Hydrochloric Acid → Hydrochloric Acid

Temperature

100 °C

A 2-dram vial was charged with 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 13A, 0.085 g, 0.200 mmol), N-methyl-2-pyrrolidinone (1 mL), (S)-ethyl piperidine-3-carboxylate (0.062 mL, 0.401 mmol) and lithium per chlorate (4.26 mg, 0.040 mmol). The vial was sealed and the contents were heated at 100° C. for 6.5 h and then left stirring at room temperature for 65 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (2×15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield a brown oil. To the brown oil was added acetonitrile (2 mL) and 6N hydrochloric acid (2 mL) and the contents were heated at 60° C. for 5 h. The reaction mixture was concentrated under reduced pressure. To the residue was added TFA (5 drops) followed by 2 mL of MeOH and the material was purified by reverse phase preparative HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Product containing fractions were isolated and concentrated. Acetonitrile (2 mL) and 6N hydrochloric acid (2 mL) were added to the resulting oil and the contents were heated at 60° C. for 2 h. The reaction mixture was concentrated and freeze dried to yield (3S)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidine-3-carboxylic acid, hydrochloric acid (0.046 g, 0.074 mmol, 37.0% yield) as a pale yellow solid.

1. customThe vial was sealed
2. waitleft
3. customThe reaction mixture was partitioned between ethyl acetate (20 mL) and brine (2×15 mL)
4. dry with materialThe ethyl acetate layer was dried over sodium sulfate
5. concentrationconcentrated
6. customto yield a brown oil
7. temperaturethe contents were heated at 60° C. for 5 h
8. concentrationThe reaction mixture was concentrated under reduced pressure
9. additionTo the residue was added TFA (5 drops)
10. customthe material was purified by reverse phase preparative HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA)
11. additionProduct containing fractions
12. customwere isolated
13. concentrationconcentrated
14. additionAcetonitrile (2 mL) and 6N hydrochloric acid (2 mL) were added to the resulting oil
15. temperaturethe contents were heated at 60° C. for 2 h
16. concentrationThe reaction mixture was concentrated
17. customfreeze dried

ORD record

ord-d8c62e31302e439ca306c40d03875c90

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09216972B2