WO1997026256A1 - New process for the preparation of bicyclic lactones - Google Patents

New process for the preparation of bicyclic lactones Download PDF

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Publication number
WO1997026256A1
WO1997026256A1 PCT/FR1997/000066 FR9700066W WO9726256A1 WO 1997026256 A1 WO1997026256 A1 WO 1997026256A1 FR 9700066 W FR9700066 W FR 9700066W WO 9726256 A1 WO9726256 A1 WO 9726256A1
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Prior art keywords
general formula
alkali metal
alcoholate
preparation
bicyclic
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PCT/FR1997/000066
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French (fr)
Inventor
André LOUPY
Alain Petit
David Abenhaim
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Pierre Fabre Medicament
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Publication of WO1997026256A1 publication Critical patent/WO1997026256A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to a new process for the preparation of bicyclic lactones of general formula I
  • Ar represents an aryl radical, preferably a phenyl.
  • bicyclic lactones are useful as intermediates to be transformed into compounds useful as medicaments, in particular 1-phenyl-2-oxo-oxa-bicyclo- (3: 1: 0) -hexane for the preparation of milnacipran of general formula
  • NaNH 2 poses at the industrial level, not only storage and processing problems, but also cost problems insofar as the solvent mixture is not recyclable and the reagent is expensive.
  • a second drawback lies in the second step in the use of concentrated aqueous sodium hydroxide at temperatures close to 100 ° C.
  • the present invention therefore relates to an improved process for the preparation of a bicyclic lactone of general formula I, so as to reduce the number of steps and to minimize the costs associated with such a process and the risks of safety and pollution, in mild conditions.
  • the first step therefore consists in reacting an alkyl aryl acetate of general formula III, in which Ar represents an aryl radical and R represents an alkyl radical, with a halomethyl epoxy of general formula IV in which X represents a halogen, in a suitable solvent in the presence of an alkali metal alcoholate.
  • alkali metal alcoholate is meant the product of the reaction of an aliphatic alcohol with an alkali metal.
  • the aliphatic alcohol is chosen from methanol, ethanol, propanol, butanol and their various isomers, preferably t-butanol.
  • the alkali metal is advantageously sodium or potassium, preferably potassium.
  • the two derivatives of general formulas III and IV are advantageously reacted in a molar ratio close to 1, preferably equal to 1, and advantageously employs up to 2 molar equivalents of alkali metal alcoholate, preferably between 1.5 and 2 equivalents, more preferably 1.9 equivalents.
  • the suitable solvent is dimethylformamide (DMF).
  • DMF dimethylformamide
  • the alkyl aryl acetate of general formula III is advantageously reacted in DMF at a concentration of less than 2 moles / liter, preferably between 1 and 1.5 moles / liter.
  • the reaction is advantageously carried out at room temperature, requiring neither heating nor cooling of the reaction medium, for a period close to 30 minutes.
  • the progress of the reaction can be controlled according to the usual techniques, and its duration may be less than or more than 30 minutes depending on this progress.
  • An alcoholate of general formula V is then obtained, in which M represents an alkali metal, Ar and R being defined above, which is then hydrolyzed directly by HCl, without requiring prior purification, for a duration of approximately 5 minutes.
  • the duration of the hydrolysis will also depend on the progress of the reaction and may, depending on the circumstances, be greater than 5 minutes. Those skilled in the art will be able to easily determine the duration of this acid hydrolysis.
  • HC1 2N is used.
  • the bicyclic lactone of general formula 1 is then isolated and if necessary purified according to the usual techniques of the prior art.
  • aryl is meant according to the present invention the usual aryl or heteroaryl radicals comprising one or more heteroatoms (N, O or S), in particular the phenyl, naphthyl, pyridyl, pyrimidinyl, and azoles radicals. They can be substituted by one or more usual substituents, in particular by one or two substituents chosen from alkyl, alkoxy or halogen radicals.
  • alkyl is meant according to the present invention a lower alkyl, preferably Cj-Cj, advantageously chosen from methyl, ethyl, propyl and butyl radicals, and their isomers, in particular isopropyl and tert-butyl.
  • halogen is meant according to the present invention fluorine, chlorine, bromine or iodine.
  • the radical X of the derivative of formula IV is preferably chosen from chlorine or bromine.
