- 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; 0112
(2021/05/08)
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- Synthesis method of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride
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The invention relates to a synthesis method of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride. The method comprises the following steps: synthesizing 2-(2-thienyl)ethyl p-toluenesulfonate from 2-thiopheneethanol and paratoluensulfonyl chloride, further reacting the 2-(2-thienyl)ethyl p-toluenesulfonate with formamide to synthesize N-2-thienylethylformamide, carrying out cyclization on the N-2-thienylethylformamide under the action of trifluoroacetic acid to produce 6,7-dihydrothieno[3,2-c]pyridine, reducing the 6,7-dihydrothieno[3,2-c]pyridine with sodium borohydride, and carrying out salification to obtain the 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride. The invention provides a novel method for synthesizing the 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride. The method has the characteristics of low cost, low toxicity and simple technique, and has industrialized application prospects.
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- 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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p. 1552 - 1557
(2016/06/09)
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- Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development
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Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed. (Chemical Equation Presented).
- Shaw, Scott A.,Balasubramanian, Balu,Bonacorsi, Samuel,Cortes, Janet Caceres,Cao, Kevin,Chen, Bang-Chi,Dai, Jun,Decicco, Carl,Goswami, Animesh,Guo, Zhiwei,Hanson, Ronald,Humphreys, W. Griffith,Lam, Patrick Y. S.,Li, Wenying,Mathur, Arvind,Maxwell, Brad D.,Michaudel, Quentin,Peng, Li,Pudzianowski, Andrew,Qiu, Feng,Su, Shun,Sun, Dawn,Tymiak, Adrienne A.,Vokits, Benjamin P.,Wang, Bei,Wexler, Ruth,Wu, Dauh-Rurng,Zhang, Yingru,Zhao, Rulin,Baran, Phil S.
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p. 7019 - 7032
(2015/07/27)
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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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Page/Page column 18
(2012/01/14)
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- Sulfur monoxide transfer from peri -substituted trisulfide-2-oxides to dienes: Substituent effects, mechanistic studies and application in thiophene synthesis
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Three peri-substituted trisulfide-2-oxides are prepared by treatment of 1,8-naphthalene dithiols with thionyl chloride and pyridine. The 1,2,3-trithiane-2-oxide ring adopts a sofa conformation in the solid state, with a pseudoaxial oxygen and evidence of ring strain (peri-interaction). Heating the trisulfide-2-oxides in the presence of a diene results in formal sulfur monoxide (SO) transfer to form unsaturated cyclic sulfoxides, along with a recyclable 1,8-naphthalene disulfide. The presence of o-methoxy or o-tert-butyl substituents on the naphthalene ring lowers the temperature and increases the rate at which SO transfer occurs. Trapping experiments and kinetic studies are consistent with the generation of triplet SO, followed by in situ trapping by diene. Transfer of SO also occurs upon irradiation at room temperature, but yields of sulfoxide are lower. Dehydration of the sulfoxides under Pummerer conditions gives thiophenes, including the naturally occurring thioperillene. Two dienes form thiophenes directly under the SO transfer conditions. The methodology is applied in a formal synthesis of the antiplatelet medication Plavix.
- Grainger, Richard S.,Patel, Bhaven,Kariuki, Benson M.,Male, Louise,Spencer, Neil
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supporting information; experimental part
p. 5843 - 5852
(2011/06/22)
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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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- Design and synthesis of non-cytotoxic tetrahydrothieno[3,2-c]pyridine derivatives exhibiting complement inhibition activity
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A series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives have been synthesized and evaluated for their activity on the activation of human complement (classical pathway) and their intrinsic haemolytic activity. The in vitro assay results of these analogues for inhibition of complement activity reveals improved inhibitory activity for some of the analogues over existing tetrahydrothienopyridine derivatives like Ticlopidine and Clopidogrel. Significantly, these analogues did not exhibit any haemolytic activity and are non-cytotoxic to human cell lines.
- Master, Hoshang E.,Khan, Shabana I.,Poojari, Krishna A.
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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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Page/Page column 9
(2008/06/13)
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- RACEMIZATION AND ENANTIOMER SEPARATION OF CLOPIDOGREL
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Processes for separation of enantiomers of clopidogrel, and converting one enantiomer of clopidogrel to another enantiomer of clopidogrel are provided. The enantiomers are separated by crystallizing the (S) enantiomer as camphor sulfonate salt from a hydrocarbon, or a mixture of a hydrocarbon and a co-solvent, preferably DMF:toluene. The (R) enantiomer is then racemized and recycled by reaction with a catalytic amount of a base, preferably with t-butoxide.
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- THIENOISOXAZOLYL AND THIENYLPYRRAZOLYL PHENOXY SUBSTITUTED PROPYL DERIVATIVES USEFUL AS D4 ANTAGONISTS
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The compounds are of the class thienoisoxazolyl- and thienylpyrrazolyl-phenoxy substituted propyl derivatives, useful as D4 antagonists. Said compounds are useful for the treatment of medical conditions mediated by inhibition of D4 receptor. These conditions comprise, for example, Attention Deficit Hyperactivity Disorder, Obsessive-Compulsive Disorder, Psychoses, Substance Abuse, Substance Dependence, Parkinson's Disease, Parkinsonism, Tardive Diskinesia, Gilles de la Tourette Syndrome, Conduct Disorder, and Oppositional Defiant Disorder. A further aspect of the invention is to provide a pharmaceutical composition, intermediates, and a method of making said class of compounds.
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Page/Page column 53
(2008/06/13)
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- Process for the preparation of thienopyridine derivatives
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This invention relates to a process for the preparation of compounds having the general formula: STR1 in which: R1 represents a hydrogen atom, an optionaly substituted alkyl, aryl or aralkyl radical; R2 and R3 are the same or different and represent independently a hydrogen atom, a lower alkyl, aryl or heterocyclic radical; and R4 represents a hydrogen atom or an alkyl, cycloalkyl, alkoxy carbonyl, carboxy, aryl or heterocyclic radical, comprising reacting a compound having the formula: STR2 in which R1, R2 and R3 are as defined above, with a compound having the formula: STR3 in which R4 is as defined above; X is a halogen atom, or an optionally substituted alkoxy, thioalkyl or amino group; and Y represents an optionally substituted alkoxy, thioalkyl or amino group, or a group of the formula: STR4 in which R is a lower alkyl or aryl radical; or both the groups X and Y, together with the carbon atom to which they are attached, form a 6-membered hexahydro-S-triazinic, trioxannic or trithianic heterocyclic nucleus, in an inert solvent, at a temperature between 0° and 150° C. and in an anhydrous medium, and, if desired, liberating the free base.
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