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项目整合精选>>>Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod
Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod
匹多莫德 3-焦谷氨酰噻唑烷-4-羧酸 Chemical Name: 3-L-Pyroglutamyl-L-thiazolidine-4-carboxylic acid; (R)-3-[(S)-5-Oxoprolyl]-4-thiazolidinecarboxylic acid; 3-(L-5-Oxo-2-pyrrolidinylcarbonyl)-L-thiazolidine-4-carboxylic acid
CAS No. 121808-62-6, 117241-40-4 (undefined stereoch.)
项目整合开发状态: Launched-1993
项目研究机构: Poli Industria Chimica (Originator), Fidia (Licensee), Max Farma (Licensee)
合成路线:The synthesis of pidotimod has been carried out using N-tert-butoxycarbonyl-L-pyroglutamic acid as starting material,in order to avoid the formation of diketopiperazine derivatives.L-Glutamic acid (I) was condensed with di-tert-butyl dicarbonate by means of triethylamine in DMF to give N-(tert-butoxycarbonyl)-L-glutamic acid (II),which is dissolved in THF and treated with dicyclohexylcarbodiimide (DCC) to obtain N-(tert-butoxycarbonyl)-L-glutamic anhydride (III).The treatment of anhydride (III) with dicyclohexylamine in THF-ethyl ether affords the dicyclohexylamine salt of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (IV),which by acidification with aqueous citric acid yields the corresponding free acid (V).The condensation of equimolecular amounts of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (V) with L-thiazolidine-4-carboxylic acid ethyl ester (VIII) by means of DCC in methylene chloride gives the coupled ester (IX),which is hydrolyzed with aqueous NaOH,and the corresponding sodium salt acidified to yield the N-tert-butoxycarbonyl derivative (X).Finally,this compound is deprotected with trifluoroacetic acid to obtain crystalline pidotimod (XI).The intermediate thiazolidine (VIII) has been obtained as follows:Esterification of L-thiazolidine-4-carboxylic acid (VI) with ethanol by means of SOCl2 gives the corresponding ethyl ester hydrochloride (VII),which by treatment with K2CO3 in water yields the free ester (VIII).
📌 参考资料/链接：
参考文献标题:Pidotimod
文献作者:Mailland,F.; Coppi,G.; Signorelli,G.
参考来源:Drugs Fut 1991,16(12),1096
📄 详细内容
合成路线:Two new related routes for the synthesis of pidotimod have been reported:1) The condensation of L-pyroglutamic acid (I) with L-thiazolidine-4-carboxylic acid ethyl ester (II) by means of dicyclohexylcarbodiimide (DCC) in methylene chloride gives the corresponding dipeptide ethyl ester (III),which is saponified with aqueous 1N NaOH.2) By condensation of the activated ester L-pyroglutamic acid pentachlorophenyl ester (IV) with L-thiazolidine-4-carboxylic acid (V) by means of triethylamine in DMF.
参考文献标题:Synthesis and preliminary pharmacological evaluation of pidotimod,its enantiomer,diastereomers and carboxamido derivatives
文献作者:Signorelli,G.; Magni,A.; Bocchiola,G.
参考来源:Arzneim-Forsch Drug Res 1994,44(12a),1402
合成路线:The synthesis of pidotimod has been carried out using N-tert-butoxycarbonyl-L-pyroglutamic acid as starting material,in order to avoid the formation of diketopiperazine derivatives.L-Glutamic acid (I) was condensed with di-tert-butyl dicarbonate by means of triethylamine in DMF to give N-(tert-butoxycarbonyl)-L-glutamic acid (II),which is dissolved in THF and treated with dicyclohexylcarbodiimide (DCC) to obtain N-(tert-butoxycarbonyl)-L-glutamic anhydride (III).The treatment of anhydride (III) with dicyclohexylamine in THF-ethyl ether affords the dicyclohexylamine salt of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (IV),which by acidification with aqueous citric acid yields the corresponding free acid (V).The condensation of equimolecular amounts of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (V) with L-thiazolidine-4-carboxylic acid ethyl ester (VIII) by means of DCC in methylene chloride gives the coupled ester (IX),which is hydrolyzed with aqueous NaOH,and the corresponding sodium salt acidified to yield the N-tert-butoxycarbonyl derivative (X).Finally,this compound is deprotected with trifluoroacetic acid to obtain crystalline pidotimod (XI).The intermediate thiazolidine (VIII) has been obtained as follows:Esterification of L-thiazolidine-4-carboxylic acid (VI) with ethanol by means of SOCl2 gives the corresponding ethyl ester hydrochloride (VII),which by treatment with K2CO3 in water yields the free ester (VIII).
参考文献标题:Synthesis and reactions of N-substituted-L-glutamic acid derivatives
文献作者:Klieger,E.; Schr鰀er,E.
参考来源:Liebigs Ann Chem 1964,673
产品链接: CAS No. 121808-62-6›› 产品链接: CAS No.117241-40-4››