EP0991793B1 - Method for preparing 2-aryl or 2-heterocyclyl chiral propionic acids and their esters - Google Patents

Method for preparing 2-aryl or 2-heterocyclyl chiral propionic acids and their esters Download PDF

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EP0991793B1
EP0991793B1 EP98933708A EP98933708A EP0991793B1 EP 0991793 B1 EP0991793 B1 EP 0991793B1 EP 98933708 A EP98933708 A EP 98933708A EP 98933708 A EP98933708 A EP 98933708A EP 0991793 B1 EP0991793 B1 EP 0991793B1
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derivative
radical
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aromatic
alkyl
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EP0991793A1 (en
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Muriel Durandetti
Isabelle Lachaise
Jean-Yves Nedelec
Jacques Perichon
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Centre National de la Recherche Scientifique CNRS
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    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/20—Processes
    • C25B3/25—Reduction

Definitions

  • the present invention relates to a process for the preparation of chiral 2-aryl or 2-heterocyclyl propionic acids ( R or S ) and their esters of very high enantiomeric purity.
  • 2-aryl or 2-heterocyclyl propionic acids and their esters are useful as anti-inflammatory drugs (ketoprofen, ibuprofen, naproxen, tiaprofen, fenoprofen, flurbiprofen, indoprofen, pirprofen, suprofen, cicloprofen, carprofen, benoxaprofen, hexaprofen, pranaprofen for example) but also as intermediaries in the preparation of medicines (EP514442, EP516729, EP518961, EP518960, EP520016, EP593639, Ep527069, EP607355, EP538099. EP678098, EP679161, EP678088, EP678089, EP766695, EP766696 for example).
  • the 2-aryl or 2-heterocyclyl propionic acids and their esters are used either in racemic form or in the form of an ( R or S ) enantiomer.
  • R or S the biological activity of these compounds is associated with a single enantiomer and it is therefore necessary to obtain these enantiomers by a simple industrial process, inexpensive and non-polluting.
  • the 2-aryl or 2-heterocyclyl propionic acids and their esters are represented by the formula: in which R 1 represents an aryl or a heterocycle which are optionally substituted and R 2 represents a hydrogen atom or an alkyl or phenylalkyl radical.
  • R 1 is (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents chosen from chlorine, bromine, fluorine, alkyl, alkoxy, alkenyl, hydroxy, hydroxyalkyl, acyl, benzoyl, amino, phenyl , chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, -CH (NH 2 ) -COOH, heterocycle of 5 to 14 chains saturated or unsaturated and containing a heteroatom chosen from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl, (c) a naphthyl radical, (d) a naphthyl radical substituted by one or more substituents chosen from chlorine,
  • heterocycles of 5 to 14 links mention may be made of carbazole, indane, thiophene, furan, 1-isoindolinone, pyrrole, 2,5-dihydropyrrole, benzoxazole, 5H [1] benzopyrano [2,3-b] pyridine, pyridine, imidazole, oxazole, quinoline, isoquinoline, pyrimidine, phenothiazine, phenoxazine, piperazine.
  • R 1 represents a 3-benzoylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 4-isobutylphenyl, 6-methoxy-2-naphthyl, 5-benzoyl-2-thienyl, 3-phenoxyphenyl, 2- radical.
  • R 2 represents a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or benzyl radical.
  • alkyl, alkoxy and alkenyl radicals contain contain 1 to 6 carbon atoms in a straight or branched chain
  • acyl radicals contain 2 to 6 carbon atoms
  • the halogen atoms are the chlorine, bromine, iodine and fluorine atoms.
  • the aromatic or heterocyclic halogenated derivatives are those of formula: R 1 - Hal in which R 1 has the same meanings as in formula (I) and Hal represents an iodine, chlorine or bromine atom.
  • Derivatives (II) and halogenated aromatic or heterocyclic derivatives are reacted in stochiometric quantities. It is better to add the derivative (II) gradually during the electrolysis.
  • the nickel complex is preferably a complex with a nitrogenous ligand and more particularly a NiBr 2 bipyridine or nickelorthophenanthroline complex. It can be prepared either extemporaneously or in situ before the start of electrolysis.
  • the amount of the nickel complex is generally between 0.01 mole and 0.2 mole per 1 mole of the aromatic halogen derivative or heterocyclic and preferably 0.1 mole per 1 mole of the halogenated derivative aromatic or heterocyclic.
  • the electrolyte is generally a quaternary ammonium salt such as tetrabutylammonium tetrafluoroborate or tetrabutylammonium bromide or a mineral salt such as sodium bromide. Its concentration is generally between 5.10 -3 M and 2.10 -2 M and, preferably 1.5.10 -2 M.
  • the solvent is generally an aprotic solvent such as dimethylformamide, N-methylpyrrolidone (preferably dimethylformamide) or a mixture of aprotic and protic solvents, preferably a mixture dimethylformamide-ethanol (80-20% to 20-80%).
  • aprotic solvent such as dimethylformamide, N-methylpyrrolidone (preferably dimethylformamide) or a mixture of aprotic and protic solvents, preferably a mixture dimethylformamide-ethanol (80-20% to 20-80%).
  • the anode is a consumable anode of aluminum or alloy aluminum such as Duralumin or an anode of zinc, iron or magnesium. It is best to use an aluminum anode.
  • the cathode has a hollow cylindrical shape and is arranged concentrically around the anode.
  • the medium temperature is generally maintained at an optimal value which depends on the nature of the aromatic or heterocyclic halogenated derivative used by immersing the reactor in a thermoregulated bath or by a double envelope system. It is generally between 15 ° C and 100 ° C, and preferably at about 20 ° C.
  • the electrolysis is carried out at constant intensity at a value between 0.1 and 1 Ampere depending on the surface of the cathode used.
  • the current density is 0.5 to 1 A / dm 2 relative to the surface of the cathode.
  • the amount of electricity required is determined by the disappearance of aromatic or heterocyclic halide followed by a method appropriate analytical (for example by phase chromatography carbonated). It is generally between 2 and 3 Faradays per mole of aromatic or heterocyclic halogenated derivative, and preferably 2.5 Faradays per mole of aromatic or heterocyclic halogenated derivative.
  • the rest of the derivative (II) is generally added as the course of electrolysis by any appropriate means (in solid form, liquid or in solution in one of the solvents constituting the medium).
  • the reaction is carried out in a tubular circulation electrolyser constituted by a central aluminum or Duralumin rod serving as anode and by a stainless steel tube serving as cathode.
  • the two electrodes are insulated by Teflon R seals which also provide sealing.
  • the cathode can be lined internally with a grid of nickel foam of cylindrical shape in order to increase its active surface.
  • the solution is set in motion by means of a pump. She penetrates in the reactor by a lateral tube situated towards its lower end and out of it by a similar tube located towards its upper end.
  • a thermostatically controlled expansion tank is placed on the middle circuit reactive.
  • the current intensity is adjusted so that the current density is similar to that used in the other type of reactor.
  • Hydrolysis of the product obtained after extraction, to obtain the acid propionic takes place in an acidic or alkaline medium.
  • it is carried out either by means of aqueous sulfuric acid 6N at reflux or else by the action of lithium hydroxide, in an inert solvent such as tetrahydrofuran, at a temperature in the region of 20 ° C.
  • Transesterification to obtain the alkyl or phenylalkyl ester is generally carried out by the action of potassium carbonate and an alcohol aliphatic (1 to 6 carbon atoms in a straight or branched chain) or a alcohol Ar-alkOH in which Ar represents a phenyl radical and alk represents an alkyl radical, at a temperature in the region of 20 ° C.
  • the derivatives of formula (II) can be obtained by condensation of the chloride of 2-chloropropionic acid with the lithium salt of (4 S , 5 R ) -1,5-dimethyl-4-phenylimidazolidine-2-one, (4 R , 5 S ) -1,5-dimethyl-4-phenylimidazolidine-2-one or (4 R ) -4-phenyloxazolidine-2-one
  • Aromatic or heterocyclic halogenated derivatives are sold or can be obtained by applying or adapting the methods described in J. Prakt. Chem., 109, 318 (1925); Gazz. Chim. Ital., 122 (12), 511-514 (1992); Tetrahedron, 50 (4), 1243-1260 (1994); J. Org. Chem., 32, 2692-2695 (1967); J. Org. Chem., 13, 916 (1948); Chem. Abst. 6878 (1955); Trav. Chim. Netherlands, 42? 507 51 923 °. Trav. Chim. Netherlands, 71, 285 (1952); J. Amer. Chem. Soc., 76, 1106 (1954); J. Chem.
  • the reaction with the acid chloride is instantaneous.
  • the solution is hydrolyzed with 30 ml of water and the temperature rises to around 20 ° C.
  • the mixture is extracted with 3 X 20 ml of ethyl acetate.
  • the product is separated on a silica column, using the pentane / ether mixture (50/50) as eluent. The yield is 75%.
  • the reaction with the acid chloride is instantaneous.
  • the solution is hydrolyzed with 30 ml of water and the temperature rises to around 20 ° C.
  • the mixture is extracted with 3 X 20 ml of ethyl acetate.
  • the product is separated on a silica column, using the pentane / ether mixture (50/50) as eluent. The yield is 75%.
  • the solution is hydrolyzed with 30 ml of water and the temperature rises to around 20 ° C.
  • the mixture is extracted with 3 X 20 ml of ethyl acetate.
  • the product is separated on a silica column, using the pentane / ether mixture (50/50) as eluent. The yield is 85%.
  • the reaction is carried out at room temperature (approximately 20 ° C). We do bubbling an inert gas (argon) saturated with vapor with the solvent mixture, for about 10 minutes. The bubbling is then maintained in the solution for the duration of the electrolysis.
  • argon inert gas
  • the electrolyser comprises an anode constituted by an aluminum bar (diameter 1 cm) placed in the center of the reactor and a foam cathode cylindrical nickel (diameter 3 cm - height 5 cm) arranged concentrically at the anode.
  • derivative (II) is carried out by adding fractions of 200 ⁇ l of 0.625 M / I solution in dimethylformamide every two minutes. After 3 hours, correspondent passing 2.7 Faradays per mole of the aromatic halogen derivative or heterocyclic, electrolysis is stopped as well as the addition of derivative (II) (addition total 12.5 millimoles).
  • the solution is hydrolyzed with 40 ml of acid hydrochloric 1 N. The solvents are removed under vacuum in an evaporator rotary. The residue is taken up in water.
  • the aqueous phase is extracted 3 times 40 ml of ethyl ether.
  • the organic phase is separated by decantation, rinsed 5 times with 40 ml of distilled water, dried over magnesium sulfate and then filtered and evaporated to dryness under reduced pressure.
  • the expected product is purified by chromatography on 100 g of silica contained in a 3 cm column in diameter (generally eluent: pentane / ether: 50/50).
  • the diastereoisomeric excess is determined by phase chromatography carbonated.
  • EXAMPLE 2 EXAMPLE OF HYDROLYSIS IN AN ALKALINE MEDIUM WITH OBTAINING THE CORRESPONDING ACID
  • EXAMPLE 3 EXAMPLE OF HYDROLYSIS IN AN ACID MEDIUM WITH OBTAINING THE CORRESPONDING ACID
  • 0.5 g of the product obtained is added to 5 ml of 8 N aqueous sulfuric acid. according to Example 1.
  • the mixture is brought to reflux and left to react for 18 to 20 hours at a temperature close to 100 ° C.
  • the aqueous phase is acidified then extracted with 2 times 20 ml of dichloromethane.
  • Organic phases are dried over magnesium sulphate and then evaporated. We thus obtain pure acid.
  • the rotary power measured and compared to the value of the literature gives enantiomeric excess.
  • EXAMPLE 4 EXAMPLE OF “TRANSESTERIFICATION” WITH OBTAINING METHYL ESTER :

