FR2537579A1 - Process for the preparation of alkyl and aryl esters of 3'-substituted and 2',3'-disubstituted 2-anilino-3-pyridinecarboxylic acids - Google Patents
Process for the preparation of alkyl and aryl esters of 3'-substituted and 2',3'-disubstituted 2-anilino-3-pyridinecarboxylic acids Download PDFInfo
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- FR2537579A1 FR2537579A1 FR8220902A FR8220902A FR2537579A1 FR 2537579 A1 FR2537579 A1 FR 2537579A1 FR 8220902 A FR8220902 A FR 8220902A FR 8220902 A FR8220902 A FR 8220902A FR 2537579 A1 FR2537579 A1 FR 2537579A1
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- GONMKTKNCXJCKJ-UHFFFAOYSA-N C[N](c1c2cccc1)(N)O[NH+]2[O-] Chemical compound C[N](c1c2cccc1)(N)O[NH+]2[O-] GONMKTKNCXJCKJ-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
La présente invention concerne un nouveau procédé de préparation d'esters alkyliques et aryliques d'acides 2-anilino-3-pyridine-carboxyliques 3'-substitués et 2',3'disubstitués de formule I
dans laquelle
est un groupe acyloxyméthyle de formule II ou fait partie d'une structure hétérocyclique de formule III -CH2-OCOC(CH3)3
tII)
in which
is an acyloxymethyl group of formula II or is part of a heterocyclic structure of formula III -CH2-OCOC (CH3) 3
tII)
R2 et R3 représentent chacun indépendamment l'un de l'autre un atome d'hydrogène, un atome de chlore, un groupe méthyle ou un groupe trifluorométhyle.R2 and R3 each independently of one another represent a hydrogen atom, a chlorine atom, a methyl group or a trifluoromethyl group.
Plus spécifiquement, la présente invention concerne un procédé de préparation d'esters pivaloyloxyméthyliques et 3-phtalidyliques de l'acide 2-(3'-(trifluorométhyl)-anilino) -3-pyridine-carboxylique et de l'acide 2-(3'-chloro-2'méthyl-anilino)-3-pyridine-carboxylique. More specifically, the present invention relates to a process for the preparation of pivaloyloxymethyl and 3-phthalidyl esters of 2- (3 '- (trifluoromethyl) -anilino) -3-pyridine-carboxylic acid and 2- (3 '-chloro-2'methyl-anilino) -3-pyridine-carboxylic.
I1 existe une littérature abondante concernant la synthèse et les propriétés thérapeutiques de ces acides auxquels appartiennent les composés de formule I. C'est ainsi que la préparation de l'acide 2-(3'-chloro-2'-méthylanilino)-3-pyridine-carboxylique qui est un agent analgésique, a eté décrite dans le brevet britannique n" 1.147.702. There is an abundant literature concerning the synthesis and the therapeutic properties of these acids to which the compounds of formula I belong. This is how the preparation of 2- (3'-chloro-2'-methylanilino) -3- acid pyridine-carboxylic which is an analgesic agent, has been described in British Patent No. 1,147,702.
De même, la synthèse de l'acide 2-(3'-(trifluorométhyl)anilino)-3-pyridine-carboxylique, qui est un agent antiinflammatoire, a été décrite dans le brevet néerlandais n" 6.414.717 et le brevet argentin n" 183.423.Likewise, the synthesis of 2- (3 '- (trifluoromethyl) anilino) -3-pyridine-carboxylic acid, which is an anti-inflammatory agent, has been described in Dutch Patent No. 6,414,717 and Argentinian Patent No. "183.423.
