HK1065791B - New process for the industrial synthesis of strontium ranelate and its hydrates - Google Patents

Description

Industrial synthesis of strontium ranelate and its hydrate

The invention relates to a method for industrially synthesizing strontium ranelate salt and hydrate thereof shown in formula (I):

(the di-strontium salt of 5- [ bis (carboxymethyl) amino ] -3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid).

Strontium ranelate salts have very valuable pharmacological and therapeutic properties, especially outstanding anti-osteoporosis properties, which make the compounds useful for the treatment of bone diseases.

Strontium ranelate salts, their preparation and their therapeutic use have been described in european patent specification EP 0415850.

However, the industrial production of compounds such as strontium ranelate requires a detailed study of all reaction steps and the choice of starting materials, reagents and solvents in order to obtain the best yields.

Applicants have developed a method for synthesizing strontium ranelate salts of formula (I) wherein these conditions have been combined, using a particularly valuable set of methods and processes.

Patent specification EP 0415850 describes the synthesis of strontium ranelate salts from ethyl tetraesters of formula (IIa):

wherein the ethyl tetraester is itself obtained from an ethyl diester of formula (IIIa):

the synthesis of intermediates of formula (IIIa) has been described in the publications Bull. Soc. Chim. France1975, 1786-1792 and J.chem. Tech. Biotechnol.1990, 47, 39-46, where diethyl 3-oxoglutarate, malononitrile and sulphur are reacted in ethanol in the presence of morpholine or diethylamine.

The advantages of this process are the use of readily available starting materials and ease of implementation; however, this method does not allow to obtain the compound of formula (IIIa) in a yield of more than 70% when scaled up to a scale of several hundred kg.

In order to synthesize the strontium ranelate salt of formula (I) on an industrial scale, the applicant has developed an efficient industrial synthesis method which allows obtaining the intermediate of formula (III) with a purity higher than 97% and a yield higher than 77% and which is reproducible on an industrial scale:

wherein R is linear or branched (C)₁-C₆) An alkyl group.

More specifically, the industrial synthesis process developed by the applicant for the industrial synthesis of strontium ranelate salts of formula (I) for the production of diesters of formula (III) uses as starting material a compound of formula (IV):

wherein R is as defined above, and wherein,

reacting a compound of formula (IV) with a malononitrile of formula (V)

In methanol in the presence of morpholine in an amount greater than 0.95 moles per mole of compound of formula (IV) to give a compound of formula (VI):

wherein R is as defined above, and wherein,

then, reacting the compound of formula (VI) with sulphur in an amount of more than 0.95 moles per mole of the compound of formula (IV);

the reaction mixture was then heated to reflux; and

the resulting compound of formula (III) is isolated by precipitation in the presence of water and then filtered.

A correspondingly improved process by employing these specific conditions, in particular by intermediate formation of the compound of formula (VI), which can be isolated if desired, enables the compound of formula (III) to be obtained in excellent purity and yield of at least 77% and is reproducible on a process scale of several hundred kg, which indicates a significant improvement in yield in the production of large tons of strontium ranelate salt.

The amount of methanol is preferably 1-3ml per gram of compound of formula (IV).

The reaction temperature between the compound of formula (IV) and the compound of formula (V) is preferably below 50 ℃.

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

In the method developed by the applicant for the industrial synthesis of strontium ranelate salts of formula (I), the second step comprises the conversion of the compound of formula (III) into the compound of formula (II):

wherein R is as defined above and R' is linear or branched (C)₁-C₆) An alkyl group.

The periodical bull. soc.chim.france1975, page 1786-1792 describes the preparation of compounds of formula (IIa) (a special case of compounds of formula (II) wherein R ═ R' stands for ethyl) by reacting 5-amino-3- (carboxymethyl) -4-cyano-2-thiophenecarboxylic acid with ethyl bromoacetate in the presence of potassium carbonate and then separating in a highly diluted aqueous organic medium.

However, the low yield of the reaction (65%), the large amount of brine waste generated by the reaction and in particular the very long reaction time (5 days) have completely hindered the application of the reaction on an industrial scale.

For the industrial synthesis of strontium ranelate salts of formula (I), the applicant has developed a simple industrial synthesis process allowing to obtain the compound of formula (II) in very good yields, significantly shorter reaction times and excellent purity, while completely avoiding brine waste.

