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WO2016030704A1 - Forme solide d'intermédiaire de ticagrelor - Google Patents

Forme solide d'intermédiaire de ticagrelor Download PDF

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Publication number
WO2016030704A1
WO2016030704A1 PCT/GB2015/052521 GB2015052521W WO2016030704A1 WO 2016030704 A1 WO2016030704 A1 WO 2016030704A1 GB 2015052521 W GB2015052521 W GB 2015052521W WO 2016030704 A1 WO2016030704 A1 WO 2016030704A1
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Prior art keywords
compound
formula
process according
formula vii
suitable solvent
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PCT/GB2015/052521
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English (en)
Inventor
Dharmaraj Ramachandra Rao
Geena Malhotra
Manjinder Singh Phull
Maruti Ghagare
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Cipla Limited
COTTRILL, Emily
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Publication of WO2016030704A1 publication Critical patent/WO2016030704A1/fr

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    • 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

Definitions

  • the present invention relates to a solid form of intermediate of ticagrelor and a commercially viable and industrially advantageous process for the preparation of ticagrelor.
  • Ticagrelor chemically is (1 S,2S,3R,5S)-3-[7- ⁇ (1 R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino ⁇ -5- propylthio-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol, and has the following chemical structure:
  • Ticagrelor is currently marketed in Europe under the trade name BRILIQUETM.
  • Ticagrelor is an antagonist of the P2Y 12 receptor. It is a platelet aggregation inhibitor. It is indicated for the treatment of thrombosis, angina, ischemic heart diseases, and coronary artery diseases.
  • U.S. Patent Nos. 6,251 ,910 discloses a variety of triazolo [4,5-d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds act as P 2T (P2Y A DP or P2T A c) receptor antagonists and they are indicated for use in therapy as inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation and anti-thrombotic agents.
  • P 2T P2Y A DP or P2T A c
  • EP1299390B discloses the process for the preparation of ticagrelor which comprises condensing 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine and 2- [[(3aft,4S,6ft,6aS)-6-amino -2,2-dimethyltetrahydro-3a - -cyclopenta[d][1 ,3]-dioxol-4-yl]oxy]-1 - ethanol.
  • L-tartaric acid salt in presence of triethyl amine at 120-125°C for 30 hours in an autoclave to form 2-[[(3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino] -2,2- dimethyltetrahydro-3a --cyclopenta-[d][1 ,3]-dioxol-4-yl]oxy]-1-ethanol as brown-red viscous oil.
  • brown-red viscous oil compound is cyclized in aqueous acetic acid below 7°C to form (2-[[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-1 ,2,3-triazolo[4,5-c/]pyrimidin-3-yl] -2,2- dimethyltetrahydro-3a --cyclopenta[d][1 ,3]-dioxol-4-yl]oxy]-1-ethanol as red-brown viscous oil.
  • trans-(1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanaminium ((2R)-2-hydroxy-2- phenylethanoate (also known as (1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid) in presence of triethylamine in acetonitrile at 20-25°C for 13 hours to form 2- [[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]
  • the object of the present invention is to provide a solid form of ticagrelor intermediate 2- [[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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 VII.
  • Another object of the present invention is to provide an improved process for the preparation of the compound of Formula VII, such that the compound of formula VII is produced in a solid form, either as a free base or as an acid addition salt.
  • Yet another object of the present invention is to provide a further conversion of solid intermediate of Formula VII into ticagrelor, such that ticagrelor is produced with high purity and yield.
  • Yet another object of the present invention is to provide an improved process for preparation of ticagrelor of formula I. SUMMARY OF THE INVENTION:
  • the invention provides a solid form of an intermediate, 2-[[(3aR,4S,6R,6aS)-6-[7- [[(1 R,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 VII.
  • the intermediate of solid form can be either the free base of the compound of formula VII, or an acid addition salt of the compound of formula VII.
  • the solid intermediate in free base form is preferably characterized by a melting point of from 92°C to 94°C. If the solid form of the intermediate of formula VII is in the form of an acid addition salt, the acid addition salt is preferably a fumarate salt or succinate salt.
  • a process for the preparation of a solid form of the compound of Formula VII either as free base or as an acid addition salt can be further used in a process for preparing ticagrelor with increased purity and yield compared to synthetic processes previously known in the art. It has also been found that a solid form of the compound of formula VII has reduced amounts of diastereomeric impurities compared with forms known in the art.
  • the process comprises coupling(1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)- Mandelic acid of Formula VI with (2-[[(3afi,4S,6fi,6aS)-6-[7-chloro-5-(propylthio)-3H-1 ,2,3- triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a - -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-[[(1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]- 5-(propylthio)-3H-1
