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WO2008035360A2 - Nouvelles formes cristallines - Google Patents

Nouvelles formes cristallines Download PDF

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Publication number
WO2008035360A2
WO2008035360A2 PCT/IN2007/000236 IN2007000236W WO2008035360A2 WO 2008035360 A2 WO2008035360 A2 WO 2008035360A2 IN 2007000236 W IN2007000236 W IN 2007000236W WO 2008035360 A2 WO2008035360 A2 WO 2008035360A2
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WO
WIPO (PCT)
Prior art keywords
candesartan
methyl
novel crystalline
tritylated
candesartan cilexetil
Prior art date
Application number
PCT/IN2007/000236
Other languages
English (en)
Other versions
WO2008035360A3 (fr
Inventor
Pandurang Balwant Deshpande
Parven Kumar Luthra
Dhiraj Mohansinh Rathod
Lalitkumar Keshavlal Katariya
Himanshu Manojkumar Mehta
Original Assignee
Alembic 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 Alembic Limited filed Critical Alembic Limited
Publication of WO2008035360A2 publication Critical patent/WO2008035360A2/fr
Publication of WO2008035360A3 publication Critical patent/WO2008035360A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to novel crystalline forms of Candesartan cilexetil and intermediate thereof. Particularly, the present invention relates to two novel crystalline forms of candesartan cilexetil which are designated as form G and form H and a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil and process for their preparation.
  • Candesartan cilexetil is 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1 -[[2-(IH-tetazole-5-yl)[1 , 1 '-biphenyl-4-yl]methyl]-IH-benzimidazole-7- carboxylate. Its molecular formula is 0 33 Ha 4 NeO 6 and mol wt is 610.66. Candesartan cilexetil is represented by structural formula (I).
  • Candesartan cilexteil is an ester prodrug of 2-ethoxy-1-[[2-(IH-tetrazole-5-yl)[1 ,1'- biphenyl-4-yl]methyl]-1 H benzimidazole-7-carboxylic acid (candesartan), known as a potent Angiotensin Il receptor antagonist. It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure.
  • Candesartan cilexetil is a white to off-white powder and is sparingly soluble in water and in methanol. It is marketed by AstraZeneca under tradename ATACAND ® .
  • 5,196,444 relates to crystal form of Candesartan Cilexetil i.e. C-type crystal (form I) and it describes a process of preparation of Candesartan cilexetil in which it is formed by reacting 2-ethoxy-1-[[2'-(N-triphenyImethyltetrazol-5-yl)biphenyl -4-yl]methyl]benzimidazole-7-carboxylic acid in dimethylformamide with cyclohexyl- 1-iodoethyl carbonate to form cilexetil trityl candesartan and its subsequent deprotection with a methanolic hydrochloric acid gives candesartan cilexetil in 47% yield after column chromatography.
  • the yield of C-type crystal obtained by this process is very low.
  • the purification of final product by chromatography is commercially not suitable and is cumbersome at an industrial scale.
  • Candesartan cilexetil such as form I and form Il and an amorphous form.
  • candesartan cilexetil is heat sensitive and therefore grinding causes unwanted degradation and loss in purity.
  • WO2004085426 discloses 1 , 4-dioxane solvate and two crystalline forms of candesartan cilexetil.
  • WO2005077941 describes a process for the preparation of polymorphic forms of Candesartan cilexetil i.e. form-Ill, form-IV, form-V, form-VI, form-VII, form-VIII, form- IX, form-X, form-XI, form-XIII, form-XIV, form-XIV-1 , form-XV, form-XVI, form-XVII, form-VIII, form-XIX, form-XX, form-XXI, form-XXII or XXIII, having less than about 5% by weight of other polymorphic forms (form-l).
  • These forms are hydrates and solvates of candesartan cilexetil.
