benzyl 3-hydroxy-2,2-dimethylpropanoate

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

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

Procedure: Add potassium hydroxide (486.7 mmol, 32.1 g) over a solution of 2,3-dihydroxy-2-methyl-propionic acid (423.2 mmol, 50 g) in 300 mL of DMF. Stir for 1 hour at 100° C. Then add benzyl bromide (584.04 mmol, 69.46 mL) and stir overnight. Cool down the mixture and dilute with ethyl acetate. Wash organic layer with water. Wash aqueous layer with ethyl acetate several times. Combine organic layers and dry over sodium sulfate, filter and concentrate under reduced pressure. 1H NMR (CDCl3, 300 MHz): δ ppm :7.36-7.32 (m, 5H), 5.1 (s, 2H), 3.5 (s, 2H), 1.21 (s, 6H). Cool down the mixture Combine organic layers and dry over sodium sulfate filter concentrate under reduced pressure

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

Procedure: To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF (200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solution was stirred at 0° C.-RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes) to give the title compound as a brown solid (10.0 g, 87%). MS 355 (MH+). at 0° C. the reaction solution was stirred at 0° C.-RT under nitrogen overnight The reaction mixture was quenched with brine extracted with EtOAc (3×) The combined organic layers were washed with brine dried over Na2SO4 After evaporation of the solvent the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes)

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

Procedure: To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF (200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solution was stirred at 0° C.-RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes) to give the title compound as a brown solid (10.0 g, 87%). MS 355 (MH+). at 0° C. the reaction solution was stirred at 0° C.-RT under nitrogen overnight The reaction mixture was quenched with brine extracted with EtOAc (3×) The combined organic layers were washed with brine dried over Na2SO4 After evaporation of the solvent the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes)

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

Procedure: To a solution of 4-hydroxybenzaldehyde (2.7 g), benzyl hydroxypivalate (4.7 g) and triphenylphosphine (6.4 g) in tetrahydrofuran (22 mL) was added diethyl azodicarboxylate (40% toluene solution, 11 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1) to give the title compound (0.97 g). the resulting mixture was extracted with diethyl ether The organic layer was washed with water dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1)

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

Procedure: To a solution of 4-hydroxybenzaldehyde (2.7 g), benzyl hydroxypivalate (4.7 g) and triphenylphosphine (6.4 g) in tetrahydrofuran (22 mL) was added diethyl azodicarboxylate (40% toluene solution, 11 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1) to give the title compound (0.97 g). the resulting mixture was extracted with diethyl ether The organic layer was washed with water dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1)

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

Procedure: To a suspension of hydroxypivalic acid (3 g) and potassium carbonate (3.9 g) in N,N-dimethylformamide (25 mL) was added benzyl bromide (2.9 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.7 g). the resulting mixture was extracted with diethyl ether The organic layer was washed with water twice dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

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

Procedure: To a suspension of hydroxypivalic acid (3 g) and potassium carbonate (3.9 g) in N,N-dimethylformamide (25 mL) was added benzyl bromide (2.9 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.7 g). the resulting mixture was extracted with diethyl ether The organic layer was washed with water twice dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure

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

Procedure: To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF (200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solution was stirred at 0° C.-RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes) to give the title compound as a brown solid (10.0 g, 87%). MS 355 (MH+). at 0° C. the reaction solution was stirred at 0° C.-RT under nitrogen overnight The reaction mixture was quenched with brine extracted with EtOAc (3×) The combined organic layers were washed with brine dried over Na2SO4 After evaporation of the solvent the residue was purified by chromatography on silica gel eluting (Elunet: 20% EtOAc in hexanes)

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

Procedure: To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF (200 mL) was carefully added NaH (60% in mineral oil, 3.5 g, 87.5 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol), and the reaction solution was stirred at 0° C.—RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Eluent: 20% EtOAc in hexanes) to give the title compound as a brown solid (10.0 g, 87%). MS 355 (MH+). at 0° C. the reaction solution was stirred at 0° C.—RT under nitrogen overnight The reaction mixture was quenched with brine extracted with EtOAc (3×) The combined organic layers were washed with brine dried over Na2SO4 After evaporation of the solvent the residue was purified by chromatography on silica gel eluting (Eluent: 20% EtOAc in hexanes)

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

Procedure: Analogously to Example 3 (step (a)), the reaction of 250 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol with 178 mg of benzyl 3-hydroxy-2,2-dimethylpropionate gave 160 mg (41%) of benzyl 3-{4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy}-2,2-dimethylpropionate.

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

Procedure: Add potassium hydroxide (486.7 mmol, 32.1 g) over a solution of 2,3-dihydroxy-2-methyl-propionic acid (423.2 mmol, 50 g) in 300 mL of DMF. Stir the solution for 1 hour at 100° C., then add benzyl bromide. Stir the solution overnight. Cool the mixture and dilute with ethyl acetate. Wash organic layer with water. Wash aqueous layer with ethyl acetate several times. Combine organic layers and dry over sodium sulfate, filter and concentrate under reduced pressure. Stir the solution overnight Cool the mixture Combine organic layers and dry over sodium sulfate filter concentrate under reduced pressure