CN107266359A - A kind of chelating agent, its synthetic method and purposes and the chelate containing the chelating agent - Google Patents

A kind of chelating agent, its synthetic method and purposes and the chelate containing the chelating agent Download PDF

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CN107266359A
CN107266359A CN201710567242.2A CN201710567242A CN107266359A CN 107266359 A CN107266359 A CN 107266359A CN 201710567242 A CN201710567242 A CN 201710567242A CN 107266359 A CN107266359 A CN 107266359A
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compound
chelating agent
solution
metal ion
mol ratio
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沈浪涛
董琳琳
杨春慧
田倩
孙钰林
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ATOM HIGH TECH Co Ltd
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

A kind of chelating agent disclosed by the invention, its general structure is as follows：The chelate constituted comprising the chelating agent with metal ion, and the method for synthesizing the chelating agent are also disclosed, (1) synthesizes the precursor compound D of the chelating agent using active ester method；(2) catalytic hydrogenation is used, the chelating agent is obtained.The purposes of the chelating agent is to be used as other purposes such as Radionuclide imaging and the medicine for the treatment of, Magnetic Resonance Imaging medicine, selectivity chelating separation trivalent metal ion.The advantage of the invention is that, because the chelating agent is sexadentate ligand, sequestering power with many trivalent metal ions is strong, therefore dosage used is small when forming chelate, it is reduced as toxic side effect during medicine, simultaneously as left end contains amino, it can be connected with some biological targeting molecules, available for preparing various targeted drugs；The mild condition (generally normal temperature) of complexation reaction occurs with metal ion for the chelating agent, simplifies the process of medicine preparation；The raw material for preparing the chelating agent is easy to get, method is easy, easy large-scale promotion.

Description

A kind of chelating agent, its synthetic method and purposes and the chelate containing the chelating agent
Technical field
The invention belongs to organic chemical synthesis technical field, specially a kind of chelating agent, its synthetic method and purposes and contain There is the chelate of the chelating agent.
Background technology
Hydroxylpyridinones (HPO) compound is the ketone containing a α hydroxyl, there is carbonylic oxygen atom and one on azacyclo- Individual hydroxyl oxygen atom, is important metal ion cheating moiety.It is with its two special toothing, the complexing power of high selectivity And significant physiologically active and the research as metal-chelator, metal Clinics and Practices medicine and metal ion decorporation medicine Focus.
Wherein, 3- hydroxyls -4- pyridones (3,4-HP) structure is similar with natural mimosine, with preferable bio-compatible Property, at physiological ph, to trivalent metal ion such as (Fe3+、Al3+、Ga3+、In3+) there is high selectivity and high affinity, can 3 are formed therewith:1 stable metal complex, the heavy metal such as iron, aluminium that can be excessive effectively in decorporation human body, plays detoxication； In addition, it is expected to diagnosis and treatment for disease, the content of iron in β-patients with thalassemia body, treatment can be such as controlled Diabetes；The Hydroxypyridinone complex of gadolinium can be used as contrast agent of magnetic resonance imaging etc..In pharmaceutical chemistry, metal chelating is designed During mixture, 3- hydroxyl -4- pyridone structure units are often important part.
1991, King's College London Hider and its team have developed N substituted 2-alkyl -3- hydroxyl -4- pyridones (DFP) compound.It has preferable Orally active, can efficiently control the Fe supply in patients with thalassemia body, mesh Preceding U.S. FDA approval is applied to clinical treatment, solves medicine cost height, fast degradation etc. after serum and hypodermic injection Problem.But it is due to the size that ligand concentration depends on sequestering power, 1,2-Dimethyl-3-hydroxypyrid-4-one is used as two teeth Part, compared with multidentate ligand, in clinical practice, required dosage is larger, and the toxic side effect to patient is big.Therefore, design synthesis Consumption and toxic side effect are small, and can be effectively formed M with metal ion:L=1:The novel multidentate part of 1 complex, is current medicine One of study hotspot of thing chemistry.
The report on Hydroxypyridinone sexadentate ligand appears in nineteen ninety earliest.It is 3- hydroxyl -2- pyridinones six Tooth ligand compound.Although also having some both at home and abroad at present on the tooth of 3- hydroxyl -4- pyridinones five or other multidentate ligands Report, but it is relatively fewer as the report of difunctional sexadentate ligand, and up to the present, synthesized such difunctional six tooth is matched somebody with somebody They seldom, are particularly applied in terms of radiodiagnosis, medicine and Magnetic Resonance Imaging medicine by body classes of compounds Even more it is rarely reported.However, the application of such bifunctional chelating agent in these areas has broad prospects and commercial value.This The design of class bifunctional chelating agent and synthesis are extremely challenging work.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of chelating agent, its synthetic method and purposes and containing the chela The chelate of mixture, its purpose realized is to obtain, containing the difunctional sexadentate ligand chelating agent of 3- hydroxyl -4- pyridones, both protecting 3- hydroxyl -4- pyridones are held to the preferable selectivity of trivalent metal ion and affinity, again can be with some biological targeting molecules Connection, fills up the blank in difunctional sexadentate ligand chelating agent market, and the chelating agent that the present invention is obtained further can be studied, and makes It plays bigger value in field of medicaments, Material Field etc., is greatly promoted bifunctional chelating agent and its complex in application The development in field.
To achieve these goals, technical scheme disclosed by the invention is：A kind of chelating agent, its general structure is as follows：
N in structure above is >=0 integer, the chelating agent be by triangle rack-like molecular skeleton of amino tricarboxylic acids, The six tooth chelating agents containing 3- hydroxyl -4- pyridone coordinating groups.The quasi-chelate compound has higher to some trivalent metal ions Selectivity and affinity, stable metal complex can be formed therewith, be expected to be used as the decorporation medicine of the metals such as aluminium, iron Thing, due to being multidentate ligand, sequestering power is strong, therefore dosage used is small when forming chelate, and the poison that can reduce decorporation medicine is secondary Effect, simultaneously as left end contains amino, can also be connected with some biological targeting molecules, image and treat as radioactive metal Medicine, Magnetic Resonance Imaging medicine, therefore, have broad application prospects.
Further, 2≤n≤5 in the general structure.
The invention also discloses the chelate containing above-mentioned chelating agent, including the chelating agent and metal ion, the gold Category ion is trivalent metal ion, and the coordination ratio of chelating agent and metal ion is 1:1.
Further, the metal ion is Al or Fe.
Further, the metal ion is Sc, Y and their radio isotope86Y、90Y、47It is any one in Sc Kind.
Further, the metal ion is lanthanide series, the stable isotope of lanthanide series, corresponding radio isotope In any one.The radio isotope includes177Lu、153Sm、149Tb。
Further, the metal ion is any one in actinides.
Further, the metal ion is In, Ga and the radio isotope of both metals111In、66Ga、67Ga、68Any one in Ga.Using above-mentioned chelating agent and trivalent metal or its radioisotopic chelation, as Decorporation medicine, Radionuclide imaging diagnostic medicine, radiation treatment medicine or the chelating of these metal ions separate these metals Material application, promote the extensive use of the quasi-chelate compound.
The invention also discloses the method for synthesizing above-mentioned chelating agent, comprise the following steps：
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, the chela is synthesized using active ester method The precursor compound D of mixture, described compound A, C, D general structure is as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation, obtains the chelating agent.This synthetic method Simply, raw material is easy to get, and cost is low, and reaction condition is gently safe, it is easy to control.
Further, compound A is using lysine class compound as raw material, first with bromoacetic acid sodium, hydrogen in the step (1) Sodium oxide molybdena reacts, then is made with hydrochloric acid reaction synthesis.
Further, lysine class compound is N- ε-benzyloxycarbonyl group -1B, N- ε-benzyloxy in the step (1) Any one in carbonyl-D-Lys or N- ε-benzyloxycarbonyl group-DL-Lys.
