WO2015118558A2 - Procédé pour la préparation de clofarabine - Google Patents

Procédé pour la préparation de clofarabine Download PDF

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Publication number
WO2015118558A2
WO2015118558A2 PCT/IN2015/000068 IN2015000068W WO2015118558A2 WO 2015118558 A2 WO2015118558 A2 WO 2015118558A2 IN 2015000068 W IN2015000068 W IN 2015000068W WO 2015118558 A2 WO2015118558 A2 WO 2015118558A2
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WIPO (PCT)
Prior art keywords
formula
compound
solvents
deoxy
fluoro
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PCT/IN2015/000068
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English (en)
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WO2015118558A3 (fr
Inventor
Srinivasan Thirumalai Rajan
Muppa Kishore Kumar
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Msn Laboratories Private Limited
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Publication of WO2015118558A2 publication Critical patent/WO2015118558A2/fr
Publication of WO2015118558A3 publication Critical patent/WO2015118558A3/fr

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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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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

Definitions

  • the present invention provides a process for the preparation of Clofarabine represented by the following s
  • Clofarabine is a purine nucleoside metabolic inhibitor. The drug has been approved both in US and Europe for the treatment of relapsed or refractory acute lymphoblastic leukemia.
  • the starting material was prepared by the process disclosed in Journal of Medicinal Chemistry, 1986, Vol. 29, No. 11, page: 2389-2392.
  • the disclosed process involve the reaction of 3-acetyl-5-benzoyl-2-deoxy-2-fluoroarabinofuranosylbromide with 2,6-dichloropurine in dichloroethane in presence of molecular sieves at 100°C for 16 hours provides 2,6-Dichloro-9-(3-0-acetyl-5-0-beri2yl-2-deoxy-2-fluoro- -D- arabinofuranosyl)-9H-purine.
  • the obtained compound was purified by flash column chromatography to give the required product in an overall yield of 32%.
  • the above disclosed route of synthesis has so many disadvantages.
  • the reaction procedure involves the usage of toxic, highly flammable and carcinogenic solvents such as dichloroethane as reaction solvent and requires higher temperatures and longer time for completion of the reaction. It involves column chromatography technique for purification of the reaction intermediate which is not suggestible. Further the above process provides the required product in very low yields.
  • the obtained ⁇ -anomer was further treated with sodium methoxide in methanol followed by chromatography purification to provide 2- Chloro-9-(2-deoxy-2-fluoro-[beta]-D-arabinofuranosyl)-6-methoxy-9H-purine.- Finally the obtained methoxy compound was treated with anhydrous ammonia in ethanol at 80°C for 16- 20 hours to provide Clofarabine.
  • US6680382 patent discloses a process for the preparation of Clofarabine by the reaction of 2-deoxy-2-fluoro-3,5-di-0-benzoyl-[alpha]-D-arabinofuranosyl bromide with chloroadenine in presence of KOBt in various solvents provides mixture of a, ⁇ -anomers of 2-chloro-9-(3,5-0-dibenzoyl-2-deoxy-2-fluoro-[beta]-D-arabinofuranosyl)adenine. Further the obtained compound was purified from different solvents and provide pure ⁇ -anomer which was further converted into Clofarabine by treating it with sodium methoxide. This process also involves longer reaction times and provides the product with less purity.
  • the present inventors overcomes the major problems encountered in the prior-art by substituting the strong base like NaH with alkali metal carbonates during the condensation of 2-deoxy-2-fluoro-3,5-di-0-benz0yl-[alpha]-D-arabinofuranosyl bromide with 2,6- dichloropurine facilitates the completion of the reaction within 5-7 hrs with excellent yield and purity of the final product. Apart from this, the formation of a-anomer is reduced to minimum levels to provide highly pure required ⁇ -anomer in high yields which also enhances the purity and yield of final clofarabine. Advantages of the present invention:
  • the present invention provides highly pure Clofarabine with enhanced yields.
  • the first aspect of the present invention is to provide a process for the preparation of pure Clofarabine compound of formula- 1 , comprising of;
  • the second aspect of the present invention is to provide a process for the preparation of 2,6-dichloro-9-(3,5-di-0-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl)-9H-purine compound of formula-5, comprising of reacting the 2-deoxy-l-a-bromo-2- -fluoro-3,5-di-0- benzoyl-D-ribofuranose compound of formula-3 with 2,6-dichloropurine compound of formula-4 in presence of alkali metal carbonate in a suitable solvent to provide 2,6-dichloro- 9-(3,5-di-0-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl)-9H-purine compound of formula-5.
  • Figure-1 Illustrates the X-ray powder diffraction pattern of crystalline Clofarabine of the present invention.
  • Figure-2 Illustrates the Differential scanning calorimetric thermogram of crystalline Clofarabine of the present invention. Detailed description of the invention:
  • suitable solvent refers to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane, pet ether, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, di-tert-butyl ether, dimethoxy methane, 1 ,2-dimethoxyethane, diglyme, 1,4-dioxane, tetrahydrofuran, 2- methyl tetrahydrofuran and the like; "ester solvents” such as methyl acetate, ethyl acetate, n- propyl acetate, isopropyl
  • suitable base refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA) and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and “organic bases” selected from but not
  • the suitable brominating agent is selected from hydrobromic acid optionally in combination with acetic acid, bromine, N-bromosuccinimide (NBS), phosphorous tribromide and the like;
  • the suitable solvent is selected from chloro solvents; acetic acid, alcohol solvents, polar solvents, hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents, polar-aprotic solvents or their mixtures;
  • the suitable inorganic base is selected from alkali metal carbonates, alkali metal hydroxides, alkali metal bicarbonates and the like;
