CN102898392A - N-acetoxyphenyl-3-[tri-tert-butoxy formyl-tetraazacyclododecane] intermediate and preparation method thereof - Google Patents
N-acetoxyphenyl-3-[tri-tert-butoxy formyl-tetraazacyclododecane] intermediate and preparation method thereof Download PDFInfo
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Abstract
The present invention discloses an N-acetoxyphenyl-3-[N,N',N"-tri-tert-butoxy formyl-1,4,7,10-tetraazacyclododecane] intermediate and a preparation method thereof. The preparation method is characterized by comprising: adding 3.3 g (6.4 mmol)-6.9 g (13.4 mmol) of 10-(2-amino-ethyl)-N,N',N"-tri-tert-butoxy formyl-1,4,7,10-tetraazacyclododecane compound (7) and 1.4 mL (10 mmol)-2.8 mL (20 mmol) of trolamine to 100-180 mL of dichloromethane, adding 6-10 mL of a dichloromethane solution of 1.3 mL (8 mmol)-2.5 mL (16 mmol) of benzyl bromoacetate in a dropwise manner at a temperature of 0-0.5 DEG C under stirring, carrying out a room temperature reaction for 48-50 hours after completing the adding, carrying out decompression to remove the solvent, and adopting ethyl acetate as an eluant to carry out column chromatography to obtain 1.8-3.8 g of a colorless and viscous N-acetoxyphenyl-3-[tri-tert-butoxy formyl-tetraazacyclododecane] intermediate liquid, wherein yield is 41.1-42.9%.
Description
Technical field
The present invention relates to a kind of N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] 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 the 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 medicine, enzyme dummy, separation and the aspects such as 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 be 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, then can be used as the alkali metal cation coordination agent on the 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 agent [YU Shi-bao, WATSON A D.Metal2based X2ray contrast media[J] .Chem.Rev. with the title complex of heavy metal formation, 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): 1142～145. 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 the organic or inorganic negatively charged ion all shown 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.
Summary of the invention
A kind of N-acetyl oxygen phenyl-3-[N of providing for for the deficiencies in the prior art is provided; N '; N " three uncle's fourth oxygen formyl radicals-1; 4; 7; 10-tetraazacyclododecanand base intermediate and preparation method thereof; be characterized in containing-side chain of tetraazacyclododecanand based structures introduces acetyl oxygen phenyl; and keep to a great extent the distinctive excellent properties of tetraazacyclododecanand, destroy the regularity of main chain, obtained the solubility intermediate; its yield is 40%; this intermediate makes the several functions material from the reaction of different functional group, is used for chemical sensor, solar cell and the photoelectric device of " molecular probe ".
Purpose of the present invention is realized that by following technical measures wherein said raw material umber is parts by weight except specified otherwise.
N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structural formula of intermediate is:
Described N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation method of intermediate may further comprise the steps:
N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] chemical equation of intermediate is as follows:
And by the preparation of following processing step and processing parameter:
1), N, N ', N " preparation of three p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, the 126g Tosyl chloride is dissolved in the solution of 300m L acetone and the solution that the 91.2g Anhydrous potassium carbonate is dissolved in 200mL water, be added drop-wise to 20.6g(0.20mol) in the diethylenetriamine, time for adding 1.2～2.0h, after dropwising, room temperature reaction 4～4.5h, then reactant is poured in the frozen water, under agitation be poured into water again, filter, filter cake with methanol wash after suction filtration, vacuum drying gets N, N ', N " the white solid 103.2g of three p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2), N, O, the preparation of two (2-hydroxyethyl) amine compound (2) of O '-three p-toluenesulfonyl
Under ice bath, 300mL is dissolved with 126g(0.66mol) dichloromethane solution of Tosyl chloride is added drop-wise to and contains 21.0g(0.2mol) diethanolamine and 100mL(0.72mol) in the reaction flask of triethylamine, control time for adding 3h, after dropwising, then room temperature reaction 4～4.5h pours reactant in the frozen water into separatory, wash 3 times, organic phase is through anhydrous Na
2SO
