methyl 2-(2,2-dimethylpropanoylamino)-6-hydroxybenzoate

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

Procedure: Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77 mL) and water (18 mL). The reaction mixture was stirred at room temperature for 1 hour. A further amount of trimethylacetyl chloride (1.85 g) was added and the mixture was stirred for 1 hour. A further amount of trimethylacetyl chloride (0.920 g) was added and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, the layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25% to give methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a white solid. the mixture was stirred for 1 hour the mixture was stirred for 30 minutes the layers were separated the organic layer was dried (Na2SO4) filtered The filtrate was concentrated in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25%

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

Procedure: A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 47, 4.57 g), propargyl bromide (80% solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20% to give methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as an oil which crystallised on standing to give a white solid. was heated at reflux for 8 hours After cooling the mixture was filtered the filtrate was concentrated in vacuo The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20%

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

Procedure: Trimethylacetyl chloride (5.57 g) was added dropwise to a vigorously stirred mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 5.15 g) and sodium bicarbonate (7.76 g) in a mixture of water (40 mL) and ethyl acetate (100 mL) and the mixture was stirred for one hour. Further trimethylacetyl chloride (5.57 g) was added and the mixture stirred overnight. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was triturated with pentane. The solid was collected by filtration and purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give methyl 2-(2,2-dimethyl-propionylamino)-6-hydroxy-benzoate (4.96 g) as a white solid. the mixture stirred overnight The organic layer was separated dried (Na2SO4) filtered The filtrate was concentrated in vacuo the residue was triturated with pentane The solid was collected by filtration purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25%

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

Procedure: Trifluoromethanesulphonic anhydride (6.2 g) was added dropwise to an ice cooled, stirred solution of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 40, 5.02 g) and pyridine (3.16 g) in DCM (70 mL) and the mixture was stirred for 1 hour. The resulting solution was washed with 2M hydrochloric acid, filtered through a phase separator and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 2-(2,2-dimethylpropionylamino)-6-trifluoromethanesulfonyloxybenzoate (7.09 g) as a colourless oil. cooled The resulting solution was washed with 2M hydrochloric acid filtered through a phase separator the filtrate was evaporated in vacuo The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15%

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

Procedure: Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77 mL) and water (18 mL). The reaction mixture was stirred at room temperature for 1 hour. A further amount of trimethylacetyl chloride (1.85 g) was added and the mixture was stirred for 1 hour. A further amount of trimethylacetyl chloride (0.920 g) was added and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, the layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25% to give methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a white solid. the mixture was stirred for 1 hour the mixture was stirred for 30 minutes the layers were separated the organic layer was dried (Na2SO4) filtered The filtrate was concentrated in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25%

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

Procedure: A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 14, 4.57 g), propargyl bromide (80% solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20% to give methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as an oil which crystallised on standing to give a white solid. was heated at reflux for 8 hours After cooling the mixture was filtered the filtrate was concentrated in vacuo The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20%

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

Procedure: A solution of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 167128, 3.8 g) and sodium bicarbonate (2.52 g) in ethyl acetate (75 mL) and water (17.5 mL) was stirred at room temperature and pivaloyl chloride (3.51 g) was added dropwise. The resultant mixture was stirred at room temperature for 1 hour. A further amount of pivaloyl chloride (1.75 g) was added and the mixture was stirred at room temperature for 2.5 hours. A further amount of pivaloyl chloride (1 g) was added and the mixture was stirred at room temperature for 4 hours and 20 minutes. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added and the layers were separated. The organic phase was washed with brine, dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25% to give methyl 2-tert-butylcarbonylamino-6-hydroxybenzoate (4.46 g) as a white solid. the mixture was stirred at room temperature for 4 hours and 20 minutes the layers were separated The organic phase was washed with brine dried (Na2SO4) filtered the filtrate was concentrated in vacuo The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25%

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

Procedure: Potassium tert-butoxide (1.81 g) was added to a solution of methyl 2-tert-butylcarbonylamino-6-hydroxybenzoate (Intermediate 79, 4.06 g) in THF (30 mL) and the mixture was heated at 60° C. β-propiolactone (1.16 g) was added dropwise and the resultant mixture was heated at 60° C. for 25 minutes, then left to stand at room temperature overnight. Ethyl acetate and water were added and the layers were separated. The aqueous phase was extracted with more ethyl acetate and acidified to pH 2 using 1M hydrochloric acid. This was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 50-100% to give methyl 2-tert-butylcarbonylamino-6-(2-carboxyethoxy)-benzoate (3.5 g) as a white solid. was added dropwise left the layers were separated The aqueous phase was extracted with more ethyl acetate This was extracted with ethyl acetate dried (Na2SO4) filtered The filtrate was concentrated in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 50-100%

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

Procedure: Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77 mL) and water (18 mL). The reaction mixture was stirred at room temperature for 1 hour. A further amount of trimethylacetyl chloride (1.85 g) was added and the mixture was stirred for 1 hour. A further amount of trimethylacetyl chloride (0.920 g) was added and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, the layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25% to give methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a white solid. the mixture was stirred for 1 hour the mixture was stirred for 30 minutes the layers were separated the organic layer was dried (Na2SO4) filtered The filtrate was concentrated in vacuo the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25%

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

Procedure: A mixture of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 47, 4.57 g), propargyl bromide (80% solution in toluene, 2.03 mL) and potassium carbonate (3.74 g) in acetone (35 mL) was heated at reflux for 8 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20% to give methyl 2-(2,2-dimethylpropionylamino)-6-(prop-2-ynyloxy)benzoate (4.74 g) as an oil which crystallised on standing to give a white solid. was heated at reflux for 8 hours After cooling the mixture was filtered the filtrate was concentrated in vacuo The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20%

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

Procedure: Trimethylacetyl chloride (5.57 g) was added dropwise to a vigorously stirred mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 5.15 g) and sodium bicarbonate (7.76 g) in a mixture of water (40 mL) and ethyl acetate (100 mL) and the mixture was stirred for one hour. Further trimethylacetyl chloride (5.57 g) was added and the mixture stirred overnight. The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was triturated with pentane. The solid was collected by filtration and purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give methyl 2-(2,2-dimethyl-propionylamino)-6-hydroxy-benzoate (4.96 g) as a white solid. the mixture stirred overnight The organic layer was separated dried (Na2SO4) filtered The filtrate was concentrated in vacuo the residue was triturated with pentane The solid was collected by filtration purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25%

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

Procedure: Trifluoromethanesulphonic anhydride (6.2 g) was added dropwise to an ice cooled, stirred solution of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 40, 5.02 g) and pyridine (3.16 g) in DCM (70 mL) and the mixture was stirred for 1 hour. The resulting solution was washed with 2M hydrochloric acid, filtered through a phase separator and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 2-(2,2-dimethylpropionylamino)-6-trifluoromethanesulfonyloxybenzoate (7.09 g) as a colourless oil. cooled The resulting solution was washed with 2M hydrochloric acid filtered through a phase separator the filtrate was evaporated in vacuo The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15%