Hexamethylphosphoramide → HCID 71232888, compound

To a mixture of 2-chloro-6-methyl-N-(2-(pyrrolidin-1-yl)ethyl)benzamide I-31 (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 I-32.

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-03de3017b6964ae580b9a1b18ce71be7

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08969363B2