FR2466450A1 - Prodn. of 4-(4'-ortho-chloro-phenyl)-4-oxo-2-methylene butyric acid - or itanoxone, by acylation of 2-chloro-bi:phenyl with itaconic animoride in 1,2-di:chloroethane - Google Patents
Prodn. of 4-(4'-ortho-chloro-phenyl)-4-oxo-2-methylene butyric acid - or itanoxone, by acylation of 2-chloro-bi:phenyl with itaconic animoride in 1,2-di:chloroethane Download PDFInfo
- Publication number
- FR2466450A1 FR2466450A1 FR7924582A FR7924582A FR2466450A1 FR 2466450 A1 FR2466450 A1 FR 2466450A1 FR 7924582 A FR7924582 A FR 7924582A FR 7924582 A FR7924582 A FR 7924582A FR 2466450 A1 FR2466450 A1 FR 2466450A1
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- Prior art keywords
- itanoxone
- phenyl
- chloro
- sep
- acylation
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- HJWLWNLAIBFKDO-UHFFFAOYSA-N 4-[4-(2-chlorophenyl)phenyl]-2-methylidene-4-oxobutanoic acid Chemical compound C1=CC(C(=O)CC(=C)C(=O)O)=CC=C1C1=CC=CC=C1Cl HJWLWNLAIBFKDO-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229950008966 itanoxone Drugs 0.000 title claims abstract description 18
- 230000010933 acylation Effects 0.000 title claims abstract description 4
- 238000005917 acylation reaction Methods 0.000 title claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title abstract 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 title 1
- 229960003750 ethyl chloride Drugs 0.000 title 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 14
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 5
- OFNISBHGPNMTMS-UHFFFAOYSA-N 3-methylideneoxolane-2,5-dione Chemical compound C=C1CC(=O)OC1=O OFNISBHGPNMTMS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- LAXBNTIAOJWAOP-UHFFFAOYSA-N 2-chlorobiphenyl Chemical group ClC1=CC=CC=C1C1=CC=CC=C1 LAXBNTIAOJWAOP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 3
- 230000008030 elimination Effects 0.000 claims abstract 2
- 238000003379 elimination reaction Methods 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- FZEPARZCAPJYHN-UHFFFAOYSA-N 2-oxocyclobutane-1-carboxylic acid Chemical compound OC(=O)C1CCC1=O FZEPARZCAPJYHN-UHFFFAOYSA-N 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 1
- -1 4-ortho-chlorophenylphenyl Chemical group 0.000 description 1
- 0 CC*c(cc1)ccc1-c1ccccc1Cl Chemical compound CC*c(cc1)ccc1-c1ccccc1Cl 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
L'invention concerne un procédé industriel d'obtention du composé chimique : l'acide (ortho chloro phényl-4' phényl)-4, oxo-4, méthylène-2 butyrique (itanoxone). Il comprend une acylation du chloro 2 biphényl par l'anhydride itaconique en présence de chlorure d'aluminium et se caractérise en ce que le solvant réactionnel est le dichloro-1-2 éthane, que la cristallisation est effectuée par addition d'acétone ou d'alcool facilitant la filtration et que la recristallisation dans le dioxanne ou le diméthyl formamide-eau est suivie d'un traitement permettant l'élimination des solvants organiques résiduaires. Le produit ainsi obtenu est utile dans le domaine thérapeutique.The invention relates to an industrial process for obtaining the chemical compound: (ortho chloro phenyl-4 'phenyl) -4, oxo-4, 2-methylene-butyric acid (itanoxone). It comprises an acylation of 2-chloro biphenyl by itaconic anhydride in the presence of aluminum chloride and is characterized in that the reaction solvent is 1-2-dichloroethane, that the crystallization is carried out by adding acetone or d alcohol facilitating filtration and that recrystallization from dioxane or dimethyl formamide-water is followed by a treatment allowing the elimination of residual organic solvents. The product thus obtained is useful in the therapeutic field.
Description
La présente invention réalisée au Centre de Recherches Pierre FABRE concerne un nouveau procédé industriel d'obtention d'Itanoxone. The present invention produced at the Pierre FABRE Research Center concerns a new industrial process for obtaining Itanoxone.
