Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • 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
• • 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
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
• • 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

• the present invention relates generally to the preparation of amino benzoyl benzofuran derivatives.
• the invention relates to a process for the preparation of 5-amino-benzoylbenzofuran derivatives of general formula:
• R 1 is hydrogen or alkyl and R 2 is hydrogen, alkyl, alkoxy or dialkylaminoalkoxy.
• R 1 represents, in particular, a linear or branched C 1 -C 8 alkyl group, in particular a linear or branched C 1 -C 4 alkyl group such as methyl, ethyl, n-propyl, isopropyl or n-butyl, and butyl or tert-butyl,
• R 2 represents in particular a linear or branched C 1 -C 8 alkyl group, especially a group C 1 -C 4 linear or branched alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl; a linear or branched C 1 -C 6 alkoxy group, in particular a linear or branched C 1 -C 4 alkoxy group such as methoxy, ethoxy, n-propoxy, iso-hydroxy, n-butoxy, sec-butoxy or tert-butoxy; still a dialkylaminoalkoxy group in which each linear or branched alkyl group is C 1 -C 5 and the linear or branched alkoxy group is C 1 -C 5 in which each linear or branched alkyl group is C 1 -C 4 such as methyl, ethyl, n-propyl, isopropyl
• R 1 is n-butyl and R 2 is 3- (di-n-butylamino) propoxy.
• this method requires the isolation of Compound A from its formation medium, the isolation of this compound, usually in the form of its oxalate, thus constituting an additional step in the preparation of dronedarone.
• aminoalkoxybenzoyl-benzofuran derivatives of EP 0 471 609 in particular dronedarone, may be synthesized, therefore, in the very medium for forming the appropriate compound of formula I.
• the 5-amino-benzofuran derivatives of formula I can be prepared by reducing a 5-nitro-benzofuran derivative of general formula:
• R 1 and R 2 have the same meaning as above, by means of a hydrogen transfer agent, in the presence of palladium-carbon as catalyst and in an ether or a mixture of ethers as solvent, which forms the compounds desired.
• R 1 is preferably n-butyl and R 2 is preferably 3- (di-n-butylamino) propoxy.
• the invention relates to a process for the preparation of sulphonamido-benzofuran derivatives of general formula:
• R 1 and R 2 have the same meaning as above and R 3 represents an alkyl group, the process according to which:
• a 5-nitro-benzofuran derivative of formula II is reduced by means of a hydrogen transfer agent, in the presence of palladium-carbon as a catalyst and in an ether or a mixture of ethers as solvent, to form a reaction medium containing a 5-amino-benzoyl-benzofuran derivative of formula I, above, in free base form, b) treating the reaction medium containing the 5-amino-benzoyl-benzofuran derivative of formula I in the form of of free base obtained above, with a halide of general formula:
• the pharmaceutically acceptable salt of the compound of formula III can be recovered from its forming medium, for example by crystallization.
• R 3 represents in particular a linear or branched C 1 -C 6 alkyl group, in particular a C 1 -C 4 linear or branched alkyl group such as methyl, ethyl, n-propyl or isopropyl, n-butyl or tert-butyl.
• R 1 is n-butyl
• R 2 is 3- (di-n-butylamino) propoxy
• R 3 is methyl in formula III above.
• the reduction by hydrogen transfer according to the invention is usually carried out in an ether or a mixture of ethers as a solvent, unlike the state of the art where this type of reaction is generally carried out in an alcohol.
• This reduction in an ether or a mixture of ethers allows a significant chemo-selectivity of the nitro function to the detriment of the ketone function also present and which is also likely to reduce alcohol.
• This selective reduction of the nitro function therefore avoids the isolation of the compound of formula I in any way, in particular by transformation. of this compound, obtained in basic form, into a salt easily separable from its formation medium.
• the ether used as a solvent is usually a dialkyl ether such as methyl tert-butyl ether or a cyclic ether, for example tetrahydrofuran, while the mixture of ethers generally corresponds to a mixture of dialkyl ether and cyclic ether, for example a mixture methyl tert-butyl ether and tetrahydrofuran.
• Methyl tert-butyl ether represents a particularly preferred solvent in the context of the present invention, in particular for the preparation of Compound A and subsequently of dronedarone.
• the hydrogen transfer agent is a formate, preferably ammonium formate or phosphinate, especially sodium phosphinate.
• This hydrogen transfer agent is used in excess of the compound of formula II, this excess being up to 3 to 5 equivalents of hydrogen transfer agent per equivalent of compound of formula II or more.
• 5 or approximately 5 equivalents of hydrogen transfer agent per equivalent of compound of formula II for example 5 or approximately 5 equivalents of dissolved hydrogen transfer agent, for example in a volume of water, are used.
• 5 equivalents of dissolved ammonium formate are used, for example, in one volume of water.
• the reduction can take place at room temperature. However, this is generally undertaken by heating the reaction medium to a temperature ranging from up to, for example, 50 ° C to 60 ° C, preferably at a temperature of the order of 40 ° C, in particular at 40 ° C.
• the invention also relates to a process for the preparation of 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) -propoxy] -benzoyl ⁇ - 5-amino-benzofuran, in which 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) -propoxy] -benzoyl ⁇ -5-nitro-benzofuran is reduced by means of formate d ammonium or sodium phosphinate as a hydrogen transfer agent, in the presence of palladium on carbon as catalyst and in methyl tert-butyl ether or a mixture of methyl tert-butyl ether and tetrahydrofuran as solvent, to form a reaction medium containing 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) -propoxy] -benzoyl ⁇ -5-amino-benz
• the invention relates to a process for the preparation of 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) -propoxy] -benzoyl 5-methanesulfonamido-benzofuran or dronedarone and its pharmaceutically acceptable salts, the process according to which:
• the pharmaceutically acceptable salt of dronedarone can be recovered from its formation medium, for example by crystallization.
• the complex formed by a 5-nitro-benzofuran derivative of formula II, a hydrogen transfer agent, palladium on carbon and an ether or a mixture of ethers as a solvent is particularly interesting as a reaction medium for the preparation of various compounds including the compounds of formula I and those of formula III above.
• Another object of the invention relates to a reaction medium, characterized in that it is formed:
• an ether such as methyl tert-butyl ether or a mixture of ethers such as a mixture of methyl tert-butyl ether and tetrahydrofuran, as solvent.
• the mixture is cooled to 23 ° C. (+/- 2 ° C.) and the palladium-based carbon is then filtered, which is then washed with methyl tert-butyl ether and water. Then decanted, at room temperature, the organic phase is washed with some water. These settling and washing operations are then repeated once more. The mixture is again decanted and the solution is concentrated at 40 ° C. under vacuum. The concentrate is then diluted with tetrahydrofuran to provide 3.47 kg of a solution of the desired compound in a mixture of methyl tert-butyl ether and tetrahydrofuran.
• the nitro function of the compound of formula II can be reduced in a standard reactor, which avoids the need to operate with hydrogen under pressure in a hydrogenation apparatus.
• the quality of the compound of formula I in base form is significantly improved since there is a formation of different impurities in fewer numbers and lower contents. This advantage makes it possible to avoid the preparation and isolation of the oxalate of the compound of formula I, an operation which poses numerous problems on an industrial scale.
• non-isolated compounds of formula I in a process for the preparation of the derivatives pharmacologically active aminoalkoxybenzoyl-benzofuran of patent EP 0 471 609 and in particular in a process for the preparation of the compounds of formula III above, makes it possible to very significantly improve the yield of this process.
• the overall yield of its synthesis, from its corresponding 5-nitro-benzofuran derivative amounts to 60% according to the state of the art to 95% by implementation of the chemo process. -selective of the invention. This improvement is related in particular to the absence of isolation of the oxalate of the compound of formula I and the associated losses.

