WO2016001851A1 - Préparation de ticagrélor - Google Patents

Préparation de ticagrélor Download PDF

Info

Publication number
WO2016001851A1
WO2016001851A1 PCT/IB2015/054947 IB2015054947W WO2016001851A1 WO 2016001851 A1 WO2016001851 A1 WO 2016001851A1 IB 2015054947 W IB2015054947 W IB 2015054947W WO 2016001851 A1 WO2016001851 A1 WO 2016001851A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
reaction
salt
ticagrelor
Prior art date
Application number
PCT/IB2015/054947
Other languages
English (en)
Inventor
Vilas Dahanukar
Ravi Ram Chandrasekhar Elati
Srinivas ORUGANTI
Rajesh Kumar Rapolu
Sreenivasulu Kurella
Original Assignee
Dr. Reddy's Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Limited filed Critical Dr. Reddy's Laboratories Limited
Publication of WO2016001851A1 publication Critical patent/WO2016001851A1/fr

Links

Classifications

    • 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • aspects of the present application relate to processes for preparing ticagrelor and to intermediates that are useful in the processes.
  • the drug compound having the adopted name "ticagrelor" has chemical names: [1 S-(1 ⁇ ,2 ⁇ ,3 ⁇ (1 S * ,2R * ),5p)]-3-[7-[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; or (1 S,2S,3fl,5S)-3-[7- ⁇ [(1 fl,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino ⁇ -5-(propylthio)-3H 1 ,2,3]-triazolo[4,5-c/
  • Ticagrelor is the active ingredient in the commercially available BRILINTA® tablets for oral administration.
  • Ticagrelor and related compounds are disclosed in International Patent Application Publication Nos. WO 00/34283 and WO 99/05143 as pharmaceutically active ⁇ 2 ⁇ (which are now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used, inter alia, as inhibitors of platelet activation, aggregation, or degranulation.
  • International Patent Application Publication Nos. WO 01 /92263 and WO 2010/030224 A1 , WO 2012085665 A2, WO 2012138981 A2 and WO 2013037942 A1 disclose processes for preparing ticagrelor.
  • An aspect of the present application provides process for preparation of Ticagrelor, comprising converting the compound of Formula II to Ticagrelor of Formula I;
  • R a and R b are independently selected from C C 6 alkyl, substituted or unsubstituted aryl, phenyl, benzyl and like.
  • R a and Rb together with the nitrogen atom to which they are attached combine to form a 5 or 6 membered saturated, partially unsaturated or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R a and R b are attached, and 0-1 additional heteroatoms selected from the group consisting of N, O and like.
  • Ri and R 2 independently are hydroxy or protected hydroxy groups.
  • Another aspect of the present application provides processes for preparing the compound of Formula I, embodiments comprising :
  • R a and Rb are independently selected from CrC 6 alkyl, substituted or unsubstituted aryl, phenyl, benzyl and like.
  • R a and Rb together with the nitrogen atom to which they are attached combine to form a 5 or 6 membered saturated, partially unsaturated or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R a and R b are attached, and 0-1 additional heteroatoms selected from the group consisting of N, O and like.
  • Ri and R 2 independently are hydroxy or protected hydroxy groups
  • X is halogen
  • aspects of the present application provide processes for preparing a compound of Formula I. Further aspects provide useful intermediate compounds for preparing a compound of Formula I, and processes for their preparation. In an aspect of the present application provides process comprising converting the compound of Formula I I to Ticagrelor of Formula I;
  • R a and R b are independently selected from C C 6 alkyl, substituted or unsubstituted aryl, phenyl, benzyl and like.
  • R a and Rb together with the nitrogen atom to which they are attached combine to form a 5 or 6 membered saturated, partially unsaturated or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R a and Rb are attached, and 0-1 additional heteroatoms selected from the group consisting of N, O and like.
  • Ri and R 2 independently are hydroxy or protected hydroxy groups.
  • the conversion comprises either of following two options viz.,
  • Reduction of amide functionality in compounds of Formulas I I and I la can be accomplished using suitable reducing agents which include, but are not limited to, lithium aluminium hydride, VitrideTM [sodium bis(2-methoxyethoxy)aluminum hydride], and any other suitable reagent, in a suitable solvent inert to the reaction medium.
  • suitable reducing agents include, but are not limited to, lithium aluminium hydride, VitrideTM [sodium bis(2-methoxyethoxy)aluminum hydride], and any other suitable reagent, in a suitable solvent inert to the reaction medium.
  • suitable reducing agents include, but are not limited to, lithium aluminium hydride, VitrideTM [sodium bis(2-methoxyethoxy)aluminum hydride], and any other suitable reagent, in a suitable solvent inert to the reaction medium.
