FR2961204A1 - Preparing aromatic carboxylic acid derivatives by nucleophilic aromatic substitution, comprises reacting carboxylic acid derivative having carboxyl function or its salts, preferably benzoic acid derivatives with metal compound - Google Patents

Abstract

Preparing aromatic carboxylic acid derivatives by nucleophilic aromatic substitution, comprises: reacting an aromatic carboxylic acid derivative supporting only one carboxyl function, or one of its salts, preferably lithium, sodium, potassium or zinc salts, preferably benzoic acid derivatives or its salts with metal compound of formula (MNu) (III), where: the carboxylic acid derivative has, in ortho of carboxy function, a leaving group, which is a fluorine atom, chlorine atom or chiral or non chiral alkoxy group (preferably methoxy group). Preparing aromatic carboxylic acid derivatives by nucleophilic aromatic substitution, comprises: reacting an aromatic carboxylic acid derivative supporting only one carboxyl function, or one of its salts, preferably lithium, sodium, potassium or zinc salts, preferably benzoic acid derivatives or its salts with metal compound of formula (MNu) (III), where: the carboxylic acid derivative has, in ortho of carboxy function, a leaving group, which is a fluorine atom, chlorine atom or chiral or non chiral alkoxy group (preferably methoxy group); the carboxylic acid derivative is substituted by at least one electroattractive group other than the leaving group, preferably by a fluorine atom; if the leaving group is a fluorine atom, and the para position is occupied by a bromine atom and the other positions are substituted by hydrogen atoms, or (III) is not isobutyl magnesium chloride (iBuMgCl) or magnesium bromide of formula (N1uMgBr); if the leaving group is a fluorine atom, and the other ortho position is occupied by a halo, and the para position is occupied by a fluorine atom and the meta position adjacent to the leaving group and the other meta position is occupied by a hydrogen atom, and (III) is not an alkylating agent in which Nu is 1-6C alkyl; the starting product is 2,3,4,6-tetrafluorobenzoic acid and (III) is not methyl magnesium bromide (CH 3MgBr); the aromatic nucleophilic substitution reaction is carried out without catalyst and without protection/deprotection of the acid function of the starting compound; and the process is selective in that the reaction leads to the formation of ketone derivatives in a very minority manner during the reaction. M : metal; Nu : a chiral or non chiral nucleophile; and N1u : ethyl group, isobutyl group or cydopentenyl group.

Description

The present invention relates to the field of chemical synthesis, and in particular the invention provides a novel nucleophilic substitution process using difluorobenzoic acids. Aromatic nucleophilic substitution is a reaction whose interest is well known and widely used in industry. However, it has drawbacks, which are widely known, including the need to use catalysts, and the need to protect / deprotect the carboxyl function (CO2H) required as a carbon anchor for subsequent chemical functionalization.

The use of catalysts is restrictive because, at the end of the reaction, they must be trapped and eliminated. They are polluting residues, and are also likely to leave traces of heavy metals in the reaction products (see for example Mnigsberger et al., Organic Process Research & Development 2003, 7, 733-742, or Pink et al. Organic Process Research & Development 2008, 12, 589-595). The obligation to protect / deprotect the carboxyl function (CO2H) is seen as a compelling necessity for nucleophilic substitution. It is generally accepted that CO2H function reacts with organometallic compounds to yield ketone derivatives, generally undesired (Jorgenson, MJ Org React 1970, 18, 1. Ahn, T. Cohen, T. Tetrahedron Lett 1994, 35, 203). As a result, the addition of a protecting group for the carboxylic function at the beginning of the nucleophilic substitution reaction appears as a mandatory passage. The protective groups used are generally sterically bulky groups, known to promote nucleophilic substitution.

