EP0000679B1 - Process for the preparation of glafenine - Google Patents

Process for the preparation of glafenine Download PDF

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Publication number
EP0000679B1
EP0000679B1 EP78400060A EP78400060A EP0000679B1 EP 0000679 B1 EP0000679 B1 EP 0000679B1 EP 78400060 A EP78400060 A EP 78400060A EP 78400060 A EP78400060 A EP 78400060A EP 0000679 B1 EP0000679 B1 EP 0000679B1
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Prior art keywords
glafenine
glycerol
quinoline
anthranilate
glyceryl
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EP78400060A
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German (de)
French (fr)
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EP0000679A1 (en
Inventor
Sylvano Casadio
Henri Dr. Cousse
Pierre Hascoet
Gilbert Dr. Mouzin
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Pierre Fabre SA
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Pierre Fabre SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms

Definitions

  • the present invention carried out at the Pierre FABRE Research Center relates to a new process for the preparation of the ⁇ -monoglyceride of 4 (2 '- carboxyphenylamino) - 7 - chloro-quinoline of formula:
  • This chemical compound is known for its analgesic properties; it is used as an active ingredient in many pharmaceutical specialties. This molecule will be mentioned below by its international common name: glafenine.
  • Glafenine (I) is prepared by condensation in hydrochloric medium of dichloro - 4,7 - quinoline (II) with methyl anthranilate (III), this intermediate methyl ester is then transesterified by glycerol acetonide (V) and finally the acid hydrolysis of the compound (VI) leads to glafenine (I) according to the reaction scheme:
  • the present invention relates to a very simple process which makes it possible to prepare glafenine under very economical conditions.
  • glafenine is prepared by condensation of the glyceryl anthranilate of formula: on 4.7 - dichloro-quinoline:
  • This condensation is preferably carried out in a hydrochloric medium.
  • the glafenine obtained is separated from the reaction medium by known methods, it can in particular be precipitated by neutralization of the reaction medium.
  • the crude glafenine obtained can be purified for example by recrystallization from a solvent or mixture of organic solvent such as the chloroform-ethanol mixture.
  • the glyceryl anthranilate is itself prepared according to the invention by condensation of glycerol on isatoic anhydride in basic medium as a condensing agent.
  • This process is preferably carried out using an excess of glycerol as solvent, so the glyceryl anthranilate is obtained in solution in glycerol and this solution can be used in the process according to the present invention without having to isolate the anthranilate. which further improves the overall yield of the process.
  • This process for the preparation of glafenine has the advantage of using only products widely available commercially and inexpensively.
  • isatoic anhydride which is experiencing an industrial development as a synthesis intermediary in the dye industry can, thanks to new synthesis processes, be obtained at prices much lower than the prices of anthranilic acid which constitutes the basic product in known syntheses of glafenine.
  • this synthetic method makes it possible to significantly increase the yields of glafenine compared to known methods, in particular by limiting the number of reaction steps.
  • reaction medium is then cooled to 20 ° C. and transferred to a 200 I tank in which it is treated slowly with 60 l of an aqueous sodium hydroxide solution N, then neutralization is completed by adding sodium bicarbonate.
  • the purification is carried out by return to a solution of glafenine hydrochloride and reprecipitation of the base gléfenine by operating as follows: to the aqueous suspension is added 2830 cm 3 of HCl with density 1.18, the hydrochloride formed dissolves, one filters on a single disc filter, one adds sodium hydroxide N, then one ends the neutralization with a solution of baking soda.
  • the precipitate is separated as previously by wringing; the crude glafenine thus obtained has, after drying, a melting point of 163 ° C.
  • glafenine is obtained with a yield varying according to the case from 65 to 75% compared to 4,7-dichloro-quinoline with an instant melting point in the Kofler block of 169-170 ° C. .
  • the present invention also relates, as a medicament, to glafenin obtained by implementing the method according to the present invention.

