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【结 构 式】 
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【分子编号】15665 【品名】ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate 【CA登记号】 |
【 分 子 式 】C22H27NO4 【 分 子 量 】369.46072 【元素组成】C 71.52% H 7.37% N 3.79% O 17.32% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of (IX) with alanine benzyl ester (X) with sodium cyanoboohydride as before gives N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine benzyl ester (XI), which is submitted to fractional crystallization with maleic acid yielding N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine benzyl ester (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol yielding the free acid (XIII). Finally, this compound is condensed with spirane (IV) through the N-hydroxysuccinimide ester, in the usual way.
| 【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 . |
| 【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
| (IV) | 27316 | methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C8H13NO2S2 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
| (X) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XI) | 27321 | ethyl 2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XII) | 15665 | ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XIII) | 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 |
合成路线2
该中间体在本合成路线中的序号：(XIV)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 |