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【结 构 式】 
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【分子编号】25362 【品名】1,4,8,11-Tetraazacyclotetradecane 【CA登记号】295-37-4 |
【 分 子 式 】C10H24N4 【 分 子 量 】200.32752 【元素组成】C 59.96% H 12.08% N 27.97% |
合成路线1
该中间体在本合成路线中的序号：(I)The title compound was obtained by alkylation of tetraazacyclo tetradecane (I) with an excess of tosylate (II) in the presence of K2CO3 in refluxing acetonitrile.
| 【1】 Trabaud, C.; Dessolin, J.; Camplo, M.; Hantz, O.; Zoulim, F.; Borel, C.; Meyer, M.; Pepe, G.; Chermann, J.-C.; Kraus, J.-L.; Design, synthesis and structure relationships of new N,N',N'',N'''-tetrakis (omega-amino alkyl) tetraazamacrocycles. Antivir Chem Chemother 1998, 9, 1, 73-84. |
| 【2】 Chermann, J.C.; Dessolin, J.; Bouygues, M.; Trabaud, C.; Kraus, J.L.; Vieghe, P.; Camplo, M.; Modelisation, synthesis and anti-HIV activities of N,N,N',N'',N'''-pentakistetraazamacrocycles salts derivatives. Bioorg Med Chem Lett 1997, 7, 10, 1353. |
合成路线2
该中间体在本合成路线中的序号：(VII)Condensation of epichlorohydrin (I) with N-benzylethanolamine (II) in the presence of sulfuric acid afforded the (chloromethyl)morpholine (III). Halogen displacement in (III) by potassium phthalimide (IV) provided the substituted phthalimide (V). Further hydrazinolysis of (V) furnished racemic (aminomethyl)morpholine (VI) (1). The desired (S) enantiomer (VII) was obtained by crystallization of (VI) as the dibenzoyl-D-tartaric acid salt, followed by liberation of the base with NaOH. Eschweiler-Clarke reductive methylation of (VII) with formaldehyde and formic acid produced the dimethylamino derivative (VIII). The N-benzyl groupof (VIII) was then cleaved by transfer hydrogenation in the presence of hydrazine and Pd/C yielding chiral morpholine (IX). Finally, coupling of this morpholine (IX) with the difluoroqyuinolone boron chelate (X) provided the title morpholino quinolone.
| 【1】 Sakurai, N.; Sano, M.; Hirayama, F.; Kuroda, T.; Uemori, S.; Moriguchi, A.; Yamamoto, K.; Ikeda, Y.; Kawakita, T.; Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents. Bioorg Med Chem Lett 1998, 8, 16, 2185. |
| 【2】 Uemori, S.; Hirayama, F.; Moriguchi, A.; Sano, M.; Yokoyama, Y.; Ikeda, Y.; Miyoshi, M.; Sakurai, N.; Yamamoto, K.; Kawakita, T.; Synthesis and anti-Helicobacter pylori activity of Y-34867, a new 7-morpholinoquinolone. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-85. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (II) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (III) | 13396 | 4-Benzyl-2-(chloromethyl)morpholine | C12H16ClNO | 详情 | 详情 | |
| (IV) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (V) | 13398 | 2-[(4-Benzyl-2-morpholinyl)methyl]-1H-isoindole-1,3(2H)-dione | C20H20N2O3 | 详情 | 详情 | |
| (VI) | 13399 | (4-Benzyl-2-morpholinyl)methylamine; (4-Benzyl-2-morpholinyl)methanamine | C12H18N2O | 详情 | 详情 | |
| (VII) | 25362 | 1,4,8,11-Tetraazacyclotetradecane | 295-37-4 | C10H24N4 | 详情 | 详情 |
| (VIII) | 25633 | N-[[(2S)-4-benzylmorpholinyl]methyl]-N,N-dimethylamine | C14H22N2O | 详情 | 详情 | |
| (IX) | 25634 | N,N-dimethyl-N-[(2R)morpholinylmethyl]amine | C7H16N2O | 详情 | 详情 | |
| (X) | 25635 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid diacetoxyboron complex | C18H16BF2NO8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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.
| 【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4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(I)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. |