WO2009157015A2 - Synthèse de l-(carbazol-4-yloxy)-3-[[2-(o-méthoxyphénoxy)éthyl]amino]-2-propanol - Google Patents

Synthèse de l-(carbazol-4-yloxy)-3-[[2-(o-méthoxyphénoxy)éthyl]amino]-2-propanol Download PDF

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Publication number
WO2009157015A2
WO2009157015A2 PCT/IN2009/000314 IN2009000314W WO2009157015A2 WO 2009157015 A2 WO2009157015 A2 WO 2009157015A2 IN 2009000314 W IN2009000314 W IN 2009000314W WO 2009157015 A2 WO2009157015 A2 WO 2009157015A2
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WO
WIPO (PCT)
Prior art keywords
carvedilol
methoxyphenoxy
carbazole
preparation
ethylamine
Prior art date
Application number
PCT/IN2009/000314
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English (en)
Other versions
WO2009157015A3 (fr
WO2009157015A8 (fr
Inventor
Purna Chandra Ray
Nagaprasada Rao Lakonda
Apuri Satyender
R. Buchi Reddy
Original Assignee
Inogent Laboratories Private Limited1
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 Inogent Laboratories Private Limited1 filed Critical Inogent Laboratories Private Limited1
Publication of WO2009157015A2 publication Critical patent/WO2009157015A2/fr
Publication of WO2009157015A3 publication Critical patent/WO2009157015A3/fr
Publication of WO2009157015A8 publication Critical patent/WO2009157015A8/fr

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Classifications

    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • the present invention relates to an improved process for the preparation of Carvedilol of formula (I) in high purity.
  • the invention relates to a process of Carvedilol wherein the process involves the use of organic base in the reaction of 4- (oxirane-2-ylmethoxy)-9H-carbazole (II) with 2-(2-methoxyphenoxy) ethylamine (III) in presence of a solvent.
  • This invention in particular to minimize bis-impurity to less than around 1.0% without any purification.
  • Carvedilol, ( ⁇ ) l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl]- amino]-2-propanol having structure (I), is a non selective ⁇ -adrenergic blocker with ⁇ r blocking activity.
  • Carvedilol has a chiral centre and can exist either as individual stereo isomer or in
  • Racemic Carvedilol is the active ingredient of COREG , which is indicated for the treatment of congestive heart failure and for the management of hypertension. Since Carvedilol is a multiple action drug, its beta-blocking activity affects the response to certain nerve impulses in parts of the body. Carvedilol is also known to be a vasodilator resulting primarily from alfa-adrenoceptor blockade. The multiple actions of Carvedilol are responsible for the anti hypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.
  • Carvedilol is prepared in low yields, Moreover, it is contaminated with high amount of bis-derivative of formula (IV).
  • N-benzylated 2-(2-methoxyphenoxy) ethylamine is used for its reaction with 4-(2,3-epoxypropoxy) carbazole for preparation of Carvedilol (I). Due to the toxic nature of N-benzyl impurity, European pharmacopeia has fixed the limits of this impurity to not more than 0.02% and practically it is very difficult to produce this impurity. Further, the catalytic hydrogenation in final stage is not advisable.
  • Patent Applications WO2004094378, WO2005080329 and WO2008038301 disclose the formation of organic acid salts of Carvedilol followed by salt cleavage and then purification of the resulting product for the reduction of bis-impurity. But, the formation and cleavage of salt further increases two steps of the process and its reaction time which is not economical in large scale.
  • the applicant of international application WO2004041783 discloses a method of preparation of Carvedilol by reacting epoxide (II) with salt of amine (III) in the presence of base, which is an alkali metal or alkaline earth metal carbonate.
  • the main object of the present invention is to provide an improved process for the preparation of Carvedilol obviating the drawbacks of the existing processes.
  • Other object of the present invention is to provide a process for the preparation of
  • Another object is to provide a more simplified, time saving, cost effective and commercially feasible process for the manufacture of Carvedilol (I).
  • Yet another object of the invention is to provide a process that can be reproducible and which will overcome the anomalies of the reported processes to provide Carvedilol (I) of high purity (ICH grade) without increasing the reaction steps.
  • the present invention relates to a process for the preparation of Carvedilol by reacting 4-(oxirane-2-ylmethoxy)-9H-carbazole (H) with 2-(2-methoxyphenoxy) ethylamine (III).
  • the starting material 4-(oxirane-2-ylmethoxy)-9H-carbazole (II) can be prepared according to the process disclosed in the Indian patent application IN 606/CHE/2008 and 2-(2-methoxyphenoxy) ethylamine (III) can be prepared from the hydrochloride salt by using aqueous sodium hydroxide and extracting it with organic solvent.
  • the present invention gives the method for the preparation of Carvedilol by reacting 2-(2-methoxyphenoxy) ethylamine (III) with 4-(oxirane-2-ylmethoxy)-9H- carbazole (II) in presence of an organic base and organic solvent.
  • the molar equivalents of the amine of formula (III) are in an amount of 1 to 2 equivalents with respect to the carbazole of formula (II), preferably 1 to 1.102 and more preferably 1 to 1.1 equivalents.
  • the organic solvents can be taken from the group of ethereal solvents, preferably monoglyme.
  • the said organic base used for the present invention is selected from primary, secondary and tertiary amines, preferably tertiary amines.
  • Tertiary amines are selected from the group of N,N-dimethylbenzylamine, N,N-dimethylbutylamine, N 5 N- dimethylcyclohexylamine, triethylamine, N-methyl-2-piperidone and tribenzylamine, preferably N,Ndiisopropylethylamine and tribenzylamine are used.
  • the amount of organic base employed is about 0.8 to 1.2 equivalents, more particularly 1.0 equivalent with respect to the carbazole of the formula (II).
  • the reaction is carried out at temperature range of room temperature to 85 0 C, preferably at 80-85 0 C.
  • the reaction typically takes about 8-12 hours for the completion.
  • the progress of the reaction can be monitored by conventional methods like HPLC/ TLC.
  • the reaction mixture is cooled to room temperature and the organic solvent is added to the mixture and further cooled to 0°- 5 0 C with stirring.
  • the obtained solid is filtered after slurry in ethylacetate to get crude Carvedilol.
  • the organic solvent employed for isolation of Carvedilol is taken from esters solvent, preferably ethyl acetate.
  • the Purity of crude Carvedilol obtained in this process is more than 98 % and having bis-impurity less than 1.0 %, particularly less than 0.7%.
  • the obtained crude Carvedilol can be purified by the conventional techniques.
  • a surprising new fact in this inventive method of production is that, the method is advantageous in obtaining crude Carvedilol having very less amount of the bis-derivative than by using the existing known methods.
  • the method of preparation of Carvedilol by this invention is also advantageous in that the new conditions of preparation in combination with purification and isolation of the Carvedilol increase purity and guarantee reliability of the production of an acceptable substance in required pharmacopeia quality and with a defined particle size.
  • Methods of production of this invention will be clear from the following examples, which, however, do not limit the same in any case.
  • This invention can be used in the pharmaceutical industry for the production of Carvedilol, which is a nonselective ⁇ -adrenergic blocking agent with ⁇ i blocking activity.

