tert-butyl propanoate

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

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

Procedure: Toluene (30 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-Chlorothiazole (900 mg, 7.53 mmol) and tert-butyl propionate (1.176 g, 9.03 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 30.1 mL, 18.06 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h at room temperature. Methyl iodide (3.85 g, 27.1 mmol) was then added. After 1 h at room temperature, the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-25% ethyl acetate in hexanes) afforded tert-butyl 2-methyl-2-(1,3-thiazol-2-yl)propanoate (1.06 g, 62%) as a pale yellow oil. MS ESI: [M+H]+ m/z 228.1. flushed flask degassed with nitrogen (20 min) to warm to room temperature stirred for 18 h at room temperature After 1 h at room temperature the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl The mixture was extracted with ethyl acetate (2×) the combined organic layers were washed with brine dried (Na2SO4) filtered evaporated

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

Procedure: Hexamethyldisilazane (5.0 mL, 31.2 mmol) was ice-cooled in an argon atmosphere, and a 1.6 mol/L butyllithium-hexane solution (19.5 mL, 31.2 mmol) was added dropwise thereto. After stirring the mixture for 30 minutes, t-butyl propionate (2.1 g, 16.1 mmol) was added dropwise to the solution, and stirred for 30 minutes. Further, Pd(dba)2 (0.45 g, 0.8 mmol) and N,N′-(2,6-diisopropylphenyl)dihydroimidazolium chloride (0.34 g, 0.8 mmol) were added thereto, the mixture was stirred for 10 minutes, and a toluene (25 mL) solution of 4-(6-bromo-10H-9-oxa-3-thiabenzo[f]azulen-4-ylidene)-1-methylpiperidine (3.0 g, 8.0 mmol) was then added dropwise thereto. The mixture was stirred overnight at room temperature, water was then added to the reaction mixture, and the product was extracted with ethyl acetate. The solvents in the organic layer were distilled off under a reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). The purified compound was dissolved in dioxane (10 mL), a 4 mol/L hydrogen chloride-dioxane solution (12.5 mL, 50 mmol) was added to the solution, and the mixture was stirred overnight. The solvents were distilled off under a reduced pressure, and the precipitated crystals were collected by filtration, to give 1.5 g (69%) of the captioned compound. cooled in an argon atmosphere stirred for 30 minutes the mixture was stirred for 10 minutes The mixture was stirred overnight at room temperature the product was extracted with ethyl acetate The solvents in the organic layer were distilled off under a reduced pressure the residue was purified by silica gel column chromatography (hexane-ethyl acetate) The purified compound was dissolved in dioxane (10 mL) the mixture was stirred overnight The solvents were distilled off under a reduced pressure the precipitated crystals were collected by filtration

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

Procedure: Toluene (30 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-Chlorothiazole (900 mg, 7.53 mmol) and tert-butyl propionate (1.176 g, 9.03 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 30.1 mL, 18.06 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h at room temperature. Methyl iodide (3.85 g, 27.1 mmol) was then added. After 1 h at room temperature, the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-25% ethyl acetate in hexanes) afforded tert-butyl 2-methyl-2-(1,3-thiazol-2-yl)propanoate (1.06 g, 62%) as a pale yellow oil. MS ESI: [M+H]+ m/z 228.1. flushed flask degassed with nitrogen (20 min) to warm to room temperature stirred for 18 h at room temperature After 1 h at room temperature the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl The mixture was extracted with ethyl acetate (2×) the combined organic layers were washed with brine dried (Na2SO4) filtered evaporated

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

Procedure: Toluene (30 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-Chlorothiazole (900 mg, 7.53 mmol) and tert-butyl propionate (1.176 g, 9.03 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 30.1 mL, 18.06 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h at room temperature. Methyl iodide (3.85 g, 27.1 mmol) was then added. After 1 h at room temperature, the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-25% ethyl acetate in hexanes) afforded tert-butyl 2-methyl-2-(1,3-thiazol-2-yl)propanoate (1.06 g, 62%) as a pale yellow oil. MS ESI: [M+H]+ m/z 228.1. flushed flask degassed with nitrogen (20 min) to warm to room temperature stirred for 18 h at room temperature After 1 h at room temperature the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl The mixture was extracted with ethyl acetate (2×) the combined organic layers were washed with brine dried (Na2SO4) filtered evaporated