Being able to free oneself of these necessities of catalysis and protection / deprotection is therefore a constant technical problem of the chemical and pharmaceutical industry. In the application FR 10 51226 (not published at the filing date), the Applicant reports an aromatic nucleophilic substitution process on an industrial scale and with a high yield, having an optimized number of steps. The Applicant, by continuing its work, found that, surprisingly, the use of difluorobenzoic acids as starting materials allowed it to avoid any nucleophilic attack on the carboxylate, yet unprotected, which has the consequence that 'no competitive ketone formation is observed, and only ipso-substitution products of interest are obtained. In particular, the presence of a first fluorine atom ortho to the carboxyl function, and a second fluorine atom at the 4- or 6-position of the aromatic ring renders the carboxylate completely inert with respect to the nucleophilic attack. . The present invention thus makes it possible to avoid the formation of by-products. Without wishing to be bound by any theory, the Applicant assumes that the fluorine atoms present on the aromatic nucleus would exert a donor electron effect by its non-binding orbitals resulting in a stabilization of the carboxyl function, which would thus lose its reactivity towards the nucleophile. The effect o (Hammett constant) of the second fluorine atom could be responsible for the increase of the charge density at the carboxyl function, making it less electrophilic and reorienting the nucleophilic attack towards the carbons carrying a fluorine atom to give the nucleophilic substitution reaction. The reaction is first on the carbon carrying the fluorine adjacent to that carrying the carboxyl function. This electronic effect of the second fluorine suppressing any attack on the carboxylic group is not known in the chemical literature.

Thus, the subject of the invention is a selective process for the preparation of difluorobenzoic acid derivatives, by aromatic nucleophilic substitution, in which a difluorobenzoic acid or a salt thereof is reacted with a NuM reagent, in which Nu is a nucleophile. chiral or not and M is a metal, said aromatic nucleophilic substitution reaction being carried out without a catalyst and without a protective / deprotection step of the carboxyl function of difluorobenzoic acid, this process being selective in that it does not obtain of ketonic derivative since no nucleophilic attack occurs on the carboxylic function during the reaction. Preferably, the difluorobenzoic acid is not substituted with an electron-withdrawing group. Advantageously, the difluorobenzoic acid carries a carboxyl function and only one. Preferably, the difluorobenzoic acid, starting product of the nucleophilic substitution reaction is a compound of general formula (II). Wherein R 1 is CO2H, R 2 is a fluorine atom, at least one of R 4 or R 6 is a fluorine atom, the other is a hydrogen atom, a fluorine atom, a alkyl group, an alkoxy group, an aryl, or an amine substituted or unsubstituted by one or two alkyl groups, - R3 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or a substituted or unsubstituted amine by one or two alkyl groups, - when R4 is not a fluorine atom, R3 and R4, or R4 and R5, together form an aromatic ring or not, or a heterocycle, optionally substituted, in particular with a functional group, when R6 is not a fluorine atom, R5 and R6 together form an aromatic ring or not, or a heterocycle, optionally substituted, in particular with a functional group. Compound (II) reacts according to the process according to the invention with a compound (III) of general formula NuM in which Nu is a nucleophile, and M is a metal, preferably Li, Mg, Zn, Cu or an MgX organomagnesium in wherein X is a halogen atom or an alkoxy group, preferably OCH3, said aromatic nucleophilic substitution reaction being carried out without a catalyst and without a step of protecting / deprotecting the acid function of the compound (II), to selectively obtain a compound of general formula (I), which corresponds to the general formula (II) in which R2 and / or that of R4 or R6 which is a fluorine atom has been substituted by Nu. Preferably, Nu is a nucleophile selected from those described in Tables 1, 2 and 3.

In a first embodiment, the NuM compound can be obtained by direct synthesis (Carey & Sundberg, Advanced Organic Chemistry, Part A Chapter 7, "Carbanions and Other Nucleophilic Carbon Species", pp. 405-448). In a second embodiment, the NuM compound can be obtained from lithium salts and anion radicals (Cohen, T., JACS 1980, 102, 1201, JACS 1984, 106, 3245, Acc. 1989, 22, 52).

