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CN1369499A - Aminophosphonic acid compounds for nuclear medicine and process for their preparation - Google Patents

Aminophosphonic acid compounds for nuclear medicine and process for their preparation Download PDF

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CN1369499A
CN1369499A CN 02113299 CN02113299A CN1369499A CN 1369499 A CN1369499 A CN 1369499A CN 02113299 CN02113299 CN 02113299 CN 02113299 A CN02113299 A CN 02113299A CN 1369499 A CN1369499 A CN 1369499A
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nuclear medicine
acid
ratio
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蒋树斌
罗顺忠
刘国平
蒲满飞
何佳恒
邴文增
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Institute of Nuclear Physics and Chemistry
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Institute of Nuclear Physics and Chemistry
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Abstract

本发明公开了一种用于核医学的氨基膦酸化合物及其制备方法。本发明的制备方法是在装有回流设备、搅拌设备和恒压进样器的在反应容器中加入胺和亚磷酸;控制反应温度,向反应容器中滴加浓酸、甲醛;然后冷却、放置、用水或无水乙醇沉淀出反应产物;本发明的制备的用于核医学的氨基膦酸化合物可以与放射性核素Tc、Re、Sm制成放射性肿瘤治疗药物。采用本发明的方法制备用于核医学的氨基膦酸化合物,其制备过程操作简单,反应条件易于达到,产率高。The present invention discloses an aminophosphonic acid compound for nuclear medicine and a preparation method thereof. The preparation method of the present invention comprises adding amine and phosphorous acid into a reaction container equipped with a reflux device, a stirring device and a constant pressure sample injector; controlling the reaction temperature, dripping concentrated acid and formaldehyde into the reaction container; then cooling, placing, and precipitating the reaction product with water or anhydrous ethanol; the aminophosphonic acid compound for nuclear medicine prepared by the present invention can be made into a radioactive tumor therapeutic drug with radioactive nuclides Tc, Re, and Sm. The aminophosphonic acid compound for nuclear medicine is prepared by the method of the present invention, and the preparation process is simple to operate, the reaction conditions are easy to achieve, and the yield is high.

