Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
  • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
  • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form

Definitions

• the present invention relates to the field of chemical synthesis, and in particular the invention provides a novel process for performing aromatic nucleophilic substitution on aromatic carboxylic acid derivatives, in the absence of a catalyst, especially in view of not exclusively, to form biaryles, symmetrical or asymmetrical.
• Aromatic nucleophilic substitution is a very commonly used chemical reaction, in which an atom attached to an aromatic ring is substituted with a nucleophilic group. It makes it possible to prepare a wide variety of aromatic compounds, especially pharmaceutical active ingredients, for example biphenyls.
• the aromatic nucleophilic substitution practiced at the industrial level is most often carried out in the presence of catalysts involving precious metals, in particular palladium.
• pharmaceutical regulations have considerably hardened in recent years to force the pharmaceutical industry to eliminate the maximum traces of these precious metals in the finished pharmaceutical active ingredients.
• EMEA European Agency for the Evaluation of Medicinal Products
• the synthetic scheme of the active ingredient requires the use of a precious metal at the end of synthesis and the standards of metal content allowed for this active ingredient are exceeded, it is necessary to find methods of elimination, which is expensive in time and money.
• C0 2 H carboxyl function
• C0 2 H function reacts with organometallic compounds to yield ketone derivatives (Jorgenson, MJ Org React 1970, 18, 1. Ahn, T., Cohen, T. Tetrahedron Lett., 1994 , 35, 203).
• the most used protecting group is the oxazoline function, and the reaction is known as the Meyers reaction (Meyers et al., Tetrahedron 2004, 60 (20), 4459).
• the carboxyl function is protected beforehand (1 ⁇ 2, scheme 1).
• the aryloxazoline 2 thus obtained is capable of promoting the displacement of ortho-alkoxy and fluoro groups by nucleophiles ("Nu") (2 ⁇ 3, Scheme 1).
• a deprotection step of 3 must then be carried out in order to release the C0 2 H function and obtain the expected compound 4.
• the oxazoline may be chiral and the reaction with aryllithians or magnesians leads to optically active biaryls.
• the reaction of Meyers is of great industrial interest, in particular for obtaining these optically active biaryls, but imposes to carry out these steps of protection / deprotection. Moreover, the Meyers reaction does not make it possible to treat compounds containing a C6 substituent other than hydrogen: these compounds are completely inert to the hydrolysis of the protected carboxyl group and do not lead to 4.
• the invention proposes a new process which allows the aromatic nucleophilic substitution, on an industrial scale and with a high yield, in an optimized number of stages.
• the invention has the industrial advantage of not requiring the use of metal catalyst and thus avoids all the current steps of purification / disposal of precious metals, including palladium type. It also has the advantage of not generating the generation of polluting residues.
• the invention has another advantage, which is not to require a protection / deprotection step, for starting compounds having a carboxyl function, for example but not exclusively benzoic acids, naphthoic acids and derivatives.
• the process according to the invention is a one-step process.
• 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.
• 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 or 4, 5 or 6 carbon atoms, in particular methyl, ethyl, propyl, butyl, an alkoxy group or a halogen atom, especially bromine, chlorine and iodine.
• 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.
• protecting the carboxyl function is meant adding 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 C0 2 H function: 2,6-di-tert-butyl-4-methoxyphenyl ester (Hattori, T. Satoh, T. Miyano, S. Synthesis 1996, 514. Koshiishi, E. ; Hattori, T .; Ichihara,. ; Miyano, SJ Chem. Soc, Perkin Trans.
• leaving group is meant a group which takes the two electrons of the sigma bond connecting it with the aromatic carbon atom during the substitution reaction by the nucleophile; according to the invention, the leaving group may be chiral or non-chiral; according to a preferred embodiment of the invention, the leaving group is chiral; according to the invention, the leaving group may be electroattractant or non-electroattractant.
• alkyl 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.
• alkoxy is meant any O-alkyl or O-aryl group, chiral or not.
• 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.
• 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.
• amine means any compound derived from NH 3 ammonia by substitution of one or more hydrogen atoms with an organic radical. According to the invention, a preferred amine is an aniline derivative.
• “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, etc. group.
• 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.
• 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.
• nucleophile that can be chiral is meant a nucleophile carrying at least one asymmetric carbon.
