2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl) -Drug Synthesis Database

【结构式】

【分子编号】29800

【品名】2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl)

【CA登记号】106-57-0

【分子式】C₄H₆N₂O₂

【分子量】114.10392

【元素组成】C 42.11% H 5.3% N 24.55% O 28.04%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Diketopiperazine (I) is protected with benzylating reagents to give N,N'-dibenzyldiketopiperazine (II), which is brominated with Br2 to the dibromo derivative (III). The treatment of (III) with benzyl alcohol affords the dibenzyl ether (IV), which is condensed with the silylated methyl 4-hydroxycrotonate (V) by means of butyllithium, yielding the coupled product (VI). The reduction of the ester group of (VI) first with LiAlH4 and then with NaBH4 yields the primary alcohol (VII), which is protected with dimethyl tert-butylsilyl chloride giving the fully protected compound (VIII). Partial deprotection of (VIII) with H2 over Pd/C in ethanol pyridine eliminates the less shielded benzyl group, affording the secondary alcohol (IX), which is acetylated with acetic anhydride to the acetate (X). Selective deprotection of (X) with acetic acid-water THR at 80 C eliminates the dimethyl tert-butylsilyl group, yielding the alcohol (XI), which is cyclized by heating at 80 C in the presence of pyridinium p-toluenesulfonate, affording the bicyclo compound (XII). The aldol condensation of (XII) with the aldehyde (XIII) by mean of butyllithium yields the alcohol (XIV), which is desilylated with tetrabutylammonium fluoride to the primary alcohol (XV).

参考文献中间体

合成目标

【1】 Nakatsuka, S. I.; Goto, T.; Total synthesis of bicyclomycin. Heterocycles 1984, 21, 1, 61-73.

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)	29800	2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl)	106-57-0	C₄H₆N₂O₂	详情	详情
(II)	29801	1,4-dibenzyl-2,5-piperazinedione		C₁₈H₁₈N₂O₂	详情	详情
(III)	29802	1,4-dibenzyl-3,6-dibromo-2,5-piperazinedione		C₁₈H₁₆Br₂N₂O₂	详情	详情
(IV)	29803	1,4-dibenzyl-3,6-bis(benzyloxy)-2,5-piperazinedione		C₃₂H₃₀N₂O₄	详情	详情
(V)	29804	methyl (E)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-butenoate		C₂₁H₂₆O₃Si	详情	详情
(VI)	29805	methyl (3R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-[(2R,5R)-1,4-dibenzyl-2,5-bis(benzyloxy)-3,6-dioxopiperazinyl]butanoate		C₅₃H₅₆N₂O₇Si	详情	详情
(VII)	29806	(3R,6R)-1,4-dibenzyl-3,6-bis(benzyloxy)-3-[(1R)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-hydroxypropyl]-2,5-piperazinedione		C₅₂H₅₆N₂O₆Si	详情	详情
(VIII)	29807	(3R,6R)-1,4-dibenzyl-3,6-bis(benzyloxy)-3-[(1R)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)propyl]-2,5-piperazinedione		C₅₈H₇₀N₂O₆Si₂	详情	详情
(IX)	29808	(3R,6R)-1,4-dibenzyl-3-(benzyloxy)-3-[(1R)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)propyl]-6-hydroxy-2,5-piperazinedione		C₅₁H₆₄N₂O₆Si₂	详情	详情
(X)	29809	(2R,5R)-1,4-dibenzyl-5-(benzyloxy)-5-[(1R)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)propyl]-3,6-dioxopiperazinyl acetate		C₅₃H₆₆N₂O₇Si₂	详情	详情
(XI)	29810	(2R,5R)-1,4-dibenzyl-5-(benzyloxy)-5-[(1R)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-hydroxypropyl]-3,6-dioxopiperazinyl acetate		C₄₇H₅₂N₂O₇Si	详情	详情
(XII)	29811	(1S,6R)-7,9-dibenzyl-6-(benzyloxy)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione		C₄₅H₄₈N₂O₅Si	详情	详情
(XIII)	29812	2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde		C₇H₁₂O₃	详情	详情
(XIV)	29813	(1S,6R)-7,9-dibenzyl-6-(benzyloxy)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione		C₅₂H₆₀N₂O₈Si	详情	详情
(XV)	29814	(1S,6R)-7,9-dibenzyl-6-(benzyloxy)-5-(hydroxymethyl)-1-[(S)-hydroxy[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methyl]-2-oxa-7,9-diazabicyclo[4.2.2]decane-8,10-dione		C₃₆H₄₂N₂O₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

