WO2014139489A1 - Method for the preparation of ticagrelor and intermediates suitable therefore - Google Patents

Method for the preparation of ticagrelor and intermediates suitable therefore Download PDF

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WO2014139489A1
WO2014139489A1 PCT/CZ2014/000028 CZ2014000028W WO2014139489A1 WO 2014139489 A1 WO2014139489 A1 WO 2014139489A1 CZ 2014000028 W CZ2014000028 W CZ 2014000028W WO 2014139489 A1 WO2014139489 A1 WO 2014139489A1
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compound
solvent
formula
crystallized
base
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PCT/CZ2014/000028
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Jaroslav Riha
Iva OBADALOVA
Ivo Strelec
Vaclav KRAMPERA
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Zentiva K.S.
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Priority to BR112015022692A priority Critical patent/BR112015022692A2/en
Publication of WO2014139489A1 publication Critical patent/WO2014139489A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to an improved method for the preparation of ticagrelor (I), which is a compound with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)- cyclopropyl] amino] -5 -(propylthio)-3 H- 1 ,2,3 -triazolo [4,5-d]pyrimidin-3 -yl] -5 -(2- hydroxyethoxy)-l,2-cyclopentanediol, which is represented by formula I.
  • Ticagrelor is the active pharmaceutical substance of the medicament BRILIQUE.
  • BRILIQUE is used for treatment or prevention of myocardial infarction, cerebrovascular events, diseases of peripheral vessels, etc. Synthesis of ticagrelor has been described in several patents or patent applications (Scheme 1 , Scheme 2):
  • Patent application WO2012138981 mentions examples of similar procedures as in the previous patents, which use condensation of aminocyclopentane-l,2-diols la, lb, lc, Id with pyrimidine 2 (X is NH 2 , N0 2 , NHCHO) and subsequent transformations providing ticagrelor.
  • This invention rovides a method for the preparation of ticagrelor I
  • R is CH 2 CH 2 OH, CH 2 COOH or CH 2 COOR 1
  • R 1 is a branched or unbranched C C 4 alkyl
  • X is NH 2 , N0 2 or NHCHO.
  • the key reaction of the entire synthesis is condensation of the amino cyclopentane diol II with pyrimidine III, providing the isolated intermediate IV.
  • the compound II was used for the reaction with pyrimidine III without any protecting groups of the hydroxyls in positions 1 and 2.
  • the previously described methods have always used aminocyclopentane-l,2-diols with protecting groups of the hydroxyls in positions 1 and 2 (e.g., compounds la, lb, lc, Id).
  • Factors that have proved to be convenient for the purity and speed of the reaction of the amino cyclopentane diol II with pyrimidine III comprise a reaction temperature in the range between 60 and 150°C, advantageously in the range of 80 to 130°C, using a tertiary amine as the base in the range of 1 to 30 molar equivalents relative to the compound II, preferably triethylamine in the range of 3 to 15 molar equivalents and an alcohol or a mixture of an alcohol and water, preferably methanol, ethanol, propanol, isopropanol or ethylene glycol, as the solvent.
  • the compound IV can be crystallized or re-crystallized in a solvent selected from the group of ethyl acetate, isopropyl acetate and acetonitrile.
  • One of the particular embodiments of the synthetic sequence shown in Scheme 3 is preferably condensation of (lS,2S,3R,5S)-3-amino-5-(2-hydroxyethoxy)cyclopentane-l,2-diol Ila with 4,6-dichloro-2-(propylthio)-pyrimidine-5-amine Ilia in the presence of triethylamine in a mixture of methanol and water at a temperature of 80 to 130 °C, producing the intermediate IVa (Scheme 4).
  • the compound IVa can be crystallized or re-crystallized from a solvent selected from the group of ethyl acetate, isopropyl acetate and acetonitrile.
  • Diazotization of the compound IVa can be carried out using isopentyl nitrite or sodium nitrite in a solvent selected from the group of acetonitrile, toluene, water or their mixtures, producing the compound Va.
  • the compound Va is a solid substance that can be easily re-purified by crystallization, preferably from MTBE.
  • the compound Va reacts, in the subsequent step, with (lR,2S)-2-(3,4-difluorophenyl)-cyclopropane amine, preferably in the form of a salt with R- mandelic acid, in the presence of a tertiary amine or inorganic base, advantageously selected from the group of triethyl amine, diisopropyl ethyl amine, sodium carbonate and potassium carbonate, providing ticagrelor I.
