FR2686340A1 - Process for the synthesis of ortho-halogenated pyridinecarboxylic acids or pyridinecarboxamides and new ortho-fluorinated pyridinecarboxylic acids or pyridinecarboxamides - Google Patents

Abstract

The present invention relates to a process for the synthesis of ortho-halogenated pyridinecarboxylic acids or pyridinecarboxamides. ortho-Halogenated pyridinecarboxylic acids are obtained by the reaction, in an organic solvent medium, of a halopyridine with an organolithium derivative, followed by reaction with CO2, then by hydrolysis and by acidification of the reaction medium. It is then possible to obtain the corresponding ortho-halogenated pyridinecarboxamides by the usual known methods. The invention also relates to (x+1)-fluoropyridine-x-carboxylic acid or (x+1)-fluoropyridine-x-carboxamide, x being equal to 2 or 3, and to 3-fluoropyridine-4-carboxylic acid or 3-fluoropyridine-4-carboxamide, which are novel compounds. ortho-Halogenated pyridinecarboxylic acids or pyridinecarboxamides are important intermediates in the synthesis of medicaments or of plant-protection derivatives.

Description

Process for the synthesis of carboxylic pyridines or orthohalogenated carboxamides and new pyridines because boxylic or orthofluorinated carboxamides.

 The present invention relates to a new process for the synthesis of orthohalogenated carboxylic pyridine acids, hereinafter referred to more briefly as "orthohalogenated carboxylic pyridines", to a new process for the synthesis of orthohalogenated carboxamide pyridines as well as to new orthofluorinated carboxylic pyridines and to the corresponding new carboxamides.

 The term "carboxylic" or "carboxamide" pyridine is understood, quite usual, to mean a pyridine ring comprising a carboxyl group (-COOHJ or carboxamide (-CONH2) directly linked to one of the carbon atoms of the ring.

 Also commonly, the terminology "orthohalogenated" means that the pyridine ring comprises a halogen atom directly connected to a carbon atom of the pyridine ring located in the ortho position, that is to say adjacent to the carbon atom of the ring carrying the carboxyl or carboxamide group. When the carbon atom of the pyridine ring carrying the carboxyl or carboxamide group is directly linked to the nitrogen atom of the ring, there is only one ring carbon located in the ortho position. There are two in the other cases.

 Orthohalogenated carboxylic pyridines or carboxamides are important intermediates in the synthesis of bleaches for detergents, drugs or phytosanitary derivatives, for example for the synthesis of pyridinyl pyrroldicarboxylates which are herbicides, for that of mercaptopyridinic acids known for their activity hypoglycemic, or for those of the corresponding nitrogen oxides in the detergent field. Furthermore, 2-halogenated nicotinic acids are intermediates in the synthesis of niflunic acid, an active ingredient as a medicament.

 In the state of the art, there is no general method for the synthesis of orthohalogenated carboxylic pyridines or carboxamides. There are only specific methods specific to one or a few orthohalogenated carboxylic pyridines or carboxamides.

 In addition, the orthofluorinated derivatives are little described, some being even new.

 US 4,081,451 describes the synthesis of 2chloronicotinic acid by hydrolysis of 3-cyano-2-pyridone followed by the reaction of 2-hydroxynicotinic acid obtained with phosphorus oxychloride, then hydrolysis of the acid chloride formed.

JT MINOR, GF HAWKINS, CA VANDERWERF and A. ROE,
JACS, 71, 1125 (1949) describe the synthesis of 2-fluoronicotinic acid (2-fluoropyridine-3-carboxylic) by oxidation of 2-fluoro 3-methyl pyridine by potassium permanganate. The yield is 30%.

 R.D. BEATY and W.K.R. MUSGRAVE, J. Chem. Soc., 3512 (1951) describe the synthesis of 2-fluoro-nicotinic acid by reaction of 2-amino nicotinic acid with HBF4 in the presence of NaNO2. The yield is 33%.

 All these methods are not satisfactory because they cannot be generalized. In addition, yields are often low and the raw materials used are difficult to access, as is the case in particular for orthofluorinated derivatives.

 Those skilled in the art are therefore looking for a simple and generalizable process for the synthesis of all orthohalogenated carboxylic pyridines or carboxamides, having a yield close to or better, higher than that obtained according to known methods.

