Hydroxylamine → HCID 53327249, compound

The crude product from step 1g, (R)-methyl 5-((3-Chloro-4-fluorophenyl)(hydroxy)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate, was dissolved in 4 mL of pyridine and 1.5 mL of 50% hydroxylamine in water producing a clear yellow solution that was then heated to 80° C. for 1 h (complete conversion). The aqueous pyridine was then evacuated by vacuum distillation and the residual oil dissolved in EtAc. Extraction with 10% citric acid removed residual pyridine and hydroxylamine. The organic phase became cloudy as deprotection of the acetonide was initiated. The EtAc was removed and the residual oil dissolved in 3 mL 70% formic acid. This solution was left to rest at RT for 30 min upon which completion of the deprotection was noted. The oil was then diluted with 20 mL of water and 70 mL of EtAc and the product was extracted into the organic phase. A black aqueous layer formed and was extracted with one 50 mL portion of EtAc. Following this extraction the organic phase was concentrated (to 20 mL) and extracted with 0.1N NaOH (2×20 mL). The aqueous layer was then removed and washed with hexane. The aqueous layer was again removed and acidified until complete precipitation of the product (acid pH) was observed. The precipitate was then extracted into EtAc and the aqueous layer back extracted. Evaporation of the solvent gave a foam product. MeCN (1 mL) was added to dissolve followed by hexane producing a biphasic mixture. Stirring for 30 min gave a crystalline powder precipitate which was filtered off yielding 0.56 g off-white powder.

1. customThe aqueous pyridine was then evacuated by vacuum distillation
2. dissolutionthe residual oil dissolved in EtAc
3. extractionExtraction with 10% citric acid removed residual pyridine and hydroxylamine
4. customThe EtAc was removed
5. dissolutionthe residual oil dissolved in 3 mL 70% formic acid
6. waitThis solution was left
7. additionThe oil was then diluted with 20 mL of water and 70 mL of EtAc
8. extractionthe product was extracted into the organic phase
9. customA black aqueous layer formed
10. extractionwas extracted with one 50 mL portion of EtAc
11. extractionthis extraction the organic phase
12. concentrationwas concentrated (to 20 mL)
13. extractionextracted with 0.1N NaOH (2×20 mL)
14. customThe aqueous layer was then removed
15. washwashed with hexane
16. customThe aqueous layer was again removed
17. customacidified until complete precipitation of the product (acid pH)
18. extractionThe precipitate was then extracted into EtAc
19. extractionthe aqueous layer back extracted
20. customEvaporation of the solvent
21. customgave a foam product
22. dissolutionto dissolve
23. customgave a crystalline powder precipitate which
24. filtrationwas filtered off

ORD record

ord-1673d2bdb2724cbc8f920f2c691dc1ea

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08664248B2