Further, synthesis compound A specific method includes：
(1) bromoacetic acid sodium solution is prepared, bromoacetic acid and concentration are mixed for 2M sodium hydroxide solution and dissolved, ice bath 0 DEG C is cooled to, obtains that bromoacetic acid sodium solution is standby, the mol ratio of lysine class compound and bromoacetic acid is 1:1.5~4, bromine second Acid is 1 with sodium hydroxide solution mol ratio:1；
(2) lysine class compound is dissolved in concentration in 2M sodium hydroxide solutions, to be slowly added dropwise under ice bath to step (1) in bromoacetic acid sodium solution, the mol ratio of lysine class compound and sodium hydroxide solution is 1:2.5~6, it is anti-at 0 DEG C 2h is answered, then stirring at normal temperature is stayed overnight；
(3) reaction solution for obtaining step (2) 2~5h of water-bath at 35 DEG C~55 DEG C, then stirring adds hydrochloric acid Solution, obtains white solid after cooling, filtering, hydrochloric acid solution is equal with the sodium hydroxide solution molal quantity for dissolving lysine；
(4) white solid that step (3) is obtained is dissolved in the sodium hydroxide solution that concentration is 1M, then stirring addition etc. The concentration of amount be 1M hydrochloric acid solution, cooling separate out white solid, by, vacuum drying 24h, obtain compound A.
Further, compound C is that, using methyl maltol as raw material, first synthesis carries benzyl protection in the step (1) 3- hydroxyl -4- pyridone coordinating groups compound B, compound B again with diamine compounds react, finally with hydrochloric acid knot Close, obtain the compound C of hydrochloride form.
Further, the source of the benzyl is benzyl chloride, and diamine compounds are 1,2- ethylenediamines, 1,3- propane diamine, Any one in Putriscine, 1,5- pentanediamine.
Further, the compound C synthetic methods include：
(1) methyl maltol is added into methanol, stirring fully dissolving；
(2) sodium hydroxide solution that concentration is 7M is added dropwise in the mixed liquor obtained to step (1), benzvl compounds is then added dropwise Thing, heating, back flow reaction is stayed overnight, and the mol ratio of methyl maltol and sodium hydroxide solution is 1：0.8~1.5, methyl maltol Mol ratio with benzyl compounds is 1：0.8~2.5；
(3) the reaction solution revolving obtained step (2) removes solvent, and obtained grease is dissolved in dichloromethane, is used NaOH solution and distillation water washing that mass concentration is 5%, then through anhydrous Na2SO4Organic phase is dried to stay overnight, then through filtering, rotation Steam, be dried in vacuo 24h, obtain compound B；
(4) diamine compounds are dissolved in absolute ethyl alcohol/water mixed solution, fully dissolving, add NaOH solution, oil Bath be heated to 50 DEG C it is standby.The mol ratio of compound B and diamine compounds is 1：0.8~2.5, absolute ethyl alcohol, water mixing are molten The volume ratio 1 of absolute ethyl alcohol and water in liquid:The mol ratio of 1, compound B and NaOH solution is 1：0.1~0.3；
(5) compound B is dissolved in absolute ethyl alcohol, agitation and dropping enters in the solution that step (4) is obtained, 60~85 DEG C of oil bath Reaction, the reaction time is 8~24h；
(6) the reaction solution revolving obtained step (5) is removed after ethanol, adds distilled water dissolving, solution is adjusted with HCl PH value is washed to 1, then with dichloromethane, and aqueous phase adjusts pH to 7 with NaOH solution, after being washed through dichloromethane, uses NaOH solution Regulation pH is extracted to 12, then with dichloromethane, retains organic phase, through anhydrous Na2SO4Dry, filter, revolving obtains brown color oil Shape thing, is dissolved in saturation HCl- methanol solutions, and adjust the pH value of solution after dissolving to 1, crystallisation by cooling；
(7) crystal for obtaining step (6) is filtered, and obtained solid again with methanol/acetonitrile is recrystallized, finally After filtering, vacuum drying 24h, compound C is obtained.
Further, the preparation method of saturation HCl- methanol solutions is to dry sodium chloride to 41.1g in the step (6) In, the dense H of 18.7ml are added dropwise2SO4, oil bath low-grade fever, produce white cigarette when have HCl gases generation, through dense H2SO4Dry, be passed through 50ml0 In DEG C absolute methanol, weigh, absorb HCl 25g, tail gas is absorbed with water, selection ice bath is to increase methanol absorption HCl to O DEG C Amount.
Further, using compound A, compound C as raw material in the step (1), anhydrous organic solvent, organic base, Nitrogen protective condition issues GCMS computer reaction, obtains precursor compound D.
Further, the active ester used is dicyclohexylcarbodiimide (DCC), 1- (3- dimethylamino-propyls) -3- second Base carbodiimide hydrochloride (EDC), n-hydroxysuccinimide (HOSU), I-hydroxybenzotriazole (HOBt), the nitrogen of O- benzos three Any one in azoles-N, N, N', N'- tetramethylurea tetrafluoro boric acid (TBTU).
Further, organic solvent is DMF, and organic base is N- methylmorpholines (NMM).
Further, synthesis precursor compound D method includes, (1) compound A activation：Compound A is added organic Solvent, stirring and dissolving, N2The mol ratio of the lower addition active ester of protection and organic base, compound A and active ester is 1：0.5~6.5, The mol ratio of compound A and organic base is 1：2.5~12, in N2Under protective condition, the activity of stirring 45min formation yellow transparents Ester solution；
(2) compound C neutralization：Compound C is added into dry DMF, N-methylmorpholine is then added, 40min is stirred, changed The mol ratio of compound C and organic base is 1：1.5~4；
(3) solution for obtaining step (1) is added dropwise in the compound C solution of step (2), compound A and compound C's Mol ratio is 1：2.5~6.5, in -20 DEG C~95 DEG C stirring reaction 18h；
(4) the reaction solution revolving obtained step (3) removes solvent, then adds dichloromethane dissolving thereto, uses quality Concentration is 5% NaOH solution and saturated common salt water washing, anhydrous Na2SO4Organic phase is dried to stay overnight；
(5) by step (4) dried crude product through filtering, revolving obtains crude solid, then divided through column chromatography From purification, separating-purifying uses 200~300 mesh silica gel, and volume ratio is 4.5-7:1:0.05 DCM/MeOH/TEA is used as elution Agent, after purification gained compound rotated, vacuum drying 24h, obtain precursor compound D.
Further, the catalytic hydrogenation is carried out under organic solvent, normal temperature and pressure conditionses.
Further, the catalyst is palladium carbon, and the mass percent of the palladium in palladium carbon is 1%~10%.
Further, the organic solvent is alcohol compound, preferably methanol.
Further, it regard the chelating agent as Radionuclide imaging medicine, radiation treatment medicine, Magnetic Resonance Imaging medicine Part and material and the decorporation medicine of these trivalent metal ions for extracting and developing trivalent metal ion.
Further, the trivalent metal is Al, Fe, Sc, Y and Y isotope86Y、90Y, lanthanide series, group of the lanthanides member Stable isotope, corresponding radio isotope, actinides, the isotope of In, Ga and two kinds of metals of element111In、66Ga、67Ga、68Any one in Ga.
Further, the radio isotope includes177Lu、153Sm、47Sc、149Tb。
The positive effect of the present invention is：The compound that the present invention is obtained has higher to some trivalent metal ions Selectivity and affinity, stable metal complex can be formed therewith, be expected to be used as the decorporation medicine of the metals such as aluminium, iron Thing, because coordination tooth is more, sequestering power is strong, is coordinated mild condition, therefore dosage used is small when forming chelate, reduces decorporation medicine The toxic side effect of thing, simultaneously as left end contains amino, can also be connected with some biological targeting molecules, aobvious as radioactive metal Picture and medicine, Magnetic Resonance Imaging medicine, have broad application prospects, and the method raw material for preparing the compound is easy to get, just Method is easy, easy large-scale promotion.
