Synthesis
c) Synthesis of 4-(3-hydroxypropyl)-2-(3-methylbut-2-enyl)phenol (3c): 3a (6.8 g, 38 mmol) was dissolved in 100 ml of EtOAc, a palladium-carbon catalyst was added, and the reaction was carried out for 24 h under 4 bar hydrogen pressure. After completion of the reaction, the catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated to dryness to give a light colored oily product (6.9 g, quantitative yield). 4 g of the above oily product was taken and dissolved in 60 ml of toluene under nitrogen protection, 1 g of NaH (60% paraffin dispersion, 25 mmol) was added and the mixture was stirred at 50 °C for 2 hours. Subsequently, isopentyl bromide (3.5 ml, 30.3 mmol) was slowly added dropwise, and the reaction mixture continued to be stirred at 35°C for 24 hours. At the end of the reaction, the mixture was poured into ice water and the pH was adjusted to acidic with 1N HCl. It was extracted with EtOAc and the organic phase was washed with brine, dried over MgSO4 and concentrated to dryness. The resulting residue was purified by rapid chromatography on silica gel (eluent: petroleum ether-EtOAc, 90:10 to 80:20 gradient elution) to give 2.7 g of a light-colored oily product (yield = 48%). The product (2.7 g) was dissolved in 20 ml of THF at 0 °C and under nitrogen protection, and 13 ml of LiAlH4 (1 M in THF) solution was added slowly and dropwise. The reaction mixture was refluxed for 2 h. The reaction was quenched with water and adjusted to acidity with 1N HCl. Extracted with ether, the organic phase was washed with saturated NaHCO3 solution, dried and concentrated to dryness to give the oily product 3c (2.31 g, yield = 97%).TLC conditions: merck silica gel 60F254, CH2Cl2-EtOAc (90:10), Rf = 0.35.
References
[1] Patent: WO2005/80354, 2005, A1. Location in patent: Page/Page column 24-25
[2] Tetrahedron Letters, 2007, vol. 48, # 21, p. 3655 - 3659
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 2753 - 2775
[4] Patent: US5962469, 1999, A
[5] Patent: US6335/459, 2002, B1. Location in patent: Example 11