Description

Be used for aminophosphonic acid compound of nuclear medicine and preparation method thereof
1, technical field
The invention belongs to the synthetic field of organic chemistry, be specifically related to a kind of preparation method who is used for the aminophosphonic acid compound of nuclear medicine.
2, background technology
Because the pollution of environment for human survival and the aging of destruction and population, the sickness rate of malignant tumour and mortality ratio are paid close attention to by common people rising year by year.According to World Health Organization's report, global annual New Development cases of cancer number has 1,000 ten thousand, dead 6,600,000 at present.In following 25 years, 300,000,000 cancer new cases will be arranged, and will have 100,000,000 examples dead.The incidence of metastatic carcinoma of bone is very high, is about 35-40 times of primary bone tumor.Almost the bone transfer can take place in the malignant tumour of any organ.Postmortem confirms that 50% cancer patients shifts with bone, and wherein the bone rate of transform of mammary cancer, lung cancer, prostate cancer is up to 70-85%.Bone tumor is except that its mortality characteristics, and bone pain, pathologic fracture etc. also causes very big misery to patient, therefore, explores with radiopharmaceuticals diagnosis and treatment bone tumor as early as possible, and improving patients ' life quality is highly significant.
Radiopharmaceuticals often exists with the form of radioactive metal and organic ligand formation title complex, and ligand structure usually determines the character of medicine.Existing bone tumor medicine as 153Sm-ethylenediamine tetraacetic methylene phosphonic acid, 186,188The Re-1-hydroxy ethylene diphosphonic acid, 99mThe part of Tc-methylenediphosphonate (MDP) remains further to be optimized and improves to improve the result of treatment of relative medicine.
Adopt the aminophosphonic acid compound that is used for nuclear medicine of ordinary method preparation, reaction conditions requires harsh, and productive rate is low.
3, summary of the invention
The purpose of this invention is to provide a kind of aminophosphonic acid compound and preparation method thereof.The aminophosphonic acid compound that is used for nuclear medicine of the present invention can be made the radioactivity anti-tumor medicine with radionuclide Tc, Re, Sm.
Adopt method preparation of the present invention to be used for the aminophosphonic acid compound of nuclear medicine, preparation process is simple to operate, and reaction conditions is easy to reach, the productive rate height.
The aminophosphonic acid compound that is used for nuclear medicine of the present invention has following general formula (I):
Figure A0211329900041
N=0-3 in the formula, R are HOCH 2-or PO 3H 2-.
Utilize amine, formaldehyde and phosphorous acid prepared in reaction aminophosphonic acid compound in acidic medium.The chemical equation of preparation is as follows:
Aminophosphonic acid compound preparation method of the present invention comprises following reactions steps:
A. adding of refluxing unit, whipping device and constant voltage sampler be housed in reaction vessel
Go into amine and phosphorous acid;
B. control reaction mixture temperature under 40 ℃ of-50 ℃ of conditions, in reaction vessel, drip
Concentrated acid;
C. reaction mixture is heated to 80 ℃-90 ℃, drips formaldehyde, the control reaction mixture
Temperature is at 60 ℃-100 ℃; Continue reaction 1-8 hour then;
D. cool off, placement, water be settled out reaction product, or be settled out reaction with dehydrated alcohol
Product;
E. reaction product water and absolute ethanol washing purifying.
Phosphorous acid required in the reaction can generate with phosphorus trichloride and water effect, and phosphorous acid also can directly be bought by market, and amine, acid, formaldehyde can directly be bought by market.
Among the aminophosphonic acid compound preparation method of the present invention:
Amine is hydroxyethylethylene diamine, triethylene tetramine.
Phosphorous acid (or formaldehyde) is 3-8 with the amount of substance ratio of hydroxyethylethylene diamine, and preferred proportion is 5;
Phosphorous acid (or formaldehyde) is 6-12 with the amount of substance ratio of triethylene tetramine, and preferred proportion is 9;
Acid is hydrochloric acid, hydroiodic acid HI, Hydrogen bromide, and acid is 3-9 with the amount of substance ratio of hydroxyethylethylene diamine, is preferably hydrochloric acid, and the amount of substance ratio is 4;
Acid is 6-12 with the amount of substance ratio of triethylene tetramine, is preferably hydrochloric acid, and the amount of substance ratio is 6;
Temperature of reaction is 60-100 ℃, is preferably 80 ℃;
Reaction times is 1-8h, and the preferred reaction time is 4h.
Nomenclature among the present invention:
Re: the representative element rhenium has or cold all isotropic substances.
186,188Re: representing nucleidic mass is 186 or 188 rhenium radionuclides.
HEDTMP: represent 2-N-hydroxyethylethylene diamine trimethylene phosphonic or its salt.
TTHMP: represent triethylene tetramine six (methylene phosphonic acid) or its salt.
The aminophosphonic acid compound for preparing can directly use.Preserve for some time if desired, also can add alkali and be prepared into corresponding salt.Alkali is sodium hydroxide, potassium hydroxide, ammonia, calcium hydroxide etc. or their aqueous solution, generates corresponding salt and is respectively sodium salt, sylvite, ammonium salt, calcium salt.After aminophosphonic acid compound was made salt, stability made moderate progress, and solubleness obviously improves, and was more suitable for preserving and using.
4, embodiment
Embodiment 1
The synthetic method of HEDTMP
In being housed, 300 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram hydroxyethylethylene diamine, 64 milliliters of concentrated hydrochloric acids, 61 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 61 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 4 hours under 80 ± 5 ℃ of water-baths, left standstill then and was cooled to room temperature.Product is precipitated as yellow jelly with dehydrated alcohol, and isolated yellow jelly dissolves with 80 ℃ of warm water, after the cooling, with dehydrated alcohol precipitation, purifying; So the yellow jelly behind the purifying 5 times cools off after the Freeze Drying Equipment drying treatment is white freeze-drying finished product yield 75% (in amine) again with 80 ℃ of warm water dissolvings.
Embodiment 2
The synthetic method of HEDTMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram hydroxyethylethylene diamine, 80 milliliters of concentrated hydrochloric acids, 80 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 100 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 20 minutes.Mixing solutions reacted 4 hours under 60 ± 5 ℃ of water-baths, left standstill then and was cooled to room temperature.Product is precipitated as yellow jelly with dehydrated alcohol, and isolated yellow jelly dissolves with 80 ℃ of warm water, after the cooling, with dehydrated alcohol precipitation, purifying; So the yellow jelly behind the purifying 5 times cools off after the Freeze Drying Equipment drying treatment is white freeze-drying finished product yield 80% (in amine) again with 80 ℃ of warm water dissolvings.
