cas 274693-26-4, 2-[[(3aS,4R,6S,6aR)-4-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy]ethanol

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PROCESS FOR THE PREPARATION OF TICAGRELOR
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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(2021/12/28)

Preparation method of R-type chiral sulfoxide compound
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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(2020/02/20)

Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity
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
(2020/09/11)

Production process of ticagrelor fine product
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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(2020/12/09)

Preparation method of ticagrelor
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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(2018/08/28)

Synthesizing method of ticagrelor
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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(2018/07/30)

Preparation method of high-purity ticagrelor
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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(2019/01/06)

Preparation method of ticagrelor
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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(2019/04/30)

For the improvement of the [...] intermediates preparation method
The invention relates to an improved preparation method for the intermediate 4, 6-dihalogen-2-(propythio)pyrimidine-5-amine used for preparing the anticoagulation drug ticagrelor, and application of the intermediate in preparation of ticagrelor. By use of a phase transfer reagent, the method reduces the halogenating reagent consumption and emission and treatment of toxic substances. Also, the obtained product has high yield and good purity. Thus, the method is a greener and more economical preparation method more suitable for industrial application.
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(2018/02/04)

For [...] novel intermediate and its preparation method
The invention discloses a novel intermediate of ticagrelor, i.e., a compound represented by a formula (I), and a preparation method thereof. The preparation method for the compound represented by the formula (I) comprises a step of subjecting a compound represented by a formula (II) or a proper salt of the compound represented by the formula (II) and a compound represented by a formula (III) to a substitution reaction, wherein R in the formulas represents substituted or unsubstituted benzyl and benzoyl groups. The invention further discloses a preparation method for a ticagrelor compound represented by a formula (A) from the novel intermediate, i.e., the compound represented by the formula (I). The method for preparing ticagrelor from the novel intermediate has the advantages of short reaction time, easy and convenient post-treatment, high yield and high product purity.
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(2018/06/21)

A for the card Grey crystal form and its preparation method
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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(2017/08/25)

Process suitable for ticagrelor industrial production
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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(2017/07/20)

A [...] crystallization and containing the pharmaceutical compositions
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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(2017/10/06)

Improved method for preparing ticagrelor
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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(2017/12/06)

Synthesis method of ticagrelor
The invention discloses a synthesis method of ticagrelor. The method comprises the steps of 1, adding thiourea and alkali to a solution where bi-aminomalonic acid diethyl ester is dissolved, wherein the mole ratio of bi-aminomalonic acid diethyl ester, thiourea and alkali is 1:(1.0-1.5):(2-2.3), and performing a reaction under the protection of nitrogen at 25-100 DEG C for 5-72 h to obtain a compound 2; 2, adding bromopropane to a solution where the compound 2 is dissolved at -2 DEG C-2 DEG C, and conducting stirring at 25-50 DEG C for 2-72 h to obtain a compound 3; 3, adding organic alkali and a chloride agent to the compound 3, raising the temperature to 20-75 DEG C, and performing a reaction for 3-8 h to obtain a compound 4; 4, synthesizing ticagrelor, wherein the compound ticagrelor is obtained by conducting substitution, loop closing, substitution and a hydrolysis reaction on the compound 4 (4,6-dichloro-2-propylthiopyrimidine-5-amine), the operation steps are greatly simplified, and the yield is drastically increased. The synthesis method of ticagrelor is simple in operation and high in reaction yield.
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(2017/09/26)

Preparation process for ticagrelor
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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(2017/08/28)

SOLID FORM OF INTERMEDIATE OF TICAGRELOR
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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(2016/03/22)

Synthesis method for ticagrelor
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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(2016/10/17)

PROCESSES FOR THE PREPARATION OF TICAGRELOR AND ITS INTERMEDIATES
The present invention provides a process for the preparation of ticagrelor. The present invention further provides compounds of Formula IV, Formula V, Formula VI, Formula VIa, Formula VII, and Formula VIII, processes for their preparation, and their use for the preparation of ticagrelor.
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(2016/04/20)

A method for preparing for card Grey
The invention provides a preparation method of ticagrelor. Compared with an existing route, the method has the steps shortened, so that the reaction yield is substantially improved, and the cost of production is greatly reduced. The ticagrelor synthetic method shown in the route provided by the invention is not described in disclosed literature.
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(2019/02/04)

Platelet aggregation inhibitor, and preparation method and application thereof
The invention provides a compound represented by a formula (I), or pharmaceutically acceptable salts, solvates, polymorphs, enantiomers or racemic mixtures thereof. In the formula (I), R1 is substituted or unsubstituted lower alkyl; R2 is phenyl or phenyl substituted by one or more halogen atoms; R3 is O(CH2)nR4, wherein n is an integer selected from 1-6, and R4 is OC(O)R5 or OP(O)(OH)2, wherein R5 is substituted or unsubstituted lower alkyl or R6NH2, wherein R6 is substituted or unsubstituted lower alkyl.
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Paragraph 0053; 0054; 0055