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

Description

La présente invention, réalisée au Centre de Recherche Pierre FABRE concerne un nouveau procédé de préparation de l'a-monoglycéride de la 4(2' - carboxyphénylamino) - 7 - chloro - quinoléine de formule:The present invention, carried out at the Pierre FABRE Research Center relates to a new process for the preparation of the α-monoglyceride of 4 (2 '- carboxyphenylamino) - 7 - chloro-quinoline of formula:

Figure imgb0001
Figure imgb0001

Ce composé chimique est connu pour ses propriétés antalgiques; il est utilisé comme principe actif dans de nombreuses spécialités pharmaceutiques. Cette molécule sera mentionnée, ci-après, par sa dénomination commune internationale : glafénine.This chemical compound is known for its analgesic properties; it is used as an active ingredient in many pharmaceutical specialties. This molecule will be mentioned below by its international common name: glafenine.

Les procédés de synthèse de la technique antérieure sont au nombre de trois:There are three methods of synthesis of the prior art:

1) La méthode de A. ALLAIS et G. ROUSSEAU (ROUSSEL UCLAF) décrite dans le brevet belge No. 636.381.1) The method of A. ALLAIS and G. ROUSSEAU (ROUSSEL UCLAF) described in Belgian patent No. 636.381.

La glafénine (I) est préparée par condensation en milieu chlorhydrique de la dichloro - 4,7 - quinoléine (II) avec l'anthranilate de méthyle (III), cet ester méthylique intermédiaire est ensuite transestérifié par l'acétonide de glycéryde (V) et enfin l'hydrolyse acide du composé (VI) conduit à la glafénine (I) selon le schéma réactionnel:

Figure imgb0002
Glafenine (I) is prepared by condensation in hydrochloric medium of dichloro - 4,7 - quinoline (II) with methyl anthranilate (III), this intermediate methyl ester is then transesterified by glycerol acetonide (V) and finally the acid hydrolysis of the compound (VI) leads to glafenine (I) according to the reaction scheme:
Figure imgb0002

2) Le procédé décrit dans le brevet français numéro 1.421.229.2) The process described in French patent number 1,421,229.

Procédé dans lequel on estérifie le chlorure de l'acide o-nitrobenzoïque par l'acétonide de glycéryle; le produit obtenu étant, après réduction du groupe nitro, condensé avec la 4,7 - dichloro - quinoléine; on obtient ainsi un composé qui, par hydrolyse acide, fournit la glafénine selon le schéma:

Figure imgb0003
Process in which the chloride of o-nitrobenzoic acid is esterified with glyceryl acetonide; the product obtained being, after reduction of the nitro group, condensed with 4,7 - dichloro - quinoline; a compound is thus obtained which, by acid hydrolysis, provides glafenine according to the scheme:
Figure imgb0003

3) La méthode de MILDNER PAVAO et MIHALIC MLADEN décrite dans le brevet allemand No. 2.251.646.3) The method of MILDNER PAVAO and MIHALIC MLADEN described in the German patent No. 2,251,646.

On condense l'ortho - chloro - benzoate de glycéryle sur la 4 - amino - 7 - chloro - quinoléine:

Figure imgb0004
We condense the glyceryl ortho - chloro - benzoate on the 4 - amino - 7 - chloro - quinoline:
Figure imgb0004

Ces procédés présentent tous de nombreux inconvénients car, soit ils utilisent des produits de départ coûteux car délicats à synthétiser, soit ils multiplient les étapes réactionnelles et, par là, augmentent le coût du procédé tout en diminuant le rendement.These processes all have numerous drawbacks because either they use expensive starting materials because they are difficult to synthesize, or they multiply the reaction stages and, thereby, increase the cost of the process while reducing the yield.

La présente invention concerne un procédé très simple qui permet de préparer la glafénine dans des conditions très économiques. Pour cela, on prépare la glafénine par condensation de l'anthranilate de glycéryle de formule:

Figure imgb0005
sur la 4,7 - dichloro - quinoléine:
Figure imgb0006
 The present invention relates to a very simple process which makes it possible to prepare glafenine under very economical conditions. For this, glafenine is prepared by condensation of the glyceryl anthranilate of formula:
Figure imgb0005
 on 4.7 - dichloro-quinoline:
Figure imgb0006

Cette condensation est conduite de préférence en milieu chlorhydrique.This condensation is preferably carried out in a hydrochloric medium.

