CN102827150B - Fullerene single-large-ring polyamine derivative and preparation method thereof - Google Patents

Fullerene single-large-ring polyamine derivative and preparation method thereof Download PDF

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CN102827150B
CN102827150B CN201210327346.3A CN201210327346A CN102827150B CN 102827150 B CN102827150 B CN 102827150B CN 201210327346 A CN201210327346 A CN 201210327346A CN 102827150 B CN102827150 B CN 102827150B
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compound
tri
tetraazacyclododecanand
tertiary
formyl radical
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CN102827150A (en
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何佳恒
刘国平
魏洪源
罗顺忠
蹇源
钟正坤
马宗平
张华明
牟婉君
钟文彬
陈琪萍
李兴亮
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Institute of Nuclear Physics and Chemistry China Academy of Engineering Physics
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Institute of Nuclear Physics and Chemistry China Academy of Engineering Physics
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Abstract

The invention discloses a fullerene single-large-ring polyamine derivative and a preparation method thereof. The preparation method is characterized in that the preparation method comprises the following steps of: dissolving 90mg (71.3mumol) to 180mg (142.6mumol) of intermediate compounds (10) of the fullerene single-large-ring polyamine derivative in 50-80ml of CHaCL2, slowly dripping 1.0ml (13.4mmol) to 2.0ml (26.8mmol) of CF3COOH under the condition of agitation, reacting for 18-24h at room temperature, and monitoring by using TLC (Thin-Layer Chromatography) till reaction materials fully disappear; and then removing solvent and other low-boiling-point impurities from reaction mixture under reduced pressure to obtain 80-157.3mg of brown solid fullerene single-large-ring polyamine derivative, wherein the yield is 85.2 percent to 90.1 percent. The structural formula of the fullerene single-large-ring polyamine derivative is shown in the specification.

Description

Soccerballene list cyclen derivatives and preparation method thereof
Technical field
The present invention relates to a kind of soccerballene list cyclen derivatives and preparation method thereof, belong to the preparation field of macromolecular material.
Background technology
Since the sixties in last century, people have had suitable accumulation to the research of Polyazamacrocycle compound, and wherein the large cyclic amine compound of most study is Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (cyclen), and its structural formula is as follows:
Why cyclen intermediate can evoke the research interest that people continue, and is because they have very strong sequestering power to metal ion, and the title complex forming has a lot of unusual functions.For example, if cyclen can be used for the aspects such as medicine, enzyme dummy, separation and carrier gases, metallic cation extraction. cyclen is suitably modified, the function of its coordination ability and the title complex that forms also can greatly be expanded, as being used as the selective coordination agent of transition metal, heavy metal, group of the lanthanides and actinide metals in biological medicine.If with side chain radicals such as ester, acid amides, pyridines, can be used as alkali metal cation coordination agent on cyclen N, highly selective extracts Na +[Guo Zi builds .1 for Wang Xiaoyong, Tan Renxiang, 4,7,10-tetraazacyclododecanand and derivative thereof synthetic].1, 4, 7, 10-tetraazacyclododecanand and derivative thereof are for the preparation of contrast medium and the radioactivity photographic developer [Zhou Chunsheng of medical diagnosis nuclear magnetic resonance, Yue Kefen, Wang Feili, Deng. chemical reagent, 2004, 26 (4): 246.BHARUCHA K R, CROSS C K, RUBIN L J. organic chemistry, 2003, 23 (2): 1292], can also serve as X ray-contrast media [YU Shi-bao with the title complex that heavy metal forms, WATSON A D.Metal2based X2ray contrast media[J]. Chem. Rev., 1999, 99 (9)].The Polyazamacrocycle such as Cyclen and derivative thereof is the functional type part that the another class after crown ether, cave ether has special ligancy, because their skeleton structure and chlorophyll, protoheme and many biological enzymes have similarity, therefore also can be applicable to [the Wei Junfa such as chemical simulation, molecular recognition, molecular magnet and biology, chemical reaction catalyst, Shi Xianying, where flat, Deng. organic chemistry, 2003,23 (10): 142～145. Wang Xiaoqings, Yang Weichun, golden Tianzhu, etc. chemical journal, 1996,54 (4): 347～350.].
Cyclen and derivative thereof are to transition-metal cation, heavy metal cation, group of the lanthanides and actinide ion, even organic or inorganic negatively charged ion is all shown to selective coordination character, its accurate behavior depends on substituent character on it, and this species diversity makes them be with a wide range of applications in various fields.
1985, during testing with laser vaporization evaporation graphite in helium flow, the people such as Englishize scholar Harold water that Clotho doctor and American scientist Richard Ai Lite history foam Lay make first the Spectra of Carbon Clusters structural molecule C being formed by 60 carbon 60(soccerballene).For this reason, Clotho doctor obtains 1996 annual Nobel chemistry Prizes and [contains the beautiful .C of root 60the discovery of molecule. chemistry teaching, 2012(2): 68～71].
C 60be one by 12 five-rings and 20 spherical icosidodecahedrons that six-ring forms, it exactly like football, diameter is 0.71nm.Each carbon atom of six-ring is all combined with other carbon atom with two keys, forms the structure of similar phenyl ring.With C 60for the soccerballene family of representative has extensively had influence on multiple fields [Wang Tingting such as chemistry, electronics, optics, magnetics and Materials science with its unique shape and good character, once peace. the progress of soccerballene a metal-organic complex. organic chemistry, Vol 28(8): 1303～1312].
Due to C 60special cage structure and function, by C 60introduce Polymer Systems as novel group, obtain having the new functional macromolecule material of excellent conduction, optical property.Say in principle C 60can introduce high molecular main chain, side chain or carry out blend with other macromolecular materials, the people such as Nagashima have reported the first C 60macromolecular material C 60pdn from experiment with studied in theory it and have the character of catalysis tolane hydrogenation.In addition, soccerballene and derivative thereof, due to its unique structure and chemical physical property, have application very widely at biomedical sector.They have anti-oxidant activity and cytoprotection, anti-microbial activity, antivirus action, carrier band medicine and oncotherapy isoreactivity.But soccerballene itself has strong hydrophobicity, solubleness in polar solvent is very low, conventionally use aromaticity solvent, as toluene, chlorobenzene, or dithiocarbonic anhydride dissolving, be difficult to directly use in Physiological Medium, this has had a strong impact on the application of soccerballene in biomedicine, and it is also too dull to study separately its molecular property, improve soccerballene water-soluble become a crucial direction [Zhu Bo. several cyclizations researchs of soccerballene. China Science & Technology University's Ph D dissertation, 2009].
The water-soluble comparatively conventional method at present of improving soccerballene has following three kinds: (1) ultrasonic fullerene water colloidal sol of preparing; (2) prepare the water-soluble inclusion complex of soccerballene; (3) at the water-soluble group of Fullerene Carbon cage surface bonding, fullerene synthesis derivative.By introducing new group, as-OH ,-COOH and---NH2 etc., give simultaneously the boring chemical property that soccerballene is new [single swan sound. the synthetic and radiation biological effect research of water-soluble fullerenes derivates, The 2nd Army Medical College Master's thesis, 2006].
Also have bibliographical information, the chemically modified meeting of soccerballene changes its toxic action greatly.Sayes etc. have compared C 60and the cytotoxicity of soluble derivative to people's epidermin archeocyte (HDF) and human liver cancer cell (HepG2).Result of study shows, the hydroxyl that soccerballene connects become with their cytotoxicity with carbonyl number negative correlation [burnt fragrant, Zhou Guoqiang, Chen Chunying. soccerballene chemically modified and biomedical applications progress. ecotoxicology report, Vol 5(4): 468～480].
