methyl 4-methoxybutanoate

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

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

Procedure: A mixture of 18.80 g of (5-bromopyridin-2-yl)hydrazine [77992-44-0] and 14.54 g of methyl 4-methoxybutyrate [29006-01-7] is heated to reflux over 16 hours. The reaction solution is subsequently cooled and purified by means of flash chromatography (SiO2 60F). The title compound is identified on the basis of the Rf value. is heated to reflux over 16 hours The reaction solution is subsequently cooled purified by means of flash chromatography (SiO2 60F)

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

Procedure: A mixture of 18.80 g of (5-bromopyridin-2-yl)hydrazine [77992-44-0] and 14.54 g of methyl 4-methoxybutyrate [29006-01-7] is heated to reflux over 16 hours. The reaction solution is subsequently cooled and purified by means of flash chromatography (SiO2 60F). The title compound is identified on the basis of the Rf value. is heated to reflux over 16 hours The reaction solution is subsequently cooled purified by means of flash chromatography (SiO2 60F)

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

Procedure: To a stirred, cooled (−78° C.) solution of 1.32 g (10.0 mmol) of methyl 4-methoxybutanoate in 15 mL of anhydrous THF under an atmosphere of nitrogen was added 10.5 mL (10.5 mmol) of a 1.0 M solution of LiHMDS in tetrahydrofuran. The resulting mixture was stirred for 1 h, then 1.09 g (10 mmol) of chlorotrimethylsilane was added. After stirring for 20 min, 1.78 g (10.0 mmol) of solid N-bromosuccinimide was added and the mixture was stirred for 2 h at −78° C., then slowly warmed to ambient temperature over 40 min. The reaction was quenched with a saturated aqueous ammonium chloride solution and then the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was dissolved in 15 mL of DMF and 5.5 g (40 mmol) of potassium carbonate followed by 3.4 g (50 mmol) of 1H-pyrazole were added. The resulting mixture was heated to 80° C. for 40 min, then cooled to ambient temperature. The reaction was diluted with 75 mL of water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to yield the title compound (0.26 g, 13%). LC-MS: m/z (ES) 199 (MH)+. After stirring for 20 min the mixture was stirred for 2 h at −78° C. The reaction was quenched with a saturated aqueous ammonium chloride solution the aqueous phase was extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with brine dried over sodium sulfate filtered evaporated to dryness in vacuo The crude residue was dissolved in 15 mL of DMF were added The resulting mixture was heated to 80° C. for 40 min cooled to ambient temperature extracted with ethyl acetate (3×50 mL) The combined extracts were washed with brine dried over magnesium sulfate filtered evaporated to dryness in vacuo The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient)

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

Procedure: To a stirred, cooled (−78° C.) solution of 1.32 g (10.0 mmol) of methyl 4-methoxybutanoate in 15 mL of anhydrous THF under an atmosphere of nitrogen was added 10.5 mL (10.5 mmol) of a 1.0 M solution of LiHMDS in tetrahydrofuran. The resulting mixture was stirred for 1 h, then 1.09 g (10 mmol) of chlorotrimethylsilane was added. After stirring for 20 min, 1.78 g (10.0 mmol) of solid N-bromosuccinimide was added and the mixture was stirred for 2 h at −78° C., then slowly warmed to ambient temperature over 40 min. The reaction was quenched with a saturated aqueous ammonium chloride solution and then the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was dissolved in 15 mL of DMF and 5.5 g (40 mmol) of potassium carbonate followed by 3.4 g (50 mmol) of 1H-pyrazole were added. The resulting mixture was heated to 80° C. for 40 min, then cooled to ambient temperature. The reaction was diluted with 75 mL of water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to yield the title compound (0.26 g, 13%). LC-MS: m/z (ES) 199 (MH)+. After stirring for 20 min the mixture was stirred for 2 h at −78° C. The reaction was quenched with a saturated aqueous ammonium chloride solution the aqueous phase was extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with brine dried over sodium sulfate filtered evaporated to dryness in vacuo The crude residue was dissolved in 15 mL of DMF were added The resulting mixture was heated to 80° C. for 40 min cooled to ambient temperature extracted with ethyl acetate (3×50 mL) The combined extracts were washed with brine dried over magnesium sulfate filtered evaporated to dryness in vacuo The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient)

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

Procedure: The title compound was prepared from 4-methoxy-butyric acid methyl ester and ethyl formate employing the procedure set forth in Step 1 of Example 87.

