Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod, -Drug Synthesis Database

【结构式】

【药物名称】Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod

【化学名称】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

【CA登记号】121808-62-6, 117241-40-4 (undefined stereoch.)

【分子式】C₉H₁₂N₂O₄S

【分子量】244.27099

【开发单位】Poli Industria Chimica (Originator), Fidia (Licensee), Max Farma (Licensee)

【药理作用】IMMUNOMODULATING AGENTS, Immunostimulants

合成路线1 合成路线2

合成路线1

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).

参考文献中间体

【1】 Klieger, E.; Schroder, E.; Synthesis and reactions of N-substituted-L-glutamic acid derivatives. Liebigs Ann Chem 1964, 673.
【2】 Mailland, F.; Coppi, G.; Signorelli, G.; Pidotimod. Drugs Fut 1991, 16, 12, 1096.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12005	L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid	56-86-0	C₅H₉NO₄	详情	详情
(II)	12895	(2S)-2-[(tert-Butoxycarbonyl)amino]pentanedioic acid	2419-94-5	C₁₀H₁₇NO₆	详情	详情
(III)	12896	tert-butyl (3S)-2,6-dioxotetrahydro-2H-pyran-3-ylcarbamate		C₁₀H₁₅NO₅	详情	详情
(IV)	12897	(2S)-1-(tert-Butoxycarbonyl)-5-oxo-2-pyrrolidinecarboxylic acid		C₁₀H₁₅NO₅	详情	详情
(V)	12897	(2S)-1-(tert-Butoxycarbonyl)-5-oxo-2-pyrrolidinecarboxylic acid		C₁₀H₁₅NO₅	详情	详情
(VI)	12899	L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid	34592-47-7	C₄H₇NO₂S	详情	详情
(VII)	12900	ethyl (4R)-1,3-Thiazolidine-4-carboxylate hydrochloride		C₆H₁₂ClNO₂S	详情	详情
(VIII)	12901	ethyl (4R)-1,3-thiazolidine-4-carboxylate		C₆H₁₁NO₂S	详情	详情
(IX)	12902	ethyl (4R)-3-[[(2S)-1-(tert-butoxycarbonyl)-5-oxopyrrolidinyl]carbonyl]-1,3-thiazolidine-4-carboxylate		C₁₆H₂₄N₂O₆S	详情	详情
(X)	12903	(4R)-3-[[(2S)-1-(tert-Butoxycarbonyl)-5-oxopyrrolidinyl]carbonyl]-1,3-thiazolidine-4-carboxylic acid		C₁₄H₂₀N₂O₆S	详情	详情

合成路线2

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.

参考文献中间体

【1】 Signorelli, G.; Magni, A.; Bocchiola, G.; Synthesis and preliminary pharmacological evaluation of pidotimod, its enantiomer, diastereomers and carboxamido derivatives. Arzneim-Forsch Drug Res 1994, 44, 12a, 1402.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12085	(2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid	4042-36-8	C₅H₇NO₃	详情	详情
(II)	12900	ethyl (4R)-1,3-Thiazolidine-4-carboxylate hydrochloride		C₆H₁₂ClNO₂S	详情	详情
(III)	12906	ethyl (4R)-3-[[(2S)-5-oxopyrrolidinyl]carbonyl]-1,3-thiazolidine-4-carboxylate		C₁₁H₁₆N₂O₄S	详情	详情
(IV)	12907	L-Pyroglutamic acid pentachlorophenyl ester; 2,3,4,5,6-pentachlorophenyl (2S)-5-oxo-2-pyrrolidinecarboxylate	28990-85-4	C₁₁H₆Cl₅NO₃	详情	详情
(V)	12899	L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid	34592-47-7	C₄H₇NO₂S	详情	详情

Extended Information