CN101775038A - Marked cyclofenil derivative and referential compound and midbody thereof, and preparation method and application - Google Patents
Marked cyclofenil derivative and referential compound and midbody thereof, and preparation method and application Download PDFInfo
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Abstract
The invention discloses a marked cyclofenil derivative as shown in formula IV, a referential compound and midbody thereof, a preparation method and an application, wherein m is equal to 0-9, n is equal to 0-6, 99mTc is 99m technetium, and CO is carbonyl group. The marked cyclofenil derivative in the invention has activity to resist breast cancer and has favorable visualization effect.
Description
Technical field
The present invention relates to a kind of labeled drug derivative and reference compound thereof and intermediate, reach preparation method and application, be specifically related to a kind of marked cyclofenil derivative and reference compound thereof and intermediate, reach preparation method and application.
Background technology
Nuclear medicine can be utilized the specific physical character of labelled nuclide in some radiopharmaceuticals, implements internal-radiation therapy when kinds of tumors and focus thereof are carried out video picture, and this unique tumor diagnosis and treatment method is subject to people's attention in clinical day by day.At present, this class has both treatment and the radionuclide of video picture dual function mainly contains
131I,
153Sm,
117mSn,
186Re,
188Re etc.Wherein,
188Re receives much attention at diagnosing tumor and treatment field with its good physico-chemical property especially.
99mTc is because its purer low-energy (140keV), short transformation period (6.03h) and good visualization resolution, radiation injury is little and advantage such as cheap and easy to get and become one of the most frequently used in the present nuclear medicine, that prospect is the most wide radionuclide.Existing radiological imaging agent more than 80% is
99mThe Tc radiopharmaceuticals.
Radiopharmaceuticals generally is
99mThe title complex of Tc.Technetium core as coordination center has following several form:
99mTc (IV) or
99mTc (III), (
99mTc=O)
3+, (O=
99mTc=O)
+And [
99mTc (CO)
3]
+, wherein [
99mTc (CO)
3]
+Be to be able to a kind of coordination core broad research, that have application prospect in recent years.
99mThe radiopharmaceutic marking method of Tc mainly contains direct mark and two kinds of methods of indirect labelling.Wherein, the indirect labelling method mainly adopts suitable bifunctional chelating agent (bifunctional chelation agent) to incite somebody to action
99mTc is connected with targeted molecular.Because [
99mTc (CO)
3]
+Directly during the mark biomolecules, mark rate is low, and tagged compound is very unstable, and some biomolecules is difficult to direct mark
[1]Therefore the mark of present most of bioactive moleculess (for example antibody, antibody fragment, polypeptide, receptor antagonist etc.) all adopts the indirect labelling method---and during the mark biomolecules, the centre connects with bifunctional chelating agent.
Cyclofenil (Cyclofenil) belongs to non-steroidal estrogenic agents (being shown below), to the selectivity of estrogen receptor be steroidal class estradiol 2-3 doubly.Research before mainly biases toward functions such as treatment menopausal symptoms, scleroderma, stimulants.People such as Seo once passed through
18F Marking ring Pfennig is used for the estrogen receptor video picture, because fluorine is substituted on the six-ring of cyclofenil (cyclofenil), though therefore cyclofenil derivative and estrogen receptor bonding properties are fine, the video picture result is unsatisfactory.
Summary of the invention
Technical problem to be solved by this invention is for the unfavorable defective of video picture result in the method that overcomes existing cyclofenil mark, and a kind of marked cyclofenil derivative and reference compound thereof and intermediate, and preparation method and application are provided.Marked cyclofenil derivative of the present invention has the anti-breast cancer activity, and has good imaging results.
The contriver calculates by relevant cyclofenil structure activity relationship and biosimulation is found: (1) must keep the rigid structure of this compound; (2) the saturated alkyl ring can guarantee that it has the avidity that is higher than estradiol to estrogen receptor (ER); (3) Huan size is greatly changing the relative binding constant to two kinds of ER; (4) keep in two egol hydroxyls of this structure one, and only need keep one of them and just can reach specific avidity.Therefore, the contriver selects to keep agent structure, only carries out structural modification to one in two reciprocity phenolic hydroxyl groups, after introducing tridentate ligand, introduce radionuclide Tc-99m again, reach reservation to the avidity of ER and can accomplish that ER β is had more highly selective, study for later development SPECT video picture.
Therefore, for solving the problems of the technologies described above, the invention provides following technical proposals.
The present invention relates to a kind of suc as formula the marked cyclofenil derivative shown in the IV;
Wherein, m=0-9, n=0-6,
99mTc is
99mTechnetium, CO are carbonyl.
The invention further relates to the preparation method of compound IV, it comprises the following step: with three hydrations, three carbonyls
99mTechnetium (Fac-[
99mTc (CO)
3(H
2O)
3]
+) and compound ii react, get final product.
Wherein, m=0-9, n=0-6,
99mTc is
99mTechnetium, CO are carbonyl.
Wherein, the method for described reaction and condition all can be the ordinary method and the condition of this type of reaction of this area, and preferable methods and condition are as follows: in the organic solvent, 20 ℃～80 ℃ of controlled temperature are in ultrasound reactor, with Fac-[
99mTc (CO)
3(H
2O)
3]
+With the compound ii reaction, get final product.
Wherein, described organic solvent can be the organic solvent of routine, one or more that preferable is in methyl alcohol, acetonitrile, acetone and the ethanol, preferred alcohol; The volume mass of solvent and compound ii than preferable be 20～200ml/g; Described three hydrations, three carbonyls
99mTechnetium (Fac-[
99mTc (CO)
3(H
2O)
3]
+) radioactive activity and the ratio between the molar weight of compound ii preferable be 0.005mci: 1mmol～200mci: 1mmol, that better is 0.2mci: 1mmol～5mci: 1mmol; What the rotating speed of described ultrasound reactor was preferable is 500～2000 rev/mins; What described temperature was preferable is 70 ℃; The time of described reaction preferable with detection reaction fully till, better is 50 minutes; After reaction was finished, preferable separated purification with HPLC.
Existing radio-labeling technology all is to carry out in the NaCl aqueous solution, and the cyclofenil among the present invention is water-soluble bad, so adjusted reaction conditions when mark, adds organic solvent such as ethanol hydrotropy, and mark rate is improved greatly.
By above-mentioned preparation method, the present invention is with the form of the indirect labelling non-steroidal estrogenic agents cyclofenil of having used radioisotope labeling for the first time.
The invention still further relates to reference compound suc as formula the marked cyclofenil derivative IV shown in the III;
Wherein, m=0-9, n=0-6, Re are the metallic element rhenium, CO is a carbonyl.
Among the present invention, what the compound III was preferable is 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene pentamethylene three rhenium carbonyl title complex (m=3, n=1), 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene hexanaphthene three rhenium carbonyl title complex (m=3, n=2) or 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene suberane three rhenium carbonyl title complexs (and m=3, n=3).
The invention further relates to the preparation method of compound III, it comprises the following step: in the organic solvent, with compound ii and tetraethyl-ammonia bromide three rhenium carbonyl title complexs ([N (Et)
4]
2[Re (CO)
3Br
3]) reaction, get final product;
Wherein, m=0-9, n=0-6, Re are the metallic element rhenium, and CO is a carbonyl, and Et is an ethyl.
