- Modified asymmetric strecker reaction of aldehyde with secondary amine: A protocol for the synthesis of S-clopidogrel (an antiplatelet agent)
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A first approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The catalytic system gave α-aminonitriles in excellent yields (up to 95
- Sadhukhan, Arghya,Saravanan,Khan, Noor-Ul H.,Kureshy, Rukhsana I.,Abdi, Sayed H. R.,Bajaj, Hari C.
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Read Online
- Iridium and bis(4-nitrophenyl)phosphoric acid catalysed amination of diol by hydrogen-borrowing methodology for the synthesis of cyclic amine: Synthesis of clopidogrel
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The borrowing hydrogen method is an environmentally benign process for the synthesis of amines, as H2O is the side product. A new green process for the amination of diol by [Ir] catalyst 15 and bis(4-nitrophenyl)phosphoric acid for the synthesis of cyclic amine is reported. This method was successfully applied for the synthesis of antiplatelet drug clopidogrel.
- Swain, Sharada Prasanna,Shri, Om,Ravichandiran
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Read Online
- Synthetic improvements in the preparation of clopidogrel
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Synthetic improvements in the preparation of clopidogrel are described. The synthesis was accomplished in four steps or one-pot in above 70% overall yield. The process featured PTC catalyzed alkaline hydrolysis of the key intermediate 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetonitrile and highly effective kinetic resolution of racemic clopidogrel using L-camphorsulphonic acid in toluene and has been successfully used in a 50-kg pilot test.
- Wang, Lixin,Shen, Jianfen,Tang, Yi,Chen, Yi,Wang, Wen,Cai, Zegui,Du, Zhenjun
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Read Online
- A facile solid-phase synthesis of (+)-(S)-clopidogrel
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Enantiomerically pure (+)-(S)-clopidogrel was prepared by solid-phase synthesis using the commercially available Wang resin. This method offers mild reaction conditions and provides the (+)-(S)-clopidogrel in overall 52% yield over six steps and with optical purity of 98.0% ee. Copyright
- Jung, Kiwon,Kim, Jae-Sun,Kim, Tae-Hyun,Kim, Jinwoong
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Read Online
- Copper (II) bromide catalysed one pot bromination and amination for the green, cost-effective synthesis of clopidogrel
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Copper (II) bromide catalyzed one pot α-bromination and followed by amination of a benzylic ester is reported. The α-bromination of ester by copper (II) bromide generates copper (I) bromide and HBr. The copper (I) bromide is oxidized to copper (II) bromide by N-Methylmorpholine-N-Oxide (NMO) in presence of HBr. The amines undergo nucleophilic substitution reaction with α-brominated ester compound. This methodology was applied for the synthesis of the familiar antiplatelet drug clopidogrel. This green process is an alternate to classical methods for the synthesis of clopidogrel, which requires, generates stochiometric amount of brominating agents and HBr, respectively.
- Kumar, K. Naveen,Mhate, Mouzma,Panchami, Hirave,Ravichandiran, V.,Swain, Sharada Prasanna
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- Preparation method of clopidogrel hydrogen sulfate and intermediate N-(2-thiopheneethyl) methyleneimine of clopidogrel hydrogen sulfate
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The invention discloses a preparation method of clopidogrel hydrogen sulfate and an intermediate N-(2-thiophene ethyl) methyleneamine of the clopidogrel hydrogen sulfate. The synthesis method of the intermediate comprises the step of carrying out an Eschweiler-Clarke methylation reaction by taking 2-thiophene ethylamine and paraformaldehyde as raw materials to obtain the N-(2-thiophene ethyl) methyleneamine. The invention also provides a method for preparing clopidogrel hydrogen sulfate. According to the synthesis method provided by the invention, the required solid product (N-(2-thiopheneethyl) methyleneimine) is synthesized in one step, the synthesis method is simple, the qualified solid compound is directly obtained, the time and the raw material cost are saved, the storage and the transportation are convenient, the purity is good, the yield is high, and the synthesis method is suitable for industrial production.
