- An NMR and DFT investigation on the interconversion of 9-substituented-N 6-hydrazone-8-azaadenine derivatives: proton migration or conformational isomerization?
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A newly synthesized N6-arylhydrazone-8-azaadenine derivatives (1) showed significant differences in NMR spectra with previously synthesized analogues, specifically, the hydrogens of N1’H and C3’H in all the titled compounds showed two groups of signals in their 1H-NMR spectra. In order to investigate whether the duplication of proton signals were related to a mixture of conformational isomers which rotated around C-N1’ bond or configurational isomers which resulted from proton migration, variable temperature NMR and 2D-NOESY experiments were carried out in conjunction with density function theory (DFT) calculations at the B3LYP/6-311G (d,p)//B3LYP/6-31G (d,p) level. The results indicated that it was the conformational isomerism rather than hydrogen transfer that induced the reproduction of proton signals, which was attributed to lower barrier energy and larger rate constant of the former process.
- Fan, Qiangwen,Wang, Yeming,Yan, Hong
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Read Online
- Synthesis and biological evaluation of: N 6derivatives of 8-azapurine as novel antiplatelet agents
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Two series of novel N6 derivatives of 8-azapurine I and II were designed as antiplatelet agents. Series I and II were N6 amino derivatives and N6 hydrazone derivatives of 8-azapurine, respectively. The compounds were synthesized in acceptable yields via conventional procedures, including nucleophilic substitution, diazotization, and amination or hydrazonation with amino alcohol and 4,6-dichloropyrimidine as starting materials. To assess the ability of the synthesized compounds as antiplatelet agents, the ADP-induced platelet aggregation assay of Born was performed both in vitro and in vivo using ticagrelor as a reference control substance. The analysis of the structure-activity relationship and molecular docking were also discussed in detail. The results demonstrated that series I and II compounds exhibited antiplatelet activity in vitro and IIh was the most active compound (IC50 = 0.20 μM) among the target compounds, being almost 4-fold better than ticagrelor (IC50 = 0.74 μM). For a preliminary assessment of the safety profile, a bleeding test (mouse tail) and a single-dose toxicity test were conducted. The use of compound IIh resulted in a shorter bleeding time, less blood loss and lower acute toxicity compared to ticagrelor. In addition, a molecular docking study was performed to investigate the binding capacity and binding mode between IIh and P2Y12. This journal is
- Tian, Nana,Wang, Juan,Wang, Yeming,Yan, Hong,Zhao, Zhichang
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p. 1414 - 1427
(2021/11/09)
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- A [...] preparation method and intermediate
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The present invention relates to a preparation method and an intermediate of ticagrelor. The preparation method comprises that a compound represented by a formula VIII and a compound represented by a formula VII or a salt thereof as raw materials to carry out a reaction, and the obtained intermediate is subjected to acetonylidene protection group removing, optionally substituted azobenzene protection group removing, and cyclization, and then reacts with a compound represented by a formula II or a salt thereof to prepare the ticagrelor. The preparation method of the present invention has characteristics of short step, high total yield, mild reaction conditions and simple post-treatment, and is suitable for industrial production.
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- A method for preparing for standard auspicious Luo river
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The invention provides a preparation method for ticagrelor. The method comprises the reaction steps shown in the specification, and concretely comprises the following steps: (1) in the presence of an alkali, coupling a formula II compound with a formula III compound to generate a formula IV compound; (2) under an acidic condition, performing reduction and deprotection on the formula IV compound, so as to obtain a formula V compound; (3) performing diazotization and ring closure on the formula V compound, so as to generate a formula VI compound; and (4) under an alkali condition, coupling the formula VI compound with a formula VII compound, so as to obtain ticagrelor shown as a formula I. The method is mild in reaction conditions and simple in post-treatment, is capable of effectively controlling impurities and improving the optical purity of the product, is suitable for industrialized production and has relatively large application value.
