　 -Drug Synthesis Database

【结构式】

【分子编号】65526

【品名】　

【CA登记号】　

【分子式】C₂₆H₃₇O₇P

【分子量】492.549342

【元素组成】C 63.4% H 7.57% O 22.74% P 6.29%

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：(XXVIII)

A different protection strategy involves masking the ring nitrogens as amide groups. Methyl acrylate (XVII) is reacted with neat ethylenediamine (XVIII) to yield the aminopropionamide derivative (XIX), which is then cyclized with dimethyl malonate (XX), producing the trioxocyclam (XXI). After condensation of (XXI) with p-dibromoxylene (IIIa), the resulting hexaoxo bis-cyclam (XXII) is reduced to the title compound employing borane-dimethyl sulfide complex in refluxing THF (10). Alternatively, protection of the linear tetraamine (XXIII) with pyruvic aldehyde (XXIV) generates the tricyclic bisaminal (XXV) along with its minor isomer (XXVI). The crude mixture of bis-aminals (XXV) and (XXVI) is then cyclized to (XXVIII) with 1,3-dibromopropane (XXVII) and K2CO3. After condensation of (XXVIII) with dibromide (IIIa), the resulting bis-ammonium dimer (XXIX) is hydrolyzed to the title compound upon heating with 3M NaOH (11). Scheme 3.

参考文献中间体

合成目标

【10】 Achmatowicz, M., Hegedus, L.S. Direct synthesis of 1,1’-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD 3100) without the use of protecting groups. J Org Chem 2003, 68(16): 6435-6.
【11】 Boschetti, F., Denat, F., Espinosa, E., Tabard, A., Dory, Y., Guilard, R. Regioselective N-functionalization of tetraazacycloalkanes. J Org Chem 2005, 70(18): 7042-53.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	18697	1,4-bis(bromomethyl)benzene	623-24-5	C₈H₈Br₂	详情	详情
(XVII)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(XVIII)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情
(XIX)	65221			C₇H₁₈N₄O	详情	详情
(XX)	19373	dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester	108-59-8	C₅H₈O₄	详情	详情
(XXI)	65222			C₁₀H₁₈N₄O₃	详情	详情
(XXII)	65223			C₂₈H₄₂N₈O₆	详情	详情
(XXIII)	53968	1,4,8,11-Tetraazaundecane; 3,7-Diaza-1,9-nonanediamine; N,N'-Bis(2-aminoethyl)-1,3-propanediamine; N,N[-Bis(2-aminoethyl)-1,3-propanediamine	4741-99-5	C₇H₂₀N₄	详情	详情
(XXIV)	25598	2-oxopropanal	78-98-8	C₃H₄O₂	详情	详情
(XXV)	65224			C₁₀H₂₀N₄	详情	详情
(XXVI)	65225			C₁₀H₂₀N₄	详情	详情
(XXVII)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(XXVIII)	65526			C₂₆H₃₇O₇P	详情	详情
(XXIX)	65227			C₃₄H₅₄Br₂N₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(Iva)

Combretastatin A-4 phosphate can be synthesized by phosphorylation of combretastatin A-4 (I) following several related strategies. Direct phosphorylation of (I) employing either bis(2,2,2-trichloroethyl) phosphorochloridate in pyridine (1, 2) or dibenzyl phosphite in the presence of CCl4 and DMAP (3-5) furnishes the corresponding bis-trichloroethyl (IIa) and dibenzyl (IIb) phosphate esters, which are subsequently deprotected to combretastatin A-4 phosphate (III) by either reductive trichloroethyl group cleavage with zinc dust and acetic acid (1, 2) or by debenzylation with chlorotrimethylsilane/sodium iodide (3-5). Alternatively, phosphitylation of (I) using di-tert-butyl N,N-diethylphosphoramidite (3, 4, 6) or bis(trimethylsilylethyl) N,N-diisopropylphosphoramidite (3-5) in the presence of tetrazole yields the phosphite esters (IVa) and (IVb), respectively, which are further oxidized to the corresponding phosphates (Va) and (Vb) using m-chloroperbenzoic acid in CH2Cl2/THF (3-6). Combretastatin A-4 phosphate (III) is then obtained by acidic cleavage of the tert-butyl ester (Va) with trifluoroacetic acid (3, 4, 6) or trifluoromethanesulfonic acid (6), or by tetrabutylammonium fluoride-promoted cleavage of the trimethylsilylethyl ester (Vb) (3-5). In a shorter procedure, phosphorylation of combretastatin A-4 (I) with POCl3 in the presence of Et3N in CH2Cl2 provides directly combretastatin A-4 phosphate (III) (7). Conversion of (III) to the title disodium salt is accomplished by treatment with methanolic NaOMe (3-5,7) or by passage through a cation exchange resin (1, 2). Scheme 1.

参考文献中间体

合成目标

【1】 Pettit, G.R., Temple, C. Jr., Narayanan, V.L. et al. Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des 1995, 10(4): 299-309.
【2】 Pettit, G.R. (Arizona State University). Combretastatin A-4 prodrug. US 5561122.
【3】 Pettit, G.R., Rhodes, M.R. Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug. Anticancer Drug Des 1998, 13(3): 183-91.
【4】 Pettit, G.R., Rhodes, M.R. (Arizona State University). Synthesis of combretastatin A-4 prodrugs and trans-isomers thereof. CA 2314238, EP 1045853, US 7018987, WO 9935150.
【5】 Gale, J., Haider, R., Hoare, J., Seyedi, F. (OxiGene, Inc.). Efficient method of synthesizing combretastatin A-4 prodrugs. US 2002119951, WO 0206279.
【6】 Griffin, R.J., Quarterman, C.P., Rathbone, D.L., Slack, J.A. (Aston Molecules Ltd.). Substd. diphenylethylenes and analogues of derivs. thereof. WO 9216486.
【7】 Gill, G.S., Grobelny, D., Flynn, B. A practical method for phosphorylation of combretastatin A-4 with phosphorus oxychloride. Org Prep Proc Int 2006, 38(6): 604-8.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Iia)	65523			C₂₂H₂₃Cl₆O₈P	详情	详情
(Iib)	65524			C₃₂H₃₃O₈P	详情	详情
(Iva)	65526			C₂₆H₃₇O₇P	详情	详情
(Ivb)	65527			C₂₈H₄₅O₇PSi	详情	详情
(Va)	65528			C₂₆H₃₇O₈P	详情	详情
(Vb)	65529			C₂₈H₄₅O₈PSi	详情	详情
(I)	60505	2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol	117048-60-9	C₁₈H₂₀O₅	详情	详情
(III)	65525	Combretastatin A4 phosphate; Fosbretabulin	222030-63-9	C₁₈H₂₁O₈P	详情	详情

Extended Information