Pranedipine tartrate, Servier-12968, S-12968
Chemical Name: (-)-2-[2-(2-Aminoethoxy)ethoxymethyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester L-(+)-tartrate
CAS No. 132194-66-2 (HCl)
项目整合开发状态: Phase III
项目研究机构: Servier (Originator)
合成路线: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.
合成路线: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.
📌 参考资料/链接：
参考文献标题:Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging
文献作者:Doll? F.; Hinnen,F.; Valette,H.; Fuseau,C.; Duval,R.; P間lion,J.-L.; Crouzel,C.
参考来源:Bioorg Med Chem 1997,5(4),749
📄 详细内容
合成路线: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.
合成路线: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).
参考文献标题:Highly efficient synthesis of [11C]S12968 and [11C]S12967,for the in vivo imaging of the cardiac calcium channels using PET
文献作者:Dolle,F.; et al.
参考来源:J Label Compd Radiopharm 2001,44(7),481