4-Methylmorpholine → 4-Methylmorpholine

HRID 341779Notes

Reaction equation

HRID 341779 reaction equation
[NH:1]([C:21]([O:23]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[CH3:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[NH2:39][CH2:38][C:21]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5])=[O:23].[CH3:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1

Participants

5

Reactant 2

HCID 79724-MethylmorpholineHCID 14429023HCID 14429023, compound

Product 2

HCID 79724-MethylmorpholineHCID 91975354HCID 91975354, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The title compound was synthesized by solid-phase methodology on a ACT90 automated peptide synthesizer (Advanced ChemTec, Louisville, Ky.) using tritylchloride-polystyrene(1%)divinylbenzene (TCP; loading: 0.96 mmol/g; PepChem, Tubingen) and Fmoc-Asp-Phe-NH2 (NovaBiochem, Laufelfingen) as starting materials. The Fmoc-protected dipeptide amide (320.4 mg; 0.72 mmol) was dissolved in 4 ml dichloromethane. After 1 eq N-methyl-morpholin (NM1) was added the solution was given to 444 mg (0.48 mmol) dry TCP resin. After 5 min an additional volume of 130 ul NNM was added yielding a total amount of 1.80 mmol NMM in solution. The mixture was shaken for further 60 min. Then the residual tritylchloride groups were capped by the addition of 0.5 ml methanol. After further 20 min the resin was filtered off and washed with dichloromethane, DMF and methanol. The resin was dried under reduced pressure. Loading of the resin was determined to be 0.057 mmol/g. The Fmoc group was removed by treatment with piperidine/dimethylformamide (1:1 v/v) for 2×10 min. Afterwards Fmoc-Gly-OH was coupled within 30 min in 30-fold excess in a double coupling procedure using 1 eq TBTU and 1 eq NMM as activing agents. After removal of the Fmoc group by the same procedure as described above Boc-Ada(Boc2)-OH was coupled manually in DMF within 17 h by using a 2.5-fold excess of the protected amino acid and equimolar amounts of TBTU and NMM for activation. Cleavage from the resin and deprotection of the peptide was performed according to example 8f). Instead of heptane trifluoroethanol (2 ml) was used to dissolve the deprotected peptide. From this solution the crude peptide was precipitated by the addition of 16 ml diethylether. After centrifugation the supernatant was discarded and the precipitate lyophilized from tert.-butanol/water (1:1 v/v). Ada-Gly-Asp-Phe-NH2.HCl (28 mg) was obtained as white lyophilisate.

Workup

  1. customdry TCP resin
  2. additionAfter 5 min an additional volume of 130 ul NNM was added

Sources & evidence

ORD record
ord-ab4101d633084b48a1b3759236e33120
Source dataset
uspto-grants-1999_01
Patent number
US05856309

Reaction notes

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