- Efficient Synthesis of (S)-(+)-Clopidogrel Bisulfate-Capped Silver Nanoparticles
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In this work primarily one-pot synthetic development in the preparation of clopidogrel bisulfate with a polymorphic crystalline form II in 90% yield was developed. This premade antiplatelet drug has been used to protect starch-stabilized silver nanoparticles (AgNPs).
- Mahmoodi, Nosrat O.,Ghavidast, Atefeh,Ashkan, Mitra,Mamaghani, Manouchehr,Zanjanchi, Mohammad Ali,Tabatabaeian, Khalil,Arabanian, Armin
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- 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 intermediate
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The present invention relates to a preparation method of a clopidogrel hydrogen sulfate intermediate. (+)-2-chlorophenylglycine methyl ester and alpha-thiopheneethanol p-toluenesulfonate are adopted as raw materials, a reaction solvent and an acid-binding agent are added for a condensation reaction, the condensation reaction process is divided into a first stage and a second stage, and when 60-95% of the condensation reaction is completed, first-stage reaction is completed; after the first-stage reaction is completed, firstly part of the reaction solvent is removed, and then second-stage reaction is carried out; and after the second-stage reaction is completed, a target product is obtained, namely the clopidogrel hydrogen sulfate intermediate. After the first-stage reaction is completed, part of the reaction solvent is removed firstly, and then the second-stage reaction is continued, so that the concentration of the reaction material can be increased in the later stage of the condensation reaction, the use amount of the reaction solvent is reduced, and racemization and side reaction in the reaction process are effectively inhibited, thereby improving the chiral purity of the product, increasing the yield, reducing the use of auxiliary materials greatly, and reducing the production cost.
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- Preparation method of clopidogrel hydrogen sulfate
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The invention relates to a preparation method of clopidogrel hydrogen sulfate. The preparation method comprises the following steps: reacting (S)-o-chlorophenylglycine methyl ester with 1, 1, 1, 3, 3,3-hexamethyldisilazane to obtain trimethylsilyl protected (S)-o-chlorophenylglycine methyl ester; in the presence of acetonitrile, superfine powder potassium carbonate and the trimethylsilyl protected (S)-o-chlorophenylglycine methyl ester, adding 2- (2-bromoethyl) thiophene, evaporating acetonitrile in batches, adding water and methyl acetate, extracting to obtain a methyl acetate solution of (S)-2-thiophene ethylamino-2-chlorophenylmethyl acetate, dropwise adding concentrated hydrochloric acid, carrying out pulping and cooling to obtain (S)-2-thiophene ethylamino methyl-2-chlorophenyl acetate hydrochloride, mixing the (S)-2-thiophene ethylamino methyl-2-chlorophenyl acetate hydrochloride with a formaldehyde aqueous solution for reaction, and carrying out reaction with concentrated sulfuric acid to obtain the clopidogrel hydrogen sulfate. According to the method, the high-purity (S)- 2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride and clopidogrel hydrogen sulfate can be obtained with high efficiency and high yield, and the method is suitable for industrial production.
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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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- 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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- 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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- 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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- Method for preparing high-purity type-II crystal form hydrogen sulfate clopidogrel
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The invention discloses a method for preparing high-purity type-II crystal form hydrogen sulfate clopidogrel. The method comprises the following steps: dissolving a first clopidogrel free alkali crudeproduct into dichloromethane, performing decontamination by using a 4wt% sodium hydroxide solution, performing alkali wash on an organic phase, and performing drying, suction filtration and concentration so as to obtain a seconda clopidogrel free alkali crude product; and adding ethyl acetate or a mixed liquid of ethyl acetate and acetonitrile, increasing the temperature to 37-39 DEG C, adding dropwise concentrated sulfuric acid to be subjected to crystallization, performing room-temperature crystallization, performing filtering, and drying filter cakes so as to obtain a final product, namelytype-II crystal form hydrogen sulfate clopidogrel. The method is mild in reaction condition and free of toxic or harmful substance, in addition, the amount of a precursor solvent is reduced, the reaction time is shortened to 4-6 hours from 14-16 hours, the energy consumption is reduced, related substances of the type-II crystal form hydrogen sulfate clopidogrel are ensured to meet various domestic and abroad standards, and generation of impurities is avoided when strong acids are added dropwise; and the obtained type-II crystal form hydrogen sulfate clopidogrel is high in purity and high in yield.