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Paragraph 0109; 0113
(2021/05/08)
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- Preparation method of clopidogrel hydrogen sulfate crystal form II
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The invention discloses a preparation method of a clopidogrel hydrogen sulfate crystal form II. The method includes: preparation of (+)o-chlorophenylglycine methyl ester; preparation of (+)alpha-(2-thiophene ethylamino)-alpha-(2-chlorphenyl)methyl acetate hydrochloride; preparation of (+)clopidogrel free alkali; preparation of (+)clopidogrel camphorsulfonic acid double salt; hydrolysis of (+)clopidogrel camphorsulfonic acid double salt; and preparation of clopidogrel hydrogen sulfate. The preparation method of the clopidogrel hydrogen sulfate crystal form II provided by the invention optimizesthe synthesis process of clopidogrel hydrogen sulfate, selects cheap and easily available materials, adopts mild reaction conditions, and can achieve safe and environment-friendly production of a high-purity product.
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Paragraph 0044; 0054; 0058; 0070; 0073
(2020/02/29)
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- Preparation method of sulfonic clopidogrel impurity
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The invention discloses a preparation method of a sulfonic clopidogrel impurity. The preparation method comprises the following steps: reacting thiophene-2-ethanol with toluenesulfonyl chloride to generate p-toluenesulfonic acid-2-thienylethyl ester; carrying out esterification on o-chlorophenylglycine and methanol to generate o-chlorophenylglycine methyl ester; resolving the o-chlorophenylglycinemethyl ester by using L(+) tartaric acid; converting into free S-(+)-o-chlorophenylglycine methyl ester in dichloromethane; carrying out a condensation reaction on the p-toluenesulfonic acid-2-thienylethyl ester and the S-(+)-o-chlorophenylglycine methyl ester under an alkaline condition; acidifying the obtained product to generate (S)-2-(2-thienylethylamino)(2-chlorphenyl)methyl acetate, carrying out a condensation reaction on the (S)-2-(2-thienylethylamino)(2-chlorphenyl)methyl acetate and formaldehyde to obtain clopidogrel, and carrying out a reaction on the clopidogrel and chlorosulfonicacid to generate sulfonic clopidogrel impurity. The preparation method of the sulfonic clopidogrel impurity has the advantages of mild reaction conditions, accessible raw materials, low cost and highyield and purity.
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Paragraph 0012; 0037-0038
(2020/08/02)
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- Synthetic hydrosulfuric acid clopidogrel and intermediate of the new method (by machine translation)
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The invention relates to a synthesis of the clopidogrel hydrogen sulfate of the new method, through 2 - thiophene ethylamine and N - benzyl - 2 - (2 - chlorophenyl) - 2 - carbonyl acetamide generate condensation reaction, generating imine; imine asymmetric hydrogenation reaction is reduced to the corresponding secondary amine. Under acidic conditions, secondary amine with formaldehyde generating ring, get the clopidogrel free base, then acidified by sulfuric acid, to obtain the clopidogrel hydrogen sulfate. The present invention provides a synthetic route of the short, relates to the reaction are classical organic chemical reaction, mild reaction conditions, the operation is simple, with high enantio-selectivity, high yield, high turn over number of characteristics, the vast majority of the substrate in the thousandths of a dosage of the catalyst obtained in the circumstances of 99% or more of the conversion and 97% -99% ee value of, to achieve the highest transformed number 100000, has extremely high industrial application value. (by machine translation)
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Paragraph 0037; 0078; 0081
(2019/04/17)
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- Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to Glyoxylates: Access to Optically Active Substituted Mandelic Acid Esters
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A rhodium-catalyzed enantioselective addition of glyoxylates to arylboronic acids promoted by a simple chiral sulfinamide-based olefin ligand under mild reaction conditions is described. The reaction provides access to a variety of optically active substituted mandelic acid esters in good yields with up to 83percent ee. The catalytic system is also applicable to pyruvate addition. The synthetic utility of this method is highlighted by a formal synthesis of the antiplatelet drug clopidogrel.