Wherein, the method for described reaction and condition all can be the ordinary method and the condition of this type of reaction of this area.Preferred condition is as follows: described organic solvent is preferable is in methyl alcohol, ethanol, acetonitrile and the acetone one or more, particular methanol; The volume mass of solvent and compound ii than preferable be 20～200ml/g; The consumption of described tetraethyl-ammonia bromide three rhenium carbonyl title complexs is preferable is 0.5～5 times of compound ii molar weight, and better is 1 times; What the temperature of described reaction was preferable is 18 ℃～60 ℃, and better is 20 ℃～30 ℃; The time of described reaction preferable with till detecting fully, preferred 0.5～1 hour.
The invention still further relates to the midbody compound II of compound IV;
Wherein, m=0-9, n=0-6.
Among the present invention, what compound ii was preferable is 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene pentamethylene (m=3, n=1), 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene hexanaphthene (m=3, n=2) or 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene suberane (and m=3, n=3).
The invention further relates to the preparation method of compound ii, it comprises the following step: in the organic solvent, chemical compounds I and compound VI are carried out nucleophilic substitution reaction, get final product;
Wherein, m=0-9, n=0-6; X is chlorine (Cl), bromine (Br) or iodine (I), and that preferable is bromine (Br).
Wherein, the method for described nucleophilic substitution reaction and condition all can be the ordinary method and the condition of this type of reaction of this area.Preferable methods and condition are as follows: in the organic solvent, under the effect of basic catalyst, chemical compounds I and compound VI are carried out nucleophilic substitution reaction, get final product; Wherein, described organic solvent is preferable is in acetone, methyl alcohol, acetonitrile and the tetrahydrofuran (THF) one or more, preferred acetone; The volume mass of solvent and chemical compounds I than preferable be 20～200ml/g; What the mol ratio of described chemical compounds I and compound VI was preferable is 0.5: 1～10: 1, and better is 1: 1～3: 1; What described basic catalyst was preferable is sodium hydroxide and/or salt of wormwood; What the mol ratio of described basic catalyst and compound VI was preferable is 1: 1～12.5: 1, and better is 1: 1～3: 1; What the temperature of described reaction was preferable is 30 ℃～70 ℃, and better is 40 ℃～50 ℃; The time of described reaction preferable with detection reaction fully till, be generally preferred 8～21 hours 6～48 hours.
Better, in aforesaid method, also can add KI, that its consumption is preferable is the 5%-30% of compound VI molar weight, preferred 10～15%.KI can with bromo cyclofenil generation replacement(metathesis)reaction, thereby make the speed of response of bromo cyclofenil and compound VI faster.
Chemical compounds I in the aforesaid method (X is chlorine or iodine) can be worth with reference to the preparation method of following chemical compounds I (X is a bromine).
The invention still further relates to the midbody compound I of compound IV;
Wherein, X is bromine (Br), m=0-9, n=0-6.
Among the present invention, that chemical compounds I is preferable is 4-brombutyl oxygen base benzene-4-hydroxy phenyl methene pentamethylene (m=3, n=1), 4-brombutyl oxygen base benzene-4-hydroxy phenyl methene hexanaphthene (m=3, n=2) or 4-brombutyl oxygen base benzene-4-hydroxy phenyl methene suberane (m=3, n=3).
The invention further relates to the preparation method of chemical compounds I (X=Br), it comprises the following step: in the organic solvent, compound V and compound VII are carried out nucleophilic substitution reaction, get final product;
M=0-9 wherein, n=0-6.
Wherein, the method for described nucleophilic substitution reaction and condition all can be the ordinary method and the condition of this type of reaction of this area.Preferable methods and condition are as follows: in the organic solvent, under the effect of basic catalyst, compound V and compound VII are carried out nucleophilic substitution reaction, get final product; Wherein, described organic solvent is preferable is in acetone, acetonitrile and the tetrahydrofuran (THF) one or more, preferred acetone; The volume mass of solvent and compound V than preferable be 20～200ml/g; What the mol ratio of described compound VII and compound V was preferable is 1.2: 1～2.4: 1, and better is 1.5: 1～1.8: 1; What described basic catalyst was preferable is Anhydrous potassium carbonate and/or potassium hydroxide; What the mol ratio of described basic catalyst and compound V was preferable is 1: 1～5: 1, and better is 1.2: 1～2.5: 1; What the temperature of described reaction was preferable is 40 ℃～70 ℃, and better is 45 ℃～55 ℃; The time of described reaction preferable with detection reaction fully till, preferred 4-8 hour.
Among the present invention, [N (Et)
4]
2[Re (CO)
3Br
3] (tetraethyl-ammonia bromide three rhenium carbonyl title complexs) can adopt prior art to synthesize (Alberto R, Egli A, Abrum U, et al, Synthesis and reactivity of[Net
4]
2[ReBr
3(CO)
3] Formation and Structural Characterization of the Clusters[Net
4] [Re (μ
3-OH) (μ-OH)
3(CO)
3] and[Net
4] [Re
2(μ-OH)
3(CO)
6] by AlkalineTitration J Chem Soc Dalton Trans, 1994,2815-2820.).
And [N (Et)
4]
2[Re (CO)
3Br
3] also can synthesize with reference to prior art (as above-mentioned document or Schibli R with the synthetic method of compound ii, Schwarzbach R, Alberto R, et al.Steps TowardHigh Specific Activity Labeling of Biomolecules for Therapeutic Application:Preparation of Precursor[
188Re (H
2O)
3(CO)
3]
+And Synthesis of Tailor-MadeBifunctional Ligand Systems.Bioconjugate Chem, 2002,13 (4): 750-756.).
The invention further relates to the application that the marked cyclofenil derivative shown in the formula IV is used for monitoring and/or treat the radiopharmaceuticals of mammary cancer or monitors and/or treat the radiopharmaceuticals of disease with the estrogen receptor therapy in preparation.
Nucleic
99mTc can the kill tumor cell,
99mPart in the Tc marker can guide nucleic to arrive tumour cell, and radionuclide can cause damage to healthy tissues inevitably in the kill tumor cell, and cyclofenil has good target to the ER acceptor.So synthetic cyclofenil
99mThe Tc title complex has lower toxic side effect.
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
Positive progressive effect of the present invention is:
(1) the present invention is with the method for the indirect labelling non-steroidal estrogenic agents cyclofenil of having used radioisotope labeling for the first time.
(2) marked cyclofenil derivative of the present invention has the anti-breast cancer activity, and has low toxic side effect, is a kind of potential cancer therapy drug.
(3) marked cyclofenil derivative of the present invention has good imaging results.
Description of drawings
Fig. 1 is the reference compound III cyclofenil bipyridine methyl amine Re (CO) of marked cyclofenil derivative IV of the present invention
3The HPLC spectrogram of title complex, t=24.36min.
Fig. 2 is a marked cyclofenil derivative IV radioactivity cyclofenil bipyridine methyl amine of the present invention
99mTc (CO)
3The HPLC spectrogram of title complex, t=24.55min.
Fig. 3 is the HPLC spectrogram of the midbody compound II cyclofenil bipyridine methyl amine of compound IV of the present invention, t=23.81min.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Raw material cyclofenil used in the following example can be synthetic according to prior art, and is synthetic voluntarily as each part document of mentioning in the above-mentioned background technology content; Formula VI compound bipyridine methyl amine derivative is a Switzerland Fluka company product.