Abstract

La présente invention concerne un procédé amélioré de préparation de Carvédilol. Le procédé selon l’invention comprend l’utilisation d’une base organique dans la réaction du 4-(oxirane-2-ylméthoxy)-9H-carbazole avec la 2-(2-méthoxyphénoxy)éthylamine en présence d’un solvant. Lors de la préparation du Carvédilol, une quantité minimale d’impureté bis est obtenue, sans purification.
PCT/IN2009/000314 2008-06-04 2009-06-01 Synthèse de l-(carbazol-4-yloxy)-3-[[2-(o-méthoxyphénoxy)éthyl]amino]-2-propanol WO2009157015A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1368/CHE/2008 2008-06-04
IN1368CH2008 2008-06-04

Publications (3)

Publication Number Publication Date
WO2009157015A2 true WO2009157015A2 (fr) 2009-12-30
WO2009157015A3 WO2009157015A3 (fr) 2010-02-25
WO2009157015A8 WO2009157015A8 (fr) 2010-04-15

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2009/000314 WO2009157015A2 (fr) 2008-06-04 2009-06-01 Synthèse de l-(carbazol-4-yloxy)-3-[[2-(o-méthoxyphénoxy)éthyl]amino]-2-propanol

Country Status (1)

Country Link
WO (1) WO2009157015A2 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4487894A (en) * 1982-09-20 1984-12-11 Plastics Engineering Company Polyimide-epoxy thermoset resins
US20070055069A1 (en) * 2003-04-21 2007-03-08 Ramanjaneyulu Gorantla S Process for the preparation of carvedilol form-ii

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4487894A (en) * 1982-09-20 1984-12-11 Plastics Engineering Company Polyimide-epoxy thermoset resins
US20070055069A1 (en) * 2003-04-21 2007-03-08 Ramanjaneyulu Gorantla S Process for the preparation of carvedilol form-ii

Also Published As

Publication number Publication date
WO2009157015A3 (fr) 2010-02-25
WO2009157015A8 (fr) 2010-04-15

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