Development of Two Scalable Syntheses of 4-Amino-5-aminomethyl-2-methylpyrimidine: Key Intermediate for Vitamin B1

Two scalable processes for the synthesis of 4-amino-5-aminomethyl-2-methylpyrimidine (2) are described. In the first approach, the less expensive 2-cyanoacetamide was reacted with Vilsmeier reagent to afford enamine 18, followed by the condensation with acetamidine to produce the 4-amino-2-methylpyrimidine-5-carbonitrile (6); subsequent hydrogenation gave 2 in 65% overall yield. In the second approach, malononitrile was treated with the ionic salt 21, prepared in situ from DMF and dimethyl sulfate, to give 18, which, without isolation was reacted with acetamidine hydrochloride to afford the common intermediate 6. Overall yield of this approach was 70%. Both methods are performed in a convenient manner suitable for industrial use.