Hydrochloric Acid → N-[3-[(4aR,7aS)-1-(3,3-dimethylbutyl)-4-hydroxy-2-oxo-5,6,7,7a-tetrahydro-4aH-cyclopenta[b]pyridin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-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 1j, 0.100 g, 0.300 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.315 mmol) and N-methylmorpholine (0.070 mL, 0.630 mmol) were added sequentially to a solution of (1R,2S)-2-(3,3-dimethyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.072 g, 0.300 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (110 mL) and ethyl acetate (2×110 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was dissolved in ethanol (4 mL) at 25° C. A 21% w/w solution of sodium ethoxide in ethanol (0.244 mL, 0.600 mmol) was added and the reaction mixture was heated to 60° C. for 2 h. After cooling to 25° C. and stirring for 16 h, the reaction mixture was slowly added to 1.0 M aqueous hydrochloric acid solution (50 mL) at 0° C. The resulting precipitate was collected by filtration and dried in vacuo, then was triturated with a small amount of methanol (ca. 0.5 mL) to afford the desired product, (4aR,7aS)-N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.083 g, 0.163 mmol, 54%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.00 (s, 9H), 1.50-1.82 (m, 6H), 1.94-2.47 (m, 4H), 2.94-3.39 (m, 2H), 3.06 (s, 3H), 3.68-3.82 (m, 2H), 6.99 (bs, 1H), 7.21 (dd, 1H, J1=28.7 Hz, J2=8.4 Hz), 7.63 (t, 1H, J=8.9 Hz), 7.67-7.69 (m, 1H). LC-MS (ESI) calcd for C22H30N4O6S2 510.16, found 511.4 [M+H+].

1. customwas partitioned between 1.0 M aqueous hydrochloric acid solution (110 mL) and ethyl acetate (2×110 mL)
2. washThe organic layers were washed with saturated aqueous brine solution (100 mL)
3. dry with materialdried over sodium sulfate
4. filtrationfiltered
5. concentrationwere concentrated in vacuo
6. dissolutionThe residue was dissolved in ethanol (4 mL) at 25° C
7. temperaturethe reaction mixture was heated to 60° C. for 2 h
8. temperatureAfter cooling to 25° C.
9. stirringstirring for 16 h
10. filtrationThe resulting precipitate was collected by filtration
11. customdried in vacuo
12. customwas triturated with a small amount of methanol (ca. 0.5 mL)

ORD record

ord-2f534f3e95d1433bb05ec11616442114

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582626B2