HCID 86716575, compound → HCID 71116130, compound

Temperature

70 °C

A mixture of 1-{[(2R,3R,75)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (235 g, 508 mmol) in formic acid (1948 mL) was heated to 70° C. for 18 h, then the solution was concentrated under reduced pressure, and diluted with sat. NaHCO3 until it was basic. The resulting mixture was extracted with DCM (3×), and the combined extracts were washed with brine and then concentrated under reduced pressure. To the residue was added EtOAc (1 L) and then it was concentrated at 60° C. to a volume of approximately 750 mL. The slurry was then allowed to cool. Once solids started to form, the slurry was slowly diluted with 500 mL of hexanes and the temperature was raised to about 60° C. An additional 500 mL of hexanes was slowly added and the temperature was raised to reflux (about 68° C.). Once at reflux, heating was stopped, and the solution was allowed to cool to RT and stir for 5 days. Then the slurry was filtered, the solids were washed with hexanes and dried under reduced pressure to give 105.5 g of product (78% yield). The filtrate was concentrated and loaded onto silica gel and purified on a 220 g column (like a plug of silica) using vacuum to pull solvent through the column, and eluted with 500 mL of DCM, then 1 L of 50% EtOAc/DCM, then 1 L of 100% DCM, then 1 L each of 2.5%, 5%, 7.5%, and 10% MeOH/DCM. Fractions were collected in 1 L portions. Fractions containing product were concentrated to afford an additional 20.4 g (15% yield) of product. MS (m/z) 268.1 (M+H+).

1. concentrationthe solution was concentrated under reduced pressure
2. additiondiluted with sat. NaHCO3 until it
3. extractionThe resulting mixture was extracted with DCM (3×)
4. washthe combined extracts were washed with brine
5. concentrationconcentrated under reduced pressure
6. additionTo the residue was added EtOAc (1 L)
7. concentrationit was concentrated at 60° C. to a volume of approximately 750 mL
8. temperatureto cool
9. customto form
10. temperaturethe temperature was raised to about 60° C
11. temperaturethe temperature was raised
12. temperatureto reflux (about 68° C.)
13. temperatureOnce at reflux
14. temperatureheating
15. temperatureto cool to RT
16. filtrationThen the slurry was filtered
17. washthe solids were washed with hexanes
18. customdried under reduced pressure

ORD record

ord-731646fc44734400a97e01fa999b11a6

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09187464B2