WO2006008753A1 - Forme cristalline et amorphe de ranolazine et son processus de fabrication - Google Patents

Forme cristalline et amorphe de ranolazine et son processus de fabrication Download PDF

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Publication number
WO2006008753A1
WO2006008753A1 PCT/IN2004/000215 IN2004000215W WO2006008753A1 WO 2006008753 A1 WO2006008753 A1 WO 2006008753A1 IN 2004000215 W IN2004000215 W IN 2004000215W WO 2006008753 A1 WO2006008753 A1 WO 2006008753A1
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WO
WIPO (PCT)
Prior art keywords
piperazine
hydroxypropyl
ranolazine
water
methoxyphenoxy
Prior art date
Application number
PCT/IN2004/000215
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English (en)
Inventor
Pandurang Balwant Deshpande
Ajay Dayaji Chauhan
Original Assignee
Unichem Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Unichem Laboratories Limited filed Critical Unichem Laboratories Limited
Priority to PCT/IN2004/000215 priority Critical patent/WO2006008753A1/fr
Publication of WO2006008753A1 publication Critical patent/WO2006008753A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to crystalline polymorph of ( ⁇ )-l-[3-(2- Metlioxyphenoxy)-2-hydroxypropyl]-4-psr-(2 > 6-diirietliylphenyl)carbamoyl methyl] piperazine dihydrochloride and its base (Ranolazine base) and new amorphous (+)- 1 - [3 -(2-Methoxyphenoxy)-2-hydroxypropyl] -4- [N-(2 ,6- dimethylphenyl) carbamoyl methyl] piperazine dmydrochloride (Ranolazine dihydrochloride) and process for the preparation there of.
  • Ranolazine dihydrochloride ( Formula-I) is a novel anti-anginal agent which has been reported to protect against biochemical electrophysiological and mermodynamic consequences of transient myocardial ischmia in the pentobarbitone-anesthetized dog,
  • US Patent 4567264 describes the preparation of Ranolazine base from basic stages by condensing [(2,6-dimethyphenyl) amino; carbonyl methyl] - chloride (II) with l-[3-(2-metlioxyphenoxy)-2- hydroxypropyl]piperazine.(III)
  • the base was purified by column chromatography and isolated as oil.
  • the hydrochloride salt was prepared in methanol using hydrochloric acid and the salt was isolated by addition of ether.
  • EP 0483932 describes the preparation of Ranolazine base by condensation of ⁇ -[ N 3 N -bis (2-cWoroetiiyl)-amino]-2,6-dimetliylacetanilide hydrochloride (IV) with l-[3-(2-methoxy phenoxy)-2-hydroxy]-propylamine (V).
  • the base was purified using column chromatography and hydrochloride was formed by treating with metholic hydrochloric acid and crystallized by addition of diethyl ether as co solvent to obtain a product with melting point 229- 230 0 C.
  • the main object of invention is to provide an industrially feasible process for preparation of (+)-l-[3-(2-Metlioxyphenoxy)-2-hydroxypropyl]-4-[N- (2,6-dimethylphenyl)carbamoyl methyl] piperazine base and dihydrochloride as a solid without the use of column chromatographic methods.
  • It is yet another object of the invention is to provide process for preparation and characterization of crystalline form of (+)-l-[3-(2-Methoxyphenoxy)-2- liydroxypropyl]-4-[N-(2,6-dimetliylphenyl)carbamoyl methyl] piperazine base.
  • It is another object of the invention is to provide a process for preparation of Ranolazine base from its hydrochloride salt.