  • the protecting group of the 1,2-diol of the compound Via, VIb or IVc can be removed in the environment of a mineral acid in a mixture of water and an alcohol, preferably selected from the group of methanol, ethanol, propanol, isopropanol and ethylene glycol, at a temperature of 0 to 120 °C, and the solution containing the compound II can be used without isolation for the subsequent reaction in accordance with Scheme 3.
  • 6-yl]oxy]ethanol L-tartrate (21.7 g, 59 mmol, Compound Vial) was dissolved in methanol (100ml). Water (10 g) and 37% HC1 (12 g) were added to the solution. The reaction mixture was stirred at 50°C for 2 hours. Then, 50 ml of methanol was removed from the reaction mixture by distillation and the mixture was stirred at 50°C for another 2 hours, thus providing intermediate Ila. Triethylamine (35.8 g) and 4,6-dichloro-2-(propylthio)-pyrimidin-5-amine (13.6 g, 57 mmol, Compound Ilia) were added to the reaction mixture and the mixture was stirred at 100°C for 40 hours.
  • the compound Va can be alternatively re-crystallized e.g. from MTBE.
  • Acetonitrile (20ml) and (lR,2S)-2-(3,4-difluorophenyl)-cyclopropane amine R-mandelate (1.64 g, 5.1 mmol) were added to the compound Va (1.95 g, 5 mmol).
  • Diisopropylethylamine (1.61 g, 12.5 mmol) was added dropwise at 25 to 30 °C. The mixture was stirred at 25 to 30°C for 4 hours. Then, water (30 ml) was added. Acetonitrile was evaporated in an evaporator at a reduced pressure. The mixture was extracted with ethyl acetate (3 x 30 ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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.

Description

METHOD FOR THE PREPARATION OF TICAGRELOR AND INTERMEDIATES SUITABLE THEREFORE
Technical Field
The invention relates to an improved method for the preparation of ticagrelor (I), which is a compound with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)- cyclopropyl] amino] -5 -(propylthio)-3 H- 1 ,2,3 -triazolo [4,5-d]pyrimidin-3 -yl] -5 -(2- hydroxyethoxy)-l,2-cyclopentanediol, which is represented by formula I.
Figure imgf000003_0001
(0
Background Art
Ticagrelor is the active pharmaceutical substance of the medicament BRILIQUE. BRILIQUE is used for treatment or prevention of myocardial infarction, cerebrovascular events, diseases of peripheral vessels, etc. Synthesis of ticagrelor has been described in several patents or patent applications (Scheme 1 , Scheme 2):
WO 0034283, WO 0192262:
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Scheme 1
Figure imgf000005_0001
Patent application WO2012138981 mentions examples of similar procedures as in the previous patents, which use condensation of aminocyclopentane-l,2-diols la, lb, lc, Id with pyrimidine 2 (X is NH2, N02, NHCHO) and subsequent transformations providing ticagrelor.
Figure imgf000006_0001
(2)
Disclosure of Invention
This invention rovides a method for the preparation of ticagrelor I,
Figure imgf000006_0002
(I)
which is based on the synthetic sequence according to Scheme 3,
Figure imgf000006_0003
Scheme 3 wherein R is CH2CH2OH, CH2COOH or CH2COOR1, R1 is a branched or unbranched C C4 alkyl and X is NH2, N02 or NHCHO. The key reaction of the entire synthesis is condensation of the amino cyclopentane diol II with pyrimidine III, providing the isolated intermediate IV. The compound II was used for the reaction with pyrimidine III without any protecting groups of the hydroxyls in positions 1 and 2. The previously described methods have always used aminocyclopentane-l,2-diols with protecting groups of the hydroxyls in positions 1 and 2 (e.g., compounds la, lb, lc, Id).
The use of the compound II without a protecting group eliminates the necessity of deprotection in the subsequent synthetic steps.
