CN102070516A - Method for preparing amlodipine - Google Patents
Method for preparing amlodipine Download PDFInfo
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- CN102070516A CN102070516A CN201110042786XA CN201110042786A CN102070516A CN 102070516 A CN102070516 A CN 102070516A CN 201110042786X A CN201110042786X A CN 201110042786XA CN 201110042786 A CN201110042786 A CN 201110042786A CN 102070516 A CN102070516 A CN 102070516A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the pharmaceutical chemistry field and particularly discloses a method for preparing amlodipine. The preparation method is as follows: the compound shown in the structural formula (II) and aminoethanol are used to perform nucleophilic substitution reaction in the presence of alkali and obtain amlodipine, wherein the X in the structural formula (II) is a leaving group; and the leaving group can be any of leaving groups which are acceptable in pharmacy, such as -OSO2CH3, -OSO2Ph, -OSO2Ph or halogen Cl, Br or I. By adopting the preparation method of the invention, amlodipine can be prepared from the known raw materials in one step, thus the steps of protecting the amino group of the intermediate and releasing the amino protective group can be avoided, the drug impurities brought to the production process can be strictly controlled, the prepared amlodipine has high purity and the safety of the drug and the high efficiency can be ensured.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of amlodipine.
Background technology
Calcium channel blocker (Calcium Channel Blockers) is also referred to as calcium antagonist (Calcium Antagonists), main by the calcium channel on blocking-up cardiac muscle and the vascular smooth muscle cell film, suppress the extracellular flow of calcium ions, the intracellular calcium level reduced and cause the cardiovascular medicine that waits tissue organ function to change, treat disease such as stenocardia, hypertension has better curative effect.
Amlodipine is a kind of long-acting calcium channel blocker, and its structural formula is suc as formula shown in the I:
Amlodipine shows good bioavailability and long transformation period in vivo, slower with the receptors bind and the speed of dissociating, therefore drug effect occurs late and the length of holding time is big to the selectively acting of vascular smooth muscle, and heart diseases such as hypertension are shown good pharmacological reaction.Amlodipine is to be used for the treatment of hypertensive choice drug at present, and its sales volume occupies the first place of world's painstaking effort tubing medicine.Therefore, exploitation productive rate height, production cost is low and be applicable to that the operational path of suitability for industrialized production will be in extremely beneficial competitive edge in intense market competition.
The synthetic method of present amlodipine, as patent application CN200610116589.7, U.S. Patent application US4; 572,909, US6; 492; 523, and US6,046; reported method such as 337; productive rate is very undesirable, and all adopts amino protected intermediates, and the impurity of being introduced by amino protecting group often remains in and is difficult in the finished product thoroughly remove.
The impurity that exists in the medicine does not have therapeutic action more or influences stability of drug and curative effect, even healthy harmful to the people.Therefore, in order to guarantee the effective and safety of medicine, the impurity of bringing in the strict control production technique is a great task of synthetic drugs, and the European drug standard clearly regulation content of impurities cannot be higher than 0.3%.The method of producing amlodipine at present needs to remove amino protecting group and obtains the free alkali of amlodipine after forming dihydropyridine ring, remove amino protecting group and often use hydrazine or azanol or methylamine to form impurity A and impurity B in reaction process, and its structural formula is as follows;
The impurity A impurity B
Impurity A and impurity B are difficult to remove in the amlodipine of method for preparing, have reduced stability of drug and quality, therefore need the preparation method of the higher amlodipine of exploitation purity.
Summary of the invention
At the problem of introducing the impurity that is difficult for removing in the method for synthetic ammonia Flordipine in the prior art; the invention provides a kind of method for preparing amlodipine; obtain amlodipine by known raw material through single step reaction; removed from intermediate has been carried out amido protecting and the step of the protection that deaminizes; controlled the impurity of the drug of bringing in the production technique, the amlodipine purity height of preparation.
In order to reach the foregoing invention purpose, the present invention adopts following technical scheme:
By compound shown in the formula (II) and monoethanolamine nucleophilic substitution reaction taking place under the alkali existence condition obtains amlodipine,
Wherein, X is the group of leaving away, and is preferably-OSO
2CH
3,-OSO
2Ph ,-OSO
2Ph-Me or Br or Cl or I.
Its reaction formula is as follows:
Adopt compound as structural formula (II) shown in as raw material, react the amlodipine that obtains almost with raw material (II) equivalent with monoethanolamine shown in the formula (III).