Outre leurs propriétés anti-inflammatoires et analgésiques, ces acides 2-anilino-3-pyridine-carboxyliques 3'-substitués et 3',2'-disubstitués exercent un effet ulcérogène sur l'épithélium gastrique. Afin d'atténuer cet effet secondaire, plusieurs dérivés apparentés ont été synthétisés. C'est ainsi que des esters amino-alkyliques d'acides 2-anilino-nicotiniques sont décrits dans le brevet français n" 2.187.317, tandis que des esters glycéryliques de ces mêmes acides sont décrits dans le brevet suisse n" 534.130 et dans le brevet sud-africain n" 68.2185.De même, différents sels d'acides 2-anilino-3-pyridinecarboxyliques substitués ont été décrits, par exemple, des sels d'éthanolamine, de lysine, d'aluminium et de bismuth sont décrits dans le brevet argentin~n 182.409, dans le brevet japonais n" 74 075713 et dans le brevet britannique n" 1.162.287. In addition to their anti-inflammatory and analgesic properties, these 3'-substituted and 3 ', 2'-disubstituted 2-anilino-3-pyridine-carboxylic acids exert an ulcerogenic effect on the gastric epithelium. In order to mitigate this side effect, several related derivatives have been synthesized. Thus, amino-alkyl esters of 2-anilino-nicotinic acids are described in French patent No. 2,187,317, while glyceryl esters of these same acids are described in Swiss patent No. 534,130 and in South African Patent No. 68.2185. Similarly, various salts of substituted 2-anilino-3-pyridinecarboxylic acids have been described, for example, salts of ethanolamine, lysine, aluminum and bismuth are described in the Argentinian patent ~ n 182,409, in the Japanese patent n "74 075713 and in the British patent n" 1,162,287.
L'objet principal de la présente invention est la nouvelle préparation d'esters de ces acides sans manifestation de l'effet secondaire caractéristique des acides analgésiques et anti-inflammatoires dont font partie ces esters (Scherrer, R. A. Whitehouse, M.W., Antiinflammatory
Agents, Chemistry and Pharmacology, 13-1, Academic Press,
New York, 1974).The main object of the present invention is the new preparation of esters of these acids without manifestation of the characteristic side effect of analgesic and anti-inflammatory acids of which these esters are a part (Scherrer, RA Whitehouse, MW, Antiinflammatory
Agents, Chemistry and Pharmacology, 13-1, Academic Press,
New York, 1974).
Lorsqu'on a soumis les esters alkyliques et aryliques d'acides 2-anilino-3-pyridine-carboxyliques ainsi obtenus à des essais sur animaux, on a observé une activité antiinflammatoire maximale. De même, ces nouveaux composés n'exercent aucun effet ulcérogène. When the alkyl and aryl esters of 2-anilino-3-pyridine-carboxylic acids thus obtained were subjected to animal tests, maximum anti-inflammatory activity was observed. Likewise, these new compounds have no ulcerogenic effect.
Dans la présente invention, on décrit la synthèse d'esters alkyliques et aryliques d'acides 2-anilino-3 pyridine-carboxyliques substitués. On effectue cette préparation en faisant réagir un ester alkylique ou arylique d'acide 2-chloro-3-pyridine-carboxylique préalablement obtenu avec de l'aniline 3-substituée ou 3,2-disubstituée. In the present invention, the synthesis of alkyl and aryl esters of substituted 2-anilino-3 pyridine-carboxylic acids is described. This preparation is carried out by reacting an alkyl or aryl ester of 2-chloro-3-pyridine-carboxylic acid previously obtained with 3-substituted or 3,2-disubstituted aniline.
Le schéma de synthèse est le suivant
R2 où R, R17et R3 ont les significations indiquées c-i-dessus,
A représente un groupe alkyl-ammonium contenant 1 à 6 atomes de carbone, tandis que X et Y représentent chacun un atome d'halogène.The summary diagram is as follows
R2 where R, R17 and R3 have the meanings indicated above,
A represents an alkyl ammonium group containing 1 to 6 carbon atoms, while X and Y each represent a halogen atom.
Ainsi qu'on l'a mentionné ci-dessus, ce procédé de préparation comprend deux étapes de synthèse. Dans la première, l'acide 2-halogéno-3-pyridine-carboxylique substitué et salifié (II) réagit avec un composé de formule III pour donner des esters alkyliques ou aryliques d'acides 2-halo3-pyridine-carboxyliques (IV). Cette réaction ne peut être effectuée que dans un milieu réactionnel polaire dans lequel les réactifs II et III sont complètement solubles et stables. As mentioned above, this preparation process comprises two stages of synthesis. In the first, the substituted and salified 2-halo-3-pyridine-carboxylic acid (II) reacts with a compound of formula III to give alkyl or aryl esters of 2-halo3-pyridine-carboxylic acids (IV). This reaction can only be carried out in a polar reaction medium in which the reactants II and III are completely soluble and stable.
