[go: up one dir, main page]

WO2018185715A1 - Improved process for the preparation of n6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid and its pharmaceutically acceptable salts - Google Patents

Improved process for the preparation of n6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid and its pharmaceutically acceptable salts Download PDF

Info

Publication number
WO2018185715A1
WO2018185715A1 PCT/IB2018/052388 IB2018052388W WO2018185715A1 WO 2018185715 A1 WO2018185715 A1 WO 2018185715A1 IB 2018052388 W IB2018052388 W IB 2018052388W WO 2018185715 A1 WO2018185715 A1 WO 2018185715A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
acid
solvents
reaction mixture
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2018/052388
Other languages
French (fr)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Venkat Reddy Ghojala
Venkat Reddy Mallepally
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MSN Laboratories Pvt Ltd
Original Assignee
MSN Laboratories Pvt Ltd
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 MSN Laboratories Pvt Ltd filed Critical MSN Laboratories Pvt Ltd
Publication of WO2018185715A1 publication Critical patent/WO2018185715A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • C07H1/04—Introducing polyphosphoric acid radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the present invention pertains to an improved process for the preparation of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its pharmaceutically acceptable salts.
  • Cangrelor belongs to P2Yi 2 platelet inhibitor and it is used as an adjunct to percutaneous coronary intervention (PCI) for reducing the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients in who have not been treated with a P2Yi 2 platelet inhibitor and are not being given a glycoprotein Ilb/IIIa inhibitor.
  • PCI percutaneous coronary intervention
  • MI myocardial infarction
  • ST stent thrombosis
  • Cangrelor is approved as a tetrasodium salt under the brand name of Kengreal® by USFDA on June 22, 2015 to Chiesi USA INC. Kengreal® available with the strength of 50MG/VIAL as powder for IV (infusion).
  • Kengreal® available with the strength of 50MG/VIAL as powder for IV (infusion).
  • the chemical structure of Can relor tetrasodium salt is shown below:
  • CN 105061431 A discloses a process for the purification of Cangrelor tetrasodium via Cangrelor ammonium salt and DEAE-SEPHADEX A-25 ion exchange resin.
  • the main drawback of the above purification process is the use of ion exchange resin which is more expensive and does not suitable for commercial scale operation.
  • the first aspect of the present invention is to provide an improved process for the preparation of N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its pharmaceutically acceptable salts.
  • the second aspect of the present invention is to provide an improved process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV).
  • the third aspect of the present invention is to provide an improved process for the preparation of ((2R, 35, AR, 5R)-3, 4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3, 3, 3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX).
  • Figure 1 Illustrates characteristic PXRD pattern of Cangrelor tetrasodium salt.
  • Figure 2 Illustrates characteristic PXRD pattern of Cangrelor tetrasodium salt obtained after lyophillization.
  • Figure 3 Illustrates characteristic PXRD pattern of crystalline Form-M of Cangrelor tetrasodium salt.
  • Figure 4 Illustrates characteristic PXRD pattern of pure amorphous form of Cangrelor tetrasodium salt obtained according to example-9.
  • the present invention provides an improved process for the preparation of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its tetrasodium salt of formula (la).
  • suitable solvent refers to the solvent selected from “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol; “chloro solvents” such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone; “hydrocarbon solvents” such as to toluene, hexane, heptane and cyclohexane; “nitrile solvents” such as acetonitrile; “ester solvents” such as ethyl acetate, methyl acetate and isopropyl acetate; “ether solvents” such as tetrahydrofuran, diethyl ether and methyl ter
  • suitable base refers to the bases selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate and the like; organic bases like alkali metal alkoxides like sodium tertiary butoxide, potassium tertiary butoxide; methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, l ,8-bis(dimethylamino)naphthalene, pyridine, 4- dimethylaminopyridine, ammonia or their aqueous solution; ammonium bases such as ammonium carbonate, ammonium hydrogen carbonate or ammonium bicarbonate, ammonium sulfate, ammonium hydrogen sulfate and the like.
  • suitable acid refers to the acid selected from inorganic acids like hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H 2 SO 4 ); organic acids like formic acid, acetic acid (AcOH), methanesulfonic acid (MsOH), p-toluenesulfonic acid (j?-TsOH), trifluoro acetic acid (TFA).
  • inorganic acids like hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H 2 SO 4 ); organic acids like formic acid, acetic acid (AcOH), methanesulfonic acid (MsOH), p-toluenesulfonic acid (j?-TsOH), trifluoro acetic acid (TFA).
  • suitable coupling agent is selected from but not limited to 1,1'- carbonyl diimidazole (CDI), morpholine, ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '- diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluoro phosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluoro phosphate (HBTU), lH-benzo triazolium 1- [bis(dimethylamino)methylene]-5chloro-hexafluoro
  • suitable sodium source is selected from but not limited to sodium chloride, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxides such as sodium methoxide, sodium ethoxide, sodium propaxide, sodium salt f C1-C5 carboxylic such as sodium formate, sodium acetate, sodium propanoate and the like.
  • the term "the protecting group (Pg)" is selected from Ci-C 6 alkanoyl, such as, for example, acetyl (also represented as -C(0)CH 3 or Ac), propionyl; -C(0)OCi-C 6 alkyl, such as, for example, carboethoxy, carbomethoxy and t-butoxycarbonyl; optionally substituted -C(0)OCi-C 6 aryl, such as, for example, benzyloxy- carbonyl and p- methoxybenzyloxycarbonyl; optionally substituted -C 1 -C 12 aryl(Ci-C3)alkyl such as, for example, benzyl, phenethyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl and 9-fluorenylmethyl; optionally substituted C -Cn aryl carbonyl, such as, for example, benzoyl; Ci-C 6 al
  • the first aspect of the present invention provides an improved process for the preparation of N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its pharmaceutically acce table salts
  • Formula (II) Formula (IV) wherein X is selected from chlorine, bromine or iodine
  • dimer impurity (XVII) is absent or below 1.0 % in the compound of formula (IV)
  • Formula (VIII) Formula (VII) wherein "Pg” is a protecting group selected from -C(0)Ri, -C(0)ORi; optionally substituted -C(0)OAr; optionally substituted -ArR l5 wherein Ri is selected from alkyl chain having C 1-5 carbon atoms.
  • Ar is a aryl group selected from phenyl; X is selected from chlorine, bromine or iodine
  • the suitable solvent refers to polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N- methyl pyrrolidone; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n- butanol and isobutanol; chloro solvents such as methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; hydrocarbon solvents such as toluene, hexane, heptane and cyclohexane; nitrile solvents such as acetonitrile, propion
  • the another embodiment of the present invention provides the isolation of compound of formula (I) or formula (la) by removing the solvent.
  • Suitable techniques used for the removal of solvent includes filtration, using rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), and the like or any other suitable techniques known in the art.
  • the preferred embodiment of the present invention provides an improved process for the preparation of tetrasodium salt of N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]- 5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (la),
  • Formula (II) Formula (IV) wherein, the dimer impurity is 1.0% or below in the compound of formula (IV) b) reacting the compound of formula (IV) with aceticanhydride and sodium acetate in presence of formic acid to get the tetra acetyl protected compound of formula (Va) which on in-situ reacting with 2-chloroethyl methyl sulfide of formula (Via) in presence of potassium carbonate in acetonitrile to get the compound of formula (Vila) which on in-situ treating with sodium hydroxide in methanol to provide (2i?,35,4i?,5i?)-2-(hydroxymethyl)-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol of formula (VIII),
  • Formula (IX) Formula (X) e) reacting the compound of formula (X) with clodronic acid in presence of tri n- butylamine in dimethylsulfoxide to provide N6-[2-(methylthio)ethyl]-2-
  • the another embodiment of the present invention provides a process for the preparation of Cangrelor tetrasodium salt of formula (la), comprising of:
  • step-h) filtering the solid, i) dissolving the obtained compound in step-h) in a suitable solvent,
  • step-a), step-d), step-g), step-i) and step-1) the suitable solvent is selected from ketone solvents, ester solvents, nitrile solvents, ether solvents, hydrocarbon solvents, chloro solvents, alcoholic solvents, water or mixtures thereof; in step-b) and step-k), the suitable sodium source is selected from but not limited to sodium chloride, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxides such as sodium methoxide, sodium ethoxide, sodium propaxide, sodium acetate or their aqueous solutions and the like.
  • the preferred embodiment of the present invention provides a process for the preparation of Cangrelor tetrasodium salt of formula (la), comprising of:
  • the another embodiment of the present invention provides the use of intermediate compounds of formulae (IX), (X) and (I) without purification in the preparation of pure Cangrelor tetrasodium of formula (la).
  • crystalline Form-M novel crystalline form of Cangrelor tetrasodium salt of formula (la), (hereinafter designated as crystalline Form-M).
  • the crystalline form-M of Cangrelor tetrasodium salt of formula (la) was characterized by its PXRD pattern as illustrated in figure-3.
  • the another embodiment of the present invention provides a process for the preparation of crystalline Form-M of Cangrelor tetrasodium salt of formula (la), comprising: a) dissolving the Cangrelor tetrasodium salt of formula (la) in water,
