Patent GB-594949-A (GB)
Title: Improvements in and relating to the synthesis of riboflavin and intermediates therefor
Filed: 1944-07-14
Abstract: Riboflavin is made by a process which comprises condensing 3 : 4-dimethylaniline with d-arabinose in the presence of an acid to form 3 : 4-dimethylphenyl-d-isoarabinosamine, which is coupled with a diazotized arylamine and the 6-arylazophenyl-d-isoarabinosamine either reduced with a powerful reducing agent which reduces both the azo group and the keto group in the sugar chain, or with a mild reducing agent which reduces only the azo group.  In the former case, the 3 : 4-dimethyl-d-rilamine produced is condensed with alloxan to form riboflavin.  In the latter case, the mild reduction produces 3 : 4-dimethyl-6-amino-phenyl-d-isoarabinosamine which is condensed in glacial acetic acid solution with alloxan using boric acid as a catalyst to form 6 : 7-dimethyl-9-(d-l1-isoarabityl) isoalloxazine, which is now further reduced to the leuco form of riboflavin.  This forms riboflavin on oxidation with air.  The 3 : 4 - dimethylphenyl - d - isoarabinosamine formed in the first stage above is separated from the simultaneously formed 3 : 4-dimethyl-aniline-d-arabinoside by distillation in steam, and the latter compound hydrolysed into its components for re-use.  The arylamine used in the second stage of the process preferably contains a water-solubilizing group.  Preferred arylamines mentioned include p-amino-benzoic acid and sulphanilic acid.  The condensation with the diazotized arylamine takes place at 5-10 DEG  C. after which the reaction mixture is made alkaline. Powerful reducing agents which are mentioned as suitable to reduce both the azo group and the keto group in the sugar chain are sodium amalgam in the presence of a stream of CO2, hydrogen in the presence of Raney nickel and hydrogen in the presence of a reduced platinum catalyst.  Mild reducing agents which reduce only the diazo group which are mentioned include sodium hydrosulphite in alkaline solution and zinc dust in acid solution.  Instead of using alloxan, its functional derivatives such as dialuric acid, isodialuric acid and alloxantine may be used.  In examples: (1) a mixture of d-arabinose, 3 : 4-dimethylaniline, benzoic acid and water is heated to form a mixture of 3 : 4-dimethylphenyl-d-isoarabinosamine and 3 : 4 - dimethylaniline - d - arabinoxide.  The arabinoxide is removed by steam distillation and the residue treated with diazotized p-aminobenzoic acid to form 3 : 4-dimethyl - 6 - (p - carboxyphenylazo) - phenyl - d - isoarabinosamine.  This compound is now reduced with hydrogen in the presence of an Adam's platinum catalyst to form 3 : 4-dimethyl-6-aminophenyl - d - ribomine which is converted into riboflavin by the known methods of Karrer or Kuhn; (2) 3 : 4-dimethyl-6-(p-carboxyphenylazo)-phenyl-d-isoarabinosamine is prepared as in example (1) is reduced with aqueous sodium hydrosulphite to form 3 : 4-dimethyl-6-aminophenyl-d-isoarabinosamine which is then condensed in glacial acetic acid solution with alloxan tetrahydrate in the presence of boric acid to form 6 : 7-dimethyl-9(d-l1-isoaribityl)-isoalloxazine.  This compound is reduced with hydrogen in the presence of an Adam's platinum catalyst to leuco-6 : 7-dimethyl-9-(d-l1-ribityl)-isoalloxazine, neutralized with acetic acid and aerated to riboflavin.