Embodiment 3
The synthetic method of HEDTMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram hydroxyethylethylene diamine, 120 milliliters of concentrated hydrochloric acids, 65 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 65 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 4 hours under 80 ± 5 ℃ of water-baths, left standstill then and was cooled to room temperature.Product is precipitated as yellow jelly with dehydrated alcohol, and isolated yellow jelly dissolves with 80 ℃ of warm water, after the cooling, with dehydrated alcohol precipitation, purifying; So the yellow jelly behind the purifying 5 times cools off after the Freeze Drying Equipment drying treatment is white freeze-drying finished product yield 85% (in amine) again with 80 ℃ of warm water dissolvings.
Embodiment 4
The synthetic method of HEDTMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram hydroxyethylethylene diamine, 64 milliliters of bromine hydrochloric acid, 61 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 100 ± 5 ℃, slowly drip 61 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 8 hours under 100 ± 5 ℃ of water-baths, left standstill then and was cooled to room temperature.Product is precipitated as yellow jelly with dehydrated alcohol, and isolated yellow jelly dissolves with 80 ℃ of warm water, after the cooling, with dehydrated alcohol precipitation, purifying; So the yellow jelly behind the purifying 5 times cools off after the Freeze Drying Equipment drying treatment is white freeze-drying finished product yield 74% (in amine) again with 80 ℃ of warm water dissolvings.
Embodiment 5
The synthetic method of HEDTMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram hydroxyethylethylene diamine, 64 milliliters of dense acid iodide, 61 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 60 ± 5 ℃, slowly drip 61 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 4 hours under 60 ± 5 ℃ of water-baths, left standstill then and was cooled to room temperature.Product is precipitated as yellow jelly with dehydrated alcohol, and isolated yellow jelly dissolves with 80 ℃ of warm water, after the cooling, with dehydrated alcohol precipitation, purifying; So the yellow jelly behind the purifying 5 times cools off after the Freeze Drying Equipment drying treatment is white freeze-drying finished product yield 5% (in amine) again with 80 ℃ of warm water dissolvings.
Embodiment 6
The synthetic method of TTHMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 36 gram triethylene tetramines, 126 milliliters of concentrated hydrochloric acids, 184 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 184 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 4 hours under 80 ± 5 ℃ of water-baths, and room temperature leaves standstill cooling then.Product is separated out with the white precipitate form, and with the warm water dissolving, cooling is after the Freeze Drying Equipment drying treatment is white freeze-drying finished product after water washing five times, yield 73% (in amine).
Embodiment 6
The synthetic method of TTHMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 36 gram triethylene tetramines, 126 milliliters of concentrated hydrochloric acids, 184 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 100 ± 5 ℃, slowly drip 170 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 1 hour under 100 ± 5 ℃ of water-baths, and room temperature leaves standstill cooling then.Product is separated out with the white precipitate form, and with the warm water dissolving, cooling is after the Freeze Drying Equipment drying treatment is white freeze-drying finished product after water washing five times, yield 73% (in amine).
Embodiment 7
The synthetic method of TTHMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram triethylene tetramines, 126 milliliters of dense bromic acids, 184 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 184 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 4 hours under 80 ± 5 ℃ of water-baths, and room temperature leaves standstill cooling then.Product is separated out with the white precipitate form, and with the warm water dissolving, cooling is after the Freeze Drying Equipment drying treatment is white freeze-drying finished product after water washing five times, yield 76% (in amine).
Embodiment 8
The synthetic method of TTHMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram triethylene tetramines, 126 milliliters of dense acid iodide, 184 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 60 ± 5 ℃, slowly drip 184 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 8 hours under 60 ± 5 ℃ of water-baths, and room temperature leaves standstill cooling then.Product is separated out with the white precipitate form, and with the warm water dissolving, cooling is after the Freeze Drying Equipment drying treatment is white freeze-drying finished product after water washing five times, yield 3% (in amine).
Embodiment 9
The synthetic method of TTHMP
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 36 gram triethylene tetramines, 150 milliliters of concentrated hydrochloric acids, 200 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 200 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 20 minutes.Mixing solutions reacted 2 hours under 90 ± 5 ℃ of water-baths, and room temperature leaves standstill cooling then.Product is separated out with the white precipitate form, and with the warm water dissolving, cooling is after the Freeze Drying Equipment drying treatment is white freeze-drying finished product after water washing five times, yield 75% (in amine).
Embodiment 10
The synthetic method of HEDTMP sodium salt
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram hydroxyethylethylene diamine, 80 milliliters of concentrated hydrochloric acids, 80 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 100 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 20 minutes.Mixing solutions reacted 4 hours under 60 ± 5 ℃ of water-baths, left standstill then and was cooled to room temperature.Product is precipitated as yellow jelly with dehydrated alcohol, and isolated yellow jelly dissolves with 80 ℃ of warm water, after the cooling, with dehydrated alcohol precipitation, purifying; So the NaOH solution 100ml that adds 1.0mol/l of the yellow jelly behind the purifying 5 times makes sodium salt, and cooling is after the Freeze Drying Equipment drying treatment is white freeze-drying finished product, yield 80% (in amine).
Embodiment 11
The synthetic method of TTHMP sylvite
In being housed, 500 milliliters of three-necked bottles of condensing reflux pipe, agitator and constant voltage sampler add 26 gram triethylene tetramines, 126 milliliters of dense bromic acids, 184 gram phosphorous acid, with mixture water-bath under agitation, bath temperature is 80 ± 5 ℃, slowly drip 184 milliliter of 36% formalin by the constant voltage sampler then, dropwised in 15 minutes.Mixing solutions reacted 4 hours under 80 ± 5 ℃ of water-baths, and room temperature leaves standstill cooling then.Product is separated out with the white precipitate form, and the KOH solution 100ml with 1.0mol/l after water washing five times makes potassium salt soln, is white freeze-drying finished product through the Freeze Drying Equipment drying treatment then, yield 76% (in amine).