Brief description of the drawings
Fig. 1 is that the reaction solution Mass Spectrometer Method collection of illustrative plates that step (1) is obtained is carried out when preparing n=4 chelating agent；
Fig. 2 is that the reaction solution Mass Spectrometer Method collection of illustrative plates that step (2) is obtained is carried out when preparing n=4 chelating agent.
Embodiment
The present invention is described in further detail below by specific embodiment.
Embodiment one：A kind of chelating agent that the present invention is provided, its general structure is as follows：
N in structure above is >=0 integer, the chelating agent be by triangle rack-like molecular skeleton of amino tricarboxylic acids, The six tooth chelating agents containing 3- hydroxyl -4- pyridone coordinating groups.
The chelating agent that the present invention is provided, those skilled in the art can use any number of raw material, method according to its general structure Synthesis.This chelating agent that the present invention is provided compensate for defect of the in the market without difunctional sexadentate ligand compound, while its is right The affinity of trivalent metal ion and the ability being connected with biological targeting molecule, cause the chelating agent to have difunctional spy again Property, further increase the possible application of the compound commercially.
Embodiment two：A kind of chelating agent that the present invention is provided, its general structure is as follows：
Further, 2≤n≤5, n preferably takes 2 or 3 or 4 or 5 in the general structure.This quasi-chelate compound n is different, then matches somebody with somebody The brachium of body is different, and brachium can influence its stability in chelating agent and metal-complexing, in theory for brachium it is longer, it is three-dimensional empty Between it is bigger, got over during coordination can coated metal, the metal complex stability of formation is higher, but the methylene base arm for coordinating coordination is difficult Water is dissolved in, the water solubility of chelating agent can be influenceed if n is excessive, brachium is different, the stability constant of correspondence chelating agent and trivalent metal The dissociation constant pKa of logK and chelating agent is also different, and the two parameters are that the two of metal and ligands are weighed in Coordinative Chemistry Individual important parameter, therefore n takes the integer between 2-5, the metal complex stability of formation is high, water-soluble also relatively best, therefore energy Enough most preferably balance coordination stabilities and water solubility.
Its preparation method be the same as Example one, those skilled in the art can use any number of raw material, side according to its general structure Method is synthesized.
Embodiment three：The present invention provide not only the chelating agent with the general structure of embodiment one, additionally provides and contains this The chelate of chelating agent and metal ion, the metal ion is the coordination ratio of trivalent metal ion, chelating agent and metal ion For 1:1, the application for the chelate that chelating agent is constituted with metal ion is shown in Table 1.
3- hydroxyl -4- pyridones are under physiological ph conditions to the affine energy of trivalent metal ion in Hydroxypyridinone homologue Power is most strong, and α hydroxy-ketones contained by such N heterocycle chelating agents for containing three 3- hydroxyl -4- pyridones are the tooth metal-complexings of O-O bis-, Therefore six oxygen atoms can be with trivalent metal ion formation 1:(M is trivalent metal to the neutral compound ML of 1 coordination, and L is to match somebody with somebody Body), this kind of complex is 6 tooth complexs, and this is the key factor for determining metal complex stability.
3- hydroxyls -4- pyridinones chelating agent is compared with existing business chelating agent (EDTA, DTPA, DOTA, DFP), tool Have required ligand concentration it is low (sequestering power it is stronger needed for ligand concentration it is lower, if conversely, sequestering power it is lower needed for ligand concentration Higher, this can increase its toxic side effect for organism, very unfavorable), coordination mild condition is (under physiological pH, normal temperature Completion can be coordinated within 5min, the coordination of such cyclic chelators such as prior art such as DOTA needs high temperature, during heating response Between it is long, be very unfavorable for some bifunctional chelating agents for containing biological targeting molecule), good biocompatibility (with Natural mimosine structure is similar), complexes stability height (by multiple tooth coordination), selectivity height (trivalent metal), blood is clear Except advantages such as fast (metabolism are fast).
The invention also discloses the method for preparing the chelating agent, comprise the following steps：
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, in anhydrous organic solvent DMF, organic base N- methylmorpholines (NMM), O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid (TBTU), nitrogen protective condition Under, the precursor compound D of the chelating agent is synthesized using active ester method, described compound A, C, D general structure are as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation.The catalytic hydrogenation is organic Solvent methanol, hydrogen, palladium carbon obtain the quality of the palladium in the chelating agent, palladium carbon for progress under the normal temperature and pressure conditionses of catalyst Percentage is 1%, and synthetic route sees below synthesis equation, and the n that E represents in end-product chelating agent, E general structures is 2.
The yield of above-mentioned preparation method is 82%.Mass spectrogram as shown in Figure 1 and Figure 2, respectively to step (1), step (2) Sampling carries out Mass Spectrometer Method after reaction, and confirmation obtains compound D and end-product chelating agent.
Example IV：The present invention provide not only the chelating agent with the general structure of embodiment one, additionally provides and contains this The chelate of chelating agent and metal ion, the metal ion is the coordination ratio of trivalent metal ion, chelating agent and metal ion For 1:1, the concrete application of the chelate is shown in Table 1.
The invention also discloses the method for preparing the chelating agent, comprise the following steps：
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, in anhydrous organic solvent DMF, organic base Under N- methylmorpholines (NMM), active ester dicyclohexylcarbodiimide (DCC), nitrogen protective condition, synthesized using active ester method Go out the precursor compound D of the chelating agent, compound A is added into anhydrous organic solvent, stirring and dissolving, the amount added is molten with energy Solution compound A is defined；N2The mol ratio of the lower addition active ester of protection and organic base, compound A and active ester is 1：0.5, chemical combination The mol ratio of thing A and organic base is 1：2.5, the activated ester solution of stirring 45min formation yellow transparents；Compound C is added into nothing Anhydrous water DMF, then adds N-methylmorpholine, stirs 40min, and the mol ratio of compound C and organic base is 1：2.5, by chemical combination Thing A, C are mixed, and compound A and compound C mol ratio is 1：2.5, in -20 DEG C of stirring reaction 18h, reaction solution revolving removes molten Agent, then dichloromethane dissolving is added thereto, it is anhydrous with the NaOH solution and saturated common salt water washing that mass concentration is 5% Na2SO4Organic phase is dried to stay overnight, then through filtering, revolving obtains crude solid, then carry out separating-purifying, separation through column chromatography Purification uses 200~300 mesh silica gel, volume ratio 4.5-7:1:0.05 be DCM/MeOH/TEA as eluent, gained after purification Compound is rotated, and is dried in vacuo 24h, is obtained precursor compound D, described compound A, C, D general structure are as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation, and the catalytic hydrogenation is organic Solvent methanol, hydrogen, palladium carbon obtain the quality of the palladium in the chelating agent, palladium carbon for progress under the normal temperature and pressure conditionses of catalyst Percentage is that the n in 10%, D general structures is 3.
It is 81.0% with the yield of above-mentioned preparation method.
Embodiment five：The present invention provide not only the chelating agent with the general structure of embodiment one, additionally provides and contains this The chelate of chelating agent and metal ion, the metal ion is the coordination ratio of trivalent metal ion, chelating agent and metal ion For 1:1, the concrete application of the chelate is shown in Table 1.