More specifically, the process developed by the applicant for the industrial synthesis of the strontium ranelate salt of formula (I) for the tetraester of formula (II) uses as starting material a compound of formula (III):

wherein R represents linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

reacting a compound of formula (III) with a compound of formula (VII):

wherein R' represents a linear or branched (C)₁-C₆) Alkyl in catalytic amount of C₈-C₁₀Reacting in the presence of a quaternary ammonium compound of type and in the presence of potassium carbonate under reflux of an organic solvent;

the reaction mixture was then filtered;

then the mixture is concentrated by distillation;

then adding a cosolvent into the mixture,

the reaction mixture was cooled and filtered,

the powder thus obtained is dried to give the compound of formula (II).

C₈-C₁₀Quaternary ammonium compounds of the type are understood to be compounds of formula (a) or mixtures of compounds of formula (a):

R₁R₂R₃R₄-N^+-X (A)

wherein R is₁Is (C)₁-C₆) Alkyl radical, R₂、R₃And R₄May be the same or different and are each (C)₈-C₁₀) Alkyl and X represents a halogen atom.

Preferably used C₈-C₁₀Type quats are the catalysts Adogen 464 * and Aliquat336 *.

Surprisingly, only C is used in comparison with other types of quaternary ammonium compounds₈-C₁₀Quaternary ammonium compounds of the type (I) are obtained with significantly reduced reaction times and very good selectivity, as shown in the following table:

catalyst and process for preparing same	Reaction time	Content of reaction mixture
			Tetrabutylammonium hydrogen sulfate (TBAHS)	12 hours	92％
N, N-bis (2-hydroxyethyl) -N-methyl-1-dodecane ammonium bromide	18 hours	82％
			Adogen 464*	5 hours	96％
Aliquat 336*	4 hours	95％

Moreover, by exploiting the specific conditions, certain simple separation operations (the operations of precipitation and then filtration have been replaced by operations of simple filtration of the reaction mixture) allow to obtain the compound of formula (II) simultaneously in very good yields (89%) and excellent purities (greater than 98%), while avoiding the pollution of the environment by brine waste.

The amount of potassium carbonate is preferably 2 to 3 moles per mole of compound of formula (III).

The amount of compound of formula (VII) is preferably 2-3 moles per mole of compound of formula (III).

The initial volume of organic solvent is preferably from 6 to 12ml per gram of compound of formula (III).

Preferred organic solvents for the reaction are acetone and acetonitrile.

The preferred co-solvent for the separation is methanol.

In the method developed by the applicant for the industrial synthesis of strontium ranelate salts of formula (I), the third step consists in converting the tetraester of formula (II) into the di-strontium salt of the corresponding tetraacid.

Patent specification EP 0415850 describes three methods for this conversion. The third process described, which comprises heating the compound of formula (IIa), a particular case of the compound of formula (II), and strontium hydroxide in a hydroalcoholic medium, then distilling off the ethanol and isolating the compound of formula (I) by precipitation, has the advantage of being very simple to carry out.

However, although operating under the conditions described for the third process, the applicant only obtained strontium ranelate salts in 80% yield and 87% purity.

The subsequent purification operation is very complicated in view of the fact that strontium ranelate salts are insoluble in most solvents. Therefore, this method is not suitable for the use of strontium ranelate salts as pharmaceutically active ingredients, since a purity of 98% or more is required as the pharmaceutically active ingredient.

The applicant has developed an industrial synthesis process which is capable of obtaining strontium ranelate not only in excellent chemical purity so that further processing is not required before use as a pharmaceutically active ingredient, but also in excellent yield.

More specifically, in the method developed by the applicant for the industrial synthesis of strontium ranelate salts of formula (I), the last step uses a compound of formula (II):

wherein R and R', which may be the same or different, each represent a linear or branched (C)₁-C₆) Alkyl, R preferably represents methyl, R' preferably represents methyl or ethyl,

wherein the compound of formula (II) is reacted with strontium hydroxide in an amount of 2 or more moles per mole of the compound of formula (II) under reflux of water for at least 5 hours;

then, the obtained precipitate is filtered while the solution is hot;

washing the obtained filter cake with boiling water;

after drying the obtained powder, the compound of formula (I) and hydrates thereof are obtained.

