- A pharmaceutical model intermediate and its preparation method
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The invention relates to a novel intermediate and its preparation method. The intermediate can be used for preparing amlodipine or pharmaceutically acceptable salts thereof; and amlodipine or salts thereof can be prepared through preparing the intermediate. The method is simple and safe to operate, avoids the use of flammable and explosive articles, and is in favor of the industrial mass production.
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Paragraph 0038; 0047; 0053-0055; 0058
(2019/01/22)
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- Synthesis process of amlodipine besylate
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The invention discloses a synthesis process of amlodipine besylate, relates to the technical field of medicine synthesis and solves the problems of low product purity and poor product quality controllability of products prepared by the existing synthesis process. According to the synthesis process, phthalic anhydride is used as raw materials; the parameters of the synthesis process are controlled;the technical flow process is shortened; the synthesis cost is reduced; the product yield is as high as 91 percent; the purity of the prepared amlodipine besylate is as high as 99.5 percent. The self-made amlodipine besylate are used as raw materials for further preparing the amlodipine besylate tablets; the product cost is reduced; the product quality controllability is high.
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- Method for preparing amlodipine besylate tablet by one-pot method
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The invention relates to a method for preparing an amlodipine besylate tablet by a one-pot method. The preparation method comprises the following steps: (1) taking phthaloyl amlodipine as a raw material, preparing an amlodipine solution in the presence of a solvent and a methylamine aqueous solution, wherein the reaction temperature is 10 to 50 DEG C, and the reaction time is 2 to 12 h; and (2) adding benzenesulfonic acid into the amlodipine solution in the step (1), stirring and mixing at 10 to 50 DEG C, and then separating to obtain the amlodipine besylate tablet. The method has the advantages that the amlodipine besylate tablet is prepared by the one-pot method, compared with the traditional preparation method of the amlodipine besylate tablet, the operation procedures are simple, a prepared amlodipine besylate tablet intermediate does not need to be separated, the loss of the amlodipine can be further reduced, the yield of the final amlodipine besylate tablet can be ensured, and the yield can be almost up to 100 percent; and meanwhile, by adopting the preparation method, impurities can be prevented from being introduced, the purity of the product can be improved, the purity can be up to 99.5 percent or above, the quality of the product is greatly ensured, and the industrial standard can be satisfied.
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Paragraph 0014
(2018/09/21)
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- Using the new crystal form [...] and production of high-purity [...]
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PROBLEM TO BE SOLVED: To provide a process for producing high-purity phthaloyl amlodipine for synthesis of an amlodipine besilate having excellent purity as a medicine.SOLUTION: Provided are TW-A type and TW-B type crystal forms of highly pure phthaloyl amlodipine. In powder X-ray diffraction, the TW-A type phthaloyl amlodipine has diffraction peaks at 2θ(°)=8.7±0.2, 11.0±0.2, 13.4±0.2, 15.7±0.2, and 24.6±0.2. In powder X-ray diffraction, the TW-B type phthaloyl amlodipine has diffraction peaks at 2θ(°)=6.6±0.2, 9.9±0.2, 11.1±0.2, 17.3±0.2, and 24.4±0.2.
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Paragraph 0016; 0069; 0070; 0074
(2017/02/17)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE FREE BASE AND ACID ADDITION SALTS THEREOF
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Disclosed herein is an improved process for preparation of Amlodipine free base and acid addition salts thereof in good yield by deprotecting Phthaloyl Amlodipine using total concentration of 25% aqueous monomethyl amine in the reaction mixture and Amlodipine free base thus obtained is treated with suitable acids in aqueous medium to yield corresponding Amlodipine salts.
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Page/Page column 11-12
(2011/10/13)
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- Amlodipine benzenesulfonate: A mechanistic investigation of its industrial preparation via detritylation of N-tritylamlodipine and related NMR studies
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Kinetics and product analysis of detritylation of N-tritylamlodipine by benzenesulfonic acid in methanol, methanol-chloroform (volume ratio 9:1), ethanol, 2-propanol, and methanol/2-propanol (mole ratio 1:1) have been investigated by HPLC; amongst these reaction conditions are ones closely similar to those of one method of manufacturing amlodipine benzenesulfonate. Kinetics of detritylation of Ntritylamlodipine have also been investigated in methanol-d4 by 1H NMR spectroscopy and the agreement with the results by HPLC is good. The rate of detritylation increases with increasing concentrations of benzenesulfonic acid, and p-methoxy-substituents in the trityl group have been shown to lead to faster reactions. In methanol, the rate is hardly affected by 10 % (vol. fraction) chloroform. These studies relate to mechanistic investigations of acid-catalysed deaminations of methoxy-substituted tritylalkylamines, and Arrhenius activation parameters (Ea and A) are similar indicating a common generic mechanism. Acid-catalysed trans-esterification has been shown by HPLC to accompany detritylation in methanol, and attendant protium-deuterium exchange in the methyl at C6 by reversible acid-catalysed iminium ion formation in the 4-aryl-1,4-dihydropyridine moiety of both N-tritylamlodipine and amlodipine has been investigated in deuteriated methanol by 1H, 13C, and 15N NMR spectroscopy.