On opère de préférence à une température comprise entre 60 et 90°C et en général à 80°C pendant un temps de l'ordre de 30 minutes à une heure.It is preferably carried out at a temperature between 60 and 90 ° C and in general at 80 ° C for a time of the order of 30 minutes to one hour.

La glafénine obtenue est séparée du milieu réactionnel par des procédés connus, on peut en particulier la précipiter par neutralisation du milieu réactionnel.The glafenine obtained is separated from the reaction medium by known methods, it can in particular be precipitated by neutralization of the reaction medium.

La glafénine brute obtenue peut être purifiée par exemple par recristallisation dans un solvant ou mélange de solvant organique tel que le mélange chloroforme-éthanol.The crude glafenine obtained can be purified for example by recrystallization from a solvent or mixture of organic solvent such as the chloroform-ethanol mixture.

L'anthranilate de glycéryle est lui-même préparé selon l'invention par condensation du glycérol sur l'anhydride isatoïque en milieu basique comme agent de condensation.

Figure imgb0007
The glyceryl anthranilate is itself prepared according to the invention by condensation of glycerol on isatoic anhydride in basic medium as a condensing agent.
Figure imgb0007

Ce procédé est décrit dans le brevet français déposé le 26 juillet 1977 au nom de la Demanderesse et ayant pour titre "Nouvel intermédiaire de synthèse: l'anthranilate de glycéryle et son procédé de préparation".This process is described in the French patent filed on July 26, 1977 in the name of the Applicant and having for title "New synthesis intermediate: glyceryl anthranilate and its preparation process".

Ce procédé est conduit de préférence en utilisant un excès de glycérol comme solvant, on obtient donc l'anthranilate de glycéryle en solution dans le glycérol et cette solution peut être utilisée dans le procédé selon la présente invention sans avoir à isoler l'anthranilate, ce qui améliore encore le rendement global du procédé.This process is preferably carried out using an excess of glycerol as solvent, so the glyceryl anthranilate is obtained in solution in glycerol and this solution can be used in the process according to the present invention without having to isolate the anthranilate. which further improves the overall yield of the process.

Ce procédé de préparation de la glafénine présente l'avantage de n'utiliser que des produits largement accessibles dans le commerce et peu coûteux.This process for the preparation of glafenine has the advantage of using only products widely available commercially and inexpensively.

Ainsi, l'anhydride isatoïque qui connaît un développement industriel en tant qu'intermédiaire de synthèse dans l'industrie des colorants peut, grâce à des nouveaux procédés de synthese, être obtenu à des prix très inférieurs aux prix de l'acide anthranilique qui constitue le produit de base dans les synthèses connues de la glafénine.Thus, isatoic anhydride which is experiencing an industrial development as a synthesis intermediary in the dye industry can, thanks to new synthesis processes, be obtained at prices much lower than the prices of anthranilic acid which constitutes the basic product in known syntheses of glafenine.

En outre, ce procédé de synthèse permet d'accroître notablement les rendements en glafénine par rapport aux procédés connus, notamment en limitant le nombre des étapes de réaction.In addition, this synthetic method makes it possible to significantly increase the yields of glafenine compared to known methods, in particular by limiting the number of reaction steps.

L'exemple suivant est destiné à illustrer le mode de mise en oeuvre préféré du procédé selon la présente invention.The following example is intended to illustrate the preferred embodiment of the method according to the present invention.

ExempleExample Préparation de l'a - monoglycéride de la.4(2' - carboxyphénylamino) 7 - chloro - quinoléine (glafénine).Preparation of a - monoglyceride of la. 4 (2 '- carboxyphenylamino) 7 - chloro-quinoline (glafenine).

Dans un réacteur de 100 I on introduit 29,3 kg de glycérol (321 moles) et on ajoute 157 g de soude en pastilles (3,9 moles) puis 5,1 kg d'anhydride isatoïque (31 moles).29.3 kg of glycerol (321 moles) are introduced into a 100 I reactor and 157 g of sodium hydroxide pellets (3.9 moles) are added, then 5.1 kg of isatoic anhydride (31 moles).

