Hydrochloric Acid → 2-methylhex-4-ynoic Acid

Diisopropylamine (26.0 g, 0.257 mmol, 3.1 eq) in 130 ml of tetrahydrofuran initially at -50° C. is treated dropwise with n-butyl-lithium (98.8 ml, 1.6M, 0.158 mol, 1.9 eq) over an 8 minute period while allowing the temperature to rise to -25° C. After 5 minutes longer at -20° C., the reaction mixture is treated dropwise with a mixture of hexamethylphosphoramide (17.8 g, 0.099 mol, 1.2 eq) and propionic acid (6.14 g, 0.083 mol, 1.0 eq) over a 7 minute period while the temperature rises to 0° C. Following addition the reaction mixture is warmed to room temperature and maintained there for 35 minutes. The contents are then cooled to 0° C. in an ice bath, treated dropwise over a 12 minute period with 1-bromo-2-butyne (11.0 g, 0.083 mol, 1.0 eq) in 8 ml of tetrahydrofuran. The temperature, which rises to 16° C. during addition, is allowed to warm to room temperature thereafter where it is maintained for 2 hours. The contents are carefully poured into 300 ml of 10% HCl with stirring (exothermic) followed by 500 ml of ether-pentane (1:1). The organic layer is separated and the aqueous phase extracted 2 more times with ether-pentane (1:1) giving 1800 ml of total extract volume. The combined extracts are washed with water 2×60 ml) and the combined organic extracts are dried over anhydrous sodium sulfate, magnesium sulfate and concentrated at reduced pressure to provide 11.1 g (over theory) of 2-methyl-4-hexynoic acid which is converted to the methyl ester by treatment with methyl iodide.

1. customto rise to -25° C
2. customrises to 0° C
3. additionaddition the reaction mixture
4. temperaturemaintained there for 35 minutes
5. temperatureThe contents are then cooled to 0° C. in an ice bath
6. additionThe temperature, which rises to 16° C. during addition
7. temperatureto warm to room temperature
8. temperaturewhere it is maintained for 2 hours
9. customThe organic layer is separated
10. extractionthe aqueous phase extracted 2 more times with ether-pentane (1:1)
11. customgiving 1800 ml of total extract volume
12. washThe combined extracts are washed with water 2×60 ml) and the combined organic extracts
13. dry with materialare dried over anhydrous sodium sulfate, magnesium sulfate
14. concentrationconcentrated at reduced pressure

ORD record

ord-080c330a3bd04739bfcd2e6bb5d74f18

Source dataset

uspto-grants-1986_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04590297