CN102617581A - 58Fe hemin, preparation method and application of 58Fe hemin to study of pharmacokinetics - Google Patents
58Fe hemin, preparation method and application of 58Fe hemin to study of pharmacokinetics Download PDFInfo
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- CN102617581A CN102617581A CN2012100681812A CN201210068181A CN102617581A CN 102617581 A CN102617581 A CN 102617581A CN 2012100681812 A CN2012100681812 A CN 2012100681812A CN 201210068181 A CN201210068181 A CN 201210068181A CN 102617581 A CN102617581 A CN 102617581A
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Abstract
The invention relates to the fields of the synthesis of medicines and pharmacokinetics, in particular to hemin containing stable isotope 58Fe and a method for synthesizing the hemin. The method comprises the following steps of: (a), oxidizing isotope 58Fe powder by using excess diluted hydrochloric acid to generate an isotope ferrous chloride solution, evaporating to remove moisture, and drying under vacuum to prepare an isotope ferrous chloride crystal; (b), reacting the prepared isotope ferrous chloride crystal with acidified protoporphyrin disodium, and controlling the pH value of a system before reaction to be 5 to 7; and (c), evaporating to remove most of reaction solvents, washing, adding an inorganic acid, regulating the pH value of the system to be 1 to 2, performing ultrasound oscillation, standing and performing suction filtration to obtain the 58Fe hemin. The invention provides a high-accuracy and high-sensitivity study method for the study of the intracorporal process of an endogenous substance, namely a core skeleton of the endogenous substance is marked by an isotope marking method, and the intracorporal process of the endogenous substance is studied quantitatively by measuring the content of the marked endogenous substance.
Description
Technical field
The present invention relates to the synthetic and pharmacokinetic studies field of medicine, be specifically related to a kind of stable isotope that contains
58The teichmann's crystals of Fe and compound method thereof.
Background technology
Teichmann's crystals is the stable form of protoheme (iron porphyrin).It is generally acknowledge in the world prevent and treat the most effectively medicine of iron-deficiency anaemia.Its principal feature is that iron-holder is high, and no GI irritation property is easy to human body is absorbed, bioavailability is good, directly is absorbed in gi tract with molecular form behind the entering human body, and uptake rate is very fast, and benefit iron effect is obvious; So a lot of scientific research personnel regard it as substitute prevailing in the market inorganic benefit chalybeate optimal selection.In addition, teichmann's crystals also is widely used in the food service industry, as the additive of numerous food, plays the functional effect of treatment iron-deficiency anaemia.
The method for preparing at present the pure article of teichmann's crystals mainly is from natural animal blood, to extract purifying to obtain teichmann's crystals; Existing before scholar is for the synthetic research report of having made of metalloporphyrin and verivate thereof, but these reports narration is simple fuzzy mostly, lacks rigorously, be difficult to reproduction; Simultaneously, about utilizing the stable isotope of iron
58Fe carries out the experiment of teichmann's crystals synthetic and still is not reported.
In the pharmacokinetic studies field, because iron is the endogenous material of human body, along with the difference of time, fluctuating largely also can appear in the concentration of iron in the blood.So to the iron content medicine; When studying like the benefit iron effect of teichmann's crystals and physiological disposition; How to get rid of the interference of body endogenous iron as far as possible, obtain accurately to reflect the physiological disposition experimental data of exogenous iron, just become the problem that the researchist is concerned about the most.Many scholars also once did this and appeared all trials, but did not find a kind of effective research method so far yet.
Summary of the invention
The invention discloses a kind of utilization
58Teichmann's crystals (I) of Fe synthetic isotope mark and preparation method thereof can be used for this endogenous substance of quantitative examination teichmann's crystals, also provides material base for the physiological disposition of setting up a kind of new other iron content medicines of quantitative examination simultaneously.
