4-tert-butyl-2-hydroxybenzaldehyde

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:0.00; pressure:0.00; stir:

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

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

Procedure: 1.83 g (13 mmol) of 2-(4-fluoro-phenyl) ethyl amine were added to 2.32 g (13 mmol) of 4-tert-butyl-2-hydroxy benzaldehyde dissolved in 130 ml methanol. The reaction mixture was stirred at rt over night under nitrogen. 492 mg (13 mmol) of sodium borohydride were added in portions and the reaction mixture was stirred for 2 h at rt. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with water and with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel; DCM, then DCM/methanol 19:1) to yield 3.26 g (83%) of 5-tert-butyl-2-{[2-(4-fluoro-phenyl)-ethylamino]-methyl}-phenol as a yellow viscous oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.24 (t, 2H), 7.09 (t, 2H), 6.95 (d, 1H), 6.71 (d, 1H), 6.68 (s, 1H), 3.76 (s, 2H), 1.23 (s, 9H). the reaction mixture was stirred for 2 h at rt The solvent was evaporated the residue was dissolved in DCM The organic layer was washed with water and with saturated aqueous NaCl solution dried over sodium sulfate filtered the solvent was evaporated The residue was purified by column chromatography (250 g silica gel

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

Procedure: A solution of 5.69 g (30 mmol) of titan tetrachloride in 15 ml DCM were added dropwise at 0° C. under nitrogen to 3.76 g (25 mmol) of 3-tert-butylphenol dissolved in 75 ml DCM. After stirring for 30 min 3.16 g (27.5 mmol) of dichloromethyl methyl ether was added. The reaction mixture was stirred for 2 h at 0° C. Carefully 30 ml of 1N aqueous HCl solution and then 90 ml water were added. The reaction mixture was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (250 g silica gel, DCM) to yield 2.32 g (52%) 4-tert-butyl-2-hydroxy benzaldehyde as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 10.62 (br s, 1H), 10.18 (s, 1H), 7.61 (d, 1H), 7.04 (d, 1H), 6.98 (s, 1H). was added The reaction mixture was extracted twice with DCM The combined organic layers were washed with saturated aqueous NaCl solution dried over sodium sulfate filtered the solvent was evaporated The residue was purified by column chromatography (250 g silica gel, DCM)

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

Procedure: A mixture of 4-tert-butylsalicylaldehyde Example 8, step 1 (1.15 g, 6.4 mm) and the ethyl ester from Step 2 (1.59 g, 7.3 mmol) was dissolved in anhydrous DMF (4 mL). With stirring, K2CO3 (1.10 g, 9.0 mmol) was added causing the reaction to become deep red. The reaction was stirred at room temperature for 100 hours, acidified with 3 N HCl, diluted with ethyl acetate and washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate/hexanes to afford a yellow oil (1.72 g, 70%): 1H NMR (CDCl3/300 MHz) 7.76 (s, 1H), 7.14 (d, 1H, J=8.1 Hz), 7.04 (dd, 1H, J=8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, J=22.4 Hz 3.0 Hz), 4.32 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.30 (s, 9H). the reaction The reaction was stirred at room temperature for 100 hours washed with saturated NaHCO3 solution, brine dried over MgSO4 filtered concentrated in vacuo yielding a brown oil This oil was purified by flash chromatography over silica gel eluting with 10% ethyl acetate/hexanes

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A one liter three-neck flask was charged with 4-tert-butylsalicylaldehyde (Step 1) (100.0 g, 0.56 mole), dimethylformamide (110 mL), and potassium carbonate (79.9 g, 0.58 mole) causing the temperature of the mixture to rise to 40° C. Ethyl 4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethylformamide (110 mL) was added and the mixture heated to 60° C. at which time the reaction temperature rose to 70° C. The reaction was cooled to 60° C., maintained at 60° C. (with added heating) for 8.5 hours and cooled to room temperature. Ethyl acetate (600 mL) and 3 N HCl (600 mL) were added, mixed, and the layers separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The combined organic phases were washed with brine-water (1:1), brine, dried over MgSO4, filtered and concentrated in vacuo, yielding a semi-solid. Hexane (600 mL) was added with mixing and the mixture was filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacua yielding a solid. This solid was dissolved in hot ethanol (600 mL). Water (190 mL) was added which induced crystallization. Filtration of the mixture and drying of the product provided the desired ester as a crystalline solid (131.3 g, 71%): mp 91.0–94.9° C. This material was of suitable purity to be used in subsequent steps without further purification. to rise to 40° C rose to 70° C The reaction was cooled to 60° C. maintained at 60° C. (with added heating) for 8.5 hours cooled to room temperature mixed the layers separated The aqueous phase was extracted with ethyl acetate The combined organic phases were washed with brine-water (1:1), brine dried over MgSO4 filtered concentrated in vacuo yielding a semi-solid with mixing the mixture was filtered The filtrate was washed with brine dried over MgSO4 filtered concentrated in vacua yielding a solid crystallization Filtration of the mixture drying of the product

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A one liter three-neck flask was charged with 4-tert-butylsalicylaldehyde (Step 1) (100.0 g, 0.56 mole), dimethylformamide (110 mL), and potassium carbonate (79.9 g, 0.58 mole) causing the temperature of the mixture to rise to 40° C. Ethyl 4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethylformamide (110 mL) was added and the mixture heated to 60° C. at which time the reaction temperature rose to 70° C. The reaction was cooled to 60° C., maintained at 60° C. (with added heating) for 8.5 hours and cooled to room temperature. Ethyl acetate (600 mL) and 3 N HCl (600 mL) were added, mixed, and the layers separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The combined organic phases were washed with brine-water (1:1), brine, dried over MgSO4, filtered and concentrated in vacuo, yielding a semi-solid. Hexane (600 mL) was added with mixing and the mixture was filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated in vacua yielding a solid. This solid was dissolved in hot ethanol (600 mL). Water (190 mL) was added which induced crystallization. Filtration of the mixture and drying of the product provided the desired ester as a crystalline solid (131.3 g, 71%): mp 91.0–94.9° C. This material was of suitable purity to be used in subsequent steps without further purification. to rise to 40° C rose to 70° C The reaction was cooled to 60° C. maintained at 60° C. (with added heating) for 8.5 hours cooled to room temperature mixed the layers separated The aqueous phase was extracted with ethyl acetate The combined organic phases were washed with brine-water (1:1), brine dried over MgSO4 filtered concentrated in vacuo yielding a semi-solid with mixing the mixture was filtered The filtrate was washed with brine dried over MgSO4 filtered concentrated in vacua yielding a solid crystallization Filtration of the mixture drying of the product