  • LAH and Vitride are employed as reducing agent in THF as a solvent.
  • Deprotection of a compound of Formula II or a compound of Formula lib is carried out using methods known in the art, such as by treatment with a suitable acid like aqueous hydrochloric acid, aqueous sulfuric acid, and the like.
  • a suitable acid like aqueous hydrochloric acid, aqueous sulfuric acid, and the like.
  • Suitable solvents will generally be inert to the reaction conditions and can be chosen from the list provided in general list of solvents.
  • methanol is employed as a solvent.
  • the present application provides processes for preparing Ticagrelor of Formula I, embodiments comprising
  • R a and Rb are independently selected from CrC 6 alkyl, substituted or unsubstituted aryl, phenyl, benzyl and like.
  • R a and R b together with the nitrogen atom to which they are attached combine to form a 5 or 6 membered saturated, partially unsaturated or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R a and R b are attached, and 0-1 additional heteroatoms selected from the group consisting of N, O and like.
  • Ri and R 2 independently are hydroxy or protected hydroxy groups.
  • Suitable bases include, but are not limited to: inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and the like; and organic bases such as triethylamine, diisopropylethylamine, morpholine, and the like.
  • Suitable solvents employed in step a) will generally be inert to the reaction conditions.
  • reaction is carried out in toluene.
  • a suitable salt of compound of Formula II is a salt of a mineral or organic acid.
  • suitable mineral acids for salt formation include hydrochloric, hydrobromic and sulphuric acid.
  • Suitable organic acids include organic acids such as acetic, trifluoroacetic, oxalic, succinic acid, formic acid and p-toluenesulphonic acids and organic chiral acids such as L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p-toluoyl-L-tartaric acid.
  • organic acid is employed and more preferably, oxalic acid is used.
  • Ri and R2 independently are hydroxy or protected hydroxy groups.
  • Some suitable protecting groups are described by T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., 1999, and other groups are described in the literature,
  • the conversion can be carried by methods mentioned in above aspect of application.
  • Yet another aspect of the present application provides a process for preparation of Ticagrelor of Formula I comprising ,
  • Ri and R 2 independently are hydroxy or protected hydroxy groups
  • R a and Rb are are independently selected from C1 -C6 alkyl, phenyl, benzyl.
  • R a and R b together with the nitrogen atom to which they are attached combine to form a 5 or 6 membered saturated, partially unsaturated or unsaturated ring consisting of: carbon atoms, the nitrogen atom to which R a and R b are attached, and 0-1 additional heteroatoms selected from the group consisting of N, O and like,
  • X is halogen
  • the reaction can be carried out in the presence of a suitable base and suitable solvent.
  • suitable bases that can be employed include, but are not limited to: inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and the like; and organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, DABCO (1 ,4- diazabicyclo[2.2.2]octane) and the like.
  • sodium bicarbonate has been employed.
  • Suitable solvents employed in step a) will generally be inert to the reaction conditions and can be selected from the list provided in the application.
  • reaction is carried out in water.
  • Reaction can be carried out optionally in presence of suitable additives include but are not limited to potassium iodide, tetrabutyl ammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), sodium iodide, lithium chloride, lithium iodide and like.
  • suitable additives include but are not limited to potassium iodide, tetrabutyl ammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), sodium iodide, lithium chloride, lithium iodide and like.
  • a suitable salt of compound of Formula VI or VII that can be employed in step a) is a salt of a mineral or organic acid.
  • Suitable mineral acids for salt formation include hydrochloric, hydrobromic, hydroiodic, nitric, and sulphuric acid.
  • Suitable organic acids include organic achiral acids such as acetic, trifluoroacetic, oxalic, succinic acid, formic acid and p-toluenesulphonic acids, and organic chiral acids such as L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p-toluoyl-L-tartaric acid.
  • organic acid is employed and more preferably, L-tartaric acid is used in case of compound of Formula VII.
  • the compounds of Formulas VI can be prepared by using an adaptation of literature methods, such as described in European Patent Application 508687 A1 , and U.S. Patent Nos. 7,067,663 and 7,799,914.
  • a suitable salt of compound of Formula IV is a salt of a mineral or organic acid.
  • suitable mineral acids for salt formation include hydrochloric, hydrobromic and sulphuric acid.