Of the present invention with
58The teichmann's crystals of Fe mark, structural formula (I) be as follows:
Of the present invention
58The preparation method of the teichmann's crystals of Fe mark comprises:
A, with isotropic substance
58The Fe powder generates the isotropic substance solution of ferrous chloride with excessive Hydrogen chloride oxidation, and the solution of ferrous chloride rotary evaporation that obtains is flung to moisture, and vacuum-drying makes isotropic substance iron protochloride crystal;
B, with the reaction of the isotropic substance iron protochloride crystal that makes and acidifying protoporphyrin disodium, the control reacting precursor is that pH is 5～7;
C, boil off most of reaction solvent after, washing, adding mineral acid regulation system pH is 1～2, sonic oscillation leaves standstill the back suction filtration, promptly gets.
Aforesaid method also further comprises recrystallization.
Wherein b step reaction temperature is preferred 110 ℃～150 ℃, preferred 0.75～11 hour of reaction times.
Wherein isotropic substance iron protochloride crystal and acidifying protoporphyrin disodium mol ratio are preferred 1.2: 1～20: 1.
The preferred N of the reaction solvent of b step wherein, dinethylformamide.
Wherein protoporphyrin disodium and N, the consumption of dinethylformamide solution preferred 1: 100～1: 200g/ml.
Preferred preparation method comprises:
A is to isotropic substance is housed
58Feed the harsh HCl gas that becomes in the flask of Fe powder and oxygen-free water until the iron powder completely dissolve, obtain
58FeCl
2Solution; With what obtain
58FeCl
2Solution is at N
2Rotary evaporation is flung to solvent in the protection environment, and vacuum-drying 12h makes isotropic substance iron protochloride crystal;
B is with N, and dinethylformamide (DMF) is a solvent, and isotropic substance iron protochloride crystal that makes and acidifying protoporphyrin disodium are carried out complex reaction; It is 5～7 that the preceding hierarchy of control of reaction is slightly acidic pH; With thin-layer chromatography monitoring, treat that the raw material protoporphyrin disappears or when no longer reducing, stopped reaction.
The c reaction finishes to remove most of solvent on the Rotary Evaporators of back, washing, and it is 1～2 that adding mineral acid regulation system pH is strongly-acid pH, and sonic oscillation 30min leaves standstill the back suction filtration, and through recrystallization and column chromatography, purifying obtains the pure article of isotropic substance teichmann's crystals.
Isotropic substance iron protochloride crystalline prepares process among the above-mentioned steps a, and wherein hydrochloric acid preferably generates hydrogen chloride gas by sodium-chlor/ammonium chloride and strong sulfuric acid response and is dissolved in the oxygen-free water and gets; Fling in the dissolving agent process in evaporation, must be with N
2Protect whole process to avoid the ferrous high ferro that is oxidized to.
Protoporphyrin disodium and reaction solvent N among the above-mentioned steps b, the ratio of dinethylformamide is preferably 1: 100～1: 200 (g/ml).The pH of described reacting precursor system should be strict be controlled at 5～7, reflux temperature is 110～150 ℃, the reaction times is 0.75～11h.Acidizing reagent is chosen as concentrated hydrochloric acid or Hydrogen chloride.
Answering hierarchy of control pH value after the washing among the above-mentioned steps c is 1～2, and sonic oscillation is fully to guarantee unnecessary inorganic iron ionic dissolving.The reagent of adjustment of acidity is chosen as concentrated hydrochloric acid.
In order to improve product purity and productive rate, also preferred product with above-mentioned preparation further comprises the product behind the suction filtration through recrystallization and/or column chromatography purification.
Said recrystallization method is with N, and dinethylformamide (DMF) is as solvent recrystallization.Preferred method is that isotropic substance teichmann's crystals bullion is dissolved among the DMF, filters, and filter cake washs with a small amount of DMF, merging filtrate.According to bullion: water: (w: v: ratio w) is dissolved with filtrating being added in the aqueous solution of tensio-active agent zephiran chloride domiphen tensio-active agent=1: 100: 13, is warming up to 90 ℃, stirs 10min.Slowly hydrochloric acid soln to the pH value of solution of dropping 20% is 1～2 in solution.After leaving standstill solution number hour, suction filtration, washing leaching cake be to neutral, drying, both highly purified isotropic substance teichmann's crystals.