This project by chemical process to 1,4,7,10-tetraazacyclododecanand and soccerballene are modified, introduce nitrogen heterocyclic ring functional group on soccerballene surface, be applied to and comprise lubricant, catalyzer, abrasive, high-strength carbon fiber, semi-conductor, device for non-linear optical, superconducting material, optical conductor, high tension battery, fuel, sensor, molecular device and for the aspect such as medical imaging and treatment to the synthetic fullerene derivate with special construction or property.This material may be critical and irreplaceable in the using value in many high and new technologies field, and it enters a practical revolution that will bring material technology in a large number, has undoubtedly important and far-reaching meaning.
Summary of the invention
The object of the invention is for the needs of current scientific research technical development and a kind of soccerballene list cyclen derivatives providing and preparation method thereof, be characterized in introducing nitrogen heterocyclic ring functional group on the side chain of soccerballene, this retains soccerballene and the distinctive excellent properties of tetraazacyclododecanand to a great extent, obtain solubility intermediate, its yield is 86%, this derivative can also make several functions material from different functional group reactions, for the chemical sensor of " molecular probe ", multiple fields such as solar cell and photoelectric device.
Object of the present invention is realized by following technical measures, and wherein said raw material umber is parts by weight except specified otherwise.
The structural formula of soccerballene list cyclen derivatives is:
The preparation method of described soccerballene list cyclen derivatives comprises the following steps:
The chemical equation of soccerballene list cyclen derivatives is as follows:
And prepare by following processing step and processing parameter:
1), N, N ', N " preparation of tri-p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, 126 g Tosyl chlorides are dissolved in to the solution of 300 mL acetone and 91.2 g Anhydrous potassium carbonates and are dissolved in the solution of 200 mL water, be added drop-wise to 20.6 g(0.20 mol) in diethylenetriamine, time for adding 1.2～2.0 h, after dropwising, room temperature reaction 4～4.5 h, then reactant is poured in frozen water, under agitation be poured into water again, filter suction filtration after methanol wash for filter cake, vacuum drying obtains N, N ', N " white solid 103.2 g of tri-p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2), N, O, the preparation of two (2-hydroxyethyl) amine compound (2) of O '-tri-p-toluenesulfonyl
Under ice bath, 300 mL are dissolved with to 126 g(0.66 mol) dichloromethane solution of Tosyl chloride is added drop-wise to and contains 21.0 g(0.2 mol) diethanolamine and 100 mL(0.72 mol) in the reaction flask of triethylamine, control time for adding 3 h, after dropwising, room temperature reaction 4～4.5 h, then pour reactant in frozen water into separatory, wash 3 times, organic phase is through anhydrous Na 2sO 4dry, to filter, evaporate to dryness filtrate obtains a yellow oil, and after recrystallizing methanol, vacuum-drying obtains N, O, white solid 99.7 g of two (2-hydroxyethyl) amine compound (2) of O '-tri-p-toluenesulfonyl, yield 88%;
3), Isosorbide-5-Nitrae, 7,10-, tetra-p-toluenesulfonyls-Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (3)
By N, N ', N " tri-p-toluenesulfonyl diethylenetriamine compound (1) 34.4 g(0.06 mol), N, O, two compound (2-hydroxyethyl) amine (2) the 34.0 g(0.06 mol of O '-tri-p-toluenesulfonyl) and 25.0 g Anhydrous potassium carbonates join the N that 300 mL are dry, in dinethylformamide, in 100～105 ° of C reaction 3～4 h of temperature, react complete, cooling, suction filtration obtains filtrate, steam most of dimethyl fumarate more muddy to solution after, splash into 150 mL methanol wash, cooling, suction filtration, filter cake washing three times, then dry 1, 4, 7, 10-tetra-(p-toluenesulfonyl)-1, 4, 7, 10-tetraazacyclododecanand compound (3) 30.1 g, productive rate 63.7%,
4), Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (4)
By Isosorbide-5-Nitrae, 7,10-tetra-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (3) 30.0 g join the dense H of 60 mL 2sO 4in, heating treats that it dissolves, in 110～115 ° of C reaction 48～50 h of temperature.React complete, under vigorous stirring, be poured in 200～250 mL dehydrated alcohols, stir 0.5～1 h, suction filtration, filter cake is dissolved in 80～100 mL water, with decolorizing with activated carbon, adds in 40～60 mL concentrated hydrochloric acids and boils, leave standstill, filter to obtain white solid, this solid be dissolved in 30～50 mL water, with potassium hydroxide solution regulate pH to strong basicity, repeatedly extract with chloroform, filtrate is after anhydrous sodium sulfate drying, and steaming desolventizes, and dry 1,4, white solid 2.62 g of 7,10-tetraazacyclododecanand compound (4), productive rate 40%;
5), N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
By 1, 4, 7, 10-tetraazacyclododecanand compound (4) 4.5 g(26.1 mmol)～9.0 g(52.2 mmol) and triethylamine 12.0 mL(86.4 mmol)～25 mL(180 mmol) be dissolved in methylene dichloride (145～255 mL), under normal temperature, slowly drip methylene dichloride 118～200 mL solution of tert-Butyl dicarbonate 17.70 g (81.1 mmol)～35 g (163 mmol), 3h drips with interior, under room temperature, stir 24～25 h, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) obtain N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, white solid 10.2～14.78 g of 10-tetraazacyclododecanand compound (5), productive rate: 56.5 %～77.2%,
6), 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
By N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.68 g (22.7 mmol)～15.84 g (33.7 mmol), K 2cO 37.64 g ?(55.1 mmol)～9.84 g ?(71.0 mmol), KI 9.10 g (54.7 mmol)～12.35 g (74.2 mmol) add in 500mL reaction flask, add again 185～192 mL acetonitriles, chloromethyl cyanide 2.02 mL(247.1 mmol)～4.08 mL(499.1 mmol), back flow reaction 70～72 h, remove solvent, add CH 2cl 2, suction filtration, removes inorganic salt, and filtrate decompression is removed solvent, column chromatography (sherwood oil: ethyl acetate=3: 2) obtain 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; white solid 10.35～14.75 g of 7,10-tetraazacyclododecanand compound (6), productive rate 89.9%～93.3%;
7), 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300 mL autoclaves; by 7.12～10.20 g 10-cyanogen-N; N '; " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand compound (6) is dissolved in the ammonia alcohol saturated solution of 115～150 mL preparation in advance; then add 0.77～1.08 g Raney's nickel, be filled with hydrogen to 1.5～1.55 Mpa after air in displacement still to N, in 24.5～26.5 ° of C reaction 48～50 h of temperature.Filtration catalizer, decompression removes solvent, is dried to obtain 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, white solid 6.5～8.3 g of 7,10-tetraazacyclododecanand compound (7).Product, without separation, is directly used in next step reaction;
8), N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8) preparation
By 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (7) 3.3 g(6.4 mmol)～6.9 g(13.4 mmol) and trolamine (TEA) 1.4 mL(10 mmol)～2.8 mL(20 mmol) join in 100～180 mL methylene dichloride, at 0～0.5 ° of C of temperature, stir the lower benzyl acetate bromide 1.3 mL(8 mmol that drip)～2.5 mL(16 mmol) 6～10 mL dichloromethane solutions, dropwise, after room temperature reaction 48～50 h, solvent is removed in decompression, then taking ethyl acetate as eluent, column chromatography obtains N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] the colourless viscous liquid 1.8～3.8g of compound (8), productive rate 41.1 %～42.9%,
9) 10-(2-carboxymethyl-amino) preparation of-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (9)
The Pd/C of N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1; 4,7,10-tetraazacyclododecanand base] compound (8) 3.0～5.5g and 0.85～1.53 g 3% is joined in reaction flask; add 20～80 mL methyl alcohol, at 1.5～1.55 Mpa H 2lower room temperature reaction 3～3.5 h; after reaction, some plate detects; raw material reaction is complete, after suction filtration, except desolventizing, obtains 10-(2-carboxymethyl-amino)-ethyl-3-[N; N '; N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand base] compound (9) white solid 2.1～4.16g, productive rate 81.2%～84.7%.
