1-Iodo-2-methoxyethane → 1-[2-(tert-Butoxycarbonyl)-4-methoxybutyl]cyclopentanecarboxylic acid

Participants

Reaction Conditions

Reaction Steps

To a solution of commercially supplied lithium diisopropylamide (9.63 kg of a 2M solution in tetrahydrofuran/n-heptane/ethylbenzene, 23.7 mol) in 1,2-dimethoxyethane (25 L) at −10° C. under an atmosphere of N2 was added a solution of 1-(3-tert-butoxy-3-oxopropyl)cyclopentane carboxylic acid (EP274234B1—see Example 35) (2.5 kg, 10.3 mol) in 1,2-dimethoxyethane (12.5 L) with stirring over a period of 4 hours whilst maintaining the reaction temperature at −10° C. The header tank was washed with 1,2-dimethoxyethane (2.5 L) and this was added to the reaction. The reaction mixture was then allowed to stir at −10° C. for 1.75 hours. To the resultant solution was added a solution of 2-iodoethyl methyl ether (2.73 kg, 14.4 mol) in 1,2-dimethoxyethane (10 L) over a period of 1.75 hours. The reaction was then stirred at this temperature for 4 hours before warming to 20° C. over a period of 4 hours. After stirring at this temperature for 8 hours the reaction was quenched by the addition of aqueous ammonium chloride (25 L of a 2.8 M solution), ethyl acetate (12.5 L) was then added. Aqueous hydrochloric acid (10 L of 5 M solution) was then added with stirring to adjust the pH to between 2 and 3. The two phases were mixed and then separated. The organic phase was then extracted three times with aqueous potassium carbonate solution (0.3 M solution; 37.5 L, 12.5 L and then 6.25 L). To the combined aqueous phases was then added n-heptane (15.6 L), and aqueous hydrochloric acid (14.5 L of a 5 M solution) with stirring until the pH of the aqueous layer was between 2 and 3. The layers were then separated and the aqueous phase was extracted with n-heptane (15.6 L). The combined organic phases were then washed with saturated brine (3.1 L) and were then concentrated under vacuum to give the crude title compound (2.50 kg, 8.32 mol, 81% yield) as a solution in n-heptane (21.8 kg total solution weight).

Provenance & Evidence