Patent GB-822908-A (GB)
Title: O-peptides and process for their production
IPC: C07K1/00
Filed: 1956-02-01
Abstract: Racemic or optically active O-peptides having the general formula <FORM:0822908/IV (a)/1> wherein <FORM:0822908/IV (a)/2> represents a free amino, benzylamino, dibenzylamino, or a tritylamino radical or an N-peptide linkage (-CO-NH-) attached to an additional amino-acid or peptide portion in the case of a polypeptide, in which last case the said additional amino-acid or peptide portion of the molecule may comprise substituents the same as those indicated in the formula, R3 represents hydrogen or an alkyl, aralkyl, aryl or heterocyclic radical, which may all be hydroxylated, R4 represents hydrogen or an alkyl, aralkyl, aryl or heterocyclic radical, which may all be hydroxylated, R4 being identical with or different from R3, <FORM:0822908/IV (a)/3> represents a free amino, benzylamino, dibenzylamino or tritylamino radical or an N-peptide linkage (-NH-CO-) attached to an additional amino-acid or peptide portion in the case of a polypeptide, in which case the said additional amino-acid or peptide portion may comprise substituents the same as those indicated in the formula, the radical <FORM:0822908/IV (a)/4> being identical with or different from the radical <FORM:0822908/IV (a)/5> -CO-R7 represents a carboxylic acid radical or an N- or O-peptide linkage attached to an additional amino-acid or peptide portion in the case of a polypeptide, in which last case the said additional amino-acid or peptide portion may comprise substituents the same as those indicated in the formula, n, n1 and n11 are the same or different and represent 0 or an integer from 1 to 8, are prepared by reacting in an inert solvent at a temperature between - 10 DEG  and +50 DEG  C. and in the presence of a basic condensation agent, e.g. a tertiary organic base, a mixed anhydride of ethyl carbonic acid or acid halide of an amino-acid or peptide thereof having the general formula <FORM:0822908/IV (a)/6> which may be optically active and of which the amino groups are monobenzylated, dibenzylated or tritylated and R3 and n have the above significance, with a hydroxy amino-acid or peptide having the general formula <FORM:0822908/IV (a)/7> which may be optically active and of which one or more amino groups are monobenzylated, dibenzylated or tritylated, with the proviso that the reactants may be used in the form of their acid addition salts, e.g. the hydrochloride salts.  The process may be modified in that (a) the product is subjected to hydrogenolysis and/or detritylation to free the amino groups, (b) the product is converted to the corresponding acid halide or mixed anhydride with ethyl carbonic acid and said halide or anhydride is condensed with the hydroxy group or amino group of an hydroxy amino-acid or peptide thereof, or (c) free amino groups formed by the hydrogenolysis and/or detritylation step may be reacted with amino-acids to form N-polypeptide linkages.  The detritylation step may be carried by treatment with an hydrogen halide such as hydrogen chloride or acetic acid, and debenzylation may be carried out by hydrogenolysis in the presence of a carbon/palladium catalyst.  