Claims (12)

1、用于核医学的氨基膦酸化合物，其特征在于具有以下结构通式(I)： 1. An aminophosphonic acid compound for nuclear medicine, characterized in that it has the following general structural formula (I): 式中n＝0-3，R为HOCH2或PO3H2。In the formula, n=0-3, R is HOCH 2 or PO 3 H 2 . 2、根据权利要求1所述的用于核医学的氨基膦酸化合物，其制备方法的特征在于包括如下反应步骤：2. The aminophosphonic acid compound used in nuclear medicine according to claim 1, wherein the preparation method is characterized in that it comprises the following reaction steps: a)在装有回流设备、搅拌设备和恒压进样器的在反应容器中加入a) Add in the reaction vessel equipped with reflux equipment, stirring equipment and constant pressure injector   胺和亚磷酸；Amines and phosphorous acids; b)控制反应混合物温度在40℃-50℃条件下，向反应器中滴加浓b) Control the temperature of the reaction mixture at 40°C-50°C, and add concentrated   酸；Acid; c)反应混合物加热到80℃-90℃后，滴加甲醛；然后继续加热c) After the reaction mixture is heated to 80°C-90°C, add formaldehyde dropwise; then continue heating   控制反应温度在60℃-100℃之间，反应时间为1-8小时；Control the reaction temperature between 60°C and 100°C, and the reaction time is 1-8 hours; d)冷却、放置、用水沉淀出反应产物，或用无水乙醇沉淀出反应d) Cool, place, and precipitate the reaction product with water, or precipitate the reaction with absolute ethanol   产物；product; e)用水或无水乙醇洗涤纯化产物。e) Washing the purified product with water or absolute ethanol. 3、根据权利要求2所述的的用于核医学的氨基膦酸化合物的制备方法，其特征在于：胺采用羟乙基乙二胺或三乙烯四胺。3. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 2, wherein the amine is hydroxyethylethylenediamine or triethylenetetramine. 4、根据权利要求2或3所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：甲醛与胺的物质的量的比为3-12，亚磷酸与胺的物质的量的比为3-12。4. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 2 or 3, characterized in that: the ratio of the amount of formaldehyde to amine is 3-12, and the amount of phosphorous acid to amine is 3-12. The ratio is 3-12. 5、根据权利要求4所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：亚磷酸与羟乙基乙二胺的物质的量的比为3-8；甲醛与羟乙基乙二胺的物质的量的比为3-8。5. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 4, characterized in that: the ratio of phosphorous acid to hydroxyethylethylenediamine is 3-8; formaldehyde to hydroxyethylethylenediamine The ratio of the amount of substances to ethylenediamine is 3-8. 6、根据权利要求5所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：亚磷酸与羟乙基乙二胺的物质的量的比为5；甲醛与羟乙基乙二胺的物质的量的比为5。6. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 5, characterized in that: the ratio of phosphorous acid to hydroxyethylethylenediamine is 5; formaldehyde to hydroxyethylethylenediamine The ratio of the amount of substances of diamine was 5. 7、根据权利要求3或4所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：亚磷酸与三乙烯四胺的物质的量的比为6-12，甲醛与三乙烯四胺的物质的量的比为6-12。7. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 3 or 4, characterized in that: the ratio of phosphorous acid to triethylenetetramine is 6-12, formaldehyde to triethylenetetramine The ratio of the amount of substance of the tetraamine is 6-12. 8、根据权利要求7所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：亚磷酸与三乙烯四胺的物质的量的比为9，甲醛与三乙烯四胺的物质的量的比为9。8. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 7, characterized in that: the ratio of phosphorous acid to triethylenetetramine is 9, and the ratio of formaldehyde to triethylenetetramine is 9. The amount ratio is 9. 9、根据权利要求2所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：反应所用的浓酸为盐酸、氢溴酸、氢碘酸的任一种，酸与胺的物质的量的比3-9。9. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 2, characterized in that: the concentrated acid used in the reaction is any one of hydrochloric acid, hydrobromic acid, and hydroiodic acid, and the difference between the acid and the amine is The ratio of the amount of substance is 3-9. 10、根据权利要求9所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：酸与胺的物质的量比为4，反应温度为85℃，反应时间为4小时。10. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 9, characterized in that: the molar ratio of acid to amine is 4, the reaction temperature is 85°C, and the reaction time is 4 hours. 11、根据权利要求2所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：制备好的氨基膦酸可加入碱制备相应的盐。11. The preparation method of aminophosphonic acid compound used in nuclear medicine according to claim 2, characterized in that: the prepared aminophosphonic acid can be added with alkali to prepare the corresponding salt. 12、根据权利要求11所述的用于核医学的氨基膦酸化合物的制备方法，其特征在于：碱为氢氧化钠、氢氧化钾、氨气、氢氧化钙的任一种。12. The method for preparing aminophosphonic acid compounds used in nuclear medicine according to claim 11, characterized in that the base is any one of sodium hydroxide, potassium hydroxide, ammonia, and calcium hydroxide.
CN 02113299 2002-01-30 2002-01-30 Aminophosphonic acid compounds for nuclear medicine and process for their preparation Pending CN1369499A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101163709B (en) * 2005-01-17 2013-01-02 N.V.索卢蒂亚欧洲公司 Process for the manufacture of aminoalkylene phosphonic acid compounds in the presence of heterogeneous catalysts
CN105017313A (en) * 2015-07-06 2015-11-04 中国工程物理研究院核物理与化学研究所 117mSn-labeled polyaminophosphonic acid system for the treatment of skeletal system diseases
CN105294769A (en) * 2015-07-06 2016-02-03 中国工程物理研究院核物理与化学研究所 99mTc-labeled polyaminophosphonic acid system for imaging of skeletal system diseases
CN106380482A (en) * 2016-08-23 2017-02-08 中国工程物理研究院核物理与化学研究所 A method of purifying triethylene tetraamine hexamethylene phosphonic acid
CN108941186A (en) * 2018-07-18 2018-12-07 武汉瑞景环境修复工程有限公司 Preparation method and reuse method, the method for rehabilitating soil of soil remediation material