L'Itanoxone est la dénomination commune internationale de l'acide (ortho chloro phényl - 4' phényl) - 4, oxo - 4, méthylène - 2 butyrique de formule
Ce composé chimique, ses applications thérapeutiques et un procédé d'obtention ont fait l'objet des brevets n" 74 10196 et 75 04912 déposés au nom de la demanderesse.This chemical compound, its therapeutic applications and a process for obtaining it have been the subject of patents Nos. 74 10196 and 75 04912 filed in the name of the applicant.
Selon le procédé antérieur, ce composé était préparé par réaction de Friedel et Crafts dans le S-tétrachloroéthane ou le nitrobenzene en présence d'un catalyseur acide de Lewis selon le schéma
<tb> <SEP> 2N <SEP> 8
<tb> <SEP> + <SEP> 2 <SEP> C <SEP> CF' <SEP> ,"",""CH2
<tb> Cl <SEP> 112 <SEP> COOH <SEP> CCH2C\C00H
<tb> <SEP> o <SEP> Cl
<tb> <SEP> Anhydride <SEP> itaconique <SEP> Itanoxone
<tb>
Au stade industriel, ce procédé présentait quelques inconvénients La filtration de l'Itanoxone était peu commode et il demeurait du solvant réactionnel.<tb><SEP> 2N <SEP> 8
<tb><SEP> + <SEP> 2 <SEP> C <SEP> CF '<SEP>, "", "" CH2
<tb> Cl <SEP> 112 <SEP> COOH <SEP> CCH2C \ C00H
<tb><SEP> o <SEP> Cl
<tb><SEP> Itaconic <SEP> Anhydrate <SEP> Itanoxone
<Tb>
At the industrial stage, this process had some disadvantages Itanoxone filtration was inconvenient and there remained the reaction solvent.
De plus, au cours de la réaction il se formait un isomère en quantité variable de 1 à 5 % de formule
<tb> <SEP> H2
<tb> <SEP> U <SEP> G-CH2-COOH
<tb> C1 <SEP> Isomère <SEP> 1
<tb> <SEP> Cl <SEP> Isomère <SEP> 1
<tb>
Ce produit correspond à la deuxième possibilité d'ouverture de l'anhydride dissymétrique.En outre, comme précisé dans le brevet n" 75 04912 il se produit une isomérisation en milieu alcalin avec basculement irréversible de la double
liaison éthylénique
<tb><SEP> U <SEP> G-CH2-COOH
<tb> C1 <SEP> Isomer <SEP> 1
<tb><SEP> Cl <SEP> Isomer <SEP> 1
<Tb>
This product corresponds to the second possibility of opening of the asymmetric anhydride. In addition, as specified in the patent No. 75 04912, there is an isomerization in an alkaline medium with irreversible reversal of the double
ethylenic bond
<tb> <SEP> CH3
<tb> <SEP> C <SEP> C <SEP> - <SEP> CH <SEP> = <SEP> C
<tb> NCOOH
<tb> <SEP> Cl <SEP> Isomère <SEP> 2
<tb>
L'objet de la présente invention est un nouveau procédé adapté à une application aisée au stade industriel. I1 comprend une acylation du chloro 2 biphényl par l'anhydride itaconique en présence de chlorure d'aluminium et se caractérise en ce aue le solvant réactionnel est le dichloro-1-2 éthane, que la cris ou d'alcool tallisation est effectuée par addition d'acétoneifaci4itant la filtration et - eau que la recristallisation dans le dioxane ou le diméthyl formamidelest suivie d'un traitement permettant l'élimination des solvants organiques résiduaires.<tb><SEP> CH3
<tb><SEP> C <SEP> C <SEP> - <SEP> CH <SEP> = <SEP> C
<tb> NCOOH
<tb><SEP> Cl <SEP> Isomer <SEP> 2
<Tb>
The object of the present invention is a novel process suitable for easy application at the industrial stage. It comprises an acylation of chloro-2-biphenyl with itaconic anhydride in the presence of aluminum chloride and is characterized in that the reaction solvent is 1-2-dichloroethane, which cries or alcoholic acid is made by addition. acetoneifaci4iting the filtration and - water that recrystallization in dioxane or dimethyl formamidelis followed by a treatment allowing the removal of residual organic solvents.