10) preparation of soccerballene list cyclen derivatives intermediate
By 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) 58 mg(0.1 mmol)～290mg(0.5mmol), soccerballene 72 mg(0.1 mmol)～360 mg(0.5mmol), paraformaldehyde 4.5 mg(0.12 mmol)～22.5mg(0.6mmol) join in 15～50 mL toluene, reaction under 110～112 ° of C of temperature stir, after backflow 6～6.5 h, decompression removes toluene, then with petrol ether/ethyl acetate (1:5, v/v) be eluent, rapid column chromatography obtains black solid 47～227.2 mg of soccerballene list cyclen derivatives midbody compound (10), productive rate 31.6%～37 %, 1h NMR (400 MHz, CDCl 3): δ=4.57 (s, 1H), 4.46 (s, 2H), 3.89 (m, 2H), 3.62-3.52 (m, 4H), 3.49-3.46 (m, 8H), 3.16 (d, 3H), 2.95-2.91 (d, 2H), 1.49-1.47 (m, 27H) ppm, 13c NMR (100 MHz, CDCl 3): δ=154.83,147.33,146.28,144.56,143.11,140.20,136.16,99.99,79.69,70.77,68.48,60.39,28.58,21.05 ppm. HRMS-MS:1263.407 ([M+1] +).
11) preparation of soccerballene list cyclen derivatives
By soccerballene list cyclen derivatives midbody compound (10) 90 mg(71.3 μ mol)～180 mg(142.6 μ mol) be dissolved in the CH of 50～80 mL 2cl 2in, in the situation that stirring, be slowly added dropwise to CF 3cOOH 1.0 mL(13.4 mmol)～2.0 mL(26.8 mmol), under room temperature, react 18～24 h, and monitor until reaction raw materials completely dissolve with TLC.Then reaction mixture decompression is removed to solvent and other lower-boiling impurity, obtain brown solid 80～157.3 mg of soccerballene list cyclen derivatives, productive rate 85.2%～90.1%. 1h NMR (400 MHz, DMSO-d 6): δ=7.92 (broad), 4.75 (s, 4H), 3.53 (s, 2H); 3.29 (s, 4H), 3.16 (s, 4H); 3.06 (s, 6H), 2.91 (s, 4H) ppm; 13C NMR (400 MHz, DMSO-d6): δ=155.5,145.9,145.4,144.7,142.6,141.8,141.6,141.4,139.5,135.4,72.1,67.1,48.2,44.3,42.2,42.0. HRMS-MS:962.332 ([M-3]+). the structural formula of soccerballene list cyclen derivatives is:
Performance test:
1, adopt infrared spectra to the structured testing of soccerballene list cyclen derivatives is confirmed, as shown in Figure 1.
2, adopt 1h-NMR has obtained confirmation to the structured testing of soccerballene list cyclen derivatives, as shown in Figure 2.
3, adopt 13c-NMR has obtained confirmation to the structured testing of soccerballene list cyclen derivatives, as shown in Figure 3.
4, adopt mass spectrum to obtain confirmation to the structured testing of soccerballene list cyclen derivatives, as shown in Figure 4.
Tool of the present invention has the following advantages:
Advantage of the present invention is the derivative that has synthesized the solubility that contains fullerene structure.Introduce modified group at side chain by this method, can widen and improve performance and the function of soccerballene, give its new function and purposes simultaneously.Be called as the chemical sensor of " molecular probe " such as can be used as, can also be used for solar cell and other photoelectric device.
Brief description of the drawings
The infrared spectrogram of the structure of Fig. 1 soccerballene list cyclen derivatives:
As shown in Figure 1, result shows 3400-2500 cm -1for the absorption peak of NH, 1667 cm -1, 1424 cm -1, 1123 cm -1for the absorption peak of CO.
The structure of Fig. 2 soccerballene list cyclen derivatives 1h-NMR spectrogram:
As shown in Figure 2, result shows 1h NMR (400 MHz, CDCl 3): δ=3.49-3.32 (m, 14H), 3.07-3.01 (m, 4H), 2.68 (s, 4H), 1.45 (s, 9H), 1.42 (s, 18H) ppm.
The structure of Fig. 3 soccerballene list cyclen derivatives 13c NMR spectrogram:
As shown in Figure 3, result shows 13c NMR (100 MHz, CDCl 3): δ=170.06,155.26,79.65,79.33,53.83,50.11,49.70,47.63,42.90,41.87,28.54,28.45 ppm.
The mass spectrum of the structure of Fig. 4 soccerballene list cyclen derivatives:
As shown in Figure 4, result shows HRMS-MS:962.332 ([M-3] +).
Embodiment
Below by embodiment so that the present invention is carried out to basic description; be necessary to be pointed out that at this present embodiment is only used to further illustrate the present invention; can not be interpreted as the restriction to invention protection domain, some nonessential improvement and adjustment that the person skilled in the art in this field can make according to the content of the invention described above.
Embodiment 1
1) N, N ', N " preparation of tri-p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, 126 g Tosyl chlorides are dissolved in to the solution of 300 m L acetone and 91.2 g Anhydrous potassium carbonates and are dissolved in the solution of 200 mL water, be added drop-wise to 20.6 g(0.20 mol) in diethylenetriamine, time for adding approximately 1.5 h.Stir at ambient temperature again 4 h.Then reactant is poured in frozen water, be then under agitation poured into water, filter, suction filtration after methanol wash for filter cake, vacuum drying obtains N, N ', N " white solid 103.2 g of tri-p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%.
2) N, O, the preparation of two (2-hydroxyethyl) amine compound (2) of O '-tri-p-toluenesulfonyl
Under ice bath, 300 mL are dissolved with to 126 g(0.66 mol) dichloromethane solution of Tosyl chloride is added drop-wise to and contains 21.0 g(0.2 mol) diethanolamine and 100 mL(0.72 mol) in the reaction flask of triethylamine, control time for adding approximately 3 h, room temperature reaction 4 h.Then reactant is poured in frozen water, separatory, washes 3 times, and organic phase is through anhydrous Na 2sO 4after dry, filter, evaporate to dryness filtrate obtains a yellow oil, and after recrystallizing methanol, vacuum-drying obtains N, O, white solid 99.7 g of two (2-hydroxyethyl) amine compound (2) of O '-tri-p-toluenesulfonyl, yield 88%.
3) Isosorbide-5-Nitrae, 7,10-, tetra-p-toluenesulfonyls-Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (3)
By N; N '; N " tri-p-toluenesulfonyl diethylenetriamine compound (1) 34.4 g(0.06 mol) and N; O; two (2-hydroxyethyl) amine compound (2) the 34.0 g(0.06 mol of O '-tri-p-toluenesulfonyl) and 25.0 g Anhydrous potassium carbonates join in the DMF that 300 mL are dry, 100 ° of C react 3 h.React complete, cooling, suction filtration obtains filtrate; steam most of DMF more muddy to solution after, splash into 150 mL methanol wash, cooling; suction filtration, filter cake washing three times, then dry 1; 4,7,10-, tetra-p-toluenesulfonyl-1; 4; 7,10-tetraazacyclododecanand compound (3) 30.1 g, productive rate 63.7%.
4) Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand (4) compound
By Isosorbide-5-Nitrae, 7,10-tetra-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (3) 30.0 g join the dense H of 60 mL 2sO 4in, heating treats that it dissolves, then 110～115 ° of C reaction 48～50 h.So, under vigorous stirring, be poured in 200 mL dehydrated alcohols, stir 0.5 h, suction filtration, filter cake is dissolved in 80mL water, with decolorizing with activated carbon, adds in 40 mL concentrated hydrochloric acids and boils, and leaves standstill, and filters to obtain white solid.This solid is dissolved in 30mL water, to strong basicity, then uses chloroform (heat) to extract repeatedly with potassium hydroxide solution adjusting pH, filtrate is after anhydrous sodium sulfate drying, steaming desolventizes, and is dried to obtain Isosorbide-5-Nitrae, white solid 2.62 g of 7,10-tetraazacyclododecanand compound (4), productive rate 40%.