  • the suitable solvent is selected from nitrile solvents, polar-aprotic solvents, chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents or their mixtures;
  • the suitable solvent is selected from chloro solvents, acetic acid, alcohol solvents, polar solvents, hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents, polar-aprotic solvents or their mixtures;
  • the suitable base is selected from organic or inorganic base, preferably alkali metal alkoxides;
  • the suitable solvent is selected from chloro solvents, acetic acid, alcohol solvents, polar solvents, hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents, polar-aprotic solvents or their mixtures;
  • the suitable solvent is selected from alcohol solvents, preferably methanol.
  • a preferred embodiment of the present invention provides a process for the preparation of pure Clofarabine compound of formula- 1, comprising of;
  • the 2-deoxy-2-fluoro-l,2,5-tri-0-benzoyl-D-ribofuranose compound of formula-2 utilized in the present invention can be synthesized by any of the processes known in the art. For example it can be synthesized by the process described in J.Org.Chem, 1985, 50, 3644- 47.
  • the 2,6-dichloropurine can be obtained from any commercial sources or it can be synthesized by any of the processes known in the art such as described in WO2003048161 A 1 , Org. Proc. Res. Dev. , 2004, 8 (6), 962-963.
  • the second aspect of the present invention provides a process for the preparation of 2,6-dichloro-9-(3,5-di-0-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl)-9H-purine compound of formula-5, comprising of reacting the 2-deoxy-l-a-bromo-2-P-fluoro-3,5-di-0- benzoyl-D-ribofuranose compound of formula-3 with 2,6-dichloropurine compound of formula-4 in presence of a suitable inorganic base in a suitable solvent to provide 2,6- dichloro-9-(3,5-di-0-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl)-9H-purine compound of formula-5.
  • the suitable inorganic base is selected from alkali metal carbonates, alkali metal hydroxides, alkali metal bicarbonates and the like, preferably cesium carbonate;
  • the suitable solvent is selected from nitrile solvents, polar-aprotic solvents, chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents or their mixtures.
  • the reaction of 2-deoxy-l-a-bromo-2-P-fluoro-3,5-di-0-benzoyl-D-ribofuranose compound of formula-3 with 2,6-dichloropurine compound of formula-4 is preferably carried out in presence of alkali metal carbonates, more preferably cesium carbonate.
  • the usage of cesium carbonate during the above coupling step is more advantageous when compared to the prior-known bases for the said step.
  • the advantage lies in that, the usage of cesium carbonate reduces the formation of isomer impurity to minimal levels and also provides the product with excellent yields.
  • the inorganic base is used in an amount ranging from 0.7 to 2.5 mole ratio, preferably 0.8 to 2.2 mole ratio, more preferably 1.0 to 2.0 mole ratio per one mole of compound of formula-3.
  • reaction of 2-deoxy-l-a-bromo-2-p-fluoro-3,5-di-0- benzoyl-D-ribofuranose compound of formula-3 with 2,6-dichloropurine compound of formula-4 is carried out at a temperature of 20-35°C, preferably at a temperature of 25-30°C.
  • a preferred embodiment of the present invention provides a process for the preparation of 2,6-dichloro-9-(3,5-di-0-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl)-9H- purine compound of formula-5, comprising of reacting the 2-deoxy-l-a-bromo-2-P-fluoro- 3,5-di-O-benzoyl-D-ribofuranose compound of formula-3 with 2,6-dichloropurine compound of formula-4 in presence of cesium carbonate in acetonitrile to provide 2,6-dichloro-9-(3,5- di-0-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl)-9H-purine compound of formula-5.
  • Clofarabine obtained by the process of the present invention is having a purity of greater than 98%, preferably greater than 99%, more preferably greater than 99.5%, most preferably greater than 99.9% by HPLC
  • Clofarabine obtained by the process of the present invention is having a-anomer impurity less than 0.05% by HPLC, preferably less than 0.02% by HPLC.
  • Clofarabine obtained by the process of the present invention is having particle size distribution of D(0.9) less than 400 ⁇ , preferably less than 200 ⁇ , more preferably less than 100 ⁇ and most preferably less than 50 ⁇ and D(4,3) less than 200 ⁇ , preferably less than 100 ⁇ , more preferably less than 50 ⁇ and most preferably less than 25 ⁇ .
  • Clofarabine obtained according to the present invention can be used in the preparation of pharmaceutical composition.
  • Clofarabine compound of formula- 1 was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • DSC Differential scanning calorimetric
  • Clofarabine obtained by the process of the present invention was analyzed by HPLC under the following conditions;
  • a liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Akzonobel Kromasil 100-5C18 250x4.6 mm, 5 ⁇ or equivalent; Flow rate: 1.2 mL/minute; Wave length: 263 nm; Injection volume: 5 ⁇ ; Column temperature: 30°C; Run time: 50 minutes; Mobile phase-A: Transfer accurately I ml of orthophosphoric acid (85%) in 1000 ml of milli-Q-water, filter the solution through 0.22 ⁇ nylon membrane filter paper.
  • Mobile phase-B Acetonitrile: water (90:10 v/v); Diluent: Methanol; Elution: Gradient.
  • Clofarabine compound of formula- 1 of the present invention can be further micronized by using conventional techniques or milled 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 mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.
  • the present invention is schematically represented as follows.
  • Example-1 Preparation of 2-deoxy-l-a-bromo-2-p-fluoro-3,5-di-0-benzoyl-D- ribofuranose (Formula-3)
  • Dichloromethane was added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. Filtered the reaction mixture, water was added to the filtrate and stirred for 10 min. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol. To the obtained compound, methanol (385 ml) was added at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 90 min at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 90 min at the same temperature. Filtered the solid, washed with methanol and suck dried.
  • Example-3 Preparation of 6-amino-2-chloro-9-(2'-deoxy-2'-fluoro-3',5'-di-0-benzoyl- p-D-arabinofuranosyl)-9H-purine (Formula-6)
  • Clofarabine dibenzoate impurity Not detected; Chloro impurity: 0.01%.
  • D(0.1) is 46.0 ⁇
  • D(0.5) is 103.7 ⁇ ⁇ ;