  • EXAMPLE 1 80 ml of DMF are successively introduced into a single-necked flask, followed by 15.02 g (0.1 mol) of methyl phenylacetate and 27.4 g (0.1 mol) of epibromhy drine.
  • Magnetic stirring is carried out and 42.64 g (0.19 mole) of potassium tert-butoxide, powdered, are gently introduced, keeping the temperature below 40 ° C. in an ice water bath. It is then left under magnetic stirring for the duration of the reaction (30 minutes) at room temperature.
  • the reaction medium is poured into a separatory funnel.
  • the organic products (lactone and trans alcohol) are extracted with 3 times 300 ml of ethyl ether.
  • the trans alcohol is removed by washing with a saturated sodium bicarbonate solution (twice 200 ml).
  • the ethereal phase is then brought to neutral pH by washing with water (twice 200 ml) and then dried over sodium sulfate. Dry evaporation gives an oily brown residue.
  • This residue is dissolved in a minimum of acetone, then poured into a water + ice mixture (with magnetic stirring).
  • the crystals obtained are filtered, drained on sintered glass, and dried at room temperature under reduced pressure of the water pump.
  • the yield obtained in crystallized lactone is 50% (17.4 g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a new process for the preparation of bicyclic lactones having the general formula (I) wherein Ar is an aryl radical, preferably phenyl. The new process of the invention in two steps comprises reacting an aryl-acetate of alkyl with halomethyl epoxy in an appropriate solvant in the presence of an alkali metal alcoolate, and proceeding directly to the acid hydrolysis of the resulting product. By implementing the process of the invention, the use of NaNH2 is avoided in the first step, and the second step of hydrolysing the nitril function by means of NaOH 10N is suppressed, but was necessary for the prior process before the acid hydrolysis by HC1 2N. The bicyclic lactones obtained by the process of the invention are particularly useful for the preparation of milnacipran (Ar = phenyl).

Description

NOUVEAU PROCEDE DE -PREPARATION DE LACTONES BICYCLIQUES NEW PROCESS FOR THE PREPARATION OF BICYCLIC LACTONS
La présente invention concerne un nouveau procédé de préparation de lactones bicycliques de formule générale IThe present invention relates to a new process for the preparation of bicyclic lactones of general formula I
Figure imgf000003_0001
dans laquelle Ar représente un radical aryle, de préférence un phenyle.
Figure imgf000003_0001
in which Ar represents an aryl radical, preferably a phenyl.
Ces lactones bicycliques sont utiles comme intermédiaires pour être transformés en composés utiles comme médicament, en particulier la 1- phényl-2-oxo-oxa-bicyclo-( 3 : l :0)-hexane pour la préparation du milnacipran de formule généraleThese bicyclic lactones are useful as intermediates to be transformed into compounds useful as medicaments, in particular 1-phenyl-2-oxo-oxa-bicyclo- (3: 1: 0) -hexane for the preparation of milnacipran of general formula
Figure imgf000003_0002
A
Figure imgf000003_0002
AT
dans laquelle Ar représente un phenyle et Et représente un éthyle, décrit dans le brevet FR 2 302 994.in which Ar represents a phenyl and Et represents an ethyl, described in patent FR 2 302 994.
Les procédés usuels de l'état de la technique permettent d'obtenir la lactone bicyclique ci-dessus en trois étapes à partir d'un aryl-acétonitrile selon le schéma réactionnel suivant :The usual processes of the state of the art make it possible to obtain the above bicyclic lactone in three stages from an aryl acetonitrile according to the following reaction scheme:
Ar - CH 2 - CN + X - CH 2 \ /Ar - CH 2 - CN + X - CH 2 \ /
O NaNH 2O NaNH 2
Ar HAr H
NC CH 2 0 _ . NaNC CH 2 0 _ . N / A
Figure imgf000003_0003
V L'inconvénient majeur de ce procédé réside dans l'emploi dans la première étape de NaNH2 dans le toluène-dioxane comme solvant. En effet,
Figure imgf000003_0003
V The major drawback of this process lies in the use in the first stage of NaNH 2 in toluene-dioxane as solvent. Indeed,
NaNH2 pose au niveau industriel, non seulement des problèmes de stockage et de mise en oeuvre, mais également des problèmes de coûts dans la mesure où le mélange solvant n'est pas recyclable et le réactif est onéreux. Un deuxième inconvénient réside dans la deuxième étape dans l'emploi de la soude concentrée aqueuse à des températures voisines de 100°C.NaNH 2 poses at the industrial level, not only storage and processing problems, but also cost problems insofar as the solvent mixture is not recyclable and the reagent is expensive. A second drawback lies in the second step in the use of concentrated aqueous sodium hydroxide at temperatures close to 100 ° C.
