tert-butyl N-[(2S)-4-methyl-1-oxopentan-2-yl]carbamate → (1-{[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester

HRID 278892Notes

Reaction equation

HRID 278892 reaction equation
Cl.[NH2:2][C@@H:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[NH:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:27]([CH:32]=O)[CH2:28][CH:29]([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:37]([O:36][C:34](=[O:35])[NH:26][CH:27]([CH2:32][NH:2][CH:3]([C:4](=[O:5])[NH:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH2:28][CH:29]([CH3:30])[CH3:31])([CH3:40])([CH3:39])[CH3:38]

Participants

6

Reactant 4

HCID 104275tert-butyl N-[(2S)-4-methyl-1-oxopentan-2-yl]carbamateHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 69584616(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride

Product 1

HCID 18711794(1-{[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl esterYield 12.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-2-Amino-3 -(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (1.68 g, 4.65 mmol, Example 7, Step A) and BOC-Leu-CHO ((tert-butoxy)-N-[1-(2-methylpropyl)-2-oxoethyl]carboxamide) (1.00 g, 4.65 mmol, Peninsula Laboratories, Belmont, Calif.) were mixed in CH2Cl2 (25 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 (1.50 g, 6.98 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty-five 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 (2×30 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The reaction gave two diastereomers which were purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile). When the solvent system, 30% EtOAc-66% benzene-4% MeOH, was used as eluant. The two diastereomers gave different Rf values on TLC (0.68 and 0.53). The compound with a Rf value of 0.68 was isolated by preparative plate as a yellow oil (0.3 g) and used in used step.

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 (2×30 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 reaction gave two diastereomers which
  13. customwere purified twice by column chromatography (eluant used in first column chromatography: 30% EtOAc-4% MeOH-66% hexanes; eluant used in second column chromatography: 100% acetonitrile)
  14. customThe two diastereomers gave different Rf values on TLC (0.68 and 0.53)

Sources & evidence

ORD record
ord-d444329183ef44dabd608a24a60d40b1
Source dataset
uspto-grants-2002_03
Patent number
US06362174B1

Reaction notes

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