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Paragraph 0029-0056
(2020/01/03)
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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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- A method for the preparation of clopidogrel hydrogen sulfate
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The invention discloses a preparation method of clopidogrel bisulfate. 2-bromo-2-(2-chlorphenyl) methyl acetate and 4,5,6,7-thiophane[3,2-c]pyridine are taken as raw materials; a proper quantity of sodium bicarbonate is added; reaction is carried out for 1 to 10 hours in a chiral ionic liquid as shown in the formula (I) at 20 to 100 DEG C; the temperature is lowered to 20 to 25 DEG C; a proper quantity of dichloromethane is added; the temperature is raised to 60 to 65 DEG C; reaction is carried out for 6 hours; the temperature is lowered to 20 to 25 DEG C; a dichloromethane solution is separated out; the temperature is lowered to -5 to 0 DEG C; concentrated sulfuric acid is added dropwise slowly; stirring and filtering are carried out; drying is carried out to obtain the clopidogrel bisulfate product. In the formula (I), R represents alkyl of which the carbon number is 1 to 10; L represents hydroxy acid radical ions. As the chiral ionic liquid is taken as a solvent and a resolving agent, the preparation method is easy to operate, high in effect, less in three waste generation, and convenient in post treatment, and the chiral ionic liquid can be used repeatedly. Therefore, the preparation method is an economic, practical and environment-friendly technology.
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Paragraph 0016; 0017; 0018; 0019; 0020; 0021-0029
(2017/08/25)
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- A method for the preparation of clopidogrel hydrogen sulfate (by machine translation)
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The invention relates to a method for the preparation of clopidogrel hydrogen sulfate, it to 2 - thiophene acetaldehyde as basic starting material, with their O-chlorobenzene glycine methyl ester condensation reaction, generating the corresponding imine intermediate, then sodium borohydride or directly for the imine intermediate nitrile sodium borohydride reduction to the corresponding secondary amine intermediate, then this kind of secondary amine intermediate ring by reaction with formaldehyde clopidogrel, acidified by sulfuric acid to obtain the target compound of the clopidogrel hydrogen sulfate. The present invention provides a synthetic route of the short, relates to the reaction are classical organic reaction, mild reaction conditions, the operation is simple, the total high yield, low cost, and is suitable for industrial production. (by machine translation)
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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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Paragraph 0042; 0043
(2017/08/30)
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- Method For Preparing Spherical Clopidogrel Hydrogen Sulfate Polymorph I
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This invention provides a new preparation method of Clopidogrel Hydrogen Sulfate spherical crystal form I, using single 2-butanol as solvent, controlling the concentration, addition way and addition speed of sulfuric acid used to salify to shorten the process time, thus separating out Clopidogrel Hydrogen Sulfate from solution system stably with spherality. And the Clopidogrel Hydrogen Sulfate obtained complies with the requirements of the follow-up process on residual solvent, bulk density and mobility.
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Paragraph 0032; 0033
(2017/06/12)
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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 0020; 0021; 0022-0038
(2017/10/07)
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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 0018; 0019; 0020; 0021; 0022; 0023; 0024-0043
(2017/09/18)
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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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- A (S)-clopidogrel sulfate or hydrochloride preparation method
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The invention discloses a method for preparing sulfate or hydrochloride of (S)-clopidogrel. The method comprises the steps as follows: (1), under the condition of existence of an organic solvent insoluble with water, an aqueous solution of formaldehyde is added to hydrochloride or sulfate of (S)-(+)-alpha-(2-thiophene ethylamino)-alpha-(2-chlorphenyl) methyl acetate for a cyclization reaction, and (S)-clopidogrel is obtained through postprocessing after the reaction is completely performed; and (2), (S)-clopidogrel obtained in the step (1) is dissolved in a solvent, sulfuric acid or hydrochloric acid is added for a salt forming reaction, and sulfate or hydrochloride of (S)-clopidogrel is obtained through postprocessing after the reaction is completely performed. According to the method, the step (1) is performed in a two-phase system, so that impurities are effectively reduced, and the purity and the yield of (S)-clopidogrel are improved; and meanwhile, the purification steps are simplified with the reduction of the impurity content, and industrialization operation is facilitated.
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Paragraph 0065; 0066
(2016/12/07)
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- I-a kind of preparation method of clopidogrel hydrogen sulfate
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The invention provides a method for preparing a (+)-(S)-clopidogrel hydrogen sulfate crystal form I. The method comprises the following steps of: firstly, adding a methyl isobutyl ketone solvent, and dropwise adding sulfuric acid diluted by using the meth
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Paragraph 0045; 0046; 0047
(2017/04/03)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULFATE FORM-I
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The present invention provides an improved process for the preparation of pure Clopidogrel bisulfate Form-I of formula (I), which comprises: reacting S(+)-methyl-2- [2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (Formula II) with Formaldehyde and R-(-) Camphor sulphonic acid to yield S (+)-Clopidogrel camphor sulfonate salt (Formula III), which is on further treatment with C1-5 carboxylic acid followed by sulphuric acid to get Clopidogrel Form-I.