  • the crystalline form-A of (+)-l-[3-(2- Memoxyphenoxy)-24iydroxypropyl]-4-[N-(2 5 6-dimemylphenyl)carbainoyl methyl] piperazine dihydrochloride is prepared by dissolving Ranolazine base in organic solvent and reacting it with hydrochloric acid in water or water miscible solvent, followed by dissolution of the crude (+)-l-[3-(2- Memoxyphenoxy)-24iydroxypropyl]-4-[N-(2,6-dimetliylphenyl)carbainoyl methyl] piperazine dihydrochloride in alcoholic solvent at reflux and crystallizing the product by slow cooling to room temperature.
  • the amorphous form of (+)-l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]-4- [N-(2,6-dimetliylphenyl)carbamoyl methyl] piperazine dihydrochlofide is obtained by dissolving Ranolazine dihydrochloride in water and drying it under vacuum.
  • the amorphous fo ⁇ n is also obtained by dissolving the crystalline product in large excess of a mixture of water and water miscible solvent (in the ratio of 5 to 95 & 95 to 5 v/v) more preferably in aqueous ethanol and evaporation under vacuum.
  • the process for preparing (+)-l-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]- 4-pS[-(2,6-dimethylphenyl)carbamoyl metliyl] piperazine dihydrochloride of present invention comprises the steps, . :
  • the organic layer is extracted with dilute hydrochloric acid, the layers are separated and the aqueous layer containing the product as hydrochloride is degassed followed by neutralization with a mixture of ammonia and water miscible solvents to obtain Ranolazine base which is filtered and dried under vacuum .
  • the Ranolazine base is also obtained by neutralizing the dihydrochloride salt in aqueous ammonia or in a mixture j of aqueous ammonia arid water miscible solvent. ; !
  • the Ranolazine dihydrochloride obtained in previous step (d) is dissolved in methanol at above 50 C and cooled to 10 C to isolate a solid product which on drying at 60-100 C with or with out vacuum yields crystalline Form-A of ( ⁇ )-l-[3-(2-Metlioxyphenoxy)-2-hydroxypropyl]-4-[N-(2,6- dimethyl ⁇ henyl)carbamoyl methyl] piperazine dihydrochloride containing 2- 4 % water as characterized by XRD as shown in Figure- 1 & DSC in Figure-II with characteristic endotlierm at around 225-226 0 C
  • step (d) The Ranolazine dihydrochloride obtained in step (d) is dissolved in aqueous ethanol above 50 0 C followed by evaporation of solvent under vacuum to obtain the amorphous form of ( ⁇ )-l-[3-(2-Methoxyphenoxy)-2- hydroxypropyl]-4-[N-(2,6-dimethylphenyl)carbamoyl methyl] piperazine
  • the invention also gives an alternate process for the preparation of (+)-l-[3 ⁇ (2-Methoxyphenoxy)-2-hydroxypropyl]-4-pS[-(2,6-drmethylphenyl) - carbamoyl methyl] piperazine base form its diliydrocliloride by neutralizing the diliydrochloride salt using a mixture of aqueous ammonia & water miscible solvent at 20-60 0 C .
  • the crystalline and amorphous Ranolazine di ⁇ liydrocliloride exhibit a broad endotherm below 100 0 C in DSC.
  • Example-1
  • the above Ranolazine base is taken in 2160 j ml j acetone and 100 hydrochloric acid gas dissolved in isopropyl alcohol is added at room temperature till pH is acidic.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un processus de préparation d'une nouvelle forme cristalline et amorphe de dichlorhydrate de piperazine (±)-1-[3-(2-méthoxyphénoxy)-2-hydroxypropyl]-4-[N-(2,6-diméthylphényl)carbamoylméthyl] et une forme cristalline de base de Ranolazine, ladite forme présentant la formule (I). Cette invention a également pour objet un médicament utilisé en tant qu'agent antiangineux.
PCT/IN2004/000215 2004-07-19 2004-07-19 Forme cristalline et amorphe de ranolazine et son processus de fabrication WO2006008753A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000215 WO2006008753A1 (fr) 2004-07-19 2004-07-19 Forme cristalline et amorphe de ranolazine et son processus de fabrication