The invention also discloses the method for preparing the chelating agent, comprise the following steps：
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, in anhydrous organic solvent DMF, organic base N- methylmorpholines (NMM), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC), nitrogen protective condition Under, the precursor compound D of the chelating agent is synthesized using active ester method, compound A is added into anhydrous organic solvent, is stirred molten Solution, the amount added is defined by energy dissolved compound A；N2The lower addition active ester of protection and organic base, compound A and active ester Mol ratio is 1：The mol ratio of 6.5, compound A and organic base is 1：12, the Acibenzolar of stirring 45min formation yellow transparents is molten Liquid；Compound C is added into anhydrous dry DMF, N-methylmorpholine is then added, 40min is stirred, compound C and organic base rub You are than being 1：4, compound A, C is mixed, compound A and compound C mol ratio is 1：6.5, in 95 DEG C of stirring reaction 18h, Reaction solution revolving removes solvent, then adds dichloromethane dissolving thereto, is eaten with mass concentration for 5% NaOH solution and saturation Salt water washing, anhydrous Na2SO4Organic phase is dried to stay overnight, then through filtering, revolving obtains crude solid, then carry out through column chromatography Separating-purifying, separating-purifying uses 200~300 mesh silica gel, volume ratio 4.5-7:1:0.05 is that DCM/MeOH/TEA is used as elution Agent, after purification gained compound rotated, vacuum drying 24h, obtain precursor compound D, described compound A, C, D structure Formula is as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation, and the catalytic hydrogenation is organic Solvent methanol, hydrogen, palladium carbon obtain the quality of the palladium in the chelating agent, palladium carbon for progress under the normal temperature and pressure conditionses of catalyst Percentage is that the n in 5%, D general structures is 4.
It is 80.3% with the yield of above-mentioned preparation method.
Embodiment six：The present invention provide not only the chelating agent with the general structure of embodiment one, additionally provides and contains this The chelate of chelating agent and metal ion, the metal ion is the coordination ratio of trivalent metal ion, chelating agent and metal ion For 1:1, the concrete application of the chelate is shown in Table 1.
The invention also discloses the method for preparing the chelating agent, comprise the following steps：
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, in anhydrous organic solvent DMF, organic base Under N- methylmorpholines (NMM), n-hydroxysuccinimide (HOSU), nitrogen protective condition, institute is synthesized using active ester method The precursor compound D of chelating agent is stated, compound A is added into anhydrous organic solvent, stirring and dissolving, the amount added is with can dissolvingization Compound A is defined；N2The mol ratio of the lower addition active ester of protection and organic base, compound A and active ester is 1：3.5, compound A with The mol ratio of organic base is 1：7, the activated ester solution of stirring 45min formation yellow transparents；Compound C is added without anhydrous water DMF, then adds N-methylmorpholine, stirs 40min, and the molal weight ratio of compound C and organic base is 1：1.5, by compound A, C are mixed, and compound A and compound C molal weight ratio is 1：3.5, in 0 DEG C of stirring reaction 18h, reaction solution revolving removes molten Agent, then dichloromethane dissolving is added thereto, it is anhydrous with the NaOH solution and saturated common salt water washing that mass concentration is 5% Na2SO4Organic phase is dried to stay overnight, then through filtering, revolving obtains crude solid, then carry out separating-purifying, separation through column chromatography Purification uses 200~300 mesh silica gel, volume ratio 4.5-7:1:0.05 be DCM/MeOH/TEA as eluent, gained after purification Compound is rotated, and is dried in vacuo 24h, is obtained precursor compound D, described compound A, C, D general structure are as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation, and the catalytic hydrogenation is organic Solvent methanol, hydrogen, palladium carbon obtain the quality of the palladium in the chelating agent, palladium carbon for reaction under the normal temperature and pressure conditionses of catalyst Percentage is that the n in 3%, D general structures is 5.
Compound A is that, using lysine class compound as raw material, first and bromoacetic acid sodium, sodium hydroxide are anti-in the step (1) Should, then be made with hydrochloric acid reaction synthesis.
Lysine class compound is N- ε-benzyloxycarbonyl group -1B in the step (1).
Further, synthesis compound A specific method includes：
(1) bromoacetic acid sodium solution is prepared.Bromoacetic acid and mass concentration are mixed for 2M sodium hydroxide solution and dissolved, Ice bath is cooled to 0 DEG C, obtains that bromoacetic acid sodium solution is standby, and the molal weight ratio of lysine class compound and bromoacetic acid is 1:1.5, Bromoacetic acid is 1 with sodium hydroxide solution mol ratio:1；
(2) lysine class compound is dissolved in mass concentration in 2M sodium hydroxide solutions, be slowly added dropwise under ice bath to In the bromoacetic acid sodium solution of step (1), the mol ratio of lysine class compound and sodium hydroxide solution is 1:2.5, it is anti-at 0 DEG C 2h is answered, then stirring at normal temperature is stayed overnight；
(3) reaction solution for obtaining step (2) water-bath 2h at 35 DEG C, then stirring adds hydrochloric acid solution, cool down, White solid is obtained after filtering, hydrochloric acid solution is equal with the sodium hydroxide solution molal quantity for dissolving lysine；
(4) white solid that step (3) is obtained is dissolved in the sodium hydroxide solution that concentration is 1M, then stirring addition etc. The concentration of amount be 1M hydrochloric acid solution, cooling separate out white solid, by, vacuum drying 24h, obtain compound A.Yield is 79.5%.
In the step (1) compound C be using methyl maltol as raw material, first synthesis with benzyl protection 3- hydroxyls- The compound B of 4- pyridone coordinating groups, compound B react with diamine compounds again, are finally combined with hydrochloric acid, obtain hydrochloric acid The compound C of salt form.
The source of the benzyl is benzyl chloride, and diamine compounds are 1,2- ethylenediamines.
The compound C synthetic methods include：
(1) methyl maltol is added into methanol, stirring fully dissolving；
(2) sodium hydroxide solution that concentration is 7M is added dropwise in the mixed liquor obtained to step (1), benzvl compounds is then added dropwise Thing, heating, back flow reaction is stayed overnight, and the molal weight ratio of methyl maltol and sodium hydroxide solution is 1：0.8, methyl maltol with The molal weight ratio of benzyl compounds is 1：0.8；
(3) the reaction solution revolving obtained step (2) removes solvent, and obtained grease is dissolved in dichloromethane, is used NaOH solution and distillation water washing that mass concentration is 5%, then through anhydrous Na2SO4Dry organic phase to stay overnight, pass through again after staying overnight Filter, revolving, are dried in vacuo 24h, obtain compound B；Yield is 87%；
(4) diamine compounds are dissolved in absolute ethyl alcohol/water mixed solution and fully dissolved, add NaOH solution, oil Bath be heated to 50 DEG C it is standby, the molal weight ratios of compound B and diamine compounds is 1：0.8, absolute ethyl alcohol, water mixed solution The volume ratio 1 of middle absolute ethyl alcohol and water:1, compound B and the molal weight ratio of NaOH solution are 1：0.1；
(5) compound B is dissolved in absolute ethyl alcohol, agitation and dropping enters in the solution that step (4) is obtained, 60~85 DEG C of oil bath Reaction, the reaction time is 8h；
(6) the reaction solution revolving obtained step (5) is removed after ethanol, adds distilled water dissolving, solution is adjusted with HCl PH value is washed to 1, then with dichloromethane, and aqueous phase adjusts pH to 7 with NaOH solution, after being washed through dichloromethane, uses NaOH solution Regulation pH is extracted to 12, then with dichloromethane, retains organic phase, through anhydrous Na2SO4Dry, filter, revolving obtains brown color oil Shape thing, is dissolved in saturation HCl- methanol solutions, and adjust the pH value of solution after dissolving to 1, crystallisation by cooling；
(7) crystal for obtaining step (6) is filtered, and obtained solid again with methanol/acetonitrile is recrystallized, finally After filtering, vacuum drying 24h, compound C is obtained.Yield is 49%.
The preparation method of saturation HCl- methanol solutions is to be dried to 41.1g in sodium chloride in the step (6), is added dropwise 18.7ml dense H2SO4, oil bath low-grade fever, produce white cigarette when have HCl gases generation, through dense H2SO4Dry, be passed through 0 DEG C of 50ml anhydrous In methanol, weighed absorption HCl 25g, and tail gas is absorbed with water.
It is 81.5% to finally give chelating agent yield.
