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WO2005116030A1 - Procede d'elaboration de tadalafil - Google Patents

Procede d'elaboration de tadalafil Download PDF

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Publication number
WO2005116030A1
WO2005116030A1 PCT/IN2005/000136 IN2005000136W WO2005116030A1 WO 2005116030 A1 WO2005116030 A1 WO 2005116030A1 IN 2005000136 W IN2005000136 W IN 2005000136W WO 2005116030 A1 WO2005116030 A1 WO 2005116030A1
Authority
WO
WIPO (PCT)
Prior art keywords
tadalafil
volumes
methyl
reaction mass
pyrido
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.)
Ceased
Application number
PCT/IN2005/000136
Other languages
English (en)
Inventor
Chava Satyanarayana
Gorantla Seeta Ramanjaneyulu
Gogulapati Venkata Panakala Rao
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.)
Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories 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 Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2005116030A1 publication Critical patent/WO2005116030A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to an optimized process for the preparation of pure (6R,12aR)-6-(l,3-Benzodioxol-5-yl)-2-methyl-l,2,3,4,6,7,12,12a-octahydropyrazino T , : 6, 1 ]pyrido [3 ,4-b] indole- 1 ,4-dione (Tadalafil) .
  • Tadalafil namely (6R,12aR)-6-( 1,3 -Benzodioxol-5-yl)-2-methyl- 1,2,3 ,4,6,7, 12, 12a- octahydropyrazino[2',l':6,l]pyrido[3,4-b]indole-l,4- dione has the formula
  • Tadalafil is a potent and selective inhibitor of cyclic guanosine S' ⁇ -monophosphate specific phosphodiesterase having a utility in a variety of therapeutic areas where such inhibition is thought to be beneficial including the treatment of cardiovascular disorders. Tadalafil and its similar compounds are reported in US Patent 5,859,006 (Equivalent to EP 740,668).
  • solubility of Tadalafil in isopropanol is only less than 1% and herein any recrystallization process which involve very large volumes of the solvent isopropanol thereby making the process unwieldy and nonoperable.
  • the main object of the present invention is to provide an optimized process for the preparation of Tadalafil.
  • Another object of the invention is to provide a process for recrystallisation of Tadalafil without the usage of large volumes of solvents.
  • Another object of the invention is to provide a process for the isolation of the Tadalafil from the reaction mass without involving the usage of large volumes of solvents, extensive workup like distillation of one solvent and dissolution in second solvent, removal of second solvent and crystallization from a third solvent.
  • Another object of the invention is to provide a process for recrystallization of Tadalafil with reduced cycle times and minimizing loss of material.
  • the present invention relates to a process for the preparation of Tadalafil from D-Tryptophan methyl ester through (6R, 12aR)-methyl l,2,3,4-tetrahydro-2- chloroacetyl-l-(3,4-methylene dioxyphenyl) - 9H - pyrido [3,4-b] indole-3-carboxylate (chloroacetyl intermediate) which on reaction with methylamine solution in short chain alcohol followed by cooling gives crude Tadalafil. Recrystallization is carried out by dissolution of crude Tadalafil in minimum volume of organic polar solvent followed by quenching the solution into water/water miscible solvents to give the pure Tadalafil in quantitative yields.
  • Tadalafil Detailed description of the Invention: The preparation and recrystallization of Tadalafil from (6R, 12aR)-Methyl 1,2,3,4- tetrahydro-2-chloroacetyl-l-(3,4-methylenedioxyphenyl) - 9H-pyrido [3,4-b]indole-3- carboxylate comprises the following steps:
  • the crude Tadalafil is recrystallized by dissolving it in about 2 to 12 volumes, preferably 4 to 8 volumes of a polar solvent selecting from DMF, 1,4-Dioxane and DMSO, followed by quenching the mass into 6 to 30 volumes of water/water miscible solvent such as methanol, ethanol, isopropanol, acetone or mixtures thereof over a period of 30 rnin to 2 hrs or water/water miscible solvent can be added to the solution of crude Tadalafil in a polar solvent.
  • a polar solvent selecting from DMF, 1,4-Dioxane and DMSO
  • Reaction mass is cooled and maintained at -10°C to 10°C preferably at -5°C to 5°C for 1 hr to 6 hrs followed by isolation, washing with acetone and drying gives the pure Tadalafil in quantitative yields of pharmaceutically acceptable quality.
  • (6R, 12aR)-Methyl-l,2,3,4-tetrahydro-2-chloroacetyl-l-(3,4-methylene dioxy phenyl) - 9H-pyrido[3,4-b]indole-3-carboxylate (Chloroacetyl intermediate) is prepared as per the reported prior art methods.
  • Methyl amine solution (25% in methanol, 163 ml) is added to a suspension of (6R,12aR) - Methyl 1,2,3,4 -tetrahydro-2 - chloroacetyl -l-(3,4 -methylenedioxy phenyl) -9H- pyrido[3,4-b]indole-3-carboxylate (Chloro acetyl intermediate) (79 g) in methanol (790 ml). Temperature of the reaction mass is raised and maintained at 50°C to 55°C for 6 hrs. The reaction mass is then cooled and maintained at 25°C to 30°C for 1 hr, filtered, washed with methanol (50 ml) and dried at 45°C to 50°C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé optimisé pour l'élaboration de Tadalafil à partir de (6R, 12aR)-méthyle 1,2,3,4-tétrahydro-2-chloro-acétyle-1-(3,4-méthylène-dioxy-phényle)-9H-pyrido[3,4-b]indole-3-carboxylate (intermédiaire chloro-acétyle) sans avoir à utiliser de grands volumes de solvant ni effectuer de distillation, d'extraction ni d'évaporation de solvants. En l'occurrence, le Tadalafil cru est isolé par refroidissement et recristallisation à partir de solvants polaires tels que le DMF, le 1,4-dioxane ou le DMSO. On procède ensuite à une adjonction de la masse de réaction dans l'eau ou un solvant miscible dans l'eau, puis on refroidit et on maintient à basse température.
PCT/IN2005/000136 2004-05-31 2005-05-02 Procede d'elaboration de tadalafil Ceased WO2005116030A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN491/CHE/2004 2004-05-31
IN491CH2004 2004-05-31