• electrostatic group is meant a functional group having the capacity to attract electrons, especially if it is substituted by an aromatic group, for example a group of the type in particular N0 2 or S0 2 R, where R is an alkyl, or CN or halogen. Amines and alkoxy are not electron-withdrawing groups.
• heterocycle is meant a 5- or 6-membered ring containing 1 to 2 heteroatoms selected from O, S, N, optionally substituted by alkyl.
• aniline derivative is meant a compound of the general formula
• 26 is a hydrogen atom, an alkyl group, an alkoxy group or an aryl
• R27, R28, R29, R30 and R31 are each independently a hydrogen atom, a halogen, an alkyl group, an aryl group, a heterocyclic group, a haloalkyl group, an alkoxy group, a nitro group, a cyano group, or - (0) m - (CH 2 ) n -R 32, or [N (H)] m - (CH 2 ) n -R 32, or two of these substituents linked to contiguous carbon atoms form an aryl ring, a ring heteroaryl, a heterocyclic group or a 4- to 7-membered cycloalkyl group,
• R26 and R27 may be involved, with the nitrogen atom to which R26 is bound and the contiguous carbon atom at this nitrogen atom, in a 5- or 6-membered aromatic or dihydroaromatic ring, with carbon atoms and 1 or 2 nitrogen atoms,
• R32 is a hydrogen atom, a hydroxy group, -C00H or a disubtituted amine.
• the alkylamines and dialkylamines are not derivatives of aniline.
• MNu is meant a reagent in which M is a metal and Nu is an independent nucleophile or aromatic ring substituent of the benzoic acid derivative of the general formula (II), said substituent being capable of - or carrying a functional group capable of reacting in the presence of a base and a metal to form MNu.
• Nu is a substitute of the aromatic ring of (II)
• the aromatic nucleophilic substitution reaction takes place intramolecularly between the MNu function formed on the substituent and the ortho leaving group of the carboxylic acid function.
• the subject of the invention is a process for the preparation of aromatic carboxylic acid derivatives, preferably of benzoic acids, by aromatic nucleophilic substitution, in which:
• said carboxylic acid derivative not being substituted: o by another electron-withdrawing group than the leaving group if appropriate,
• a para-substituted phenyl group in particular by a para-substituted benzyloxy-substituted phenyl, when the leaving group is a fluorine or a chlorine;
• MNu reagent in which M is a metal and Nu is a chiral nucleophile or not, said aromatic nucleophilic substitution reaction being carried out without a catalyst and without a step of protecting / deprotecting the acid function of the starting compound.
• the aromatic carboxylic acid derivative starting product of the reaction is a benzoic acid derivative of general formula (II)
• RI is C0 2 H
• R2 is a fluorine or chlorine atom or an alkoxy group, chiral or not, preferably OCH 3 .
• RI is a fluorine or chlorine atom or an alkoxy group, which may or may not be chiral, preferably OCH 3 and R 2 is C0 2 H
• R3 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl or an amine substituted or not by one or two alkyl groups, or R3 forms, with R4, an aromatic or non-aromatic ring, or an optionally substituted heterocycle, in particular by a functional group, or is a substituent being capable of reacting in the presence of a base and a metal to form MNu;
• R4 is a hydrogen atom, an alkyl group, an alkoxy group, preferably OCH 3, aryl or amino unsubstituted or substituted with one or two alkyl groups, or R 4 forms with R 3 an aromatic or nonaromatic ring or a heterocycle , optionally substituted, in particular by a functional group, or R4 forms a ring with R5 an aromatic ring or not, or a heterocycle, optionally substituted, in particular with a functional group, or is a substituent being capable of reacting in the presence of a base and a metal to form MNu; 5 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or an amine substituted or not by one or two alkyl groups, or R5 forms, with R4, an aromatic or non-aromatic ring, or an optionally substituted heterocycle, in particular by a functional group, or R5 forms with R6 an aromatic ring or not, or a heterocycle, optionally substituted, in particular
• R 6 is a hydrogen atom, an alkyl group, an alkoxy group, an aryl or an amine substituted or not by one or two alkyl groups, or R 6 forms, with R 5, an aromatic or non-aromatic ring, or an optionally substituted heterocycle, in particular by a functional group, or is a substituent being capable of reacting in the presence of a base and a metal to form MNu; which reacts with a compound (III) of general formula NuM wherein 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 a group alkoxy, which may or may not be chiral, preferably OCH 3 , 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 obtain a compound of the general formula (I), which corresponds to the general formula (I
• the reaction is carried out at -78 ° C. and the reflux of the solvent.
