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
• • 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
  • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
  • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
  • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
  • B01J23/44—Palladium
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B45/00—Formation or introduction of functional groups containing sulfur
  • C07B45/04—Formation or introduction of functional groups containing sulfur of sulfonyl or sulfinyl groups
• • 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
  • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

• the present invention relates generally to a process for the preparation of sulfonamido-benzofuran derivatives.
• the invention relates to a process for the preparation of 5-sulfonamido-benzofuran derivatives of general formula:
• R represents an alkyl or aryl group and R 1 and R 2 , which may be identical or different, each represent hydrogen or an alkyl or aryl group.
• Ri or R 2 represents in particular an alkyl group, linear or branched dC 8 including a linear alkyl group or branched C 1 -C 4 such as methyl, ethyl, n-propyl isopropyl, n-butyl or tert-butyl or a substituted or unsubstituted phenyl group.
• 2-n-butyl-5-sulfonamido-benzofuran described in patent application WO 02/48132 has proved particularly useful as an intermediate product for the final preparation of aminoalkoxybenzoyl-benzofuran derivatives especially for the preparation of 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) propoxy] -benzoyl ⁇ -5-methanesulfonamidobenzofuran commonly known as dronedarone and its pharmaceutically acceptable salts.
• This methanesulphonamido-benzofuran derivative has been described in patent EP0471609 as well as its therapeutic applications, particularly in the cardiovascular field where it has proved particularly advantageous for example as an antiarrhythmic agent.
• the 5-sulfonamido-benzofuran derivatives of formula I can be prepared by coupling a benzofuran derivative of general formula:
• R 1 and R 2 have the same meaning as before and X represents chlorine, bromine or iodine or a sulphonate group of general formula:
• R 3 represents a trifluoromethane (-CF 3 ) or imidazolyl group, with a sulphonamide derivative of general formula:
• R has the same meaning as above and in the presence of a basic agent and a catalyst system formed of a complex between a palladium compound and a ligand, which provides the desired compounds.
• the palladium complex used in the process of the invention is generally in the form of a palladium (0) compound such as, for example:
• biarylphosphines are, in general, substituted in various ways.
• the aryl ring such as phenyl, which does not carry the phosphorus atom can be mono- or especially polysubstituted, for example by the isopropyl group, whereas the aryl ring, in particular phenyl, carrying the phosphorus atom can to be, moreover, mono- or polysubstituted.
• this aryl ring has no substituents other than the phosphorus atom.
• the phosphorus atom can itself be substituted, for example mono- or, especially, disubstituted, for example by alkyl or cycloalkyl groups such as tert-butyl or cyclohexyl.
• L1 ligand 2- (di-tert-butylphosphino) -2 ', 4', 6'-triisopropyl-1,1'-biphenyl, hereinafter referred to as "L1 ligand",
• L2 ligand 2- (Dicyclohexylphosphino) -2 ', 4', 6'-triisopropyl-1,1'-biphenyl, hereinafter referred to as "L2 ligand",
• L3 ligand 2- (Dicyclohexylphosphino) -2 ', 6'-dimethoxy-1,1'-biphenyl, hereinafter referred to as "L3 ligand",
• L4 ligand 2- (di-tert-butylphosphino) -3,4,5,6-tetramethyl-2 ', 4', 6'-triisopropyl-1,1'-biphenyl, hereinafter referred to as "L4 ligand”.
• the ligand L1 is particularly advantageous.
• the basic agent used in the process according to the invention may be chosen from, in particular, alcoholates, but more generally from weaker bases such as phosphates or carbonates, for example alkali metal phosphates or alkali metal carbonates. such as tripotassium phosphate, potassium carbonate or cesium carbonate.
• the coupling reaction is carried out hot, for example at a temperature between 60 ° C and 120 ° C, and in a suitable solvent.
• This may be an alcohol such as for example tert-butanol, an ether such as for example tetrahydrofuran or dioxane or a hydrocarbon, preferably aromatic, such as for example toluene.
• dioxane is a solvent of choice in the context of the present invention.
• the starting compounds of formula II can be prepared in different ways according to their chemical structure, as described below.
• the ester of formula VII is then saponified in a solvent, especially an ether, and in the presence of a suitable basic agent such as an alkali metal hydroxide to form the corresponding salt of a carboxylic acid derivative which is then treated with a strong acid, in a solvent such as an aromatic hydrocarbon, to give the carboxylic acid derivative of formula VIII wherein R 1, R 2 and X 1 have the same meaning as above.
• a suitable basic agent such as an alkali metal hydroxide
• the carboxylic acid derivative of formula VIII is then cyclized by heating in the presence of a benzenesulphonyl halide and an acid acceptor such as a tertiary amine, the reaction generally taking place by heating in a solvent such as an aromatic hydrocarbon, to give the compounds of formula IX wherein X 1, R 1 and R 2 have the same meaning as before, i.e. the desired compounds of formula II.
• R ' 3 represents a trifluoromethane or imidazolyl group represent another object of the present invention.
• the temperature of the reaction medium is reduced to 20% and then 100 ml of deionized water are added slowly, leading to the demixing of an oil.
• This oil is decanted and separated from the aqueous phase, then washed with 100 ml of water. After decantation and separation, the oil is diluted with 60 ml of toluene and this organic phase is washed again with 100 ml of deionized water. This last aqueous phase is counter-extracted 60 ml of ethyl acetate.
• the organic phases are combined and then concentrated on a rotary evaporator to obtain 34.9 g of the desired compound X in the form of an orange-yellow oil.
• the temperature of the reaction medium is brought to 20 ° C. and 25.5 g of sodium chloride (0.43 mol) in 130 ml of deionized water and then 270 ml of toluene are added.
• the reaction medium is acidified by slowly adding 20 ml of a 37% hydrochloric acid solution, without exceeding 25%.
• the two phases are decanted and separated, then the organic phase is washed with 80 ml of deionized water. After separation of the phases, the organic phase is concentrated under vacuum on a rotary evaporator to yield 54.7 g of a red oil, which crystallizes in the cold state.
• the temperature of the reaction medium is brought to 20 ° C.
• Excess benzenesulfonyl chloride is destroyed by the addition of 250 ml of 5% aqueous sodium hydroxide solution.
• the phases are decanted and separated and the organic phase is washed with a mixture of 70 ml of deionized water and 6.8 ml of 37% hydrochloric acid.
• the phases are decanted and separated and the organic phase is washed with 75 ml of deionized water.
• the organic phase is washed with a solution of 7.73 g of sodium hydroxide dissolved in 67 ml of deionized water.
• the phases are decanted and separated then the organic phase is washed with a solution of 7.53 g of sodium chloride in 70 ml of deionized water.
• the pH of the aqueous phase is adjusted to between 5 and 8 with a 7% hydrochloric acid solution.
• the phases are decanted and separated then the organic phase is concentrated on a rotary evaporator to yield 37.2 g of a brown oil.
• This oil is purified by chromatography on silica gel (eluent: methylcyclohexane / ethyl acetate: 80/20) to give 24.3 g of the desired compound XII as a yellow oil.
• reaction medium is then stirred and heated at reflux of the solvent or at 100 ° C for 24 hours, while monitoring the evolution of the reaction by TLC (eluent: ethyl acetate / methylcyclohexane 20/80) or by HPLC.
• TLC eluent: ethyl acetate / methylcyclohexane 20/80
• HPLC HPLC
• reaction medium is then stirred and heated at 100 ° C. for 24 hours.
• the reaction medium is then diluted with 40 ml of ethyl acetate and the first crystallization stream is filtered on Buchner. After isolation of a second jet, 3.6 g of desired compound I are isolated as a snow-white powder.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Materials Engineering (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Plural Heterocyclic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Furan Compounds (AREA)
• Catalysts (AREA)