Wherein X is a leavings group in the structural formula (II), and described leavings group can be any pharmaceutically acceptable leavings group as-OSO
2CH
3,-OSO
2Ph ,-OSO
2Ph-Me or halogen (as Cl, Br or I), X is Br in certain embodiments, in further embodiments, X is Cl; In certain embodiments, X is I.
In certain embodiments, this reaction can be carried out under differing temps in the different inert solvent.
In certain embodiments, described alkali is highly basic, weak base or its combination.In further embodiments, described alkali is sodium, potassium, potassium hydride KH, sodium hydride, lithium hydride, hydrolith or similar active alkali or its combination.In certain embodiments, described alkali is potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate or similar active alkali or its combination.In certain embodiments, described alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide or its combination.In certain embodiments, described alkali is salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus or similar active alkali or its combination.In certain embodiments, described alkali is sodium, potassium, potassium hydride KH, sodium hydride, lithium hydride, hydrolith, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate or saleratus or its combination.
In certain embodiments, described inert solvent is alcoholic solvent or its combination of aprotic solvent, weak nucleophilic.
In certain embodiments, described inert solvent is aprotic solvent tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, dimethoxy ethane, diethylene glycol dimethyl ether, triglyme or its combination.
In certain embodiments, described inert solvent is the alcohol of weak nucleophilic, as methyl alcohol, ethanol, Virahol, the trimethyl carbinol or its combination.In certain embodiments, the alcohol of described weak nucleophilic is Virahol.The alcohol of described weak nucleophilic is the trimethyl carbinol in further embodiments.In further embodiments, the alcohol of described weak nucleophilic is methyl alcohol.
In certain embodiments, described inert solvent is aprotic solvent DMF, DMSO, tetramethyl-sulfone, dimethyl sulfone or its combination.
In certain embodiments, this reaction can carried out to the inert solvent reflux temperature for-30 ℃.In certain embodiments temperature of reaction be-10 ℃ to the inert solvent reflux temperature.Temperature of reaction is a room temperature in certain embodiments.
The used monoethanolamine of this method amount can be equivalent or excessive with respect to compound shown in the formula (II), be 1 to 7 equivalent in certain embodiments.Be 1 to 5 equivalent in certain embodiments.Be 2 to 5 equivalents in further embodiments.Be 3 to 5 equivalents in further embodiments.
The amount of the used alkali of this method can be equivalent (mole) or excessive (mole) with respect to compound shown in the formula (II), is 1 to 7 equivalent in certain embodiments.Be 1 to 5 equivalent in certain embodiments.Be 2 to 5 equivalents in further embodiments.Be 3 to 5 equivalents in further embodiments.
Raw materials used and the reaction reagent of the present invention can prepare in accordance with known methods, also can buy from the market; Can be as compound as described in the structural formula (II) according to document SyntheticCommun.16 (5), the preparation method of 529-534 (1986) or European patent EP 212340 or WO2000047560 report makes.
Method described herein can comprise in addition that using suitable reaction conditions, some nonrestrictive examples to comprise uses for example salt form of alkali, catalyzer or production amlodipine of other inert solvents, reagent.Method described herein also can comprise known purification process such as crystallization, chromatography (liquid and gas etc.), extraction, distillation, development and reversed-phase HPLC etc.Reaction conditions for example temperature, reaction times, pressure and gas (as rare gas element, air) can suitably be adjusted according to reaction.
The amlodipine of the present invention's preparation can pass through purifying or can directly be used to prepare the various pharmacy acceptable salts of amlodipine.In certain embodiments, the amlodipine of the present invention's preparation can generate Amlodipine with the acid of amine reaction with any, or obtains these salt by additive method such as the ion exchange method of being put down in writing on the books document.Some nonrestrictive salt examples comprise hydrochloride, benzene sulfonate, hydrobromate, phosphoric acid salt, vitriol, perchlorate and organic acid salt such as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate.Other pharmacy acceptable salt examples comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxyl-esilate, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate or the like.
The method for preparing amlodipine described herein; its advantage is that amino does not need protection; obtain amlodipine from known raw material through single step reaction; removed from intermediate is carried out amido protecting and the step of the protection that deaminizes, the yield height has been saved production cost widely; simultaneously; the impurity of the drug of bringing in the production technique has been controlled in preparation method's strictness described herein, and the final product salt purity that is directly made by crude product is up to 99.9%, guaranteed really the safety of medicine with effectively.
Description of drawings
Fig. 1 is the nuclear magnetic spectrogram of amlodipine;
Fig. 2 is the nuclear magnetic spectrogram of amlodipine benzenesulphonate;
Fig. 3 is an amlodipine benzenesulphonate HPLC collection of illustrative plates.
