Acetic Acid → HCID 67357408, compound

Trimethylaluminum (2M in Toluene, 2116 μl, 4.23 mmol) was slowly added (gas evolution) to a solution of pyridin-4-ylmethanamine (458 mg, 4.23 mmol) in toluene (10 ml) at room temperature and under a nitrogen atmosphere. The reaction was stirred for 2 hours at room temperature. Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204, 500 mg, 0.85 mmol) was added as a solution in 5 ml of toluene. The reaction was stirred at 45° C. for three days. The reaction was cooled to room temperature and then quenched drop wise with 3 ml of 1N HCl (vigorous gas evolution). The crude reaction was poured into a Biotage Isolute® HM-N tube (10 ml capacity) packed with a small amount of glass wool to prevent clogging. A Biotage sodium sulfate column (2.5 g) was attached to the bottom of the Isolute® tube. The reaction mixture was allowed to gravity elute through the tube and washed through with 2-3 column volumes of ethyl acetate. The eluent was concentrated. The residue was dissolved in THF (10 ml) and stirred at room temperature with acetic acid (0.097 ml, 1.70 mmol) and TBAF (1N in THF, 0.935 ml, 0.94 mmol) for 16 hours. The reactions were diluted with 1 ml of water and shaken vigorously. The sample was added to a Varian Chem Elute® CE 1003 tube with a Biotage sodium sulfate column (2.5 g) on the bottom of it. The sample was gravity eluted with 2-3 column volumes of ethyl acetate and concentrated. The residue purified by silica gel column chromatography. Fractions were combined and concentrated to give the title compound (241 mg, 0.552 mmol, 65%).

1. stirringThe reaction was stirred at 45° C. for three days
2. temperatureThe reaction was cooled to room temperature
3. customquenched drop wise with 3 ml of 1N HCl (vigorous gas evolution)
4. customThe crude reaction
5. additionwas poured into a Biotage Isolute® HM-N tube (10 ml capacity)
6. washelute through the tube
7. washwashed through with 2-3 column volumes of ethyl acetate
8. concentrationThe eluent was concentrated
9. dissolutionThe residue was dissolved in THF (10 ml)
10. stirringshaken vigorously
11. additionThe sample was added to a Varian Chem
12. washElute® CE 1003 tube with a Biotage sodium sulfate column (2.5 g) on the bottom of it
13. washeluted with 2-3 column volumes of ethyl acetate
14. concentrationconcentrated
15. customThe residue purified by silica gel column chromatography
16. concentrationconcentrated

ORD record

ord-b975d79eee4b4c04ac7ccac3f586eaf1

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08658641B2