- Chen, Diao,Liu, Jian-Guo,Xu, Ming-Hua,Zhang, Xu
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supporting information
p. 1693 - 1697
(2019/08/26)
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- A preparation method of clopidogrel hydrogen sulfate type II
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The invention discloses a preparation method of clopidogrel hydrogen sulfate type II. According to the method, clopidogrel hydrogen sulfate type II is prepared by taking clopidogrel free alkali as a raw material, and a preparation method of clopidogrel free alkali comprises the following steps: (1) preparing a reaction mixed solution of R-chloromandelic acid methyl ester by the reaction of R-chloromandelic acid and methanol in an organic solvent and in the presence of a catalyst; (2) mixing the reaction mixed solution of R-chloromandelic acid methyl ester with an organic base and a catalyst, reacting in the presence of benzenesulfonyl chloride to obtain a reaction mixed solution of methyl 2-benzenesulfonyl-2-chlorophenylacetate; (3) mixing the reaction mixed solution of methyl 2-benzenesulfonyl-2-chlorophenylacetate obtained in the step (2) with 4,5,6,7-Tetrahydrothieno[3,2,c] pyridine hydrochloride and potassium carbonate for reaction to obtain the clopidogrel free alkali. According to the method, the solvent does not need to be supplemented in the last two steps, the solvent is directly used, and the reaction liquid concentration time is saved.
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Paragraph 0114; 0120; 0121; 0154-0158
(2019/07/11)
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- A preparation method of clopidogrel hydrogen sulfate type II
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The invention discloses a preparation method of clopidogrel hydrogen sulfate type II. The method comprises the following steps: (4) taking clopidogrel free alkali as a raw material, and reacting the clopidogrel free alkali with (1R)-(-)-10-camphorsulfonic acid in a reaction solvent to obtain clopidogrel camphorsulfonate, and hydrolyzing under an alkaline condition to obtain clopidogrel free alkali; and then preparing the clopidogrel hydrogen sulfate type II by taking the clopidogrel free alkali obtained in the step (4) as a raw material. The synthetic route is simple, the used solvent is cheap, the cost is saved, the generation of waste liquid is reduced, the recycling of the solvent is improved, and the prepared clopidogrel hydrogen sulfate type II has the characteristics of high purity,good quality, high yield, good stability, suitability for industrial mass production and the like.
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Paragraph 0097; 0103; 0104; 0137
(2019/07/11)
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- Preparation method of high-purity clopidogrel
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The invention relates to a preparation method of high-purity clopidogrel (formula I). The preparation method comprises the following steps: firstly, performing reaction on a compound as shown in formula II and a compound as shown in formula III in an acetone solvent under the existence of alkali, filtering reactants to remove insolubles, and adding sulfuric acid into filtrate for separation and crystallization, thus obtaining clopidogrel disulfate with the optical purity of 98 percent or above; neutralizing the clopidogrel disulfate with inorganic alkali in dichloromethane and water, obtaining clopidogrel free alkali, salifying the clopidogrel free alkali and benzenesulfonic acid in an alcohol solvent, then adding an alkane solvent for separation and crystallization, thus obtaining clopidogrel benzene sulfonate (formula V) with the optical purity of 99.9 or above, and applying the clopidogrel benzene sulfonate to a medicine preparation, or neutralizing the clopidogrel disulfate with the inorganic alkali in the dichloromethane and the water, thus obtaining the clopidogrel free alkali with the optical purity of 99.9 percent, and applying the clopidogrel free alkali to preparation of pharmaceutically acceptable salt and a medicine preparation.
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- Synthesis method of clopidogrel hydrogen sulfate
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The invention discloses a synthesis method of clopidogrel hydrogen sulfate. The synthesis method takes o-phenylphthalic chloroacetic acid and 4,5,6,7tetrahydrothiophene[3,2-c] as raw materials and comprises the following steps: (1) carrying out acylation reaction; (2) carrying out bromination reaction; (3) carrying out esterification reaction; (4) preparing a clopidogrel base crude product; (5) extracting clopidogrel base; (5) carrying out racemic racemate reductionresolution; (7) preparing the clopidogrel hydrogen sulfate. According to the synthesis method of the clopidogrel hydrogen sulfate, disclosed by the invention, reasonable raw material selection and process route design are carried out, so that on one hand, a process flow is simplified and synthesis operation is easy to realize; on the other hand, reaction conditions are reduced, the reaction conditions are moderate and the method is easily smoothly carried out; the obtained finished product clopidogrel hydrogen sulfate has high yield and good quality; industrial production is easy to realize and a market prospect is wide.
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- Preparation method of Clopidogrel sulfate crystal form I
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The invention provides a high-yield method suitable for industrial production preparation of a high-stability Clopidogrel sulfate crystal form II. According to the method, ester is used as a solvent; a small amount of lower alcohol is added into the solvent; the content of water in the solvent is strictly controlled, so that the Clopidogrel sulfate crystal form II is stably produced.
