Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

• the present invention relates to a process for the preparation of 4- (alkyl) -3-alkoxy-anineline type compounds from metaaminophenol
• R 1 represents a linear or branched C1-Cn alkyl group.
• R 2 represents an alkyl group, linear or branched in G-Cu, i
• the compounds of formula (I) are known and constitute very interesting synthetic intermediates which can in particular be condensed with compounds of alkoxyalkylidenemalonate type then cyclized to lead to quinoline or quinolone derivatives, widely used in human health and animal health
• esters of 4-hydroxyquinoleole-3-carboxylic acids such as methylbenzoquate (methyl ester of 7-benzyloxy-6-butyl-1, 4-dihydro-4-oxo-3 acid -quinoline carboxylic) which serve, in the field of animal health, in particular anticoccidians, used in the feeding of poultry in batteries
• This synthesis comprises the reaction of an aniline suitably substituted in position 3 and optionally in position 4 relative to the function) amine placed on the cycle, with a derivative of the alkoxymethylenemalonate type then the hot cvc sation of the resulting product
• the desired substituted aniline is obtained by 0- alkylation of the hydroxyl function of 3-acetylam ⁇ nophenol using an allylic halide transposition to lead to 3-hydroxyacetanihde 4-subst ⁇ tue corresponding then new O-substetion of the hydroxyl function using an appropriate halide and finally release of the amine function by hydrolysis
• This synthesis involves a large number of steps, some of which are not selective and lead to isomers or by-products which must be separated.
• the objective of the present invention is to provide a method for dissolving disubstituted anilines which is simple and relatively inexpensive, notably comprising a limited number of operations.
• Another object of the invention is to provide such a method
• the object of the invention is to provide a process for the preparation of compounds of formula (I) as defined above, characterized in that it comprises the steps consisting in:
• the group R 1 is preferably chosen from alkyl, linear or branched, or aralkyl groups such as methyl, n-propyl isopropyl, cyclopropylmethylene, 3-phenylpropyl, p-methylbenzyl, p-chlorobenzyl, o- chlorobenzyle, o, p-d ⁇ chlorobenzyle, p-nitrobenzyle, decvle and represents even more preferably the benzyl group
• the group R 2 preferably represents a linear or branched CF 1 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl and more preferably still represents the group n -propyle
• CF 1 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl and more preferably still represents the group n -propyle
• R 2 advantageously represents an alkyl group, linear or branched, in C ⁇ -C ⁇ It is used in an amount at least stoichiometric and preferably in an amount of at least two equivalents often around 2.2 equivalents
• a carboxylic acid chloride (R COCl) can also be used. It is advisable, in general, to react metaaminophenol with the acylation reagent with reaction times between 1 and 2 hours and with fairly high temperatures generally understood. between 100 ° C and 200 ° C preferably at the boiling temperature of the reaction solvent
• the solvent of lo the reaction is constituted by the acylating reagent itself associated with the corresponding carboxylic acid Step 2
• the catalyst is preferably aluminum chloride A1C1.
• Two equivalents of catalyst are advantageously used relative to metaaminophenol e !
• This step consists in achieving a reduction of the group in position 4 of the compound (IV)
• the reduction reaction is advantageously carried out by "hydrogenation in the presence of an industrial catalyst, in particular of the palladium on carbon type.
• a dihvdrogenic pressure of between 4 and 20 bars is used, preferably of the order of 12 bars.
• Palladium on carbon is preferably used as catalyst at levels which correspond to those usually used in
• the catalyst is used in a proportion of 1 to 2% (w / w) of metal relative to the product to be hydrogenated and preferably in a proportion between 1 4 and 1.6%
• the reaction is carried out in the presence of an acid, for example chosen from 1 phospho ⁇ que or acetic sulfu ⁇ que acid, and preferably in the presence of an acid, for example chosen from 1 phospho ⁇ que or acetic sulfu ⁇ que acid, and preferably in the presence of an acid, for example chosen from 1 phospho ⁇ que or acetic sulfu ⁇ que acid, and preferably in the presence of an acid, for example chosen from 1 phospho ⁇ que or acetic sulfu ⁇ que acid, and preferably in the presence