4Drying is filtered, and evaporate to dryness filtrate gets a yellow oil, and after recrystallizing methanol, vacuum-drying gets N, O, the white solid 99.7g of two (2-hydroxyethyl) amine compound (2) of O '-three p-toluenesulfonyl, yield 88%;
3), Isosorbide-5-Nitrae, 7,10-, four p-toluenesulfonyls-Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (3)
With N, N ', N " three p-toluenesulfonyl diethylenetriamine compound (1) 34.4g(0.06mol), N; O; two compound (2-hydroxyethyl) amine compound (2) 34.0g(0.06mol of O '-three p-toluenesulfonyl) and the 25.0g Anhydrous potassium carbonate join in the DMF of 300mL drying, in 100～105 ° of C reactions of temperature, 3～4h; react complete; cool off, suction filtration gets filtrate, steam most of dimethyl fumarate to solution after the muddiness; splash into the 150mL methanol wash, cooling, suction filtration, filter cake washing three times, then dry 1,4,7,10-four (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)
With Isosorbide-5-Nitrae, 7,10-four (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 C reactions of temperature, 48～50h.React complete, under vigorous stirring, be poured in 200～250mL dehydrated alcohol, stir 0.5～1h, suction filtration, filter cake is dissolved in 80～100mL water, uses decolorizing with activated carbon, adds in 40～60mL concentrated hydrochloric acid to boil, leave standstill, filter to get white solid, this solid is dissolved in 30～50mL water, regulate pH to strong basicity with potassium hydroxide solution, repeatedly extract with chloroform, filtrate is behind anhydrous sodium sulfate drying, and steaming desolventizes, and dry 1,4, the white solid 2.62g of 7,10-tetraazacyclododecanand compound (4), productive rate 40%;
5), N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
With 1,4,7,10-tetraazacyclododecanand compound (4) 4.5g(26.1mmol)～9.0g(52.2mmol) and triethylamine 12.0mL(86.4mmol)～25mL(180mmol) be dissolved in methylene dichloride (145～255mL), slowly drip methylene dichloride 118～200mL solution of tert-Butyl dicarbonate 17.70g (81.1mmol)～35g (163mmol) under the normal temperature, 3h drips with interior, under room temperature, stir 24～25h, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) get N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; the white solid 10.2～14.78g of 10-tetraazacyclododecanand compound (5), productive rate: 56.5%～77.2%;
6), 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
With N, N ', N " three uncle's 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), KI9.10g (54.7mmol)～12.35g (74.2mmol) adds in the 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
2, suction filtration is removed inorganic salt, and filtrate decompression is removed solvent, column chromatography (sherwood oil: ethyl acetate=3: 2) get 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 10.35～14.75g of 7,10-tetraazacyclododecanand compound (6), productive rate 89.9%～93.3%;
7), the 10-(2-amino-ethyl)-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In the 300mL autoclave; with 7.12～10.20g 10-cyanogen-N; N '; " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand compound (6) is dissolved in the ammonia alcohol saturated solution of in advance preparation of 115～150mL; then add 0.77～1.08g Raney's nickel are filled with hydrogen to 1.5～1.55Mpa behind the air in the displacement still to N, in 24.5～26.5 ° of C reactions of temperature, 48～50h.Filtration catalizer, decompression removes solvent, the dry 10-(2-amino-ethyl that gets)-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 6.5～8.3g of 7,10-tetraazacyclododecanand compound (7); Product need not to separate, and is directly used in next step reaction;
8), N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
With the 10-(2-amino-ethyl)-N; N '; N " three uncle's fourth oxygen formyl radicals-1; 4; 7; 10-tetraazacyclododecanand compound (7) 3.3g(6.4mmol)～6.9g(13.4mmol) and trolamine (TEA) 1.4mL(10mmol)～2.8mL(20mmol) join in 100～180mL methylene dichloride, at 0～0.5 ° of C of temperature, stir the lower benzyl acetate bromide 1.3mL(8mmol that drips)～2.5mL(16mmol) 6～10mL dichloromethane solution; dropwise; solvent is removed in decompression behind room temperature reaction 48～50h, and then take ethyl acetate as eluent, column chromatography gets N-acetyl oxygen phenyl-3-[N; N '; N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand base] the colourless viscous liquid 1.8～3.8g of intermediate; productive rate 41.1%～42.9%, N-acetyl oxygen phenyl-3-[N, N '; N "-three uncle's fourth oxygen formyl radicals-1; 4,7,10-tetraazacyclododecanand base] structural formula of intermediate is:
N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] intermediate is used for chemical sensor, solar cell and the photoelectric device of molecular probe.
