ethyl 2-(4-hydroxycyclohexyl)acetate

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

Procedure: To a mixture of 2-(4-hydroxycyclohexyl)acetic acid ethyl ester (3 g, 16.1 mmol), iodine (6.13 g, 24.2 mmol), imidazole (1.64 g, 24.2 mmol), and triphenylphosphine (6.34 g, 24.2 mmol) was added dichloromethane (100 mL) at room temperature under nitrogen atmosphere. The resulting brown suspension was stirred for 15 h at which time TLC analysis indicated the absence of starting material. Then, the solvent was removed under vacuum and most of the residue was dissolved in ethyl acetate (˜500 mL) and some of the residue was not dissolved which was found to be Ph3PO by 1H NMR. The ethyl acetate solution was washed two times with a solution of water and methanol (3:1) to remove the remaining triphenylphosphineoxide and then washed with brine solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the crude residue which was purified using an ISCO (120 g) column chromatography eluting with ethyl acetate in hexanes (0-50%). The desired fractions were combined and the solvent was removed under vacuum to obtain 2-(4-iodocyclohexyl)acetic acid ethyl ester (3.39 g, 71.1% yield) as a viscous light yellow oil. 1H NMR of this product indicated that it contained 30-40% of elimination product (olefin) which was not separable on TLC. Then, the solvent was removed under vacuum and most of the residue was dissolved in ethyl acetate (˜500 mL) some of the residue was not dissolved which The ethyl acetate solution was washed two times with a solution of water and methanol (3:1) to remove the remaining triphenylphosphineoxide washed with brine solution The organic layer was dried over anhydrous MgSO4 filtered concentrated to give the crude residue which was purified eluting with ethyl acetate in hexanes (0-50%) the solvent was removed under vacuum

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

Procedure: 115 g 4-hydroxy-phenylacetic acid ethyl ester is hydrogenated in a mixture of 10 ml one molar sodium ethylate solution and 350 ml ethanol for 72 hours at 160° C. and 200 bar using Raney-Nickel. The preparation is subsequently evaporated and the remaining oil is distilled in a high vacuum. 76.4 g 4-hydroxycyclohexane-acetic acid ethyl ester is obtained with a boiling point of 120°-121° C./2 mm Hg. TLC (mobile solvent: dichloromethane/methanol 9:1). Rf=0.8. The preparation is subsequently evaporated the remaining oil is distilled in a high vacuum

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

Procedure: Stir a mixture of (4-hydroxy-phenyl)-acetic acid ethyl ester (78.86 g), Rhodium on aluminum oxide (40%, 31.87 g) and ethanol (1 L) on a hydrogenation parr shaker at 60 psi, 60° C. for 18 hours. Remove the reaction from parr shaker. Filter the mixture through celite and concentrate the to afford 81.25 g (99%) of the title compound. Remove the reaction from parr shaker Filter the mixture through celite and concentrate the

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

Procedure: To a mixture of 2-(4-hydroxycyclohexyl)acetic acid ethyl ester (3 g, 16.1 mmol), iodine (6.13 g, 24.2 mmol), imidazole (1.64 g, 24.2 mmol), and triphenylphosphine (6.34 g, 24.2 mmol) was added dichloromethane (100 mL) at room temperature under nitrogen atmosphere. The resulting brown suspension was stirred for 15 h at which time TLC analysis indicated the absence of starting material. Then, the solvent was removed under vacuum and most of the residue was dissolved in ethyl acetate (˜500 mL) and some of the residue was not dissolved which was found to be Ph3PO by 1H NMR. The ethyl acetate solution was washed two times with a solution of water and methanol (3:1) to remove the remaining triphenylphosphineoxide and then washed with brine solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the crude residue which was purified using an ISCO (120 g) column chromatography eluting with ethyl acetate in hexanes (0-50%). The desired fractions were combined and the solvent was removed under vacuum to obtain 2-(4-iodocyclohexyl)acetic acid ethyl ester (3.39 g, 71.1% yield) as a viscous light yellow oil. 1H NMR of this product indicated that it contained 30-40% of elimination product (olefin) which was not separable on TLC. Then, the solvent was removed under vacuum and most of the residue was dissolved in ethyl acetate (˜500 mL) some of the residue was not dissolved which The ethyl acetate solution was washed two times with a solution of water and methanol (3:1) to remove the remaining triphenylphosphineoxide washed with brine solution The organic layer was dried over anhydrous MgSO4 filtered concentrated to give the crude residue which was purified eluting with ethyl acetate in hexanes (0-50%) the solvent was removed under vacuum