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【结 构 式】 
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【药物名称】Gludapcin, FK-156 【化学名称】D-Lactyl-L-alanyl-gamma-D-glutamyl-(L)-meso-diaminopimelyl-(L)-glycine 【CA登记号】76490-22-7 【 分 子 式 】C20H33N5O11 【 分 子 量 】519.51291 |
【开发单位】Fujisawa (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Immunomodulators |
合成路线1
A new synthesis of FK-156 has been described: The esterification of meso-2,6-bis(benzyloxycarbonylamino)pimelic acid (I) with diazomethane gives the corresponding dimethyl ester (II), which is submitted to selective hydrolysis with a protease from Bacillus licheniformis, yielding the D-monoester (III). The reaction of (III) with PCl5 in dichloromethane affords the carboxyanhydride (IV), which is condensed with glycine 4-nitrobenzyl ester (V) by means of DIEA in dichloromethane to give the dipeptide (VI). The condensation of (VI) with tert-butoxycarbonyl-D-glutamic acid 1-benzyl ester (VII) by means of BOP and DIEA in dichloromethane-DMF affords the protected tripeptide (VIII), which is selectively deprotected with trifluoroacetic acid to the tripeptide (IX) with a free NH2 group. The condensation of (IX) with O-acetyl-D-lactyl-L-alanine (X) by means of BOP and DIEA as before yields the protected final peptide (XI), which is finally deprotected by hydrogenation with H2 over Pd/C in ethanol-formic acid and saponified with 1N NaOH. O-Acetyl-D-lactyl-L-alanine (X) is prepared as follows: The reaction of D-alanine (XII) with NaNO2 and acetic acid gives O-acetyl-D-lactic acid (XIII), which is condensed with L-alanine benzyl ester (XIV) with BOP and DIEA as before, yielding O-acetyl-D-lactyl-L-alanine benzyl ester (XV), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol-formic acid to (X).
| 【1】 Kolodziejczyk, A.S.; Stoev, S.; Kolodziejczyk, A.M.; New convenient synthesis of immunostimulating peptides containing meso-diaminopimelic acid - Syntheses of FK-565 and. Int J Pept Protein Res 1992, 39, 4, 382. |
| 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) | 10131 | dimethyl (2R,6S)-2,6-bis[[(benzyloxy)carbonyl]amino]heptanedioate | C25H30N2O8 | 详情 | 详情 | |
| (III) | 10132 | (2S,6R)-2,6-Bis[[(benzyloxy)carbonyl]amino]-7-methoxy-7-oxoheptanoic acid | C24H28N2O8 | 详情 | 详情 | |
| (IV) | 10133 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolan-4-yl]pentanoate | C17H20N2O7 | 详情 | 详情 | |
| (V) | 10134 | 4-Nitrobenzyl 2-aminoacetate | C9H10N2O4 | 详情 | 详情 | |
| (VI) | 10135 | methyl (2R,6S)-6-amino-2-[[(benzyloxy)carbonyl]amino]-7-([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate | C25H30N4O9 | 详情 | 详情 | |
| (VII) | 10136 | (4R)-5-(Benzyloxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid; N-t-BOC-D-glutamic acid alpha-benzyl ester | 34404-30-3 | C17H23NO6 | 详情 | 详情 |
| (VIII) | 10137 | 14-benzyl 5-methyl (5R,9S,14R)-18,18-dimethyl-9-[([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16-trioxo-1-phenyl-2,17-dioxa-4,10,15-triazanonadecane-5,14-dicarboxylate | C42H51N5O14 | 详情 | 详情 | |