Performance test:
1, adopt infrared spectra to N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structured testing of intermediate is confirmed, as shown in Figure 1.
2, adopt
1H-NMR is to N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structured testing of intermediate obtained confirmation, as shown in Figure 2.
3, adopt
13C-NMR is to N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structured testing of intermediate obtained confirmation, as shown in Figure 3.
4, adopt mass spectrum to N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structured testing of intermediate obtained confirmation, as shown in Figure 4.
The present invention has following advantage:
The present invention has synthesized N-acetyl oxygen phenyl-3-[N; N '; N " three uncle's fourth oxygen formyl radicals-1; 4,7,10-tetraazacyclododecanand base] intermediate; this method is introduced modified group at its side chain; improve and widened its performance and function, is used for chemical sensor, solar cell and the photoelectric device of molecular probe.
Description of drawings
Fig. 1 is N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] infrared spectrogram of structure of intermediate
As shown in Figure 1, the result shows: 2973cm
-1Be the absorption peak of NH, 1680cm
-1, 1457cm
-1, 1412cm
-1, 1363cm
-1, 1247cm
-1, 1153cm
-1It is the absorption peak of CO.
Fig. 2 is N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structure of intermediate
1H-NMR figure:
As shown in Figure 2, the result shows
1H NMR (400MHz, 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.
Fig. 3 is N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structure of intermediate
13C-NMR figure:
As shown in Figure 3, the result shows
13C NMR (100MHz, 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.
Fig. 4 is N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] mass spectrum of structure of intermediate:
As shown in Figure 4, the result shows HRMS-MS:664.734 ([M]
+).
Embodiment
Below by embodiment so that the present invention is carried out basic description; be necessary to be pointed out that at this present embodiment only is used for the present invention is further specified; can not be interpreted as the restriction to the 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 three p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, the 126g Tosyl chloride is dissolved in the solution of 300mL acetone and the solution that the 91.2g Anhydrous potassium carbonate is dissolved in 200mL water, be added drop-wise to 20.6g(0.20mol) in the diethylenetriamine, the about 1.5h of time for adding.Stir at ambient temperature again 4h.Then reactant is poured in the frozen water, then under agitation is poured into water, filter, filter cake with methanol wash after suction filtration, vacuum drying gets N, N ', N " the white solid 103.2g of three p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2) N, O, the preparation of two (2-hydroxyethyl) amine compound (2) of O '-three p-toluenesulfonyl
Under ice bath, 300mL is dissolved with 126g(0.66mol) dichloromethane solution of Tosyl chloride is added drop-wise to and contains 21.0g(0.2mol) diethanolamine and 100mL(0.72mol) in the reaction flask of triethylamine, the about 3h of control time for adding, room temperature reaction 4h, then reactant is poured in the frozen water, separatory is washed 3 times, and organic phase is through anhydrous Na
2SO
4After the drying, filter, evaporate to dryness filtrate gets a yellow oil, and after recrystallizing methanol, vacuum-drying gets N, O, the white solid 99.7g of two (2-hydroxyethyl) amine compound (2) of O '-three p-toluenesulfonyl, yield 88%;
3) Isosorbide-5-Nitrae, 7,10-, four p-toluenesulfonyls-Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (3)
With N; N '; N " three p-toluenesulfonyl diethylenetriamine compound (1) 34.4g(0.06mol) and N; O; two (2-hydroxyethyl) amine compound (2) 34.0g(0.06mol of O '-three p-toluenesulfonyl) and the 25.0g Anhydrous potassium carbonate join among the DMF of 300mL drying, 100 ° of C react 3h.React complete, cooling, suction filtration gets filtrate, steams most of DMF to solution after the muddiness, splashes into the 150mL methanol wash, cooling, suction filtration, then filter cake washing three times dries to get Isosorbide-5-Nitrae, 7,10-four p-toluenesulfonyls-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (3) 30.1g, productive rate 63.7%;
4) Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (4)
With Isosorbide-5-Nitrae, 7,10-four (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, and then 110～115 ° of C react 48～50h, so under vigorous stirring, be poured in 200～250mL dehydrated alcohol, stir 0.5～1.0h, suction filtration, filter cake are dissolved in 80～100mL water, use decolorizing with activated carbon, add in 40～60mL concentrated hydrochloric acid and boil, leave standstill, filter to get white solid.This solid is dissolved in 30～50mL water, regulate pH to strong basicity with potassium hydroxide solution, then use 50～60 ° of C chloroform extractions of temperature 3～5 times, filtrate is behind anhydrous sodium sulfate drying, and steaming desolventizes, and dry 1,4, the white solid 2.62g of 7,10-tetraazacyclododecanand compound (4), productive rate 40%;
5) N, N ', N " three uncle's 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(26.1mmol) and triethylamine 12.0mL(86.4mmol) be dissolved in methylene dichloride 145mL, slowly drip under the normal temperature (Boc)
2The methylene dichloride 118mL solution of O 17.7g (81.1mmol) drips in the 3h.Stir 24～25h again under room temperature, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) get N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 10.20g of 7,10-tetraazacyclododecanand compound (5), productive rate: 76.5%.
1H?NMR(400MHz,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 " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In the 500mL reaction flask, add N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.68g (22.7mmol), K
2CO
37.64g (55.4mmol), KI 9.10g (54.8mmol) adds the 185mL acetonitrile again, chloromethyl cyanide 2.02mL(224.1mmol), back flow reaction 70～72h removes solvent, adds CH
2Cl
2, suction filtration is removed inorganic salt, and filtrate decompression is removed solvent, column chromatography (sherwood oil: ethyl acetate=3: 2) get 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 10.33g of 7,10-tetraazacyclododecanand compound (6), productive rate 92.4%.
1H?NMR(400MHz,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)-and N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In the 300mL autoclave; with 10-cyanogen-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7; 10-tetraazacyclododecanand compound (6) 7.12g is dissolved in the ammonia alcohol saturated solution of in advance preparation of 115mL, then adds the 0.77g Raney's nickel are filled with hydrogen to 1.5～1.55Mpa behind the air in the displacement still; react 48～50h under 24.5～26.5 ° of C of temperature; react complete after, filtration catalizer, decompression removes solvent; the dry 10-(2-amino-ethyl that gets)-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 6.5g of 7,10-tetraazacyclododecanand compound (7).Product need not to separate, and is directly used in next step reaction;
8) N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
With 6.9g(13.4mmol) the 10-(2-amino-ethyl)-N; N '; N " three uncle's fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8mL(20mmol) TEA join in the 180mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature; drip 2.5mL(16mmol) the 10mL dichloromethane solution of benzyl acetate bromide, room temperature reaction 48～50h.Solvent is removed in decompression, and then take ethyl acetate as eluent, column chromatography gets N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colourless viscous liquid 3.8g of intermediate, productive rate 41.1%.
1H?NMR(400MHz,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(100MHz,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。
Embodiment 2
According to 1 among the embodiment 1)～4) preparation method prepares compound (1)～(4)
5) N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 5.0g(29.0mmol) and triethylamine 12.4mL(89.3mmol) be dissolved in methylene dichloride 150mL, slowly drip under the normal temperature (Boc)
2The methylene dichloride 120mL solution of O 17.72g (81.2mmol) drips in the 3h.Stir 24～25h again under room temperature, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) get N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 10.50g of 7,10-tetraazacyclododecanand compound (5), productive rate: 76.8%.