  • Suitable organic acids include organic acids such as acetic, trifluoroacetic, oxalic, succinic acid, formic acid and p-toluenesulphonic acids and organic chiral acids such as L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p-toluoyl-L-tartaric acid.
  • Ri and R2 independently are hydroxy or protected hydroxy groups and X is halogen.
  • Suitable nitrite employed in step b) could be selected from isoamyl nitrite, sodium nitrite and like. In a preferred embodiment, sodium nitrite is employed.
  • Suitable solvents employed in step b) will generally be inert to the reaction conditions.
  • reaction is carried out in water.
  • Suitable acid in step b) can be inorganic or organic acid.
  • Inorganic acid selected includes but not limited to hydrochloric, hydrobromic, hydroiodic, nitric and sulphuric acid.
  • Suitable organic acids include acetic, trifluoroacetic and like.
  • organic acid is employed and more preferably, acetic acid is used, c) reacting the compound of Formula IV with a compound of Formula II I, or a salt thereof, to afford a compound of Formula II; and
  • R a and Rb, Ri and R 2 are as described above.
  • Suitable base and suitable solvent employed can be selected from above mentioned aspect of the application.
  • toluene is employed as a solvent and diisopropylethyl amine is employed as a base.
  • Compounds of Formula II can be isolated in any physical form or in the form of a salt to improve the purity.
  • a suitable salt of compound of Formula II is a salt of a mineral or organic acid and can be selected from the list mentioned in above aspect of invention.
  • the compound of Formula III can be prepared by using methods known in the art or by the method included in the present application. If a salt of the compound of Formula III is employed, then a free base may be generated in situ during the reaction.
  • the said conversion can be done as described in above aspect of application.
  • Yet another aspect of the present application comprises a process for preparation of Ticagrelor wherein one or more intermediate compounds may not be isolated and used in organic solution itself for the next step.
  • compound of Formula VI can be reacted with compound of Formula VII to give compound of Formula V, which optionally without isolation on cyclization leads to compound of Formula IV, which optionally without isolation on subsequent reaction with compound of Formula III results in a compound of Formula II, which optionally without isolation can further be converted to a compound of Formula I.
  • the present application also provides novel intermediate compounds of Formula VII, Formula V, Formula IV, Formula II and Formula lla.
  • the said compounds in racemic as well as optically active forms and in all physical forms are included within the scope of application.
  • present application provide compounds of Formula V with specific groups i.e. compounds of Formula V and Formula V",
  • present application provide compounds of Formula IV with specific groups i.e. compounds of Formula IV and Formula IV",
  • present application provides a compound of Formula II with specific groups i.e. compounds of Formula ⁇ and Formula II",
  • Another aspect of the present application provides processes for preparing a compound of Formula VI I, comprising:
  • Ri and R 2 independently are hydroxy or protected hydroxy groups
  • R 3 is a C1-6 alkyl or benzyl group (wherein the phenyl ring of a benzyl group is optionally substituted by cyano, C1-4 alkyl, Ci -4 alkoxy, CF 3 , or OCF 3 ), X is halogen.
  • the reaction is conducted in the presence of a base, suitable bases including, but not limited to: alkali metal Ci -6 alkoxides, such sodium methoxide, potassium tertiary-butoxide, and sodium tertiary-butoxide; and alkali metal hydrides, such as sodium hydride.
  • alkali metal Ci -6 alkoxides such sodium methoxide, potassium tertiary-butoxide, and sodium tertiary-butoxide
  • alkali metal hydrides such as sodium hydride.
  • sodium hydride is employed.
  • solvents include polar aprotic solvents, cyclic and aliphatic ethers such as THF, diethyl ether, diisopropyl ether, or methyl tert-butyl ether, and aromatic solvents such as benzene, toluene, xylene, and the like.
  • the solvent can be a mixture of two or more solvents.
  • dimethylformamide is used as a solvent.
  • Deprotection of a compound of Formula Vi la can be carried out by methods known in the art, for example by hydrogenation, such as with a metal catalyst (such as palladium on carbon) in the presence of a suitable solvent that is inert to the reaction conditions at the desired temperature and pressure conditions.
  • a solvent is a C1-4 aliphatic alcohol, such as methanol or ethanol.
  • Pd/C in presence of ammonium formate is employed.
  • a salt can be prepared from the compound of Formula Vi la.
  • a salt of compound of Formula Vi la can be prepared by reacting compound of formula Vi la with the desired acid, in a suitable solvent that is inert to the reaction conditions.