  • WO2005123721 A1 describes a process for the preparation of two crystalline forms i.e. form A, form B and an amorphous form. The process disclosed hereinabove are tedious, time consuming and operationally difficult at industrial scale.
  • WO2006048237 A1 describes a process for the preparation of form 5, form 6, form 7, form 8 and amorphous form. These forms are prepared by dissolving candesartan cilexetil in a chlorinated solvent, optionally concentrate thus obtain solution then liquid hydrocarbon is added to the solution to precipitate out these forms.
  • a primary object of the present invention is to provide novel crystalline forms of Candesartan cilexetil i.e. form G and form H.
  • Another object of the present invention is to provide a process for the preparation novel crystalline forms of Candesartan cilexetil i.e. form G and form H, which is simple and easy to handle at an industrial scale and cost effective.
  • Another object of the present invention is to provide a process for the preparing candesartan form G comprising steps of i) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution ii) cooling the said solution at O 0 C to 5 0 C
  • Yet another object of the present invention is to provide a process for the preparing candesartan form H comprising a step of heating candesartan cilexetil form G at 75°C under reduced pressure.
  • a further object of the present invention is to provide novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
  • An aspect of the present invention is to provide novel crystalline forms of Candesartan cilexetil i.e. form G and form H.
  • Another aspect of the present invention is to provide a process for the preparing candesartan form G comprising steps of iii) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution iv) cooling the said solution at 0 0 C to 5°C
  • Yet another aspect of the present invention is to provide a process for the preparing candesartan form H comprising a step of heating candesartan cilexetil form G at 75°C under reduced pressure.
  • a further aspect of the present invention is to provide novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
  • Figure-1 is an X-ray powder diffraction pattern of candesartan cilexetil form
  • Figure-2 is an X-ray powder diffraction pattern of candesartan cilexetil form
  • Figure-3 is an X-ray powder diffraction pattern of novel crystalline form of candesartan
  • Figure-4 is an X-ray powder diffraction pattern of novel crystalline form of tritylated candesartan
  • Figure-5 is an X-ray powder diffraction pattern of novel crystalline form of tritylated candesartan cilexetil
  • a novel crystalline form of Candesartan cilexetil designated as form G, characterized by an X-ray powder diffraction spectrum having peaks at about 6.1 , 7.2, 9.1 , 10.9, 11.9, 12.6, 13.1 , 16.4, 20.0, 20.8 and 23.3 ⁇ 0.2 degree two-theta.
  • Figure-1 depicts the X-ray powder diffraction spectrum of candesartan cilexetil form G.
  • a process for preparation of the form G of candesartan cilexetil comprising steps of i) dissolving candesartan cilexetil form C or mixture of forms in acetone and optionally heating until it becomes clear solution ii) cooling the said solution at 0 0 C to 5°C
  • a novel crystalline form of Candesartan cilexetil designated as form H, characterized by an X-ray powder diffraction spectrum having peaks at about 9.2, 12.0, 13.0, 15.3, 16.1, 16.7, 17.2, 20.7, 21.0, 25.7 and 32.8 ⁇ 0.2 degree two-theta.
  • Figure-2 depicts the X-ray powder diffraction spectrum of candesartan cilexetil form H.
  • a process for preparation of the form H of candesartan cilexetil comprising a step of heating candesartan cilexetil form G at 75 0 C under reduced pressure.
