CHEMICAL CONSTITUTION AND SYNTHESIS 



L-leucine, a-hydroxy-jS/S-dimethyl-y-butyrolactone and a homologous 

 lactone, C17H12O3, which gave an inactive substance when coupled with 

 j3-alanine. Although pantothenic acid was not actually isolated, there 

 is little doubt that it was the active constituent of the concentrate. 



Kuhn and Wieland ^® synthesised pantothenic acid by condensing 

 pantolactone with /3-alanine benzyl ester and cataJytically hydro- 

 genating the product to remove the benzyl group. The racemic 

 pantothenic acid so obtained was resolved by means of quinine or 

 cinchonidine. The latter was preferred, as the cinchonidine salt of 

 D-pantothenic acid was less soluble than that of the L-isomer, enabling 

 it to be isolated in good yield, whereas quinine D-pantothenate was 

 more soluble than the salt of the L-isomer and therefore more difficult 

 to isolate. 



Other variants of the general method for the preparation of panto- 

 thenic acid were described by H. C. Parke and E. J. Lawson.^^ Fusion 

 at 150° C. of the sodium salt of DL- and D-pantoic acid with ^-alanine 

 gave a 90 and 60 % yield respectively of sodium DL-pantothenate 

 and sodium D-pantothenate. A novel method of preparing sodium 

 DL-pantothenate was fusion at 100° C. of DL-pantamide with the 

 sodium salt of jS-alanine ; this gave a 70 % yield. Finally, sodium 

 D-pantothenate was prepared in 90 % yield by heating pantolactone 

 with the sodium salt of ^-alanine in isopropanol. 



Patents covering these different methods of preparation were 

 filed by various commercial firms. Merck & Co., for example, pro- 

 tected the preparation of pantothenic acid by reacting ^-alanine, its 

 salts or esters, with an a-keto- or a-hydroxy-acid capable of lacto- 

 nising ; ^^ by fusing j3-alanine or a salt with pantolactone ; ^^ or by 

 reacting pantolactone with /S-alanine and an ester of /S-alanine in 

 presence of an alkali metal or alkaline earth metal hydroxide or 

 alcoholate at 0° C. in an alcoholic or aqueous medium. 20 DL-Panto- 

 thenic acid was resolved by means of quinine, quinine methydroxide, 

 cinchonidine, brucine, strychnine or ephedrine.^^ Alternatively, pantoic 

 acid was resolved by fractional crystallisation of an alkaloidal salt, 22 

 and D- or L-pantothenic acid was prepared from the appropriate lactone 

 by reaction with /S-alanine.^^ The condensation of D-pantolactone 

 with /S-alanine was also patented by F. Hoffmann-La Roche & Co. 2* 



A mmiber of novel methods were patented by F. Hoffmann-La 

 Roche & Co., and Roche Products Ltd. Thus esters of pantothenic 

 acid were prepared by catalytic hydrogenation of ^-nitropropionic 

 esters in presence of pantolactone. ^^ The reaction of pantolactone 

 with j8-alanine in alcoholic or aqueous alcoholic solution was also 

 protected.^^ A third method of preparation was to react panto- 

 lactone with the acetal of j8-aminopropionaldehyde and convert the 

 resulting pantothenic aldehyde acetal to calcium pantothenate by 



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