Diisopropylethylamine → 2-(4-Fluorophenyl)-6-(n-(2-hydroxyethyl)methylsulfonamido)-n-methyl-5-(3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

HRID 1688212Notes

Reaction equation

HRID 1688212 reaction equation
Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[O:54][C:55]3[CH:65]=[C:64]([N:66]([CH2:71][CH2:72][OH:73])[S:67]([CH3:70])(=[O:69])=[O:68])[C:63]([C:74]4[CH:75]=[C:76]([CH:80]=[CH:81][CH:82]=4)[C:77](O)=[O:78])=[CH:62][C:56]=3[C:57]=2[C:58](=[O:61])[NH:59][CH3:60])=[CH:49][CH:48]=1>CN(C=O)C.CCOC(C)=O>[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[O:54][C:55]3[CH:65]=[C:64]([N:66]([CH2:71][CH2:72][OH:73])[S:67]([CH3:70])(=[O:69])=[O:68])[C:63]([C:74]4[CH:82]=[CH:81][CH:80]=[C:76]([C:77](=[O:78])[NH:12][C:9]5([C:4]6[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=6)[CH2:11][CH2:10]5)[CH:75]=4)=[CH:62][C:56]=3[C:57]=2[C:58]([NH:59][CH3:60])=[O:61])=[CH:49][CH:48]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 533931811-(2-Pyridyl)cyclopropylamine DihydrochlorideHCID 59275652HCID 59275652, compound

Product 1

HCID 592755842-(4-Fluorophenyl)-6-(n-(2-hydroxyethyl)methylsulfonamido)-n-methyl-5-(3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamideYield 32.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

1-(pyridin-2-yl)cyclopropanamine dihydrochloride (24 mg, 0.114 mmol) was added to a stirring solution of HATU (54 mg, 0.142 mmol), DIEA (50 μL, 0.285 mmol), and 3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (50 mg, 0.095 mmol) in DMF (950 μL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (20 mg, 32%). 1H NMR (500 MHz, DMSO-d6) d ppm 9.20 (1H, s), 8.49-8.57 (1H, m), 8.45 (1H, d, J=3.97 Hz), 7.97-8.05 (3H, m), 7.96 (1H, s), 7.94 (1H, d, J=7.93 Hz), 7.80 (1H, d, J=7.93 Hz), 7.64-7.69 (1H, m), 7.63 (1H, s), 7.56 (1H, t, J=7.63 Hz), 7.37-7.47 (3H, m), 7.15 (1H, dd, J=6.41, 4.88 Hz), 4.91 (1H, br. s.), 3.51-3.60 (1H, m), 3.22 (3H, s), 2.89-2.98 (3H, m), 2.81 (3H, d), 1.50-1.60 (2H, m), 1.23-1.33 (2H, m). LC-MS retention time: 1.37 min; m/z (MH+): 643. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-V is detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=7.17 min, purity=98%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=7.89 min, purity=99%.

Workup

  1. washwashed
  2. dry with materialThe organic phase was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customwas purified by preparative reverse phase HPLC on a C18 column
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-b33045d07f5445d797ab573fc1fce7cb
Source dataset
uspto-grants-2012_04
Patent number
US08148382B2

Reaction notes

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