  • ticagrelor or a salt thereof comprising 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.
  • the solid form of the compound of formula VII is prepared by the process of the present invention for preparing the compound of formula VII.
  • the improved process involves the use of the pure intermediate of the compound fo formula VII which is isolated in solid form with a high purity and yield. Said process eliminates laborious workup and extensive purifications. Hence, the process is simple, easy and user friendly.
  • a route of synthesis for the preparation of Ticagrelor can be represented as shown in below:
  • step III is carried out to synthesise the compound of formula VII.
  • (1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid of Formula VI is coupled with (2-[[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3 --1 ,2,3-triazolo[4,5-d] pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a --cyclopenta[d[[1 ,3]dioxol-4-yl]oxy]-1 -ethanol) of formula V in the presence of a suitable base and a first suitable solvent at a suitable temperature to form 2- [[(3aR,4S,6R,6aS)-6-[7-[[(1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amin
  • the isolated intermediate of ticagrelor (Formula VII) is in the solid form and has high yield, high purity and high stability.
  • this solid form is the free base and is characterised by a melting point in the range of from about 92.0 to 94.0°C.
  • the free base solid of the compound of formula VII is characterised by a differential scanning calorimetry spectrum substantially as defined in figure 3.
  • the solid form of the isolated intermediate (Formula VII) of the present invention can be easily handled and further processed and converted to ticagrelor having high purity and higher yield.
  • the suitable base may comprise, but is not limited to, an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal alkoxide, ammonia, an organic amine, or any combination thereof.
  • the suitable base comprises sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; sodium methoxide, potassium tert-butoxide; sodium carbonate, potassium carbonate, calcium carbonate; sodium bicarbonate, potassium bicarbonate, calcium carbonate; ammonia, tertiary amine (such as a tri (C1 -6 alkyl) amine), diisopropylamine, dimethyl amine, diisopropylethylamine, diisopropylmethylamine, pyridine, piperidine, morpholine and N-methyl piperidine, or any combination thereof.
  • the suitable base comprises an organic amine such as N,N- diisopropylethylamine.
  • the suitable first solvent may comprise, but is not limited to an organic solvent.
  • the organic solvent comprises a to C 10 aliphatic alcohol, a to C 10 alkane, a halogenated hydrocarbon, an alkyl nitrile, an alkyl ketone, an alkyl sulphoxide, an alkyl amide, or any combination thereof.
  • the organic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (DCM or CH 2 CI 2 ), C C 4 alcohols such as methanol, ethanol, isopropanol, isobutanol, n-butanol, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, alkane solvents such as pentane, hexane, heptane, or any combination thereof.
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • DCM or CH 2 CI 2 methylene chloride
  • C C 4 alcohols such as methanol, ethanol, isopropanol, isobutanol, n-butanol, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, alkane solvents such as pent
  • Step-Ill reaction is carried out at a temperature in the range of 0 ° C to 150°C, preferably 20 to 30°C, more preferably at 25 ° C to 30°C.
  • the reaction mixture of step III is preferably quenched in water and then extracted in a second suitable organic solvent.
  • the third suitable organic solvent preferably comprises water, an ether, an ester, a halogenated hydrocarbon, a ketone, an aromatic and aliphatic hydrocarbon, or any combination thereof. More preferably, the second suitable organic solvent comprises tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, acetone, toluene, xylene, cyclohexane, heptane or combinations thereof.
  • the organic layer is then optionally washed with aqueous acid, optionally followed by basic solution.
  • the basic solution comprises an organic base such as triethylamine (TEA) or diisopropylethylamine (DIPEA), or an inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K 2 C0 3 ), sodium carbonate (Na 2 C0 3 ); or any combination thereof.
  • the organic layer of the second suitable solvent is then preferably distilled, for example, by heating under reduced pressure so as to evaporate the solvent.
  • the obtained residue of formula VII is then admixed with the third suitable solvent; before the compound of formula VII in solid form is isolated from the third suitable solvent.
  • the compound of formula VII can be isolated as an acid addition salt.
  • the third suitable solvent is preferably a non polar solvent.
  • nonpolar solvents comprise to C 10 aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, or any combination thereof.
  • the non polar solvent comprises hexane, n-heptane, pentane, octane; cyclopentane, cyclohexane; dichloromethane, chloroform; benzene, toluene, or combinations thereof.
  • the coupling reaction between the compound of formula VI with the compound of formula V is carried out for a time period of from 1 to 4 hours.
  • the coupling reaction between the compound of formula VI with the compound of formula V is carried out at atmospheric pressure and does not require the use of an autoclave.
