Chloroacetyl chloride → N-(4-methoxybenzyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

Participants

Reaction Conditions

Reaction Steps

A 250 mL round bottom flask was charged with 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (INTERMEDIATE J, 2.450 g, 6.24 mmol) and K2CO3 (2.59 g, 18.73 mmol), and diluted with DMF (62.4 mL) under an inert atmosphere. The reaction mixture was cooled to 0° C. in an ice-water bath, and 2-chloroacetyl chloride (0.596 mL, 7.49 mmol) was added (color change from orange to light yellow suspension). After stirring for 5 minutes, the reaction was warmed to rt. After 30 minutes, complete conversion to the first alkylation was observed (M+H=468), along with some fully cyclized material. The reaction was heated to 50° C. for 2 h until complete conversion to the cyclized oxazinone. The reaction was cooled to rt, and diluted with sat aq. ammonium chloride and then extracted with ethyl acetate. The organics were washed with brine, then dried over magnesium sulfate and concentrated under a vacuum. Upon attempts to transfer using DCM and a small amount of ether, it was observed that a solid crashed out of solution. The solids were filtered, and washed with ether to yield 1.37 g of N-(4-methoxybenzyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE K) as a light pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3 H) 4.67 (s, 2 H) 5.13 (s, 2 H) 6.83-6.92 (m, 2 H) 7.04 (d, J=8.41 Hz, 1 H) 7.30 (d, J=8.80 Hz, 2 H) 7.37 (d, J=2.05 Hz, 1 H) 7.56 (dd, J=8.41, 2.15 Hz, 1 H) 8.41 (s, 1 H) 11.21 (s, 1 H). m/z (ESI) 432.9 (M+H)+.

Provenance & Evidence