tri(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,4,8-tricarboxylate -Drug Synthesis Database

【结构式】

【分子编号】25363

【品名】tri(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,4,8-tricarboxylate

【CA登记号】

【分子式】C₂₅H₄₈N₄O₆

【分子量】500.67948

【元素组成】C 59.97% H 9.66% N 11.19% O 19.17%

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)

Protection of tetraazacyclotetradecane (I) with Boc2O, followed flash chromatography, provided the tri-N-Boc derivative (II) and an unseparable mixture of three isomeric di-N-Boc macrocycles (III). Alkylation of this mixture with ethyl 5-bromovalerate gave a mixture of mono- and dialkylated compounds (IV), from which the required isomer (V) was isolated by flash chromatography. Then, condensation of tri-Boc derivative (II) and monoalkylated di-Boc derivative (V) with alpha-alpha'-dibromo-p-xylene (VI) yielded the desired unsymmetrical bis-macrocycle (VII) along with two symmetrical bis-macrocycle dimers. Subsequent hydrolysis of this mixture with NaOH in the presence of a catalytic amount of Triton B, followed by chromatographic separation, provided pure carboxylic acid (VIII). Further coupling of (VIII) with azidothymidine (IX) using benzotriazol-1-yloxy-tris(pyrrolidino) phosphonium hexafluorophosphate (PyBOP), and final acid deprotection of the Boc groups furnished the title compound.

参考文献中间体

合成目标

【1】 Dessolin, J.; Galea, P.; Vlieghe, P.; Chermann, J.-C.; Kraus, J.-L.; New bicyclam-AZT conjugates: Design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor. J Med Chem 1999, 42, 2, 229.

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)	25364	di(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,4-dicarboxylate		C₂₀H₄₀N₄O₄	详情	详情
(IIIb)	25365	di(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,8-dicarboxylate		C₂₀H₄₀N₄O₄	详情	详情
(IIIc)	25366	di(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,11-dicarboxylate		C₂₀H₄₀N₄O₄	详情	详情
(IVa),(V)	25367	di(tert-butyl) 4-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,11-dicarboxylate		C₂₇H₅₂N₄O₆	详情	详情
(IVb)	25368	di(tert-butyl) 4-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,8-dicarboxylate		C₂₇H₅₂N₄O₆	详情	详情
(IVc)	25369	di(tert-butyl) 8-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,4-dicarboxylate		C₂₇H₅₂N₄O₆	详情	详情
(IVd)	25370	di(tert-butyl) 4,8-bis(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,11-dicarboxylate		C₃₄H₆₄N₄O₈	详情	详情
(IVe)	25371	di(tert-butyl) 4,11-bis(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,8-dicarboxylate		C₃₄H₆₄N₄O₈	详情	详情
(IVf)	25372	di(tert-butyl) 8,11-bis(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecane-1,4-dicarboxylate		C₃₄H₆₄N₄O₈	详情	详情
(I)	25362	1,4,8,11-Tetraazacyclotetradecane	295-37-4	C₁₀H₂₄N₄	详情	详情
(II)	25363	tri(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,4,8-tricarboxylate		C₂₅H₄₈N₄O₆	详情	详情
(VI)	18697	1,4-bis(bromomethyl)benzene	623-24-5	C₈H₈Br₂	详情	详情
(VII)	25373	tri(tert-butyl) 11-(4-[[4,8-bis(tert-butoxycarbonyl)-11-(5-ethoxy-5-oxopentyl)-1,4,8,11-tetraazacyclotetradecan-1-yl]methyl]benzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8-tricarboxylate		C₆₀H₁₀₆N₈O₁₂	详情	详情
(VIII)	25374	5-[4,8-bis(tert-butoxycarbonyl)-11-(4-[[4,8,11-tris(tert-butoxycarbonyl)-1,4,8,11-tetraazacyclotetradecan-1-yl]methyl]benzyl)-1,4,8,11-tetraazacyclotetradecan-1-yl]pentanoic acid		C₅₈H₁₀₂N₈O₁₂	详情	详情
(IX)	25317	1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione	101703-35-9	C₁₀H₁₃N₅O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The macrocyclic tetraamine cyclam (I) is protected with p-toluenesulfonyl chloride at a 1:2 molar ratio, yielding the target tritosyl derivative (II) along with di- and monotosylated derivatives, which can be separated by fractional crystallization from MeOH (1). Subsequent condensation of (II) with α,α’-p-dibromoxylene (IIIa) gives the hexatosyl bis-cyclam (IV), which is finally deprotected by treatment with hot concentrated H2SO4 or with HBr in AcOH (1, 2). Alternatively, protection of (I) with di-tert-butyl dicarbonate provides the tri-Boc derivative (V), which is dimerized to (VI) by treatment with p-dibromoxylene (IIIa) and Na2CO3. Deprotection of (VI) is then effected by heating with aqueous HCl (3, 4). Similarly, treat-ment of the macrocyclic amine (I) with an excess of ethyl trifluoroacetate in the presence of Et 3N affords the tris-tri-fluoroacetyl cyclam (VII) as the major product. Subsequent condensation of (VII) with either p-dibro-moxylene (IIIa) or p-dichloroxylene (IIIb) in the presence of KI gives the trifluoroacetyl-protected compound (VIII), which is finally deprotected by treatment with NaOH or K2CO3 in MeOH (5, 6). Scheme 1.