5) N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 4.5g(26.1 mmol) and triethylamine 12.0 mL(86.4 mmol) be dissolved in methylene dichloride 145 mL, under normal temperature, slowly drip (Boc) 2the methylene dichloride 118 mL solution of O 17.7 g (81.1 mmol), drip in 3h.Under room temperature, stir 24～25 h, decompression removes solvent again, column chromatography (sherwood oil: ethyl acetate=1: 1) obtain N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, white solid 10.20 g of 7,10-tetraazacyclododecanand compound (5), productive rate: 76.5 %. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.61?(s,?4H),?3.36?(s,?4H),?3.28?(s,?4H),?2.86?(s,?4H),?1.46?(s,?9H),?1.44?(s,?18H)?ppm。
6) 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500mL reaction flask, add N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.68 g (22.7 mmol), K 2cO 37.64 g (55.4 mmol), KI 9.10 g (54.8 mmol), then add 185 mL acetonitriles, chloromethyl cyanide 2.02 mL(224.1 mmol), back flow reaction 70～72 h, remove solvent, add CH 2cl 2, suction filtration, removes inorganic salt, and filtrate decompression is removed solvent; column chromatography (sherwood oil: ethyl acetate=3: 2) obtain 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; white solid 10.33 g of 7,10-tetraazacyclododecanand compound (6), productive rate 92.4%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.81?(s,?2H),?3.47?(s,?4H),?3.35?(s,?8H),?2.83?(s,?4H),?1.46?(s,?9H),?1.43?(s,?18H)?ppm。
7) 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300 mL autoclaves, by 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (6) 7.12 g are dissolved in the ammonia alcohol saturated solution of 115 mL preparation in advance, then add 0.77 g Raney's nickel, in displacement still, after air, be filled with hydrogen to 1.5～1.55Mpa, under 24.5～26.5 ° of C of temperature, react 48～50 h, after completion of the reaction, filtration catalizer, decompression removes solvent, be dried to obtain 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, white solid 6.5 g of 10-tetraazacyclododecanand compound (7).Product, without separation, is directly used in next step reaction.
8) preparation of N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8)
By 6.9 g(13.4 mmol) 10-(2-amino-ethyl)-N; N '; N " tri-tertiary fourth oxygen formyl radical-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8 mL(20 mmol) TEA joins in 180 mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature; drip 2.5 mL(16 mmol) and 10 mL dichloromethane solutions of benzyl acetate bromide, room temperature reaction 48～50 h.Solvent is removed in decompression, and then taking ethyl acetate as eluent, column chromatography obtains N-acetyl oxygen phenyl-3-[N; N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] colourless viscous liquid 3.8 g of compound (8), productive rate 41.1 %(two step productive rates). 1H?NMR?(400?MHz,?CDCl 3)：δ?=?7.29?(s,?5H),?5.10?(s,?2H),?3.42-3.21?(m,?14H),?2.71-2.60?(m,?8H),?1.40?(s,?9H),?1.37?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3)：δ?=171.89,?155.94,?155.53,?155.20,?135.52,?128.44,?128.23,?128.21,?79.21,?79.00,?77.66,?77.34,?77.02,?66.30,?54.55,?49.86,?47.80,?45.10,?28.57,?28.36。
9) 10-(2-carboxymethyl-amino) preparation of-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (9)
The Pd/C of N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8) 3.6 g and 1.05 g 3% is joined in reaction flask, add 50 mL methyl alcohol, at 1.5～1.55 Mpa H 2lower room temperature reaction 3 h, after reaction, some plate detects, and raw material reaction is complete, removes desolventizing after suction filtration; obtain 10-(2-carboxymethyl-amino) and-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] compound (9) white solid 2.42g, productive rate 84.7%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.49-3.32?(m,?14H),?3.07-3.01?(m,?4H),?2.68?(s,?4H),?1.45?(s,?9H),?1.42?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=?170.06,?155.26,?79.65,?79.33,?53.83,?50.11,?49.70,?47.63,?42.90,?41.87,?28.54,?28.45?ppm。
10) preparation of soccerballene list cyclen derivatives midbody compound (10)
By 58 mg 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) 72 mg(0.1 mmol), soccerballene 4.5 mg(0.1 mmol), paraformaldehyde (0.12 mmol) joins in 15 mL toluene, then stir lower reaction in 110～115 ° of C, after backflow 6～6.5 h, decompression removes toluene, then with petrol ether/ethyl acetate (1:5, v/v) be eluent, rapid column chromatography obtains the black solid 43.9mg of soccerballene list cyclen derivatives midbody compound (10), productive rate 35.8 %. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?4.57?(s,?1H),?4.46?(s,?2H),?3.89?(m,?2H),?3.62-3.52?(m,?4H),?3.49-3.46?(m,?8H),?3.16?(d,?3H),?2.95-2.91(d,?2H),?1.49-1.47(m,?27H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=154.83,?147.33,?146.28,?144.56,?143.11,?140.20,?136.16,?99.99,?79.69,?70.77,?68.48,?60.39,?28.58,?21.05?ppm.?HRMS-MS:?1263.407([M+1] +)。
11) preparation of soccerballene list cyclen derivatives
By soccerballene list cyclen derivatives intermediate (10) 90 mg(71.3 μ mol) be dissolved in the CH of 50 mL 2cl 2in, in the situation that stirring, be slowly added dropwise to CF 3cOOH 1.0 mL(13.4 mmol), under room temperature, react 18～24 h, and monitor until reaction raw materials completely dissolve with TLC.Then reaction mixture decompression is removed to solvent and other lower-boiling impurity, obtain brown solid 80 mg of soccerballene list cyclen derivatives, productive rate 86%. 1H?NMR?(400?MHz,?DMSO-d 6):?δ?=?7.92(broad),?4.75?(s,?4H),?3.53?(s,?2H),?3.29?(s,?4H),?3.16?(s,?4H),?3.06?(s,?6H),?2.91?(s,?4H)?ppm;?13C?NMR?(400?MHz,?DMSO-d6):?δ?=?155.5,?145.9,?145.4,?144.7,?142.6,?141.8,?141.6,?141.4,?139.5,?135.4,?72.1,?67.1,?48.2,?44.3,?42.2,?42.0.?HRMS-MS:?962.332?([M-3] +)。
Embodiment 2
According to 1 in embodiment 1)～4) preparation method prepares compound (1)～(4)
5) N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 5.0 g(29.0 mmol) and triethylamine 12.4 mL(89.3 mmol) be dissolved in methylene dichloride 150 mL, under normal temperature, slowly drip (Boc) 2the methylene dichloride 120 mL solution of O 17.72 g (81.2 mmol), drip in 3h.Under room temperature, stir 24～25 h, decompression removes solvent again, and column chromatography (sherwood oil: ethyl acetate=1:1) obtains N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, white solid 10.50 g of 7,10-tetraazacyclododecanand compound (5), productive rate: 76.8 %. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.60?(s,?4H),?3.37(s,?4H),?3.28?(s,?4H),?2.86?(s,?4H),?1.45?(s,?9H),?1.44?(s,?18H)?ppm。
6) 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500mL reaction flask, add N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.74 g (22.8 mmol), K 2cO 37.74 g (56.09 mmol), KI 9.29 g (55.96 mmol), then add 190 mL acetonitriles, chloromethyl cyanide 2.05 mL(250.80 mmol), back flow reaction 70～72 h, remove solvent, add CH 2cl 2, suction filtration, removes inorganic salt, and filtrate decompression is removed solvent, and column chromatography (sherwood oil: ethyl acetate=3:2) obtains 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, white solid 10.55 g of 7,10-tetraazacyclododecanand compound (6), productive rate 91%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.82?(s,?2H),?3.47?(s,?4H),?3.37?(s,?8H),?2.83?(s,?4H),?1.46?(s,?9H),?1.44?(s,?18H)?ppm。
7) 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300 mL autoclaves, by 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (6) 7.15 g are dissolved in the ammonia alcohol saturated solution of 120 mL preparation in advance, then add 0.78 g Raney's nickel, in displacement still, after air, be filled with hydrogen to 1.5～1.55 Mpa, under 24.5～26.5 ° of C, react 48～50 h, after completion of the reaction, filtration catalizer, decompression removes solvent, be dried to obtain 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, white solid 6.9 g of 10-tetraazacyclododecanand compound (7).Product, without separation, is directly used in next step reaction.