On chauffe lentement, le gaz carbonique formé est aspiré par l'intermédiaire d'une pompe dont le débit est de 10 m3/heure; la température est maintenue environ 1 heure entre 60 et 90°C.It is heated slowly, the carbon dioxide formed is sucked in via a pump, the flow rate of which is 10 m 3 / hour; the temperature is maintained for approximately 1 hour between 60 and 90 ° C.

A ce stade on obtient une solution d'anthranilate d'a-glycéryle dans le glycérol.At this stage, a solution of α-glyceryl anthranilate in glycerol is obtained.

A cette solution on ajoute 66,35 1 d'acide chlorhydrique 0,5 N et 5,2 kg de 4,7 - dichloro - quinoléine recristallisée, la température est ramenée aux environs de 80°C pendant 40 minutes environ.To this solution is added 66.35 l of 0.5N hydrochloric acid and 5.2 kg of recrystallized 4.7-dichloro-quinoline, the temperature is brought back to around 80 ° C. for approximately 40 minutes.

Le milieu réactionnel est ensuite refroidi à 20°C et transvasé dans une cuve de 200 I dans laquelle il est traité lentement par 60 1 d'une solution aqueuse de soude N puis la neutralisation est terminée par addition de bicarbonate de soude.The reaction medium is then cooled to 20 ° C. and transferred to a 200 I tank in which it is treated slowly with 60 l of an aqueous sodium hydroxide solution N, then neutralization is completed by adding sodium bicarbonate.

La glafénine précipite lentement, le mélange réactionnel est envoyé par l'intermédiaire d'une pompe DELASCO dans une essoreuse. Le solide ainsi récupéré est remis en suspension dans 100 I d'eau.Glafenine precipitates slowly, the reaction mixture is sent via a DELASCO pump in a wringer. The solid thus recovered is resuspended in 100 l of water.

La purification est effectuée par retour à une solution de chlorhydrate de glafénine et reprécipitation de la gléfénine base en opérant de la façon suivante: à la suspension aqueuse on rajoute 2830 cm3 d'HCI de densité 1,18, le chlorhydrate formé se dissout, on filtre sur filtre monodisque, on rajoute de la soude N, puis on termine la neutralisation par une solution de bicarbonate de soude.The purification is carried out by return to a solution of glafenine hydrochloride and reprecipitation of the base gléfenine by operating as follows: to the aqueous suspension is added 2830 cm 3 of HCl with density 1.18, the hydrochloride formed dissolves, one filters on a single disc filter, one adds sodium hydroxide N, then one ends the neutralization with a solution of baking soda.

Le précipité est séparé comme précédemment par essorage; la glafénine brute ainsi obtenue a, après séchage, un point de fusion de 163°C.The precipitate is separated as previously by wringing; the crude glafenine thus obtained has, after drying, a melting point of 163 ° C.

Une recristallisation dans 100 I de chloroforme et 4 I d'éthanol à 95° permet une purification complémentaire.Recrystallization from 100 I of chloroform and 4 I of 95 ° ethanol allows additional purification.

Après séchage à l'étuve sous vide la glafénine est obtenue avec un rendement variant selon les cas de 65 à 75% par rapport à la 4,7 - dichloro - quinoléine avec un point de fusion instantané au bloc Kofler de 169-170°C.After drying in a vacuum oven, glafenine is obtained with a yield varying according to the case from 65 to 75% compared to 4,7-dichloro-quinoline with an instant melting point in the Kofler block of 169-170 ° C. .

