CN102827149B - Fullerene monomacrocyclic polyamine derivative and preparation method thereof - Google Patents
Fullerene monomacrocyclic polyamine derivative and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a fullerene monomacrocyclic polyamine derivative and a preparation method of the fullerene monomacrocyclic polyamine derivative. The method is characterized by comprising the following steps: adding 58mg (0.1mmol)-290mg (0.5mmol) of 10-(2-carboxymethyl-amino)-ethyl-3-[N, N ', N ' '-tri-tert-butoxyformyl-1, 4, 7, 10-tetraazacyclododecyl] compound (9), 72mg (0.1mmol)-360mg (0.5mmol) of fullerene, 4.5mg (0.12mmol)-22.5mg (0.6mmol) of paraformaldehyde into 15-50mL of toluene, stirring at 110-112 DEG C for reaction, and refluxing for 6-6.5 hours; removing toluene under a reduced pressure; performing rapid column chromatography by using petroleum ether/ethyl acetate (1:5, v/v) as an eluant to obtain 47-227.2mg of black solid of fullerene monomacrocyclic polyamine derivative intermediate with a yield of 31.6%-37%.
Description
Technical field
The present invention relates to a kind of soccerballene list cyclen derivatives intermediate 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 formed title complex 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, etc. chemical reagent, 2004,26 (4): 246.BHARUCHA K R, CROSS C K, RUBIN L J. organic chemistry, 2003,23 (2): 1292], can also be as X ray-contrast media [YU Shi-bao, WATSON A D.Metal2based X2ray contrast media[J] with the title complex of heavy metal formation. 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 has 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): 1 142～145. 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 in various fields, be with a wide range of applications.
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 representing has extensively had influence on a plurality of fields [Wang Tingting such as chemistry, electronics, optics, magnetics and Materials science with its unique shape and good character, once peaceful. 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
60as novel group, introduce Polymer Systems, 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 also has the character of catalysis tolane hydrogenation from testing and having studied it in theory.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, on soccerballene surface, introduce nitrogen heterocyclic ring functional group, to the synthetic fullerene derivate with special construction or property, be applied to 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 aspects such as medical imaging and treatments.The using value of this material in many high and new technologies field may be critical and irreplaceable, 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 intermediate 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, obtained solubility intermediate, its yield is 37%, this intermediate can also make several functions material from different functional group reactions, chemical sensor for " molecular probe ", solar cell, photoelectric device, a plurality of fields such as biomedicine.
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 intermediate is:
The preparation method of described soccerballene list cyclen derivatives intermediate comprises the following steps:
The chemical equation of soccerballene list cyclen derivatives intermediate 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 m L acetone and the solution that 91.2 g Anhydrous potassium carbonates are dissolved in 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 4.0～4.5 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 4.0～4.5 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 compound (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 3.0～4.0 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 60mL
2sO
4in, heating treats that it dissolves, in 110～115 ° of C reaction 48～50h 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, standing, filter to obtain white solid, this solid is dissolved in 30～50 mL water, with potassium hydroxide solution, regulate pH to strong basicity, with chloroform, repeatedly extract, 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)～9.0g(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 118～200mL 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 500 mL reaction flasks, 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), the 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 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, dropping benzyl acetate bromide 1.3 mL(8 mmol under stirring) 6～10 mL dichloromethane solutions～2.5 mL(16 mmol), dropwise, after room temperature reaction 48～50 h, solvent is removed in decompression, then take 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) the 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 Mpa H
2lower room temperature reaction 3.0～3.5 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 2.1～4.16 g, productive rate .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)～290 mg(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 mg～227.2 mg of soccerballene list cyclen derivatives intermediate, 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]
+)., the structural formula of soccerballene list cyclen derivatives intermediate is:
Performance test:
1, adopt infrared spectra to the structured testing of soccerballene list cyclen derivatives intermediate is confirmed, as shown in Figure 1.
2, adopt
1h-NMR has obtained confirmation to the structured testing of soccerballene list cyclen derivatives intermediate, as shown in Figure 2.
3, adopt
13c NMR has obtained confirmation to the structured testing of soccerballene list cyclen derivatives intermediate, as shown in Figure 3.
4, adopt mass spectrum to obtain confirmation to the structured testing of soccerballene list cyclen derivatives intermediate, as shown in Figure 4.
