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【结 构 式】 
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【分子编号】10898 【品名】benzyl (2R)-2-aminopropanoate 【CA登记号】 |
【 分 子 式 】C10H13NO2 【 分 子 量 】179.21876 【元素组成】C 67.02% H 7.31% N 7.82% O 17.85% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(XIII)This compound can be obtained by two related ways: 1) The condensation of 2-O-(p-toluenesulfonyl)-D-lactoyl chloride (IV) with 1-methyl-2-oxoimidazolidine-4(S)-carboxylic acid tert-butyl ester (VIII) by means of potassium tert-butoxide in THF gives 1-methyl-2-oxo-3-[2(R)-(p-toluenesulfonyloxy)propionyl]imidazolidine-4(S)-carboxylic acid tert-butyl ester (IX), which is then condensed with 2(S)-amino-4-phenylbutyric acid ethyl ester (X) by means of triethylamine in DMSO yielding 3-[N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-1-methyl-2-oxoimidazolidine-4(S)-carboxylic acid tert-butyl ester (XI). Finally, this compound is hydrolyzed with HCl in dioxane - water. The starting compounds (IV) and (VIII) are obtained as follows: a) The condensation of D-lactic acid methyl ester with p-toluenesulfonyl chloride and triethylamine gives the corresponding sulfonate (II), which is hydrolyzed with NaOH to the free acid (III). Finally, this compound is treated with refluxing SOCl2 to give acid chloride (IV). b) The esterification of 3-(benzyloxycarbonyl)-2-oxoimidazolidine-4(S)-carboxylic acid (V) with tert-butanol gives the corresponding ester (VI), which is methylated with methyl iodide and K2CO3 to 3-(benzyloxycarbonyl)-1-methyl-2-oxoimidazolidine-4(S)-carboxylic acid tert-butyl ester (VII). This compound is debenzylated by hydrogenation with H2 over Pd/C to afford imidazolidine ester (VIII). 2) The condensation of 2(S)-bromo-4-phenylbutyric acid ethyl ester (XII) with L-alanine benzyl ester (XIII) by means of K2CO3 in DMSO gives N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine benzyl ester (XIV), which is debenzylated by hydrogenation as before yielding the free acid (XV). The esterification of (XV) with N-hydroxysuccinimide gives the corresponding active ester (XVI), which is finally condensed with imidazolidine ester (VIII) by means of potassium tert-butoxide to afford the precursor (XI) already obtained.
| 【1】 Yoneda, N.; Kato, S.; Hayashi, K.; Ochiai, K. (Tanabe Seiyaku Co., Ltd.); Agents for the treatment of hypertension. JP 1985013715 . |
| 【2】 Yoneda, N.; Kato, J.; Hayashi, K.; Ochiani, T.; Kinashi, K. (Tanabe Seiyaku Co., Ltd.); Quinolinecarboxylic acid derivs. and method for their preparation. EP 0095163; ES 8603427; US 4508727 . |
| 【3】 Hayashi, K.; Kubota, H. (Tanabe Seiyaku Co., Ltd.); Process for preparing optically active 2-oxoimidazolidine derivs. EP 0373881 . |
| 【4】 Kato, J.; Hayashi, K.; Ishida, R.; Yoneda, N.; Ochiai, T.; Kubo, M.; Nunami, K.-I.; Studies on angiotensin converting enzyme inhibitors. 4. Synthesis and angiotensin converting enzyme inhibitory activities of 3-acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic acid derivatives. J Med Chem 1989, 32, 2, 289. |
| 【5】 Hayashi, K.; Kubota, H.; Yamagishi, M.; Nunami, K.-I.; Nishimoto, S.; Studies on angiotensin converting enzyme inhibitors. V. The diastereoselective synthesis of 2-oxoimidazolidine derivatives. Chem Pharm Bull 1991, 39, 6, 1374. |
| 【6】 Prous, J.; Castaner, J.; Imidapril Hydrochloride. Drugs Fut 1992, 17, 7, 551. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 | |
| (I) | 11591 | methyl (2R)-2-hydroxypropanoate | 17392-83-5 | C4H8O3 | 详情 | 详情 |
| (II) | 15653 | Methyl (2S)-2-{[(4-methylphenyl)sulfonyl]oxy}propanoate | C11H14O5S | 详情 | 详情 | |
| (III) | 15654 | (2R)-2-[[(4-methylphenyl)sulfonyl]oxy]propionic acid | C10H12O5S | 详情 | 详情 | |
| (IV) | 15655 | (1R)-2-chloro-1-methyl-2-oxoethyl 4-methylbenzenesulfonate | C10H11ClO4S | 详情 | 详情 | |
| (V) | 15656 | (4S)-3-[(benzyloxy)carbonyl]-2-oxotetrahydro-1H-imidazole-4-carboxylic acid | C12H12N2O5 | 详情 | 详情 | |
| (VI) | 15657 | 1-benzyl 5-(tert-butyl) (5S)-2-oxotetrahydro-1H-imidazole-1,5-dicarboxylate | C16H20N2O5 | 详情 | 详情 | |
| (VII) | 15658 | 1-benzyl 5-(tert-butyl) (5S)-3-methyl-2-oxotetrahydro-1H-imidazole-1,5-dicarboxylate | C17H22N2O5 | 详情 | 详情 | |
| (VIII) | 15659 | tert-butyl (4S)-1-methyl-2-oxotetrahydro-1H-imidazole-4-carboxylate | C9H16N2O3 | 详情 | 详情 | |
| (IX) | 15660 | tert-butyl (4S)-1-methyl-3-((2R)-2-[(4-methylphenyl)sulfonyl]propanoyl)-2-oxotetrahydro-1H-imidazole-4-carboxylate | C19H26N2O7S | 详情 | 详情 | |
| (X) | 15661 | ethyl (2S)-2-amino-4-phenylbutanoate | C12H17NO2 | 详情 | 详情 | |
| (XI) | 15662 | tert-butyl (4S)-3-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1-methyl-2-oxotetrahydro-1H-imidazole-4-carboxylate | C24H35N3O6 | 详情 | 详情 | |
| (XII) | 15663 | ethyl (2S)-2-bromo-4-phenylbutanoate | C12H15BrO2 | 详情 | 详情 | |
| (XIII) | 10898 | benzyl (2R)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XIV) | 15665 | ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XV) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
| (XVI) | 15667 | ethyl (2S)-2-([(1S)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethyl]amino)-4-phenylbutanoate | C19H24N2O6 | 详情 | 详情 |