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
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• General Health & Medical Sciences (AREA)
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• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Materials Engineering (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Furan Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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• 2010
  • 2010-07-19 FR FR1055824A patent/FR2962731B1/fr not_active Expired - Fee Related
• 2011
  • 2011-07-18 JP JP2013520184A patent/JP2013531054A/ja active Pending
  • 2011-07-18 WO PCT/FR2011/051710 patent/WO2012010788A1/fr active Application Filing
  • 2011-07-18 CN CN2011800449848A patent/CN103108869A/zh active Pending
  • 2011-07-18 AU AU2011281421A patent/AU2011281421A1/en not_active Abandoned
  • 2011-07-18 KR KR1020137003998A patent/KR20130129180A/ko not_active Application Discontinuation
  • 2011-07-18 EP EP11754698.6A patent/EP2595976A1/de not_active Withdrawn
  • 2011-07-18 CA CA2805815A patent/CA2805815A1/fr not_active Abandoned
  • 2011-07-18 RU RU2013107023/04A patent/RU2013107023A/ru not_active Application Discontinuation
  • 2011-07-18 SG SG2013004296A patent/SG187140A1/en unknown
  • 2011-07-18 BR BR112013001335A patent/BR112013001335A2/pt not_active Application Discontinuation
  • 2011-07-18 MX MX2013000773A patent/MX2013000773A/es not_active Application Discontinuation
• 2013
  • 2013-01-16 US US13/742,816 patent/US8884033B2/en active Active

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