azanium;acetate

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonium acetate (2.53 g, 32.79 mmol) was added to an ambient temperature solution of benzyl {2-[(4,4-dimethyl-2-oxohexyl)amino]-1-[4-(5-fluoropyridin-2-yl)benzyl]-1-methyl-2-oxoethyl}carbamate (350 mg, 0.66 mmol) in xylenes (minimal volume). After stirring in a sealed tube at 160° C. for 1 hr, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 515. extracted with ethyl acetate The combined organic extracts were washed with brine dried (sodium sulfate) concentrated High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonium acetate (1.18 g, 15.4 mmol) was added to an ambient temperature solution of N-(4,4-dimethyl-2-oxohexyl)-2-[4-(5-fluoropyridin-2-yl)benzyl]-5-oxopyrrolidine-2-carboxamide in xylenes (minimal volume). After stirring in a sealed tube at 160° C. for 1 hr, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 421. the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate The aqueous phase was extracted with ethyl acetate The combined organic extracts were washed with brine dried (sodium sulfate) concentrated in vacuo High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonium acetate (1.47 g, 19 mmol) was added to an ambient temperature solution of tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (200 mg, 0.38 mmol) in xylenes (10 mL). After stirring at 160° C. in a sealed tube overnight, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane followed by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded tert-butyl 2-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate. The organic phase was dried (magnesium sulfate) filtered concentrated in vacuo eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonium acetate (1.17 g, 79 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propanamide (650 mg, 1.58 mmol) in xylene (10 mL). After stirring at 15° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded N-{2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide. the reaction mixture was quenched with saturated aqueous sodium bicarbonate extracted with ethyl acetate and methylene chloride The combined organic extracts were dried (magnesium sulfate) concentrated in vacuo

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonium acetate (1.17 g, 15.2 mmol) was added to an ambient temperature solution of tert-butyl [4-(4-{2-(acetylamino)-3-[(4,4-dimethyl-2-oxohexyl)amino]-3-oxopropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (160 mg, 0.30 mmol) in xylene (5 mL). After stirring at 150° C. for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. (M+H) found: 509. the reaction mixture was quenched with saturated aqueous sodium bicarbonate extracted with ethyl acetate and methylene chloride The combined organic extracts were dried (magnesium sulfate) concentrated in vacuo

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonium acetate (48 g, 620 mmol) was added to an ambient temperature solution of benzyl {1-(4-bromobenzyl)-2-[(4,4-dimethyl-2-oxohexyl)amino]-2-oxoethyl}carbamate (6.23 g, 12.4 mmol) in xylene (124 mL). After stirring at 150° C. for 2 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford benzyl {2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}carbamate which was used in the subsequent step without further purification. the reaction mixture was quenched with saturated aqueous sodium bicarbonate extracted with methylene chloride The combined organic extracts were dried (magnesium sulfate) concentrated in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 1-[2-(4-fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-4-carboxylic acid tert-butyl ester (100 g, 231 mmoles), ammonium acetate (178.3 g; 2.31 moles, 10 eq), and methanol (1000 mL). The reactor used for this transformation is a coiled 1/16″ I.D. stainless steel tube (total internal volume of tubing in oven is 541 mol). Heat the reactor in an oven to 140° C. Control the back pressure in this tube at 250 psig by a regulator to allow super-heating of the solution above its normal boiling point. Pump the solution prepared above continuously through the heated tube under pressure at 6.01 mL/min (affording a total residence time in the heated tube of 90 minutes). As the solution exits the oven, cool it back to 20° C. in a tube-in-tube heat exchanger. Once the entire solution process through the reactor (8 hours total processing time), concentrate the resulting orange solution under vacuum at 30° C. to a total volume of 600 mL. Add acetonitrile (200 mL) and heat the solution to 50° C. Add water (700 mL) drop wise with seeding over 2 hours to crystallize the product. Cool the resulting slurry to 20° C. and filter the solid, then wash with 20% MeOH in water (2×200 mL). Dry the resulting solid under vacuum at 50° C. Re-slurry the solid in acetonitrile (200 mL) at 50° C. Cool the slurry to ambient temperature, filter the solid and wash with acetonitrile (100 mL) to afford 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (54.43 g, 132 mmoles, 57%) as an off white solid. Control the back pressure in this tube at 250 psig by a regulator to allow super-heating of the solution above its normal boiling point prepared above continuously through the heated tube under pressure at 6.01 mL/min ( affording a total residence time in the heated tube of 90 minutes) cool it back to 20° C. in a tube-in-tube heat exchanger Once the entire solution process through the reactor (8 hours total processing time), concentrate the resulting orange solution under vacuum at 30° C. to a total volume of 600 mL Add acetonitrile (200 mL) and heat the solution to 50° C to crystallize the product Cool the resulting slurry to 20° C. filter the solid wash with 20% MeOH in water (2×200 mL) Dry the resulting solid under vacuum at 50° C at 50° C Cool the slurry to ambient temperature filter the solid wash with acetonitrile (100 mL)

