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【结 构 式】

【分子编号】10894

【品名】tert-butyl 2-[(2R,6S)-2,6-diamino-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]-1-hydrazinecarboxylate

【CA登记号】

【 分 子 式 】C17H34N6O6

【 分 子 量 】418.4938

【元素组成】C 48.79% H 8.19% N 20.08% O 22.94%

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:(III)

The cyclization of 2,2'-di(benzyloxycarbonylamino)pimelic acid (I) with PCl5 in methylene chloride gives the bis-N-carboxy anhydride (II), which by reaction with tert-butyl carbazate (A) is converted into the bis(tert-butyloxycarbonylhydrazide) compound (III). The enzymatic hydrolysis of (III) with an aminopeptidase from Streptomyces sapporonensis affords the mono-tert-butoxycarbonylhydrazide (IV), which by selective protection of the amino group with benzyloxycarbonyl chloride (B) under copper chelate conditions yields the selectively protected hydrazide (V). Full protection of (V) with tert-butoxycarbonyl anhydride (C) affords the fully protected monohydrazide (VI), which is condensed with benzyl glycinate (VII) to give the protected dipeptide (VIII). Hydrogenolysis of (VIII) with H2 over Pd/C in methanol-acetic acid yields the di-tert-butoxycarbonyldipeptide (IX), which is condensed with 2-acetoxypropanoylalanylglutamic acid monobenzyl ester (X) by means of isobutoxycarbonyl chloride (D) yielding the protected FK-156 (XI).

1 Hemmi, K.; Nakaguchi, O.; Hashimoto, M.; Taleno, H.; Kitaura, Y.; Okada, S.; An efficient method for selective amino acid protection of meso-2,2'-diaminocarboxylic acid: An improved synthesis of FK-156. Tetrahedron Lett 1982, 23, 6, 693-696.
2 Okada, S.; Hemmi, K.; Takano, H.; Hashimoto, M.; Nakaguchi, O.; Kitaura, Y.; Aratani, M.; Miyazaki, Y.; Studies of a new immunoactive peptide, FK-156. IV. Synthesis od FK-156 and its geometric isomer. J Antibiot 1982, 35, 10, 1300-11.
3 Okahara, M.; Nakahara, K.; Gotoh, T.; Hashimoto, M..; Kino, T.; Aoki, H.; Imanaka, H.; Kohsaka, M.; Nishiura, T.; Kuroda, Y.; Studies on a new immunoactive peptide, FK-156. II. Fermentation, extraction and chemical and biological charaterization. J Antibiot 1982, 35, 10, 1286-92.
4 Gotoh, T.; Imoraka, H.; Nakahara, K.; Tanaka, H.; Uchida, I.; Kawai, Y.; Studies on a new immunoactive peptide, FK-156. III. Structure elucidation. J Antibiot 1982, 35, 10, 1293-99.
5 Imanaka, H.; Nakahaa, K.; Gotoh, T.; Aoki, H.; Iwami, M.; Studies on a new immunoactive peptide, FK-156. I. Taxonomy of the producing strains. J Antibiot 1982, 35, 10, 1280-85.
6 Kitaura, Y.; Nakaguchi, O.; Hemmi, K.; Aratani, M.; Takeno, H.; Okada, S.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New peptides, processes for their preparation and pharmaceutical compsns. containing them. EP 0027260 .
7 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 .
8 Arya, V.P.; Blancafort, P.; Castaner, J.; Serradell, M.N.; FK-156. Drugs Fut 1983, 8, 8, 667.
9 Hemmi, K.; Takeno, H.; Okada, S.; Nakaguchi, O.; Kitaura, Y.; Hashimoto, M.; 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, 7026.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(A) 10893 tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate 870-46-2 C5H12N2O2 详情 详情
(D) 36103 2-[(Chlorocarbonyl)oxy]-2-methylpropane; tert-Butoxycarbonyl chloride C5H9ClO2 详情 详情
(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) 10894 tert-butyl 2-[(2R,6S)-2,6-diamino-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]-1-hydrazinecarboxylate C17H34N6O6 详情 详情
(IV) 10895 (2S,6R)-2,6-Diamino-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid C12H24N4O5 详情 详情
(V) 10896 (2S,6R)-6-Amino-2-[[(benzyloxy)carbonyl]amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid C20H30N4O7 详情 详情
(VI) 10897 (2S,6R)-2-[[(Benzyloxy)carbonyl]amino]-6-[(tert-butoxycarbonyl)amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoic acid C25H38N4O9 详情 详情
(VII) 13601 benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride 1738-68-7 C9H11NO2 详情 详情
(VIII) 36100 tert-butyl 2-[(2R,6S)-6-[[(benzyloxy)carbonyl]amino]-7-[[2-(benzyloxy)-2-oxoethyl]amino]-2-[(tert-butoxycarbonyl)amino]-7-oxoheptanoyl]-1-hydrazinecarboxylate C34H47N5O10 详情 详情
(IX) 36101 2-([(2S,6R)-2-amino-6-[(tert-butoxycarbonyl)amino]-7-[2-(tert-butoxycarbonyl)hydrazino]-7-oxoheptanoyl]amino)acetic acid C19H35N5O8 详情 详情
(X) 36102 (4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid C20H26N2O8 详情 详情
(XI) 36104 (4R,7S,10R,15S)-10-[(benzyloxy)carbonyl]-15-[(4R)-4-[(tert-butoxycarbonyl)amino]-5-[2-(tert-butoxycarbonyl)hydrazino]-5-oxopentyl]-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid C39H59N7O15 详情 详情
(C) 13214 Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate 24424-99-5 C10H18O5 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

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
Extended Information