WO2007017893A2 - Preparation d'une nouvelle forme cristalline de perindopril erbumine monohydrate - Google Patents

Preparation d'une nouvelle forme cristalline de perindopril erbumine monohydrate Download PDF

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Publication number
WO2007017893A2
WO2007017893A2 PCT/IN2006/000155 IN2006000155W WO2007017893A2 WO 2007017893 A2 WO2007017893 A2 WO 2007017893A2 IN 2006000155 W IN2006000155 W IN 2006000155W WO 2007017893 A2 WO2007017893 A2 WO 2007017893A2
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Prior art keywords
perindopril erbumine
crystalline form
monohydrate
formula
perindopril
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Ceased
Application number
PCT/IN2006/000155
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English (en)
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WO2007017893A3 (fr
WO2007017893B1 (fr
Inventor
Ashish Ujagare
D. A. Kochrekar
Pushpalata Sarjekar
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Arch Pharmalabs Ltd
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Arch Pharmalabs Ltd
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Publication of WO2007017893A2 publication Critical patent/WO2007017893A2/fr
Publication of WO2007017893A3 publication Critical patent/WO2007017893A3/fr
Publication of WO2007017893B1 publication Critical patent/WO2007017893B1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel crystalline form of Perindopril erbumine monohydrate of Formula (III). More particularly the present invention relates to a process for the preparation of the novel crystalline form of Perindopril erbumine monohydrate of Formula (III).
  • Perindopril is disclosed in US Patent 4508729. Preparative processes described in this US patent are carried out in alcoholic medium, and in the presence of neutral dehydrating agent and an organic or inorganic cyanoborohydride. Deprotection processes can be carried out where necessary, for example with reference to hydrolysis and/or hydrogenolysis.
  • US Patent 4914214 discloses the process for preparation of perindopril and its t-butylamine salt.
  • the process comprises condensation of protected ester of (2S, 3aS, 7aS)-2-carboxyperhydroindole with the (S, S) diastereoisomer of N- [(S)-I -carbethoxybutyl]-(S)-alanine, followed by deprotection employing charcoal containing 5% palladium and water, t-butylamine is then added to yield t-butyl amine salt of perindopril.
  • Perindopril erbumine and its pharmaceutically acceptable salts are active as angiotensin converting enzyme (ACE) inhibitors and thus are commercially valuable antihypertensive agents.
  • ACE angiotensin converting enzyme
  • Its pharmaceutically acceptable salts, especially t-butylamine / erbumine salt is represented by Formula (II).
  • Perindopril t-butylamine / erbumine monohydrate is represented by Formula (III).
  • Perindopril Erbumine Monohydrate Formula (III) GB2395195 discloses different XRD patterns of Perindopril erbumine monohydrate. It further teaches different methods for preparation of Perindopril erbumine monohydrate as follows: a. Perindopril erbumine is suspended in acetone to which a calculated amount of water is added. The contents are heated to dissolve the solid and cooled to 10 0 C. Solid is separated by filtration and then dried. b. Perindopril erbumine is suspended in ethyl acetate to which an appropriate quantity of water is added and the contents are heated to dissolve the solid and cooled to 10 0 C. Solid is separated by filtration and then dried. c.
  • Perindopril erbumine is suspended in acetonitrile to which known quantity of water is added and the contents are heated to dissolve and cooled. Solid is obtained by filtration and then dried. d. Perindopril erbumine is suspended in ethyl acetate. The contents are heated to dissolve and then cooled to 10 0 C. Solid is obtained by filtration and air dried.
  • WO2005068425 discloses the new crystalline form of Perindopril, Where purification of obtained crude perindopril is done by filtration through the column. Columns are prepared with silica gel and is eluted with methylene dichloride / ethanol (94/6 v/v). Amorphous Perindopril so obtained is then dissolved in ethyl ether and crystallized first at room temperature followed by cooling to get new crystalline form having the melting range of 110-114 0 C.
  • WO2005037788 discloses a process for preparation of crystalline perindopril erbumine.
  • the process comprises reacting a solution of perindopril in a solvent selected from N, N-dimethylformamide or dimethyl acetals of lower aliphatic aldehydes and ketones with tertiary butylamine and crystallization of the erbumine salt thus obtained by heating the reaction mixture to reflux, filtering hot, cooling gradually to 2O 0 C to 3O 0 C, and further cooling to O 0 C to 15 0 C for 30 minutes to 1 hour and finally filtering off and drying the crystals.
