methyl 2,2-dimethyl-3-phenylmethoxypropanoate

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

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

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

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

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

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of methyl 3-(benzyloxy)-2,2-dimethylpropanoate prepared according to Step A (952 mg, 4.28 mmol), in THF (11 mL) was added aqueous 1M NaOH (5.14 mL, 5.14 mmol). Little to no progress was seen at ambient temperature. Additional NaOH (˜7 mL, ˜7 mmol) was then added and the temperature was raised to 65° C., for 20 hours. After cooling to ambient temperature, the bulk of the THF was removed in vacuo. Aqueous 3M HCl (˜5 mL, ˜15 mmol) was then slowly added, resulting in the formation of a precipitate. This mixture was filtered through filter paper, and washed with a minimal amount of water. After placing under a strong vacuum for a few hours, the title compound was obtained. MS: m/z=231 (M+23 (Na+)). was seen at ambient temperature After cooling to ambient temperature the bulk of the THF was removed in vacuo resulting in the formation of a precipitate This mixture was filtered through filter paper washed with a minimal amount of water After placing under a strong vacuum for a few hours

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

Procedure: To a stirred solution of methyl 3-hydroxy-2,2-dimethylpropanoate (600. mg, 4.54 mmol) in DMF (9.0 mL), cooled to 0° C., was added NaH (120. mg, 4.99 mmol). After warming to ambient temperature for 30 minutes, the reaction was cooled to 0° C., prior to the introduction of benzyl bromide (854 mg, 4.99 mmol). After warming to ambient temperature, the reaction was heated to 50° C. for 4 hours, before being allowed to return to ambient temperature. The bulk of the DMF was removed in vacuo, and the residue was diluted with water and EtOAc. The organic layer was washed several times with water and then once with saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue which was applied to a silica gel column for purification, eluting with 100% DCM. The resulting impure material was applied again to silica gel and eluted with a gradient of CH2Cl2:hexanes—85:15 to 100:0. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=223 (M+1). the reaction was cooled to 0° C. After warming to ambient temperature the reaction was heated to 50° C. for 4 hours to return to ambient temperature The bulk of the DMF was removed in vacuo the residue was diluted with water and EtOAc The organic layer was washed several times with water The organics were then dried over sodium sulfate filtered concentrated in vacuo to yield a residue which was applied to a silica gel column for purification eluting with 100% DCM eluted with a gradient of CH2Cl2 Clean product-containing fractions concentrated in vacuo

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

Procedure: A solution of potassium hydroxide (1.8 g, 338 mmol) and 3-benzyloxy-2,2-dimethyl-propionic acid methyl ester in ethanol (50.0 mL) is refluxed for 24 h. The solvent is removed under reduced pressure, the crude is diluted with water and extracted with ethyl acetate. The water phase is acidified with 1N aq. HCl (pH ˜2-3) and extracted with ethyl acetate. The combined organic layers are washed with water and brine; the organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2.5 g of 3-benzyloxy-2,2-dimethyl-propionic acid as a brown solid that is used in the next step without any further purification. Yield: 32%, over two steps; m/z 209 [M+H]. The solvent is removed under reduced pressure the crude is diluted with water extracted with ethyl acetate extracted with ethyl acetate The combined organic layers are washed with water and brine the organic phase is dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: 60% Sodium hydride in mineral oil (2.3 g, 56.8 mmol) is added to a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (5.0 g, 37.8 mmol) in THF (80 mL) at 0° C., followed by the addition of benzylbromide (7.3 g, 42.6 mmol). The reaction mixture is slowly brought to room temperature, stirred for 8 h and then quenched with ice water and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over Na2SO4 filtered and concentrated. The crude product is purified by column chromatography to afford 5.0 g of 3-benzyloxy-2,2-dimethyl-propionic acid methyl ester as a brown liquid; m/z 223 [M+H]. is slowly brought to room temperature quenched with ice water extracted with ethyl acetate The organic phase is washed with water and brine dried over Na2SO4 filtered concentrated The crude product is purified by column chromatography