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un procédé de préparation de clofarabine.
PCT/IN2015/000068 2014-02-04 2015-02-04 Procédé pour la préparation de clofarabine WO2015118558A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN518/CHE/2014 2014-02-04
IN518CH2014 IN2014CH00518A (fr) 2014-02-04 2015-02-04

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WO2015118558A3 WO2015118558A3 (fr) 2015-11-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105601688A (zh) * 2015-12-23 2016-05-25 国药一心制药有限公司 一种氯法拉滨中间体及氯法拉滨的制备方法
CN106397518A (zh) * 2016-10-18 2017-02-15 武汉百科药物开发有限公司 一种氯法拉滨的合成方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2400470C (fr) * 2000-02-18 2008-11-18 Southern Research Institute Procedes de synthese de 2-chloro-9-(2-deoxy-2-fluoro-.beta.-d-arabinofuranosyl)-9h-purine-6-amine
WO2003011877A2 (fr) * 2001-08-02 2003-02-13 Ilex Oncology Inc. Procede de preparation de nucleosides puriniques
CN101555267A (zh) * 2008-04-09 2009-10-14 杭州容立医药科技有限公司 一种核苷酸类似物克罗拉滨的合成方法
CN101265284B (zh) * 2008-05-07 2011-04-27 深圳万乐药业有限公司 氯法拉滨的合成方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105601688A (zh) * 2015-12-23 2016-05-25 国药一心制药有限公司 一种氯法拉滨中间体及氯法拉滨的制备方法
CN106397518A (zh) * 2016-10-18 2017-02-15 武汉百科药物开发有限公司 一种氯法拉滨的合成方法

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