Synthesizing of reference example formula V compound cyclofenil (cyclofenil)
According to document (Katzenellenbogen, J.A.; J Med Chem, 2006,49,2496) synthetic cycofenil and derivative thereof, concrete steps are as follows: add 1.2g (18.5mmol) zinc powder in there-necked flask, vacuumize logical N
2Displacement, reciprocal three times.Add the anhydrous THF of 15ml, the cryosel cooling is slowly to wherein adding TiCl
4(1.64g 8.62mmol), has yellow smog to emit after the adding, reaction system becomes yellow-green colour.Remove ice bath, be warming up to 100 ℃, backflow 2h; Be cooled to room temperature, contain 4,4 to wherein injecting '-dihydroxy benaophenonel (500mg, 2.33mmol) and the mixing solutions of the anhydrous THF (15ml) of all kinds of cyclic ketones (2.33mmol), backflow 2h.Use NaHCO
3Saturated solution cancellation reaction.Dichloromethane extraction (3 * 20mL), anhydrous sodium sulfate drying filters, and is spin-dried for solvent, get or with normal hexane/methylene dichloride recrystallization through flash post wash-out, a white solid, productive rate 70%; Below the cyclofenil compound for making when cyclic ketones is cyclopentanone, pimelinketone, suberone is used Va, Vb and Vc respectively.
Embodiment 1 bromo cyclofenil (cyclofenil) compound (chemical compounds I, X=Br, m=3, n=2) synthetic:
Adding compound V (n=2) in there-necked flask (500mg, 1.79mmol), anhydrous K
2CO
3(1.20g 8.8mmol), vacuumizes logical N
2Displacement, reciprocal three times.To wherein injecting 30ml acetone, 46 ℃ of temperature controls stir 0.5h.Then to wherein slowly dripping 1, (400mg 1.86mmol), under the uniform temp condition, reacts 8h to the 4-dibromobutane.The muddy shape solution of gained pink.Filtration is washed with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (sherwood oil): V (ethyl acetate)=10: 1 was leacheate, arrived faint yellow thick product I 185.2mg, productive rate 25% fast through the flash post.
Its appraising datum is as follows:
IR(KBr)v：3264.47，2921.43，2843.59，1609.53，1503.29，1237.68，893.14，583.88cm
-1.
1H?NMR(CDCl
3，500MHz)δ：7.00(d，J＝8.64Hz，2H)，6.98(d，J＝8.45Hz，2H)，6.79(d，J＝8.6Hz，2H)，6.72(d，J＝8.55Hz，2H)，4.6(s，1H)，3.97(t，J＝6.0Hz，2H)，3.49(t，J＝6.4Hz，2H)，2.23(t，J＝5.6Hz，4H)，2.06(m，2H)，1.92(m，2H)，1.50-1.60(m，6H).
Embodiment 2Cyclofenil-bipyridine methyl amine (compound ii, m=3, n=2) synthetic
In a there-necked flask, add chemical compounds I (X=Br, m=3, n=2) (145mg, 0.35mmol), anhydrous K
2CO
3(150mg, 1.09mmol).Vacuumize logical N
2Displacement, reciprocal three times, to wherein injecting 20ml acetone, 44 ℃ of reactions of temperature control 0.5h.Then to wherein add compound VI 2,2 '-bipyridine methyl amine (120mg, 0.603mmol), the reaction 18h.(3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (methylene dichloride): V (methyl alcohol)=50: 1 through flash post wash-out or so that V (methylene dichloride): V (methyl alcohol)=plate separated in 10: 1.Get colourless viscous liquid 82.1mg, productive rate 44%;
Its appraising datum is as follows:
IR(KBr)v：2921.23，2843.59，2108.92，1605.45，1501.29，1429.74，1237.68，1160.05，833.14，763.80，575.71cm
-1；
1H?NMR(CDCl
3，400MHz)δ：8.50(d，J＝4.8Hz，2H)，7.62(t，J＝7.8Hz，2H)，7.54(d，J＝8.0Hz，2H)，7.14(t，J＝6.0Hz，2H)，6.98(d，J＝8.0Hz，2H)，7.92(d，J＝8.0Hz，2H)，6.76(d，J＝8.0Hz，2H)，6.71(d，J＝8.0Hz，2H)，3.87(s，4H)，3.81(t，J＝5.4Hz，2H)，2.63(s，2H)，2.24(s，4H)，1.71(s，4H)，1.58(s，6H)；
ESI-HRMS?calcd?for?C
35H
40N
3O
2[M+1]
+534.3121，found?534.3104.
Embodiment 3 cyclofenil bipyridine methyl amine Re (CO)
3Title complex (compound III, m=3, n=2) synthetic
1. three rhenium carbonyls ([N (Et)
4]
2[Re (CO)
3Br
3], tetraethyl-ammonia bromide three rhenium carbonyl title complexs) synthetic (referring to above-mentioned document)
Under the condition of nitrogen protection; take by weighing 0.2527g (0.6mmol) bromination tetraethyl-amine (Switzerland Fluka company product) and 0.2076g (0.5mmol) bromo pentacarbonyl rhenium (Switzerland Fluka company product); add solvent diethylene glycol dimethyl ether 50.0mL; under the condition of magnetic agitation, slowly be heated to 80 ℃ earlier; react that solid dissolves fully after 10 minutes; be warming up to 120 ℃ of reactions 8 hours again, have this moment faint yellow solid to generate in the solution.Filtered while hot is washed several times with cold diethylene glycol dimethyl ether and anhydrous diethyl ether, places moisture eliminator dry.Dry back yellow powder is used absolute ethanol washing again, filters, and vacuum-drying gets product, gets 0.3727g light yellow solid product, and productive rate is 95%.
2.Cyclofenil-the coordination of bipyridine methyl amine and three rhenium carbonyls
Take by weighing after compound ii 50mg (0.09mmol) compound is dissolved in 3.0mL methyl alcohol, add 77.2mg (0.1mmol) tetraethyl-ammonia bromide three rhenium carbonyls, room temperature (25 ℃) stirs 40min, solution is the water white transparency shape, steaming desolventizes, and with the developping agent of V (methylene dichloride): V (methyl alcohol)=10: 1, wash-out gets thick product 65mg faint yellow solid fast on silicagel column, V (methylene dichloride): V (normal hexane)=1: 2 mixing solutions recrystallization then, productive rate 90%; Recording inactive cyclofenil bipyridine methyl amine Re title complex with ultraviolet monitor is 24.36min in the retention time of HPLC, as shown in Figure 1.
Its appraising datum is as follows: IR (KBr) v:3107.49,2921.23,2030.42,1920.09,1605.45,1511.46,1237.68,1033.37,841.32,543.02cm
-1
1H?NMR(CDCl
3，400MHz)δ：8.64(d，J＝5.6Hz，2H)，7.88(d，J＝8.0Hz，2H)，7.72(t，J＝7.6Hz，2H)，7.17(t，J＝6.6Hz，2H)，6.97(d，J＝8.0Hz，2H)，6.88(m，4H)，6.76(d，J＝8.0Hz，2H)，6.03(s，1H)，5.99(s，1H)，4.35(s，1H)，4.31(s，1H)，3.95(t，J＝5.6Hz，2H)，3.80-3.85(m，2H)，2.20-2.30(m，6H)，1.81(t，J＝6.2，2H)，1.60-1.70(m，6H)；
Anal.Calcd?for[C
38H
39N
3O
5Re]Br·1/2CH
2Cl
2：C?49.9198，H?4.3525，N4.6659：found?C?49.83，H?4.37，N?4.40.
