Ethanol → HCID 136132960, compound

Temperature

25 °C

[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.133 g, 0.376 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.157 g, 0.413 mmol) and 4-methylmorpholine (0.083 mL, 0.755 mmol) were added sequentially to a solution of rac-2-[(4-fluoro-benzylamino)-methyl]-4-methyl-pentanoic acid ethyl ester (0.106 g, 0.377 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (10 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.732 mL, 2.26 mmol) was added and the reaction mixture was heated to 70° C. for 22 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-isobutyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.097 g, 0.170 mmol, 45%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.73 (3H, d, J=5.5 Hz), 0.77 (3H, d, J=5.5 Hz), 1.17-1.21 (1H, m), 1.31-1.33 (2H, m), 2.60 (1H, bs), 2.95 (3H, s), 3.16 (1H, d, J=13.3 Hz), 3.58 (1H, dd, J1=4.8 Hz, J2=12.5 Hz), 4.24 (2H, d, J=5.4 Hz), 4.34 (1H, d, J=15.0 Hz), 4.85 (1H, d, J=14.6 Hz), 7.15-7.19 (2H, m), 7.25 (1H, s), 7.37-7.40 (2H, m), 7.64 (1H, t, J=5.9 Hz). LC-MS (ESI) calculated for C23H27FN4O6S3 570.11. found 571.2 [M+H+].

1. concentrationwas concentrated in vacuo
2. customThe residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
3. dry with materialThe organic layers were dried over sodium sulfate
4. concentrationwere concentrated in vacuo
5. dissolutionThe residue was dissolved in ethanol (10 mL) at 25° C
6. temperaturethe reaction mixture was heated to 70° C. for 22 h
7. temperatureAfter cooling to 25° C.
8. customthe reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
9. dry with materialThe organic layers were dried over sodium sulfate
10. concentrationwere concentrated in vacuo
11. customThe residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes)

ORD record

ord-3b8ac4ef3804427782353d4cbc02f941

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08097613B2