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

HRID 1854740Notes

Reaction equation

HRID 1854740 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]([CH2:51][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[CH2:51][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 904023045-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)-2-methoxybenzoic acid

Product 1

HCID 854732155-(3-((2-(1,2,4-oxadiazol-3-yl)propan-2-yl)carbamoyl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)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) (33 mg, 0.087 mmol) was added to stirring solution of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)-2-methoxybenzoic acid (30 mg, 0.058 mmol), N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.17 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (14 mg, 0.087 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: 25-100% 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 material was further 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 methanol:water with 20-mM ammonium acetate; Gradient: 0-100% 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 10.7 mg, and its estimated purity by LCMS analysis was 97%. 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: 3.12 min; M+H: 626. 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: 4.00 min; M+H: 626. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.67 (s, 1H), 8.53-8.46 (m, 1H), 8.08-8.01 (m, 2H), 7.88 (s, 1H), 7.72 (s, 1H), 7.62-7.57 (m, 1H), 7.40 (s, 2H), 7.35-7.29 (m, 1H), 4.03 (s, 3H), 3.04-2.96 (m, 2H), 2.83-2.69 (m, 5H), 1.72 (s, 6H).

Workup

  1. customThe crude reaction mixture
  2. customwas then purified via preparative LC/MS with the following conditions
  3. waitGradient: 25-100% B over 20 minutes
  4. customa 5-minute hold
  5. additionFractions containing the desired product
  6. customdried via centrifugal evaporation
  7. customThe material was further purified via preparative LC/MS with the following conditions
  8. waitGradient: 0-100% B over 20 minutes
  9. customa 5-minute hold
  10. additionFractions containing the desired product
  11. customdried via centrifugal evaporation
  12. custom40° C.
  13. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
  14. customa 0.5-minute hold
  15. custom40° C.
  16. waitGradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes
  17. customa 0.5-minute hold

Sources & evidence

ORD record
ord-12df89c44b774f30bfeea9bf6d0446c2
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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