Aminoguanidine → [1,2,3]Thiadiazolo[5,4-d]pyrimidine

Reaction equation

F[C:2](F)(F)[C:3](O)=O.N1(CC(O)=O)CCOCC1.[S:18]1[CH:22]=C[N:20]=[N:19]1.[C:23](N)([NH2:26])=[N:24]N.C(OC=C(C(OCC)=O)C(OCC)=O)C>>[N:20]1[C:3]2[CH:2]=[N:24][CH:23]=[N:26][C:22]=2[S:18][N:19]=1

Participants

Reactant 4

HCID 2146Aminoguanidine

HCID 6871Diethyl (ethoxymethylene)malonate

HCID 675181,2,3-Thiadiazole

HCID 69732510(4-Morpholinyl)acetic acid trifluoroacetic acid salt

Product 1

HCID 45080540[1,2,3]Thiadiazolo[5,4-d]pyrimidine

Procedure

5-Hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamides. As described in Chart BL, (4-morpholinyl)acetic acid trifluoroacetic acid salt BL.1 (J. Med. Chem. 1994, 37, 4538-4554) is cyclized to the thiadiazole BL.2 with aminoguanidine in polyphosphoric acid. Condensation of BL.2 with diethyl ethoxymethylenemalonate followed by thermal cyclization affords thiadiazolopyrimidine BL.3. The resulting ester BL.3 is then saponified to afford the corresponding acid BL.4 which is then coupled with a benzylamine (e.g. 4-chlorobenzylamine) mediated by 1,1′-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula BL.5. A specific example of heterocycle W19.2 in which R8=OH is also prepared as described in Chart BL. Thiadiazole BL.2 is heated in xylenes with diethyl 2-(((4-chlorobenzyl)amino)carbonyl)malonate (prepared by the reaction of 4-chlorobenzylamine with triethyl methanetricarboxylate) to afford thiadiazolopyrimidine BL.6.