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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
  • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• • 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
• • 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
• • 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, in general, to the preparation of amino benzofuran derivatives.
• the invention relates to a process for the preparation of 5-amino-benzofuran derivatives of general formula:
• R 1 is hydrogen or alkyl and R 2 is alkyl or dialkylaminoalkyl.
• R represents in particular an alkyl group
• linear or branched dC 8 include an alkyl group, linear or branched C 1 -C 4 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl or tert-butyl,
• R 2 represents in particular an alkyl group
• linear or branched dC 8 include an alkyl group, linear or branched C 1 -C 4 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec butyl or tert-butyl or a dialkylaminoalkyl group in which each linear or branched alkyl group is in CC 8 in which each linear or branched alkyl group is in CC 4 such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
• R 2 represents 3- (di-n-butylamino) -propyl.
• R 2 represents 3- (di-n-butylamino) -propyl.
• EP 0471609 discloses a process for the synthesis of 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) propoxy] benzoyl ⁇ -5-amino benzofuran using 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) -propoxy] -benzoyl ⁇ -5-nitrobenzofuran which is reduced under pressure with the hydrogen in the presence of platinum oxide as a catalyst, which produces the desired compound.
• WO 03/040120 describes a process for the preparation of Dronedarone, in 6 steps, using a Friedel-Crafts reaction.
• this document does not describe the preparation of Dronedarone comprising a simple step of treating a 5-N-alkylamido-benzofuran derivative of formula (IIa) according to the invention with a strong acid.
• the 5-amino-benzofuran derivatives of formula I can be prepared by treating, with a strong acid such as a hydracid, for example hydrochloric acid, a 5-N-alkylamido-benzofuran derivative of general formula:
• R 1 and R 2 have the same meaning as above and R 3 represents a linear or branched C 1 -C 4 alkyl group, for example methyl, to form an acid addition salt of the compound of formula I, which salt is itself treated, if necessary, with a basic agent such as an alkali metal hydroxide, to produce this compound of formula I in free base form.
• a basic agent such as an alkali metal hydroxide
• strong acid is meant any chemical compound which has a very high affinity for providing protons in the reaction medium and which is characterized, in aqueous solution, by a pKa less than or equal to 1.
• strong acid is meant in particular any hydracid such as selected from hydrochloric acid, hydrobromic acid or hydrofluoric acid.
• basic agent any chemical compound which has a strong affinity for H + protons and which is characterized, in aqueous solution, by a pKa greater than 7.
• base agent is meant in particular all types of bases as chosen from organic bases, weak bases and strong bases, especially chosen from tertiary amines, alkali metal carbonates and alkali metal hydroxides.
• strong base is meant any chemical compound which has a very high affinity for H + protons and which is characterized, in aqueous solution, by a pKa greater than 14.
• strong base is meant in particular any hydroxide of alkali metal, as selected from sodium or potassium hydroxide.
• the acid treatment can be carried out in a polar solvent such as an alcohol, for example ethanol, by means of an acid generally in excess, for example from 1 to 6 equivalents of this acid per equivalent of compound of formula II.
• a polar solvent such as an alcohol, for example ethanol
• the acid addition salt of the compound of formula I can be treated with a basic agent, after isolation of the reaction medium in which it is formed or, conversely, in situ, that is to say within this same reaction medium.
• the starting compounds of formula II may be prepared according to the following reaction scheme: ⁇
• This amide of formula IV is then reacted with an ester of formula V in which R 1 has the same meaning as above, R 4 represents a linear or branched alkyl group at dC 4 and Hal represents a halogen, for example bromine, in the presence of a basic agent generally a weak base such as an alkali metal carbonate and by heating in a polar solvent so as to form an ester of formula VI in which R 1, R 3 and R 4 have the same meaning as above.
• the ester of formula VI is then saponified in the presence of a strong base generally an alkali metal hydroxide, the reaction usually taking place at room temperature. and a suitable solvent, for example an ether, to give a carboxylic acid derivative salt which is treated with a strong acid, such as a hydric acid, for example hydrochloric acid, which provides a derivative of carboxylic acid of formula VII wherein R 1 and R 3 have the same meaning as above.
• a strong base generally an alkali metal hydroxide
• a suitable solvent for example an ether
• the compound of formula VII thus produced is then cyclized to a benzofuran derivative of formula VIII in which R 1 and R 3 have the same meaning as above and this, in the presence of an organic base, generally a tertiary amine and a halide of benzenesulfonyl.
• an organic base generally a tertiary amine and a halide of benzenesulfonyl.
• the reaction is usually conducted by heating in a suitable solvent, generally an aprotic solvent such as an aromatic hydrocarbon or an ether.
• the benzofuran derivative of formula VIII thus obtained is then coupled with an acyl halogen of formula IX in which R 5 represents an alkyl group, linear or branched, in CC 4 for example methyl and Hal has the same meaning as previously for example chlorine and this, in the presence of a Lewis acid for example ferric chloride and in a non-polar solvent for example a halogenated compound.
• the reaction medium thus obtained is then hydrolysed in the presence of a strong acid, for example a hydric acid, to produce a ketone of formula X in which R 1, R 3 and R 5 have the same meaning as above.