Embodiment seven：The present invention provide not only the chelating agent with the general structure of embodiment one, additionally provides and contains this The chelate of chelating agent and metal ion, the metal ion is the coordination ratio of trivalent metal ion, chelating agent and metal ion For 1:1, the concrete application of the chelate is shown in Table 1.
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, in anhydrous organic solvent DMF, organic base Under N- methylmorpholines (NMM), I-hydroxybenzotriazole (HOBt), nitrogen protective condition, synthesize described using active ester method The precursor compound D of chelating agent, anhydrous organic solvent is added by compound A, stirring and dissolving, and the amount added is can dissolve chemical combination Thing A is defined；N2The mol ratio of the lower addition active ester of protection and organic base, compound A and active ester is 1：3.5, compound A is with having The mol ratio of machine alkali is 1：7, the activated ester solution of stirring 45min formation yellow transparents；Compound C is added into anhydrous dry DMF, Then add N-methylmorpholine, stir 40min, the mol ratio of compound C and organic base is 1：3, compound A, C is mixed, changed Compound A and compound C mol ratio is 1：3.5, in 0 DEG C of stirring reaction 18h, reaction solution revolving removes solvent, then adds thereto Enter dichloromethane dissolving, with the NaOH solution and saturated common salt water washing that mass concentration is 5%, anhydrous Na2SO4Dry organic phase Overnight, then through filtering, revolving obtains crude solid, then carries out separating-purifying through column chromatography, and separating-purifying uses 200~300 Mesh silica gel, volume ratio 4.5-7:1:0.05 be DCM/MeOH/TEA as eluent, gained compound is rotated after purification, very Sky dries 24h, obtains precursor compound D, described compound A, C, D general structure are as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation, and the catalytic hydrogenation is organic Solvent methanol, hydrogen, palladium carbon obtain the quality of the palladium in the chelating agent, palladium carbon for progress under the normal temperature and pressure conditionses of catalyst Percentage is that the n in 3%, D general structures is 5.
Compound A is that, using lysine class compound as raw material, first and bromoacetic acid sodium, sodium hydroxide are anti-in the step (1) Should, then be made with hydrochloric acid reaction synthesis.
Lysine class compound is N- ε-benzyloxycarbonyl group-D-Lys in the step (1).
Further, synthesis compound A specific method includes：
(1) bromoacetic acid sodium solution is prepared, bromoacetic acid and concentration are mixed for 2M sodium hydroxide solution and dissolved, ice bath 0 DEG C is cooled to, bromoacetic acid sodium solution is obtained standby.Lysine class compound and the mol ratio of bromoacetic acid are 1:4, bromoacetic acid and hydrogen Sodium hydroxide solution mol ratio is 1:1；
(2) lysine class compound is dissolved in concentration in 2M sodium hydroxide solutions, to be slowly added dropwise under ice bath to step (1) in bromoacetic acid sodium solution, the mol ratio of lysine class compound and sodium hydroxide solution is 1:6,2h is reacted at 0 DEG C, Then stirring at normal temperature is stayed overnight；
(3) reaction solution for obtaining step (2) water-bath 5h at 55 DEG C, then stirring adds hydrochloric acid solution, cool down, White solid is obtained after filtering, hydrochloric acid solution is equal with the sodium hydroxide solution molal quantity for dissolving lysine；
(4) white solid that step (3) is obtained is dissolved in the sodium hydroxide solution that concentration is 1M, then stirring addition etc. The concentration of amount be 1M hydrochloric acid solution, cooling separate out white solid, by, vacuum drying 24h, obtain compound A.Yield is 79%.
In the step (1) compound C be using methyl maltol as raw material, first synthesis with benzyl protection 3- hydroxyls- The compound B of 4- pyridone coordinating groups, compound B react with diamine compounds again, are finally combined with hydrochloric acid, obtain hydrochloric acid The compound C of salt form.
The source of the benzyl is benzyl chloride, and diamine compounds are 1,2- ethylenediamines.
The compound C synthetic methods include：
(1) methyl maltol is added into methanol, stirring fully dissolving；
(2) sodium hydroxide solution that concentration is 7M is added dropwise in the mixed liquor obtained to step (1), benzvl compounds is then added dropwise Thing, heating, back flow reaction is stayed overnight, and the mol ratio of methyl maltol and sodium hydroxide solution is 1：1.5, methyl maltol and benzyl The mol ratio of compound is 1：2.5；
(3) the reaction solution revolving obtained step (2) removes solvent, and obtained grease is dissolved in dichloromethane, is used NaOH solution and distillation water washing that mass concentration is 5%, then through anhydrous Na2SO4Dry organic phase to stay overnight, pass through again after staying overnight Filter, revolving, are dried in vacuo 24h, obtain compound B；Yield is 87%；
(4) diamine compounds are dissolved in absolute ethyl alcohol/water mixed solution and fully dissolved, add NaOH solution, oil Bath be heated to 50 DEG C it is standby, the mol ratios of compound B and diamine compounds is 1：2.5, nothing in absolute ethyl alcohol, water mixed solution The volume ratio 1 of water-ethanol and water:The mol ratio of 1, compound B and NaOH solution is 1：0.3；
(5) compound B is dissolved in absolute ethyl alcohol, agitation and dropping enters in the solution that step (4) is obtained, 60~85 DEG C of oil bath Reaction, the reaction time is 24h；
(6) the reaction solution revolving obtained step (5) is removed after ethanol, adds distilled water dissolving, solution is adjusted with HCl PH value is washed to 1, then with dichloromethane, and aqueous phase adjusts pH to 7 with NaOH solution, after being washed through dichloromethane, uses NaOH solution Regulation pH is extracted to 12, then with dichloromethane, retains organic phase, through anhydrous Na2SO4Dry, filter, revolving obtains brown color oil Shape thing, is dissolved in saturation HCl- methanol solutions, and adjust the pH value of solution after dissolving to 1, crystallisation by cooling；
(7) crystal for obtaining step (6) is filtered, and obtains yellow solid, again with methanol/acetonitrile is recrystallized, most After filtering, vacuum drying 24h, compound C is obtained.Yield is 49%.
The preparation method of saturation HCl- methanol solutions is to be dried to 41.1g in sodium chloride in the step (6), is added dropwise 18.7ml dense H2SO4, oil bath low-grade fever, produce white cigarette when have HCl gases generation, through dense H2SO4Dry, be passed through 0 DEG C of 50ml anhydrous In methanol, weighed absorption HCl 25g, and tail gas is absorbed with water.
It is 80.5% to finally give chelating agent yield.
Embodiment eight：The present invention provide not only the chelating agent with the general structure of embodiment one, additionally provides and contains this The chelate of chelating agent and metal ion, the metal ion is the coordination ratio of trivalent metal ion, chelating agent and metal ion For 1:1, the concrete application of the chelate is shown in Table 1.
The invention also discloses the method for preparing the chelating agent, comprise the following steps：
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, in anhydrous organic solvent DMF, organic base N- methylmorpholines (NMM), O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid (TBTU), nitrogen protective condition Under, the precursor compound D of the chelating agent is synthesized using active ester method, compound A is added into anhydrous organic solvent, is stirred molten Solution, the amount added is defined by energy dissolved compound A；N2Addition active ester and organic base under atmosphere, compound A and active ester Mol ratio is 1：The mol ratio of 3.5, compound A and organic base is 1：7, the activated ester solution of stirring 45min formation yellow transparents； Compound C is added into anhydrous dry DMF, N-methylmorpholine is then added, 40min, compound C and organic base mol ratio is stirred For 1：3.5, compound A, C is mixed, compound A and compound C mol ratio is 1：3.5, in 0 DEG C of stirring reaction 18h, reaction Liquid revolving removes solvent, then adds dichloromethane dissolving thereto, NaOH solution and saturated aqueous common salt with mass concentration for 5% Washing, anhydrous Na2SO4Organic phase is dried to stay overnight, then through filtering, revolving obtains crude solid, then separated through column chromatography Purification, separating-purifying uses 200~300 mesh silica gel, volume ratio 4.5-7:1:0.05 be DCM/MeOH/TEA as eluent, it is pure Gained compound is rotated after change, is dried in vacuo 24h, is obtained precursor compound D, described compound A, C, D general structure It is as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation, and the catalytic hydrogenation is organic Solvent methanol, hydrogen, palladium carbon obtain the quality of the palladium in the chelating agent, palladium carbon for progress under the normal temperature and pressure conditionses of catalyst Percentage is that the n in 3%, D general structures is 5.
