Process for the preparation of gadolinium complex of (4S)-4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid disodium (Gadoxetate disodium)

A process for the preparation of a gadolinium complex of (4S)-4-(4-Ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid disodium (Gadoxetate disodium) of formula 1

• comprising the steps of:
• i) protecting the amino group of L-tyrosine of formula 12 with di-tert-butyl dicarbonate (Boc2O) in the presence of a base to get boc-protected L-tyrosine of formula 13;
• ii) alkylating the Boc-protected L-tyrosine of formula 13 with diethyl sulfate in a solvent to obtain a compound of formula 14;
• iii) converting the compound of formula 14 in to anhydride or ester in situ by reacting with a reagent followed by reduction with a reducing agent to obtain (S)-tert-butyl (1-(4-ethoxyphenyl)-3-hydroxypropan-2-yl) carbamate of formula 15;
• iv) protecting the hydroxyl group in the (S)-tert-butyl (1-(4-ethoxyphenyl)-3-hydroxypropan-2-yl) carbamate of formula 15 with methanesulfonyl chloride in the presence of a base to obtain (S)-2-((tert-butoxycarbonyl)amino)-3-(4-ethoxyphenyl) propyl methanesulfonate of formula 16;
• v) condensing the (S)-2-((tert-butoxy carbonyl) amino)-3-(4-ethoxyphenyl) propyl methanesulfonate of formula 16 with ethylenediamine in a solvent to obtain (S)-tert-butyl (1-((2-aminoethyl) amino)-3-(4-ethoxyphenyl)propan-2-yl)carbamate of formula 17;
• vi) deprotecting the amino protecting group from the (S)-tert-butyl (1-((2-aminoethyl) amino)-3-(4-ethoxyphenyl) propan-2-yl)carbamate of formula 17 in the presence of an acid to obtain (S)-N1-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine acid salt of formula 18b or 18c, which optionally, is further converted in to a free base that is a compound of formula 18a, in situ by reaction with a base;
• vii) alkylating the (S)-N1-(2-aminoethyl)-3-(4-ethoxyphenyl) propane-1,2-diamine acid salt of formula 18b or 18c or the free base that is the compound of formula 18a with tertiary butyl bromoacetate in the presence of potassium carbonate to provide (S)-tert-butyl 2,2′-(2-((2-(bis(2-tert-butoxy-2-oxoethyl) amino)-3-(4-ethoxyphenyl)propyl) (2-tert-butoxy-2-oxoethyl)amino) ethyl azanediyl) diacetate of formula 3;
• viii) deprotecting the tertiary butyl group of the (S)-tert-butyl 2,2′-(2-((2-(bis(2-tert-butoxy-2-oxoethyl) amino)-3-(4-ethoxyphenyl)propyl) (2-tert-butoxy-2-oxoethyl)amino) ethyl azanediyl) diacetate of formula 3 with aqueous sodium hydroxide to obtain (S)-2,2′-((2-((2-(bis(carboxymethyl)amino)-3-(4-ethoxyphenyl)propyl) (carboxymethyl) amino)ethyl)azanediyl)diacetic acid of formula 4;
• ix) converting the (S)-2,2′-((2-((2-(bis(carboxymethyl)amino)-3-(4-ethoxyphenyl) propyl) (carboxymethyl) amino)ethyl)azanediyl)diacetic acid of formula 4 to Gadolinium salt by treating with Gadolinium(III) oxide in the presence of sodium hydroxide to obtain the Gadoxetate Disodium of formula 1