• the reaction is carried out in an aprotic polar solvent, preferably anhydrous THF (tetrahydrofuran), diethyl ether, benzene, toluene or a hydrocarbon such as pentane, hexane, heptane or the like. octane.
• the compound NuM is preferably added dropwise at a temperature of between -78 ° C. and the reflux of the solvent.
• the solution is stirred and then hydrolyzed with water.
• the hydrolysis is carried out at low temperature.
• 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.
• At least one equivalent of NuM is used for one equivalent of starting aromatic carboxylic acid derivative.
• one equivalent of NuM per group starting from the starting molecule to be substituted is added.
• At least one equivalent of a metal base is used to a starting aromatic carboxylic acid derivative equivalent to form the salt corresponding metal of the acid function of the aromatic carboxylic acid derivative, and at least one equivalent of NuM is added per leaving group of the starting molecule to be substituted.
• the starting compound is an aromatic carboxylic acid salt
• at least one equivalent of NuM is used for one equivalent of the starting aromatic acid derivative salt in order to form the corresponding metal salt of the acid function and at least one equivalent of NuM is added per group starting from the starting molecule to be substituted.
• the starting compound is an aromatic carboxylic acid salt
• at least one equivalent of a metal base preferably butyllithium, sodium hydride, potassium hydride or lithium hydride is used for one equivalent of the starting aromatic acid derivative salt in order to form the corresponding metal salt of the acid function, and at least one equivalent of NuM is added per group starting from the molecule of departure to be substituted.
• the expected yields for the reaction process according to the invention are between 40 and 100%, preferably 45 to 90%, more preferably 60 to 90%. Special cases
• R 1 is C0 2 H
• R 2 is alkoxy, preferably OCH 3
• R 3 to R 6 are as defined above.
• R 2 is C0 2 H
• R 1 is alkoxy, preferably OCH 3 and R 3 to R 6 are as defined above.
• in para of the acid function is a hydrogen atom.
• R1 is C0 2 H
• R4 is a hydrogen atom and R2, R3, R5 and R6 are as defined above.
• R2 is C0 2 H
• R5 is a hydrogen atom and R1, R3, R4 and R6 are as defined above.
• the compound of general formula (II) is such that RI is C0 2 H, R2 is a halogen atom, preferably fluorine or an alkoxy group, chiral or not , preferably methoxy, and R3 to R6 are as defined above and are each preferably a hydrogen atom.
• the compound of general formula (II) is such that R 1 is C0 2 H, R 2 is a halogen atom, preferably fluorine, or an alkoxy group, chiral or not, preferably methoxy, R3 and R4, or R4 and R5, or R5 and R6 together form an optionally substituted ring, such that the starting aromatic carboxylic acid derivative is a naphthalene derivative having the general formulas (Ha , Ilb or Ile) below, wherein R7, R8, R9 and R10 are each independently hydrogen, alkyl, alkoxy, aryl, or an amine substituted or unsubstituted by one or two alkyl groups ; and the substituents R3, R4, R5 and R6 not involved in the ring are as defined above.
• MNu is not sBuLi or tBu-Li or PhLi.
• MNu when the leaving group is a methoxy, MNu is not soluble.
• an asymmetric carbon is present on said aromatic carboxylic acid derivative product starting from the reaction, preferably on said benzoic acid derivative of general formula (II) and / or on the nucleophile, and the compound of general formula (I) obtained is asymmetrical.
• the aromatic acid derivative, preferably said benzoic acid derivative of the general formula (II) carries at least one chiral leaving group.
• an asymmetric carbon is present on the starting group of the aromatic carboxylic acid derivative and / or on the nucleophile, and the compound of general formula (I) obtained is asymmetrical.
• reaction medium is supplemented with a chiral ligand; this ligand has the function of providing chirality to the product (I) of the reaction of the invention.
• said chiral ligand may be selected from chiral diamines, chiral diethers, chiral aminoethers, chiral multidentate aminoethers and bisazoline ligands. Examples of chiral ligands that can be used are given in Table 1.
• Nu when in ortho of the acidic function is a fluorine or chlorine atom, Nu is not a substituted amine or not, in particular Nu is not an aniline derivative, more particularly Nu is not 4- [2- (3,4-dichlorophenyl) ethyl] aniline.