Compound A is that, using lysine class compound as raw material, first and bromoacetic acid sodium, sodium hydroxide are anti-in the step (1) Should, then be made with hydrochloric acid reaction synthesis.
Lysine class compound is N- ε-benzyloxycarbonyl group-DL-Lys in the step (1).
Further, synthesis compound A specific method includes：
(1) bromoacetic acid sodium solution is prepared.Bromoacetic acid and concentration are mixed for 2M sodium hydroxide solution and dissolved, ice bath 0 DEG C is cooled to, bromoacetic acid sodium solution is obtained standby.Lysine class compound and the mol ratio of bromoacetic acid are 1:4, bromoacetic acid and hydrogen Sodium hydroxide solution mol ratio is 1:1；
(2) lysine class compound is dissolved in concentration in 2M sodium hydroxide solutions, to be slowly added dropwise under ice bath to step (1) in bromoacetic acid sodium solution, the mol ratio of lysine class compound and sodium hydroxide solution is 1:4,2h is reacted at 0 DEG C, Then stirring at normal temperature is stayed overnight；
(3) reaction solution for obtaining step (2) water-bath 5h at 55 DEG C, then stirring adds hydrochloric acid solution, cool down, White solid is obtained after filtering, hydrochloric acid solution is equal with the sodium hydroxide solution molal quantity for dissolving lysine；
(4) white solid that step (3) is obtained is dissolved in the sodium hydroxide solution that concentration is 1M, then stirring addition etc. The concentration of amount be 1M hydrochloric acid solution, cooling separate out white solid, by, vacuum drying 24h, obtain compound A.Yield is 79%.
In the step (1) compound C be using methyl maltol as raw material, first synthesis with benzyl protection 3- hydroxyls- The compound B of 4- pyridone coordinating groups, compound B react with diamine compounds again, are finally combined with hydrochloric acid, obtain hydrochloric acid The compound C of salt form.
The source of the benzyl is benzyl chloride, and diamine compounds are 1,3- propane diamine, Putriscine, 1,5- pentanediamine In any one.
The compound C synthetic methods include：
(1) methyl maltol is added into methanol, stirring fully dissolving；
(2) sodium hydroxide solution that concentration is 7M is added dropwise in the mixed liquor obtained to step (1), benzvl compounds is then added dropwise Thing, heating, back flow reaction is stayed overnight, and the mol ratio of methyl maltol and sodium hydroxide solution is 1：1.5, methyl maltol and benzyl The mol ratio of compound is 1：2.5；
(3) the reaction solution revolving obtained step (2) removes solvent, and obtained grease is dissolved in dichloromethane, is used NaOH solution and distillation water washing that mass concentration is 5%, then through anhydrous Na2SO4Dry organic phase to stay overnight, pass through again after staying overnight Filter, revolving, are dried in vacuo 24h, obtain compound B；Yield is 87%；
(4) diamine compounds are dissolved in absolute ethyl alcohol/water mixed solution and fully dissolved, add NaOH solution, oil Bath be heated to 50 DEG C it is standby, the mol ratios of compound B and diamine compounds is 1：2.5, nothing in absolute ethyl alcohol, water mixed solution The volume ratio 1 of water-ethanol and water:The mol ratio of 1, compound B and NaOH solution is 1：0.3；
(5) compound B is dissolved in absolute ethyl alcohol, agitation and dropping enters in the solution that step (4) is obtained, 60~85 DEG C of oil bath Reaction, the reaction time is 24h；
(6) the reaction solution revolving obtained step (5) is removed after ethanol, adds distilled water dissolving, solution is adjusted with HCl PH value is washed to 1, then with dichloromethane, and aqueous phase adjusts pH to 7 with NaOH solution, after being washed through dichloromethane, uses NaOH solution Regulation pH is extracted to 12, then with dichloromethane, retains organic phase, through anhydrous Na2SO4Dry, filter, revolving obtains brown color oil Shape thing, is dissolved in saturation HCl- methanol solutions, and adjust the pH value of solution after dissolving to 1, crystallisation by cooling；
(7) crystal for obtaining step (6) is filtered, and obtains yellow solid, again with methanol/acetonitrile is recrystallized, most After filtering, vacuum drying 24h, compound C is obtained.Yield is 49%.
The preparation method of saturation HCl- methanol solutions is to be dried to 41.1g in sodium chloride in the step (6), is added dropwise 18.7ml dense H2SO4, oil bath low-grade fever, produce white cigarette when have HCl gases generation, through dense H2SO4Dry, be passed through 0 DEG C of 50ml anhydrous In methanol, weighed absorption HCl 25g, and tail gas is absorbed with water.
It is 82% to finally give chelating agent yield.
Embodiment nine：The chelating agent (following E) with the general structure of embodiment one that the present invention is provided, its preparation method Including：
(1) compound A synthesis
5.96g bromoacetic acids are weighed, 2M NaOH solution 21.5ml are added, stirring and dissolving, ice bath is cooled to 0 DEG C.By 6.0g N- ε-benzyloxycarbonyl group -1B is dissolved in 32ml 2M NaOH solutions, and the NaOH being slowly added dropwise under ice bath to bromoacetic acid is molten In liquid.Ice bath is to 2h is reacted at 0 DEG C, and then stirring at normal temperature is stayed overnight.By water-bath 2h at 50 DEG C of reaction solution, then stirring is added 64.3ml 1M HCl solutions, cooled and filtered obtains white solid.White solid is dissolved in 1M NaOH solutions, then stirred The 1M HCl solutions of equivalent are added, cooling separates out white solid, and filtering is dried in vacuo 24h.White solid powder 6.7g is obtained, Yield is 79%.
1H NMR(400MHz,DMSO-d6)δ12.06(s,3H；COOH),7.32(m,5H；PhH),4.98(s,2H； PhCH2), 3.48 (d, J=17.9Hz, 2H；COCH2N),3.30(s,1H；CH2), CHN 2.94 (q, J=6.4Hz, 2H； OCONHCH2CH2),1.31(m,4H；CH2CH2CH2CH2)。
ESI/MS：397.2[M+H]+
(2) compound B synthesis
10.0g methyl maltols are weighed, 100ml methanol, stirring and dissolving is added.12ml 7M NaOH solutions are added dropwise, then 10.6ml benzyl chlorides are added dropwise, heating, back flow reaction is stayed overnight.Reaction solution revolving removes solvent, and obtained grease is dissolved in In 50ml dichloromethane, washed with 5% NaOH solution (3 × 30ml) and distilled water (2 × 30ml), anhydrous Na2SO4Drying has Machine is mutually stayed overnight.Filtering, revolving is dried in vacuo 24h.Yellow oil 15.33g is obtained, yield is 87%.
