FR2697521A1 - Prodn. of ethyl picolinate from 2-cyano-pyridine - via ethyl pyridine-2-carboximidate formation in situ. - Google Patents

Prodn. of ethyl picolinate from 2-cyano-pyridine - via ethyl pyridine-2-carboximidate formation in situ. Download PDF

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FR2697521A1
FR2697521A1 FR9213207A FR9213207A FR2697521A1 FR 2697521 A1 FR2697521 A1 FR 2697521A1 FR 9213207 A FR9213207 A FR 9213207A FR 9213207 A FR9213207 A FR 9213207A FR 2697521 A1 FR2697521 A1 FR 2697521A1
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ethyl
pyridine
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FR2697521B1 (en
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Allaigre Jean-Pierre
Desbois Jacquesremer Corinne
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Norchim
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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
    • C07D213/81—Amides; Imides

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

Prodn. of ethyl picolinate (I) comprises: (a) reacting 2-cyanopyridine (II) with an alkali metal alkoxide to form ethyl pyridine-2-carboximidate (III) in situ; (b) hydrolysing (III) to progressive acidification of the reaction mixt; (c) neutralising the reaction mixt. by adding a weak base; and (d) isolating (I) by distn. Step (a) is effected with NaOEt formed in situ by adding Na to EtOH. Step (b) comprises adding a weak organic acid (esp. acetic or propionic acid), removing the alcohol, taking up the residue in an aq. medium, and adding a strong mineral acids, esp. HCl, HBr, or H2SO4. Step (c) comprises adding Na2CO3, K2CO3, Bu(OH)2 or Ca(OH)2. USE/ADVANTAGE - (I) is used in the formulation of certain herbicides and is also useful as a pharmaceutical intermediate. The process gives high yields (e.g. 78%) of high purity (I).

Description

La présente invention se rapporte à un nouveau procédé de synthèse du picolinate d'éthyle. The present invention relates to a new process for the synthesis of ethyl picolinate.

Le picolinate d'éthyle, ou ester éthylique de l'acide 2-pyridine carboxylique, est un produit utilisé dans la composition de certains herbicides, ainsi que comme intermédiaire de synthèse pour la fabrication de produits à usage pharmaceutique. Ethyl picolinate, or ethyl ester of 2-pyridine carboxylic acid, is a product used in the composition of certain herbicides, as well as as a synthetic intermediate for the manufacture of products for pharmaceutical use.

Il répond à la formule suivante

Figure img00010001
It responds to the following formula
Figure img00010001

Classiquement, il est préparé par un procédé comprenant une première étape d'oxydation de la 2-méthylpyridine ou 2-picoline en acide picolinique ou acide 2- pyridine carboxylique ; et une deuxième étape d'estérification de l'acide picolinique pour aboutir au picolinate d'éthyle selon le schéma réactionnel suivant

Figure img00010002

(IOWA STATE COLL. J. SCI.21, 41 (1946)
Cette méthode est coûteuse et peu aisée, du fait du caractère polluant de la phase d'oxydation, ainsi que du caractère amphotère de l'acide picolinique, ce qui rend son isolement difficile.Conventionally, it is prepared by a method comprising a first step of oxidizing 2-methylpyridine or 2-picoline to picolinic acid or 2-pyridine carboxylic acid; and a second step of esterification of picolinic acid to result in ethyl picolinate according to the following reaction scheme
Figure img00010002

(IOWA STATE COLL. J. SCI. 21, 41 (1946)
This method is expensive and not very easy, due to the polluting nature of the oxidation phase, as well as the amphoteric nature of picolinic acid, which makes its isolation difficult.

C'est pourquoi la présente invention a pour objet un procédé de préparation du picolinate d'éthyle, caractérisé en ce que a) on fait réagir de la 2-cyanopyridine avec un éthanolate alcalin, pour
former in situ un imidate de formule I

Figure img00020001

b) on hydrolyse le composé de formule I par acidification progressive du
milieu réactionnel, c) on neutralise le milieu par addition d'une base faible, d) on isole le picolinate d'éthyle par distillation.This is why the present invention relates to a process for the preparation of ethyl picolinate, characterized in that a) reacting 2-cyanopyridine with an alkaline ethanolate, to
form an imidate of formula I in situ
Figure img00020001

b) the compound of formula I is hydrolyzed by progressive acidification of the
reaction medium, c) the medium is neutralized by addition of a weak base, d) the ethyl picolinate is isolated by distillation.