  • Suitable acid for salt preparation includes but are not limited to: inorganic acids such as hydrohalic acids (for example, hydrofluoric, hydrochloric, hydrobromic, and hydroiodic acids) or other inorganic acids (for example, nitric, perchloric, sulfuric, and phosphoric acids); organic acids, such as organic carboxylic acids (for example, xinafoic, oxalic, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, 2- or 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 2- or 4-chlorobenzoic, salicylic, succinic, malic, hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, oleic, and glutaric acids), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2- hydroxyethanesulph
  • the present application also provides novel intermediate compounds of Formula Vila and Formula VII.
  • the said compounds in racemic as well as optically active forms and in all physical forms are included within the scope of application.
  • present application provides compounds of Formula VII with specific groups i.e. compounds of Formula VII' and Formula VII",
  • present application provides compounds of Formula Vila with specific groups i.e. compounds of Formula Vila' and Formula ",
  • the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification, may be carried out at ambient temperatures, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Furthermore, many of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rates and yields. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, or any of their combinations.
  • Suitable solvents inert to the reaction conditions include but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamyl alcohol and ethylene glycol; ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; nitriles, such as acetonitrile; polar aprotic solvents, such as ⁇ , ⁇ -dimethylformamide, N,N- dimethylacet
  • the compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH.
  • a conventional method well known to those skilled in the art such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH.
  • Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques.
  • the suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like.
  • An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
  • Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity.
  • precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product.
  • Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any
  • the compounds at various stages of the process may be recovered using conventional techniques known in the art.
  • useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like.
  • the isolation may be optionally carried out at atmospheric pressure or under a reduced pressure.
  • the solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
  • Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure.
  • Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
  • a recovered solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
  • Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula.
  • a "room” or “ambient” temperature includes temperatures from about 15°C to about 35°C, from about 20°C to about 30°C, or about 25°C.
  • pure When a molecule or other material is identified herein as “pure”, it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, “pure” also means 99% of one enantiomer or diastereomer, as appropriate. “Substantially” pure means, the same as “pure except that the lower limit is about 98% pure or more and likewise, “essentially” pure means the same as “pure” except that the lower limit is about 95% pure.
  • the term “overnight” refers to a time interval from about 14 hours to about 24 hours, or about 14 hours to about 20 hours, for example, about 16 hours.
  • Any organic solvents may be used alone, or any two or more may be used in combination, or one or more may be used in combination with water in desired ratios.
  • EXAMPLE 2 Preparation of benzyl ((3aS,4R,6S,6aR)-6-(2-(diphenylamino)-2- oxoethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (FORMULA Vila).
  • the mixture is stirred at - 30°C for about 45 minutes, then a solution of 2-bromo-N,N-diphenylacetamide (22.65 g) in dimethyl formamide (60 mL) is added at the same temperature.
  • the reaction mixture is allowed to attain room temperature and stirred at the same for 3 hours and completion of the reaction is monitored by TLC.
  • the reaction mixture is quenched with ice-cold water (200 mL) and extracted with ethyl acetate (3x150 mL).
  • the organic layer is combined and washed with water (3x100 mL), brine (100 mL) and then organic layer is then subjected to complete distillation under vacuum at 45°C.
  • the crude so obtained is treated with MTBE (150 mL) and stirred at room temperature for overnight followed by filtration of obtained solid to afford the title compound.
  • the reaction mixture is diluted with water (60 mL), layers are separated and aqueous layer is extracted with toluene (2x30 mL). The combined organic layers are washed with brine (60 mL) and then subjected to complete distillation under vacuum at 45°C to afford the crude compound.
