Classifications

• • 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 enantomeric purity.
• 2-aryl or 2-heterocyclyl propionic acids and their esters are useful as anti-inflammatory drugs (ketoprofen, i uprofen, naproxen, tiaprofen, fenoprofen, flurbiprofen, indoprofen, pirprofen, suprofe ⁇ , cicloprofen, carprofen, hexapr ) but also as intermediates in the preparation of drugs (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 racomic form or in the form of an enantiomer (R or S).
• R or S an enantiomer
• the biological activity of these compounds is associated with a single enantiomer and it is therefore necessary to obtain these ⁇ nanliomers by a simple, inexpensive and non-polluting industrial process.
• 2-ary acids! or 2-heterocyclyl propionics and their esters are represented by the formula:
• R is (a) a phenyl radical, (b) a phenyl radical substituted by one or more substituents chosen from chlorine, bromine, fluorine, alkyl, alkoxy, alkonyl, hydroxy, hydroxyalkyl, acyl, benzoyl, a ino, phenyl, chlorophenyl, bromoph ⁇ nyl, fluorophônyle, phe ⁇ oxy, cyano, polyfluoroalkyle, polyfluoroalkoxy, alkoxycarbonyle, -CH (NH 2 ) -COOH.
• acyl benzoyl, amino, phenyl, chlorophenyl, bromoph ⁇ nyle, fluorophônyle, phenoxy, cyano, polyfluoroalkyle, polyfluoroalkoxy, alkoxycarbonyle, heterocycle of 5 to 14 members saturated or unsaturated and containing one or more heterôroatomes chosen among nitrogen. oxygen or sulfur optionally substituted with chlorine, bromine, fluorine, alkyl, phenyl. chlorophenyl, bromoph ⁇ nyle, fluorophônyle.
• R 1 represents a 3-benzoylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl radical.
• Orophenyl benzoxazol ⁇ -5-yl, 4-cyclohexylphônyle, pyridine-2-yle, 5H [1] benzopyrano [2,3-b] pyridine-7-yl ⁇ , 3-trifluoromethoxyphenyl, 3-acetylph ⁇ nyle.
• R ⁇ represents a hydrogen atom or a methyl ⁇ radical. ethyl, propyl, isopropyl, butyl, ter -butyl or benzyl.
• the alkyl, alkoxy and alk ⁇ yl ⁇ radicals contain 1 to 6 carbon atoms in a straight or branched chain
• the acyl radicals contain 2 to 6 carbon atoms
• the halogen atoms are the chlorine, bromine, iodine and fluorine atoms
• R 3 represents a radical of formula
• Hal represents a halogen atom and, preferably, a chlorine atom, and of an aromatic or heterocyclic halogen 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.
• 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).
• the aromatic or heterocyclic halogen derivatives are those of formula:
• R has the same meanings as in formula (I) and Hal represents an atom of iodine, chlorine or bromine.
• the derivatives (II) and the aromatic or heterocyclic halogen derivatives are reacted in stochiometric quantities. It is preferable 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 nickel-orthoph ⁇ nanthrolin ⁇ complex. It can be prepared either ext ⁇ mpora ⁇ ment 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 or heterocyclic halogen derivative and preferably 0.1 mole per 1 mole of the aromatic or heterocyclic halogen derivative.
• 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-methylpyrrolidono (preferably dimethyrtormamide) or a mixture of aprotic and protic solvents, preferably a mixture of dimethylformamide-ethanol (80-20% to 20-80%).
• the anode is a consumable anode made of aluminum or an aluminum alloy such as Duralumin or an anode made of zinc, iron or magnesium. It is best to use an aluminum anode.
• the cathode is not decisive for this type of reaction. It can consist of another conductive material which cannot be attacked under the conditions of the experiment, such as stainless steel (in the form of frit in particular), copper, nickel or a fabric of carbon fibers. 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.
• the temperature of the medium is generally maintained at an optimum value which depends on the nature of the aromatic or heterocyclic halogen derivative used by immersing the reactor in a thermoregulated bath or by a double jacket system. It is generally between 15 ° C and 100 ° C, and preferably around 20 ° C.
• the electrolys ⁇ 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 quantity of electricity required is determined by the disappearance of the aromatic or heterocyclic halide followed by an appropriate analytical method (for example by gas chromatography). It is generally between 2 and 3 Faradays per mole of aromatic or heterocyclic halogen derivative, and preferably 2.5 Faradays per mole of aromatic or heterocyclic halogen derivative.
• the electrolytic reduction is carried out in an electrolytic unit without a separate compartment containing the solvent in which is dissolved:
• the nickel catalyst (preferably 10 mol% relative to the starting aromatic or heterocyclic halogen derivative).
• the rest of the derivative (II) is generally added as the electrolysis takes place by any suitable means (in solid, liquid form or in solution in one of the solvents constituting the medium).
• the electrolyzer includes:
• an inert gas supply argon or nitrogen for example
• inert gas supply argon or nitrogen for example
• the reaction is carried out in a tubular electrolyser with circulation constituted by a central bar of aluminum or Duralumin serving as anode and by a stainless steel tube serving as cathode.
