Thionyl Chloride → Benzamide

Temperature

0 °C

To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed on a rotovap, and the residue suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in DMF (2 mL), cooled to 0° C., and 2-(azetidin-3-yl)propan-2-ol hydrochloride (101 mg, 0.663 mmol) and DBU (0.10 mL, 0.663 mmol) were added. After stirring for 16 hours at RT, the reaction mixture was concentrated and purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-34)azetidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene) as a white powder benzamide (26 mg, 21.4% yield). MS, m/z (C31H40FN5O3): calcd, 549.3. found, 549.9 [M+H].

1. customThe solvent was removed on a rotovap
2. concentrationre-concentrated
3. customto remove residual thionyl chloride
4. temperaturecooled to 0° C.
5. stirringAfter stirring for 16 hours at RT
6. concentrationthe reaction mixture was concentrated
7. custompurified by reverse-phase preparative HPLC
8. extractionextracted with EtOAc (×2)
9. washThe combined organic layers were washed with brine
10. dry with materialdried over anhydrous magnesium sulfate
11. filtrationfiltered
12. concentrationconcentrated

ORD record

ord-926708714f9b4a728142bf73b30c5324

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09115127B2