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Description

La présente invention concerne un procédé de préparation d'acides 2-aryl ou 2-hétérocyclyl propioniques chiraux (R ou S) et leurs esters de très haute pureté énantiomérique.The present invention relates to a process for the preparation of chiral 2-aryl or 2-heterocyclyl propionic acids ( R or S ) and their esters of very high enantiomeric purity.

Les acides 2-aryl ou 2-hétérocyclyl propioniques et leurs esters sont utiles comme médicaments antiinflammatoires (ketoprofen, ibuprofen, naproxen, tiaprofen, fenoprofen, flurbiprofen, indoprofen, pirprofen, suprofen, cicloprofen, carprofen, benoxaprofen, hexaprofen, pranaprofen par exemple) mais aussi comme intermédiaires dans la préparation de médicaments (EP514442, EP516729, EP518961, EP518960, EP520016, EP593639, Ep527069, EP607355, EP538099. EP678098, EP679161, EP678088, EP678089, EP766695, EP766696 par exemple).2-aryl or 2-heterocyclyl propionic acids and their esters are useful as anti-inflammatory drugs (ketoprofen, ibuprofen, naproxen, tiaprofen, fenoprofen, flurbiprofen, indoprofen, pirprofen, suprofen, cicloprofen, carprofen, benoxaprofen, hexaprofen, pranaprofen for example) but also as intermediaries in the preparation of medicines (EP514442, EP516729, EP518961, EP518960, EP520016, EP593639, Ep527069, EP607355, EP538099. EP678098, EP679161, EP678088, EP678089, EP766695, EP766696 for example).

Les acides 2-aryl ou 2-hétérocyclyl propioniques et leurs esters sont utilisés soit sous forme racémique ou sous forme d'un énantiomère (R ou S). Généralement, l'activité biologique de ces composés est associée à un seul énantiomère et il est donc nécessaire d'obtenir ces énantiomères par un procédé industriel simple, peu coûteux et non polluant.The 2-aryl or 2-heterocyclyl propionic acids and their esters are used either in racemic form or in the form of an ( R or S ) enantiomer. Generally, the biological activity of these compounds is associated with a single enantiomer and it is therefore necessary to obtain these enantiomers by a simple industrial process, inexpensive and non-polluting.

De nombreux procédés de préparation de ces composés ont été développés mais conduisent généralement aux composés racémiques et les énantiomères doivent ensuite être séparés par résolution chimique ou transformation microbienne.Many processes for the preparation of these compounds have been developed but generally lead to racemic compounds and enantiomers must then be separated by chemical resolution or microbial transformation.

De préférence, les acides 2-aryl ou 2-hétérocyclyl propioniques et leurs esters sont représentés par la formule :

Figure 00010001
dans laquelle R1 représente un aryle ou un hétérocycle qui sont éventuellement substitués et R2 représente un atome d'hydrogène ou un radical alkyle ou phénylalkyle.Preferably, the 2-aryl or 2-heterocyclyl propionic acids and their esters are represented by the formula:
Figure 00010001
in which R 1 represents an aryl or a heterocycle which are optionally substituted and R 2 represents a hydrogen atom or an alkyl or phenylalkyl radical.

Plus particulièrement, R1 est (a) un radical phényle, (b) un radical phényle substitué par un ou plusieurs substituants choisis parmi chlore, brome, fluor, alkyle, alcoxy, alcényle, hydroxy, hydroxyalkyle, acyle, benzoyle, amino, phényle, chlorophényle, bromophényle, fluorophényle, phénoxy, cyano, polyfluoroalkyle, polyfluoroalcoxy, alcoxycarbonyle, -CH(NH2)-COOH, hétérocycle de 5 à 14 chaínons saturé ou non saturé et contenant un hétéroatome choisi parmi azote, oxygène ou soufre éventuellement substitué par chlore, brome, fluor, alkyle, phényle, chlorophényle, bromophényle, fluorophényle, (c) un radical naphtyle, (d) un radical naphtyle substitué par un ou plusieurs substituants choisis parmi chlore, brome, fluor, alkyle, alcoxy, alcényle, hydroxy, hydroxyalkyle, acyle, benzoyle, amino, phényle, chlorophényle, bromophényle, fluorophényle, phénoxy, cyano, polyfluoroalkyle, polyfluoroalcoxy, alcoxycarbonyle, hétérocycle de 5 à 14 chaínons saturé ou non saturé et contenant un ou plusieurs hétéroatomes choisis parmi azote, oxygène ou soufre éventuellement substitué par chlore, brome, fluor, alkyle, phényle, chlorophényle, bromophényle, fluorophényle, (e) un radical 9H-fluorényle, (f) un radical anthracényle, (g) un radical phénanthrényle, (h) un hétérocycle de 5 à 14 chaínons saturé ou insaturé contenant un ou plusieurs hétéroatomes choisis parmi azote, oxygène et soufre, (i) un hétérocycle de 5 à 14 chaínons saturé ou insaturé contenant un ou plusieurs hétéroatomes choisis parmi azote, oxygène et soufre et substitué par un ou plusieurs substituants choisis parmi chlore, brome, fluor, alkyle, alcoxy, acyle, benzoyle, amino, phényle, chlorophényle, bromophényle, fluorophényle, phénoxy, cyano, polyfluoroalkyle, polyfluoroalcoxy, alcoxycarbonyle, hétérocycle de 5 à 14 chaínons saturé ou non saturé et contenant un ou plusieurs hétéroatomes choisis parmi azote, oxygène ou soufre éventuellement substitué par chlore, brome, fluor, alkyle, phényle, chlorophényle, bromophényle, fluorophényle.More particularly, R 1 is (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents chosen from chlorine, bromine, fluorine, alkyl, alkoxy, alkenyl, hydroxy, hydroxyalkyl, acyl, benzoyl, amino, phenyl , chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, -CH (NH 2 ) -COOH, heterocycle of 5 to 14 chains saturated or unsaturated and containing a heteroatom chosen from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl, (c) a naphthyl radical, (d) a naphthyl radical substituted by one or more substituents chosen from chlorine, bromine, fluorine, alkyl, alkoxy, alkenyl, hydroxy , hydroxyalkyl, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, heterocycle of 5 to 14 saturated links o u unsaturated and containing one or more heteroatoms chosen from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl, (e) a 9H-fluorenyl radical, (f) an anthracenyl radical , (g) a phenanthrenyl radical, (h) a heterocycle of 5 to 14 saturated or unsaturated chains containing one or more heteroatoms chosen from nitrogen, oxygen and sulfur, (i) a heterocycle of 5 to 14 saturated or unsaturated chains containing one or several heteroatoms chosen from nitrogen, oxygen and sulfur and substituted by one or more substituents chosen from chlorine, bromine, fluorine, alkyl, alkoxy, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, heterocycle of 5 to 14 saturated or unsaturated links and containing one or more heteroatoms chosen from nitrogen, oxygen or sulfur, where appropriate Lement substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl.

Parmi les hétérocycles de 5 à 14 chaínons, on peut citer le carbazole, l'indane, le thiophène, le furane, la 1-isoindolinone, le pyrrole, le 2,5-dihydropyrrole, le benzoxazole, la 5H[1]benzopyrano[2,3-b]pyridine, la pyridine, l'imidazole, l'oxazole, la quinoléine, l'isoquinoléine, la pyrimidine, la phénothiazine, la phénoxazine, la pipérazine.Among the heterocycles of 5 to 14 links, mention may be made of carbazole, indane, thiophene, furan, 1-isoindolinone, pyrrole, 2,5-dihydropyrrole, benzoxazole, 5H [1] benzopyrano [2,3-b] pyridine, pyridine, imidazole, oxazole, quinoline, isoquinoline, pyrimidine, phenothiazine, phenoxazine, piperazine.

