1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → Ethyl trans(+/-)-2-[(5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindol-2-yl)carbonyl]cyclopropanecarboxylate

HRID 43564Notes

Reaction equation

HRID 43564 reaction equation
[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21](OC(C)(C)C)=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[CH2:35]([O:37][C:38]([C@@H:40]1[CH2:42][C@H:41]1C(O)=O)=[O:39])[CH3:36].CCN=C=NCCCN(C)C>ClCCl.CO.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]([C@@H:41]2[CH2:42][C@H:40]2[C:38]([O:37][CH2:35][CH3:36])=[O:39])=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]

Participants

8

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 11535603(1R,2R)-2-(ethoxycarbonyl)cyclopropane-1-carboxylic acidHCID 21866389Hydrogen chloride-ethyl acetateHCID 67549798tert-Butyl 5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindole-2-carboxylate

Product 1

HCID 68416710Ethyl trans(+/-)-2-[(5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindol-2-yl)carbonyl]cyclopropanecarboxylateYield 65%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

tert-Butyl 5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindole-2-carboxylate (described in Example (92a), 0.17 g, 0.42 mmol) was dissolved in dichloromethane (3 mL) and methanol (1 mL). A 4 N hydrochloric acid/ethyl acetate solution (15 ml, 60 mmol) was added, followed by stirring for 20 minutes. The solvent was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (5 mL) and DMA (5 mL). trans-2-(Ethoxycarbonyl)cyclopropanecarboxylic acid (described in Wessjohann, Ludger A.; Fulhorst, Michael; Zakharova, Svetlana, Pol. J. Chem., 80, 4, 2006, 673-678, 87 mg, 0.55 mmol), WSC (191 mg, 1 mmol) and DMAP (10 mg) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10) to obtain 117 mg of the title compound as a light brown solid (65%).

Workup

  1. customThe solvent was evaporated under reduced pressure
  2. dissolutionThe resulting residue was dissolved in dichloromethane (5 mL)
  3. stirringthe mixture was stirred at room temperature for one hour
  4. concentrationThe reaction solution was concentrated
  5. additiondiluted with ethyl acetate
  6. washwashed with water and brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. concentrationconcentration under reduced pressure
  9. customthe residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=95/5, 90/10)

Sources & evidence

ORD record
ord-1bd74a415a924493a0b015650a7b719c
Source dataset
uspto-grants-2013_09
Patent number
US08536197B2

Reaction notes

Loading…