Water → 1,1-Dimethylethyl 4-[2-amino-1-(2-fluorophenyl)ethyl]-1-piperazinecarboxylate

HRID 1376024Notes

Reaction equation

HRID 1376024 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:28]#[N:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Na+]>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH2:28][NH2:29])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]

Participants

6

Reactant 4

HCID 962Water2×HCID 14798Sodium HydroxideHCID 21226445Aluminium lithium hydrideHCID 58786566HCID 58786566, compound

Product 1

HCID 587864641,1-Dimethylethyl 4-[2-amino-1-(2-fluorophenyl)ethyl]-1-piperazinecarboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-40 °C

Procedure

1M LAH in THF (250 mL, 250 mmol) was cooled to −40° C. and 4-[Cyano-(2-fluoro-phenyl)-methyl]-piperazine-1-carboxylic acid tert-butyl ester (7) (20 g, 62.66 mmol) in THF (100 mL) was added slowly via addition funnel. The reaction mixture was allowed to stir for 2 h at −40° C. and then allowed to warm to 0° C. Reaction progress was monitored by H1 NMR. The reaction mixture was then cooled to −40° C. again and H2O (9.5 mL) was added. The reaction mixture was then diluted with THF (1 L) followed by the addition of 15% NaOH (9.5 mL) and H2O (28.5 mL). The solution was then allowed to warm to room temperature. The aluminum salts were removed by filtration and the filtrate was concentrated to dryness. The resulting residue was taken up in EtOAc (500 mL) and H2O (500 mL) and the aqueous layer was made acidic (pH=4) by cautious addition of a 25% aqueous solution of KHSO4. The aqueous phase was then made basic (pH=10) with SN NaOH and the product was extracted into EtOAc (500 ml) and concentrated to dryness. The starting material (nitrile) can be recovered by concentration of the original organic phase and purified by recrystallization from MeOH. The yield was 9.2 g (466) pure product.

Workup

  1. temperatureto warm to 0° C
  2. customReaction progress
  3. temperatureThe reaction mixture was then cooled to −40° C. again
  4. temperatureto warm to room temperature
  5. customThe aluminum salts were removed by filtration
  6. concentrationthe filtrate was concentrated to dryness
  7. additionby cautious addition of a 25% aqueous solution of KHSO4
  8. extractionthe product was extracted into EtOAc (500 ml)
  9. concentrationconcentrated to dryness
  10. customThe starting material (nitrile) can be recovered by concentration of the original organic phase
  11. custompurified by recrystallization from MeOH

Sources & evidence

ORD record
ord-659a2770ebbd432fae35fae37ea1f81c
Source dataset
uspto-grants-2007_01
Patent number
US07169777B2

Reaction notes

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