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

HRID 1854747Notes

Reaction equation

HRID 1854747 reaction equation
CN([C:4]([O:8][N:9]1N=[N:16][C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=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:55][C:35]3=[N:36][C:37]([NH:49][CH2:50][C:51]([F:54])([F:53])[F:52])=[C:38]([C:40]4[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=4)[C:43]([OH:45])=O)[CH:39]=[C:34]3[C:33]=2[C:56](=[O:59])[NH:57][CH3:58])=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C.Cl.O1C=NC(C2(N)CCC2)=N1>CN(C=O)C>[O:8]1[CH:4]=[N:15][C:10]([C:11]2([NH:16][C:43]([C:42]3[CH:41]=[C:40]([C:38]4[CH:39]=[C:34]5[C:33]([C:56]([NH:57][CH3:58])=[O:59])=[C:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[O:55][C:35]5=[N:36][C:37]=4[NH:49][CH2:50][C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][CH:46]=3)=[O:45])[CH2:12][CH2:13][CH2:14]2)=[N:9]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 904023871-(1,2,4-Oxadiazol-3-yl)cyclobutan-1-amine 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 854732175-(3-((1-(1,2,4-oxadiazol-3-yl)cyclobutyl)carbamoyl)phenyl)-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) (29 mg, 0.077 mmol) was added to stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (25 mg, 0.051 mmol), N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.15 mmol) and 1-(1,2,4-oxadiazol-3-yl)cyclobutanamine hydrochloride (14 mg, 0.077 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt. for 30 min. The crude material was 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: 40-80% 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 4.0 mg, and its estimated purity by LCMS analysis was 100%. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column:Waters Acquity UPLC BEH C18, 2.1×50 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: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min. retention time: 2.95 min; M+H: 609. Injection 2 conditions: Column:Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min. retention time: 3.02 min; M+H: 609. Proton NMR was acquired in deuterated DMSO. 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.31 (s, 1H), 8.42-8.32 (m, 1H), 8.01-7.90 (m, 4H), 7.69 (s, 1H), 7.66-7.55 (m, 2H), 7.39-7.29 (m, 2H), 6.65-6.59 (m, 1H), 4.23-4.11 (m, 2H), 2.79 (d, J=4.3 Hz, 3H), 2.68-2.55 (m, 4H), 2.10-2.00 (m, 2H).

Workup

  1. customThe crude material was purified via preparative LC/MS with the following conditions
  2. waitGradient: 40-80% B over 20 minutes
  3. customa 5-minute hold
  4. additionFractions containing the desired product
  5. customdried via centrifugal evaporation
  6. custom50° C.
  7. waitGradient: 0-100% B over 3 minutes
  8. customa 0.75-minute hold
  9. custom50° C.
  10. waitGradient: 0-100% B over 3 minutes
  11. customa 0.75-minute hold

Sources & evidence

ORD record
ord-1f33966bf71949f7bc1d8e5f1c8d8bfc
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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