Toluene → HCID 59275556, compound

HRID 1877654Notes

Reaction equation

HRID 1877654 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]5)[C:24]([O:37][CH3:38])=[CH:23][C:22]=4[CH3:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[C:40]1(C)C=CC=C[CH:41]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32]6[N:35]=[C:40]([CH3:41])[O:34][N:33]=6)[CH2:30][CH2:31]5)[C:24]([O:37][CH3:38])=[CH:23][C:22]=4[CH3:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1

Participants

3

Reactant 2

HCID 1140TolueneHCID 178485248HCID 178485248, compound

Product 1

HCID 59275556HCID 59275556, compound

Procedure

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide was prepared from 2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylbenzofuran-3-carboxamide under similar conditions as described but using PhMe as a solvent. The crude mixture was purified by preparative TLC (20×20 cm×500 um plates, 5% MeOH/CH2Cl2) to give the product, which was further 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: 7.95-8.47 min. (UV detection at 220 nm). Analytical TLC Rf=0.38 (5% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.97 (dd, J=7.93, 5.49, 2H), 7.87 (s, 1H), 7.62 (d, J=8.24, 1H), 7.58 (s, 1H), 7.33 (d, J=8.55, 1H), 7.27 (t, J=8.39, 2H), 7.11 (s, 1H), 4.05 (s, 3H), 2.96 (s, 3H), 2.54 (s, 3H), 2.36 (s, 3H), 1.60 (m, 2H), 1.45 (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=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=555.34, HPLC Rt=1.735 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=7.75 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.93 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 3.5 um, 4.6×150 mm, Rt=11.98 min.

Workup

  1. customThe crude mixture was purified by preparative TLC (20×20 cm×500 um plates, 5% MeOH/CH2Cl2)
  2. customto give the product, which
  3. customwas further purified by Shimadzu-VP preparative reverse phase HPLC
  4. customthe separation method
  5. customB=100, Gradient time=10 min
  6. customtime=12 min, Flow Rate=25 mL/min, Column
  7. customWaters-Sunfire 19×100 mm S5, Fraction Collection
  8. custom7.95-8.47 min. (UV detection at 220 nm)
  9. customB=100, Gradient time=2 min
  10. customtime=3 min, Flow Rate=5 ml/min, Column
  11. customB=100, Gradient time=15 min
  12. customtime=18 min, Flow Rate=1 ml/min, Column
  13. customB=100, Gradient time=15 min
  14. customtime=18 min, Flow Rate=1 ml/min, Column

Sources & evidence

ORD record
ord-6565a00d255742eea1f54cf67ffd9579
Source dataset
uspto-grants-2012_11
Patent number
US08309558B2

Reaction notes

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