I1 est connu que les réactions de Friedel et Crafts sont habituellement effectuées dans des solvants tels que nitrobenzène (difficile à éliminer) sulfure de carbone (toxique, inflammable et nauséabond). Or, selon l'invention, il a été observé qu'un certain solvant permet la réalisation de ce type de réaction dans des conditions plus favorables, assurant l'obtention d'un milieu réactionnel homogène et la possibilité de chauffer à une température suffisante pour que la réaction soit terminée en 4 heures environ. It is known that Friedel and Crafts reactions are usually performed in solvents such as nitrobenzene (difficult to remove), carbon disulfide (toxic, flammable and foul-smelling). However, according to the invention, it has been observed that a certain solvent allows the realization of this type of reaction under more favorable conditions, ensuring the production of a homogeneous reaction medium and the possibility of heating to a temperature sufficient to that the reaction is complete in about 4 hours.
Le solvant choisi est le dichloro-l-2 éthane. I1 est à noter que les solvants chlorés de point d'ébullition plus bas, tels que chlorure de méthylène ne permettent pas des rendements aussi élevés que ceux obtenus avec le dichloro-l-2 éthane, et surtout entrainent une immobilisation plus prolongée des appareils (24 h au lieu de 4 h environ).The solvent chosen is dichloro-1-2 ethane. It should be noted that chlorinated solvents with a lower boiling point, such as methylene chloride, do not allow yields as high as those obtained with dichloro-1-ethane, and above all lead to more prolonged immobilization of the devices ( 24 hours instead of 4 hours).
Après hydrolyse et décantation, l'addition d'acétone ou d'alcool (1 à 4 volumes) à la phase organique émulsionnée permet une bonne cristallisation de l'Itanoxone et augmente la rapidité de filtration.After hydrolysis and decantation, the addition of acetone or alcohol (1 to 4 volumes) to the emulsified organic phase allows good crystallization of Itanoxone and increases the rate of filtration.
I1 est à noter de plus que les isomères concomitants 1 et 2, très solubles, sont éliminés dans le filtrat, ce qui est un avantage appréciable du nouveau procédé. It should also be noted that the highly soluble concomitant isomers 1 and 2 are removed in the filtrate, which is an appreciable advantage of the new process.
Mode opératoire
Selon la présente invention 100 moles de chloro-2 biphényle (188,6 kg) sont mis en solution dans 500 litres de dichloro-1-2 éthane en chauffant à800C environ.Operating mode
According to the present invention 100 moles of 2-chlorobiphenyl (188.6 kg) are dissolved in 500 liters of 1-2-dichloroethane by heating to about 800C.
Après avoirramené la température à 20"C, ajouter 210 moles de chlorure d'aluminium (275 kg). A cette solution bien agitée dans un réacteur de 1500 litres, ajouter en une heure 95 moles d'anhydride itaconique en solution dans le dichloro-1-2 éthane.After having heated the temperature to 20 ° C., add 210 moles of aluminum chloride (275 kg) to this well-stirred solution in a 1500-liter reactor, add in one hour 95 moles of itaconic anhydride in solution in dichloromethane. 1-2 ethane.
L'évolution de la réaction est suivie par le dégagement d'acide chlorhydrique.The evolution of the reaction is followed by the evolution of hydrochloric acid.
Après 2 heures d'agitation à température ambiante, chauffer progressivement 1 heure à 50 environ et 1 heure à environ 80"C (reflux du solvant) ; le dégagement gazeux est aspiré et neutralisé par une solution de soude.After stirring for 2 hours at room temperature, gradually heat for 1 hour at approximately 50 and 1 hour at approximately 80 ° C. (reflux of the solvent), the gas evolution is sucked up and neutralized with a sodium hydroxide solution.
Lorsque le dégagement gazeux est terminé le milieu réactionnel est transvasé dans un réacteur contenant de la glace et de l'acide chlorhydrique concentré, et après isolement, la phase organique est traitée par 500 et 1000 litres d'acétone sous agitation. Les cristaux formés sont facilement collectés sur filtre presse, lavés et séchés.When the evolution of gas is complete the reaction medium is transferred to a reactor containing ice and concentrated hydrochloric acid, and after isolation, the organic phase is treated with 500 and 1000 liters of acetone with stirring. The crystals formed are easily collected on a filter press, washed and dried.
Le rendement ainsi obtenu en produit brut fondant à 208"C est de 80 à 85 7. The yield thus obtained of crude product melting at 208 ° C. is 80 to 85%.
par rapport à l'anhydride itaconique.compared to itaconic anhydride.
Procédé de purification le produit brut ainsi obtenu contient - du solvant réactionnel - les isomères 1 et 2.Purification process The crude product thus obtained contains - the reaction solvent - isomers 1 and 2.