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- 6-hydrazone radical-8-aza-purine compound and preparing method and application thereof
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The invention relates to a 6-hydrazone radical-8-aza-purine compound and a preparing method and an application thereof and belongs to the fields of preparation of novel compounds and medicine application. The general molecular formula of the compound is shown in the description, wherein R1 is hydroxide radical, methylol group and hydroxyethoxy, R2 is hydrogen, hydroxide radical, and fluorine, R3 is methyl, ethyl, propyl and 3,3-trifluoropropyl group, and R4 is aryl group, substitutional aryl group, ceteroary, and substitutional ceteroary. A midbody is used as reaction substrate, wherein the formula of the midbody is shown in the description, the midbody and a hydrazine and aldehydes compound are subjected to a condensation reaction, and the 6-hydrazone radical-8-aza-purine compound is obtained. According to the novel 6-hydrazone radical-8-aza-purine compound, the antiplatelet aggregation activity is high, the bleeding side effect is low, and the compound can be used for preparing the antiplatelet aggregation medicine and preventing and treating the related thrombotic disease.
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Paragraph 0075-0078
(2017/09/02)
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- INTERMEDIATE OF TICAGRELOR AND PREPARATION METHOD THEREFOR, AND PREPARATION METHOD FOR TICAGRELOR
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Disclosed are intermediates of Ticagrelor and a preparation method therefor, and a preparation method for Ticagrelor. Specifically, disclosed is an intermediate, namely, a compound of Formula (VI), for preparing Ticagrelor. Further disclosed is a method for preparing the intermediate and a method for preparing Ticagrelor by using the intermediate. Ticagrelor is prepared by using the intermediate, so that the synthesis process is simple, and a defect that long reaction times under high temperature that are required in the existing methods are avoided. The method is suitable for mass production in industry, energy consumption is reduced, pollution of the environment is reduced, and discharge of waste is reduced.
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- PREPARATION OF TICAGRELOR
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Provided are processes for preparing Ticagrelor and its intermediates that are useful in the processes. Also provided are salts of Ticagrelor, their processes and solid dispersion of Ticagrelor having Ticagrelor in amorphous form.
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Paragraph 0195
(2015/03/16)
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- A PRODUCTION METHOD AND A NEW CRYSTALLINE FORM OF AN INTERMEDIATE OF SYNTHESIS OF TICAGRELOR
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The invention relates to preparation of ticagrelor of formula I and comprises a reaction of a compound of formula IV with a deprotection agent in a solvent to a compound of formula V, which is advantageously isolated by crystallization and subsequently used for the preparation of ticagrelor. The substituent R in formulae IV and V is CH2CH2OH, CH2COOH, or CH2COOR1; R1 is a branched or unbranched R1-C4 alkyl; and X is NH2, NO2f or NHCHO.
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Page/Page column 17
(2015/05/26)
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- A PROCESS FOR PREPARATION OF TICAGRELOR AND INTERMEDIATES THEREOF
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An improved process for the preparation of ticagrelor and its intermediates thereof; wherein the said process substantially eliminates the potential impurities.
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Page/Page column 92-93
(2014/07/21)
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- METHOD FOR THE PREPARATION OF TICAGRELOR AND INTERMEDIATES SUITABLE THEREFORE
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A method for the preparation of ticagrelor of formula I, wherein the key reaction of the entire synthesis is condensation of an amino cyclopentane diol with pyrimidine, providing the isolated intermediate of formula IV. The amino cyclopentane diol is used for the reaction with pyrimidine without any protecting group on the hydroxyls in positions 1 and 2. Using the compound without a protecting group eliminates the necessity of deprotection in the subsequent synthetic steps.
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- SYNTHESIS OF TRIAZOLOPYRIMIDINE COMPOUNDS
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The present invention relates to the field of organic synthesis and describes the synthesis of specific intermediates suitable for the preparation of triazolopyrimidine compounds such as ticagrelor.
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- Synthesis of triazolopyrimidine compounds
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The present invention relates to the field of organic synthesis and describes the synthesis of specific intermediates suitable for the preparation of triazolopyrimidine compounds such as ticagrelor.
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- NEW INTERMEDIATES AND PROCESSES FOR PREPARING TICAGRELOR
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The present invention is related to new intermediates and processes for preparing Ticagrelor disclosed in this patent application.
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Page/Page column 83
(2012/10/18)
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