  • a solvent selected from N, N-dimethylformamide or dimethyl acetals of lower aliphatic aldehydes and ketones
  • the present invention has addressed the difficulties faced by the processes disclosed in prior art and have developed an excellent process for the purification of Perindopril erbumine monohydrate from (99%) pure material resulting into high purity (99.8%) and exhibiting characteristic 2 ⁇ values.
  • the object of the present invention is to provide a novel process for the preparation of a novel crystalline form of Perindopril erbumine monohydrate, which results in removal of undesirable impurities giving highly pure product.
  • Another object of the present invention is to provide a novel process for the purification of Perindopril erbumine which is of 99.8% purity.
  • Yet another object of the present invention is to provide a novel process for making Perindopril erbumine free from the described impurities.
  • novel polymorph of Perindopril erbumine monohydrate exhibits the characteristic 2 ⁇ as under: 8.87, 9.43, 9.60, 15.36, 15.96, 16.02, 19.97, 21.00, 21.13, 21.5, 22.14, 24.13 and 26.48. *
  • the novel process for preparing a novel crystalline form of Perindopril erbumine monohydrate is advantageous in terms of better removal of undesirable impurities and has a better solubility profile so as to achieve a highly pure product with characteristic 2 ⁇ values.
  • Perindopril erbumine monohydrate was measured under the following experimental conditions: where instrument used was analytical "X" pertpro, MPD system/multipurpose diffractometer, Holland. MPD system/multipurpose diffractometer, Holland. Measurement Temperature was 25 0 C, Anode material used was Cu and Generator setting was 3OmA 1 40 kV. The Measurement range of (°2 ⁇ ) was 4 to 49.98°, and Step size (°2 ⁇ ) was 0.0170, the PSD mode was scanning and scan type is continuous.
  • the present invention as disclosed herein relates to a novel and improved process for preparing a novel crystalline form of Perindopril erbumine monohydrate of Formula(lll) and to make the process disclosed in prior art free from impurities as well as cost effective.
  • Perindopril erbumine obtained by process disclosed in prior art remains associated with pharmacopoeial (EP-5) specified impurities viz. B, D and F shown by the structures given below and some unknown non-polar impurities.
  • EP-5 pharmacopoeial
  • impurities associated with Perindopril erbumine have different nature towards water.
  • impurity B is highly water soluble while impurity F is insoluble in water.
  • Perindopril Erbumine is prepared as per the process disclosed in the prior art. The process is reproduced as follows:
  • (2S, 3aS, 7aS)-Octahydroindole-2-benzyloxycarbonyl tosylate an important intermediate required for the purpose is made by reacting octahydrohydro indole-2-carboxylic acid, para toluene sulphonic acid and benzyl alcohol using aromatic hydrocarbon as solvent, wherein preferred solvent is selected from toluene, xylene and most preferred solvent used is toluene followed by heating the contents at 85-125°C preferably at 100- 118°C. Reflux is continued till water is completely removed.
  • Reaction mass is cooled to -5 to 15°C preferably at 0-5 0 C followed by addition of hexane and cooling is continued for 3-5 hours preferably 2-3 hours.
  • Product is collected by filtration and is vacuum dried at 35-65 0 C preferably at 40-45 0 C. Crude so obtained is purified using isopropanol resulting into purity of (NLT 98%) with yield of 85-95% with respect to octahydro indole- 2-carboxylic acid.
  • Solvent is removed under the reduced pressure followed by stripping of toluene and also with cyclohexane to remove the excess of thionyl chloride followed by addition of water. Aqueous layer is separated and reacted with sodium pyruvate in acidic condition. Contents so obtained are subjected for hydrogenation using 5%Pd/C at 25-50°C preferably at 35-40 0 C for 3-7 hours preferably 5-6 hours preferably after the reaction mixture is charcoalised to avoid the poisoning of catalyst due to the inorganic impurities coming from thionyl chloride. After completion of hydrogenation, catalyst is filtered off and sent for the recovery. Water is removed from the contents under the reduced pressure & crude so obtained is finally purified by using acetonitrile resulting into 98% purity.
  • Product so obtained remains associated with water in the range 7-9% thus providing monohydrate of the product.
  • (2a, 3aS, L 7aS)-1 -[N-[I (S)-carboethoxybutyl]-alanyl]-2-[benzyloxy) carbonyl-octahydro indole is obtained by the procedure which comprises of condensation of N-[(S)-1-carboethoxybutyI]-(S)-alanine (98%) and (2S, 3aS, 7aS)-octahydroindole-2-benzyloxycarbonyl tosylate (98%) using 1- hydroxybenzotriazole, dicyclhexylcarbodiimide, triethylamine and ethyl acetate as solvent.