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Paragraph 0014; 0015; 0016
(2017/09/18)
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- Preparation method for clopidogrel hydrogen sulfate crystal form II
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The invention provides a method which is high in yield and is suitable for industrial production of high-stability clopidogrel hydrogen sulfate crystal form II. According to the method, the ester is used as a solvent, few low alcohols are added into the solvent and the clopidogrel hydrogen sulfate crystal form II is stably produced in the manner of strictly controlling the water content in the solvent.
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Paragraph 0015; 0016; 0017
(2017/10/07)
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- A 2, 5 - dihydroxy benzene sulfonic acid clopidogrel and its preparation method (by machine translation)
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The invention discloses a 2, 5 - dihydroxy benzene sulfonic acid clopidogrel, its structural general formula is: 2. 5 - dihydroxy benzene sulfonic acid of clopidogrel process includes the steps of: (1) to hydroxyl-phenol with the role of the concentrated sulfuric acid, to chloroform as reaction solvent, refluxing the reaction condition, generating a 2, 5 - dihydroxy benzene sulfonic; (2) the clopidogrel hydrogen sulfate salt in alkaline conditions of clopidogrel free obtained; (3) using ethyl acetate as reaction solvent, under normal temperature conditions 2, 5 - dihydroxy benzene sulfonic acid with the clopidogrel reaction production 2, 5 - dihydroxy benzene sulfonic acid clopidogrel. Compounds of the invention have strong inhibiting thrombus and platelet aggregation effects and bad reaction of small advantages. (by machine translation)
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Paragraph 0031; 0032; 0033
(2017/08/26)
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- A compound clopidogrel hydrogensulfate method for the preparation of
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The invention relates to a preparation method of clopidogrel disulfate. The preparation method comprises the following steps of step one. carrying out esterification reaction, namely preparing (+/-) DL-2-Chlorophenylglycine methyl ester; step two. carrying out splitting reaction, namely preparing (+) DL-2-Chlorophenylglycine methyl ester; step three. carrying out activating reaction, namely preparing alpha-thiophene ethanol p-toluenesulfonates; step four. carrying out substitution reaction, namely preparing (+) alpha-(2-thiophene ethylamino)-2-(2-chlorobenzene) methyl acetate hydrochloride; step five. carrying out ring closing reaction, namely preparing clopidogrel; and step six. carrying out salt-forming reaction, namely preparing the clopidogrel disulfate. The preparation method has the advantages that the preparation technology is optimized and improved, reaction conditions are mild, the splitting and the racemization are truly and synchronously carried out, and an obtained crude product has high specific rotation; a catalyst is used in the substitution reaction, so that the reaction time is shortened; the ring closing reaction is carried out at 40 DEG C under the condition of avoiding light, so that the purity of the product is relatively high; and the period of the whole synthetic route is shortened, the aftertreatment operation is simple, and therefore, the preparation method is suitable for mass production.
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Paragraph 0112-0114
(2017/01/26)
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- Prodrugs of anti-platelet agents
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The invention relates to the compounds of formula I, formula II, formula Ia, formula IIb or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II, formula Ia, formula IIb and methods for treating or preventing atherothrombosis may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment or management of ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.
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Page/Page column 49-50; 52
(2015/11/27)
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- SPHERICAL PARTICLES OF CLOPIDOGREL BISULFATE, PHARMACEUTICAL COMPOSITION COMPRISING THE SAME, AND PREPARATION METHOD THEREOF
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Disclosed are spherical particles of clopidogrel bisulfate and a pharmaceutical composition containing the same. The spherical particles can be used for preparing a tablet having sufficient hardness through direct compression, by improving unformulable properties of clopidogrel bisulfate such as compressibility, flowability and strong surface electrostatic charges, reduce a problem in compressing tablets such as weight variation, sticking, etc., and the risk of form conversion, and improve physiochemical stability. Therefore, the spherical particles of the present invention may be used as therapeutics for arteriosclerosis, stroke, myocardial infarction and atherosclerosis.
