- NEW USE OF TRIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES
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Triazolo[4,5-d]pyrimidine derivatives of formula (I) for use in prognosis and/or diagnosis of bacterial infection in a host mammal and method of imaging thereof. Formula (I) wherein R1 is C3-5 alkyl optionally substituted by one or m
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- Method for preparing ticagrelor advanced intermediate by applying continuous flow reaction technology
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The invention discloses a method for preparing a ticagrelor advanced intermediate by using a continuous flow reaction technology. The method comprises the following steps: reacting TGM-1 with sodium nitrite in a first microchannel reactor, carrying out diazotization reaction, cyclizing to synthesize triazole, and carrying out butt coupling on TGM-2 and an intermediate TGC under the action of an alkali reagent in a second microchannel reactor to obtain the target product isopropylidene ticagrelor TGI. According to the scheme, the whole preparation process is simple, operation is convenient, itis possible to prepare the macromolecular compound isopropylidene ticagrelor through the continuous flow reaction technology by reasonably designing reaction parameters, and the preparation yield of the method is high; and compared with a traditional reaction kettle batch-type chemical synthesis method, the method of the invention has the advantages of high-speed mixing, narrow reactant retentiontime, good repeatability, almost no amplification effect, convenience in real-time monitoring of the reaction process, high safety performance and the like, and is beneficial to large-scale productionand application of the substance.
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Paragraph 0011; 0035-0039; 0044-0048; 0053-0057
(2021/03/11)
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- PROCESS FOR THE PREPARATION OF TICAGRELOR
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The present invention relates to a process for the preparation of ticagrelor, which provides a product of high purity, in particular, with no detectable levels of Nnitrosmine impurities. The process comprises a first step of treating 2- [[(3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol starting material with sodium nitrite, followed by acidic washing; in a second step, the 2-[[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H- cyclopenta-1,3-dioxol-4-yl]oxy]ethanol obtained in the previous step is coupled with trans-(1 fl,2S)-2-(3,4-difluorophenyl)cyclopropylamine, and the reaction is followed by a first washing at basic pH a second washing at acidic pH; and in an third step, the compound obtained in the previous step is deprotected by treatment with mineral acid, followed by acidic washing.
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Page/Page column 11-12
(2021/12/28)
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- S-type chiral sulfoxide compound preparation method
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The invention belongs to the field of chemical synthesis, and particularly relates to an S-type chiral sulfoxide compound preparation method, which mainly comprises four steps of cyclization, substitution, catalytic oxidation and hydrolysis removal of isopropylidene, wherein a catalytic oxidation reaction is carried out by adopting a certain catalyst and a certain catalytic system (a metal organiccatalyst, a chiral reagent and water) according to a certain ratio and according to a certain sequence to obtain the high-purity S-type chiral sulfoxide compound. According to the invention, the reaction conditions are mild, the high-purity S-type chiral sulfoxide compound can be obtained with high yield under the optimal conditions, and the subsequent research on the biological activity of the S-type chiral sulfoxide compound is facilitated.
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Paragraph 0048-0051
(2020/02/10)
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- Production process of ticagrelor fine product
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The present invention discloses a production process of a ticagrelor fine product. The process comprises the steps of adopting 4,6-dichloro-5-amino-2-propylthiopyrimidine (IIa) and a compound (IIb) asstarting raw materials, and carrying out five processes including a substitution process I, a cyclization process, a substitution process II, a hydrolysis process and a refining process to finally obtain the ticagrelor fine product. The method provides a ticagrelor production process, uses cheap and easily available raw materials, has the advantages of low production cost, simple reaction conditions, convenient post-treatment, high yield and high product purity, and is more suitable for industrial production.
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- Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity
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Based on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines structurally related to ticagrelor were synthesized and examined as putative antiplatelet and antibacterial agents. The aim was to assess the possibility of dissociating the two biological properties and to find novel 1,2,3-triazolo[4,5-d]pyrimidines expressing antiplatelet activity and devoid of in vitro antibacterial activity. The new compounds synthesized were known metabolites of ticagrelor as well as structurally simplified analogues. Some of them were found to express antiplatelet activity and to lose the antibacterial activity, supporting the view that the two activities were not necessarily linked.
