CN104817494B - A kind of method of one pot process flupirtine maleate - Google Patents
A kind of method of one pot process flupirtine maleate Download PDFInfo
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- CN104817494B CN104817494B CN201510192785.1A CN201510192785A CN104817494B CN 104817494 B CN104817494 B CN 104817494B CN 201510192785 A CN201510192785 A CN 201510192785A CN 104817494 B CN104817494 B CN 104817494B
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- flupirtine maleate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Abstract
The invention discloses a kind of method of one pot process flupirtine maleate; with 2; the nitropyridine of 6 dichloro 3 is starting material; key intermediate 2 is made through ammonolysis; the nitropyridine of 6 diaminourea 3; it is acylated again with 4-Fluorobenzaldehyde condensation, Pd/C catalytic hydrogen reductions, ethyl chloroformate, flupirtine maleate is made into salt in maleic acid; the selected process route of the present invention is simple; it is easy to operate; it is each to walk process without isolation and realize that " one kettle way " is produced; manufacturing cost is effectively reduced, yield and product purity is improved, suitable for industrial scale production.
Description
Technical field
The invention belongs to chemicals preparing technical field, and in particular to a kind of side of one pot process flupirtine maleate
Method.
Background technology
Flupirtine maleate, chemical name：2- amino -3- acyl group ethyoxyl amino -6- to luorobenzyl pyridine maleate, its
Structural formula is： 。
Flupirtine maleate is a kind of central nonopioid analgesic developed by German AWD companies, is triamido pyrrole
Pyridine class compound, its mechanism of action is：Flupirtine maleate is a kind of selection sexual centre K ~+Channel Opener, is had simultaneously
Indirect asparatate（NMDA）Receptor antagonist attribute, G- G-protein linked receptors can be activated and stimulate the potassium of nerve cell from
Subchannel, causes hyperpolarization and the neuronal excitability reduction of neuron membrane so that the neuron membrane of tranquillization stabilize from
And reach analgesic purpose.Its analgesic activity is independent of any central opiate sample material, not by naloxone antagonism, will not induce and appoint
What relies on or is not necessarily to incremental dose to maintain clinical efficacy, and known opiate receptor not to have any compatibility.In addition,
Serotonin receptor antagonist will not also suppress its analgesic effect, to α 1- or α 2- adrenocepters without related compatibility,
There is good tolerance on Clinical practice.
From the point of view of the comprehensive flupirtine maleate synthetic method reported, at present, widely used synthetic route is：With 2,6-
Dichloro-3-nitropyridine is starting material, and key intermediate 2- amino -3- nitro -6- chloropyridines are obtained through ammonolysis, then right through 6
Fluorin benzyl amine replaces, and reduces, acylated, and flupirtine maleate sterling is made into processes such as salt.But preparing key intermediate 2- ammonia
During base -3- nitro -6- chloropyridines, due to ammonolysis agent（Ammonia or ammoniacal liquor）It can not quantify and control, easily excessive response is produced
Raw 2,6- diaminourea -3- nitropyridines are, it is necessary to it be further purified in subsequent step processing and to by 2,6- diaminourea -3-
The process contaminants that nitropyridine is subsequently produced carry out quality control, add the industrial production cost of whole piece route, this is current
Prepare greatest problem present in flupirtine maleate process.
Chinese patent CN201110112934.0 is reported with 2,6- dichloro-3-nitropyridines as raw material, chosen property ammonia
2- amino -3- nitro -6- chloropyridines are solved, then are condensed with 4-Fluorobenzylamine, 2- amino -3- nitro -6- are obtained to fluorobenzylamino
It is acylated after pyridine, hydrogenating reduction with ethyl chloroformate, then with maleic acid into salt.Chinese patent CN201210381705.3,
CN201310292276.7 and CN201410344088.9 are reported using 2- amino -3- nitro -6- chloropyridines finished products as raw material, with
4-Fluorobenzylamine is condensed to yield 2- amino -3- nitro -6- to fluorobenzylamino pyridine, is acylated after reduction with ethyl chloroformate, finally
With maleic acid into salt.