On obtient le sel d'acide 2-halo-3-pyridine-carboxylique dans un solvant polaire tel que l'acétone, l'acétonitrile, le diméthylformamide et le diméthylacétamide. Ce sel est obtenu à la suite de la réaction de l'acide 2-chloro-3-pyridine-carboxylique avec des alkyl inférieurs-amines telles que l'éthanolamine, la triéthylamine, la cyclohexylamine, la triméthylamine et la diméthylamine, la triéthylamine étant la base organique préférée. The salt of 2-halo-3-pyridine-carboxylic acid is obtained in a polar solvent such as acetone, acetonitrile, dimethylformamide and dimethylacetamide. This salt is obtained following the reaction of 2-chloro-3-pyridine-carboxylic acid with lower alkylamines such as ethanolamine, triethylamine, cyclohexylamine, trimethylamine and dimethylamine, triethylamine being the preferred organic base.
Ensuite, le sel de l'acide 2-halo-3-pyridine-carboxylique (II) et le 3-bromophtalide réagissent ensemble pour donner un ester phtalidylique d'un acide 2-halo-3-pyridine-carboxylique et, pour cette réaction, on utilise le même milieu que celui dans lequel la salification a été effectuée préalablement. Le rapport molaire utilisé entre le composé (II) et le 3-bromophtalide varie entre 1:1 et 1:5. Par conséquent, on effectue la salification et l'estérification dans le même milieu réactionnel. Ce milieu doit dissoudre les réactifs sans les dégrader. Par suite de la présence d'eau au cours de la réaction, le 3-bromophtalide est hydrolysé en acide phtalaldéhydrique et, par conséquent, le rendement du procédé diminue. Dès lors,-pour obtenir les rendements maxima, il convient d'utiliser des solvants anhydres.Then, the salt of 2-halo-3-pyridine-carboxylic acid (II) and 3-bromophthalide react together to give a phthalidyl ester of a 2-halo-3-pyridine-carboxylic acid and, for this reaction , the same medium is used as that in which the salification was carried out beforehand. The molar ratio used between compound (II) and 3-bromophthalide varies between 1: 1 and 1: 5. Consequently, salification and esterification are carried out in the same reaction medium. This medium must dissolve the reagents without degrading them. As a result of the presence of water during the reaction, the 3-bromophthalide is hydrolyzed to phthalaldehyde and therefore the yield of the process decreases. Therefore, to obtain the maximum yields, anhydrous solvents should be used.
La réaction entre le sel d'acide 2-halo-3-pyridinecarboxylique et le chlorure de pivaloyloxyméthyle en vue d'obtenir l'ester pivaloyloxyméthylique de l'acide 2-halo3-pyridine-carboxylique (IV) est effectuée de la même manière que la réaction décrite ci-dessus. Le rapport molaire de ces réactifs se situe dans l'intervalle de 1,5 à 2,5 moles de chlorure d'alkyle par mole d'acide. On effectue la synthèse du chlorure de pivaloyloxyméthyle en mélangeant des quantités équimoléculaires de chlorure de pivaloyle et de paraformaldéhyde en présence de ZnCl2 (Rassmussen et Leonard), "J. Am. Chem. Soc." 89, 1967). La réaction entre le chlorure de pivaloyloxyméthyle et le sel d'acide 2-halo-3-pyridinecarboxylique doit être effectuée dans un système anhydre, étant donné que l'eau hydrolyse le chlorure d'alkyle en formant l'alcool alkylique correspondant. The reaction between the 2-halo-3-pyridinecarboxylic acid salt and pivaloyloxymethyl chloride in order to obtain the pivaloyloxymethyl ester of 2-halo3-pyridine-carboxylic acid (IV) is carried out in the same way as the reaction described above. The molar ratio of these reactants is in the range of 1.5 to 2.5 moles of alkyl chloride per mole of acid. The synthesis of pivaloyloxymethyl chloride is carried out by mixing equimolecular amounts of pivaloyl chloride and paraformaldehyde in the presence of ZnCl2 (Rassmussen and Leonard), "J. Am. Chem. Soc." 89, 1967). The reaction between pivaloyloxymethyl chloride and the 2-halo-3-pyridinecarboxylic acid salt must be carried out in an anhydrous system, since water hydrolyzes the alkyl chloride to form the corresponding alkyl alcohol.
La séparation du composé formé de formule I dépend des propriétés de chaque composé formé. C'est ainsi que l'on sépare les esters phtalidyliques d'acides 2-halo-3pyridine-carboxyliques en ajoutant de l'eau au milieu réactionnel. The separation of the compound formed of formula I depends on the properties of each compound formed. This is how phthalidyl esters are separated from 2-halo-3pyridine-carboxylic acids by adding water to the reaction medium.