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(2014/06/23)
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- SPHERICAL PARTICLES OF CLOPIDOGREL BISULFATE, PHARMACEUTICAL COMPOSITION INCLUDING SAME, AND METHOD FOR MANUFACTURING SAME
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The present invention relates to spherical particles of clopidogrel bisulfate and a pharmaceutical composition containing the same. The inventive spherical particles can be used for preparing a tablet having sufficient hardness through direct compression, by improving unformulable properties of clopidogrel bisulfate such as compressibility, flowability and strong surface electrostatic charges, reduce a problem in compressing tablets such as weight variation, sticking, etc., and the risk of form conversion, and improve physiochemical stability. Therefore, the spherical particles of the present invention may be used as therapeutics for arteriosclerosis, stroke, myocardial infarction and atherosclerosis.
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Paragraph 0049
(2014/06/11)
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- Deuterated clopidogrel analogues as a new generation of antiplatelet agents
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Clopidogrel (CPG) is an antithrombotic prodrug that needs hepatic cytochrome P450 (CYP) enzymes for its bioactivation. The clinical effects of CPG have been associated with high intersubject variability and a certain level of resistance. Recently, comprehensive biotransformation studies of CPG support that the observed clinical uncertainty stems from the low bioactivation efficiency, which is attributed to extensive attritional metabolism (e.g., hydrolysis of the methyl ester functionality and oxidation of the piperidine moiety). With the goal of potentiating the desired thiophene 2-oxidation through minimal structural modification, we have adopted the strategy of targeted metabolism shift and have designed and synthesized deuterated piperidine analogues of CPG. In vitro studies showed that the prodrug activation percentages have been significantly increased for the deuterated analogues as a result of stability enhancement of the piperidine moiety. In a pharmacological study with a rat model, oral administration of the deuterated analogues also demonstrated higher inhibitory activity than that of CPG against adenosine diphosphate (ADP) induced platelet aggregation. These deuterated analogues represent a new generation of antiplatelet agents with the potential to overcome the major clinical drawbacks of CPG.
- Zhu, Yaoqiu,Zhou, Jiang,Jiao, Bo
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supporting information
p. 349 - 352
(2013/05/09)
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- PRODRUGS OF ANTI-PLATELET AGENTS
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Disclosed is the compounds of formula (I), formula (II), formula (la), formula (IIb) or its pharmaceutical acceptable salts, polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising and effective amount of formula (I), formula (II), formula (la), formula (lIb) and may be used to treatment or management of ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovasculard diseases and blood colts.
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Paragraph 00101; 00110; 00111
(2013/12/03)
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- An asymmetric synthesis of clopidogrel hydrogen sulfate
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An asymmetric synthesis of (S)-(+)-clopidogrel hydrogen sulfate has been developed through application of a Strecker reaction with [(1S)-1-(4- methoxyphenyl)ethyl]amine hydrochloride as a chiral auxiliary. Addition of 2-chlorobenzaldehyde to a solution of sodium cyanide and [(1S)-1-(4- methoxyphenyl)ethyl]amine hydrochloride gave diastereoisomerically pure (2S)-(2-chlorophenyl){[(1S)-1-(4-methoxyphenyl)ethyl]amino}acetonitrile hydro chloride. Cleavage of the chiral auxiliary and concomitant hydrolysis of the nitrile group then gave enantiomerically pure (2S)-2-(2-chlorophenyl)glycine hydrochloride, a key intermediate for (S)-(+)-clopidogrel. Georg Thieme Verlag Stuttgart. New York.
- Sashikanth, Suthrapu,Raju, Veeramalla,Somaiah, Sripathi,Rao, Peddisrinivasa,Reddy, Karnativenugopal
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p. 621 - 624
(2013/04/23)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF ATHEROTHROMBOSIS
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The disclosures herein provide compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for peroral administration- transdermal administration, transmucosal, syrups, topical, extended release, sustained release, or injection. Such compositions may foe used to treatment of vascular disorders or conditions such as thrombotic cerebrovascular or cardiovascular disease or its associated complications.
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- COMPOSITIONS AND METHODS FOR TREATING ATHEROTHROMBOSIS
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Provided are compounds of formula (I), pharmaceutical acceptable salts, polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising the compounds may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup or injection, and may be used for the treatment or management of ischemia, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULFATE
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The present invention provides an improved process for the preparation of Clopidogrel of Formula (I) or its pharmaceutically acceptable salts, and its intermediate of Formula (II). Formula (I) Formula (II).