Plus particulièrement, R1 représente un radical 3-benzoylphényle, 2-aminophényle, 3-aminophényle, 4-aminophényle, 4-isobutylphényle, 6-méthoxy-2-naphtyle, 5-benzoyl-2-thiényle, 3-phénoxyphényle, 2-fluoro-4-biphényle, 3-fluoro-4-biphényle, 1-oxo-2-isoindolinyle, 3-chloro-4-(2,5-dihydro-1H-pyrrole-1-yl)phényle, 4-(2-thiénylcarbonyl)phényle, 9H-fluoréne-2-yle, 6-chloro-9H-carbazole-3-yle, 2-(4-chlorophényl)benzoxazole-5-yle, 4-cyclohexylphényle, pyridine-2-yle, 5H[1]benzopyrano[2,3-b]pyridine-7-yle, 3-trifluorométhoxyphényle, 3-acétylphényle.More particularly, R 1 represents a 3-benzoylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 4-isobutylphenyl, 6-methoxy-2-naphthyl, 5-benzoyl-2-thienyl, 3-phenoxyphenyl, 2- radical. fluoro-4-biphenyl, 3-fluoro-4-biphenyl, 1-oxo-2-isoindolinyl, 3-chloro-4- (2,5-dihydro-1H-pyrrole-1-yl) phenyl, 4- (2- thienylcarbonyl) phenyl, 9H-fluorine-2-yl, 6-chloro-9H-carbazole-3-yl, 2- (4-chlorophenyl) benzoxazole-5-yl, 4-cyclohexylphenyl, pyridine-2-yl, 5H [1 ] benzopyrano [2,3-b] pyridine-7-yl, 3-trifluoromethoxyphenyl, 3-acetylphenyl.

Plus particulièrement, R2 représente un atome d'hydrogène ou un radical méthyle, éthyle, propyle, isopropyle, butyle, tert-butyle ou benzyle.More particularly, R 2 represents a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or benzyl radical.

Saut mention contraire, dans les définitions précédentes et celles qui suivent, les radicaux alkyle, alcoxy et alcényle contiennent contiennent 1 à 6 atomes de carbone en chaíne droite ou ramifiée, les radicaux acyle contiennent 2 à 6 atomes de carbone et les atomes d'halogène sont les atomes de chlore, de brome, d'iode et de fluor.Otherwise, in the preceding definitions and those which follow, the alkyl, alkoxy and alkenyl radicals contain contain 1 to 6 carbon atoms in a straight or branched chain, acyl radicals contain 2 to 6 carbon atoms and the halogen atoms are the chlorine, bromine, iodine and fluorine atoms.

Il est connu que la réduction électrochimique d'un mélange d'ester méthylique d'acide 2-chloropropionique chiral et d'iodobenzène, en présence d'un catalyseur au nickel ne conduit pas au produit chiral désiré mais conduit à l'ester racémique (M. DURANDETTI et coli., J. Org. Chem., 61, 1748-1755 (1996)). It is known that the electrochemical reduction of an ester mixture methyl chiral 2-chloropropionic acid and iodobenzene, in the presence of a nickel catalyst does not lead to the desired chiral product but leads to the racemic ester (M. DURANDETTI et al., J. Org. Chem., 61, 1748-1755 (1996)).

Il a maintenant été trouvé de manière surprenante qu'il est possible de préparer les acides 2-aryl ou 2-hétérocyclyl propioniques chiraux et leurs esters avec un très bon excès énantiomérique par réduction électrochimique d'un mélange d'un dérivé d'acide proplonique de formule :

Figure 00040001
dans laquelle R3 représente un radical de formule :
Figure 00040002
et Hal représente un atome d'halogène et, de préférence, un atome de chlore, et d'un dérivé halogéné aromatique ou hétérocyclique dans lequel l'halogène est de préférence un atome d'iode, de brome ou de chlore, en présence d'un complexe de nickel comme catalyseur et d'un électrolyte dans une cellule d'électrolyse munie d'électrodes, en milieu solvant organique, puis soit hydrolyse pour obtenir le dérivé d'acide propionique soit transestérification pour obtenir l'ester.It has now surprisingly been found that it is possible to prepare the chiral 2-aryl or 2-heterocyclyl propionic acids and their esters with a very good enantiomeric excess by electrochemical reduction of a mixture of a proplonic acid derivative of formula:
Figure 00040001
in which R 3 represents a radical of formula:
Figure 00040002
and Hal represents a halogen atom and, preferably, a chlorine atom, and an aromatic or heterocyclic halogenated derivative in which the halogen is preferably an iodine, bromine or chlorine atom, in the presence of 'a nickel complex as catalyst and an electrolyte in an electrolysis cell provided with electrodes, in an organic solvent medium, then either hydrolysis to obtain the propionic acid derivative or transesterification to obtain the ester.

Les dérivés de formula (II) pour lesquels R3 représente un reste A ou C conduisent aux acides 2-aryl ou 2-hétérocyclyl propioniques (R) et les dérivés de formule (II) pour lesquels R3 représente un reste B conduisent aux acides 2-aryl ou 2-hétérocyclyl propioniques (S). The derivatives of formula (II) for which R 3 represents a residue A or C lead to 2-aryl or 2-heterocyclyl propionic acids ( R ) and the derivatives of formula (II) for which R 3 represents a residue B lead to acids 2-aryl or 2-heterocyclyl propionics ( S ).

De préférence, les dérivés halogénés aromatiques ou hétérocycliques sont ceux de formule : R1-Hal dans laquelle R1 a les mêmes significations que dans la formule (I) et Hal représente un atome d'iode, de chlore ou de brome.Preferably, the aromatic or heterocyclic halogenated derivatives are those of formula: R 1 - Hal in which R 1 has the same meanings as in formula (I) and Hal represents an iodine, chlorine or bromine atom.

Les dérivés (II) et les dérivés halogénés aromatiques ou hétérocycliques sont mis en réaction en quantités stochiométriques. Il est préférable d'ajouter le dérivé (II) progressivement au cours de l'électrolyse.Derivatives (II) and halogenated aromatic or heterocyclic derivatives are reacted in stochiometric quantities. It is better to add the derivative (II) gradually during the electrolysis.

Le complexe de nickel est, de préférence, un complexe avec un ligand azoté et plus particulièrement un complexe NiBr2bipyridine ou nickelorthophénanthroline. Il peut être préparé soit extemporanément soit in situ avant le début de l'electrolyse.The nickel complex is preferably a complex with a nitrogenous ligand and more particularly a NiBr 2 bipyridine or nickelorthophenanthroline complex. It can be prepared either extemporaneously or in situ before the start of electrolysis.

La quantité du complexe de nickel est généralement comprise entre 0,01 mole et 0,2 mole pour 1 mole du dérivé halogéné aromatique ou hétérocyclique et de préférence 0,1 mole pour 1 mole du dérivé halogéné aromatique ou hétérocyclique.The amount of the nickel complex is generally between 0.01 mole and 0.2 mole per 1 mole of the aromatic halogen derivative or heterocyclic and preferably 0.1 mole per 1 mole of the halogenated derivative aromatic or heterocyclic.

L'électrolyte est généralement un sel d'ammonium quaternaire tel que le tétrafluoroborate de tétrabutylammonium ou le bromure de tétrabutylammonium ou un sel minéral tel que le bromure de sodium. Sa concentration est généralement comprise entre 5.10-3 M et 2.10-2 M et, de préférence 1,5.10-2 M.The electrolyte is generally a quaternary ammonium salt such as tetrabutylammonium tetrafluoroborate or tetrabutylammonium bromide or a mineral salt such as sodium bromide. Its concentration is generally between 5.10 -3 M and 2.10 -2 M and, preferably 1.5.10 -2 M.

Le solvant est généralement un solvant aprotique tel que diméthylformamide, N-méthylpyrrolidone (de préférence le diméthylformamide) ou un mélange de solvants aprotique et protique, de préférence un mélange diméthylformamide-éthanol (80-20 % à 20-80%). The solvent is generally an aprotic solvent such as dimethylformamide, N-methylpyrrolidone (preferably dimethylformamide) or a mixture of aprotic and protic solvents, preferably a mixture dimethylformamide-ethanol (80-20% to 20-80%).

L'anode est une anode consommable en aluminium ou en alliage d'aluminium comme le Duralumin ou une anode en zinc, en fer ou en magnésium. Il est préférable d'utiliser une anode en aluminium.The anode is a consumable anode of aluminum or alloy aluminum such as Duralumin or an anode of zinc, iron or magnesium. It is best to use an aluminum anode.

La nature de la cathode n'est pas déterminante pour ce type de réaction. Elle peut être constituée par un autre matériau conducteur inattaquable dans les conditions de l'expérience comme l'acier inoxydable (sous forme de fritté notamment), le cuivre, le nickel ou un tissu de fibres de carbone. De préférence, elle est constituée d'une grille en mousse de nickel présentant une grande surface spécifique. Selon un mode préféré de mise en oeuvre du procédé, la cathode a une forme cylindrique creuse et est disposée concentriquement autour de l'anode.The nature of the cathode is not decisive for this type of reaction. She may consist of another conductive material which cannot be attacked in conditions of experience like stainless steel (in the form of sintered in particular), copper, nickel or a fabric of carbon fibers. Of preferably, it consists of a nickel foam grid having a large specific surface. According to a preferred embodiment of the method, the cathode has a hollow cylindrical shape and is arranged concentrically around the anode.