Surprisingly, the mere replacement of the ethanol/water mixture by water not only significantly improves the purity of the resulting strontium ranelate salt, but also its yield.

Moreover, the distillation step of the ethanol is omitted, which further simplifies the process.

The amount of water in the reaction mixture is preferably greater than or equal to 8ml per gram of compound of formula (II).

The amount of strontium hydroxide is preferably 2 to 2.5 moles per mole of the compound of formula (II).

The present invention will be illustrated by examples.

Examples 1A and 1B illustrate the first step in the process of the present invention for the industrial synthesis of strontium ranelate salts; examples 2A, 2B, 2C and 2D illustrate the second step in the process of the invention; finally, example 3 illustrates the third and last step in the process of the present invention.

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

400kg of dimethyl 3-oxoglutarate, 158kg of malononitrile and 560 liters of methanol were charged to the reactor, followed by 199.6kg of morpholine while maintaining the temperature of the reaction mixture below 40 ℃.

Then 73.6kg of sulphur was added and the mixture was subsequently 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.

Thus, 5-amino-4-cyano 3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylic acid methyl ester was obtained in 77% yield and 98% chemical purity.

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

400kg of dimethyl 3-oxoglutarate, 158kg of malononitrile and 560 liters of methanol were charged to the reactor, followed by 199.6kg of morpholine while maintaining the temperature of the reaction mixture below 40 ℃.

The resulting compound of formula (VI) or the addition salt of methyl 3- (dicyanomethylene) -5-hydroxy-5-methoxy-4-pentenoate with morpholine was isolated after cooling the mixture by filtration and then reacted with 73.6kg of sulphur in methanol.

The 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.

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

To the reactor were added 400kg of 5-amino-3- (carboxymethyl) -4-cyano-2-thiophenecarboxylic acid, 478kg of potassium carbonate, 2810 l of acetone, 16kg of Adogen 464 * and 529.6kg of methyl bromoacetate.

The temperature was brought to 60 ℃. After refluxing for 5 hours, the reaction mixture was cooled and then filtered. The resulting filtrate was concentrated.

Adding methanol; the resulting suspension was cooled and filtered, and then the powder was dried.

Thus, 5- [ bis (2-methoxy-2-oxoethyl) amino ] -4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylic acid methyl ester was obtained in a yield of greater than 85% and a chemical purity of greater than 98%.

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

Methyl 5- [ bis (2-methoxy-2-oxoethyl) amino ] -4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylate is obtained in the same manner as in example 1, but with Aliquat336 * instead of Adogen 464 *.

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

Methyl 5- [ bis (2-methoxy-2-oxoethyl) amino ] -4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylate was obtained in the same manner as in example 1 except that acetonitrile was used instead of acetone.

Example 2D: 5- [ bis (2-ethoxy-2-oxoethyl) amino]-4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylic acid methyl ester

Methyl 5- [ bis (2-ethoxy-2-oxoethyl) amino ] -4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylate was obtained in the same manner as in example 1 except that 578.1kg of ethyl bromoacetate was used instead of 529.6kg of methyl bromoacetate.

Example 3: 5- [ bis (carboxymethyl) amino group]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid strontium salt octahydrate

770kg of strontium hydroxide and 5500 liters of water are charged to the reactor, followed by 550kg of methyl 5- [ bis (2-methoxy-2-oxoethyl) amino ] -4-cyano-3- (2-methoxy-2-oxoethyl) -2-thiophenecarboxylate. Heating to reflux for at least 5 hours; the reaction mixture was then filtered while hot, the filter cake was washed with boiling water, and the resulting powder was dried.

Therefore, the strontium salt 5- [ bis (carboxymethyl) amino ] -3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid octahydrate was obtained in 96% yield and 98% chemical purity.