 The present invention relates in particular to such a method. The Applicant has discovered that, unexpectedly, any orthohalogenated carboxylic pyridine, including those which have never been synthesized before, can be obtained by reaction of a halopyridine with an organolithium derivative, followed by a reaction with COz then hydrolysis and acidification of the reaction medium.

 Even more unexpectedly, the Applicant has discovered that in the case of an unsubstituted 3-halopyridine in positions 2 and 4, it was possible, by judicious selection of operating conditions, to selectively obtain either the 2-carboxylic derivative or the 4carboxylic derivative.

 The corresponding carboxamide derivatives can then be obtained by means known to a person skilled in the art making it possible to transform a -COOH function into a -CONH2 function.

 The method according to the invention is simple to implement, which in particular limits the formation of annoying pyridine effluents, carried out from halopyridines which are commercial raw materials and easily accessible, generalizable to all orthohalogenated carboxylic pyridines or carboxamides. , especially orthofluorinated, including those that had never been synthesized before.

 In addition, for the orthohalogenated carboxylic pyridines or carboxamides which are already known, the yields obtained by the process according to the invention are higher than those obtained by the known processes.

The present invention therefore relates to a process for the synthesis of orthohalogenated carboxylic pyridines. It is characterized in that a halopyridine is reacted, in an organic solvent medium, with an organolithium derivative, in that one then adds
CO2 in the reaction medium, then in that it hydrolyzes and acidifies this medium.

 The present invention also relates to a process for the synthesis of orthohalogenated carboxamide pyridines. It is characterized in that the orthohalogenated carboxylic pyridines are first synthesized by the aforementioned process according to the invention, then in that these are transformed, preferably after having isolated them from the reaction medium, into corresponding carboxamides by known means. As an example of known means, mention may be made of the prior reaction of orthohalogenated carboxylic pyridines with a conventional halogenating agent, such as PCls, PCl3 or SOCl2, to transform the carboxyl function into the carboxylic acid halide function, followed by a reaction with the ammonia to transform the halide function of carboxylic acid into carboxamide function.

 According to the present invention, the halogen of halopyridine is preferably chosen from the group consisting of chlorine, bromine and fluorine, preferably fluorine.

 The halogen located in the ortho position of the corresponding orthohalogenated carboxylic pyridine obtained is the same as that of the starting halogenopyridine. It is indeed found that overall, the process according to the invention results in the fixing of a carboxyl group in the ortho position of the halogen of the halopyridine.

 Furthermore, the pyridine ring of halopyridine, and consequently that of the orthohalogenated carboxylic pyridine obtained, can comprise, in addition to this halogen atom, one or other substituents, for example and in a nonlimiting manner a group. alkyl or alkoxy, provided that a carbon atom of the pyridine ring directly linked to the carbon atom of the halogen-carrying ring is not substituted.

 According to the invention, the organolithium derivative is preferably chosen from the group consisting of alkyllithians, aryllithians and N, N-disubstituted aliphatic lithium amides.

 As regards the alkyllithians, preference is given to those comprising an optionally substituted linear or branched C1 to C8 alkyl chain, for example n butyllithium.

 As regards the aryllithians, the aromatic ring, which may be heterocyclic, may comprise one or more rings and / or be substituted, for example by a C1 to C4 alkyl chain. Phenyllithium is perfectly suitable.

 Preferably, when the halopyridine is reacted with an alkyllithian or an aryllithian, this reaction is carried out in the presence of a lithium complexing agent, preferably in an equimolar amount relative to the lithian derivative, for example an ether. crown or a tertiary diamine such as diazabicyclooctane (DABCO) or N-methylmorpholine, which makes it possible to obtain unexpectedly better yields.

 This complexation is generally carried out at a temperature below O'C, for example between -20 ° C and -70 ° C.

 As regards the N, N-disubstituted aliphatic lithium amides, these are preferably obtained in situ in the reaction medium, for example by reaction of an alkyllithian with an aliphatic secondary amine. Examples of an alkylyllith that may be mentioned include those comprising a C1 to C8 alkyl chain, in particular n-butyllithium, and as examples of aliphatic secondary amine, diisopropylamine and tetramethylpiperidine. The molar ratio between the alkyllithian and the aliphatic secondary amine is generally close to 1. However, an excess, for example of 5 to 50%, of one or other of the compounds can be used. This reaction is preferably carried out at a temperature below 0 "C, for example between -50 C and 0 C.