Said column chromatography method, purpose are in order to guarantee the abundant recovery of product in the filter cake in the recrystallization process.Get in the recrystallization and to filter last filter cake behind the bullion, fully dissolve sonic oscillation with DMF.Add proper silica gel, underpressure distillation removes and desolvates.This is treated isolating sample transfer to chromatography column, and earlier with methyl alcohol: the eluent of methylene dichloride=1: 50 separates; Constantly change the eluent ratio, adjustment polarity, collect methyl alcohol: the elutriant of methylene dichloride=1: 10, mix concentrating, dry up with nitrogen in 60 ℃ of water-baths.Can obtain the pure article of isotropic substance teichmann's crystals of purity＞96%.
The contriver finds in the research process: secondly the pH value of system when utilizing the difficult point of the synthetic teichmann's crystals of iron isotope mainly to be to control in the reaction process with aftertreatment is the temperature of reacting and the mol ratio of two kinds of reaction raw materials.All about the synthetic report of metalloporphyrin analogue the pH value of reaction system is not all made detailed research before.When the present invention is disclosed in protoporphyrin disodium and inorganic metal reactant salt,, then can suppress the carrying out of complex reaction as if system pH peracid; If the inclined to one side alkali of pH of system, protoporphyrin can form sodium-salt form two again and from solvent DMF, separate out, and inorganic metal salt can become alkali, the solvability reduction; Event needs the pH of guarantee system to be faint acidity, is controlled at 5～7 optimums.Chinese patent CN 1418885A discloses a kind of preparation method of ferriporphyrin sodium salt, crystallization when in its last handling process, only being neutralized to pH=4 with protonic acid.But the present invention discloses, and in last handling process, needs the pH of regulation system to be strongly-acid, with 1～2 the best; If acidity is strong inadequately, then react remaining inorganic metal ion and can be mixed in the product, influence degree of purity of production.
Aspect the temperature of reaction selection, the temperature of before selecting about the synthetic report of metalloporphyrin analogue is≤70 ℃, or narrate ambiguous.Introduce in the compound method of the disclosed metalloporphyrin of Chinese patent CN 1944434A and under coldcondition, react with mixed solvent; The temperature of reaction that provides among the preparation method of the disclosed ferriporphyrin sodium salt of Chinese patent CN 1418885A is 10～70 ℃.But the present invention reacts in single solvent and higher TR, has also obtained the very high product of purity; The TR that the present invention selects is 110～150 ℃, and the temperature of finding reaction affects degree of purity of production with the feed ratio common of raw material.
At present current metalloporphyrin compound method is and drops into excessive inorganic metal salt (be generally protoporphyrin molar weight 3～8 times) to guarantee the abundant reaction of protoporphyrin; In this case, the level of response of this building-up reactions is very complete, and no coupling product generates, and the teichmann's crystals purity that obtains is generally more than 98%.But in this invention, consider the Financial cost of stable isotope iron powder, must guarantee the abundant reaction of inorganic molysite as much as possible, take into account the yield of reaction principal product simultaneously.
Aspect the purification process selection of reactant, the method that the present invention has selected recrystallization to combine with column chromatography, this method can guarantee when obtaining high purity product, farthest to realize the recycling of product.About the method for protoheme recrystallization, forefathers had done a lot of researchs.Classic methods comprises: ice acetic acid method, acid acetone method, alkali extraction and acid precipitation shallow lake method and surfactant method.Before several method because of needing the organic reagent of labor, environment is caused bigger pollution, production unit is had relatively high expectations and to obtain product crystal formation behind the purifying uncertain and do not adopted by the present invention.Aspect surfactant selection, forefathers use Nonoxynol-9 more, tetradecyl betaine, Hydrocerol A or the above several kinds of tensio-active agents that mix and form.The kinds of surfactants that the present invention adopts is the zephiran chloride domiphen, uses the resulting isotropic substance teichmann's crystals of this tensio-active agent crystal purity higher, and regular shape, unanimity are the narrow rhomboid of red-brown.Collect in the recrystallization process and be dissolved in the surplus products in the solution,, collect corresponding elution fraction, can reclaim and obtain highly purified product, realize the maximum purification process of bullion that synthesizes with the method gradient elution of silica gel column chromatography.
