Carbamic acid, ethyl ester → 1-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

Temperature

100 °C

A mixture of ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.259 g, 2.310 mmol) in NMP (8.89 mL) was heated at 100° C. for 15 min. 1-(((3S,5S)-5-methyl-1-oxaspiro[2.5]octan-5-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile (0.500 g, 1.777 mmol) was then added. The reaction mixture was stirred overnight (stopped heating at some point because of storm power outage). The reaction mixture was heated at 100° C. and stirred for an additional 6 h. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.065 g, 0.578 mmol) were added and stirred for 16 h. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.130 g, 1.156 mmol) were then added and heated at 110° C. for 16 h. The reaction mixture was heated at 130° C. for 2 days. Additional ethyl carbamate (0.237 g, 2.67 mmol) and KOtBu (0.065 g, 0.578 mmol) were added and mixture stirred for additional 3 h. The reaction mixture was heated at 110° C. for an additional 3 days, followed by the addition of 2N NaOH (30 mL) and EtOAc (75 mL). The layers were then separated and the organic layer washed with water (3×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The compound was loaded onto florisil and purified using silica gel chromatography CISCO): 1-3.5% MeOH/DCM (18 min), 3.5% (7 min), 25 g silica. Product eluted at 13 min. The product was dried under high vacuum at 40° C. overnight. 1-{[(5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile was obtained as a white solid (336 mg, 55.4% yield). MS (m/z) 325 (M+H+).

1. temperaturestopped heating at some point because of storm power outage)
2. temperatureThe reaction mixture was heated at 100° C.
3. stirringstirred for an additional 6 h
4. stirringstirred for 16 h
5. temperatureheated at 110° C. for 16 h
6. temperatureThe reaction mixture was heated at 130° C. for 2 days
7. stirringmixture stirred for additional 3 h
8. temperatureThe reaction mixture was heated at 110° C. for an additional 3 days
9. customThe layers were then separated
10. washthe organic layer washed with water (3×50 mL)
11. dry with materialThe organic layer was dried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated
14. custompurified
15. custom1-3.5% MeOH/DCM (18 min), 3.5% (7 min), 25 g silica
16. washProduct eluted at 13 min
17. customThe product was dried under high vacuum at 40° C. overnight

ORD record

ord-da52bb1f5d8d493eb94fba5c0c506b82

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09187464B2