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

HRID 1875010Notes

Reaction equation

HRID 1875010 reaction equation
[Cl:1][C:2]1[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[CH:5][NH:4][C:3]=1[C:12]([O:14]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.[NH2:51][CH2:52][C:53]1[C:54]([F:70])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:64]#[N:65])[C:56]([Cl:59])=[CH:57][CH:58]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.CN(C=O)C>[Cl:1][C:2]1[C:6]([C:7]([N:9]([CH3:10])[CH3:11])=[O:8])=[CH:5][NH:4][C:3]=1[C:12]([NH:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([C:64]#[N:65])[CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:54]=1[F:70])=[O:14]

Participants

10

Reactant 6

HCID 3939Lithium HydroxideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 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 68487372methyl 3-chloro-4-[(dimethylamino)carbonyl]-1H-pyrrole-2-carboxylate

Product 1

HCID 594516273-chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N4,N4-dimethyl-1H-pyrrole-2,4-dicarboxamideYield 6.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
35 °C

Procedure

To a solution of methyl 3-chloro-4-[(dimethylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.038 g, 0.165 mmol) in THF (3 mL) and water (1 mL) was added lithium hydroxide (0.039 g, 1.648 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 (0.075 g, 0.198 mmol), DIPEA (0.043 ml, 0.247 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.051 g, 0.165 mmol). The solution was stirred for 2 h at RT. Purication 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,N4-dimethyl-1H-pyrrole-2,4-dicarboxamide (0.0053 g, 6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.16 (br. s., 1H) 8.13 (t, 1H) 7.83 (d, 1H) 7.46-7.54 (m, 3 H) 7.38 (t, 1H) 7.16 (d, 1H) 4.56 (d, 2H) 2.95 (s, 6H). MS: m/z 509.1 (M+1).

Workup

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

Sources & evidence

ORD record
ord-2822aa913f7e4147bcf5196b3075ac18
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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