solution was stirred for 5 hr. maintaining the pH at 4.5-5 with further additions of sodium hydroxide solution. The ethanol was removed by evaporation, the aqueous residue acidified and the product collected by extraction with ethyl acetate. Evaporation of the ethyl acetate gave a brown oil (4.2 g.). that was esterified conventionally with diazomethane to give a mixture of the syn and anti methyl esters of the title compound as an oil (4.04 g.). The solution was stirred for 5 hr The ethanol was removed by evaporation the product collected by extraction with ethyl acetate Evaporation of the ethyl acetate gave a brown oil (4.2 g.) to give

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

Procedure: (3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 1.30 g, 4.70 mmol) was stirred in methanol (9.5 mL) and warmed in a 70° C. oil bath. O-Isopropyl-hydroxylamine hydrochloride (786 mg, 7.04 mmol) was added. After 7 h, the reaction mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 0.2 M aqueous potassium bisulfate solution (50 mL), 50% aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 33% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid methyl ester as a faintly yellow oil contaminated with an unknown impurity (645 mg, <41%): LC-MS (ESI) m/e calcd for C13H16ClNO5S [M+] 333.04, found 334 [M+H+]. to cool concentrated in vacuo The residue was dissolved in ethyl acetate (100 mL) washed with 0.2 M aqueous potassium bisulfate solution (50 mL), 50% aqueous sodium bicarbonate solution (50 mL) and brine (50 mL) The organic phase was dried over magnesium sulfate concentrated in vacuo Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 33% ethyl acetate/hexanes)

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

Procedure: A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), 2-(aminooxy)propane hydrochloride (0.43 g) and pyridine (10 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 79%). The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

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

Procedure: A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), 2-(aminooxy)propane hydrochloride (0.43 g) and pyridine (10 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 79%). The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 36%). The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.059 g, 11%). The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-(2-oxopropyl)-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.4 g), 2-(aminooxy)propane hydrochloride (1.8 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.059 g, 11%). The ethyl acetate layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography

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

Procedure: In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (1.77 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with O-isopropylhydroxylamine hydrochloride (420 mg) in a similar manner as described in Example 24-(i) to give the titled compound (1.46 g) as a pale yellow powder.

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

Procedure: A mixture of phenylglyoxylic acid (3.0 g.), isopropoxyamine hydrochloride (2.5 g.), ethanol (100 ml) and water (50 ml) was stirred and adjusted to pH 4.5 to 5 with sodium hydroxide solution (2N). The solution was stirred for 5 hr. maintaining the pH at 4.5-5 with further additions of sodium hydroxide solution. The ethanol was removed by evaporation, the aqueous residue acidified and the product collected by extraction with ethyl acetate. Evaporation of the ethyl acetate gave a brown oil (4.2 g.). that was esterified conventionally with diazomethane to give a mixture of the syn and anti methyl esters of the title compound as an oil (4.04 g.). The solution was stirred for 5 hr The ethanol was removed by evaporation the product collected by extraction with ethyl acetate Evaporation of the ethyl acetate gave a brown oil (4.2 g.) to give

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

Procedure: A mixture of phenylglyoxylic acid (3.0 g.), isopropoxyamine hydrochloride (2.5 g.), ethanol (100 ml) and water (50 ml) was stirred and adjusted to pH 4.5 to 5 with sodium hydroxide solution (2N). The solution was stirred for 5 hr. maintaining the pH at 4.5-5 with further additions of sodium hydroxide solution. The ethanol was removed by evaporation, the aqueous residue acidified and the product collected by extraction with ethyl acetate. Evaporation of the ethyl acetate gave a brown oil (4.2 g.). that was esterified conventionally with diazomethane to give a mixture of the syn and anti methyl esters of the title compound as an oil (4.04 g.). The solution was stirred for 5 hr The ethanol was removed by evaporation the product collected by extraction with ethyl acetate Evaporation of the ethyl acetate gave a brown oil (4.2 g.) to give

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

Procedure: 1,3-Diaminoacetone dihydrochloride monohydrate (2.0 g, 11.2 mmol) was dissolved in refluxing methanol and O-(1-methylethyl)hydroxylamine hydrochloride (2.5 g, 22.4 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 24 hours the solvent was removed in Vacuo. Crystallization from methanol/ethyl acetate afforded 1.00 g (47%) light-brown material. Mp. 170.0° C. was added After refluxing for 48 hours the solvent was evaporated The crude product was dissolved in methanol an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux After 24 hours the solvent was removed in Vacuo Crystallization from methanol/ethyl acetate

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

Procedure: 1,3-Diaminoacetone dihydrochloride monohydrate (2.0 g, 11.2 mmol) was dissolved in refluxing methanol and O-(1-methylethyl)hydroxylamine hydrochloride (2.5 g, 22.4 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 24 hours the solvent was removed in Vacuo. Crystallization from methanol/ethyl acetate afforded 1.00 g (47%) light-brown material. Mp. 170.0° C. was added After refluxing for 48 hours the solvent was evaporated The crude product was dissolved in methanol an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux After 24 hours the solvent was removed in Vacuo Crystallization from methanol/ethyl acetate