Ammonium Chloride → tert-Butyl 4-(1-hydroxypropyl)benzoate

t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in ether (300 ml), followed by the dropwise addition of ethylmagnesium bromide.(3M ethereal solution, 33 ml) under cooling with ice. The obtained mixture was stirred. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ether. The organic layer was distilled to remove the solvent. The residue was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 22.3 g of t-butyl 4-(1-hydroxypropyl)benzoate. This product was dissolved in petroleum ether (500 ml), followed by the addition of active manganese dioxide (165 g). The obtained mixture was heated under reflux for 30 hours. After the completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to give 21.1 g of a propiophenone compound (corresponding to a compound represented by the formula (18) wherein R4 is Et and R7 is t-Bu). Then, this compound was subjected to the Horner-Emmons reaction. That is, potassium t-butoxide (19 g) was added to a solution of ethyl diethylphosphonoacetate (36 ml) in THF (400 ml). The obtained mixture was stirred at room temperature for 30 minutes, followed by the addition of a solution of the propiophenone compound (21.1 g) in THF (40 ml). The obtained mixture was stirred at 55 to 65° C. for 1.5 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride to give 22.7 g of an α,β-unsaturated ester compound (corresponding to a compound represented by the formula (19) wherein R4 is Et and R7 is t-Bu). This ester compound was catalytically reduced with 10% palladium-carbon (0.5 g) in methanol (300 ml) and added to a mixture comprising 1N aqueous sodium hydroxide (150 ml) and methanol (150 ml). The obtained mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was made weakly acidic with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was distilled to remove the solvent and the residue was purified by short silica gel column chromatography to give 17.7 g of 3-[p-(t-butoxycarbonyl)phenyl]-3-ethylpropionic acid. This acid was dissolved in THF (200 ml), followed by the dropwise addition of a 1M solution of BH3 in THF (80 ml) under cooling with ice. The obtained mixture was stirred at room temperature for one hour. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ethyl acetate. The organic layer was distilled to remove the solvent and the residue was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:1) to give 16.7 g of t-butyl 4-(3-hydroxy-1-ethylpropyl)benzoate. This product was dissolved in ether (400 ml), followed by the addition of triethylamine (44 ml) and methanesulfonyl chloride (9.8 ml) under cooling with ice. The obtained mixture was stirred to complete a reaction. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ether. The organic layer was distilled to remove the solvent, by which a mesylate was obtained. This mesylate was dissolved in acetone (400 ml), followed by the addition of sodium iodide (40 g). The obtained mixture was heated under reflux. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and the obtained mixture was extracted with ether. The organic layer was distilled to remove the solvent and the residue was subjected to silica gel column chromatography and eluted with a solvent (ether/hexane=1:15) to give 20 g of the title compound as a colorless oil (55%).