• the acid is advantageously introduced in proportions varying from 0 5 to 2 mol% relative to the product to be hydrogenated and preferably in a proportion of approximately l 5%
• the reaction is carried out in a protic solvent among which mention may be made of lower alcohols, in particular methanol and ethanol, monoglyme 1 ⁇ (ethylene glycol methyl ether), monoisopropyl glycol and l-methoxy-2-propanol methanol. or ethanol being preferred
• a protic solvent among which mention may be made of lower alcohols, in particular methanol and ethanol, monoglyme 1 ⁇ (ethylene glycol methyl ether), monoisopropyl glycol and l-methoxy-2-propanol methanol. or ethanol being preferred
• the reaction temperature can be between 50 and 100 ° C and preferably around 85 ° C
• the hydrogen compound (V) can be recovered in solid form by simple precipitation in water
• This last step consists in O-substituting the free hydroxyl function of the compound (V) previously obtained in step 3 and in protecting the amine function 2 ⁇
• a compound, of the chloride type of formula R'Cl is advantageously used, suitable according to the final compound (I) desired, which is reacted with the compound (V) in the presence of a base such as NaOH, KOH Na 2 Co or K 2 CO, in particular K 2 CO.
• This reaction is carried out in an aprotic solvent such as acetone) acetonitrile or dimethylformamide (DMF), advantageously in dimeth lformamide at a temperature between 50 and 100 ° C, preferably around 60 ° C
• an aprotic solvent such as acetone
• acetonitrile or dimethylformamide (DMF)
• DMF dimethylformamide
• the reaction time is generally between 4 and 8 hours on average between 5 and 6 hours " ⁇
• An excess of chloride (R'Cl) of between 1 4 and 1 9 equivalents, preferably 1 5 equivalents is advantageously used
• the base is used with an excess of 1 to 2 equivalents, preferably 1, 7 equivalents
• the 0-substituted product in position 3 may not be isolated, in which case it is directly reacted with a base for the protection of the amine function.
• this intermediate (I) for example by precipitation, by forming the corresponding hydrochloride.
• the compounds of formula (I) constitute synthesis intermediates which are particularly useful in the preparation of esters of 4-hydroxyquinoline-3-carboxylic acids or the like.
• esters are generally obtained by reaction of a compound of 2o dialkylalkoxyalkylidenemalonate type with a compound of the substituted aniline type of formula (I) followed by cychsation as described in particular in the document FR-A-1 487 336 cited above
• the invention also relates to the use of a compound of formula (I) for obtaining such derivatives
• the phenolic ester from step 1 is subjected to a Fries rearrangement, using two equivalents of AJCl. 99% compared to the starting metaaminophenol
• the temperature is maintained at 65 ° C ⁇ 5 ° C and then raised to 130 ° C
• reaction mixture is then hydrolyzed in a water-propanol-mono or dichlorobenzene mixture.
• the rearranged product (IV) crystallizes and can be isolated by
• the reactor is re-inflated to 12 bars as soon as the pressure reaches 7 5 bars
• the temperature continues to rise to 8 ° C as soon as there is no longer a decrease in pressure, the heating is stopped, the temperature is allowed to drop to 25 ° C, the dihydrogen is carefully degassed and the a nitrogen purge is carried out
• the reaction mass is filtered on a frit in order to recover the catalyst
• the filtrate is neutralized with sodium hydroxide ⁇ _ 2 This is then carried filtrate 1 minute at reflux of ethanol and poured into 200 ml of cold water
• the product precipitates, the mixture is left to stir for half a day and filtered on a buchner. 3.54 g of hydrogen product is recovered.
• the purity in HPLC is 90% hence a yield of 75% pure product
• Example 8 illustrates an alternative embodiment of steps 1 and 2 of the method of the invention.
• Example 9 illustrates an alternative embodiment of step 4 of the method according to the invention.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Saccharide Compounds (AREA)
• Silicon Compounds (AREA)

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• 1997
  • 1997-06-16 FR FR9707444A patent/FR2764601B1/fr not_active Expired - Lifetime
• 1998
  • 1998-06-16 IT ITTO980522 patent/ITTO980522A1/it unknown
  • 1998-06-16 WO PCT/FR1998/001264 patent/WO1998057921A1/fr not_active Application Discontinuation
  • 1998-06-16 CN CN 98807249 patent/CN1244543C/zh not_active Expired - Lifetime
  • 1998-06-16 EP EP98932216A patent/EP0994846A1/fr not_active Withdrawn
  • 1998-06-16 BR BR9810037-8A patent/BR9810037A/pt not_active Application Discontinuation

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