II. CHEMISTRY AND INDUSTRIAL PREPARATION 41 



and Chanley.'-^* The reduced glycol was then selectively acetylated, and the 

 monoacetate LXXX was dehydrated with p-toluenesulfonic acid in boiling 

 benzene or toluene. A mixture of about 50 % of vitamin A acetate, anhydro- 

 vitaniin A, and unchanged starting material was obtained. Further purifica- 

 tion was effected by chromatography and by converting the final product 

 into crystalline vitamin A anthraquinone-2-carboxylate, the identity of 

 which was confirmed by comparison with an authentic sample, ultraviolet 

 absorption spectra, and biological tests. Although this process is of theoreti- 

 cal interest, it does not afford an advantage over the processes outlined in 

 Fig. 7. The preparation of the key intermediates LXXM and LXXMI in- 

 volves several steps, some of which give low yields of the desired products, 

 and the o\'erall yields of the vitamin itself are low. Moreover, the use of the 

 expensive reagent, LiAlH4 , should always be considered in any economical 

 synthesis. 



The alternative route by way of compound LXXXII and the Cis-ketone 

 LXXXVI is less satisfactory, since it is subject to the same hmitations in- 

 herent in the methods outlined in Fig. 6. 



/. Industrial Preparation 



For a long time vitamin A and vitamin A products have been of consid- 

 erable commercial importance, and in 1950 the demand for vitamin A in 

 the United States alone was estimated at 120 trillion U.S.P. units.^^^ One 

 of the oldest methods of concentrating the vitamin from fish liver oils has 

 already been described elsewhere. With the advent of commercial methods 

 of molecular or high-vacuum distillations low-potency oils were concen- 

 trated successfully by this method without much loss of potency .^^ Prior 

 to the development of economical synthetic methods most of the high- 

 potency concentrates, in the form of esters or mixtures of esters and the 

 \'itamin, were produced industrially by this method. 



Of all the synthetic processes the most economical one and the one pre- 

 ferred and widely practiced in the United States by Hoffmann-La Roche, 

 Pfizer, and Merck, and by Hoffman-La Roche in Europe is that which uses 

 Ci4-aldehyde as the key intermediate. The first two methods outlined in 

 Fig. 7 give approximately the same over-all yields of \'itamin A. However, 

 the first process was originally adopted industrially by Hoffmann- 

 La Roche'*^ • '^® and is essentially the one used by the others. In some of 

 the formulations of this process the structure LXVa of the Cw-aldehyde is 

 used, although from the practical point of view it is immaterial, since the 

 aldehyde used by all the investigators in this field was essentially the same. 



The starting materials for this process include citral, the main constituent 



'"•^ J. D. Chanley and H. Sobotka, J. Am. Chem. Soc. 71, 4140 (1949). 

 '59 Staff Report, Ind. Eng. News 29, 1316 (1951) . 



