1,2-Dichloroethane → HCID 178429081, Verbindung

A 20 mL vial was charged with 5-chloro-3-(((trans)-4-(dimethylamino)cyclohexyl)oxy)-2-methylbenzoic acid (120 mg, 0.385 mmol), 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one, hydrochloride (80 mg, 0.423 mmol), EDC (111 mg, 0.577 mmol), HOAT (89 mg, 0.577 mmol), N,N-dimethylformamide (DMF) (3 mL), and NMM (1.015 mL, 9.24 mmol). The reaction was stirred for 16 h, at which time it was poured into a stirring solution of water (5 mL) and sat Na2CO3 (20 mL). The mixture was stirred at room temperature 1 h, but no precipitate had formed. EtOAc was added and the layers were separated. White precipitate formed in the aqueous layer. The precipitate was filtered and determined to not be the title product. LCMS showed the product in both layers, so the layers were re-combined and concentrated in vacuo. The solid residue was diluted with MeOH (3 mL) and DMSO (1 mL) and the insolubles were filtered off. The solution was purified by reverse phase HPLC (Phenomenex Gemini-NX axia 30×100 mm, 5μ, C18; 15-45% acetonitrile/0.1% formic acid in water). Since the product was running close to the solvent front, the gradient was changed to 5-45% 0.1% formic acid in water/acetonitrile and the remaining sample was purified by this method. The desired fractions were concentrated to a glassy solid. The residue was dissolved in MeOH (3 mL) and filtered through ISOLUTE® Si-Carbonate (2 g) to remove the formic acid. The ISOLUTE® Si-Carbonate was washed with MeOH (3 mL) and the combined methanol layers were concentrated in vacuo. The ISOLUTE® Si-Carbonate filtration step was repeated and the MeOH washing concentrated in vacuo to give 5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-3-(((trans)-4-(dimethylamino)cyclohexyl)oxy)-2-methylbenzamide (45 mg, 0.100 mmol, 26.0% yield), as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (br. s., 1H), 8.22 (br. s., 1H), 7.11 (d, J=2.02 Hz, 1H), 6.78 (d, J=1.77 Hz, 1H), 5.87 (br. s., 1H), 4.27-4.41 (m, J=4.52, 4.52, 8.40 Hz, 1H), 4.19 (d, J=5.05 Hz, 2H), 2.31 (s, 3H), 2.17-2.21 (m, 1H), 2.17 (s, 6H), 2.16 (s, 3H), 2.03 (s, 5H), 1.78 (br. s., 2H), 1.37 (t, J=9.98 Hz, 4H). MS(ES) [M+H]+ 446.1.

1. stirringThe mixture was stirred at room temperature 1 h
2. customno precipitate had formed
3. customthe layers were separated
4. customWhite precipitate
5. customformed in the aqueous layer
6. filtrationThe precipitate was filtered
7. concentrationconcentrated in vacuo
8. additionThe solid residue was diluted with MeOH (3 mL) and DMSO (1 mL)
9. filtrationthe insolubles were filtered off
10. customThe solution was purified by reverse phase HPLC (Phenomenex Gemini-NX axia 30×100 mm, 5μ, C18; 15-45% acetonitrile/0.1% formic acid in water)
11. customSince the product was running close to the solvent front
12. customthe remaining sample was purified by this method
13. concentrationThe desired fractions were concentrated to a glassy solid
14. dissolutionThe residue was dissolved in MeOH (3 mL)
15. filtrationfiltered through ISOLUTE® Si-Carbonate (2 g)
16. customto remove the formic acid
17. washThe ISOLUTE® Si-Carbonate was washed with MeOH (3 mL)
18. concentrationthe combined methanol layers were concentrated in vacuo
19. filtrationThe ISOLUTE® Si-Carbonate filtration step
20. concentrationthe MeOH washing concentrated in vacuo

ORD-Eintrag

ord-4f4f4c53fa6a4217b902ceae52972aa0

Quelldatensatz

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09382234B2