8) preparation of N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8)
By 6.7 g(13.0 mmol) 10-(2-amino-ethyl)-N; N '; N " tri-tertiary fourth oxygen formyl radical-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8 mL(20 mmol) TEA joins in 175 mL methylene dichloride, under 0～0.5 ° of C agitation condition; drip 2.5 mL(16 mmol) and 10 mL dichloromethane solutions of benzyl acetate bromide, room temperature reaction 48～50 h.Solvent is removed in decompression, and then taking ethyl acetate as eluent, column chromatography obtains N-acetyl oxygen phenyl-3-[N; N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] colourless viscous liquid 3.7 g of compound (8), productive rate 40.9 %(two step productive rates). 1H?NMR?(400?MHz,?CDCl 3)：δ?=?7.27?(s,?5H),?5.11?(s,?2H),?3.45-3.21?(m,?14H),?2.70-2.61?(m,?8H),?1.42?(s,?9H),?1.35?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3)：δ?=171.82,?155.88,?155.52,?155.20,?135.51,?128.46,?128.24,?128.19,?79.20,?79.03,?77.66,?77.34,?77.02,?66.32,?54.57,?49.86,?47.82,?45.11,?28.59,?28.32。
9) 10-(2-carboxymethyl-amino) preparation of-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (9)
The Pd/C of 3.0 g N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8) and 0.88 g 3% is joined in reaction flask, add 20 mL methyl alcohol, at 1.5～1.55 Mpa H 2lower room temperature reaction 3 h; after reaction, some plate detects; raw material reaction is complete, after suction filtration, except desolventizing, obtains 10-(2-carboxymethyl-amino)-ethyl-3-[N; N '; N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand base] white solid 2.1 g of compound (9), productive rate 83.6%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.47-3.32?(m,?14H),?3.06-3.01?(m,?4H),?2.67?(s,?4H),?1.45?(s,?9H),?1.42?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=?170.06,?155.25,?79.68,?79.31,?53.83,?50.12,?49.71,?47.63,?42.90,?41.86,?28.53,?28.44?ppm。
10) preparation of soccerballene list cyclen derivatives midbody compound (10)
By 116 mg(0.2 mmol) 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) 144 mg(0.2mmol) soccerballene, 7.5 mg(0.2 mmol) paraformaldehyde joins in 18mL toluene, reaction under 110～115 ° of C of temperature stir, after backflow 6～6.5 h, decompression removes toluene, then with petrol ether/ethyl acetate (1:5, v/v) be eluent, rapid column chromatography obtains black solid 94.1 mg of soccerballene list cyclen derivatives midbody compound (10), productive rate 37%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?4.55?(s,?1H),?4.44?(s,?2H),?3.87?(m,?2H),?3.62-3.53?(m,?4H),?3.49-3.46?(m,?8H),?3.16?(d,?3H),?2.95-2.91(d,?2H),?1.49-1.47(m,?27H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=154.83,?147.32,?146.28,?144.56,?143.13,?140.21,?136.17,?99.99,?79.69,?70.77,?68.46,?60.38,?28.57,?21.05?ppm.?HRMS-MS:?1263.404([M+1] +)。
11) preparation of soccerballene list cyclen derivatives
Soccerballene list cyclen derivatives midbody compound (10) 100mg(79.2 μ mol) be dissolved in the CH of 50 mL 2cl 2in, in the situation that stirring, be slowly added dropwise to CF 3cOOH 1.2 mL(16.08 mmol), under room temperature, react 18～24 h, and monitor until reaction raw materials completely dissolve with TLC.Then reaction mixture decompression is removed to solvent and other lower-boiling impurity, obtain brown solid 87.1 mg of soccerballene list cyclen derivatives, productive rate 85.2%. 1H?NMR?(400?MHz,?DMSO-d 6):?δ?=?7.91(broad),?4.75?(s,?4H),?3.52?(s,?2H),?3.28?(s,?4H),?3.15?(s,?4H),?3.07?(s,?6H),?2.91?(s,?4H)?ppm;? 13C?NMR?(400?MHz,?DMSO-d 6):?δ?=?155.5,?145.8,?145.4,?144.8,?142.5,?141.8,?141.6,?141.3,?139.4,?135.4,?72.2,?67.2,?48.2,?44.3,?42.2,?41.9.?HRMS-MS:?962.337([M-3] +)。
Embodiment 3
According to 1 in embodiment 1)～4) preparation method prepares compound (1)～(4)
5) N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (4) 6.0 g(34.8mmol) and triethylamine 15 mL(108.0 mmol) be dissolved in methylene dichloride 160 mL, under normal temperature, slowly drip (Boc) 2o 20.42 g(93.6mmol) methylene dichloride 130 mL solution, in 3 h, drip.Under room temperature, stir 24h～25 h, decompression removes solvent again, and column chromatography (sherwood oil: ethyl acetate=1:1) obtains N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, white solid 11.72 g of 7,10-tetraazacyclododecanand compound (5), productive rate: 74.3 %. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.61?(s,?4H),?3.36?(s,?4H),?3.27?(s,?4H),?2.85?(s,?4H),?1.46?(s,?9H),?1.44?(s,?18H)?ppm。
6) 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500 mL reaction flasks, add N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 12.05 g (25.58 mmol), K 2cO 38.50 g (61.59 mmol), KI 9.20 g (55.42 mmol), then add 190 mL acetonitriles, chloromethyl cyanide 3.00 mL(367.02 mmol), back flow reaction 70～72 h, remove solvent, add CH 2cl 2, suction filtration, removes inorganic salt, and filtrate decompression is removed solvent; column chromatography (sherwood oil: ethyl acetate=3:2) obtains 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; white solid 10.94 g of 7,10-tetraazacyclododecanand compound (6), productive rate 89.9%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.81?(s,?2H),?3.46?(s,?4H),?3.37?(s,?8H),?2.83?(s,?4H),?1.46?(s,?9H),?1.43?(s,?18H)?ppm。
7) 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300 mL autoclaves, by 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (6) 8.25 g are dissolved in the ammonia alcohol saturated solution of 130 mL preparation in advance, then add 0.85 g Raney's nickel, in displacement still, after air, be filled with hydrogen to 1.5～1.55 Mpa, under 24.5～26.5 ° of C of temperature, react 48～50 h, after completion of the reaction, filtration catalizer, decompression removes solvent, be dried to obtain 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, white solid 7.16 g of 10-tetraazacyclododecanand compound (7).Product, without separation, is directly used in next step reaction.