According to a third embodiment, the NuM compound can be obtained by metal-halogen exchange (Parham, W. E .; Bradcher, C.K.Acc., Chem Res 1982, 15, 300-305). In a fourth embodiment, the NuM compound can be obtained by directed metallation (V. Sneckius, Chem Rev, 1990, 90, 879, JOC 1989, 54, 4372). According to a preferred embodiment of the invention, the NuM compound is obtained by reaction of the nucleophile and n-BuLi. In a preferred embodiment, NuM was not obtained by addition of M to Nu in the presence of LiHMDS. Advantageously, the reaction is carried out at -78 ° C. and the reflux of the solvent. Preferably, the reaction is carried out in an aprotic polar solvent, preferably anhydrous THF (tetrahydrofuran) or diethyl ether. Advantageously, the compound NuM is preferably added dropwise at a temperature of between -78 ° C. and the reflux of the solvent. Preferably, the solution is stirred and then hydrolyzed with water. The pH is adjusted to 1 with an aqueous solution of hydrochloric acid (2N) and the solution is extracted with a suitable solvent, for example ethyl acetate. The organic phase is then dried and concentrated under vacuum. The crude product is recrystallized or chromatographed. According to one embodiment of the invention, at least two NuM equivalents are used for one equivalent of starting difluorobenzoic acid. Advantageously, in addition to these two equivalents, a NuM equivalent is added per group starting from the starting molecule to be substituted. If the starting compound is a difluorobenzoic acid salt, at least one NuM equivalent is used for one equivalent of the starting difluorobenzoic acid salt. Advantageously, in addition to this equivalent, a NuM equivalent is added per group starting from the starting molecule to be substituted. The reaction is completely selective because no ketone is formed. The expected yields for the reaction process according to the invention are between 45 and 100%, preferably 45 to 90%, more preferably 60 to 90%. According to a preferred embodiment, an asymmetric carbon is present on the nucleophile, and the compound of general formula (I) obtained is asymmetrical.

According to a particular embodiment of the process according to the invention, the compound of general formula (II) is such that: - R1 is CO2H, - R2 and R6 are each independently a fluorine atom, and - R3, R4, R5 are each independently a hydrogen atom.

Reaction of this particular compound with NuM nucleophile gives only the monosubstituted or disubstituted product. The corresponding ketones are not formed and the carboxyl function is resistant to nucleophilic attack. The monosubstituted product or a mixture of the following mono- and disubstituted products is thus obtained: ## STR1 ## According to another particular embodiment of the process according to the invention, the compound of general formula (II) is such that: - R1 is CO2H, - R2 and R4 are each independently a fluorine atom, and - R3, R5, R6 are each independently a hydrogen atom Reaction of this particular compound with a nuM nucleophile gives only the monosubstituted product. The corresponding ketones are not formed and the carboxyl function is resistant to nucleophilic attack. The monosubstituted product or a mixture of mono- and disubstituted products is obtained. COZH Tables 1, 2 and 3 below show several preferred NuM reagents. Nu M Alkyl, preferably Li, Mg, Cu, Zn, or MgX where X is CH3 or C2H5 is halogen or alkoxy alkenyl, optionally Li, Mg, Cu, Zn, or MgX where X is substituted with halogen or alkoxyalkynyl optionally Li, Mg, Cu, Zn, or MgX where X is substituted by halogen or Aryl alkoxy optionally Li, Mg, Cu, Zn, or MgX where X is substituted by halogen or alkoxy s-Bu Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy t-Bu Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy n-Bu Li, Mg, Cu, Zn, or MgX where X is a halogen or alkoxy 4-MeOC6H4 Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy 4-Me2NC6H4 Li, Mg, Cu, Zn, or MgX where X is halogen or NuM NuM Nu N alkoxy Li, Mg, Cu, Zn, or MgX where X is a halogen or alkoxy ® Li, Mg, Cu, Zn, or MgX where X is a halogen or alkoxy Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy N, Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy N Li, Mg, Cu, Zn, or MgX o X is a halogen or alkoxy Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy (Li, Mg, Cu, Zn, or MgX where X is x halogen or alkoxy) Li, Mg, Cu, Zn, or MgX where X is X, a halogen or a P (Aryl) 2 alkoxy, Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy PArylAlkyl Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy O (C1-6alkyl) Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy S (C1-6alkyl) Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy NH, Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy R ® R, where RRRR in one is a group hydrogen, alkyl, an alkoxy, an aryl, or an amine substituted or unsubstituted by one or two C1-12alkyl, with the proviso that the reaction does not use as a base LiHMDS Table 1 Nu MN (C1-6alkyl) 2 Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy NH (C1-6alkyl) Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy NEt2 Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy N (CH2CH2) 2NMe Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy NMeBn Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy NBn2 Li, Mg, Cu, Zn, or MgX where X is a halogen or alkoxy NMePh Li, Mg, Cu, Zn, or MgX where X is a halogen or an alkoxy NHt-Bu Li, Mg, Cu, Zn, or MgX where X is a halogen or alkoxy NPh 2 Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy Table 2 According to a first preferred embodiment of the invention, in Tables 1 and 2, M is Li or mg. Advantageously, in Tables 1 and 2, when M is MgX with X is a halogen, the halogen is chosen from F, Br, Cl. Advantageously, when M is MgX with X is an alkoxy, the alkoxy is OCH3 OR OC2H5 . According to a preferred embodiment of the invention, M is MgBr or MgOCH3. Preferred chiral NuM compounds according to the invention are exemplified in Table 3 below.

