Dicyclohexylcarbodiimide → Fmoc-NH-L-Leu-L-Ile-D-Phe-CH2OH

HRID 1442634Notes

Reaction equation

HRID 1442634 reaction equation
C([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH:37]1[C:49]2[CH:48]([CH2:50][O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>N1CCCCC1.CN(C=O)C>[C:52]([NH:54][C@H:55]([C:60]([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])([O:51][CH2:50][CH:48]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:49]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:53]

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 1549133Fmoc-leucineHCID 42632374Fmoc-NH-L-Ile-D-Phe-CH2OH

Product 1

HCID 131727876Fmoc-NH-L-Leu-L-Ile-D-Phe-CH2OHYield 48.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8082PiperidineSolvent

Conditions

Temperature
25 °C

Procedure

Dipeptide Fmoc-NH-L-Ile-D-Phe-CH2OH (1a) (520 mg, 1.06 mmol) was taken in 20% piperidine in DMF (2 mL) and stirred for 15 minutes at 25° C., TLC examination showed complete removal of the Fmoc protecting group (NH2-L-Ile-D-Phe-CH2OH), further confirmed by LC/MS examination, which showed M+−1 (263.3) peak. The reaction mixture was concentrated in vacuo, excess of the piperidine was removed by co-evaporating with toluene (2×10 mL), the free amino dipeptide was further dried over high vacumn for 30 minutes, and then redissolved in dry DMF (2 mL) and added to the mixture of N-(9-fluorenylmethoxycarbonyl)-L-leucine (38.1 mg, 1.06 mmol), DCC (262.0 mg, 1.27 mmol) and HOBt (171.4 mg, 1.27 mmol) in dry DMF (20 mL) at 25° C. The stirring was further continued for 14 h at 25° C. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (3% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.5), LC/MS also showed molecular ion peak corresponding to the tripeptide 2a with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 3% MeOH: CH2Cl2 to give 310 mg of the tripeptide Fmoc-NH-L-Leu-L-Ile-D-Phe-CH2OH (2a) as a white solid. Checked on LC/MS which showed M++1 (600.3) and M++Na (622.3).

Workup

  1. customremoval of the Fmoc protecting group (NH2-L-Ile-D-Phe-CH2OH)
  2. concentrationThe reaction mixture was concentrated in vacuo, excess of the piperidine
  3. customwas removed by co-evaporating with toluene (2×10 mL)
  4. dry with materialthe free amino dipeptide was further dried over high vacumn for 30 minutes
  5. dissolutionredissolved in dry DMF (2 mL)
  6. waitThe stirring was further continued for 14 h at 25° C
  7. customAfter 14 h white colored crystals precipitated out (DCU), which
  8. filtrationwas filtered
  9. customThe crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column
  10. washeluted with 3% MeOH

Sources & evidence

ORD record
ord-df42826734f94208ac1546e4856fb70e
Source dataset
uspto-grants-2010_02
Patent number
US07659244B2

Reaction notes

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