La température du milieu est généralement maintenue à une valeur optimale qui dépend de la nature du dérivé halogéné aromatique ou hétérocyclique utilisé en plongeant le réacteur dans un bain thermorégulé ou par un système de double enveloppe. Elle est généralement comprise entre 15°C et 100°C, et, de préférence, à environ 20°C.The medium temperature is generally maintained at an optimal value which depends on the nature of the aromatic or heterocyclic halogenated derivative used by immersing the reactor in a thermoregulated bath or by a double envelope system. It is generally between 15 ° C and 100 ° C, and preferably at about 20 ° C.

L'électrolyse est effectuée à intensité constante à une valeur comprise entre 0,1 et 1 Ampère selon la surface de la cathode employée. De préférence, la densité de courant est de 0,5 à 1 A/dm2 par rapport à la surface de la cathode.The electrolysis is carried out at constant intensity at a value between 0.1 and 1 Ampere depending on the surface of the cathode used. Preferably, the current density is 0.5 to 1 A / dm 2 relative to the surface of the cathode.

La quantité d'électricité nécessaire est déterminée par la disparition de l'halogénure aromatique ou hétérocyclique suivie par une méthode analytique appropriée (par exemple par chromatographie en phase gazeuse). Elle est généralement comprise entre 2 et 3 Faradays par mole de dérivé halogéné aromatique ou hétérocyclique, et de préférence de 2,5 Faradays par mole de dérivé halogéné aromatique ou hétérocyclique. The amount of electricity required is determined by the disappearance of aromatic or heterocyclic halide followed by a method appropriate analytical (for example by phase chromatography carbonated). It is generally between 2 and 3 Faradays per mole of aromatic or heterocyclic halogenated derivative, and preferably 2.5 Faradays per mole of aromatic or heterocyclic halogenated derivative.

Selon un mode de mise en oeuvre du procédé selon l'Invention, la réduction électrolytique est effectuée dans un électrolyseur sans compartiment séparé contenant le solvant dans lequel est dissous :

  • l'électrolyte support,
  • le dérivé halogéné aromatique ou hétérocyclique à une concentration comprise entre 0,01 M/l et 1 M/l (de préférence 0,25 M/l)
  • le catalyseur au nickel (de préférence 10 % en mole par rapport au dérivé halogéné aromatique ou hétérocyclique de départ).
  • le dérivé (II) (de préférence 3% en mole par rapport au dérivé halogéné aromatique ou hétérocyclique).
According to one embodiment of the method according to the invention, the electrolytic reduction is carried out in an electrolyser without a separate compartment containing the solvent in which is dissolved:
  • the support electrolyte,
  • the aromatic or heterocyclic halogenated derivative at a concentration of between 0.01 M / l and 1 M / l (preferably 0.25 M / l)
  • the nickel catalyst (preferably 10 mol% relative to the starting aromatic or heterocyclic halogenated derivative).
  • the derivative (II) (preferably 3 mol% relative to the aromatic or heterocyclic halogenated derivative).

Le reste de dérivé (II) est généralement ajouté au fur et à mesure du déroulement de l'électrolyse par tout moyen approprié (sous forme solide, liquide ou en solution dans un des solvants constituant le milieu).The rest of the derivative (II) is generally added as the course of electrolysis by any appropriate means (in solid form, liquid or in solution in one of the solvents constituting the medium).

L'électrolyseur comporte :

  • une anode consommable,
  • une cathode,
  • un système d'agitation,
  • une arrivée de gaz inerte (argon ou azote par exemple) afin de maintenir la solution à l'abri de l'oxygène de l'air pendant l'électrolyse. Il est avantageux de désaérer la solution par barbotage du gaz inerte 10 minutes avant la début de l'électrolyse,
  • un système de régulation de la température,
  • une alimentation électrique stabilisée.
The electrolyser includes:
  • a consumable anode,
  • a cathode,
  • a stirring system,
  • an inert gas supply (argon or nitrogen for example) in order to keep the solution away from oxygen in the air during electrolysis. It is advantageous to deaerate the solution by bubbling inert gas 10 minutes before the start of electrolysis,
  • a temperature control system,
  • a stabilized power supply.

Selon une variante, la réaction est effectuée dans un électrolyseur tubulaire à circulation constitué par un barreau central d'aluminium ou de Duralumin servant d'anode et par un tube en acier inoxydable servant de cathode. Les deux électrodes sont isolées par des joints en TéflonR qui assurent également l'étanchéité. La cathode pourra être garnie intérieurement par une grille de mousse de nickel de forme cylindrique afin d'en augmenter la surface active.According to a variant, the reaction is carried out in a tubular circulation electrolyser constituted by a central aluminum or Duralumin rod serving as anode and by a stainless steel tube serving as cathode. The two electrodes are insulated by Teflon R seals which also provide sealing. The cathode can be lined internally with a grid of nickel foam of cylindrical shape in order to increase its active surface.

La solution est mise en mouvement au moyen d'une pompe. Elle pénètre dans le réacteur par une tubulure latérale située vers son extrémité inférieure et en sort par une tubulure analogue située vers son extrémité supérieure. Un vase d'expansion thermostaté est disposé sur le circuit du milieu réactionnel.The solution is set in motion by means of a pump. She penetrates in the reactor by a lateral tube situated towards its lower end and out of it by a similar tube located towards its upper end. A thermostatically controlled expansion tank is placed on the middle circuit reactive.

L'intensité du courant est réglée de façon à ce que la densité de courant soit semblable à celle utilisée dans l'autre type de réacteur.The current intensity is adjusted so that the current density is similar to that used in the other type of reactor.

L'hydrolyse du produit obtenu après extraction, pour obtenir l'acide propionique, s'effectue en milieu acide ou en milieu alcalin. De préférence, elle s'effectue soit au moyen d'acide sulfurique 6N aqueux au reflux ou bien par action de l'hydroxyde de lithium, au sein d'un solvant inerte tel que le tétrahydrofuranne, à une température voisine de 20°C.Hydrolysis of the product obtained after extraction, to obtain the acid propionic, takes place in an acidic or alkaline medium. Preferably, it is carried out either by means of aqueous sulfuric acid 6N at reflux or else by the action of lithium hydroxide, in an inert solvent such as tetrahydrofuran, at a temperature in the region of 20 ° C.

La transestérification pour obtenir l'ester alkylique ou phénylalkylique s'effectue généralement par action du carbonate de potassium et d'un alcool aliphatique (1 à 6 atomes de carbone en chaíne droite ou ramifiée) ou un alcool Ar-alkOH dans lequel Ar représente un radical phényle et alk représente un radical alkyle, à une température voisine de 20°CTransesterification to obtain the alkyl or phenylalkyl ester is generally carried out by the action of potassium carbonate and an alcohol aliphatic (1 to 6 carbon atoms in a straight or branched chain) or a alcohol Ar-alkOH in which Ar represents a phenyl radical and alk represents an alkyl radical, at a temperature in the region of 20 ° C.

Les dérivés de formule (II) peuvent être obtenus par condensation du chlorure de l'acide 2-chloropropionique avec le sel de lithium de la (4S, 5R)-1,5-diméthyl-4-phénylimidazolidine-2-one, de la (4R, 5S)-1,5-diméthyl-4-phénylimidazolidine-2-one ou de la (4R)-4-phényloxazolidine-2-oneThe derivatives of formula (II) can be obtained by condensation of the chloride of 2-chloropropionic acid with the lithium salt of (4 S , 5 R ) -1,5-dimethyl-4-phenylimidazolidine-2-one, (4 R , 5 S ) -1,5-dimethyl-4-phenylimidazolidine-2-one or (4 R ) -4-phenyloxazolidine-2-one