D'autre part, l'ester pivaloyloxyméthylique de l'acide 2-halo-3-pyridine-carboxylique formé est extrait de son milieu réactionnel dans lequel on a préalablement ajouté de l'eau, en utilisant des solvants chlorés, de préférence, le chlorure de méthylène. On the other hand, the pivaloyloxymethyl ester of the 2-halo-3-pyridine-carboxylic acid formed is extracted from its reaction medium to which water has previously been added, using chlorinated solvents, preferably the methylene chloride.
La deuxième étape de synthèse décrite dans la présente invention consiste à faire réagir des esters alkyliques ou aryliques d'acides 2-halo-3-pyridine-carboxyliques de formule IV avec de l'aniline 3-substituée ou 2,3disubstituée de formule V. On effectue cette réaction dans un solvant inerte porté au reflux (alcool amylique, toluène, xylène) ou en faisant fondre ces réactifs. Au cours de la réaction, par mole du composé formé (I), on obtient une mole d'halogénure d'hydrogène ; en conséquence, il est préférable d'utiliser 2 moles d'aniline (V) par mole d'ester (IV). On peut effectuer cette réaction avec l'acide 2-bromo3-pyridine-carboxylique ou 1' acide 2-chloro-3-pyridinecarboxylique, le dérivé chloré donnant les rendements maxima. The second synthetic step described in the present invention consists in reacting alkyl or aryl esters of 2-halo-3-pyridine-carboxylic acids of formula IV with 3-substituted or 2,3-substituted aniline of formula V. This reaction is carried out in an inert solvent brought to reflux (amyl alcohol, toluene, xylene) or by melting these reagents. During the reaction, per mole of the compound formed (I), one mole of hydrogen halide is obtained; therefore, it is preferable to use 2 moles of aniline (V) per mole of ester (IV). This reaction can be carried out with 2-bromo3-pyridine-carboxylic acid or 2-chloro-3-pyridinecarboxylic acid, the chlorinated derivative giving the maximum yields.
On sépare les composés formés de formule I de leurs milieux réactionnels en refroidissant le système et en filtrant la substance cristallisée. On peut purifier ces composés par recristallisation dans des solvants tels que l'acétate d'éthyle, l'acétate de propyle, l'acétate d'isobutyle, le méthanol et le n-butanol. Si l'on obtient les composés de formule I en faisant fondre les réactifs, on peut les purifier par cristallisation dans ces solvants ou par traitement avec de l'acide chlorhydrique dilué. The compounds formed of formula I are separated from their reaction media by cooling the system and filtering the crystallized substance. These compounds can be purified by recrystallization from solvents such as ethyl acetate, propyl acetate, isobutyl acetate, methanol and n-butanol. If the compounds of formula I are obtained by melting the reagents, they can be purified by crystallization from these solvents or by treatment with dilute hydrochloric acid.
La présente invention sera mieux comprise à la lecture des exemples ci-après qui toutefois ne la limitent nullement. The present invention will be better understood on reading the examples below which, however, in no way limit it.
Exemple I 2-chloro-3-pyridine-carboxylate de phtalidyle. Example I Phthalidyl 2-chloro-3-pyridine carboxylate.
A 600 ml d'acétone, on ajoute 31,5 g d'acide 2chloro-3-pyridine-carboxylique et on forme une suspension par agitation. On ajoute 40 ml de triéthylamine et, 30 minutes après cette addition, on verse 42,6 g de 3-bromophtalide dans le mélange réactionnel agité. On chauffe le système à reflux pendant 4 heures. Ensuite, on le verse dans 2.000 ml d'eau à 50 C. Pour obtenir le composé précipité, on refroidit le mélange réactionnel tout en agitant continuellement. On recueille le solide par filtration, on le lave avec de l'eau froide, puis on le sèche sous vide à 40"C. On obtient un rendement de 67 % (38,7 g) de 2-chloro3-pyridine-carboxylate de phtalidyle (point de fusion 137-138"C). To 600 ml of acetone, 31.5 g of 2-chloro-3-pyridine-carboxylic acid are added and a suspension is formed by stirring. 40 ml of triethylamine are added and, 30 minutes after this addition, 42.6 g of 3-bromophthalide are poured into the stirred reaction mixture. The system is heated at reflux for 4 hours. Then, it is poured into 2,000 ml of water at 50 ° C. To obtain the precipitated compound, the reaction mixture is cooled while stirring continuously. The solid is collected by filtration, washed with cold water, then dried under vacuum at 40 ° C. A yield of 67% (38.7 g) of 2-chloro3-pyridine-carboxylate is obtained. phthalidyl (melting point 137-138 "C).