1H NMR (400MHz, Chloroform-d) δ 7.58 (d, J=5.6Hz, 1H；6-PyH),7.36(m,5H；PhH), 6.34 (d, J=5.6Hz, 1H；5-PyH),5.15(s,2H；CH2Ph),2.08(s,3H；CH3)。
ESI/MS：217.1[M+H]+, 239.1 [M+Na]+
(3) compound C4 synthesis
4.076g Putriscines are weighed, are dissolved in 25ml/50ml absolute ethyl alcohols/aqueous solution, 4ml 2M NaOH are added Solution, oil bath heating is to 50 DEG C.10.0g compounds B is dissolved in 25ml absolute ethyl alcohols, agitation and dropping is into above-mentioned solution, oil 60~65 DEG C of reactions of bath are stayed overnight.Revolving removes ethanol, adds 50ml distilled water, 2M HCl regulations pH value of solution~1, dichloromethane (2 × 25ml) washing, aqueous phase 2M NaOH solutions regulation pH value of solution~7, dichloromethane (4 × 50ml) washing, aqueous phase 2M NaOH solution adjusts pH value of solution~12, dichloromethane (4 × 50ml) extraction, anhydrous Na2SO4Dry organic phase.Filtering, revolving, is obtained To pale tan oil, saturation HCl- methanol solutions are dissolved in pH~1, crystallisation by cooling.Filtering, obtains yellow solid, and methanol/ Acetonitrile is recrystallized.Filtering, is dried in vacuo 24h.Yellow solid powder 5.54g is obtained, yield is 49%.
1H NMR(400MHz,D2O)δ7.46(m,5H；), PhH 7.17 (d, J=7.2Hz, 1H；5-PyH),5.17(s,2H； CH2), Ph 4.30 (t, J=7.6Hz, 2H；CH2), Py 3.03 (t, J=7.6Hz, 2H；NH2CH2(CH2)3Py),2.40(s,3H； CH3),1.85m,2H；(CH2)2CH2CH2Py),1.71(m,2H；CH2CH2(CH2)2Py)。
ESI/MS：287.2[M+H]+
The preparation of saturation HCl- methanol solutions：
Device is connected, has been inspected after air-tightness, has been dried sodium chloride toward the interior 41.1g that adds of three-necked flask, be added dropwise 18.7ml dense H2SO4, oil bath low-grade fever, right-hand member conduit has the generation of HCl gases when having white cigarette, through dense H2SO4Dry, be passed through 50ml 0 In DEG C absolute methanol, weighed absorption HCl 25g, and tail gas is absorbed with water.
(4) compound D4 synthesis
Compound A activation：0.634g compound A are weighed, 20ml dry DMFs, stirring and dissolving, N is added2Added under atmosphere 1.7g TBTU and 0.85ml N-methylmorpholines, N2Protection, the active ester solution of stirring 45min formation yellow transparents.
Compound C4 neutralization：1.7g compound C4 are weighed, 20ml dry DMFs are added, 1.04ml N- methyl is then added Morpholine, stirs 40min.
Yellow reactive ester solution is added dropwise in the compound C4 solution after neutralizing, reaction 18h is stirred at room temperature.Revolving is removed The dissolving of 50ml dichloromethane is added in solvent, crude product, with 5% NaOH solution (3 × 30ml) and saturated aqueous common salt (2 × 30ml) wash, anhydrous Na2SO4 dries organic phase and stayed overnight.Filtering, revolving obtains crude solid, and column chromatography carries out separation and carried It is pure, 200~300 mesh silica gel, DCM/MeOH/TEA (4.5-7:1:0.05v/v/v) as eluent, after purification gained compound Rotated, be dried in vacuo 24h.Light yellow solid powder 0.8g is obtained, yield is 42%.
1H NMR(400MHz,DMSO-d6) δ 7.56 (dd, J=7.5,4.1Hz, 3H；6-PyH),7.33(m,20H；PhH), 6.12 (dd, J=7.5,4.8Hz, 3H；5-PyH),4.98(m,8H；CH2Ph),3.82(m,6H；CH2Py),3.05(m,6H； CONHCH2(CH2)3), Py 2.91 (q, J=6.6Hz, 2H；OCONHCH2CH2),2.14(s,9H；CH3),1.51(m,6H；CONH (CH2)2CH2CH2Py),1.35(m,6H；CONHCH2CH2(CH2)2Py).
MALDI-TOF/MS：1201.6[M+H]+
(5) compound E4 synthesis
0.35g 10%Pb/C are weighed in three-necked flask, vacuum nitrogen gas repeatedly for three times, vacuumizes and is flushed with hydrogen gas repeatedly three It is secondary, 0.583g compounds D4 is dissolved in 30ml methanol, in syringe injection flask, 1atm H2, normal-temperature reaction 18h.Filtering, Revolving, is dried in vacuo 24h.Yellow solid powder 0.318g is obtained, yield is 82%.
1H NMR(400MHz,D2O) δ 7.43 (dd, J=7.1,3.4Hz, 3H；6-PyH), 6.35 (ddd, J=7.1,2.7, 1.1Hz,3H；5-PyH), 3.95 (dt, J=18.1,7.4Hz, 6H；CH2Py),3.22(m,6H；CONHCH2(CH2)3Py), 2.28(m,9H；CH3),1.56(m,6H；CONH(CH2)2CH2CH2Py),1.32(m,6H；CONHCH2CH2(CH2)2Py).
MALDI-TOF/MS：797.7[M+H]+
Chemical equation in above-mentioned synthesis is as follows：
The main application such as table 1 for the chelate that metal ion is constituted with chelating agent in above-described embodiment：
Table 1：Different metal constitutes the application after chelate with this chelating agent
The preferred embodiments of the present invention are the foregoing is only, are not intended to limit the invention, for the skill of this area For art personnel, the present invention can have various modifications and variations.Within the spirit and principles of the invention, that is made any repaiies Change, equivalent substitution, improvement etc., should be included in the scope of the protection.

Claims (10)

1. a kind of chelating agent, it is characterised in that the general structure of the chelating agent is as follows：
The integer that n in structure above is >=0, the chelating agent is by triangle rack-like molecular skeleton of amino tricarboxylic acids, contained Six tooth chelating agents of 3- hydroxyl -4- pyridone coordinating groups.
2. chelating agent according to claim 1, it is characterised in that 2≤n≤5 in the general structure.
3. a kind of chelate, it is characterised in that the chelate includes the chelating agent and metal ion described in claim 1, described Metal ion is trivalent metal ion, and the coordination ratio of chelating agent and metal ion is 1:1.
4. chelate according to claim 3, it is characterised in that the metal ion is Al or Fe.
5. chelate according to claim 3, it is characterised in that the metal ion is Sc, Y and Y isotope86Y、90Any one in Y.
6. chelate according to claim 3, it is characterised in that the metal ion is lanthanide series, lanthanide series Any one in stable isotope, corresponding radio isotope.
7. chelate according to claim 6, it is characterised in that the radio isotope includes177Lu、153Sm、149Tb。
8. chelate according to claim 3, it is characterised in that the metal ion is any one in actinides；
The metal ion can also be In, Ga and the radio isotope of both metals111In、66Ga、67Ga、68In Ga Any one.
