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

HRID 1854760Notes

Reaction equation

HRID 1854760 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:57][C:35]3=[N:36][C:37]([NH:51][CH2:52][C:53]([F:56])([F:55])[F:54])=[C:38]([C:40]4[CH:41]=[CH:42][C:43]([O:49][CH3:50])=[C:44]([CH:48]=4)[C:45]([OH:47])=O)[CH:39]=[C:34]3[C:33]=2[C:58](=[O:61])[NH:59][CH3:60])=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.Cl.[O:72]1[CH:76]=[N:75][C:74]([C:77]([NH2:80])([CH3:79])[CH3:78])=[N:73]1>CN(C=O)C>[O:72]1[CH:76]=[N:75][C:74]([C:77]([NH:80][C:45]([C:44]2[CH:48]=[C:40]([C:38]3[CH:39]=[C:34]4[C:33]([C:58]([NH:59][CH3:60])=[O:61])=[C:32]([C:29]5[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=5)[O:57][C:35]4=[N:36][C:37]=3[NH:51][CH2:52][C:53]([F:55])([F:54])[F:56])[CH:41]=[CH:42][C:43]=2[O:49][CH3:50])=[O:47])([CH3:79])[CH3:78])=[N:73]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 866747552-(1,2,4-Oxadiazol-3-yl)propan-2-amine hydrochlorideHCID 904023155-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)-2-methoxybenzoic acid

Product 1

HCID 854714175-(3-((2-(1,2,4-oxadiazol-3-yl)propan-2-yl)carbamoyl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methyl-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (22 mg, 0.058 mmol) was added to stirring solution of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)-2-methoxybenzoic acid (20 mg, 0.039 mmol), N-ethyl-N-isopropylpropan-2-amine (0.020 mL, 0.12 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (10 mg, 0.058 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt for 30 min. The crude reaction mixture was then purified via preparative LC/MS with the following conditions: Column:Waters XBridge C18, 19×200 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 9.5 mg, and its estimated purity by LCMS analysis was 97%. Two analytical LC/MS injections were used todetermine 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: 3.02 min; M+H: 627. 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; MobilePhase 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: 3.85 min; M+H: 627. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.65 (s, 1H), 8.39-8.31 (m, 1H), 7.97 (dd, J=8.9, 5.5 Hz, 2H), 7.79-7.73 (m, 1H), 7.60 (s, 1H), 7.54 (dd, J=8.5, 2.1 Hz, 1H), 7.37-7.28 (m, 3H), 6.58-6.53 (m, 1H), 4.22-4.08 (m, 2H), 4.01 (s, 3H), 2.79 (d, J=4.6 Hz, 3H), 1.73 (s, 6H).

Workup

  1. customThe crude reaction mixture
  2. customwas then 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-edb820cbfc8047f8bbee78ead5c750d4
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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