Process for preparing biotin

A process for the production of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid or 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride starting from a meso-2,3-bis(benzylamino)succinic acid dialkali metal salt, comprising:

• a) reacting meso-2,3-bis(benzylamino)succinic acid dialkali metal salt with phenyl chloroformate in a monophasic solvent system consisting of an about 2:1 to 1:1 mixture of a water-miscible ether and aqueous alkali metal hydroxide solution at a temperature not exceeding about 40° C.,
• b) converting the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt by acidification into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, and
• c) isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid or converting the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid in step b) into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride by heating with acetic anhydride in an aromatic hydrocarbon as the organic solvent;
• and isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride.

A process for the production of biotin comprising:

• a) providing an intermediate in the biotin production pathway comprising:
• i) reacting a meso-2,3-bis(benzylamino)succinic acid dialkali metal salt with phenyl chloroformate in a monophasic solvent system consisting of an about 2:1 to 1:1 mixture of a water-miscible ether and aqueous alkali metal hydroxide solution at a temperature not exceeding about 40° C.,
• ii) converting the resulting 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid dialkali metal salt by acidification into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, and
• iii) isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid or converting the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid in step ii) into 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride by heating with acetic anhydride in an aromatic hydrocarbon as the organic solvent;
• and isolating the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride;
• and
• b) using the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid or the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride for further reactions in the biotin production pathway.