Sodium hydride → HCID 86686871, compound

At 0° C., under a blanket of nitrogen, to a solution of (1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentanol (24) (226.500 g, 725.026 mmol) in tetrahydrofuran (1150 mL) was added NaH, 60% in mineral oil (86.995 g, 2175.1 mmol) portionwise, maintaining a temperature of less than 10° C. A solution of 4,6-dichloropyrimidine (118.81 g, 797.53 mmol) in tetrahydrofuran (1150 mL) was then added over 30 minutes maintaining a temperature of less than 5° C. The mixture was allowed to warm to ambient temperature and stirred for 24 hours. HPLC analysis indicated that the reaction mixture contained 74% starting material. The reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 ml), maintaining a temperature of less than 10° C. The tetrahydrofuran layer was separated and concentrated to ˜2 volumes (500 mL). The aqueous layer was extracted twice with ethyl acetate (1150 mL). The organic layers were combined and washed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 mL). The organics were then concentrated. The residue was taken up in tetrahydrofuran (2300 mL) and cooled to 0° C. under a blanket of nitrogen. NaH, 60% in mineral oil (86.995 g, 2175.1 mmol) was added portionwise maintaining a temperature of less than 10° C. Mixture was allowed to warm to ambient temperature and stirred for 16 hours. HPLC analysis indicated reaction was complete. The reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 mL). The tetrahydrofuran layer was separated and concentrated to ˜2 volumes (500 mL). The aqueous layer was extracted twice with ethyl acetate (1150 mL). The organic layers were combined and washed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 ml). The organics were then concentrated to give the crude intermediate 4-((1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentyloxy)-6-chloropyrimidine. This crude reaction mixture was taken in to the next step without further purification.

1. temperaturemaintaining a temperature of less than 10° C
2. temperaturemaintaining a temperature of less than 5° C
3. customThe reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 ml)
4. temperaturemaintaining a temperature of less than 10° C
5. customThe tetrahydrofuran layer was separated
6. concentrationconcentrated to ˜2 volumes (500 mL)
7. extractionThe aqueous layer was extracted twice with ethyl acetate (1150 mL)
8. washwashed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 mL)
9. concentrationThe organics were then concentrated
10. temperaturecooled to 0° C. under a blanket of nitrogen
11. temperaturemaintaining a temperature of less than 10° C
12. temperatureto warm to ambient temperature
13. stirringstirred for 16 hours
14. customreaction
15. customThe reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 mL)
16. customThe tetrahydrofuran layer was separated
17. concentrationconcentrated to ˜2 volumes (500 mL)
18. extractionThe aqueous layer was extracted twice with ethyl acetate (1150 mL)
19. washwashed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 ml)
20. concentrationThe organics were then concentrated

ORD record

ord-f2db17a81b7b4826ad040a7029167e8f

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08809356B2