La présente invention concerne donc un procédé amélioré de préparation d'une lactone bicyclique de formule générale I, de manière à diminuer le nombre d'étapes et à minimiser les coûts liés à un tel procédé et les risques de sécurité et de pollution, dans des conditions douces.The present invention therefore relates to an improved process for the preparation of a bicyclic lactone of general formula I, so as to reduce the number of steps and to minimize the costs associated with such a process and the risks of safety and pollution, in mild conditions.
Le procédé selon l'invention est résumé par le schéma réactionnel ci-dessous :The process according to the invention is summarized by the reaction scheme below:
Figure imgf000004_0001
Figure imgf000004_0001
MM
Figure imgf000004_0002
v
Figure imgf000004_0002
v
La première étape consiste donc à faire réagir un aryl-acétate d'alkyle de formule générale III, dans laquelle Ar représente un radical aryle et R représente un radical alkyle, avec un halométhyl époxy de formule générale IV dans laquelle X représente un halogène, dans un solvant approprié en présence d'un alcoolate de métal alcalin.The first step therefore consists in reacting an alkyl aryl acetate of general formula III, in which Ar represents an aryl radical and R represents an alkyl radical, with a halomethyl epoxy of general formula IV in which X represents a halogen, in a suitable solvent in the presence of an alkali metal alcoholate.
Par alcoolate de métal alcalin, on entend le produit de la réaction d'un alcool aliphatique avec un métal alcalin. L'alcool aliphatique est choisi parmi le méthanol, l'éthanol, le propanol, le butanol et leurs différents isomères, de préférence le t-butanol. Le métal alcalin est -avantageusement le sodium ou le potassium, de préférence le potassium.By alkali metal alcoholate is meant the product of the reaction of an aliphatic alcohol with an alkali metal. The aliphatic alcohol is chosen from methanol, ethanol, propanol, butanol and their various isomers, preferably t-butanol. The alkali metal is advantageously sodium or potassium, preferably potassium.
Les deux dérivés de formules générales III et IV sont avantageuse¬ ment mis à réagir dans un rapport molaire voisin de 1, de préférence égal à 1 , et on emploie avantageusement jusqu'à 2 équivalents molaires d'alcoolate de métal alcalin, de préférence entre 1,5 et 2 équivalents, plus préférentiel¬ lement de 1,9 équivalents.The two derivatives of general formulas III and IV are advantageously reacted in a molar ratio close to 1, preferably equal to 1, and advantageously employs up to 2 molar equivalents of alkali metal alcoholate, preferably between 1.5 and 2 equivalents, more preferably 1.9 equivalents.
D'une manière avantageuse, le solvant approprié est le diméthyl- formamide (DMF). L'aryl-acétate d'alkyle de formule générale III est avantageusement mis à réagir dans le DMF à une concentration inférieure à 2 moles/litre, de préférence comprise entre 1 et 1,5 moles/litre.Advantageously, the suitable solvent is dimethylformamide (DMF). The alkyl aryl acetate of general formula III is advantageously reacted in DMF at a concentration of less than 2 moles / liter, preferably between 1 and 1.5 moles / liter.
La réaction s'effectue avantageusement à température ambiante, ne nécessitant ni chauffage ni refroidissement du milieu réactionnel, pour une durée voisine de 30 minutes. Bien entendu, l'avancement de la réaction peut être contrôlé selon les techniques usuelles, et sa durée pourra être inférieure ou supérieure à 30 minutes en fonction de cet avancement.The reaction is advantageously carried out at room temperature, requiring neither heating nor cooling of the reaction medium, for a period close to 30 minutes. Of course, the progress of the reaction can be controlled according to the usual techniques, and its duration may be less than or more than 30 minutes depending on this progress.