- Goffin, Eric,Jacques, Nicolas,Lancellotti, Patrizio,Musumeci, Lucia,Nchimi, Alain,Pirotte, Bernard,Oury, Cécile
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- Preparation method of R-type chiral sulfoxide compound
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The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of an R-type chiral sulfoxide compound. The preparation method mainly comprises the four steps of ring formation, substitution, catalytic oxidation
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Paragraph 0048-0051
(2020/02/20)
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- Ticagrelor condensation impurity preparation method
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The invention belongs to the field of chemical synthesis, and particularly relates to a ticagrelor condensation impurity preparation method, which mainly comprises three steps of cyclization, couplingand isopropylidene removal. According to the present invention, a coupling reaction is performed by combining an alkaline non-metal catalyst and a certain reaction temperature, and an isopropylideneremoval reaction is performed by using trace 2, 3-dichloro-5, 6-dicyano-p-benzoquinone, such that the yield of the target product can be significantly improved, the purity can achieve 97.80% without column chromatography purification, and the method is environmentally-friendly, safe, simple and easy to perform; and the method can adopt the one-pot boiling synthesis method to prepare the target product, so that the tedious experiment steps are reduced, the conditions are mild, and the method is suitable for large-scale industrial production of ticagrelor condensation impurities.
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Paragraph 0058-0061
(2020/02/08)
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- Preparation method of ticagrelor medicinal crystal form II
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The invention relates to a preparation method of ticagrelor, in particular to a preparation method of a ticagrelor medicinal crystal form II. The invention provides a new method of preparing the ticagrelor medicinal crystal form II from 2-(3AR, 4S, 6R, 6AS)-6-(5-amino-6-chloro-2-propylthio-4-pyrimidinyl)amino tetrahydro-2, 2-dimethyl-4H-cyclopenteno-1, 3-dioxolane-4-yl]oxo]-ethanol. The method hasthe characteristics of stable process, high crystal form purity, small and uniform particle size, and is easy for large-scale production.
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Paragraph 0031; 0032
(2019/09/14)
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- Preparation method of ticagrelor
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The invention relates to synthesis of a pharmaceutical compound and in particular relates to a preparation method of ticagrelor. The method disclosed by the invention comprises the steps as follows: step 1, synthesizing an intermediate Im-1; step 2, synthesizing an intermediate Im-2; step 3, synthesizing an intermediate Im-3; step 4, synthesizing a crude product Im-4; and step 5, carrying out refining, namely recrystallizing the crude product of ticagrelor by using 10-15 times of mixed solution of dichloromethane and tertiary butanol, and carrying out washing, filtering and drying to obtain arefined product of ticagrelor, wherein the volume ratio of dichloromethane to tertiary butanol in the mixed solution of dichloromethane and tertiary butanol is 1:(2-3).
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- Synthesizing method of ticagrelor
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The invention relates to synthesis of a medicine compound, in particular to a synthesizing method of ticagrelor. The synthesizing method comprises the following steps of S1, synthesizing an intermediate Im-1; S2, synthesizing an intermediate Im-2; S3, synthesizing an intermediate Im-3; S4, synthesizing a crude product Im-4; S5, refining: recrystallizing a crude product of the ticagrelor by a mixedsolution of dichloromethane and tertiary butanol, washing, filtering, and drying, so as to obtain a refined product of the ticagrelor.
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- Preparation method of high-purity ticagrelor
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The invention discloses a preparation method of high-purity ticagrelor. The preparation method comprises the following steps: preparing intermediates TG-1, TG-2, TG-3 and TG-4; and refining the ticagrelor. According to the preparation method, matching of reactants is adjusted, the reaction time and temperature are optimized, and a post-processing manner is adopted; a specific catalyst and a specific devitrification solvent are selected, so that the reaction efficiency of the intermediates is improved, the reaction time is shortened and the purity of the intermediates is improved; after a crudeproduct of the ticagrelor is obtained, different devitrification solvents and a staged crystallization process are adopted to obtain the ticagrelor with high purity, so that the production cost is reduced, the advantages of being high efficiency and clean in production are achieved, and the operability is strong; and the purity of the obtained ticagrelor product is not lower than 99.8%, and no single impurity exceeds 0.06%.
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- Preparation method of ticagrelor
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The invention provides a preparation method of ticagrelor. According to the preparation method, a compound shown in a formula (i) is used as a raw material, and the ticagrelor is prepared by means ofcondensation, ring formation, condensation and deprotection; the preparation method is simple and convenient in technological process and easy to operate, thus being suitable for large-scale production; furthermore, the preparation method provided by the invention is mild in synthesis conditions, high in product yield and good in product purity, can effectively control the preparation cost, and reduces the medication burden of patients.
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- Conformational analysis of ticagrelor: effect of noncovalent interaction on conformational population
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In order to track the source of duplicated peaks in the 1H-NMR spectrum of Ticagrelor, variable-temperature NMR (VT-NMR) experiment was carried out with temperature increasing from 300 to 343?K. The result showed that the phenomenon was brought forth by coexistence of conformational isomers. Subsequently, conformational search was carried out by molecular mechanics (MM) stimulations associating with quantum mechanics (QM) calculations. The results revealed that the isomers resulting in duplicated proton peaks were introduced by the rotation of 2,4-diflurophenyl group on C3’position of cyclopropyl. Finally, noncovalent interaction (NCI) topological analysis of the conformers exhibited that CH-π interactions and H-bonds play important roles in controlling the population of conformers of ticagrelor.
