1,2-Dichloroethane → HCID 59547344, compound

Participants

Reaction Steps

Cyclohexylacetic acid (48 mg, 337 μmol, 1.4 eq.), EDC (65 mg, 337 μmol, 1.4 eq.) and HOBt (52 mg, 337 μmol, 1.4 eq.) were combined in DMF (0.3 mL) and stirred for 0.5 hrs. at room temp. (5S,8S)-tert-butyl 7-((S)-2-amino-3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (F1) (105 mg, 243 μmol, 1 eq.) and DIEA (118 μL 675 μmol, 2.8 eq.) were added to this mixture and the resulting mixture was stirred for 24 hrs at room temp. 1.0 M histamine (aq., 120 μL, 0.5 eq.) was added and the mixture was stirred for 0.5 h. Ethyl acetate was added and the mixture was washed with 1N HCl then 1M K2CO3 and extracted with ethyl acetate (2×). The combined organic layers were concentrated and chromatography using hexanes and ethyl acetate gave 50 mg of (5S,8S)-tert-butyl 7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (G1). 1H NMR (300 MHz, DMSO) 7.90 (d, 1 H), 7.53 (d, 2 H), 7.44-7.37 (m, 2H), 7.14 (m, 1H), 4.47 (d, 1H), 4.30-3.99 (m, 3H), 3.89-3.83 (m, 1H), 3.18 (d, 1H), 2.79-2.67 (m, 1H), 2.27-2.00 (m, 3H), 1.7-1.55 (m, 5H), 1.45-1.39 (m, 11H), 1.2-1.1 (m, 4H), 0.98-0.91 (m, 9H). Later optimization showed that steps E to G could be replaced by doing a single coupling on E1 with (S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoic acid. NMR confirmed that epimerization was not occurring.

Provenance & Evidence