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【结 构 式】 
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【分子编号】14073 【品名】(2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid 【CA登记号】13726-76-6 |
【 分 子 式 】C11H22N4O4 【 分 子 量 】274.32024 【元素组成】C 48.16% H 8.08% N 20.42% O 23.33% |
合成路线1
该中间体在本合成路线中的序号：(I)The synthesis of GYKI-14766 is as follows: N2-tert-Butoxycarbonyl-L-arginine (I) was converted to the N6-benzyloxycarbonyl derivative (II). Treatment of (II) with isobutoxycarbonyl chloride and N-methylmorpholine gave the aminolactam (III). Dicyclohexylcarbodiimide-mediated esterification of N-benzyloxycarbonyl-D-phenylalanine (IV) with 2,4,5-trichlorophenol gave the active ester (V), which was coupled with L-proline to the dipeptide (VI). Methylation with iodomethane afforded the N-methyl derivative isolated as the cyclohexylamine salt (VII). The fragments (III) and (VII) were coupled via the mixed anhydride of (VII), generated as in the case of (II), giving the tripeptide lactam (VIII). Reduction with lithium aluminum hydride at low temperature converted (VIII) to the aldehyde (IX), which was finally deprotected to the end product.
| 【1】 Nogradi, M.; GYKI-14766. Drugs Fut 1992, 17, 12, 1087. |
| 【2】 Széll, E.; Bagdy, D.; Bajusz, S.; et al.; Highly active and selective anticoagulants: D-Phe-Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation and its stable N-methyl derivative, D-MePhe-Pro-Arg-H. J Med Chem 1990, 33, 6, 1729-35. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16126 | 2,4,5-trichlorophenol | 95-95-4 | C6H3Cl3O | 详情 | 详情 | |
| (I) | 14073 | (2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | 13726-76-6 | C11H22N4O4 | 详情 | 详情 |
| (II) | 14074 | (2S)-5-[(Amino[[(benzyloxy)carbonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C19H28N4O6 | 详情 | 详情 | |
| (III) | 14075 | tert-butyl N-[(3S)-1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxotetrahydro-3(2H)-pyridinyl]carbamate | C19H26N4O5 | 详情 | 详情 | |
| (IV) | 14076 | (2R)-3-Phenyl-2-[[(2-phenylacetyl)oxy]amino]propionic acid | C17H17NO4 | 详情 | 详情 | |
| (V) | 14077 | 2,4,5-trichlorophenyl (2R)-3-phenyl-2-[[(2-phenylacetyl)oxy]amino]propanoate | C23H18Cl3NO4 | 详情 | 详情 | |
| (VI) | 14078 | (2S)-1-((2R)-3-Phenyl-2-[[(2-phenylacetyl)oxy]amino]propanoyl)tetrahydro-1H-pyrrole-2-carboxylic acid | C22H24N2O5 | 详情 | 详情 | |
| (VII) | 14079 | (2R)-1-((2S)-2-[[(Cyclohexylamino)oxy]carbonyl]pyrrolidinyl)-2-[methyl[(2-phenylacetyl)oxy]amino]-3-phenyl-1-propanone | C29H37N3O5 | 详情 | 详情 | |
| (VIII) | 14080 | tert-butyl (1R)-2-((2S)-2-[[((3S)-1-[amino[(tert-butoxycarbonyl)imino]methyl]-2-oxopiperidinyl)amino]carbonyl]pyrrolidinyl)-1-benzyl-2-oxoethyl(methyl)carbamate | C31H46N6O7 | 详情 | 详情 | |
| (IX) | 14081 | tert-butyl (E)-amino[((4S)-4-[[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropanoyl]pyrrolidinyl)carbonyl]amino]-5-oxopentyl)amino]methylidenecarbamate | C31H48N6O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Solution-phase synthesis: Protection of the side-chain of Boc-Arg-OH (IX) by treatment with Cbz-Cl in aqueous NaHCO3 yields Boc-Arg(Cbz)-OH (X), which is then converted into arginine lactam (XI) by a first treatment with isobutyl chloroformate (i-BuO2CCl) and NMM in THF followed by Boc deprotection with HCl/dioxane. Condensation of N-deprotected lactam (XI) with protected dipeptide (XII) by means of BOP/DIEA in DMF provides the tripeptide lactam (XIII), which is finally reduced with LiAlH4 in THF and hydrogenated over Pd/C for protecting group removal.
| 【1】 Marlowe, C.K.; Sinha, U.; Scarborough, R.M.; Gunn, A.C.; Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: Structures based on the (D)-Arg-Gly-Arg tripeptide sequence. Bioorg Med Chem Lett 2000, 10, 1, 13. |
| 【2】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. EP 0846125; JP 1999507626; US 5919765; WO 9640743 . |
| 【3】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. US 5721214 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 14073 | (2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | 13726-76-6 | C11H22N4O4 | 详情 | 详情 |
| (X) | 14074 | (2S)-5-[(Amino[[(benzyloxy)carbonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C19H28N4O6 | 详情 | 详情 | |
| (XI) | 43542 | benzyl (E)-amino[(3S)-3-amino-2-oxopiperidinyl]methylidenecarbamate | C14H18N4O3 | 详情 | 详情 | |
| (XII) | 43543 | (E,10R)-5-amino-10-[(benzylsulfonyl)amino]-3,11-dioxo-1-phenyl-2-oxa-4,6,12-triaza-4-tetradecen-14-oic acid | C23H29N5O7S | 详情 | 详情 | |
| (XIII) | 43544 | benzyl (E)-amino([(4R)-5-[(2-[[(3S)-1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxopiperidinyl]amino]-2-oxoethyl)amino]-4-[(benzylsulfonyl)amino]-5-oxopentyl]amino)methylidenecarbamate | C37H45N9O9S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIX)Simultaneous coupling of five N-Boc-arginin (XIX) residues to the free amino groups of the peptide template (XVIII), followed by acid deprotection of the Boc groups, furnished (XX). To this were assembled five N-Boc-proline residues (XXI) to provide, after acid deprotection, resin (XXII). Then, reductive condensation with Boc-protected lysinal (XXIII) furnished the protected pseudopeptide adduct (XXIV). Finally, simultaneous cleavage from the resin and removal of protecting groups was effected by treatment with anhydrous hydrogen fluoride.
| 【1】 Callebaut, C.; et al.; Inhibition of HIV infection by pseudopeptides blocking viral envelope glycoprotein-mediated membrane fusion and cell death. Virology 1996, 218, 1, 181. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 42143 | (3S,6S,9R,15R)-3,9-bis(4-aminobutyl)-1-[(2S)-1-((5S,8S)-5-(4-aminobutyl)-16-(4-chlorophenyl)-8-[[(2S)-2,6-diaminohexanoyl]amino]-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-anoyl)pyrrolidinyl]-6-[3-(cyclohexyloxy)-3-oxopropyl]-15-[[(4-methylbenzyl)s | C70H111ClN14O15S | 详情 | 详情 | |
| (XIX) | 14073 | (2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | 13726-76-6 | C11H22N4O4 | 详情 | 详情 |
| (XX) | 42144 | C100H171ClN34O24S | 详情 | 详情 | ||
| (XXI) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (XXII) | 42145 | C81H126ClN19O17SArg4Pro4 | 详情 | 详情 | ||
| (XXIII) | 42146 | tert-butyl (1S)-5-[(tert-butoxycarbonyl)amino]-1-formylpentylcarbamate | C16H30N2O5 | 详情 | 详情 | |
| (XXIV) | 42147 | C205H350ClN53O50S | 详情 | 详情 |