4-Methylmorpholine → Boc-Val-Asp(OAllyl)-OBzl

HRID 413997Notes

Reaction equation

HRID 413997 reaction equation
[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[OH2:16].O[C:18]1[C:26]2N=NN[C:22]=2[CH:21]=[CH:20][CH:19]=1.C1(N=C=N[CH:36]2[CH2:41][CH2:40]CCC2)CCCCC1.C[N:43]1[CH2:48][CH2:47][O:46][CH2:45]C1.[C:49]([O:52]CC)(=[O:51])[CH3:50]>CN(C)C=O>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:43][C@H:48]([C:47]([O:46][CH2:45][C:18]1[CH:26]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[CH2:50][C:49](=[O:51])[O:52][CH2:40][CH:41]=[CH2:36])=[O:8])[CH:3]([CH3:4])[CH3:5]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 8857Ethyl Acetate2×HCID 10868DicyclohexylcarbodiimideHCID 83693Boc-L-ValineHCID 178526939HCID 178526939, compound

Product 1

HCID 131723903Boc-Val-Asp(OAllyl)-OBzl

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
5 °C

Procedure

To a solution of Boc-Val-OH (25.4 g, 116.7 mmol) in ethyl acetate (85 mL) is added hydroxybenzotriazole hydrate (16.55 g, 122.5 mmol) in dimethylformamide (122.3 mL). The mixture is cooled to 5° C. and a solution of dicyclohexylcarbodiimide (25.2 g, 122.5 mmol) in ethyl acetate (58.7 mL) is added over 1 hour during which time the temperature rises to about 18° C. and dicyclohexyl urea precipitates. Cooling is ceased and the mixture is stirred for 2 hours and a solution of HCl.H2N-Asp(OAllyl)-OBzl (35 g, 116.7 mmol) in 189 mL of dimethylformamide is added over 25 minutes. N-methylmorpholine (12.8 mL) is added slowly and over 0.5 hours to attain a reaction mixture pH of 7 and the mixture is stirred at ambient temperature for 36 hours. The reaction mixture is filtered to remove dicyclohexyl urea, the filtrate is diluted with methyl-t-butyl ether, stirred for 2 hours, then refiltered. The filtrate is washed with 100 mL water, 100 mL 0.5M aqueous citric acid, 100 mL water, 100 mL saturated aqueous, sodium bicarbonate, 100 mL brine, dried (magnesium sulfate), filtered, and concentrated to give 41.3 g of Boc-Val-Asp(OAllyl)-OBzl as an oil. (Mcalc 462; M+1obsvd 463).

Workup

  1. customrises to about 18° C.
  2. customdicyclohexyl urea precipitates
  3. temperatureCooling
  4. stirringthe mixture is stirred at ambient temperature for 36 hours
  5. filtrationThe reaction mixture is filtered
  6. customto remove dicyclohexyl urea
  7. additionthe filtrate is diluted with methyl-t-butyl ether
  8. stirringstirred for 2 hours
  9. washThe filtrate is washed with 100 mL water, 100 mL 0.5M aqueous citric acid, 100 mL water, 100 mL saturated aqueous
  10. dry with materialsodium bicarbonate, 100 mL brine, dried (magnesium sulfate)
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-66a0667433f44556aa97120d5060f43e
Source dataset
uspto-grants-2003_05
Patent number
US06569993B1

Reaction notes

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