  • Perindopril erbumine i.e. (2S,3aS,7aS)-1-[N-[1(s)-carboethoxybutyl]- alanyl]-octahydro indole]-2-carboxylic acid tertiary butylamine salt of (98%) purity is obtained by process comprising of debenzylation of (2S,3aS,7aS)-1-[N-[1(s)-carboethoxybutyl]-alanyl-2[(benzyloxy)carbonyl octahydro indole] using Pd/C as catalyst and ethanol as solvent at 5-30 0 C preferably 10-20 0 C for 1-4 hours preferably 1.5-2.5 hours.
  • Reaction mass is then taken for the recovery of solvent under reduced pressure keeping temperature is the range of 15-35°C preferably 20-30°C more preferably at 25-28 0 C is resulting into Perindopril base which is then converted lnsitu into Perindopril erbumine of 98% purity by adding tert. butyl amine in to it using ethylacetate as solvent. Salt thus obtained is further purified from ethyl acetate to get purity of 99%.
  • Perindopril erbumine monohydrate of high purity and exhibiting novel crystalline form of Perindopril erbumine is prepared by dissolving Perindopril erbumine obtained by process described above having ⁇ 99% purity in water. Aqueous layer containing product is then taken for recovery of water till water content reaches to 10-20% in the reaction mass which is further reduced using polar solvent like water soluble ketone , where most preferred solvent is acetone as co-solvent keeping the temperature at 25-55°C preferably at 35-45°C, till the water content reaches to 5-7% preferably of 5.0%.
  • Solid thus obtained is slurried in acetone, cooled at 2-20 0 C preferably at 5 to 15° C and then filtered off. Solid is then dried at a temperature 25-75°C preferably at 45 to 50°C more preferably 30-35 0 C under vacuum till constant weight is achieved. Moisture content (NMT 4%), HPLC purity ( ⁇ 99.8%) Differential scanning calorimetry (167-170°C).
  • the novel polymorph of perindopril erbumine monohydrate thus obtained exhibits characteristic XRD pattern as under: 8.87, 9.43, 9.60, 15.36, 15.96, 16.02, 19.97, 21.00, 21.13, 21.5, 22.14, 24.13, 26.48.
  • the most preferred volatile solvent according to present invention is acetone.
  • a novel process for purification of Perindoprl erbumine of the present invention resulted in HPLC purity of about ⁇ 99%.
  • a novel crystalline form of Perindopril erbumine monohydrate as obtained by the purification of the present invention is highly pure with HPLC purity of -99.8%.
  • Example 2 lnsitu preparation of N-[(S)-1-carboethoxybutyl]-(S)-alanine with high purity: To the mixture of Alcohol (20It) and L-Norvaline (1.5 kg, 12.8mol) presaturated with hydrogen chloride, thionyl chloride (1.1 L 1 15.15mol) is charged slowly keeping the temperature in the range of 15-2O 0 C. Contents are then heated to reflux at 65-70 0 C for 3-6 hours. Ethyl alcohol is completely evaporated, reaction mass is then added with fresh toluene (2X1.5It) and removed under reduced pressure to remove the excess of thionyl chloride.
  • Example A Perindopril erbumine (150 g) of 99% purity as obtained in the above example is dissolved in DM water (0.450L) which was then extracted with (0.023 L) of toluene. Aqueous layer was collected and water was removed from the contents under the reduced pressure till water content reaches to 10-20% in the reaction mass which is further reduced using acetone as co-solvent keeping the temperature in the range of 20-45 0 C preferably at 25-3O 0 C, till the moisture content is reached to the required (5-7%). Finally product so obtained was slurried in acetone (0.75L) and contents were cooled to 5-15 0 C and filtered off. Product was dried under vacuum at 25-35°C till required water content was reached.
  • Perindopril erbumine (6.75kg) of 99% purity was dissolved in DM water (16.9L) which was then extracted with (0.68L) toluene. Aqueous layer was separated and aqueous layer was collected and water was removed from the contents under reduced pressure till water content reaches to 10-20% in the reaction mass which is further reduced using acetone as co-solvent in the range of 20-45 0 C preferably at 25-30 0 C, till the moisture content reached to the required (5-7%). Finally product so obtained was slurried in acetone (0.75L) and contents were cooled to 5-15°C and filtered off. Product was dried under vacuum at 25- 35°C till required water content was reached.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme cristalline de périndopril erbumine monohydrate de la formule (III) possédant les valeurs 2? caractéristiques 8.87, 9.43, 9.60, 15.36, 15.96, 16.02, 19.97, 21.00, 21.13, 21.5, 22.14, 24.13, et 26.48. L'invention porte, en particulier, sur un procédé de préparation de la nouvelle forme cristalline de périndopril erbumine monohydrate de la formule (III).
PCT/IN2006/000155 2005-05-05 2006-05-04 Preparation d'une nouvelle forme cristalline de perindopril erbumine monohydrate Ceased WO2007017893A2 (fr)