  • the crude compound is purified by column chromatography using ethyl acetate and hexane (80:20).
  • Lithium aluminium hydride (940 mg) is added over a period of 10 minutes and mixture is stirred at 0°C for 1 hour. The reaction mixture is then stirred at room temperature for 5 hours and progress of the reaction is monitored by TLC. Then mixture is cooled to 0-5°C and quenched with ice cold water (100 mL) and then diluted with ethyl acetate (30 mL). The layers are separated and organic layer after drying is used for next step.
  • the reaction mixture is stirred at room temperature for 48 hours and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (50 mL), layers are separated. The organic layer is sequentially washed with water (50 mL), brine solution (50 mL) followed by complete distillation under vacuum at 45°C. The crude compound is dissolved in ethyl acetate (12 mL) and then hexane (50 mL) is added. The mixture is stirred for 2 hours followed by isolation of solid by filtration. The obtained solid is dissolved in ethyl acetate (12 mL) and treated with charcoal followed by filtration. The filtrate is subjected to complete distillation and obtained solid is purified by column chromatography using ethyl acetate:hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.
  • reaction mixture is stirred at same temperature for 1 hour and progress of the reaction is monitored by TLC. Additional amount of Vitride (0.13 mL) is added to the mixture and stirred for additional 6 hours. After completion of reaction, reaction mixture is cooled to 0- 5°C and quenched with saturated sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer is subjected to complete distillation under reduced pressure and obtained material is purified by column chromatography using ethyl acetate: hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.
  • Lithium aluminium hydride (15 mg) is added over a period of 1 0 minutes and mixture is stirred at 0°C for 1 hour. The progress of the reaction is monitored by TLC. After completion of the reaction, mixture is quenched with ice cold water (5 mL) and diluted with ethyl acetate (10 mL). The layers are separated and organic layer after drying is subjected to complete distillation followed by purification using preparative TLC using 40% ethyl acetate in hexane to afford the title compound.
  • the mixture is stirred at RT for 1 hour.
  • the progress of the reaction is monitored by TLC and after completion, the reaction mixture is quenched with ice cold water followed by extraction with ethyl acetate.
  • the organic layer is separated and subjected to distillation to afford the title compound.
  • EXAMPLE 13 Preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula VII")
  • a flask is charged with benzyl ((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2- morpholino-2-oxoethoxy)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate, ethanol (1 0 g), ammonium formate (4.35 g) and 10% Pd/C (1 g).
  • reaction mixture is heated to 80°C and then stirred for 2 hours.
  • the progress of the reaction is monitored by TLC and after completion of the reaction, mixture is cooled to room temperature, filtered and washed with ethyl acetate (100 mL).
  • the filtrate is distilled under reduced pressure and obtained compound is purified by column chromatography using methanol-DCM (5:95) to afford the title compound.
  • EXAMPLE 17 Preparation 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-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol
  • reaction mixture is stirred for 1 hour at room temperature and progress of the reaction is monitored by TLC. On completion, the mixture is quenched with sodium potassium tartrate (5 mL). The mixture is extracted with ethyl acetate (10 mL), then layers are separated and organic layer is subjected to distillation under vacuum at 45°C. The obtained material is dissolved in THF (20 mL) and slowly lithium aluminiumhydride (0.1 17 g) is added to the mixture at 0-5°C. Then mixture is stirred at room temperature for 1 hour and progress of the reaction is monitored by TLC. On completion of reaction, it is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (15 mL). The layers are separated and organic layer is used for next step.
  • reaction mixture is stirred at room temperature for overnight and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (20 mL), layers are separated. The organic layer is washed with brine solution (20 mL) followed by complete distillation under vacuum at 45°C. The crude compound is purified by column chromatography using ethyl acetate:hexane (7:10) and methanol :d ic h I oro methane (5:95) to afford the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation de ticagrélor et des intermédiaires qui sont utiles dans les procédés.
PCT/IB2015/054947 2014-07-02 2015-07-01 Préparation de ticagrélor WO2016001851A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3264/CHE/2014 2014-07-02
IN3264CH2014 2014-07-02