Nu MBCD Li, Mg ® ~ k C Li, Mg ADBC Li, Mg AD Li, Mg, Cu, Zn ® Li, Mg, Cu, Zn N ~ Li, Mg, Cu, Zn N ~ Li, Mg, Cu, Zn 1, 1.9e Li, Mg, Cu, Zn Li, Mg, Cu, Zn® Li, Mg, Cu, Zn N, Nu M vw Li, Mg, Cu, Zn N Li, Mg, Cu, Zn N Li, Mg, Cu, Zn Li N, Mg, Cu, Zn Li, Mg, Li, Mg Li X, Mg Li, Mg NR'R2 Li, Mg SiR'R2R3 Li, Mg ORS Li, Mg SR Li, Mg Table 3: chiral element Preferably, M is Li, MgBr; preferably Nu is n-BulI, s-BulI, t-BulI, methyl, phenyl, 2-MeC6H4, 2-MeOC6H4, 4-MeC6H4, 4-MeOC6H4 or naphthalene. Preferred NuM compounds are n-BulI, s-BulI, t-BulI, MeLi, PhLi, PhMgBr, 2-MeC6H4Li, 2-MeOC6H4Li, 4-MeC6H4Li, 4-MeOC6H4Li, 1-LiNaphthalene, 2-LiNaphthalene. Definitions For the purposes of the present invention, the term "aryl" means a mono- or polycyclic system of 5 to 20, preferably 6 to 12, carbon atoms having one or more aromatic rings (when there are two rings, reference is made to a biaryl) including phenyl group, biphenyl group, 1-naphthyl group, 2-naphthyl group, tetrahydronaphthyl group, indanyl group, and binaphthyl group. The term aryl also means any aromatic ring comprising at least one heteroatom selected from oxygen, nitrogen or sulfur. The aryl group may be substituted with 1 to 3 substituents chosen independently of each other, from a hydroxyl group, a linear or branched alkyl group comprising 1, 2, 3, 4, 5 or 6 carbon atoms, in particular methyl, ethyl, propyl, butyl, an alkoxy group or a halogen atom, especially bromine, chlorine and iodine. The term "catalyst" refers to any product involved in the reaction to increase the rate of this reaction, but is regenerated or eliminated during or at the end of the reaction. By "protecting the carboxyl function (CO2H)" is meant to add on said function a group annihilating the reactivity of the carboxyl function with respect to nucleophiles; this group may be an oxazoline; many chemical groups other than the oxazoline function have been used to protect the CO2H function: 2,6-di-tert-butyl-4-methoxyphenyl ester (Hattori, T. Satoh, T. Miyano, S. Synthesis 1996, 514. Koshiishi, E. Hattori, T. Ichihara, N. Miyano, SJ Chem Soc., Perkin Trans., 1, 2002, 377), Amide (Kim, D .; Wang, L., Hale, JJ; Lynch, CL, Budhu, RJ, MacCoss, M, Mills, SG, Malkowitz, L, Gould, SL, Martino, JA, Springer, MS, Hazuda, D, Miller, M, Kessler, J, Hrin Carver, G., Carella, A., Henry, K., Lineberger, J, Schleif, WA, Emini, EA Bioorg, Chem Chem Lett, 2005, 15 (8), 2129), alkylamide ( Guo, Z. Schultz, AG Tetrahedron Lett., 2001, 42 (9), 1603), dialkylamides (Hoarau, C., Couture, A. Deniau, E., Grandclaudon, P. Synthesis 2000), 1-imidazolyls ( Figge, A., Altenbach, HJ, Brauer, DJ, Tielmann, P. Tetrahedron: Asymmetry 2002, 13 (2), 137), 2-oxazolyls (Cram, DJ, Bryant, JA, Doxsee, KM Chem Lett, 1987). , 19), 2-thiazolyls, etc ... By "leaving group" is meant a group that takes the two electrons of the sigma bond connecting it with the aromatic carbon atom during the substitution reaction by the nucleophile. By "alkyl" is meant any saturated linear or branched hydrocarbon chain of 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, more preferably methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl , isobutyl, tert-butyl. By "alkoxy" is meant any O-alkyl or O-aryl group. By "alkenyl" is meant any linear or branched hydrocarbon chain bearing at least one double bond, of 2 to 12 carbon atoms, preferably of 2 to 6 carbon atoms.

