Abstract:
The present invention refers to a process for the preparation of 2-bromomethyl-6-methyl-benzoic acid (I) and derivatives thereof by selective bromination of 2,6-dimethylbenzoic acid (II) with sodium bromate and hydrobromic acid in the presence of light.

Description:
FIELD OF THE INVENTION  
         [0001]    The present invention refers to 2-bromomethyl-6-methyl-benzoic acid (I) and a process for the preparation thereof. Compound (I) is a useful intermediate for the synthesis of several products of medicinal interest, such as prostaglandins, antitumour agents and peroxisome proliferator-activated receptor ligands.  
                         
 
         STATE OF THE ART  
         [0002]    Derivatives of 2,6-dimethyl-benzoic acid (II) are useful building blocks for the synthesis of several products of medicinal interest.  
                         
 
           [0003]    Among them, 2-bromomethyl-6-methyl-benzoic acid methyl ester (IIIa), used for the preparation of peroxisome proliferator-activated receptor (PPAR) ligands, can be mentioned.  
                         
 
           [0004]    2-Bromomethyl-6-methyl-benzoic acid methyl ester is usually synthesised by bromination of 2,6-dimethyl-benzoic acid methyl ester (IVa), as reported in literature [WO0064888, WO0064876, Chem. Ber. (1777), 110(4), 1403-20 and DE 2442069].  
                         
 
           [0005]    The reaction disclosed in WO064876 is carried out in carbon tetrachloride and the reagents are N-bromo-succinimide and benzoyl peroxide. Despite purification by flash chromatography, the product is obtained with 85% purity, the remainder being unreacted 2,6-dimethyl-benzoic acid methyl ester.  
           [0006]    Another drawback of this method is that if the desired final product contains the carboxylate in the free form or an ester other than the methyl one, 2-bromomethyl-6-methyl-benzoic acid methyl ester (IIIa) must undergo hydrolysis and/or esterification. This problem can be better understood when considering the synthesis of 7-methyl-3H-isobenzofuranone (V), which is also present in compounds of biological interest.  
                         
 
           [0007]    Compound (V) is synthesised by reduction of 3-methyl-phthalic acid anhydride with sodium borohydride, L-Selectride and lithium trialkyl borohydride. A convenient alternative route would be represented by the ring-closure of compound (I).  
           [0008]    It would be therefore useful to provide a method that allows the bromination of 2,6-dimethyl benzoic acid and that affords 2-bromomethyl-6-methyl-benzoic acid (I) in high yield and purity.  
           [0009]    The benzylic bromination usually occurs using a bromine source such as N-bromo-hydantoine and N-bromo-succinimide, in the presence of a catalyst and light either at room or higher temperature.  
           [0010]    These conditions allow very low selectivity towards monobrominated compounds. In fact, the monobromo derivative that forms is exposed to a bromine source and can further react giving a mixture of polybrominated derivatives, which is very difficult to purify.  
         DESCRIPTION OF THE INVENTION  
         [0011]    It has now been found that the reaction of 2,6-dimethyl-benzoic acid (II) with sodium bromate and hydrobromic acid in the presence of light gives 2-bromomethyl-6-methyl benzoic acid (I) in high yield and purity.  
           [0012]    In particular, the process of the invention provides the following advantages:  
           [0013]    1. Bromine is generated in situ at low temperature and during the reaction the brominating agent is never present in an excess;  
           [0014]    2. Compound (I) crystallizes out while compound (II) remains in solution, which strongly decreases polybromination.  
           [0015]    According to the present invention, 2,6-dimethyl-benzoic acid is dissolved in an organic halogenated solvent, preferably selected from the group consisting of methylene chloride, dichloroethane, chloroform, more preferably methylene chloride, and added to a sodium bromate aqueous solution. The molar ratio of 2,6-dimethylbenzoic acid to sodium bromate ranges from 3:0.8 to 3:1.2 and is preferably 3:1.  
           [0016]    The mixture is cooled down to 0-10° C., preferably to 5° C., then added with a solution of hydrobromic acid in equimolar amount in respect of 2,6-dimethyl benzoic acid and in the presence of light, preferably in the presence of a light source with a wavelength ranging from 200 to 750 nm. The exposure to the light is critical to obtain high yield and selectivity. Experiments performed in the dark failed.  
           [0017]    2-Bromomethyl-6-methyl benzoic acid (I) crystallizes out from the mixture; this represents a further advantage of the present invention, because the product can be easily isolated by filtration without troublesome working up.  
           [0018]    Compound (I) is usually obtained with high purity, i.e. free from 2,6-dibromomethyl benzoic acid. Small amounts of lactone (V) may be present, but this is not a drawback, since compound (I) is usually a synthon of compound (V) or of other products whose preparation involves ring opening of compound (V).  
           [0019]    Compound (V) is typically obtained from compound (I) by treatment with equimolar amounts of an organic base selected from tertiary amines or weak inorganic bases, preferably N-ethyl-diisopropylamine or sodium bicarbonate.  
           [0020]    Compound (I) can be conveniently used for the preparation of esters of general formula (III)  
                         