Factors that have proved to be convenient for the purity and speed of the reaction of the amino cyclopentane diol II with pyrimidine III comprise a reaction temperature in the range between 60 and 150°C, advantageously in the range of 80 to 130°C, using a tertiary amine as the base in the range of 1 to 30 molar equivalents relative to the compound II, preferably triethylamine in the range of 3 to 15 molar equivalents and an alcohol or a mixture of an alcohol and water, preferably methanol, ethanol, propanol, isopropanol or ethylene glycol, as the solvent.
The compound IV can be crystallized or re-crystallized in a solvent selected from the group of ethyl acetate, isopropyl acetate and acetonitrile.
One of the particular embodiments of the synthetic sequence shown in Scheme 3 is preferably condensation of (lS,2S,3R,5S)-3-amino-5-(2-hydroxyethoxy)cyclopentane-l,2-diol Ila with 4,6-dichloro-2-(propylthio)-pyrimidine-5-amine Ilia in the presence of triethylamine in a mixture of methanol and water at a temperature of 80 to 130 °C, producing the intermediate IVa (Scheme 4). The compound IVa can be crystallized or re-crystallized from a solvent selected from the group of ethyl acetate, isopropyl acetate and acetonitrile.
Diazotization of the compound IVa can be carried out using isopentyl nitrite or sodium nitrite in a solvent selected from the group of acetonitrile, toluene, water or their mixtures, producing the compound Va. The compound Va is a solid substance that can be easily re-purified by crystallization, preferably from MTBE. The compound Va reacts, in the subsequent step, with (lR,2S)-2-(3,4-difluorophenyl)-cyclopropane amine, preferably in the form of a salt with R- mandelic acid, in the presence of a tertiary amine or inorganic base, advantageously selected from the group of triethyl amine, diisopropyl ethyl amine, sodium carbonate and potassium carbonate, providing ticagrelor I.
Figure imgf000008_0001
If the compound Via, VIb or IVc is used as a precursor of the compound II (Scheme 5, wherein R is CH2CH2OH, CH2COOH or CH2COOR1 and R1 is a branched or unbranched C C4 alkyl), the protecting group of the 1,2-diol of the compound Via, VIb or IVc can be removed in the environment of a mineral acid in a mixture of water and an alcohol, preferably selected from the group of methanol, ethanol, propanol, isopropanol and ethylene glycol, at a temperature of 0 to 120 °C, and the solution containing the compound II can be used without isolation for the subsequent reaction in accordance with Scheme 3.
Figure imgf000009_0001
Scheme 5
One of the particular embodiments of the reaction in accordance with Scheme 5 is deprotection of 2-[[(3aS,4R,6S,6aR)-4-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH- cyclopenta[d][l ,3]dioxol-6-yl]oxy]ethanol L-tartrate (compound Vial, Scheme 6) in the environment of hydrochloric or sulphuric acid in a mixture of methanol and water. The solution containing the compound Ila can be used without isolation for the subsequent reaction in accordance with Scheme 4.
Figure imgf000009_0002
Scheme 6 Examples
The invention is described .in a more detailed way in the working examples below. These examples, which illustrate the improvement of the method in accordance with the invention, exclusively have an illustrative character and do not limit the scope of the invention in any respect.
Example 1: Preparation of (lS,2S,3R,5S)-3-[(5-amino-6-chloro-2-( ropylthio)-pyrimidin-4-yl)amino]-5- (2-hydroxyethoxy)cyclopentane-l ,2-diol (IVa)
Figure imgf000010_0001
( ial) 2-[[(3aS,4R,6S,6aR)-4-amino-2,2-dim^
6-yl]oxy]ethanol L-tartrate (21.7 g, 59 mmol, Compound Vial) was dissolved in methanol (100ml). Water (10 g) and 37% HC1 (12 g) were added to the solution. The reaction mixture was stirred at 50°C for 2 hours. Then, 50 ml of methanol was removed from the reaction mixture by distillation and the mixture was stirred at 50°C for another 2 hours, thus providing intermediate Ila. Triethylamine (35.8 g) and 4,6-dichloro-2-(propylthio)-pyrimidin-5-amine (13.6 g, 57 mmol, Compound Ilia) were added to the reaction mixture and the mixture was stirred at 100°C for 40 hours.
