RIBOFLAVINE 



4. SYNTHESIS OF RIBOFLAVINE 



In the synthetic method used by R. Kuhn et al.}' ^ calcium D-gluco- 

 nate was converted into D-arabinose by oxidation with ferric acetate 

 and hydrogen peroxide {cf. R. C. Hockett and C. S. Hudson ^), and 

 the D-arabinose was converted into D-ribose by way of acetobromo- 

 D-arabinose, diacetyl-D-arabinal, and D-arabinal, the overall yield 

 being about 10 %. The oxime of D-ribose was reduced to D-ribamine 

 and this was condensed with 1 : 2 -dimethyl -4 : 5-dinitrobenzene by 

 heating in 80 % alcohol for six hours at 130° C, giving i : 2-dimethyl- 

 4-nitro-5-(D-i'-ribitylamino-)-benzene. This was reduced to the 

 corresponding amino derivative by catalytic hydrogenation in presence 

 of platinum oxide, and the product was condensed with alloxan 

 tetrahydrate in acetic acid solution containing boric acid. A 70 % 

 yield of riboflavine, m.p. 291 to 292° C, was obtained. 



Kuhn et al. also prepared 4-amino-i : 2-dimethyl-5(D-i'-ribityl- 

 amino)-benzene in two other ways. In the first method, i : 2- 

 dimethyl-4 : 5-dinitrobenzene was converted by treatment with 

 ammonia into 5-amino-i : 2-dimethyl-4-nitro-benzene, which with phos- 

 gene yielded 4 : 5-dimethyl-2-nitro-phenylisocyanate. On treatment 

 with alcohol this gave the corresponding carbethoxyamino compound, 

 which on catalytic reduction gave 6-amino-i-carbethoxyamino- 

 3 : 4-dimethyl-benzene. On reductive condensation with ribose 

 followed by hydrolysis, 4-amino-i : 2-dimethyl-5-(D-i'-ribitylamino)- 

 benzene was obtained. 



In the second method, which was used for the preparation of the 

 corresponding arabityl compound, 5-amino-i : 2-dimethyl-4-nitro- 

 benzene was heated with D-arabinose and the product was hydro- 

 genated. These three methods of synthesis are summarised in the 

 scheme shown on the opposite page. 



The method used by the Swiss workers * differed somewhat from 

 that of Kuhn et al. They nitrated o-xylene to give 3 : 4-dimethyl-i- 

 nitrobenzene, which they reduced catalytically to 3 : 4-dimethyl- 

 aniline, the overall yield being less than 20 %. The dimethyl-aniline 

 was then converted into 3 : 4-dimethyl-i-carbethoxyaminobenzene by 

 treatment with chloroformic ester, and this was nitrated to give 

 i-carbethoxyamino-3 : 4-dimethyl-6-nitro-benzene, which was then 

 reduced catalytically to the corresponding amino compound. This 

 was treated with ribose, obtained by the same route as in Kuhn's 

 method, in the presence of hydrogen under pressure and a nickel 

 catalyst, yielding 2-carbethoxyamino-/^ : 5-dimethyl-phenyl-D-ribamine. 

 This was hydrolysed and decarboxylated, and the resulting 2-amino- 

 /\ : 5-dimethyl-phenyl-D-ribamine was condensed with alloxan in 

 presence of boric acid. 



140 