Les dérivés halogénés aromatiques ou hétérocycliques sont commercialisés ou peuvent être obtenus par application ou adaptation des méthodes décrites dans J. Prakt. Chem., 109, 318 (1925); Gazz. Chim. Ital., 122 (12), 511-514 (1992); Tetrahedron, 50 (4), 1243-1260 (1994); J. Org. Chem., 32, 2692-2695 (1967); J. Org. Chem., 13, 916 (1948); Chem. Abst. 6878 (1955); Recueil Trav. Chim. Pays-Bas, 42? 507 51923°. Recueil Trav. Chim. Pays-Bas, 71, 285 (1952); J. Amer. Chem. Soc., 76, 1106 (1954); J. Chem. Soc., 653-656 (1934); Recueil Trav, Chim. Pays-Bas, 69, 1083-1101 (1950); Eur. J. Mod. Chem. Chim. Ther., 23, 477-482 (1988); Chem. Abst., 59, 2752; Monatsh. Chem., 126 (5), 569-578 (1995); J. Amer. Chem. Soc., 75, 745 (1953); J. Org. Chem., 25, 1590-1595(1960); J. Org. Chem., 25, 1194-1198 (1960); Gazz. Chim. Ital., 122 (12), 511-514 (1992); Synlett, (4), 353-355 (1996); Organometallics, 10 (4), 1183-9 (1991); Chem. Abst., 100 : 174586 et 124 : 175743; Monatsch. Chem., 91, 319-330 (1960); Chem. Abst., 106 : 196047; J. Amer. Chem. Soc., 59, 2699 (1937); J. Amer. Chem. Soc., 75, 1115 (1953); Recueil Trav. Chim. Pays-Bas, 68, 5 (1949); J. Chem. Soc. Perkin Trans II, 1232-1235 (1978); J. Amer. Chem. Soc., 75, 1115 (1953); Gazz. Chim. Ital., 25 II, 361 (1895); Chem. Abst., 99 : 70710; Chem. Abst., 106 : 152883; Chem. Abst., 105 : 61017; C.R. Hebd. Seances Acad. Sci., 207, 676 (1938), 213, 655 (1941), 205, 991 (1937), 215, 578 (1942); Bull. Soc. Chim. Fr, 38, 726 (1939), 11, 127 (1944) et 10, 198 (1943); ; C. R. Acad. Sci., 207, 676 (1938) et 213, 655 (1941); J. Amer. Chem. Soc., 62, 1550 (1940); J. Chem. Soc. Perkin Trans II, 559 (1976); J. Chem. Soc., 503 (1929); Chem. Abst., 83 : 131564, 119 : 249672; Chem. Pharm. Bull., 12 (10), 1135-1138 (1964); Chem. Abst., 85 : 123755; 99 : 70710; 88 : 62380 et les brevets US5254776, US4107169, JP88-68627, FR2471962, ES510415, US4107169. Aromatic or heterocyclic halogenated derivatives are sold or can be obtained by applying or adapting the methods described in J. Prakt. Chem., 109, 318 (1925); Gazz. Chim. Ital., 122 (12), 511-514 (1992); Tetrahedron, 50 (4), 1243-1260 (1994); J. Org. Chem., 32, 2692-2695 (1967); J. Org. Chem., 13, 916 (1948); Chem. Abst. 6878 (1955); Trav. Chim. Netherlands, 42? 507 51 923 °. Trav. Chim. Netherlands, 71, 285 (1952); J. Amer. Chem. Soc., 76, 1106 (1954); J. Chem. Soc., 653-656 (1934); Trav, Chim. Netherlands, 69, 1083-1101 (1950); Eur. J. Mod. Chem. Chim. Ther., 23, 477-482 (1988); Chem. Abst., 59, 2752; Monatsh. Chem., 126 (5), 569-578 (1995); J. Amer. Chem. Soc., 75, 745 (1953); J. Org. Chem., 25, 1590-1595 (1960); J. Org. Chem., 25, 1194-1198 (1960); Gazz. Chim. Ital., 122 (12), 511-514 (1992); Synlett, (4), 353-355 (1996); Organometallics, 10 (4), 1183-9 (1991); Chem. Abst., 100: 174586 and 124: 175743; Monatsch. Chem., 91, 319-330 (1960); Chem. Abst., 106: 196047; J. Amer. Chem. Soc., 59, 2699 (1937); J. Amer. Chem. Soc., 75, 1115 (1953); Trav. Chim. Netherlands, 68, 5 (1949); J. Chem. Soc. Perkin Trans II, 1232-1235 (1978); J. Amer. Chem. Soc., 75, 1115 (1953); Gazz. Chim. Ital., 25 II, 361 (1895); Chem. Abst., 99: 70710; Chem. Abst., 106: 152883; Chem. Abst., 105: 61017; C.R. Hebd. Seances Acad. Sci., 207, 676 (1938), 213, 655 (1941), 205, 991 (1937), 215, 578 (1942); Bull. Soc. Chim. Fr, 38, 726 (1939), 11, 127 (1944) and 10, 198 (1943); ; C. R. Acad. Sci., 207, 676 (1938) and 213, 655 (1941); J. Amer. Chem. Soc., 62, 1550 (1940); J. Chem. Soc. Perkin Trans II, 559 (1976); J. Chem. Soc., 503 (1929); Chem. Abst., 83: 131564, 119: 249672; Chem. Pharm. Bull., 12 (10), 1135-1138 (1964); Chem. Abst., 85: 123755; 99: 70710; 88: 62380 and patents US5254776, US4107169, JP88-68627, FR2471962, ES510415, US4107169.

Les exemples suivants illustrent l'invention.The following examples illustrate the invention.

EXEMPLE A - PREPARATION DU CATALYSEUR NICKELBr2BIPYRIDINE IN SITU EN MILIEU APROTIQUE: EXAMPLE A - PREPARATION OF THE NICKELBr 2 BIPYRIDINE CATALYST IN SITU IN AN APROTIC MEDIUM :

Dans 40 ml de diméthylformamide, on ajoute sous agitation 0,27 gramme de bromure de nickel hydraté jusqu'à dissolution. Puis on ajoute par petites fractions 0,15 gramme de 2-2' bipyridine. L'agitation est maintenue une nuit à température ambiante (20°C environ). On obtient une solution vert foncé (A) contenant 10-3 mole de catalyseur.0.27 grams of hydrated nickel bromide are added to 40 ml of dimethylformamide until stirring. Then 0.15 gram of 2-2 'bipyridine is added in small portions. Stirring is continued overnight at room temperature (approximately 20 ° C). A dark green solution (A) containing 10 -3 mole of catalyst is obtained.

EXEMPLE B - PREPARATION DU CATALYSEUR NICKELBr2BIPYRIDINE IN SITU EN MILIEU PROTIQUE :EXAMPLE B - PREPARATION OF THE NICKELBr 2 BIPYRIDINE CATALYST IN SITU IN A PRACTICAL ENVIRONMENT:

Dans 32 ml d'éthanol absolu, on ajoute sous agitation 0,27 gramme de bromure de nickel hydraté jusqu'à dissolution. Puis on ajoute par petites fractions 0,15 gramme de 2-2' bipyridine. L'agitation est maintenue une nuit à température ambiante (20°C environ). Il se forme un précipité vert foncé de catalyseur : le complexe nickel-bipyridine. Après tiédissement, on ajoute 8 ml de diméthylformamide et agite jusqu'à dissolution du précipité. On obtient ainsi une solution (B) contenant 10-3 mole de catalyseur.0.27 gram of hydrated nickel bromide is added to 32 ml of absolute ethanol until stirring. Then 0.15 gram of 2-2 'bipyridine is added in small portions. Stirring is continued overnight at room temperature (approximately 20 ° C). A dark green precipitate of catalyst is formed: the nickel-bipyridine complex. After cooling, 8 ml of dimethylformamide are added and the mixture is stirred until the precipitate has dissolved. A solution (B) containing 10 -3 mole of catalyst is thus obtained.

EXEMPLE C - PREPARATION DU DERIVE DE FORMULE (II) POUR LEQUEL R3 EST UN RESTE A ET Hal EST UN ATOME DE CHLOREEXAMPLE C - PREPARATION OF THE DERIVATIVE OF FORMULA (II) FOR WHICH R 3 IS A RESET A AND Hal IS A CHLORINE ATOM

On mélange 50 g de (-)éphédrine (0,248 mole) avec 45 g d'urée (0,75 mole). Le mélange est chauffé une demi-heure à 170°C puis une heure à 200°C. Après refroidissement, on ajoute 150 ml d'eau à la masse huileuse blanche. Le précipité blanc ainsi obtenu est filtré, rincé avec HCl 5%, puis rincé à l'eau. On recristallise le précipité blanc dans 40 ml de méthanol; on obtient 17,6 g de (4S, 5R)-1,5-diméthyl-4-phénylimidazolidine-2-one, soit 37%. On évapore le filtrat, puis on recristallise le précipité dans 10 ml de méthanol, on obtient 6,2 g de (4S, 5R)-1,5-diméthyl-4-phénylimidazolidine-2-one, soit 13%.50 g of (-) ephedrine (0.248 mole) are mixed with 45 g of urea (0.75 mole). The mixture is heated for half an hour at 170 ° C and then one hour at 200 ° C. After cooling, 150 ml of water are added to the white oily mass. The white precipitate thus obtained is filtered, rinsed with 5% HCl, then rinsed with water. The white precipitate is recrystallized from 40 ml of methanol; 17.6 g of (4 S , 5 R ) -1,5-dimethyl-4-phenylimidazolidine-2-one are obtained, ie 37%. The filtrate is evaporated, then the precipitate is recrystallized from 10 ml of methanol, 6.2 g of (4 S , 5 R ) -1,5-dimethyl-4-phenylimidazolidine-2-one, ie 13%, are obtained.

Le rendement total en (4S, 5R)-1,5-diméthyl-4-phénylimidazolidine-2-one est ainsi de 50%.The total yield of (4 S , 5 R ) -1,5-dimethyl-4-phenylimidazolidine-2-one is thus 50%.

On introduit 0,05 mole de (4S, 5R)-1,5-diméthyl-4-phénylimidazolidine-2-one dans 50 ml de tétrahydrofuranne fraíchement distillé. La solution est refroidie à -78°C à l'aide d'un bain acétate d'éthyle-carboglace, puis on ajoute, à l'aide d'une ampoule à brome dégazée et sous flux d'argon, par un goutte à goutte rapide, 35 ml de butyllithium 1,6 M dans l'hexane (1,12 équivalent). On laisse réagir le mélange une heure sous agitation à -78°C, puis on ajoute goutte à goutte 6 ml du chlorure de l'acide 2-chloropropionique (1,25 équivalent). La réaction avec le chlorure d'acide est instantanée. La solution est hydrolysée par 30 ml d'eau et la température est remontée à environ 20°C. Le mélange est extrait par 3 X 20 ml d'acétate d'éthyle. Le produit est séparé sur colonne de silice, en utilisant le mélange pentane/éther (50/50) comme éluant. Le rendement est de 75%.0.05 mole of (4 S , 5 R ) -1,5-dimethyl-4-phenylimidazolidine-2-one is introduced into 50 ml of freshly distilled tetrahydrofuran. The solution is cooled to -78 ° C. using an ethyl acetate-dry ice bath, then a drop is added using a degassed dropping funnel and under a stream of argon. rapid drop, 35 ml of 1.6 M butyllithium in hexane (1.12 equivalent). The mixture is left to react for one hour with stirring at -78 ° C., then 6 ml of 2-chloropropionic acid chloride (1.25 equivalent) are added dropwise. The reaction with the acid chloride is instantaneous. The solution is hydrolyzed with 30 ml of water and the temperature rises to around 20 ° C. The mixture is extracted with 3 X 20 ml of ethyl acetate. The product is separated on a silica column, using the pentane / ether mixture (50/50) as eluent. The yield is 75%.