Embodiment 4
99mSynthesizing of the cyclofenil of Tc mark-bipyridine methyl amine (compound IV)
1.Fac-[
99mTc (CO)
3(H
2O)
3]
+Radiological chemistry synthetic
Reagents and Conditions:(a) K
2[BH
3CO
2], KNaC
4H
4O
6, K
2B
4O
7Rt, 15min; Fac-[
99mTc (CO)
3(H
2O)
3]
+Synthetic mainly be according to document (Journal of Pharmaceuticaland Biomedical Analysis, 2007, method 43:1576-1579.) is slightly changed.
A.15.0mg KNaC
4H
4O
64H
2O, the 4.0mg anhydrous Na
2CO
36.0mg NaBH
4, be mixed in the bottle of 10mL.
B. fill CO 30min to wherein feeding.
C. in above-mentioned bottle, add the new drip washing of 1-2mL
99mTcO
4 -Solution (10mCi), 70-75 ℃ of water-bath 30min is cooled to room temperature.
2. adopt Fac-[
188Re (CO)
3(H
2O)
3]
+Cyclofenil bipyridine methyl amine ligand is carried out radiolabeled step:
Get Fac-[
99mTc (CO)
3(H
2O)
3]
+Solution (5mci) 0.4mL adds 10
-4Mol/L cyclofenil bipyridine methyl amine (compound ii, m=3, n=2) ethanolic soln 1.2mL, seal with sealing film, place ultrasound reactor (1300 rev/mins of rotating speeds), 80 ℃ of temperature, time 50min, [the HPLC system: Merck-Hitachi L-7000system (is connected with UV detector and EG﹠amp to adopt high performance liquid chromatography (HPLC) then; G Berthold LB 508 radioactive detectors), chromatographic column is the C-18ec reversed-phase column, Φ 4.6mm * 250mm, 5 μ m; HPLC gradient (solution A: anhydrous methanol; Solution B: 0.05M TEAP triethylamine phosphate buffered soln, pH=2.75) drip washing gradient: 0-3min 85%B; 3-6min 75%B; 6-9min 65%B; 9-22min 2%B; 22-25min 75%B; 25-30min 85%B, c flow velocity are that 1mL/min. analyzes, separates, and separate the back radiochemical purity and reach 95%.Record radioactivity bipyridine methyl amine with radiological monitor
99mTc (CO)
3Title complex is 24.55min in HPLC retention time under similarity condition, as shown in Figure 2.
Embodiment 5 bromo cyclofenil (cyclofenil) compounds (chemical compounds I, X=Br, m=3, n=1) synthetic:
(500mg, 1.88mmol), (100mg 1.79mmol), vacuumizes logical N to potassium hydroxide to add compound V (n=1) in there-necked flask
2Displacement, reciprocal three times.To wherein injecting the 30ml acetonitrile, 40 ℃ of temperature controls stir 0.5h.Then to wherein slowly dripping 1, (497mg 2.26mmol), under the uniform temp condition, reacts 8h to the 4-dibromobutane.The muddy shape solution of gained pink.Filtration is washed with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (sherwood oil): V (ethyl acetate)=10: 1 was leacheate, arrived faint yellow thick product compound I (X=Br, m=3, n=1) 173.4mg, productive rate 23% fast through the flash post.
Its appraising datum is as follows:
1H?NMR(CDCl
3，400MHz)δ：7.09(d，J＝8.1Hz，2H)，7.05(d，J＝8.0Hz，2H)，6.81(d，J＝8.4Hz，2H)，6.75(d，J＝8.1Hz，2H)，4.83(s，1H)，3.99(t，J＝6.6Hz，2H)，3.50(t，J＝6.4Hz，2H)，2.39(s，4H)，2.08(m，2H)，1.95(m，2H)，1.66-1.69(m，4H)；IR(KBr)v：2949.38，2876.28，1601.36，1507.38，1168.22，927.13，837.23，604.71，579.80cm
-1.
Embodiment 6 bromo cyclofenil (cyclofenil) compounds (chemical compounds I, X=Br, m=7, n=1) synthetic:
(500mg, 1.88mmol), (100mg 1.79mmol), vacuumizes logical N to potassium hydroxide to add compound V (n=1) in there-necked flask
2Displacement, reciprocal three times.To wherein injecting the 30ml acetonitrile, 40 ℃ of temperature controls stir 0.5h.Then to wherein slowly dripping 1, (615mg 2.26mmol), under the uniform temp condition, reacts 8h to 8-two bromooctanes.The muddy shape solution of gained pink.Filtration is washed with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (sherwood oil): V (ethyl acetate)=10: 1 was leacheate, arrived faint yellow thick product compound I (X=Br, m=7, n=1) 174.4mg, productive rate 20.3% fast through the flash post.
Its appraising datum is as follows:
1H?NMR(CDCl
3，400MHz)δ：7.08(d，J＝8.56Hz，2H)，7.04(d，J＝8.45Hz，2H)，6.81(d，J＝8.5Hz，2H)，6.72(d，J＝8.64Hz，2H)，4.85(s，1H)，3.93(t，J＝6.43Hz，2H)，3.40(t，J＝6.82，2H)，2.37(s，4H)，1.85(m，2H)，1.78(m，2H)，1.64-1.68(m，4H)，1.45-1.55(m，8H)；IR(KBr)v：2945.63，2826.89，1632.12，1501.23，1157.12，964.23，612.31，582.64cm
-1.
Embodiment 7 bromo cyclofenil (cyclofenil) compounds (chemical compounds I, X=Br, m=3, n=3) synthetic:
(500mg, 1.7mmol), (741mg 5.37mmol), vacuumizes logical N to Anhydrous potassium carbonate to add compound V (n=3) in there-necked flask
2Displacement, reciprocal three times.To wherein injecting the 30ml acetonitrile, 40 ℃ of temperature controls stir 0.5h.Then to wherein slowly dripping 1, (441mg 2.04mmol), under the uniform temp condition, reacts 8h to the 4-dibromobutane.The muddy shape solution of gained pink.Filtration is washed with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (sherwood oil): V (ethyl acetate)=10: 1 was leacheate, arrived faint yellow thick product compound I (X=Br, m=3, n=3) 208.7mg, productive rate 28.6% fast through the flash post.
Its appraising datum is as follows:
1H?NMR(CDCl
3，500MHz)δ：7.04(d，J＝8.6Hz，2H)，7.00(d，J＝8.5Hz，2H)，6.79(d，J＝8.6Hz，2H)，6.73(d，J＝8.5Hz，2H)，4.73(s，1H)，3.96(t，J＝6.0Hz，2H)，3.48(t，J＝6.7Hz，2H)，2.31(s，4H)，2.05(m，2H)，1.92(m，2H)，1.50-1.62(m，8H)；IR(KBr)v：3407.49，2921.23，2847.67，2373.67，1609.53，1503.29，1233.60，837.23cm
-1.