Selon la présente invention les isomères sont éliminés par recristallisation dans un solvant tel que le diméthyl formamide - eau ou le dioxanne.According to the present invention the isomers are removed by recrystallization in a solvent such as dimethylformamide-water or dioxane.
Après filtration et séchage, il n'est pas possible d'éliminer le solvant résiduaire au dessous de 5000 ppm même par lavage à l'acétone par exemple.After filtration and drying, it is not possible to remove the residual solvent below 5000 ppm even by washing with acetone, for example.
Selon la présente invention, le solvant intégré aux cristaux est éliminé par mise en solution de l'Itanoxone dans l'eau sous forme de sel de sodium suivie d'une précipitation en milieu acide.According to the present invention, the solvent integrated in the crystals is removed by dissolving the itanoxone in water in the form of sodium salt followed by precipitation in acidic medium.
Afin d'éviter le basculement de la double liaison, à une suspension d'itanoxone dans l'eau, ajouter en refroidissant en 1 heure un léger défaut d'une solution de soude ; l'itanoxone se dissout au fur et à mesure de la formation du sel desodium.In order to avoid tilting of the double bond, to a suspension of itanoxone in water, add while cooling in 1 hour a slight defect of a soda solution; itanoxone dissolves as the sodium salt is formed.
En opérant ainsi la solution du sel de sodium reste à un pH < 9,5 et la réaction dtisomérisation est négligeable.By operating thus the solution of the sodium salt remains at a pH <9.5 and the isomerization reaction is negligible.
L'itanoxone en léger excès servant de tampon est éliminée par filtration (elle peut être recyclée). Le filtrat est refroidi dans une cuve et acidifié par addition d'une solution d'acide chlorhydrique. En milieu acide, le sel est neutralisé et l'itanoxone (F = 212 ) précipite exempte de solvants organiques et d'isomères. The slightly excess itanoxone buffer is removed by filtration (it can be recycled). The filtrate is cooled in a tank and acidified by adding a hydrochloric acid solution. In acidic medium, the salt is neutralized and itanoxone (F = 212) precipitates free of organic solvents and isomers.
Caractéristiques du produit obtenu
Caractéristiques analytiques Organoleptiques : inodore, insipide, couleur blanc cassé Point de fusion instantané : 213 + 1" Analyse centésimale : calculé C : 67,89 ; H : 4,36 ; C1 : 11,79
trouvé C : 67,80 ; H : 4,30 ; C1 : 11,69
correspondant à la formule : C17 H13 C1 03. Characteristics of the product obtained
Analytical characteristics Organoleptic: odorless, tasteless, off-white color Instant melting point: 213 + 1 "Centesimal analysis: calculated C: 67.89; H: 4.36; C1: 11.79
found C, 67.80; H, 4.30; C1: 11.69
corresponding to the formula: C17 H13 C1 03.
Insoluble dans l'eau, soluble à 0,8 7. dans l'acétone, 0,5 % dans l'alcool,
3,9 % dans le dioxanne, 28 % dans le DMF et 38,4 % dans le DMSO.Insoluble in water, soluble at 0.8% in acetone, 0.5% in alcohol,
3.9% in dioxane, 28% in DMF and 38.4% in DMSO.
Caractéristiques physicochimiques Spectrographie
IR (KBr) : 1690 (COOH) ; 1675 (C=O) ; 1610 (C=C aromatiques) cm W : max (95 % éthanol) 267 (log 4,24) nm. Physicochemical characteristics Spectrography
IR (KBr): 1690 (COOH); 1675 (C = O); 1610 (aromatic C = C) cm W: max (95% ethanol) 267 (log 4.24) nm.
RMN (DMSO d6 + TMS)6 4,1 (s, 2H, CO-CH2) ; 5,85 (d, 1H, J = 1,2 Hz
trans HC = C COOH) ; 6, 3 (d, 1H, J = 1,2 Hz, cis HC - C - COOH
7,3-7,9 (m, 7H, COOH + protons aromatiques) ; 8,1 (d, 2H, J = 8 Hz
protons aromatiques en ortho du carbonyle) ppm.NMR (DMSO d6 + TMS) δ 4.1 (s, 2H, CO-CH 2); 5.85 (d, 1H, J = 1.2 Hz
trans HC = C COOH); 6, 3 (d, 1H, J = 1.2 Hz, cis HC - C - COOH
7.3-7.9 (m, 7H, COOH + aromatic protons); 8.1 (d, 2H, J = 8 Hz
aromatic protons in ortho carbonyl) ppm.
