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【结 构 式】 
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【分子编号】30898 【品名】(2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid 【CA登记号】 |
【 分 子 式 】C13H18N2O4 【 分 子 量 】266.297 【元素组成】C 58.63% H 6.81% N 10.52% O 24.03% |
合成路线1
该中间体在本合成路线中的序号：(I)Conversion of amino acid (I) into its methyl ester derivative (II) by means of SOCl2 in MeOH, followed by coupling with ethyl isocyanatoacetate (III) and Et3N in CH2Cl2/THF yields derivative (IV). Cyclization of (IV) by means of H2O/HCl affords hydantoin (V), which reacts with 2-methylthio-2-imidazoline (VI) in an aqueous NaOH solution to provide cyclic guanidine derivative (VII). Treatment of amino acid (VIII) with isobutylene (IX) and H2SO4 in dioxane affords t-Bu ester (X), which then couples with (VII) by means of HOBt and DCC in DMF to furnish derivative (XI). Finally, tert-butyl ester is hydrolyzed by treatment with TFA in the presence of 1,2-dimercaptoethane.
| 【1】 Knolle, J.; Peyman, A.; Wehner, V.; et al.; RGD mimetics containing a central hydantoin scaffold: alphavbeta3 vs alphaIIbbeta3 selective requirements. Bioorg Med Chem Lett 2000, 10, 2, 179. |
| 【2】 Wehner, V.; Knolle, J.; Stilz, H.U.; Carniato, D.; Gourvest, J.-F.; Gadek, T.; McDowell, R. (Aventis SA); Inhibitors of bone resorption and vitronectin receptor antagonists. DE 19626701; DE 19635522; EP 0796855 . |
| 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) | 30898 | (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (II) | 42993 | methyl (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoate | C14H20N2O4 | 详情 | 详情 | |
| (III) | 18312 | ETHYL ISOCYANATOACETATE; ethyl 2-isocyanatoacetate | 2949-22-6 | C5H7NO3 | 详情 | 详情 |
| (IV) | 42994 | 12-ethyl 8-methyl (8S)-3,10-dioxo-1-phenyl-2-oxa-4,9,11-triazadodecane-8,12-dicarboxylate | C19H27N3O7 | 详情 | 详情 | |
| (V) | 42295 | (2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]propanamide | C25H32N4O2S | 详情 | 详情 | |
| (VI) | 42996 | 4,5-dihydro-1H-imidazol-2-yl methyl sulfide; 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole | 5464-11-9 | C4H8N2S | 详情 | 详情 |
| (VII) | 42997 | 2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetic acid | C11H17N5O4 | 详情 | 详情 | |
| (VIII) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (IX) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (X) | 18009 | tert-butyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (XI) | 42998 | tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetyl)amino]propanoate | C26H37N7O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The fully protection of Nomega-(benzyloxycarbonyl)-L-ornithine (I) by usual methods gives Nomega-(benzyloxycarbonyl)-Nalpha-(tert-butoxycarbonyl)-L-ornithine tert-butyl ester (II), which is selectively deprotected at the omega amino group with H2 over Pd/C yielding the ornithine (III). The reaction of (III) with thiophosgene affords the isothiocyanate (IV), which is treated with hydrazine to afford the aminothiourea (V). Finally, this compound is deprotected with 4M HCl.
| 【1】 Ichimori, K.; Stuehr, D.J.; Synthesis and evaluation of new sulfur-containing L-arginine-derived inhibitors of nitric oxide synthase. J Med Chem 1999, 42, 10, 1842. |
| 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) | 30898 | (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (II) | 30899 | tert-butyl (2S)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoate | C22H34N2O6 | 详情 | 详情 | |
| (III) | 30900 | tert-butyl (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 30901 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate | C15H26N2O4S | 详情 | 详情 | |
| (V) | 30904 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(hydrazinocarbothioyl)amino]pentanoate | C15H30N4O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The fully protection of Nomega-(benzyloxycarbonyl)-L-ornithine (I) by usual methods gives Nomega-(benzyloxycarbonyl)-Nalpha-(tert-butoxycarbonyl)-L-ornithine tert-butyl ester (II), which is selectively deprotected at the omega amino group with H2 over Pd/C yielding the ornithine (III). The reaction of (III) with thiophosgene affords the isothiocyanate (IV), which is treated with hydroxylamine to afford the hydroxythiourea (V). The methylation of (V) with methyl iodide and NaH affords the S-methyl derivative (VI), which is finally deprotected with 4M HCl.
| 【1】 Ichimori, K.; Stuehr, D.J.; Synthesis and evaluation of new sulfur-containing L-arginine-derived inhibitors of nitric oxide synthase. J Med Chem 1999, 42, 10, 1842. |
| 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) | 30898 | (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (II) | 30899 | tert-butyl (2S)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoate | C22H34N2O6 | 详情 | 详情 | |
| (III) | 30900 | tert-butyl (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 30901 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate | C15H26N2O4S | 详情 | 详情 | |
| (V) | 30902 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(hydroxyamino)carbothioyl]amino]pentanoate | C15H29N3O5S | 详情 | 详情 | |
| (VI) | 30903 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(Z)-(hydroxyamino)(methylsulfanyl)methylidene]amino]pentanoate | C16H31N3O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The fully protection of Nomega-(benzyloxycarbonyl)-L-ornithine (I) by usual methods gives Nomega-(benzyloxycarbonyl)-Nalpha-(tert-butoxycarbonyl)-L-ornithine tert-butyl ester (II), which is selectively deprotected at the omega amino group with H2 over Pd/C yielding the ornithine (III). The reaction of (III) with thiophosgene affords the isothiocyanate (IV), which is treated with hydrazine to afford the aminothiourea (V). The methylation of (V) with methyl iodide and NaH affords the S-methyl derivative (VI), which is finally deprotected with 4M HCl.
| 【1】 Ichimori, K.; Stuehr, D.J.; Synthesis and evaluation of new sulfur-containing L-arginine-derived inhibitors of nitric oxide synthase. J Med Chem 1999, 42, 10, 1842. |
| 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) | 30898 | (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (II) | 30899 | tert-butyl (2S)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoate | C22H34N2O6 | 详情 | 详情 | |
| (III) | 30900 | tert-butyl (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 30901 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate | C15H26N2O4S | 详情 | 详情 | |
| (V) | 30904 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(hydrazinocarbothioyl)amino]pentanoate | C15H30N4O4S | 详情 | 详情 | |
| (VI) | 30905 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(Z)-hydrazino(methylsulfanyl)methylidene]amino]pentanoate | C16H32N4O4S | 详情 | 详情 |