benzyl 4-hydroxy-2,2-dimethylbutanoate

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: To a solution of 4-hydroxy-2,2-dimethylbutanoic acid phenylmethyl ester (1.11 g), in dichloromethane in an ice bath, was added dimethylaminopyridine (0.72 g) followed by a solution of decanoyl chloride (0.95 g) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours and was filtered. The filtrate was evaporated and the residue was chromatographed on silica gel eluting with dichloromethane to afford 1.4 g (74.5%) of 2,2-dimethyl-4-[(1-oxodecyl)oxy]butanoic acid phenylmethyl ester. A portion was evaporatively distilled to give an analytical sample as a colorless oil: bp 190° C./0.15 mm; IR (CHCl3) 1720 (C=O) and 697 cm-1 (Ph); NMR (CDCl3) δ 0.87 (t, 3, CH3), 1.25-1.60 (m, 20, CH2 and CH3), 1.93 (t, 2, CH2), 2.23 (t, 2, CH2), 4.11 (t, 2, CH 2), 5.11 (s, 2, CH2) and 7.33 (s, 5, Ph); MS m/e 376 and 91. was filtered The filtrate was evaporated the residue was chromatographed on silica gel eluting with dichloromethane

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

Procedure: To a solution of 4-hydroxy-2,2-dimethylbutanoic acid phenylmethyl ester (1.11 g), in dichloromethane in an ice bath, was added dimethylaminopyridine (0.72 g) followed by a solution of decanoyl chloride (0.95 g) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours and was filtered. The filtrate was evaporated and the residue was chromatographed on silica gel eluting with dichloromethane to afford 1.4 g (74.5%) of 2,2-dimethyl-4-[(1-oxodecyl)oxy]butanoic acid phenylmethyl ester. A portion was evaporatively distilled to give an analytical sample as a colorless oil: bp 190° C./0.15 mm; IR (CHCl3) 1720 (C=O) and 697 cm-1 (Ph); NMR (CDCl3) δ 0.87 (t, 3, CH3), 1.25-1.60 (m, 20, CH2 and CH3), 1.93 (t, 2, CH2), 2.23 (t, 2, CH2), 4.11 (t, 2, CH 2), 5.11 (s, 2, CH2) and 7.33 (s, 5, Ph); MS m/e 376 and 91. was filtered The filtrate was evaporated the residue was chromatographed on silica gel eluting with dichloromethane

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

Procedure: A mixture of benzyl bromide (37.4 g) and 4-hydroxy-2,2-dimethylbutanoic acid, monopotassium salt, (3.4 g) in dimethylformamide (35 mL) was stirred at room temperature for 18 hours. The precipitate was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel eluting with 2:1 dichloromethane:ethyl acetate to give 3.95 g (89%) of 4-hydroxy-2,2-dimethylbutanoic acid phenylmethyl ester as a colorless oil. A sample was evaporatively distilled to give the analytical sample: bp 160°-165° C./0.25 mm; IR (CHCl3) 3595 (OH), 1707 (C=O) and 687 cm-1 (C6H5); NMR (CDCl3) δ 1.23 (s, 6, CH3), 1.85 (t, 2, CH2), 3.67 (t, 2, CH2), 5.11 (s, 2, CH2) and 7.34 (s, 5, Ph); MS m/e 222,91. The precipitate was filtered off the filtrate was evaporated The residue was chromatographed on silica gel eluting with 2:1 dichloromethane

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Step C To a solution of oxalyl chloride (2.8 mL, 22 mmol) (Aldrich) in dichloromethane (40 mL) at −78° C. was added the solution of dimethyl sulfoxide (3.1 mL, 44 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester (4.5 g, 20 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (10 mL, 72 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 2,2-dimethyl-4-oxo-butyric acid benzyl ester as a colorless oil (Yield: 2.9 g, 66%). the reaction mixture was slowly warmed up to room temperature stirred at room temperature for 45 min The organic layers were separated the aqueous layer was extracted with dichloromethane washed with 10% of HCl, saturated NaHCO3, brine dried over MgSO4 concentrated

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

Procedure: Step B To the mixture of 4-hydroxy-2,2-dimethyl-butanoic acid monopotassium salt (60 mmol) and benzyl bromide (8.55 mL, 72 mmol) were added NaI (10.8 g, 72 mmol) and K2CO3 (8.29 g, 60 mmol). The reaction mixture was stirred at reflux for 18 h. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash column chromatography (EtOAc: hexanes=1:2) to give 4-hydroxy-2,2-dimethyl-butyric acid benzyl ester as a colorless oil (9 g, 67%) at reflux for 18 h The precipitate was filtered off the filtrate was evaporated The residue was purified by flash column chromatography (EtOAc: hexanes=1:2)

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

Procedure: A mixture of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (7 g; 14.55 mmol), 4-hydroxy-2,2-dimethylbutyric acid phenylmethyl ester (3.88 g;17.46 mmol), DEAD (3.04 g; 17.46 mmol) was dissolved in 180 ml of THF at 00C and then (Ph)3P (4.575 g; 17.46 mmol) was added at 0° C. The above mixture was stirred overnight at room temperature and concentrated in vacuo, and the residue was purified by column chromatography (2×, silica gel; 12-33% ethyl acetate/hexane;methylene chloride/hexane, 1/4-30/1) to afford 3.65 g (37%) of 4-isopropyl-6-[3-methyl-3-(phenylmethyloxycarbonyl)butoxy]-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-O(CH2)2 C(CH3)2CO2Ph) as a solid. concentrated in vacuo the residue was purified by column chromatography (2×, silica gel; 12-33% ethyl acetate/hexane;methylene chloride/hexane, 1/4-30/1)