1H?NMR(400MHz,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 " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In the 500mL reaction flask, add N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.74g (22.8mmol), K
2CO
37.74g (56.09mmol), KI 9.29g (55.96mmol) adds the 190mL acetonitrile again, chloromethyl cyanide 2.05mL(250.80mmol), back flow reaction 70～72h removes solvent, adds CH
2Cl
2, suction filtration is removed inorganic salt, and filtrate decompression is removed solvent, column chromatography (sherwood oil: ethyl acetate=3: 2) get 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 10.55g of 7,10-tetraazacyclododecanand compound (6), productive rate 91%.
1H?NMR(400MHz,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)-and N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In the 300mL autoclave; with 10-cyanogen-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7; 10-tetraazacyclododecanand compound (6) 7.15g is dissolved in the ammonia alcohol saturated solution of in advance preparation of 120mL, then adds the 0.78g Raney's nickel are filled with hydrogen to 1.5～1.55Mpa behind the air in the displacement still; react 48～50h under 24.5～26.5 ° of C; react complete after, filtration catalizer, decompression removes solvent; the dry 10-(2-amino-ethyl that gets)-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 6.9g of 7,10-tetraazacyclododecanand compound (7).Product need not to separate, and is directly used in next step reaction;
8) N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
With 6.7g(13.0mmol) the 10-(2-amino-ethyl)-N; N '; N " three uncle's fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8mL(20mmol) TEA join in the 175mL methylene dichloride, under 0～0.5 ° of C agitation condition; drip 2.5mL(16mmol) the 10mL dichloromethane solution of benzyl acetate bromide, room temperature reaction 48～50h.Solvent is removed in decompression, and then take ethyl acetate as eluent, column chromatography gets N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colourless viscous liquid 3.7g of intermediate, productive rate 40.9%.
1H?NMR(400MHz,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(100MHz,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。
Embodiment 3
According to 1 among the embodiment 1)～4) preparation method prepares compound (1)～(4)
5) N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 6.0g(34.8mmol) and triethylamine 15mL(108.0mmol) be dissolved in methylene dichloride 160mL, slowly drip under the normal temperature (Boc)
2O 20.42g(93.6mmol) methylene dichloride 130mL solution drips in the 3h.Stir 24～25h again under room temperature, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) get N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 11.72g of 7,10-tetraazacyclododecanand compound (5), productive rate: 74.3%.
1H?NMR(400MHz,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 " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In the 500mL reaction flask, add N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 12.05g (25.58mmol), K
2CO
38.50g (61.59mmol), KI 9.20g (55.42mmol) adds the 190mL acetonitrile again, chloromethyl cyanide 3.00mL(367.02mmol), back flow reaction 70～72h removes solvent, adds CH
2Cl
2, suction filtration is removed inorganic salt, and filtrate decompression is removed solvent; column chromatography (sherwood oil: ethyl acetate=3: 2) get 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 10.94g of 7,10-tetraazacyclododecanand compound (6), productive rate 89.9%.
1H?NMR(400MHz,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)-and N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In the 300mL autoclave; with 10-cyanogen-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7; 10-tetraazacyclododecanand compound (6) 8.25g is dissolved in the ammonia alcohol saturated solution of in advance preparation of 130mL, then adds the 0.85g Raney's nickel are filled with hydrogen to 1.5～1.55Mpa behind the air in the displacement still; react 48～50h under 24.5～26.5 ° of C of temperature; react complete after, filtration catalizer, decompression removes solvent; the dry 10-(2-amino-ethyl that gets)-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 7.16g of 7,10-tetraazacyclododecanand (7).Product need not to separate, and is directly used in next step reaction;
8) N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
With 6.0g(11.6mmol) the 10-(2-amino-ethyl)-N; N '; N " three uncle's fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8mL(20mmol) TEA join in the 180mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature; drip 2.5mL(16mmol) the 10mL dichloromethane solution of benzyl acetate bromide, room temperature reaction 48～50h.Solvent is removed in decompression, and then take ethyl acetate as eluent, column chromatography gets N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colourless viscous liquid 3.2g of intermediate, productive rate 40.2%.