Tool of the present invention has the following advantages:
Advantage of the present invention is to have synthesized the intermediate that contains fullerene structure, and it can obtain the compound of several functions from different functional groups by several steps.At side chain, introduce modified group by this method, can widen and improve performance and the function of soccerballene, give its new function and purposes simultaneously.Such as can be used as, be called as the chemical sensor of " molecular probe ", can also be for solar cell and other photoelectric devices.
Accompanying drawing explanation
The infrared spectrogram of the structure of Fig. 1 soccerballene list cyclen derivatives intermediate
As shown in Figure 1, result shows 2924 cm
-1for the absorption peak of CH, 1683 cm
-1, 1455 cm
-1, 1411 cm
-1, 1363 cm
-1, 1246 cm
-1, 1154 cm
-1it is the absorption peak of CO.
The structure of Fig. 2 soccerballene list cyclen derivatives intermediate
1h-NMR figure:
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 intermediate
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 intermediate
As shown in Figure 4, result shows HRMS-MS:1263.407 ([M+1]
+)
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 the solution that 91.2 g Anhydrous potassium carbonates are dissolved in 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, standing, filters to obtain white solid.This solid is dissolved in 30mL water, with potassium hydroxide solution, regulates pH to strong basicity, then use chloroform (heat) extraction repeatedly, 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 24～25h again, decompression removes solvent, 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 1.5～1.55 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 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, then take ethyl acetate as eluent, and 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) the 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 intermediate
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 in 110～115 ° of C, stir lower reaction, 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 intermediate, 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]
+).
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 3 h.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 10.50 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; 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 10.55 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, then take ethyl acetate as eluent, and 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) the 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 3h, after reaction, some plate detects, and raw material reaction is complete, removes desolventizing after suction filtration; obtain 10-(2-carboxymethyl-amino) white solid 2.1 g of-ethyl-3-[N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7,10-tetraazacyclododecanand base] 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 intermediate
By 116mg(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 the black solid 94.1mg of soccerballene list cyclen derivatives intermediate, 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]
+).
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, drip in 3 h.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 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 500mL reaction flask, 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 3.0 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) obtain 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, then take ethyl acetate as eluent, and 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) the 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 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 4.16 g, 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 intermediate
By 168 mg(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), 11.3mg paraformaldehyde (0.3 mmol) joins in 25 mL toluene, then in 110～115 ° of C, stir lower reaction, 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 intermediate, 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]
+).
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 3 h.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 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) obtain 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 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 take 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) the 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 intermediate
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 in 110～115 ° of C, stir lower reaction, 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 intermediate, 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]
+).
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 compound (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 3 h.Under room temperature, stir 24～25h again, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1:1) obtain N, N ', N " tri-tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, white solid 14.78 g 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 70～72 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 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) 7.5 mL dichloromethane solutions of benzyl acetate bromide, solvent is removed in room temperature reaction 48～50 h decompressions, then take 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) the 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 intermediate
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 in 110～115 ° of C, stir lower reaction, 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 intermediate, 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]
+).
Claims (1)
1. a preparation method for soccerballene list cyclen derivatives intermediate, is characterized in that the method comprises the following steps:
The chemical equation of soccerballene list cyclen derivatives intermediate 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 the solution that 91.2g Anhydrous potassium carbonate is dissolved in 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 ℃ 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 (4) compound
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 ℃ 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, standing, filter to obtain white solid, this solid is dissolved in 30～50mL water, with potassium hydroxide solution, regulate pH to strong basicity, with chloroform, carry out 3～5 extractions, 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 compound (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 7.12g～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 ℃ 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 ℃ of temperature, stir 6～10mL dichloromethane solution of lower benzyl acetate bromide 1.3mL (the 8mmol)～2.5mL of dropping (16mmol), dropwise, after room temperature reaction 48～50h, solvent is removed in decompression, then take 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), two step productive rates 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-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] Pd/C of compound (8) 3.0～5.5g and 0.85～1.53g3% joins in reaction flask, adds 20～80mL methyl alcohol, at 1.5Mpa H
2lower room temperature reaction 3～3.5h, 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 ', the tertiary fourth oxygen of N '-tri-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 ℃ 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 intermediate, productive rate 31.6%～37%.
1h NMR (400MHz, 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 (100MHz, CDCl
3): δ=154.83,147.33,146.28,144.56,143.11,140.20,136.16,99.99,79.69,70.77,68.48,60.39,28.58,21.05ppm, HRMS-MS:1263.407 ([M+1]
+), the structural formula of soccerballene list cyclen derivatives intermediate is:
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