Embodiment 8Cyclofenil-bipyridine methyl amine (compound ii, m=3, n=1) synthetic
In a there-necked flask, add chemical compounds I (X=Br, m=3, n=1) (120mg, 0.30mmol), sodium hydroxide (24mg, 0.603mmol).Vacuumize logical N
2Displacement, reciprocal three times, to wherein injecting 20ml methyl alcohol, 30 ℃ of reactions of temperature control 0.5h.Then to wherein add compound VI 2,2 '-bipyridine methyl amine (120mg, 0.603mmol), and KI (5mg, 0.03mmol), the reaction 18h.(3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (methylene dichloride): V (methyl alcohol)=50: 1 through flash post wash-out or so that V (methylene dichloride): V (methyl alcohol)=plate separated in 10: 1.Get colourless viscous liquid 66.6mg, productive rate 43%;
Its appraising datum is as follows:
1H?NMR(CDCl
3，500MHz)δ：8.51(d，J＝8.6Hz，2H)，7.63(t，J＝6.0Hz，2H)，7.54(d，J＝7.6Hz，2H)，7.14(t，J＝6.2Hz，2H)，7.06(d，J＝8.4Hz，2H)，7.04(d，J＝8.0Hz，2H)，6.77(d，J＝8.4Hz，2H)，6.74(d，J＝8.4Hz，2H)，3.80-3.90(m，6H)，2.60(t，J＝6.4Hz，2H)，2.38(d，J＝7.6Hz，4H)，1.60-1.80(m，8H)；IR(KBr)v：2431.88，1593.19，1470.60，1364.36，1164.13，1045.63，833.14，755.51，579.80cm
-1；ESI-HRMS?calcd?for?C
34H
38N
3O
2[M+1]
+520.2964，found?520.2966.
Embodiment 9Cyclofenil-bipyridine methyl amine (compound ii, m=7, n=1) synthetic
In a there-necked flask, add chemical compounds I (X=Br, m=3, n=1) (120mg, 0.26mmol), Anhydrous potassium carbonate (582mg, 4.221mmol).Vacuumize logical N
2Displacement, reciprocal three times, to wherein injecting 20ml methyl alcohol, 30 ℃ of reactions of temperature control 0.5h.Then to wherein add compound VI 2,2 '-bipyridine methyl amine (120mg, 0.603mmol), and KI (5mg, 0.03mmol), the reaction 18h.(3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (methylene dichloride): V (methyl alcohol)=50: 1 through flash post wash-out or so that V (methylene dichloride): V (methyl alcohol)=plate separated in 10: 1.Get colourless viscous liquid 54.5mg, productive rate 36%;
Its appraising datum is as follows:
1H?NMR(CDCl
3，500MHz)δ：8.51(d，J＝4.76Hz，2H)，7.64(t，J＝7.62Hz，2H)，7.54(d，J＝7.83Hz，2H)，7.13(t，J＝6.07Hz，2H)，7.07(d，J＝8.56Hz，2H)，7.02(d，J＝8.47Hz，2H)，6.79(d，J＝8.61Hz，2H)，6.75(d，J＝8.48Hz，2H)，3.92(t，J＝6.43，2H)，3.81(s，4H)，2.51(t，J＝7.35Hz，2H)，2.38(m，4H)，1.60-1.80(m，6H)，1.50(m，2H)，1.36(m，2H)，1.15-1.30(m，6H)；IR(KBr)v：2421.68，1591.29，1456.23，1360.26，1169.23，1049.13，839.24，759.11，569.02cm
-1；ESI-HRMScalcd?for?C
38H
46N
3O
2[M+1]
+576.3590，found?576.3577.
Embodiment 10Cyclofenil-bipyridine methyl amine (compound ii, m=3, n=3) synthetic
In a there-necked flask, add chemical compounds I (X=Br, m=3, n=3) (120mg, 0.28mmol), sodium hydroxide (24mg, 0.60mmol).Vacuumize logical N
2Displacement, reciprocal three times, to wherein injecting 20ml methyl alcohol, 30 ℃ of reactions of temperature control 0.5h.Then to wherein add compound VI 2,2 '-bipyridine methyl amine (120mg, 0.603mmol), and KI (5mg, 0.03mmol), the reaction 18h.(3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (methylene dichloride): V (methyl alcohol)=50: 1 through flash post wash-out or so that V (methylene dichloride): V (methyl alcohol)=plate separated in 10: 1.Get colourless viscous liquid 70.4mg, productive rate 46%;
Its appraising datum is as follows:
1H?NMR(CDCl
3，500MHz)δ：8.49(d，J＝4.2Hz，2H)，7.61(t，J＝7.7Hz，2H)，7.53(d，J＝7.8Hz，2H)，7.12(t，J＝5.4Hz，2H)，7.01(d，J＝8.6Hz，2H)，6.96(d，J＝8.4Hz，2H)，6.77(d，J＝8.5Hz，2H)，6.71(d，J＝8.6Hz，2H)，3.86(s，4H)，3.80(t，J＝5.7Hz，2H)，2.61(s，2H)，2.30(s，4H)，1.68-1.70(m，4H)，1.56(s，8H)；IR(KBr)v：3440.18，3076.50，2831.33，2230.65，1617.71，1519.64，1266.29，1033.37，816.80，522.59cm
-1；ESI-HRMS?calcd?for?C
36H
42N
3O
2[M+1]
+548.3253，found548.3259.
Embodiment 11 cyclofenil bipyridine methyl amine Re (CO)
3Title complex (compound III, m=3, n=1) synthetic
Take by weighing after compound ii 50mg (0.09mmol) compound is dissolved in 3.0mL ethanol, add 34.7mg (MW:772,0.045mmol) tetraethyl-ammonia bromide three rhenium carbonyls, room temperature (18 ℃) stirs 40min, and solution is the water white transparency shape, and steaming desolventizes, developping agent with V (methylene dichloride): V (methyl alcohol)=10: 1, fast wash-out gets thick product 65mg faint yellow solid on silicagel column, V (methylene dichloride): V (normal hexane)=1: 2 mixing solutions recrystallization then, productive rate 89%;
Its structure is identified as follows:
1H?NMR(CDCl
3，500MHz)δ：8.63(d，J＝5.4Hz，2H)，7.88(d，J＝7.8Hz，2H)，7.74(t，J＝7.7Hz，2H)，7.17(t，J＝6.58Hz，2H)，7.04(d，J＝8.6Hz，2H)，6.97(d，J＝7.2Hz，2H)，6.75-6.83(m，4H)，6.03(s，1H)，5.99(s，1H)，5.31(s，1H)，4.35(s，1H)，4.31(s，1H)，4.00(t，J＝5.8，2H)，3.84(t，J＝8.4，2H)，2.35(d，J＝7.2，4H)，2.23(t，J＝5.9，2H)，1.87(t，J＝6.23Hz，2H)，1.60-1.70(m，4H)；IR(KBr)v：2921.23，2847.67，2026.33，1916.00，1605.45，1503.29，1241.77，1029.28，829.06，763.68cm
-1；Anal.Calcd?for[C
37H
37N
3O
5Re]Br·2/5CH
2Cl
2：C?49.7018，H?4.2156，N4.6493；found?C?49.46，H?3.848，N?4.618.