Chromatographie
- gel de silice 60 F 254 Merck
- solvant : méthanol-chloroforme 15/85
- hauteur de migration : 15 cm
- révélation Uv, iode
- Rf : 0,41
Contrôle de pureté Recherche -du DMF par CPV
- Colonne Poropak Q, 2 m, 1/8", inox
- Température colonne : 2300C - détecteur et injecteur : 2500C
- Gaz vecteur : azote pression 1,5 bar
- Détecteur à ionisation de flamme
- Atténuation : 8
- Injection de 1 pi de solution de 1 g d'itanoxone, 2 ml de soude à 20 %,
0,2 ml de butanol (étalon interne) complétés à 10 ml avec l'acétone.chromatography
- silica gel 60 F 254 Merck
- solvent: methanol-chloroform 15/85
- migration height: 15 cm
- Uv revelation, iodine
- Rf: 0.41
Purity Control Research - DMF by CPV
- Poropak Q column, 2 m, 1/8 ", stainless steel
- Column temperature: 2300C - detector and injector: 2500C
- Vector gas: nitrogen pressure 1.5 bar
- Flame ionization detector
- Attenuation: 8
Injection of 1 μl of solution of 1 g of itanoxone, 2 ml of 20% sodium hydroxide,
0.2 ml of butanol (internal standard) supplemented to 10 ml with acetone.
- Concentration très inférieure à 500 ppm. - Concentration well below 500 ppm.
Recherche des isomères 1 et 2 par CCM
- Gel de silice 60 F 254 Merck
- Solvant : méthanol - chloroforme 15/85
- Dépôt 5 pl d'une solution à 1 Z d'itanoxone dans le THF
- Hauteur de migration : 15 cm
- Révélation : UV, iode.Search for isomers 1 and 2 by TLC
- silica gel 60 F 254 Merck
Solvent: methanol - chloroform 15/85
- Deposit 5 μl of a 1% solution of itanoxone in THF
- Migration height: 15 cm
- Revelation: UV, iodine.
La gamme étalon montre que l'on peut détecter 0,1 % des autres isomères dans l'itanoxone :
isomère 1 Rf : 0,37
isomère 2 Rf : 0,26
Selon l'invention les concentrations en isomère 1 et 2 sont inférieures à 0,3 %. The standard range shows that it is possible to detect 0.1% of the other isomers in itanoxone:
isomer 1 Rf: 0.37
isomer 2 Rf: 0.26
According to the invention, the concentrations of isomer 1 and 2 are less than 0.3%.
Claims (1)
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7924582A FR2466450A1 (en) | 1979-10-01 | 1979-10-01 | Prodn. of 4-(4'-ortho-chloro-phenyl)-4-oxo-2-methylene butyric acid - or itanoxone, by acylation of 2-chloro-bi:phenyl with itaconic animoride in 1,2-di:chloroethane |
| NL8004622A NL8004622A (en) | 1979-10-01 | 1980-08-14 | METHOD FOR PREPARING ITANOXON ON AN INDUSTRIAL SCALE |
| MX10142280U MX6469E (en) | 1979-10-01 | 1980-08-26 | IMPROVED PROCEDURE FOR OBTAINING PURE ITANOXONE |
| HU80802185A HU179386B (en) | 1979-10-01 | 1980-09-05 | Industrial process for producing 4-bracket-4-o-chloro-phenyl-bracket closed-phenyl-4-oxo-2-methylene-butyric acid of high purty |
| IT8068420A IT8068420A0 (en) | 1979-10-01 | 1980-09-15 | INDUSTRIAL PROCEDURE FOR THE PURIFICATION AND OBTAINMENT OF PHARMACEUTICAL QUALITY Itanoxone |
| ZA00805678A ZA805678B (en) | 1979-10-01 | 1980-09-15 | Industrial process for the purification and obtaining of "itanoxone" of pharmaceutical quality |
| AU62755/80A AU535964B2 (en) | 1979-10-01 | 1980-09-26 | Itanoxone preparation |
| SE8006785A SE8006785L (en) | 1979-10-01 | 1980-09-29 | ITANOXON |
| AR282693A AR225056A1 (en) | 1979-10-01 | 1980-09-29 | AN INDUSTRIAL PROCEDURE FOR OBTAINING ITANOXONE THAT INCLUDES THE CHLORINE-2-BIPHENYL ACYLLATION BY ITACONIC ANHYDRIDE IN THE PRESENCE OF ALUMINUM CHLORIDE |
