Synthesis
The chemical synthesis of Apafant was reported: Precursor: Dan’s book said there is keto present but absent in the database and the patent. Reaction of the Diethyl 2-(4-oxobutyl)propanedioate, PC88403880 (1) with the 2-Chlorobenzoylacetonitrile [609-772-9] (2) in the presence of sulfur leads to formation of the aminothiophene, Diethyl 2-(5-amino-4-(2-chlorobenzoyl)thiophen-2-ylmethyl)malonate, PC13670761 (3). Saponification of the esters with caustic potash is accompanied by decarboxylation. The re-esterification of the monoacid with methanol then gives 2-Amino-3-(2-chlorobenzoyl)-5-(2-carbomethoxyethyl)thiophene [100827-77-8] (4). Construction of the diazepine ring starts by alkylation of the amino group with bromoacetamide in the presence of base to afford, Methyl 3-[5-[(2-aminoacetyl)amino]-4-(2-chlorobenzoyl)thiophen-2-yl]propanoate, PC13670766 (5). Heating with silica causes the side-chain amide nitrogen to react with the ketone to form a cyclic imine affording 7-(2-Carbomethoxyethyl)-5-(2-chlorophenyl)-thieno-1,4-diazepin-2-one [100827-80-3] (6). The amide carbonyl is converted to a thioamide with phosphorus pentoxide giving, Methyl 3-[5-(2-chlorophenyl)-2-sulfanylidene-1,3-dihydrothieno[2,3-e][1,4]diazepin-7-yl]propanoate, PC136015497 (7). Reaction of this last intermediate with hydrazine gives a cyclic aminoamidine (8). Condensation of that product with orthoacetic acid ester leads to 4-(2-Chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-2-propanoic Acid Methyl Ester, [100827-83-6] (9). Ester–amide interchange of this last product with morpholine completes the synthesis of apafant (10). == References ==