8) preparation of N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8)
By 6.0 g(11.6 mmol) 10-(2-amino-ethyl)-N; N '; N " tri-tertiary fourth oxygen formyl radical-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8 mL(20 mmol) TEA joins in 180 mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature; drip 2.5 mL(16 mmol) and 10 mL dichloromethane solutions of benzyl acetate bromide, room temperature reaction 48～50 h.Solvent is removed in decompression, and then taking ethyl acetate as eluent, column chromatography obtains N-acetyl oxygen phenyl-3-[N; N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] colourless viscous liquid 3.2 g of compound (8), productive rate 40.2%(two step productive rates). 1H?NMR?(400?MHz,?CDCl 3)：δ?=?7.28?(s,?5H),?5.10?(s,?2H),?3.41-3.23?(m,?14H),?2.70-2.59?(m,?8H),?1.42?(s,?9H),?1.36?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3)：δ?=171.87,?155.98,?155.50,?155.23,?135.55,?128.42,?128.26,?128.23,?79.24,?79.02,?77.62,?77.32,?77.00,?66.32,?54.53,?49.82,?47.83,?45.12,?28.56,?28.33。
9) 10-(2-carboxymethyl-amino) preparation of-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (9)
The Pd/C of 5.5 g N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8) and 1.53 g 3% is joined in reaction flask, add 80 mL methyl alcohol, at 1.5～1.55 Mpa H 2lower room temperature reaction 3 h, after reaction, some plate detects, and raw material reaction is complete, removes desolventizing after suction filtration; obtain 10-(2-carboxymethyl-amino) and-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] compound (9) white solid 4.16g, productive rate 82%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.48-3.32?(m,?14H),?3.08-3.00?(m,?4H),?2.68?(s,?4H),?1.43?(s,?9H),?1.42?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=?170.04,?155.27,?79.63,?79.31,?53.82,?50.16,?49.69,?47.62,?42.91,?41.85,?28.54,?28.45?ppm。
10) preparation of soccerballene list cyclen derivatives midbody compound (10)
By 168mg(0.3 mmol) 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) 216 mg soccerballenes (0.3 mmol), 11.3 mg paraformaldehydes (0.3 mmol) join in 25 mL toluene, then stir lower reaction in 110～115 ° of C, after backflow 6～6.5 h, decompression removes toluene, then with petrol ether/ethyl acetate (1:5, v/v) be eluent, rapid column chromatography obtains black solid 137 mg of soccerballene list cyclen derivatives midbody compound (10), productive rate 35.6%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?4.56?(s,?1H),?4.46?(s,?2H),?3.87?(m,?2H),?3.60-3.51?(m,?4H),?3.48-3.47?(m,?8H),?3.15?(d,?3H),?2.95-2.91(d,?2H),?1.49-1.46(m,?27H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=154.82,?147.31,?146.28,?144.55,?143.11,?140.21,?136.16,?99.98,?79.69,?70.78,?68.48,?60.38,?28.58,?21.05?ppm.?HRMS-MS:?1263.405([M+1] +)。
11) preparation of soccerballene list cyclen derivatives
By soccerballene list cyclen derivatives midbody compound (10) 120 mg(95.07 μ mol) be dissolved in the CH of 60 mL 2cl 2in, in the situation that stirring, be slowly added dropwise to CF 3cOOH 1.3 mL(17.42 mmol), under room temperature, react 18～24 h, and monitor until reaction raw materials completely dissolve with TLC.Then reaction mixture decompression is removed to solvent and other lower-boiling impurity, obtain brown solid 105.2 mg of soccerballene list cyclen derivatives, productive rate 85.7%. 1H?NMR?(400?MHz,?DMSO-d 6):?δ?=?7.92(broad),?4.75?(s,?4H),?3.53?(s,?2H),?3.29?(s,?4H),?3.16?(s,?4H),?3.06?(s,?6H),?2.91?(s,?4H)?ppm;? 13C?NMR?(400?MHz,?DMSO-d 6):?δ?=?155.5,?145.8,?145.4,?144.6,?142.5,?141.7,?141.5,?141.4,?139.5,?135.4,?72.1,?67.2,?48.1,?44.2,?42.2,?42.0.?HRMS-MS:?962.335([M-3] +)。
Embodiment 4
According to 1 in embodiment 1)～4) preparation method prepares compound (1)～(4)
5) N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 7.5 g(43.5 mmol) and triethylamine 18.5 mL(134.0 mmol) be dissolved in methylene dichloride 170 mL, under normal temperature, slowly drip (Boc) 2the methylene dichloride 140 mL solution of O 26.55 g (122.2 mmol), drip in 3h.Under room temperature, stir 24～25 h, decompression removes solvent again, and column chromatography (sherwood oil: ethyl acetate=1:1) obtains N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, white solid 14.72 g of 7,10-tetraazacyclododecanand compound (5), productive rate: 74.1 %. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.60?(s,?4H),?3.36?(s,?4H),?3.28?(s,?4H),?2.86?(s,?4H),?1.45?(s,?9H),?1.44?(s,?18H)?ppm。
6) 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500mL reaction flask, add N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 13.05 g (27.7 mmol), K 2cO 39.04 g (65.50 mmol), KI 11.20 g (67.47 mmol), then add 190 mL acetonitriles, chloromethyl cyanide 4.00 mL(489.37 mmol), back flow reaction 70～72 h, remove solvent, add CH 2cl 2, suction filtration, removes inorganic salt, and filtrate decompression is removed solvent; column chromatography (sherwood oil: ethyl acetate=3:2) obtains 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; white solid 13.72 g of 7,10-tetraazacyclododecanand compound (6), productive rate 93.3%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.82?(s,?2H),?3.45?(s,?4H),?3.37?(s,?8H),?2.83?(s,?4H),?1.45?(s,?9H),?1.44?(s,?18H)?ppm。
7) 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300 mL autoclaves, by 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (6) 9.26 g are dissolved in the ammonia alcohol saturated solution of 150 mL preparation in advance, then add 1.02 g Raney's nickels, in displacement still, after air, be filled with hydrogen to 1.5～1.55 Mpa, under 24.5～26.5 ° of C of temperature, react 48～50 h, after completion of the reaction, filtration catalizer, decompression removes solvent, be dried to obtain 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, the white solid 8.3g of 10-tetraazacyclododecanand compound (7).Product, without separation, is directly used in next step reaction.
8) preparation of N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8)
By 3.3 g(6.5 mmol) 10-(2-amino-ethyl)-N; N '; N " tri-tertiary fourth oxygen formyl radical-1; 4; 7,10-tetraazacyclododecanand compound (7) and 1.4 mL(10 mmol) TEA joins in 100 mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature; drip 1.3 mL(8 mmol) and 6 mL dichloromethane solutions of benzyl acetate bromide, room temperature reaction 48～50 h.React complete, then taking ethyl acetate as eluent, column chromatography obtains N-acetyl oxygen phenyl-3-[N; N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] colourless viscous liquid 1.8 g of compound (8), productive rate 42.9 %(two step productive rates). 1H?NMR?(400?MHz,?CDCl 3)：δ?=?7.24?(s,?5H),?5.08?(s,?2H),?3.42-3.21?(m,?14H),?2.71-2.58?(m,?8H),?1.41?(s,?9H),?1.37?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3)：δ?=171.88,?155.93,?155.52,?155.21,?135.51,?128.45,?128.22,?128.20,?79.22,?79.01,?77.67,?77.33,?77.01,?66.27,?54.58,?49.88,?47.82,?45.11,?28.55,?28.38。
9) 10-(2-carboxymethyl-amino) preparation of-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (9)
The Pd/C of 4.8 g N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8) and 1.40 g 3% is joined in reaction flask, add 60 mL methyl alcohol, at 1.5～1.55 Mpa H 2lower room temperature reaction 3 h, after reaction, some plate detects, and raw material reaction is complete, removes desolventizing after suction filtration; obtain 10-(2-carboxymethyl-amino) and-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] compound (9) white solid 3.26 g, productive rate 81.2%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.47-3.31?(m,?14H),?3.06-3.00?(m,?4H),?2.66?(s,?4H),?1.456(s,?9H),?1.44?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=?170.02,?155.24,?79.63,?79.31,?53.83,?50.12,?49.71,?47.62,?42.90,?41.88,?28.54,?28.45?ppm。
10) preparation of soccerballene list cyclen derivatives midbody compound (10)
By 232 mg (0.4 mmol) 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) 288 mg(0.4 mmol) soccerballene, 15 mg(0.4 mmol) paraformaldehyde joins in 50 mL toluene, then stir lower reaction in 110～115 ° of C, after backflow 6～6.5 h, decompression removes toluene, then with petrol ether/ethyl acetate (1:5, v/v) be eluent, rapid column chromatography obtains the black solid 172.3mg of soccerballene list cyclen derivatives midbody compound (10), productive rate 31.9 %. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?4.57?(s,?1H),?4.48?(s,?2H),?3.87?(m,?2H),?3.62-3.52?(m,?4H),?3.49-3.47?(m,?8H),?3.16?(d,?3H),?2.94-2.91(d,?2H),?1.49-1.47(m,?27H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=154.81,?147.33,?146.28,?144.56,?143.12,?140.20,?136.16,?99.99,?79.70,?70.75,?68.48,?60.39,?28.56,?21.04?ppm.?HRMS-MS:?1263.407([M+1] +).
