4-Methylmorpholine → N-[(1,1-Dimethylethoxy)carbonyl]-L-alanyl-L-proline phenylmethyl ester

HRID 1388745Notes

Reaction equation

HRID 1388745 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH:30]1[CH2:44][CH2:43][CH2:42][C@H:31]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:30]1[CH2:44][CH2:43][CH2:42][C@H:31]1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 85082Tert-butoxycarbonylalanineHCID 2733413Proline benzyl ester hydrochloride

Product 1

HCID 13068139N-[(1,1-Dimethylethoxy)carbonyl]-L-alanyl-L-proline phenylmethyl esterYield 88.6%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of t-butoxycarbonyl-L-alanine (2.48 g., 13.1 mmole) in 23 ml. of dry chloroform at -15° (ice-salt bath) is treated with N-methylmorpholine (1.47 ml., 13.1 mmole) followed by isobutyl chloroformate (1.8 ml., 13.1 mmole) to give a precipitate. After 15 minutes, L-proline, phenylmethyl ester, hydrochloride salt (3.18 g., 13.1 mmole) and N-methylmorpholine (1.47 ml., 13.1 mmole) are added. Gas evolution ensues and the mixture is kept below -10° for one hour, then allowed to warm to room temperature, and stirred overnight under argon. The mixture is diluted with ethyl acetate, filtered, and the filtrate evaporated to dryness. The residue is taken up in ethyl acetate and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, saturated sodium chloride, dried (Na2SO4) and evaporated. The residue is purified by flash chromatography on silica gel (210 g.) eluting with ethyl acetate/hexane (1:2) to give t-butoxycarbonyl-L-alanyl-L-proline, phenylmethyl ester (4.37 g.) as a colorless oil; Rf (ethyl acetate/hexane, 1:1) is 0.47.

Workup

  1. customto give a precipitate
  2. waitGas evolution ensues and the mixture is kept below -10° for one hour
  3. filtrationfiltered
  4. customthe filtrate evaporated to dryness
  5. washwashed successively with 5% potassium bisulfate, saturated sodium bicarbonate, saturated sodium chloride
  6. dry with materialdried (Na2SO4)
  7. customevaporated
  8. customThe residue is purified by flash chromatography on silica gel (210 g.)
  9. washeluting with ethyl acetate/hexane (1:2)

Sources & evidence

ORD record
ord-036696f32901491890e9cc846b5bfdb0
Source dataset
uspto-grants-1984_02
Patent number
US04432971

Reaction notes

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