3,3-dimethylbutanoic acid

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: To a solution of t-butylacetic acid (0.025 mol, 3 g) in methanol is added tetrabutylammonium hydroxide (1M/methanol, 25 ml). The mixture is stirred for 1 h and the solvent removed to a residue. The residue is dissolved in 150 ml of methylene chloride and 150 ml of water and a solution of O-chloromethyl S-ethyl carbonothioate (0.025 mol, 3.85 f) in 50 ml of methylene chloride added. The mixture is stirred at room temperature for 24 h. The methylene chloride layer is separated, washed with water, brine and dried over sodium sulfate. The solvent is removed under vacuo and the residue stirred in 300 ml of ether for 24 h. The resulting white solid is filtered, the solid discarded and the solvent removed from the filtrate to give 6 g of a crude oil. the solvent removed to a residue The residue is dissolved in 150 ml of methylene chloride The mixture is stirred at room temperature for 24 h The methylene chloride layer is separated washed with water, brine dried over sodium sulfate The solvent is removed under vacuo the residue stirred in 300 ml of ether for 24 h The resulting white solid is filtered the solvent removed from the filtrate

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

Procedure: 0.46 ml (3.6 mmol) of 3,3-dimethylbutyric acid, 741 mg (3.6 mmol) of dicyclohexyl carbodiimide and 13 mg (0.09 mmol) of 4-(1-pyrrolidinyl)pyridine were added to a solution of 1.00 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] in 15 ml of methylene chloride, whilst ice-cooling. The resulting mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for a further 19 hours. At the end of this time, the solvent was removed by distillation under reduced pressure and the resulting residue was mixed with 20 ml of diethyl ether. Any insoluble material was removed by filtration and then washed twice with diethyl ether, using 5 ml for each washing. The filtrate and the washings were then combined and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 555 mg (47% yield) of the title compound. prepared stirred at room temperature for a further 19 hours At the end of this time, the solvent was removed by distillation under reduced pressure the resulting residue was mixed with 20 ml of diethyl ether Any insoluble material was removed by filtration washed twice with diethyl ether the solvent was removed by distillation under reduced pressure The resulting residue was purified by flash column chromatography through silica gel by volume mixture of hexane and ethyl acetate as the eluent

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

Procedure: The title compound, off-white solid (85 mg, 80%), MS (ISP) m/z=427.5 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 3,3-dimethyl-butyric acid.

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

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

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

Procedure: At 0° C., EDC (0.45 g, 2.4 mmol) was added to a solution of tert-butylacetic acid (0.30 mL, 2.3 mmol), and 1-hydroxy-7-azabenzotriazole (0.32 g, 2.4 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 20 min at 0° C. 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (0.50 g, 2.4 mmol) was added. Ethyldiisopropylamine (0.40 mL, 2.4 mmol) was added. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 10% aqueous sodium hydrogen sulfate solution (100 mL). A 1 N solution of sodium hydroxide was added to the aqueous solution until pH 12 was obtained. It was extracted with ethyl acetate (2×100 mL). These organic extracts were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 125 mg of the title compound. The reaction mixture was stirred for 16 h at room temperature washed with 10% aqueous sodium hydrogen sulfate solution (100 mL) A 1 N solution of sodium hydroxide was added to the aqueous solution until pH 12 was obtained It was extracted with ethyl acetate (2×100 mL) These organic extracts were dried over magnesium sulfate The solvent was removed in vacuo The crude product was purified by flash chromatography on silica (40 g)