EP2820028A1 - Procédé de préparation de citicoline pure (cdp-choline) - Google Patents

Procédé de préparation de citicoline pure (cdp-choline)

Info

Publication number
EP2820028A1
EP2820028A1 EP13755755.9A EP13755755A EP2820028A1 EP 2820028 A1 EP2820028 A1 EP 2820028A1 EP 13755755 A EP13755755 A EP 13755755A EP 2820028 A1 EP2820028 A1 EP 2820028A1
Authority
EP
European Patent Office
Prior art keywords
citicoline
acid
choline
dicarboxylic acid
salts
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.)
Withdrawn
Application number
EP13755755.9A
Other languages
German (de)
English (en)
Other versions
EP2820028A4 (fr
Inventor
Rajiv Kumar
Yogendra CHAUHAN
Vilas DHAKE
Vijay Tambe
Atul WAGH
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.)
Frichem Private Ltd
Original Assignee
Frichem Private 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 Frichem Private Ltd filed Critical Frichem Private Ltd
Publication of EP2820028A1 publication Critical patent/EP2820028A1/fr
Publication of EP2820028A4 publication Critical patent/EP2820028A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the present invention relates to industrially feasible and economical process for preparing highly pure Citicoline (CDP-Choline) or sodium salt of Citicoline with the aid of dicarboxylic acid or its salts.
  • CDP-Choline naturally occurring nucleotide, is a neuroprotective indicated for the treatment of ischemic stroke and head trauma in patients.
  • Cicoline (CDP-Choline) is represented by formula (I).
  • US patent no. 3,666,748 discloses a process for preparing Citicoline sodium by reaction of 4- morpholino-N,N'-dicyclohexylcarboxamidine chloride salt of choline phosphormorpholidate (I) with cytidine-5-monophosphate in free form or its salts with base in a solvent such as o- chlorophenol, m-cresol, acetonitrile, pyridine and the like.
  • the Citicoline thus obtained is purified through a column chromatograph packed with activated carbon followed by elution to get ammonium salt of citicoline, which is further converted to citicoline followed by citicoline sodium.
  • US patent no. 3,787,392 discloses a process for preparing Citicoline by adding the acidic calcium phosporyl choline chloride tetra hydrate to the solution of morpholidiate cytidine 5- monophosphate and DCC in methanol followed by isolation and purification by means of chromatography column containing anion exchanger (Dowex 1x2 type formate form; 50-100 mesh) which is further converted to its sodium salt by neutralizing with sodium hydroxide. Further, US patent no.
  • 3,803,125 discloses a process for preparing citicoline by reacting morpholidiate cytidine 5 '-monophosphate with calcium phosporyl choline chloride tetra hydrate in solvent system of an aliphatic alcohol or dialkyl ketone or dimethyl formamide at pH from 1 to 6.5.
  • the product thus obtained is further isolated; purified by means of chromatography column containing anion exchanger; concentrated; and neutralized with aqueous solution of sodium hydroxide to get citicoline sodium.
  • the present invention provides a process for preparation of Citicoline sodium, which does not suffer from the above-mentioned disadvantages and provides desired compound with high yield and quality, in a short period of time, without formation of substantial amounts of disconcerting by-products.
  • One more object of the invention is to provide industrially feasible process to attain highly pure sodium salt of Citicoline (CDP-Choline) with minimum impurities where the purity attained is > 99%, measured by HPLC.
  • the present invention provides a process of removing the soluble impurities by means of dicarboxylic acid or its salt, during the preparation of sodium salt of Citicoline (CDP-Choline).
  • the invention provides a process for preparing Citicoline (CDP-Choline), wherein the process comprises reacting a cytidine S'-monophospahte or its amide salts with calcium phosphoryl choline chloride tetra hydrate or its amide salts in presence of dicyclohexyl carbodiimide (DCC) and a solvent, wherein a dicarboxylic acid or its salt is employed in the process to obtain citicoline with a purity of more than 99% measured by HPLC.
  • DCC dicyclohexyl carbodiimide
  • the process of the present invention further provides a process for preparing highly pure sodium salt of citicoline by reacting the pure citicoline obtained by the process of this invention with aqueous solution of sodium hydroxide.
  • the dicarboxylic acid used in the present invention is either in the form of free acid or its base salts.
  • the dicarboxylic acid is selected from the group consisting of oxalic acid, malonic acid, succininc acid, glutaric acid.
  • the base of dicarboxylic acid is selected from the group consisting of organic bases such as amidates, amines or inorganic base such as alkali or alkaline earth metal.
  • the solvent for carrying out the process is selected from the group consisting of aliphatic alcohols from C1-4 atoms, ketones such as acetone, methyl isobutyl ketone and the like or mixture thereof.
  • the solvent employed in the process is methanol.
  • the dicarboxylic acid or its salts lessen the solubility of inorganic impurities such as calcium chloride, calcium hydroxide, unreacted choline phosphate, 5- CMP. This results in obtaining higly pure Citicoline or sodium salt of Citicoline without employing column chromatography.
  • a process that employs dicarboxylic acid or its salts for lessening soluble inorganic impurities like calcium chloride, calcium hydroxide as well as unreacted choline phosphate, 5-CMP etc., during the process for preparing Citicoline or sodium salt of Citicoline, having HPLC purity > 99%.
  • CDP-Choline a process for preparing Citicoline (CDP-Choline) where the process comprises condensing cytidine 5'- monophospahte or its amidate salts with calcium phosphoryl choline chloride tetra hydrate or its amidate salts in presence of dicyclohexyl carbodiimide (DCC).
  • DCC dicyclohexyl carbodiimide
  • the reaction of cytidine 5 '-monophospahte or its amidate salt with calcium phosphoryl choline chloride or its amidate salt is generally carried out in a solvent selected from the group consisting of but not limited to aliphatic alcohols from Ci_4-atoms; ketone such as acetone, methyl isobutyl ketone and the like or mixture thereof; preferably methanol.
  • the reaction temperature generally ranges from 60°C to the reflux of the solvent employed.
  • dicarboxyhc acid is exercised either in the form of free acid or its base salts, provided that dicarboxyhc acid or its salts are employed at different juncture during the Citicoline (CDP-Chloine) synthesis.
  • Dicarboxyhc acid may include oxalic acid, malonic acid, succinic acid, glutaric acid and the like.
  • the base used herein for preparing the dicarboxyhc acid salt is selected from the group consisting of but not limited to organic bases such as amidates, amines; or inorganic base such as alkali or alkaline earth metal.
  • Amidates used herein may be used as mono and dialkyl-substituted amidates, the alkyl radicals of Ci_ 4 atoms, such as dimethylamidate, mono and diethyl-amidate, mono and dipropyl amidate, isopropyl-amidates and butyl-amidates, as well as the mixed amidates.
  • the alkyl radicals which are joined together directly or via a heteroatom to form a ring, for example, the morpholidates, piperidates, cyclohexylimidates and anilidates may also be used.
  • Amines including triethylamine, diisopropyl amine, etc. may also be used herein.
  • dicarboxyhc acid or its base salt is dependent on the starting material taken for the Citicoline preparation.
  • Dicarboxyhc acid is used herein at the start of the reaction, when cytidine 5 '-monophospahte is reacted with phosphoryl choline chloride amidates.
  • dicarboxyhc acid or its base salt is exercised with calcium phosphoryl choline chloride first to get the phosphoryl chlorine chloride, which is then converted to its amidates salt by reacting it with amidanes.
  • dicarboxyhc acid or its amidates contribute an important role in preparation of highly pure Citicoline having purity > 99% without the use of column chromatography.
  • the dicarboxyhc acid or its salts employed in the process convert the soluble impurities, generated during the reaction, into insoluble impurities, and the desired product with diminished amounts of impurities remains soluble in the solvent of reaction. Thereby insoluble impurities can be removed by a simple method of filtration, instead of non- feasible, prolonged column chromatography.
  • the citicoline produced by the process of this invention is easily recovered by known methods.
  • the resulting reaction mixture is extracted with a solvent, and the solvent extract is distilled out to obtain crude citicoline.
  • the solution of citicoline in water is purified by means of charcoal treatment and then concentrated to dryness to recover the objective compound with the purity of > 99%.
  • citicoline is treated with sodium hydroxide to get citicoline sodium with purity of > 99% measured by HPLC.
  • the reaction mass was cooled and filtered to get crude Citicoline by adding IPA. Further, morpholidiate salt of oxalic acid (138.3 gm) was added to the solution of crude citicoline in methanol at 30-35°C followed by the addition of IPA to get the precipitated Citicoline, which is further treated with activated charcoal in water followed by filtration. To filtrate containing purified Citicoline, aqueous solution of sodium hydroxide was added at room temperature followed by addition of ethanol and the temperature of reaction mass was raised to 50-55°C. The precipitated product was filtered and dried where the purity of citicoline sodium is > 99% measured by HPLC. (265 gm).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de Citicoline (CDP‑Choline) à pureté élevée ou d'un sel de sodium de Citicoline à l'aide d'un acide dicarboxylique ou de ses sels. Le procédé de la présente invention conduit à une Citicoline ayant une pureté supérieure à 99 % mesurée par HPLC.
EP13755755.9A 2012-02-28 2013-02-28 Procédé de préparation de citicoline pure (cdp-choline) Withdrawn EP2820028A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN540MU2012 2012-02-28
PCT/IB2013/051585 WO2013128393A1 (fr) 2012-02-28 2013-02-28 Procédé de préparation de citicoline pure (cdp-choline)