  • the second aspect of the present invention provides an improved process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV), comprising;
  • step-a) reacting the mixture obtained in step-a) with the compound of formula (III) in presence of a suitable base to get the compound of formula (IV) wherein the dimer impurity is absent or below 1.0 % or prefarebly below 0.5% in the compound of formula (IV)
  • the suitable solvent refers to polar aprotic solvents, alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents or mixture of solvents thereof
  • the suitable base refers alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, alkali metal alkoxides, organic bases and the like; after completion of step-b) the reaction mixture is optionally treated with charcoal for colour improvement and removing of the impurities; the compound of formula (IV) can be isolated as a solid through crystallization from a suitable solvent selected from solvents defined in step-a).
  • the preferred embodiment of the present invention provides an improved process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV), comprising;
  • step-a) reacting the mixture obtained in step-a) with 3 -chloro- 1 , 1 , 1 -trifluoropropane in presence of potassium carbonate;
  • the third aspect of the present invention provides an improved process for the preparation of ((2 ?,35,4R,5R)-3, 4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX), comprising:
  • Formula (II) Formula (IV) b) reacting the compound of formula (IV) with suitable protecting agent in presence of suitable base and suitable acid to get tetra protected compound of formula (V) which on in-situ reacting with the compound of general formula (VI) in presence of a suitable base in a suitable solvent to get the compound of formula (VII) which on in- situ treating with deprotecting agent in a suitable solvent to provide the compound of formula (VIII);
  • Formula (VIH) Formula (VII) wherein "Pg” is a protecting group selected from -C(0)Ri, -C(0)ORi; optionally substituted -C(0)OAr; optionally substituted -ArRi, wherein Ri is selected from alkyl chain having C 1-5 carbon atoms.
  • Ar is a aryl group selected from phenyl; X is selected from chlorine, bromine or iodine
  • the suitable solvent refers to polar aprotic solvents, alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents or mixture of solvents thereof; in step-b2) and step-c) "the suitable base” refers to the base selected from alkali metal hydroxides, alkali metal carbonates and ammonium carbonate, alkali metal bicarbonates, organic bases such as pyridine, dimethylaminopyridine, N-methylmorpholine, ethylamine, diisopropylethylamine, triethylamine, alkali metal alkoxides and the like; in step-b), “the suitable acid” refers to the acids selected from inorganic acids like hydrochloric acid (HC1), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H 2 SO 4
  • the preferred embodiment of the present invention provides an improved process for the preparation of ((2i?,35,4i?,5i?)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX), comprising:
  • Formula (II) Formula (IV) b) reacting the compound of formula (IV) with aceticanhydride and sodium acetate in presence of formic acid to get the tetra acetyl protected compound of formula (Va) which on in-situ reacting with 2-chloroethyl methyl sulfide of formula (Via) in presence of potassium carbonate in acetonitrile to get the compound of formula (Vila) which on in-situ treating with sodium hydroxide in methanol to provide (2i?,35,4i?,5i?)-2-(hydroxymethyl)-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-
  • step-b) reacting the compound of formula (VIII) obtained in step-b) with the mixture of triethylphosphate, phosphorous oxychloride and ammonium carbonate to provide the compound of formula (IX)
  • the another embodiment of the present invention provides pure amorphous form of Cangrelor tetrasodium having more than 99.0% purity by HPLC. More preferably morethan 99.75% purity by HPLC.
  • the pure amorphous form of Cangrelor tetrasodium salt containing not more than 1.0% or prefarebly not more than 0.5% or more prefarebly not more than 0.3% of one or more impurities such as adenosine impurity of formula (VIII), mono phosphoryl impurity of formula (IX), morpholine impurity of formula (X), clodronic acid impurity of formula (XI), mono phosphoryl dimer impurity of formula (XII), mono sulfoxide impurity of formula (XIII), sulfoxide impurity of formula (XIV), purine impurity of formula (XV) and purine sulfoxide impurity of formula (XVI)
  • impurities such as adenosine impurity of formula (VIII), mono phosphoryl impurity of formula (IX), morpholine impurity of formula (X), clodronic acid impurity of formula (XI), mono phosphoryl dimer impur
  • compositions comprising therapeutically effective amount of amorphous Cangrelor tetrasodium salt and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions containing Cangrelor tetrasodium salt of the present invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • the oral pharmaceutical composition may contain one or more additional excipients such as diluents, binders, disintegrants and lubricants.
  • diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof.
  • binders are selected from L-hydroxy propyl cellulose, povidone, hydroxypropyl methyl cellulose, hydroxylethyl cellulose and pre- gelatinized starch.
  • Exemplary disintegrants are selected from croscarmellose sodium, cros- povidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose.
  • Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide.
  • a specific lubricant is selected from magnesium stearate, zinc stearate, calcium stearate and colloidal
  • Cangrelor tetrasodium of formula (la) obtained by the present invention having the particle size D(90) about 10 to 200 microns.
  • Cangrelor tetrasodium of formula (la) obtained by the present invention is also showing particle size of D90 about 50 microns or below.
  • the compound produced by the present invention can be further micronized or milled by the conventional methods to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • "Pg” is a protecting group refers to - C(0)Ri, -C(0)ORi; optionally substituted -C(0)OAr; optionally substituted -ArRi, wherein Ri is selected from alkyl chain having C 1-5 carbon atoms.
  • Ar is a aryl group selected from phenyl, naphthyl, furanyl or any other aromatic group known in the art.
  • starting material of compound of formula (II) can be prepared by the methods known from US 3989682 or any other methods known in the art.
  • a liquid chromatograph is equipped with variable wavelength UV Detector
  • Buffer 6.6g of di ammonium hydrogen ortho phosphate added to 1000 mL of milli-Q-water. Adjust its pH to 7.2 with diluted ortho, phosphoric acid.
  • a liquid chromatograph is equipped with variable wavelength UV Detector
  • Buffer l.OmL of orthophoshoric acid and 3gr of anhydrous 1 -octanesulfonic acid into 1000 mL of milli-Q-water.
  • Example-4 Preparation of (2R, 35, 4R, 5R)-2-(hydroxymethyl)-5-(6-((2-methylthio)ethyl amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran -3,4-diol of formula (VIII)
  • Phosphorous oxychloride 39.8 ml was slowly added to the triethyl phosphate (300 ml) at 25-30°C under nitrogen atmosphere and stirred for 45 min at 25-30°C and then cooled to 0-2°C.
  • Ammonium carbonate (4.15 gms) was added to the above reaction mixture at 0-2°C and stirred for 20 min at same temperature.
  • Example-6 Preparation of ((2R,35,4R,5R)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl) amino)-2-(3,3,3-trifluoropropyl)thio-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl hydrogen morpholinophosphonate of formula (X)
  • Example-7 Preparation of tetrasodium salt of N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl) -5 '-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la) (Cangrelor tetrasodium salt)
  • Dimethylsulfoxide 500 ml was added to the above reaction mixture at 25-30°C.
  • Aqueous sodium chloride solution was added to the reaction mixture and stirred for 10 min at 25-30°C.
  • Acetone 1000 ml was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at same temperature. Filtered the precipitated solid, washed with acetone and then dried the material.
  • Methanol 1000 ml was added to the reaction mixture at 25-30°C and stirred for 2 hours at same temperature. Filtered the solid compound and washed with methanol. Water (550 ml) was added to the obtained compound and stirred for 30 min at 25- 30°C. Filtered the reaction mixture through highflow bed and washed with water.
  • Aqueous sodium bicarbonate solution was added to the filtrate and stirred for 15 min at 25-30°C.
  • Methanol 750 ml was added to the reaction mixture at 25-30°C and stirred for 2 hours at same temperature. Filtered the precipitated solid, washed with methanol and then dried. Water (250 ml) was added to the above obtained compound at 25-30°C and stirred for 15 min at same temperature. Filtered the reaction mixture through hyflow bed and washed with water. Slowly added aqueous sodium bicarbonate solution to the filtrate and stirred for 15 min at 25- 30°C. Methanol (280 ml) was added to the above reaction mixture and stirred for 60 min at 25-30°C. Filtered the precipitated solid, washed with methanol and then dried to get crude compound.
  • the obtained compound was purified by flash chromatography using Milli-Q-water and acetonitrile (9: 1) as eluent and then lyophilized the obtained solution to get title compound. (Yield: 35 gms, purity by HPLC: 99.75%); water content: 8-10%, sodium content: 8-12%).
  • Example-8 Preparation of crystalline Form-M of tetrasodium salt of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la).
  • Example-9 Preparation of pure amorphous tetrasodium salt of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid (Cangrelor tetrasodium salt)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to an improved process for the preparation of N6-[2- (methylthio)ethyl]-2-[(3,3,3,­trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula-(I), its pharmaceutically acceptable salts and its polymorphic forms. (Formula I) (I) The present invention also related to an improved process for the preparation of (2R,3R,4S,5R)- 2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran- 3,4-diol of formula (IV) by greatly reducing the formation of dimer impurity of formula (XVII). The present invention also related to an improved process for the preparation of ((2R, 3S, 4R, 5R)-3, 4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin- 9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX) with more yield and high purity.

