Trifluoroacetic acid → 2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide

HRID 44103Notes

Reaction equation

HRID 44103 reaction equation
C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:37][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=4[CH3:36])[C:26]([O:28]C(C)(C)C)=O)[CH:22]=[C:17]3[C:16]=2[C:38](=[O:41])[NH:39][CH3:40])=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C.Cl.[N:52]1[CH:57]=[CH:56][CH:55]=[N:54][C:53]=1[C:58]1([NH2:61])[CH2:60][CH2:59]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:37][C:18]3=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]([C:26](=[O:28])[NH:61][C:58]5([C:53]6[N:54]=[CH:55][CH:56]=[CH:57][N:52]=6)[CH2:60][CH2:59]5)[CH:33]=[CH:34][C:35]=4[CH3:36])[CH:22]=[C:17]3[C:16]=2[C:38]([NH:39][CH3:40])=[O:41])=[CH:11][CH:10]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 569656581-(Pyrimidin-2-yl)cyclopropan-1-amine hydrochlorideHCID 67217768Tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate

Product 1

HCID 594114212-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamideYield 61.1%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

TFA (544 μL, 7.06 mmol) was added to a stirring solution of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (65 mg, 0.141 mmol) in DCE (1.4 mL) at rt. It was allowed to stir for 2 hours then concentrated. The white solid was taken up in DMF (1.5 mL) and treated with DIEA (123 μL, 0.706 mmol), 1-(pyrimidin-2-yl)cyclopropanamine hydrochloride (29.1 mg, 0.169 mmol) followed by HATU (81 mg, 0.212 mmol) at rt. The reaction was allowed to stir for 1 hour and then was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide (45 mg, 0.086 mmol, 61.1% yield) consistent by LCMS and NMR. 1H NMR (300 MHz, DMSO-d6) d ppm 9.19 (1H, s), 8.66 (2H, d, J=4.76 Hz), 8.45-8.57 (1H, m), 8.40 (1H, d, J=1.83 Hz), 8.10 (1H, d, J=1.83 Hz), 8.00-8.08 (2H, m), 7.85-7.94 (2H, m), 7.35-7.50 (3H, m), 7.26 (1H, t, J=4.76 Hz), 2.83 (3H, d, J=4.39 Hz), 2.31 (3H, s), 1.55-1.67 (2H, m), 1.27-1.39 (2H, m). LC-MS retention time: 1.75 min; m/z (MH'): 522. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 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 5 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 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Workup

  1. concentrationthen concentrated
  2. stirringto stir for 1 hour
  3. customwas purified by preparative reverse phase HPLC on a C18 column
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-a54f3490026d4fa3a8569fd0c6d60a1e
Source dataset
uspto-grants-2013_09
Patent number
US08536338B2

Reaction notes

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