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【结 构 式】 
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【药物名称】Plerixafor Hydrochloride, AMD-3100, SDZ-SID-791, SID-791, JM-3100 (former code name), Mozobil 【化学名称】1,4-Bis(1,4,8,11-tetraazacyclotetradec-1-ylmethyl)benzene octahydrochloride dihydrate 【CA登记号】110078-46-1 (anhydrous, free base), 155148-31-5 (anhydrous) 【 分 子 式 】C28H66Cl8N8O2 【 分 子 量 】830.4980 |
【开发单位】Genzyme Corp. (US) (through its recent acquisition of AnorMED). 【药理作用】Chemokine CXCR4 (SDF-1) antagonist, Stem cell-mobilizing agent |
合成路线1
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.
| 【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
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.
| 【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3
The tetraazacyclotetradecane (I) is protected as the chromium tridentate complex (XXX) upon heating with chromium hexacarbonyl in deaerated dibutyl ether. Subsequent condensation of the cyclam-Cr(CO)3 complex (XXX) with p-dibromoxylene (IIIa) produces the chromium-protected bis-cyclam (XXXI), which is deprotected to plerixafor by oxidation with air in aqueous HCl (12, 13). Alternatively, protection of (I) as the phosphorotriamide (XXXII) can be accomplished by reaction with tris(dimethylamino)phosphine, followed by oxidation with CCl4 and NaOH (12) or by treatment with POCl3 and Et3N (14). After condensation of (XXXII) with dibromide (IIIa), the dimeric bis-phosphoramide obtained (XXXIII) is hydrolyzed to the title compound by treatment with diluted HCl (12, 14). Scheme 4.
| 【12】 Handel, H., Yaouanc, J.-J., Zegzouti, A.F. et al. (Centre National de la Recherche Scientifique [CNRS]). Process for the preparation of monofunctionalized cyclic tetramines. US 5047527. |
| 【13】 Yaouanc, J.-J., Le Bris, N., Le Gall, G., Clément, J.-C., Handel, H., des Abbayes, H. Mono N-functionalization of cyclic and linear tetraamines via their tridentate tricarbonylchromium complexes. J Chem Soc Chem Commun 1991, 206-7. |
| 【14】 Guillaume, D., Marshall, G.R. Efficient one-pot synthesis of JM3100. Synth Commun 1998, 28(15): 2903-6. |
合成路线4
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.
| 【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 |