After that, the reaction mixture was cooled down. The mixture was concentrated in an evaporator at a reduced pressure to the volume of ca. 60 ml. Ethyl acetate (250 ml) was added and the mixture was concentrated to a volume of ca. 200 ml. Water (100 ml) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (100ml). The combined organic phase was dried over Na2S04 and concentrated in an evaporator at a reduced pressure to a volume of ca. 150 ml. After cooling to 5°C the separated precipitate was removed by aspiration and dried in vacuo. 16 g (74%) of the crude product was obtained, which was re-crystallized from acetonitrile. 14.5 g (67%) of the compound IVa was obtained with HPLC purity higher than 97%.
MW of 378.87 (C14H23C1N404S) was verified by means of HR MS.
1H NMR (250 MHz, dmso-d6, 25 °C): δ 7.00 (d, J=6.9Hz, 1H); 4.85 (brs, 2H); 4.79 (d, J=4.3Hz, 1H); 4.72 (d, J=6.1Hz, 1H); 4.54 (m, 1H); 4.19 (quintet, J=7.4Hz, 1H); 3.89 (m, 1H); 3.80 (m, 1H); 3.64 (m, 1H); 3.38-3.53 (m, 4H); 2.94 (m, 2H); 2.53 (m, 1H); 1.63 (sextet, J=7.4Hz, 2H); 1.25 (m, 1H); 0.95 (t, J=7.6Hz, 3H).
Example 2:
Preparation of (lS,2S,3R,5S)-3-(7-cMoro-5-(propyltMo)-3H-[l,2,3]triazolo[4,5-d]pyrimidin- 3-yl)-5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (Va)
Figure imgf000011_0001
(IVa) (Va) The compound IVa (10.94 g, 28.9 mmol) was dissolved in acetonitrile (232 ml) at 50 °C. Isopentyl nitrite (5.09 g, 43.5 mmol) was added dropwise at 50°C and the reaction mixture was stirred at 50°C for 4 hours. The solvents were evaporated in an evaporator at a reduced pressure, which provided a pinkish solid substance. 11.1 g (98%) of the compound Va was obtained, which was used without further purification for the subsequent reaction described in Example 3.
The compound Va can be alternatively re-crystallized e.g. from MTBE.
MW of 389.86 (C14H20ClNsO S) was verified by means of HR MS.
1H NMR (250 MHz, dmso-d6, 25 °C): δ 5.13 (quartet, J=8.9Hz, 1H); 4.62 (dd, J=8.6Hz, J=4.8Hz, 1H); 3.97 (dd, J=4.7Hz, J=1.6Hz, 1H); 3.79 (m, 1H); 3.51 (m, 4H); 3.21 (dt, J=7.0Hz, J=1.8Hz, 2H); 2.72 (m, 1H); 2.14 (m, 1H); 1.75 (sextet, J=7.3Hz, 2H); 1.02 (t, J=7.3Hz, 3H). Example 3:
Preparation of (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-
^ropyltMo)-3H-[l,2,3]triazolo[4,5-d]pyrimi
diol (I, Ticagrelor)
Figure imgf000012_0001
Acetonitrile (20ml) and (lR,2S)-2-(3,4-difluorophenyl)-cyclopropane amine R-mandelate (1.64 g, 5.1 mmol) were added to the compound Va (1.95 g, 5 mmol). Diisopropylethylamine (1.61 g, 12.5 mmol) was added dropwise at 25 to 30 °C. The mixture was stirred at 25 to 30°C for 4 hours. Then, water (30 ml) was added. Acetonitrile was evaporated in an evaporator at a reduced pressure. The mixture was extracted with ethyl acetate (3 x 30 ml). The combined organic phase was washed with water (20 ml) and evaporated in an evaporator at a reduced pressure, providing 2.54 g of a solid substance. The crude product was re-crystallized from acetonitrile. 2.29g (88%) of the compound I (Ticagrelor) was obtained with HPLC purity higher than 99%.
MW of 522.57 (C23H28F2N604S) was verified by means of HR MS.
1H NMR (500 MHz, dmso-d6, 100 °C): δ 8.84 (b, 1H); 7.27 (m, 2H); 7.07 (m, 1H); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m, 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m, 2H); 1.53 (m, 1H); 1.36 (m, 1H); 0.93 (t, J=7.1Hz, 3H).