On obtient alors un alcoolate de formule générale V, dans laquelle M représente un métal alcalin, Ar et R étant définis ci-dessus, lequel est ensuite hydrolyse directement par HC1, sans nécessiter une purification préalable, pour une durée d'environ 5 minutes. Bien entendu, la durée de l'hydrolyse dépendra également de l'avancement de la réaction et pourra selon les circonstances être supérieure à 5 minutes. L'homme du métier saura déterminer sans difficulté la durée de cette hydrolyse acide. D'une manière avantageuse, on emploie HC1 2N. La lactone bicyclique de formule générale 1 est ensuite isolée et le cas échéant purifiée selon les techniques usuelles de l'état de la technique.An alcoholate of general formula V is then obtained, in which M represents an alkali metal, Ar and R being defined above, which is then hydrolyzed directly by HCl, without requiring prior purification, for a duration of approximately 5 minutes. Of course, the duration of the hydrolysis will also depend on the progress of the reaction and may, depending on the circumstances, be greater than 5 minutes. Those skilled in the art will be able to easily determine the duration of this acid hydrolysis. Advantageously, HC1 2N is used. The bicyclic lactone of general formula 1 is then isolated and if necessary purified according to the usual techniques of the prior art.
Par aryle, on entend selon la présente invention les radicaux aryles ou hétéroaryles usuels comprenant un ou plusieurs hétéroatomes (N, O ou S), en particulier les radicaux phenyle, naphtyle, pyridyle, pyrimidinyle, et les azoles. Ils peuvent être substitués par un ou plusieurs substituants usuels, en particulier par un ou deux substituants choisis parmi les radicaux alkyle, alkoxy ou les halogènes.By aryl is meant according to the present invention the usual aryl or heteroaryl radicals comprising one or more heteroatoms (N, O or S), in particular the phenyl, naphthyl, pyridyl, pyrimidinyl, and azoles radicals. They can be substituted by one or more usual substituents, in particular by one or two substituents chosen from alkyl, alkoxy or halogen radicals.
Par alkyle, on entend selon la présente invention un alkyle inférieur, de préférence en Cj-Cj, avantageusement choisi parmi les radicaux méthyle, éthyle, propyle et butyle, et leurs isomères, en particulier iso¬ propyle et tertio-butyle. Cette définition s'applique également aux restes alkyles des alkoxy. Par halogène, on entend selon la présente invention le fluor, le chlore, le brome ou l'iode. Pour la mise en oeuvre de la première étape, le radical X du dérivé de formule IV est de préférence choisi parmi le chlore ou le brome. D'autres caractéristiques du procédé selon l'invention apparaîtront à la lumière de l'exemple de synthèse ci-après pour Ar représentant un phenyle.By alkyl is meant according to the present invention a lower alkyl, preferably Cj-Cj, advantageously chosen from methyl, ethyl, propyl and butyl radicals, and their isomers, in particular isopropyl and tert-butyl. This definition also applies to the alkyl residues of alkoxy. By halogen is meant according to the present invention fluorine, chlorine, bromine or iodine. For the implementation of the first step, the radical X of the derivative of formula IV is preferably chosen from chlorine or bromine. Other characteristics of the process according to the invention will appear in the light of the synthesis example below for Ar representing a phenyle.
Exemple 1 Dans un ballon monocol, on introduit successivement 80 ml de DMF puis 15,02 g (0, 1 mole) de phénylacétate de méthyle et 27,4 g (0, 1 mole) d 'épibromhy drine.EXAMPLE 1 80 ml of DMF are successively introduced into a single-necked flask, followed by 15.02 g (0.1 mol) of methyl phenylacetate and 27.4 g (0.1 mol) of epibromhy drine.
On met sous agitation magnétique et on introduit doucement 42,64 g (0, 19 mole) de tert-butylate de potassium en poudre, en maintenant la température inférieure à 40°C dans un bain d'eau glacée. On laisse ensuite sous agitation magnétique pendant la durée de la réaction (30 minutes) à température ambiante.Magnetic stirring is carried out and 42.64 g (0.19 mole) of potassium tert-butoxide, powdered, are gently introduced, keeping the temperature below 40 ° C. in an ice water bath. It is then left under magnetic stirring for the duration of the reaction (30 minutes) at room temperature.
