CN106674123A - Tritiated metronidazole and preparation method thereof - Google Patents
Tritiated metronidazole and preparation method thereof Download PDFInfo
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- CN106674123A CN106674123A CN201611239674.2A CN201611239674A CN106674123A CN 106674123 A CN106674123 A CN 106674123A CN 201611239674 A CN201611239674 A CN 201611239674A CN 106674123 A CN106674123 A CN 106674123A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
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Abstract
The invention belongs to the field of radioactive isotope labeling preparation, and particularly relates to tritiated metronidazole and a preparation method thereof. The preparation method includes: using 2-methyl-5-nitroimidazole as a raw material to react with N-iodosuccinimide to obtain 4-iodine-2-methyl-5nitroimidazole; under catalysis of palladium carbon, enabling 4-iodine-2-methyl-5nitroimidazole and tritium gas to be in tritium-halogen exchange to generate 4-3H-2-methyl-5-nitroimidazole; enabling 4-3H-2-methyl-5-nitroimidazole to react with ethylene oxide to obtain 4-3H-metronidazole. A synthetic product is purified through a prepared liquid phase to obtain4-3H-metronidazole with high specific activity (22.08Ci/g), high radiochemical purity (greater than or equal to 98%) and high chemical purity (greater than or equal to 98%). The tritiated metronidazole can be used as a radioactive tracer in studying absorption, distribution, metabolism and residue elimination of metronidazole in animal bodies.
Description
Technical field
The invention belongs to radio chemistry tracer synthesis field, and in particular to a kind of tritiated metronidazole and its preparation side
Method.The present invention is marked using radiosiotope tritium to the C4 positions of metronidazole, so as to using radiosiotope tracer method
Study the tracer can in animal body be absorbed, be distributed, metabolism and elimination regularity research with application.
Background technology
Metronidazole (metronidazole, metronidazole) belong to nitre imidazoleses, be mainly used in treat by obligate anaerobe, protozoon and
What the birdss blackhead disease and the infection of pig Serpulina that the infection of the disease that spirochaete infection causes, such as ameba causes caused
Dysentery.It has the advantages that good anti-bacterial effect, safe, economical and practical, is once widely used in veterinary clinic and livestock-raising
In industry.But related toxicologic study shows that it has potential carcinogenecity and mutagenicity, in order to ensure food safety, many states
Family all forbids it is used for food animal with purposes such as anti-stress, promotion growths, only allows to be used as medicine, but in animal
Must not detect in derived food.But metronidazole still suffers from Misuse and abuse phenomenon in actual production, causes it dynamic
Residual in object is exceeded, and the residual in food animal tissue has a strong impact on the health of food safety monitoring and the mankind.
Lack metabolism, residual in animal body to metronidazole in the content of food safety evaluation on toxicology test determination
With the research in terms of elimination.Due to drug metabolism, excretion and remain it is closely bound up with food safety, therefore development radioactive tracer
Method research metronidazole absorbs in animal body, is distributed, the rule of metabolism and excretion, discloses target of the metronidazole in food animal body
Tissue and marker is remained, be to formulate MRL and off-drug period to provide foundation, so as to being the medicine in animal food
In residual monitoring provide scientific method.
Because radiosiotope has sensitivity high as tracer, measuring method is simple and easy to do, can position exactly
And the features such as meet the physiological condition of institute's object of study, be widely used to medicine, to disclose medicine in vivo point
Cloth, metabolism and discharge process.This technology is also that United States food and drag administration (FDA) recommends development medicine disposition to grind
Study carefully prefered method (FDA, 2010).3H or14C passes through H the or C atoms on displacement drug target molecule, to reach tracer study
Purpose.They all belong to mental retardation β emitter, with the requirement simplicity in terms of radioactive shield, waste process and decontamination, determination efficiency
High the features such as (Gu et al, 2010a), be the most frequently used radioactive indicator.Tritiated compound passes through with tritium gas as raw material
Catalysis reduction, tritium-halogen replacement etc. react to prepare tritiated compound.Tracer experiment is being carried out using tritiated compound
When, it has to be noted that the isotope effect of hydrogen, autoradiolysises and the stability problem of tritiated compound under experimental conditions, in the hope of obtaining
Obtain correct experimental result.