| (IX) | 10138 | methyl (2R,6S)-6-[[(4R)-4-amino-5-(benzyloxy)-5-oxopentanoyl]amino]-2-[[(benzyloxy)carbonyl]amino]-7-([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate | C37H43N5O12 | 详情 | 详情 | |
| (X) | 10139 | (2S)-2-[[(2R)-2-(Acetoxy)propanoyl]amino]propionic acid | C8H13NO5 | 详情 | 详情 | |
| (XI) | 10140 | 14-benzyl 5-methyl (5R,9S,14R,17S,20R)-17,20-dimethyl-9-[([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16,19,22-pentaoxo-1-phenyl-2,21-dioxa-4,10,15,18-tetraazatricosane-5,14-dicarboxylate | C45H54N6O16 | 详情 | 详情 | |
| (XII) | 10141 | D-Alanine; D-2-Aminopropionic Acid | 338-69-2 | C3H7NO2 | 详情 | 详情 |
| (XIII) | 10142 | (2R)-2-(Acetoxy)propionic acid | 18668-00-3 | C5H8O4 | 详情 | 详情 |
| (XIV) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XV) | 10144 | benzyl (2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoate | C15H19NO5 | 详情 | 详情 |
合成路线2
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3
Hydrogenolysis of (XI) with H2 over Pd/C in methanol-acetic acid eliminates the benzyl group giving (XII), which is treated with K2CO3 to eliminate the acetyl group affording (XIII). Treatment of (XIII) with trifluoroacetic acid eliminates the tert-butoxy groups giving FK-156 hydrazide (XIV), which is finally oxidized and hydrolyzed with sodium periodate and H2SO4.
| 【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】 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. |
| 【3】 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. |
| 【4】 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. |
| 【5】 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. |
| 【6】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 . |
| 【7】 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 . |
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XII) | 36105 | (4R,7S,10R,15S)-15-[(4R)-4-[(tert-butoxycarbonyl)amino]-5-[2-(tert-butoxycarbonyl)hydrazino]-5-oxopentyl]-10-carboxy-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid | C32H53N7O15 | 详情 | 详情 | |
| (XIII) | 36106 | (5S,10R,13S,16R)-5-[(4R)-4-[(tert-butoxycarbonyl)amino]-5-[2-(tert-butoxycarbonyl)hydrazino]-5-oxopentyl]-10-carboxy-16-hydroxy-13-methyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid | C30H51N7O14 | 详情 | 详情 | |
| (XIV) | 36107 | (5S,10R,13S,16R)-5-[(4R)-4-amino-5-hydrazino-5-oxopentyl]-10-carboxy-16-hydroxy-13-methyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid | C20H35N7O10 | 详情 | 详情 |
合成路线4
The reaction of the dianhydride (II) with benzyl carbazate (E) gives the bis(benzyloxycarbonylhydrazide) compound (XXI), which by an enzymatic treatment with an aminopeptidase from Streptomyces sapporonensis yields the monohydrazide (XXII). The protection of (XXII) with benzyloxycarbonyl chloride (B) affords the protected monohydrazide (XXIII), which is cyclized by treatment with SOCl2 giving the monocarboxy anhydride (XXIV). Hydrolysis of (XXIV) with HCl yields amino acid (XXV), which is condensed with glycine (XXVI) to afford the dipeptide (XXVII). The condensation of (XXVII) with (X) gives the protected FK-156 (XXVIII), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol-acetic acid affording FK-156 still protected with an acetoxy and a hydrazine group (XXIX).