L'hydrolyse de l'alcoolate formé et la lactonisation sont effectuées avec HCI 2N. Dans une ampoule à brome, on introduit 300 ml d'une solution de HCI 2N. Celui-ci est ajouté lentement de façon à maintenir la température inférieure à 30°C. Le mélange réactionnel, initialement brun et opaque, devient orange translucide. On laisse alors 5 minutes à température ambiante sous agitation magnétique après la fin de l'introduction de HCI.The hydrolysis of the alcoholate formed and the lactonization are carried out with HCI 2N. 300 ml of a 2N HCl solution are introduced into a dropping funnel. This is added slowly so as to keep the temperature below 30 ° C. The reaction mixture, initially brown and opaque, becomes translucent orange. Then allowed 5 minutes at room temperature with magnetic stirring after the end of the introduction of HCl.
Le milieu réactionnel est versé dans une ampoule à décanter. On extrait les produits organiques (lactone et alcool trans) par 3 fois 300 ml d'éther éthylique. On élimine l'alcool trans par lavages avec une solution saturée de bicarbonate de sodium (2 fois 200 ml). La phase éthérée est ensuite ramenée à pH neutre par lavages à l'eau (2 fois 200 ml) puis séchée sur sulfate de sodium. L'évaporation à sec donne un résidu huileux marron. On dissout ce résidu dans un minimum d'acétone, puis on coule dans un mélange eau + glace (sous agitation magnétique). Les cristaux obtenus sont filtrés, essorés sur verre fritte, et séchés à température ambiante sous pression réduite de la trompe à eau. Le rendement obtenu en lactone cristallisée est de 50 % ( 17,4 g). Par la mise en oeuvre du procédé selon l'invention on évite l'utilisation de NaNH2 dans la première étape, et on supprime la deuxième étape d'hydrolyse de la fonction nitrile par NaOH ION, nécessaire pour le procédé antérieur avant d'effectuer l'hydrolyse acide par HCI 2N. The reaction medium is poured into a separatory funnel. The organic products (lactone and trans alcohol) are extracted with 3 times 300 ml of ethyl ether. The trans alcohol is removed by washing with a saturated sodium bicarbonate solution (twice 200 ml). The ethereal phase is then brought to neutral pH by washing with water (twice 200 ml) and then dried over sodium sulfate. Dry evaporation gives an oily brown residue. This residue is dissolved in a minimum of acetone, then poured into a water + ice mixture (with magnetic stirring). The crystals obtained are filtered, drained on sintered glass, and dried at room temperature under reduced pressure of the water pump. The yield obtained in crystallized lactone is 50% (17.4 g). By implementing the process according to the invention, the use of NaNH 2 is avoided in the first step, and the second step of hydrolysis of the nitrile function is eliminated by NaOH ION, necessary for the previous process before carrying out acid hydrolysis with HCl 2N.

Claims

REVENDICATIONS
1 / Procédé de préparation de lactones bicycliques de formule générale I1 / Process for the preparation of bicyclic lactones of general formula I
Figure imgf000008_0001
Figure imgf000008_0001
dans laquelle Ar représente un radical aryle, caractérisé en ce que l'on fait réagir un aryl-acétate d'alkyle de formule générale III,in which Ar represents an aryl radical, characterized in that an alkyl aryl acetate of general formula III is reacted,
Ar - CH 2 - CO - OR I I IAr - CH 2 - CO - OR I I I
dans laquelle Ar représente un radical aryle et R représente un radical alkyle, avec un halométhyl époxy de formule générale IV,in which Ar represents an aryl radical and R represents an alkyl radical, with a halomethyl epoxy of general formula IV,
X - CH 2 ^-7 I V 0 X - CH 2 ^ -7 IV 0
dans laquelle X représente un halogène, dans un solvant approprié en présence d'un alcoolate de métal alcalin, pour obtenir un alcoolate de formule générale V,in which X represents a halogen, in a suitable solvent in the presence of an alkali metal alcoholate, to obtain an alcoholate of general formula V,
Figure imgf000008_0002
V dans laquelle M représente un métal alcalin, Ar et R étant définis ci-dessus, lequel est ensuite hydrolyse directement par HCI pour obtenir la lactone bicyclique de formule générale I, qui est ensuite isolée et le cas échéant purifiée. 2/ Procédé selon la revendication 1 , caractérisé en ce que l'alcoolate de métal alcalin est le produit de la réaction d'un alcool aliphatique avec un métal alcalin, l'alcool aliphatique étant choisi parmi le méthanol, l'éthanol, le propanol, le butanol et leurs différents isomères, de préférence le t-butanol et le métal alcalin étant le sodium ou le potassium, de préférence le potassium. 3/ Procédé selon l'une des revendications 1 ou 2, caractérisé en ce que le solvant approprié est le diméthylformamide (DMF).
