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

HRID 1854758Notes

Reaction equation

HRID 1854758 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: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](O)=[O:44])[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.[O:70]1[CH:74]=[N:73][C:72]([C:75]([NH2:78])([CH3:77])[CH3:76])=[N:71]1>CN(C=O)C>[O:70]1[CH:74]=[N:73][C:72]([C:75]([NH:78][C:43]([C:42]2[CH:41]=[C:40]([C:38]3[CH:39]=[C:34]4[C:33]([C:56]([NH:57][CH3:58])=[O:59])=[C:32]([C:29]5[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=5)[O:55][C:35]4=[N:36][C:37]=3[NH:49][CH2:50][C:51]([F:53])([F:52])[F:54])[CH:48]=[CH:47][CH:46]=2)=[O:44])([CH3:77])[CH3:76])=[N:71]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 904025453-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid

Product 1

HCID 854714155-(3-((2-(1,2,4-oxadiazol-3-yl)propan-2-yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamideYield 49%

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) (117 mg, 0.308 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 (100 mg, 0.205 mmol), N-ethyl-N-isopropylpropan-2-amine (0.11 mL, 0.62 mmol) and 2-(1,2,4-oxadiazol-3-yl)propan-2-amine hydrochloride (50 mg, 0.31 mmol) in DMF (1 mL) at rt. The mixture was allowed to stir at rt for 1 h. The reaction mixture was then purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 5-(3-((2-(1,2,4-oxadiazol-3-yl)propan-2-yl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridine-3-carboxamide (61 mg, 0.10 mmol, 49% yield)) consistent by LCMS and NMR. LC-MS retention time: 1.73 min; m/z (MH+): 597. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 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 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.70 (s, 1H), 8.40-8.32 (m, 1H), 8.01-7.94 (m, 2H), 7.93 (s, 1H), 7.90-7.85 (m, 1H), 7.69 (s, 1H), 7.64-7.57 (m, 2H), 7.38-7.31 (m, 2H), 6.63 (t, J=6.4 Hz, 1H), 4.26-4.12 (m, 2H), 2.80 (d, J=4.8 Hz, 3H), 1.70 (s, 6H).

Workup

  1. customThe reaction mixture was then purified by preparative reverse phase HPLC on a C18 column
  2. concentrationconcentrated

Sources & evidence

ORD record
ord-6a656d664ef74e898a9a01928b0bb620
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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