Cyclohexanecarboxaldehyde → (S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-[cyclohexyl-methyl-(3-methyl-butyl)-amino]-propionamide monohydrochloride

HRID 568089Notes

Reaction equation

HRID 568089 reaction equation
[ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([NH:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:31]1([CH:37]=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([N:25]([CH2:37][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

Participants

6

Reactant 4

HCID 16275CyclohexanecarboxaldehydeHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 70094314(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-(3-methyl-butylamino)-propionamide monohydrochloride

Product 1

HCID 70222538(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-[cyclohexyl-methyl-(3-methyl-butyl)-amino]-propionamide monohydrochlorideYield 58%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-3-(4-Benzyloxy-phenyl)-N-tert-butyl-2-(3-methyl-butylamino)-propionamide mono-hydrochloride (1.0 g, 2.3 mmol, Example 2) and cyclohexanecaboxaldehyde (0.28 g, 2.3 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (25 mL). After stirring at ambient temperature under a nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.73 g, 3.4 mmol). The resulting reaction mixture was stirred for 30 minutes at 0° C., followed by an additional 12 hours at ambient temperature. Saturated aqueous NaHCO3 solution (25 mL) 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 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (20% EtOAc in hexanes). The free amine was dissolved in 10 mL of ethyl ether and treated with ethereal HCl to afford 0.70 g (58%) of the pure titled compound as a white foam; mp 70-81° C.

Workup

  1. temperaturethe solution was cooled to 0° C. in an ice-water bath
  2. customThe resulting reaction mixture
  3. stirringwas stirred for 30 minutes at 0° C.
  4. waitfollowed by an additional 12 hours at ambient temperature
  5. stirringthe resulting mixture was stirred for 5 minutes
  6. customThe two layers were separated
  7. extractionthe aqueous layer was extracted with CH2Cl2 (2×30 mL)
  8. dry with materialThe combined organic solution was dried over Na2SO4
  9. concentrationThe solution was concentrated in vacuo
  10. customaffording a viscous oil
  11. customThe crude product was further purified by flash chromatography (20% EtOAc in hexanes)
  12. dissolutionThe free amine was dissolved in 10 mL of ethyl ether
  13. additiontreated with ethereal HCl

Sources & evidence

ORD record
ord-5fb28ef0494141b58875fd1ab33da943
Source dataset
uspto-grants-2001_01
Patent number
US06180677B2

Reaction notes

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