(2016/10/20)

AN IMPROVED PROCESS FOR PREPARATION OF TICAGRELOR AND INTERMEDIATES THEREOF
An improved, industrially viable, environment friendly and economically significant process for preparation of Ticagrelor is disclosed alongwith novel intermediates for the Ticagrelor synthesis.
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Page/Page column 14; 15

(2016/09/22)

Preparation method of Ticagrelor and intermediates thereof
Disclosed in the present invention is a method for preparing Ticagrelor (I), comprising the following steps: a cyclization reaction of 5-amino-1,4-di-substituted-1,2,3-triazole (II) and dialkyl carbonate (HI), to obtain 9-substituted-2,6-dihydroxy-8-azapurine (IV); chlorination of intermediate (IV), to obtain 9-substituted-2,6-dichloro-8-azapurine (V); an amination reaction of intermediate (V) and trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (VI) generates 9-substituted-6-amino-substituted-2-chloro-8-azapurine (VII); and a propanethiolation reaction of intermediate (VII) and propanethiol (VIII), to obtain Ticagrelor (I). The preparation method is simple in process, has a high chemical and chiral purity and provides a new preparation method for industrializing Ticagrelor. In addition, also provided in the present invention are intermediates of Ticagrelor and a preparation method thereof, wherein raw materials of the preparation method are easily available, the conditions thereof are mild, and the yield thereof is high.
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(2016/05/10)

PREPARATION OF TICAGRELOR
The present application relate to processes for preparing Ticagrelor and to intermediates that are useful in the processes.
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(2016/01/25)

PREPARATION OF TICAGRELOR
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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(2015/03/16)

NOVEL PROCESSES FOR PREPARING TRIAZOLO [4,5-D]- PYRIMIDINES, INCLUDING TICAGRELOR, VIANEW INTERMEDIATES AND NEW ROUTE OF SYNTHESIS.
The present invention relates to novel processes for preparing triazolo [4,5-d] pyrimidines, including Ticagrelor, via new intermediates and new routes of synthesis. The synthesis begins with readily available and inexpensive starting material such as 5-nitro-2,4,6-trichloropyrimidine and leads to series of novel intermediates, which are commercially viable and industrially advantageous (solid intermediates, high yields and convenient experimental condition) for the preparation of highly pure Ticagrelor.
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(2015/11/10)

A PROCESS FOR PREPARATION OF TICAGRELOR AND INTERMEDIATES THEREOF
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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(2014/07/21)

Synthesis of Triazolopyrimidine Compounds
The present invention relates to the field of organic synthesis and describes the synthesis of specific triazolopyrimidine compounds and intermediates thereof as well as related derivatives.
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(2013/05/09)

SYNTHESIS OF TRIAZOLOPYRIMIDINE COMPOUNDS
The present invention relates to the field of organic synthesis and describes the synthesis of specific triazolopyrimidine compounds and intermediates thereof as well as related derivatives.
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(2013/05/21)

SYNTHESIS OF TRIAZOLOPYRIMIDINE COMPOUNDS
The present invention relates to the field of organic synthesis and describes the synthesis of specific triazolopyrimidine compounds and intermediates thereof as well as related derivatives, suitable for the preparation of Ticagrelor (TCG).
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Page/Page column 43

(2013/03/28)

Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents
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
p. 3598 - 3602
(2012/07/14)

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
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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Page/Page column 5-7

(2012/11/07)

NOVEL PROCESSES FOR PREPARING TRIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF
Provided herein is a novel process for the preparation of triazolo[4,5-d]pyrimidine derivatives. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of highly pure ticagrelor or a pharmaceutically acceptable salt thereof. Provided further herein is a novel process for the preparation of substituted cyclopentanamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of a ticagrelor intermediate, 2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3]- dioxol-4-yl]oxy]- 1 -ethanol.
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(2012/07/13)

NEW INTERMEDIATES AND PROCESSES FOR PREPARING TICAGRELOR
The present invention is related to new intermediates and processes for preparing Ticagrelor disclosed in this patent application.
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(2012/10/18)

CYCLOPROPYL MODULATORS OF P2Y12 RECEPTOR
The present invention relates to new cyclopropyl modulators of P2Y12 receptor activity, pharmaceutical compositions thereof, and methods of use thereof.
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(2011/02/24)

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
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 10

(2010/04/06)