Reaction of 2-(2-chlorobenzoyl)acetonitrile (I) with 4-(4-isobutylphenyl)butyraldehyde (II) and sulfur in DMF/NEt3 gives 2-amino-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl)ethyl]thiophene (III), which is acylated with 2-chloropropionyl chloride (IV) in chloroform to give 2-(2-chloropropionamido)-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl) ethyl]thiophene (V). Compound (V) is treated with sodium iodide in THF followed by liquid ammonia to give 2-(2-aminopropionamido)-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl) ethyl]thiophene (VI), which is cyclized in isopropanol and acetic acid to give 5-(2-chlorophenyl)-5-[2-(4-isobutylphenyl)ethyl]-3-methyl-2,3-dihydro-1H-thieno[2,3-e]-1,4-diazepin-2-one (VII). Compound (VII) gives 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-2,3-dihydro-1H-thieno[2,3-e]-1,4-diazepin-2-thione (VIII) upon treatment with Lawesson's reagent. Finally, (VIII) is cyclized with hydrazine hydrate and ethyl orthoformiate.
A new synthesis of Y-24180 has been published: The reaction of 2-(2-chlorobenzoyl)acetonitrile (I) with 4-(4-isobutylphenyl)butyraldehyde (II) and sulfur by means of triethylamine in DMF gives the benzoylthiophene (III), which is condensed with 2-phthalimidopropionyl chloride (IV) yielding the propionamidothiophene (V). Elimination of the phthalimido group of (V) first with hydrazine and then with HCl affords the alanylaminothiophene (VI), which is cyclized by means of acetic acid giving 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-2,3-dihydro-1 H-thieno[3,2-f][1,4]diazepin-2-one (VII). The reaction of (VII) with P2S5 yields the corresponding thioketone (VIII), which by reaction with hydrazine is converted into the hydrazone (IX). Finally, this compound is cyclized with triethyl orthoacetate (X).