Hydrochloric Acid → Thymodepressin

HRID 1642029Notes

Reaction equation

HRID 1642029 reaction equation
[NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6].Cl.ClCCl.C[O:30]C(C)(C)C>>[CH:16]1[CH:17]=[C:18]2[C:10]([CH2:9][C@@H:8]([NH:7][C:5]([CH2:4][CH2:3][C@@H:2]([NH2:1])[C:22]([OH:24])=[O:30])=[O:6])[C:19]([OH:21])=[O:20])=[CH:11][NH:12][C:13]2=[CH:14][CH:15]=1.[NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6]

Participants

6

Reactant 4

HCID 313Hydrochloric Acid3×HCID 6344DichloromethaneHCID 15413tert-Butyl methyl etherHCID 66756032HCID 66756032, compound2×

Product 2

HCID 7275810ThymodepressinHCID 66756032HCID 66756032, compound

Procedure

A solution of the base addition salt of D-isoglutamyl-D-tryptophan is prepared by the acid deprotection of the dipeptide Boc-D-Glu-(γ-D-Trp-OR2)-α-OR1, wherein each of R1 and R2 is independently selected from the group consisting of benzyl and C1-C4 alkyl. For example, HCl deprotection of Boc-D-Glu-(γ-D-Trp-OR2)-α-OR1 in an inert solvent such as dichloromethane, affords the HCl salt of H-D-Glu-(γ-D-Trp-OR2)-α-OR1. For the combination where R1 is benzyl and R2 is methyl, the product HCl.H-D-Glu-(γ-D-Trp-OR2)-α-OR1 precipitates out of dichloromethane and can be removed by filtration. Treatment of the acid addition salt with a metal hydroxide in an inert solvent such as methanol for one phase homogeneous hydrolysis or with tert-butyl methyl ether for two phase hydrolysis affords H-D-iGlu-D-Trp-OH base addition salt in solution. Upon extraction of the reaction mixture with a water immiscible solvent such as ethyl acetate or tert-butyl methyl ether, the aqueous phase is neutralized to pH of about 6 to about 7 and the solution is evaporated to reduced the volume to an estimated ratio of less than about 1 part solute:8 parts water. The solute, as predicted by the speciation calculations as shown in FIG. 8, is the base addition salt (in mono carboxylate form) of H-D-iGlu-D-Trp-OH. If sodium hydroxide is used as the metal hydroxide, the solute will be the mono sodium form of the H-D-iGlu-D-Trp-OH in water. Adjustment of this solution to pH of about 2.5 to about 3.0 will result in the precipitation of solid thymodepressin, H-D-iGlu-D-Trp-OH.

Workup

  1. customH-D-Glu-(γ-D-Trp-OR2)-α-OR1 precipitates out of dichloromethane
  2. customcan be removed by filtration
  3. additionTreatment of the acid addition salt with a metal hydroxide in an inert solvent such as methanol
  4. customfor one phase homogeneous hydrolysis
  5. customaffords
  6. extractionUpon extraction of the reaction mixture with a water immiscible solvent such as ethyl acetate or tert-butyl methyl ether
  7. customthe solution is evaporated
  8. additionthe base addition salt (in mono carboxylate form) of H-D-iGlu-D-Trp-OH

Sources & evidence

ORD record
ord-4ed33a7246664eb5be86da27326e33af
Source dataset
uspto-grants-2012_02
Patent number
US08119606B2

Reaction notes

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