This invention is that the physiological disposition research of endogenous material provides a kind of novelty; Split hair caccuracy; Highly sensitive research method; Promptly utilize isotope-labeled method that the core skeleton of endogenous material is partly carried out mark, come its physiological disposition of quantitative examination through the endogenous material content of measuring mark.
Description of drawings
Fig. 1 is
58The mass spectrum of the teichmann's crystals of Fe mark
Fig. 2 is that rat single dose filling stomach gives 40mg/kg
58Plasma Concentration-time curve behind the Fe teichmann's crystals
Embodiment
Embodiment 1
1. take by weighing the 0.240g isotropic substance
58The Fe powder (ISOFLEX USA, San Franciso, No.26-01-58-4030); Be transferred in single neck flask; Add the 25ml oxygen-free water, below single neck bottle liquid level, feed the HCl gas (generating) of harsh one-tenth by sodium-chlor/ammonium chloride and strong sulfuric acid response, oil bath heat until
58The Fe powder thoroughly disappears.Under the nitrogen protection, the moisture in Rotary Evaporators Back stroke dereaction liquid obtains isotropic substance iron protochloride solid; Dry 12h in the vacuum drying oven obtains isotropic substance iron protochloride crystal.
2. having stirrer; Adding 2.0918g protoporphyrin disodium in three mouthfuls of round-bottomed flasks of the 500ml of TM and air reflux exchanger (Tokyo HuaCheng Industry Co., Ltd, the rich island 6-15-9 in North Area, Tokyo, Lot.GG01); With about 220ml DMF is dissolution with solvents; Add the acidifying of 770ul concentrated hydrochloric acid, sonic oscillation fully dissolves, and this moment, system pH was 6～7.The isotropic substance iron protochloride crystal of gained in the step 1 is added in the reaction system, and under agitation controlled temperature is 120 ℃, reaction 11h, and with the shade of thin-layer chromatography point plate monitoring raw material point, the back stopped reaction by the time the color of raw material point no longer shoals.The pH of assaying reaction stop buffer is to guarantee its slightly acidic, and underpressure distillation goes out most of DMF, and cooling adds the cold distilled water flushing of 1200ml.Add the acidifying of 12ml concentrated hydrochloric acid, measuring its pH is 1～2, and sonic oscillation 30min leaves standstill suspension liquid; Suction filtration discards filtrating, and dry back recrystallization obtains the pure article of isotropic substance teichmann's crystals.
3. get isotropic substance teichmann's crystals bullion 2g, fully dissolve stirring with 150ml DMF.Filter, filter cake is with 5ml DMF washing, merging filtrate.In filtrating, add 500ml water and 26g zephiran chloride domiphen, be warming up to 90 ℃, stir 10min.Hydrochloric acid soln to the pH value of solution of dropping 20% is 1～2 in solution.After leaving standstill solution number hour, suction filtration, washing leaching cake be to neutral, drying, both highly purified isotropic substance teichmann's crystals.
4. get and filter last filter cake behind the bullion in the step, fully dissolve sonic oscillation with DMF.Add proper silica gel, underpressure distillation removes and desolvates.This is treated isolating sample transfer to chromatography column, and earlier with methyl alcohol: the eluent of methylene dichloride=1: 50 separates; Constantly change the eluent ratio, adjustment polarity, collect methyl alcohol: the elutriant of methylene dichloride=1: 10, mix concentrating, dry up with nitrogen in 60 ℃ of water-baths.RP-HPLC analyzes, and purity is 96.7%, satisfies the purity requirement of isotropic substance teichmann's crystals.