Claims

Claims
1. A method for the reparation of ticagrelor of formula I,
Figure imgf000013_0001
(I) characterized in that the compound Via, VIb or Vic,
Figure imgf000013_0002
wherein R is CH2CH2OH, CH2COOH or CHzCOOR1 and R1 is a branched or unbranched CrC4 alkyl,
preferably in the form of a salt, is reacted with a deprotection agent in a solvent and/or mixture of solvents (step a), wherein the obtained compound of formula II,
Figure imgf000013_0003
(II) wherein R is CH2CH2OH, CH2COOH or CHaCOOR1 and R1 is a branched or unbranched C1-C4 alkyl,
is transformed in situ by reaction with the compound of formula III,
Figure imgf000013_0004
wherein X is N¾,
in the presence of a base in a solvent and/or mixture of solvents, to the compound of formula IV which is crystallized or re-crystallized from a solvent (step b),
Figure imgf000014_0001
wherein R is CH2CH2OH, CH2COOH or CH2COOR1, R1 is a branched or unbranched Q-C alkyl and X is NH2, which is then transformed to ticagrelor of formula I.
The method according to claim 1, characterized in that a mineral acid is used as the deprotection agent in step a).
The method according to claims 1 and 2, characterized in that hydrochloric or sulphuric acid is used as the mineral acid in step a).
The method according to claim 1, characterized in that a solvent selected from methanol, ethanol, propanol, isopropanol, ethylene glycol, water or their mixtures is used as the solvent in step a).
5. The method according to claim 1, characterized in that step a) is carried out at a temperature of 0 to 120°C.
6. The method according to claim 1 , characterized in that the compound II produced in step a) is used without isolation in step b).
7. The method according to claim 1, characterized in that a tertiary amine is used as the base in step b).
8. The method according to claim 1, characterized in that a solvent selected from methanol, ethanol, propanol, isopropanol, ethylene glycol, water or their mixtures is used as the solvent in step b).
9. The method according to claim 1, characterized in that step b) is carried out at a temperature of 60 to 150°C, preferably in the range of 80 to 130°C.
10. The method according to claim 1, characterized in that the compound IV is crystallized or re-crystallized from a solvent selected from ethyl acetate, isopropyl acetate and acetonitrile.
11. The compound of formula IV,
Figure imgf000015_0001
wherein R is CH2CH2OH, CH2COOH, CH2COOR1, R1 is a branched or unbranched C C4 alkyl and X is NH2.
12. A method for the reparation of ticagrelor of formula I,
Figure imgf000015_0002
(I) characterized in that the compound Vial,
Figure imgf000015_0003
(Vial) preferably in the form of a salt, is reacted in a solvent and/or mixture of solvents with a deprotection agent (step al), wherein the obtained compound of formula Ha,
Figure imgf000016_0001
(Ha) is transformed in situ by reaction with the compound of formula Ilia
Figure imgf000016_0002
in the presence of a base in a solvent and/or mixture of solvents, to the compound of formula IVa,
Figure imgf000016_0003
(IVa)
which is crystallized or re-crystallized from a solvent (step bl), and which is reacted with a diazotization agent in a solvent in step cl, producing the compound of formula Va,
Figure imgf000016_0004
which, in step dl, is reacted with (lR,2S)-2-(3,4-difluorophenyl)-cyclopropane amine, preferably in the form of a salt, to ticagrelor of formula I in a solvent and/or mixture of solvents in the presence of a base.
13. The method according to claim 12, characterized in that the compound Vial used in step al) is used in the form of a salt with L-tartaric acid.
14. The method according to claim 12, characterized in that a mineral acid is used as the deprotection agent in step al).
15. The method according to claims 12 and 14, characterized in that hydrochloric or sulphuric acid is used as the mineral acid in step al). 16. The method according to claim 12, characterized in that a solvent selected from methanol, ethanol, propanol, isopropanol, ethylene glycol, water or their mixtures is used as the solvent in step al).
17. The method according to claim 12, characterized in that step al) is carried at a temperature of 0 to 120°C.
18. The method according to claim 12, characterized in that the compound Ila produced in step al) is used without isolation in step bl). 19. The method according to claim 12, characterized in that a tertiary amine is used as the base in step bl).
20. The method according to claim 19, characterized in that triethylamine is used as the base in step bl).
21. The method according to claim 12, characterized in that a solvent selected from methanol, ethanol, propanol, isopropanol, ethylene glycol, water or their mixtures is used as the solvent in step bl). 22. The method according to claim 12, characterized in that step bl is carried out at a temperature of 60 to 150°C, preferably in the range of 80 to 130°C.
