- Process improvements of prasugrel hydrochloride: An adenosine diphosphate receptor antagonist
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An improved process for the synthesis of prasugrel hydrochloride with an overall yield of 58%, 99.9% purity, and meeting all other quality requirements is described.
- Aalla, Sampath,Gilla, Goverdhan,Metil, Dattatray Shamrao,Anumula, Raghupathi Reddy,Vummenthala, Prabhaker Reddy,Padi, Pratap Reddy
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- A "bunch" method for preparing method for prasugrel
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The present invention relates to a method for preparing prasugrel through a one-pot-porridge method. According to the method, in the presence of an alkali, 5,6,7,7a-tetrahydrothieno[3,2-c]pyridine-2(4H)-one hydrochloride and cyclopropyl-2-bromo-2-(2-fluorophenyl)ethyl ketone react and then continuously react with acetic anhydride without an intermediate treatment, and finally the target compound prasugrel is collected from the reaction products. The technical scheme of the present invention has the following characteristics that: the hydroxyl protection is not required, the use of DMF, toluene and other strongly-toxic and high-boiling point solvents is avoided, the process is safe and easy to control, the steps are simplified, the post-treatment is simple, the purity and the yield of the product is maintained or improved, the cost is reduced, and the large-scale production is easily achieved.
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Paragraph 0032-0041
(2019/04/04)
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- A high-purity prasugrel preparation method
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A high-purity prasugrel preparation method, compared with the prior art, the invention adopts the new preparation process, by acylation and esterification, condensation, dehydrohalogenation, hydrolysis, cyclization and acetylation can be for preparing high-purity prasugrel, mild conditions, yield is higher; at the same time 1 - alkenyl - [six hydrogen pyrazoles - 1 - (α - cyclopropyl carbonyl - 2 - fluorobenzyl) - 2 - yl] - acetic acid R ester alkali is added to the catalyst so that the hydrolysis reaction can be carried through to the end, further improves the reaction yield, in addition to the 2 - acetoxy - 5 - (α - cyclopropyl carbonyl - 2 - fluorobenzyl) - 4, 5, 6, 7 - tetrahydro-thieno [3, 2 - c] pyridine has further purification, to obtain a high purity prasugrel, and the unexpected technical effects.
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Paragraph 0031; 0032
(2018/07/30)
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- Synthesis of a novel series of amino acid prodrugs based on thienopyridine scaffolds and evaluation of their antiplatelet activity
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The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2-hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research.
- Lu, Nan,Li, Lingjun,Zheng, Xuemin,Zhang, Shijun,Li, Yuquan,Yuan, Jing,Wei, Qunchao,Xu, Youjun,Meng, Fancui
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- PROCESS FOR THE PREPARATION OF HIGH-PURITY PRASUGREL
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The field of invention relates to a novel process, suitable for industrial scale manufacture, for the preparation of high-purity 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl acetate, prasugrel, of Formula (I). Especially in large-scale production, one of the main causes of piling up the impurities is the use of ether solvents consequently in each step in this procedure ethers are excluded. Avoiding the ethers resulted new conditions for production of intermediates in the different steps of our procedure. Conditions were determined so that each step from the beginning contributes to minimizing the impurity content of the end-product.
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- Intermediate for synthetizing prasugrel, preparation method of intermediate, and method for synthetizing prasugrel
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The present invention discloses an intermediate for synthetizing prasugrel, a preparation method of the intermediate, and a method for synthetizing prasugrel by using the intermediate. In the invention, cyclopropyl-2-fluorobenzyl ketone reacts with different chlorine source compounds under the action of an oxidizing agent to obtain the intermediate, and the intermediate is subjected to condensation with 2-Oxo-2,4, 5,6,7,7a-Tetrahydrothieno[3,2-c]pyridine-2(4H)-one hydrochloride and then is subjected to acetylation to obtain prasugrel; and the synthetizing route is simple, the cost is low, and operation is convenient.
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- A Simple and Efficient Method for the Preparation of α-Halogenated Ketones Using Iron(III) Chloride and Iron(III) Bromide as Halogen Sources with Phenyliodonium Diacetate as Oxidant
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α-Halogenated ketones are both unique structure moieties existing in biologically natural products and valuable synthetic intermediates for the preparation of functional molecules. An efficient and scalable method for the preparation of α-halogenated ketone using iron (III) chloride and iron (III) bromide as halogen sources with phenyliodonium diacetate as oxidant has been developed, featuring mild reaction conditions, environmentally friendly reagents, and wide substrate scope. Notably, the three-step synthesis of drug prasugrel was achieved using this developed method as a key step with 30% yield on gram-scale. Additionally, the reaction mechanism involving chloride cation was proposed based on some preliminary control experiments. (Figure presented.).
