424 THIAMINE 



A Japanese circumvention process is even more clumsy: it starts from 

 2-methyl-4-amino-5-formylaminomethylpyrimidine and introduces a mer- 

 capto group into the pentanolone chain (7,7-diaceto-7-mercaptopropanol). 



(CH3— C0)2 C(SH)CH2— CH2OH 



For the ring closure to thiamine (at 100 to 110° in formic acid containing 

 hydrogen chloride) a yield of 40 % is claimed. ^^ 



D. PATENT SITUATION 



As the patent laws vary from country to country, the patent situation 

 for every new important compound shows variations in different countries. 

 In the case of thiamine these variations are especially pronounced, as the 

 three groups mentioned above filed their basic patent applications within 

 a short time. Additional applications originated from the laboratories of 

 Roche in Basle and Welwyn, the Merck laboratories at Rahway and Darm- 

 stadt, and some outsiders. 



In this country the Willi ams-Buchman group (assignors to Research 

 Corporation, New York) predominates and has a strong position on the 

 basis of composition of matter claims, protecting not only the important 

 intermediates of the pyrimidine and thiazole groups but also the halo- 

 genated pentanolone chain for the thiazole ring closure. It is interesting 

 that the product claims for 2-methyl-4-amino-5-aminomethylpyrimidine 

 and 4-methyl-5-/3-ethoxythiazole of Williams are based not on their syn- 

 thesis but on the degradation of thiamine, a procedure which has no 

 value for building up the end product but which was essential for the 

 knowledge of the structure and formed the basis of the subsequent synthesis 

 of these intermediates. In Germany the I. G. Farbenindustrie has the 

 strongest position on the basis of the patents of Andersag and Westphal 

 which try to claim all possible ways, including such remote possibilities as 

 the fluoro compounds as halogenated intermediates. These inventors were 

 also successful in getting patent protection for the Todd and Bergel process 

 in Germany, Great Britain, and the United States, as their patent applica- 

 tion for this process was filed in Germany as early as January 29, 1936. The 

 strong patent position of Hoffmann-La Roche is based on their claims for 

 the thioformylation of amines and the ring closure to the thiazolium ring. 



In the United States the whole field from the first patented intermediates 

 to the end product is covered by about 35 patents. The first application 

 for the end product of Williams and CHne was filed June 15, 1936, whereas 

 Andersag and Westphal had filed their first German application for the 

 same step on January 29 of the same year (but with the correct position 

 of the alkyl groups only as of March 24, 1936 as shown by the Brit. Pat. 



68 T. Matukawa and M. Ohta, U.S. Pat. 2,184,720 (December 26, 1939). 



I 