Publications (1)

Publication Number Publication Date
WO2016001851A1 true WO2016001851A1 (fr) 2016-01-07

Family

ID=55018530

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/054947 WO2016001851A1 (fr) 2014-07-02 2015-07-01 Préparation de ticagrélor

Country Status (1)

Country Link
WO (1) WO2016001851A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (fr) * 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine
US20030148888A1 (en) * 2000-06-02 2003-08-07 Ulf Larsson Novel triazolo pyrimidine compounds
WO2013150495A2 (fr) * 2012-04-05 2013-10-10 Dr. Reddy's Laboratories Limited Préparation de ticagrelor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (fr) * 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine
US20030148888A1 (en) * 2000-06-02 2003-08-07 Ulf Larsson Novel triazolo pyrimidine compounds
WO2013150495A2 (fr) * 2012-04-05 2013-10-10 Dr. Reddy's Laboratories Limited Préparation de ticagrelor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds

Similar Documents

Publication Publication Date Title
JP6340391B2 (ja) 置換された５−フルオロ−１ｈ−ピラゾロピリジン類を製造するための方法
US7476737B2 (en) Eszopiclone process
JP5833626B2 (ja) ラパチニブの調製プロセス及び中間体
BG65866B1 (bg) Триазолпиримидинови съединения
CN106831737B (zh) 维帕他韦及其衍生物的制备
WO2017221189A1 (fr) Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci
WO2015037016A2 (fr) Procédé amélioré de préparation de ticagrelor et d'intermédiaires de celui-ci
WO2016030704A1 (fr) Forme solide d'intermédiaire de ticagrelor
JP2018518489A (ja) アプレミラスト及びその中間体の調製方法
KR102477924B1 (ko) 인돌 카르복스아미드 화합물을 제조하는 방법
US20090093630A1 (en) Chiral synthesis of diazepinoquinolines
EP3004113A2 (fr) Préparation de ticagrélor
EP2666771A1 (fr) Synthèse de dérivés aminocyclopentanétriols
WO2008090046A1 (fr) Nouveau procédé servant à préparer de la 3,5-di-omicron-acyl-2-fluoro-2-c-méthyl-d-ribono-gamma-lactone
WO2016001851A1 (fr) Préparation de ticagrélor
JP2005507858A (ja) ザレプロンを生産する方法
CA3076980A1 (fr) Intermediaire de linagliptine cristallin et procede de preparation de linagliptine
EP3351534A1 (fr) Procédé de production de nouveaux dérivés de 4-benzazonine
JP2023011699A (ja) ３位置換５－アミノ－６Ｈ－チアゾロ［４，５－ｄ］ピリミジン－２，７－ジオン化合物の製造法
EP2004644A1 (fr) Procede de preparation de tadalafil
KR102441327B1 (ko) 다이아미노피리미딘 유도체 또는 이의 산부가염의 신규의 제조방법
JP2022543990A (ja) アリピプラゾールラウロキシルの調製のためのプロセス
WO2024064745A1 (fr) Synthèse de reldesemtiv
WO2012001357A1 (fr) Forme cristalline de la prulifloxacine et procédés pour sa préparation
UA78955U (en) Process for the preparation of 7-aryl(hetaryl)-5-oxo-2,3,6,7-tetrahydrothiazolo[3,2-a]pyrimidine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15814714

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15814714

Country of ref document: EP

Kind code of ref document: A1