- Tang, Shi-Zhong,Zhao, Wenshuang,Chen, Tao,Liu, Yang,Zhang, Xiao-Ming,Zhang, Fu-Min
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supporting information
p. 4177 - 4183
(2017/12/18)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PRASUGREL INTERMEDIATES
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The present invention relates to an improved method for preparing 2-oxo prasugrel, 5-(andalpha;-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2,-c]pyridine (chemical formula 1), which is a major intermediate of prasugrel. More specifically, the present invention provides an improved method which is characterized by adding water as a catalyst and dividedly feeding an inorganic basic composition when 2-oxo prasugrel is synthesized through a condensation reaction between andalpha;-cyclopropylcarbonyl-2-fluorobenzylbromide represented by chemical formula 2 and 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2,-c]pyridine hydrochloride represented by chemical formula 3.COPYRIGHT KIPO 2017
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Paragraph 0062; 0067; 0069-0071; 0072; 0076; 0078
(2017/12/01)
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- An anti-platelet drug prasugrel method for the preparation of (by machine translation)
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The invention discloses an anti-platelet drug prasugrel method for preparing, the method includes: 1) the 1 [...] cyclopropyl -2 the [...] (the 2 [...] phenyl) - 2 the and iodine monobromide[...] ethanone and the 1 [...] butyl -3 the imidazolium methyl bromination[...] contact is obtained by reacting the 1 [...] cyclopropyl -2 the- [...] the 2 [...] (the 2 [...] phenyl) - 2 the [...] ethanone; 2) and in iodine under the presence of alkali, the step 1) product with the 2 [...] oxo -2, 4, 5, 6, 7 the [...] the 7a [...] tetrahydro-thieno [3,2 the ??c] pyridine hydrochloride is obtained by reacting the 5 [...] (α-cyclopropane carbonyl -2 the [...] fluorobenzyl) - 2 the [...] oxo -2, 4, 5, 6, 7, 7a-tetrahydro-thieno [3,2 the ??c] pyridine; 3) steps 2) product with triethylamine mixed, then instillment second grade anhydride, shall prasugrel stirring reaction. The method of preparing the prasugrel of this invention high yield, is easy to be treated, is suitable for industrial production. (by machine translation)
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- Method for preparing prasugrel intermediate
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The invention discloses a method for preparing a prasugrel intermediate 5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-1,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine. The method comprises a following reaction route. As a result of experiments, the method provided by the invention has the advantages of simple operation, mild reaction conditions, low requirement on equipment, inexpensive and easy-to-obtain raw materials, high yield, and low production cost. An adopted solvent can synchronously recovered. The method can be easily applied in large-scale productions. The method meets the requirements of prasugrel industrialized production, and has industrial application value.
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Paragraph 0061; 0062; 0063; 0064; 0065
(2016/10/10)
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- Thiopheneglyoxylic pyridine derivative and its preparation method and medical use
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The invention belongs to the field of pharmaceutical chemistry technology, and particularly discloses thienopyridine derivatives, and preparation methods and a medical use thereof. Through structural modification of clopidogrel and prasugrel, a series of new thienopyridine derivative compounds are synthesized and mainly include derivatives esterified with ligustrazine formic acid and shikimic acid; the compounds go into a body, then are rapidly metabolized into effective metabolites and ligustrazine formic acid or shikimic acid, successfully keep away from metabolism of CYP2C19 enzyme, can be directly metabolized into active compounds to play a pharmacological function, thereby solving the clopidogrel resistance problem, effectively improving the compound antithrombotic activity, and also having no significant effect on hemorrhage risk; and the compounds have relatively ideal protective function on liver and kidney, and also have potential therapeutic significance for other cardiovascular diseases.
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Paragraph 0081; 0084
(2016/12/01)
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- Method for preparing thrombosis-resisting medicine namely prasugrel
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The invention discloses a method for preparing a thrombosis-resisting medicine namely prasugrel. The method comprises the following steps of (1) performing nitrogen protection, in the presence of copper iodide, XPhos and alkali, enabling 1-cyclopropyl-2-bromine-2-(2-fluorophenyl)-2-ethanone and 2-oxo-2, 4, 5, 6, 7-7a-tetrahydro thieno [3,2-c] pyridine hydrochloride to be subjected to a reaction so as to obtain 5-(alpha-cyclopropane carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-thieno [3,2-c] pyridine; and (2) mixing the 5-(alpha-cyclopropane carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-thieno [3,2-c] pyridine obtained in the step (1) with anion exchange resin, then adding acetyl chloride, and performing a stirring reaction so as to obtain the prasugrel. The method for preparing the prasugrel disclosed by the invention is high in yield, easy to treat and suitable for industrialized production.
