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【结 构 式】

【分子编号】52438

【品名】3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid

【CA登记号】

【 分 子 式 】C27H25NO4

【 分 子 量 】427.49984

【元素组成】C 75.86% H 5.89% N 3.28% O 14.97%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XI)

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).

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

该中间体在本合成路线中的序号:(XI)

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).

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
Extended Information