Description

Improved process for the preparation of N6-r2-(methylthio)ethyll-2- r(3,3,3-trifluoropropyl)thiol -5 '-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid and its pharmaceutically acceptable salts
Related application
This patent application claims the benefit of priority of our Indian patent application number 201741012360 filed on 06th April 2017 which is incorporated herein by reference.
Field of the invention
The present invention pertains to an improved process for the preparation of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its pharmaceutically acceptable salts.
Figure imgf000003_0001
Formula (I)
Background of the invention
N6-[2-(Methylthio)ethyl]-2-[(3,3,3,-trifluoropropyl)thio]-5'-adenylic acid, monoan hydride with (dichloromethylene)bisphosphonic acid (or) dichloro(((((2R,3R,4S,5R)-3,4- dihydroxy-2-(6-(2-(methylthio)ethylamino)-2-(3,3,3-trifluoropropylthio)-purin-9-yl)tetra hydrofuran-5-yl)methoxy)(hydroxy)phosphoryloxy)(hydroxy)phosphoryl)methylphosphonic acid of formula (I) is generically known as Cangrelor. Cangrelor belongs to P2Yi2 platelet inhibitor and it is used as an adjunct to percutaneous coronary intervention (PCI) for reducing the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients in who have not been treated with a P2Yi2 platelet inhibitor and are not being given a glycoprotein Ilb/IIIa inhibitor. Cangrelor is approved as a tetrasodium salt under the brand name of Kengreal® by USFDA on June 22, 2015 to Chiesi USA INC. Kengreal® available with the strength of 50MG/VIAL as powder for IV (infusion). The chemical structure of Can relor tetrasodium salt is shown below:
Figure imgf000004_0001
Formula-(Ia)
US 5721219 (published on February 24, 1998) discloses Cangrelor and its pharmaceutically acceptable salts.
US 5721219, Journal of Medicinal Chemistry 1999, 42, 213-220, Drugs of future 2008, 33(2), 101-110 discloses a process for the preparation of 2-(3,3,3-trifluoropropylthio)- adenosine of formula (IV) (intermediate of Cangrelor) via stirring the mixture of adenosine-2- thione monohydrate, dimethylformamide and sodium hydride for 1 hour followed by reaction with l-chloro-3,3,3-trifluoropropane to provide 2-(3,3,3-trifluoropropylthio)-adenosine.
The major drawback in the above reported process is stirring of the mixture of adenosine-2-thione monohydrate, dimethylformamide and sodium hydride for 1 hour leads to dimerization of adenosine-2-thione to form dimer impurity of formula (XVII) at about 10%. Controlling of this dimer impurity is very important as it causes for the lower yield of 2- (3,3,3-trifluoropropylthio)-adenosine with low purity and also requires multiple purification methods to remove the said dimer impurity. Accordingly this process is expensive, tedious, time consuming, not eco-friendly and not suitable for industrial scale up.
Chemical structure of dimer impurity of formula (XVII) is shown below:
Figure imgf000005_0001
ormu a
Journal of Medicinal Chemistry 1999, 42, 213-220 also discloses a process for the preparation of ((2i?,35,4i?,5i?)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX) via reaction of N5-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio) adenosine formula (VIII) in triethylphosphate solution with phosphorous oxychloride and purified through ion-exchange chromatography on a sulfonic acid resin (Dowex 50W (Η+ form)) to provide the product of formula (IX).
The main drawback of the above process is the alone use of phosphorous oxychloride which leads longer time for the completion of reaction to produce the compound of formula (IX) with lower yield and high impurities.
Further, another drawback of the above process is the use of ion-exchange chromatography on a sulfonic acid resin (Dowex 50W (Η+ form)) which is more cost and does not suitable for commercial scale operations.
CN 105061431 A discloses a process for the purification of Cangrelor tetrasodium via Cangrelor ammonium salt and DEAE-SEPHADEX A-25 ion exchange resin.
The main drawback of the above purification process is the use of ion exchange resin which is more expensive and does not suitable for commercial scale operation.
Hence, in view of the above drawbacks in prior art methods, there is need in the art for an improved process for the preparation of Cangrelor tetrasodium salt and its intermediate compounds in straight forward steps. Advantages of the present invention: avoiding the dimerization of adenosine-2-thione monohydrate during the preparation of 2-(3,3,3-trifluoropropylthio)-adenosine of formula (IV),
accelerating the condensation reaction of adenosine-2-thione monohydrate with 3- chloro-l, l , l-trifluoropropane which carrying out if in presence of a base to afford high yield of compound of formula (IV),
our inventors unexpectedly found that when the reaction of (2R, 3R, 45, 5i?)-2-(6- amino-2-((3, 3, 3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydro furan-3,4-diol of formula (VIII) was carried out with the reagent (mixture of phosphorous oxychloride, triethyl phosphate and a base) provided the compound of formula (IX) with more yield, less impurities in shortest time.
resin free process for the purification / isolation of Cangrelor tetrasodium and its intermediate compound of formula (IX) which is simple, cost effective, eco-friendly and viable for industrial scale up.
Brief description of the invention
The first aspect of the present invention is to provide an improved process for the preparation of N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its pharmaceutically acceptable salts.
The second aspect of the present invention is to provide an improved process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV).
The third aspect of the present invention is to provide an improved process for the preparation of ((2R, 35, AR, 5R)-3, 4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3, 3, 3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX).
Brief description of the drawings Figure 1 : Illustrates characteristic PXRD pattern of Cangrelor tetrasodium salt.
Figure 2: Illustrates characteristic PXRD pattern of Cangrelor tetrasodium salt obtained after lyophillization.
Figure 3: Illustrates characteristic PXRD pattern of crystalline Form-M of Cangrelor tetrasodium salt.
Figure 4: Illustrates characteristic PXRD pattern of pure amorphous form of Cangrelor tetrasodium salt obtained according to example-9.
Detailed description of the invention
The present invention provides an improved process for the preparation of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its tetrasodium salt of formula (la).
Unless otherwise specified, as used herein the term "suitable solvent" refers to the solvent selected from "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol; "chloro solvents" such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone; "hydrocarbon solvents" such as to toluene, hexane, heptane and cyclohexane; "nitrile solvents" such as acetonitrile; "ester solvents" such as ethyl acetate, methyl acetate and isopropyl acetate; "ether solvents" such as tetrahydrofuran, diethyl ether and methyl tert -butyl ether; "polar solvents" such as water, "polar aprotic solvents" such as dimethylformamide, dimethylacetamide and dimethylsulf oxide, N-methyl pyrrolidone or mixture of solvents thereof.
As used herein the term "suitable base" refers to the bases selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate and the like; organic bases like alkali metal alkoxides like sodium tertiary butoxide, potassium tertiary butoxide; methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, l ,8-bis(dimethylamino)naphthalene, pyridine, 4- dimethylaminopyridine, ammonia or their aqueous solution; ammonium bases such as ammonium carbonate, ammonium hydrogen carbonate or ammonium bicarbonate, ammonium sulfate, ammonium hydrogen sulfate and the like.
As used herein the term "suitable acid" refers to the acid selected from inorganic acids like hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H2SO4); organic acids like formic acid, acetic acid (AcOH), methanesulfonic acid (MsOH), p-toluenesulfonic acid (j?-TsOH), trifluoro acetic acid (TFA).
As used herein, the term suitable coupling agent is selected from but not limited to 1,1'- carbonyl diimidazole (CDI), morpholine, Ν,Ν'-dicyclohexylcarbodiimide (DCC), Ν,Ν'- diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluoro phosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluoro phosphate (HBTU), lH-benzo triazolium 1- [bis(dimethylamino)methylene]-5chloro-hexafluorophosphate (1-) 3-oxide (HCTU), O- (benzotriazol-l-yl)-N,N,N',N'-tetramethyl uronium tetrafluoroborate (TBTU), alkyl/aryl haloformates selected from but not limited to ethyl chloroformate, benzylchloroformate; diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), (benzotriazol-l-yloxy) tris(dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride, j?-toluenesulfonyl chloride and the like.
As used herein, the term "suitable sodium source" is selected from but not limited to sodium chloride, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxides such as sodium methoxide, sodium ethoxide, sodium propaxide, sodium salt f C1-C5 carboxylic such as sodium formate, sodium acetate, sodium propanoate and the like.
As used herein, the term "the protecting group (Pg)" is selected from Ci-C6 alkanoyl, such as, for example, acetyl (also represented as -C(0)CH3 or Ac), propionyl; -C(0)OCi-C6 alkyl, such as, for example, carboethoxy, carbomethoxy and t-butoxycarbonyl; optionally substituted -C(0)OCi-C6 aryl, such as, for example, benzyloxy- carbonyl and p- methoxybenzyloxycarbonyl; optionally substituted -C1-C12 aryl(Ci-C3)alkyl such as, for example, benzyl, phenethyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl and 9-fluorenylmethyl; optionally substituted C -Cn aryl carbonyl, such as, for example, benzoyl; Ci-C6 alkylsulfonyl, such as, for example, methanesulfonyl (mesyl).
The first aspect of the present invention provides an improved process for the preparation of N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) and its pharmaceutically acce table salts
Figure imgf000009_0001
Formula (I)
which comprising:
a) reacting (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) with the compound of general formula (III) in presence of suitable base in a suitable solvent to provide the compound of formula
Figure imgf000009_0002
Formula (II) Formula (IV) wherein X is selected from chlorine, bromine or iodine
wherein the dimer impurity (XVII) is absent or below 1.0 % in the compound of formula (IV)
Figure imgf000010_0001
b) reacting the compound of formula (IV) with a suitable protecting agent in presence of suitable base and suitable acid to get tetra protected compound of formula (V) which on in-situ reacting with the compound of general formula (VI) in presence of suitable base in a suitable solvent to get the compound of formula (VII) which on in-situ treating with a suitable deprotecting agent in a suitable solvent to provide the compound of formula (VIII),
Figure imgf000010_0002
Formula (IV) ormu a
Step-b2 Formula (VI)
Figure imgf000010_0003
Formula (VIII) Formula (VII) wherein "Pg" is a protecting group selected from -C(0)Ri, -C(0)ORi; optionally substituted -C(0)OAr; optionally substituted -ArRl5 wherein Ri is selected from alkyl chain having C1-5 carbon atoms. Ar is a aryl group selected from phenyl; X is selected from chlorine, bromine or iodine