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Paragraph 0029-0047; 0063-0068
(2017/05/23)
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- Bioactivation of Clopidogrel and Prasugrel: Factors Determining the Stereochemistry of the Thiol Metabolite Double Bond
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The antithrombotics of the tetrahydrothienopyridine series, clopidogrel and prasugrel, are prodrugs that must be metabolized in two steps to become pharmacologically active. The first step is the formation of a thiolactone metabolite. The second step is a further oxidation with the formation of a thiolactone sulfoxide whose hydrolytic opening leads to a sulfenic acid that is eventually reduced into the corresponding active cis thiol. Very few data were available on the formation of the isomer of the active cis thiol having a trans configuration of the double bond, the most striking result in that regard being that both cis and trans thiols were formed upon the metabolism of clopidogrel by human liver microsomes in the presence of glutathione (GSH), whereas only the cis thiol was detected in the sera of patients treated with this drug. This article shows that trans thiols are also formed upon the microsomal metabolism of prasugrel or its thiolactone metabolite in the presence of GSH and that metabolites having the trans configuration of the double bond are only formed when microsomal incubations are done in the presence of thiols, such as GSH, N-acetyl-cysteine, and mercaptoethanol. Intermediate formation of thioesters resulting from the reaction of GSH with the thiolactone sulfoxide metabolite appears to be responsible for trans thiol formation. Addition of human liver cytosol to the microsomal incubations led to a dramatic decrease of the formation of the trans thiol metabolites. These data suggest that cytosolic esterases would accelerate the hydrolytic opening of thiolactone sulfoxide intermediates and disfavor the formation of thioesters resulting from the reaction of these intermediates with GSH that is responsible for trans isomer formation. This would explain why trans thiols have not been detected in the sera of patients treated with clopidogrel.
- Dansette, Patrick M.,Levent, Dan,Hessani, Assia,Mansuy, Daniel
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p. 1338 - 1345
(2015/06/25)
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- IMPROVED PROCESS FOR THE PREPARATION OF PRASUGREL AND INTERMEDIATE THEREOF
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The invention relates to an industrial scale process for the preparation of l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (1) and the use of this compound for the preparation of prasugrel.
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- PROCESS FOR PREPARING PRASUGREL
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The present invention is directed to an improved process for preparing, prasugrel and maleate salt of Prasugrel and, optionally other pharmaceutically acceptable salts from, prasugrel and said maleate salt, in high yields and purity, which can be used at industrial scale. The process of the present invention comprises the steps of bromination, condensation, acetylating and optionally converting into maleate salt and, if desired, conversion into another pharmaceutically acceptable salt from it. The present process is advantageous in terms of productivity, efficacy, purity and also prevents the use of toxic substances.
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- Identification and synthesis of impurities formed during prasugrel hydrochloride preparation
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Prasugrel hydrochloride (1), an important platelet inhibitor is used for the reduction of thrombotic cardiovascular events. During laboratory I optimization and later its bulk synthesis the formation of various impurities was observed. The impurities formed were monitored and their structures were tentatively assigned on the basis of their fragmentation patterns in LC-MS. Most of the impurities were synthesized and their assigned constitutions confirmed by co-injection in HPLC. We describe herein the formation, synthesis and characterization of these impurities. Present study will be of immense help to others to obtain chemically pure prasugrel hydrochloride.
- Umasankara Sastry,Nageswrara Rao,Appi Reddy,Gandhi
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p. 7783 - 7789
(2013/09/23)
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- Processes For Preparing Prasugrel And Pharmaceutically Acceptable Salts Thereof
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Disclosed are improved processes for preparing prasugrel compound of formula-(1), its intermediates and pharmaceutically acceptable salts.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PRASUGREL HYDROCHLORIDE AND ITS INTERMEDIATES
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The present invention provides an improved process for the preparation of prasugrel and its pharmaceutical acceptable salt. Prasugrel chemically known as 2-acetoxy-5-(a- cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine or 5-[2- cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2,-c]pyridine- 2yl acetate and having the structural formula (I) and its pharmaceutically acceptable salts. The present invention also provides an improved process for the preparation of cyclopropyl 2-fluorobenzyl ketone, 2-Fluoro-a-cyclopropyl carbonylbenzyl bromide, 5,6,7,7a Tetrahydro-4H- theino-[3,2-c]- pyridone-2 p-toluenesulfonate and its hydrochloride salt.
