Patent Watch

November 12, 2012

Improve the yield of a vitamin B1 precursor. Inventors R. Karge, U. Letinois, and G. Shiefer describe a method for synthesizing compound 3, an important intermediate in the production of thiamine (vitamin B1). 4-Aminopyrimidines related to 3 contain structural elements found in many antibiotics and herbicides. The inventors summarize several processes for making 3 and report such shortcomings as poor yields and the use of highly toxic reagents.

The synthesis of 3 shown in the figure takes place in two steps, starting with the reaction of sodium salt 1 with NH4Cl to give 2 as a viscous oil in 75% yield and 75.6% purity. The reaction is carried out in mixed solvents; toluene–i-PrOH is preferred. The crude product is partially purified by passing a solution of it in 1:9 v/v MeOH–CH2Cl2 over SiO2. The product is recovered in 67% yield with 90% purity.

The authors repeated the reaction in alternative solvent mixtures at reflux to change the reaction temperature and time. Higher temperatures reduce reaction times, but yield and purity decrease. Using increased quantities of NH4Cl also reduces yield and purity. The example in the patent uses only 88%-pure 1, so the low yield and purity of 2 are not surprising.

In the second step, 2 is treated with Me4NOH·5H2O in MeCN to produce 3 in 58% yield. The conversion of 2 is 90%, but the purity of 3 is not reported. When the second step is carried out at higher temperature or with alternative bases, the yield is lower. The patent includes 1H and 13C NMR data for 2 but not for 3.

The inventors claim that compound 2 is novel. The claims also cover related compounds in which the aldehyde group is replaced by acetyl or the methyl group on the pyrimidine ring is a different alkyl group. Details for preparing these compounds are not provided. The patent also includes proposed routes for preparing 1 and for making vitamin B1 from 3, but again no details are provided. (DSM IP Assets B.V. [Heerlen, The Netherlands]. US Patent 8,252,927, Aug. 28, 2012; Keith Turner)

What do you think of Patent Watch? Let us know.