The content of the invention
It is an object of the invention to overcome the defect of prior art, there is provided a kind of tritium-labeled metronidazole and its preparation side
Method.Present invention synthesis simultaneously prepares marker site clearly, and specific activity is high and the high tritium-labeled metronidazole of radiochemicsl purity.It is existing
Research shows that imidazole ring is more stable in metabolic process in vivo, and imidazole ring C-4 positions are carried out positioning tritiated can avoid radiation
Property nucleic lose in metabolic process in vivo, be suitable for metronidazole tracer study in animal body.
The technical scheme is that and carry out tritiated, tritiated first nitre in the C-4 positions of metronidazole using tritium halogen exchange process
Azoles structure is as follows：
Inventor's early stage discloses other drugs and carries out tritium-labeled method using tritium halogen exchange process, generally in order to
Tritium source is made full use of as far as possible and the safety of radiolabeled test is considered, synthetic route wishes to be put into tritiated when designing
Final step is realized.Following route is devised for this inventor：With 2- 5-nitro imidazoles as initiation material, in N, N- bis-
The bromo- 2- 5-nitro imidazoles of 4-, Jing under acid condition are obtained in methylformamide solution with the reaction of N- bromo-succinimides
Ethyleneoxide addition reacts, and obtains the bromo- 2- 5-nitro imidazoles of 4-, finally exchanges with tritium gas generation tritium halogen and obtains tritiated
Metronidazole, synthetic route is as follows：
But find in actual building-up process, using second step reaction 4- bromo- 2- 5-nitro imidazoles during the method with
Oxirane cannot be carried out, and by converting various reaction condition such as reaction temperatures, response time, reaction pressure cannot all obtain 4-
Bromo- metronidazole；The iodo- 2- 5-nitro imidazoles of 4- are adopted for raw material, in acid condition addition occurs with oxirane anti-
Should, cannot also obtain the metronidazole of iodo.Analysis reason is likely due to after bromine or iodine is connected on imidazole ring, makes imidazole ring blunt
Change, it is impossible to additive reaction occurs with oxirane.
Inventor, with reference to the synthetic route of metronidazole, has redesigned the conjunction of tritium mark metronidazole on the basis of early-stage Study
Into route.First halogen substiuted is carried out to the H-4 of 2- 5-nitro imidazoles, after the metronidazole of bromine or iodo is obtained, first
After carrying out tritium halogen exchange, tritiated 4- is obtained3H-2- 5-nitro imidazoles, finally again with ethyleneoxide addition, obtain mesh
Mark product.It is the tritium atomic time when what is connected on 4 carbon of 2- 5-nitro imidazoles such as design, ring in acid condition
Oxidative ethane additive reaction is easily carried out.But, due to there is nitro to exist in the structure of nitroimidazole, when the exchange of tritium halogen is carried out
Also agent can be reduced and is reduced into amido.For this purpose, bromine or iodo 2- methyl-5-nitro miaow of the present inventor using aforementioned preparation
Azoles, first using hydrogen-halogen reduction, carries out high-efficient liquid phase analysis yield, from response time, temperature and reaction pressure etc. to reduzate
Aspect is optimized to reaction, finally optimizes a most suitable reduction reaction conditionses, makes reaction both ensure that tritium halogen exchanged complete,
The nitro in nitroimidazole structure is avoided to be reduced again.