Spectre d'absorption des rayons infrarouges (nujol) fortes bandes d'absorption à 1780, 1750, 1580, 1415, 2380, 1270, 1245, 1225, 1140, 1060, 995 et 940 cl~1. Absorption spectrum of infrared rays (nujol) strong absorption bands at 1780, 1750, 1580, 1415, 2380, 1270, 1245, 1225, 1140, 1060, 995 and 940 cl ~ 1.
Analyse élémentaire : pour C14H8NCl
Calculé : C 58,05 ; H 2,78; N 4,84; C1 12,24.Elementary analysis: for C14H8NCl
Calculated: C 58.05; H 2.78; N 4.84; C1 12.24.
Trouvé : C 58,21 ; H 3,00; N 4,65; C1 12,19.Found: C 58.21; H 3.00; N 4.65; C1 12.19.
Exemple II 2-chloro-3-pyridine-carboxylate de pivaloyloxyméthyle. Example II Pivaloyloxymethyl 2-chloro-3-pyridine carboxylate.
Dans une suspension agitée de 23,7 g d'acide 2-chloro3-pyridine-carboxylique dans 500 ml d'acétone, on ajoute 30,7 ml de triéthylamine. Après avoir agité pendant 30 minutes, on verse 22,5 ml de chlorure de pivaloyloxyméthyle dans le mélange réactionnel et on chauffe le système à reflux pendant 2 heures. Ensuite, on refroidit le système à 15-20"C, puis on le verse dans 1.000 ml d'eau froide. On extrait le composé formé avec du chlorure de méthylène (deux fois 100 ml), puis on élimine la couche aqueuse. A l'extrait organique résiduel, on ajoute 10 g de sulfate de magnésium anhydre, puis on procède à une séparation par filtration. On distille l'extrait organique sous pression normale pour séparer le chlorure de méthylène.Après distillation de la quantité totale de chlorure de méthylène, on soumet le système de distillation à un vide de 0,17 mm de Hg pour séparer le composé formé. La fraction distillée se sépare à une température de 131 à 133"C et elle correspond au 2chloro-3-pyridine-carboxylate de pivaloyloxyméthyle. In a stirred suspension of 23.7 g of 2-chloro3-pyridine-carboxylic acid in 500 ml of acetone, 30.7 ml of triethylamine are added. After stirring for 30 minutes, 22.5 ml of pivaloyloxymethyl chloride is poured into the reaction mixture and the system is heated to reflux for 2 hours. Then, the system is cooled to 15-20 "C, then it is poured into 1,000 ml of cold water. The compound formed is extracted with methylene chloride (twice 100 ml), then the aqueous layer is removed. A the residual organic extract, 10 g of anhydrous magnesium sulfate are added, followed by separation by filtration, and the organic extract is distilled under normal pressure to separate the methylene chloride. methylene, the distillation system is subjected to a vacuum of 0.17 mm Hg to separate the compound formed. The distilled fraction separates at a temperature of 131 to 133 "C and it corresponds to 2-chloro-3-pyridine-carboxylate pivaloyloxymethyl.
Rendement : 53,5 /O (21,8 g). Yield: 53.5 / O (21.8 g).
Sectre d'absorption des rayons infrarouges (couche pelliculaire) fortes blandes d'absorption à 2990, 1745, 1570, 1440,
-1 1290, 1270, 1150, 1130, 1110, 1055, 1030, 1005 et 975 cm
Analyse élémentaire pour C12H14C1 N.Infrared ray absorption sector (film layer) strong absorption bladders at 2990, 1745, 1570, 1440,
-1 1290, 1270, 1150, 1130, 1110, 1055, 1030, 1005 and 975 cm
Elementary analysis for C12H14C1 N.
Calculé : C 53,05; H 5,19; C1 13,05; N 5,15.Calculated: C 53.05; H 5.19; C1 13.05; N 5.15.