Embodiment
The invention discloses a kind of method for preparing amlodipine, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as being included in the present invention.Method of the present invention is described by preferred embodiment, and the related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
In order to make those skilled in the art understand technical scheme of the present invention better, the present invention is described in further detail below in conjunction with specific embodiment.
Embodiment 1: the method for the invention prepares amlodipine
Under the nitrogen protection; add anhydrous THF in round-bottomed flask, add potassium tert.-butoxide (5.0eq), it is even to be stirred to system; drip thanomin (4.0eq) at 25 ℃; after dropwising, continue to stir 1 hour, be cooled to 0 ℃; under this temperature, drip 3-ethyl ester-5-methyl esters-2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid; the tetrahydrofuran solution of 4 dihydropyridines (1.0eq) slowly was warmed up to room temperature reaction about 3 hours after dropwising, add the shrend reaction of going out; vacuum steams THF; dichloromethane extraction merges organic phase, washing; anhydrous sodium sulfate drying; filter, vacuum steams methylene dichloride, gets the amlodipine crude product.
Embodiment 2: the method for the invention prepares amlodipine
5 normal sodium hydrides are suspended in the exsiccant tetrahydrofuran (THF), slowly add 5 normal monoethanolamines.Hydrogen discharges and finishes, and backflow 30min naturally cools to room temperature.Add 1 equivalent 3-ethyl ester-5-methyl esters 2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid under the room temperature, the tetrahydrofuran solution of 4 dihydropyridines at room temperature reacted two hours.Post-treating method such as embodiment 1 obtain the amlodipine crude product.
Embodiment 3: the method for the invention prepares amlodipine
5 equivalent sodium Metal 99.5s are dissolved in the 5 equivalent thanomins, stir 0.5h, be cooled to 0 ℃, drip 1 equivalent 3-ethyl ester-5-methyl esters 2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid then, the tetrahydrofuran solution of 4 dihydropyridines.Reaction is 4 hours under the room temperature.Add the shrend reaction of going out, vacuum steams THF, and dichloromethane extraction merges organic phase, washing, and anhydrous sodium sulfate drying filters, and vacuum steams methylene dichloride, gets the amlodipine crude product.
Embodiment 4: the method for the invention prepares amlodipine
Under the nitrogen protection; add dry toluene in round-bottomed flask, add potassium tert.-butoxide (5.0eq), it is even to be stirred to system; drip thanomin (4.0eq) at 25 ℃; after dropwising, continue to stir 1 hour, be cooled to 0 ℃; under this temperature, drip 3-ethyl ester-5-methyl esters-2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid; the tetrahydrofuran solution of 4 dihydropyridines (1.0eq) slowly is warmed up to 25 ℃ of reactions about 3 hours after dropwising, add the shrend reaction of going out; vacuum steams THF; dichloromethane extraction merges organic phase, washing; anhydrous sodium sulfate drying; filter, vacuum steams methylene dichloride, gets the amlodipine crude product.
Embodiment 5: the method for the invention prepares amlodipine
1.1 normal lithium hydride is suspended in the exsiccant methyl tertiary butyl ether, slowly adds 1.2 normal monoethanolamines.Hydrogen discharges and finishes, and backflow 30min naturally cools to room temperature.Add 1 equivalent 3-ethyl ester-5-methyl esters 2-brooethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid under the room temperature, the methyl tertbutyl ethereal solution of 4 dihydropyridines at room temperature reacted 3 hours.Post-treating method such as embodiment 1 obtain the amlodipine crude product.
Embodiment 6: the method for the invention prepares amlodipine
Under the nitrogen protection; add anhydrous THF in round-bottomed flask, add potassium tert.-butoxide (3.0eq), it is even to be stirred to system; drip thanomin (3.0eq) at 25 ℃; after dropwising, continue to stir 1 hour, be cooled to 0 ℃; under this temperature, drip 3-ethyl ester-5-methyl esters-2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid; the tetrahydrofuran solution of 4 dihydropyridines (1.0eq) slowly is warmed up to 25 ℃ of reactions about 3 hours after dropwising, add the shrend reaction of going out; vacuum steams THF; dichloromethane extraction merges organic phase, washing; anhydrous sodium sulfate drying; filter, vacuum steams methylene dichloride, gets the amlodipine crude product.
