Triethylamine → HCID 60194461, compound

Participants

Reaction Conditions

Reaction Steps

Alternatively, the besylate salt of the chiral 5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]can be coupled with methanesulfonylacetic acid using n-propylphosphonic anhydride via a simplified one-pot process instead of the CDI two-pot method. Triethylamine (0.825 g, 1.3 eq.) was added drop-wise over 1 minute at about 18-22° C. to methanesulfonylacetic acid (0.615 g, 1.3 eq.) and chiral-5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran] (Preparation 8, 2.1 g, 3.39 mmol) in 9.3 mL ethyl acetate (EtOAc). The addition funnel was rinsed with 0.5 mL EtOAc and the resulting mixture stirred for a minimum of 2 hours and cooled to <10° C. To this mixture, 50% n-propylphosphonic anhydride in EtOAc (4.313 g, 2.0 eq) was added drop-wise over 15 minutes at <10° C. The addition funnel was then rinsed with 1.5 mL EtOAc. The reaction mixture was warmed to 35° C. and stirred overnight. (HPLC >97% with <1% starting material). To the reaction was added 1.0 g Celite filter aid and filtered through a 1 g celite plug in a 15 mL coarse frit glass funnel and rinsed with 4 mL EtOAc (2×). In process chiral HPLC was 98.8% S-enantiomer and 1.2% R-enantiomer; HPLC >97%. Filtrate was washed with 4 mL water (3×), 4 mL 10% NH4Cl, 4 mL water and the organic layer concentrated to the amorphous S form of 1-(5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)-2-(methylsulfonyl)ethanone (foam, 70-80% yield). 1H NMR, 600 MHz (d6-CDCl3) δ ppm: 7.65 (m, 5H), 5.19 (br s, 2H), 4.70 (m, 2H), 4.48 (d, 1H), 4.38 (d, 1H), 4.12 (d, 1H), 3.90 (d, 2H), 3.72 (d, 1H), 3.23 (s, 3H); m/z (CI) 581 [M+H].

Provenance & Evidence