The present invention has found during actual experiment, when using bromo 2- 5-nitro imidazoles, optimizes reducing condition
Still there is the side reaction that nitro is reduced afterwards；Even if tritium gas pressure is down to into 30mmHg, still there are most nitros to be reduced
Product.When using iodo 2- 5-nitro imidazoles, under reducing condition after optimization, the by-product that nitro is reduced
Seldom.It is final to determine that synthetic route design is as follows：React with N- N-iodosuccinimides in N,N-dimethylformamide solution
The iodo- 2- 5-nitro imidazoles of 4- are obtained, with palladium carbon (Pd/C) as catalyst, tritium gas dehalogenation is obtained 4-3H-2- methyl -5-
Nitroimidazole, finally obtains tritiated metronidazole with reacting ethylene oxide.Synthetic route is as follows：
A kind of preparation method of tritiated metronidazole is applicant provided, is prepared as follows：
(1) raw material 2- 5-nitro imidazoles, Ran Houjia are added in being furnished with the reaction vessel of thermometer and agitator sum
Enter appropriate DMF, being heated to 40 DEG C makes after material dissolution, be dividedly in some parts N- N-iodosuccinimides, 2- first
The ratio of the amount of base -5- nitroimidazoles and N- N-iodosuccinimide materials is 1:1~1:5, after reacting 5h at 80 DEG C, will react
Liquid is cooled to room temperature, and isopyknic frozen water is added in reactant liquor, is filtrated to get yellow solid, and filter cake is successively with 10% thio sulfur
Acid sodium aqueous solution and the distilled water wash of freezing, filter gained solid ethyl alcohol recrystallization, are vacuum dried to obtain light yellow crystal shape
The iodo- nitroimidazoles of 2- methyl -5 of 4-；
(2) the iodo- 2- 5-nitro imidazoles of 50mg 4- are accurately weighed to be put in 5ml reaction bulbs, adds 2mL methanol to be allowed to
It is completely dissolved, adds 5mg 10%Pd/C, high-purity tritium gas is passed through on tritiated device, adjustment reaction pressure is 30~100mmHg,
React under the conditions of 25~60 DEG C after 15-60min and reclaim tritium gas, be centrifuged off Pd/C, reactant liquor is removed under reduced pressure into methanol, obtain 4
-3H-2- 5-nitro imidazole crude products；
(3) it is 5 that mass concentration is prepared in being furnished with the reaction vessel of thermometer, agitator and airway:1 formic acid/dense
After sulfuric acid solution, the 4- for adding step (2) to obtain in mixed acid solution3H-2- 5-nitro imidazoles, take another two mouthfuls instead
Bottle is answered, appropriate oxirane is added, it is slow constant in reaction vessel with grass tube and previous reaction container UNICOM
Oxirane is passed through, keeps reaction temperature to be 60~100 DEG C, after 8~24h of reaction, appropriate sodium hydroxide is added in reactant liquor
Solution adjusts pH to 7.5~8.5, is extracted three times with ethyl acetate solvent, merges organic faciess, then with after anhydrous sodium sulfate drying
Filter, filtrate decompression is evaporated off after solvent to obtain tritiated metronidazole crude product；
(4) product obtained by step (3) is prepared into liquid phase and (prepares a kind of purifier apparatus that liquid phase is referred to, Yi Zhonggao
Effect liquid phase preparation system) isolated and purified, preparation condition is：10 μm of Venusil XBP-C18 chromatographic columns, 21.5 × 150mm,
Mobile phase adopts volume ratio for 15:85 methanol and deionized water, coutroi velocity is 5.0mL/min, and ultraviolet detection wavelength is
280nm, column temperature is 30 DEG C；The retention time mobile phase composition corresponding with metronidazole is collected, solvent is removed after merging and is obtained product
Tritiated metronidazole sterling.
Preferably：The reaction pressure for controlling tritium gas in step (2) is 50mmHg, and the response time is 20min.
Preferably：The reaction temperature of the tritium gas reduction in step (3) is 25 DEG C.
Preferably：The formic acid in mixed acid system described in step (3) is 5 with the mass ratio of concentrated sulphuric acid：1, instead
Temperature is answered for 80 DEG C, the response time is 12 hours.
Compared with prior art, the present invention has advantage following prominent：
(1) raw material is easy to get：Tritium gas used by the present invention can be provided at home, and other are all common agents and raw material.
(2) technique environmental pollution of the invention is few, it is easy to control, Tritium reaction is carried out in tritiated device, No leakage
Danger, the response time is short, and desirable pressure and reaction temperature are low, and other steps are all synthesis, whole abandoned reagents in micro scope
5mL is less than with raw material.
(3) the target compound tritiated metronidazole radiochemicsl purity and chemical purity obtained by the present invention is high, meets medicine
The requirement of research is disposed in animal body.
(4) the target compound tritiated metronidazole obtained by the present invention mark position is clear and definite, specific activity is high, and labelling
On tritium stablize, the tracer test requirement that medicine is studied in target animals internal metabolism can be met.
Description of the drawings
Fig. 1：It is the structural formula of the tritiated metronidazole of the present invention.
Fig. 2:It is the synthetic route of initial design of the present invention, expected resultss can not be realized in actual implementation process.
Fig. 3 is the synthetic route of present invention optimization.(difference of the two is：Reacting ethylene oxide shown in Fig. 2 front,
It is tritiated rear, and the Tritium reaction shown in Fig. 3, front, reacting ethylene oxide is rear).
