Lithium Hydroxide → 4-(1-{[2-Oxo-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indole-7-carbonyl]-amino}-cyclopropyl)-benzoic acid

HRID 1951653Notes

Reaction equation

HRID 1951653 reaction equation
[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([C:11]([OH:13])=O)[CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.C[O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][C:31]([CH:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1.Cl.[CH2:39](N=C=NCCCN(C)C)C.CN1CCOCC1.[Li+].[OH-]>CN(C=O)C.C1COCC1.CO>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([C:11]([NH:36][C:34]3([C:31]4[CH:32]=[CH:33][C:28]([C:27]([OH:26])=[O:37])=[CH:29][CH:30]=4)[CH2:39][CH2:35]3)=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=1

Participants

9

Reactant 5

HCID 3939Lithium HydroxideHCID 79724-MethylmorpholineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 20134240Methyl 4-(1-aminoethyl)benzoateHCID 582977002-Oxo-1-(4-trifluoromethyl-benzyl)-2,3-dihydro-1H-indole-7-carboxylic acid

Product 1

HCID 582976764-(1-{[2-Oxo-1-(4-trifluoromethylbenzyl)-2,3-dihydro-1H-indole-7-carbonyl]-amino}-cyclopropyl)-benzoic acidYield 42.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 0.40 g of 2-oxo-1-(4-trifluoromethyl-benzyl)-2,3-dihydro-1H-indole-7-carboxylic acid, 0.29 g of (±)4-(1-amino-ethyl)-benzoic acid methyl ester, 0.19 g of HOBT-hydrate, 0.30 g of ethyl-dimethylaminopropyl-carbodiimide hydrochloride (EDC1) and 0.150 ml of N-methylmorpholine in 7 ml of DMF was stirred at room temperature for 16 h. The reaction was then quenched with 10 ml of water and 5 ml of sat. NaHCO3 solution. The resulting mixture extracted with 25 ml of EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude methyl ester (0.3 g) which was dissolved in 5 ml THF, 5 mL MeOH and treated with 4 mL of 1N LiOH solution. After stirring at 50° C. for 12 h, the reaction mixture was concentrated under reduced pressure to remove THF and MeOH. The residue was diluted with 8 mL of water and treated with 1 mL of AcOH with vigorous stirring. After stirring for 2 h, the solid was collected by filtration and air-dried to give 0.25 g of the title compound as a white powder.

Workup

  1. customThe reaction was then quenched with 10 ml of water and 5 ml of sat. NaHCO3 solution
  2. extractionThe resulting mixture extracted with 25 ml of EtOAc
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give the crude methyl ester (0.3 g) which
  7. stirringAfter stirring at 50° C. for 12 h
  8. concentrationthe reaction mixture was concentrated under reduced pressure
  9. customto remove THF and MeOH
  10. additionThe residue was diluted with 8 mL of water
  11. additiontreated with 1 mL of AcOH with vigorous stirring
  12. stirringAfter stirring for 2 h
  13. filtrationthe solid was collected by filtration
  14. customair-dried

Sources & evidence

ORD record
ord-1c79f4f10c994344b4aca2e4c0d471ae
Source dataset
uspto-grants-2013_03
Patent number
US08404736B2

Reaction notes

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