Triphenylphosphine → 4-(3-Chloro-4-fluorophenyl)-3-(4-{[2-(tritylamino)ethyl]amino}-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one

Temperature

0 °C

A solution of 2-(tritylamino)ethanol (10 g, 33 mmol) [EP599220 and J. Org. Chem. (2001), 66, 7615] and triphenylphosphine (8.7 g, 33 mmol) in tetrahydrofuran (65 mL) at 0° C. was treated with diisopropyl azodicarboxylate (7.0 mL, 35 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (9.3 g, 24 mmol) in tetrahydrofuran (28 mL), and stirred at 25° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate (350 mL), cooled to 0° C., treated with 1N HCl (200 mL), and stirred at 25° C. for 1 h. The reaction mixture was treated with additional 1N HCl (150 mL) and stirred at 25° C. for 3 h. The organic layer was separated, washed with saturated sodium bicarbonate (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow foam which was reconcentrated from hexanes to give an oily solid. The oily solid was treated with methyl tert-butyl ether (50 mL) and stirred to give a heterogeneous mixture. The solid was filtered, washed with methyl ten-butyl ether (30 mL), and dried to give the desired product (10 g, 74%) as a white solid. LCMS for C31H24ClFN6O3Na (M+Na)+: m/z=605.2. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (dd, J=6.7, 2.6 Hz, 1 H), 7.71-7.66 (m, 1 H), 7.60 (dd, J=9.1, 8.8 Hz, 1 H), 7.40-7.37 (m, 6 H), 7.28-7.23 (m, 6 H), 7.18-7.12 (m, 3 H), 6.59 (dd, J=5.9, 5.6 Hz, 1 H), 3.37-3.31 (m, 2 H), 2.96 (dd, J=7.6, 7.6 Hz, 1 H), 2.27-2.19 (m, 2 H).

1. stirringstirred at 25° C. for 16 h
2. concentrationThe reaction mixture was concentrated
3. additiondiluted with ethyl acetate (350 mL)
4. temperaturecooled to 0° C.
5. additiontreated with 1N HCl (200 mL)
6. stirringstirred at 25° C. for 1 h
7. additionThe reaction mixture was treated with additional 1N HCl (150 mL)
8. stirringstirred at 25° C. for 3 h
9. customThe organic layer was separated
10. washwashed with saturated sodium bicarbonate (200 mL) and brine (100 mL)
11. dry with materialdried over anhydrous sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated to a yellow foam which
14. customto give an oily solid
15. stirringstirred
16. customto give a heterogeneous mixture
17. filtrationThe solid was filtered
18. washwashed with methyl ten-butyl ether (30 mL)
19. customdried

ORD record

ord-7b9ea03cabd14be88fc627224011a630

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08822511B2