| 【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】 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. |
| 【3】 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. |
| 【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】 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. |
| 【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 |
| (E) | 36108 | benzyl 1-hydrazinecarboxylate | 5331-43-1 | C8H10N2O2 | 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 | |
| (X) | 36102 | (4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid | C20H26N2O8 | 详情 | 详情 | |
| (XXI) | 36109 | benzyl 2-((2R,6S)-2,6-diamino-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoyl)-1-hydrazinecarboxylate | C23H30N6O6 | 详情 | 详情 | |
| (XXII) | 36110 | (2S,6R)-2,6-diamino-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid | C15H22N4O5 | 详情 | 详情 | |
| (XXIII) | 36111 | (2S,6R)-2,6-bis[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid | C31H34N4O9 | 详情 | 详情 | |
| (XXIV) | 36112 | benzyl 2-[(2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolidin-4-yl]pentanoyl]-1-hydrazinecarboxylate | C24H26N4O8 | 详情 | 详情 | |
| (XXV) | 36113 | (2S,6R)-2-amino-6-[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoic acid | C23H28N4O7 | 详情 | 详情 | |
| (XXVI) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (XXVII) | 36114 | 2-[((2S,6R)-2-amino-6-[[(benzyloxy)carbonyl]amino]-7-[2-[(benzyloxy)carbonyl]hydrazino]-7-oxoheptanoyl)amino]acetic acid | C25H31N5O8 | 详情 | 详情 | |
| (XXVIII) | 36115 | (4R,7S,10R,15S)-10-[(benzyloxy)carbonyl]-15-((4R)-4-[[(benzyloxy)carbonyl]amino]-5-[2-[(benzyloxy)carbonyl]hydrazino]-5-oxopentyl)-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid | C45H55N7O15 | 详情 | 详情 | |
| (XXIX) | 36116 | (4R,7S,10R,15S)-15-[(4R)-4-amino-5-hydrazino-5-oxopentyl]-10-carboxy-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid | C22H37N7O11 | 详情 | 详情 |
合成路线5
The reaction of (XXIX) with Br2 eliminates the hydrazino group giving acetyl-FK-156 (XXX), which is finally treated with Na2CO3 to eliminate the acetate group.
| 【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】 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. |
| 【3】 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. |
| 【4】 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. |
| 【5】 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. |
| 【6】 Kitaura, Y.; Nakaguchi, O.; Hemmi, K. (Fujisawa Pharmaceutical Co., Ltd.); New lactyl tetrapeptide, processes for preparation thereof and pharmaceutical compsns. containing it. EP 0011283 . |
| 【7】 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 . |
| 【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 |
|---|---|---|---|---|---|---|
| (XXIX) | 36116 | (4R,7S,10R,15S)-15-[(4R)-4-amino-5-hydrazino-5-oxopentyl]-10-carboxy-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid | C22H37N7O11 | 详情 | 详情 | |
| (XXX) | 36117 | (4R,7S,10R,15S)-15-[(4R)-4-amino-4-carboxybutyl]-10-carboxy-4,7-dimethyl-2,5,8,13,16-pentaoxo-3-oxa-6,9,14,17-tetraazanonadecan-19-oic acid | C22H35N5O12 | 详情 | 详情 |
合成路线6
The lactyl dipeptide (X) is obtained as follows: The condensation of tert-butoxycarbonylalanine (XV) with glutamic acid (XVI) gives tert-butoxycarbonylalanylglutamic acid (XVII), which is esterified partially with benzyl bromide (F) yielding the mono ester (XVIII). Elimination of the tert-butoxycarbonyl group of (XVIII) with trifluoroacetic acid affords alanylglutamic acid monobenzyl ester (XIX), which is finally condensed with 2-acetoxypropionyl chloride (XX) to afford (X).
| 【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】 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. |
| 【3】 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. |
| 【4】 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. |
| 【5】 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. |
| 【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 |
|---|---|---|---|---|---|---|
| (F) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 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 | |
| (XV) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (XVI) | 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 |
| (XVII) | 36118 | (2R)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)pentanedioic acid | C13H22N2O7 | 详情 | 详情 | |
| (XVIII) | 36119 | (4R)-5-(benzyloxy)-4-([(2S)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-5-oxopentanoic acid | C20H28N2O7 | 详情 | 详情 | |
| (XIX) | 36120 | (4R)-4-[[(2S)-2-aminopropanoyl]amino]-5-(benzyloxy)-5-oxopentanoic acid | C15H20N2O5 | 详情 | 详情 | |
| (XX) | 36121 | 2-chloro-1-methyl-2-oxoethyl acetate | 36394-75-9 | C5H7ClO3 | 详情 | 详情 |