EXEMPLE D - PREPARATION DU DERIVE DE FORMULE (II) POUR LEQUEL R3 EST UN RESTE B ET Hal EST UN ATOME DE CHLOREEXAMPLE D - PREPARATION OF THE DERIVATIVE OF FORMULA (II) FOR WHICH R 3 IS A RESID B AND Hal IS A CHLORINE ATOM

On mélange 50 g de (+)éphédrine (0,248 mole) avec 45 g d'urée (0,75 mole). Le mélange est chauffé une demi-heure à 170°C puis une heure à 200°C. Après refroidissement, on ajoute 150 ml d'eau à la masse huileuse blanche. Le précipité blanc ainsi obtenu est filtré, rincé avec HCl 5%, puis rincé à l'eau. On recristallise le précipité blanc dans 40 ml de méthanol, on obtient 17,6 g de (4R, 5S)-1,5-dlméthyl-4-phénylimidazolidine-2-one, soit 37%. On évapore le filtrat, puis on recristallise le précipité dans 10 ml de méthanol, on obtient 6,2 g de (4R, 5S)-1,5-diméthyl-4-phénylimidazolidine-2-one, soit 13%. Le rendement total en (4R, 5S)-1,5-diméthyl-4-phénylimidazolidine-2-one est ainsi de 50%. 50 g of (+) ephedrine (0.248 mole) are mixed with 45 g of urea (0.75 mole). The mixture is heated for half an hour at 170 ° C and then one hour at 200 ° C. After cooling, 150 ml of water are added to the white oily mass. The white precipitate thus obtained is filtered, rinsed with 5% HCl, then rinsed with water. The white precipitate is recrystallized from 40 ml of methanol, 17.6 g of (4 R , 5 S ) -1.5-dlmethyl-4-phenylimidazolidine-2-one, ie 37%, are obtained. The filtrate is evaporated, then the precipitate is recrystallized from 10 ml of methanol, 6.2 g of (4 R , 5 S ) -1.5-dimethyl-4-phenylimidazolidine-2-one, ie 13%, are obtained. The total yield of (4 R , 5 S ) -1,5-dimethyl-4-phenylimidazolidine-2-one is thus 50%.

On introduit 0,05 mole de (4R, 5S)-1,5-diméthyl-4-phénylimidazolidine-2-one dans 50 ml de tétrahydrofuranne fraíchement distillé. La solution est refroidie à -78°C à l'aide d'un bain acétate d'éthyle-carboglace, puis on ajoute, à l'aide d'une ampoule à brome dégazée et sous flux d'argon, par un goutte à goutte rapide, 35 ml de butyllithium 1,6 M dans l'hexane (1,12 équivalent). On laisse réagir le mélange une heure sous agitation à -78°C, puis on ajoute goutte à goutte 6 ml du chlorure de l'acide 2-chloropropionique (1,25 équivalent). La réaction avec le chlorure d'acide est instantanée. La solution est hydrolysée par 30 ml d'eau et la température est remontée à environ 20°C. Le mélange est extrait par 3 X 20 ml d'acétate d'éthyle. Le produit est séparé sur colonne de silice, en utilisant le mélange pentane/éther (50/50) comme éluant. Le rendement est de 75%.0.05 mole of (4 R , 5 S ) -1,5-dimethyl-4-phenylimidazolidine-2-one is introduced into 50 ml of freshly distilled tetrahydrofuran. The solution is cooled to -78 ° C. using an ethyl acetate-dry ice bath, then a drop is added using a degassed dropping funnel and under a stream of argon. rapid drop, 35 ml of 1.6 M butyllithium in hexane (1.12 equivalent). The mixture is left to react for one hour with stirring at -78 ° C., then 6 ml of 2-chloropropionic acid chloride (1.25 equivalent) are added dropwise. The reaction with the acid chloride is instantaneous. The solution is hydrolyzed with 30 ml of water and the temperature rises to around 20 ° C. The mixture is extracted with 3 X 20 ml of ethyl acetate. The product is separated on a silica column, using the pentane / ether mixture (50/50) as eluent. The yield is 75%.

EXEMPLE E - PREPARATION D'UN DERIVE DE FORMULE (II) POUR LEQUEL R EST UN RESTE C ET Hal EST UN ATOME DE CHLOREEXAMPLE E - PREPARATION OF A DERIVATIVE OF FORMULA (II) FOR WHICH R IS A REST C AND Hal IS A CHLORINE ATOM

On mélange 0,05 mole de (R)(-)2-amino-2-phényl éthanol avec 0,15 mole d'urée. Le mélange est chauffé une demi-heure à 170°C puis une heure à 200°C. Après refroidissement, on ajoute 150 ml d'eau à la masse huileuse blanche. On obtient un précipité blanc qui est solubilisé dans 100 ml d'éther et la solution est filtrée. Le filtrat contient la (4R)-4-phényloxazolidine-2-one pure. Le résidu blanc recueilli sur le filtre est repris par 50 ml d'acétate d'éthyle. On filtre et on récupère une 2ème fraction de (4R)-4-phényloxazolidine-2-one pure dans le filtrat. Le rendement total en (4R)-4-phényloxazolidine-2-one des 2 fractions collectées est de 65%.0.05 mole of ( R ) (-) 2-amino-2-phenyl ethanol is mixed with 0.15 mole of urea. The mixture is heated for half an hour at 170 ° C and then one hour at 200 ° C. After cooling, 150 ml of water are added to the white oily mass. A white precipitate is obtained which is dissolved in 100 ml of ether and the solution is filtered. The filtrate contains pure (4 R ) -4-phenyloxazolidine-2-one. The white residue collected on the filter is taken up in 50 ml of ethyl acetate. It is filtered and a second fraction of (4 R ) -4-phenyloxazolidine-2-one is recovered in the filtrate. The total yield of (4 R ) -4-phenyloxazolidine-2-one of the 2 fractions collected is 65%.

On introduit 0,05 mole de (4R)-4-phényloxazolidine-2-one dans 50 ml de tétrahydrofuranne fraíchement distillé. La solution est refroidie à -78°C à l'aide d'un bain acétate d'éthyle-carboglace, puis on ajoute, à l'aide d'une ampoule à brome sous flux d'argon, par un goutte à goutte rapide, 35 ml de butyllithium 1,6 M dans l'hexane (1,12 équivalent). On laisse réagir le mélange une heure sous agitation à -78°C, puis on ajoute goutte à goutte 6 ml du chlorure de l'acide 2-chloropropionique (1,25 équivalent). La réaction avec le chlorure d'acide est instantanée. La solution est hydrolysée par 30 ml d'eau et la température est remontée à environ 20°C. Le mélange est extrait par 3 X 20 ml d'acétate d'éthyle. Le produit est séparé sur colonne de silice, en utilisant le mélange pentane/éther (50/50) comme éluant. Le rendement est de 85%.0.05 mole of (4 R ) -4-phenyloxazolidine-2-one is introduced into 50 ml of freshly distilled tetrahydrofuran. The solution is cooled to -78 ° C using an ethyl acetate-dry ice bath, then added, using a dropping funnel under argon flow, by a rapid drop by drop 35 ml of 1.6 M butyllithium in hexane (1.12 equivalent). The mixture is left to react for one hour with stirring at -78 ° C., then 6 ml of 2-chloropropionic acid chloride (1.25 equivalent) are added dropwise. The reaction with the acid chloride is instantaneous. The solution is hydrolyzed with 30 ml of water and the temperature rises to around 20 ° C. The mixture is extracted with 3 X 20 ml of ethyl acetate. The product is separated on a silica column, using the pentane / ether mixture (50/50) as eluent. The yield is 85%.

EXEMPLE 1 : PROCEDE GENERALEXAMPLE 1: GENERAL PROCEDURE

A 40 ml de solution (A) introduit dans l'électrolyseur, on ajoute :

  • 0,2 g (6.10-4 mole) de tétrafluoroborate de tétrabutylammonium
  • 10-2 mole du dérivé halogéné aromatique ou hétérocyclique
  • 3.10-4 mole du dérivé (II) (soit 3 % en mole par rapport au dérivé halogéné aromatique ou hétérocyclique)
To 40 ml of solution (A) introduced into the electrolyser, the following is added:
  • 0.2 g (6.10 -4 mole) of tetrabutylammonium tetrafluoroborate
  • 10 -2 mole of the aromatic or heterocyclic halogenated derivative
  • 3.10 -4 mole of the derivative (II) (i.e. 3 mol% relative to the aromatic or heterocyclic halogenated derivative)

La réaction est effectuée á température ambiante (20°C environ). On fait barboter un gaz inerte (argon) saturé en vapeur du mélange de solvant, pendant environ 10 minutes. Le barbotage est ensuite maintenu dans la solution pendant toute la durée de l'électrolyse.The reaction is carried out at room temperature (approximately 20 ° C). We do bubbling an inert gas (argon) saturated with vapor with the solvent mixture, for about 10 minutes. The bubbling is then maintained in the solution for the duration of the electrolysis.

