Hydrochloric Acid → (9R)-6,7,8,9-Tetrahydro-9-hydroxy-5H-cyclohepta(b)pyridin-5-one

Temperature

0 °C

In a 1 L round-bottomed flask was (S)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (19.14 g, 108 mmol) (obtained by enzyme reduction of the diketone) in THF (300 mL) to give a light orange solution. 4-Nitrobenzoic acid (27.1 g, 162 mmol) and Ph3P (42.5 g, 162 mmol) were added under nitrogen, and the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (31.9 mL, 162 mmol) was added dropwise. The mixture was allowed to gradually warm to rt and stirred overnight (5:00 pm). The color changed to tan. 15 h: LCMS showed complete conversion. 80 ml water was added followed by LiOH (7.76 g, 324 mmol). The mixture was stirred at rt for 2 h (some LiOH was not completely dissolved). 2 h: LCMS showed complete conversion (product/dehydrated ˜7/1 by intergration). THF was stripped off and the remaining mixture was slowly acidified with 40 ml concentrated HCl (12N). 300 ml EtOAc was added. The mixture was shaken in a 1 L separating funnel (10 ml hexane was added for better separation). The layers were separated and the organic layer was extracted with water (2×50 mL). The combined aqueous layers were washed with EtOAc (4×100 mL). The tan aqueous solution was then basified slowly with 50 mL 10N NaOH and was extracted with EtOAc (4×150 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (2×100 mL). The combined tan organic layers (TLC showed desired product, dehydrated product and some baseline) were washed with brine, dried and concentrated to a tan oil (crude weight: 19.24 g, 100%), which was directly used in the next step. MS (ESI)[M+H+]=178.24.

1. customto give a light orange solution
2. temperatureto gradually warm to rt
3. custom15 h
4. dissolutionwas not completely dissolved)
5. custom2 h
6. stirringThe mixture was shaken in a 1 L
7. customseparating funnel
8. addition(10 ml hexane was added for better separation)
9. customThe layers were separated
10. extractionthe organic layer was extracted with water (2×50 mL)
11. washThe combined aqueous layers were washed with EtOAc (4×100 mL)
12. extractionwas extracted with EtOAc (4×150 mL)
13. extractionextracted with EtOAc (2×100 mL)
14. washsome baseline) were washed with brine
15. customdried
16. concentrationconcentrated to a tan oil (crude weight

ORD record

ord-592d0e98a29e42f393ed6456a84f9146

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08143403B2