Ethanol → (1R,2S,7R,8S)-N-[3-(3-benzyl-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl)-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide

Temperature

25 °C

(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.200 g, 0.600 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.121 g, 0.631 mmol) and N-methylmorpholine (0.139 mL, 1.26 mmol) were added sequentially to a solution of (1S,2R,3S,4R)-3-benzylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.164 g, 0.600 mmol) in N,N-dimethylformamide (5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.972 mL, 3.00 mmol) was added and the reaction mixture was heated at 60° C. for 1 h. After cooling to 25° C., the reaction mixture was partitioned between a 1.0M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 40 to 100% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)—N-[3-(3-benzyl-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (0.120 g, 0.222 mmol, 37%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.21 (2H, m), 1.39-1.61 (4H, m), 2.52 (1H, bs), 2.64 (1H, bs), 3.05 (3H, s), 3.30 (2H, bs), 3.54 (1H, d, J=9.5 Hz), 4.43 (1H, d, J=16.4 Hz), 4.99 (1H, d, J=15.5 Hz), 7.23-7.28 (2H, m), 7.33 (2H, m), 7.48-7.51 (2H, m), 7.55-7.57 (2H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C25H26N4O6S2 542.13, found 543.2 [M+H+].

1. customwas partitioned between 1.0M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
2. dry with materialThe organic layers were dried over sodium sulfate
3. filtrationfiltered
4. concentrationconcentrated in vacuo
5. dissolutionThe residue was dissolved in ethanol (15 mL) at 25° C
6. temperaturethe reaction mixture was heated at 60° C. for 1 h
7. temperatureAfter cooling to 25° C.
8. customthe reaction mixture was partitioned between a 1.0M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
9. dry with materialThe organic layers were dried over sodium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe residue was purified by flash column chromatography (Teledyne Isco RediSep column; 40 to 100% ethyl acetate in hexanes)

ORD record

ord-5783eb7f91a14fe5a1c23add32fe460c

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09156832B2