GB785012A - New n-acylated hydroxy prolines and their use in obtaining d-hydroxyproline and l-hydroxyproline - Google Patents

Abstract

The invention comprises N - 3,5 - dinitro benzoylated DL-, D- and L-hydroxy prolines and salts of the acylated D- and L-hydroxy prolines with, as resolution agent, D-(-) and L-(+)-threo-1-p-nitrophenyl-2-amino propane-1,3-diol respectively and their use in the formation of D- and L-hydroxy proline free from one another. The dinitrobenzoylated DL-hydroxy proline may be prepared by direct acylation or by reacting 3,5-dinitrobenzoyl chloride with an ester or other like functional derivative of hydroxy proline followed by regeneration of the acylated amino acid. The separate acylated D-and L-hydroxy prolines are produced from the acylated DL derivatives by reaction with the D- or L-form of the resolution agent in an inert solvent in which only one of the two acylated hydroxy proline enantiomorphs gives a salt with the resolution agent which is sparingly soluble in the solvent, separating the salts of the two enantiomorphs by means of their differing solubility and liberating the N-3,5-dinitro-benzoyl-D- and L-hydroxyprolines from their separated salts by treatment with a base followed by acidification. The difitrobenzoyl D-and L-hydroxy prolines are then saponified separately to give the D- and L-hydroxyprolines. Suitable solvents are water, aqueous dioxane, alcohol or other water-miscible organic solvent. Under these conditions the D- and L-forms of the resolution agent give insoluble salts with the D- and L-forms respectively of the acylated hydroxy prolines; the corresponding D-L- and LD-salts remain in solution. In examples: (1) DL-hydroxy proline is acylated with 3,5-dinitrobenzyl chloride, in aqueous NaOH; (2) the L-form of the resolution agent is added to N-3,5-dinitrobenzoyl-D,L-hydroxy proline dissolved in aqueous dioxane with stirring at 25 DEG C.; the resulting precipitated resolution salt of the acylated L-hydroxy proline is removed, treated with aqueous NaOH, the liberated resolution agent is removed and the residual aqueous solution is acidified and worked up to recover the resolved acylated L-hydroxy proline which is hydrolysed to L-hydroxy proline with aqueous HCl; the aqueous dioxane solution, after removal of the precipitated resolution salt, is evaporated to dryness, dissolved in aqueous NaOH, liberated resolution agent removed and the remaining solution is acidified and worked up to recover resolved acylated D-hydroxy proline which on hydrolysis as above yields D-hydroxy proline; (3) the crude acylated D-hydroxy proline obtained in (2) is treated with the D-form of the resolution in the manner described in (2) whereby the resolution salt of the acylated D-hydroxy proline is recovered and is converted as above to the resolved acylated D-hydroxy proline and then to D-hydroxy proline in purer form. Specification 785,013 is referred to.