23. The method according to claim 12, characterized in that the compound IVa is crystallized or re-crystallized from a solvent selected from ethyl acetate, isopropyl acetate and acetonitrile. 24. The compound of formula IVa.
Figure imgf000018_0001
(IVa)
25. The method according to claim 12, characterized in that isopentyl nitrite or sodium nitrite is used as the diazotization agent in step cl).
26. The method according to claim 12, characterized in that a solvent selected from acetonitrile, toluene, water or their mixtures is used as the solvent in step cl).
27. The compound of formula Va.
Figure imgf000018_0002
28. The method according to claim 12, characterized in that (lR,2S)-2-(3,4- difluorophenyl)-cyclopropane amine used in step dl) is used in the form of a salt with R-mandelic acid.
29. The method according to claim 12, characterized in that a tertiary amine or inorganic base is selected as the base in step dl).
30. The method according to claims 12 and 29, characterized in that the tertiary amine is selected from triethylamine and diisopropyl ethylamine and the inorganic base is selected from sodium carbonate and potassium carbonate.
PCT/CZ2014/000028 2013-03-14 2014-03-14 Method for the preparation of ticagrelor and intermediates suitable therefore WO2014139489A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015067230A1 (en) * 2013-11-08 2015-05-14 Zentiva, K.S. A production method and a new crystalline form of an intermediate of synthesis of ticagrelor
CN106928233A (en) * 2015-12-31 2017-07-07 上海医药集团股份有限公司 The salt of quinolines, its crystal formation, preparation method, composition and application
CN115160320A (en) * 2022-06-27 2022-10-11 南通常佑药业科技有限公司 Preparation method of chiral pyrimidotriazole ticagrelor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (en) 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
WO2001092263A1 (en) 2000-06-02 2001-12-06 Astrazeneca Ab Novel triazolo pyrimidine compounds
WO2001092262A1 (en) 2000-06-02 2001-12-06 Astrazeneca Ab New crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound
WO2012138981A2 (en) 2011-04-06 2012-10-11 Teva Pharmaceutical Industries Ltd. New intermediates and processes for preparing ticagrelor
WO2013092900A1 (en) * 2011-12-23 2013-06-27 Lek Pharmaceuticals D.D. Synthesis of triazolopyrimidine compounds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102311437A (en) * 2010-07-01 2012-01-11 北京迈劲医药科技有限公司 Preparation method of platelet-aggregation-resisting medicament Ticagrelor
EP2607355A1 (en) * 2011-12-23 2013-06-26 LEK Pharmaceuticals d.d. Synthesis of triazolopyrimidine compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (en) 1998-12-04 2000-06-15 Astrazeneca Ab Novel triazolo(4,5-d)pyrimidine compounds
WO2001092263A1 (en) 2000-06-02 2001-12-06 Astrazeneca Ab Novel triazolo pyrimidine compounds
WO2001092262A1 (en) 2000-06-02 2001-12-06 Astrazeneca Ab New crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound
WO2012138981A2 (en) 2011-04-06 2012-10-11 Teva Pharmaceutical Industries Ltd. New intermediates and processes for preparing ticagrelor
WO2013092900A1 (en) * 2011-12-23 2013-06-27 Lek Pharmaceuticals D.D. Synthesis of triazolopyrimidine compounds

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015067230A1 (en) * 2013-11-08 2015-05-14 Zentiva, K.S. A production method and a new crystalline form of an intermediate of synthesis of ticagrelor
CN105940003A (en) * 2013-11-08 2016-09-14 赞蒂瓦有限合伙公司 A production method and a new crystalline form of an intermediate of synthesis of ticagrelor
CN106928233A (en) * 2015-12-31 2017-07-07 上海医药集团股份有限公司 The salt of quinolines, its crystal formation, preparation method, composition and application
CN106928233B (en) * 2015-12-31 2021-02-12 上海医药集团股份有限公司 Salt of quinoline compound, crystal form, preparation method, composition and application thereof
CN115160320A (en) * 2022-06-27 2022-10-11 南通常佑药业科技有限公司 Preparation method of chiral pyrimidotriazole ticagrelor

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