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【结 构 式】 
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【分子编号】12899 【品名】L-(-)-Thiazolidine-4-carboxylic acid; (4R)-1,3-Thiazolidine-4-carboxylic acid; (R)-(-)-Thiazolidine-4-carboxylic acid 【CA登记号】34592-47-7 |
【 分 子 式 】C4H7NO2S 【 分 子 量 】133.17112 【元素组成】C 36.08% H 5.3% N 10.52% O 24.03% S 24.08% |
合成路线1
该中间体在本合成路线中的序号：(I)The benzoylation of thiazolidine-4(R)-carboxylic acid (I) with benzoyl chloride (II) by means of NaOH in acetone water gives the corresponding N-benzoyl derivative (III), which is then condensed with alpha-(R)-methylbenzylamine (IV) by means of isobutyl chloroformate and triethylamine in dichloromethane.
| 【1】 Matsui, T.; Nagano, M.; KLitamura, K.; Shimizu, F. (Sankyo Co., Ltd.); Amino acid derivatives having anti-tumor activity and compositions containing them.. EP 0173441; ES 8703830; US 4904680 . |
| 【2】 Castaner, J.; Prous, J.; RS-0481. Drugs Fut 1988, 13, 7, 627. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 | |
| (I) | 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 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 22557 | (4R)-3-benzoyl-1,3-thiazolidine-4-carboxylic acid | C11H11NO3S | 详情 | 详情 | |
| (IV) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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).
| 【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3
该中间体在本合成路线中的序号：(V)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.
| 【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 |