Ce procédé consiste donc à préparer l'imidate correspondant, puis à l'hydrolyser in situ pour former directement le picolinate d'éthyle. This process therefore consists in preparing the corresponding imidate, then in hydrolyzing it in situ to directly form ethyl picolinate.

Le schéma réactionnel est le suivant

Figure img00020002
The reaction scheme is as follows
Figure img00020002

IN SITU
Il est essentiel que l'étape d'hydrolyse soit effectuée de façon progressive et contrôlée afin de stabiliser la réaction au stade de l'ester et de ne pas poursuivre jusqu'à obtention de l'acide ; pour cela on procède en deux temps principaux.IN SITU
It is essential that the hydrolysis step is carried out in a gradual and controlled manner in order to stabilize the reaction at the ester stage and not to continue until the acid is obtained; for this we proceed in two main stages.

Dans un premier temps on ajoute au milieu réactionnel, qui est un milieu alcoolique, un acide organique faible, qui permet une neutralisation ménagée du milieu. Firstly, a weak organic acid is added to the reaction medium, which is an alcoholic medium, which allows gentle neutralization of the medium.

L'acide organique faible est de préférence choisi parmi l'acide acétique et l'acide propionique. The weak organic acid is preferably chosen from acetic acid and propionic acid.

Le milieu est ensuite concentré et le résidu est repris par de l'eau, afin de se placer en milieu aqueux. The medium is then concentrated and the residue is taken up in water, in order to be placed in an aqueous medium.

On ajoute alors, dans un second temps, un acide minéral fort que l'on laisse en contact pendant un temps suffisant pour permettre l'hydrolyse de l'imidate. Then added, in a second step, a strong mineral acid which is left in contact for a sufficient time to allow the hydrolysis of the imidate.

L'acide minéral fort est de préférence choisi parmi l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique. The strong mineral acid is preferably chosen from hydrochloric acid, hydrobromic acid, sulfuric acid.

On procède ensuite à la neutralisation du milieu par une base faible. We then proceed to neutralize the medium with a weak base.

De préférence la base faible est choisie parmi le carbonate de sodium, le carbonate de potassium, l'hydroxyde de baryum, l'hydroxyde de calcium. Preferably the weak base is chosen from sodium carbonate, potassium carbonate, barium hydroxide, calcium hydroxide.

Selon un mode de réalisation préféré, l'éthanolate alcalin utilisé lors de l'étape a) du procédé est un éthanolate de sodium. According to a preferred embodiment, the alkaline ethanolate used during step a) of the process is a sodium ethanolate.

Cet éthanolate peut être formé in situ, par addition de sodium à de l'éthanol, en particulier sous atmosphère d'azote. This ethanolate can be formed in situ, by adding sodium to ethanol, in particular under a nitrogen atmosphere.

L'exemple qui suit est destiné à illustrer l'invention sans en limiter la portée. The example which follows is intended to illustrate the invention without limiting its scope.

EXEMPLE
Dans un ballon contenant 100 ml d'éthanol, on introduit 0,15 équivalent de sodium, sous atmosphère d'azote et refroidissement. EXAMPLE
0.15 equivalent of sodium is introduced into a flask containing 100 ml of ethanol, under a nitrogen atmosphere and cooling.

Après dissolution totale du sodium, 10,4 g (0,1 mole) de 2-cyanopyridine sont introduits en une seule fois. La réaction est exothermique. Le milieu est maintenu en contact 6 heures à 500 C. After the sodium has completely dissolved, 10.4 g (0.1 mole) of 2-cyanopyridine are introduced all at once. The reaction is exothermic. The medium is kept in contact for 6 hours at 500 C.

Après refroidissement et neutralisation par addition d'acide acétique, le milieu est concentré sous pression réduite jusqu'à obtention d'une huile résiduelle. After cooling and neutralization by addition of acetic acid, the medium is concentrated under reduced pressure until a residual oil is obtained.

Le concentrat est repris par 70 ml d'eau distillée, et deux équivalents d'acide chlorhydrique 5N. The concentrate is taken up in 70 ml of distilled water and two equivalents of 5N hydrochloric acid.

Après un contact d'une nuit à température ambiante, le milieu est neutralisé sous refroidissement par du carbonate de sodium jusqu'à pH 7. After overnight contact at room temperature, the medium is neutralized under cooling with sodium carbonate to pH 7.