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

Procedure: To a solution of ethyl 1-methyl-1-(4-bromomethylphenyl)ethanesulfonate (0.64 g, 1.89 mol) and N-diphenylmethyleneglycine t butyl ester (0.586 g, 1.98 mmol) in THF (6.5 mL) cooled on ice was added sodium bis(trimethylsilyl)amide (2M in THF, 1.04 mL). After 30 minutes the solvent was evaporated, the residue was taken up in acetic acid (2 mL), water (2 mL) and methanol (4 mL), and stirred at rt for 4 hours. The methanol was evaporated, water was added, and the mixture was washed with hexane/ether 1/1 (2×20 mL). The organic phase was washed with water. The combined aqueous phase was cooled on ice, and adjusted to pH 7 with sodium bicarbonate. Dioxane was added followed by benzyl chloroformate (0.38 mL, 2.65 mmol) and the mixture was stirred coming to rt overnight. Water was added, and the mixture was acidified to pH 3 with 1N H2SO4. The mixture was extracted with ethyl acetate, and the organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (10% to 20% ethyl acetate/hexane) gave crude 2-(R,S)-benzyloxycarbonylamino-3-[4'-(1"-ethyloxysulfonyl-1"-methyl)ethyl)benzene]propanoic acid t butyl ester (0.645 g, 68%). To a solution of the crude ester in methylene chloride (9 mL) cooled on ice was added trifluoroacetic acid (1.5 mL). The mixture was stirred for 4 hours, warming to rt. The reaction was quenched with cold aqueous sodium bicarbonate, and extracted with methylene chloride. The solvent was evaporated, and chromatography of the residue over silica gel (methylene chloride to 10% methanol/methylene chloride) gave 2-(R,S)-benzyloxycarbonylamino-3-[4'-(1"-ethyloxysulfonyl-1"-methyl)ethyl)benzene]propanoic acid (0.396 g, 0.88 mmol, 69%). After 30 minutes the solvent was evaporated The methanol was evaporated water was added the mixture was washed with hexane/ether 1/1 (2×20 mL) The organic phase was washed with water The combined aqueous phase was cooled on ice Dioxane was added the mixture was stirred coming to rt overnight The mixture was extracted with ethyl acetate the organic phase was dried filtered evaporated

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

Procedure: To a solution of ethyl 1-methyl-1-(4-bromomethylphenyl)ethanesulfonate (0.64 g, 1.89 mol) and N-diphenylmethyleneglycine t butyl ester (0.586 g, 1.98 mmol) in THF (6.5 mL) cooled on ice was added sodium bis(trimethylsilyl)amide (2M in THF, 1.04 mL). After 30 minutes the solvent was evaporated, the residue was taken up in acetic acid (2 mL), water (2 mL) and methanol (4 mL), and stirred at rt for 4 hours. The methanol was evaporated, water was added, and the mixture was washed with hexane/ether 1/1 (2×20 mL). The organic phase was washed with water. The combined aqueous phase was cooled on ice, and adjusted to pH 7 with sodium bicarbonate. Dioxane was added followed by benzyl chloroformate (0.38 mL, 2.65 mmol) and the mixture was stirred coming to rt overnight. Water was added, and the mixture was acidified to pH 3 with 1N H2SO4. The mixture was extracted with ethyl acetate, and the organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (10% to 20% ethyl acetate/hexane) gave crude 2-(R,S)-benzyloxycarbonylamino-3-[4'-(1"-ethyloxysulfonyl-1"-methyl)ethyl)benzene]propanoic acid t butyl ester (0.645 g, 68%). To a solution of the crude ester in methylene chloride (9 mL) cooled on ice was added trifluoroacetic acid (1.5 mL). The mixture was stirred for 4 hours, warming to rt. The reaction was quenched with cold aqueous sodium bicarbonate, and extracted with methylene chloride. The solvent was evaporated, and chromatography of the residue over silica gel (methylene chloride to 10% methanol/methylene chloride) gave 2-(R,S)-benzyloxycarbonylamino-3-[4'-(1"-ethyloxysulfonyl-1"-methyl)ethyl)benzene]propanoic acid (0.396 g, 0.88 mmol, 69%). After 30 minutes the solvent was evaporated The methanol was evaporated water was added the mixture was washed with hexane/ether 1/1 (2×20 mL) The organic phase was washed with water The combined aqueous phase was cooled on ice Dioxane was added the mixture was stirred coming to rt overnight The mixture was extracted with ethyl acetate the organic phase was dried filtered evaporated

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

Procedure: 32.3 g of diisopropylamine are introduced into 200 ml of tetrahydrofuran and, with cooling with a CO2/acetone cooling bath, 200 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise. 49.2 ml of propionic acid tert-butyl ester are then added dropwise at approximately −75° C. and the mixture is stirred at that temperature for 45 minutes. At approximately −75° C. a solution of 32.6 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid ethyl ester (Example P1) in 40 ml of tetrahydrofuran (THF) is then added dropwise and the mixture is stirred at that temperature for 1 hour, after which it is diluted with 250 ml of tert-butyl methyl ether. A mixture of 100 ml of water and 200 ml of glacial acetic acid is added, the phases are separated, the aqueous phase is extracted again, and the combined organic phases are washed with water. After drying over magnesium sulfate, filtration and concentration to dryness in vacuo are carried out. 51 g of the desired compound are obtained in the form of an oil (crude product). with cooling with a CO2/acetone cooling bath At approximately −75° C. the mixture is stirred at that temperature for 1 hour is added the phases are separated the aqueous phase is extracted again the combined organic phases are washed with water After drying over magnesium sulfate, filtration and concentration to dryness in vacuo