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Page/Page column 8
(2014/08/19)
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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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Page/Page column
(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 0050
(2014/06/11)
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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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- PROCESS FOR PREPARATION OF CLOPIODOGREL BISULFATE 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 4
(2012/09/22)
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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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- 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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- 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 16
(2011/10/31)
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- PROCESS FOR THE PREPARATION OF CLOPIDOGREL HYDROGEN SULPHATE FORM 1
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The present invention relates to a process for the preparation of Form 1 of (+)-(S)-∞-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester hydrogen sulphate commonly known as clopidogrel bisulphate. The present invention further relates to a process for reducing the residual amount of methyl isobutyl ketone and controlling the amount of mesityl oxide in clopidogrel hydrogen sulphate Form 1 by washing with ethyl acetate. Formula (I).
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Page/Page column 9
(2010/05/13)
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- PROCESS FOR MAKING POLYMORPH FROM I OF (S) - (+) -METHYL-ALPHA- (2-CHLOROPHENYL) -6, 7-DYHIDRO-THIENO- [3, 2-c] PYRIDINE-5 (4H) -ACETATE HYDROGEN SULFATE
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The invention relates to a process for the preparation of the pharmaceutically applicable polymorph Form I of (S)-(+)-methyl-α-(2-chlorophenyl)-6,7-dyhidro-thieno[3,2-c]-pyridine-5(4H)-acetate hydrogen sulfate of formula I; by reacting (S)-(+)-methyl-α-(2
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Page/Page column 6
(2009/04/24)
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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 19
(2008/12/08)
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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 48-49
(2008/06/13)
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- Process for the preparation of crystalline clopidogrel hydrogen sulphate Form I
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The present invention describes an improved industrial process for crystallizing polymorph Form I of (+) clopidogrel hydrogen sulphate (also called clopidogrel bisulphate) in either a Type-I solvent or a Type-II. Type I solvent is an organic solvent conta
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Page/Page column 5
(2008/12/07)
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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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- PROCESS FOR PREPARATION OF PURE POLYMORPHIC FORM 1 OF CLOPIDOGREL HYDROGENSULFATE
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Process for the preparation of substantially pure polymorphic Form 1 of clopidogrel hydrogensulfate, wherein the reaction of optically active clopidogrel base with sulfuric acid is carried out in the mixture of at least two solvents, chosen from group I,
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Page/Page column 13
(2008/12/04)
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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 17
(2008/06/13)
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- PROCESS FOR PREPARING CLOPIDOGREL BISULPHATE
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Provided are processes for the preparation of clopidogrel bisulphate Form I.
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Page/Page column 7
(2008/06/13)
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- 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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p. 487 - 489
(2012/12/31)
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- PROCESS FOR PREPARATION OF CLOPIDOGREL BISULPHATE FORM-1
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Disclosed herein is a cost effective and industrially feasible process for the preparation of (+) Clopidogrel bisulphate. The present invention further discloses a novel method of precipitation of (+) Clopidogrel bisulphate Form I directly from solvent mix of methanol and acetone in presence of sulfuric acid at a temperature of 25-40° C.
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Page/Page column 4-5
(2008/06/13)
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- A PROCESS FOR PREPARATION OF METHYL-(+)-(S)-ALPHA-(2-CHLOROPHENYL)-6,7-DIHYDROTHIENO[3,2-C]PYRIDINE-5(4H)-ACETIC ACID METHYL ESTER OR SALTS THEREOF HAVING HIGHER CHIRAL PURITY AND PRODUCTS THEREOF
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A process for preparation of Methyl-(+)-(S)-alpha-(2-chlorophenyl) -6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester or salts thereof [clopidogrel or salts thereof of Formula (I)] having higher chiral purity and products thereof is provided. A process for purification of the compound prepared is also provided to enhance its efficacy by enhancing its optical rotation and chiral purity. In Formula (I), R is selected from a group comprising alkyl, alkoxy, hydroxy, amine etc., and R1 is selected from the group comprising C1-4 alkyl, C1-4 alkoxy, hydroxy, nitro & halogen. The particular salt of interest of the present invention is the hydrogen sulfate of compound of the Formula (I), wherein R and R1 are -OCH3 and chloro-group at position 2 respectively.
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- Industrial process for preparation a polmorph of clopidogrel hydrogen sulphate
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An improved process for the manufacture of Clopidogrel starting from 2-(2-thienyl) ethylamine, which eliminates the isolation of an unstable intermediate like 2-(2-thienyl) ethyl formimine by subjecting it to a one pot cyclization to get 4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II and further reacting with halo-compound of Formula III (where X is Cl or Br) at 20 to 90 °C temperature characterized in a solvent like water and/or dichloroethane in presence of organic or inorganic bases is disclosed herein. This invention further discloses a process for resolution of racemic clopidogrel into its optical antipodes and converting the dextroclopidogrel base into its known polymorphs namely 'Form I' or 'Form II' in solvents selected from methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, mixture of ethyl acetate and methyl propyl ketone, mixture of ethyl acetate and methyl isopropyl ketone, or mixture of ethyl acetate and diethyl ketone or ethyl acetate.
