Diisopropylethylamine → 2-(4-fluorophenyl)-N-methyl-5-(3-((1-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl)carbamoyl)phenyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamide

HRID 1854750Notes

Reaction equation

HRID 1854750 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:31][C:11]3=[N:12][C:13]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:14]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[CH:15]=[C:10]3[C:9]=2[C:32](=[O:35])[NH:33][CH3:34])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:46][C:47]1[N:51]=[C:50]([C:52]2([NH2:55])[CH2:54][CH2:53]2)[O:49][N:48]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:31][C:11]3=[N:12][C:13]([NH:25][CH2:26][C:27]([F:28])([F:29])[F:30])=[C:14]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH:55][C:52]5([C:50]6[O:49][N:48]=[C:47]([CH3:46])[N:51]=6)[CH2:54][CH2:53]5)[CH:17]=4)[CH:15]=[C:10]3[C:9]=2[C:32]([NH:33][CH3:34])=[O:35])=[CH:6][CH:7]=1

Participants

6

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 569656561-(3-Methyl-1,2,4-oxadiazol-5-yl)cyclopropanamine hydrochlorideHCID 904025453-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid

Product 1

HCID 854733492-(4-fluorophenyl)-N-methyl-5-(3-((1-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropyl)carbamoyl)phenyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (40 mg, 0.082 mmol) was taken up in DMF (1 ml) and treated with N-ethyl-N-isopropylpropan-2-amine (43 μl, 0.25 mmol), 1-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropanamine hydrochloride (17 mg, 0.098 mmol) followed by 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (47 mg, 0.12 mmol). The reaction was allowed to stir for 1 h. Then the reaction was quenched with MeOH (1 mL) and the crude mixture was purified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column:Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 20-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.4 mg, and its estimated purity by LCMS analysis was 98%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min. retention time: 2.87 min; M+H: 609. Injection 2 conditions: Column:Waters BEH C18, 2.0×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min. retention time: 3.84 min; M+H: 609. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.42-8.32 (m, 1H), 7.98-7.92 (m, 4H), 7.69-7.61 (m, 3H), 7.34 (t, J=8.9 Hz, 2H), 6.61 (t, J=6.3 Hz, 1H), 4.21-4.14 (m, 2H), 2.79 (d, J=4.6 Hz, 3H), 2.26 (s, 3H), 1.67-1.63 (m, 2H), 1.52-1.47 (m, 2H).

Workup

  1. customThen the reaction was quenched with MeOH (1 mL)
  2. customthe crude mixture was purified via preparative LC/MS with the following conditions
  3. waitGradient: 20-100% B over 20 minutes
  4. customa 5-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation
  7. custom40° C.
  8. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
  9. customa 0.5-minute hold
  10. custom40° C.
  11. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
  12. customa 0.5-minute hold

Sources & evidence

ORD record
ord-995ef53ba4f24b53888db7b68d66c8e4
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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