Triethylamine → 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-phenyl}-amide

To a mixture of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid (200 mg, 0.435 mmol) in 2 mL of CH2Cl2 was added a drop of DMF and approximately 2 mL of oxalyl chloride dropwise (gas evolution observed). The resulting mixture was stirred at room temperature for 72 hours, then concentrated to produce a solid, which was triturated with ether, then suspended in 5 mL of THF. To this suspension was added triethylamine (110 mg, 151 μL, 1.088 mmol), followed by N-hydroxy-isobutyramidine (54 mg, 0.529 mmol). The resulting reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, and washed twice with saturated NH4Cl solution. The organic phase was then dried over Na2SO4, filtered, and concentrated. The residue was re-dissolved in 5 mL of THF, and treated with 4 N TBAF solution in THF (excess, ca. 2 mL). The mixture was stirred at room temperature overnight, and then diluted with EtOAc. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes) to produce 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-phenyl}-amide as an off-white solid. HRMS calcd for C27H26F3N5O3 (M+H) 526.2061, obsd 526.2059.

1. concentrationconcentrated
2. customto produce a solid, which
3. customwas triturated with ether
4. customThe resulting reaction mixture
5. stirringwas stirred at room temperature overnight
6. washwashed twice with saturated NH4Cl solution
7. dry with materialThe organic phase was then dried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated
10. dissolutionThe residue was re-dissolved in 5 mL of THF
11. additiontreated with 4 N TBAF solution in THF (excess, ca. 2 mL)
12. stirringThe mixture was stirred at room temperature overnight
13. additiondiluted with EtOAc
14. washThe organic phase was washed with water
15. dry with materialdried over Na2SO4
16. filtrationfiltered
17. concentrationconcentrated
18. customThe crude product was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes)

ORD-Eintrag

ord-09421f4f581f4422ac8fb59da784fc17

Quelldatensatz

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08211914B2