Methylamine → N-((3R,4S)-3,4-Dihydro-3-(((methylamino)carbonyl)oxy)-6-(4-(3-oxetanyl)-1-piperazinyl)-2H-1-benzopyran-4-yl)-4-fluorobenzamide

Suspend 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4 yl]benzamide (10.0 g, 23.4 mmol) in THF (200 mL) and add 1,1 carbonyldiimidazole (4.9 g, 30.4 mmol). Stir at ambient temperature for 3 hr. Cool the reaction mixture to −5° C. and add 2 M methyl amine (in THF, 21 mL, 42.1 mmol) over 15 min. Stir the resulting mixture at −5-0° C. for 3 hr. Add 2 N NaOH (100 mL) and stir the mixture for 1 hr. at 10-30° C. Separate the layers and wash the organics with 2 N NaOH (4×100 mL). Add water (200 mL) and concentrate the mixture under reduced pressure to approximately twenty volumes (based on starting material). Add THF (200 mL) and stir at ambient temperature for 1 hr. Filter the mixture and transfer the product wetcake back to a clean reaction vessel. Add THF (200 mL) and water (200 mL) and stir at ambient temperature for 1 hr. Isolate the technical grade title compound by filtration and vacuum dry at 80° C. (9.0 g, 80%).

1. temperatureCool the reaction mixture to −5° C.
2. stirringStir the resulting mixture at −5-0° C. for 3 hr
3. stirringstir the mixture for 1 hr
4. customat 10-30° C
5. customSeparate the layers
6. washwash the organics with 2 N NaOH (4×100 mL)
7. concentrationAdd water (200 mL) and concentrate the mixture under reduced pressure to approximately twenty volumes (based on starting material)
8. stirringAdd THF (200 mL) and stir at ambient temperature for 1 hr
9. filtrationFilter the mixture
10. stirringAdd THF (200 mL) and water (200 mL) and stir at ambient temperature for 1 hr

ORD record

ord-52f83cdc4e724aa0afe9bfc12f8a7c14

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08227468B2