(2S)-5-[(Amino[[(benzyloxy)carbonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】14074

【品名】(2S)-5-[(Amino[[(benzyloxy)carbonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid

【CA登记号】

【分子式】C₁₉H₂₈N₄O₆

【分子量】408.45468

【元素组成】C 55.87% H 6.91% N 13.72% O 23.5%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

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.

参考文献中间体

合成目标

【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：(X)

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.

参考文献中间体

合成目标

【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

Extended Information