Lithium Hydroxide → 3-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N4-(2-hydroxyethyl)-1H-pyrrole-2,4-dicarboxamide

HRID 1875014Notes

Reaction equation

HRID 1875014 reaction equation
[Cl:1][C:2]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])=[CH:5][NH:4][C:3]=1[C:13]([O:15]C)=O.[OH-].[Li+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][CH2:53][C:54]1[C:55]([F:71])=[C:56]([O:61][C:62]2[CH:63]=[C:64]([CH:67]=[C:68]([Cl:70])[CH:69]=2)[C:65]#[N:66])[C:57]([Cl:60])=[CH:58][CH:59]=1>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[C:6]([C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8])=[CH:5][NH:4][C:3]=1[C:13]([NH:52][CH2:53][C:54]1[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([O:61][C:62]2[CH:63]=[C:64]([C:65]#[N:66])[CH:67]=[C:68]([Cl:70])[CH:69]=2)[C:55]=1[F:71])=[O:15]

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 68487062methyl 3-chloro-4-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate

Product 1

HCID 594514363-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N4-(2-hydroxyethyl)-1H-pyrrole-2,4-dicarboxamideYield 38%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
35 °C

Procedure

To a solution of methyl 3-chloro-4-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.048 g, 0.195 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.047 g, 1.946 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), HATU (0.089 g, 0.234 mmol), DIPEA (0.051 ml, 0.292 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.061 g, 0.195 mmol). The solution was stirred for 4 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)-N4-(2-hydroxyethyl)-1H-pyrrole-2,4-dicarboxamide (0.039 g, 38% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.25 (br. s., 1H) 8.15 (t, 1H) 7.83 (d, 1H) 7.78 (t, 1H) 7.51-7.56 (m, 2H) 7.48 (dt, 2H) 7.37 (t, 1H) 4.57 (d, 2H) 3.46 (t, 2H) 3.25 (q, 2H). MS: m/z 525.0 (M+1).

Workup

  1. customThe solvent was evaporated
  2. stirringThe solution was stirred for 4 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-89d356e403dc47468b31bd9098daeb40
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

Loading…