Embodiment 7: the method for the invention prepares amlodipine
According to the described method of embodiment 1-6, under the nitrogen protection, make compound shown in the formula (II)
Wherein, X is-OSO
2CH
3,-OSO
2Ph ,-OSO
2Ph-Me or Br or I and in alkali existence condition, inert solvent nucleophilic substitution reaction takes place with monoethanolamine, alkali is selected from sodium, potassium, potassium hydride KH, sodium hydride, lithium hydride, hydrolith, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus or its combination.Described inert solvent is selected from tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, dimethoxy ethane, diethylene glycol dimethyl ether, triglyme, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, DMF, DMSO, tetramethylene sulfone, dimethyl sulfone or its combination, at room temperature reacts 3 hours.Post-treating method such as embodiment 1 obtain the amlodipine crude product.
Embodiment 8: the preparation of amlodipine benzenesulphonate
5 normal sodium hydrides are suspended in the exsiccant tetrahydrofuran (THF), slowly add 5 normal monoethanolamines.Hydrogen discharges and finishes, and backflow 30min naturally cools to room temperature.Add 1 equivalent 3-ethyl ester-5-methyl esters 2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid under the room temperature, the tetrahydrofuran solution of 4 dihydropyridines at room temperature reacted two hours.Add the shrend reaction of going out, vacuum steams THF, and dichloromethane extraction merges organic phase, washing, and anhydrous sodium sulfate drying filters, and vacuum steams methylene dichloride, gets the amlodipine crude product, and amlodipine is carried out magnetic resonance detection, and its nuclear magnetic spectrogram is as shown in Figure 1.
Virahol is joined in the amlodipine crude product, slowly drip the aqueous isopropanol of Phenylsulfonic acid, be heated to 55 ℃ simultaneously, dropwise the continuation stirring and begin to drop to room temperature, crystallization 12 hours after one hour.Filtration obtains the amlodipine benzenesulphonate crude product, crude product joined be heated to 55 ℃ in the Virahol and stir cooling after a hour, crystallization 2 hours, filter, obtain amlodipine benzenesulphonate, from 3-ethyl ester-5-methyl esters-2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4 dihydropyridines are to two step of final product amlodipine benzenesulphonate productive rate 60%.
Embodiment 9: the preparation of amlodipine benzenesulphonate
5 equivalent sodium Metal 99.5s are dissolved in the 5 equivalent thanomins, stir 0.5h, be cooled to 0 ℃, drip 1 equivalent 3-ethyl ester-5-methyl esters 2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid then, the tetrahydrofuran solution of 4 dihydropyridines.Reaction is 4 hours under the room temperature.Add the shrend reaction of going out, vacuum steams THF, and dichloromethane extraction merges organic phase, washing, and anhydrous sodium sulfate drying filters, and vacuum steams methylene dichloride, gets the amlodipine crude product.
Virahol is joined in the amlodipine crude product, slowly drip the aqueous isopropanol of Phenylsulfonic acid, be heated to 55 ℃ simultaneously, dropwise the continuation stirring and begin to drop to 0 ℃, crystallization 12 hours after one hour.Filtration obtains the amlodipine benzenesulphonate crude product, crude product is joined be heated to 55 ℃ of stirrings cooling afterwards in a hour in the Virahol, and crystallization 2 hours filters, and obtains amlodipine benzenesulphonate.Amlodipine benzenesulphonate is carried out magnetic resonance detection, its nuclear magnetic spectrogram as shown in Figure 2, from 3-ethyl ester-5-methyl esters-2-chloromethyl-4-(2-chloro-phenyl-)-6-methyl isophthalic acid, 4 dihydropyridines are to final product amlodipine benzenesulphonate two step productive rate 58%.
Embodiment 10: the amlodipine benzenesulphonate purity detecting
Amlodipine benzenesulphonate to embodiment 8,9 arbitrary embodiment preparations carries out purity detecting with HPLC, and testing conditions is as follows:
Instrument: Agilent RRLC 1200; The DAD detector
Chromatographic column: waters Xbridge C18 5um 4.6*250mm
Moving phase: PH8.90Buffe: acetonitrile=50: 50
PH8.90Buffer:0.025moL/L three hypophosphite monohydrate hydrogen dipotassiums are transferred PH to 8.90 with dilute phosphoric acid
Sample size: 1uL
Flow velocity: 1mL/min, stand-by time: 37min, back working time: 6min, column temperature: 25 ℃
Detect wavelength: 240nm, 215nm.
Detected result is seen Fig. 3, shows that the amlodipine benzenesulphonate purity of the method for the invention preparation is 99.9146%.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a method for preparing amlodipine obtains amlodipine by compound shown in the formula (II) and monoethanolamine alkali existence condition generation nucleophilic substitution reaction,
Wherein, X is a leavings group.