Embodiment 12 cyclofenil bipyridine methyl amine Re (CO)
3Title complex (compound III, m=7, n=1) synthetic
Take by weighing after compound ii 50mg (0.09mmol) compound is dissolved in the 3.0mL acetonitrile, add 173.7mg (MW:772,0.225mmol) tetraethyl-ammonia bromide three rhenium carbonyls, 40 ℃ are stirred 40min, and solution is the water white transparency shape, and steaming desolventizes, developping agent with V (methylene dichloride): V (methyl alcohol)=10: 1, fast wash-out gets thick product 65mg faint yellow solid on silicagel column, V (methylene dichloride): V (normal hexane)=1: 2 mixing solutions recrystallization then, productive rate 90%;
Its structure is identified as follows:
1H?NMR(CDCl
3，500MHz)δ：8.65(d，J＝3.77Hz，2H)，7.91(d，J＝8.43Hz，2H)，7.79(t，J＝8.67Hz，2H)，7.19(t，J＝6.04Hz，2H)，7.06(d，J＝5.87Hz，2H)，6.94(d，J＝8.73Hz，2H)，6.82(d，J＝10.98，2H)，6.07(s，1H)，5.92(s，1H)，4.36(s，1H)，4.32(s，1H)，3.97(t，J＝6.37，2H)，3.80-3.85(m，2H)，2.10(m，4H)，1.80-2.05(m，6H)，1.30-1.50(m，4H)，1.09-1.25(m，6H)；IR(KBr)v：3427.34，2927.12，2362.32，2024.41，1917.23，1248.22，832.92，741.15cm
-1；Anal.Calcdfor[C
41H
45N
3O
5Re]Br·9/5CH
2Cl
2：C?47.6508，H?4.5408，N?3.8951；found?C47.83，H?4.34，N?3.86.
Embodiment 13 cyclofenil bipyridine methyl amine Re (CO)
3Title complex (compound III, m=3, n=3) synthetic
Take by weighing after compound ii 50mg (0.09mmol) compound is dissolved in 3.0mL acetone, add 347.4mg (MW:772,0.45mmol) tetraethyl-ammonia bromide three rhenium carbonyls, 60 ℃ are stirred 40min, and solution is the water white transparency shape, and steaming desolventizes, developping agent with V (methylene dichloride): V (methyl alcohol)=10: 1, fast wash-out gets thick product 65mg faint yellow solid on silicagel column, V (methylene dichloride): V (normal hexane)=1: 2 mixing solutions recrystallization then, productive rate 90%;
Its structure is identified as follows:
1H?NMR(CDCl
3，400MHz)δ：8.63(d，J＝5.6Hz，2H)，7.86(d，J＝7.6Hz，2H)，7.72(t，J＝7.6Hz，2H)，7.16(t，J＝6.6Hz，2H)，7.01(d，J＝7.6Hz，2H)，6.94(d，J＝8.0Hz，4H)，6.85(d，J＝8.0Hz，2H)，6.76(d，J＝7.6Hz，2H)，5.97(s，1H)，5.92(s，1H)，5.31(s，1H)，4.35(s，1H)，4.31(s，1H)，3.94(t，J＝5.4Hz，2H)，3.79-3.85(m，2H)，2.29(s，4H)，2.21(t，J＝6.4Hz，2H)，1.80(t，J＝6.0Hz，2H)，1.60-1.70(m，8H)；IR(KBr)v：3423.84，2917.14，2369.85，2030.42，1907.83，1241.77，838.14，771.85cm
-1；Anal.Calcd?for[C
39H
41N
3O
5Re]Br·6/5CH
2Cl
2：C?48.2932，H?4.3754，N?4.2029；found?C?48.32，H?4.39，N?4.16.
Embodiment 14 bromo cyclofenil (cyclofenil) compounds (chemical compounds I, X=Br, m=3, n=2) synthetic:
(500mg, 1.79mmol), (100mg 1.79mmol), vacuumizes logical N to potassium hydroxide to add compound V (n=2) in there-necked flask
2Displacement, reciprocal three times.To wherein injecting the 30ml acetonitrile, 40 ℃ of temperature controls stir 0.5h.Then to wherein slowly dripping 1, (523mg 2.42mmol), under the uniform temp condition, reacts 8h to the 4-dibromobutane.The muddy shape solution of gained pink.Filtration is washed with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (sherwood oil): V (ethyl acetate)=10: 1 was leacheate, arrived faint yellow thick product compound I (X=Br, m=3, n=2) 594.3mg, productive rate 80% fast through the flash post.
Embodiment 15 bromo cyclofenil (cyclofenil) compounds (chemical compounds I, X=Br, m=3, n=2) synthetic:
(500mg, 1.79mmol), (100mg 1.79mmol), vacuumizes logical N to potassium hydroxide to add compound V (n=2) in there-necked flask
2Displacement, reciprocal three times.To wherein injecting the 30ml tetrahydrofuran (THF), 70 ℃ of temperature controls stir 0.5h.Then to wherein slowly dripping 1, (928mg 4.30mmol), under the uniform temp condition, reacts 8h to the 4-dibromobutane.The muddy shape solution of gained pink.Filtration is washed with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (sherwood oil): V (ethyl acetate)=10: 1 was leacheate, arrived faint yellow thick product compound I (X=Br, m=3, n=2) 572mg, productive rate 77% fast through the flash post.
Embodiment 16 bromo cyclofenil (cyclofenil) compounds (chemical compounds I, X=Br, m=3, n=2) synthetic:
(500mg, 1.79mmol), (741mg 5.37mmol), vacuumizes logical N to Anhydrous potassium carbonate to add compound V (n=2) in there-necked flask
2Displacement, reciprocal three times.To wherein injecting 30ml acetone, 55 ℃ of temperature controls stir 0.5h.Then to wherein slowly dripping 1, (696mg 3.22mmol), under the uniform temp condition, reacts 8h to the 4-dibromobutane.The muddy shape solution of gained pink.Filtration is washed with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (sherwood oil): V (ethyl acetate)=10: 1 was leacheate, arrived faint yellow thick product compound I (X=Br, m=3, n=2) 572mg, productive rate 77% fast through the flash post.
Embodiment 17Cyclofenil-bipyridine methyl amine (compound ii, m=3, n=2) synthetic
In a there-necked flask, add chemical compounds I (X=Br, m=3, n=2) (125mg, 0.302mmol), sodium hydroxide (24mg, 0.603mmol).Vacuumize logical N
2Displacement, reciprocal three times, to wherein injecting 20ml methyl alcohol, 30 ℃ of reactions of temperature control 0.5h.Then to wherein add compound VI 2,2 '-bipyridine methyl amine (120mg, 0.603mmol), and KI (5mg, 0.03mmol), the reaction 18h.(3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (methylene dichloride): V (methyl alcohol)=50: 1 through flash post wash-out or so that V (methylene dichloride): V (methyl alcohol)=plate separated in 10: 1.Get colourless viscous liquid 64.5mg, productive rate 40%;
Embodiment 18Cyclofenil-bipyridine methyl amine (compound ii, m=3, n=2) synthetic
In a there-necked flask, add chemical compounds I (X=Br, m=3, n=2) (1.25g, 3.015mmol), Anhydrous potassium carbonate (582mg, 4.221mmol).Vacuumize logical N
2Displacement, reciprocal three times, to wherein injecting the 20ml acetonitrile, 50 ℃ of reactions of temperature control 0.5h.Then to wherein add compound VI 2,2 '-bipyridine methyl amine (120mg, 0.603mmol), and KI (30mg, 0.18mmol), the reaction 18h.(3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (methylene dichloride): V (methyl alcohol)=50: 1 through flash post wash-out or so that V (methylene dichloride): V (methyl alcohol)=plate separated in 10: 1.Get colourless viscous liquid 135mg, productive rate 42%;
Embodiment 19Cyclofenil-bipyridine methyl amine (compound ii, m=3, n=2) synthetic
In a there-necked flask, add chemical compounds I (X=Br, m=3, n=2) (2.50g, 6.03mmol), Anhydrous potassium carbonate (1.04g, 7.54mmol).Vacuumize logical N
2Displacement, reciprocal three times, to wherein injecting the 20ml tetrahydrofuran (THF), 70 ℃ of reactions of temperature control 0.5h.Then to wherein add compound VI 2,2 '-bipyridine methyl amine (120mg, 0.603mmol), and KI (18mg, 0.11mmol) reaction 18h.(3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.With V (methylene dichloride): V (methyl alcohol)=50: 1 through flash post wash-out or so that V (methylene dichloride): V (methyl alcohol)=plate separated in 10: 1.Get colourless viscous liquid 138mg, productive rate 43%;
Embodiment 20 cyclofenil bipyridine methyl amine Re (CO)
3Title complex (compound III, m=3, n=2) synthetic
Take by weighing after compound ii 50mg (0.09mmol) compound is dissolved in 3.0mL ethanol, add 34.7mg (MW:772,0.045mmol) tetraethyl-ammonia bromide three rhenium carbonyls, room temperature (18 ℃) stirs 40min, and solution is the water white transparency shape, and steaming desolventizes, developping agent with V (methylene dichloride): V (methyl alcohol)=10: 1, fast wash-out gets thick product 65mg faint yellow solid on silicagel column, V (methylene dichloride): V (normal hexane)=1: 2 mixing solutions recrystallization then, productive rate 89%; Recording inactive cyclofenil bipyridine methyl amine Re title complex with ultraviolet monitor is 24.36min in the retention time of HPLC, as shown in Figure 1.