1H?NMR(400MHz,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(100MHz,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。
Embodiment 4
According to 1 among the embodiment 1)～4) preparation method prepares compound (1)～(4)
5) N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 7.5g(43.5mmol) and triethylamine 18.5mL(134.0mmol) be dissolved in methylene dichloride 170mL, slowly drip under the normal temperature (Boc)
2The methylene dichloride 140mL solution of O 26.55g (122.2mmol) drips in the 3h.Stir 24～25h again under room temperature, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) get N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 14.72g of 7,10-tetraazacyclododecanand compound (5), productive rate: 74.1%.
1H?NMR(400MHz,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 " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In the 500mL reaction flask, add N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 13.05g (27.7mmol), K
2CO
39.04g (65.50mmol), KI 11.20g (67.47mmol) adds the 190mL acetonitrile again, chloromethyl cyanide 4.00mL(489.37mmol), back flow reaction 70～72h removes solvent, adds CH
2Cl
2, suction filtration is removed inorganic salt, and filtrate decompression is removed solvent, column chromatography (sherwood oil: ethyl acetate=3: 2) get 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 13.72g of 7,10-tetraazacyclododecanand compound (6), productive rate 93.3%.
1H?NMR(400MHz,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)-and N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In the 300mL autoclave; with 10-cyanogen-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7; 10-tetraazacyclododecanand compound (6) 9.26g is dissolved in the ammonia alcohol saturated solution of in advance preparation of 150mL, then adds the 1.02g Raney's nickel are filled with hydrogen to 1.5～1.55Mpa behind the air in the displacement still; react 48～50h under 24.5～26.5 ° of C of temperature; react complete after, filtration catalizer, decompression removes solvent; the dry 10-(2-amino-ethyl that gets)-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 8.3g of 7,10-tetraazacyclododecanand compound (7).Product need not to separate, and is directly used in next step reaction;
8) N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
With 3.3g(6.5mmol) compound (7) and 1.4mL(10mmol) TEA join in the 100mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature, drip 1.3mL(8mmol) the 6mL dichloromethane solution of benzyl acetate bromide, room temperature reaction 48～50h.React complete, then take ethyl acetate as eluent, column chromatography gets N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colourless viscous liquid 1.8g of intermediate, productive rate 42.9%.
1H?NMR(400MHz,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?(100MHz,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。
Embodiment 5
According to 1 among the embodiment 1)～4) preparation method prepares compound (1)～(4),
5) N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 9.0g(52.2mmol) and triethylamine 25mL(180mmol) be dissolved in methylene dichloride 255mL, slowly drip under the normal temperature (Boc)
2The methylene dichloride 200mL solution of O 35g (163mmol) drips in the 3h.Stir 24～25h again under room temperature, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) get N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 14.78g of 7,10-tetraazacyclododecanand compound (5), productive rate: 56.5%.
1H?NMR(400MHz,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 " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In the 500ml reaction flask, add N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 15.84g (33.7mmol), K
2CO
39.84g (71.30mmol), KI 12.35g (74.40mmol) adds the 192mL acetonitrile again, chloromethyl cyanide 4.08mL(499.1mmol), back flow reaction 70～72h removes solvent, adds CH
2Cl
2, suction filtration is removed inorganic salt, and filtrate decompression is removed solvent, column chromatography (sherwood oil: ethyl acetate=3: 2) get 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 14.75g of 7,10-tetraazacyclododecanand compound (6), productive rate 90.7%.