Compare above patent, patent CN201110112934.0, for raw material, is being synthesized with 2,6- dichloro-3-nitropyridines
Excessive response is easy to during this intermediate of 2- amino -3- nitro -6- chloropyridines and produces accessory substance 2,6- diaminourea -3- nitre
Yl pyridines, it is necessary to which the 2- amino -3- nitro -6- chloropyridines obtained to ammonolysis, which carry out purification process, could throw the next step, therefore
Whole piece process route can not possibly accomplish continuous operation.Patent CN201210381705.3, CN201310292276.7 and
CN201410344088.9 is using 2- amino -3- nitro -6- chloropyridines as raw material, although solves and generates impurity 2, and 6- diaminourea -
The problem of 3- nitropyridines, continuous operation can be achieved, but 2- amino -3- nitro -6- chloropyridines obviously compare the chloro- 3- nitre of 2,6- bis-
Yl pyridines are expensive, prepare cost higher.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of method of one pot process flupirtine maleate, entirely
Synthetic mesophase process can operate continuously without purifying, simplify operating process, reduce production cost, improve product quality
With yield, it is adaptable to industrialization generation.
The technical solution adopted by the present invention is：A kind of method of one pot process flupirtine maleate, comprises the following steps：
（1）Ammonia, which is passed through, with 2,6- dichloro-3-nitropyridines for starting material, after being dissolved by heating in fatty alcohol obtains centre through ammonolysis
Body 2,6- diaminourea -3- nitropyridines；（2）Under nitrogen protection, midbody 2,6-diamino -3- nitropyridines with to fluorobenzene first
Aldehyde is condensed, and heating response obtains intermediate 2-amino -3- nitro -6- for 4-8 hours to the sub- picolilamine of fluorobenzene；（3）Toward 2- ammonia
Base -3- nitro -6- then pass to hydrogen, through urging to adding catalyst Pd/C in the fatty alcohol solution of the sub- picolilamine of fluorobenzene
Change and intermediate 2 is obtained after hydro-reduction, 3- diaminourea -6- are to fluorobenzylamino pyridine, or add after catalyst Pd/C, in nitrogen
Ammonium formate is added under gas shielded, heating response obtains intermediate 2 for 10-14 hours, and 3- diaminourea -6- are to fluorobenzylamino pyridine；
（4）Under nitrogen protection, to 2,3- diaminourea -6- in the fatty alcohol solution of fluorobenzylamino pyridine add ethyl chloroformate and
Acid binding agent obtains Flupirtine after carrying out acylation reaction；（5）It will be obtained after the fatty alcohol solution of Flupirtine under nitrogen protection suction filtration
Filtrate, be added in maleic acid fatty alcoholic solution, heating stirring obtains flupirtine maleate with maleic acid after 4-6 hours into salt,
Wherein, 2,6- dichloro-3-nitropyridines：4-Fluorobenzaldehyde：Ethyl chloroformate：Ammonium formate：The mol ratio of maleic acid is 1:1.0~
1.2：1.0~1.2：4~10：1.5 ~ 3.5, the acid binding agent is organic base or inorganic base.
The present invention to be collectively referred to as route as follows：
。
It is preferred that, the fatty alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol or isobutanol.
It is furthermore preferred that the fatty alcohol is ethanol.
It is preferred that, the heating-up temperature is 40 ~ 120 DEG C.
It is furthermore preferred that the heating-up temperature is the reflux temperature of aliphatic alcohol solvent used.
It is preferred that, the weight ratio of 2, the 6- dichloro-3-nitropyridines and catalyst Pd/C is 1:0.01~0.1.
It is preferred that, the catalyst Pd/C is 10%Pd/C.
It is preferred that, the organic base is trimethylamine, triethylamine, DIPEA, ethylenediamine or pyridine, inorganic base
For sodium acid carbonate, sodium carbonate, saleratus or potassium carbonate.
It is furthermore preferred that the acid binding agent is triethylamine.
Beneficial effects of the present invention：A kind of method for one pot process flupirtine maleate that the present invention is provided, is realized complete
Process " one kettle way " is synthesized.This method allows 2,6- dichloro-3-nitropyridine excessive responses, is fully converted into 2,6- diaminourea -3-
Nitropyridine, is that key intermediate directly carries out the next step with 2,6- diaminourea -3- nitropyridines, so instant invention overcomes
The impurity 2 produced in existing process, harmful effect of the 6- diaminourea -3- nitropyridines to subsequent step, overcomes step-by-step processing
The intermediate 2 brought, the problems such as 3- diaminourea -6- are to fluorobenzylamino pyridine and Flupirtine easy oxidation discoloration is realized also
Former schiff bases and reduction nitro one step are completed, and by ammonolysis, condensation, reduction, acylation, into steps such as salt are integrated into continuous operation,
Each step intermediate without isolation process and realize that " one kettle way " is produced so that whole route pilot process, can be continuous without purifying
Operation, simplifies operating process, reduces production cost, improve product quality and yield, it is adaptable to industrialization generation.