L'électrolyseur comporte une anode constituée par un barreau d'aluminium (diamètre 1 cm) disposé au centre du réacteur et une cathode en mousse de nickel cylindrique (diamètre 3 cm - hauteur 5 cm) disposée concentriquement à l'anode.The electrolyser comprises an anode constituted by an aluminum bar (diameter 1 cm) placed in the center of the reactor and a foam cathode cylindrical nickel (diameter 3 cm - height 5 cm) arranged concentrically at the anode.

L'intensité du courant est maintenue à une valeur constante de 0,25 ampères avec une alimentation stabilisée, jusqu'à disparition totale du dérivé halogéné aromatique ou hétérocyclique. L'addition de dérivé (II) est réalisée par ajout de fractions de 200 µl de solution à 0,625 M/I dans du diméthylformamide toutes les deux minutes. Après 3 heures, correspondant au passage de 2,7 Faradays par mole du dérivé halogéné aromatique ou hétérocyclique, l'électrolyse est arrêtée ainsi que l'ajout du dérivé (II) (ajout total 12,5 millimole). La solution est hydrolysée avec 40 ml d'acide chlorhydrique 1 N. Les solvants sont chassés sous vide à l'évaporateur rotatif. Le résidu est repris à l'eau. La phase aqueuse est extraite par 3 fois 40 ml d'éther éthylique. La phase organique est séparée par décantation, rincée 5 fois par 40 ml d'eau distillée, séchée sur sulfate de magnésium puis filtrée et évaporée à sec sous pression réduite. Le produit attendu est purifié par chromatographie sur 100 g de silice contenus dans une colonne de 3 cm de diamètre (généralement éluant : pentane/éther : 50/50).Current intensity is maintained at a constant value of 0.25 amps with a stabilized supply, until the derivative completely disappears aromatic or heterocyclic halogenated. The addition of derivative (II) is carried out by adding fractions of 200 µl of 0.625 M / I solution in dimethylformamide every two minutes. After 3 hours, correspondent passing 2.7 Faradays per mole of the aromatic halogen derivative or heterocyclic, electrolysis is stopped as well as the addition of derivative (II) (addition total 12.5 millimoles). The solution is hydrolyzed with 40 ml of acid hydrochloric 1 N. The solvents are removed under vacuum in an evaporator rotary. The residue is taken up in water. The aqueous phase is extracted 3 times 40 ml of ethyl ether. The organic phase is separated by decantation, rinsed 5 times with 40 ml of distilled water, dried over magnesium sulfate and then filtered and evaporated to dryness under reduced pressure. The expected product is purified by chromatography on 100 g of silica contained in a 3 cm column in diameter (generally eluent: pentane / ether: 50/50).

L'excès diastéréoisomérique est déterminé par chromatographie en phase gazeuse.The diastereoisomeric excess is determined by phase chromatography carbonated.

EXEMPLE 2 : EXEMPLE D'HYDROLYSE EN MILIEU ALCALIN AVEC OBTENTION DE L'ACIDE CORRESPONDANTEXAMPLE 2 EXAMPLE OF HYDROLYSIS IN AN ALKALINE MEDIUM WITH OBTAINING THE CORRESPONDING ACID

On dissout 0,5 g du produit obtenu selon l'exemple 1 dans 5 ml de tétrahydrofuranne puis on ajoute 0,003 g d'hydroxyde de lithium monohydraté. On laisse réagir 18 à 20 heures à une température voisine de 20°C. On ajoute 20 ml d'eau et on extrait par 2 tois 20 ml de dichlorométhane. La phase aqueuse est acidifiée puis extraite par 2 fois 20 ml de dichlorométhane. Les phases organiques sont séchées sur sulfate de magnésium puis évaporées. On obtient ainsi l'acide pur. Le pouvoir rotatoire mesuré et comparé à la valeur de la littérature donne l'excès énantiomérique.0.5 g of the product obtained according to Example 1 is dissolved in 5 ml of tetrahydrofuran then 0.003 g of lithium hydroxide is added monohydrate. It is left to react for 18 to 20 hours at a temperature close to 20 ° C. 20 ml of water are added and 20 ml of dichloromethane. The aqueous phase is acidified and then extracted twice 20 ml of dichloromethane. The organic phases are dried over sulfate magnesium and then evaporated. Pure acid is thus obtained. The power rotary measured and compared to the value of the literature gives the excess enantiomeric.

EXEMPLE 3 : EXEMPLE D'HYDROLYSE EN MILIEU ACIDE AVEC OBTENTION DE L'ACIDE CORRESPONDANTEXAMPLE 3 EXAMPLE OF HYDROLYSIS IN AN ACID MEDIUM WITH OBTAINING THE CORRESPONDING ACID

Dans 5 ml d'acide sulfurique 8 N aqueux, on ajoute 0,5 g du produit obtenu selon l'exemple 1. On porte au reflux et on laisse réagir 18 à 20 heures à une température voisine de 100°C. On neutralise par de la soude à 5 % et on extrait par 2 fois 20 ml de dichlorométhane. La phase aqueuse est acidifiée puis extraite par 2 fois 20 ml de dichlorométhane. Les phases organiques sont séchées sur sulfate de magnéslum puis évaporées. On obtient ainsi l'acide pur. Le pouvoir rotatoire mesuré et comparé à la valeur de la littérature donne l'excès énantiomérique. 0.5 g of the product obtained is added to 5 ml of 8 N aqueous sulfuric acid. according to Example 1. The mixture is brought to reflux and left to react for 18 to 20 hours at a temperature close to 100 ° C. We neutralize with 5% sodium hydroxide and extracted with 2 times 20 ml of dichloromethane. The aqueous phase is acidified then extracted with 2 times 20 ml of dichloromethane. Organic phases are dried over magnesium sulphate and then evaporated. We thus obtain pure acid. The rotary power measured and compared to the value of the literature gives enantiomeric excess.

EXEMPLE 4 : EXEMPLE DE « TRANSESTERIFICATION » AVEC OBTENTION DE L'ESTER METHYLIQUE : EXAMPLE 4: EXAMPLE OF “TRANSESTERIFICATION” WITH OBTAINING METHYL ESTER :

Dans 20 ml de méthanol, on introduit 2 g du produit obtenu à l'exemple 1 auquel on ajoute 0,1 g de carbonate de potassium. On laisse réagir de quelques minutes à 6 heures, jusqu'à transformation complète. La solution est hydrolysée avec 20 ml d'une solution aqueuse de NaCI et extraite par 31 fois 20 ml d'éther. Les phases organiques sont rincées par une solution aqueuse de NaCl, puis séchées sur sulfate de magnésium. Après évaporation de l'éther, l'ester méthyllque est séparé sur colonne de silice avec un mélange pentane/éther (95/5). La mesure du pouvoir rotatoire, comparée aux données de la littérature donne l'excès énantiomérique.2 g of the product obtained in Example 1 are introduced into 20 ml of methanol to which 0.1 g of potassium carbonate is added. We let react a few minutes to 6 hours, until complete transformation. The solution is hydrolyzed with 20 ml of an aqueous NaCl solution and extracted with 31 times 20 ml of ether. The organic phases are rinsed with a solution aqueous NaCl, then dried over magnesium sulfate. After evaporation of the ether, the methyl ester is separated on a silica column with a pentane / ether mixture (95/5). The measurement of rotary power, compared with the data in the literature gives the enantiomeric excess.

En utilisant la méthode générale décrite ci-dessus, on obtient les résultats suivants : RESULTATS SELON L'EXEMPLE 1 (II)
R3 dérivé halogéné aromatique ou hétérocyclique configuration du produit obtenu excès énantiomérique (excès diastéréo-isomérique) Rendement C iodobenzene R 52% (ed 63%) 50% A iodobenzene R 90% (ed 96%) 57% A 3-trifluorométhyl bromobenzène R 87% (ed 92%) 51% B 3-trifluorométhyl bromobenzène S 80% (ed 92%) 51% B 2-méthoxy bromobenzène S (ed 93%) 57% B 3-bromoaniline S 79% (ed 95%) 54% B 3-bromo thiophéne S (ed 92%) 30% B 3-bromopyridine S (ed 93%) 45% B 6-méthoxy 2-bromonaphtalène S 85% (ed 93%) 62% B 4-phényl-3-fluoro bromobenzène S 82% (ed 92%) 58% B 3-acétyl bromobenzène S (ed 91%) 61% B 3-trifluorométhyl chlorobenzène S (ed91%) 52% Using the general method described above, the following results are obtained: RESULTS ACCORDING TO EXAMPLE 1 (II)
R 3 aromatic or heterocyclic halogenated derivative configuration of the product obtained enantiomeric excess (diastereoisomeric excess) Yield VS iodobenzene R 52% (ed 63%) 50% AT iodobenzene R 90% (ed 96%) 57% AT 3-trifluoromethyl bromobenzene R 87% (ed 92%) 51% B 3-trifluoromethyl bromobenzene S 80% (ed 92%) 51% B 2-methoxy bromobenzene S (ed 93%) 57% B 3-bromoaniline S 79% (ed 95%) 54% B 3-bromo thiophene S (ed 92%) 30% B 3-bromopyridine S (ed 93%) 45% B 6-methoxy 2-bromonaphthalene S 85% (ed 93%) 62% B 4-phenyl-3-fluoro bromobenzene S 82% (ed 92%) 58% B 3-acetyl bromobenzene S (ed 91%) 61% B 3-trifluoromethyl chlorobenzene S (ed91%) 52%

En opérant comme à l'exemple 2 ou 3, on obtient les acides correspondants aux produits obtenus ci-dessus.By operating as in Example 2 or 3, the corresponding acids are obtained to the products obtained above.