RP-HPLC：
Hypersil C18 post 4.6mm * 200mm, 20 ℃
Moving phase: methyl alcohol: acetonitrile: water: acetic acid: pyridine=40: 40: 19: 1: 0.6
Flow velocity: 1ml/min
Wavelength: 399nm (UV-detector)
Productive rate: 9.74min (96.7%)
Its mass spectrum is seen Fig. 1, and leading ion peak ownership is explained:
1. m/z 617.132 peaks: [M-Cl]
+
2. m/z 559.194 peaks: [M-Cl-C
2H
3O
2]
+
(3. m/z 499.983 peaks: [M-Cl-C
2H
3O
2-C
2H
3O
2]
+
Embodiment 2
1. take by weighing the 0.8589g isotropic substance
58The Fe powder (ISOFLEX USA, San Franciso, No.26-01-58-4030); Be transferred in single neck flask; Add the 20ml oxygen-free water, below single neck bottle liquid level, feed the HCl gas (generating) of harsh one-tenth by sodium-chlor/ammonium chloride and strong sulfuric acid response, oil bath heat until
58The Fe powder thoroughly disappears.Under the nitrogen protection, the moisture in Rotary Evaporators Back stroke dereaction liquid obtains isotropic substance iron protochloride solid; Dry 12h in the vacuum drying oven obtains isotropic substance iron protochloride crystal.
2. having stirrer; Adding 0.4652g protoporphyrin disodium in three mouthfuls of round-bottomed flasks of the 100ml of TM and air reflux exchanger (Tokyo HuaCheng Industry Co., Ltd, the rich island 6-15-9 in North Area, Tokyo, Lot.GG01); With about 50ml DMF is dissolution with solvents; Add the acidifying of 130ul concentrated hydrochloric acid, sonic oscillation fully dissolves, and this moment, system pH was 5～6.The isotropic substance iron protochloride crystal of gained in the step 1 is added in the reaction system, and under agitation controlled temperature is 110 ℃, reaction 0.75h, and with the shade of thin-layer chromatography point plate monitoring raw material point, the back stopped reaction by the time the color of raw material point no longer shoals.The pH of assaying reaction stop buffer is to guarantee its slightly acidic, and underpressure distillation goes out most of DMF, cooling, and the cold distilled water that adds 600ml washes.Add the acidifying of 10ml concentrated hydrochloric acid, measuring its pH is 1～2, and sonic oscillation 30min leaves standstill suspension liquid; Suction filtration discards filtrating, and dry back recrystallization obtains highly purified isotropic substance teichmann's crystals, analyzes with RP-HPLC, and purity is 98.68%.
RP-HPLC：
Hypersil C18 post 4.6mm * 200mm, 20 ℃
Moving phase: methyl alcohol: acetonitrile: water: acetic acid: pyridine=40: 40: 19: 1: 0.6
Flow velocity: 1ml/min
Wavelength: 399nm (UV-detector)
Productive rate: 9.74min (98.68%)
Embodiment 3
Repeat the process of embodiment 2, change is that the reaction mol ratio of controlling isotropic substance iron powder and protoporphyrin disodium was respectively 1: 10 and 1: 15.Can obtain purity and be respectively 91.89% and 94.85% pure article of isotropic substance teichmann's crystals.
Embodiment 4
Repeat the process of embodiment 2, change is that the temperature of controlling complex reaction is respectively 100 ℃, 110 ℃ and 150 ℃.Can obtain purity and be respectively 90.83%, 93.26% and 95.11% pure article of isotropic substance teichmann's crystals.
Get 6 of cleaning level SD rats, male and female half and half.Get and prepare
58Fe teichmann's crystals solution; Press 40mg/kg dosage gastric infusion; Get blank blood before the administration, get blood 300 μ L in 0.5h, 1h, 1.5h, 2h, 4h, 8h, 15h, 24h and 36h through eyeground vein after the administration and place the eppendorf pipe mixing that has added heparin in advance, rapidly in the centrifugal 5min of 14000rpm; Get blood plasma 150 μ L, preserve for-70 ℃ and supply test.Measure in the plasma sample with icp ms (ICP-MS)
58The concentration of Fe just can obtain giving
58The plasma concentration curve of Fe teichmann's crystals and corresponding pharmacokinetic parameter.The result sees table 1, table 2 and Fig. 2:
ICP-MS (X SERIES 2, Thermo SCIENTIFIC) condition determination: ion source is the ICP source, the concentric spraying gun of adopting quartz glass (0.8mL/m), and the quartzy torch pipe of monolithic devices, the 1.5mm bore sprays.The spraying gun argon flow amount is 0.95L/min.Detecting pattern is the CCT pattern.Detector inert stage voltage is 1830v, and the detector pulses step voltage is 3500v, and radio frequency power is 1200w; Cooling gas flow is 14.3L/min, and the sample lifting capacity is 1mL/min, and the sample lifting time is 40s; Multiplicity is 3 times, selects iron Fe (58) respectively, nickel (58); Chromium Cr (53), germanium Ge (72) is a scan element, scan mode is for jumping peak scanning.