Publications (2)

Publication Number Publication Date
EP2820028A1 true EP2820028A1 (fr) 2015-01-07
EP2820028A4 EP2820028A4 (fr) 2015-08-26

Family

ID=49081721

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13755755.9A Withdrawn EP2820028A4 (fr) 2012-02-28 2013-02-28 Procédé de préparation de citicoline pure (cdp-choline)

Country Status (2)

Country Link
EP (1) EP2820028A4 (fr)
WO (1) WO2013128393A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104031105B (zh) * 2014-06-06 2015-07-15 回音必集团(江西)东亚制药有限公司 一种胞磷胆碱钠的制备方法
CN105732752A (zh) * 2016-03-18 2016-07-06 新乡学院 一种胞二磷胆碱及其合成方法
CN106146590A (zh) * 2016-06-29 2016-11-23 陈建峰 一种胞磷胆碱钠的制备方法
CN110684066B (zh) * 2019-05-22 2020-12-08 广东金城金素制药有限公司 胞二磷胆碱药物制剂及其脑梗塞急性期意识障碍的新用途
CN113563377A (zh) * 2021-07-15 2021-10-29 浙江蓝波新材料科技有限公司 一种新型磷酰胆碱合成工艺技术方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3666748A (en) * 1967-12-18 1972-05-30 Takeda Chemical Industries Ltd Method for production of cytidine (or deoxycytidine)-5{40 -diphosphate choline and intermediates therefor
DE2059429C2 (de) * 1970-12-02 1986-10-23 Boehringer Mannheim Gmbh, 6800 Mannheim Verfahren zur Herstellung von Nucleosiddiphosphatestern
CN102010454B (zh) * 2010-12-02 2012-03-07 胡建荣 一种胞磷胆碱钠化合物及其新方法

Also Published As

Publication number Publication date
EP2820028A4 (fr) 2015-08-26
WO2013128393A1 (fr) 2013-09-06

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