Chloromethyl Methyl Ether → 2-Allyl-2-methoxymethyl malonic acid

온도

0 °C

A solution of 1.0 mL (1.0 equiv, 0.005 mol) of diethyl allylmalonate in 15 mL of dry THF is cooled to 0° C. with an ice/water bath. 210 mg (1.05 equiv, 0.0052 mol) of solid NaH (60% in oil) is added and the mixture stirred for 20 min at 0° C. To the resulting solution is added dropwise 0.305 mL (1.05 equiv, 0.0052 mols) of methoxymethyl chloride at 0° C. The reaction is stirred at 0° C. for 20 min., allowed to warm to RT and stirred 16 h. the reaction mixture is filtered to remove solids and the solvent from the filtrate in vacuo. 50 mL of H2O is added and the mixture extracted with ethyl acetate (2×80 mL). The organic layer is dried over MgSO4 and concentrated in vacuo. The crude product is dissolved in 20 mL of ethanol/water 9/1 and cooled to 0° C. with an ice/water bath. To this solution is added dropwise 695 mg (6.0 equiv, 0.024 mol) of potassium hydroxide dissolved in 10 mL of ethanol/water 9/1. The solution is stirred at RT for 3 days, and then the solvent is removed in vacuo 10 mL of H2O is added and the mixture was extracted with ethyl acetate (2×80 mL). The organic layer is dried over MgSO4 and concentrated in vacuo to yield 500 mg of 2-allyl-2-methoxymethyl malonic acid. 350 mg (1.0 equiv, 0.0019 mol) of 2-allyl-2-methoxymethyl malonic acid is dissolved in 30 mL of CH2Cl2 and cooled in a salt/ice/water bath to -5° C. 0.65 mL (4.0 equiv, 0.0075 mols) of oxalyl chloride is added dropwise at -5° C. The reaction mixture is allowed to stir at RT for 2 h, and then the solvent is removed in vacuo. The crude product is dissolved in 20 mL of dry THF and added dropwise to a solution of 592 mg (0.8 equiv, 0.0015 mol) of N-isopropyl-N-phenyl-2-(2-phenylamino-phenylamino)-acetamide in dry 20 mL of dry THF cooled to 0° C. The reaction mixture is heated at reflux for 22 h, cooled to RT and the solvent is removed in vacuo. 60 mL of brine/ethyl acetate 1/1 are added and the mixture is extracted with ethyl acetate (2×30 mL). The organic extract is dried over MgSO4 and the solvent removed in vacuo. Purification by silica gel flash chromatography with hexane/ethyl acetate 2/1 as eluent gave 550 mg of the title compound as a brown gum: 1H NMR (CDCl3, 300 MHz) δ7.39-6.78 (m, 13H), 6.20-5.65 (m, 1H), 5.04-5.00 (m, 2H), 4.73 (d, J=17.1, 1H), 3.98-3.84 (2s, 3H), 3.43 (s, 3H), 2.80 (s, 2H), 2.33-2.27 (m, 2H), 1.10-1.03 (m, 6H); Rf =0.30 in hexane/EtOAc 2/1.

1. stirringThe reaction is stirred at 0° C. for 20 min.
2. temperatureto warm to RT
3. stirringstirred 16 h. the reaction mixture
4. filtrationis filtered
5. customto remove solids
6. addition50 mL of H2O is added
7. extractionthe mixture extracted with ethyl acetate (2×80 mL)
8. dry with materialThe organic layer is dried over MgSO4
9. concentrationconcentrated in vacuo
10. dissolutionThe crude product is dissolved in 20 mL of ethanol/water 9/1
11. temperaturecooled to 0° C. with an ice/water bath
12. stirringThe solution is stirred at RT for 3 days
13. customthe solvent is removed in vacuo 10 mL of H2O
14. additionis added
15. extractionthe mixture was extracted with ethyl acetate (2×80 mL)
16. dry with materialThe organic layer is dried over MgSO4
17. concentrationconcentrated in vacuo

ORD 기록

ord-097c41514a9140dd92fbfc728123797d

출처 데이터셋

uspto-grants-1999_01

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US05859007