1H?NMR(400MHz,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)-and N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In the 300mL autoclave; with 10-cyanogen-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; 7; 10-tetraazacyclododecanand compound (6) 10.20g is dissolved in the ammonia alcohol saturated solution of in advance preparation of 150mL, then adds the 1.08g Raney's nickel are filled with hydrogen to 1.5～1.55Mpa behind the air in the displacement still; react 48～50h under 24.5～26.5 ° of C of temperature; react complete after, filtration catalizer, decompression removes solvent; the dry 10-(2-amino-ethyl that gets)-N; N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 8.02g of 7,10-tetraazacyclododecanand compound (7).Product need not to separate, and is directly used in next step reaction;
8) N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
With 5.8g(11.3mmol) the 10-(2-amino-ethyl)-N; N '; N " three uncle's fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8mL(17mmol) TEA join in the 135mL methylene dichloride, under 0～0.5 ° of C agitation condition of temperature; drip 2.2mL(13.8mmol) the 7.5mL dichloromethane solution of benzyl acetate bromide; solvent is removed in room temperature reaction 48～50h decompression, and then take ethyl acetate as eluent, column chromatography gets N-acetyl oxygen phenyl-3-[N; N '; N "-three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand base]] the colourless viscous liquid 2.8g of intermediate, productive rate 41.7%.
1H?NMR(400MHz,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(100MHz,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。
Claims (3)
1.N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] intermediate, it is characterized in that the structural formula of this intermediate is:
2. described N-acetyl oxygen phenyl-3-[N according to claim 1, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation method of intermediate, it is characterized in that the method may further comprise the steps:
N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] chemical equation of intermediate is as follows:
And by the preparation of following processing step and processing parameter:
1), N, N ', N " preparation of three p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, the 126g Tosyl chloride is dissolved in the solution of 300mL acetone and the solution that the 91.2g Anhydrous potassium carbonate is dissolved in 200mL water, be added drop-wise to 20.6g(0.20mol) in the diethylenetriamine, time for adding 1.2～2.0h, after dropwising, room temperature reaction 4～4.5h, then reactant is poured in the frozen water, under agitation be poured into water again, filter, filter cake with methanol wash after suction filtration, vacuum drying gets N, N ', N " the white solid 103.2g of three p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2), N, O, the preparation of two (2-hydroxyethyl) amine compound (2) of O '-three p-toluenesulfonyl
Under ice bath, 300mL is dissolved with 126g(0.66mol) dichloromethane solution of Tosyl chloride is added drop-wise to and contains 21.0g(0.2mol) diethanolamine and 100mL(0.72m0l) in the reaction flask of triethylamine, control time for adding 3h, after dropwising, then room temperature reaction 4～4.5h pours reactant in the frozen water into separatory, wash 3 times, organic phase is through anhydrous Na
2SO
4Drying is filtered, and evaporate to dryness filtrate gets a yellow oil, and after recrystallizing methanol, vacuum-drying gets N, O, the white solid 99.7g of two (2-hydroxyethyl) amine compound (2) of O '-three p-toluenesulfonyl, yield 88%;
3), Isosorbide-5-Nitrae, 7,10-, four p-toluenesulfonyls-Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (3)
With N, N ', N " three p-toluenesulfonyl diethylenetriamine compound (1) 34.4g(0.06mol), N; O; two (2-hydroxyethyl) amine compound (2) 34.0g(0.06mol of O '-three p-toluenesulfonyl) and the 25.0g Anhydrous potassium carbonate join in the DMF of 300mL drying, in 100～105 ° of C reactions of temperature, 3～4h; react complete; cool off, suction filtration gets filtrate, steam most of dimethyl fumarate to solution after the muddiness; splash into 150～160mL methanol wash, cooling, suction filtration, filter cake washing three times, then dry 1,4,7,10-four (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)
With Isosorbide-5-Nitrae, 7,10-four (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 C reactions of temperature, 48～50h, react complete, under vigorous stirring, be poured in 200～250mL dehydrated alcohol, stir 0.5～1.0h, suction filtration, filter cake are dissolved in 80～100mL water, use decolorizing with activated carbon, add in 40～60mL concentrated hydrochloric acid and boil, leave standstill, filter to get white solid, this solid is dissolved in 30～50mL water, regulate pH to strong basicity with potassium hydroxide solution, carry out 3～5 extractions with chloroform, filtrate is behind anhydrous sodium sulfate drying, steaming desolventizes, dry Isosorbide-5-Nitrae, 7 of getting, the white solid 2.62g of 10-tetraazacyclododecanand compound (4), productive rate 40%;
5), N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
With 1,4,7,10-tetraazacyclododecanand compound (4) 4.5g(26.1mmol)～9.0g(52.2mmol) and triethylamine 12.0mL(86.4mmol)～25mL(180mmol) be dissolved in methylene dichloride 145mL～255mL, slowly drip methylene dichloride 118～200mL solution of tert-Butyl dicarbonate 17.70g (81.1mmol)～35g (163mmol) under the normal temperature, 3h drips with interior, under room temperature, stir 24～25h, decompression removes solvent, column chromatography (sherwood oil: ethyl acetate=1: 1) get N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; the white solid 10.2～14.78g of 10-tetraazacyclododecanand compound (5), productive rate: 56.5%～77.2%;
6), 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
With N, N ', N " three uncle's 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) adds in the 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
2, suction filtration is removed inorganic salt, and filtrate decompression is removed solvent, column chromatography (sherwood oil: ethyl acetate=3: 2) get 10-cyanogen-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 10.35g～14.75g of 7,10-tetraazacyclododecanand compound (6), productive rate 89.9%～93.3%;
7), the 10-(2-amino-ethyl)-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In the 300mL autoclave; with 7.12～10.20g 10-cyanogen-N; N '; " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand compound (6) is dissolved in the ammonia alcohol saturated solution of in advance preparation of 115～150mL; then add 0.77～1.08g Raney's nickel are filled with hydrogen to 1.5～1.55Mpa behind the air in the displacement still to N, in 24.5～26.5 ° of C reactions of temperature, 48～50h.Filtration catalizer, decompression removes solvent, the dry 10-(2-amino-ethyl that gets)-N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 6.5～8.3g of 7,10-tetraazacyclododecanand compound (7).Product need not to separate, and is directly used in next step reaction;
8), N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
With the 10-(2-amino-ethyl)-N, N ', N " three uncle's fourth oxygen formyl radicals-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; at 0～0.5 ° of C of temperature; stir the lower benzyl acetate bromide 1.3mL(8mmol that drips)～2.5mL(16mmol) 6～10mL dichloromethane solution, dropwise, solvent is removed in decompression behind room temperature reaction 48～50h, then take ethyl acetate as eluent, column chromatography gets N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand base] the colourless viscous liquid 1.8～3.8g of intermediate, productive rate 41.1%～42.9%(two steps productive rate); N-acetyl oxygen phenyl-3-[N, N ', N " three uncle's fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structural formula of intermediate is:
3. described N-acetyl oxygen phenyl-3-[N according to claim 1, N ', N " three uncle's fourth oxygen formyl radicals-1; 4,7,10-tetraazacyclododecanand base] purposes of intermediate; it is characterized in that this intermediate is used for chemical sensor, solar cell and the photoelectric device of molecular probe.
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| CN113549025A (en) * | 2021-07-14 | 2021-10-26 | 江苏美迪克化学品有限公司 | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101605768A (en) * | 2006-12-08 | 2009-12-16 | 慕尼黑科技大学 | Sequestrant |
| WO2011073137A2 (en) * | 2009-12-18 | 2011-06-23 | Bayer Schering Pharma Aktiengesellschaft | Compounds for imaging apoptotic cell death |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101605768A (en) * | 2006-12-08 | 2009-12-16 | 慕尼黑科技大学 | Sequestrant |
| WO2011073137A2 (en) * | 2009-12-18 | 2011-06-23 | Bayer Schering Pharma Aktiengesellschaft | Compounds for imaging apoptotic cell death |
Non-Patent Citations (2)
| Title |
|---|
| PASCAL KADJANE，等: "A straightforward and convenient pathway for the synthesis of functional bismacrocyclic ligands", 《TETRAHEDRON LETTERS》 * |
| ROLAND REICHENBACH-KLINKE，等: "NADH Model Systems Functionalized with Zn(II)-Cyclen as Flavin Binding SitesStructure Dependence of the Redox Reaction within Reversible Aggregates", 《J.AM.CHEM.SOC》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113549025A (en) * | 2021-07-14 | 2021-10-26 | 江苏美迪克化学品有限公司 | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof |
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