By "alkynyl" is meant any linear or branched hydrocarbon chain bearing at least one triple bond, of 2 to 12 carbon atoms, preferably of 2 to 6 carbon atoms. By "amine" is meant any compound derived from ammonia NH 3 by substitution of one or more hydrogen atoms with an organic radical. By "functional group" is meant a submolecular structure comprising an assembly of atoms conferring reactivity specific to the molecule which contains it, for example an oxy, carbonyl, carboxy, sulphonyl group, etc.

By "nucleophile" is meant an acyclic or cyclic compound, the characteristic of which is to comprise at least one atom carrying a free doublet, charged or not. According to a preferred embodiment of the invention, the term "nucleophile" means an acyclic or cyclic compound, the characteristic of which is to include at least one carrier atom of a charged free doublet, preferably negatively charged. By "nucleophile that can be chiral" is meant a nucleophile carrying at least one asymmetric carbon.

By "electron-withdrawing group" is meant a functional group having the ability to attract electrons, especially if it is substituted by an aromatic group, for example a group of the type in particular NO2 or 502R or CN or halogen. By "heterocycle" is meant a 5- or 6-membered ring containing 1 to 2 heteroatoms selected from O, S, N, optionally substituted by alkyl. The invention will be better understood on reading the following examples, which illustrate, without limitation, the method according to the invention.