 According to the invention, the reaction between the halopyridine and the organolithium derivative is carried out in an organic solvent medium.

Preferably, the organic solvent is an oxygenated solvent or a mixture of oxygenated solvents, preferably an ether such as tetrahydrofuran (THF), dimethoxyethane or diethyl ether. It is also possible to use this or these oxygenated solvents in mixture with an aliphatic hydrocarbon. Mixtures
THF / hexane are very suitable.

 In general, the concentration of halopyridine and / or the organolithium derivative in the organic solvent is between 0.1 mol / l and 1.3 mol / l and the molar ratio between halopyridine and the organolithium derivative is included between 0.9 and 1.1.

 This reaction between the halopyridine and the organolithium derivative is generally carried out at a temperature between O'C and -100C, preferably between -70 C and -30'C.

 When the halopyridine is a 3-halopyridine unsubstituted in positions 2 and 4, a mixture of the 2-carboxylic derivative and of the 4-carboxylic derivative is generally obtained. Unexpectedly, it is found, in particular when the 3-halopyridine is a 3fluoropyridine, that one can obtain, by judicious selection of the operating conditions, selectively either the 2-carboxylic derivative or the 4-carboxylic derivative and therefore optionally selectively either the 2carboxamide derivative, ie the 4-carboxamide derivative.

 When the organolithium derivative is an alkyllithian or an aryllithian and the reaction temperature of this derivative with 3-halo pyridine is between -50 ° C. and -100 ° C., a 2-carboxylic 3-halo pyridine is selectively obtained and then optionally the corresponding carboxamide. As previously described more generally, better yields are obtained in this case when the reaction is carried out in the presence of a lithium complexing agent such as those mentioned above.

 When the organolithium derivative is an N, N-disubstituted aliphatic lithium amide and the reaction temperature of this derivative with 3-halopyridine is between -50 ° C. and -100 ° C., a 4-carboxylic 3-halopyridine is then obtained selectively. optionally the corresponding carboxamide.

 After reaction between the halopyridine and the organolithium derivative, CO2 is added, for example in the form of dry ice, preferably in excess, in the reaction medium, which is left to react, at a temperature generally between -50 ° C. and 0 C, for example around -30 C, with the product of the reaction between the halopyridine and the organolithium derivative.

 The reaction medium is then hydrolyzed and acidified, preferably after 1 having warmed up, for example to 0 ° C. or more, which makes it possible to obtain the desired orthohalogenated carboxylic pyridine, which, in general, precipitates during acidification, and which can thus be easily recovered by filtration and identified according to the usual methods, in particular by measuring the melting point and by mass spectrometries (MS), nuclear magnetic resonance of the proton or of carbon (1 H NMR, 13 C NMR) and infrared (IR).

 The present invention also relates to new carboxylic pyridines or orthofluorinated carboxamides, namely on the one hand the (x + 1) -fluoropyridines x-carboxylic or carboxamide with x = 2 or 3, in particular 3-fluoropyridine 2-carboxylic, 3-fluoropyridine 2-carboxamide, 4-fluoropyridine 3-carboxylic and 4-fluoropyridine 3-carboxamide whose pyridine ring contains no other substituent, and on the other hand the 3-fluoropyridines 4-carboxylic or carboxamide, in particular the 3-fluoropyridine 4-carboxylic and 3-fluoropyridine 4-carboxamide, the pyridine ring of which contains no other substituent.

 These new orthofluorinated carboxylic pyridines or carboxamides can be obtained, as already mentioned, by the aforementioned process according to the invention from the corresponding fluoropyridines. They are moreover particularly useful as intermediates for the synthesis of ureas which are interesting phytosanitary derivatives.

 The following nonlimiting examples illustrate the invention and the advantages which it provides.

Example 1 Synthesis of 2-fluoropyridine 3-carbo
xylic (2-fluoronicotinic acid)
In a reactor containing 200 ml of THF, 25 ml of a solution of n-butyllithium in hexane, the n-butyllithium concentration of which is 2.5 M (i.e. 0.063 mole of n- butyllithium), and 9 ml of diisopropylamine (0.060 mole). The temperature is allowed to rise to C and this temperature is maintained for 20 min.

