Ethanol → 1-[(4-fluorophenyl)methyl]-4-hydroxy-3-(7-iodo-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-3-yl)-5,6,7,8,9,9a-hexahydro-4aH-cyclohepta[b]pyridin-2-one

Temperature

25 °C

(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 24b, 0.959 g, 2.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.527 g, 2.75 mmol) and N-methylmorpholine (0.605 mL, 5.50 mmol) were added sequentially to a solution of cis-2-(4-fluoro-benzylamino)-cycloheptanecarboxylic acid methyl ester (prepared as described in Example 2b, 0.732 g, 2.62 mmol) in N,N-dimethylformamide (20 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3 h, and then was concentrated in vacuo. The residue 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 (60 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (3.40 mL, 10.4 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; 10-70% ethyl acetate in hexanes) to afford the desired product, 1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,8,9,9a-octahydro-cyclohepta[b]pyridin-2-one (0.534 g, 0.891 mmol, 34%) as a beige foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.25-1.42 (2H, m), 1.50-1.57 (3H, m), 1.76-1.98 (1H, m), 1.93 (3H, s), 3.30 (1H, bs), 3.55-3.59 (1H, m), 4.27 (1H, d, J=15.1 Hz), 5.02 (1H, d, J=14.9 Hz), 7.11-7.18 (2H, m), 7.25-7.29 (1H, m), 7.30-7.32 (1H, m), 7.39-7.42 (2H, m), 7.91-7.96 (1H, m), 8.02 (1H, s). LC-MS (ESI) calcd for C24H23FIN3O4S 595.04, found 596.2 [M+H+].

1. concentrationwas concentrated in vacuo
2. customThe residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL)
3. dry with materialThe organic layers were dried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. dissolutionThe residue was dissolved in ethanol (60 mL) at 25° C
7. temperaturethe reaction mixture was heated to 60° C. for 1 h
8. temperatureAfter cooling to 25° C.
9. customthe reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL)
10. dry with materialThe organic layers were dried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customThe residue was purified by flash column chromatography (Teledyne Isco RediSep Column; 10-70% ethyl acetate in hexanes)

ORD record

ord-70c2ac45146c4c86ac3610ae13d200ed

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582626B2