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

HRID 1874977Notes

Reaction equation

HRID 1874977 reaction equation
[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])[NH:4][C:3]=1[C:17]([O:19]C)=O.[OH-].[K+].[Li+].[OH-].[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.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>C1COCC1.CN(C=O)C.CO>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:8])[NH:4][C:3]=1[C:17]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:19]

Participants

10

Reactant 6

HCID 3939Lithium HydroxideHCID 14797Potassium 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 68480534Methyl 3-chloro-5-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)-1H-pyrrole-2-carboxylate

Product 1

HCID 594515473-Chloro-N2-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-N5-[2-(1-pyrrolidinyl)ethyl]-1H-pyrrole-2,5-dicarboxamideYield 9%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

Methyl 3-chloro-5-({[2-(1-pyrrolidinyl)ethyl]amino}carbonyl)-1H-pyrrole-2-carboxylate (0.080 g, 0.268 mmol) was dissolved in THF and MeOH (2 mL of each). Potassium hydroxide (2 mL, 1 N) was added to the solution and heated to 60° C. After stirring overnight no reaction was observed. LiOH (2 mL, 1 N) was added and the reaction stirred at 60° C. overnight. The reaction mixture was evaporated to a solid and partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to a solid. The solid was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.031 mL, 0.241 mmol) in DMF (2 mL). HATU (0.092 g, 0.241 mmol) was added to the mixture and the reaction stirred for 2 hours. The reaction mixture was partitioned between EtOAc and water and the layers separated. The organic layer was washed with 15% Na2CO3, dried over MgSO4 and evaporated. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.008 g, 9%) as a solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 7.81-7.95 (m, 2H), 7.64 (t, 1H), 7.45-7.52 (m, 1H), 7.41-7.45 (m, 1H), 7.39 (d, 2H), 6.77 (s, 1H), 4.72 (d, 2H), 3.51 (q, 2H), 2.72-2.78 (m, 2H), 2.59-2.69 (m, 4H), 1.71-1.80 (m, 4H). LCMS: m/z 577.9 (M+1).

Workup

  1. stirringthe reaction stirred at 60° C. overnight
  2. customThe reaction mixture was evaporated to a solid
  3. custompartitioned between EtOAc and 1 N HCl
  4. customThe organic layer was separated
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated to a solid
  8. stirringthe reaction stirred for 2 hours
  9. customThe reaction mixture was partitioned between EtOAc and water
  10. customthe layers separated
  11. washThe organic layer was washed with 15% Na2CO3
  12. dry with materialdried over MgSO4
  13. customevaporated
  14. customPurification

Sources & evidence

ORD record
ord-78d028c5c127413fb60e5a2b83116c06
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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