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

Temperature

25 °C

N,N-diisopropylethylamine (1.79 mL, 10.3 mmol) and (benzotriazol-1yloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (1.52 g, 3.44 mmol) were added sequentially to a solution of (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6l, 1.0 g, 3.43 mmol) and (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852, 1.26 g, 3.44 mmol) in N,N-dimethylformamide (25 mL) at 25° C. The resulting solution was stirred at 25° C. for 19 h, and then was concentrated in vacuo. The residue was partitioned between 1.0M 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 resulting orange oil was dissolved in ethanol (50 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (3.33 mL, 10.3 mmol) was added and the reaction mixture was heated at 60° C. for 3 h. After cooling to 25° C., the reaction mixture was concentrated in vacuo to approximately 5 mL volume and was then partitioned between 1.0M 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; 0 to 60% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1, 4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (1.0 g, 1.69 mmol, 49%), as a pale yellow foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.21 (3H, m), 1.38-1.41 (1H, m), 1.46-1.61 (3H, m), 2.62 (1H, d, J=2.4 Hz), 2.98 (1H, d, J=9.4 Hz), 3.52 (1H, d, J=9.3 Hz), 4.40 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=15.6 Hz), 7.14 (2H, d, J=17.9 Hz), 7.11-7.16 (2H, m), 7.30-7.34 (3H, m), 7.97 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 8.07 (1H, d, J=1.5 Hz). LC-MS (ESI) calcd for C24H21FIN3O4S 593.03, found 594.2 [M+H+].

1. concentrationwas concentrated in vacuo
2. customThe residue was partitioned between 1.0M 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 resulting orange oil was dissolved in ethanol (50 mL) at 25° C
7. temperaturethe reaction mixture was heated at 60° C. for 3 h
8. temperatureAfter cooling to 25° C.
9. concentrationthe reaction mixture was concentrated in vacuo to approximately 5 mL volume
10. customwas then partitioned between 1.0M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL)
11. dry with materialThe organic layers were dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes)

ORD record

ord-5bcb2106494349d99e775a2ffcf349d8

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09156832B2