Caractéristiques de la glafénine ainsi obtenue:

  • Formule brute: C19H17CI N204.
  • Masse moléculaire: 372,8.
  • L'analyse élémentaire est en accord avec les normes traditionnellement exigées.
  • La teneur résiduelle en chloroforme est inférieure à 1.000 ppm.
  • Chromatographie en couche mince:
    • -support: silice Merck F 254
    • -révélateur: lampe à ultra-violets ou vapeurs d'iode
    • -solvant:
      • a) acétate d'éthyle, Rf - 0,4
      • b) butanol-acide acétique-eau, 6/2/2/. Rf = 0,66.
  • Spectrographie infra-rouge:
    • Appareil Perkin Elmer modèle 177.
    • Pastilles KBr.
  • Bandes d'absorption caractéristiques:
    • vc=o (ester) à 1680 cm-1
    • vc=c (aromatiques) 1580 et 1620 cm-1
    • voH et vNH bande large entre 3100 et 3500 cm-1.
Characteristics of the glafenin thus obtained:
  • Gross formula: C 19 H 17 CI N 2 0 4 .
  • Molecular mass: 372.8.
  • Elementary analysis is in accordance with traditionally required standards.
  • The residual chloroform content is less than 1,000 ppm.
  • Thin layer chromatography:
    • -support: Merck F 254 silica
    • -revelator: ultraviolet lamp or iodine vapor
    • -solvent:
      • a) ethyl acetate, Rf - 0.4
      • b) butanol-acetic acid-water, 6/2/2 /. Rf = 0.66.
  • Infrared spectrography:
    • Perkin Elmer model 177 camera.
    • KBr.
  • Characteristic absorption bands:
    • v c = o (ester) at 1680 cm- 1
    • v c = c (aromatic) 1580 and 1620 cm- 1
    • v oH and v NH wide band between 3100 and 3500 cm- 1 .

Ce spectre est superposable à celui d'un authentique chimique obtenu différemment.This spectrum is superimposable on that of an authentic chemical obtained differently.

La présente invention concerne également, à titre de médicament, la glafénine obtenue par la mise en oeuvre du procédé selon la présente invention.The present invention also relates, as a medicament, to glafenin obtained by implementing the method according to the present invention.

Claims (4)

1. A process for the preparation of 4(2' - carboxyphenylamino) - 7 - chloro - quinoline - α - monoglyceride, characterised in that:
(i) glycerol is condensed on isatoic anhydride in a basic medium in order to obtain glyceryl anthranilate, and
(ii) glyceryl anthranilate is condensed with 4,7-dichloroquinoline and the desired product is recovered.
2. A process according to claim 1, characterised in that glycerol is condensed on isatoic anhydride in an excess of glycerol and that the resulting reaction solution is used directly for condensation with 4,7 - dichloro - quinoline.
3. A process according to one of claims 1 and 2, characterised in that the second condensation step is carried out in a hydrochloric medium.
4. A process according to one of claims 1 to 3, characterised in that the desired product is recovered by precipitating 4(2' - carboxyphenylamino) - 7 - chloroquinoline - α - monoglyceride by neutralising the reaction medium.
EP78400060A 1977-07-26 1978-07-18 Process for the preparation of glafenine Expired EP0000679B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7722900 1977-07-26
FR7722900A FR2398733A1 (en) 1977-07-26 1977-07-26 NEW PROCESS FOR PREPARING GLAFENIN

Publications (2)

Publication Number Publication Date
EP0000679A1 EP0000679A1 (en) 1979-02-07
EP0000679B1 true EP0000679B1 (en) 1981-06-24

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EP (1) EP0000679B1 (en)
JP (1) JPS5424881A (en)
CA (1) CA1107737A (en)
DE (1) DE2860803D1 (en)
ES (1) ES472072A1 (en)
FR (1) FR2398733A1 (en)
IT (1) IT1156878B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2549830B1 (en) * 1983-07-25 1987-04-30 Corbiere Jerome NEW PROCESS FOR OBTAINING SUBSTITUTED QUINOLEINS

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EP0000679A1 (en) 1979-02-07
CA1107737A (en) 1981-08-25
FR2398733A1 (en) 1979-02-23
IT7850438A0 (en) 1978-07-24
FR2398733B1 (en) 1980-02-29
IT1156878B (en) 1987-02-04
ES472072A1 (en) 1979-03-16
JPS5424881A (en) 1979-02-24
DE2860803D1 (en) 1981-10-01

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