274693-27-5 Usage
Uses
1. Used in Cardiovascular Applications:
Ticagrelor is used as an antiplatelet agent for the prevention of thromboembolic events in patients with acute coronary syndrome (ACS). It provides faster, greater, and more consistent ADP-receptor inhibition than Clopidogrel, making it an effective strategy for managing atherothrombotic events associated with ACS and potentially resulting from percutaneous coronary intervention (PCI, stent implantation).
2. Used in Pharmaceutical Industry:
Ticagrelor is used as a platelet aggregation inhibitor for the treatment of acute coronary syndrome (ACS). It is the first reversible oral P2Y12 receptor antagonist, which also inhibits CYP2C9 and 4-hydroxylation with IC50 of 10.5 μM and 8.2 μM, respectively. This makes it a valuable compound in the development of new therapies for cardiovascular diseases.
Indications and Usage
Ticagrelor, a new platelet aggregation inhibitor successfully developed by AstraZeneca (U.S.), is the world’s first reversible combination orally-administered P2Y12 adenosine diphosphate receptor antagonist.
It is used to reduce cardiovascular death and heart attacks in patients with acute coronary syndrome (ACS.) Rapid onset after oral administration, and can effectively improve symptoms of patients with ACS. Thienopyridines is a reversible P2Y12 inhibitor, so it is particularly applicable towards patients who need to undergo anticoagulant therapy before surgery.
Mechanisms of Action
Reversibly acts on the 2 purine receptor (purinoceptor 2, P2,) subtype P2Y12, of vascular smooth muscle cells (VSMC,) does not require metabolic activation, and has a significant inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP.)
Clinical Research
Ticagrelor was approved by the U.S. Food and Drug Administration (FDA) on the basis of PLATO clinical studies. PLATO was a 43 country, 862 center randomized, double-blind, multi-centered study which included 18,624 patients hospitalized for ACS. Patients were randomly given either aspirin plus ticagrelor, or aspirin plus clopidogrel, two antiplatelet regimens. The study showed a 16% reduction in risk of heart attack, stroke, or death in the group taking Ticagrelor compared to those who took clopidogrel. The PLATO study demonstrated the benefits of Ticagrelor for patient survival, and is currently widely recommended as a treatment strategy for ACS. In addition, at the same time it reduces operative myocardial infarction and thrombosis after stent implantation, it also does not increase the overall risk of fatal bleeding and other serious adverse effects.
Ticagrelor however has two shortcomings. First, it must be taken twice a day, compared to once a day for clopidogrel, and secondly, it may cause adverse effects such as breathing difficulties, significantly more than with the latter. Its half-life is only 12 hours, and taken twice a day, a challenge for patients with poor compliance. In practice, it has also been found that around 20% of patients treated with clopidogrel do not follow their prescriptions, and these patients are even less likely to take the prescribed doses when using ticagrelor. Thus, as a rapidly reversible drug, direct withdrawal will likely increase the risk of acute thrombosis, causing myocardial infection or stroke.
Originator
Astra-Zeneca (United Kingdom)
Clinical Use
Ticagrelor, discovered and developed by AstraZeneca, is a platelet
adenosine diphosphate (ADP) P2Y12 (P2T) reversible receptor
antagonist approved in the E.U. in 2010 and launched in Germany
and the UK in 2011 for the treatment of patients with acute coronary
syndromes (ACS). It was approved in the U.S. and Canada in
2011 following successful clinical trial results in patients with
ACS which showed it to be superior to preexisting drugs for reducing death due to vascular causes. Ticagrelor is an oral drug
indicated for use in combination with acetylsalicylic acid (aspirin)
for the prevention of atherothrombotic events in adult patients
with ACS (unstable angina, non-ST elevation myocardial infarction
(NSTEMI), or ST elevation myocardial infarction (STEMI)). Unlike
its competitors prasugrel and clopidogrel, which require bioactivation,
ticagrelor is not a prodrug and does not require in vivo activation.
It has a rapid onset of action, relatively rapid reversibility,
greater potency, and exhibits consistency in platelet inhibition.
Following dosing, ticagrelor reaches Cmax in about 1.5 h, with formation
of a major metabolite with equipotent intrinsic activity to
the parent compound.