Embodiment 21 cyclofenil bipyridine methyl amine Re (CO)
3Title complex (compound III, m=3, n=2) synthetic
Take by weighing after compound ii 50mg (0.09mmol) compound is dissolved in the 3.0mL acetonitrile, add 173.7mg (MW:772,0.225mmol) tetraethyl-ammonia bromide three rhenium carbonyls, 40 ℃ are stirred 40min, and solution is the water white transparency shape, and steaming desolventizes, developping agent with V (methylene dichloride): V (methyl alcohol)=10: 1, fast wash-out gets thick product 65mg faint yellow solid on silicagel column, V (methylene dichloride): V (normal hexane)=1: 2 mixing solutions recrystallization then, productive rate 90%; Recording inactive cyclofenil bipyridine methyl amine Re title complex with ultraviolet monitor is 24.36min in the retention time of HPLC, as shown in Figure 1.
Embodiment 22 cyclofenil bipyridine methyl amine Re (CO)
3Title complex (compound III, m=3, n=2) synthetic
Take by weighing after compound ii 50mg (0.09mmol) compound is dissolved in 3.0mL acetone, add 347.4mg (MW:772,0.45mmol) tetraethyl-ammonia bromide three rhenium carbonyls, 60 ℃ are stirred 40min, and solution is the water white transparency shape, and steaming desolventizes, developping agent with V (methylene dichloride): V (methyl alcohol)=10: 1, fast wash-out gets thick product 65mg faint yellow solid on silicagel column, V (methylene dichloride): V (normal hexane)=1: 2 mixing solutions recrystallization then, productive rate 90%; Recording inactive cyclofenil bipyridine methyl amine Re title complex with ultraviolet monitor is 24.36min in the retention time of HPLC, as shown in Figure 1.
Embodiment 23
99mThe cyclofenil of Tc mark-bipyridine methyl amine (compound IV, m=3, n=2) synthetic
Adopt Fac-[
188Re (CO)
3(H
2O)
3]
+Cyclofenil bipyridine methyl amine ligand is carried out radiolabeled step:
Get Fac-[
99mTc (CO)
3(H
2O)
3]
+(0.6 * 10
-6Mci) solution 0.4mL adds 10
-4Mol/L formula II compound cyclofenil bipyridine methyl amine (m=3, n=2) methanol solution 1.2mL, seal with sealing film, place ultrasound reactor (2000 rev/mins of rotating speeds), 70 ℃ of temperature, time 50min, [the HPLC system: Merck-Hitachi L-7000system (is connected with UV detector and EG﹠amp to adopt high performance liquid chromatography (HPLC) then; G Berthold LB 508 radioactive detectors), chromatographic column is the C-18ec reversed-phase column, Φ 4.6mm * 250mm, 5 μ m; HPLC gradient (solution A: anhydrous methanol; Solution B: 0.05M TEAP triethylamine phosphate buffered soln, pH=2.75) drip washing gradient: 0-3min 85%B; 3-6min 75%B; 6-9min 65%B; 9-22min 2%B; 22-25min 75%B; 25-30min85%B, c flow velocity are that 1mL/min. analyzes, separates, and separate the back radiochemical purity and reach 95%.Record radioactivity bipyridine methyl amine with radiological monitor
99mTc (CO)
3Title complex is 24.55min in HPLC retention time under similarity condition, as shown in Figure 2.
Embodiment 24
99mThe cyclofenil of Tc mark-bipyridine methyl amine (compound IV, m=3, n=2) synthetic
Adopt Fac-[
188Re (CO)
3(H
2O)
3]
+Cyclofenil bipyridine methyl amine ligand is carried out radiolabeled step:
Get Fac-[
99mTc (CO)
3(H
2O)
3]
+(0.024mci) solution 0.4mL adds 10
-4Mol/L formula II compound cyclofenil bipyridine methyl amine (m=3, n=2) acetonitrile solution 1.2mL, seal with sealing film, place ultrasound reactor (500 rev/mins of rotating speeds), 20 ℃ of temperature, time 50min, [the HPLC system: Merck-Hitachi L-7000system (is connected with UV detector and EG﹠amp to adopt high performance liquid chromatography (HPLC) then; G Berthold LB 508 radioactive detectors), chromatographic column is the C-18ec reversed-phase column, Φ 4.6mm * 250mm, 5 μ m; HPLC gradient (solution A: anhydrous methanol; Solution B: 0.05M TEAP triethylamine phosphate buffered soln, pH=2.75) drip washing gradient: 0-3min 85%B; 3-6min 75%B; 6-9min 65%B; 9-22min 2%B; 22-25min 75%B; 25-30min85%B, c flow velocity are that 1mL/min. analyzes, separates, and separate the back radiochemical purity and reach 95%.Record radioactivity bipyridine methyl amine with radiological monitor
99mTc (CO)
3Title complex is 24.55min in HPLC retention time under similarity condition, as shown in Figure 2.
Embodiment 25
99mThe cyclofenil of Tc mark-bipyridine methyl amine (compound IV, m=3, n=2) synthetic
Adopt Fac-[
188Re (CO)
3(H
2O)
3]
+Cyclofenil bipyridine methyl amine ligand is carried out radiolabeled step:
Get Fac-[
99mTc (CO)
3(H
2O)
3]
+(0.012mci) solution 0.4mL adds 10
-4Mol/L formula II compound cyclofenil bipyridine methyl amine (m=3, n=2) acetone soln 1.2mL, seal with sealing film, place ultrasound reactor (1300 rev/mins of rotating speeds), 80 ℃ of temperature, time 50min, [the HPLC system: Merck-Hitachi L-7000system (is connected with UV detector and EG﹠amp to adopt high performance liquid chromatography (HPLC) then; G Berthold LB 508 radioactive detectors), chromatographic column is the C-18ec reversed-phase column, Φ 4.6mm * 250mm, 5 μ m; HPLC gradient (solution A: anhydrous methanol; Solution B: 0.05M TEAP triethylamine phosphate buffered soln, pH=2.75) drip washing gradient: 0-3min 85%B; 3-6min 75%B; 6-9min 65%B; 9-22min 2%B; 22-25min 75%B; 25-30min85%B, c flow velocity are that 1mL/min. analyzes, separates, and separate the back radiochemical purity and reach 95%.Record radioactivity bipyridine methyl amine with radiological monitor
99mTc (CO)
3Title complex is 24.55min in HPLC retention time under similarity condition, as shown in Figure 2.
