|
【结 构 式】 
|
【分子编号】36102 【品名】(4R)-4-[((2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoyl)amino]-5-(benzyloxy)-5-oxopentanoic acid 【CA登记号】 |
【 分 子 式 】C20H26N2O8 【 分 子 量 】422.43512 【元素组成】C 56.87% H 6.2% N 6.63% O 30.3% |
与该中间体有关的原料药合成路线共 3 条
合成路线1
该中间体在本合成路线中的序号：(X)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：(X)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3
该中间体在本合成路线中的序号：(X)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 |
Extended Information