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- PROCESS FOR PREPARING CLOPIDOGREL
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A process for preparing clopidogrel or a salt thereof.
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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-dihydrotliieno [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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- RECOVERY OF CLOPIDOGREL BISULFATE
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A process for preparing a racemic clopidogrel acid salt comprises reacting clopidogrel camphor sulfonic acid with an acid. The clopidogrel camphor sulfonic acid can be present in a residue from separating a clopidogrel camphor sulfonic acid optical isomer.
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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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- PROCESS FOR PREPARING CLOPIDOGREL HYDROGEN SULFATE OF FORM I
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The invention relates to a process for the preparation of form I clopidogrel hydrogen sulfate through suspending clopidogrel hydrogen sulfate in an alkane.
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- Process for making crystalline form I of clopidogrel hydrogen sulphate
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A process for preparation of crystalline Form I of clopidogrel hydrogen sulphate, that include separating the crystalline Form I of clopidogrel hydrogen sulphate from a solution of clopidogrel freebase in a solvent, which is 2-propanol or 2-butanol is provided.
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- Stereoselective process for the preparation of Clopidogrel
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Preparation of (2-halophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) compounds (Ia) or their salts comprises converting benzene derivatives (II) with an optically active amino alcohol to form a first mixture of diastereomers. Preparation of (2-halophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) compounds of formula (Ia) or its salt comprises converting benzene derivatives of formula (II) with an optically active amino alcohol to a first mixture of diastereomers. X : halo; and Y, Z : leaving groups. Independent claims are also included for the following: (1) a mixture of benzene diastereomers of formulae (IVa) and (IVb); (2) a compound (IVa); (3) a mixture of thiazo piperidine diastereomers of formulae (VIa) and (VIb); (4) compound (VIa); (5) a mixture of thiophene diastereomers of formulae (VIIIa) and (VIIIb); (6) a compound (VIIIa); and (7) preparation of 1-dimethylamino-propan-2-ol compound of formula (a) comprising reacting a diastereomeric mixtures of 1-dimethylamino-propan-2-ol of formulae (b) and (c) with L-(-)-di-O-benzoyl-L-(-)-tartaric acid (L-(-)-DBTA) and separating the L-(-)-DBTA salts of the compounds. A* : 1-30C hydrocarbon (containing 5 heteroatoms of S, O, N or halo and substituted with 5 substituents of OH, oxo, CN or nitro group) or one or more optically active units; and either R 1>, R 2>H, 1-20C hydrocarbon containing 4 heteroatoms of S, O, N or halo and substituted with 5 substituents of OH, oxo, CN or nitro groups); or C+R 1>+R 2> or R 1>+R 2>+heteroatom of A* : 5-10 membered ring (optionally saturated and optionally containing further 1-3 heteroatoms of N, O or S adjacent to the N, then a ring member is substituted with up to 5 substituents of 1-6C alkyl, 1-6C alkenyl, 1-6C alkoxy, 5-10C (hetero)aryl, 3-8C cycloalkyl, 2-8C heterocycloalkyl, halo, OH, oxo, CN or nitro (especially 1-6C alkyl, 5-10C hetero(aryl), 3-8C cycloalkyl or 2-8C heterocycloalkyl or N+R 1>+R 2> forms 3-8C saturated or unsaturated ring optionally with 1-6C alkyl or halo substituted and adjacent to N 1-2 further heteroatom of S, N or O). [Image] [Image] [Image] ACTIVITY : Anticoagulant; Thrombolytic. MECHANISM OF ACTION : Thrombocyte aggregation inhibitor.
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- CRYSTALLISATION OF SOLID FORMS OF CLOPIDOGREL ADDITION SALTS
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The invention relates to a process for the preparation of form 1 and form 2 of clopidogrel hydrogen sulfate, a process for the preparation of amorphous clopidogrel hydrogen sulfate, the 2-propylsulfate of clopidogrel, the perchlorate of clopidogrel and methods for the preparation of these compounds.
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- CRYSTALLINE CLOPIDOGREL NAPHTHALENESULFONATE OR HYDRATE THEREOF, METHOD FOR PREPARING SAME AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
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A crystalline clopidogrel naphthalenesulfonate or a hydrate thereof, a method for preparing same, and a pharmaceutical composition containing same are provided.
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