Hydrochloric Acid → HCID 22622484, compound

Temperature

70 °C

1-Methyl-2-pyrrolidinone (90 ml) (NMP) was added to anhydrous potassium carbonate (27.6 g, 0.2 mol) under argon. To the stirred mixture was added in portions 5-bromosalicylaldehyde (20.1 ml, 0.1 mol) and the mixture stirred for 10 minutes. Bromomethylcyclopropane (14.4 ml, 0.1 5mol) was dissolved in NMP (10 ml) and added dropwise over 15 minutes below 30 ° C. The reaction temperature was increased to 35-40 ° C. for 3 hours, 70 ° C. for 1 hour and then cooled to 35 ° C. Ethylamine hydrochloride (13.85 g, 0.17 mol) was dissolved in methanol (60 ml), and added quickly to the mixture which was then heated at 35-40 ° C. for 3 hours and stirred overnight (allowing it to cool to ambient temperature). The reaction mixture was then cooled in ice. Sodium borohydride (5.3 g, 0.14 mol) was dissolved in NMP (58 ml ) and added dropwise [effervescence and exotherm to 15° C.] and the mixture heated to 40-45° C. for 2 hours. The reaction mixture was then cooled in ice. 2N Hydrochloric acid (250 mls) was added dropwise keeping the temperature below 30 ° C. The mixture was transferred to a separating funnel and extracted with ethyl acetate (×2). The combined organic layers were washed with 20% brine/water (×3) and brine (×1), dried over Na2SO4, filtered and evaporated. The residue was dissolved in ethyl acetate (100 ml) and cooled in ice. Hydrogen chloride gas was then bubbled through the stirred solution. The title compound as the hydrochloride salt precipitated and was filtered off, washed with ethyl acetate (×2) and dried under high vacuum (12.6 g, 28.5%).

1. additionadded dropwise over 15 minutes below 30 ° C
2. temperaturecooled to 35 ° C
3. additionadded quickly to the mixture which
4. temperaturewas then heated at 35-40 ° C. for 3 hours
5. stirringstirred overnight
6. temperature(allowing it to cool to ambient temperature)
7. temperatureThe reaction mixture was then cooled in ice
8. additionadded dropwise [effervescence and exotherm to 15° C.]
9. temperaturethe mixture heated to 40-45° C. for 2 hours
10. temperatureThe reaction mixture was then cooled in ice
11. customthe temperature below 30 ° C
12. customThe mixture was transferred to a separating funnel
13. extractionextracted with ethyl acetate (×2)
14. washThe combined organic layers were washed with 20% brine/water (×3) and brine (×1)
15. dry with materialdried over Na2SO4
16. filtrationfiltered
17. customevaporated
18. dissolutionThe residue was dissolved in ethyl acetate (100 ml)
19. temperaturecooled in ice
20. customHydrogen chloride gas was then bubbled through the stirred solution
21. customThe title compound as the hydrochloride salt precipitated
22. filtrationwas filtered off
23. washwashed with ethyl acetate (×2)
24. customdried under high vacuum (12.6 g, 28.5%)

ORD record

ord-528f3287b95047a7adad2c9c72872b03

Source dataset

uspto-grants-2002_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06365603B1