2-Bromo-5-methylpyridine → ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate

Temperature

120 °C

Sodium tert-butoxide (135 mg, 1.41 mmol)) was added to a suspension of ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 16) (450 mg, 1.28 mmol), 2-bromo-5-methylpyridine (439 mg, 2.55 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (40 mg, 0.102 mmol) and tris(dibenzyldieneacetone)dipalladium(0) (47 mg, 0.051 mmol) in anhydrous toluene (4.5 mL). The mixture was heated under microwave irradiation to 120° C. for 1 h in a sealed vial. The mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic phases were dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue. The residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient) to give a residue. This residue was dissolved in a mixture of EtOAc (0.6 mL) and cyclohexane (0.4 mL). The solution was treated with cyclohexane (3 mL) to give an emulsion, which was allowed to stand at room temperature over a weekend. The solution was decanted from the precipitated dark brown oil and concentrated to dryness under a stream of nitrogen to give an oil. This oil was triturated with cyclohexane (2×3 mL), the residual gum isolated by decanting off the cyclohexane, dissolved in EtOAc and concentrated to dryness under a stream of nitrogen to give crude ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate as a pale brown foam (240 mg) which was used directly in the next step without further purification.

1. customThe mixture was partitioned between EtOAc and water
2. extractionthe aqueous layer was extracted twice with EtOAc
3. customthe combined organic phases were dried
4. concentrationconcentrated in vacuo
5. customto give a residue
6. customThe residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient)
7. customto give a residue
8. customto give an emulsion, which
9. waitto stand at room temperature over a weekend
10. customThe solution was decanted from the precipitated dark brown oil
11. concentrationconcentrated to dryness under a stream of nitrogen
12. customto give an oil
13. customThis oil was triturated with cyclohexane (2×3 mL)
14. customthe residual gum isolated
15. customby decanting off the cyclohexane
16. dissolutiondissolved in EtOAc
17. concentrationconcentrated to dryness under a stream of nitrogen

ORD record

ord-79e4024c7a74495db9fdea5fcbf6d621

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08993554B2