Hexamethylphosphoramide → HCID 71232888, compound

To a mixture of 2-chloro-6-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamide 66 (1.33 g, 5.0 mmol, 1.0 eq) and HMPA (0.87 mL, 5.0 mmol, 1.0 eq) in THF (12.5 mL) at −60° C. under argon, n-butyllithium solution (2.5 M in hexanes, 5.0 mL, 12.5 mmol, 2.5 eq) was added dropwise while keeping the temperature below 60° C. The resulting mixture was stirred between −70° C. and −60° C. for 30 min. To this mixture, (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.39 g, 6.0 mmol, 1.2 eq) was added quickly. The resulting mixture was allowed to slowly warm to RT (over 1 h) and then stirred at RT for an additional 2 h. The reaction mixture was cooled to 0° C., quenched with water (5.0 mL), and then acidified with aqueous HCl (5 M) to adjust the pH to 5-6. The mixture was concentrated in vacuo. The residue was suspended in a mixture of MeOH (20 mL) and H2O (5.0 mL), concentrated HCl (10.0 mL) was added and the resulting mixture was stirred at reflux for 2 h. The mixture was cooled to −5° C. and basified with saturated aqueous NH4OH to adjust the pH to 8-9. The precipitate was filtered off and the filtrate was extracted with DCM (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product, (S)-3-(1-aminoethyl)-8-chloro-2-(2-(pyrrolidin-1-yl)ethyl)isoquinolin-1(2H)-one 67.

1. customthe temperature below 60° C
2. stirringstirred at RT for an additional 2 h
3. temperatureThe reaction mixture was cooled to 0° C.
4. customquenched with water (5.0 mL)
5. concentrationThe mixture was concentrated in vacuo
6. additionThe residue was suspended in a mixture of MeOH (20 mL) and H2O (5.0 mL), concentrated HCl (10.0 mL)
7. additionwas added
8. stirringthe resulting mixture was stirred
9. temperatureat reflux for 2 h
10. temperatureThe mixture was cooled to −5° C.
11. filtrationThe precipitate was filtered off
12. extractionthe filtrate was extracted with DCM (3×20 mL)
13. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
14. filtrationfiltered
15. concentrationThe filtrate was concentrated in vacuo
16. customthe residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM)

ORD record

ord-8482b310a43948fc9736da23cf3c077f

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09056877B2