Abstract:
Process for the industrial synthesis of compounds of formula (I):  
                         
 
     wherein R and R′ which are the same or different, each represent linear or branched (C 1 -C 6 )alkyl.  
     Application to the synthesis of bivalent salts of ranelic acid and more especially strontium ranelate and its hydrates.

Description:
[0001]    The present invention relates to a process for the industrial synthesis of tetraesters of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid and to the application thereof in the industrial production of bivalent salts of ranelic acid and their hydrates.  
           [0002]    More specifically, the present invention relates to a new process for the industrial synthesis of compounds of formula (I):  
                         
 
           [0003]    wherein R and R′ which are the same or different, each represent a linear or branched (C 1 -C 6 )alkyl group.  
           [0004]    The compounds of formula (I) obtained according to the process of the invention are useful in the synthesis of ranelic acid, its strontium, calcium or magnesium salts of formula (II):  
                         
 
           [0005]    wherein M represents strontium, calcium or magnesium,  
           [0006]    and hydrates of the said salts.  
         BACKGROUND OF THE INVENTION  
         [0007]    The bivalent salts of ranelic acid have very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties, making these compounds useful in the treatment of bone diseases.  
         DESCRIPTION OF THE PRIOR ART  
         [0008]    The bivalent salts of ranelic acid, and more especially strontium ranelate, the preparation thereof and the therapeutic use thereof have been described in the European Patent Specification EP 0 415 850.  
           [0009]    In view of the pharmaceutical interest of that compound, it has been important to be able to synthesise the intermediate of formula (I) by using an effective industrial synthesis process, allowing the compound of formula (I) to be obtained in a good yield and with excellent purity, but which is also readily transferable to the industrial scale.  
           [0010]    The journal Bull. Soc. Chim. France 1975, pp. 1786-1792, describes obtaining a compound of formula (I) (R═R′ =ethyl) by reacting 5-amino-3-(carboxymethyl)-4-cyano-2-thiophenecarboxylic acid with ethyl bromoacetate, in the presence of potassium carbonate, followed by isolation in a highly dilute aqueous-organic medium.  
           [0011]    However, the low yield of that reaction (65%), the large amount of aqueous saline waste generated by that reaction and, above all, the very long reaction time (5 days) have completely precluded use of that reaction on an industrial scale.  
           [0012]    The Applicant has now developed a simple industrial synthesis process which allows the compound of formula (I) to be obtained in a very good yield, with a considerably shorter reaction time and excellent purity and in which the aqueous saline waste is completely avoided.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0013]    More specifically, the present invention relates to a process for the industrial synthesis of compounds of formula (I),  
           [0014]    which process is characterised in that a compound of formula (III):  
                         
 
           [0015]    wherein R represents a linear or branched (C 1 -C 6 )alkyl group,  
           [0016]    is reacted with a compound of formula (IV):  
                         
 
           [0017]    wherein R′ represents a linear or branched (C 1 -C 6 )alkyl group,  
           [0018]    in the presence of a catalytic amount of a C 8 -C 10 -type quaternary ammonium compound,  
           [0019]    and in the presence of potassium carbonate,  
           [0020]    at the reflux of an organic solvent;  
           [0021]    the reaction mixture is subsequently filtered;  
           [0022]    the mixture is then concentrated by distillation;  
           [0023]    a co-solvent is then added,  
           [0024]    and the reaction mixture is cooled and filtered  
           [0025]    to yield, after drying of the powder thereby obtained, the compound of formula (I).  
           [0026]    A C 8 -C 10 -type quaternary ammonium compound is understood to be a compound of formula (A) or a mixture of compounds of formula (A):  
           R 1 R 2 R 3 R 4 —N +− X  (A)  
           [0027]    wherein R 1  represents a (C 1 -C 6 )alkyl group, R 2 , R 3  and R 4 , which are the same or different, each represent a (C 8 -C 10 )alkyl group, and X represents a halogen atom. C 8 -C 10 -type quaternary ammonium compounds to which preference is given are the catalysts Adogen 464® and Aliquat 336®.  
           [0028]    Surprisingly, only the use of a C 8 -C 10 -type quaternary ammonium compound allows the compound of formula (I) to be obtained both with a greatly reduced reaction time and with very good selectivity, in contrast to other types of quaternary ammoniums, as the following Table shows:  
                                           Duration   Content of reaction       Catalyst   of reaction   mixture                   Tetrabutylammonium hydrogen sulphate   12 hours   92%       (TBAHS)       N,N-bis(2-hydroxyethyl)-N-methyl   18 hours   82%       1-dodecanaminium bromide       Adogen 464 ®    5 hours   96%       Aliquat 336 ®    4 hours   95%                  
 
           [0029]    Furthermore, the somewhat simplified isolation (the precipitation step followed by filtration has been replaced by simple filtration of the reaction mixture) allows, by virtue of the particular conditions developed, the compound of formula (I) to be obtained not only in a very good yield (89%) but also with excellent purity (greater than 98%), whilst avoiding the burden on the environment that the aqueous saline waste represented.  
           [0030]    The amount of potassium carbonate is preferably from 2 to 3 mol per mol of compound of formula (III).  
           [0031]    The amount of compound of formula (IV) is preferably from 2 to 3 mol per mol of compound of formula (III).  
           [0032]    The initial volume of organic solvent is preferably from 6 to 12 ml per gram of compound of formula (III).  
           [0033]    Organic solvents that are preferred for the reaction are acetone and acetonitrile.  
           [0034]    A co-solvent that is preferred for isolation is methanol.  
           [0035]    Methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate and methyl 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate, particular and preferred cases of the compounds of formula (I), are new compounds which are useful as synthesis intermediates in the chemical or pharmaceutical industry, especially in the synthesis of strontium ranelate and accordingly form an integral part of the present invention.  
           [0036]    The Examples hereinbelow illustrate the invention but do not limit it in any way. 
       
    
    
     EXAMPLE 1  
     Methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate  
       [0037]    Introduce into a reactor 400 kg of 5-amino-3-(carboxymethyl)-4-cyano-2-thiophenecarboxylic acid, 478 kg of potassium carbonate, 2810 litres of acetone, 16 kg of Adogen 464% and 529.6 kg of methyl bromoacetate.  
         [0038]    Bring the temperature to 60° C. After refluxing for 5 hours, cool the reaction mixture and then filter it. Concentrate the filtrate obtained.  
         [0039]    Add methanol; cool and filter the suspension obtained, and then dry the powder.  
         [0040]    Methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate is thereby obtained in a yield greater than 85% and with a chemical purity greater than 98%.  
       EXAMPLE 2  
     Methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate  
       [0041]    Methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate is obtained in the same manner as Example 1, but replacing Adogen 464® by Aliquat 336®.  
       EXAMPLE 3  
     Methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate  
       [0042]    Methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate is obtained in the same manner as Example 1, but replacing the acetone by acetonitrile.  
       EXAMPLE 4  
     Methyl 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate  
       [0043]    Methyl 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate is obtained in the same manner as Example 1, but replacing the 529.6 kg of methyl bromoacetate by 578.1 kg of ethyl bromoacetate.