Citric Acid → HCID 86684900, compound

Temperature

2 °C

Methyl-cyclopropanecarboxylic acid (56.4 g, 552 mmol) was dissolved in dichloromethane (365 mL) and dimethylformamide (405 μl, 5.2 mmol) was added. The mixture was cooled to 2° C. and oxalyl chloride (70.8 g, 547 mmol) was added dropwise. It was allowed to warm and stirred for 90 min at room temperature. After that, it was added to a suspension of (1S,4S)-3-oxo-2-oxa-5-azonia-bicyclo[2.2.1]heptane methanesulfonate (110 g, 526 mmol) in dichloromethane (400 mL). The resulting suspension was cooled to 2° C. and triethylamine (256 mL, 1.84 mol) was added slowly (exothermic). After stirring for 70 min at room temperature, a solution of citric acid (81.0 g, 421 mmol) in water (550 mL) was added at 2° C. After separation of the phases, the aqueous phase was extracted with dichloromethane (300 mL). The combined organic extracts were washed with water (400 mL) and concentrated in vacuo to a volume of ca. 500 mL. Ethyl acetate (330 mL) was added and the residual dichloromethane was distilled off in vacuo (internal temperature 40° C.). Further ethyl acetate (50 mL) was added, internal temperature was increased to 50° C. and heptane (800 mL) was added slowly. Crystallization started after addition of ca. 300 mL heptane. The suspension was stirred for 12 h at room temperature and filtered. The crystals were washed with cold heptane (400 mL) and dried in vacuo at 40° C. to afford the title compound as colorless crystals (88.45 g, 86%). mp. 101-102° C. MS (ESI & APCI): m/z=196.1 [M+H]+. 1H NMR (CDCl3, 600 MHz); δ 0.60-0.67 (m, 2H), 0.87-0.91 (m, 1H), 1.13-1.17 (m, 1H), 1.39 (s, 3H), 2.04 (dd, J=1.2 Hz, 10.9 Hz, 1H), 2.32 (d, J=10.8 Hz, 1H), 3.59 and 3.69 (AB, JAB=11.5 Hz, each 1H), 4.97 (s, 1H), 5.18 (s, 1H).

1. temperatureto warm
2. temperatureThe resulting suspension was cooled to 2° C.
3. stirringAfter stirring for 70 min at room temperature
4. customAfter separation of the phases
5. extractionthe aqueous phase was extracted with dichloromethane (300 mL)
6. washThe combined organic extracts were washed with water (400 mL)
7. concentrationconcentrated in vacuo to a volume of ca. 500 mL
8. additionEthyl acetate (330 mL) was added
9. distillationthe residual dichloromethane was distilled off in vacuo (internal temperature 40° C.)
10. additionFurther ethyl acetate (50 mL) was added
11. temperatureinternal temperature was increased to 50° C.
12. additionheptane (800 mL) was added slowly
13. customCrystallization
14. additionafter addition of ca. 300 mL heptane
15. stirringThe suspension was stirred for 12 h at room temperature
16. filtrationfiltered
17. washThe crystals were washed with cold heptane (400 mL)
18. customdried in vacuo at 40° C.

ORD record

ord-129ead3dbd5c4e3087cdbf05a7d3729b

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796471B2