Synthesis
The initial discovery of the drug
and SAR studies were published in 2007, including the initial discovery
patent applications. Since then, a number of patents
have been published with various improvements made for largescale
synthesis of the drug. While the molecule has been
synthesized using various modifications of the common intermediates,
the large-scale preparation proceeds via a convergent strategy
involving the coupling of three key intermediates as shown in the Scheme below.
Several routes to the synthesis of cyclopentyl amino alcohol 235
have been reported. Most of these routes are based on reaction of
cyclopentene acetate 238 with the appropriate amine, which is
commercially available. Interestingly, one route targeting
deuterated ticagrelor used a nitroxide Diels–Alder reaction with
cyclopentadiene to incorporate the amine into the ring system.
The most likely process-scale preparation of the key cyclopentyl
amine required for ticagrelor is highlighted in the scheme below.Commercially available enantiopure acetate 238 was reacted
with sodium di-tert-butyloxy diimide under catalytic palladiummediated
amination conditions to give bis-Boc amide 239 in 92%
yield. Dihydroxylation of cyclopentene 239 using catalytic osmium
tetraoxide and N-methyl morpholine N-oxide (NMO) in THF/water
quantatively resulted in the cis-diol 240. The free amine was liberated
with 6 N HCl followed by in situ ketalizaion of the cis-diol
hydrochloride salt 241 in 92% yield. Cbz carbamate 242 was quantitatively
synthesized from 241 under standard conditions. Alcohol
242 was treated with potassium t-butoxide and bromoethyl acetate
(243), the ester intermediate of which was reduced in situ
with lithium borohydride to alcohol 244 in 86% overall yield (two steps). Hydrogenolysis at 1.2 bar of hydrogen pressure with
5% Pd/C gave amino alcohol intermediate 235 in 83% yield. This
amine (235) was mixed with oxalic acid to provide the oxalate salt
in 82% yield, which was subsequently used for the final synthesis of
ticagrelor.The large-scale preparation of ticagrelor necessitated the synthesis
of dichloroamino pyrimidine thioether 236, for which there
are several reported routes. The synthesis is initiated with
the construction of thiol barbituric acid 247 (Scheme below). This
intermediate was formed from the reaction of dimethyl malonate
(245) with thiourea (246) in the presence of sodium methoxide.
These conditions provided the sodium salt of the pyrimidone thiol
247 in 83% yield, which was isolated via filtration from the reaction
mixture. Salt 247 was then reacted with propyliodide in aqueous
methanolic sodium hydroxide followed by HCl quench to provide
the desired thioether 248 in 76% yield. Nitration of pyrimidinol thioether
248 was achieved by treatment with fuming nitric acid in
acetic acid, furnishing the nitro pyrimidinol 249 in 75% yield. Subsequent
bis-chlorination with POCl3 converted 249 to dichloropyrimidine
thioether 250 in near quantitative yield. In an earlier
publication, a selective reduction of the nitro dichloropyrimide thioether
250 was demonstrated by hydrogenation at 3 bar hydrogen
pressure using 3%Pt/0.6%V/C catalyst to provide the amino dichloropyrimidine
thioether 236 in 95% yield. It is also of note that
for the larger kilo-scale reaction, selective hydrogenation was
accomplished with Pt/V/C (2% Pt; 1% V on carbon) catalyst with
8 bar of hydrogen pressure to give the crude amino dichloropyrimidine
thioether 236.While a number of routes have been described for the preparation
of cyclopropyl amine intermediate 237,184–187,193–196 the large
scale route used is described (Scheme below).195 Condensation of
malonic acid and 3,4-difluorobenzaldehyde (251) with piperidine
in pyridine gave acid 252 in 88% yield after acidic work-up. Acid
chloride 253 was prepared using thionyl chloride, which was
followed by esterification with L-menthol and pyridine to give Lmenthol
ester 254 in 93% over 2 steps. Cyclopropanation with
dimethylsulfoxonium methylide in DMSO gave desired trans cyclopropane
255 in 40% yield and 92% ee after recrystallization.