The invention also comprises N-benzylated, tritylated and benzyltritylated O-peptides of the above general formula and their hydrochloride salts, in particular the following compounds: O-(N-trityl-glycyl)-DL-N - trityl - serine, O - (NN - dibenzyl - glycyl)-DL - N - trityl - serine, O - (NN - dibenzylglycyl) - DL - serine, O - (N - trityl - glycyl)-DL - NN - dibenzyl - serine, O - glycyl - DL-NN - dibenzyl - serine, and O - [D(+) - NN-dibenzyl - a - amino - butyryl] - D(-) - NN - dibenzyl-threonine and the hydrochlorides of O - (NN - dibenzyl - glycyl) - DL - NN - dibenzyl - serine, O - (NN - dibenzyl - glycyl)-DL - NN - dibenzyl - threonine, O - glycyl - DL-threonine, O - [D(+) - a  - amino - butyryl]-D(-) - threonine, O - (N - benzyl - glycyl) - DL-N - benzyl - serine, O - (N - benzyl - glycyl)-DL - N - benzyl - threonine and O - [D(+) - N-benzyl - a  - amino - butyryl] - D(-) - N - benzylthreonine. In the examples: (1) O-glycyl-DL-serine is prepared (a) by reacting DL-NN-dibenzyl-serine with the hydrochloride of NN-dibenzyl-glycyl chloride or the mixed anhydride of ethyl carbonic acid and NN-dibenzyl-glycine with DL-NN-dibenzyl-serine to form the hydrochloride and free base form respectively of O-(NN - dibenzyl - glycyl) - DL - NN - dibenzyl-serine and hydrogenating this compound in the form of its hydrochloride to form the hydrochloride of O-(N-benzyl-glycyl)-DL-N-benzyl-serine or the hydrochloride of O-glycyl-DL-serine, or (b) by reacting the mixed anhydride of ethyl carbonic acid and N-trityl-glycine with DL-N-trityl-serine to form O-(N-trityl-glycyl)-DL-N-trityl-serine and treating this compound with hydrochloric acid to form the hydrochloride of O-glycyl-DL-serine, the detritylation step is also carried out by refluxing with acetic acid; (2) the mixed anhydride of ethyl carbonic acid and NN-dibenzyl-glycine is reacted with DL - N - trityl - serine to form O - (NN - dibenzyl - glycyl) - DL - N - trityl - serine, this compound is treated with hydrochloric acid to form (NN - dibenzyl - glycyl) - DL - serine which is then hydrogenated in the form of its hydrochloride salt to form the hydrochloride of O-glycyl-DL-serine; (3) the mixed anhydride of ethyl carbonic acid and N-trityl-glycine is reacted with DL-NN-dibenzyl-serine to form O - (N - trityl - glycyl) - DL - NN - dibenzyl-serine, this compound is treated with hydrochloric acid to form O-glycyl-DL-NN-dibenzyl-serine which is then hydrogenated in the form of its hydrochloride salt to form the hydrochloride of O-glycyl-DL-serine; (4) O-(NN-dibenzyl - glycyl) - DL - NN - dibenzyl - threonine hydrochloride is prepared by reacting DL-NN-dibenzyl chloride hydrochloride with DL-NN-dibenzyl-threonine, and by reacting the mixed anhydride of ethyl carbonic acid and NN - dibenzyl - glycine with DL - NN - dibenzyl-threonine and then with hydrochloric acid, and the hydrochlorides of O-(N-benzyl-glycyl)-DL - N - benzyl - threonine and O - glycyl - DL-threonine and then obtained by hydrogenating the product; (5) the mixed anhydride of ethyl carbon acid and D(+)-NN-dibenzyl-a -aminobutyric acid is reacted with D(-)-NN-dibenzyl-threonine to form O-[D(+)-NN-dibenzyl-a -amino - butyryl] - D(-) - NN - dibenzyl - threonine, and this compound is hydrogenated in the form of its hydrochloride salt to form the hydrochlorides of O-[D(+)-N-benzyl-a -amino-butyryl] - D(-) - N - benzyl - threonine and O-[D(+) - a  - amino - bytyryl] - D(-) - threonine.  A mixture of NN-dibenzyl-glycine and DL-NN - dibenzyl - serine, of N - trityl - glycine and DL-N-trityl serine and of D(+)-aminobutyric acid and D-(-)-threonine are obtained by hydrolysing the hydrochloride of O-(NN-dibenzyl-glycyl) - DL - NN - dibenzyl - serine and O-(N - trityl - glycyl) - DL - N - trityl - serine with potassium hydroxide and the hydrochloride of O - [D(+) - a  - amino - butyryl] - D(-) - threonine with hydrochloric azid respectively.  The components of the mixtures may be separated.  The mixed anhydride of ethyl carbonic acid and NN-dibenzyl-glycine is prepared by reacting NN-dibenzyl-glycine and ethyl chloroformate. The mixed anhydrides of ethyl carbonic acid and N - trityl - glycine and of D(+) - NN - dibenzyl-a -amino-butyric acid are prepared in a similar manner.  Specifications 744,584, 770,575, 791,319, 812,541 and 812,543 are referred to.