- Furlan, Borut,Grdadolnik, Simona Golic,Hocevar, Stanko,Kocjan, Darko,Levec, Janez,Maskill, Howard,Navratilova, Hana,Pospisil, Jiri,Potacek, Milan,Urleb, Uros,Zmitek, Janko
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experimental part
p. 299 - 309
(2010/03/30)
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- The effect of ion pairing on the skin permeation of amlodipine
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The purpose of the present study was to evaluate the effect of ion pairing on the skin permeation of amlodipine. Amlodipine base (AM) was first prepared from amlodipine besilate (AM-B), then amlodipine adipate (AM-A), amlodipine oxalate (AM-O) and amlodipine maleate (AM-M) were prepared using AM and the corresponding organic acids. Differential scanning calorimetry (DSC) thermogram studies demonstrated the formation of complexes between AM and the various acids. In vitro percutaneous absorption of AM and its complexes was evaluated through excised rat skin using 2-chamber diffusion cells. The results showed that AM had the greatest steady-state flux and lowest permeability coefficient of the five compounds from the El system (ethanol : isopropyl myristate (IPM) = 2:8), and its four complexes all exhibited a lower flux and higher permeability coefficient than AM.
- Jiang, Yuxuan,Fang, Liang,Niu, Xicao,Ma, Rui,He, Zhonggui
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experimental part
p. 356 - 360
(2009/04/04)
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- A PROCESS FOR THE PREPARATION OF AMLODIPINE BENZENESULFONATE
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The present invention relates to novel alkyl 2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy) acetoacetate, wherein alkyl represents C1C4 alkyl group, preferably ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, as useful intermediate in the novel process for the preparation of amlodipine benzenesulfonate in high overall yield and high purity, containing substantially less then 0.1 Area % of 3,5-diethyl (±)-2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4- dihydro-6-methyl-3,5-pyridinedicarboxylate as the single remaining impurity. No other impurities are contained in obtained pure crystalline amlodipine benzenesulfonate. Preferably, 2-chlorobenzaldehyde is contacted with ethyl-4-[2-(N- tritylamino)ethoxy]acetoacetate in an organic solvent, preferably ethanol, to form ethyl-2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, which is converted without isolation from the reaction mixture, preferably with methyl (E)-3- aminocrotonate to form 3-ethyl 5-methyl (±)-2-[2-(N-tritylamino)ethoxymethyl]-4-(2- chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate ("tritylamlodipine"), which is converted without isolation from the reaction mixture with benzenesulfonic acid in an organic solvent, preferably ethanol, followed by isolation and purification of amlodipine benzenesulfonate. C1-C4 alkyl alcohols, especially methanol, ethanol, isopropanol and mixtures thereof, are used as an organic solvent. Amlodipine benzenesulfonate (besylate) is useful as antiishemic and antihypertensive agent.
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Page/Page column 8-10
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF AMLODIPINE BESYLATE
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The present invention provides a process for the preparation of amlodipine, which comprises purging of methylamine gas under stirring in phthaloyl amlodipine in presence of an organic solvent selected from the group consisting of toluene and isopropyl alcohol.
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Page/Page column 5
(2010/11/28)
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- PROCESS FOR PREPARING AMLODIPINE
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A process for preparing phthalimidoamlodipine, which is useful as an intermediate for the preparation of amlodipine and its salts.
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Page/Page column 7
(2010/11/28)
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- A PROCESS FOR THE PREPARATION OF AMLODIPINE BENZENESULPHONATE
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A process for the preparation of amlodipine benzenesulphonate is disclosed, wherein a salt of amlodipine with an inorganic or organic acid is reacted with alkali metal benzenesulphonate in an aqueous medium or in a mixture water-alcohol C1-C2. Amlodipine benzenesulphonate is used for the preparation of a medicament having calcium channel blocking activity, useful in the treatment of the coronary disease and arterial hypertension.
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Page/Page column 4
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF AMLODIPINE SALTS
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A process for the preparation of salts of amlodipine comprises subjecting a compound of formula (II) to a deprotection reaction and converting the amlodipine free base thus obtained to a salt (1) without isolating amlodipine free base. Preferably, the maleate, besylate, malate or fumarate salt is made.