 
           [0021]    wherein R represents  
           [0022]    a straight or branched alkyl chain, preferably a C 1 -C 4  straight or branched alkyl chain.  
           [0023]    Compounds of formula (III) can be prepared, according to conventional methods well known to the skilled person, by reacting compound (I) or a reactive form thereof with an alcohol ROH wherein R is as defined above.  
           [0024]    Preferred are compounds of formula (III) wherein R is methyl or ethyl (methyl- and ethyl-esters IIIa and IIIb), prepared via derivatisation of compound (I) with thionyl chloride in the presence of N,N-dimethyl formamide followed by solvolysis with methanol and ethanol, respectively.  
           [0025]    The present invention will be described in greater detail in the following examples. 
       
    
    
     EXAMPLES  
     Example  
       [0026]    2-bromomethyl-6-methyl-benzoic Acid (I)  
         [0027]    A solution of sodium bromate (16.6 g; 0.11 mol) in water (85 ml) was added to a stirred solution of 2,6-dimethyl-benzoic acid (50 g; 0.33 mol) in methylene chloride (200 ml).  
         [0028]    The mixture was then cooled and exposed to the sunlight while a 48% solution of hydrobromic acid (38 ml; 0.33 mol) and water (38 ml) was added dropwise in 5 hours keeping the temperature below 5° C.  
         [0029]    During the addition a white solid crystallized out and the mixture was kept for further 4 hours under stirring.  
         [0030]    The white solid was filtered, washed with water (50 ml) and methylene chloride (30 ml).  
         [0031]    The wet cake was then slurried in methylene chloride (38 ml), filtered and dried overnight under vacuum at room temperature yielding 22 g of 6-methyl-2-bromomethyl-benzoic acid.  
         [0032]    [0032] 1 H-N.M.R. (CDCl 3 ) δ2.55 (s, CH 3 —Ar, 3H); 4.74 (s, CH 2 —Br, 2H); 7.3 (m, Ar, 3H).  
         [0033]    I.R. (KBr) 1690 cm 31 1  (C═O); 2800-2900 cm −1  (O—H).  
       Example 2  
       [0034]    2-bromomethyl-6-methyl-benzoic Acid Methyl Ester (IIIa)  
         [0035]    A solution of 2-bromomethyl-6-methyl benzoic acid (6 g; 0.026 mol) in methylene chloride (ml 60) was added dropwise to a stirred solution of thionyl chloride (3.8 ml; 0.052 mol) and N,N-dimethyl formamide (6 ml) in methylene chloride, cooled at 0° C.  
         [0036]    The mixture was stirred for 30 minutes, then added to a cooled solution of methanol in methylene chloride.  
         [0037]    Water was then added and the organic phase was separated.  
         [0038]    The solvent was evaporated off under vacuum with moderate heating.  
         [0039]    Cyclohexane (50 ml) was added to the crude product and washed with water (25×3 ml) and once with brine; the organic phase was dried over Na 2 SO 4 , filtered and the solvent was evaporated off under vacuum yielding 5 g of 2-bromomethyl-6-methyl-benzoic acid methyl ester, which was stored in the refrigerator.  
