Hydrochloric Acid → (2-Chloro-3,4-difluorophenyl)methanamine hydrochloride

Temperature

70 °C

2-Chloro-3,4-difluorobenzamide (11.85 g, 62 mmol) was dissolved in tetrahydrofuran (200 ml) and treated with 1M borane tetrahydrofuran (247 ml, 247 mmol). The mixture was heated to 70° C. and stirred for 18 hrs. The mixture was then cooled in an ice-water bath and concentrated aqueous hydrogen chloride (150 ml) was added dropwise. Heating, with stirring, at 70° C. was then resumed for a further 2 hrs. The mixture was then allowed to cool and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml). The aqueous layer was separated and the pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide. The resulting cloudy suspension was extracted with ethyl acetate (4×200 ml) and the combined organic extracts were then passed through a hydrophobic frit and reduced in volume to ˜200 ml. The mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml) resulting in formation of a precipitate. The solvent was evaporated in vacuo to give a white solid. The solid was recrystallised from methylated spirit (60 ml) to give three crops of pure [(2-chloro-3,4-difluorophenyl)methyl]amine hydrochloride (combined mass=4.46 g) as a white solid.

1. temperatureThe mixture was then cooled in an ice-water bath
2. temperatureHeating
3. stirringwith stirring, at 70° C.
4. waitwas then resumed for a further 2 hrs
5. temperatureto cool
6. customthe solvent was evaporated in vacuo
7. customThe residue was partitioned between ethyl acetate (200 ml) and 2N aqueous hydrogen chloride (200 ml)
8. customThe aqueous layer was separated
9. additionthe pH was adjusted to 8-9 by dropwise addition of 5N aqueous sodium hydroxide
10. extractionThe resulting cloudy suspension was extracted with ethyl acetate (4×200 ml)
11. additionThe mixture was then acidified by the addition of 1M ethereal hydrogen chloride (100 ml)
12. customresulting in formation of a precipitate
13. customThe solvent was evaporated in vacuo
14. customto give a white solid
15. customThe solid was recrystallised from methylated spirit (60 ml)

ORD record

ord-0468b6b9958447ba9dfc89b4d9e62c53

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08048907B2