Claims (14)

1. A method for industrially synthesizing strontium ranelate salt of formula (I) and its hydrate:

the method is characterized in that a compound of formula (IV)

Wherein R represents linear or branched (C)₁-C₆) Alkyl, with malononitrile of the formula (V)

In methanol in the presence of morpholine in an amount greater than 0.95 moles per mole of compound of formula (IV) to give a compound of formula (VI):

wherein R is as defined above, and wherein,

then, reacting the compound of formula (VI) with sulphur in an amount of more than 0.95 moles per mole of the compound of formula (IV);

the reaction mixture was then heated to reflux; and

the resulting compound is isolated by precipitation in the presence of water and then filtered to give the compound of formula (III),

wherein R is as defined above, and wherein,

a compound of formula (III) with a compound of formula (VII):

wherein R' represents a linear or branched (C)₁-C₆) An alkyl group, a carboxyl group,

in catalytic amount of C₈-C₁₀Reacting in the presence of a quaternary ammonium compound of type (IV) and in the presence of potassium carbonate under reflux of an organic solvent;

the reaction mixture was then filtered;

then the mixture is concentrated by distillation;

then adding a cosolvent into the mixture,

the reaction mixture was cooled and filtered,

drying the powder thus obtained to give the compound of formula (II),

wherein R and R' are as defined above.

Reacting the compound of formula (II) with strontium hydroxide in an amount greater than or equal to 2 moles per mole of the compound of formula (H) under reflux of water for at least 5 hours;

then, the obtained precipitate is filtered while the solution is hot;

washing the obtained filter cake with boiling water;

after drying the powder obtained, a compound of formula (I) and hydrates thereof are obtained,

wherein, C₈-C₁₀The quaternary ammonium compound of formula (a) is a compound of formula (a) or a mixture of compounds of formula (a):

R₁R₂R₃R₄-N^+-X (A)

wherein R is₁Is represented by (C)₁-C₆) Alkyl radical, R₂、R₃And R₄May be the same or different, each represents (C)₈-C₁₀) Alkyl and X represents a halogen atom.

2. A method for industrially synthesizing strontium ranelate salts of formula (I) and hydrates thereof:

the method is characterized in that a compound of formula (II):

wherein R and R', which may be the same or different, each represent a linear or branched (C)₁-C₆) An alkyl group, with strontium hydroxide in an amount of greater than or equal to 2 moles per mole of the compound of formula (II) under reflux of water for at least 5 hours;

then, the obtained precipitate is filtered while the solution is hot;

washing the obtained filter cake with boiling water;

after drying the obtained powder, the compound of formula (I) and hydrates thereof are obtained.

3. A synthesis process according to claim 1 or 2, characterized in that during the synthesis of the compound of formula (III) the amount of methanol used is from 1 to 3ml per gram of the compound of formula (IV).

4. A synthesis according to claim 1, characterized in that the reaction temperature between the compound of formula (IV) and the compound of formula (V) is lower than 50 ℃.

5. A synthesis process according to claim 1, characterized in that the reflux time for the reaction of the compound of formula (VI) with sulphur is from 1 hour 30 minutes to 3 hours.

6. A synthesis process according to claim 1, characterized in that during the synthesis of the compound of formula (II), potassium carbonate is used in an amount of 2 to 3 moles per mole of the compound of formula (III).

7. Synthesis process according to claim 1 or 6, characterized in that the amount of compound of formula (VII) is between 2 and 3 moles per mole of compound of formula (III).

8. A synthesis process according to claim 1, characterized in that in the reaction of the compound of formula (III) with the compound of formula (VII), the initial volume of organic solvent used is 6-12ml per gram of compound of formula (III).

9. A synthesis process according to claim 1, characterized in that in the reaction of the compound of formula (III) with the compound of formula (VII), the organic solvent used is acetone or acetonitrile.

10. A synthesis process according to claim 1, characterized in that in the isolation of the compound of formula (II), the co-solvent used is methanol.

11. A synthesis process according to claim 1, characterized in that the chemical purity of the compound of formula (II) obtained is greater than 98%.

12. A synthesis process according to claim 13, characterized in that in the reaction of the compound of formula (II) with strontium hydroxide, the amount of water used is greater than or equal to 8ml per gram of compound of formula (II).

13. A synthesis method according to claim 1, characterized in that the amount of strontium hydroxide is 2-2.5 moles per mole of compound of formula (II).

14. A synthesis process according to claim 1, characterized in that R represents a methyl group and R' represents a methyl or ethyl group.