Publications (1)

Publication Number Publication Date
WO2005116030A1 true WO2005116030A1 (fr) 2005-12-08

Family

ID=35450828

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2005/000136 Ceased WO2005116030A1 (fr) 2004-05-31 2005-05-02 Procede d'elaboration de tadalafil

Country Status (1)

Country Link
WO (1) WO2005116030A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006091975A1 (fr) * 2005-02-25 2006-08-31 Teva Pharmaceutical Industries Ltd. Processus pour synthetiser le tadalafil
US7417044B2 (en) 2005-02-25 2008-08-26 Teva Pharmaceutical Industries Ltd. Tadalafil having a large particle size and a process for preparation thereof
EP2238979A1 (fr) * 2009-04-06 2010-10-13 LEK Pharmaceuticals d.d. Ingrédient pharmaceutique actif absorbé sur un support solide
US8063214B2 (en) * 2004-10-28 2011-11-22 Dr. Reddy's Laboratories Limited Polymorphic forms of tadalafil
CN104262340A (zh) * 2014-09-19 2015-01-07 济南诚汇双达化工有限公司 一种他达拉非的制备方法
CN116574102A (zh) * 2023-04-11 2023-08-11 广东九明制药有限公司 一种他达拉非的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859006A (en) * 1994-01-21 1999-01-12 Icos Corporation Tetracyclic derivatives; process of preparation and use
WO2002036593A1 (fr) * 2000-11-06 2002-05-10 Lilly Icos Llc Derives d'indole utilises comme inhibiteurs de pde5
WO2004011463A1 (fr) * 2002-07-31 2004-02-05 Lilly Icos, Llc. Reaction de pictet-spengler modifiee et produits prepares a partir de cette derniere

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859006A (en) * 1994-01-21 1999-01-12 Icos Corporation Tetracyclic derivatives; process of preparation and use
WO2002036593A1 (fr) * 2000-11-06 2002-05-10 Lilly Icos Llc Derives d'indole utilises comme inhibiteurs de pde5
WO2004011463A1 (fr) * 2002-07-31 2004-02-05 Lilly Icos, Llc. Reaction de pictet-spengler modifiee et produits prepares a partir de cette derniere

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8063214B2 (en) * 2004-10-28 2011-11-22 Dr. Reddy's Laboratories Limited Polymorphic forms of tadalafil
WO2006091975A1 (fr) * 2005-02-25 2006-08-31 Teva Pharmaceutical Industries Ltd. Processus pour synthetiser le tadalafil
US7417044B2 (en) 2005-02-25 2008-08-26 Teva Pharmaceutical Industries Ltd. Tadalafil having a large particle size and a process for preparation thereof
EP2238979A1 (fr) * 2009-04-06 2010-10-13 LEK Pharmaceuticals d.d. Ingrédient pharmaceutique actif absorbé sur un support solide
CN104262340A (zh) * 2014-09-19 2015-01-07 济南诚汇双达化工有限公司 一种他达拉非的制备方法
CN104262340B (zh) * 2014-09-19 2016-08-31 济南诚汇双达化工有限公司 一种他达拉非的制备方法
CN116574102A (zh) * 2023-04-11 2023-08-11 广东九明制药有限公司 一种他达拉非的制备方法

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