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WO2013014480A1 - Procédé de préparation de dronédarone utilisant un composé intermédiaire amide - Google Patents

Procédé de préparation de dronédarone utilisant un composé intermédiaire amide Download PDF

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Publication number
WO2013014480A1
WO2013014480A1 PCT/HU2012/000065 HU2012000065W WO2013014480A1 WO 2013014480 A1 WO2013014480 A1 WO 2013014480A1 HU 2012000065 W HU2012000065 W HU 2012000065W WO 2013014480 A1 WO2013014480 A1 WO 2013014480A1
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Prior art keywords
formula
compound
salts
preparation
pharmaceutically acceptable
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Ceased
Application number
PCT/HU2012/000065
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English (en)
Inventor
Antal Friesz
Zsolt DOMBRÁDY
Marianna CSATÁRINÉ NAGY
Csaba HUSZÁR
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Sanofi SA
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Sanofi SA
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Publication of WO2013014480A1 publication Critical patent/WO2013014480A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • 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
    • A61P9/06—Antiarrhythmics

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- yl]methanesulfon-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.
  • HCl hydrochloride
  • 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 larmaceutically acceptable salts thereof
  • the present invention avoids the drawbacks of the procedures mentioned before, because formation of dronedarone in the final step is completed by reducing the carbonyl group in the amide.
  • This type of reaction is advantageous because only small amount of byproducts are formed during the reduction process.
  • the last step of the synthetic route can be performed with good yield using this type of reduction and the purity of the product is also satisfactory.
  • the reactants of this reaction are not expensive and are widely used in the chemical laboratory praxis. We found that the new compound of formula (II) can be reduced effectively with the invented method.
  • the compound of formula (X) is known form patent WO 02/48132 (Sanofi).
  • the other intermediary compounds used in synthesis of dronedarone are new. Further aspects of the invention are the novel intermediary compounds and the methods for the preparation thereof (see below in the "Detailed description of the invention” part).
  • 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:
  • Compound (X) is known from EP 0 471 609 (Sanofi).
  • the reaction can be carried out in presence or absence of solvent.
  • solvent which can be e.g. a Ci -4 alcohol, typically methanol or ethanol.
  • a basic catalyst which can be selected from the group of of alkali alkoxydes 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.
  • 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.
  • 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 ( VIII ) 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 an 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.
  • Compound (X) is known from EP 0 471 609 (Sanofi).
  • the hydrogenation process is carried out similarly like in above step B).
  • the hydrogenation is carried out in the presence of catalyst, e.g. palladium catalyst.
  • the above compound of formula (XII) is acylated with a compound of formula Pg-X (XIII), where Pg is a usual protecting group, typically an A-CO- group, where A is alkyl, alkoxy, aryl or aryloxy group, e.g. benzoyl, and X is a usual leaving group which typically stands for halogen, hydroxyl, RS0 2 0- , wherein R is alkyl, optionally substituted with one or more halogen(s), or aryl, typically phenyl optionally substituted with one or more substituent selected from the group of alkyls, halogens and nitro, where X is typically a halogen, e.g. chlorine.
  • Pg is a usual protecting group, typically an A-CO- group, where A is alkyl, alkoxy, aryl or aryloxy group, e.g. benzoyl
  • X is a usual leaving group which typically stands for halogen, hydroxy
  • reaction is carried out in inert solvent in presence acid binding agent, e.g. pyridine.
  • acid binding agent e.g. pyridine.
  • Pg is a usual protecting group, typically an A-CO- group, where A is alkyl, alkoxy, aryl or aryloxy group, e.g. benzoyl, protecting group, is alkylated with a compound of formula (VI)
  • X is a usual leaving group which typically stands for halogen, hydroxyl,
  • RSO2O- wherein R is alkyl, optionally substituted with one or more halogen(s) or phenyl optionally substituted with one or more substituent selected from the group of alkyl, halogens and nitro, where X is typically a halogen, e.g. chlorine.
  • the reaction can be carried out in indifferent solvent or solvent mixture.
  • solvent is selected from the group of dichloromethane,
  • dichloroethane chlorobenzene, toluene, tetrahydrofuran.
  • the reaction is performed at temperature between 10 to 130°C , Typically reaction is carried out at the boiling point of the solvent.
  • a) contains a further step where the compound of formula (III) is reacted with a halogenating agent (typically with thionyl chloride) at first and the obtained acid chloride derivative is reacted with dibutylamine of formula (IV).
  • a halogenating agent typically with thionyl chloride
  • the solvent can be selected from halogenated solvents, and the temperature is typically between 10 to 50°C .
  • the reaction can be carried out in a solvent in presence of acid binding agent.
  • the solvent is selected from the group of acetone, methylethyl keton, acetonitrile and dimethylformamide.
  • the acid binding agent is sodium or potassium carbonate.
  • a catalyst should be applied, e.g. dicyclohexyl carbodiimide.
  • the reductive agent can be selected from the group of LiAlH 4 , borane, sodium dimethylamino borohydrate, chloroplatinic acid combined with hydrosilanes, sodium borohydride combined with methanesulfonic acid and with CoCl 2 .
  • the reduction is carried out using a) borane in THF as solvent or b) sodium borohydride and methanesulfonic acid.
  • reaction is carried out in dimethylsulfoxyde as solvent.
  • the temperature applied in the reaction is typically between 0 °C and the boiling point of the solvent (which can be a solvent mixture, as it was mentioned above), e.g. between 60- 120°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, fumaric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, 2-hydroxyethanesulfonic acid, maleic acid, oxalic 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.
  • the hydrogen halogenide salts are typical, especially the hydrogen chloride salt.
  • the further starting materials are commercially available or can be prepared by applying known synthetic ways.
  • Pg is an A-CO- protecting group, group where A is alkyl, alkoxy, aryl or aryloxy group.
  • the mesylation can be carried out as it was disclosed above in point C).
  • 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 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.
  • alkyl includes straight or branched aliphatic hydrocarbon chains of 1 to 6 carbon atoms, e.g., methyl, ethyl, isopropyl and t-butyl.
  • alkoxy includes alkyl-O- groups.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • aryl includes aromatic monocyclic or multicyclic ring systems comprising 6 to about 14 carbon atoms, preferably 6 to about 10 carbon atoms.
  • suitable aryl groups include phenyl and naphthyl.
  • aryloxy includes aryl-O- groups.
  • the term includes fluoro, chloro, bromo and iodo atoms.
  • the reaction mixture was cooled down to 20 °C, 8 ml of 10 % aq NaOH solution and 10 ml of dichloromethane were added to the mixture.
  • the aqueous phase was washed with 2 x 10 ml of dichloromethane.
  • the dichloromethane phases were combined and washed with 10 ml of aq. 0.1 M sodium hydroxide solution and extracted with 2 x 10 ml of aq. 10 % HC1 solution.
  • the acidic phase was neutralized with aq. NaOH solution, extracted with 2 x 5 ml of dichloromethane and the dichloromethane was evaporated.
  • the product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to70 °C . To this solution 0.24 g of oxalic acid dissolved inl .5 ml of methylethyl ketone is added at 70° C. After cooling to 20 °C in 6 hours the mixture is stirred at 10 °C for 1 hour and filtered. To the obtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and 0.63g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated.
  • dichloromethane solution was washed with 2 x 20 ml of water, 1 x 20 ml of 5% sodium hydrocarbonate and with 20 ml of water. The solvent was evaporated.
  • the dark solution was stirred at this temperature for 30 mins and was washed with 1 x 60 ml of water, 1 x 60 ml of 5 % aqueous hydrochloric acid, with 1 x 60 ml of water and with 1 x 60 ml of 5 % aqueous sodium hydrocarbonate solution.
  • the dichloromethane solution crystallized after standing over several hours. The crystals were filtered and died at 20 °C.
  • the crude material was dissolved in 300 ml of abs ethanol and heated to 80°C. It was cooled to 10°C and the separated crystals filtered.