En opérant comme décrit à l'exemple 4, on obtient les esters méthyliques correspondants aux produits obtenus ci-dessus.By operating as described in Example 4, the methyl esters are obtained corresponding to the products obtained above.

Claims (36)

  1. Method for preparing chiral 2-aryl or 2-heterocyclyl propionic acids and the esters thereof characterized in that a mixture of a propionic acid derivative with formula:
    Figure 00330001
    in which R3 represents a radical of formula:
    Figure 00330002
    and Hal represents a halogen atom and an aromatic or heterocyclic halogen derivative is electrochemically reduced in the presence of a nickel complex as catalyst and of an electrolyte in an electrolysis cell provided with electrodes, in organic solvent medium, then either the product is hydrolysed to obtain the propionic acid derivative or transesterified to obtain the ester.
  2. Method according to claim 1, wherein the halogen atom in the derivative of formula (II) is a chlorine atom.
  3. Method according to one of claims 1 or 2, wherein the halogen of the aromatic or heterocyclic halogen derivative is an iodine, bromine or chlorine atom.
  4. Method according to one of claims 1 to 3, for preparing compounds of formula:
    Figure 00330003
    in which R1 represents an optionally substituted aryl or heterocyclic group and R2 represents a hydrogen atom or an alkyl radical (a straight or branched chain of 1 to 6 carbon atoms) or a phenylalkyl radical whose alkyl moiety contains a straight or branched chain of 1 to 6 carbon atoms.
  5. Method according to claim 4 for preparing compounds of formula (I), wherein R1 is (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents selected from chlorine, bromine, fluorine, alkyl, alkoxy, alkenyl, hydroxy, hydroxyalkyl, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, -CH(NH2)-COOH, saturated or unsaturated heterocycle with 5 to 14 members and containing a heteroatom selected from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl, (c) a naphthyl radical, (d) a naphthyl radical substituted by one or more substituents selected from chlorine, bromine, fluorine, alkyl, alkoxy, alkenyl, hydroxy, hydroxyalkyl, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl, (e) a 9H-fluorenyl radical, (f) an anthracenyl radical, (g) a phenanthrenyl radical, (h) a saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur, (i) a saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur and substituted by one or more substituents selected from chlorine, bromine, fluorine, alkyl, alkoxy, acyl, benzoyl, amino, phenyl, chlorophenyl, bromophenyl, fluorophenyl, phenoxy, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkoxycarbonyl, saturated or unsaturated heterocycle with 5 to 14 members and containing one or more heteroatoms selected from nitrogen, oxygen or sulfur optionally substituted by chlorine, bromine, fluorine, alkyl, phenyl, chlorophenyl, bromophenyl, fluorophenyl and R2 represents a hydrogen atom or an alkyl or phenylalkyl radical, the alkyl, alkoxy and alkenyl radicals containing a straight or branched chain of 1 to 6 carbon atoms, and the acyl radicals containing 2 to 6 carbon atoms.
  6. Method according to one of claims 4 or 5 for preparing compounds of formula (I), wherein R2 represents a hydrogen atom or a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or benzyl radical.
  7. Method according to one of claims 4, 5 or 6 for preparing compounds of formula (I), wherein R1 represents or contains a heterocycle with 5 to 14 members, this being selected from carbazole, indan, thiophene, furan, 1-isoindolinone, pyrrole, 2,5-dihydropyrrole, benzoxazole, 5H[1]benzopyrano[2,3-b]pyridine, pyridine, imidazole, oxazole, quinoline, isoquinoline, pyrimidine, phenothiazine, phenoxazine, piperazine.
  8. Method according to one of claims 4 to 7 for preparing compounds of formula (I), wherein R1 represents a 2-aminophenyl, 3-benzoylphenyl, 3-aminophenyl, 4-aminophenyl, 4-isobutylphenyl, 6-methoxy-2-naphthyl, 5-benzoyl-2-thienyl, 3-phenoxyphenyl, 2-fluoro-4-biphenyl, 3-fluoro-4-biphenyl, 1-oxo-2-isoindolinyl, 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl, 4-(2-thienylcarbonyl)phenyl, 9H-fluoren-2-yl, 6-chloro-9H-carbazol-3-yl, 2-(4-chlorophenyl)benzoxazol-5-yl, 4-cyclohexylphenyl, pyridin-2-yl, 5H[1]benzopyrano[2,3-b]pyridin-7-yl, 3-trifluoromethoxyphenyl, 3-acetylphenyl radical.
  9. Method according to one of claims 1 to 8, wherein the derivative of formula (II) and the aromatic or heterocyclic halogen derivative are reacted together in stoichiometric amounts.
  10. Method according to one of claims 1 to 9, wherein the derivative of formula (II) is added progressively during the electrolysis.
  11. Method according to one of claims 1 to 10, wherein the nickel complex is a complex with a nitrogen-containing ligand.
  12. Method according to claim 11, wherein the nickel complex with a nitrogen-containing ligand is a NiBr2bipyridine or nickelorthophenanthroline complex.
  13. Method according to one of claims 1 to 12, wherein the quantity of the nickel complex is between 0.01 mole and 0.2 mole based on 1 mole of the aromatic or heterocyclic halogen derivative.
  14. Method according to claim 13, wherein the quantity of the nickel complex is 0.1 mole based on 1 mole of the aromatic or heterocyclic halogen derivative.
  15. Method according to one of claims 1 to 14, wherein the electrolyte is a quaternary ammonium salt or an inorganic salt.
  16. Method according to claim 15, wherein the electrolyte is a quaternary ammonium salt or an inorganic salt selected from tetrabutylammonium tetrafluoroborate, tetrabutylammonium bromide or sodium bromide.
  17. Method according to one of claims 1 to 16, wherein the concentration of the electrolyte is between 5.10-3 M and 2.10-2 M.
  18. Method according to claim 17, wherein the concentration of the electrolyte is 1.5.10-2 M.
  19. Method according to one of claims 1 to 18, wherein the solvent is an aprotic solvent or a mixture of aprotic and protic solvents.
  20. Method according to claim 19, wherein the solvent is dimethylformamide, N-methylpyrrolidone or a dimethylformamide-ethanol mixture (80-20 % to 20-80 %).
  21. Method according to one of claims 1 to 20, wherein the anode is a consumable anode of aluminium, an aluminium alloy, zinc, iron or magnesium.
  22. Method according to one of claims 1 to 21, wherein the cathode is of stainless steel, copper, nickel or carbon fibres.
  23. Method according to claim 22, wherein the cathode has a hollow cylindrical shape and is arranged concentrically around the anode.
  24. Method according to one of claims 1 to 23, wherein the temperature of the medium is between 15°C and 100°C.
  25. Method according to one of claims 1 to 24, wherein the electrolysis is carried out at a constant intensity of between 0.1 and 1 Ampere.
  26. Method according to claim 25, wherein the current density is from 0.5 to 1 A/dm2 with respect to the cathode surface area.
  27. Method according to one of claims 1 to 26, wherein the quantity of electricity is between 2 and 3 Faradays based on a mole of aromatic or heterocyclic halogen derivative.
  28. Method according to claim 27, wherein the quantity of electricity is 2.5 Faradays based on a mole of aromatic or heterocyclic halogen derivative.
  29. Method according to one of claims 1 to 28, wherein the electrolytic reduction is carried out in an electrolyser without a separate compartment containing the solvent in which is dissolved the base electrolyte, the aromatic or heterocyclic halogen derivative, the nickel catalyst, part of the derivative of formula (II), the remainder of the derivative (II) being added in small portions during the electrolysis, and the electrolyser comprises a consumable anode, a cathode, a stirring system, an inlet for inert gas, a temperature regulation system and a stabilized electrical supply.
  30. Method according to claim 29, wherein the aromatic or heterocyclic halogen derivative is used at a concentration of between 0.01 M/l and 1 M/l, the nickel catalyst at a concentration of 10 % in moles based on the initial aromatic or heterocyclic halogen derivative and the derivative of formula (II) at a concentration of 3 % in moles based on the initial aromatic or heterocyclic halogen derivative, the remainder of the derivative of formula (II) being added in small portions during the electrolysis.
  31. Method according to one of claims 1 to 28, wherein the reaction is carried out in a tubular circulating electrolyser comprising a central aluminium or Duralumin bar as anode and a stainless steel tube as cathode.
  32. Method according to one of claims 1 to 31, wherein the hydrolysis of the product obtained after extraction, to obtain the propionic acid, is performed in acid medium.
  33. Method according to claim 32, wherein the hydrolysis is carried out by means of 6N aqueous sulfuric acid, under reflux.
  34. Method according to one of claims 1 to 31, wherein the hydrolysis of the product obtained after extraction, to obtain the propionic acid, is carried out in basic medium.
  35. Method according to claim 34, wherein the hydrolysis is carried out by means of lithium hydroxide, in tetrahydrofuran, at a temperature of about 20°C.
  36. Method according to one of claims 1 to 31, wherein the transesterification to obtain the alkyl or phenylalkyl ester is carried out by the action of potassium carbonate and an aliphatic alcohol (a straight or branched chain of 1 to 6 carbon atoms) or an alcohol Ar-alkOH in which Ar represents a phenyl radical and alk represents an alkyl radical (a straight or branched chain of 1 to 6 carbon atoms), at a temperature of about 20°C.
EP98933708A 1997-06-25 1998-06-24 Method for preparing 2-aryl or 2-heterocyclyl chiral propionic acids and their esters Expired - Lifetime EP0991793B1 (en)

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