Embodiment
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Embodiment 1：
2,6- dichloro-3-nitropyridines (5kg, 25.9mol) are added in the reactor equipped with 50L methanol, at 50-60 DEG C
Stirring to it is complete it is molten after, be passed through ammonia and react 10 hours, TLC monitoring raw material reactions stop reaction completely, generate yellow suspension.
Question response is cooled to room temperature, is passed through into reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, slowly
4-Fluorobenzaldehyde is added dropwise（3.5kg, 28.5mol）, back flow reaction about 8 hours, TLC monitoring raw materials reaction i.e. stopping reaction completely.
Question response liquid is cooled to room temperature, adds 10% Pd/C 400g, is passed through 25 DEG C of hydrogen and reacts 20 hours, TLC monitoring raw material reactions
Stop reaction completely.Under nitrogen protection, ethyl chloroformate is added dropwise（3.1kg, 28.5mol）And triethylamine（3.9kg,
38.8mol）, react 4 hours at 25 DEG C, TLC monitoring raw material reactions stop reaction completely.Filtered under nitrogen, filtrate adds
To 50L maleic acid（4.5kg, 38.8mol）In methanol solution, dissolving 4 hours is heated to reflux, cooling stirring cooling crystallization obtains class
White solid, is dried in vacuo at 35 DEG C, and net weight 6.7kg, yield 61.3% detects that product purity is 97.4% through HPLC.
Embodiment 2：
2,6- dichloro-3-nitropyridines (5kg, 25.9mol) are added in the reactor equipped with 40L ethanol, at 50-60 DEG C
Stirring to it is complete it is molten after, be passed through ammonia and react 8 hours, TLC monitoring raw material reactions stop reaction completely, generate yellow suspension.
Question response is cooled to room temperature, is passed through in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, is added dropwise into reaction solution
4-Fluorobenzaldehyde（3.8kg, 31.1mol）, back flow reaction about 4 hours, TLC monitoring raw materials reaction i.e. stopping reaction completely.Treat anti-
Answer liquid to be cooled to room temperature, add 10% Pd/C 500g and ammonium formate 9.8kg, nitrogen protection is lower to continue heating reflux reaction about 14
Hour, TLC monitoring raw material reactions stop reaction completely.Question response liquid is cooled to room temperature, under nitrogen protection, and chloro-carbonic acid is added dropwise
Ethyl ester（3.4kg, 31.1mol）And N, N- diisopropylethylamine（4.7kg, 36.3mol）, react 2 hours at 25 DEG C, TLC monitorings
Raw material reaction stops reaction completely.Filtered under nitrogen, filtrate is added to 40L maleic acid（4.5kg, 38.8mol）Ethanol
In solution, dissolving 2 hours is heated to reflux, cooling stirring cooling crystallization is obtained to be dried in vacuo at off-white powder, 35 DEG C, net weight
8.4kg, yield 76.4%, is detected through HPLC, and product purity is 96.5%.
Embodiment 3：
2,6- dichloro-3-nitropyridines (5kg, 25.9mol) are added in the reactor equipped with 60L isopropanols, 50-60 DEG C
Lower stirring to it is complete it is molten after, be passed through ammonia and react 8 hours, TLC monitoring raw material reactions stop reaction completely, and generation yellow is suspended
Liquid.Question response is cooled to room temperature, is passed through into reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection,
4-Fluorobenzaldehyde is added dropwise（3.5kg, 28.5mol）, back flow reaction about 5 hours, TLC monitoring raw materials reaction i.e. stopping reaction completely.
Question response liquid is cooled to room temperature, adds 10% Pd/C 450g and ammonium formate 9.6kg, and nitrogen protection is lower to continue heating reflux reaction
About 14 hours, TLC monitoring raw material reactions stopped reaction completely.Question response liquid is cooled to room temperature, under nitrogen protection, and chlorine is added dropwise
Ethyl formate（3.1kg, 28.5mol）And triethylamine（3.9kg, 38.8mol）, react 4 hours at 25 DEG C, TLC monitoring raw materials are anti-
Should be to stop reaction completely.Filtered under nitrogen, filtrate is added to 50L maleic acid（4.5kg, 38.8mol）Aqueous isopropanol
In, dissolving 2 hours is heated to reflux, cooling stirring cooling crystallization is obtained to be dried in vacuo at off-white powder, 35 DEG C, and net weight 8.6kg is received
Rate 78.2%, is detected through HPLC, and product purity is 95.2%.
