Trifluoroacetic acid → HCID 68407776, compound

To a solution of tert-butyl [(4-oxocyclohexyl)methyl]carbamate (5.0 g, 22.00 mmol) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml). The mixture was stirred for 1 h at room temperature, and then concentrated and co-concentrated with toluene (5 ml). A suspension of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2, 6.13 g, 20 mmol), o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (15.2 g, 40.1 mmol), 1-hydroxybenzotriazole (4.0 g, 29.6 mmol), and diisopropylethylamine (20 ml, 115 mmol) in dichloromethane (100 ml) was stirred for 5 min at room temperature, and then a solution of the deprotected amine in dichloromethane (100 ml) was added. The mixture was stirred overnight at 25° C. The mixture was filtered and then diluted with 300 ml of saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with 2×100 ml of dichloromethane. The combined organics were washed with 100 ml of brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. The resulting product was repurified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% acetone in hexanes over 10 column volumes. The resulting product was crystallized from dichloromethane to provide the title compound (5.52 g, 13.29 mmol, 66.4% yield). Mass spectrum (ESI) 416.0 (M+1).

1. concentrationconcentrated
2. stirringwas stirred for 5 min at room temperature
3. stirringThe mixture was stirred overnight at 25° C
4. filtrationThe mixture was filtered
5. additiondiluted with 300 ml of saturated sodium bicarbonate solution
6. customThe phases were separated
7. extractionthe aqueous phase was extracted with 2×100 ml of dichloromethane
8. washThe combined organics were washed with 100 ml of brine
9. dry with materialdried (sodium sulfate)
10. concentrationconcentrated
11. customThe residue was purified by flash chromatography on a Biotage Horizon, 65i column
12. washeluting with 1 column volume of 100% dichloromethane
13. customThe resulting product was repurified by flash chromatography on a Biotage Horizon, 65i column
14. washeluting with 1 column volume of 100% hexanes
15. customThe resulting product was crystallized from dichloromethane

ORD record

ord-a55c2ad604be4b1bb3d97249c8883243

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08436028B2