Acetamidomalonic acid diethyl ester → HCID 21849426, compound

Temperature

50 °C

To a round bottom flask was added anhydrous EtOH (60 mL). Na (1.58 g, 68.66 mmol) was portion wise added into EtOH. To a clear solution of NaOEt was drop wise added a solution of diethyl acetamido malonate (14.92 g, 68.66 mmol) in Ethanol (140 mL) over 30 min. The resulting mixture was then heated at 50° C. for 1.5 h and then reflux for 10 min. The solution became cloudy and light brownish indicating formation of deprotonated diethyl acetamido malonic ester. To the reaction mixture at reflux was added 2 (16.76 g, 68.66 mmol) in ethanol (120 mL) portionwise over 1 h. The reaction mixture was maintained at reflux for 4.5 days, while monitoring the reaction progress using TLC. The reaction mixture was allowed to cool to room temperature and then evaporated to dryness. To the residue, DI water (100 mL) was added and extracted with diethyl ether (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to the dryness. The residue was purified via column chromatography on silica gel eluting with 30% EtOAc/hexanes to afford a mixture of 3 and diethyl acetamido malonate (12.3 g) and the mixture was used for the next reaction without further purification. Compound 3 was prepared for characterization in a small quantity. To a round bottom flask was added anhydrous EtOH (10 mL). Na (28.3 mg, 1.23 mmol) was portionwise added into EtOH. To the clear NaOEt solution was added a solution of diethyl acetamido malonate (267 mg, 1.23 mmol) in Ethanol (5 mL) dropwise over 30 min. The resulting mixture was then heated at 50° C. for 1.5 h and then reflux for 10 min. The solution became cloudy and light brownish indicating formation of deprotonated diethyl acetamido malonic ester. To the reaction mixture at reflux was portionwise added 2 (300 mg, 1.23 mmol) in ethanol (5 mL) over 1 h. The reaction mixture was maintained at reflux for 4.5 days while monitoring the reaction progress using TLC. The reaction mixture was allowed to cool to room temperature and then evaporated to dryness. The residue was purified via column chromatography on silica gel eluting with 30% EtOAc/hexanes to afford pure product 3. 1H NMR (CDCl3, 300 MHz) δ 1.23 (t, J=7.7 Hz, 6H), 1.45-1.60 (m, 2H), 2.04 (s, 3H), 2.39 (t, J=8.5 Hz, 2H), 2.73 (t, J=7.7 Hz, 2H), 4.22 (q, J=7.2 Hz, 4H), 7.29 (d, J=7.7 Hz, 2H), 8.24 (d, J=8.5 Hz, 2H); 13C NMR (CDCl3, 300 MHz) δ 13.82, 22.88, 24.91, 31.65, 35.13, 62.44, 66.17, 123.50, 128.98, 146.28, 149.41, 167.78, 169.01.; HRMS (Positive ion FAB) Calcd for C18H24N2O7 [M+H]+ m/z 381.1662. Found: [M+H]+ m/z 381.1653.

1. temperaturereflux for 10 min
2. temperatureTo the reaction mixture at reflux
3. temperatureThe reaction mixture was maintained
4. temperatureat reflux for 4.5 days
5. temperatureto cool to room temperature
6. customevaporated to dryness
7. additionTo the residue, DI water (100 mL) was added
8. extractionextracted with diethyl ether (3×150 mL)
9. dry with materialThe combined organic layers were dried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo to the dryness
12. customThe residue was purified via column chromatography on silica gel eluting with 30% EtOAc/hexanes
13. customto afford
14. customthe mixture was used for the next reaction without further purification
15. customCompound 3 was prepared for characterization in a small quantity
16. temperatureThe resulting mixture was then heated at 50° C. for 1.5 h
17. temperaturereflux for 10 min
18. temperatureTo the reaction mixture at reflux
19. temperatureThe reaction mixture was maintained
20. temperatureat reflux for 4.5 days
21. temperatureto cool to room temperature
22. customevaporated to dryness
23. customThe residue was purified via column chromatography on silica gel eluting with 30% EtOAc/hexanes

ORD record

ord-12f838316ddd4e0ab4b1e186f74f3fdb

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115094B2