• This ketone of formula X is then dealkylated by heating in the presence of aluminum chloride and in a non-polar solvent usually a halogenated solvent such as chlorobenzene to form a 4-hydroxyphenyl derivative of formula XI in which R 1 and R 3 have the same meaning as before.
• the compound of formula XI is reacted with an alkyl halide of formula XII in which R 2 has the same meaning as above and Hal has the same meaning as above, for example chlorine, the reaction taking place in the presence of a basic agent such as an alkali metal carbonate and by heating usually in a polar solvent such as a ketone to produce the desired compound of formula II.
• a basic agent such as an alkali metal carbonate
• a polar solvent such as a ketone
• Another subject of the present invention relates to N-phenylalkylamide derivatives of general formula:
• R 3 has the same meaning as above and Y represents hydrogen or a group of general formula:
• R / and R 6 each represent, independently of one another, hydrogen or a linear or branched alkyl group, in CC 4
• N-phenyl-alkylamide derivatives of general formula XIII mention may be made of those in which R 3 represents a linear or branched alkyl group at CC 4 and Y represents a group of general formula XIV:
• R / and R 6 each independently represent hydrogen or a linear or branched alkyl group at CC 4 .
• N-phenylalkylamide derivatives of formula XIII may be those in which: a) R 3 represents methyl and Y represents group XIV in which R represents n-butyl and R 6 represents methyl,
• R 3 represents methyl and Y represents group XIV in which R represents n-butyl and R 6 represents hydrogen.
• Another object of the present invention relates to 5-N-alkylamido-benzofuran derivatives of the general formula.
• R 2 ' is hydrogen, a linear or branched alkyl group of CC 4 or a dialkylaminoalkyl group in which each linear or branched alkyl group is C 1 -C 4
• R 2 ' is hydrogen, a linear or branched alkyl group of CC 4 or a dialkylaminoalkyl group in which each linear or branched alkyl group is C 1 -C 4 .
• R / is n-butyl
• R 3 is methyl
• R 2 ' is hydrogen, methyl or 3- (di-n-butylamino) propyl.
• subgroups of the 5-N-alkylamido-benzofuran derivatives of formula XV may be those wherein: a) R / is n-butyl, R 3 is methyl, and Z is the group XVI wherein R 2 ' represents hydrogen,
• R / represents n-butyl
• R 3 represents methyl
• Z represents group XVI in which R 2 'represents methyl
• R / represents n-butyl
• R 3 represents methyl
• Z represents group XVI in which R 2 'represents 3- (di-n-butylamino) -propyl.
• a further object of the present invention is the use of compounds of formula II for the preparation of dronedarone and its pharmaceutically acceptable salts.
• R 3 has the same meaning as above, for example methyl, with a strong acid such as a hydro acid for example hydrochloric acid, to form an addition salt (also called “acid addition salt”) ) 2-n-butyl-3- ⁇ 4- [3- (di-n-butylamino) -propoxy] -benzoyl ⁇ -5-amino-benzofuran of the formula:
• the dichloromethane layer is washed with water (3 x 10 ml) and then this phase is concentrated on a rotary evaporator to give 9 g of brown crystals. These crystals are re-empted with 20 ml of water and then crushed with a spatula to recover finely divided crystals suspended in water. It is then filtered, which gives 8.9 g of wet crystals which are taken up in 25 ml of methyl tert-butyl ether. 5 ml of methanol are added and the mixture is then refluxed for 1 hour in the presence of black (0.1 g). The hot reaction mixture is filtered through Celite and then concentrated to 50%. 4 g of a precipitate of 98% organic purity are thus recovered. The filtrate is concentrated again and then stirred at room temperature which causes the appearance of a new precipitate which is filtered and dried. In this way 1.6 g of the desired compound is recovered.
• the reaction mixture is cooled to about 50 ° C and hydrolyzed by adding 4 ml of water.
• the toluene phase and the aqueous phase are decanted and drawn off.
• To this organic phase 2 ml of water and 0.2 of 36% hydrochloric acid are added. Stirring is carried out for 5 min, decanting and withdrawing the two phases.
• the toluene phase is washed with 2 ml of water, decanted and withdrawn the two phases.
• the organic phase is washed with a solution of 0.9 g of 23% sodium hydroxide in 1.5 ml of water.
• the toluene phase is stirred, decanted and washed with a solution of 2 g of 10% sodium chloride.
• the two phases are decanted, the two phases are withdrawn and the toluene phase is concentrated on a rotary evaporator to recover 1.1 g of the desired compound in the form of a brown oil.
• reaction medium While stirring, the reaction medium is allowed to return to ambient temperature, which causes the appearance of a precipitate which is kept in contact with an ice bath (5 ° C.) for 10 min.
• the reaction medium is filtered and pale yellow crystals are recovered. It is dried in an oven under vacuum and ⁇ ' ⁇ which provides 10.1 g of crystals. These crystals are taken up in ethyl acetate (4 volumes) and the mixture is then brought to reflux until dissolution takes place.
• the reaction medium is allowed to return to ambient temperature and then the crystals formed are filtered on sintered glass.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Furan Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 2010
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