| DK412880A DK412880A (en) | 1979-10-01 | 1980-09-30 | PROCEDURE FOR PREPARING 4- (4-ORTHOCHLORPHENYL-PHENYL) -4-OXO-2-METHYLENOIC ACID |
| CA000361311A CA1152103A (en) | 1979-10-01 | 1980-10-01 | Purification process and preparation of itanoxone suitable for therapeutic use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7924582A FR2466450A1 (en) | 1979-10-01 | 1979-10-01 | Prodn. of 4-(4'-ortho-chloro-phenyl)-4-oxo-2-methylene butyric acid - or itanoxone, by acylation of 2-chloro-bi:phenyl with itaconic animoride in 1,2-di:chloroethane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2466450A1 true FR2466450A1 (en) | 1981-04-10 |
| FR2466450B1 FR2466450B1 (en) | 1983-06-24 |
Family
ID=9230249
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR7924582A Granted FR2466450A1 (en) | 1979-10-01 | 1979-10-01 | Prodn. of 4-(4'-ortho-chloro-phenyl)-4-oxo-2-methylene butyric acid - or itanoxone, by acylation of 2-chloro-bi:phenyl with itaconic animoride in 1,2-di:chloroethane |
Country Status (10)
| Country | Link |
|---|---|
| AR (1) | AR225056A1 (en) |
| AU (1) | AU535964B2 (en) |
| CA (1) | CA1152103A (en) |
| DK (1) | DK412880A (en) |
| FR (1) | FR2466450A1 (en) |
| HU (1) | HU179386B (en) |
| IT (1) | IT8068420A0 (en) |
| NL (1) | NL8004622A (en) |
| SE (1) | SE8006785L (en) |
| ZA (1) | ZA805678B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0325925A1 (en) * | 1988-01-15 | 1989-08-02 | Hoechst Aktiengesellschaft | Method for the purification of 2-hydroxy-naphthalene-6-carboxylic acid |
| WO2000026169A1 (en) * | 1998-11-04 | 2000-05-11 | Bayer Aktiengesellschaft | METHOD FOR THE TECHNOLOGICAL PRODUCTION OF 4'- CHLORO- α- METHYLENE- η- OXO-(1,1'- BIPHENYL)- 4'-BUTANE ACID |
-
1979
- 1979-10-01 FR FR7924582A patent/FR2466450A1/en active Granted
-
1980
- 1980-08-14 NL NL8004622A patent/NL8004622A/en not_active Application Discontinuation
- 1980-09-05 HU HU80802185A patent/HU179386B/en unknown
- 1980-09-15 IT IT8068420A patent/IT8068420A0/en unknown
- 1980-09-15 ZA ZA00805678A patent/ZA805678B/en unknown
- 1980-09-26 AU AU62755/80A patent/AU535964B2/en not_active Ceased
- 1980-09-29 SE SE8006785A patent/SE8006785L/en not_active Application Discontinuation
- 1980-09-29 AR AR282693A patent/AR225056A1/en active
- 1980-09-30 DK DK412880A patent/DK412880A/en not_active Application Discontinuation
- 1980-10-01 CA CA000361311A patent/CA1152103A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0325925A1 (en) * | 1988-01-15 | 1989-08-02 | Hoechst Aktiengesellschaft | Method for the purification of 2-hydroxy-naphthalene-6-carboxylic acid |
| WO2000026169A1 (en) * | 1998-11-04 | 2000-05-11 | Bayer Aktiengesellschaft | METHOD FOR THE TECHNOLOGICAL PRODUCTION OF 4'- CHLORO- α- METHYLENE- η- OXO-(1,1'- BIPHENYL)- 4'-BUTANE ACID |
Also Published As
| Publication number | Publication date |
|---|---|
| NL8004622A (en) | 1981-04-03 |
| ZA805678B (en) | 1981-09-30 |
| HU179386B (en) | 1982-10-28 |
| AR225056A1 (en) | 1982-02-15 |
| SE8006785L (en) | 1981-04-02 |
| AU535964B2 (en) | 1984-04-12 |
| DK412880A (en) | 1981-04-02 |
| CA1152103A (en) | 1983-08-16 |
| FR2466450B1 (en) | 1983-06-24 |
| AU6275580A (en) | 1981-04-09 |
| IT8068420A0 (en) | 1980-09-15 |
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