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- PREPARATION OF PRASUGREL HYDROCHLORIDE
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The present application relates to process for the preparation of prasugrel, its pharmaceutically acceptable salts, and its intermediates.
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Page/Page column 28-29
(2012/02/15)
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- NOVEL AND IMPROVED PROCESSES FOR THE PREPARATION OF PRASUGREL, ITS INTERMEDIATES AND PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to novel and improved processes for the preparation of prasugrel compound of formula-(1), its intermediates and pharmaceutically acceptable salts.
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Page/Page column 47-48
(2011/04/26)
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- A PROCESS FOR MAKING PRASUGREL
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The present invention relates to A compound of general Formula (A), and/or acid addition salts thereof, wherein R is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group and R1,R2 is independently a C1-C10 alkyl group, optionally having one or more carbons substituted by a hydroxy group, or R1,R2 together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring, to a process of making and use in making prasugrel.
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- IMPROVED PROCESS FOR THE PREPARATION OF PRASUGREL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved process for the preparation of prasugrel compound of formula- 1 and its pharmaceutically acceptable salts thereof.
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Page/Page column 16
(2009/06/27)
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- PROCESSES FOR THE PREPARATION OF PRASUGREL, AND ITS SALTS AND POLYMORPHS
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Processes for the preparation of prasugrel and its pharmaceutically acceptable salts thereof. Also disclosed are polymorphic forms of prasugrel hydrochloride and processes for their preparation.
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Page/Page column 41
(2009/06/27)
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- Oral dosage forms including an antiplatelet agent and an acid inhibitor
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The present disclosure provides oral dosage forms comprising an antiplatelet agent and an acid inhibitor, as well as methods of treating subjects with an antiplatelet agent and an acid inhibitor.
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Page/Page column 20-21
(2008/06/13)
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- MEDICINAL COMPOSITION
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A pharmaceutical composition containing a drug (A), a waxy substance (B), and synthetic aluminum silicate and/or hydrous silicon dioxide (C). The invention provides a granular pharmaceutical composition suitable for providing a pharmaceutical characterized in that adhesion of granules thereof onto a granulation apparatus during granulation is minimized and caking of the granules is suppressed.
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- Acid addition salts of hydropyridine derivatives
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Acid addition salts of 2-acetoxy-5-(α-cyclopropyl-carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine. The acid addition salts of tetrahydrothienopyridine derivatives of the present invention exhibit excellent oral absorption, metabolization into the active compound, and platelet aggregation-inhibiting effects, low toxicity, and excellent storage and handling stabilities, and are useful as medicaments, preferably preventive or therapeutic agents (particularly therapeutic agents) for diseases caused by a thrombus or an embolus, still more preferably preventive or therapeutic agents (particularly therapeutic agents) for thrombosis or embolism.
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- MEDICINAL COMPOSITIONS
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The present invention relates to a granular pharmaceutical composition comprising a drug having a disagreeable taste, a wax and a sugar alcohol; a method for preparing the same; and a pharmaceutical product for oral administration, comprising the granular composition. The product excellently masks a disagreeable taste possessed by a drug and provides good sensation upon oral administration, and therefore is easily ingested by even the elderly, children, and patients suffering dysphagia. Moreover, the product is suitable for administration using tube.
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- Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
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Compounds of formula (I): STR1 wherein: R1 is hydrogen, alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkylthio, haloalkylthio, amino, alkanoyl, haloalkanoyl, carboxy, alkoxycarbonyl, carbamoyl, cyano, nitro, alkanesulfonyl, haloalkanesulfonyl or sulfamoyl; R2 is optionally substituted alkanoyl, optionally substituted alkenoyl, optionally substituted cycloalkylcarbonyl, substituted benzoyl, or 5,6-dihydro-1,4,2-dioxazin-3-yl; R3 is hydrogen, hydroxy, optionally substituted alkoxy, aralkyloxy, alkanoyloxy, alkenoyloxy, cycloalkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aralkyloxycarbonylxy, phthalidyloxy, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methoxy, optionally substituted amino or nitro; Y is --NH-- or oxygen or sulfur; n is 1 to 5; and tautomers and salts of said compounds of formula (I), have the ability to inhibit blood platelet aggregation, and can thus be used for treatment and prophylaxis of thrombosis and embolisms.
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