WO2013014478A1 - Procédé d'amination réductrice pour la préparation de dronédarone, utilisant un composé intermédiaire carboxyle - Google Patents

Procédé d'amination réductrice pour la préparation de dronédarone, utilisant un composé intermédiaire carboxyle Download PDF

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Publication number
WO2013014478A1
WO2013014478A1 PCT/HU2012/000063 HU2012000063W WO2013014478A1 WO 2013014478 A1 WO2013014478 A1 WO 2013014478A1 HU 2012000063 W HU2012000063 W HU 2012000063W WO 2013014478 A1 WO2013014478 A1 WO 2013014478A1
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WIPO (PCT)
Prior art keywords
formula
compound
preparation
acid
salts
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Application number
PCT/HU2012/000063
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English (en)
Inventor
Antal Friesz
Zsolt DOMBRÁDY
Original Assignee
Sanofi
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.)
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Publication date
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Publication of WO2013014478A1 publication Critical patent/WO2013014478A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • This invention relates to a novel process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, to novel intermediary compounds used in this process and their preparation.
  • Dronedarone is a known drug for the treatment of arrhythmia and has the chemical name of N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5- yljmethanesulfon-amide [see also formula (I) below].
  • There are some known processes for the preparation of dronedarone as follows:
  • the novelty of the process is based on the adaptation of the Friedel-Crafts reaction in the first step.
  • the process and the intermediary compounds used for the preparation of the benzoylchloride compound of the first step are also disclosed in this document.
  • the further steps of the process are identical with the final steps of the synthetic route disclosed in EP 0471609 [Process A], but in the claims the whole synthetic route is claimed, up to
  • the first one [Process A] is the so called linear synthesis.
  • the different parts of the dronedarone are stepwise built up on the starting compound.
  • This method is the least economical because the step by step building of the chemical groups is performed where more and more complicated and expensive molecules are applied which rises the costs of preparation.
  • it comprises complicated and dangerous reaction step because aluminium chloride is used in the cleaving reaction of the methoxy group which makes the industrial feasibility more complicated.
  • process C is simpler and more economical taken into consideration the number of the reaction steps.
  • HC1 hydrochloride salt
  • the crude dronedarone hydrochloride salt is prepared with a yield of 90% which was further purified and finally the crude dronedarone base was produced with a yield of 86%.
  • This base is reacted with hydrogen chloride gas dissolved in isopropanol which results in pure dronedarone hydrochloride salt. No yield was given for this reaction step.
  • the main aspect of the invention is a process for preparation of dronedarone (I) and pharmaceutically acceptable salts thereof
  • the present invention relates to a process for the preparation of dronedarone and pharmaceutically acceptable salts thereof.
  • the whole process - starting from compounds available commercial sources - reads as follows:
  • the reaction can be carried out in presence or absence of solvent.
  • solvent which can be e.g. a C alcohol, typically methanol or ethanol.
  • a strong basic catalyst which can be selected from the group of alkyl alcoholates and quaternary ammonium hydroxides, and it can be e.g. benzyltrimethylammonium hydroxide.
  • reaction is carried out in the excess of acrylonitrile as solvent at the boiling point of the solvent, e.g. about 70 to 90 °C .
  • solvent e.g. about 70 to 90 °C .
  • strong water free ammonium quaternary hydroxides or alkali alkoxydes can be applied as catalyst.
  • the hydrogenation is carried out in the presence of catalyst, e.g. palladium catalyst.
  • catalyst e.g. palladium catalyst.
  • the hydrogenation process is carried out in a solvent typically, e.g. the solvent is selected from the group of Ci -4 alcohols, ethyl acetate and cyclohexane, e.g. the solvent is methanol or ethanol.
  • the reaction is carried out in an indifferent solvent, typically in the presence of an acid binding agent.
  • the solvent is selected from the group of dichloromethane, dichloroethane and chlorobenzene.