Dioxopiperazine (X) was diacetylated in refluxing acetic anhydride to yield (XI). Aldol condensation of (XI) with the precursor aldehyde (VI) using potassium tert-butoxide in THF gave the mono-arylidene piperazine (XII). Further condensation of (XII) with the intermediate aldehyde (IX) in the presence of Cs2CO3 in DMF furnished the deacetylated bis-arylidene piperazine (XIII). The methyl ester group of (XIII) was finally hydrolyzed to the title carboxylic acid using NaOH in H2O/MeOH/THF.

参考文献中间体

合成目标

【1】 Folkes, A.; et al.; Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1. Bioorg Med Chem Lett 2001, 11, 19, 2589.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	53129	N-(4-formylphenyl)-2-thiophenecarboxamide	n/a	C₁₂H₉NO₂S	详情	详情
(IX)	53131	methyl 8-(4-formylphenoxy)octanoate	n/a	C₁₆H₂₂O₄	详情	详情
(X)	29800	2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl)	106-57-0	C₄H₆N₂O₂	详情	详情
(XI)	19188	1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE	3027-05-2	C₈H₁₀N₂O₄	详情	详情
(XII)	53132	N-{4-[(4-acetyl-3,6-dioxo-2-piperazinylidene)methyl]phenyl}-2-thiophenecarboxamide	n/a	C₁₈H₁₅N₃O₄S	详情	详情
(XIII)	53133	methyl 8-(4-{[3,6-dioxo-5-((Z)-{4-[(2-thienylcarbonyl)amino]phenyl}methylidene)-2-piperazinylidene]methyl}phenoxy)octanoate	n/a	C₃₂H₃₃N₃O₆S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

2,5-Piperazinedione (I) is acylated with acetic anhydride at 110 oC in the presence of catalytic NaOAc to afford the diacetyl derivative (II). Claisen condensation of N,N’-diacetyl-2,5-piperazinedione (II) with 5-tert-butylimidazole-4-carbaldehyde (III) by means of Cs2CO3 in DMF at room temperature leads to the monoacetylated (imidazolylmethylene) piperazinedione (IV), which is finally condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at 80 °C. In a related alternative method, diketopiperazine (II) is first condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at room temperature, yielding the benzylidene piperazinedione (VI), which is subsequently condensed with the imidazole-aldehyde (III) by means of Cs2CO3 in hot DMF .

参考文献中间体

合成目标

【1】 Hayashi, Y., Grodberg, J., Palladino, M. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins dehydrophenylahistins and analogs thereof. EP 1529044, JP 2006511534, WO 2004054498.
【2】 Palladino, M.A., Lloyd, G.K., Hayashi, Y., Nicholson, B. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof. EP 1711487, JP 2007520565, WO 2005077940.
【3】 Palladino, M., Lloyd, G.K., Hayashi, Y. (Nereus Pharmaceuticals, Inc). Analogs of dehydrophenylahistins and their therapeutic use. EP 1926724, US 2007078138, WO 2007035841.

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)	29800	2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl)	106-57-0	C₄H₆N₂O₂	详情	详情
(II)	19188	1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE	3027-05-2	C₈H₁₀N₂O₄	详情	详情
(III)	69002	5-tert-butylimidazole-4-carbaldehyde;5-(1,1-dimethylethyl)-1H-Imidazole-4-carboxaldehyde;4-(1,1-dimethylethyl)-1H-Imidazole-5-carboxaldehyde	714273-83-3	C₈H₁₂N₂O	详情	详情
(IV)	69003	(Z)-1-acetyl-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione		C₁₄H₁₈N₄O₃	详情	详情
(V)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(VI)	19189	1-acetyl-3-[(Z)-benzylidene]-2,5-piperazinedione		C₁₃H₁₂N₂O₃	详情	详情

Extended Information