A synthesis of S-12968 has been published: The cyclization of 4-[2-(2-phthalimidoethoxy)ethoxy]-3-oxobutyric acid ethyl ester (I) with 2-(2,3-dichlorobenzylidene)-3-oxobutyric acid 2-cyanoethyl ester (II) and ammonium formate in hot ethanol gives the protected racemic 1,4-dihydropyridine (III), which is submitted to a chiral preparative HPLC to obtain the (R)-(-)-enantiomer (IV). The deprotection of (IV) with aqueous methylamine affords (S)-(-)-2-[2-(2-aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-1,4-di hydropyridine-3,5-dicarboxylic acid 3-monoethyl ester (V). Finally, this compound is methylated with diazomethane in ethyl ether/methanol. The starting compound, the dichlorobenzylidene derivative (II) has been obtained as follows: The condensation of Meldrum's acid (X) with acetic acid (XII) by means of CDI and pyridine as before gives 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (XIII), which is submitted to ring opening with 3-hydroxypropionitrile (XIV) in refluxing toluene yielding 2-cyanoethyl acetoacetate (XV). Finally, the condensation of (XV) with 2,3-dichlorobenzaldehyde (XVI) by means of piperidine and hexanoic acid in refluxing benzene affords the dichlorobenzylidene derivative (II) used as the second starting compound.
The starting compound phthalimido derivative (I) could be obtained as follows: The condensation of 2-[2-(2-chloroethoxy)ethoxy]ethanol (VI) with potassium phthalimide (VII) in refluxing DMF gives the expected phthalimido derivative (VIII), which is oxidized with the Jones reagent in acetone yielding 2-[2-(2-phthalimidoethoxy)ethoxy]acetic acid (IX). The condensation of (IX) with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (X) by means of carbonyldiimidazole (CDI) and pyridine in dichloromethane affords 2,2-dimethyl-5-[2-[2-(2-phthalimidoethoxy)ethoxy]acetyl]-1,3-dioxane-4,6-dione (XI), which is finally treated with refluxing ethanol to obtain the phthalimido derivative (I) used as starting material.
This compound has been obtained by three related ways: 1. Dihydropyridine amino acid (V) is methylated with (11C-labeled)-diazomethane (VI) in ethyl ether/methanol to afford the target compound. 2. The methylation of the dihydropyridine amino acid (V) can also be performed with (11C-labeled)-methyl iodide (VII) and trimethylbenzylammonium hydroxide in DMF/EtOH. 3. The preceding methylation can also been performed with (11C-labeled)-methyl triflate (VIII) and trimethylbenzylammonium hydroxide in DMF/EtOH. The (11C-labeled)-diazomethane (VI), (11C-labeled)-methyl iodide (VII) and (11C-labeled)-methyl triflate (VIII) have been obtained as follows: a. The chlorination of (11C-labeled)-methane (IX) with chlorine and CuCl2 at 330 C gives labeled chloroform (X), which is then treated with hydrazine and KOH in ethanol to yield the desired (11C-labeled)-diazomethane (VI). b. The reduction of (11C-labeled)-CO2 (XI) with LiAlH4 in THF gives (11C-labeled)-methanol (XII), which is treated with 57% IH to yield the desired (11C-labeled) methyl iodide (VII). c. Finally, the reaction of (11C-labeled)-methyl iodide (VII) with silver triflate affords the desired (11C-labeled)-methyl triflate (VIII).