Ethanol → cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-7-yl}-methanesulfonamide

Temperature

25 °C

(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (prepared as described in Example 25 h, 0.365 g, 1.10 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.223 g, 1.16 mmol) and N-methylmorpholine (0.256 mL, 2.33 mmol) were added sequentially to a solution of cis-2-(4-fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (prepared as described in Example 2b, 0.310 g, 1.10 mmol) in N,N-dimethylformamide (6 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (30 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (1.44 mL, 4.44 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 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; 30-100% ethyl acetate in hexanes) to afford cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,8,9,9a-octahydro-1H-cyclohepta[b]pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (0.340 g, 0.610 mmol, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: (1:1 mixture of tautomers) 0.86-0.90 (m), 1.15-1.19 (m), 1.27-1.36 (m), 1.46-1.66 (m), 2.01-2.05 (m), 3.06 (s), 3.31 (s), 3.50-3.54 (m), 3.98-4.41 (1H, m), 4.26-4.33 (m), 4.95-5.05 (m), 5.52 (d, J=16.1 Hz), 5.61 (d, J=15.9 Hz), 5.69 (d, J=15.4 Hz), 5.89 (d, J=16.4 Hz), 7.15-7.26 (m), 7.40-7.41 (m), 7.48-7.51 (m), 7.57-7.61 (m), 10.14 (s), 10.18 (s). LC-MS (ESI) calcd for C26H28FN3O6S2 561.14, found 562.4 [M+H+].

1. customwas partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 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 (30 mL) at 25° C
6. temperaturethe reaction mixture was heated to 60° C. for 1 h
7. temperatureAfter cooling to 25° C.
8. customthe reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 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; 30-100% ethyl acetate in hexanes)

ORD record

ord-418fbf6e3eba4a638551fb4a98c4eec6

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582626B2