Fig. 4：It is the high-efficient liquid phase chromatogram of the tritiated metronidazole of present invention synthesis.
Specific embodiment
The present invention will be further described for following embodiment.These embodiments are served only for that the present invention is further described,
Protection scope of the present invention is not represented, nonessential modification and adjustment that other people make according to the present invention still belong to this
Bright protection domain.
Embodiment 1
(1) 2- 5-nitro imidazoles are sequentially added in being furnished with the reaction vessel of thermometer with agitating device
6.35g, N, N- dimethylformamide 50ml, 40 DEG C of stirring and dissolving raw materials are dividedly in some parts N- N-iodosuccinimide 11.25g, and 80
DEG C reaction 5h after, reactant liquor is cooled to into 20 DEG C, isopyknic frozen water is added in reactant liquor, be filtrated to get yellow solid, filter
Cake successively with 10% sodium thiosulfate solution and the distilled water wash of freezing, filters gained solid ethyl alcohol recrystallization, vacuum
Dry the iodo- nitroimidazoles of 2- methyl -5 of light yellow crystal shape 4-, yield is 65%.
(2) 2- 5-nitro imidazoles are sequentially added in being furnished with the reaction vessel of thermometer with agitating device
6.35g, N, N- dimethylformamide 60ml, 40 DEG C of stirring and dissolving raw materials are dividedly in some parts N- N-iodosuccinimide 16.87g, and 80
DEG C reaction 5h after, reactant liquor is cooled to into 20 DEG C, isopyknic frozen water is added in reactant liquor, be filtrated to get yellow solid, filter
Cake successively with 10% sodium thiosulfate solution and the distilled water wash of freezing, filters gained solid ethyl alcohol recrystallization, vacuum
Dry the iodo- nitroimidazoles of 2- methyl -5 of light yellow crystal shape 4-, yield is 80%.
(3) 2- methyl -5- are sequentially added in being furnished with the reaction vessel of thermometer and Dropping funnel with agitating device
Nitroimidazole 6.35g, N, N- dimethylformamide 60ml, 40 DEG C of stirring and dissolving raw materials are slowly added dropwise bromine 12g, frozen water cooling
After reaction 4h, isopyknic frozen water is added in reactant liquor, be filtrated to get yellow solid, filter cake successively uses 10% sodium thiosulfate
Aqueous solution and freezing distilled water wash, filter gained solid ethyl alcohol recrystallization, be vacuum dried light yellow crystal shape 4- is bromo-
The nitroimidazole of 2- methyl -5, yield is 75%.
Embodiment 2
(1) magneton is sequentially added in 5mL micro-reaction bottles, is subsequently adding the bromo- 2- methyl -5- of 4- of the preparation of embodiment 1
Nitroimidazole 50mg, adds 3mL methanol to be allowed to be completely dissolved, and the palladium carbon (Pd/C) for adding the concentration of 5mg 10% makees catalyst.
Reaction bulb is placed on hydrogenation apparatuss and is passed through high-purity hydrogen, replaced three times, adjustment reaction pressure is 100mmHg, is kept for 25 DEG C and is stirred
Mix reaction 30min.Stopped reaction, centrifugation removes Pd/C, 2- 5-nitro imidazoles, Jing will be obtained after remaining liq evaporated under reduced pressure
HPLC is analyzed, and yield is 47%.
(2) magneton is sequentially added in 5mL micro-reaction bottles, is subsequently adding the bromo- 2- methyl -5- of 4- of the preparation of embodiment 1
Nitroimidazole 50mg, adds 3mL methanol to be allowed to be completely dissolved, and adds the Pd/C of the concentration of 2.5mg 10%.Reaction bulb is placed in
High-purity hydrogen is passed through on hydrogenation apparatuss, is replaced three times, adjustment reaction pressure is 50mmHg, keeps 25 DEG C of stirring reactions 20min.Stop
Only react, centrifugation removes Pd/C, say and obtain after remaining liq evaporated under reduced pressure 2- 5-nitro imidazoles, Jing HPLC are analyzed, and yield is
35%.
