572 



BIOTIN 



III. Industrial Preparation^ 



PAUL GYORGY 



Biotiii is being produced commercially by a synthesis developed in the 

 Research Laboratories of Hoffman-LaRoche, Inc.^ It differs entirely from 

 the previously published syntheses and is characterized by the fact that a 

 meso-diaminosuccinic acid derivative is being used as an intermediate. This 

 automatically leads to the required cis structure of the final product, which 

 is also obtained in optically active form, since the resolution into optical 

 antipodes is being carried out at an intermediate stage. The following for- 

 mulas describe the synthesis. 



Br 

 HC- 



COOH 



HC=CH 



I 

 COOH 



I 



CO 



/ \ 



R— N N— R 



I I 



HC CH 



COOH COOH 



Br 



— CH 



I I 



COOH COOH 



II 



R 



NH 



I 

 HC— 



R 



I 

 NH 



I 

 -CH 



I I 



COOH COOH 



III 



IV 



R— n' 



I 

 HC- 



I 

 H2C 



CO 



/ \ 



R — N N — R 



I I 



HC CH 



I I 



CO CO 



\ / 



o 



V 



CO 



R — N 



I 

 HC- 



I 

 CH3COO— CH 



N— R 

 ■CH 

 CO 



O 



VI 



CO 



CO 



N— R 



•I 

 -CH 



I 

 CO 



R— N 

 HC- 

 H2C 



N— R 



I 

 -CH OH 



1/ 

 C 



s 



VII 



CH2CH2CH20C2H6 



VIII 



1 The information contained in this section was kindly furnished by Dr. M. W. 



GoldV)erg of the Research Laboratories of Hoffmann-La Roche, Inc. Nutley, N. J. 

 *M. W. Goldberg and L. H. Sternbach, U. S. Pats. 2,489,232-2,489,238, November 



22, 1949. 



I 



