-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】9(S)-Benzyl-1,13(S)-dimethyl-3,7,10,14,19-pentaoxo-12(S)-(2-phenylvinyl)-1,4,8,11,15-pentaazacyclononadecane-5(R),16(R)-dicarboxylic acid

【CA登记号】

【分子式】C₃₃H₃₉N₅O₉

【分子量】649.70688

【开发单位】University of Birmingham (Originator)

【药理作用】Pharmacological Tools, PP-1 Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The synthesis of the intermediate (S,S)-3-(Fmoc-amino)-2-methyl-5-phenyl-4-pentenoic acid (XI) has been performed as follows: The Horner-Wadsworth-Emmons condensation of cinnamaldehyde (I) with phosphonate (II) by means of NaH in THF gives (E,E)-5-phenyl-2,4-pentadienoic acid ethyl ester (III), which is condensed with (S)-N-benzyl-N-(alpha-methylbenzyl)amine (IV) by means of BuLi in THF to yield the chiral adduct (V). The reaction of (V) with LDA affords the corresponding lithium enolate, which is methylated with methyl iodide in THF to afford the enantioselectively methylated compound (VI). The hydrogenation of (VI) with H2 over Pd(OH)2 in methanol/water/HOAc provides (S,S)-3-amino-2-methyl-5-phenylpentanoic acid methyl ester (VII), which is treated with Boc2O and NaHCO3 in dioxane/water to give the N-protected ester (VIII). The reaction of (VIII) with NBS in CCl4, followed by treatment with DBU at 60 C, yields the pentenoic ester derivative (IX), which is treated first with LiOH and then with TFA to provide (S,S)-3-amino-2-methyl-5-phenyl-4-pentanoic acid (X). Finally, this compound is N-protected by reaction with Fmoc-Cl and K2CO3 in dioxane/water to furnish the target pentenoic acid intermediate (XI).

参考文献中间体

【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696.

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)	41712	(E)-3-phenyl-2-propenal	14371-10-9	C₉H₈O	详情	详情
(II)	13272	Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate	5927-18-4	C₅H₁₁O₅P	详情	详情
(III)	52431	methyl 5-phenyl-2,4-pentadienoate		C₁₂H₁₂O₂	详情	详情
(IV)	38470	(1S)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1S)-1-phenylethyl]amine	38235-77-7	C₁₅H₁₇N	详情	详情
(V)	52432	methyl 5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate		C₂₇H₂₉NO₂	详情	详情
(VI)	52433	methyl 2-methyl-5-phenyl-3-[(1-phenylethyl)(phenylmethyl)amino]-4-pentenoate		C₂₈H₃₁NO₂	详情	详情
(VII)	52434	methyl 3-amino-2-methyl-5-phenylpentanoate		C₁₃H₁₉NO₂	详情	详情
(VIII)	52435	methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenylpentanoate		C₁₈H₂₇NO₄	详情	详情
(IX)	52436	methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoate		C₁₈H₂₅NO₄	详情	详情
(X)	52437	3-amino-2-methyl-5-phenyl-4-pentenoic acid		C₁₂H₁₅NO₂	详情	详情
(XI)	52438	3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid		C₂₇H₂₅NO₄	详情	详情

合成路线2

The deprotection of Wang-RESIN-coupled N-Fmoc-D-aspartic acid alpha-methyl ester (XII) with piperidine in DMF gives the free RESIN-coupled aspartic acid monoester (XIII), which is condensed with N-Fmoc-sarcosine (XIV) by means of PyBOP in DMF to yield the dipeptide (XV). Deprotection with piperidine affords (XVI), and coupling with PyBOP was repeated with the L-glutamate (XVII) to afford tripeptide (XVIII); with deprotected (XIX) and the intermediate amino acid (XI) to provide tetrapeptide (XX); and with deprotected (XXI) and -Fmoc-L-phenylalanine (XXII) to furnish finally the protected RESIN-bounded pentapeptide (XXIII).