Table 1. rat oral gavage gives 40mg/kg
58Plasma Concentration behind the Fe teichmann's crystals (ng/mL)
Table 2. rat oral gavage gives 40mg/kg
58Pharmacokinetic parameters behind the Fe teichmann's crystals
Claims (8)
- One kind with 58The teichmann's crystals of Fe mark, structural formula (I) be as follows:
- 2. claim 1 58The preparation method of the teichmann's crystals of Fe mark comprises:A, with isotropic substance 58The Fe powder generates the isotropic substance solution of ferrous chloride with excessive Hydrogen chloride oxidation, and the solution of ferrous chloride rotary evaporation that obtains is flung to moisture, and vacuum-drying makes isotropic substance iron protochloride crystal;B, with the reaction of the isotropic substance iron protochloride crystal that makes and acidifying protoporphyrin disodium, the control reacting precursor is that pH is 5～7;C, boil off most of reaction solvent after, washing, adding mineral acid regulation system pH is 1～2, sonic oscillation leaves standstill the back suction filtration, promptly gets.
- 3. the preparation method of claim 2 also comprises the product behind the suction filtration through recrystallization and column chromatography purification.
- 4. the preparation method of claim 2, wherein b step reaction temperature is 110 ℃～150 ℃, the reaction times is 0.75～11 hour.
- 5. the preparation method of claim 2, wherein isotropic substance iron protochloride crystal and acidifying protoporphyrin disodium mol ratio are 1.2: 1～20: 1.
- 6. the preparation method of claim 2, wherein the reaction solvent of b step is N, dinethylformamide.
- 7. the preparation method of claim 6, wherein protoporphyrin disodium and N, the consumption of dinethylformamide solution is 1: 100～1: 200g/ml.
- 8. claim 1 58The teichmann's crystals of Fe mark is used for the purposes of the affinity tag of quantitatively determined medicine internal metabolism process.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102967649A (en) * | 2012-05-24 | 2013-03-13 | 新疆科丽生物技术有限公司 | Application of inductively coupled plasma mass spectrometry in drug testing of hemin |
| CN104478905A (en) * | 2014-12-15 | 2015-04-01 | 江西师范大学 | Novel copper-chloridized hemoglobin organic frame structure with three-dimensional porous flower ball-shaped structure and preparation method thereof |
| CN105267223A (en) * | 2015-10-08 | 2016-01-27 | 中国科学院合肥物质科学研究院 | Plasma procoagulant adjuvant |
| CN110568058A (en) * | 2019-09-27 | 2019-12-13 | 浙江艾摩柯斯环境科技有限公司 | ICP-MS-based method for rapidly determining activity of anammox sludge |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102967649A (en) * | 2012-05-24 | 2013-03-13 | 新疆科丽生物技术有限公司 | Application of inductively coupled plasma mass spectrometry in drug testing of hemin |
| CN104478905A (en) * | 2014-12-15 | 2015-04-01 | 江西师范大学 | Novel copper-chloridized hemoglobin organic frame structure with three-dimensional porous flower ball-shaped structure and preparation method thereof |
| CN105267223A (en) * | 2015-10-08 | 2016-01-27 | 中国科学院合肥物质科学研究院 | Plasma procoagulant adjuvant |
| CN105267223B (en) * | 2015-10-08 | 2018-04-13 | 中国科学院合肥物质科学研究院 | A kind of plasma promotees blood coagulation adjuvant |
| CN110568058A (en) * | 2019-09-27 | 2019-12-13 | 浙江艾摩柯斯环境科技有限公司 | ICP-MS-based method for rapidly determining activity of anammox sludge |
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|---|---|
| CN102617581B (en) | 2013-11-06 |
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