Embodiment 4：
2,6- dichloro-3-nitropyridines (5kg, 25.9mol) are added in the reactor equipped with 40L ethanol, at 50-60 DEG C
Stirring to it is complete it is molten after, be passed through ammonia and react 8 hours, TLC monitoring raw material reactions stop reaction completely, generate yellow suspension.
Question response is cooled to room temperature, is passed through in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, is added dropwise into reaction solution
4-Fluorobenzaldehyde（3.5kg, 28.5mol）, back flow reaction about 4 hours, TLC monitoring raw materials reaction i.e. stopping reaction completely.Treat anti-
Answer liquid to be cooled to room temperature, add 10% Pd/C 500g and ammonium formate 9.8kg, nitrogen protection is lower to continue heating reflux reaction about 14
Hour, TLC monitoring raw material reactions stop reaction completely.Question response liquid is cooled to room temperature, adds sodium carbonate（4.1kg,
38.9mol）, then under nitrogen protection, ethyl chloroformate is added dropwise（3.1kg, 28.5mol）, react 6 hours at 25 DEG C, TLC prisons
Survey raw material reaction and stop reaction completely.Filtered under nitrogen, filtrate is added to 50L maleic acid（4.5kg, 38.8mol）Second
In alcoholic solution, dissolving 2 hours is heated to reflux, cooling stirring cooling crystallization is obtained to be dried in vacuo at off-white powder, 35 DEG C, net weight
7.5kg, yield 68.7%, is detected through HPLC, and product purity is 96.1%.
Embodiment 5：
2,6- dichloro-3-nitropyridines (5kg, 25.9mol) are added in the reactor equipped with 50L ethanol, at 50-60 DEG C
Stirring to it is complete it is molten after, be passed through ammonia and react 8 hours, TLC monitoring raw material reactions stop reaction completely, generate yellow suspension.
Question response is cooled to room temperature, is passed through in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, is added dropwise into reaction solution
4-Fluorobenzaldehyde（3.2kg, 25.9mol）, back flow reaction about 4 hours, TLC monitoring raw materials reaction i.e. stopping reaction completely.Treat anti-
Answer liquid to be cooled to room temperature, add 10% Pd/C 50g and ammonium formate 6.5kg, nitrogen protection is lower to continue heating reflux reaction about 14
Hour, TLC monitoring raw material reactions stop reaction completely.Question response liquid is cooled to room temperature, adds sodium carbonate（3.7kg,
35.4mol）, then under nitrogen protection, ethyl chloroformate is added dropwise（2.8kg, 25.9mol）, react 6 hours at 25 DEG C, TLC prisons
Survey raw material reaction and stop reaction completely.Filtered under nitrogen, filtrate is added to 40L maleic acid（6.0kg, 51.8mol）Second
In alcoholic solution, dissolving 2 hours is heated to reflux, cooling stirring cooling crystallization is obtained to be dried in vacuo at off-white powder, 35 DEG C, net weight
7.6kg, yield 70%, is detected through HPLC, and product purity is 96.3%.
Embodiment 6：
2,6- dichloro-3-nitropyridines (5kg, 25.9mol) are added in the reactor equipped with 60L isopropanols, 50-60 DEG C
Lower stirring to it is complete it is molten after, be passed through ammonia and react 8 hours, TLC monitoring raw material reactions stop reaction completely, and generation yellow is suspended
Liquid.Question response is cooled to room temperature, is passed through into reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection,
4-Fluorobenzaldehyde is added dropwise（3.5kg, 28.5mol）, back flow reaction about 5 hours, TLC monitoring raw materials reaction i.e. stopping reaction completely.
Question response liquid is cooled to room temperature, adds 10% Pd/C 500g and ammonium formate 16.3kg, continues to be heated to reflux instead under nitrogen protection
Should be about 14 hours, TLC monitoring raw material reactions stop reaction completely.Question response liquid is cooled to room temperature, under nitrogen protection, is added dropwise
Ethyl chloroformate（3.1kg, 28.5mol）And triethylamine（3.9kg, 38.8mol）, react 4 hours at 25 DEG C, TLC monitoring raw materials
Reaction stops reaction completely.Filtered under nitrogen, filtrate is added to 60L maleic acid（10.5kg, 90.7mol）Isopropanol is molten
In liquid, dissolving 2 hours is heated to reflux, cooling stirring cooling crystallization is obtained to be dried in vacuo at off-white powder, 35 DEG C, net weight 8.2kg,
Yield 75%, is detected through HPLC, and product purity is 95.3%.