Above-mentioned raw material or the reagent that does not specify is conventional commercially available prod.
Claims (18)
1. one kind suc as formula the marked cyclofenil derivative shown in the IV;
Wherein, m=0-9, n=0-6,
99mTc is
99mTechnetium, CO are carbonyl.
2. the preparation method of marked cyclofenil derivative as claimed in claim 1 is characterized in that comprising the following step: with three hydrations, three carbonyls
99mTechnetium and Compound I I react, and get final product;
Wherein, m=0-9, n=0-6,
99mTc is
99mTechnetium, CO are carbonyl.
3. preparation method as claimed in claim 2 is characterized in that: described marked cyclofenil derivative IV is made by following method: in the organic solvent, 20 ℃～80 ℃ of controlled temperature are in ultrasound reactor, with three hydrations, three carbonyls
99mTechnetium and Compound I I reaction get final product.
4. preparation method as claimed in claim 3 is characterized in that: described organic solvent is one or more in methyl alcohol, acetonitrile, acetone and the ethanol; Described three hydrations, three carbonyls
99mRatio between the molar weight of the radioactive activity of technetium and Compound I I is 0.005mci: 1mmol～200mci: 1mmol; The rotating speed of described ultrasound reactor is 500～2000 rev/mins; Described temperature is 70 ℃; The time of described reaction with detection reaction fully till; After described reaction is finished, separate purification with HPLC.
5. the reference compound of the marked cyclofenil derivative IV shown in formula III;
Wherein, m=0-9, n=0-6, Re are the metallic element rhenium, CO is a carbonyl.
6. reference compound as claimed in claim 5 is characterized in that: described reference compound III is 4-[two (a 2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene pentamethylene three rhenium carbonyl title complexs, 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene hexanaphthene three rhenium carbonyl title complexs or 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene suberane three rhenium carbonyl title complexs.
7. as the preparation method of claim 5 or 6 described reference compounds, it is characterized in that comprising the following step: in the organic solvent, with Compound I I and tetraethyl-ammonia bromide three rhenium carbonyl title complexs ([N (Et)
4]
2[Re (CO)
3Br
3]) reaction, get final product;
Wherein, m=0-9, n=0-6, Re are the metallic element rhenium, and CO is a carbonyl, and Et is an ethyl.
8. preparation method as claimed in claim 7 is characterized in that: described organic solvent is one or more in methyl alcohol, ethanol, acetonitrile and the acetone; The consumption of described tetraethyl-ammonia bromide three rhenium carbonyl title complexs is 0.5～5 times of Compound I I molar weight; The temperature of described reaction is 18 ℃～60 ℃; The time of described reaction is with till detecting fully.
9. the midbody compound II of a compound IV;
Wherein, m=0-9, n=0-6.
10. Compound I I as claimed in claim 9 is characterized in that: described Compound I I is 4-[two (a 2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene pentamethylene, 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene hexanaphthene or 4-[two (2-methylene radical pyridine)] butyl oxygen base phenyl-4-hydroxy phenyl methene suberane.
11. the preparation method as claim 9 or 10 described Compound I I is characterized in that comprising the following step: in the organic solvent, Compound I and compound VI are carried out nucleophilic substitution reaction, get final product;
Wherein, X is chlorine, bromine or iodine; M=0-9, n=0-6.
12. preparation method as claimed in claim 11 is characterized in that: described Compound I I is made by following method: in the organic solvent, under the effect of basic catalyst, Compound I and compound VI are carried out nucleophilic substitution reaction, get final product; Wherein, described organic solvent is one or more in acetone, methyl alcohol, acetonitrile and the tetrahydrofuran (THF); The mol ratio of described Compound I and compound VI is 0.5: 1～10: 1; Described basic catalyst is sodium hydroxide and/or salt of wormwood; The mol ratio of described basic catalyst and compound VI is 1: 1～12.5: 1; The temperature of described reaction is 30 ℃～70 ℃; The time of described reaction with detection reaction fully till.
13. preparation method as claimed in claim 12 is characterized in that: add KI in described preparation method, its consumption is the 5%-30% of compound VI molar weight.
14. the midbody compound I of a compound IV;
Wherein, X is a bromine, m=0-9, n=0-6.
15. Compound I as claimed in claim 14 is characterized in that: described Compound I is 4-brombutyl oxygen base benzene-4-hydroxy phenyl methene pentamethylene, 4-brombutyl oxygen base benzene-4-hydroxy phenyl methene hexanaphthene or 4-brombutyl oxygen base benzene-4-hydroxy phenyl methene suberane.
16. the preparation method as claim 14 or 15 described Compound I is characterized in that comprising the following step: in the organic solvent, compound V and compound VI I are carried out nucleophilic substitution reaction, get final product;
M=0-9 wherein, n=0-6.
17. preparation method as claimed in claim 16 is characterized in that: described Compound I is made by following method: in the organic solvent, under the effect of basic catalyst, compound V and compound VI I carry out nucleophilic substitution reaction, get final product; Wherein, described organic solvent is one or more in acetone, acetonitrile and the tetrahydrofuran (THF); The mol ratio of described compound VI I and compound V is 1.2: 1～2.4: 1; Described basic catalyst is Anhydrous potassium carbonate and/or potassium hydroxide; The mol ratio of described basic catalyst and compound V is 1: 1～5: 1; The temperature of described reaction is 40 ℃～70 ℃; The time of described reaction with detection reaction fully till.
18. be used for monitoring and/or treat the radiopharmaceuticals of mammary cancer or with the application of the radiopharmaceuticals of monitoring of estrogen receptor therapy and/or treatment disease in preparation suc as formula the marked cyclofenil derivative shown in the IV.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643423A (en) * | 2011-02-18 | 2012-08-22 | 中国科学院上海应用物理研究所 | 99mTc complex, preparation method, intermediate and application thereof |
| CN102786394A (en) * | 2012-07-30 | 2012-11-21 | 中国医学科学院医药生物技术研究所 | Substituent bis-aryl methylene naphthenic base derivative as well as preparation method and application thereof |
-
2009
- 2009-01-14 CN CN200910045292A patent/CN101775038A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643423A (en) * | 2011-02-18 | 2012-08-22 | 中国科学院上海应用物理研究所 | 99mTc complex, preparation method, intermediate and application thereof |
| CN102643423B (en) * | 2011-02-18 | 2015-09-30 | 中国科学院上海应用物理研究所 | A kind of 99mtc title complex, its preparation method, intermediate and application thereof |
| CN102786394A (en) * | 2012-07-30 | 2012-11-21 | 中国医学科学院医药生物技术研究所 | Substituent bis-aryl methylene naphthenic base derivative as well as preparation method and application thereof |
| CN102786394B (en) * | 2012-07-30 | 2017-03-01 | 中国医学科学院医药生物技术研究所 | Replace double aryl methylene cycloalkyl derivatives and its preparation method and application |
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