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【结 构 式】

【分子编号】10901

【品名】(4R)-5-(Benzyloxy)-4-(heptanoylamino)-5-oxopentanoic acid

【CA登记号】

【 分 子 式 】C19H27NO5

【 分 子 量 】349.42712

【元素组成】C 65.31% H 7.79% N 4.01% O 22.89%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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

该中间体在本合成路线中的序号:(XI)

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
Extended Information