2-Methyltetrahydrofuran → N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-fluoro-3-(trifluoromethyl)quinoxalin-2-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide

Temperature

5 °C

To a stirring solution of (2R,6S,13aS,14aR,16aS,Z)-2-(7-fluoro-3-(trifluoromethyl)quinoxalin-2-yloxy)-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (5.13 g) and NMP (12.9 g) was added carbonyl diimidazole (1.83 g) as a solution in NMP (7.7 g). After 30 min, cyclopropylsulfonamide (1.81 g) was added to the reaction mixture as a solution in NMP (5.13 g). The solution was cooled to 5° C. and then DBU (4.0 g) was charged to the reaction mixture. The reaction was allowed to proceed for 15 h and then diluted with isopropyl acetate (IPAc) (33.5 g) and 2-methyltetrahydrofuran (33.5 g). The organic solution was washed with a 2.0 M aqueous solution of H3PO4 (51.3 g), a 5:3:1 solution of 2.0 M H3PO4, H2O, 10% aqueous solution of NaCl (total volume of 50 mL), water (5×25 g), and then concentrated to 25 mL by distillation. The organic solution was diluted with IPAc (25.0 g) and then concentrated back to 25 mL by distillation. This process was repeated three times. The concentrated product-containing solution was diluted with IPAc (108 g), filtered, and then concentrated again to 25 mL. The product-containing solution was distilled, maintaining a constant volume by the addition of ethanol (106 g). Ethanol (35 mL) was then added. Water (3.0 g) was then added to the product solution and the mixture was heated to 80° C. and then cooled to 20° C. over 12 h. The slurry was filtered and the cake was rinsed with ethanol (10 mL). The cake was dried under vacuum to provide the product (4.64 g, 79% yield) as a white, crystalline solid: 1H NMR (400 MHz, DMSO-D6) δ ppm 11.14 (s, 1H), 9.02 (s, 1H), 8.69 (d, J=6.7 Hz, 1H), 8.27 (dd, J=9.1, 5.9 Hz, 1H), 7.79 (dd, J=9.6, 2.3 Hz, 1H), 7.72 (td, J=8.7, 2.3 Hz, 1H), 6.09 (s, 1H), 5.95 (br s, 1H), 5.61 (q, J=8.5 Hz, 1H), 5.12 (t, J=9.5 Hz, 1H), 4.65 (d, J=11.7 Hz, 1H), 4.50 (t, J=8.2 Hz, 1H), 4.38-4.28 (m, 1H), 3.96 (dd, J=11.3, 2.4 Hz, 1H), 2.96-2.88 (m, 1H), 2.69-2.55 (m, 2H), 2.52-2.44 (m, 1H), 2.42 (s, 3H), 2.31 (q, J=8.7 Hz, 1H), 1.96 (q, J=11.4 Hz, 1H), 1.77-1.66 (m, 1H), 1.63-1.56 (m, 2H), 1.45-1.28 (m, 5H), 1.27-1.16 (m, 2H), 1.15-0.95 (m, 4H). LC-MS (ESI): m/z=792.2 [M+H].

1. waitto proceed for 15 h
2. washThe organic solution was washed with a 2.0 M aqueous solution of H3PO4 (51.3 g)
3. concentrationa 5:3:1 solution of 2.0 M H3PO4, H2O, 10% aqueous solution of NaCl (total volume of 50 mL), water (5×25 g), and then concentrated to 25 mL by distillation
4. additionThe organic solution was diluted with IPAc (25.0 g)
5. concentrationconcentrated back to 25 mL by distillation
6. additionThe concentrated product-containing solution
7. additionwas diluted with IPAc (108 g)
8. filtrationfiltered
9. concentrationconcentrated again to 25 mL
10. distillationThe product-containing solution was distilled
11. temperaturemaintaining a constant volume
12. additionby the addition of ethanol (106 g)
13. additionEthanol (35 mL) was then added
14. additionWater (3.0 g) was then added to the product solution
15. temperaturethe mixture was heated to 80° C.
16. temperaturecooled to 20° C. over 12 h
17. filtrationThe slurry was filtered
18. washthe cake was rinsed with ethanol (10 mL)
19. customThe cake was dried under vacuum

ORD record

ord-0c5eaae6bfca4c1490d2fb156f402c6c

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08748374B2