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

Procedure: To a stirred, cooled (−78° C.) solution of 1.32 g (10.0 mmol) of methyl 4-methoxybutanoate in 15 mL of anhydrous THF under an atmosphere of nitrogen was added 10.5 mL (10.5 mmol) of a 1.0 M solution of LiHMDS in tetrahydrofuran. The resulting mixture was stirred for 1 h, then 1.09 g (10 mmol) of chlorotrimethylsilane was added. After stirring for 20 min, 1.78 g (10.0 mmol) of solid N-bromosuccinimide was added and the mixture was stirred for 2 h at −78° C., then slowly warmed to ambient temperature over 40 min. The reaction was quenched with a saturated aqueous ammonium chloride solution and then the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was dissolved in 15 mL of DMF and 5.5 g (40 mmol) of potassium carbonate followed by 3.4 g (50 mmol) of 1H-pyrazole were added. The resulting mixture was heated to 80° C. for 40 min, then cooled to ambient temperature. The reaction was diluted with 75 mL of water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to yield the title compound (0.26 g, 13%). LC-MS: m/z (ES) 199 (MH)+. After stirring for 20 min the mixture was stirred for 2 h at −78° C. The reaction was quenched with a saturated aqueous ammonium chloride solution the aqueous phase was extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with brine dried over sodium sulfate filtered evaporated to dryness in vacuo The crude residue was dissolved in 15 mL of DMF were added The resulting mixture was heated to 80° C. for 40 min cooled to ambient temperature extracted with ethyl acetate (3×50 mL) The combined extracts were washed with brine dried over magnesium sulfate filtered evaporated to dryness in vacuo The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient)

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

Procedure: A mixture of 18.80 g of (5-bromopyridin-2-yl)hydrazine [77992-44-0] and 14.54 g of methyl 4-methoxybutyrate [29006-01-7] is heated to reflux over 16 hours. The reaction solution is subsequently cooled and purified by means of flash chromatography (SiO2 60F). The title compound is identified on the basis of the Rf value. is heated to reflux over 16 hours The reaction solution is subsequently cooled purified by means of flash chromatography (SiO2 60F)

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

Procedure: To a stirred, cooled (−78° C.) solution of 1.32 g (10.0 mmol) of methyl 4-methoxybutanoate in 15 mL of anhydrous THF under an atmosphere of nitrogen was added 10.5 mL (10.5 mmol) of a 1.0 M solution of LiHMDS in tetrahydrofuran. The resulting mixture was stirred for 1 h, then 1.09 g (10 mmol) of chlorotrimethylsilane was added. After stirring for 20 min, 1.78 g (10.0 mmol) of solid N-bromosuccinimide was added and the mixture was stirred for 2 h at −78° C., then slowly warmed to ambient temperature over 40 min. The reaction was quenched with a saturated aqueous ammonium chloride solution and then the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was dissolved in 15 mL of DMF and 5.5 g (40 mmol) of potassium carbonate followed by 3.4 g (50 mmol) of 1H-pyrazole were added. The resulting mixture was heated to 80° C. for 40 min, then cooled to ambient temperature. The reaction was diluted with 75 mL of water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to yield the title compound (0.26 g, 13%). LC-MS: m/z (ES) 199 (MH)+. After stirring for 20 min the mixture was stirred for 2 h at −78° C. The reaction was quenched with a saturated aqueous ammonium chloride solution the aqueous phase was extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with brine dried over sodium sulfate filtered evaporated to dryness in vacuo The crude residue was dissolved in 15 mL of DMF were added The resulting mixture was heated to 80° C. for 40 min cooled to ambient temperature extracted with ethyl acetate (3×50 mL) The combined extracts were washed with brine dried over magnesium sulfate filtered evaporated to dryness in vacuo The crude residue was purified by reverse phase HPLC (TMC Pro-Pac C18; 0-75% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient)

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

Procedure: The title compound was prepared from 4-methoxy-butyric acid methyl ester and ethyl formate employing the procedure set forth in Step 1 of Example 87.

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

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

Procedure: 1.8 mol of sodium hydride was added to the solvent ethylene glycol dimethyl ether, and 1 mol of methyl 4-methoxybutanoate was added thereto and stirred at room temperature for 10 minutes. Then, 1.2 mol of t-butylmethylketone was added to the solution which was then stirred at 92° C. for 19 hours. Then, the solution was cooled to room temperature and quenched in 36% hydrochloric acid, after which water and dimethylether were added to and mixed with the solution, and water was removed therefrom. The resulting organic material was washed with 1 wt % sodium hydroxide and then with saturated saline and concentrated, and the residue was fractionated, thereby obtaining the intermediate 8-methoxy-2,2-dimethyloctan-3,5-dione at a yield of 14%. was added was then stirred at 92° C. for 19 hours Then, the solution was cooled to room temperature quenched in 36% hydrochloric acid after which water and dimethylether were added to and mixed with the solution, and water was removed The resulting organic material was washed with 1 wt % sodium hydroxide with saturated saline and concentrated