HK1096661B - An intermediate for the industrial synthesis of substituted thiophenecarboxylate - Google Patents

Description

Intermediates in the industrial synthesis of substituted thiophenecarboxylates

the invention relates to a method for the industrial synthesis of the methyl diester of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid and to the use of said compound for the industrial production of the divalent salts of ranelic acid (ranelic acid) and its hydrates.

More particularly, the present invention relates to a novel process for the industrial synthesis of compounds of formula (I):

the compounds of formula (I) obtained according to the process of the invention can be used for the synthesis of raney acids, their strontium, calcium or magnesium salts of formula (II):

wherein M represents strontium, calcium or magnesium,

and hydrates of the salts.

The divalent salts of raney acid have very valuable pharmacological and therapeutic properties, especially significant anti-osteoporosis properties, making these compounds useful in the treatment of bone diseases.

The divalent salts of raney acid, more particularly strontium raney acid, their preparation and their therapeutic use are disclosed in european patent specification EP 0415850.

This patent specification describes the synthesis of strontium ranelate starting from ethyl tetraesters of formula (III):

the compounds of formula (III) are themselves obtainable starting from the ethyl diester of formula (IV):

the synthesis of intermediates of formula (IV) has been described in the publications Bull. Soc. Chim.France 1975, pp1786-1792 and J.chem.Tech.Biotechnol.1990,47pp.39-46, which are obtained by reacting diethyl 3-oxoglutarate, malononitrile and sulfur with one another in ethanol in the presence of morpholine or diethylamine.

The method has the advantages of using easily available raw materials and being simple to practice; however, when applied on a scale of several hundred kg, the compounds of formula (IV) cannot be obtained with a conversion of more than 70%.

In view of the pharmaceutical value and the production tonnage of strontium ranelate, it is important to be able to synthesize diesters of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid in excellent purity and at least 77% yield, and this is reproducible on an industrial scale.

The applicant has now developed an efficient industrial synthesis process which enables the methyl diester of formula (I) to be obtained in a yield of at least 77% and a purity of more than 97%.

The compounds of formula (I) thus obtained are particularly useful for the synthesis of raney acids, their strontium, calcium or magnesium salts and hydrates of said salts, more particularly strontium raney acid and hydrates thereof, wherein a compound of formula (I) is reacted with an ester of bromoacetic acid to give the corresponding tetraester which is then converted into raney acid or its strontium, calcium or magnesium salts.

More particularly, the present invention relates to a process for the industrial synthesis of compounds of formula (I),

the process is characterized in that dimethyl 3-oxoglutarate of formula (V):

with malononitrile of formula (VI):

in the presence of methanol, the reaction mixture is,

in the presence of more than 0.95mol/mol of morpholine of the compound of formula (V),

to give a compound of formula (VII):

then reacting the compound of formula (VII) with more than 0.95mol/mol of sulphur of the compound of formula (V);

the reaction mixture is then heated to reflux;

and isolating the compound of formula (I) thus obtained by precipitation in the presence of water and subsequent filtration.

The process, improved by using these very specific conditions and in particular by the intermediate formation of the compound of formula (VII), which can be isolated if desired, thus allows the compound of formula (I) to be obtained in excellent purity and in yields of at least 77%, and this is reproducible on a scale of several hundred kg, which greatly increases the yield due to the large production tonnage of strontium ranelate.

The amount of methanol is preferably from 1 to 3ml/g of compound of formula (V).

The temperature of the reaction between the compounds of formula (V) and (VI) is preferably less than 50 ℃.

The reflux reaction time after the addition of sulfur is preferably 1 hour 30 minutes to 3 hours.

The methyl 5-amino-4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylate of formula (I) and the intermediates of formula (VII) are novel compounds which can be used as synthesis intermediates in the chemical or pharmaceutical industry, in particular in the synthesis of strontium ranelate, and thus form an integral part of the present invention.

The invention therefore also relates to a process for the synthesis of raney acids, their strontium, calcium or magnesium salts and hydrates of said salts, starting from a compound of formula (I):

reacting a compound of formula (I) with an ester of bromoacetic acid to give the corresponding tetraester, which tetraester is then converted into raney acid or a strontium, calcium or magnesium salt thereof, characterized in that the compound of formula (I) is obtained by the process of the present invention for the synthesis of a compound of formula (I). The invention furthermore relates, inter alia, to a process for the synthesis of strontium ranelate and its hydrates, starting from compounds of formula (I):

the process for the synthesis of strontium ranelate is characterized in that a compound of formula (I) is obtained by the process of the invention for the synthesis of a compound of formula (I).

The examples which follow illustrate the invention, but do not limit it in any way.

Example 1: 5-amino-4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylic acid methyl ester

400kg of dimethyl 3-oxoglutarate, 158kg of malononitrile and 560 l of methanol were charged into the reactor, and 199.6kg of morpholine were then added while the temperature of the reaction mixture was kept below 40 ℃.

Then 73.6kg of sulfur was added and the resulting mixture was refluxed.

After 2 hours of reaction, the reflux was stopped and water was added until precipitation occurred. The resulting precipitate was filtered off, washed and dried.

This gave methyl 5-amino-4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylate in 77% yield and 98% chemical purity.

Example 2: 5-amino-4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylic acid methyl ester

400kg of dimethyl 3-oxoglutarate, 158kg of malononitrile and 560 l of methanol were charged into the reactor, and 199.6kg of morpholine were then added while the temperature of the reaction mixture was kept below 40 ℃.

After cooling the resulting mixture, the thus obtained compound of formula (VII) or the addition salt of methyl 3- (dicyanomethylene) -5-hydroxy-5-methoxy-4-pentenoate with morpholine was isolated by filtration and then reacted with 73.6kg of sulfur in methanol.

The resulting mixture was then refluxed.

After 2 hours of reaction, the reflux was stopped and water was added until precipitation occurred. The resulting precipitate was filtered off, washed and dried.

Claims (1)

1. A compound of formula (VII):