4-Methylmorpholine → Boc-Tyr-D-Met-Gly-OMe

HRID 1680573Notes

Reaction equation

HRID 1680573 reaction equation
[C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42].CN(C)CCN>CN(C)C=O>[C:1]([NH:8][C@H:9]([C:18]([NH:37][C@@H:38]([C:43]([NH:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])=[O:44])[CH2:39][CH2:40][S:41][CH3:42])=[O:20])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]

Participants

7

Reactant 5

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 66053N,N-DimethylethylenediamineHCID 117439L-Tyrosine, N-(1,1-dimethylethoxy)carbonyl-HCID 13216977methyl D-methionyl-glycinate hydrochloride

Product 1

HCID 13216983Boc-Tyr-D-Met-Gly-OMe

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
-40 °C

Procedure

To a solution of 16.88 g of Boc-L-tyrosine in 50 ml of dry dimethylformamide is added 6.65 ml of N-methylmorpholine. The reaction mixture is cooled to -40° C. and 7.84 ml of isobutylchloroformate is added. The reaction mixture is allowed to warm to 0° C. over a 15 minute period then 13.32 g of methyl D-methionyl-glycinate hydrochloride dissolved in 50 ml of dimethylformamide is added followed immediately by 5.2 ml of N-methylmorpholine. The reaction mixture is stirred for 30 minutes at 0° C. After storage overnight at 5° C., 3 ml of N,N-dimethylethylenediamine is added and the reaction mixture is stirred for 15 minutes at room temperature. The solvent is removed under vacuum at 35° C. and 1 mm of pressure and oily residue is dissolved in a mixture of 100 ml of water and 700 ml of ethyl acetate. The ethyl acetate layer is separated and washed three times with 80 ml of a 0.5 M solution of potassium bisulfate, 2 times with 80 ml of water, 2 times with 80 ml of a 0.5 solution of potassium carbonate, and 3 times with 100 ml of a 10% solution of sodium sulfate then dried over magnesium sulfate. The solvent is removed under pressure. The residue is dissolved in 1.2 liters of 5% ethyl acetate in chloroform and purified by low pressure chromatography on silica gel then reduced to dryness under reduced pressure and recrystallized from ethyl acetate to give methyl Boc-L-tyrosyl-D-methionyl-glycinate which is represented by the following formula

Workup

  1. temperatureto warm to 0° C. over a 15 minute period
  2. additionis added
  3. stirringthe reaction mixture is stirred for 15 minutes at room temperature
  4. customThe solvent is removed under vacuum at 35° C.
  5. dissolution1 mm of pressure and oily residue is dissolved in a mixture of 100 ml of water and 700 ml of ethyl acetate
  6. customThe ethyl acetate layer is separated
  7. washwashed three times with 80 ml of a 0.5 M solution of potassium bisulfate, 2 times with 80 ml of water, 2 times with 80 ml of a 0.5 solution of potassium carbonate, and 3 times with 100 ml of a 10% solution of sodium sulfate
  8. dry with materialthen dried over magnesium sulfate
  9. customThe solvent is removed under pressure
  10. dissolutionThe residue is dissolved in 1.2 liters of 5% ethyl acetate in chloroform
  11. custompurified by low pressure chromatography on silica gel
  12. customrecrystallized from ethyl acetate

Sources & evidence

ORD record
ord-b1dae608b16d4ddf969b15bb5ec57438
Source dataset
uspto-grants-1981_06
Patent number
US04273704

Reaction notes

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