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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)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation de dronédarone de formule (I) et de ses sels pharmaceutiquement acceptables. L'invention est caractérisée en ce qu'un composé de formule (II) est réduit, 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/HU2012/000065 2011-07-26 2012-07-23 Procédé de préparation de dronédarone utilisant un composé intermédiaire amide Ceased WO2013014480A1 (fr)

Applications Claiming Priority (2)

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EP11462011 2011-07-26
EPEP11462011.5 2011-07-26

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Cited By (13)

* 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
WO2015031352A1 (fr) 2013-08-27 2015-03-05 Gilead Sciences, Inc. Procédé de synthèse de dronédarone et des sels de celle-ci
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 (4)

* 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
WO2009044143A2 (fr) * 2007-10-02 2009-04-09 Cambrex Karlskoga Ab Procédé de préparation de benzofuranes

Patent Citations (4)

* 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
WO2009044143A2 (fr) * 2007-10-02 2009-04-09 Cambrex Karlskoga Ab Procédé de préparation de benzofuranes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANAL. CHEM., vol. 50, no. 9, 1978
ANAL.CHEM., vol. 50, no. 9, 1978
J. AM. CHEM. SOC, vol. 73, 1951, pages 3168 - 71
SYNTHESIS, 1983, pages 319 - 22

Cited By (16)

* 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
US9611242B2 (en) 2011-03-29 2017-04-04 Sanofi Process for preparation of dronedarone by N-butylation
US9174959B2 (en) 2011-03-29 2015-11-03 Sanofi Process for preparation of dronedarone by N-butylation
US9193703B2 (en) 2011-03-29 2015-11-24 Sanofi Process for preparation of dronedarone by mesylation
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
WO2015031352A1 (fr) 2013-08-27 2015-03-05 Gilead Sciences, Inc. Procédé de synthèse de dronédarone et des sels de celle-ci

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