Figure imgf000008_0002
V in which M represents an alkali metal, Ar and R being defined above, which is then hydrolyzed directly by HCl to obtain the bicyclic lactone of general formula I, which is then isolated and if necessary purified. 2 / A method according to claim 1, characterized in that the alkali metal alcoholate is the product of the reaction of an aliphatic alcohol with an alkali metal, the aliphatic alcohol being chosen from methanol, ethanol, propanol , butanol and their various isomers, preferably t-butanol and the alkali metal being sodium or potassium, preferably potassium. 3 / Method according to one of claims 1 or 2, characterized in that the appropriate solvent is dimethylformamide (DMF).
4/ Procédé selon la revendication 3, caractérisé en ce que l'aryl- acétate d'alkyle de formule générale III est mis à réagir dans le DMF à une concentration inférieure à 2 moles/litre, de préférence comprise entre 1 et 1,5 moles/litre.4 / A method according to claim 3, characterized in that the alkyl aryl acetate of general formula III is reacted in DMF at a concentration of less than 2 moles / liter, preferably between 1 and 1.5 moles / liter.
5/ Procédé selon l'une des revendications 1 à 4, caractérisé en ce que la réaction s'effectue à température ambiante, pour une durée voisine de 30 minutes. 6/ Procédé selon l'une des revendications 1 à 5, caractérisé en ce que l'on effectue l'hydrolyse acide sans purification préalable de l'alcoolate de formule générale V.5 / A method according to one of claims 1 to 4, characterized in that the reaction is carried out at room temperature, for a period close to 30 minutes. 6 / A method according to one of claims 1 to 5, characterized in that the acid hydrolysis is carried out without prior purification of the alcoholate of general formula V.
7/ Procédé selon l'une des revendications 1 à 6, caractérisé en ce que l'on effectue l'hydrolyse acide avec HCI 2N. 8/ Procédé selon l'une des revendications 1 à 7, caractérisé en ce que la lactone bicyclique de formule générale I est ensuite transformée en composés utiles comme médicament.7 / Method according to one of claims 1 to 6, characterized in that the acid hydrolysis is carried out with HCl 2N. 8 / Method according to one of claims 1 to 7, characterized in that the bicyclic lactone of general formula I is then transformed into compounds useful as medicament.
9/ Procédé selon l'une des revendications 1 à 8, caractérisé en ce que Ar représente un phenyle. 10/ Procédé selon l'une des revendications 8 ou 9, caractérisé en ce que le médicament est le milnacipran. 9 / Method according to one of claims 1 to 8, characterized in that Ar represents a phenyle. 10 / Method according to one of claims 8 or 9, characterized in that the drug is milnacipran.
PCT/FR1997/000066 1996-01-16 1997-01-15 New process for the preparation of bicyclic lactones WO1997026256A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0910521B1 (en) * 1996-07-11 2002-09-25 Volvo Car Corporation Arrangement for a vehicle steering wheel

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2302994A1 (en) * 1975-03-06 1976-10-01 Fabre Sa Pierre 1 Aryl 2 hydroxymethyl cyclopropane carboxylic acids - and lactones, pharmaceutical intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2302994A1 (en) * 1975-03-06 1976-10-01 Fabre Sa Pierre 1 Aryl 2 hydroxymethyl cyclopropane carboxylic acids - and lactones, pharmaceutical intermediates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MOUZIN G ET AL: "A convenient synthesis of bifunctional vicinal cyclopropanes", SYNTHESIS, no. 4, 1978, CENT. RECH. PIERRE FABRE;CASTRES; FR., pages 304 - 305, XP002015733 *

Cited By (1)

* Cited by examiner, † Cited by third party
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EP0910521B1 (en) * 1996-07-11 2002-09-25 Volvo Car Corporation Arrangement for a vehicle steering wheel

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