         [0040]    [0040] 1 H-N.M.R. (CDCl 3 ) δ 2.37 (s, CH 3 —Ar, 3H); 3.98 (s, COOCH 3 , 3H); 4.57 (s, CH 2 —Br, 2H); 7.25 (m, Ar, 3H) I.R. (CCl 4 ) 1732 cm −1  (C═O); 1277 cm −1  (C—O).  
       Example 3  
       [0041]    2-bromomethyl-6-methyl-benzoic Acid Ethyl Ester (IIIb)  
         [0042]    A solution of 2-bromomethyl-6-methyl-benzoic acid (5 g; 0.022 mol) in methylene chloride (55 ml) was added dropwise to a stirred solution of thionyl chloride (3.2 ml; 0.044 mol) and N,N-dimethyl formamide (5 ml) in methylene chloride, cooled at 0° C.  
         [0043]    The mixture was stirred for 30 minutes, then added to a cooled solution of ethanol in methylene chloride.  
         [0044]    Water was added and the organic phase was separated.  
         [0045]    The solvent was evaporated off under vacuum with moderate heating.  
         [0046]    Cyclohexane (40 ml) was added to the crude product and washed with water (25×3 ml) and once with brine; the organic phase was dried over Na 2 SO 4 , filtered and the solvent was evaporated off yielding 4 g of 2-bromomethyl-6-methyl-benzoic acid ethyl ester, which was stored in the refrigerator.  
         [0047]    [0047] 1 H-N.M.R. (CDCl 3 ) δ 1.44 (t, CH 3 —CH 2 , 3H, J=2H z ); 2.38 (s, CH 3 —Ar, 3H); 4.47 (q, CH 2 —CH 3 , 2H, J=2H z ); 4.58 (s, CH 2 —Br, 2H); 7.25 (m, Ar, 3H). I.R. (CCI 4 ) 1728 cm 31 1  (C═O); 1274 cm 31 1  (C—O).  
       Example 4  
       [0048]    7-methyl-3H-isobenzofuran-1-one (V)  
         [0049]    Method 1  
         [0050]    N-ethyldiisopropylamine (4.48 ml; 0.026 mol) was added dropwise to a stirred solution of 2-bromomethyl-6-methyl-benzoic acid (6 g; 0.026 mol) in methylene chloride (60 ml), cooled with an ice bath.  
         [0051]    The solution was kept 1 hour under stirring at room temperature then water was added (50 ml) and the mixture was acidified with hydrochloric acid 37% to pH=4.0.  
         [0052]    The organic phase was separated, washed with water (50 ml), dried over Na 2 SO 4 , and filtered. Methylene chloride was evaporated off under vacuum yielding g 3.8 of a white solid.  
         [0053]    [0053] 1 H-N.M.R. (CDCl 3 ) δ2.73 (s, CH 3 —Ar, 3H); 5.26 (s, CH 2 —O, 2H); 7.28 (m, Ar, 2H); 7.54 (m, Ar, 1H).  
         [0054]    I.R. (KBr) 1750 cm 31 1  (C═O).  
         [0055]    Method 2  
         [0056]    [0056] 2 -bromomethyl-6-methyl-benzoic acid (10 g; 0.044 mol) was added portionwise to a stirred solution of sodium bicarbonate (3.7 g; 0.044 mol) at room temperature. After 1 hour at room temperature the white solid was filtered, washed with water and dried under vacuum yielding 5 g of compound (V).  
         [0057]    [0057] 1 H-N.M.R. (CDCl 3 ) δ2.73 (s, CH 3 —Ar, 3H); 5.26 (s, CH 2 —O, 2H); 7.28 (m, Ar, 2H); 7.54 (m, Ar, 1H).  
         [0058]    I.R. (KBr) 1750 cm 31 1  (C═O).