Applications Claiming Priority (2)

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IN562MU2005 2005-05-05
IN562/MUM/2005 2005-05-05

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WO2007017893A2 true WO2007017893A2 (fr) 2007-02-15
WO2007017893A3 WO2007017893A3 (fr) 2007-05-10
WO2007017893B1 WO2007017893B1 (fr) 2007-06-21

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009000909A3 (fr) * 2007-06-27 2010-03-18 Krka, Tovarna Zdravil D.D. Novo Mesto Sels de périndopril
WO2008120241A3 (fr) * 2007-03-29 2010-11-11 Ipca Laboratories Limited Nouveaux solvates alcooliques de périndopril erbumine
WO2012044189A1 (fr) 2010-09-29 2012-04-05 Instituto Superior Técnico Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2395195A (en) * 2002-11-18 2004-05-19 Cipla Ltd Preparation of perindopril from carboxy-protected precursor, & perindopril monohydrates for use as angiotensin converting enzyme (ACE) inhibitors
CA2530550C (fr) * 2003-06-24 2017-04-04 Christoph Straessler Nouvelles formes cristallines de perindopril erbumine
AU2003263584A1 (en) * 2003-08-21 2005-03-10 Hetero Drugs Limited Process for pure perindopril tert-butylamine salt
SI21881A (sl) * 2004-10-15 2006-04-30 Diagen, Smartno Pri Ljubljani, D.O.O. Nove kristalne oblike perindopril erbumin hidratov, postopek za njihovo pripravo in farmacevtske oblike, ki vsebujejo te spojine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008120241A3 (fr) * 2007-03-29 2010-11-11 Ipca Laboratories Limited Nouveaux solvates alcooliques de périndopril erbumine
WO2009000909A3 (fr) * 2007-06-27 2010-03-18 Krka, Tovarna Zdravil D.D. Novo Mesto Sels de périndopril
EA017835B1 (ru) * 2007-06-27 2013-03-29 Крка, Товарна Здравил, Д.Д., Ново Место Кальциевая соль периндоприла, фармацевтическая композиция, содержащая указанную соль, и способ получения такой композиции
US8470869B2 (en) 2007-06-27 2013-06-25 Krka, Tovarna Zdravil D.D. Novo Mesto Salts of perindopril
WO2012044189A1 (fr) 2010-09-29 2012-04-05 Instituto Superior Técnico Forme cristalline hydratée inédite de l'erbumine de périndopril, ses procédés de préparation et son utilisation dans des préparations pharmaceutiques

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WO2007017893A3 (fr) 2007-05-10
WO2007017893B1 (fr) 2007-06-21

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