Hydrolysis of the ester followed by reaction with thionyl chloride
gave acid chloride 257 in 61% overall yield in two steps. Acid chloride 257 was then reacted with sodium azide in the presence
of sodium carbonate and tetrabutyl ammonium bromide in a biphasic
mixture of toluene and water to give the acyl azide intermediate,
which was immediately subjected to warm toluene to
furnish, after acidic workup, the key intermediate cyclopropyl
amine 237 in 88% yield and 92% ee. This enantioenriched intermediate was then mixed with R-(-)-mandelic acid to provide the
mandelic acid salt of amine 237 (258).With all three intermediates available from the above mentioned
routes, the final assembly of ticagrelor was accomplished
as outlined in the scheme below. First, oxalate salt of cyclopentyl amine
235 was coupled with dichloroaminopyrimidine thioether 236 in the presence of triethylamine and at elevated temperature to give
diamine intermediate 259 in 88% yield after crystallization. Diamine
259 was then subjected to diazotization with sodium nitrite
in acetic acid and toluene at ～30°C, leading to the formation of triazole
260. This intermediate was immediately reacted with 258
(madelic acid salt of cyclopropyl amine 237) to give intermediate
261, which was subsequently taken forward to the final deprotection
step. Reaction of ketal 261 with concentrated HCl in methanol
and toluene at 15°C provided ticagrelor (XXII) in 82–90% yield
over the 3 steps.
Drug interactions
Potentially hazardous interactions with other drugs Antibacterials: concentration possibly increased by clarithromycin - avoid; concentration possibly increased by erythromycin; concentration reduced by rifampicin. Anticoagulants: concentration of dabigatran increased. Antifungals: concentration increased by ketoconazole - avoid. Antivirals: concentration possibly increased by atazanavir and ritonavir - avoid. Cardiac glycosides: concentration of digoxin increased. Ciclosporin: possibly increases ciclosporin concentration. Ergot alkaloids: concentration of ergot alkaloids possibly increased. Lipid-regulating drugs: concentration of simvastatin increased - increased risk of toxicity.
Metabolism
CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor. The primary route of ticagrelor elimination is via hepatic metabolism. The primary route of elimination for the active metabolite is most likely via biliary secretion.
references
[1] zhou d1, andersson tb, grimm sw. in vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome p450 reaction phenotyping, inhibition, induction, and differential kinetics. drug metab dispos. 2011 apr;39(4):703-10. [2] li y1, landqvist c, grimm sw. disposition and metabolism of ticagrelor, a novel p2y12 receptor antagonist, in mice, rats, and marmosets. drug metab dispos. 2011 sep;39(9):1555-67. doi: 10.1124/dmd.111.039669. epub 2011 jun 13.
Check Digit Verification of cas no
The CAS Registry Mumber 274693-27-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,7,4,6,9 and 3 respectively; the second part has 2 digits, 2 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 274693-27:
(8*2)+(7*7)+(6*4)+(5*6)+(4*9)+(3*3)+(2*2)+(1*7)=175
175 % 10 = 5
So 274693-27-5 is a valid CAS Registry Number.
InChI:InChI=1/C23H28F2N6O4S/c1-2-7-36-23-27-21(26-15-9-12(15)11-3-4-13(24)14(25)8-11)18-22(28-23)31(30-29-18)16-10-17(35-6-5-32)20(34)19(16)33/h3-4,8,12,15-17,19-20,32-34H,2,5-7,9-10H2,1H3,(H,26,27,28)/t12-,15?,16?,17-,19-,20+/m0/s1
274693-27-5Relevant articles and documents
PROCESS FOR THE PREPARATION OF TICAGRELOR
-
Paragraph 11-13, (2021/12/28)
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.
Preparation method of platelet aggregation inhibitor ticagrelor
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Paragraph 0021; 0025-0027; 0031-0032, (2020/11/12)
The invention discloses a preparation method of platelet aggregation inhibitor ticagrelor, and belongs to the field of drug synthesis. According to the method, a compound 2 and a compound 3 are used as raw materials, substitution reaction, cyclization reaction, amination reaction and deprotection are sequentially carried out, a crude product is recrystallized by ethyl acetate and normal hexane toobtain the ticagrelor, and the purity of the ticagrelor is up to 99.5% or above. Compared with methods reported in existing literatures, the method has the advantages that the reaction route is obviously shortened, the process stability is high, use of toxic solvents and high-pollution reagents is avoided, and the method is relatively more environmentally friendly and suitable for large-scale production.