 The reaction medium is then cooled to -? O'C, then 5 ml of 2-fluoropyridine (0.058 mole) dissolved in 20 ml of THF is added dropwise. Leave to react for 4 h at -70 ° C. After reaction, excess dry ice is added and the mixture is left to react for 1 h at -30 ° C.

The temperature is then allowed to rise to 0 C and then hydrolyzed with 150 ml of water. An ether extraction is then carried out and the aqueous phase is recovered which is then acidified with a hydrochloric acid solution to pH = 3. I1 forms a white precipitate which is filtered and dried. This product, which decomposes at 164-166 "C, is, according to the 1 H NMR and 13 C NMR spectra, 2-fluoropyridine 3-carboxylic. These spectra also indicate that this product is pure. The yield of pure product isolated is 80% relative to the starting 2fluoropyridine.

Example 2 Synthesis of 2-fluoropyridine 3-carboxamide
(2-fluoronicotinamide)
6 g of the 2-fluoropyridine 3-carboxylic acid prepared according to Example 1 are brought to reflux for 27 hours in 50 ml of thionyl chloride.

 The excess SOC12 is removed on a rotary evaporator. 50 ml of THF are then added. Cool to 0 C and then NH3 is bubbled for 30 min. A precipitate forms. Evaporated to dryness then the precipitate is taken up in acetone which is then eliminated by evaporation. The crude product obtained is purified by recrystallization from water. 4.3 g of purified product are thus recovered, the melting point of which is 120 ° C. and which is, according to the 1 H NMR and 13 C NMR spectra, 2-fluoropyridine 3carboxamide. These spectra also indicate that this product is pure. The yield of isolated pure product is 72% relative to the starting acid.

EXAMPLE 3 Synthesis of 3-fluoropyridine 4-carboxy
lique
The procedure is as for Example 1 but using 3-fluoropyridine instead of 2-fluoropyridine. The product obtained, the melting point of which is greater than 250 ° C., is, according to the 1 H NMR and 13 C NMR spectra, 3-fluoropyridine 4-carboxylic. These spectra further indicate that this product is pure and that there is therefore not formed, within the limits of detection of the method, of 3-fluoropyridine 2-carboxylic.

 The yield of isolated pure product is 93% relative to the starting 3-fluoropyridine.

Example 4 Synthesis of 3-fluoropyridine 4-carboxamide
A suspension of 4 g of 3-fluoropyridine 4-carboxylic acid prepared according to Example 3, is brought to reflux in 40 ml of thionyl chloride for 2.5 h.

After evaporation of the excess SOC12, 60 ml of THF are added. Cool to 0 C and then NH3 is bubbled for 30 min. Evaporated to dryness and then the solid obtained is taken up with acetone. After evaporation of the acetone, the crude product obtained is recrystallized from water. 2.78 g of purified product are thus recovered, the melting point of which is 133 ° C. and which is, according to the 1 H NMR and 13 C NMR spectra, 3-fluoropyridine 4carboxamide. These spectra also indicate that this product is pure. The yield of isolated pure product is 70% relative to the starting acid.

EXAMPLE 5 Synthesis of 3-fluoropyridine 2-carboxy
lique
5.6 g (0.05 mole) of diazabicyclooctane are introduced into a 500 ml three-necked flask fitted with a stirrer and a thermometer. After purging with argon, 200 ml of ether are introduced and then cooled to -70C. Then added 20 ml of a solution of n-butyllithium in hexane, the concentration of n-butyllithium is 2.5 M (or 0.05 mole of n-butyllithium). The temperature is allowed to rise to -204C and this temperature is maintained for 1 hour. It is then cooled to -70 ° C., then a solution of 3-fluoropyridine obtained is added dropwise, obtained by mixing 4.8 g (0.05 mole) of 3-fluoropyridine and 15 ml of ether. excess dry ice and 80 ml of CO2 saturated THF are added, the temperature is allowed to rise to -30 ° C. and this temperature is maintained for 1 hour.

Then hydrolyzed, at 0 C, with 150 ml of water, extracted with ether and then the aqueous phase is acidified, at 0 C, with a hydrochloric acid solution. A precipitate is formed which is filtered and dried. This product, the melting point of which is 162-C, is, according to the 1 H NMR and 13 C NMR spectra, 3-fluoropyridine 2carboxylic. These spectra further indicate that this product is pure and that it has therefore not formed, within the detection limits of the method, of 3-fluoropyridine 4-carboxylic. The yield of isolated pure product is 27% relative to the starting 3-fluoropyridine.