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Page/Page column 8
(2011/02/24)
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- IMPROVED PROCESS FOR PREPARATION OF CLOPIODOGREL BISULFATE CRYSTALLINE FORM-1
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An improved process for preparing crystalline form-1 of (S)-methyl 2-(2-chlorophenyl)-2-{6, 7-dihydrothieno[3, 2-c] pyridine-5(4H)-yl}acetate bisulfate (clopidogrel bisulfate) of formula I is provided The preparation comprises the straight conversion of an uncyclized material of (S)-methyl 2-[2- (thiophen-2-yl)ethylamino]-2-(2-chlorophenyl)acetate hydrochloride into clopidogrel bisulfate crystalline form-1 without any degradation of clopidogrel base
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Page/Page column 9
(2011/06/11)
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- Methods for predicting the response to statins
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The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.
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- METHOD FOR MANUFACTURING CRYSTALLINE FORM (I) OF CLOPIDOGREL HYDROGEN SULPHATE
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The present invention provides a method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate(clopidogrel hydrogen sulfate), including reacting a clopidogrel free base with concentrated sulfuric acid in the presence of a mixed solvent containing water in an amount of 4 to 14% by weight based on the weight of the clopidogrel free base and 2-butanol.
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- METHOD OF PRODUCING OPTICALLY ACTIVE AMINO ACID DERIVATIVE
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The present application relates to a method for producing an optically active α-amino acid derivative, comprising steps of reacting an α-haloester derivative represented by the general formula (1): of which alcohol part of the ester group is an optically active alcohol derivative, with an amine compound; then deprotecting the obtained compound; further carrying out an ester exchange reaction. According to the present invention method, it is possible to easily produce an optically active α-amino acid ester derivative which is useful as an intermediate for drugs with high selectivity.
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Page/Page column 15
(2011/04/18)
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- A PROCESS FOR PREPARATION OF CRYSTALLINE FORM I OF CLOPIDOGREL BISULFATE
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The present invention relates to process for preparation of crystalline Form I of clopidogrel bisulfate comprising steps of preparing clear solution of clopidogrel free base in ethyl acetate, which is cooled to a temperature varying from about -7 to about - 10°C and reacted with concentrated sulphuric acid while maintaining said temperature, thereafter slowly warmed to room temperature, and then heated to reflux, which on cooling to room temperature, filtration, washing and vacuum drying results in crystalline Form 1 of clopidogrel bisulfate.
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Page/Page column 17-18
(2011/10/31)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULFATE FORM I
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The present invention relates to an improved process for the preparation of Clopidogrel bisulfate Form I from clopidogrel free base. Whereas Clopidogrel free base is isolated from Clopidogrel acid addition salt.
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Page/Page column 6
(2011/05/11)
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- Processes for the preparation of clopidogrel
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The invention relates to processes for the preparation of clopidogrel and salts thereof. The inventors have developed a process for preparing racemic clopidogrel by racemizing R(?) clopidogrel. The process includes the step of reacting R(?) clopidogrel with a powered anhydrous base in one or more solvents.
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Page/Page column 3
(2010/06/14)
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- Chemo-enzymatic approach to the synthesis of the antithrombotic clopidogrel
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The (S)-2-chlorophenylglycine moiety is well recognized in the structure of (S)-clopidogrel, a known antithrombotic drug. We prepared an enantiomerically pure chiral building block via an enzyme-catalyzed resolution of (RS)-N-Boc-2-chlorophenylglycine methylester. The best results were obtained by means of an immobilized subtilisin, the cross-linked enzyme aggregate (Alcalase-CLEA). The high enantiomeric excess of the synthon obtained remained the same over the course of clopidogrel synthesis; the simplicity of the process makes this pathway suitable for large-scale preparation.
- Ferraboschi, Patrizia,Mieri, Maria De,Galimberti, Fiorella
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experimental part
p. 2136 - 2141
(2010/10/03)
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- PROCESS FOR THE PREPARATION OF CLOPIDOGREL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention provides a process for the preparation of clopidogrel and its pharmaceutically acceptable salts thereof comprises the resolving racemic methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate by the salt formation of methyl alpha-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)(2-chlorophenyl)-acetate with excess levorotatory camphor-10-sulfonic acid to get a maximum yield of camphor sulphonate salt of methyl S-(+)-alpha-5-(4,5,6,7-tetrahydro[3,2-e]thienopyridyl)(2-chlorophenyl)-acetate and transforming the camphor sulphonate salt to clopidogrel or its pharmaceutically acceptable salts thereof.