c) reacting the compound of formula (VIII) with a mixture of phosphorous oxychloride & triethyl phosphate and suitable base to produce ((2/?,35,4i?,5i?)-3,4-dihydroxy-5-(6- ((2-(methylthio)ethyl)amino)-2-(3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)tetrahydro furan-2-yl)methyl dihydrogenphosphate of formula (IX),
Figure imgf000011_0001
Formula (VIII) Formula (IX)
wherein the compound of formula (IX) is optionally isolated
d) reacting the compound of formula (IX) with a suitable coupling agent in a suitable solvent to produce the compound of formula (X),
Figure imgf000011_0002
Formula (IX) Formula (X)
wherein the compound of formula (X) is optionally isolated
e) reacting the compound of formula (X) with clodronic acid in presence of a suitable base in a suitable solvent to provide N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl)-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (I),
Figure imgf000011_0003
Formula (X) Formula (I) f) optionally converting the compound of formula (I) into its pharmaceutically acceptable salts. wherein in step-a), step-b2), step-c), step-d) and step-e) the suitable solvent refers to polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N- methyl pyrrolidone; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n- butanol and isobutanol; chloro solvents such as methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; hydrocarbon solvents such as toluene, hexane, heptane and cyclohexane; nitrile solvents such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, methyl acetate and isopropyl acetate; ether solvents such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether or mixture of solvents thereof; in step-a), step-b2) step-c) and step-e), the suitable base refers to the base selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, ammonium carbonate; organic bases such as alkali metal alkoxides, pyridine, dimethylaminopyridine, N-methylmorpholine, ethylamine, diisopropylethylamine, triethylamine and the like; in step-bl) the suitable acid refers to the acids selected from inorganic acids like hydrochloric acid (HC1), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H2SO4); organic acids like formic acid, acetic acid (AcOH), methanesulfonic acid (MsOH), p-toluenesulfonic acid (j?-TsOH), trifluoroacetic acid (TFA); in step-b2) the suitable base used in protection is selected from alkali or alkaline salts of C1-C5 carboxylic acids such as sodium acetate, potassium acetate, sodium propanoate, sodium formate and the like; in step-b3) the deprotecting agent is selected from suitable acid or suitable base in a suitable solvent which are same as defined in step-bl), step-b2); in step- d) the suitable coupling agent is selected from morpholine, CDI, DCC, DIC, EDC.HC1, HATU, HBTU, HCTU, TBTU, ethyl chloroformate, benzylchloroformate, DPPA, BOP, PyBOP and the like; in step-f) the pharmaceutically acceptable salts can be prepared by the methods known in the art.
The another embodiment of the present invention provides the isolation of compound of formula (I) or formula (la) by removing the solvent. Suitable techniques used for the removal of solvent includes filtration, using rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable techniques known in the art.
The preferred embodiment of the present invention provides an improved process for the preparation of tetrasodium salt of N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]- 5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (la),
Figure imgf000013_0001
Formula (la)
comprising:
a) reacting (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) with 3-chloro-l,l,l-trifluoropropane of formula (Ilia) in presence of potassium carbonate in dimethylformamide to provide (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxy methyl)tetrahydrofuran-3,4-diol of formula (IV),
Figure imgf000013_0002
Formula (II) Formula (IV) wherein, the dimer impurity is 1.0% or below in the compound of formula (IV) b) reacting the compound of formula (IV) with aceticanhydride and sodium acetate in presence of formic acid to get the tetra acetyl protected compound of formula (Va) which on in-situ reacting with 2-chloroethyl methyl sulfide of formula (Via) in presence of potassium carbonate in acetonitrile to get the compound of formula (Vila) which on in-situ treating with sodium hydroxide in methanol to provide (2i?,35,4i?,5i?)-2-(hydroxymethyl)-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol of formula (VIII),
Figure imgf000014_0001
c) reacting the compound of formula (VIII) with a mixture of phosphorous oxychloride, triethyl phosphate and ammonium carbonate to provide ((2i?,35,4i?,5i?)-3,4- dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-(3,3,3-trifluoropropyl)thio)-9H-purin- 9-yl)tetrahydrofuran -2-yl)methyl dihydrogenphosphate of formula (IX),
Figure imgf000014_0002
Formula (ΥΠΙ) Formula (DC)
d) reacting the compound of formula (IX) with morpholine in presence of dicyclohexylcarbodiimide in feri-butanol to produce ((2/?,35,4/?,5/?)-3,4-dihydroxy-5- (6-((2-(methylthio)ethyl)amino)-2-(3,3,3-trifluoropropyl)thio-9H-purin-9- yl)tetrahydrofuran-2-yl)methyl hydrogen morpholinephosphonate of formula (X),
Figure imgf000015_0001
Formula (IX) Formula (X) e) reacting the compound of formula (X) with clodronic acid in presence of tri n- butylamine in dimethylsulfoxide to provide N6-[2-(methylthio)ethyl]-2-
[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with
(dichloromethylene) bisphosphonic acid of formula (I),
Figure imgf000015_0002
Formula (X) Formula (I)
f) converting the compound of formula (I) into tetrasodium salt of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la).
The another embodiment of the present invention provides a process for the preparation of Cangrelor tetrasodium salt of formula (la), comprising of:
a) dissolving N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid of formula (I) in a suitable solvent,
b) treating the reaction mixture with a suitable sodium source,
c) stirring the reaction mixture,
d) adding suitable second solvent to the reaction mixture,
e) stirring the reaction mixture,
f) filtering the precipitated solid,
g) slurrying the obtained solid in a suitable solvent at suitable temperature,
h) filtering the solid, i) dissolving the obtained compound in step-h) in a suitable solvent,
j) filtering the reaction mixture,
k) treating the reaction mixture with a suitable aqueous sodium source,
1) adding suitable organic solvent to the reaction mixture,
m) filtering the reaction mixture,
n) optionally repeating the steps (g to m) to get Cangrelor tetrasodium salt of formula (la). wherein in step-a), step-d), step-g), step-i) and step-1) the suitable solvent is selected from ketone solvents, ester solvents, nitrile solvents, ether solvents, hydrocarbon solvents, chloro solvents, alcoholic solvents, water or mixtures thereof; in step-b) and step-k), the suitable sodium source is selected from but not limited to sodium chloride, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxides such as sodium methoxide, sodium ethoxide, sodium propaxide, sodium acetate or their aqueous solutions and the like.
The preferred embodiment of the present invention provides a process for the preparation of Cangrelor tetrasodium salt of formula (la), comprising of:
a) dissolving N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid in dimethylsulfoxide, b) treating the reaction mixture with aqueous sodium chloride solution,
c) stirring the reaction mixture,
d) adding acetone to the reaction mixture,
e) stirring the reaction mixture,
f) filtering the precipitated solid,
g) slurrying the obtained solid in methanol at 25-30°C,
h) filtering the solid,
i) dissolving the obtained compound in step-h) in water,
j) filtering the reaction mixture,
k) treating the reaction mixture with aqueous sodium bicarbonate solution,
1) adding methanol to the reaction mixture,
m) filtering the reaction mixture, n) optionally repeating the steps (g to m) to get Cangrelor tetrasodium salt of formula (la).
The another embodiment of the present invention provides the use of intermediate compounds of formulae (IX), (X) and (I) without purification in the preparation of pure Cangrelor tetrasodium of formula (la).
In yet another embodiment of the present invention also provides novel crystalline form of Cangrelor tetrasodium salt of formula (la), (hereinafter designated as crystalline Form-M). The crystalline form-M of Cangrelor tetrasodium salt of formula (la) was characterized by its PXRD pattern as illustrated in figure-3.
The another embodiment of the present invention provides a process for the preparation of crystalline Form-M of Cangrelor tetrasodium salt of formula (la), comprising: a) dissolving the Cangrelor tetrasodium salt of formula (la) in water,
b) optionally, filtering the reaction mixture,
c) treating the reaction mixture with aqueous sodium bicarbonate solution,
d) adding methanol to the reaction mixture,
e) filtering the product to get crystalline Form-M of of formula (la).
The second aspect of the present invention provides an improved process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV), comprising;
a) providing (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) in a suitable solvent;
b) reacting the mixture obtained in step-a) with the compound of formula (III) in presence of a suitable base to get the compound of formula (IV) wherein the dimer impurity is absent or below 1.0 % or prefarebly below 0.5% in the compound of formula (IV) wherein in step-a) the suitable solvent refers to polar aprotic solvents, alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents or mixture of solvents thereof; in step-b) the suitable base refers alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, alkali metal alkoxides, organic bases and the like; after completion of step-b) the reaction mixture is optionally treated with charcoal for colour improvement and removing of the impurities; the compound of formula (IV) can be isolated as a solid through crystallization from a suitable solvent selected from solvents defined in step-a). Prefarebly chloro solvents such as methylene chloride.
The preferred embodiment of the present invention provides an improved process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV), comprising;
a) providing (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) in dimethylformamide;
b) reacting the mixture obtained in step-a) with 3 -chloro- 1 , 1 , 1 -trifluoropropane in presence of potassium carbonate;
c) isolating (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5- (hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV). wherein, the dimer impurity is below 1.0% or prefarebly below 0.5% or absent in the compound of formula (IV).
The third aspect of the present invention provides an improved process for the preparation of ((2 ?,35,4R,5R)-3, 4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX), comprising:
a) reacting the compound of formula (II) in a suitable solvent with the compound of formula (III) in presence of a suitable base to provide the compound of formula (IV);
Figure imgf000019_0001
Formula (II) Formula (IV) b) reacting the compound of formula (IV) with suitable protecting agent in presence of suitable base and suitable acid to get tetra protected compound of formula (V) which on in-situ reacting with the compound of general formula (VI) in presence of a suitable base in a suitable solvent to get the compound of formula (VII) which on in- situ treating with deprotecting agent in a suitable solvent to provide the compound of formula (VIII);
