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 PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- piperazine
- hydroxypropyl
- ranolazine
- water
- methoxyphenoxy
- Prior art date
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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
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 |
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WO2006008753A1 true WO2006008753A1 (fr) | 2006-01-26 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2004/000215 WO2006008753A1 (fr) | 2004-07-19 | 2004-07-19 | Forme cristalline et amorphe de ranolazine et son processus de fabrication |
Country Status (1)
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WO (1) | WO2006008753A1 (fr) |
Cited By (9)
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)
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 |
-
2004
- 2004-07-19 WO PCT/IN2004/000215 patent/WO2006008753A1/fr active Application Filing
Patent Citations (2)
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)
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)
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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