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【结 构 式】

【分子编号】12897

【品名】(2S)-1-(tert-Butoxycarbonyl)-5-oxo-2-pyrrolidinecarboxylic acid

【CA登记号】

【 分 子 式 】C10H15NO5

【 分 子 量 】229.23284

【元素组成】C 52.4% H 6.6% N 6.11% O 34.9%
与该中间体有关的原料药合成路线共 2 条
合成路线1合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

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
合成目标
【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

该中间体在本合成路线中的序号：(V)

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
合成目标
【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
Extended Information