Example 6 Synthesis of 3-fluoropyridine 2-carboxamide
2 g of the 3-fluoropyridine 2-carboxylic acid prepared according to Example 5 are brought to reflux for 64 h in 25 ml of SOC12. After evaporation of excess
SOCl2, 40 ml of THF are added. Cool to 0 C and then NH3 is bubbled for 30 min. Evaporated to dryness then the precipitate is taken up with acetone which is then eliminated by evaporation. The crude product obtained is purified by recrystallization from ethanol.

 The purified product, whose melting point is 142 C, is, according to the 1 H NMR and 13 C NMR spectra, 3-fluoropyridine 2-carboxamide. These spectra also indicate that this product is pure. The yield of isolated pure product is 85% relative to the starting acid.

Claims (14)

Claims 1. Process for the synthesis of orthohalogenated carboxylic pyridines, characterized in that a halopyridine is reacted, in an organic solvent medium, with an organolithium derivative, in that CO2 is then added to the reaction medium and then in that it is hydrolyzed and acidifies this medium. 2. Process for the synthesis of orthohalogenated carboxamide pyridines, characterized in that one implements the method according to claim 1, then in that the orthohalogenated carboxylic pyridines are converted into corresponding carboxamide. 3. Synthesis process according to claim 2 characterized in that the orthohalogenated carboxylic pyridines are reacted with a halogenating agent, then with ammonia. 4. Synthesis method according to any one of claims 1 and 2 characterized in that the halogen is selected from the group consisting of fluorine, le.chlore and bromine, preferably fluorine. 5. Synthesis method according to any one of the preceding claims, characterized in that the organolithium derivative is chosen from the group consisting of alkyllithians, aryllithians and N, N-disubstituted aliphatic lithium amides. 6. Synthesis process according to claim 5 characterized in that the halopyridine is reacted with an alkyllithian or an aryllithian in the presence of a lithium complexing agent. 7. Synthesis process according to claim 6 characterized in that the complexing agent is a crown ether or a tertiary diamine. 8. Synthesis process according to claim 5 characterized in that the aliphatic lithium amide N, Ndisubstitué is obtained in situ in the reaction medium by reaction of an alkyllithien with an aliphatic secondary amine. 9. Synthesis process according to any one of the preceding claims, characterized in that the organic solvent is an oxygenated solvent, preferably an ether, alone or as a mixture with an aliphatic hydrocarbon. 10. A process for the synthesis of 2-carboxylic 3-halopyridines according to claim 1 or 4 characterized in that a 3halogenopyridine is reacted, in an organic solvent medium and at a temperature between -50 ° C. and -100 ° C., with an alkyllithian or a aryllithian, preferably in the presence of a lithium complexing agent, in that CO2 is then added to the reaction medium, and then that this medium is hydrolyzed and acidified. 11. A process for the synthesis of 3-halopyridines 2carboxamide according to claim 2 characterized in that the process according to claim 10 is used to obtain the intermediate orthohalogenated carboxylic pyridines. 12. A process for the synthesis of 4-carboxylic 3-halopyridines according to claim 1 or 4, characterized in that a 3halopyridine is reacted, in an organic solvent medium and at a temperature between -50 ° C. and -100 ° C., with an amide of aliphatic lithium N, N-disbustitué, in that one then adds C02 in the reaction medium, then in that one hydrolyzes and acidifies this medium. 13. A process for the synthesis of 3-halo pyridines 4carboxamide according to claim 2 characterized in that the process according to claim 12 is used to obtain the intermediate orthohalogenated carboxylic pyridines. 14. (x + 1) -fluoropyridines x-carboxylic and (x + 1) fluoropyridines x-carboxamide, x being equal to 2 or 3, as well as 3-fluoropyridines 4-carboxylic and 3fluoropyridines 4-carboxamide, preferably the 3fluoropyridine 2-carboxylic, 3-fluoropyridine 2carboxamide, 4-fluoropyridine 3-carboxylic, 4fluoropyridine 3-carboxamide, 3-fluoropyridine 4carboxylic and 3-fluoropyridine 4-carboxamide.