[go: up one dir, main page]

WO2018185715A1 - Procédé amélioré pour la préparation d'un monoanhydride de l'acide n6-[2-(méthylthio)éthyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adénylique avec de l'acide (dichlorométhylène)bisphosphonique et de ses sels pharmaceutiquement acceptables - Google Patents

Procédé amélioré pour la préparation d'un monoanhydride de l'acide n6-[2-(méthylthio)éthyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adénylique avec de l'acide (dichlorométhylène)bisphosphonique et de ses sels pharmaceutiquement acceptables 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
English (en)
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/fr
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

La présente invention concerne un procédé amélioré pour la préparation d'un monoanhydride de l'acide N6-[2-(méthylthio)éthyl]-2-[(3,3,3, trifluoropropyl)thio]-5'-adénylique avec de l'acide (dichlorométhylène)bisphosphonique de formule (I), de ses sels pharmaceutiquement acceptables et de ses formes polymorphes. (Formule I) (I) La présente invention concerne également un procédé amélioré pour la préparation de (2R,3R,4S,5R)-2-(6-amino-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)-5-(hydroxyméthyl)tétrahydrofuran-3,4-diol de formule (IV) en réduisant fortement la formation de l'impureté dimère de formule (XVII). La présente invention concerne également un procédé amélioré pour la préparation d'un dihydrogénophosphate de ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-((2-(méthylthio)éthyl)amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)tétrahydrofuran-2-yl)méthyle de formule (IX) avec un rendement plus élevé et une pureté élevée.
PCT/IB2018/052388 2017-04-06 2018-04-06 Procédé amélioré pour la préparation d'un monoanhydride de l'acide n6-[2-(méthylthio)éthyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adénylique avec de l'acide (dichlorométhylène)bisphosphonique et de ses sels pharmaceutiquement acceptables Ceased WO2018185715A1 (fr)

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 (fr) 2018-10-11

Family

ID=63712483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/052388 Ceased WO2018185715A1 (fr) 2017-04-06 2018-04-06 Procédé amélioré pour la préparation d'un monoanhydride de l'acide n6-[2-(méthylthio)éthyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adénylique avec de l'acide (dichlorométhylène)bisphosphonique et de ses sels pharmaceutiquement acceptables

Country Status (1)

Country Link
WO (1) WO2018185715A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019114674A1 (fr) * 2017-12-12 2019-06-20 亚宝药业集团股份有限公司 Procédé de préparation de sel tétrasodique de cangrelor
CN112724181A (zh) * 2020-12-30 2021-04-30 盐城锦明药业有限公司 一种制备坎格雷洛（Cangrelor）中间体腺苷-2-硫酮的方法
CN112898347A (zh) * 2021-03-02 2021-06-04 北京阳光诺和药物研究股份有限公司 一种坎格雷洛关键中间体的制备方法
CN115389695A (zh) * 2022-08-24 2022-11-25 南京理工大学 一种五唑钠样品纯度的离子色谱检测方法

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 (zh) * 2014-01-06 2014-05-07 南京正科制药有限公司 一种坎格雷洛晶型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 (zh) * 2014-01-06 2014-05-07 南京正科制药有限公司 一种坎格雷洛晶型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 (fr) * 2017-12-12 2019-06-20 亚宝药业集团股份有限公司 Procédé de préparation de sel tétrasodique de cangrelor
US11440934B2 (en) 2017-12-12 2022-09-13 Yabao Pharmaceutical Group Co., Ltd. Method for preparing cangrelor tetrasodium salt
CN112724181A (zh) * 2020-12-30 2021-04-30 盐城锦明药业有限公司 一种制备坎格雷洛（Cangrelor）中间体腺苷-2-硫酮的方法
CN112724181B (zh) * 2020-12-30 2022-09-13 盐城师范学院 一种制备坎格雷洛(Cangrelor)中间体腺苷-2-硫酮的方法
CN115181138A (zh) * 2020-12-30 2022-10-14 盐城锦明药业有限公司 一种制备坎格雷洛（Cangrelor）中间体腺苷-2-硫酮的方法
CN115181138B (zh) * 2020-12-30 2025-10-31 盐城师范学院 一种制备坎格雷洛（Cangrelor）中间体腺苷-2-硫酮的方法
CN112898347A (zh) * 2021-03-02 2021-06-04 北京阳光诺和药物研究股份有限公司 一种坎格雷洛关键中间体的制备方法
CN115389695A (zh) * 2022-08-24 2022-11-25 南京理工大学 一种五唑钠样品纯度的离子色谱检测方法
CN115389695B (zh) * 2022-08-24 2024-03-22 南京理工大学 一种五唑钠样品纯度的离子色谱检测方法

Similar Documents

Publication Publication Date Title
WO2018185715A1 (fr) Procédé amélioré pour la préparation d'un monoanhydride de l'acide n6-[2-(méthylthio)éthyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adénylique avec de l'acide (dichlorométhylène)bisphosphonique et de ses sels pharmaceutiquement acceptables
DE69509173T2 (de) 2-(2-Amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propandiol-Derivate
EP3299356B1 (fr) Procédé de préparation de pleuromutilines
JP4100955B2 (ja) ４”−置換−９−デオキソ−９ａ−アザ−９ａ−ホモエリスロマイシンａ誘導体類の製造法
EP2321302B1 (fr) Procédé de préparation d'azacitidine et polymorphes
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 (cs) 2-Aminokarbonyl-9H-purinové deriváty
CN1426418A (zh) 膦酸酯核苷酸化合物
JP4667542B2 (ja) カルバペネム−３−カルボン酸エステル誘導体
AU2011257938A1 (en) Process for the preparation of pleuromutilins
EP3081569A1 (fr) Dérivé d'imidazole utilisé en tant qu'agent antiviral et son utilisation pour la préparation d'un médicament
WO2017130217A1 (fr) Procédé de préparation de d-glucitol, 1,5- anhydro-1-c-[4-chloro-3-[[4-[[(3s)-tétrahydro-3-furanyl] oxy]phényl] méthyl]phényl]-, (1s) et ses formes cristallines
EP3774781B1 (fr) Nouveaux dérivés de l'albicidine, leur utilisation et leur synthèse
EP3676265B1 (fr) Procédé de synthèse de depsipeptides cycliques
CN1305484A (zh) 3－(2－氧－[1,3′]二吡咯烷基－3－基亚基甲基)－头孢
FR2808797A1 (fr) Nouveaux derives de l'uridine, leur procede de preparation et leur application comme medicaments
PL201891B1 (pl) Dwie odmiany polimorficzne difosforanu (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[[2,6-dideoksy-3-C-metylo-3-O-metylo-4-C-[(propyloamino)metylo]-α-L-rybo-heksopiranozylo]oksy]-2-etylo-3,4,10-trihydroksy-3,5,8,10,12,14-heksametylo-11-[[3,4,6-trideoksy-3-(dimetyloamino)-ß-D-ksylo-heksapiranozylo]oksy]-1-oksa-6-azacyklopentadekan-15-onu, sposób ich wytwarzania, sposób przeprowadzania ciekłokrystalicznego lub krystalicznego difosforanu w wolną od zanieczyszczeń wolną zasadę, środek farmaceutyczny i zastosowanie wolnej zasady ciekłokrystalicznego lub krystalicznego difosforanu
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 (ko) 아마톡신 유도체 및 이의 제조방법
HK40039214A (en) Method for the synthesis of cyclic depsipeptides
WO2005023826A2 (fr) Composes nucleosides polymorphes
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