Diisopropylethylamine → 3-Chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N5-(2-hydroxyethyl)-1H-pyrrole-2,5-dicarboxamide

HRID 1874966Notes

Reaction equation

HRID 1874966 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([OH:39])=O.[NH2:40][CH2:41][C:42]1[C:43]([F:59])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:53]#[N:54])[C:45]([Cl:48])=[CH:46][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH2:34][CH2:35][OH:36])=[O:32])[NH:28][C:27]=1[C:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([C:53]#[N:54])[CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:43]=1[F:59])=[O:39]

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 594513923-{[3-(Aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrileHCID 684835273-Chloro-5-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylic acid

Product 1

HCID 594515883-Chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N5-(2-hydroxyethyl)-1H-pyrrole-2,5-dicarboxamideYield 16.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

HATU (0.061 g, 0.161 mmol) was added to a DMF (2 mL) solution of 3-chloro-5-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylic acid (0.037 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.028 mL, 0.161 mmol). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. The residue was subjected to silica gel column chromatography (EtOAc/hexanes) to afford an impure solid. A second purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.014 g, 15%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.00 (br. s., 1H), 7.86 (d, 1H), 7.63 (s, 1H), 7.33-7.52 (m, 3H), 6.86 (d, 1H), 4.71 (d, 1H), 3.65 (t, 1H), 3.39-3.57 (m, 5H). LCMS: m/z 525.3 (M+1).

Workup

  1. customThe reaction mixture was partitioned between water and EtOAc
  2. washThe organic layer was washed with a 15% solution of Na2CO3
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. customevaporated
  6. customto afford an impure solid
  7. customA second purification

Sources & evidence

ORD record
ord-890f221afdf4443e93bc04ceaae4c5a4
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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