Method for preparing ticagrelor
-
, (2020/12/09)
The present invention discloses a method for preparing ticagrelor. In the method, 4,6-dihalo-5-nitro-2-propylthiopyrimidine (II) as raw materials and a series of reactions of substitution, reduction,ring formation, substitution, deprotection, etc. are conducted to obtain the ticagrelor. The method has cheap and readily available raw materials, simple process conditions, convenient post-processing, high total yield, and is more suitable for industrial production.
Synthesis method for ticagrelor
-
, (2020/12/09)
The invention discloses a synthesis method for ticagrelor. The synthesis method comprises the following steps: (a) allowing 6-halogenated-2-propylthio-8-azapurine serving as a raw material to react with (1R,2S)-2-(3,4-difluorophenyl)cyclopropylcarbamic acid tert-butyl ester in alkali and an organic solvent at a room temperature so as to obtain an intermediate (II); (b) dissolving the intermediate(II) and a compound (III) in an organic solvent at a room temperature, and carrying out a reaction under the action of triphenylphosphine and diethyl azodicarboxylate so as to obtain an intermediate (IV); and (c) deprotecting the intermediate (IV) under the action of acid so as to obtain ticagrelor (I). The method provided by the invention has the advantages of cheap and easily-available raw materials, low production cost, short reaction steps, mild reaction conditions, convenient post-treatment and high yield, and is more applicable to industrial production.
Production process of ticagrelor fine product
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Paragraph 0020; 0025-0026; 0027; 0032-0033; 0034; 0039-0040, (2020/12/09)
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.
Synthesis of ticagrelor analogues belonging to 1,2,3-triazolo[4,5-d]pyrimidines and study of their antiplatelet and antibacterial activity
Goffin, Eric,Jacques, Nicolas,Lancellotti, Patrizio,Musumeci, Lucia,Nchimi, Alain,Pirotte, Bernard,Oury, Cécile
, (2020/09/11)
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.
Preparation method of amorphous ticagrelor
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Paragraph 0019-0025, (2019/10/01)
The invention discloses a preparation method of amorphous ticagrelor, which comprises the steps of preparation of a ticagrelor crude product and preparation of amorphous ticagrelor. The preparation method has the advantages that: 1, a preparation technology of an amorphous ticagrelor product is simple and convenient, mild in technological condition and strong in operability; a single solvent can be used in the reaction for preparing the amorphous product at the same time; the solvent can be recycled for many times; less waste liquid and less pollution are generated; and the production cost islowered by 20-30% as compared with the production cost of the traditional preparation method at the same time; and 2, the solvents used are low boiling point volatile solvents; the product is easy todry to remove the solvents to meet ICH (International Conference on Harmonization) standard requirements in a drying procedure; and large-scale industrial production is facilitated.
Crystal form I of Ticagrelor Fumarateand its preparing method
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Paragraph 0036-0037, (2019/12/10)
The present invention relates to: a type I crystal which is a novel crystalline form of ticagrelor fumarate; and a method for manufacturing the same. The type I crystal according to the present invention is very hygroscopic and is very advantageous for storage and distribution, thereby having an advantage that it is also very advantageous for storage and distribution of formulations made by using the same. In addition, the type I crystal according to the present invention exhibits a spherical shape and has a similar size of crystalline, thereby exhibiting very good physical properties to make formulations such as reducing sticking phenomenon during tableting, being easily mixed with other additives, and ensuring a content uniformity. On the other hand, a manufacturing method according to the present invention can manufacture the type I crystal having a high yield and purity with a simple process.COPYRIGHT KIPO 2020
A method for the preparation of intermediate [...]
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, (2019/01/14)
The invention relates to a preparation method of a ticagrelor intermediate, specifically to a preparation method of a compound or its salt which is used as a medical intermediate and is as shown in the formula (2) and an application of the compound (2) or its salt in preparation of a triazolopyrimidine compound. According to the method provided by the invention, synthetic process is simple and reaction post-treatment is greatly simplified. By the technical scheme for preparation of the triazolopyrimidine compound, the whole synthetic process is easy to carry out, and yield of the intermediate for preparation of the triazolopyrimidine compound is greatly increased. The preparation method is especially suitable for industrial production.
For [...] novel intermediate and its preparation method
-
, (2018/06/21)
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.