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

Procedure: Add tert-butyl 4-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethylcarbamoyl)-piperidine-1-carboxylate (1.50 g, 3.48 mmol) to a mixture of ammonium acetate (1.40 g, 18.1 mmol), and glacial acetic acid (10 mL) and heat at reflux for 15 h. Cool the mixture to room temperature and concentrated in vacuo. Dissolve the residue in ethyl acetate (50 mL) and adjust to pH 8 with saturated NaHCO3. Extract the aqueous layer with ethyl acetate (2×50 mL). Combine the organic layers, dry (Na2SO4), filter, and concentrate in vacuo. Purify the residue by silica gel chromatography (80 g, eluting with a gradient of 10% to 20% methanol/ethyl acetate, 1.5 L) to provide 4-(4-(3-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)piperidine (491 mg, 45%). heat at reflux for 15 h concentrated in vacuo Dissolve the residue in ethyl acetate (50 mL) Extract the aqueous layer with ethyl acetate (2×50 mL) Combine the organic layers, dry (Na2SO4) filter concentrate in vacuo Purify the residue by silica gel chromatography (80 g eluting with a gradient of 10% to 20% methanol/ethyl acetate, 1.5 L)

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

Procedure: The above ketone (760 mg, 3.689 mmol) was dissolved in methanol (40 ml). Then, ammonium acetate (2.841 g, 36.896 mmol), sodium cyanoborohydride (232 mg, 3.389 mmol) and molecular sieves (3 Å, 7.6 g) were added. The mixture was stirred at room temperature for two days. The solid was filtered and the filtrate was concentrated. The residue was dissolved in water and concentrated aqueous HCl was added dropwise until the pH ≈2. The mixture was then extracted with ethyl acetate to remove the unfinished ketone and other by-products. The water layer was basified to pH≈10 with aqueous sodium hydroxide (1M), and was extracted with dichloromethane and the organic layers were combined, dried over magnesium sulfate and concentrated to afford 290 mg of 1-(5,7-difluoro-naphthalen-2-yl)-ethylamine (38% yield). The solid was filtered the filtrate was concentrated The residue was dissolved in water concentrated aqueous HCl was added dropwise until the pH ≈2 The mixture was then extracted with ethyl acetate to remove the unfinished ketone and other by-products was extracted with dichloromethane dried over magnesium sulfate concentrated

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

Procedure: To a solution of 1-pyrazin-2-yl-ethanone (2.0 g, 15.85 mmol) and ammonium acetate (19.337 g, 158.5 mmol) in methanol (50 mL) was added sodium cyanoborohydride (0.7 g, 11.1 mmol) in one portion. The reaction mixture was stirred overnight at room temperature. After removal of methanol, water (20 mL) was added to the residue and the resulting solution was basified by addition of sodium hydroxide to pH=13. The aqueous solution was extracted with dicholromethane and the combined organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 14.62 g of 1-pyrazin-2-yl-ethylamine, yield: 75%. MS (M+H)=124. After removal of methanol, water (20 mL) was added to the residue the resulting solution was basified by addition of sodium hydroxide to pH=13 The aqueous solution was extracted with dicholromethane the combined organic phase was dried over sodium sulfate Removal of the solvent under reduced pressure

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-[2-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (147.8 mg) was taken into m-xylenes (2.0 mL) and heated at 135° C. Solid ammonium acetate (120 mg, 1.5 mmol) was added and the reaction was stirred at 135° C. After 180 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude reaction product was partitioned between EtOAc and water. The organic layer was collected and dried over sodium sulfate. Filtration and evaporation of solvents gave the crude product (142 mg). the reaction was cooled to room temperature the volatiles were removed in vacuo The crude reaction product was partitioned between EtOAc and water The organic layer was collected dried over sodium sulfate Filtration and evaporation of solvents

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 15 mL Xylenes was added to 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium acetate (20 eq., 1.5 g). The mixture was heated in microwave at 140° C. for 60 minutes. The mixture was diluted with EtOAc and washed with sat. NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI−: calc'd for C20H24BrN3O2: 418.33. Found: 418. (M+H+). washed with sat. NaHCO3 aqueous solution The organic layer was concentrated down purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane)