CN102898392B - N-acetyl oxygen benzyl-3-[-three tertiary fourth oxygen formyl radical-tetraazacyclododecanand bases] intermediate and preparation method thereof - Google Patents
N-acetyl oxygen benzyl-3-[-three tertiary fourth oxygen formyl radical-tetraazacyclododecanand bases] intermediate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand base] intermediate and preparation method thereof, be characterized in 10-(2-amino-ethyl)-N, N ', N "-three tertiary 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) joins in 100mL ~ 180mL methylene dichloride, temperature 0 DEG C ~ 0.5 DEG C, stir the lower 6 ~ 10mL dichloromethane solution dripping benzyl acetate bromide 1.3mL (8mmol) ~ 2.5mL (16mmol), dropwise, after room temperature reaction 48 ~ 50h, solvent is removed in decompression, then be eluent with ethyl acetate, column chromatography obtains N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand base] the colorless viscous shape liquid 1.8g ~ 3.8g of intermediate, productive rate 41.1% ~ 42.9%.
Description
Technical field
The present invention relates to a kind of N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary 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 cyclen intermediate can evoke the research interest that people continue, and be because they have very strong sequestering power to metal ion, and the title complex formed has much unusual function.Such as, if cyclen can be used for medicine, enzyme dummy, separation and the aspect such as carrier gases, metallic cation extraction. cyclen is suitably modified, its coordination ability and form title complex function also can greatly expand, 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 on cyclen N, then can be used as alkali metal cation coordination agent, highly selective extracts Na
+[Wang Xiaoyong, Tan Renxiang, Guo Zi build .1, the synthesis of 4,7,10-tetraazacyclododecanand and derivative thereof].1,4,7,10-tetraazacyclododecanand and derivative thereof are for the preparation of the contrast medium of medical diagnosis nuclear magnetic resonance and radio-contrast agent [Zhou Chunsheng, 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], the title complex formed with heavy metal can also as x-ray contrast agent [YUShi-bao, WATSON A D.Metal2based X2ray contrast media [J] .Chem.Rev., 1999,99 (9)].The Polyazamacrocycle such as Cyclen and derivative thereof is the functional type part that 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 chemical simulation, molecular recognition, molecular magnet and the [Wei Junfa such as biology, chemical reaction catalyst, Shi Xianying, where put down, 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 selective coordination character is all shown to organic or inorganic negatively charged ion, 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
The object of the invention is a kind of N-acetyl oxygen phenyl-3-[N for providing for the deficiencies in the prior art, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand base intermediate and preparation method thereof, be characterized in introducing acetyl oxygen benzyl containing on the side chain of-tetraazacyclododecanand based structures, retain the distinctive excellent properties of tetraazacyclododecanand to a great extent, destroy the regularity of main chain, obtain soluble intermediate, its yield is 40%, this intermediate and different functional groups react obtained several functions material, for the chemical sensor of " molecular probe ", solar cell and photoelectric device.
Object of the present invention is realized by following technical measures, and wherein said raw material number is parts by weight except specified otherwise.
N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structural formula of intermediate is:
Described N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation method of intermediate comprises the following steps:
N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] chemical equation of intermediate is as follows:
And by following processing step and processing parameter preparation:
1), N, N ', N " preparation of-three p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, 126g Tosyl chloride is dissolved in the solution that the solution of 300m L acetone and 91.2g Anhydrous potassium carbonate are 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 filter cake methanol wash, vacuum drying obtains N, N ', N " the white solid 103.2g of-three p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2) preparation of, N, O, O '-three p-toluenesulfonyls two (2-hydroxyethyl) amine compound (2)
Under ice bath, dichloromethane solution 300mL being dissolved with 126g (0.66mol) Tosyl chloride is added drop-wise in the reaction flask containing 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 in frozen water by reactant, separatory, wash 3 times, organic phase is through anhydrous Na
2sO
4drying, filter, evaporate to dryness filtrate obtains a yellow oil, and after recrystallizing methanol, vacuum-drying obtains N, the white solid 99.7g of O, O '-three p-toluenesulfonyls two (2-hydroxyethyl) amine compound (2), 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 "-three p-toluenesulfonyl diethylenetriamine compound (1) 34.4g (0.06mol); N; two compound (2-hydroxyethyl) amine compound (2) 34.0g (0.06mol) of O, O '-three p-toluenesulfonyls and the washing of 25.0g absolute alcohol, cooling; suction filtration; filter cake washes three times, then dries to obtain Isosorbide-5-Nitrae; 7,10-tetra-(p-toluenesulfonyl)-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)
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, heating treats that it dissolves, in temperature 110 ~ 115 DEG C reaction 48 ~ 50h.React complete, with vigorous stirring, be poured in 200 ~ 250mL dehydrated alcohol, stir 0.5 ~ 1h, suction filtration, filter cake is dissolved in 80 ~ 100mL water, with decolorizing with activated carbon, adds in 40 ~ 60mL concentrated hydrochloric acid and boils, leave standstill, filter to obtain 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 after 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 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) is dissolved in methylene dichloride (145 ~ 255mL), methylene dichloride 118 ~ 200mL solution of tert-Butyl dicarbonate 17.70g (81.1mmol) ~ 35g (163mmol) is slowly dripped under normal temperature, drip within 3h, in stirred at ambient temperature 24 ~ 25h, decompression removes solvent, with sherwood oil: ethyl acetate=1: 1 is eluent, column chromatography obtains N, N ', N "-three tertiary fourth oxygen formyl radicals-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 "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
By N, N ', N "-three 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), KI9.10g (54.7mmol) ~ 12.35g (74.2mmol) adds in 500ml reaction flask, add 185 ~ 192mL acetonitrile again, chloromethyl cyanide 2.02mL (247.1mmol) ~ 4.08mL (499.1mmol), back flow reaction 70 ~ 72h, remove solvent, add CH
2cl
2suction filtration, removing inorganic salt, filtrate decompression removes solvent, with sherwood oil: ethyl acetate=3: 2 is eluent, column chromatography obtains 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-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 "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave; by 7.12 ~ 10.20g10-cyanogen-N; N '; "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7; 10-tetraazacyclododecanand compound (6) is dissolved in the ammonia alcohol saturated solution that 115 ~ 150mL prepared in advance; then add 0.77 ~ 1.08g Raney's nickel, be filled with hydrogen to 1.5 ~ 1.55Mpa after air in displacement still to N, in temperature 24.5 ~ 26.5 DEG C reaction 48 ~ 50h.Filtration catalizer, decompression removes solvent, dry 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the white solid 6.5 ~ 8.3g of 7,10-tetraazacyclododecanand compound (7); Product, without the need to being separated, is directly used in next step reaction;
8), N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
By 10-(2-amino-ethyl)-N, N ', N "-three tertiary 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) joins in 100 ~ 180mL methylene dichloride, temperature 0 ~ 0.5 DEG C, stir the lower 6 ~ 10mL dichloromethane solution dripping benzyl acetate bromide 1.3mL (8mmol) ~ 2.5mL (16mmol), dropwise, after room temperature reaction 48 ~ 50h, solvent is removed in decompression, then be eluent with ethyl acetate, column chromatography obtains N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand base] the colorless viscous shape liquid 1.8 ~ 3.8g of intermediate, productive rate 41.1% ~ 42.9%, N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand base] structural formula of intermediate is:
N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary 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 benzyl-3-[N, N ', N "-three tertiary 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 to N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structured testing of intermediate obtains confirmation, as shown in Figure 2.
3, adopt
13c-NMR to N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structured testing of intermediate obtains confirmation, as shown in Figure 3.
4, adopt mass spectrum to N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structured testing of intermediate obtains confirmation, as shown in Figure 4.
Tool of the present invention has the following advantages:
The present invention has synthesized N-acetyl oxygen benzyl-3-[N; N '; N "-three tertiary fourth oxygen formyl radicals-1; 4,7,10-tetraazacyclododecanand base] intermediate; this method introduces modified group at its side chain; improve and widened its performance and function, for the chemical sensor of molecular probe, solar cell and photoelectric device.
Accompanying drawing explanation
Fig. 1 be N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] infrared spectrogram of structure of intermediate
As shown in Figure 1, result shows: 2973cm
-1for 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 be N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structure of intermediate
1h-NMR schemes:
As shown in Figure 2, 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 be N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structure of intermediate
13c-NMR schemes:
As shown in Figure 3, 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 be N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] mass spectrum of structure of intermediate:
As shown in Figure 4, result shows HRMS-MS:664.734 ([M]
+).
Embodiment
Below by embodiment to carry out basic description to the present invention; what be necessary to herein means out is that the present embodiment is only used to further illustrate the present invention; the restriction to invention protection domain can not be interpreted as, 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, 126g Tosyl chloride is dissolved in the solution that the solution of 300mL acetone and 91.2g Anhydrous potassium carbonate are dissolved in 200mL water, be added drop-wise in 20.6g (0.20mol) diethylenetriamine, time for adding is about 1.5h.Stir 4h at ambient temperature again.Then reactant is poured in frozen water, be then under agitation poured into water, filter, suction filtration after filter cake methanol wash, vacuum drying obtains N, N ', N " the white solid 103.2g of-three p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2) preparation of N, O, O '-three p-toluenesulfonyl two (2-hydroxyethyl) amine compound (2)
Under ice bath, dichloromethane solution 300mL being dissolved with 126g (0.66mol) Tosyl chloride is added drop-wise in the reaction flask containing 21.0g (0.2mol) diethanolamine and 100mL (0.72mol) triethylamine, control time for adding and be about 3h, room temperature reaction 4h, then reactant is poured in frozen water, separatory, wash 3 times, organic phase is through anhydrous Na
2sO
4after drying, filter, evaporate to dryness filtrate obtains a yellow oil, and after recrystallizing methanol, vacuum-drying obtains N, the white solid 99.7g of O, O '-three p-toluenesulfonyls two (2-hydroxyethyl) amine compound (2), 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 "-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 25.0g Anhydrous potassium carbonate join in the DMF of 300mL drying, 100 DEG C of reaction 3h.React complete, cooling, suction filtration obtains filtrate, steam most of DMF more muddy to solution after, instillation 150mL methanol wash, cooling, suction filtration, filter cake washes three times, then dry 1,4,7,10-tetra-p-toluenesulfonyl-1,4,7,10-tetraazacyclododecanand compound (3) 30.1g, productive rate 63.7%;
4) Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (4)
By Isosorbide-5-Nitrae, 7,10-tetra-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (3) 30.0g joins the dense H of 60mL
2sO
4in, heating treats that it dissolves, then 110 ~ 115 DEG C of reaction 48 ~ 50h, so with vigorous stirring, be poured in 200 ~ 250mL dehydrated alcohol, stir 0.5 ~ 1.0h, suction filtration, filter cake is dissolved in 80 ~ 100mL water, with decolorizing with activated carbon, add in 40 ~ 60mL concentrated hydrochloric acid and boil, leave standstill, filter to obtain white solid.This solid is dissolved in 30 ~ 50mL water, regulates pH to strong basicity with potassium hydroxide solution, then use temperature 50 ~ 60 DEG C of chloroform extractions 3 ~ 5 times, filtrate is after anhydrous sodium sulfate drying, and steaming desolventizes, and dry 1,4,7,10-tetraazacyclododecanand compound (4)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 4.5g (26.1mmol) and triethylamine 12.0mL (86.4mmol) is dissolved in methylene dichloride 145mL, slowly drips (Boc) under normal temperature
2the methylene dichloride 118mL solution of O17.7g (81.1mmol), drips in 3h.Again in stirred at ambient temperature 24 ~ 25h, decompression removes solvent, with sherwood oil: ethyl acetate=1: 1 is eluent, and column chromatography obtains N; N ', N "-three tertiary 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 tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500mL reaction flask, add N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.68g (22.7mmol), K
2cO
37.64g (55.4mmol), KI9.10g (54.8mmol), then add 185mL acetonitrile, chloromethyl cyanide 2.02mL (224.1mmol), back flow reaction 70 ~ 72h, removes solvent, adds CH
2cl
2, suction filtration, removing inorganic salt, filtrate decompression removes solvent; with sherwood oil: ethyl acetate=3: 2 is eluent, and column chromatography obtains 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1; the white solid 10.33g of 4,7,10-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)-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave, by 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (6) 7.12g is dissolved in the ammonia alcohol saturated solution that 115mL prepared in advance, then 0.77g Raney's nickel is added, hydrogen to 1.5 ~ 1.55Mpa is filled with after air in displacement still, 48 ~ 50h is reacted at temperature 24.5 ~ 26.5 DEG C, after completion of the reaction, filtration catalizer, decompression removes solvent, dry 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, the white solid 6.5g of 10-tetraazacyclododecanand compound (7).Product, without the need to being separated, is directly used in next step reaction;
8) N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
By 6.9g (13.4mmol) 10-(2-amino-ethyl)-N; N '; "-three tertiary fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8mL (20mmol) TEA join in 180mL methylene dichloride, under temperature 0 ~ 0.5 DEG C of agitation condition; drip the 10mL dichloromethane solution of 2.5mL (16mmol) benzyl acetate bromide, room temperature reaction 48 ~ 50h for N.Solvent is removed in decompression, is then eluent with ethyl acetate, column chromatography obtain N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colorless viscous shape 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 in embodiment 1) ~ 4) preparation method prepares compound (1) ~ (4)
5) N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 5.0g (29.0mmol) and triethylamine 12.4mL (89.3mmol) is dissolved in methylene dichloride 150mL, slowly drips (Boc) under normal temperature
2the methylene dichloride 120mL solution of O17.72g (81.2mmol), drips in 3h.Again in stirred at ambient temperature 24 ~ 25h, decompression removes solvent, with sherwood oil: ethyl acetate=1: 1 is eluent, and column chromatography obtains N; N ', N "-three tertiary 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 tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500mL reaction flask, add N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 10.74g (22.8mmol), K
2cO
37.74g (56.09mmol), KI9.29g (55.96mmol), then add 190mL acetonitrile, chloromethyl cyanide 2.05mL (250.80mmol), back flow reaction 70 ~ 72h, removes solvent, adds CH
2cl
2, suction filtration, removing inorganic salt, filtrate decompression removes solvent; with sherwood oil: ethyl acetate=3: 2 is eluent, and column chromatography obtains 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1; the white solid 10.55g of 4,7,10-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)-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave, by 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (6) 7.15g is dissolved in the ammonia alcohol saturated solution that 120mL prepared in advance, then 0.78g Raney's nickel is added, hydrogen to 1.5 ~ 1.55Mpa is filled with after air in displacement still, 48 ~ 50h is reacted at 24.5 ~ 26.5 DEG C, after completion of the reaction, filtration catalizer, decompression removes solvent, dry 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, the white solid 6.9g of 10-tetraazacyclododecanand compound (7).Product, without the need to being separated, is directly used in next step reaction;
8) N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
By 6.7g (13.0mmol) 10-(2-amino-ethyl)-N; N '; N "-three tertiary fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8mL (20mmol) TEA join in 175mL methylene dichloride, under 0 ~ 0.5 DEG C of agitation condition; drip the 10mL dichloromethane solution of 2.5mL (16mmol) benzyl acetate bromide, room temperature reaction 48 ~ 50h.Solvent is removed in decompression, is then eluent with ethyl acetate, column chromatography obtain N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colorless viscous shape 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 in embodiment 1) ~ 4) preparation method prepares compound (1) ~ (4)
5) N, N ', N "-three tertiary 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) is dissolved in methylene dichloride 160mL, slowly drips (Boc) under normal temperature
2the methylene dichloride 130mL solution of O20.42g (93.6mmol), drips in 3h.Again in stirred at ambient temperature 24 ~ 25h, decompression removes solvent, with sherwood oil: ethyl acetate=1: 1 is eluent, and column chromatography obtains N; N ', N "-three tertiary 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 tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500mL reaction flask, add N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 12.05g (25.58mmol), K
2cO
38.50g (61.59mmol), KI9.20g (55.42mmol), then add 190mL acetonitrile, chloromethyl cyanide 3.00mL (367.02mmol), back flow reaction 70 ~ 72h, removes solvent, adds CH
2cl
2, suction filtration, removing inorganic salt, filtrate decompression removes solvent; with sherwood oil: ethyl acetate=3: 2 is eluent, and column chromatography obtains 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1; the white solid 10.94g of 4,7,10-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)-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave, by 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (6) 8.25g is dissolved in the ammonia alcohol saturated solution that 130mL prepared in advance, then 0.85g Raney's nickel is added, hydrogen to 1.5 ~ 1.55Mpa is filled with after air in displacement still, 48 ~ 50h is reacted at temperature 24.5 ~ 26.5 DEG C, after completion of the reaction, filtration catalizer, decompression removes solvent, dry 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, the white solid 7.16g of 10-tetraazacyclododecanand (7).Product, without the need to being separated, is directly used in next step reaction;
8) N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
By 6.0g (11.6mmol) 10-(2-amino-ethyl)-N; N '; "-three tertiary fourth oxygen formyl radicals-1; 4; 7,10-tetraazacyclododecanand compound (7) and 2.8mL (20mmol) TEA join in 180mL methylene dichloride, under temperature 0 ~ 0.5 DEG C of agitation condition; drip the 10mL dichloromethane solution of 2.5mL (16mmol) benzyl acetate bromide, room temperature reaction 48 ~ 50h for N.Solvent is removed in decompression, is then eluent with ethyl acetate, column chromatography obtain N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colorless viscous shape 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 in embodiment 1) ~ 4) preparation method prepares compound (1) ~ (4)
5) N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 7.5g (43.5mmol) and triethylamine 18.5mL (134.0mmol) is dissolved in methylene dichloride 170mL, slowly drips (Boc) under normal temperature
2the methylene dichloride 140mL solution of O26.55g (122.2mmol), drips in 3h.Again in stirred at ambient temperature 24 ~ 25h, decompression removes solvent, with sherwood oil: ethyl acetate=1: 1 is eluent, and column chromatography obtains N; N ', N "-three tertiary 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 tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500mL reaction flask, add N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 13.05g (27.7mmol), K
2cO
39.04g (65.50mmol), KI11.20g (67.47mmol), then add 190mL acetonitrile, chloromethyl cyanide 4.00mL (489.37mmol), back flow reaction 70 ~ 72h, removes solvent, adds CH
2cl
2, suction filtration, removing inorganic salt, filtrate decompression removes solvent; with sherwood oil: ethyl acetate=3: 2 is eluent, and column chromatography obtains 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1; the white solid 13.72g of 4,7,10-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)-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave, by 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (6) 9.26g is dissolved in the ammonia alcohol saturated solution that 150mL prepared in advance, then 1.02g Raney's nickel is added, hydrogen to 1.5 ~ 1.55Mpa is filled with after air in displacement still, 48 ~ 50h is reacted at temperature 24.5 ~ 26.5 DEG C, after completion of the reaction, filtration catalizer, decompression removes solvent, dry 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, the white solid 8.3g of 10-tetraazacyclododecanand compound (7).Product, without the need to being separated, is directly used in next step reaction;
8) N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
3.3g (6.5mmol) compound (7) and 1.4mL (10mmol) TEA are joined in 100mL methylene dichloride, under temperature 0 ~ 0.5 DEG C of agitation condition, drip the 6mL dichloromethane solution of 1.3mL (8mmol) benzyl acetate bromide, room temperature reaction 48 ~ 50h.Reacting complete, is then eluent with ethyl acetate, column chromatography obtain N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] the colorless viscous shape 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 in embodiment 1) ~ 4) preparation method prepares compound (1) ~ (4),
5) N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (5)
Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (4) 9.0g (52.2mmol) and triethylamine 25mL (180mmol) is dissolved in methylene dichloride 255mL, slowly drips (Boc) under normal temperature
2the methylene dichloride 200mL solution of O35g (163mmol), drips in 3h.Again in stirred at ambient temperature 24 ~ 25h, decompression removes solvent, with sherwood oil: ethyl acetate=1: 1 is eluent, and column chromatography obtains N; N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes; the white solid 14.78g of 7,10-tetraazacyclododecanand compound (5), productive rate: 56.5%.
1H NMR(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 tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
In 500ml reaction flask, add N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand compound (5) 15.84g (33.7mmol), K
2cO
39.84g (71.30mmol), KI12.35g (74.40mmol), then add 192mL acetonitrile, chloromethyl cyanide 4.08mL (499.1mmol), back flow reaction 70 ~ 72h, removes solvent, adds CH
2cl
2, suction filtration, removing inorganic salt, filtrate decompression removes solvent; with sherwood oil: ethyl acetate=3: 2 is eluent, and column chromatography obtains 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1; the white solid 14.75g of 4,7,10-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)-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave, by 10-cyanogen-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (6) 10.20g is dissolved in the ammonia alcohol saturated solution that 150mL prepared in advance, then 1.08g Raney's nickel is added, hydrogen to 1.5 ~ 1.55Mpa is filled with after air in displacement still, 48 ~ 50h is reacted at temperature 24.5 ~ 26.5 DEG C, after completion of the reaction, filtration catalizer, decompression removes solvent, dry 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, the white solid 8.02g of 10-tetraazacyclododecanand compound (7).Product, without the need to being separated, is directly used in next step reaction;
8) N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
By 5.8g (11.3mmol) 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (7) and 2.8mL (17mmol) TEA join in 135mL methylene dichloride, under temperature 0 ~ 0.5 DEG C of agitation condition, drip the 7.5mL dichloromethane solution of 2.2mL (13.8mmol) benzyl acetate bromide, solvent is removed in room temperature reaction 48 ~ 50h decompression, then be eluent with ethyl acetate, column chromatography obtains N-acetyl oxygen phenyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand base]] the colorless viscous shape 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 (1)
1.N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation method of intermediate, it is characterized in that the method comprises the following steps:
N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] chemical equation of intermediate is as follows:
And by following processing step and processing parameter preparation:
1), N, N ', N " preparation of-three p-toluenesulfonyl diethylenetriamine compounds (1):
Under ice bath, 126g Tosyl chloride is dissolved in the solution that the solution of 300mL acetone and 91.2g Anhydrous potassium carbonate are 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 filter cake methanol wash, vacuum drying obtains N, N ', N " the white solid 103.2g of-three p-toluenesulfonyl diethylenetriamine compounds (1), productive rate 91%;
2) preparation of, N, O, O '-three p-toluenesulfonyls two (2-hydroxyethyl) amine compound (2)
Under ice bath, dichloromethane solution 300mL being dissolved with 126g (0.66mol) Tosyl chloride is added drop-wise in the reaction flask containing 21.0g (0.20mol) diethanolamine and 100mL (0.72mol) triethylamine, control time for adding 3h, after dropwising, room temperature reaction 4 ~ 4.5h, then pours in frozen water by reactant, separatory, wash 3 times, organic phase is through anhydrous Na
2sO
4drying, filter, evaporate to dryness filtrate obtains a yellow oil, and after recrystallizing methanol, vacuum-drying obtains N, the white solid 99.7g of O, O '-three p-toluenesulfonyls two (2-hydroxyethyl) amine compound (2), 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 "-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 25.0g Anhydrous potassium carbonate join the N of 300mL drying, in dinethylformamide, in temperature 100 ~ 105 DEG C reaction 3 ~ 4h, react complete, cooling, suction filtration obtains filtrate, steam most of dimethyl fumarate more muddy to solution after, instillation 150 ~ 160mL methanol wash, cooling, suction filtration, filter cake washes three times, then dry 1, 4, 7, 10-tetra-(p-toluenesulfonyl)-1, 4, 7, 10-tetraazacyclododecanand compound (3) 30.1g, productive rate 63.7%,
4), Isosorbide-5-Nitrae, the preparation of 7,10-tetraazacyclododecanand compound (4)
By Isosorbide-5-Nitrae, 7,10-tetra-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand compound (3) 30.0g joins the dense H of 60mL
2sO
4in, heating treats that it dissolves, in temperature 110 ~ 115 DEG C reaction 48 ~ 50h, react complete, with vigorous stirring, be poured in 200 ~ 250mL dehydrated alcohol, stir 0.5 ~ 1.0h, suction filtration, filter cake is dissolved in 80 ~ 100mL water, with decolorizing with activated carbon, add in 40 ~ 60mL concentrated hydrochloric acid and boil, leave standstill, filter to obtain white solid, this solid is dissolved in 30 ~ 50mL water, regulate pH to strong basicity with potassium hydroxide solution, 3 ~ 5 extractions are carried out with chloroform, 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 "-three 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) ~ 25.0mL (180mmol) is dissolved in methylene dichloride 145 ~ 255mL, methylene dichloride 118 ~ 200mL solution of tert-Butyl dicarbonate 17.70g (81.1mmol) ~ 35.0g (163mmol) is slowly dripped under normal temperature, drip within 3h, in stirred at ambient temperature 24 ~ 25h, decompression removes solvent, use sherwood oil subsequently: ethyl acetate ﹦ 1: 1 (v/v) is eluent, column chromatography obtains N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, white solid 10.2 ~ the 14.78g of 10-tetraazacyclododecanand compound (5), productive rate: 56.5% ~ 77.2%,
6), 10-cyanogen methyl-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (6)
By N, N ', N "-three 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 KI 9.10g (54.7mmol) ~ 12.35g (74.2mmol) adds in 500ml reaction flask, add 185 ~ 192mL acetonitrile again, chloromethyl cyanide 2.02mL (247.1mmol) ~ 4.08mL (499.1mmol), back flow reaction 70 ~ 72h, remove solvent, add CH
2cl
2suction filtration, removing inorganic salt, filtrate decompression removes solvent, sherwood oil: ethyl acetate ﹦ 3: 2 (v/v) is eluent, column chromatography obtains 10-cyanogen methyl-N, N ', N "-three tertiary fourth oxygen formyl radicals-1; 4; the white solid 10.3g ~ 14.75g of 7,10-tetraazacyclododecanand compound (6), productive rate 89.9% ~ 93.3%;
7), 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, the preparation of 7,10-tetraazacyclododecanand compound (7)
In 300mL autoclave, by 7.12 ~ 10.20g 10-cyanogen methyl-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (6) is dissolved in the ammonia alcohol saturated solution that 115 ~ 150mL prepared in advance, then 0.77 ~ 1.08g Raney's nickel is added, hydrogen to 1.50 ~ 1.55Mpa is filled with after air in displacement still, in temperature 24.5 ~ 26.5 DEG C reaction 48 ~ 50h, filtration catalizer, decompression removes solvent, dry 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, white solid 6.5 ~ the 8.3g of 10-tetraazacyclododecanand compound (7), product is without the need to being separated, be directly used in next step reaction,
8), N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] preparation of intermediate
By 10-(2-amino-ethyl)-N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand compound (7) 3.3g (6.4mmol) ~ 6.9g (13.4mmol) and trolamine 1.4mL (10.0mmol) ~ 2.8mL (20mmol) joins in 100 ~ 180mL methylene dichloride, temperature 0 ~ 0.5 DEG C, stir the lower 6 ~ 10mL dichloromethane solution dripping benzyl acetate bromide 1.3mL (8mmol) ~ 2.5mL (16mmol), dropwise, after room temperature reaction 48 ~ 50h, solvent is removed in decompression, then be eluent with ethyl acetate, column chromatography obtains N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radicals-1, 4, 7, 10-tetraazacyclododecanand base] the colorless viscous shape liquid 1.8 ~ 3.8g of intermediate, productive rate 41.1% ~ 42.9%, N-acetyl oxygen benzyl-3-[N, N ', N "-three tertiary fourth oxygen formyl radical-Isosorbide-5-Nitraes, 7,10-tetraazacyclododecanand base] structural formula of intermediate is:
。
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