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000215 WO2006008753A1 (fr) 2004-07-19 2004-07-19 Forme cristalline et amorphe de ranolazine et son processus de fabrication

Publications (1)

Publication Number Publication Date
WO2006008753A1 true WO2006008753A1 (fr) 2006-01-26

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047388A2 (fr) * 2006-10-20 2008-04-24 Ind-Swift Laboratories Limited Procédé amélioré de préparation de ranolazine
WO2008139492A2 (fr) * 2007-05-15 2008-11-20 Natco Pharma Limited Procédé de préparation de base de ranolazine de haute pureté
WO2008157240A1 (fr) * 2007-06-13 2008-12-24 Auspex Pharmaceuticals, Inc. Pipérazines substituées
WO2009153651A1 (fr) * 2008-06-19 2009-12-23 Medichem, S.A. Procédé de préparation d’un dérivé de pipérazine
WO2010029436A2 (fr) * 2008-09-09 2010-03-18 Actavis Group Ptc Ehf Nouvelles formes solides de sels de ranolazine
WO2010043976A2 (fr) * 2008-10-15 2010-04-22 Actavis Group Ptc Ehf Ranolazine très pure ou sel de celle-ci de qualité pharmaceutique acceptable
WO2010097805A1 (fr) * 2009-02-24 2010-09-02 Lupin Limited Procédé pour la préparation de ranolazine
EP2328873A2 (fr) * 2008-08-28 2011-06-08 Dr. Reddy's Laboratories Ltd. Préparation de ranolazine
WO2011160396A1 (fr) 2010-06-25 2011-12-29 上海冠杰生物医药科技有限公司 Procédé pour la préparation de ranolazine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4567264A (en) * 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
EP0483932A1 (fr) * 1990-10-31 1992-05-06 Richter Gedeon Vegyeszeti Gyar R.T. Procédé pour la préparation de dérivés de la pipérazine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4567264A (en) * 1983-05-18 1986-01-28 Syntex (U.S.A.) Inc. Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
EP0483932A1 (fr) * 1990-10-31 1992-05-06 Richter Gedeon Vegyeszeti Gyar R.T. Procédé pour la préparation de dérivés de la pipérazine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WANG, LI-SHENG ET AL: "Synthesis of anti-angina drug ranolazine", XP002327205, retrieved from STN Database accession no. 2004:185653 *
GUANGXI DAXUE XUEBAO, ZIRAN KEXUEBAN , 28(4), 301-303 CODEN: GDXZEB; ISSN: 1001-7445, 2003 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047388A3 (fr) * 2006-10-20 2009-10-15 Ind-Swift Laboratories Limited Procédé amélioré de préparation de ranolazine
WO2008047388A2 (fr) * 2006-10-20 2008-04-24 Ind-Swift Laboratories Limited Procédé amélioré de préparation de ranolazine
WO2008139492A2 (fr) * 2007-05-15 2008-11-20 Natco Pharma Limited Procédé de préparation de base de ranolazine de haute pureté
WO2008139492A3 (fr) * 2007-05-15 2009-03-12 Natco Pharma Ltd Procédé de préparation de base de ranolazine de haute pureté
WO2008157240A1 (fr) * 2007-06-13 2008-12-24 Auspex Pharmaceuticals, Inc. Pipérazines substituées
WO2009153651A1 (fr) * 2008-06-19 2009-12-23 Medichem, S.A. Procédé de préparation d’un dérivé de pipérazine
EP2328873A2 (fr) * 2008-08-28 2011-06-08 Dr. Reddy's Laboratories Ltd. Préparation de ranolazine
EP2328873A4 (fr) * 2008-08-28 2011-09-07 Reddys Lab Ltd Dr Préparation de ranolazine
WO2010029436A2 (fr) * 2008-09-09 2010-03-18 Actavis Group Ptc Ehf Nouvelles formes solides de sels de ranolazine
WO2010029436A3 (fr) * 2008-09-09 2011-05-05 Actavis Group Ptc Ehf Nouvelles formes solides de sels de ranolazine
WO2010043976A3 (fr) * 2008-10-15 2010-06-10 Actavis Group Ptc Ehf Ranolazine très pure ou sel de celle-ci de qualité pharmaceutique acceptable
WO2010043976A2 (fr) * 2008-10-15 2010-04-22 Actavis Group Ptc Ehf Ranolazine très pure ou sel de celle-ci de qualité pharmaceutique acceptable
WO2010097805A1 (fr) * 2009-02-24 2010-09-02 Lupin Limited Procédé pour la préparation de ranolazine
WO2011160396A1 (fr) 2010-06-25 2011-12-29 上海冠杰生物医药科技有限公司 Procédé pour la préparation de ranolazine

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