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of methyl 3-(benzyloxy)-2,2-dimethylpropanoate prepared according to Step A (952 mg, 4.28 mmol), in THF (11 mL) was added aqueous 1M NaOH (5.14 mL, 5.14 mmol). Little to no progress was seen at ambient temperature. Additional NaOH (˜7 mL, ˜7 mmol) was then added and the temperature was raised to 65° C., for 20 hours. After cooling to ambient temperature, the bulk of the THF was removed in vacuo. Aqueous 3M HCl (˜5 mL, ˜15 mmol) was then slowly added, resulting in the formation of a precipitate. This mixture was filtered through filter paper, and washed with a minimal amount of water. After placing under a strong vacuum for a few hours, the title compound was obtained. MS: m/z=231 (M+23 (Na+)). was seen at ambient temperature After cooling to ambient temperature the bulk of the THF was removed in vacuo resulting in the formation of a precipitate This mixture was filtered through filter paper washed with a minimal amount of water After placing under a strong vacuum for a few hours

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

Procedure: To a stirred solution of methyl 3-hydroxy-2,2-dimethylpropanoate (600. mg, 4.54 mmol) in DMF (9.0 mL), cooled to 0° C., was added NaH (120. mg, 4.99 mmol). After warming to ambient temperature for 30 minutes, the reaction was cooled to 0° C., prior to the introduction of benzyl bromide (854 mg, 4.99 mmol). After warming to ambient temperature, the reaction was heated to 50° C. for 4 hours, before being allowed to return to ambient temperature. The bulk of the DMF was removed in vacuo, and the residue was diluted with water and EtOAc. The organic layer was washed several times with water and then once with saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue which was applied to a silica gel column for purification, eluting with 100% DCM. The resulting impure material was applied again to silica gel and eluted with a gradient of CH2Cl2:hexanes—85:15 to 100:0. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=223 (M+1). the reaction was cooled to 0° C. After warming to ambient temperature the reaction was heated to 50° C. for 4 hours to return to ambient temperature The bulk of the DMF was removed in vacuo the residue was diluted with water and EtOAc The organic layer was washed several times with water The organics were then dried over sodium sulfate filtered concentrated in vacuo to yield a residue which was applied to a silica gel column for purification eluting with 100% DCM eluted with a gradient of CH2Cl2 Clean product-containing fractions concentrated in vacuo

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

Procedure: To a stirred solution of methyl 3-hydroxy-2,2-dimethylpropanoate (600. mg, 4.54 mmol) in DMF (9.0 mL), cooled to 0° C., was added NaH (120. mg, 4.99 mmol). After warming to ambient temperature for 30 minutes, the reaction was cooled to 0° C., prior to the introduction of benzyl bromide (854 mg, 4.99 mmol). After warming to ambient temperature, the reaction was heated to 50° C. for 4 hours, before being allowed to return to ambient temperature. The bulk of the DMF was removed in vacuo, and the residue was diluted with water and EtOAc. The organic layer was washed several times with water and then once with saturated brine. The organics were then dried over sodium sulfate, filtered and concentrated in vacuo, to yield a residue which was applied to a silica gel column for purification, eluting with 100% DCM. The resulting impure material was applied again to silica gel and eluted with a gradient of CH2Cl2:hexanes—85:15 to 100:0. Clean product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=223 (M+1). the reaction was cooled to 0° C. After warming to ambient temperature the reaction was heated to 50° C. for 4 hours to return to ambient temperature The bulk of the DMF was removed in vacuo the residue was diluted with water and EtOAc The organic layer was washed several times with water The organics were then dried over sodium sulfate filtered concentrated in vacuo to yield a residue which was applied to a silica gel column for purification eluting with 100% DCM eluted with a gradient of CH2Cl2 Clean product-containing fractions concentrated in vacuo