　 -Drug Synthesis Database

【结构式】

【分子编号】65209

【品名】　

【CA登记号】　

【分子式】C₇₀H₉₀N₈O₁₂S₆

【分子量】1427.92732

【元素组成】C 58.88% H 6.35% N 7.85% O 13.45% S 13.47%

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：(IV)

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

合成路线2

该中间体在本合成路线中的序号：(IV)

In a different procedure, the acyclic tetraamine (IX) is protected with p-toluenesulfonyl chloride to afford a separable mixture of ditosyl (X) and tritosyl compounds (XI). Condensation of (X) with p-dibromoxylene (IIIa) provides the tetratosyl dimer (XII), which is further tosylated to (XIII) by means of p-toluenesulfonyl chloride and K2CO3. Alternatively, the hexatosyl dimer (XIII) can be obtained by condensation of the trisulfonylated tetraamine (XI) with p-dibromoxylene (IIIa) in the presence of N,N-diisopropylethylamine. Ring closure of (XIII) to furnish the bis-macrocycle (IV) is then accomplished by reaction with ethylene glycol ditosylate (XIV) in the presence of Cs2CO3 or under phase-transfer conditions. Subsequent acidic deprotection of (IV) gives the target compound (7). In a related approach, the open-chain tetraamine (IX) is protected with ethyl trifluoroacetate and N,N-diisopropylethylamine to afford the triacyl derivative (XV) as the main product, which is further condensed with dibromide (IIIa), yielding the trifluoroacetyl-protected dimer (XVI). The hexatrifluoroacetyl compound (XVI) is then converted to the hexatosyl analogue (XIII) by alkaline amide hydrolysis, followed by treatment with p-toluenesulfonyl chloride. Ring closure of (XIII) with ethylene glycol ditosylate (XIV) and subsequent acidic deprotection as above gives plerixafor (8, 9). Scheme 2.

参考文献中间体

合成目标

【7】 Prashad, M., Kapa, P. (Johnson Matthey plc). Process for preparing 1,1’-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. WO 9634860.
【8】 Xu, D., Kapa, P., Repic, O., Blacklock, T.J. (Johnson Matthey plc). Process for preparing 1,1’-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. WO 9630349.
【9】 Xu, D., Mattner, P.G., Prasad, K., Repic, O., Blacklock, T.J. An expeditious synthesis of a biscyclam with an aromatic linker. Tetrahedron Lett 1996, 37(30): 5301-4.

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
(IV)	65209			C₇₀H₉₀N₈O₁₂S₆	详情	详情
(IX)	65213	N,N'-bis(3-aminopropyl)diaminoethane; N,N'-Bis(3-aminopropyl)-1,2-ethanediamine	10563-26-5	C₈H₂₂N₄	详情	详情
(X)	65214			C₂₂H₃₄N₄O₄S₂	详情	详情
(XI)	65215			C₂₉H₄₀N₄O₆S₃	详情	详情
(XII)	65216			C₅₂H₇₄N₈O₈S₄	详情	详情
(XIII)	65217			C₆₆H₈₆N₈O₁₂S₆	详情	详情
(XIV)	65218	1,2-Ethanediol ditosylate; 1,2-Bis(p-toluenesulfonyloxy)ethane	6315-52-2	C₁₆H₁₈O₆S₂	详情	详情
(XV)	65219			C₁₄H₁₉F₉N₄O₃	详情	详情
(XVI)	65220			C₃₆H₄₄F₁₈N₈O₆	详情	详情

Extended Information