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【结 构 式】 
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【分子编号】12895 【品名】(2S)-2-[(tert-Butoxycarbonyl)amino]pentanedioic acid 【CA登记号】2419-94-5 |
【 分 子 式 】C10H17NO6 【 分 子 量 】247.24812 【元素组成】C 48.58% H 6.93% N 5.67% O 38.83% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(I)The cyclization of N-Boc-L-glutamic acid (I) with paraformaldehyde in refluxing DCE gives the oxazolidinone (II), which is benzylated with benzyl bromide and LiHMDS in THF yielding the benzyl derivative (III). The reaction of (II) with CDI in THF affords the activated acid (IV), which is condensed with the protected glutamic acid (V) by means of LiHMDS in THF to provide the adduct (VI). The decarboxylation of the allyloxycarbonyl group of (VI) by means of a Pd catalyst furnishes the compound (VII), which is deprotected and cyclized by hydrogenation with H2 over Pd/C and PtO2 to give the substituted proline (VIII). The lactam cyclization of (VIII) by means of NaOH in methanol, followed by crystallization yields the bicyclic carboxylic acid (IX), which is condensed with the arginine derivative (X) by means of EDC, HOBT and DIEA in THF affording the adduct (XI). The oxidation of the OH group of (XI) with DMP in dichloromethane gives the precursor (XII), which is finally deprotected by a treatment with TFA and PhS-Me. The intermediate arginine derivative (X) has been obtained as follows: The condensation of the fully protected arginine aldehyde derivative (XIII) with benzothiazole (XIV) by means of n-BuLi in ethyl ether gives the adduct (XV), which is then treated with TFA in order to eliminate the Boc protecting groups and furnish the desired arginine derivative intermediate (X).
| 【1】 Lee, M.S.; Eguchi, M.; Gardner, B.S.; Boatman, P.D.; Kahn, M.; Kim, H.-O.; Nakanishi, H.; Synthesis of dipeptide secondary structure mimetics. Proc. 15th Am. Pep. Symposium, Kluwer Acad. Publ. 1998, 212. |
| 【2】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
| 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) | 12895 | (2S)-2-[(tert-Butoxycarbonyl)amino]pentanedioic acid | 2419-94-5 | C10H17NO6 | 详情 | 详情 |
| (II) | 41838 | 3-[(4S)-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propionic acid | C11H17NO6 | 详情 | 详情 | |
| (III) | 41839 | 3-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propionic acid | C18H23NO6 | 详情 | 详情 | |
| (IV) | 41840 | tert-butyl (4R)-4-benzyl-4-[3-(1H-imidazol-1-yl)-3-oxopropyl]-5-oxo-1,3-oxazolidine-3-carboxylate | C21H25N3O5 | 详情 | 详情 | |
| (V) | 41841 | 5-allyl 1-benzyl (2S)-2-[[(benzyloxy)carbonyl]amino]pentanedioate | C23H25NO6 | 详情 | 详情 | |
| (VI) | 41842 | 1-allyl 5-benzyl (4S)-2-[3-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propanoyl]-4-[[(benzyloxy)carbonyl]amino]pentanedioate | C41H46N2O11 | 详情 | 详情 | |
| (VII) | 41843 | tert-butyl (4R)-4-benzyl-4-((6S)-7-(benzyloxy)-6-[[(benzyloxy)carbonyl]amino]-3,7-dioxoheptyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C37H42N2O9 | 详情 | 详情 | |
| (VIII) | 41844 | (2S,5R)-5-[2-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]ethyl]-2-pyrrolidinecarboxylic acid | C22H30N2O6 | 详情 | 详情 | |
| (IX) | 41485 | 4-chloro-1-methyl-2-nitrobenzene；4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene | 89-59-8 | C7H6ClNO2 | 详情 | 详情 |
| (X) | 40421 | N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C33H35N5O2S | 详情 | 详情 | |
| (XI) | 41846 | tert-butyl (3S,6R,8aR)-3-[([(1S)-1-[1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxooctahydro-6-indolizinylcarbamate | C54H61N7O6S | 详情 | 详情 | |
| (XII) | 41847 | tert-butyl (3S,6R,8aR)-3-[([(1S)-1-(1,3-benzothiazol-2-ylcarbonyl)-4-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxooctahydro-6-indolizinylcarbamate | C54H59N7O6S | 详情 | 详情 | |
| (XIII) | 41848 | tert-butyl (Z)-([(4S)-4-[(tert-butoxycarbonyl)amino]-5-oxopentyl]amino)[[(4-methoxyphenyl)(diphenyl)methyl]amino]methylidenecarbamate | C36H46N4O6 | 详情 | 详情 | |
| (XIV) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
| (XV) | 41849 | tert-butyl (Z)-([(4S)-5-(1,3-benzothiazol-2-yl)-4-[(tert-butoxycarbonyl)amino]-5-hydroxypentyl]amino)[[(4-methoxyphenyl)(diphenyl)methyl]amino]methylidenecarbamate | C43H51N5O6S | 详情 | 详情 |