• Nu when in ortho of the acidic function is a fluorine atom, Nu is not a substituted amine or not.
• the compound (II) is such that the leaving group (R1 or R2) is a fluorine or chlorine atom, and the nucleophile of the compound of general formula NuM is an aniline derivative .
• the NuM compound is obtained according to the synthesis modes described below, it being understood that NuM is not the product of a reaction of the nucleophile and a base metal selected from lithium hydride, sodium hydride, potassium hydride, calcium hydride, lithium diisopropylamide, lithium amide, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, magnesium ethoxide, LiHMDS.
• the NuM compound is obtained by reaction of the nucleophile and butyllithium.
• 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).
• the NuM compound can be obtained from lithium salts and anion radicals (T.
• the compound NuM can be obtained by metal-halogen exchange: Parham, W. E .; Bradcher, C. K. Acc. Chem. Res. 1982, 15, 300-305.
• the compound NuM can be obtained by directed metallation (V. Sneckius, Chem Rev, 1990, 90, 879, JOC 1989, 54, 4372.
• the NuM compound is obtained by reaction of the nucleophile and a base, in particular a metal or organometallic base,
• the base is not LiHMDS or a mixture of lithium hydride and diethoxyethane.
• the metal base is not selected from the group consisting of lithium hydride, hydride sodium, potassium hydride, calcium hydride, lithium diisopropylamide, lithium amide, sodium amide, potassium amide, sodium methoxide, sodium ethoxide, tert.
• the base is butyllithium, and in this embodiment, advantageously, the NuM compound is obtained by reaction of the nucleophile and n-BuLi, tert-BuLi or sec-BuLi.
• the base is chiral, and brings chirality to NuM.
• Nu is a nucleophile selected from those described in Tables 2,3 and 4.
• NEt 2 Li Mg, Cu, Zn, or MgX where X is a
• NMeBn Li Mg, Cu, Zn, or MgX where X is a
• NBn 2 Li Mg, Cu, Zn, or MgX where X is a
• NMePh Li Mg, Cu, Zn, or MgX where X is a
• NPh 2 Li Mg, Cu, Zn, or MgX where X is a
• M is Li or Mg.
• M is Li, Mg, Cu, Zn, or MgX where X is halogen or alkoxy and N is N (C 1-6 alkyl) 2 , NH (C 1-6 alkyl), NEt 2 , N (CH 2 CH 2 ) 2 NMe, NMeBn, NBn 2 , NMePh, NHt-Bu or NPh 2 .
• the halogen is chosen from F, Br, Cl.
• M is MgX with X is an alkoxy
• the alkoxy is OCH 3 OR OC 2 H 5 .
• M is MgBr or MgOCH 3 .
• Preferred chiral NuM compounds according to the invention are exemplified below:
• each unsubstituted position of an aromatic ring of one of Tables 2 to 4 may be substituted by a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or an amine substituted or not by one or two Cl-12alkyl groups.
• the compound of formula (I) obtained makes it possible to subsequently obtain a benzo [c] phenantridine.
• benzo [c] phenanthridine obtainable by a reaction involving in particular an aromatic nucleophilic substitution are given in Table 5 below: benzo [c] phenanthridine benzo [c] [1, 7] phenanthroline benzo [c] [1, 8] phenanthroline benzo [c] [1, 9] phenanthroline
• the substituents R20, R21, R22, R23, R24 and R25 are each independently a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or a substituted or unsubstituted amine. by one or two CI_ i 2 alkyl groups.
• the compound of formula (I) obtained makes it possible subsequently to obtain fagorinin or ethoxidine, the formulas of which are given in Table 6.
• the reaction including implementing an aromatic nucleophilic substitution and resulting in these compounds is of the following form:
• M is Li or Mg
• R20, R21, R22, R23, R24 and R25 are each independently a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or a substituted amine. or not by one or two alkyl groups Ci_i 2.
• the process leads to a product of formula (I) which is benzo [c] phenanthridine, benzo [c] [1,7] phenanthroline, benzo [c] [1,8] ] phenantroline, benzo [c] [1,9] phenanthroline, benzo [c] [1,10] phenantroline, pyridazino [4,5-c] phenanthridine.