Trouvé : C 53,09; H 5,29; C1 13,06; N 4,85.Found: C 53.09; H 5.29; C1 13.06; N 4.85.
Exemple III 2-(3 ' -trifluorométhyl-anilino) -3-pyridine-carboxylate de phtalidyle. Example III 2- (3 '-trifluoromethyl-anilino) -3-pyridine-phthalidyl carboxylate.
Tout en chauffant à reflux, à 80 ml de xylène, on ajoute 32,2 g de m-trifluorométhylaniline. Ensuite, on verse 29 g de 2-chloro-3-pyridine-carboxylate de phtalidyle (divisé en deux fractions) dans le système réactionnel à des intervalles de 15 minutes entre chaque addition. On maintient le mélange réactionnel à reflux pendant 5 heures, puis on le refroidit en plongeant le ballon réactionnel dans un bain de glace et d'eau. Afin d'assurer la cristallisation complète du produit formé, on maintient le mélange réactionnel pendant 2 heures à 0-5" C. On recueille le précipité par filtration et on le sèche sous vide à 40C C. On obtient un rendement de 82,3 % (34,1 g) de 2-(3-trifluorométhylanilino) -3-pyridine-carboxylate de phtalidyle (point de fusion 159-162 C). While heating at reflux, to 80 ml of xylene, 32.2 g of m-trifluoromethylaniline are added. Then, 29 g of phthalidyl 2-chloro-3-pyridine carboxylate (divided into two fractions) are poured into the reaction system at intervals of 15 minutes between each addition. The reaction mixture is maintained at reflux for 5 hours, then cooled by immersing the reaction flask in an ice and water bath. In order to ensure complete crystallization of the product formed, the reaction mixture is maintained for 2 hours at 0-5 "C. The precipitate is collected by filtration and dried under vacuum at 40 ° C. A yield of 82.3 is obtained % (34.1 g) of 2- (3-trifluoromethylanilino) -3-pyridine-phthalidyl carboxylate (melting point 159-162 C).
En cristallisant ce composé avec 6 volumes d'acétate d'éthyle, on obtient 28,4 g (rendement : 68,5 /O) d'un produit d'un point de fusion de 164-165 C. By crystallizing this compound with 6 volumes of ethyl acetate, 28.4 g (yield: 68.5 / O) of a product with a melting point of 164-165 C. are obtained.
Spectre d'absorption des rayons infrarouges (nujol) fortes bandes d'absorption à 3300, 1785, 1695, 1610, 1570, 1520, 1340, 1320, 1260, 1160, 1120, 1090, 1050 et 970 cm . Absorption spectrum of infrared rays (nujol) strong absorption bands at 3300, 1785, 1695, 1610, 1570, 1520, 1340, 1320, 1260, 1160, 1120, 1090, 1050 and 970 cm.
Analyse élémentaire pour C21H1FN04. Elementary analysis for C21H1FN04.
Calculé : C 60,87, H 3,16; F 13,76; N 6,76.Calculated: C 60.87, H 3.16; F 13.76; N 6.76.
Trouvé : C 60,50; H 3,22; F 13,62; N 6,79.Found: C 60.50; H 3.22; F 13.62; N 6.79.
Exemple IV 2-(2 ' -méthyl-3' -chloro-anilino) -3-pyridine-carboxylate de pivaloyloxyméthyle. Example IV 2- (2 '-methyl-3' -chloro-anilino) -3-pyridine-pivaloyloxymethyl carboxylate.
Dans un ballon approprié, on verse 21,7 g de 2chloro-3-pyridine-carboxylate de pivaloyloxyméthyle et 28,4 g de 3-chloro-2-méthylaniline. Pour amorcer la réaction, on chauffe le mélange à 140"C. Au cours du procédé, la température du système s'élève à 1900C. Au terme de la réaction, on abaisse la température. Ensuite, on refroidit le mélange réactionnel à la température ambiante. A ce mélange, on ajoute de l'acide chlorhydrique dilué, puis on broie le composé formé en petites particules que l'on met en suspension dans le milieu. On sépare le solide par filtration et on lave le gâteau avec de l'eau. Ensuite, on dissout le solide dans du méthanol chaud et on le cristallise en refroidissant la solution méthanolique. On sépare le produit cristallisé et on le sèche sous vide à 40"C. 21.7 g of pivaloyloxymethyl 2-chloro-3-pyridine-carboxylate and 28.4 g of 3-chloro-2-methylaniline are poured into a suitable flask. To initiate the reaction, the mixture is heated to 140 "C. During the process, the system temperature rises to 1900 C. At the end of the reaction, the temperature is lowered. Then, the reaction mixture is cooled to the temperature To this mixture, dilute hydrochloric acid is added, then the compound formed is ground into small particles which are suspended in the medium, the solid is filtered off and the cake is washed with Then the solid is dissolved in hot methanol and crystallized while cooling the methanolic solution. The crystallized product is separated and dried in vacuo at 40 "C.
