1. Bromine (12.5 mL, 244 mmol) was added slowly dropwise to a solution of cyclopropylbenzene (25.0 g, 212 mmol) in chloroform (430 mL) at -78 °C with stirring for 45 minutes.
2. 10% aqueous sodium sulfite and water were added and extracted with chloroform. The organic phase was separated, washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate.
3. Filtered and concentrated under reduced pressure, purified by silica gel column chromatography (hexane) to give 1-bromo-4-cyclopropylbenzene (35.5 g, 85%).
4. tetrakis(triphenylphosphine)palladium (5.33 g, 4.61 mmol) and 3-butyn-1-ol (31.5 g, 450 mmol) were added to a solution of 1-bromo-4-cyclopropylbenzene (35.5 g, 180 mmol) in piperidine (345 mL) and stirred for 3 hours at 80 °C under nitrogen protection.
5. Concentrate under pressure, add ethyl acetate and 1N HCl aqueous solution, extract. The organic phase was washed sequentially with 1N HCl, saturated NaHCO3 and saturated NaCl aqueous solutions and dried over anhydrous magnesium sulfate.
6. After filtration and concentration under reduced pressure, purification by silica gel column chromatography (hexane:ethyl acetate, 4:1-3:1) afforded 4-(4-cyclopropylphenyl)but-3-yn-1-ol (30.2 g, 90%).
7. 6N H2SO4 aqueous solution (250 mL) was added to a solution of 4-(4-cyclopropylphenyl)but-3-yn-1-ol (27.8 g, 149 mmol) in methanol (300 mL) and refluxed for 6 hours.
8. Methanol was evaporated under pressure reduction and extracted by adding ethyl acetate. The organic phase was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate.
9. Concentrate under reduced pressure after filtration and purify by silica gel column chromatography (hexane:ethyl acetate, 4:1-2:1) to obtain 1-(4-cyclopropylphenyl)-4-hydroxybutan-1-one (18.7 g, 61%).
10. Hydrazine monohydrate (10.4 mL) and KOH (14.4 g) were added to a solution of 1-(4-cyclopropylphenyl)-4-hydroxybutan-1-one (17.5 g, 85.8 mmol) in ethylene glycol (90 mL) and refluxed at 180 °C for 6 hours.
11. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaCl and dried over anhydrous magnesium sulfate.
12. Concentrate under reduced pressure after filtration and purify by silica gel column chromatography (hexane:ethyl acetate, 5:1-3:1) to obtain 4-(4-cyclopropylphenyl)butan-1-ol (15.8 g, 97%).
13. TEMPO (905 mg, 5.79 mmol) and sodium hydrogen phosphate buffer (300 mL, 0.67 M, pH 6.7) were added to a solution of 4-(4-cyclopropylphenyl)butan-1-ol (15.7 g, 83.0 mmol) in acetonitrile (300 mL) and stirred at 35 °C for 10 min.
14. aqueous NaClO2 solution (16.4 g, 80 mL water) was added, 2% aqueous hypochlorite solution (42.3 mL) was added dropwise and stirred at 35°C for 2 hours.
15. 1N NaOH aqueous solution (250 mL) was added, poured into ice water (300 mL) containing Na2SO3 (30 g) and stirred for 5 min. Ether extraction.
16. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with ether. The organic phase is dried with anhydrous magnesium sulfate.
17. Filtration and concentration under reduced pressure afforded 4-(4-cyclopropylphenyl)butyric acid (15.8 g, 88%) as a white solid.
