Step 1: 2,4-dihydroxy-6-pentyl-isophthalic acid dimethyl ester9.6g (0.2 mole) of sodium hydride (50% oil suspension) is added portionwise in a nitrogen atmosphere, with stirring and ice cooling (internal temperature 10°C) to the mixture of 34.8g (0.2 mole) of 3-oxoglutaric acid dimethyl ester and 30.8g (0.2 mole) of 2-octynoic acid methyl ester in 500mL of anhydrous benzene. The ice bath is removed and the yellowish stirred for a further 15 min at room temp before the second portion of 11.2g of sodium hydride is added without cooling. The reaction mixture is refluxed for 1 h and the resulting yellow suspension poured (after cooling) on 600g of ice. The aqueous phase is separated and extracted with 500mL of ether. The extract is combined with the organic phase and the whole extracted twice with 200mL of 0.2 N NaOH. The alkaline solution is combined with the aqueous phase, the whole filtered through purified diatomaceous earth and acidifiedwith conc. HCl. After cooling, the colourless emulsion is extracted with 500mL of ether, the extract dried over MgSO
4 and concentrated by evaporation. After drying in vacuo, 47.3g of crude product is obtained as yellow crystallizing oil. This is then dissolved in 50mL of IPA and 2,4-dihydroxy-6-pentyl-isophthalic acid dimethyl ester precipitates immediately in the form of large needles. After standing for ~14 h in a refrigerator, the crystals are filtered off with suction, washed with small amount of cold IPA and dried. Yield: 33.82g of the title product as yellowish crystals; mp 59-60°C.
Step 2: 2,4-dihydroxy-6-phenyl-isophthalic acid83.4g (0.282 mole) of the product from previous step is refluxed in 810mL of 0.67 N NaOH for 2 h under nitrogen. The reaction mixture is cooled, 500mL of ether is added, and the whole carefully acididfied with 50mL of conc. HCl (CO
2 evolution!). The mixture is shaken in separatory funnel, the ether layer separated and the aqueous layer subsequently extracted with 200mL of ether. The ether extracts are dried over MgSO
4 and concentrated in vacuo. Yield: 65.2g of crude 2,4-dihydroxy-6-phenyl-isophthalic acid as an oil.
Step 3: OlivetolThe crude product from Step 2 is stirred with 200mL of sulfuric acid (volume ratio of conc. H
2SO
4 to water is 5:1) until a clear solution is formed. This is allowed to stand at room temp for 1 h. The solution is then poured into a 3-necked flask in which 500g of ice has been placed, and the formed suspension is stirred fro 14 h in a nitrogen atmosphere. The suspension obtained after cooling is extracted twice with 500mL of ether. The combined extracts are extracted four times with 200mL of 2 N NaOH, the basic extracts combined, cooled with ice and acidified with 160mL of conc. HCl. The reaction product in the form of oil is taken up in 500mL of ether, the solution is washed with water, dried over MgSO
4, and concentrated in vacuo to obtain 49.5g of crude product as reddish oil. Purification is effected y distillation in high vacuum. The olivetol distilling over at 126-130°C/0.002-0.001 mmHg is obtained firstly as a pale yellow viscous oil, which fully crystallizes on standing, mp 48-50°C. Yield: 45.2g (89.3%).
Reference: Patent US4249027