On obtient le 2-(2 '-méthyl-3 '-chloro-anilino)-3-pyridine- carboxylate de pivaloyloxyméthyle (point de fusion 90-91"C) avec un rendement de 77,6 % (22,5 g).Obtained 2- (2 '-methyl-3' -chloro-anilino) -3-pyridine-pivaloyloxymethyl carboxylate (melting point 90-91 "C) with a yield of 77.6% (22.5 g) .
Spectre d'absorption des rayons infrarouges (BrK) fortes bandes d'absorption à : 1755, 1710, 1625, 1585, 1530, 1460, -l 1440, 1405, 1255, 1150, 1110, 1070, 1055 et 975 cm
Analyse élémentaire pour C19H 21C1N204. Absorption spectrum of infrared rays (BrK) strong absorption bands at: 1755, 1710, 1625, 1585, 1530, 1460, -l 1440, 1405, 1255, 1150, 1110, 1070, 1055 and 975 cm
Elementary analysis for C19H 21C1N204.
Calculé : C 60,56; H 5,62; C1 9,41; N 7,43.Calculated: C 60.56; H 5.62; C1 9.41; N 7.43.
Trouvé : C 60,67; H 5,59; C1 9,37; N 7,48.Found: C 60.67; H 5.59; C1 9.37; N 7.48.
Exemple V 2-( 3' -chloro-2 ' -méthyl-anilino) -3-pyridine-carboxylate de phtalidyle. Example V 2- (3 '-chloro-2' -methyl-anilino) -3-phthalidyl pyridine carboxylate.
On répète l'exemple III en substituant la mtrifluorométhylaniline à la 3-chloro-2-méthyî-aniline. On obtient 31,8 g de 2-(3'-chloro-2'-méthylanilino)-3-pyridine- carboxylate de phtalidyle (point de fusion : 178-180"C) aven un rendement de 80,5 %. Example III is repeated by substituting mtrifluoromethylaniline for 3-chloro-2-methyl-aniline. 31.8 g of 2- (3'-chloro-2'-methylanilino) -3-pyridine-phthalidyl carboxylate are obtained (melting point: 178-180 "C) in a yield of 80.5%.
Spectre d'absorption des rayons infrarouges (BrK) fortes bandes d'absorption à : 1785, 1710, 1620, 1580, 1425, 1400, 1240, 1050 et 955 cm
Analyse élémentaire pour C21H15C1N2 0
Calculé : C 63,89; H 3,83; C1 8,98; N 7,09.Absorption spectrum of infrared rays (BrK) strong absorption bands at: 1785, 1710, 1620, 1580, 1425, 1400, 1240, 1050 and 955 cm
Elementary analysis for C21H15C1N2 0
Calculated: C 63.89; H 3.83; C1 8.98; N 7.09.
Trouvé : C 64,20; H 3,87; C1 9,21; N 6,89.Found: C 64.20; H 3.87; C1 9.21; N 6.89.
Exemple VI 2-(3'-trifluorométhyl-anilino)-3-pyridine-carboxylate de pivaloyloxyméthyle. Example VI 2- (3'-trifluoromethyl-anilino) -3-pyridine-pivaloyloxymethyl carboxylate.
On répète l'exemple -1V en utilisant de la mtrifluorométhylaniline au lieu 'de 3-chloro-2-méthylaniline. Example -1V is repeated using mtrifluoromethylaniline instead of 3-chloro-2-methylaniline.
On obtient 26,5 g de 2-(3'-trifluorométhyl-anilino)-3pyridine-carboxylate de pivaloyloxyméthyle (point de fusion : 55-56"C). 26.5 g of pivaloyloxymethyl 2- (3'-trifluoromethyl-anilino) -3pyridine carboxylate are obtained (melting point: 55-56 "C).
