Triethylamine → Methyl-(2-{4-[(4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl)-amino]phenyl}ethyl)-carbamic acid isobutyl ester

HRID 1937735Notes

Reaction equation

HRID 1937735 reaction equation
[O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][N:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.CC[N:16]([CH2:19][CH3:20])[CH2:17]C.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>>[CH2:25]([O:24][C:22](=[O:23])[N:16]([CH3:17])[CH2:19][CH2:20][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][N:5]=2)=[O:13])=[CH:3][CH:2]=1)[CH:26]([CH3:28])[CH3:27]

Participants

4

Reactant 3

HCID 8471Triethylamine2×HCID 62365Isobutyl chloroformateHCID 114239274-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

Product 1

HCID 70162177Methyl-(2-{4-[(4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl)-amino]phenyl}ethyl)-carbamic acid isobutyl esterYield 54%

Procedure

A suspension of 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (200 mg, 1.1 mmol) in isobutyl chloroformate (10 mL) was treated with Et3N (0.46 mL, 3.3 mmol) portionwise at room temperature. After 30 min. further Et3N (0.46 mL, 3.3 mmol) was added and the mixture stirred for 30 min. The mixture was evaporated and residue suspended in 1,2-DCE (15 mL). The foregoing amine (0.37 g, 1.7 mmol) added and the solution was heated at reflux for 6 h. The solvent was evaporated, the residue suspended in EtOH (1.5 mL) and then treated with 4N NaOH (5 mL). The mixture was heated at reflux for 1 h. Water (50 mL) was added to the cooled mixture, the aqueous phase extracted with 10% MeOH/DCM (×3) and the combined organic layers dried (MgSO4) and evaporated. The residue was purified by silica plug chromatography, using MeOH:DCM (6:94) as eluent, to give title compound (250 mg, 54%) a cream solid. 1H NMR (400 MHz, CDCl3) δ0.94 (6H, d, J=6.4), 1.88-1.98 (2H, m), 2.19-2.27 (2H, m), 2.7 (2H, t, J=6.1 Hz), 2.77-2.92 (5H, m), 2.98 (2H, t, J=5.8 Hz), 3.40-3.51 (2H, m), 3.85 (2H, d, J=6.44 Hz), 7.18-7.26 (2H, m), 7.74 (2H, d, J=7.9 Hz), 11.30 (1H, br, s), 12.26 (1H, s). MS, (CI)+413 (M+H)+.

Workup

  1. customThe mixture was evaporated
  2. temperaturethe solution was heated
  3. temperatureat reflux for 6 h
  4. customThe solvent was evaporated
  5. additiontreated with 4N NaOH (5 mL)
  6. temperatureThe mixture was heated
  7. temperatureat reflux for 1 h
  8. additionWater (50 mL) was added to the cooled mixture
  9. extractionthe aqueous phase extracted with 10% MeOH/DCM (×3)
  10. dry with materialthe combined organic layers dried (MgSO4)
  11. customevaporated
  12. customThe residue was purified by silica plug chromatography

Sources & evidence

ORD record
ord-48483abd5667493bab94c0b3ecac7711
Source dataset
uspto-grants-2002_05
Patent number
US06395905B1

Reaction notes

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