SYNTHESIS 



Hoffmann-la Roche. The two patents were very similar, differing 

 only in one or two minor details, but the I.G. patent was filed first 

 and therefore has priority. It covers the condensation of " N-mono- 

 substituted aromatic o-diamines " with " alloxan, its monosubstitu- 

 tion products or its derivatives " and so includes the preparation of 

 riboflavine from 4-amino-i : 2-dimethyl-5-(D-i'-ribitylamino) -benzene 

 by Kuhn's first and second methods and by Karrer's first method, 

 although the Swiss workers used a different method for preparing the 

 carbethoxyamino compound. Karrer's second method is also implicitly 

 covered. Hoffmann-La Roche patented the condensation of N-sub- 

 stituted aromatic o-diamines with alloxan in presence of equimolecular 

 proportions of alloxantin.'^" 



The I.G. filed a second patent ^ covering Kuhn's third method, 

 that is, condensation of ribose with 5-amino-i : 2-dimethyl-4-nitro- 

 benzene and reduction of the resulting Schiff's base to i : 2-dimethyl-4- 

 nitro-5-(D-i'-ribityl amino) -benzene. This was condensed with alloxan 

 under reducing conditions to give riboflavine. 



A variant of the above methods was used later by R. Kuhn and 

 R. Strobele.^ 3 : 4-Dimethyl-6-nitro-aniline was condensed with ribose 

 and the resulting Schiff's base was catalytically reduced to the 

 diamine, which with alloxan gave a 16 % yield of riboflavine. The 

 Schiff's base was also partially reduced to the o-phenylene-diamine 

 glycoside, which was acetylated and the product condensed with 

 alloxan to give the corresponding acetylated flavine glycoside. This, 

 on hydrolysis, yielded the free glycoside. 



Preparation of Ribose 



The outstanding difficulty in the synthesis of riboflavine lies in the 

 preparation of ribose. The method used by Karrer was identical with 

 that used by Kuhn et al. (page 140), i kg. of calcium gluconate yielding 

 about 24 g. of ribose, which had to be separated from arabinose by 

 fractional crystallisation of the bromophenylhydrazones. 



COOH 



H- 

 HO 

 H— 

 H- 



—OH 

 H 

 OH 

 OH 



CHO 



COOH 



COOH 



HO 

 H— 

 H 



— H 



—OH 



—OH 



HO— 

 H— 

 H— 



CH2OH 

 Gluconic 

 acid 



CHjOH 

 Arabinose 



-H 



epimerlzation f^ 



► 



in pyridine 



—OH H— 



—OH 



H— 



CH2OH 

 Arabonic 

 acid 



—OH 

 —OH 

 —OH 



CH.OH 

 Ribonic 

 acid 



143 