Applications Claiming Priority (2)

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• 2010
  • 2010-03-30 FR FR1052334A patent/FR2958290B1/fr not_active Expired - Fee Related
• 2011
  • 2011-03-30 SG SG2012071965A patent/SG184315A1/en unknown
  • 2011-03-30 KR KR1020127028218A patent/KR20130018809A/ko not_active Withdrawn
  • 2011-03-30 MX MX2012011344A patent/MX2012011344A/es not_active Application Discontinuation
  • 2011-03-30 US US13/638,500 patent/US9334254B2/en active Active
  • 2011-03-30 CA CA2794436A patent/CA2794436A1/fr not_active Abandoned
  • 2011-03-30 EP EP11720315A patent/EP2552899A1/fr not_active Withdrawn
  • 2011-03-30 JP JP2013501913A patent/JP2013523699A/ja not_active Withdrawn
  • 2011-03-30 AU AU2011236671A patent/AU2011236671A1/en not_active Abandoned
  • 2011-03-30 BR BR112012024792A patent/BR112012024792A2/pt not_active IP Right Cessation
  • 2011-03-30 CN CN201180026858XA patent/CN102933568A/zh active Pending
  • 2011-03-30 WO PCT/FR2011/050707 patent/WO2011124827A1/fr active Application Filing
  • 2011-03-30 RU RU2012146086/04A patent/RU2012146086A/ru not_active Application Discontinuation
• 2012
  • 2012-09-27 IL IL222191A patent/IL222191A0/en unknown

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