Figure imgf000019_0002
Formula (VIH) Formula (VII) wherein "Pg" is a protecting group selected from -C(0)Ri, -C(0)ORi; optionally substituted -C(0)OAr; optionally substituted -ArRi, wherein Ri is selected from alkyl chain having C1-5 carbon atoms. Ar is a aryl group selected from phenyl; X is selected from chlorine, bromine or iodine
c) reacting the compound of formula (VIII) with a mixture of triethylphosphate and phosphorous oxychloride and suitable base to provide the compound of formula (IX)
Figure imgf000020_0001
Formula (ΥΠΙ) Formula (ΓΧ) wherein in step-a), step-b2), step-b3) and step-c) the suitable solvent refers to polar aprotic solvents, alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents or mixture of solvents thereof; in step-b2) and step-c) "the suitable base" refers to the base selected from alkali metal hydroxides, alkali metal carbonates and ammonium carbonate, alkali metal bicarbonates, organic bases such as pyridine, dimethylaminopyridine, N-methylmorpholine, ethylamine, diisopropylethylamine, triethylamine, alkali metal alkoxides and the like; in step-b), "the suitable acid" refers to the acids selected from inorganic acids like hydrochloric acid (HC1), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (H2SO4); organic acids like formic acid, acetic acid (AcOH), methanesulfonic acid (MsOH), p-toluenesulfonic acid (j?-TsOH), trifluoroacetic acid (TFA); in step-b 1) the suitable base used in protection is selected from alkali or alkaline salts of C1-C5 carboxylic or di carboxylic acids such as sodium acetate, potassium acetate, sodium propanoate, sodium formate and the like; in step-b3) the deprotecting agent is suitable acid or suitable base in a suitable solvent which are same as defined in step-b 1), step-b2).
The preferred embodiment of the present invention provides an improved process for the preparation of ((2i?,35,4i?,5i?)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX), comprising:
a) reacting(2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) in dimethylformamide with 3 -chloro- 1, 1, 1- trifluoropropane of formula (Ilia) in presence of potassium carbonate to provide the compound of formula (IV),
Figure imgf000021_0001
Formula (II) Formula (IV) b) reacting the compound of formula (IV) with aceticanhydride and sodium acetate in presence of formic acid to get the tetra acetyl protected compound of formula (Va) which on in-situ reacting with 2-chloroethyl methyl sulfide of formula (Via) in presence of potassium carbonate in acetonitrile to get the compound of formula (Vila) which on in-situ treating with sodium hydroxide in methanol to provide (2i?,35,4i?,5i?)-2-(hydroxymethyl)-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-
Formula (IV)
/
Formula (Vni)
Figure imgf000021_0002
c) reacting the compound of formula (VIII) obtained in step-b) with the mixture of triethylphosphate, phosphorous oxychloride and ammonium carbonate to provide the compound of formula (IX)
Figure imgf000022_0001
Formula (VIS) Formula (IX)
The another embodiment of the present invention provides pure amorphous form of Cangrelor tetrasodium having more than 99.0% purity by HPLC. More preferably morethan 99.75% purity by HPLC.
wherein the pure amorphous form of Cangrelor tetrasodium salt containing not more than 1.0% or prefarebly not more than 0.5% or more prefarebly not more than 0.3% of one or more impurities such as adenosine impurity of formula (VIII), mono phosphoryl impurity of formula (IX), morpholine impurity of formula (X), clodronic acid impurity of formula (XI), mono phosphoryl dimer impurity of formula (XII), mono sulfoxide impurity of formula (XIII), sulfoxide impurity of formula (XIV), purine impurity of formula (XV) and purine sulfoxide impurity of formula (XVI)
The chemical structures of impurities of formulae (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), below:
Figure imgf000022_0002
Formula (VIII) Formula (IX) Formula (X)
Figure imgf000022_0003
Formula (ΧΙΠ)
Formula (XI) Formula (XII)
Figure imgf000023_0001
Formula (XIV)
The other aspect of the present invention provides pharmaceutical compositions comprising therapeutically effective amount of amorphous Cangrelor tetrasodium salt and one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions containing Cangrelor tetrasodium salt of the present invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The oral pharmaceutical composition may contain one or more additional excipients such as diluents, binders, disintegrants and lubricants. Exemplary diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof. Exemplary binders are selected from L-hydroxy propyl cellulose, povidone, hydroxypropyl methyl cellulose, hydroxylethyl cellulose and pre- gelatinized starch. Exemplary disintegrants are selected from croscarmellose sodium, cros- povidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose. Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide. A specific lubricant is selected from magnesium stearate, zinc stearate, calcium stearate and colloidal
Si02.
Cangrelor tetrasodium of formula (la) obtained by the present invention having the particle size D(90) about 10 to 200 microns. Cangrelor tetrasodium of formula (la) obtained by the present invention is also showing particle size of D90 about 50 microns or below.
The compound produced by the present invention can be further micronized or milled by the conventional methods to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
Process for the preparation of Can relor tetrasodium by the present invention is shown below:
Figure imgf000024_0001
Formula (Π)
Formula (VI)
Base / solvent
Formula (V)
Mixture of phosphorous oxychloride,
triethylphosphate & base
Formula (VIO)
Formula (X)
Figure imgf000024_0002
Cangrelor tetrasodium formula (la) wherein X is selected from chlorine, bromine or iodine. "Pg" is a protecting group refers to - C(0)Ri, -C(0)ORi; optionally substituted -C(0)OAr; optionally substituted -ArRi, wherein Ri is selected from alkyl chain having C1-5 carbon atoms. Ar is a aryl group selected from phenyl, naphthyl, furanyl or any other aromatic group known in the art.
In the present invention, starting material of compound of formula (II) can be prepared by the methods known from US 3989682 or any other methods known in the art.
HPLC method of analysis:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector
Column: Ymc Triart CI 8, 250*4.6mm, 8-5μπι, 12nm (or) equivalent
Flow rate: l.O mL/min.
Wavelength: 240 nm
Column temperature: 45 °C
Run time: 66 min
Diluent: acetonitrile: methanol: milli-Q-water (25:25:50) v/v/v
Needle wash: Diluent
Elution: Gradient
Mobile Phase-A: Buffer: acetonitrile (90: 10) v/v
Mobile Phase-B: acetonitrile: Buffer (60:40) v/v
Buffer: 6.6g of di ammonium hydrogen ortho phosphate added to 1000 mL of milli-Q-water. Adjust its pH to 7.2 with diluted ortho, phosphoric acid.
UPLC method of analysis:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector
Column: ACQUITY UPLC CSH™ C18, 100*2.1mm, 1.7μιη
Flow rate: 0.3 mL/min.
Wavelength: 270 nm
Column temperature: 35°C
Run time: 26 min
Diluent: dimethylsulfoxide Needle wash: Diluent
Elution: Gradient
Buffer: l.OmL of orthophoshoric acid and 3gr of anhydrous 1 -octanesulfonic acid into 1000 mL of milli-Q-water.
PXRD analysis of Cangrelor tetrasodium salt of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:
Examples:
Example-1: Preparation of (2R, 3R, 45, 5R)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)- 9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV)
(2i?,3i?,45,5i?)-2-(6-Amino-2-mercapto-9H)-purin-9-yl)-5-(hydroxymethyl)tetrahydro furan-3,4-diol (50 gms) was added to dimethylformamide (200 ml) at 25-30°C and stirred for 10 min. at same temperature. 3-Chloro-l, l, l-trifluoropropane (26.56 gms) and potassium carbonate (57.6 gms) were added to the above reaction mixture at 25-30°C. Heated the reaction mixture to 60-65 °C and stirred for 6 hours at same temperature. Filtered the reaction mixture through hyflow bed and washed with dimethylformamide. Distilled off the solvent up to 70-80% from the filtrate under reduced pressure. Ethyl acetate (500 ml) was added to the above concentrated filtrate and stirred for 10 min at 25-30°C. Water (250 ml) was added to the reaction mixture and separated the aqueous and organic layers. Extracted the aqueous layer with ethyl acetate. Combined the total organic layers and dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methylene chloride. Methylene chloride was added to the above obtained compound and stirred for 30 min at 35-40°C and cooled the reaction mixture to 25-30°C and again stirred for 3 hours. Filtered the precipitated solid, washed with methylene chloride and then dried to get the title compound.
Yield: 52.25 gms, Melting Range: 121-129°C, Purity: 99.0% by HPLC, dimer impurity: 0.16%, adenosine impurity: not detected.
Example-2: Preparation of (2R, 3R, 45, 5R)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)- 9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV)
(2i?,3i?,45,5i?)-2-(6-Amino-2-mercapto-9H)-purin-9-yl)-5-(hydroxymethyl)tetrahydro furan-3,4-diol (12.5 gms) was added to dimethylformamide (50 ml) at 25-30°C and stirred for 10 min. at same temperature. 3-Chloro-l , l, l-trifluoropropane (6.64 gms) and potassium carbonate ( 14.4 gms) were added to the above reaction mixture at 25-30°C. Heated the temperature of reaction mixture to 60-65 °C and stirred for 6 hours at same temperature. Filtered the reaction mixture through hyflow bed and washed with dimethylformamide. Distilled off the 70-80% of the solvent from the filtrate under reduced pressure. Ethyl acetate (125 ml) was added to the above concentrated filtrate and stirred for 10 min at 25-30°C. Water (60 ml) was added to the reaction mixture and separated the aqueous and organic layers. Extracted the aqueous layer with ethyl acetate. Combined the total organic layers and dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methylene chloride. Methylene chloride (125 ml) was added to the above obtained material and stirred for 30 min at 40-45°C and cooled the reaction mixture to 25-30°C and again stirred for 3 hours. Filtered the compound, washed with methylene chloride and then dried to get the title compound.
Yield: 13.0 gms; Purity: 99.9% by UPLC, dimer impurity: 0.24%, adenosine impurity: 0.01 %.
Example-3: Preparation of (2R, 35, 4R, 5R)-2-(hydroxymethyl)-5-(6-((2-methylthio)ethyl amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran -3,4-diol of formula (VIII)
(2i?,3i?,45,5i?)-2-(6-Amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxy- -methyl)tetrahydrofuran-3,4-diol (100 gms), acetic anhydride (500 ml) and sodium acetate (20.7 gms) were added in a round bottom flask at 25-30°C. Heated the reaction mixture to 75- 80°C and stirred for 8 hours at same temperature. Formic acid (50 ml) was added to the above reaction mixture at 75-80°C and stirred for 2 hours at same temperature. Distilled off the reaction mixture under reduced pressure. Methylene chloride (1000 ml) was added to the above residue and stirred for 10 min. The above reaction mixture was washed with water followed by aqueous sodium bicarbonate solution and separated the organic and aqueous layers. Charcoal was added to the organic layer and stirred for 20 min at 25-30°C. Filtered the reaction mixture through hyflow bed and washed with methylene chloride. Distilled off the solvent completely from the organic layer under reduced pressure.