  • the step of mixing the residue of the compound of formula VII with the third suitable solvent comprises stirring the third suitable solvent and compound of formula VII for a time period of from 15 minutes to 6 hours, before isolation of the solid form of the compound of formula VII.
  • the solid form of the compound of formula VII prepared by the process of the invention described above, can be further converted to an acid addition salt of the compound of formula VII.
  • the acid addition salt of the compound of formula VII is also in a solid form.
  • this process comprises reacting the solid compound of formula VII with an acid in a suitable solvent for a time period of preferably from 15 minutes to an hour.
  • the reaction is carried out at a temperature of from 60°C to 80°C.
  • the suitable solvent is a C1 to C 6 aliphatic alcohol such as isopropanol.
  • the acid employed for preparation of a salt of compound of formula VII preferably comprises but is not limited to organic acids, such as fumaric acid, succinic acid, oxalic acid, formic acid, acetic acid, and combinations thereof; or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and combinations thereof.
  • the salts of compounds of formula VII are preferably fumarate and succinate salts.
  • the fumarate salt of compound of formula VII is characterized by XRD as provided in Figure 1 .
  • the present invention provides the fumarate salt of a compound of formula VII with an XRD pattern substantially as shown in figure 1.
  • the succinate salt of compound of formula VII can be characterized by XRD as provided in Figure 2.
  • the present invention provides the succinate salt of a compound of formula VII with an XRD pattern substantially as shown in figure 2.
  • the present invention also provides a process for preparing Ticagrelor of formula I or a salt thereof
  • the process comprises deprotection of 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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 VII using a suitable acid in a suitable solvent to obtain ticagrelor of formula I.
  • the solid form of the compound of formula VII is prepared according to the process of the invention for preparing the solid form of the compound of formula VII as discussed above.
  • Suitable acids employed in step IV for deprotection preferably comprises but is not limited to an inorganic acid such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid; an organic acid such as acetic acid, trifluoro acetic acid; or any combination thereof.
  • an inorganic acid such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid
  • organic acid such as acetic acid, trifluoro acetic acid
  • Suitable solvents employed in step IV may comprise but are not limited to water, alcohols such as methanol, ethanol, isopropanol, isobutanol, n-butanol; ketones such as acetone; esters such as ethyl acetate; ethers such as tetrahydrofuan; aliphatic and alicyclic hydrocarbons such as hexane, heptane, cyclohexane; halogenated hydrocarbons such as methylene dichloride, chloroform; aromatic hydrocarbons such as toluene or xylene; nitriles such as acetonitrile; polar aprotic solvents; organic acids such as acetic acid; and any mixtures or combinations thereof.
  • alcohols such as methanol, ethanol, isopropanol, isobutanol, n-butanol
  • ketones such as acetone
  • esters such as ethyl acetate
  • the suitable solvent comprises a mixture of water and isopropanol.
  • the solid form of the compound of formula VII used in the process of preparing Ticagrelor can be the free base form, or an acid addition salt thereof.
  • Preferable acid addition salts comprise the hydrochloride, sulphate, hydrobromide, phosphate, lactate, malonate, oxalate, succinate or fumarate salts.
  • the acid addition salt is the fumarate or succinate salt of the compound of formula VII.
  • the reaction is carried out for a time period of from 1 hours to 3 hours.
  • the reaction is carried out at room temperature.
  • the process of the invention for the preparation of ticagrelor may also comprise converting ticagrelor into therapeutically useful medicaments.
  • alkali nitrates and nitrites preferred for use in the present invention are those having potassium, sodium, cesium, or rubidium as the alkali component; or organic nitrite such as tert butyl nitrite, n-butyl nitrite, amyl nitrite, iso-amyl nitrite; or combinations thereof.
  • Suitable solvents may comprise organic solvents such as dimethylformamide (DMF); dimethylsulfoxide (DMSO); methylene chloride (DCM or CH 2 CI 2 ); C C 4 alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol; esters such as ethyl acetate; nitriles such as acetonitrile; ketones such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); alkane solvents such as pentane, hexane, heptane, sulfolane ionic liquid, ethylene glycol, hexamethylphosphoramide (HMPA), and combinations thereof.
  • organic solvents such as dimethylformamide (DMF); dimethylsulfoxide (DMSO); methylene chloride (DCM or CH 2 CI 2 ); C C 4 alcohols such as methanol,
  • the compound of formula V may be prepared and isolated prior to the reaction with the compound of formula VI in the process of the present invention.
  • the compound of formula V may be prepared in situ from the reaction of a compound of formula IV and an alkali metal nitrate or organic nitrite such that the compound of formula VII in a solid form is prepared from the compound of formula IV without isolation of any intermediates.
