4-tert-Butylbenzaldehyde → (S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride

HRID 990339Notes

Reaction equation

HRID 990339 reaction equation
[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([NH:20][CH3:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1.[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([N:20]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=2)[CH3:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=1

Participants

6

Reactant 4

HCID 703244-tert-ButylbenzaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 9823702(S)-4-methyl-2-(methylamino)pentanoic acid [4,4-bis(4-fluorophenyl)butyl]amide hydrochloride

Product 1

HCID 86758545(S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-4-Methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride (0.25 g, 0.58 mmol, Example 12) and 4-t-butylbenzaldehyde (94 mg, 0.58 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (10 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.18 g, 0.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Six milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified first by flash chromatography (25% EtOAc in hexanes), then by preparative plate (5% acetonitrile in chloroform). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 130 mg (42% over 2 steps) of the pure titled compound as a white foam: mp 87-95° C. APCI-MS m/z 535.0 (MH+).

Workup

  1. temperaturethe solution was cooled to 0° C. in an ice-water bath
  2. customThe resulting reaction mixture
  3. stirringwas stirred for, in succession, 30 minutes at 0° C.
  4. custom12 hours
  5. customat ambient temperature
  6. stirringthe resulting mixture was stirred for 5 minutes
  7. customThe two layers were separated
  8. extractionthe aqueous layer was extracted with CH2Cl2 (2×10 mL)
  9. dry with materialThe combined organic solution was dried over Na2SO4
  10. concentrationThe solution was concentrated in vacuo
  11. customaffording a viscous oil
  12. customThe crude product was purified first by flash chromatography (25% EtOAc in hexanes)
  13. dissolutionThe free amine was dissolved in 5 mL of ethyl ether
  14. additiontreated with ethereal HCl

Sources & evidence

ORD record
ord-490f865295bb41fa9cc96a0e391c7784
Source dataset
uspto-grants-2002_10
Patent number
US06458781B1

Reaction notes

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