Sulfuric Acid → HCID 136183453, compound

3-Methyladipic acid 1 (1.60 g, 10 mmol) was heated under reflux in ethanol/conc. sulfuric acid solution (35 mL, v/v=2.5/1) for 8 h. The solution was neutralized with ammonium hydroxide to pH=7, then diluted with ethyl acetate (100 mL) and washed with water. The organic phase was dried with anhydrous sodium sulfate and evaporated to afford a light yellow liquid which was used in the next step without further purification. The resulting liquid was diluted in anhydrous toluene (100 mL) and sodium (0.23 g) was added to the solution in part. The mixture was heated under reflux for 3 h and cooled, neutralized with 1N hydrochloric acid solution and washed with water. After drying with anhydrous sodium sulfate, the organic phase was evaporated to afford a light brown liquid. The liquid was used in the next step without further purification. The light brown liquid was diluted with t-BuOH. Acetamidine (1.13 g, 12 mmol) and potassium tert-butoxide (1.34 g, 12 mmol) were added, and the mixture was heated under reflux overnight. The reaction mixture was cooled and the precipitate was filtered. The residue was washed with warm methanol twice (30 mL×1, 15 mL×1). The filtrate and washings were combined and evaporated under reduced pressure, and the residue was purified by column chromatography using chloroform/methanol (100/1) as eluent to afford 345 mg (21% yield total for 3 steps) as a white solid. TLC Rf0.30 (CHCl3/CH3OH, 10:1); mp: 173.9-175.4° C. 1H NMR (DMSO-d6): δ 1.05-1.07 (d, 3 H, CH3), δ 2.24 (s, 3 H, CH3), δ 2.13-2.34, 2.73-2.90 (m, 5 H, CH2CHCH2), δ 12.16 (br, 1H, OH, exch). Anal. (C9H12N2O) C, H, N: calcd, 65.83, 7.37, 17.06; found, 65.85, 7.36, 17.12.

1. washwashed with water
2. dry with materialThe organic phase was dried with anhydrous sodium sulfate
3. customevaporated
4. customto afford a light yellow liquid which
5. customwas used in the next step without further purification
6. additionThe resulting liquid was diluted in anhydrous toluene (100 mL)
7. additionsodium (0.23 g) was added to the solution in part
8. temperatureThe mixture was heated
9. temperatureunder reflux for 3 h
10. temperaturecooled
11. washwashed with water
12. dry with materialAfter drying with anhydrous sodium sulfate
13. customthe organic phase was evaporated
14. customto afford a light brown liquid
15. customThe liquid was used in the next step without further purification
16. additionThe light brown liquid was diluted with t-BuOH
17. temperaturethe mixture was heated
18. temperatureunder reflux overnight
19. temperatureThe reaction mixture was cooled
20. filtrationthe precipitate was filtered
21. washThe residue was washed with warm methanol twice (30 mL×1, 15 mL×1)
22. customevaporated under reduced pressure
23. customthe residue was purified by column chromatography
24. customto afford 345 mg (21% yield total for 3 steps) as a white solid

ORD record

ord-9922922a769d4ad79e87a9be8885bc79

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08946239B2