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【结 构 式】 
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【药物名称】FR-41565, FK-565 【化学名称】N-Heptanoyl-D-gamma-glutamyl-L-erythro-alpha,epsilon-diaminopimelyl-D-alanine 【CA登记号】79335-75-4 【 分 子 式 】C22H38N4O9 【 分 子 量 】502.56956 |
【开发单位】Fujisawa (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Immunomodulators, Immunostimulants, Oncolytic Drugs |
合成路线1
1) The cyclization of meso-2,6-bis(benzyloxycarbonylamino)heptanedioic acid (I) with PCl5 gives the corresponding bis oxazolidinedione (II), which is treated with tert-butyl carbazate (III) yielding the bis hydrazide (IV). Enzymatic hydrolysis of (IV) with Streptomyces sapporonensis affords the (S)-monoacid (V), which is selectively protected with benzyl chloroformate and copper chelate (VI). A second protection reaction of (VI) with tert-butoxycarbonyl anhydride gives the amino protected acid (VII) , which is condensed with D-alanine benzyl ester (VIII) by means of isobutyl chloroformate to afford the acylated D-alanine (IX). Elimination of the benzyloxycarbonyl groups of (IX) by hydrogenolysis yields compound (X) with a free amino group, which is condensed with N-heptanoyl-D-glutamic acid 1-benzyl monoester (XI) to give the protected FK-565 precursor (XII). Finally, this compound is deprotected with trifluoroacetic acid and sodium periodate.
| 【1】 Takeno, H.; Kitaura, Y.; Hashimoto, M.; Hemmi, K.; Nakaguchi, O.; Okada, S.; Total synthesis of FK-156 isolated from a Streptomyces as an immunostimulating peptide: Application of a novel copper chelate amino protection. J Am Chem Soc 1981, 103, 23, 7026-8. |
| 【2】 Hoshi, A.; Castaner, J.; FK-565. Drugs Fut 1994, 19, 3, 243. |
| 【3】 Hashimoto, M.; Hemmi, K.; Aratani, M.; Nakaguchi, O.; Kitaura, Y.; Yonishi, S.; Okada, S.; Takeno, H.; Synthesis and RES-stimulating activity of bacterial cell-wall peptidoglycan peptides related to FK-156. Experientia 1982, 38, 1101-3. |
| 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) | 10130 | (2R,6S)-2,6-Bis[[(benzyloxy)carbonyl]amino]heptanedioic acid | C23H26N2O8 | 详情 | 详情 | |
| (II) | 10892 | (4R)-4-[3-[(4S)-2,5-Dioxo-1,3-oxazolan-4-yl]propyl]-1,3-oxazolane-2,5-dione | C9H10N2O6 | 详情 | 详情 | |
| (III) | 10893 | tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate | 870-46-2 | C5H12N2O2 | 详情 | 详情 |
| (IV) | 10894 | tert-butyl 2-[(2R,6S)-2,6-diamino-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]-1-hydrazinecarboxylate | C17H34N6O6 | 详情 | 详情 | |
| (V) | 10895 | (2S,6R)-2,6-Diamino-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid | C12H24N4O5 | 详情 | 详情 | |
| (VI) | 10896 | (2S,6R)-6-Amino-2-[[(benzyloxy)carbonyl]amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid | C20H30N4O7 | 详情 | 详情 | |
| (VII) | 10897 | (2S,6R)-2-[[(Benzyloxy)carbonyl]amino]-6-[(tert-butoxycarbonyl)amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid | C25H38N4O9 | 详情 | 详情 | |
| (VIII) | 10898 | benzyl (2R)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (IX) | 10899 | tert-butyl 2-[(2R,6S)-6-[[(benzyloxy)carbonyl]amino]-7-[[(1R)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-2-[(tert-butoxycarbonyl)amino]-7-oxoheptanoyl]-1-hydrazinecarboxylate | C35H49N5O10 | 详情 | 详情 | |
| (X) | 10900 | (2R)-2-([(2S,6R)-2-Amino-6-[(tert-butoxycarbonyl)amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]amino)propionic acid | C20H37N5O8 | 详情 | 详情 | |
| (XI) | 10901 | (4R)-5-(Benzyloxy)-4-(heptanoylamino)-5-oxopentanoic acid | C19H27NO5 | 详情 | 详情 | |
| (XII) | 10902 | (2R)-2-([(2S,6R)-2-[[(4R)-5-(Benzyloxy)-4-(heptanoylamino)-5-oxopentanoyl]amino]-6-[(tert-butoxycarbonyl)amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]amino)propionic acid | C39H62N6O12 | 详情 | 详情 |
合成路线2
2) The methylation of meso-2,6-bis(benzyloxycarbonylamino)heptanedioic acid (I) with diazomethane gives the corresponding dimethyl ester (XIII), which is submitted to a selective hydrolysis with a protease type VIII enzyme yielding the monoester (XIV). The cyclization of (XIV) with PCl5 affords the oxazolidinedione (XV), which is condensed with D-alanine 4-nitrobenzyl ester (XVI) to give compound (XVII) with a free amino group that is condensed with D-glutamic acid monoester (XI) affording the fully protected FK-565 derivative (XVIII), which is first debenzylated by hydrogenolysis to methyl ester (XIX), and finally hydrolyzed with NaOH.
| 【1】 Kolodziejczyk, A.M.; Stoev, S.; Kolodziejczyk, A.S.; New convenient synthesis of immunostimulating peptides containing meso-diaminopimelic acid. Syntheses of FK-565 and FK-156. Int J Peptide Protein Res 1992, 39, 282-7. |
| 【2】 Hoshi, A.; Castaner, J.; FK-565. Drugs Fut 1994, 19, 3, 243. |
| 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) | 10130 | (2R,6S)-2,6-Bis[[(benzyloxy)carbonyl]amino]heptanedioic acid | C23H26N2O8 | 详情 | 详情 | |
| (XI) | 10901 | (4R)-5-(Benzyloxy)-4-(heptanoylamino)-5-oxopentanoic acid | C19H27NO5 | 详情 | 详情 | |
| (XIII) | 10131 | dimethyl (2R,6S)-2,6-bis[[(benzyloxy)carbonyl]amino]heptanedioate | C25H30N2O8 | 详情 | 详情 | |
| (XIV) | 10132 | (2S,6R)-2,6-Bis[[(benzyloxy)carbonyl]amino]-7-methoxy-7-oxoheptanoic acid | C24H28N2O8 | 详情 | 详情 | |
| (XV) | 10133 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolan-4-yl]pentanoate | C17H20N2O7 | 详情 | 详情 | |
| (XVI) | 10906 | 4-nitrobenzyl (2R)-2-aminopropanoate | C10H12N2O4 | 详情 | 详情 | |
| (XVII) | 10907 | methyl (2R,6S)-6-amino-2-[[(benzyloxy)carbonyl]amino]-7-([(1R)-1-methyl-2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate | C26H32N4O9 | 详情 | 详情 | |
| (XVIII) | 10908 | 14-benzyl 5-methyl (5R,9S,14R)-9-[([(1R)-1-methyl-2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16-trioxo-1-phenyl-2-oxa-4,10,15-triazadocosane-5,14-dicarboxylate | C45H57N5O13 | 详情 | 详情 | |
| (XIX) | 10909 | (2R)-5-[[(1S,5R)-5-Amino-1-([[(1R)-1-carboxyethyl]amino]carbonyl)-6-methoxy-6-oxohexyl]amino]-2-(heptanoylamino)-5-oxopentanoic acid | C23H40N4O9 | 详情 | 详情 |