Improved preparation of a safety-catch linker for the solid phase synthesis of peptide acids finally released into aqueous buffers

Tetrahedron Letters

Volumn 39, Issue 1-2, 1998, Pages 17-18

  Panke, Gerhard ^a   Frank, Ronald ^a  

^a HELMHOLTZ CENTRE FOR INFECTION RESEARCH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOLIC ACID DERIVATIVE;

AQUEOUS SOLUTION; ARTICLE; CARBOXY TERMINAL SEQUENCE; CRYSTALLIZATION; NONHUMAN; PEPTIDE SYNTHESIS; PROTEIN PURIFICATION; SAFETY; SOLID PHASE EXTRACTION;

EID: 0031962917     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)10562-7     Document Type: Article

References (6)

1. Hoffmann S., Frank R. Tetrahedron Lett. 35:1994;7763-7766.
2. Hoffmann, S. New Convergent Strategies in the Synthesis of Complex Peptide Structures, Technical University of Braunschweig 1995.
3. Hoffmann, S.; Frank, R.; German pat. no. DP 43 19 475.3 / DP 43 20 260.8, PCT / EP 94 / 01 896.
4. Synthesis of 2-(5-methyl-1H-imidazol-4-yl)-2-hydroxy-acetic acid hydrochloride (2): To a suspension of 10 g (90.91 mmol) of 4-methyl-5-imidazolylcarbaldehyde (1) in 120 ml of water 13 g of potassium cyanide, 16 ml of conc. hydrochloric acid and 35 ml of acetic anhydride are added at 0 °C successively. The reaction mixture is stirred for 1 h at 0 °C and for 24 h at room temperature. After the addition of 280 ml of 6 N hydrochloric acid the solution is refluxed for 2 h followed by stirring for 24 h at 80 °C. The solvent is removed and the residue is dried in vacuo. Then it is refluxed with 500 ml of abs. ethanol for 10 min and filtered off after cooling. The sludge is refluxed again with 250 ml of abs. ethanol and the combined filtrates are evaporated. A saturated ethanolic solution is made and cooled to 0 °C. The precipitate is filtered off, the filtrate is evaporated and the residual solid is dried in vacuo. The obtained hydrochloride of the ethyl ester (10.87 g; 49.30 mmol; 54%) is added to 460 ml of 6 N hydrochloric acid and is refluxed overnight. Removal of the solvent and drying in vacuo yield 9.27 g (48.16 mmol; 53 %) of 2 as a light brown solid. - The analytical data of compound 2 agree with those described in literature.
5. 3 see: Carpino, L.A. J. Amer. Chem Soc. 1957, 79, 4427.
6. Synthesis of dicyclohexylammonium 2-(1-tert.-butoxycarbonyl-5-methyl-imidazol-4-yl)-2-hydroxy-acetate (3): In a dry reaction flask 500 mg (2.60 mmol) of hydrochloride 2 are dissolved under nitrogen atmosphere at 0 °C in 10 ml of abs. dimethylformamide and 1.08 ml (7.79 mmol) of triethylamine are added. After the addition of 743 mg (5.19 mmol) of tert-butoxycarbonyl azide the reaction mixture is stirred for 2 d at 4 °C. Then the dimethylformamide is removed in vacuo completely. The residue is suspended in dioxane and filtered off. 0.52 ml (2.60 mmol) of dicyclohexylamine are added to the filtrate before it is evaporated to dryness from the dioxane under reduced pressure. The residue is treated with excess ether. The precipitated product is filtered off and washed with ether. The filtrate and washing phase are combined, evaporated and the remaining residue is again submitted to the above described ether precipitation procedure. Collectively, 692 mg (1.58 mmol; 61 %) of product are obtained as a light brown solid. The same yield and purity is obtained at a twentyfold scale. - The analytical data of compound 3 agree with those described in literature with additional signals resulting from the dicyclohexylammonium ion.