Examples All reactions are carried out under an inert atmosphere with anhydrous solvents (Gordon, J.A., Ford, R.A. The Chemist's Companion, Wiley J. and Sons, New York, 1972). THF is distilled using an anhydrous THF station GTS100 (Glass Technology). The alkyllithiens are periodically titrated with N-benzylbenzamide (Burchat, AF, Chong, JM Nielsen, NJ Organomet Chem, 1997, 542, 281) S-butyllithium (1.4 M in cyclohexane solution), n-butyllithium (1.6 M in solution in hexane), t-butyllithium (1.7 M in pentane solution) and phenyllithium (1.8M in solution in dibutylether) are marketed by Acros Chemicals and Aldrich Chemical Company. . The proton 1H nuclear magnetic resonance spectra (400 MHz or 200 MHz) and carbon 13C (50 MHz or 100.6 MHz) were made on a Bruker AC 400 or DPX 200. The chemical shifts δ are expressed in parts per million (ppm) Tetramethylsilane (TMS) is used as an internal reference when CDCl3 is used as the solvent. In the case of acetone-d6 and DMSO d6, chemical shifts are given relative to the solvent signal. The coupling constants are expressed in Hertz (Hz). The following abbreviations are used to describe the NMR spectra: s (singlet), d (doublet), dd (doublet split), t (triplet), q (quadruplet), m (multiplet), seven (septuplet). The mass spectra were recorded in chemical impact mode or field ionization mode on a high resolution spectrometer (GCT Premier Micromass HighResolution). The accuracy obtained for accurate mass measurements is 4 digits.

The elementary analyzes were carried out by the ICSN microanalysis center of Gif sur Yvette. The infrared spectra were recorded on a Nicolet® Avatar® 370 DTGS spectrometer. The melting points were measured on a Büchi Melting Point B-540 apparatus.

Example 1 - Preparation of 2-n-butyl-6-fluorobenzoic acid (3) n-Bu 3 To a solution of 2,6-difluorobenzoic acid (791 mg, 5 mmol) in anhydrous THF (30 mL) n-BuLi (6.9 mL, 11 mmol, 1.6 M hexane solution) is added at -78 ° C. The reaction mixture is stirred at this temperature for 2 h and then iodomethane (1.25 mL, 12 mmol) is added. The solution is hydrolysed at room temperature with water (20 mL) and the two phases are separated. The aqueous phase is washed with ethyl acetate (3 × 40 mL). The aqueous phase is then acidified to a pH of 1 and extracted with ethyl acetate (3x40 mL). The combined organic phases are dried over MgSO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (cyclohexane: ethyl acetate 95: 5) to give 2-butyl-6-fluorobenzoic acid (425 mg, 2.17 mmol, 43%) as an oil. yellow. Addition of iodomethane prior to hydrolysis does not alter the reaction. 1H NMR (400MHz, CDCl3) δ: 11.04 (bs, 1H), 7.35 (td, JHF = 5.7Hz, J = 8.0Hz, 1H, H5), 7.05 (d, J = 7.6Hz, 1H, H4) , 6.97 (dd, J = 8.2 Hz, JHF 9.6 Hz, 1H, H6), 2.81 (t, J = 7.8 Hz, 2H), 1.62 (m, 2H) 1.38 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 171.6, 160.3 (d, J = 253 Hz), 144.2 (d, J = 1.3 Hz), 131.9 (d, J = 9.2 Hz), 120.0 (d, J = 14.3 Hz) ), 125.5 (d, J = 3.2 Hz), 113.4 (d, J = 21.8 Hz), 33.5, 33.2, 22.5, 13.8. IR (ATR, cm-1): 2960, 2873, 2662, 2873, 1704, 1615, 1576, 1467, 1405, 1293, 1125, 805, 775. HRMS [M + NH4] + calculated for C11H17NO2F: 214.1243, measured: 214.1246.

