Ammonium Chloride → HCID 178485246, compound

HRID 1877617Notes

Reaction equation

HRID 1877617 reaction equation
[C:1]([C:3]1([NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=4[CH:34]=3)[CH:14]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl-].[NH4+].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C=O)C.CO>[NH:38]1[C:1]([C:3]2([NH:6][C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]4[CH:16]=[CH:17][C:18]5[O:22][C:21]([C:23]6[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=6)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=5[CH:34]=4)[CH:14]=3)=[O:8])[CH2:4][CH2:5]2)=[N:2][N:40]=[N:39]1

Participants

6

Reactant 3

HCID 25517Ammonium Chloride3×HCID 33557Sodium Azide3×HCID 59275429HCID 59275429, compound

Product 1

HCID 178485246HCID 178485246, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

To a mixture of 5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (25.1 mg, 0.054 mmol) in DMF (1 mL) at r.t. under N2 was added ammonium chloride (8.62 mg, 0.161 mmol), and then sodium azide (6.98 mg, 0.107 mmol). The mixture was stirred at 120° C. for about 4 hours. The mixture was cooled to r.t., and added with another 18 mg of NH4Cl and then 14 mg of NaN3. The mixture was stirred at 120° C. for 14.5 hours. The mixture was cooled to r.t., and added with another 26 mg of NH4Cl, followed by 21 mg of NaN3. The mixture was re-stirred at 120° C. for 24 hours. The mixture was cooled to r.t., and diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.82-7.27 min. (UV detection at 220 nm). 1H NMR (500 MHz, CD3OD) δ 7.97 (m, J=9.00, 5.34, 2H), 7.85 (d, J=1.22, 1H), 7.84 (dd overlapping with d, J=1.83, 1H), 7.67 (d, J=8.24, 1H), 7.65 (d, J=1.22, 1H), 7.45 (d, J=7.63, 1H), 7.39 (dd, J=8.55, 1.83, 1H), 7.29 (t, J=8.85, 2H), 2.95 (s, 3H), 2.36 (s, 3H), 1.70 (m, 2H), 1.58 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)+=511.28, HPLC Rt=1.595 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=5.10 min; Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=4.23 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3, Rt=10.58 min.

Workup

  1. temperatureThe mixture was cooled to r.t.
  2. stirringThe mixture was stirred at 120° C. for 14.5 hours
  3. temperatureThe mixture was cooled to r.t.
  4. stirringThe mixture was re-stirred at 120° C. for 24 hours
  5. temperatureThe mixture was cooled to r.t.
  6. custompurified by Shimadzu-VP preparative reverse phase HPLC
  7. customthe separation method
  8. customB=100, Gradient time=10 min
  9. customtime=12 min, Flow Rate=25 mL/min, Column
  10. customWaters-Sunfire 19×100 mm S5, Fraction Collection
  11. custom6.82-7.27 min. (UV detection at 220 nm)
  12. customB=100, Gradient time=2 min
  13. customtime=3 min, Flow Rate=4 ml/min, Column
  14. customB=100, Gradient time=15 min
  15. customtime=18 min, Flow Rate=1 ml/min, Column
  16. customB=100, Gradient time=15 min
  17. customtime=18 min, Flow Rate=1 ml/min, Column

Sources & evidence

ORD record
ord-87eb41dc111f45bcbf364c4eef9e80a5
Source dataset
uspto-grants-2012_11
Patent number
US08309558B2

Reaction notes

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