  • the compound 2-[[(3a ?,4S,6 ?,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]-2,2- dimethyl tetrahydro-3a4 --cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol of formula IV may be prepared by condensing 5-amino-4,6-dichloro-2-(propylthio)pyrimidine of formula II with 2-[[(3a ?, 4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3a --cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol, L- tartaric acid salt of formula III in presence of a suitable base and catalyst in a suitable solvent at a suitable temperature.
  • reaction is carried out in the absence of a catalyst.
  • the base may comprise an organic base such as ammonia; secondary and tertiary amines such as a tri (C1-6 alkyl) amines;, diisopropylamine, dimethyl amine, diisopropylethylamine, diisopropylmethylamine; aromatic amines such as pyridine, and morpholine; piperidine, and N- methyl piperidine, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; alkoxides such as sodium methoxide, potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate, calcium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, calcium bicarbonate; and combinations thereof.
  • organic base such as ammonia
  • secondary and tertiary amines such as a tri (C1-6 alkyl) amines
  • Suitable solvents comprise but are not limited to organic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane, hexamethylphosphoramide (HMPA), methylene chloride (DCM or CH 2 CI 2 ), C C 4 alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, alkane solvents such as pentane, hexane, heptane and combinations thereof.
  • organic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane, hexamethylphosphoramide (HMPA), methylene chloride (DCM or CH 2 CI 2 ), C C 4 alcohols such as methanol, ethanol, isopropanol, n-butanol
  • Suitable catalysts comprise metal halides, quaternary ammonium halides and quaternary phosphonium halides.
  • Preferred catalysts include sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, tetraethyl ammonium chloride, tetraethyl ammonium bromide, tetraethyl ammonium iodide, tetrabutyl ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, methyltrioctylammonium chloride (aliquot 336), tetraethylphosphonium chloride, tetraethylphosphonium bromide and tetraethylphosphonium iodide, crown ethers, linear ethers, heterocyclic ammonium salts, phosphonium salts like he
  • the reaction is carried out at a temperature in the range of 0°C to 200°C, preferably 95 to 1 15°C.
  • the present invention also provides processes for the preparation of the compounds of formula IV and formula V.
  • the present invention provides a multi-step synthesis of ticagrelor, the compound of formula I from the compounds of formula II and formula III.
  • the compounds of formula II and II I are reacted to form the compound of formula IV, which can be converted into the compound of formula V, which can be converted into the compound of formula VII via reaction with the compound of formula VI, before the compound of formula VII is converted to the compound of formula I.
  • all of the reactions are done at atmospheric pressure.
  • none of the reactions require the use of an autoclave.
  • Figures 1 a and 1 b are X-ray powder diffractograms (XRD) of fumarate salt of compound of formula VII.
  • Figure 2a and 2b are X-ray powder diffractograms (XRD) of succinate salt of compound of formula VII.
  • FIG. 3 is a differential scanning calorimetry (DSC) spectrum of the solid free base form of the compound of formula VII.
  • Example 1 Preparation of compound of Formula IV To a reaction flask 24 g (0.06533moles) 2-[[(3aft,4S,6ft,6aS)-6-amino -2,2-dimethyltetrahydro- 3aH-cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol, L-tartaric acid in 40 ml sulfolane, 40 ml (0.296moles) of ⁇ , ⁇ -diisopropylethylamine and 2 g of tetra butyl ammonium iodide were charged and the reaction mixture was stirred for 20-25 minutes 10 g (0.04199moles) of 5-amino-4,6- dichloro-2-(propylthio)pyrimidine in 10 ml sulfolane was charged and the reaction mixture was heated to 95°C to 105°C for 3-4 hours. The reaction mixture was quen
  • reaction mixture was quenched with 375 ml of water at 25-30°C.
  • the pH of the reaction mass was adjusted to 6.5 to 7.5 using glacial acetic acid and stirred for 2 hours.
  • the obtained product was filtered and washed with water. Dried the material under vacuum at 55-60°C.
  • the reaction mixture was concentrated under reduced pressure and to the residue 1 10ml water and 1 10ml ethyl acetate were added and stirred for 5 minutes.
  • the organic layer was separated and washed with 50 ml 1 N HCI followed by 50 ml water followed by 100ml 5% sodium bicarbonate solution, the organic layer was separated and concentrated under vacuum to obtain oil.
  • the reaction mixture was quenched with 100ml water at 10-15°C and extracted two times each with 50 ml ethyl acetate.
  • the organic layer was washed two times each with 25ml 1 N HCI solution followed by 25ml water followed by 50ml 5% sodium bicarbonate solution.
  • the organic layer was separated and distilled under reduced vacuum at 40°C to obtain residue.
  • the residue was stirred with 30ml heptane for 4-5 hours at 25°C to 30°C, filtered and dried under vacuum at 50°C to 55°C for 12 hours to obtain compound of formula VII.
  • reaction mixture was cooled to 0°C to 5°C and neutralized with 30 ml aqueous ammonia and extracted two times with 25 ml ethyl acetate, ethyl acetate layers were combined and washed with 25 ml water. Ethyl acetate layer was distilled under reduced pressure at 40°C. Ticagrelor was isolated from 20% acetone in heptane mixture and dried under vacuum at 45°C to 50°C.
  • Example 11 Preparation of compound of Formula VII succinate salt.