Claims (9)
1. a kind of method of one pot process flupirtine maleate, it is characterised in that：Comprise the following steps：（1）It is chloro- with 2,6- bis-
3- nitropyridines be starting material, in fatty alcohol dissolve by heating after be passed through ammonia through ammonolysis obtain midbody 2,6-diamino-
3- nitropyridines；（2）Under nitrogen protection, midbody 2,6-diamino -3- nitropyridines are condensed with 4-Fluorobenzaldehyde, and heating is anti-
Answer and obtain within 4-8 hours intermediate 2-amino -3- nitro -6- to the sub- picolilamine of fluorobenzene；（3）Past -6- pairs of 2- amino -3- nitros
Catalyst Pd/C is added in the fatty alcohol solution of fluorobenzene Asia picolilamine, hydrogen is then passed to, after catalytic hydrogen reduction
To intermediate 2,3- diaminourea -6- are to fluorobenzylamino pyridine, or add after catalyst Pd/C, and first is added under nitrogen protection
Sour ammonium, heating response obtains intermediate 2 for 10-14 hours, and 3- diaminourea -6- are to fluorobenzylamino pyridine；（4）In nitrogen protection
Under, carry out acyl to adding ethyl chloroformate and acid binding agent in the fatty alcohol solution of fluorobenzylamino pyridine to 2,3- diaminourea -6-
Flupirtine is obtained after changing reaction；（5）The filtrate that will be obtained after the fatty alcohol solution of Flupirtine under nitrogen protection suction filtration, is added to horse
Come in sour fatty alcohol solution, heating stirring obtains flupirtine maleate with maleic acid after 4-6 hours into salt, wherein, 2,6- bis- is chloro-
3- nitropyridines：4-Fluorobenzaldehyde：Ethyl chloroformate：Ammonium formate：The mol ratio of maleic acid is 1:1.0~1.2：1.0~1.2：4~
10：1.5 ~ 3.5, the acid binding agent is organic base or inorganic base.
2. a kind of method of one pot process flupirtine maleate according to claim 1, it is characterised in that：The fat
Alcohol is methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol or isobutanol.
3. a kind of method of one pot process flupirtine maleate according to claim 2, it is characterised in that：The fat
Alcohol is ethanol.
4. a kind of method of one pot process flupirtine maleate according to claim 1, it is characterised in that：The heating
Temperature is 40 ~ 120 DEG C.
5. a kind of method of one pot process flupirtine maleate according to claim 1 or 4, it is characterised in that：It is described
Heating-up temperature is the reflux temperature of aliphatic alcohol solvent used.
6. a kind of method of one pot process flupirtine maleate according to claim 1, it is characterised in that：Described 2,6-
Dichloro-3-nitropyridine and catalyst Pd/C weight ratio are 1:0.01~0.1.
7. a kind of method of one pot process flupirtine maleate according to claim 1, it is characterised in that：The catalysis
Agent Pd/C is 10%Pd/C.
8. a kind of method of one pot process flupirtine maleate according to claim 1, it is characterised in that：It is described organic
Alkali is trimethylamine, triethylamine, DIPEA, ethylenediamine or pyridine, and inorganic base is sodium acid carbonate, sodium carbonate, carbonic acid
Hydrogen potassium or potassium carbonate.
9. a kind of method of one pot process flupirtine maleate according to claim 1, it is characterised in that：It is described to tie up acid
Agent is triethylamine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
| CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
| WO2014128465A1 (en) * | 2013-02-20 | 2014-08-28 | Cancer Therapeutics Crc Pty Ltd | 2-(hetero)aryl-benzimidazole and imidazopyridine derivatives as inhibitors of asparagime emethyl transferase |
-
2015
- 2015-04-22 CN CN201510192785.1A patent/CN104817494B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
| WO2014128465A1 (en) * | 2013-02-20 | 2014-08-28 | Cancer Therapeutics Crc Pty Ltd | 2-(hetero)aryl-benzimidazole and imidazopyridine derivatives as inhibitors of asparagime emethyl transferase |
| CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
Non-Patent Citations (1)
| Title |
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| TRANSITION METAL ION COMPLEXES OF SCHIFF-BASES. SYNTHESIS, CHARACTERIZATION AND ANTIBACTERIAL PROPERTIES;Zahid H. Chohan 等;《Metal Based Drugs》;20010619;第8卷(第3期);第137-143页 * |
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