- Preparation method of key intermediate A of ticagrelor
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The invention discloses a preparation method of a key intermediate A of ticagrelor. The method comprises the following steps: (1) synthesis of an intermediate 9, (2) synthesis of an intermediate 10, and (3) synthesis of a key intermediate A. The synthesis of the intermediate 9 comprises the following steps: dropwise adding glacial acetic acid into a mixture of the intermediate 4, tetrahydrofuran and zinc powder at room temperature, stirring the mixture, keeping the temperature for 24 hours, neutralizing the reaction product with liquid caustic soda to neutrality, evaporating the solvent, and extracting, drying, filtering and concentrating the reaction product to obtain the intermediate 9. The invention discloses a preparation method of a key intermediate A of ticagrelor. On the basis of the existing preparation technology, through further improvement and optimization, the synthesis process is greatly shortened, the production cost is reduced, the safe and convenient preparation methodof the ticagrelor key intermediate A suitable for industrial large-scale production is provided, and the preparation method has good economic benefits and wide application prospects.
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Paragraph 0049-0054
(2020/05/29)
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- Production method of key intermediate of ticagrelor
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The invention discloses a production method of a key intermediate compound I of ticagrelor. The production method comprises the following steps: (1) subjecting a compound II and di-tert-butyl dicarbonate to a reaction to obtain a compound III; (2) subjecting the compound III and 2-bromoacetate to a reaction, and conducting recrystallization to obtain a compound IV; (3) subjecting the compound IV to the action of a reducer to obtain a compound V; and (4) subjecting the compound V and a Boc removal reagent to obtain the compound I. Compared with the prior art, the production method of the key intermediate compound I of the ticagrelor has the advantages that the technology is simple, the purity of a finished product is high, the production cost is low, industrial production is easy, and the like.
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Paragraph 0074-0088
(2020/01/12)
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- Bio-synthesis method for ticagrelor intermediate and the intermediate therefrom
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The invention discloses a bio-synthesis method for a ticagrelor intermediate and the intermediate therefrom. The method includes steps of: oxidizing a compound (2) to prepare a compound (3); performing an ortho-diol protection reaction to obtain a compound (4); performing an addition reaction to the compound (4) with ethylene oxide to obtain a compound (5); and performing bioconversion to the compound (5) to prepare the ticagrelor intermediate compound (1). Reaction equations in the method are represented in the specification. The synthesis method has advantages of creative technical route, simple operation, high synthesis yield and product purity, low cost and extensive source of raw materials and is suitable for industrial production. The ticagrelor intermediate can serve as an intermediate raw material for preparation of ticagrelor.
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Paragraph 0032; 0043; 0044; 0045; 0052; 0057; 0062
(2018/11/04)
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- Preparation method for ticagrelor intermediate
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The invention discloses a preparation method for a ticagrelor intermediate. The preparation method comprises the following steps: 1) subjecting o-substituted benzaldoxime and cyclopentadiene to a contact reaction so as to obtain a compound as shown in a formula I; 2) oxidizing the compound as shown in the formula I with hydrogen peroxide under the catalysis of osmium tetroxide so as to obtain a compound as shown in a formula II; 3) reacting the compound as shown in the formula II with acetone under the catalysis of p-toluenesulfonic acid so as to obtain a compound as shown in a formula III; 4) reacting the compound as shown in the formula III with 2-bromoethanol in the presence of alkali so as to obtain a compound as shown in a formula IV; and 5) reducing the compound as shown in the formula IV so as to obtain the ticagrelor intermediate. The method provided by the invention uses cheap and easily available raw material, reduces production cost, and does not need any chiral raw material; a cycloaddition reaction enables a highly stereoselective product to be obtained; and the method is short in steps and high in reaction yield and provides a novel approach for synthesis of ticagrelor.
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- Synthesis process of ticagrelor intermediate
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The invention discloses a synthesis process of a ticagrelor intermediate. The synthesis process of the ticagrelor intermediate is characterized by including the steps: 1) under acidic condition, contacting benzaldoxime with cyclopentadiene for reaction so as to obtain a compound shown in formula I; 2) under the catalysis of osmium tetroxide, using hydrogen peroxide to oxidize the compound shown in the formula I so as to obtain a compound shown in formula II; 3) under the catalysis of p-toluenesulfonic acid, reacting the compound shown in the formula II and acetone to obtain a compound shown in formula III; 4) in the presence of an alkali, reacting the compound shown in the formula III with 2-bromoethyl alcohol so as to obtain a compound shown in formula IV; 5) reducing the compound shown in the formula IV so as to obtain the ticagrelor intermediate. The raw materials used here in the method provided herein are low in cost and easy to obtain, so that production cost; the use of chiral materials is not required, a high stereoselectivity product can be acquired through cycloaddition reaction, the steps are short, the reaction yield is very high, and a new approach for the synthesis of ticagrelor is provided.
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- Method for preparing ticagrelor key intermediate
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The invention relates to a chemical synthesis method of ticagrelor key intermediate 2-[[(3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolane-4-yl] oxy]ethanol (a key intermediate A). The method comprises the following steps: taking D-ribose as a raw material, and carrying out ten chemical reaction steps of 1-locus methylation and 2,3-loci isopropylidene protection, 4-locus derivatization, iodination, furan ring-opening, hydroxylamine reaction, palladium on carbon catalytic hydrogenation, amino Cbz protection, hydroxy protection, sodium borohydride reduction ester, Cbz removal protection and the like, thereby obtaining the key intermediate A. The raw materials are cheap and readily available, the preparation process is high in operability, steps of optical resolution, chiral induction and the like are avoided, the total yield is relatively high, and the product quality is better; particularly due to the use of sodium borohydride reduction ester, the preparation cost of ticagrelor is greatly reduced; and the method is suitable for large-scale industrial production.
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- Process for Preparing Cyclopentylamine Derivatives and Intermediates Thereof
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Disclosed herein is an improved process for the preparation of substituted cyclopentanamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Particularly described is an improved, commercially viable and industrially advantageous process for the preparation of a ticagrelor intermediate, [3aR-(3aα,4α,6α,6aα]-2-[[6-amino-2,2-dimethyltetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol, alternatively named, 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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- Synthesis of Aminocyclopentanetriol Derivatives
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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. The present invention provides in particular a process for the preparation of a compound of formula V comprising: a) providing a compound of formula IV , and b) reducing the compound of formula IV with activated zinc in the presence of copper to give the compound of formula V.
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Paragraph 0088; 0089
(2014/01/07)
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- NOVEL PROCESSES FOR PREPARING TRIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF
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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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Page/Page column 53
(2012/07/13)
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- IMPROVED PROCESS FOR PREPARING CYCLOPENTYLAMINE DERIVATIVES AND INTERMEDIATES THEREOF
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Disclosed herein is an improved process for the preparation of substituted cyclopentanamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Particularly described is an improved, commercially viable and industrially advantageous process for the preparation of a ticagrelor intermediate, [3aR-(3aα,4α,6α,6aα]-2-[[6-amino-2,2-dimethyltetrahydro-4H-cyclopenta-1,3-dioxol-4- yl]oxy]-ethanol, alternatively named, 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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- 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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- 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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- 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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Page/Page column 39
(2011/02/24)
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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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- Triazolo(4,5-d)pyrimidine compounds
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Triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation. The compounds of the invention have the formula (I) as follows: wherein R, X and R1through R3are as defined in the specification.
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