Dissolved the above obtained residue in acetonitrile (300 ml) at 25-30°C and added 2- chloroethyl methyl sulfide (33.57 gms), potassium carbonate (104.7 gms). Heated the reaction mixture to 70-75 °C and stirred for 20 hours at same temperature. Cooled the reaction mixture to 25-30°C, filtered through hyflow bed and washed with methanol.
Sodium hydroxide (15.17 gms) was added to the above filtrate at 25-30°C and stirred for 15 min at same temperature. Heated the reaction mixture to 45-50°C and stirred for 4 hours at same temperature. Cooled the reaction mixture to 10-15°C and added water (600 ml) and then stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with water and then dried to get the titled compound. The above obtained compound was dissolved in methanol (1000 ml) at 55-60°C. Water (500 ml) was added to the above reaction mixture at 55-60°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hours at same temperature. Filtered the precipitated solid, washed with water and then dried to get the titled compound.
Yield: 63.1 gms, Melting Range: 165-170°C.
Example-4: Preparation of (2R, 35, 4R, 5R)-2-(hydroxymethyl)-5-(6-((2-methylthio)ethyl amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran -3,4-diol of formula (VIII)
(2i?,3i?,45,5i?)-2-(6-Amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxy methyl)tetrahydrofuran-3,4-diol (12gms) was added to aceticanhydride (65.2ml) at 25-30°C and stirred for 10 min at same temperature. Sodium acetate (2.52 gms) was added to the above reaction mixture at 25-30° and raised the temperature to 75-80°C and stirred for 8 hours at same temperature. Added formic acid (12 ml) to the above reaction mixture at 75-80°C and stirred for 8 hours at same temperature respectively. Distilled off the solvent from the reaction mixture under reduced pressure. Methylene chloride (120 ml) was added to the above material at 25-30°C and stirred for 10 min. The above reaction mixture was washed with water and separated the organic and aqueous layers. Washed the organic layer with aqueous sodium bicarbonate solution and separated the aqueous and organic layers. Charcoal was added to the organic layer and stirred for 20 min. Filtered the reaction mixture through hyflow bed and washed with methylene chloride. Distilled off the solvent completely from the organic layer under reduced pressure.
Dissolved the above obtained compound in acetonitrile (36 ml) at 25-30°C and added 2-chloroethyl methyl sulfide (4.0 gms), potassium carbonate (12.6 gms). Heated the reaction mixture to 70-75°C and stirred for 12 hours at same temperature. Cooled the reaction mixture to 25-30°C, filtered through hyflow bed and washed with methanol.
Sodium hydroxide (1.8 gms) was added to the above filtrate at 25-30°C and stirred for 15 min at same temperature. Heated the reaction mixture to 50-55°C and stirred for 4 hours at same temperature. Cooled the reaction mixture to 10-15°C and added water (72 ml) and then stirred for 1 hour at same temperature. Filtered the precipitated solid, washed with water and then dried. Methanol (120 ml) was added to the above obtained material at 55-60°C and stirred for 10 min. Water (60 ml) was added to the above reaction mixture at 55-60°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hours at same temperature. Filtered the precipitated solid, washed with water and then dried to get the title compound.
Yield: 10.3 gms; Purity: 98.9% by HPLC; mono sulfoxide impurity of formula (XIII): 0.01%, trifluoromercapto adenosine impurity of formula (IV): 0.15%, purine impurity of (XV)
Example-5: Preparation of ((2R,35,4R,5R)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl) amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX)
Phosphorous oxychloride (39.8 ml) was slowly added to the triethyl phosphate (300 ml) at 25-30°C under nitrogen atmosphere and stirred for 45 min at 25-30°C and then cooled to 0-2°C. Ammonium carbonate (4.15 gms) was added to the above reaction mixture at 0-2°C and stirred for 20 min at same temperature.
(2i?,35,4i?,5i?)-2-(Hydroxymethyl)-5-(6-((2-methylthio)ethylamino-2-((3,3,3-trifluoro propyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (50 gms) in 200 ml of triethyl phosphate solution was added to the above reagent mixture at 0-5°C and stirred for 6 hours at the same temperature. Water (500 ml) followed by methylene chloride (250 ml) were added to the reaction mixture at 0-5°C and stirred for 10 min at same temperature. Separated the both aqueous and organic layers. The aqueous layer was treated with charcoal and then neutralized with aqueous ammonium bicarbonate solution and stirred for 60 min at 0-5°C. Filtered the precipitated solid, washed with water and then dried to get the title compound. (Yield: 70 gms).
The compound of formula (IX) obtained by the above example is used in the next stage without purification.
Example-6: Preparation of ((2R,35,4R,5R)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl) amino)-2-(3,3,3-trifluoropropyl)thio-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl hydrogen morpholinophosphonate of formula (X)
Tert-butanol (1000 ml) and water (1200 ml) were added to ((2/?,3S,4R,5R)-3,4- dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl) tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX) (70 gms) at 25-30°C and stirred for 10 min at same temperature. Morpholine (15.7 gms) was added to the above reaction mixture at 25-30°C and stirred for 10 min at same temperature. Heated the reaction mixture to 85-90°C and stirred for 10 min at same temperature. Dicyclohexylcarbodiimide (37.14 gms) in 200 ml of tert-butanol was added to the reaction mixture at 85-90°C and stirred for 8 hours at same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure at below 80°C. Cooled the reaction mixture to 25-30°C and stirred for 45 min at same temperature. Filtered the reaction mixture and washed with water. Distilled off the water completely from the filtrate under reduced pressure at below 80°C. Methylene chloride (250 ml) was added to the above obtained compound and stirred for 30 min at 25-30°C. Filtered the reaction mixture through hyflow bed and washed with methylene chloride. Distilled off the solvent completely from the filtrate under atmospheric condition and followed by under reduced pressure to get the title compound.
The compound of formula (X) obtained by the above example is used in the next stage without purification.
Example-7: Preparation of tetrasodium salt of N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl) -5 '-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la) (Cangrelor tetrasodium salt)
((2i?,35,4i?,5i?)-3,4-Dihydroxy-5-(6-((2-(methylthio)ethyl) amino)-2-(3,3,3-trifluoro propyl)thio-9H-purin-9-yl)tetrahydrofuran-2-yl)methylhydrogenmorpholinephosphonate (70 gms) was added to dimethylsulfoxide (300 ml) and stirred for 10 min. Tri n-butylamine (10.19 gms) was added to the above reaction mixture and stirred for 10 min. A solution of tri n- butylamine and clodronic acid (40.4 gms of clodronic acid and 31.5 gms of tri n-butylamine were dissolved in 200 ml of dimethylsulfoxide) was slowly added to the above reaction mixture at 25-30°C and stirred for 10 hrs at same temperature to get reaction mixture containing Cangrelor of formula (I).
Dimethylsulfoxide (500 ml) was added to the above reaction mixture at 25-30°C. Aqueous sodium chloride solution was added to the reaction mixture and stirred for 10 min at 25-30°C. Acetone (1000 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at same temperature. Filtered the precipitated solid, washed with acetone and then dried the material. Methanol (1000 ml) was added to the reaction mixture at 25-30°C and stirred for 2 hours at same temperature. Filtered the solid compound and washed with methanol. Water (550 ml) was added to the obtained compound and stirred for 30 min at 25- 30°C. Filtered the reaction mixture through highflow bed and washed with water. Aqueous sodium bicarbonate solution was added to the filtrate and stirred for 15 min at 25-30°C. Methanol (750 ml) was added to the reaction mixture at 25-30°C and stirred for 2 hours at same temperature. Filtered the precipitated solid, washed with methanol and then dried. Water (250 ml) was added to the above obtained compound at 25-30°C and stirred for 15 min at same temperature. Filtered the reaction mixture through hyflow bed and washed with water. Slowly added aqueous sodium bicarbonate solution to the filtrate and stirred for 15 min at 25- 30°C. Methanol (280 ml) was added to the above reaction mixture and stirred for 60 min at 25-30°C. Filtered the precipitated solid, washed with methanol and then dried to get crude compound.
The PXRD pattern of the crude compound was illustrated in Fig. 1.
The obtained compound was purified by flash chromatography using Milli-Q-water and acetonitrile (9: 1) as eluent and then lyophilized the obtained solution to get title compound. (Yield: 35 gms, purity by HPLC: 99.75%); water content: 8-10%, sodium content: 8-12%).
The PXRD pattern of above obtained compound was illustrated in Fig.2.
Example-8: Preparation of crystalline Form-M of tetrasodium salt of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la).
Water (200 ml) was added to tetrasodium salt of N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl)-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid (40 gms) at 25-30°C and stirred for 15 min at same temperature. Filtered the reaction mixture through hyflow bed and washed with water. Slowly added aqueous sodium bicarbonate solution (7.0 gms dissolved in 100 ml of water) to the filtrate and stirred for 15 min at 25-30°C. Methanol (200 ml) was added to the above reaction mixture and stirred for 60 min at 25-30°C. Filtered the precipitated solid, washed with methanol and then dried to get title compound. (Yield: 39 gms)
The PXRD pattern of above obtained compound was illustrated in Fig.3. Example-9: Preparation of pure amorphous tetrasodium salt of N6-[2- (methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid (Cangrelor tetrasodium salt)
Crude Cangrelor tetrasodium salt (35 gms) was subjected to preparative HPLC and lyophilization to afford the pure amorphous Cangrelor tetrasodium salt.
Preparative HPLC Method:
Apparatus: preparative HPLC system is to be equipped with variable wavelength UV- Detector.
Column: collapsed column 250 x 50 mm, (silica based CI 8, 10 μπι media)
Flow rate: 60 mL/min;
Wavelength: 242 nm;
Run time: 58.0 mins;
Mobile phase-A: milli Q water (pH: 6.5-7.5)
Mobile phase-B: acetonitrile: water (80 : 20) v/v
Diluent: Mobile phase-A
The PXRD pattern of obtained pure amorphous compound was illustrated in Figure 4.
Yield: 26.4 gms, Purity: 99.83% by HPLC, water: 4.4% (by KFR method), sodium content: 10.0% w/w. sulfoxide impurity of formula (XI): 0.01%, purine sulfoxide impurity of formula (XIII): 0.01%, mono phosphoryl impurity of formula (VI): 0.02%, adenosine impurity of formula (V): not detected, purine impurity of formula (XII): not detected, mono phosphoryl dimer impurity of formula (IX): not detected, clodronic acid impurity of formula (VIII): 0.02% (by Ion chromatography).