(3) magneton is sequentially added in 5mL micro-reaction bottles, is subsequently adding the iodo- 2- methyl -5- of 4- of the preparation of embodiment 1
Nitroimidazole 60mg, adds 3mL methanol to be allowed to be completely dissolved, and adds the Pd/C of 5mg 10%.Reaction bulb is placed in into hydrogenation dress
Put and be passed through high-purity hydrogen, replace three times, adjustment reaction pressure is 50mmHg, keeps 25 DEG C of stirring reactions 20min.Stop anti-
Should, centrifugation removes Pd/C, and 2- 5-nitro imidazoles are obtained after remaining liq evaporated under reduced pressure, and Jing HPLC are analyzed, and yield is 89%.
(4) magneton is sequentially added in 5mL micro-reaction bottles, is subsequently adding the iodo- 2- methyl -5- of 4- of the preparation of embodiment 1
Nitroimidazole 60mg, adds 3mL methanol to be allowed to be completely dissolved, and adds the Pd/C of 5mg 10%.Reaction bulb is placed in into hydrogenation dress
Put and be passed through high-purity hydrogen, replace three times, adjustment reaction pressure is 100mmHg, keeps 25 DEG C of stirring reactions 10min.Stop anti-
Should, centrifugation removes Pd/C, and 2- 5-nitro imidazoles are obtained after remaining liq evaporated under reduced pressure, and Jing HPLC analysis yields are 79%.
(5) magneton is sequentially added in 5mL micro-reaction bottles, is subsequently adding the iodo- 2- methyl -5- of 4- of the preparation of embodiment 1
Nitroimidazole 60mg, adds 3mL methanol to be allowed to be completely dissolved, and adds the Pd/C of 5mg 10%.Reaction bulb is placed in into tritiated dress
Put and be passed through on (tritiated device is commercial products, purchased from RC TRITEC companies of Switzerland) high-purity tritium gas, adjustment reaction pressure is
50mmHg, keeps 25 DEG C of stirring reactions 20min.Stopped reaction, with liquid nitrogen freezing, reclaims remaining tritium gas, thaws under room temperature, centrifugation
Pd/C is removed, 4-3H-2- 5-nitro imidazoles will be obtained after remaining liq evaporated under reduced pressure.
Explanation：As with hydrogenation tritiated device is, the gas difference being simply passed through.Step (1), (2), (3), (4)
It is that condition, the hydrogen of employing are groped in cold test；Step (5) is heat test, is tested using tritium gas
Embodiment 3
(1) formic acid 100mg, concentrated sulphuric acid are separately added in being furnished with the reaction vessel of thermometer, agitator and airway
20mg, is configured to mixed acid solution, and 2- 5-nitro imidazole 25mg are added in mixed acid solution, separately takes two mouthfuls of reaction bulbs,
5ml oxirane, UNICOM's reaction system is added to be slowly introducing oxirane in reaction vessel, after reacting 12h at 80 DEG C,
Appropriate 1M sodium hydroxide solutions are added to adjust pH to 8 in reactant liquor, plus 5ml ethyl acetate solvents are extracted three times, are associated with
Machine phase, is filtered with after anhydrous sodium sulfate drying, and filtrate decompression is evaporated off after solvent to obtain metronidazole 29.5mg, and yield is
88%.
(2) formic acid 75mg, concentrated sulphuric acid are separately added in being furnished with the reaction vessel of thermometer, agitator and airway
15mg, is configured to mixed acid solution, and 2- 5-nitro imidazole 50mg are added in mixed acid solution, separately takes two mouthfuls of reaction bulbs,
5ml oxirane, UNICOM's reaction system is added to be slowly introducing oxirane in reaction vessel, after reacting 12h at 60 DEG C,
Appropriate 1M sodium hydroxide solutions are added to adjust PH to 8 in reactant liquor, plus 5ml ethyl acetate solvents are extracted three times, are associated with
Machine phase, will filter after anhydrous sodium sulfate drying, and filtrate decompression is evaporated off after solvent obtaining metronidazole 50mg, and yield is 75%.