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

Procedure: 32.3 g of diisopropylamine are introduced into 200 ml of tetrahydrofuran and, with cooling with a CO2/acetone cooling bath, 200 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise. 49.2 ml of propionic acid tert-butyl ester are then added dropwise at approximately −75° C. and the mixture is stirred at that temperature for 45 minutes. At approximately −75° C. a solution of 32.6 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid ethyl ester (Example P1) in 40 ml of tetrahydrofuran (THF) is then added dropwise and the mixture is stirred at that temperature for 1 hour, after which it is diluted with 250 ml of tert-butyl methyl ether. A mixture of 100 ml of water and 200 ml of glacial acetic acid is added, the phases are separated, the aqueous phase is extracted again, and the combined organic phases are washed with water. After drying over magnesium sulfate, filtration and concentration to dryness in vacuo are carried out. 51 g of the desired compound are obtained in the form of an oil (crude product). with cooling with a CO2/acetone cooling bath At approximately −75° C. the mixture is stirred at that temperature for 1 hour is added the phases are separated the aqueous phase is extracted again the combined organic phases are washed with water After drying over magnesium sulfate, filtration and concentration to dryness in vacuo

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

Procedure: Toluene (30 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-Chlorothiazole (900 mg, 7.53 mmol) and tert-butyl propionate (1.176 g, 9.03 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 30.1 mL, 18.06 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h at room temperature. Methyl iodide (3.85 g, 27.1 mmol) was then added. After 1 h at room temperature, the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-25% ethyl acetate in hexanes) afforded tert-butyl 2-methyl-2-(1,3-thiazol-2-yl)propanoate (1.06 g, 62%) as a pale yellow oil. MS ESI: [M+H]+ m/z 228.1. flushed flask degassed with nitrogen (20 min) to warm to room temperature stirred for 18 h at room temperature After 1 h at room temperature the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl The mixture was extracted with ethyl acetate (2×) the combined organic layers were washed with brine dried (Na2SO4) filtered evaporated

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

Procedure: Toluene (30 mL) was placed in a nitrogen-flushed flask and degassed with nitrogen (20 min). 2-Chlorothiazole (900 mg, 7.53 mmol) and tert-butyl propionate (1.176 g, 9.03 mmol) were added, and the mixture was cooled to 0° C. NaHMDS (0.6 M in toluene, 30.1 mL, 18.06 mmol) was added. The reaction was stirred for 2 h at 0° C., allowed to warm to room temperature, and stirred for 18 h at room temperature. Methyl iodide (3.85 g, 27.1 mmol) was then added. After 1 h at room temperature, the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl. The mixture was extracted with ethyl acetate (2×), and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-25% ethyl acetate in hexanes) afforded tert-butyl 2-methyl-2-(1,3-thiazol-2-yl)propanoate (1.06 g, 62%) as a pale yellow oil. MS ESI: [M+H]+ m/z 228.1. flushed flask degassed with nitrogen (20 min) to warm to room temperature stirred for 18 h at room temperature After 1 h at room temperature the orange reaction was quenched (under nitrogen) with aqueous saturated NH4Cl The mixture was extracted with ethyl acetate (2×) the combined organic layers were washed with brine dried (Na2SO4) filtered evaporated

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

Procedure: Hexamethyldisilazane (5.0 mL, 31.2 mmol) was ice-cooled in an argon atmosphere, and a 1.6 mol/L butyllithium-hexane solution (19.5 mL, 31.2 mmol) was added dropwise thereto. After stirring the mixture for 30 minutes, t-butyl propionate (2.1 g, 16.1 mmol) was added dropwise to the solution, and stirred for 30 minutes. Further, Pd(dba)2 (0.45 g, 0.8 mmol) and N,N′-(2,6-diisopropylphenyl)dihydroimidazolium chloride (0.34 g, 0.8 mmol) were added thereto, the mixture was stirred for 10 minutes, and a toluene (25 mL) solution of 4-(6-bromo-10H-9-oxa-3-thiabenzo[f]azulen-4-ylidene)-1-methylpiperidine (3.0 g, 8.0 mmol) was then added dropwise thereto. The mixture was stirred overnight at room temperature, water was then added to the reaction mixture, and the product was extracted with ethyl acetate. The solvents in the organic layer were distilled off under a reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). The purified compound was dissolved in dioxane (10 mL), a 4 mol/L hydrogen chloride-dioxane solution (12.5 mL, 50 mmol) was added to the solution, and the mixture was stirred overnight. The solvents were distilled off under a reduced pressure, and the precipitated crystals were collected by filtration, to give 1.5 g (69%) of the captioned compound. cooled in an argon atmosphere stirred for 30 minutes the mixture was stirred for 10 minutes The mixture was stirred overnight at room temperature the product was extracted with ethyl acetate The solvents in the organic layer were distilled off under a reduced pressure the residue was purified by silica gel column chromatography (hexane-ethyl acetate) The purified compound was dissolved in dioxane (10 mL) the mixture was stirred overnight The solvents were distilled off under a reduced pressure the precipitated crystals were collected by filtration