• formula (I) is benzo [c] phenanthridine, benzo [c] [1,7] phenanthroline, benzo [c] [1,8] ] phenantroline, benzo [c] [1,9] phenanthroline, benzo [c] [1,10] phenantroline, pyridazino [4,5-c] phenanthridine.
• M is Li or Mg
• R20, R21, R22, R23, R24 and R25 are each independently a hydrogen atom, an alkyl group, an alkoxy group, an aryl, or a substituted amine. or not by one or two alkyl groups Ci_i 2.
• the product of formula (I) is apogossypol, gossypol or a derivative of these compounds, obtained by reacting the following compound of formula (IId) with the following NuM:
• Ethylmagnesium bromide (3M in solution in diethyl ether) and vinylmagnesium bromide (1M in solution in THF) are marketed by Acros Chemicals and Aldrich Chemical Company.
• the amines are distilled on CaH 2 and stored under argon.
• Tetramethylsilane is used as an internal reference when CDCl 3 is used as a solvent.
• 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.
• Elemental analyzes were performed by the ICSN's microanalysis center - Gif sur Yvette. The infrared spectra were recorded on a Nicolet® Avatar® 370 DTGS spectrometer. Melting points were measured on a Buchi Melting Point B-540.
• amine primary or secondary, n mmol
• ⁇ -BuLi 1.6 M in hexane, n mmol
• the solution is stirred at 0 ° C for 30 min and then at room temperature for 1 h before use.
• the solution is stirred at 0 ° C for 30 min before use.
• the aqueous phase is extracted with ethyl acetate (3 * 50 mL).
• the residue is taken up in dichloromethane (300 mL) and stirred overnight. After filtration, the solution is dried over MgSO 4 and concentrated under reduced pressure. After recrystallization, acid 4 is isolated as a white solid (583 mg, 88% from 1 and 464 mg, 70% from 2).
• P f 211-215 ° C.
• the pH of the aqueous phase is adjusted to 1 by the addition of a solution of HCl (2M) and the aqueous phase is extracted with dichloromethane (3 * 50 mL). The combined organic phases are dried over MgSO 4 , filtered and concentrated under reduced pressure. After recrystallization (MeOH / H 2 O 6/4), the acid (5) is isolated as a white solid (617 mg, 85% from 1; 316 mg, 65% from 2) .
• the acid (8) is obtained in the form of a green solid (416 mg, 70% conversion).
• the pH of the aqueous phase is adjusted to 7 by the addition of a solution of HCl (2M) and the aqueous phase is extracted with dichloromethane (3 * 50 mL).
• the combined organic phases are dried over MgSO 4 and concentrated under reduced pressure.
• the crude product obtained is purified by chromatography on silica gel (dichloromethane / methanol eluent: 98/2 to 96/4) to yield 88 mg of acid 28.
• the combined organic phases are dried over MgSO 4 and concentrated under reduced pressure.
• 2- (N-methyl-N-phenyl) -6- (diethyl) benzoic acid To a solution of lithium diethylamide (5.5 mmol, prepared according to the general procedure in 20 mL of THF) at -30 ° C is added dropwise 2- (IV-methyl-IV-phenyl) acid. 6-fluorobenzoic acid (261 mg, 1.1 mmol) in solution in anhydrous THF (10 mL). The solution is stirred at -30 ° C for 1 h and then allowed to warm to room temperature overnight. The reaction medium is hydrolysed at room temperature with distilled water (20 mL) and the two phases are separated.
• the aqueous phase (AQ-1) is extracted with ethyl acetate (3 * 20 mL) and the combined organic phases (ORGA1) were dried over MgS0 4.
• the ORGA1 phase mainly corresponds to carboxylate derived from 2- (IV-methyl-IV-phenyl) -6- (diethyl) benzoic acid.
• the combined organic phases (ORGA2) were dried over MgS0 4. After recrystallization of the ORGA2 phase (ethyl acetate / cyclohexane), an additional 240 mg of 2- (IV-methyl-IV-phenyl) -6- (diethyl) benzoic acid are obtained, (overall yield: 320 mg, 98.0%). %).
• P f 149-150 ° C.
• 1-phenyl-naphthalene-2-carboxylic acid is obtained in the form of a pale yellow solid (600 mg, 80% from 1-fluoronaphthalene-2-carboxylic acid, 600 mg, 80% from 1-methoxynaphthalene-2-carboxylic acid).

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