(3) formic acid 100mg, concentrated sulphuric acid are separately added in being furnished with the reaction vessel of thermometer, agitator and airway
20mg, is configured to mixed acid solution, and the 4- prepared in 2 times (5th) items of above-described embodiment is added in mixed acid solution3H-2- methyl-
5- nitroimidazole 25mg, separately take two mouthfuls of reaction bulbs, add 5ml oxirane, UNICOM's reaction system to delay in reaction vessel
Slowly oxirane is passed through, after 80 DEG C of reaction 12h, adds appropriate sodium hydroxide solution granule to adjust pH to 8 in reactant liquor, plus
5ml ethyl acetate solvents are extracted three times, merge organic faciess, are filtered with after anhydrous sodium sulfate drying, and filtrate decompression is evaporated off into solvent
Tritiated metronidazole 29.8mg is obtained afterwards, and yield is 89%.
The same manner as in Example 3, the present embodiment is first to have carried out step (1) and reaction condition is groped in step (2) cold test, so
After carry out (3) heat test.
Embodiment 4
Polishing purification is carried out with preparation efficient liquid phase to the tritiated metronidazole of the gained of embodiment 3, by following technical parameter
And condition：Liquid-phase condition：10 μm of Venusil XBP-C18 chromatographic columns, 21.5 × 150mm, mobile phase adopts volume ratio for 15:85
Methanol and deionized water, coutroi velocity is 5.0mL/min, and ultraviolet detection wavelength is 280nm, and column temperature is 30 DEG C.Collect and retain
The time mobile phase composition corresponding with metronidazole, vacuum distillation removes lyophilization after methanol, obtains high-purity 4- tritium-metronidazole
25.6mgHPLC purity is more than 99%.
In addition to above embodiment, the present invention can also have other embodiment.All employing equivalents or equivalent transformation
Embodiment, all fall within the present invention claimed scope.
Claims (4)
1. a kind of tritium-labeled metronidazole, it is characterised in that chemical constitution is as follows：
2. a kind of preparation method of tritiated metronidazole, it is characterised in that comprise the following steps：
(1) raw material 2- 5-nitro imidazoles are added in being furnished with the reaction vessel of thermometer and agitator, is subsequently adding appropriate
DMF, being heated to 40 DEG C makes after material dissolution, is dividedly in some parts N- N-iodosuccinimides, the 2- first
The ratio of the amount of base -5- nitroimidazoles and N- N-iodosuccinimide materials is 1:1~1:5, reacting liquid temperature is risen to into 80 DEG C,
Stopped reaction after stirring reaction 5h；Question response liquid is cooled to room temperature, and isopyknic frozen water is added in reactant liquor, is filtrated to get Huang
Color solid, filter cake successively with 10% sodium thiosulfate solution and the distilled water wash of freezing, filter obtained by solid ethanol in
60 DEG C of heating for dissolving, filter while hot insoluble matter, and filtrate is placed on 0 DEG C of cooling, treat that yellow crystals are separated out, and crystal are filtered out, true
After being dried in empty drying baker the iodo- 2- 5-nitro imidazoles of light yellow crystal shape 4-, the iodo- 2- methyl-5-nitros miaow of the 4-
The structural formula of azoles is as follows：
(2) the iodo- 2- 5-nitro imidazoles of 50mg 4- are accurately weighed to be put in 5ml reaction bulbs, adds 2mL methanol to be allowed to complete
Dissolving, adds 5mg 10%Pd/C, and high-purity tritium gas is passed through on tritiated device, and adjustment reaction pressure is 30~100mmHg, is reacted
Temperature is 25~60 DEG C, and tritium gas is reclaimed with liquid nitrogen freezing after 10~60min of stirring reaction, is centrifuged off Pd/C, and reactant liquor is subtracted
Pressure is evaporated off methanol, obtains 4-3H-2- 5-nitro imidazole crude products, the 4-3The structural formula of H-2- 5-nitro imidazoles is such as
Shown in lower：
(3) it is 5 that mass concentration is prepared in being furnished with the reaction vessel of thermometer, agitator and airway:1 formic acid/concentrated sulphuric acid
Mixed acid solution after, the 4- obtained by step (2) is added in mixed acid solution3H-2- 5-nitro imidazoles, take another two mouthfuls
Reaction bulb, adds appropriate oxirane, with grass tube and aforesaid reaction vessel UNICOM, is slowly introducing in reaction vessel
Oxirane, the 4-3The ratio of the amount of H-2- 5-nitro imidazoles and oxirane material is 1:10~1:50,60~
After 100 DEG C of reaction 8h, appropriate sodium hydroxide solution adjustment pH to 7.5~8.5 is added in reactant liquor, extracted with ethyl acetate solvent
Take three times, merge organic faciess, filtered with after anhydrous sodium sulfate drying, filtrate decompression is evaporated off after solvent to obtain tritiated first nitre
Azoles crude product；
(4) the tritiated metronidazole crude product obtained by step (3) is isolated and purified with preparation liquid phase, preparation condition is：
Venusil XBP-C18 chromatographic columns, 10 μm, 21.5 × 150mm, mobile phase adopts volume ratio for 15:85 methanol and deionization
Water, flow velocity is 5.0mL/min, and ultraviolet detection wavelength is 280nm, and column temperature is 30 DEG C；Collect retention time corresponding with metronidazole
Mobile phase composition, after merging remove solvent obtain product 4-3H- metronidazoles, the 4-3The structural formula of H- metronidazoles is as described below
3. the preparation method of a kind of tritium-labeled metronidazole according to claim 3, it is characterised in that：Control in step (2)
The reaction pressure of tritium gas processed is 45~60mmHg, and reaction temperature is 20-50 DEG C, and the response time is 15-30min.