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Page/Page column 8-9
(2008/06/13)
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- ISOLATION OF DIHYDROPYRIDINE DERIVATIVE AND PREPARATION SALTS THEREOF
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The title compound is isolated in pure form by using a crystallization process and converted to its pharmaceutically acceptable salts. The crystallization process affects stability and purity of the amlodipine salts. All known impurities and one unknown impurity, which forms during the synthesis of the amlodipine salts, were isolated, characterized, and synthesized. A new method allowing the quantitative HPLC analysis of all related impurities of amlodipine salts in a single chromatogram was developed.
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- Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate
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Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate [2-{(2-aminoethoxy)-methyl-4-(2-chlorophenyl) 3-ethoxy carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} benzene sulphonate]. Phthalic anhydride is condensed with monoethanol amine at 150-190° C. The resulting N-(2-hydroxyethyl) phthalimide is coupled with 4-chloroethyl acetoacetate in the presence of sodium hydride in an organic solvent in an inert atmosphere at ?11 to ?15° C. Ethyl-4-[-2(phthalimido) ethoxy] acetoacetate formed is coupled with orthochloro benzaldehyde in the presence of pyridine salt at 70-90° C. Ethyl-2-(2-chloro benzylidine)4-[-2(phthalimido) ethoxy] acetoacetate fanned is condensed with methyl amino crotonate at 20-40° C. in the presence of acetic acid to form phthaloyl amlodipine [2-(2-Phthalimidoethoxy) methyl-3-carboethoxy 1(chlorophenyl)-S-carbomethoxy-6-methyl-1,4-dihydropyridin] which is purified by dissolving in an organic solvent in the ratio 1:2-1:5 w/v and precipitated by the addition of water at 35-60° C. Purified phthaloyl amlodipine is hydrolysed with methylamine in the presence of a protic solvent at 20-50° C. Amlodipine base [2-(aminoethoxy) methyl-3-carboethoxy-4-(2-chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] formed is reacted with benzene sulfonic acid. The resulting amlodipine besylate is purified in an organic solvent at 30-70° C. and precipitated by the addition of an insoluble solvent.
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- Crystalline organic acid salt of amlodipine
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A novel crystalline organic acid salt of amlodipine having improved physiochemical properties, a preparation method thereof and a pharmaceutical composition comprising the same are provided.
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- Organic acid salt of amlodipine
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Disclosed are a novel organic acid salt of amlodipine, its preparation method, and a pharmaceutical composition containing the same as a therapeutically active ingredient.
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- Crystalline organic acid salt of amlodipine
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A novel crystalline organic acid salt of amlodipine having improved physiochemical properties, a preparation method thereof and a pharmaceutical composition comprising the same are provided.
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Page/Page column 3
(2008/06/13)
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- TWO CRYSTALLINE HYDRATE FORMS OF AMLODIPINE BENZENESULFONATE OF HIGH PURITY, PROCESSES FOR THEIR PREPARATION AND USE
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The novel crystalline amlodipine benzenesulfonate dihydrate of high purity is disclosed, as well as the process for preparation of the novel crystalline amlodipine benzenesulfonate dihydrate of high purity and the crystalline amlodipine benzenesulfonate monohydrate of high purity, suitable for the preparation of pharmaceutical formulations for the treatment of cardiac diseases or hypertension, and their use as intermediate compounds in the improved process of purification of the nonhydrate benzenesulfonate (besylate) salt of amlodipine.The process for preparation of the crystalline amlodipine benzenesulfonate dihydrate is carried in the way that from the C1-C5 alcoholic solution of amlodipine benzenesulfonate with water while stirring at a temperature of 20°C or lower the crystals of pure amlodipine benzenesulfonate dihydrate are separated, and isolated.The process for preparation of the crystalline amlodipine benzenesulfonate monohydrate is carried in the way that from the C1-C5 alcoholic solution of amlodipine benzenesulfonate with water while stirring at a temperature of 30°C or higher the crystals of pure amlodipine benzenesulfonate monohydrate are separated, and isolated.
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Page 18; 19; 23-25
(2010/02/04)
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- Process for preparing amlodipine benzenesulphonate
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The invention relates to a novel process of amalodipine benzenesulphonate of formula (I) by reacting a new 2-[/2-carboxy-benzoyl)-aminoethoxy/methyl/]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-di-hydropyridine derivative of general formula (II) wherein X represents hydrogen or alkali metal or alkali earth metal or quaternary ammonium—with benzenesulphonic acid.
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- Process for the preparation of a dihydropyridine derivative
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The invention relates to a new process for the preparation of amlodipine besylate of the Formula Amlodipine besylate of the Formula I is a valuable known blood pressure decreasing antianginal agent. The advantage of the process of the present invention is that it can be carried out in a simple way with high yields and there is no need to isolate the amlodipine base.
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