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Page/Page column 3
(2010/02/17)
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- Process for the preparation of optically enriched clopidogrel
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The invention relates to a process for the preparation of substantially optically pure or optically enriched clopidogrel or a pharmaceutically acceptable salt or solvate thereof. The invention also relates to a process for the preparation of a pharmaceutical formulation comprising substantially optically pure clopidogrel, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least one pharmaceutically acceptable carrier.
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Page/Page column 7
(2009/10/18)
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- Attrition-enhanced deracemization in the synthesis of clopidogrel - A practical application of a new discovery
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The recently discovered technique of deracemization by means of attrition-induced grinding of a solid conglomerate in contact with a solution wherein racemization occurs has been used with a derivative of 2-chlorophenyl glycine, the key chiral component in the synthesis of Clopidogrel (Plavix). Deracemization of the racemate proceeds to a single enantiomer and in essentially absolute enantiomeric excess. Further conversion of enantiomerically pure material to Clopidogrel was achieved in 88% yield.
- Van Der Meijden, Maarten W.,Leeman, Michel,Gelens, Edith,Noorduin, Wim L.,Meekes, Hugo,Van Enckevort, Willem J.P.,Kaptein, Bernard,Vlieg, Elias,Kellogg, Richard M.
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experimental part
p. 1195 - 1198
(2010/04/22)
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- Ru-catalyzed enantioselective preparation of methyl (R)-o-chloromandelate and its application in the synthesis of (S)-Clopidogrel
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The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C6H2SO2-DPEN as the catalyst and HCOOH-Et3N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition. The synthesis of (S)-Clopidogrel was also studied.
- Yin, Lu,Shan, Wenjun,Jia, Xian,Li, Xingshu,Chan, Albert S.C.
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experimental part
p. 2092 - 2095
(2009/10/31)
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- RACEMIZATION PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF CLOPIDOGREL HYDROGEN SULPHATE
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The invention relates to a process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate hydrogen sulphate (also known as S-(+)-clopidogrel hydrogen sulphate) of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate, or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.
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Page/Page column 9-10
(2009/07/18)
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- PROCESS FOR THE PREPARATION OF POLYMORPHIC FORMS OF CLOPIDOGREL HYDROGEN SULFATE
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The present invention relates to a novel process for the preparation of polymorphic forms of clopidogrel hydrogen sulfate, namely methyl(+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I). Particularly the present invention relates to the process for the preparation of form (I) and amorphous clopidogrel hydrogen sulfate.
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Page/Page column 4
(2009/04/24)
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- PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULPHATE FORM I
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The invention relates to a process for the preparation of crystalline form-I of S- (+)-clopidogrel bisulphate.
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Page/Page column 11; 12
(2009/07/25)
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- PROCESS FOR THE PREPARATION OF CLOPIDOGREL HYDROGEN SULFATE CRYSTALLINE FORM I
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The present invention relates to a process for the preparation of clopidogrel and, more particularly, to an improved process for the preparation of clopidogrel hydrogen sulfate crystalline Form I by addition of dilute sulfuric acid to a solution of clopidogrel free base in butyl acetate.
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Page/Page column 10
(2010/01/30)
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- PREPARATION OF CLOPIDOGREL AND ITS ANALOGUES METHYL TETRAHYDROTHIENOPYRIDINE ACETATE COMPOUNDS
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The present invention disclosed a preparation method of Clopidogrel (X=2-Cl) and its analogues of methyl tetrahydrothienopyridine acetate (I) by using halogen phenyl acetonitrile (VIII) as starting material and tetrahydrothienopyridine acetonitrile (IV), tetrahydrothienopyridine acetate (V) as key intermediates, and further using kinetic resolution to prepare the optical active Clopidogrel and compounds of methyl tetrahydrothenopridine acetate of formula (XII). The Clopidogrel of present invention is a novel high effective and safety drug for inhibition of platelet aggregation. This invention applied systematic technique of racemization of unwanted optical active enantiomer, recover recycle and reuse of resolution agent etc., with greater economic advantages and suitable for commercial scale industrial production. Wherein: X represents atoms of hydrogen, fluorine, chlorine, bromine or iodine, M represents an alkali metal ion.