11) preparation of soccerballene list cyclen derivatives
By soccerballene list cyclen derivatives midbody compound (10) 180mg(142.6 μ mol) be dissolved in the CH of 80 mL 2cl 2in, in the situation that stirring, be slowly added dropwise to CF 3cOOH 2.0 mL(26.8 mmol), under room temperature, react 18～24 h, and monitor until reaction raw materials completely dissolve with TLC.Then reaction mixture decompression is removed to solvent and other lower-boiling impurity, obtain the brown solid 163.3mg of soccerballene list cyclen derivatives, productive rate 88.2%. 1H?NMR?(400?MHz,?DMSO-d 6):?δ?=?7.92(broad),?4.75?(s,?4H),?3.54?(s,?2H),?3.29?(s,?4H),?3.16?(s,?4H),?3.06?(s,?6H),?2.91?(s,?4H)?ppm;? 13C?NMR?(400?MHz,?DMSO-d 6):?δ?=?155.6,?145.7,?145.4,?144.6,?142.6,?141.8,?141.7,?141.5,?139.5,?135.3,?72.1,?67.1,?48.3,?44.3,?42.2,?42.0.?HRMS-MS:?962.332([M-3] +)。
Embodiment 5
According to 1 in embodiment 1)～4) preparation method prepares compound (1)～(4),
5) N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (4) 9.0 g(52.2 mmol) and triethylamine 25 mL(180 mmol) be dissolved in methylene dichloride 255 mL, under normal temperature, slowly drip (Boc) 2the methylene dichloride 200 mL solution of O 35 g (163mmol), drip in 3h.Under room temperature, stir 24～25 h, decompression removes solvent again, and column chromatography (sherwood oil: ethyl acetate=1:1) obtains N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 14.78g of 7,10-tetraazacyclododecanand compound (5), productive rate: 56.5 %. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.61?(s,?4H),?3.35?(s,?4H),?3.28?(s,?4H),?2.85?(s,?4H),?1.46?(s,?9H),?1.44?(s,?18H)?ppm。
6) 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500ml reaction flask, add N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 15.84 g (33.7 mmol), K 2cO 39.84 g (71.30 mmol), KI 12.35 g (74.40 mmol), then add 192 mL acetonitriles, chloromethyl cyanide 4.08 mL(499.1 mmol), back flow reaction 70～72h, removes solvent, adds CH 2cl 2, suction filtration, removes inorganic salt, and filtrate decompression is removed solvent; column chromatography (sherwood oil: ethyl acetate=3:2) obtains 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; white solid 14.75 g of 7,10-tetraazacyclododecanand compound (6), productive rate 90.7%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.82?(s,?2H),?3.45?(s,?4H),?3.37?(s,?8H),?2.84?(s,?4H),?1.46?(s,?9H),?1.45?(s,?18H)?ppm。
7) 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300 mL autoclaves, by 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (6) 10.20 g are dissolved in the ammonia alcohol saturated solution of 150 mL preparation in advance, then add 1.08 g Raney's nickels, in displacement still, after air, be filled with hydrogen to 1.5～1.55 Mpa, under 24.5～26.5 ° of C of temperature, react 48～50 h, after completion of the reaction, filtration catalizer, decompression removes solvent, be dried to obtain 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, white solid 8.02 g of 10-tetraazacyclododecanand compound (7).Product, without separation, is directly used in next step reaction.
8) preparation of N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8)
By 5.8 g(11.3 mmol) 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (7) and 2.8 mL(17mmol) TEA joins in 135 mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature, drip 2.2 mL(13.8 mmol) the 7.5mL dichloromethane solution of benzyl acetate bromide, solvent is removed in room temperature reaction 48～50 h decompressions, then taking ethyl acetate as eluent, column chromatography obtains N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] colourless viscous liquid 2.8 g of compound (8), productive rate 41.7%(two step productive rates). 1H?NMR?(400?MHz,?CDCl 3)：δ?=?7.28?(s,?5H),?5.09?(s,?2H),?3.43-3.22?(m,?14H),?2.73-2.59?(m,?8H),?1.40?(s,?9H),?1.37?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3)：δ?=171.86,?155.92,?155.52,?155.23,?135.48,?128.47,?128.22,?128.19,?79.22,?78.99,?77.67,?77.33,?77.02,?66.28,?54.54,?49.84,?47.78,?45.09,?28.56,?28.35.
9) 10-(2-carboxymethyl-amino) preparation of-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (9)
The Pd/C of 3.2 g N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] compound (8) and 0.85 g 3% is joined in reaction flask, add 50 mL methyl alcohol, at 1.5～1.55 Mpa H 2lower room temperature reaction 3 h, after reaction, some plate detects, and raw material reaction is complete, removes desolventizing after suction filtration; obtain 10-(2-carboxymethyl-amino) and-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] compound (9) white solid 2.25 g, productive rate 79.8%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?3.49-3.32?(m,?14H),?3.07-3.02?(m,?4H),?2.68?(s,?4H),?1.45?(s,?9H),?1.42?(s,?18H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=?170.06,?155.26,?79.67,?79.35,?53.84,?50.11,?49.72,?47.61,?42.90,?41.87,?28.55,?28.46?ppm.
10) preparation of soccerballene list cyclen derivatives midbody compound (10)
By 290 mg (0.5 mmol) 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) 360 mg(0.5 mmol) soccerballene, 22.5 mg paraformaldehydes (0.6 mmol) join in 15 mL toluene, then stir lower reaction in 110～115 ° of C, after backflow 6～6.5 h, decompression removes toluene, then with petrol ether/ethyl acetate (1:5, v/v) be eluent, rapid column chromatography obtains the black solid 227.2mg of soccerballene list cyclen derivatives midbody compound (10), productive rate 31.6%. 1H?NMR?(400?MHz,?CDCl 3)：δ?=?4.56?(s,?1H),?4.46?(s,?2H),?3.89?(m,?2H),?3.61-3.52?(m,?4H),?3.49-3.47?(m,?8H),?3.16?(d,?3H),?2.95-2.91(d,?2H),?1.49-1.48(m,?27H)?ppm;? 13C?NMR?(100?MHz,?CDCl 3):?δ?=154.84,?147.33,?146.27,?144.56,?143.13,?140.19,?136.17,?100.00,?79.69,?70.75,?68.48,?60.38,?28.58,?21.04?ppm.?HRMS-MS:?1263.406([M+1] +)。
11) preparation of soccerballene list cyclen derivatives
By soccerballene list cyclen derivatives midbody compound (10) 180 mg(142.6 μ mol) be dissolved in the CH of 80 mL 2cl 2in, in the situation that stirring, be slowly added dropwise to CF 3cOOH 2.0 mL(26.8 mmol), under room temperature, react 18～24 h, and monitor until reaction raw materials completely dissolve with TLC.Then reaction mixture decompression is removed to solvent and other lower-boiling impurity, obtain brown solid 163.3 mg of soccerballene list cyclen derivatives, productive rate 88.2%. 1H?NMR?(400?MHz,?DMSO-d 6):?δ?=?7.92(broad),?4.75?(s,?4H),?3.54?(s,?2H),?3.29?(s,?4H),?3.16?(s,?4H),?3.06?(s,?6H),?2.91?(s,?4H)?ppm;? 13C?NMR?(400?MHz,?DMSO-d 6):?δ?=?155.6,?145.7,?145.4,?144.6,?142.6,?141.8,?141.7,?141.5,?139.5,?135.3,?72.1,?67.1,?48.3,?44.3,?42.2,?42.0.?HRMS-MS:?962.332([M-3] +)。

Claims (1)

1. a preparation method for soccerballene list cyclen derivatives, is characterized in that the method comprises the following steps:
The chemical equation of soccerballene list cyclen derivatives is as follows:
And prepare by following processing step and processing parameter:
1), N, N ', N " preparation of tri-p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, 126g Tosyl chloride is dissolved in to the solution of 300mL acetone and 91.2g Anhydrous potassium carbonate and is dissolved in the solution of 200mL water, be added drop-wise in 20.6g (0.20mol) diethylenetriamine, time for adding 1.2～2.0h, after dropwising, room temperature reaction 4～4.5h, then reactant is poured in frozen water, under agitation be poured into water again, filter suction filtration after methanol wash for filter cake, vacuum drying obtains N, N ', N " the white solid 103.2g of tri-p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2), N, O, the preparation of two (2-hydroxyethyl) amine compound (2) of O '-tri-p-toluenesulfonyl