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Abstract

La présente invention concerne un procédé de préparation d'une forme solide d'un composé de formule (VII) (Formule (VII)) qui comprend le couplage d'acide (1R,2S)-2-(3,4-difluorophényl)cyclopropanamine (R)-mandélique de formule (VI) avec du (2-[[(3a R,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-2,2- diméthyltétrahydro-3aH-cyclopenta[d[[1,3]dioxol-4-yl]oxy]-1-éthanol) de formule (V) en présence d'une base appropriée et d'un premier solvant approprié à une température appropriée pour former du 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1R,2S)-2-(3,4-difluorophényl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3- triazolo[4,5-d]pyrimidin-3-yl]-2,2-diméthyltétrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy]-1-éthanol de formule (VII) ; et l'isolement du composé de formule (VII) à l'aide d'un second solvant approprié de façon à produire le composé de formule (VII) sous forme solide. Un procédé de préparation de Ticagrelor de formule (I) ou d'un sel de ce dernier (Formule (I)) comprend la conversion d'un composé de formule (VII) sous une forme solide soit sous forme de base libre soit comme sels d'addition d'acide de ce dernier, en un composé de formule (I).
PCT/GB2015/052521 2014-08-30 2015-09-01 Forme solide d'intermédiaire de ticagrelor WO2016030704A1 (fr)

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CN115181101A (zh) * 2022-06-01 2022-10-14 浙江东亚药业股份有限公司 一种替格瑞洛合成中间体的制备方法

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CN108892670A (zh) * 2018-07-12 2018-11-27 江西国药有限责任公司 一种高纯度替格瑞洛的制备方法
CN111978305A (zh) * 2019-05-24 2020-11-24 南京一心和医药科技有限公司 一种替格瑞洛中间体的制备工艺
CN111978326A (zh) * 2019-05-24 2020-11-24 南京一心和医药科技有限公司 一种替格瑞洛精品的生产工艺
CN111978305B (zh) * 2019-05-24 2023-01-20 南京一心和医药科技有限公司 一种替格瑞洛中间体的制备工艺
CN110467619A (zh) * 2019-08-08 2019-11-19 山西德元堂药业有限公司 一种替格瑞洛的制备方法
CN110684029A (zh) * 2019-10-29 2020-01-14 株洲千金药业股份有限公司 一种替格瑞洛缩合杂质的制备方法
CN115181101A (zh) * 2022-06-01 2022-10-14 浙江东亚药业股份有限公司 一种替格瑞洛合成中间体的制备方法

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