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101163709B (en) * 2005-01-17 2013-01-02 N.V.索卢蒂亚欧洲公司 Process for the manufacture of aminoalkylene phosphonic acid compounds in the presence of heterogeneous catalysts
CN105017313A (en) * 2015-07-06 2015-11-04 中国工程物理研究院核物理与化学研究所 117mSn-labeled polyaminophosphonic acid system for the treatment of skeletal system diseases
CN105294769A (en) * 2015-07-06 2016-02-03 中国工程物理研究院核物理与化学研究所 99mTc-labeled polyaminophosphonic acid system for imaging of skeletal system diseases
CN105294769B (en) * 2015-07-06 2018-12-07 中国工程物理研究院核物理与化学研究所 For disease of skeletal system imaging99mMore alpha-amino phosphonate systems of Tc label
CN106380482A (en) * 2016-08-23 2017-02-08 中国工程物理研究院核物理与化学研究所 A method of purifying triethylene tetraamine hexamethylene phosphonic acid
CN106380482B (en) * 2016-08-23 2018-01-09 中国工程物理研究院核物理与化学研究所 The purification process of triethylene tetramine base hexa-methylene phosphonic acids
CN108941186A (en) * 2018-07-18 2018-12-07 武汉瑞景环境修复工程有限公司 Preparation method and reuse method, the method for rehabilitating soil of soil remediation material

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