Diisopropylamine → 1-(2-Methoxyethyl)Cyclopentane Carboxylate Methyl Ester

Temperature

-70 °C

To a 3 L3-necked round-bottomed flask equipped with a thermometer and dropping funnel were added diisopropylamine (136 mL, 0.98 mol) and tetrahydrofuran (750 mL). The solution was stirred under nitrogen and cooled in an ice-bath. Through the dropping funnel was added n-butyllithium (2.5 M in hexanes; 376 mL, 0.94 mol), and the solution was allowed to stir at 0° C. for 30 min and then cooled to −70° C. Through the dropping funnnel was added a solution of cyclopentanecarboxylic acid, methyl ester (83.04 g, 0.65 mol) in tetrahydrofuran (135 mL). The solution was stirred at −70° C. for 1 h and then a solution of 2-bromoethyl methyl ether (55.5 mL, 0.59 mol) in tetrahydrofuran (135 mL) was added. The solution was stirred at −70° C. for 1 h and then the cooling bath was removed. The solution was stirred at room temperature overnight, then poured into saturated ammonium chloride solution (2 L) and extracted with ether (3×500 mL). The combined ether layers were washed with saturated brine (6×400 mL), dried (Na2SO4), filtered, evaporated, and distilled under vacuum to give 1-(2-methoxyethyl) cyclopentanecarboxylic acid, methyl ester (71.39 g, 59%) as a pale yellow liquid (bp 94-102° C. at 8 mm). This was dissolved in a mixture of tetrahydrofuran (340 mL), methanol (340 mL) and 1 M sodium hydroxide solution (425 mL). The mixture was stirred and heated at 55-60° C. for 24 h and then concentrated under reduced pressure to remove tetrahydrofuran and methanol. Water (400 mL) was added and the solution was extracted with ether (2×200 mL). The aqueous layer was acidified to pH 1 with 1 N HCl (500 mL), and extracted with ether (300 mL, then 2×200 mL). The combined ether layers were washed with saturated brine (2×200 mL), dried (Na2SO4), filtered, and evaporated to give 1-(2-methoxyethyl)cyclopentanecarboxylic acid (63.68 g, 97%) as a yellow liquid.

1. customTo a 3 L3-necked round-bottomed flask equipped with a thermometer
2. temperaturecooled in an ice-bath
3. stirringto stir at 0° C. for 30 min
4. stirringThe solution was stirred at −70° C. for 1 h
5. stirringThe solution was stirred at −70° C. for 1 h
6. customthe cooling bath was removed
7. stirringThe solution was stirred at room temperature overnight
8. additionpoured into saturated ammonium chloride solution (2 L)
9. extractionextracted with ether (3×500 mL)
10. washThe combined ether layers were washed with saturated brine (6×400 mL)
11. dry with materialdried (Na2SO4)
12. filtrationfiltered
13. customevaporated
14. distillationdistilled under vacuum

ORD record

ord-de537835d2f347ea8877fb7056ff0546

Source dataset

uspto-grants-2001_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06331640B1