- Fan, Qiangwen,Tan, Hongbo,Wang, Yeming,Song, Xiuqing,Yan, Hong
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p. 1663 - 1670
(2018/07/03)
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- Preparation process for ticagrelor
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The invention discloses a preparation process for ticagrelor. By adding organic weak base to neutralize acetic acid and acetic acid generated from degrading of ethyl acetate in the process of preparing the ticagrelor, oxide impurities generated in ticagrelor final products are avoided; a test proves that oxide impurity sulphone and sulfoxide in original final products are removed effectively; and according to the preparation process, the product quality is improved greatly, and the process is simple, feasible and suitable for industrialized production.
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- A [...] crystallization and containing the pharmaceutical compositions
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The invention provides a ticagrelor crystal and a medicinal composition comprising the same. The purity of the ticagrelor crystal is greater than 99 percent, and an impurity N is less than 0.1 percent. The crystal is prepared by adopting a one-pot method and is obtained by adopting a further crystal refining method. By adopting the methods, the ticagrelor with the purity being obviously improved can be obtained, and the raw material and medicinal composition with excellent quality are further acquired.
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- A for the card Grey crystal form and its preparation method
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The invention relates to a crystal form of an anti-thrombotic medicament ticagrelor, a preparation method for the crystal form, a medicinal composition containing the crystal form and an application of the crystal form to the preparation of the anti-thrombotic medicines. The crystal form of ticagrelor is a crystal form A with a structure as shown below. A Cu-Kalpha radiation mode is adopted. An X-ray powder diffraction pattern of the crystal form A, represented by an angle 2Theta has characteristic diffraction peaks at the following positions: 6.2+/-0.2 degrees, 11.5+/-0.2 degrees, 15.0+/-0.2 degrees and 20.6+/-0.2 degrees. The crystal form A of ticagrelor has the advantages of convenience of the preparation method, high stability and preparation adaptability and the like, so that the crystal form A is industrially practical.
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- Process suitable for ticagrelor industrial production
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The invention discloses a process suitable for ticagrelor industrial production, which comprises the following steps of step 1, using tartrate of a compound III as a starting material, using sulfolane and diisopropylethylamine as a solvent, and reacting for 3 hours at 105-108DEG C; step 2, using mild tetrahydrofuran and oxalic acid dihydrate as a solvent, and using diisopropylethylamine to replace triethylamine in an original study patent, thereby reducing reaction time, and reducing a potential genotoxicity risk of the triethylamine; and step 3, an optimized reaction temperature in the invention is -5-0DEG C; using methyl tertiary butyl ether to replace ethyl acetate as an extraction agent; using an ethyl acetate and cyclohexane mixing solvent to replace a methyl tertiary butyl ether and cyclohexane mixing solvent to purify a finished product; wherein polarity of the ethyl acetate is greater than that of the methyl tertiary butyl ether; using the methyl tertiary butyl ether during extraction and using the ethyl acetate during purification may remove impurities and improve purity to the greatest extend.
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- Improved method for preparing ticagrelor
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The invention discloses an improved method for preparing ticagrelor. The method comprises the following steps of conducting an acid binding agent reaction kettle heating reaction on ethylene glycol, FTG-SM1, FTG-SM2 and triethylamine; then conducting extracting, concentrating and methyl alcohol/water salify crystallization to obtain TFG-3; conducting diazotization, loop closing, an FTG-SM3 substitution reaction and acidification protecting group separation continuous reaction on FTG-3 in methylbenzene to obtain a coarse product of ticagrelor; conducting recrystallization on the coarse product to obtain a finished product. According to the improved method for preparing ticagrelor, cheap reagents and raw materials are utilized, and the technology cost is lowered; regarding refining of a middle body FTG-1, a methyl alcohol/water system is adopted, and the content of related substances is effectively controlled; by conducting three-step reaction continuous compounding, solvents are saved, the operation is simplified, and the technology cycle is shortened; the dose of the solvent is less, the pollution is lowered, and the method is environmentally friendly. The improved method for preparing ticagrelor is simple and safe in operation condition and simple in after-treatment, the product is easy to obtain, high in yield and high in purity. The technology cost is low, and the improved method is suitable for industrial large-scale production.