  • the present invention is to provide a novel crystalline form of candesartan, tritylated candesartan and tritylated candesartan cilexetil.
  • FIG. 1 One aspect of the present invention, there is provided a novel crystalline form of candesartan, characterized by an X-ray powder diffraction spectrum having peaks at about 10.4, 11.6, 13.8, 19.1 , 20.6, 20.8, 21.8, 22.6, 23.3, 26.1 , 28.3 and 30.3 ⁇ 0.2 degree two-theta.
  • Figure-3 depicts the X-ray powder diffraction spectrum of a novel crystalline form of candesartan.
  • a novel crystalline form of candesartan is prepared by reacting methyl 1-[(2'-cyanobiphenyl-4-yl) methyl]-2- ethoxy-benzimidazole-7-carboxylate with sodium azide, tri butyl tin chloride in the presence of o-xylene at 135-15O 0 C to obtain methyl 2-ethoxy- 1-[(2'- ⁇ 1H-tetrazole-5- yl ⁇ biphenyl-4-yl)-methyl] benzimidazole-7-carboxylate which is hydrolyzed in the presence of sodium hydroxide at 80-85 0 C and recrystallized in acetone to obtain novel crystalline form of Candesartan (2-ethoxy- 1-[(2'- ⁇ 1 H-tetrazole-5-yl ⁇ biphenyl-4- yl)-methyl] benzimidazole-7-carboxylic acid).
  • a novel crystalline form of tritylated candesartan characterized by an X-ray powder diffraction spectrum having peaks at about 8.7, 9.4, 9.7, 11.6, 14.0, 14.4, 14.9, 18.2, 20.8, 21.1, 21.7, 23.1 , 25.4, 26.5 and 27.0 ⁇ 0.2 degree two-theta.
  • Figure-4 depicts the X-ray powder diffraction spectrum of novel crystalline form of tritylated candesartan.
  • a novel crystalline form of tritylated candesartan is prepared by reacting 2-ethoxy- 1 ⁇ [(2'- ⁇ 1 H-tetrazole-5-yl ⁇ biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid with trityl chloride solution in the presence of acetone and triethylamine to obtain novel crystalline form of tritylated candesartan (2-ethoxy- 1-[(2'- ⁇ N-tri phenyl methyl tetrazole-5-yl ⁇ biphenyl- 4-yl)-methyl] benzimidazole-7-carboxylic acid ).
  • a novel crystalline form of tritylated candesartan cilexetil characterized by an X-ray powder diffraction spectrum having peaks at about 8.6, 9.0, 9.7, 10.3, 12.0, 12.8, 15.2, 15.8, 16.2, 16.5, 17.3, 19.5, 19.8, 21.0, 21.4, 22.1 , 22.4 and 26.1 ⁇ 0.2 degree two-theta.
  • Figure- 5 depicts the X-ray powder diffraction spectrum of novel crystalline form of tritylated candesartan cilexetil.
  • a novel crystalline form of tritylated candesartan cilexetil is prepared by reacting 2-ethoxy- 1-[(2'- ⁇ N-tri phenyl methyl tetrazole-5-yl ⁇ biphenyl-4-yl)-methyl] benzimidazole-7-carboxylic acid with cyclohexyl 1-chloroethylcarbonate in the presence of dimethylformamide, potassium ' carbonate to obtain tritylated candesartan cilexetil which is recrystallized in acetone to obtain novel crystalline form of tritylated candesartan cilexetil (( ⁇ )-1- (cyclohexyloxycarbonyloxy) ethyl-2-ethoxy- 1-[(2'- ⁇ N-tri phenyl methyl tetrazole-5- yl ⁇ biphenyl-4-yl)-methyl] benzimidazole
  • a solution of sodium azide (71.15 g) in D. M. water (214 ml) was prepared in round bottom flask and cooled to 0-10° C.
  • Tri-n-butyl tin chloride (237.58 g) was added to the reaction mass at 0-10° C within 30-60 minutes. Reaction mixture was stirred for 2 hours at 0-10° C.
  • O-xylene (1000 ml) was added to it and stirred. The o-xylene layer was separated and washed with 20 % brine solution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles formes cristallines de candésartan cilexétil conçues sous forme G et H et une nouvelle forme cristalline de candésartan, de candésartan tritylé et de candésartan cilexétil tritylé, ainsi qu'un procédé pour leur préparation.
PCT/IN2007/000236 2006-06-13 2007-06-12 Nouvelles formes cristallines WO2008035360A2 (fr)