Example 2 - Preparation of 2,6-di-sec-butylbenzoic acid (4) CO2H s-Bu-s-Bu 4 This compound is prepared from 2,6-difluorobenzoic acid (791 mg, 5 mmol) and s-BuLi (10.7 mL, 15.0 mmol, 1.4 M in cyclohexane solution) according to the procedure of Example 1. The reaction mixture is stirred at 0 ° C. for 4 h and then recovered and Recrystallized (cyclohexane / ethyl acetate) afforded 2,6-di-sec-butylbenzoic acid (650 mg, 2.77 mmol, 55%) as a white solid (mp 125-126 ° C. ). Addition of iodomethane prior to hydrolysis does not alter the reaction. 1H NMR (400 MHz, CDCl3) δ: 7.36 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 2.73 (sext, J = 7.0 Hz, 2H), 1.75-1.55 ( m, 4H), 1.27 (dd, J = 1.6 Hz, J = 6.8 Hz, 6H), 0.85 (t, J = 7.4 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ: 176.2, 143.2, 133.4, 129.5, 122.8, 38.7, 30.9, 22.0, 12.1. IR (ATR, cm-1): 2955, 2925, 2864, 1705, 1594, 1585, 1456, 1390, 1379, 1260, 1134, 1003, 908, 803, 764, 699, 609. HRMS [M + NH] + calcd for C15H26NO2: 252.1964, measured: 252.1963. Example 3 - Preparation of 3-fluorobiphenyl-2-carboxylic acid (10) This compound is prepared from 2,6-difluorobenzoic acid (474 mg, 3 mmol) and PhLi (4.55 mL, 6.6 mmol, 1.45 M in solution in di-n-butyl ether) according to the general procedure. The reaction mixture is stirred at -30 ° C for 2h. The compound is recovered and purified by chromatography column on silica gel (cyclohexane: ethyl acetate 95: 5 to 90:10) to obtain 3-fluorobiphenyl-2-carboxylic acid (185 mg, 0.856 mmol, 29% ) as a yellow solid (mp 122.5 - 125 ° C). 1H NMR (200 MHz, CDCl3) δ: 7.53-7.40 (m, 6H), 7.22-7.09 (m, 2H). 13C NMR (50 MHz, CDCl3) δ: 171.1, 159.8 (d, J = 252.6 Hz), 142.8 (d, J = 2.4 Hz), 139.0 (d, J = 2.3 Hz), 131.7 (d, J = 9.1 Hz). ), 128.5 (2 * C), 128.2 (2 * C), 128.1, 125.7 (d, J = 3.2 Hz), 120.3 (d, J = 15.7 Hz), 114.7 (d, J = 21.6 Hz). IR (ATR, cm-1): 2860, 2654, 1690, 1612, 1567, 1460, 1401, 1293, 1267, 1238, 1127, 1097, 897, 803, 771, 702, 549. HRMS [M] + calculated for C13H9FO2: 216.0587, measured: 216.0587.

Example 4 - Preparation of 3-fluoro-4-methoxybiphenyl-2-carboxylic acid acid To a solution of 1-bromo-4-methoxybenzene (2.057 g, 1.40 mL, 11 mmol) in anhydrous THF (20 mL) n-BuLi (7.9 mL, 11 mmol, 1.39M in hexanes solution) is added dropwise at -78 ° C. The reaction mixture is stirred at this temperature for 1 h, then warmed to -50 ° C and 2,6-difluorobenzoic acid (791 mg, 5 mmol) in solution in anhydrous THF is then added. The reaction mixture is warmed to -30 ° C and stirred at this temperature for 2h. The solution is hydrolysed at room temperature with water (25 mL) and the two phases are separated. The aqueous phase is washed with ethyl acetate (3 × 40 mL). The aqueous phase is then acidified to a pH of 1 and extracted with ethyl acetate (3x40 mL). The combined organic phases are dried over MgSO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (cyclohexane: ethyl acetate 95: 5 to 8: 2). 3-Fluoro-4-methoxy-biphenyl-2-carboxylic acid (803 mg, 3.26 mmol, 65%) is obtained as a colorless oil.

1H NMR (200 MHz, CDCl3) δ: 7.50-7.30 (m, 3H), 7.20-7.06 (m, 2H), 6.97-6.90 (m, 2H), 3.84 (s, 3H).