  • the acid binding agent is a tertiary nitrogen base, for example pyridine or triethylamine.
  • a mesylating reagent should be applied. It can be any reagent which can be used for inserting a CH3SO2- group into the free amino group of compound of general formula (V). It is practical to use methanesulfonic anhydride or methanesulfonyl halogenide, e.g. methanesulfonyl chloride.
  • the hydrolysis is carried out in the presence of acid.
  • the acid can be a strong inorganic acid, e.g. hydrochloric acid.
  • the hydrolysis is carried out in water in presence of a phase transfer catalyst, e.g. triethyl-benzyl-ammonium chloride.
  • the reaction can be carried out in the presence of acid and alkali borohydride, typically sodium borohydride.
  • the reaction should be carried out among acidic conditions.
  • Such acids can be applied which are not reduced among the applied conditions.
  • methansulfonic acid, boric acid, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid etc. can be applied.
  • the excess of compound (II) can be applied to ensure the acidic conditions.
  • the reaction can be carried out in indifferent solvent or solvent mixture.
  • solvent is selected from the group of THF, diethyleneglycol, dimethyl ether,
  • dichloroethane dichloromethane, e.g. it can be THF or dichloroethane.
  • reaction is performed at temperature between 0 to 70 °C. Typically reaction is carried out between 50 to 55 °C.
  • the applicable acid for the preparation of pharmaceutically acceptable salts can be any inorganic or organic acid which forms an acid addition salt with the compound of general formula (I).
  • Exemplary acids which can form an acid addition salt are as follows: acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, methansulfonic acid, ethansulfonic acid, boric acid, butyric acid, citric acid, ethanesulfonic acid, fumaric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, 2- hydroxyethanesulfonic acid, maleic acid, oxalic acid, methanesulfonic acid, nitric acid, salicylic acid, tartaric acid, sulfuric acid (forming sulfate or bisulfate anion), sulfonic acid (such as those mentioned herein), succinic acid, toluenesulfonic acid and the like.
  • a salt formation can be carried out (on the amide part of it) by a strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide.
  • a strong base e.g. an alkaline hydroxide, typically by sodium hydroxide.
  • these salts have less practical importance, but they are within the scope of salts which can be prepared by the claimed process. It means that the phrase "salts" embraces both the acid addition salts and the salts formed by bases (basic salts) in case of compounds of general formula (I).
  • the further starting materials are commercially available or can be prepared by applying known synthetic ways.
  • alkyl includes straight or branched aliphatic hydrocarbon chains of 1 to 6 carbon atoms, e.g., methyl, ethyl, isopropyl and t-butyl.
  • the product is isolated as a base typically (if the compound has a free amino or an alkylated amino group). If desired, the isolated base can be converted into a salt (acid adition salt) thereof, which is typically a pharmaceutically acceptable salt [the possible acids are mentioned under point I)].
  • the acid addition salt can be prepared directly if the relating acid is in the final reaction mixture from which the solid product is made (however, this way is not applied in case of these compounds where the base type form has practical importance).
  • the salt formation can be made on the free COOH group, too.
  • This reaction can be carried among usual basic reaction conditions, typically applying a base, e.g. an alkaline hydroxide (e.g. sodium hydroxide).
  • a base e.g. an alkaline hydroxide (e.g. sodium hydroxide).
  • the temperature is chosen according to the general practice of a person skilled in organic chemistry. Typically the temperature is between 10 °C and the boiling point of the applied solvent (which can be the mixture of the mentioned solvents in a specific embodiment). Applicable temperature values can be found in the examples. All the above reactions are carried out under atmospheric pressure with the exception of the hydrogenation steps where higher pressure also can be applied, typically up to 20 bar, e.g. 5 to 10 bar.
  • methanesulfochloride was added in 5 mins and the mixture was stirred at 30-35°C for 3 hours.
  • the mixture was cooled to 20°C and washed with 2 x 15 ml of water, 2 x 15 ml of NaHC0 3 of 5% and lx 15 ml of water.
  • the phases were separated and the dichloromethane evaporated.