9. a kind of method for synthesizing chelating agent described in claim 1, it is characterised in that this method comprises the following steps：
(1) using the compound A containing three hydroxy-acid groups, compound C as raw material, the chelating agent is synthesized using active ester method Precursor compound D, described compound A, C, D general structure is as follows,
Compound A：
Compound C：
Compound D：
(2) the precursor compound D for obtaining step (1) uses catalytic hydrogenation, obtains the chelating agent；
Compound A is, using lysine class compound as raw material, first to be reacted with bromoacetic acid sodium, sodium hydroxide in the step (1), then It is made with hydrochloric acid reaction synthesis；
Lysine class compound is N- ε-benzyloxycarbonyl group -1B, N- ε-benzyloxycarbonyl group-D-Lys in the step (1) Or any one in N- ε-benzyloxycarbonyl group-DL-Lys；
Synthesis compound A specific method includes：
(1) bromoacetic acid sodium solution is prepared, bromoacetic acid is mixed with concentration for 2M sodium hydroxide solution, stirring and dissolving, ice bath is cold But to 0 DEG C, obtain that bromoacetic acid sodium solution is standby, the mol ratio of lysine class compound and bromoacetic acid is 1:1.5~4, bromoacetic acid It is 1 with sodium hydroxide solution mol ratio:1；
(2) lysine class compound is dissolved in concentration in 2M sodium hydroxide solutions, to be slowly added dropwise under ice bath to step (1) In bromoacetic acid sodium solution, the mol ratio of lysine class compound and sodium hydroxide solution is 1:2.5~6,2h is reacted at 0 DEG C, Then stirring at normal temperature is stayed overnight；
(3) reaction solution for obtaining step (2) 2~5h of water-bath at 35 DEG C~55 DEG C, then stirring adds hydrochloric acid solution, White solid is obtained after cooling, filtering, hydrochloric acid solution is equal with the sodium hydroxide solution molal quantity for dissolving lysine；
(4) white solid that step (3) is obtained is dissolved in the sodium hydroxide solution that concentration is 1M, and then stirring adds equivalent Concentration is 1M hydrochloric acid solution, and cooling separates out white solid, and vacuum dried 24h obtains compound A；
Compound C is that, using methyl maltol as raw material, first synthesis carries the 3- hydroxyl -4- pyrroles of benzyl protection in the step (1) The compound B of pyridine ketone coordinating group, compound B react with diamine compounds again, are finally combined with hydrochloric acid, obtain hydrochloride shape The compound C of formula；
The source of the benzyl is benzyl chloride, and diamine compounds are 1,2- ethylenediamines, 1,3- propane diamine, Putriscine, 1, Any one in 5- pentanediamines；
The compound C synthetic methods include：
(1) methyl maltol is added into methanol, stirred, fully dissolving；
(2) sodium hydroxide solution that concentration is 7M is added dropwise in the mixed liquor obtained to step (1), benzyl compounds is then added dropwise, Heating, back flow reaction is stayed overnight, and the mol ratio of methyl maltol and sodium hydroxide solution is 1：0.8~1.5, methyl maltol and benzyl The mol ratio of based compound is 1：0.8~2.5；
(3) reaction solution for obtaining step (2) removes solvent through revolving, and obtained grease is dissolved in dichloromethane, uses matter It is 5% NaOH solution and distillation water washing to measure concentration, then through anhydrous Na2SO4Organic phase is dried to stay overnight, then through filtering, revolving, 24h is dried in vacuo, compound B is obtained；
(4) diamine compounds are dissolved in absolute ethyl alcohol/water mixed solution, fully dissolving, add NaOH solution, oil bath adds Hot to 50 DEG C standby, and the mol ratio of compound B and diamine compounds is 1：0.8~2.5, in absolute ethyl alcohol, water mixed solution The volume ratio 1 of absolute ethyl alcohol and water:The mol ratio of 1, compound B and NaOH solution is 1：0.1~0.3；
(5) compound B is dissolved in absolute ethyl alcohol, agitation and dropping enters in the solution that step (4) is obtained, 60~85 DEG C of oil bath is anti- Should, the reaction time is 8~24h；
(6) after the reaction solution for obtaining step (5) removes ethanol through revolving, distilled water dissolving is added, pH value of solution is adjusted with HCl Value is washed to 1, then with dichloromethane, and aqueous phase adjusts pH to 7 with NaOH solution, after being washed through dichloromethane, is adjusted with NaOH solution Section pH is extracted to 12, then with dichloromethane, retains organic phase, through anhydrous Na2SO4Dry, filter, revolving obtains brown yellow oil Thing, is dissolved in saturation HCl- methanol solutions, and adjust the pH value of solution after dissolving to 1, crystallisation by cooling；
(7) crystal for obtaining step (6) is filtered, and obtained solid again with methanol/acetonitrile is recrystallized, eventually passed After filter, vacuum drying 24h, compound C is obtained；
The preparation method of saturation HCl- methanol solutions is in the step (6)：Dried to 41.1g in sodium chloride, 18.7ml is added dropwise Dense H2SO4, oil bath low-grade fever, produce white cigarette when have HCl gases generation, through dense H2SO4Dry, be passed through in 0 DEG C of absolute methanol of 50ml, Weigh, absorb HCl 25g, tail gas is absorbed with water；
Using compound A, compound C as raw material in the step (1), under anhydrous organic solvent, organic base, nitrogen protective condition Synthetic reaction is carried out, precursor compound D is obtained；
The active ester used is dicyclohexylcarbodiimide (DCC), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochloride Salt (EDC), n-hydroxysuccinimide (HOSU), I-hydroxybenzotriazole (HOBt), O- BTAs-N, N, N', N'- tetra- Any one in MU tetrafluoro boric acid (TBTU)；
Organic solvent is DMF, and organic base is N- methylmorpholines NMM；
Synthesis precursor compound D method includes, (1) compound A activation：Compound A is added into anhydrous organic solvent, stirring Dissolving, N2The mol ratio of the lower addition active ester of protection and organic base, compound A and active ester is 1：0.5~6.5, compound A with The mol ratio of organic base is 1：2.5~12, in N2Under protective condition, the active ester solution of stirring 45min formation yellow transparents；
(2) compound C neutralization：Compound C is added into dry DMF, N-methylmorpholine is then added, 40min, compound is stirred The mol ratio of C and organic base is 1：1.5~4；
(3) solution for obtaining step (1) is added dropwise in the compound C solution of step (2), compound A and compound C mole Than for 1：2.5~6.5, in -20 DEG C~95 DEG C stirring reaction 18h；
(4) reaction solution for obtaining step (3) removes solvent through revolving, then adds dichloromethane dissolving thereto, dense with quality The NaOH solution and saturated common salt water washing for 5% are spent, anhydrous Na is used2SO4Organic phase is dried to stay overnight；
(5) by step (4) dried crude product through filtering, revolving obtains crude solid, then carry through column chromatography progress separation It is pure.Separating-purifying uses 200~300 mesh silica gel, volume ratio 4.5-7:1:0.05 is used as eluent, purifying for DCM/MeOH/TEA Gained compound is rotated afterwards, is dried in vacuo 24h, is obtained precursor compound D；
The catalytic hydrogenation is carried out under organic solvent, hydrogen, normal temperature and pressure conditionses；
The catalyst is that the mass percent of palladium in palladium carbon, palladium carbon is 1%~10%；
The organic solvent is alcohol compound；
The alcohol compound is methanol.
10. the purposes of chelating agent described in a kind of claim 1, it is characterised in that regard the chelating agent as Radionuclide imaging medicine Application；
Using the chelating agent as radiation treatment medicine application；
Using the chelating agent as Magnetic Resonance Imaging medicine application；
The chelating agent is used for extracting and developing trivalent metal ion；
The trivalent metal is Al, Fe, Sc, Y and Y isotope86Y、90Y, the stable isotope of lanthanide series, put accordingly Injectivity isotope, actinides, the radio isotope of In, Ga and both metals111In、66Ga、67Ga、68It is any in Ga It is a kind of；
The radio isotope includes177Lu、153Sm、149Tb。
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CN112915217A (en) * 2021-01-29 2021-06-08 原子高科股份有限公司 Prostate cancer targeted prodrug and synthesis method thereof
CN115420812A (en) * 2022-05-25 2022-12-02 复旦大学附属华山医院 Method for detecting calcitronic acid in urine and application thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484726A (en) * 2018-03-19 2018-09-04 深圳大学 A kind of hepatoma-targeting type ruthenium complex and the preparation method and application thereof
CN108484726B (en) * 2018-03-19 2021-08-03 深圳大学 Liver cancer targeted ruthenium complex and preparation method and application thereof
CN112915217A (en) * 2021-01-29 2021-06-08 原子高科股份有限公司 Prostate cancer targeted prodrug and synthesis method thereof
CN115420812A (en) * 2022-05-25 2022-12-02 复旦大学附属华山医院 Method for detecting calcitronic acid in urine and application thereof
CN115420812B (en) * 2022-05-25 2024-03-19 复旦大学附属华山医院 Method for detecting calcic acid in urine and application thereof
CN116041257A (en) * 2023-02-02 2023-05-02 杭州谱康医学科技有限公司 Metal chelating ligand, preparation method and application thereof

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