13C NMR (50 MHz, CDCl3) δ: 171.1, 159.8 (d, J = 252.1 Hz), 159.6, 142.4 (d, J = 2.5 Hz), 131.6 (d, J = 9.2 Hz), 131.4 (d, J = 2.4 Hz), 129.4 (2 ° C), 125.7 (d, J = 3.1 Hz), 120.3 (d, J = 15.7 Hz), 114.2 (d, J = 21.5 Hz), 114.0 (2 ° C), 55.2. IR (ATR, cm-1): 1703, 1698, 1610, 1514, 1462, 1455, 1288, 1236, 1178, 1094, 1029, 896, 806, 781, 692, 587. HRMS [M + H] + calculated for C14H12FO3: 247.0770, measured: 247.0780.

Claims (5)

REVENDICATIONS1. Process for the preparation of aromatic carboxylic acid derivatives by aromatic nucleophilic substitution, in which a difluorobenzoic acid or a salt thereof is reacted, said acid not being substituted by an electron-withdrawing group carrying a carboxyl function and only one, with a NuM reagent, in which Nu is a chiral nucleotide or not and M is a metal, said aromatic nucleophilic substitution reaction being carried out without a catalyst and without a step of protecting / deprotecting the acid function of said difluorobenzoic acid derivative, said reaction being selective in that it does not lead to the formation of ketones. 2. Method according to claim 1, characterized in that said difluorobenzoic acid is a compound of general formula (II) R5 R3 R4 in which - R1 is CO2H - R2 is a fluorine atom, - R3 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or an amine which may or may not be substituted by one or two alkyl groups or when R 6 is a fluorine atom, R 3 and R 4 may together form an aromatic or non-aromatic ring, or a heterocycle, optionally substituted, especially with a functional group, - at least one of R4 or R6 is a fluorine atom, it being understood that when R4 is a fluorine atom, R5 is a hydrogen atom and R6 is a hydrogen atom; hydrogen, a fluorine atom, an alkyl group, an alkoxy group, an aryl, or an amine substituted or unsubstituted by one or two alkyl groups or R5 and R6 together form an aromatic or non-aromatic ring, or an optionally substituted heterocycle , especially by a functional group, and o when R6 is an atom of fluorine, R4 is a hydrogen atom, a fluorine atom, an alkyl group, an alkoxy group, an aryl, or an amine substituted or unsubstituted with one or two alkyl groups; and R5 is a hydrogen atom or R4 and R5 together form an aromatic ring or not, or a heterocycle, optionally substituted, in particular with a functional group, or R3 and R4, may together form an aromatic ring or not, or a heterocycle, optionally substituted, in particular with a functional group, and R5 is a hydrogen atom, is brought into contact with said reagent of general formula NuM in which Nu is a nucleophile, and M is a metal, preferably Li, Mg , Zn, Cu or an organomagnesium MgX wherein X is a halogen atom or an alkoxy group, preferably OCH3r said aromatic nucleophilic substitution reaction being carried out without catalyst and without step of protection / deprotection of the acid function of the compound (II ), to obtain a compound of the general formula (I), which corresponds to the general formula (II) in which R2 and / or that of R4 or R6 which is a fluorine atom has been substituted by Nu. 3. Method according to one of claims 1 or 2, wherein NuM is such that M is Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy, and Nu is as described below: Nu Alkyl, preferably CH3 or C2H5 alkenyl, optionally substituted optionally substituted Alkynyl Aryl optionally substituted s-Bu t-Bu n-Bu 4-MeOC6H4 4-Me2NC6H4 δ. Wherein R is a hydrogen atom, an alkyl group, an alkoxy group, an aryl group, or an amine substituted or unsubstituted with a compound of formula (I), one or two Cl 2 alkyl groups, with the proviso that the reaction does not use as the base HMDS. Process according to any one of claims 1 to 3, wherein NuM is such that M is Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy and N is N (C1-6alkyl) 2, NH (C1-6alkyl), NEt2N (CH2CH2) 2NMe, NMeBn, NBn2, NMePh, NHt-Bu NPh2. 5. The process according to any one of claims 1 to 4, wherein NuM is such that M is Li, Mg, and Nu is as described below: Nu N) 1 / * N e / N * N * erss ^ Nude *