4-Methylmorpholine → N-Benzyl-L-alaninamide

HRID 568114Notes

Reaction equation

HRID 568114 reaction equation
C(N[C@H](C(O)=O)C([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C(O)=O)(OC(C)(C)C)=O.O.OC1[C:34]2[N:33]=N[NH:31][C:30]=2[CH:29]=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CC[O:54]CC1>C(OCC)(=O)C.CN(C)C=O>[C:15]1([CH2:14][NH:33][C:34](=[O:54])[C@H:30]([CH3:29])[NH2:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1

Participants

7

Reactant 4

HCID 79724-Methylmorpholine2×HCID 10868DicyclohexylcarbodiimideHCID 14032956HCID 14032956, compoundHCID 178526939HCID 178526939, compound

Product 1

HCID 10442257N-Benzyl-L-alaninamide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

To a mechanically-stirred, 18° C. solution of 37.5 g (116 mmole) of BOC-β-benzyl-(L)-aspartic acid in 270 mL ethyl acetate is added a solution of 17.75 g (116 mmole) of hydroxybenzotriazole hydrate in 25 mL of dimethylformamide. A solution of 24.5 g (119 mmole) of dicyclohexylcarbodiimide in 50 mL of ethyl acetate is then added over 30 minutes, using a water bath to keep the reaction temperature at or below 25° C. The reaction mixture is stirred for 1 hour, then a syrup of 33 g (116 mmole) of 3-cyclohexyl-(L)-alanineamide ester mono (trifluoroacetate) in 25 mL of dimethylformamide is added at 23° C., followed by dropwise addition of neat N-methylmorpholine over 2 minutes. The reaction mixture is allowed to warm to 30° C. during the N-methylmorpholine addition. The reaction mixture is stirred at ambient temperature overnight. The reaction mixture is filtered to remove dicyclohexyl urea, and the filtrate is diluted with ethyl acetate, washed twice with water, once with brine, twice saturated aqueous sodium bicarbonate, and once with 1:1 0.5N citric acid/brine. The organic phase is dried with magnesium sulfate, filtered, and diluted with heptane. The mixture is allowed to stand overnight, and the resulting crystals are collected by filtration, washed twice with heptane, and dried under vacuum to give a first crop of 37.5 g and a second crop of 9.5 g. Both crops show acceptable HPLC purity and are physically combined to afford 47 g of N-[(1,1-dimethylethoxy)carbonyl]-(L)-α-aspartyl-3-cyclohexyl-(L-alanineamide phenylmethyl ester (85 yield). MS (FAB) m/7 476 (M+H)+.

Workup

  1. custombelow 25° C
  2. stirringThe reaction mixture is stirred at ambient temperature overnight
  3. filtrationThe reaction mixture is filtered
  4. customto remove dicyclohexyl urea
  5. additionthe filtrate is diluted with ethyl acetate
  6. washwashed twice with water, once with brine, twice saturated aqueous sodium bicarbonate
  7. dry with materialThe organic phase is dried with magnesium sulfate
  8. filtrationfiltered
  9. additiondiluted with heptane
  10. waitto stand overnight
  11. filtrationthe resulting crystals are collected by filtration
  12. washwashed twice with heptane
  13. customdried under vacuum
  14. customto give a first crop of 37.5 g

Sources & evidence

ORD record
ord-9ec97a530968459fa259c3cf87c48c76
Source dataset
uspto-grants-2001_01
Patent number
US06180759B2

Reaction notes

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