Triethylamine → tert-Butyl N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)sulfamoylcarbamate

HRID 881204Notes

Reaction equation

HRID 881204 reaction equation
Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=3)[C:14](=[O:24])[O:13][N:12]=2)=[N:8][O:9][N:10]=1.Cl[S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[Br:23][C:18]1[CH:17]=[C:16]([N:15]2[C:14](=[O:24])[O:13][N:12]=[C:11]2[C:7]2[C:6]([NH:5][CH2:4][CH2:3][NH:2][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:27])=[O:28])=[N:10][O:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 15677406tert-butyl N-(chlorosulfonyl)carbamateHCID 666064613-(4-((2-Aminoethyl)amino)-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride

Product 1

HCID 68052882tert-Butyl N-(2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)amino)ethyl)sulfamoylcarbamate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-15 °C

Procedure

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, 1H), 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.72 (m, 1H), 7.59 (t, J=8.6 Hz, 1H), 6.58 (t, J=5.7 Hz, 1H), 3.38 (dd, J=12.7, 6.2 Hz, 2H), 3.10 (dd, J=12.1, 5.9 Hz, 2H), 1.41 (s, 9H).

Workup

  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

Sources & evidence

ORD record
ord-aab10afc4d3e4f0c9c888babeb019018
Source dataset
uspto-grants-2015_03
Patent number
US08993605B2

Reaction notes

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