4. the preparation method of a kind of tritiated metronidazole according to claim 1, it is characterised in that：Formic acid in mixed acid system
It is 5 with the mass ratio of concentrated sulphuric acid：Isosorbide-5-Nitrae-3The ratio of the amount of H-2- 5-nitro imidazoles and oxirane material is 1:10~
1:20, reaction temperature is 60-80 DEG C.
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| CN108218786A (en) * | 2018-03-23 | 2018-06-29 | 兰亚朝 | Produce the preparation method of metronidazole API |
| CN110171902A (en) * | 2018-05-04 | 2019-08-27 | 武汉武药制药有限公司 | A kind of integrated conduct method of metronidazole waste water |
| CN111574459A (en) * | 2020-05-15 | 2020-08-25 | 石家庄四药有限公司 | Preparation method of metronidazole |
| CN113817003A (en) * | 2021-10-27 | 2021-12-21 | 浙江爱索拓科技有限公司 | Radioactive isotope tritium labeled catalpol and synthetic method thereof |
| CN114075142A (en) * | 2020-10-20 | 2022-02-22 | 上海安谱实验科技股份有限公司 | Metronidazole labeled by stable isotope and synthetic method thereof |
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| CN104529911A (en) * | 2014-12-31 | 2015-04-22 | 华中农业大学 | Method for preparing tritium-labeling aditoprim |
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| US20100331540A1 (en) * | 2008-02-01 | 2010-12-30 | Haruki Shimodaira | Method for producing compound having deuterated aromatic ring or heterocyclic ring |
| CN103570631A (en) * | 2013-11-21 | 2014-02-12 | 华中农业大学 | Preparation method of tritiated diaveridine |
| CN104119281A (en) * | 2014-07-29 | 2014-10-29 | 华中农业大学 | Preparation method of tritium labeled diaveridine |
| CN104529911A (en) * | 2014-12-31 | 2015-04-22 | 华中农业大学 | Method for preparing tritium-labeling aditoprim |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108218786A (en) * | 2018-03-23 | 2018-06-29 | 兰亚朝 | Produce the preparation method of metronidazole API |
| CN110171902A (en) * | 2018-05-04 | 2019-08-27 | 武汉武药制药有限公司 | A kind of integrated conduct method of metronidazole waste water |
| CN110171902B (en) * | 2018-05-04 | 2022-01-11 | 武汉武药制药有限公司 | Comprehensive treatment method of metronidazole wastewater |
| CN111574459A (en) * | 2020-05-15 | 2020-08-25 | 石家庄四药有限公司 | Preparation method of metronidazole |
| CN111574459B (en) * | 2020-05-15 | 2021-05-04 | 石家庄四药有限公司 | Preparation method of metronidazole |
| CN114075142A (en) * | 2020-10-20 | 2022-02-22 | 上海安谱实验科技股份有限公司 | Metronidazole labeled by stable isotope and synthetic method thereof |
| CN113817003A (en) * | 2021-10-27 | 2021-12-21 | 浙江爱索拓科技有限公司 | Radioactive isotope tritium labeled catalpol and synthetic method thereof |
| CN113817003B (en) * | 2021-10-27 | 2023-11-24 | 浙江爱索拓标记医药科技有限公司 | Radioisotope tritium-labeled catalpol and synthesis method thereof |
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