Title of Invention

" PROCESS FOR THE INDUSTRIAL SYNTHESIS OF METHYL DIESTER OF 5-AMINO-3-CARBOXYMETHYL-4-CYANO-2-THIOPHENECARBOXYLIC ACID"

Abstract Process for the industrial synthesis of methyl diester of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid of formula I:
Full Text The present invention relates to a process for the industrial synthesis of the methyl diester of 5-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.
More specifically, the present invention relates to a new process for the industrial synthesis of the compound of formula (I) :
(Formula Removed)
The compound of formula (I) obtained according to the process of the invention is useful in the synthesis of ranelic acid, its strontium, calcium or magnesium salts of formula (II):
(Formula Removed)
wherein M represents strontium, calcium or magnesium,
and hydrates of the said salts.
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.
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.
That Patent Specification describes the synthesis of strontium ranelate starting from the ethyl tetraester of formula (III) :
(Formula Removed)
which is itself obtainable starting from the ethyl diester of formula (IV) :
(Formula Removed)
Synthesis of the intermediate of formula (IV) has been described in the publication Bull. Soc. Chim. France 1975, pp. 1786-1792 and in the publication J. Chem. Tech. Biotechnol. 1990, 47, pp. 39-46, by reaction between diethyl 3-oxoglutarate, malononitrile and sulphur in ethanol, in the presence of morpholine or diethylamine.
That process has the advantage of using readily accessible starting materials and of being simple to put into practice; however, when transferred to the scale of several hundred kilograms, it does not allow the compound of formula (IV) to be obtained in a yield greater than 70 %.
In view of the pharmaceutical interest of strontium ranelate and the tonnages produced, it has been important to be able to synthesise a diester of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid of excellent purity, in a yield of at least 77 %, which is reproducible on an industrial scale.
The Applicant has now developed an effective industrial synthesis process allowing the methyl diester of formula (I) to be obtained in a yield of at least 77 % and with a purity greater than 97 %.
The compound of formula (I) thereby obtained is especially useful in the synthesis of ranelic acid, its strontium, calcium or magnesium salts and hydrates of the said salts, more especially strontium ranelate and its hydrates, wherein it is reacted with an ester of bromoacetic acid to yield the corresponding tetraester, which is then converted into ranelic acid or into a strontium, calcium or magnesium salt thereof.
More specifically, the present invention relates to a process for the industrial synthesis of the compound of formula (I),
which process is characterised in that dimethyl 3-oxoglutarate of formula (V) :
(Formula Removed)
is reacted with malonitrile of formula (VI):
(Formula Removed)
in methanol,
in the presence of morpholine in an amount greater than 0.95 mol per mol of compound of
formula (V),
to yield the compound of formula (VII) :
(Formula Removed)
which is then reacted with sulphur in an amount greater than 0.95 mol per mol of
compound of formula (V);
the reaction mixture is then heated at reflux;
and the compound of formula (I) thereby obtained is isolated by precipitation in the
presence of water, followed by filtration.
The process, accordingly improved by the use of these very specific conditions, and especially by the intermediate formation of the compound of formula (VII), which can, if desired, be isolated, allows the compound of formula (I) to be obtained with excellent purity and in a yield of at least 77 % which is reproducible on the scale of several hundred kilograms, which represents a major gain in yield in view of the large tonnages of strontium ranelate produced.
The amount of methanol is preferably from 1 to 3 ml per gram of compound of formula (V).
The temperature of reaction between the compounds of formulae (V) and (VI) is preferably less than 50°C.
The reaction time at reflux after addition of the sulphur is preferably from 1 hour 30 minutes to 3 hours.
Methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula (I) and the intermediate of formula (VII) 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.
The Examples hereinbelow illustrate the invention but do not limit it in any way.
EXAMPLE 1 : Methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophene-carboxylate
Introduce into a reactor 400 kg of dimethyl 3-oxoglutarate, 158 kg of malononitrile and 560 litres of methanol and then, whilst maintaining the temperature of the reaction mixture below 40°C, 199.6 kg of morpholine.
Then introduce 73.6 kg of sulphur and subsequently bring the mixture to reflux.
After reacting for 2 hours, stop refluxing and add water until precipitation occurs. Filter off the precipitate obtained, wash it and dry it.
Methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate is thereby obtained in a yield of 77 % and with a chemical purity of 98 %.
EXAMPLE 2 : Methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophene-carboxylate
Introduce into a reactor 400 kg of dimethyl 3-oxoglutarate, 158 kg of malononitrile and 560 litres of methanol and then, whilst maintaining the temperature of the reaction mixture below 40°C, 199.6 kg of morpholine.
The compound of formula (VII) thereby obtained, or the addition salt of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with morpholine, is isolated by filtration after cooling of the mixture and is then reacted with 73.6 kg of sulphur in methanol.
The mixture is then brought to reflux.
After reacting for 2 hours, stop refluxing and add water until precipitation occurs. Filter off the precipitate obtained, wash it and dry it.