Under ice bath, the dichloromethane solution that 300mL is dissolved with to 126g (0.66mol) Tosyl chloride is added drop-wise in the reaction flask that contains 21.0g (0.2mol) diethanolamine and 100mL (0.72mol) triethylamine, control time for adding 3h, after dropwising, room temperature reaction 4～4.5h, then pours reactant in frozen water into separatory, wash 3 times, organic phase is through anhydrous Na 2sO 4dry, to filter, evaporate to dryness filtrate obtains a yellow oil, and after recrystallizing methanol, vacuum-drying obtains N, O, the white solid 99.7g of two (2-hydroxyethyl) amine compound (2) of O '-tri-p-toluenesulfonyl, yield 88%;
3), Isosorbide-5-Nitrae, 7,10-, tetra-p-toluenesulfonyls-Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (3)
By N, N ', N " tri-p-toluenesulfonyl diethylenetriamine compound (1) 34.4g (0.06mol), N, O, two (2-hydroxyethyl) amine compound (2) 34.0g (0.06mol) of O '-tri-p-toluenesulfonyl and 25.0g Anhydrous potassium carbonate join the N that 300mL is dry, in dinethylformamide, in 100～105 DEG C of reaction 3～4h of temperature, react complete, cooling, suction filtration obtains filtrate, steam most of dimethyl fumarate more muddy to solution after, splash into 150～160mL methanol wash, cooling, suction filtration, filter cake washing three times, then dry 1, 4, 7, 10-tetra-(p-toluenesulfonyl)-1, 4, 7, 10-tetraazacyclododecanand compound (3) 30.1g, productive rate 63.7%,
4), Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (4)
By Isosorbide-5-Nitrae, 7,10-tetra-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (3) 30.0g joins the dense H of 60mL 2sO 4in, its dissolving is treated in heating, in 110～115 DEG C of reaction 48～50h of temperature, react complete, under vigorous stirring, be poured in 200～250mL dehydrated alcohol, stir 0.5～1.0h, suction filtration, filter cake is dissolved in 80～100mL water, with decolorizing with activated carbon, add in 40～60mL concentrated hydrochloric acid and boil, leave standstill, filter to obtain white solid, this solid is dissolved in 30～50mL water, with potassium hydroxide solution regulate pH to strong basicity, carrying out 3～5 times with chloroform extracts, filtrate is after anhydrous sodium sulfate drying, steaming desolventizes, dry 1, 4, 7, the white solid 2.62g of 10-tetraazacyclododecanand compound (4), productive rate 40%,
5), N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
By 1, 4, 7, 10-tetraazacyclododecanand (4) 4.5g (26.1mmol)～9.0g (52.2mmol) and triethylamine 12.0mL (86.4mmol)～25mL (180mmol) are dissolved in methylene dichloride 145～255mL, under normal temperature, slowly drip methylene dichloride 118～200mL solution of tert-Butyl dicarbonate 17.70g (81.1mmol)～35g (163mmol), 3h drips with interior, under room temperature, stir 24～25h, decompression removes solvent, with sherwood oil: ethyl acetate=1: 1 is eluent, column chromatography obtains N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, white solid 10.2～the 14.78g of 10-tetraazacyclododecanand compound (5), productive rate: 56.5%～77.2%,
6), 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
By N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.68g (22.7mmol)～15.84g (33.7mmol), K 2cO 37.64g (55.1mmol)～9.84g (71.0mmol) and KI9.10g (54.7mmol)～12.35g (74.2mmol) add in 500ml reaction flask, add again 185～192mL acetonitrile, chloromethyl cyanide 2.02mL (247.1mmol)～4.08mL (499.1mmol), back flow reaction 70～72h, remove solvent, add CH 2cl 2suction filtration, removes inorganic salt, and filtrate decompression is removed solvent, with sherwood oil: ethyl acetate=3: 2 is eluent, column chromatography obtains 10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-1; 4; the white solid 10.35～14.75g of 7,10-tetraazacyclododecanand compound (6), productive rate 89.9%～93.3%;
7), 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave, by 7.12～10.20g10-cyanogen-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (6) is dissolved in the ammonia alcohol saturated solution of 115～150mL preparation in advance, then add 0.77～1.08g Raney's nickel, in displacement still, after air, be filled with hydrogen to 1.5～1.55Mpa, in 24.5～26.5 DEG C of reaction 48～50h of temperature, filtration catalizer, decompression removes solvent, be dried to obtain 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, white solid 6.5～the 8.3g of 10-tetraazacyclododecanand compound (7), product is without separation, be directly used in next step reaction,
8), N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of compound (8)
By 10-(2-amino-ethyl)-N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand compound (7) 3.3g (6.4mmol)～6.9g (13.4mmol) and trolamine 1.4mL (10mmol)～2.8mL (20mmol) join in 100～180mL methylene dichloride, 0～0.5 DEG C of temperature, stir 6～10mL dichloromethane solution of the lower benzyl acetate bromide 1.3mL of dropping (8mmol)～2.5mL (16mmol), dropwise, after room temperature reaction 48～50h, solvent is removed in decompression, then taking ethyl acetate as eluent, column chromatography obtains N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] the colourless viscous liquid 1.8～3.8g of compound (8), productive rate 41.1%～42.9%,
9) 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of compound (9)
By N-acetyl oxygen phenyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] Pd/C of compound (8) 3.0～5.5g and 0.85～1.53g3% joins in reaction flask, add 20～80mL methyl alcohol, room temperature reaction 3～3.5h under 1.5Mpa H2, after reaction, some plate detects, raw material reaction is complete, after suction filtration, remove desolventizing, obtain 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) white solid 2.1～4.16g, productive rate 81.2%～84.7%,
10) preparation of soccerballene list cyclen derivatives midbody compound (10)
By 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-1, 4, 7, 10-tetraazacyclododecanand base] compound (9) 58mg (0.1mmol)～290mg (0.5mmol), soccerballene 72mg (0.1mmol)～360mg (0.5mmol), paraformaldehyde 4.5mg (0.12mmol)～22.5mg (0.6mmol) joins in 15～50mL toluene, under 110～112 DEG C of stirrings of temperature, react, after backflow 6～6.5h, decompression removes toluene, then with petrol ether/ethyl acetate (1:5, v/v) be eluent, rapid column chromatography obtains the black solid 47～227.2mg of soccerballene list cyclen derivatives midbody compound (10), productive rate 31.6%～37%,
11) preparation of soccerballene list cyclen derivatives
Soccerballene list cyclen derivatives midbody compound (10) 90mg (71.3 μ mol)～180mg (142.6 μ mol) is dissolved in to the CH of 50～80mL 2cl 2in, in the situation that stirring, be slowly added dropwise to CF 3cOOH1.0mL (13.4mmol)～2.0mL (26.8mmol), under room temperature, react 18～24h, and monitor until reaction raw materials completely dissolve with TLC, then reaction mixture decompression is removed to solvent and other lower-boiling impurity, obtain the brown solid 80～157.3mg of soccerballene list cyclen derivatives, productive rate 85.2%～90.1%; The structural formula of soccerballene list cyclen derivatives is:
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