参考文献中间体

合成目标

【1】 Ciampolini, M., Fabbrizzi, L., Perotti, A., Poggi, A., Seghi, B., Zanobini, F. Dinickel and dicopper complexes with N,N-linked bis(cyclam) ligands. An ideal system for the investigation of electrostatic effects on the redox behavior of pairs of metal ions. Inorg Chem 1987, 26(21): 3527-33.
【2】 Bridger, G.J., Skerlj, R.T., Thornton, D. et al. Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker. J Med Chem 1995, 38(2): 366-78.
【3】 Brandès, S., Gros, C., Denat, F., Pullumbi, P., Guilard, R. New facile and convenient synthesis of bispolyazamacrocyles using Boc protection. Determination of geometric parameters of dinuclear copper(II) complexes using ESR spectroscopy and molecular mechanics calculations. Bull Soc Chim Fr 1996, 133(1): 65-73.
【4】 Dessolin, J., Galea, P., Vlieghe, P., Chermann, J.-C., Kraus, J.-L. New bicyclam-AZT conjugates: Design, synthesis, anti-HIV evaluation, and their interction with CXCR-4 coreceptor. J Med Chem 1999, 42(2): 229-41.
【5】 Giandomenico, C.M., Yang, W. (AnorMED, Inc.). Process for preparation of N-1 protected N ring nitrogen containing cyclic polyamines and products thereof. WO 0226721.
【6】 Yan, W., Giandomenico, C.M., Sartori, M., Moore, D.A. Facile N-1 protection of cyclam, cyclen and 1,4,7-triazacyclonanene. Tetrahedron Lett 2003, 44: 2481-3.

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
(IIIb)	55918	1,4-Bis(chloromethyl)benzene; alpha,alpha'-Dichloro-p-xylene; p-Xylylene dichloride	623-25-6	C₈H₈Cl₂	详情	详情
(I)	25362	1,4,8,11-Tetraazacyclotetradecane	295-37-4	C₁₀H₂₄N₄	详情	详情
(II)	65208			C₃₁H₄₂N₄O₆S₃	详情	详情
(IV)	65209			C₇₀H₉₀N₈O₁₂S₆	详情	详情
(V)	25363	tri(tert-butyl) 1,4,8,11-tetraazacyclotetradecane-1,4,8-tricarboxylate		C₂₅H₄₈N₄O₆	详情	详情
(VI)	65210			C₅₈H₁₀₂N₈O₁₂	详情	详情
(VII)	65211			C₁₆H₂₁F₉N₄O₃	详情	详情
(VIII)	65212			C₄₀H₄₈F₁₈N₈O₆	详情	详情

Extended Information