Hydrochloric Acid → (S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-carbamic acid tert-butyl ester

HRID 990363Notes

Reaction equation

HRID 990363 reaction equation
[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].Cl>CC(O)=O.CO>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][N:27]1[CH2:26][CH2:25][N:24]([CH:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=2)[CH2:29][CH2:28]1)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 104275tert-butyl N-[(2S)-4-methyl-1-oxopentan-2-yl]carbamateHCID 1529321-(Bis(4-fluorophenyl)methyl)piperazineHCID 5003444Sodium cyanoborohydride

Product 1

HCID 53854298(S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)-carbamic acid tert-butyl esterYield 41.3%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent2×

Procedure

(S)-(1-Formyl-3-methyl-butyl)-carbamic acid tert-butyl ester (0.39 mg, 1.8 mmol) and 1-bis(4-fluorophenyl)methyl piperazine (0.50 g, 1.7 mmol) were dissolved in 1% HOAc in methanol (8 mL) under nitrogen atmosphere at ambient temperature. After stirring at that temperature for 1 hour, a solution of sodium cyanoborohydride (250 mg, 3.6 mmol) in methanol was added. The resulting reaction mixture was stirred at ambient temperature for 24 hours at which time TLC showed no starting aldehyde. 3N aqueous HCl was added in 5 mL portions until bubbling subsided; pH was adjusted to 8 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (3×25 mL), the combined organic solution was washed with brine (50 mL) and dried over MgSO4. The solution was concentrated in vacuo affording an amber oil. The crude product was further purified by flash chromatography (20%-30% EtOAc in hexanes) affording 342 mg (41%) of the pure titled compound as a clear oil. APCI-MS m/z 488.3 (MH+).

Workup

  1. customThe resulting reaction mixture
  2. stirringwas stirred at ambient temperature for 24 hours at which time TLC
  3. customuntil bubbling
  4. extractionThe resulting mixture was extracted with EtOAc (3×25 mL)
  5. washthe combined organic solution was washed with brine (50 mL)
  6. dry with materialdried over MgSO4
  7. concentrationThe solution was concentrated in vacuo
  8. customaffording an amber oil
  9. customThe crude product was further purified by flash chromatography (20%-30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-a8e98da608d4448a86e07d08ed96f24a
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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