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Page/Page column 24
(2008/12/06)
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- A PROCESS FOR PREPARING (S)-(+)-CLOPIDOGREL BASE AND ITS SALTS
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The present invention relates to an improved processes for the preparation of Methyl (+)-(S)-(2-chlorophenyl)-(6,7dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate [Clopidogrel base, (I)] and their various pharmaceutically acceptable salts.
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Page/Page column 4
(2008/12/05)
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- PROCESS FOR THE SYNTHESIS OF CLOPIDOGREL AND NEW FORMS OF PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to a new process for the preparation of clopidogrel and to new polymorphic forms of clopidogrel salts, to processes for their preparation and to a pharmaceutical formulation containing the new forms.
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Page/Page column 44
(2008/06/13)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention provides an improved process for the preparation of clopidogrel and its pharmaceutically acceptable salts, especially hydrogen chloride and hydrogen bromide by dissolving clopidogrel base in a suitable single or mixture of solvents followed by adding suitable acid and isolating the corresponding acid addition salts of clopidogrel compound of formula-1. Also provides an improved process for the preparation of clopidogrel hydrogen sulfate form-1; Formula (I).
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Page/Page column 14
(2008/06/13)
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- PROCESSES FOR THE PREPARATION OF CLOPIDOGREL
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The invention relates to processes for the preparation of clopidogrel and salts thereof. The inventors have developed a process for preparing racemic clopidogrel by racemizing R(-) clopidogrel. The process includes the step of reacting R(-) clopidogrel with a powered anhydrous base in one or more solvents.
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Page/Page column 6
(2009/01/20)
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- Method of Preparing Clopidogrel and Intermediates Used Therein
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Optically pure clopidogrel can be prepared in a high yield by optically resolving a racemic form of the compound of formula (II) using an optically active amine to form the optically active form of the compound of formula (III) or its acid-addition salt; and methylating the compound of formula (III) or its acid-addition salt.
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Page/Page column 6
(2008/12/08)
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- Preparation of Clopidogrel and Its Analogues Methyl Tetrahydrothienopyridine Acetate Compuunds
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The present invention disclosed a preparation method of Clopidogrel (X=2-Cl) and its analogues of methyl tetrahydrothienopyridine acetate (I) by using halogen phenyl acetonitrile (VIII) as starting material and tetrahydrothienopyridine acetonitrile (IV), tetrahydrothienopyridine acetate (V) as key intermediates, and further using kinetic resolution to prepare the optical active Clopidogrel and compounds of methyl tetrahydrothenopridine acetate of formula (XII). The Clopidogrel of present invention is a novel high effective and safety drug for inhibition of platelet aggregation. This invention applied systematic technique of racemization of unwanted optical active enantiomer, recover recycle and reuse of resolution agent etc., with greater economic advantages and suitable for commercial scale industrial production. Wherein: X represents atoms of hydrogen, fluorine, chlorine, bromine or iodine, M represents an alkali metal ion.
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Page/Page column 17
(2008/12/08)
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- PROCESS FOR HIGH YIELD PRODUCTION OF CLOPIDOGREL BY RACEMIZATION OF RESIDUAL LIQUID
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The present invention relates to a process for preparing S-(+)-clopidogrel in high yield by means of racemization of filtrate, and particularly to a process comprising (a) conducting an optical resolution by converting racemic carboxylic acid of clopidogrel to diastereomer salt using (+)-cinchonine, (b) preparing carboxylic acid of S-(+)-clopidogrel by extraction using an appropriate solvent under an acidic condition, (c) preparing optically pure S-(+)-clopidogrel by reacting the carboxylic acid of S-(+)-clopidogrel with methanol, wherein a filtrate, which remains after collecting the diastereomer salt as solid precipitates, is recycled after being converted to a racemic carboxylic acid of clopidogrel via racemization under a basic condition, thereby maximizing the yield of S-(+)-clopidogrel.
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Page/Page column 17-18; 19
(2008/06/13)
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