• the two electrodes are insulated by Tétlo ⁇ 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. It enters the reactor through lateral tubing situated towards its lower end and leaves it through similar tubing situated towards its upper end.
• a thermostatically controlled expansion vessel is placed on the circuit of the reaction medium.
• the current intensity is adjusted so that the current density is similar to that used in the other type of reactor.
• the hydrolysis of the product obtained after extraction, to obtain propionic acid is carried out in an acid medium or in an alkaline medium.
• it is carried out either by means of 6N aqueous sulfuriqu ⁇ acid under reflux or by the action of lithium hydroxide, in an inert solvent such as tetrahydrofuran, è a temperature of 20 ⁇ C.
• the tra ⁇ sestrification to obtain the alkyl or phenylalkyl ester is generally carried out by the action of potassium carbonate and an aliphatic alcohol (1 to 6 carbon atoms in a straight or branched chain) or an Ar-alkOH alcohol in which Ar represents a phenyl ⁇ radical and alk represents an alkyl radical, at a temperature in the region of 20 Q C
• the derivatives of formula (II) can be obtained by condensation of the chloride of 2-chloropropionic acid with the lithium salt of (AS, 58) - 1, 5-dimethyl-4-phenylimidazolldin-2-one, of (4 ⁇ , 5S) -1,5-dim ⁇ thyl-4-phônylimidazolidine-2-one or of (4fî) - 4 * phenyloxazolidin ⁇ -2-one
• Aromatic or heterocyclic halogen derivatives are commercially available or can be obtained by application or adaptation of the methods described in J. PrakL 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 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 uantluent. The yield is 75%.
• (+) ôphedrine (0.248 mole) are mixed with 45 g of urea (0.75 mole). The mixture is heated for half an hour at 17 ° 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 (4/7.5S) -1.5-dlmethyl-4-phenylimidazolidine-2-ono, or 37%, are obtained.
• the solution is cooled to -78 ° C using an acthyle-dry ice acetate bath, then 35 ml of 1.6 M butyllithium in hexane are added using a degassed bromine bulb and under a stream of argon, by rapid drip " (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 is raised to approximately 20 ° C.
• the mixture is extracted with 3 ⁇ 20 ml of ethyl acetate. silica column, using the pentane / ether mixture (50/50) as elua ⁇ t
• the yield is 75%.
• the solution is hydrolysed with 30 ml of water and the temperature is raised to about 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 uantluent. The yield is 85%.
• the reaction is carried out at room temperature (approximately 20 ° C).
• An inert gas (argon) saturated with vapor of the solvent mixture is bubbled for approximately 10 minutes. The bubbling is then maintained in the solution throughout the duration of the electrolysis.
• the electrolyzer comprises an anode consisting of an aluminum bar (1 cm diameter) placed in the center of the reactor and a cylindrical cathode nickel foam (dlamôtre 3 cm - 5 cm height) disposed concentriqu ⁇ lies to the anode.
• the intensity of the current is maintained at a constant value of 0.25 amperes with a stabilized supply, until complete disappearance of the aromatic or heterocyclic halogen derivative.
• the addition of derivative (II) is carried out by adding fractions of 200 ⁇ l of solution at 0.625 M / l in dimethylformamide every two minutes. After 3 hours, corresponding to the passage of 2.7 Faradays per mole of the aromatic or heterocyclic halogen derivative, the electrolysis is stopped as well as the addition of the derivative (II) (total addition 12.5 millimole).
• the solution is hydrolyzed with 40 ml of 1N hydrochloric acid. The solvents are removed under vacuum from the rotary evaporator. The residue is taken up in water.
• the aqueous phase is extracted with 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 sulphate then filtered and evaporated to dryness under reduced pressure.
• the expected product is purified by chromatography on 100 g of silica contained in a column 3 cm in diameter (generally eluent: pentane / oter: 50/50).
• the diastereoisomeric excess is determined by gas chromatography.
• 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 15
• EXAMPLE 4 EXAMPLE OF "TRANSESTERIFICATION" WITH OBTAINING METHYL ESTER:
• Example 2 2 g of the product obtained in Example 1 are added to 20 ml of methanol to which 0.1 g of potassium carbonate is added. It is left to react for a few minutes to 6 hours, until complete transformation.
• the solution is hydrolyzed with 20 ml of an aqueous NaCl solution and extracted with 3 times 20 ml of ether.
• the organic phases are rinsed with an aqueous NaCl solution, then dried over magnesium sulfate. After evaporating the ether, the methyl ester is separated on a silica column with a pentane / ether mixture (95/5). The measurement of the rotary power, compared to the data of the literature gives the enantiomeric excess.

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• 1997
  • 1997-06-25 FR FR9707908A patent/FR2765246B1/fr not_active Expired - Fee Related
• 1998
  • 1998-06-24 WO PCT/FR1998/001336 patent/WO1999000535A1/fr active IP Right Grant
  • 1998-06-24 DE DE69802809T patent/DE69802809D1/de not_active Expired - Lifetime
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