Abstract

La présente invention concerne un nouveau procédé de préparation de dronédarone de formule (I) et de ses sels pharmaceutiquement acceptables. Ce procédé est caractérisé en ce qu'un composé de formule (II) subit une amination avec un composé de formule (III) dans des conditions réductrices: et que le produit obtenu est isolé et, si on le souhaite, converti en un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également de nouveaux composés intermédiaires et leur préparation.
PCT/HU2012/000063 2011-07-26 2012-07-23 Procédé d'amination réductrice pour la préparation de dronédarone, utilisant un composé intermédiaire carboxyle WO2013014478A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP11462009 2011-07-26
EPEP11462009.9 2011-07-26

Publications (1)

Publication Number Publication Date
WO2013014478A1 true WO2013014478A1 (fr) 2013-01-31

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WO (1) WO2013014478A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8686180B2 (en) 2010-04-01 2014-04-01 Sanofi Process for preparing aminobenzofuran derivatives
US8796489B2 (en) 2010-03-02 2014-08-05 Sanofi Ketobenzofuran derivatives, method for synthesizing same, and intermediates
US9174959B2 (en) 2011-03-29 2015-11-03 Sanofi Process for preparation of dronedarone by N-butylation
US9174958B2 (en) 2010-06-18 2015-11-03 Sanofi Process for the preparation of dronedarone
US9193703B2 (en) 2011-03-29 2015-11-24 Sanofi Process for preparation of dronedarone by mesylation
US9221777B2 (en) 2012-01-20 2015-12-29 Sanofi Process for preparation of dronedarone by the use of dibutylaminopropanol reagent
US9221778B2 (en) 2012-02-13 2015-12-29 Sanofi Process for preparation of dronedarone by removal of hydroxyl group
US9238636B2 (en) 2012-05-31 2016-01-19 Sanofi Process for preparation of dronedarone by Grignard reaction
US9249119B2 (en) 2012-02-14 2016-02-02 Sanofi Process for the preparation of dronedarone by oxidation of a sulphenyl group
US9334254B2 (en) 2010-03-30 2016-05-10 Sanofi Process for preparing sulfonamidobenzofuran derivatives
US9382223B2 (en) 2012-02-22 2016-07-05 Sanofi Process for preparation of dronedarone by oxidation of a hydroxyl group
US9499507B2 (en) 2011-11-29 2016-11-22 Sanofi Method for preparing 5-amino-benzoyl-benzofuran derivatives

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609A1 (fr) 1990-08-06 1992-02-19 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
WO2002048132A1 (fr) 2000-12-11 2002-06-20 Sanofi-Synthelabo Derive de methanesulfonamido-benzofurane, son procede de preparation et son utilisation comme intermediaire de synthese
WO2002048078A1 (fr) 2000-12-11 2002-06-20 Sanofi-Synthelabo Chlorhydrate du 2-butyl-3-(4-'3-(dibutylamino)propoxy!benzoyl)-5-nitro-benzofurane et sa preparation
WO2003040120A1 (fr) * 2001-11-08 2003-05-15 Isp Investments Inc. Procede de preparation de dronedarone
WO2011070380A1 (fr) * 2009-12-08 2011-06-16 Sanofi-Aventis Nouveau procédé de préparation de la dronédarone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609A1 (fr) 1990-08-06 1992-02-19 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
WO2002048132A1 (fr) 2000-12-11 2002-06-20 Sanofi-Synthelabo Derive de methanesulfonamido-benzofurane, son procede de preparation et son utilisation comme intermediaire de synthese
WO2002048078A1 (fr) 2000-12-11 2002-06-20 Sanofi-Synthelabo Chlorhydrate du 2-butyl-3-(4-'3-(dibutylamino)propoxy!benzoyl)-5-nitro-benzofurane et sa preparation
WO2003040120A1 (fr) * 2001-11-08 2003-05-15 Isp Investments Inc. Procede de preparation de dronedarone
WO2011070380A1 (fr) * 2009-12-08 2011-06-16 Sanofi-Aventis Nouveau procédé de préparation de la dronédarone

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796489B2 (en) 2010-03-02 2014-08-05 Sanofi Ketobenzofuran derivatives, method for synthesizing same, and intermediates
US9334254B2 (en) 2010-03-30 2016-05-10 Sanofi Process for preparing sulfonamidobenzofuran derivatives
US8686180B2 (en) 2010-04-01 2014-04-01 Sanofi Process for preparing aminobenzofuran derivatives
US9174958B2 (en) 2010-06-18 2015-11-03 Sanofi Process for the preparation of dronedarone
US9193703B2 (en) 2011-03-29 2015-11-24 Sanofi Process for preparation of dronedarone by mesylation
US9174959B2 (en) 2011-03-29 2015-11-03 Sanofi Process for preparation of dronedarone by N-butylation
US9611242B2 (en) 2011-03-29 2017-04-04 Sanofi Process for preparation of dronedarone by N-butylation
US9499507B2 (en) 2011-11-29 2016-11-22 Sanofi Method for preparing 5-amino-benzoyl-benzofuran derivatives
US9221777B2 (en) 2012-01-20 2015-12-29 Sanofi Process for preparation of dronedarone by the use of dibutylaminopropanol reagent
US9708281B2 (en) 2012-01-20 2017-07-18 Sanofi Process for preparation of dronedarone by the use of dibutylaminopropanol reagent
US9221778B2 (en) 2012-02-13 2015-12-29 Sanofi Process for preparation of dronedarone by removal of hydroxyl group
US9701654B2 (en) 2012-02-13 2017-07-11 Sanofi Process for preparation of dronedarone by removal of hydroxyl group
US9249119B2 (en) 2012-02-14 2016-02-02 Sanofi Process for the preparation of dronedarone by oxidation of a sulphenyl group
US9382223B2 (en) 2012-02-22 2016-07-05 Sanofi Process for preparation of dronedarone by oxidation of a hydroxyl group
US9238636B2 (en) 2012-05-31 2016-01-19 Sanofi Process for preparation of dronedarone by Grignard reaction

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