2. the method for claim 1 is characterized in that, shown in the formula (II) in the compound X be-OSO
2CH
3,-OSO
2Ph ,-OSO
2Ph-Me or Br or Cl or I.
3. the method for claim 1 is characterized in that, described nucleophilic substitution reaction carries out in inert solvent.
4. the method for claim 1, it is characterized in that described alkali is selected from sodium, potassium, potassium hydride KH, sodium hydride, lithium hydride, hydrolith, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium isopropylate, lithium hydroxide, sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus or its combination.
5. method as claimed in claim 3 is characterized in that, described inert solvent is selected from alcoholic solvent or its combination of aprotic solvent or weak nucleophilic.
6. method as claimed in claim 5, it is characterized in that described aprotic solvent is selected from DMF, DMSO, tetramethyl-sulfone, dimethyl sulfone, tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, dimethoxy ethane, diethylene glycol dimethyl ether, triglyme or its combination.
7. method as claimed in claim 5 is characterized in that, the alcoholic solvent of described weak nucleophilic is methyl alcohol, ethanol, Virahol, the trimethyl carbinol or its combination.
8. as each described method of claim 2-7, it is characterized in that the temperature of reaction of described nucleophilic substitution reaction is-30 ℃ of reflux temperatures to described inert solvent.
9. as each described method of claim 1-8, it is characterized in that monoethanolamine is 1-7 equivalent or 1-5 equivalent or 2-5 equivalent or 3-5 equivalent with respect to compound shown in the formula (II).
10. as each described method of claim 1-9, it is characterized in that described alkali is 1-7 equivalent or 1-5 equivalent or 2-5 equivalent or 3-5 equivalent with respect to compound shown in the formula (II).
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| CN201110042786XA CN102070516A (en) | 2011-02-22 | 2011-02-22 | Method for preparing amlodipine |
| CN201280003318.4A CN103168030B (en) | 2011-02-22 | 2012-02-21 | Method for preparing amlodipine |
| PCT/CN2012/071413 WO2012113325A1 (en) | 2011-02-22 | 2012-02-21 | Method for preparing amlodipine |
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| CN201110042786XA CN102070516A (en) | 2011-02-22 | 2011-02-22 | Method for preparing amlodipine |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012113325A1 (en) * | 2011-02-22 | 2012-08-30 | 广东东阳光药业有限公司 | Method for preparing amlodipine |
| CN103922996A (en) * | 2013-01-11 | 2014-07-16 | 广东东阳光药业有限公司 | Novel intermediate of medicine, and its preparation method |
| CN107573279A (en) * | 2017-09-01 | 2018-01-12 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of synthetic method of Amlodipine Besylate Tablet degradation impurity |
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| US6046337A (en) * | 1997-08-12 | 2000-04-04 | Egis Gyogyszergyar Rt. | Process for the preparation of a dihydropyridine derivative |
| US6492523B2 (en) * | 2001-03-13 | 2002-12-10 | Hanmi Pharm. Co., Ltd. | Method for preparing amlodipine |
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| US6784297B2 (en) * | 2002-09-04 | 2004-08-31 | Kopran Limited | Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate |
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| CN102070516A (en) * | 2011-02-22 | 2011-05-25 | 广东东阳光药业有限公司 | Method for preparing amlodipine |
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2011
- 2011-02-22 CN CN201110042786XA patent/CN102070516A/en active Pending
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2012
- 2012-02-21 WO PCT/CN2012/071413 patent/WO2012113325A1/en active Application Filing
- 2012-02-21 CN CN201280003318.4A patent/CN103168030B/en active Active
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012113325A1 (en) * | 2011-02-22 | 2012-08-30 | 广东东阳光药业有限公司 | Method for preparing amlodipine |
| CN103922996A (en) * | 2013-01-11 | 2014-07-16 | 广东东阳光药业有限公司 | Novel intermediate of medicine, and its preparation method |
| CN103922996B (en) * | 2013-01-11 | 2019-01-04 | 广东东阳光药业有限公司 | A kind of drug new intermediate and preparation method thereof |
| CN107573279A (en) * | 2017-09-01 | 2018-01-12 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of synthetic method of Amlodipine Besylate Tablet degradation impurity |
| CN107573279B (en) * | 2017-09-01 | 2020-06-09 | 扬子江药业集团江苏海慈生物药业有限公司 | Synthesis method of amlodipine besylate degradation impurities |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103168030A (en) | 2013-06-19 |
| WO2012113325A1 (en) | 2012-08-30 |
| CN103168030B (en) | 2014-10-08 |
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Application publication date: 20110525 |