参考文献中间体

【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	52438	3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid		C₂₇H₂₅NO₄	详情	详情
(XII)	52439	3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₂₀H₁₉NO₆	详情	详情
(XIII)	52440	3-amino-4-(methyloxy)-4-oxobutanoic acid		C₅H₉NO₄	详情	详情
(XIV)	52441	2-[{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}(methyl)amino]acetic acid		C₁₈H₁₇NO₄	详情	详情
(XV)	52442	3-({2-[{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}(methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₂₃H₂₄N₂O₇	详情	详情
(XVI)	52443	3-{[2-(methylamino)acetyl]amino}-4-(methyloxy)-4-oxobutanoic acid		C₈H₁₄N₂O₅	详情	详情
(XVII)	52444	4-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-5-(methyloxy)-5-oxopentanoic acid		C₂₁H₂₁NO₆	详情	详情
(XVIII)	52445	1-(9H-fluoren-9-yl)-9-methyl-5,13-bis[(methyloxy)carbonyl]-3,8,11-trioxo-2-oxa-4,9,12-triazapentadecan-15-oic acid		C₂₉H₃₃N₃O₁₀	详情	详情
(XIX)	52446	3-({2-[[4-amino-5-(methyloxy)-5-oxopentanoyl](methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₁₄H₂₃N₃O₈	详情	详情
(XX)	52447	1-(9H-fluoren-9-yl)-6,13-dimethyl-9,17-bis[(methyloxy)carbonyl]-3,7,12,15-tetraoxo-5-(2-phenylethenyl)-2-oxa-4,8,13,16-tetraazanonadecan-19-oic acid		C₄₁H₄₆N₄O₁₁	详情	详情
(XXI)	52448	3-({2-[[4-[(3-amino-2-methyl-5-phenyl-4-pentenoyl)amino]-5-(methyloxy)-5-oxopentanoyl](methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₂₆H₃₆N₄O₉	详情	详情
(XXII)	19030	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine	35661-40-6	C₂₄H₂₁NO₄	详情	详情
(XXIII)	52449	1-(9H-fluoren-9-yl)-9,16-dimethyl-12,20-bis[(methyloxy)carbonyl]-3,6,10,15,18-pentaoxo-8-(2-phenylethenyl)-5-(phenylmethyl)-2-oxa-4,7,11,16,19-pentaazadocosan-22-oic acid		C₅₀H₅₅N₅O₁₂	详情	详情

合成路线3

The reaction of (XXIII) with piperidine deprotects the terminal NH2 group, and treatment with TFA cleaves the resin bond, leaving the free pentapeptide (XXIV). The cyclization of (XXIV) by means of BOP-Cl and DIEA in DMF/dichloromethane gives the cyclic pentapeptide dimethyl ester (XXV), which is finally hydrolyzed with LiOH in THF/water to afford the target cyclic pentapeptide.

参考文献中间体

【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXIII)	52449	1-(9H-fluoren-9-yl)-9,16-dimethyl-12,20-bis[(methyloxy)carbonyl]-3,6,10,15,18-pentaoxo-8-(2-phenylethenyl)-5-(phenylmethyl)-2-oxa-4,7,11,16,19-pentaazadocosan-22-oic acid	C₅₀H₅₅N₅O₁₂	详情	详情
(XXIV)	52450	18-amino-7,14-dimethyl-3,11-bis[(methyloxy)carbonyl]-5,8,13,17-tetraoxo-19-phenyl-15-(2-phenylethenyl)-4,7,12,16-tetraazanonadecan-1-oic acid	C₃₅H₄₅N₅O₁₀	详情	详情
(XXV)	52451	dimethyl 1,13-dimethyl-3,7,10,14,19-pentaoxo-12-(2-phenylethenyl)-9-(phenylmethyl)-1,4,8,11,15-pentaazacyclononadecane-5,16-dicarboxylate	C₃₅H₄₃N₅O₉	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)