Lithium Hydroxide → 3-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-pyrrole-2,4-dicarboxamide

HRID 1875006Notes

Reaction equation

HRID 1875006 reaction equation
[NH2:1][C:2]([C:4]1[C:5]([Cl:13])=[C:6]([C:9]([O:11]C)=O)[NH:7][CH:8]=1)=[O:3].[OH-].[Li+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][CH2:50][C:51]1[C:52]([F:68])=[C:53]([O:58][C:59]2[CH:60]=[C:61]([CH:64]=[C:65]([Cl:67])[CH:66]=2)[C:62]#[N:63])[C:54]([Cl:57])=[CH:55][CH:56]=1>C1COCC1.O.CN(C=O)C>[Cl:13][C:5]1[C:4]([C:2]([NH2:1])=[O:3])=[CH:8][NH:7][C:6]=1[C:9]([NH:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([O:58][C:59]2[CH:60]=[C:61]([C:62]#[N:63])[CH:64]=[C:65]([Cl:67])[CH:66]=2)[C:52]=1[F:68])=[O:11]

Participants

9

Reactant 5

HCID 3939Lithium HydroxideHCID 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 68487265methyl 4-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylate

Product 1

HCID 594514093-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-pyrrole-2,4-dicarboxamideYield 21.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
35 °C

Procedure

To a solution of methyl 4-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylate (0.04 g, 0.197 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.047 g, 1.974 mmol). The reaction mixture was stirred overnight at 35° C. The solvent was evaporated and the resulting solid placed under high vacuum. To the intermediate mixture was added DMF (1 mL), DIPEA (0.052 ml, 0.296 mmol), HATU (0.090 g, 0.237 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.061 g, 0.197 mmol). The solution was stirred for 1 h at RT. Purification was accomplished by HPLC. The desired fractions were neutralized with saturated sodium bicarbonate, extracted with EtOAc (3×5 mL), the organic layers combined, dried over sodium sulfate, filtered and evaporated to afford 3-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-pyrrole-2,4-dicarboxamide (0.020 g, 21% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.18 (br. s., 1H) 8.15 (t, 1H) 7.83 (d, 1H) 7.46-7.56 (m, 4H) 7.37 (t, 1H) 7.30 (br. s., 1H) 7.05 (br. s., 1H) 4.57 (d, 2H). MS: m/z 481.0 (M+1).

Workup

  1. customThe solvent was evaporated
  2. stirringThe solution was stirred for 1 h at RT
  3. customPurification
  4. extractionextracted with EtOAc (3×5 mL)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated

Sources & evidence

ORD record
ord-888f1925d36b47efacdc9a076629025f
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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