Le milieu est extrait par trois fois 100 ml d'éther éthylique. The medium is extracted with three times 100 ml of ethyl ether.

Les phases éthérées sont rassemblées et concentrées sous pression réduite. The ethereal phases are combined and concentrated under reduced pressure.

Après distillation sous vide, on isole le picolinate d'éthyle d'une pureté de 98% avec un rendement de 78%.  After vacuum distillation, the ethyl picolinate of 98% purity is isolated with a yield of 78%.

Claims (7)

REVENDICATIONS 1. Procédé de préparation du picolinate d'éthyle, caractérisé en ce que a) on fait réagir de la 2-cyanopyridine avec un éthanolate alcalin, pour 1. Process for the preparation of ethyl picolinate, characterized in that a) reacting 2-cyanopyridine with an alkaline ethanolate, to former in situ un imidate de formule I  form an imidate of formula I in situ
Figure img00050001
Figure img00050001
 b) on hydrolyse- le composé de formule I par acidification progressive du b) the compound of formula I is hydrolyzed by progressive acidification of the milieu réactionnel, c) on neutralise le milieu par addition d'une base faible, d) on isole le picolinate d'éthyle par distillation. reaction medium, c) the medium is neutralized by addition of a weak base, d) the ethyl picolinate is isolated by distillation. 2. Procédé de préparation selon la revendication l, caractérisé en ce que l'étape b) comprend les étapes suivantes i) on ajoute au milieu de réaction un acide organique faible, ii) après élimination de la phase alcoolique, on se place en milieu aqueux, iii) on ajoute un acide minéral fort. 2. Preparation process according to claim l, characterized in that step b) comprises the following steps i) a weak organic acid is added to the reaction medium, ii) after elimination of the alcoholic phase, the medium is placed aqueous, iii) a strong mineral acid is added. 3. Procédé de préparation selon l'une des revendications I ou 2, caractérisé en ce que l'éthanolate alcalin est un éthanolate de sodium. 3. Preparation process according to one of claims I or 2, characterized in that the alkaline ethanolate is a sodium ethanolate. 4. Procédé de préparation de picolinate d'éthyle selon la revendication 3, caractérisé en ce que l'éthanolate est formé in situ par addition de sodium à de l'éthanol.  4. Process for the preparation of ethyl picolinate according to claim 3, characterized in that the ethanolate is formed in situ by addition of sodium to ethanol. 5. Procédé de préparation selon l'une des revendications I à 4, caractérisé en ce que l'acide organique faible de l'étape b) est choisi parmi l'acide acétique et l'acide propionique.  5. Preparation process according to one of claims I to 4, characterized in that the weak organic acid of step b) is chosen from acetic acid and propionic acid. 6. Procédé de préparation selon l'une des revendications 1 à 5, caractérisé en ce que l'acide minéral fort de l'étape b) est choisi parmi l'acide chlorhydrique, l'acide bromhydrique, l'acide sulfurique. 6. Preparation process according to one of claims 1 to 5, characterized in that the strong mineral acid of step b) is chosen from hydrochloric acid, hydrobromic acid, sulfuric acid. 7. Procédé de préparation selon l'une des revendications l à 6; caractérisé en ce que dans l'étape c), la base faible est choisie parmi le carbonate de sodium, le carbonate de potassium, l'hydroxyde de baryum, l'hydroxyde de calcium.  7. Preparation process according to one of claims 1 to 6; characterized in that in step c), the weak base is chosen from sodium carbonate, potassium carbonate, barium hydroxide, calcium hydroxide.
FR9213207A 1992-11-04 1992-11-04 Process for the synthesis of ethyl picolinate. Expired - Fee Related FR2697521B1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4268658A (en) * 1979-12-28 1981-05-19 General Electric Company Process for preparing polycarbonates using iminoethers as catalysts
EP0200051A2 (en) * 1985-04-22 1986-11-05 Hoechst Aktiengesellschaft Process for the preparation of imidates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4268658A (en) * 1979-12-28 1981-05-19 General Electric Company Process for preparing polycarbonates using iminoethers as catalysts
EP0200051A2 (en) * 1985-04-22 1986-11-05 Hoechst Aktiengesellschaft Process for the preparation of imidates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 78, no. 25, 25 Juin 1973, Columbus, Ohio, US; abstract no. 159392m, WATANABE H. ET AL. *

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