Hydrochloric Acid → HCID 131732649, compound

Temperature

100 °C

To a flask charged with 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide (for a preparation see Intermediate 32) (197 mg, 0.5 mmol), sodium tert-butoxide (240 mg, 2.500 mmol), tris(dibenzylideneacetone)dipalladium(0) (229 mg, 0.250 mmol) and 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (197 mg, 0.500 mmol) was added degassed toluene (4 mL). The resulting mixture was treated with 2-chloropyrazine (0.134 mL, 1.500 mmol) then stirred under nitrogen at 100° C. for ˜45 min. The mixture was cooled to room temperature and most of the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and a saturated NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with saturated aqueous NaHCO3 (×3), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DCM and loaded on a SCX column (20 g). The cartridge was eluted with DCM then with ammonia in MeOH (2N). The methanolic ammonia fractions were concentrated in vacuo and further purified by chromatography (25 g column, elution with 2N ammonia in MeOH/DCM gradient) to give a residue which was dissolved in 1,4-dioxane (4 ml). The solution was treated with hydrogen chloride in 1,4-dioxane (4N, 0.5 mL). The precipitate formed was isolated by filtration and dried at 60° C. under vacuum for 2 h to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyrimidin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-(dimethylamino)ethyl)benzamide, Hydrochloride (93 mg, 0.183 mmol, 36.5% yield) as a white solid. LCMS (HpH, 2 min), Rt=0.79 min, MH+=473.

1. additionwas added
2. customdegassed toluene (4 mL)
3. temperatureThe mixture was cooled to room temperature and most of the solvent
4. customwas evaporated in vacuo
5. customThe residue was partitioned between EtOAc
6. customa saturated NaHCO3 solution and the layers were separated
7. extractionThe aqueous phase was extracted with EtOAc
8. washthe combined organic phases were washed with saturated aqueous NaHCO3 (×3)
9. dry with materialdried over MgSO4
10. concentrationconcentrated in vacuo
11. dissolutionThe residue was dissolved in DCM
12. washThe cartridge was eluted with DCM
13. concentrationThe methanolic ammonia fractions were concentrated in vacuo
14. customfurther purified by chromatography (25 g column, elution with 2N ammonia in MeOH/DCM gradient)
15. customto give a residue which
16. customThe precipitate formed
17. customwas isolated by filtration
18. customdried at 60° C. under vacuum for 2 h

ORD record

ord-aeff446669db45e0a98978791ab83712

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08993554B2