Applications Claiming Priority (2)

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IN928MU2006 2006-06-13
IN928/MUM/2006 2006-06-13

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WO2008035360A3 WO2008035360A3 (fr) 2008-10-16

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs
WO2010060564A1 (fr) 2008-11-27 2010-06-03 Bayer Schering Pharma Aktiengesellschaft Forme galénique pharmaceutique contenant de la nifédipine ou de la nisoldipine et un antagoniste de l'angiotensine ii et/ou un diurétique
WO2010146409A2 (fr) 2009-06-19 2010-12-23 Nangenex, Inc. Compositions de nanoparticules de candésartan cilexétil, leur procédé de préparation et compositions pharmaceutiques les contenant
WO2011092666A1 (fr) 2010-01-29 2011-08-04 Ranbaxy Laboratories Limited Procede ameliore de preparation de candesartan cilexetil, formes polymorphes de n-trityl candesartan et leurs utilisations
CN107709313A (zh) * 2015-06-05 2018-02-16 浙江华海药业股份有限公司 一种制备三苯甲基坎地沙坦的方法
CN109627234A (zh) * 2019-01-30 2019-04-16 浙江省食品药品检验研究院 一种坎地沙坦酯晶体及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
WO2004085426A1 (fr) * 2003-03-27 2004-10-07 Hetero Drugs Limited Nouvelles formes cristallines de candesartan cilexetil
WO2005077941A2 (fr) * 2004-02-11 2005-08-25 Teva Pharmaceutical Industries Ltd. Polymorphes de candesartan cilexetil
WO2005123721A2 (fr) * 2004-06-18 2005-12-29 Ranbaxy Laboratories Limited Formes amorphes et polymorphes de candesartan cilexetil
EP1655298A1 (fr) * 2004-11-03 2006-05-10 LEK Pharmaceuticals d.d. Formes polymorphes du candesartan cilexetil

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0459136A1 (fr) * 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
WO2004085426A1 (fr) * 2003-03-27 2004-10-07 Hetero Drugs Limited Nouvelles formes cristallines de candesartan cilexetil
WO2005077941A2 (fr) * 2004-02-11 2005-08-25 Teva Pharmaceutical Industries Ltd. Polymorphes de candesartan cilexetil
WO2005123721A2 (fr) * 2004-06-18 2005-12-29 Ranbaxy Laboratories Limited Formes amorphes et polymorphes de candesartan cilexetil
EP1655298A1 (fr) * 2004-11-03 2006-05-10 LEK Pharmaceuticals d.d. Formes polymorphes du candesartan cilexetil

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BRITAIN ET AL: "Polymorphism in Pharmaceutical Solids passage" POLYMORPHISM IN PHARMACEUTICAL SOLIDS, 1999, pages 235-238, XP002278123 *
CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS" TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1998, pages 163-208, XP001156954 ISSN: 0340-1022 *
FERNANDEZ, DANIEL ET AL: "Candesartan cilexetil, an antihypertensive agent containing an extended double ester chain" ACTA CRYSTALLOGRAPHICA, SECTION E: STRUCTURE REPORTS ONLINE, vol. E61, no. 2, 2005, pages O309-O312, XP002474295 *
HIROKAZU MATSUNAGA ET AL: "Solid-state characterization of candesartan cilexetil (TCV-116): crystal structure and molecular mobility" CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 47, no. 2, February 1999 (1999-02), pages 182-186, XP002957606 ISSN: 0009-2363 cited in the application *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs
WO2010060564A1 (fr) 2008-11-27 2010-06-03 Bayer Schering Pharma Aktiengesellschaft Forme galénique pharmaceutique contenant de la nifédipine ou de la nisoldipine et un antagoniste de l'angiotensine ii et/ou un diurétique
US9993432B2 (en) 2008-11-27 2018-06-12 Bayer Intellectual Property Gmbh Pharmaceutical dosage form comprising nifedipine or nisoldipine and an angiotensin II antagonist and/or a diuretic
WO2010146409A2 (fr) 2009-06-19 2010-12-23 Nangenex, Inc. Compositions de nanoparticules de candésartan cilexétil, leur procédé de préparation et compositions pharmaceutiques les contenant
WO2011092666A1 (fr) 2010-01-29 2011-08-04 Ranbaxy Laboratories Limited Procede ameliore de preparation de candesartan cilexetil, formes polymorphes de n-trityl candesartan et leurs utilisations
CN107709313A (zh) * 2015-06-05 2018-02-16 浙江华海药业股份有限公司 一种制备三苯甲基坎地沙坦的方法
CN107709313B (zh) * 2015-06-05 2020-10-23 浙江华海药业股份有限公司 一种制备三苯甲基坎地沙坦的方法
CN109627234A (zh) * 2019-01-30 2019-04-16 浙江省食品药品检验研究院 一种坎地沙坦酯晶体及其制备方法

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