Rendement : 84,3 %.Yield: 84.3%.
Spectre d'absorption des rayons infrarouges (BrK) fortes bandes d'absorption à 1740, 1700, 1615, 1585, 1340, 1260, 1160, 1125, 1085, 1065, 1040, 1010 et 980 cm 1
Analyse élémentaire pour ClgHl9F3N204. Absorption spectrum of infrared rays (BrK) strong absorption bands at 1740, 1700, 1615, 1585, 1340, 1260, 1160, 1125, 1085, 1065, 1040, 1010 and 980 cm 1
Elementary analysis for ClgHl9F3N204.
Calculé : C 57,57; H 4,83; F 14,38; N 7,07.Calculated: C 57.57; H 4.83; F 14.38; N 7.07.
Trouvé : C 57,72; H 4,60; F 14,40; N 7,30.Found: C 57.72; H 4.60; F 14.40; N 7.30.
Bien entendu diverses modifications peuvent être apportées par l'homme de l'art aux dispositifs ou procédés qui viennent d'être décrits uniquement à titre d'exemples non limitatifs sans sortir du cadre de l'invention. Of course, various modifications can be made by those skilled in the art to the devices or methods which have just been described only by way of nonlimiting examples without departing from the scope of the invention.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8220902A FR2537579B1 (en) | 1982-12-10 | 1982-12-10 | PROCESS FOR THE PREPARATION OF ALKYL AND ARYL ESTERS OF 3-ANILINO-3-PYRIDINE-CARBOXYLIC ACIDS 3'-SUBSTITUTED AND 2 ', 3'-DISUBSTITUTED |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8220902A FR2537579B1 (en) | 1982-12-10 | 1982-12-10 | PROCESS FOR THE PREPARATION OF ALKYL AND ARYL ESTERS OF 3-ANILINO-3-PYRIDINE-CARBOXYLIC ACIDS 3'-SUBSTITUTED AND 2 ', 3'-DISUBSTITUTED |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2537579A1 true FR2537579A1 (en) | 1984-06-15 |
| FR2537579B1 FR2537579B1 (en) | 1985-07-26 |
Family
ID=9280058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8220902A Expired FR2537579B1 (en) | 1982-12-10 | 1982-12-10 | PROCESS FOR THE PREPARATION OF ALKYL AND ARYL ESTERS OF 3-ANILINO-3-PYRIDINE-CARBOXYLIC ACIDS 3'-SUBSTITUTED AND 2 ', 3'-DISUBSTITUTED |
Country Status (1)
| Country | Link |
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| FR (1) | FR2537579B1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1147702A (en) * | 1966-02-28 | 1969-04-02 | Scherico Ltd | Substituted Nicotinic Acids and methods for the manufacture thereof |
| FR2193580A1 (en) * | 1972-07-26 | 1974-02-22 | Synthelabo | Trifluoro methoxy anilino aryl carboxylic acids - analgesics, prepd. from ortho halo benzoic or pyridine carboxylic acids and trifluoro methoxy anilines |
| FR2223016A1 (en) * | 1973-03-28 | 1974-10-25 | Scherico Ltd | |
| BE858864A (en) * | 1977-09-20 | 1978-01-16 | Bago Sa Labor | NEW ESTERS OF PHENYL- AND PYRIDINE-3-CARBOXYLIC ACIDS AND PROCESS FOR THEIR PREPARATION |
-
1982
- 1982-12-10 FR FR8220902A patent/FR2537579B1/en not_active Expired
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1147702A (en) * | 1966-02-28 | 1969-04-02 | Scherico Ltd | Substituted Nicotinic Acids and methods for the manufacture thereof |
| FR2193580A1 (en) * | 1972-07-26 | 1974-02-22 | Synthelabo | Trifluoro methoxy anilino aryl carboxylic acids - analgesics, prepd. from ortho halo benzoic or pyridine carboxylic acids and trifluoro methoxy anilines |
| FR2223016A1 (en) * | 1973-03-28 | 1974-10-25 | Scherico Ltd | |
| BE858864A (en) * | 1977-09-20 | 1978-01-16 | Bago Sa Labor | NEW ESTERS OF PHENYL- AND PYRIDINE-3-CARBOXYLIC ACIDS AND PROCESS FOR THEIR PREPARATION |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2537579B1 (en) | 1985-07-26 |
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