Claims

Claims:
1. A process for the preparation of N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]- 5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (I) or its pharmaceutically acceptable salts,
Figure imgf000034_0001
Formula (I)
which comprising:
a) reacting (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) with the compound of formula (III) in presence of suitable base in a suitable solvent to provide the compound of formula (IV),
Figure imgf000034_0002
Formula (II) Formula (IV) wherein, X is selected from chlorine, bromine or iodine b) reacting the compound of formula (IV) with a suitable protecting agent in presence of suitable base and suitable acid to get tetra protected compound of formula (V) which on in-situ reacting with the compound of formula (VI) in presence of a suitable base in a suitable solvent to get the compound of formula (VII) which on in-situ treating with a suitable deprotecting agent in a suitable solvent to provide the compound of formula (VIII),
Figure imgf000035_0001
Formula (IV) Formula (V)
Step-b2 Formula (VI)
Figure imgf000035_0002
Formula (VIII) Formula (VII) wherein "Pg" is a protecting group selected from -C(0)Ri, -C(0)ORi; optionally substituted -C(0)OAr; optionally substituted -ArRi, wherein Ri is selected from alkyl chain having C1-5 carbon atoms. Ar is a aryl group selected from phenyl; X is selected from chlorine, bromine or iodine c) reacting the compound of formula (VIII) with a mixture of phosphorous oxychloride, triethyl phosphate and suitable base to produce ((2i?,3S,4i?,5i?)-3,4-dihydroxy-5-(6- ((2-(methylthio)ethyl)amino)-2-(3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)tetrahydro furan-2-yl)methyl dihydrogenphosphate of formula (IX),
Figure imgf000035_0003
Formula (VIII) Formula (IX) d) reacting the compound of formula (IX) with a suitable coupling agent in a suitable solvent to produce the compound of formula (X),
Figure imgf000036_0001
Formula (IX) Formula (X)
e) reacting the compound of formula (X) with clodronic acid in presence of a suitable base in suitable solvent to provide N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with(dichloromethylene) bisphosphonic acid of formula (I),
Figure imgf000036_0002
f) optionally converting the compound of formula (I) into its pharmaceutically acceptable salts.
2. The process according to claim 1, wherein in step-a), step-b2), step-d) and step-e) the suitable solvent is selected from polar aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and isobutanol; chloro solvent such as methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; ketone solvent selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; hydrocarbon solvents such as toluene, hexane, heptane and cyclohexane; nitrile solvent selected from acetonitrile, propionitrile; ester solvent such as ethyl acetate, methyl acetate and isopropyl acetate; ether solvent such as tetrahydrofuran, diethyl ether and methyl tert-butyl ether or mixture of solvents thereof; in step-a), step-b2) step-c) and step- e) the suitable base is selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, organic bases such as pyridine, dimethylaminopyridine, N- methylmorpholine, ethylamine, diisopropylethylamine, triethylamine; in step-bl) the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid; organic acids such as formic acid, acetic acid, methanesulfonic acid; the suitable base is selected from alkali or alkaline salts of C1-C5 carboxylic or di carboxylic acids such as sodium acetate, potassium acetate, sodium propanoate, sodium formate and the like; in step-d) the suitable coupling agent is selected from l, l'-carbonyldiimidazole (CDI), Ν,Ν'-dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropyl carbodiimide (DIC), 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 1- [bis(dimethylamino) methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate (HBTU), lH-benzo triazolium l-[bis(dimethylamino)methylene]-5chloro- hexafluorophosphate (1-) 3-oxide (HCTU), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyl uronium tetrafluoroborate (TBTU), ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), ((benzotriazol-l-yloxy) tris(dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP).
3. A process for the preparation of tetrasodium salt of N6-[2-(methylfhio)efhyl]-2- [(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula la),
Figure imgf000037_0001
Formula (la)
comprising:
a) reacting (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) with 3-chloro-l, l , l-trifluoropropane of formula (Ilia) in presence of potassium carbonate in dimethylformamide to provide (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxy methyl)tetrahydro furan-3,4-diol of formula (IV),
Figure imgf000038_0001
Formula (II) Formula (IV)
reacting the compound of formula (IV) with aceticanhydride and sodium acetate in presence of formic acid to provide the tetra acetyl protected compound of formula (Va) which on in-situ reacting with 2-chloroethyl methyl sulfide of formula (Via) in presence of potassium carbonate in acetonitrile to provide the compound of formula (Vila) which on in-situ treating with sodium hydroxide in methanol to provide the compound of formula (VIII),
Figure imgf000038_0002
c) reacting the compound of formula (VIII) with a mixture of phosphorous oxychloride & triethyl phosphate and ammonium carbonate to provide ((2i?,35,4i?,5i?)-3,4- dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-(3,3,3-trifluoropropyl)thio)-9H-purin- 9-yl)tetrahydrofuran -2-yl)methyl dihydrogenphosphate of formula (IX),
Figure imgf000039_0001
Formula (Vni) Formula (ΓΧ) d) reacting the compound of formula (IX) with morpholine in presence of dicyclohexylcarbodiimide in feri-butanol to produce ((2i?,35,4i?,5i?)-3,4-dihydroxy-5- (6-((2-(methylthio)ethyl)amino)-2-(3,3,3-trifluoropropyl)thio-9H-purin-9- yl)tetrahydrofuran-2-yl)methyl hydrogen morpholinephosphonate of formula (X),
Figure imgf000039_0002
Formula (IX) Formula (X) e) reacting the compound of formula (X) with clodronic acid in presence of tri n- butylamine in dimethylsulfoxide to provide N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with
(dichloromethylene)bisphosphonic acid of formula (I),
Figure imgf000039_0003
Formula (X) Formula (I) f) converting the compound of formula (I) into its tetrasodium salt of N6-[2-
(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la) by treating with a suitable sodium source in a suitable solvent or mixture of solvents.
4. A process for the preparation of tetrasodium salt of N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la), comprising of:
a) dissolving N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene )bisphosphonic acid in a suitable solvent, b) treating the reaction mixture with a suitable sodium source,
c) stirring the reaction mixture,
d) adding suitable second solvent to the reaction mixture,
e) stirring the reaction mixture,
f) filtering the precipitated solid,
g) slurrying the obtained solid in a suitable solvent at suitable temperature,
h) filtering the solid,
i) dissolving the obtained compound in step-h) in a suitable solvent,
j) filtering the reaction mixture,
k) treating the reaction mixture with a suitable aqueous sodium source,
1) adding suitable organic solvent to the reaction mixture,
m) filtering the reaction mixture,
n) optionally repeating the steps (g to m) to get the compound of formula (la).
5. The process according to claim 4, wherein in step-a), step-d), step-g), step-i) and step-1) the suitable solvent is selected from ketone solvents, ester solvents, nitrile solvents, ether solvents, hydrocarbon solvents, chloro solvents, alcoholic solvents, water or mixtures thereof; in step-b) and step-k) the suitable sodium source is selected from sodium chloride, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium alkoxides such as sodium methoxide, sodium ethoxide, sodium propaxide, sodium acetate.
6. A process for the preparation of tetrasodium salt of N6-[2-(methylthio)ethyl]-2- [(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid of formula (la), comprising of:
a) dissolving N6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene)bisphosphonic acid in dimethylsulfoxide ,
b) treating the reaction mixture with aqueous sodium chloride solution,
c) stirring the reaction mixture,
d) adding acetone to the reaction mixture,
e) stirring the reaction mixture,
f) filtering the precipitated solid,
g) slurrying the obtained solid in methanol at 25-30°C,
h) filtering the solid,
i) dissolving the obtained compound in step-h) in water,
j) filtering the reaction mixture,
k) treating the reaction mixture with aqueous sodium bicarbonate solution,
1) adding methanol to the reaction mixture,
m) filtering the reaction mixture,
n) optionally repeating the steps (g to m) to get the compound of formula (la).
7. Crystalline Form-M of Cangrelor tetrasodium salt of formula (la) characterized by its PXRD pattern as shown in figure-3.
8. A process for the preparation of crystalline Form-M of Cangrelor tetrasodium salt of formula (la), comprising:
a) dissolving the Cangrelor tetrasodium salt of formula (la) in water,
b) optionally, filtering the reaction mixture,
c) treating the reaction mixture with aqueous sodium bicarbonate solution,
d) adding methanol to the reaction mixture,
e) filtering the reaction mixture to get crystalline Form-M of Cangrelor tetrasodium salt of formula (la).
9. A process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)- 9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV)
Figure imgf000042_0001
Formula (IV)
having dimer impurity of formula (XVII) less than 1.0%, preferably less than 0.5%, more preferably less than
Figure imgf000042_0002
comprising;
a) providing (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) in a suitable solvent,
b) reacting the reaction mixture obtained in step-a) with the compound of formula (III) in presence of a suitable base;
c) isolating the product obtained in step-b) to provide pure (2i?,3i?,45,5i?)-2-(6-amino-2- ((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4- diol of formula (IV) wherein in step-a) the suitable solvent refers to polar aprotic solvents, alcoholic solvents, chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents or mixture of solvents thereof; in step-b) the suitable base refers to alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, alkali metal alkoxides, organic bases and the like; in step-c) the compound of formula (IV) is isolated as a solid through crystallization from a suitable solvent selected from the solvents defined in step-a).
10. A process for the preparation of (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)- 9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV),
Figure imgf000043_0001
Formula (IV)
having dimer impurity of formula (XVII) less than 1.0%, preferably less than 0.5%, more preferably less than
Figure imgf000043_0002
comprising;
a) providing (2i?,3i?,45,5i?)-2-(6-amino-2-mercapto-9H-purin-9-yl)-5-(hydroxymethyl) tetrahydrofuran-3,4-diol of formula (II) in dimethylformamide;
b) reacting the reaction mixture obtained in step-a) with 3-chloro-l, l, l-trifluoropropane in presence of potassium carbonate to provide (2i?,3i?,45,5i?)-2-(6-amino-2-((3,3,3- trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol of formula (IV).
11. A process for the preparation of ((2i?,35,4i?,5i?)-3, 4-dihydroxy-5-(6-((2- (methylthio)ethyl)amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2- yl)methyl dihydrogenphosphate of formula (IX),
Figure imgf000044_0001
Formula (IX)
comprising of:
a) reacting the compound of formula (II) with the compound of general formula (III) in presence of a suitable base in a suitable solvent to provide the compound of formula
(IV);
Figure imgf000044_0002
Formula (II) Formula (IV) wherein, X is selected from chlorine, bromine or iodine b) reacting the compound of formula (IV) with suitable protecting agent in presence of suitable base and suitable acid to get the tetra protected compound of formula (V) which on in-situ reacting with the compound of general formula (VI) in presence of a suitable base in a suitable solvent to get the compound of formula (VII) which on in- situ treating with deprotecting agent in a suitable solvent to provide the compound of formula (VIII);
Figure imgf000045_0001
Formula (IV) Formula (V)
Step-b2 Formula (VI) Base / solvent
Figure imgf000045_0002
Formula (VIII) Formula (VII) wherein "Pg" is a protecting group selected from -C(0)Ri , -C(0)ORi ; optionally substituted -C(0)OAr; optionally substituted -ArRi, wherein Ri is selected from alkyl chain having C1-5 carbon atoms. Ar is a aryl group selected from phenyl; X is selected from chlorine, bromine or iodine c) reacting the compound of formula (VIII) with a mixture of trie thy lphosphate, phosphorous oxychloride and base to provide the compound of formula (IX)
Figure imgf000045_0003
Formula (VIII) Formula (IX) wherein, in step-a), step-b2) and step-c) the suitable solvent refers to polar aprotic solvents, alcoholic solvents chloro solvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents or their mixture of solvents thereof; in step-b2), step-c) and step- d) "the suitable base" refers to the base selected from alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates, organic bases such as pyridine, dimethylaminopyridine, N-methylmorpholine, ethylamine, diisopropylethylamine, triethylamine, alkali metal alkoxides and the like; in step-bl), "the suitable acid" refers to the acids selected from HC1, HBr, HI, H2SO4; organic acids selected from formic acid, AcOH, MsOH, j?-TsOH, TFA; the suitable base is selected from alkali or alkaline salts of C1-C5 carboxyhc or di carboxyhc acids selected from sodium acetate, potassium acetate, sodium propanoate and sodium formate.
12. A process for the preparation of ((2i?,35,4i?,5i?)-3,4-dihydroxy-5-(6-((2- (methylthio)ethyl)amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2- yl)methyl dihydrogenphosphate of formula (IX)
Figure imgf000046_0001
Formula (IX)
comprising of:
a) reacting the compound of formula (II) with 3-chloro-l,l, l-trifluoropropane in presence of potassium in dimethylformamide carbonate to provide the compound of formula (IV),
Figure imgf000046_0002
Formula (II) Formula (IV) b) reacting the compound of formula (IV) with aceticanhydride and sodium acetate in presence of formic acid to get the tetra acetyl protected compound of formula (Va) which on in-situ reacting with 2-chloroethyl methyl sulfide of formula (Via) in presence of potassium carbonate in acetonitrile to get the compound of formula (Vila) which on in-situ treating with sodium hydroxide in methanol to provide compound of formula (VIII),
Formula (IV)
Formula (VIII)
Figure imgf000047_0001
c) reacting the compound of formula (VIII) obtained in step-b) with the mixture of triethylphosphate, phosphorous oxychloride and ammonium carbonate to provide ((2i?,35,4i?,5i?)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3-trifluoro propyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl dihydrogenphosphate of formula (IX)
Figure imgf000047_0002
Formula (Vin) Formula (IX)
13. A process for the preparation of ((2i?,35,4i?,5i?)-3,4-dihydroxy-5-(6-((2- (methylthio)ethyl)amino)-2-((3,3,3-trifluoro propyl)thio)-9H-purin-9-yl)tetrahydrofuran- 2-yl)methyl dihydrogenphosphate of formula (IX) comprising reaction of the compound of formula (VIII) with the mixture of triethylphosphate, phosphorous oxychloride and ammonium carbonate.
14. Use of compounds of formulae (IX), (X) and (I) in the preparation of pure Cangrelor tetrasodium of formula (la) by without any further purification.
15. Use of Cangrelor tetrasodium obtained according to the claims 1, 3, 4 and 6 in the preparation of pharmaceutical compositions.
16. The pure amorphous form of Cangrelor tetrasodium obtained according to the claims 4 and 6 used in pharmaceutical compositions.
17. Use of crystalline Form-M of Cangrelor tetrasodium in the preparation of pharmaceutical composition.
PCT/IB2018/052388 2017-04-06 2018-04-06 Improved process for the preparation of n6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid and its pharmaceutically acceptable salts Ceased WO2018185715A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741012360 2017-04-06
IN201741012360 2017-04-06

