反应详情

温度

-15 °C

A 22 L flask was charged with 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (661 g, 1.57 mol) and 8.5 L dichloromethane. After cooling to −15° C. with an ice/salt bath, the solution of tert-butyl [chlorosulfonyl]carbamate (prepared as above) was added at a rate so that the temperature did not exceed −10° C. (addition time 7 min). After stirring for 10 min, triethylamine (1085 mL, 7.78 mol) was added at a rate so that the temperature did not exceed −5° C. (addition time 10 min). The cold bath was removed, the reaction was allowed to warm to 10° C., split into two portions, and neutralized with 10% conc HCl (4.5 L each portion). Each portion was transferred to a 50 L separatory funnel and diluted with ethyl acetate to completely dissolve the white solid (˜25 L). The layers were separated, and the organic layer was washed with water (5 L), brine (5 L), and the solvents removed in vacuo to afford an off-white solid. The solid was triturated with MTBE (2×1.5 L) and dried to a constant weight to afford a white solid. A total of 4113 g starting material was processed in this manner (5409 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.08 (dd, J=6.2, 2.5 Hz, 1 H), 7.72 (m, 1 H), 7.59 (t, J=8.6 Hz, 1 H), 6.58 (t, J=5.7 Hz, 1 H), 3.38 (dd, J=12.7, 6.2 Hz, 2 H), 3.10 (dd, J=12.1, 5.9 Hz, 2 H), 1.41 (s, 9 H).

1. customdid not exceed −10° C.
2. addition(addition time 7 min)
3. customdid not exceed −5° C.
4. addition(addition time 10 min)
5. customThe cold bath was removed
6. temperatureto warm to 10° C.
7. customsplit into two portions
8. customEach portion was transferred to a 50 L separatory funnel
9. additiondiluted with ethyl acetate
10. dissolutionto completely dissolve the white solid (˜25 L)
11. customThe layers were separated
12. washthe organic layer was washed with water (5 L), brine (5 L)
13. customthe solvents removed in vacuo
14. customto afford an off-white solid
15. customThe solid was triturated with MTBE (2×1.5 L)
16. customdried to a constant weight
17. customto afford a white solid