Niclosamide → HCID 14552297, compound

(S)-2-tert-butyl 1-(4-chloro-2-(2-chloro-4-nitrophenylcarbamoyl)phenyl pyrrolidine-1,2-dicarboxylate (Compound 26). (S)-tert-butyl 1-(chlorocarbonyl)pyrrolidine-2-carboxylate was prepared following the procedure disclosed in U.S. Pat. No. 4,866,087 to Greenlee et al with minor modification. A solution of 1.06 g (6.19 mmol) (S)-2-tert-butyl pyrrolidine-2-carboxylate and diisopropylethylamine (3.2 mL, 18.57 mmol) in dichloromethane (5.0 mL) was introduced dropwise into a solution of 1.84 g (6.19 mmol) bis(trichloromethyl)carbonate in dichloromethane (5.0 mL) at ice-bath temperature. The mixture was allowed to warm to room temperature and was stirred for one hour. The reaction mixture was washed with 1N aqueous HCl, dried over magnesium sulfate, and concentrated to an oil. The residue was dissolved in chloroform (5.0 mL) and added dropwise to a suspension of 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (1.82 g, 5.57 mmol) in pyridine (25 mL) containing 20 mg 4-dimethylaminopyridine. The reaction mixture was stirred at room temperature for 72 hours, then partitioned between ethyl acetate and 1N aqueous HCl, dried over magnesium sulfate, and concentrated to a solid. The product was isolated using silica gel chromatography with 3 ethyl acetate: 7 hexanes as elution solvent. The product was recrystallized from ethyl acetate/hexanes. 1H NMR reveals the existence of approximately a 1:1 ratio of rotational isomers. 1H NMR (CDCl3): δ1.331 (s, 4.5H, tert-butyl ester), 1.369 (s, 4.5H, tert-butyl ester), 1.833 (m, 3H, pyrrolidine C4 methylene and pyrrolidine C3 syn-H), 2.181 (m, 1H, pyrrolidine C3 anti-H), 3.500 (m, 2H, pyrrolidine C5 methylene), 4.113 (m, 0.5H, pyrrolidine methine), 4.362 (m, 0.5H, pyrrolidine methine), 7.158 (d, J=9 Hz, 0.5H, H3), 7.334 (d, J=9 Hz, 0.5H, H3), 7.661 (m, 1H, H4), 7.762 (m, 1H, H6), 8.131 (m, 1H, H6′), 8.312 (m, 1H, H5′), 8.388 (m, 1H, H3′), 10.274 (s, 0.5H, NH), 10.347 (s, 0.5H, NH).

1. washThe reaction mixture was washed with 1N aqueous HCl
2. dry with materialdried over magnesium sulfate
3. concentrationconcentrated to an oil
4. dissolutionThe residue was dissolved in chloroform (5.0 mL)
5. stirringThe reaction mixture was stirred at room temperature for 72 hours
6. custompartitioned between ethyl acetate and 1N aqueous HCl
7. dry with materialdried over magnesium sulfate
8. concentrationconcentrated to a solid
9. customThe product was isolated
10. wash7 hexanes as elution solvent
11. customThe product was recrystallized from ethyl acetate/hexanes

ORD record

ord-9e485b13e49b4a13821a1a5f99b18a3e

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08211882B2