Publications (1)

Publication Number Publication Date
WO2018185715A1 true WO2018185715A1 (en) 2018-10-11

Family

ID=63712483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/052388 Ceased WO2018185715A1 (en) 2017-04-06 2018-04-06 Improved process for the preparation of n6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid and its pharmaceutically acceptable salts

Country Status (1)

Country Link
WO (1) WO2018185715A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019114674A1 (en) * 2017-12-12 2019-06-20 亚宝药业集团股份有限公司 Method for prepare cangrelor tetrasodium salt
CN112724181A (en) * 2020-12-30 2021-04-30 盐城锦明药业有限公司 Method for preparing Cangrelor intermediate adenosine-2-thioketone
CN112898347A (en) * 2021-03-02 2021-06-04 北京阳光诺和药物研究股份有限公司 Preparation method of cangrelor key intermediate
CN115389695A (en) * 2022-08-24 2022-11-25 南京理工大学 A kind of ion chromatography detection method of sodium pentazole sample purity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5721219A (en) * 1993-02-10 1998-02-24 Astra Pharmaceuticals Ltd. N-alkyl-2-substituted ATP analogues and administration to inhibit platelet aggregation
US20080095866A1 (en) * 2004-09-14 2008-04-24 Ajinomoto Omnichem S.A. Topical Compositions Containing Phosphorylated Polyphenols
CN103772461A (en) * 2014-01-06 2014-05-07 南京正科制药有限公司 Cangrelor crystal form I

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5721219A (en) * 1993-02-10 1998-02-24 Astra Pharmaceuticals Ltd. N-alkyl-2-substituted ATP analogues and administration to inhibit platelet aggregation
US20080095866A1 (en) * 2004-09-14 2008-04-24 Ajinomoto Omnichem S.A. Topical Compositions Containing Phosphorylated Polyphenols
CN103772461A (en) * 2014-01-06 2014-05-07 南京正科制药有限公司 Cangrelor crystal form I

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANTHONY H.INGALL ET AL.: "ANTAGONISTS OF THE PLATELET P2T RECEPTOR: A NOVEL APPROACH TO ANTITHROMBOTIC THERAPY", J. MED. CHEM. 1999, vol. 42, 28 January 1999 (1999-01-28), pages 213 - 220, XP002937224 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019114674A1 (en) * 2017-12-12 2019-06-20 亚宝药业集团股份有限公司 Method for prepare cangrelor tetrasodium salt
US11440934B2 (en) 2017-12-12 2022-09-13 Yabao Pharmaceutical Group Co., Ltd. Method for preparing cangrelor tetrasodium salt
CN112724181A (en) * 2020-12-30 2021-04-30 盐城锦明药业有限公司 Method for preparing Cangrelor intermediate adenosine-2-thioketone
CN112724181B (en) * 2020-12-30 2022-09-13 盐城师范学院 Method for preparing Cangrelor intermediate adenosine-2-thioketone
CN115181138A (en) * 2020-12-30 2022-10-14 盐城锦明药业有限公司 Method for preparing Cangrelor intermediate adenosine-2-thioketone
CN115181138B (en) * 2020-12-30 2025-10-31 盐城师范学院 Method for preparing cangrelor (Cangrelor) intermediate adenosine-2-thione
CN112898347A (en) * 2021-03-02 2021-06-04 北京阳光诺和药物研究股份有限公司 Preparation method of cangrelor key intermediate
CN115389695A (en) * 2022-08-24 2022-11-25 南京理工大学 A kind of ion chromatography detection method of sodium pentazole sample purity
CN115389695B (en) * 2022-08-24 2024-03-22 南京理工大学 An ion chromatography method for detecting the purity of sodium pentazole samples

Similar Documents

Publication Publication Date Title
WO2018185715A1 (en) Improved process for the preparation of n6-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid, monoanhydride with (dichloromethylene) bisphosphonic acid and its pharmaceutically acceptable salts
DE69509173T2 (en) 2- (2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3-propanediol derivatives
EP3299356B1 (en) Process for the preparation of pleuromutilins
JP4100955B2 (en) Process for the preparation of 4 "-substituted-9-deoxo-9A-aza-9A-homoerythromycin A derivatives
EP2321302B1 (en) Azacitidine process and polymorphs
US20220251052A1 (en) Improved process for the preparation of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or its pharmaceutically acceptable salts and polymorphs thereof
CZ20023875A3 (en) 2-Aminocarbonyl-9H-purine derivatives
CN1426418A (en) Phosphate nucleotide compound'
JP4667542B2 (en) Carbapenem-3-carboxylic acid ester derivatives
AU2011257938A1 (en) Process for the preparation of pleuromutilins
EP3081569A1 (en) Imidazole derivative used as antiviral agent and use thereof in preparation of medicament
WO2017130217A1 (en) The present invention relates to process for the preparation of d-glucitol, 1,5- anhydro-1-c-[4-chloro-3-[[4-[[(3s)-tetrahydro-3-furanyl] oxy]phenyl] methyl]phenyl]-, (1s) and its crystalline forms thereof.
EP3774781B1 (en) Novel albicidin derivatives, their use and synthesis
EP3676265B1 (en) Method for the synthesis of cyclic depsipeptides
CN1305484A (en) 3-(2-oxo[1,3']bihyrrolidinyl-3-ylidenemethyl)-cephems
FR2808797A1 (en) New uridine derivatives N-substituted by disaccharide residue, useful as antibiotics with strong activity against Gram positive bacteria
PL201891B1 (en) Diphosphate salt of a 4''-substituted-9-deoxo-9a-aza-9a-homoerythromycin derivative and its pharmaceutical composition
US20220315605A1 (en) IMPROVED PROCESS FOR THE PREPARATON OF PURE (1'R,6R,6aR,7R,13S,14S,16R)-5-(ACETYLOXY)-3',4',6,6a,7,13,14,16-OCTAHYDRO-6',8,14-TRIHYDROXY-7',9-DIMETHOXY-4,10,23-TRIMETHYLSPIRO[6,16-(EPITHIOPROPANOXYMETH ANO)-7,13-IMINO-12H-1,3-DIOXOLO[7,8]ISOQUINO[3,2-b][3]BENZAZOCINE-20,1'(2'H)-ISOQUINOLIN]-19-ONE POLYMORPH THERE OF
KR102092817B1 (en) Amatoxin derivatives and methods for their preparation
HK40039214A (en) Method for the synthesis of cyclic depsipeptides
WO2005023826A2 (en) Polymorphic nucleoside compounds
MXPA00012391A (en) Derivatives of 3-(2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems
US20090069255A1 (en) Deuterium-enriched clarithromycin
HK1183294A (en) Crystalline form of a pleuromutilin
HK1183294B (en) Crystalline form of a pleuromutilin

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: 18781703

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: 18781703

Country of ref document: EP

Kind code of ref document: A1