We Claim:
1. Process for the industrial synthesis of methyl diester of 5-amino-3-
carboxymethyl-4-cyano-2-thiophenecarboxylic acid of formula I:
(Formula Removed)
characterized in that dimethyl 3-oxoglutarate of formula (V):
(Formula Removed)
is reacted with malononitrile of formula (VI):
(Formula Removed)
in methanol,
in the presecnce of morpholine in an amount greater than 0.95 mol per
mol of compound of formula (V),
to yield the compound of formula (VII) :
(Formula Removed)
which is then reacted with sulphur in an amount greater than 0.95 mol
per mol of compound of formula (V);
the reaction mixture is then heated at reflux;
and the compound of formula (I) thereby obtained is isolated by
precipitation in the presence of water, followed by filtration.
2. Synthesis process as claimed in claim 1, wherein the amount of
methanol is from 1 to 3 ml per gram of compound of formula (V).
3. Synthesis process as claimed in claim 1 or claim 2, wherein the
temperature of reaction between the compounds of formulae (V) and (VI)
is less than 50°C.
4. Synthesis process as claimed in any one of claims 1 to 3, wherein the
reaction time at reflux after addition of the sulphur is from 1 hour 30
minutes to 3 hours.

Documents:

978-delnp-2005-abstract.pdf

978-DELNP-2005-Claims.pdf

978-delnp-2005-complete specification (as files).pdf

978-delnp-2005-complete specification (granted).pdf

978-delnp-2005-correspondence-others.pdf

978-delnp-2005-correspondence-po.pdf

978-DELNP-2005-Description (Complete).pdf

978-delnp-2005-form-1.pdf

978-delnp-2005-form-18.pdf

978-delnp-2005-form-2.pdf

978-delnp-2005-form-3.pdf

978-delnp-2005-form-5.pdf

978-delnp-2005-gpa.pdf

978-delnp-2005-pct-210.pdf

978-delnp-2005-pct-409.pdf

978-delnp-2005-petition-137.pdf

978-delnp-2005-petition-138.pdf


Patent Number 243809
Indian Patent Application Number 978/DELNP/2005
PG Journal Number 46/2010
Publication Date 12-Nov-2010
Grant Date 09-Nov-2010
Date of Filing 14-Mar-2005
Name of Patentee LES LABORATOIRES SERVIER
Applicant Address 12, PLACE, DE LA DEFENSE, 92415 COURBEVOIE CEDEX,FRANCE.
Inventors:
# Inventor's Name Inventor's Address
1 LUCILE VAYSSE-LUDOT 150, ROUTE DE RANCON, F-76490 SAINT-WANDRILLE-RANCON, FRANCE.
2 JEAN-PIERRE LECOUVE 93, RUE DU DOCTEUR VIGNE, F-76600 LE HAVRE, FRANCE.
3 PASCAL LANGLOIS 3 ,ALLEE DU BASSIN, F-76210 SAINT-JEAN DE LA NEUVILLE, FRANCE
PCT International Classification Number C07D 333/38
PCT International Application Number PCT/FR2003/002776
PCT International Filing date 2003-09-22
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 02/11764 2002-09-24 France