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- SOLID FORM OF INTERMEDIATE OF TICAGRELOR
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A process for the preparation of a solid form of a compound of formula (VII) (Formula (VII)) comprises coupling(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid of Formula (VI) with (2-[[(3a R,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,2- dimethyltetrahydro-3aH-cyclopenta[d[[1,3]dioxol-4-yl]oxy]-1-ethanol) of formula (V) in the presence of a suitable base and a first a suitable solvent at a suitable temperature to form 2- [[(3aR,4S,6R,6aS)-6-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3- triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy]-1- ethanol of formula (VI)I; and isolating the compound of formula (VII) using a second suitable solvent so as to produce the compound of formula (VII) in solid form. A process for preparing Ticagrelor of formula (I) or a salt thereof (Formula (I)) comprises the conversion of a compound of formula (VII) in a solid form either as free base or as an acid addition salts thereof, into a compound of formula (I).
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- Synthesis method for ticagrelor
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The invention discloses a synthesis method for ticagrelor.The synthesis method includes the following steps that 1, a compound I and a compound II are subjected to a coupling reaction under alkali existence, and then a compound III is obtained through extraction and recrystallization; 2, the compound III is subjected to a diazo reaction, extraction and washing, and a compound IV is obtained; 3, the compound IV is coupled with a compound V under the alkaline condition, and a compound VI is obtained through extraction, washing and concentration; 4, the compound VI is subjected to a deprotection reaction under the acid condition, and a compound VII, namely, ticagrelor is obtained through extraction and recrystallization.A solvent selected in the preparation method is free of toxins and environmentally friendly, the impurity removal process is simple, cost is low, and the yield and purity of the obtained product are both high.
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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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- 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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- OPTICALLY ACTIVE SALTS OF (3AR,4S,6R,6AS)-6-AMINO-2,2-DIMETHYLTETRAHYDRO-3AH- CYCLOPENTA-[D] [1,3]DIOXOL-4-OL AND A METHOD OF THEIR PREPARATION
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Diastereomeric salts of the compound of formula I with D-(-)-mandelic and R-(-)-3- chloromandelic acid, a method of for the preparation thereof and their use in the synthesis of the drug ticagrelor.
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- Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents
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Ticagrelor (1) is the first reversible P2Y12 receptor antagonist blocking adenine diphosphate (ADP)-induced platelet aggregation with rapid onset and offset of effects. In this study, synthesis of ticagrelor and its derivatives has been accomplished in a convergent way. The compound design was based on modifications of ticagrelor and its major metabolite (33) in order to ameliorate their pharmacokinetic properties and dosing profile. The final compounds (1a-g, 35a-g) were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. The assay results showed that some compounds (e.g., 1b, 1d, 33, 35b, 35f) exhibited comparable potency with that of ticagrelor.
- Zhang, Hao,Liu, Jun,Zhang, Luyong,Kong, Lingyi,Yao, Hequan,Sun, Hongbin
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p. 3598 - 3602
(2012/07/14)
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- CYCLOPROPYL MODULATORS OF P2Y12 RECEPTOR
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The present invention relates to new cyclopropyl modulators of P2Y12 receptor activity, pharmaceutical compositions thereof, and methods of use thereof.
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- A PROCESS FOR PREPARING [1S- [1-ALPHA, 2-ALPHA, 3-BETA (1S*, 2R*) 5-BETA] ] -3- [7- [2- (3, 4-DIF LUOROPHENYL) -CYCLOPROPYLAMINO] - 5- (PROPYLTHIO) -3H-1, 2, 3-TRIAZOLO [4, 5-D] PYRIMIDIN-3-YL] -5- (2- HYDROXYETHOXY) CYCLOPENTANE-1, 2-DIOL AND TO ITS INTERMEDIATES
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The present invention is directed to a process for preparing [1S-[1α,2α,3β(1S*,2R*),5β]]- 3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol and to intermediates useful in the process.
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Page/Page column 9
(2010/04/06)
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- From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis
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Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y12 receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
- Springthorpe, Brian,Bailey, Andrew,Barton, Patrick,Birkinshaw, Timothy N.,Bonnert, Roger V.,Brown, Roger C.,Chapman, David,Dixon, John,Guile, Simon D.,Humphries, Robert G.,Hunt, Simon F.,Ince, Francis,Ingall, Anthony H.,Kirk, Ian P.,Leeson, Paul D.,Leff, Paul,Lewis, Richard J.,Martin, Barrie P.,McGinnity, Dermot F.,Mortimore, Michael P.,Paine, Stuart W.,Pairaudeau, Garry,Patel, Anil,Rigby, Aaron J.,Riley, Robert J.,Teobald, Barry J.,Tomlinson, Wendy,Webborn, Peter J.H.,Willis, Paul A.
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p. 6013 - 6018
(2008/04/02)
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- Novel triazolo pyrimidine compounds
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The present invention relates to a pyrimidine compound (I) useful as a pharmaceutical intermediate, to a process for preparing said pyrimidine compound, to intermediates used in said process, and to the use of said pyrimidine compound in the preparation of pharmaceuticals.
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