EP2523947A1 - Procédé de préparation de ranélate de strontium - Google Patents

Procédé de préparation de ranélate de strontium

Info

Publication number
EP2523947A1
EP2523947A1 EP11703731A EP11703731A EP2523947A1 EP 2523947 A1 EP2523947 A1 EP 2523947A1 EP 11703731 A EP11703731 A EP 11703731A EP 11703731 A EP11703731 A EP 11703731A EP 2523947 A1 EP2523947 A1 EP 2523947A1
Authority
EP
European Patent Office
Prior art keywords
acid
carboxymethyl
process according
strontium
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11703731A
Other languages
German (de)
English (en)
Inventor
Sándor GARADNAY
Nikoletta Szalma
József NEU
József Törley
Ádám DEMETER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Nyrt
Original Assignee
Richter Gedeon Nyrt
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Nyrt filed Critical Richter Gedeon Nyrt
Publication of EP2523947A1 publication Critical patent/EP2523947A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid

Definitions

  • the present invention relates to a process for the synthesis of distrontium 5-[bis(2-oxido-2- oxoethyl)amino] -4-cyano-3 -(2-oxido-2-oxoethyl)thiophene-2-carboxylate (strontium ranelate) of formula (I) starting from tetraammonium 5-[bis(2-oxido-2-oxoethyl)amino]-4-cyano-3-(2- oxido-2-oxoethyl)thiophene-2-carboxylate the novel compound of formula (II) which is also the subject of the invention.
  • Strontium ranelate the bis-strontium salt of ranelic acid has proved to have very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties. It is suggested to act through dual effects on bone metabolism, by increased bone formation and decreased bone resorption, resulting in rebalance of bone turnover in favour of bone formation. These properties make strontium ranelate very useful in the treatment of bone diseases.
  • EP 0415850 and related U.S. Patent No. 5,128,367 disclose the synthesis of strontium ranelate for the first time. Since then, further processes of the preparation have been described (for example in WO 2004/029036, WO 2007/020527, US 2009/082578).
  • EP 0415850 discloses three ways of the synthesis of strontium ranelate starting from the ethyl tetraester of ranelic acid.
  • the first process involves heating the ethyl tetraester of ranelic acid at reflux in an aqueous alcoholic medium in the presence of a sodium hydroxide solution and the hydrolyzing the heated solution in an acidic medium.
  • the obtained acid is thereafter converted into its sodium salt and then converted into sodium ranelate using strontium hydroxide or strontium chlored in water.
  • Another process for preparing strontium ranelate disclosed in EP 0415850 includes heating the ethyl tetraester of ranelic acid at reflux in a 50/50 mixture by volume of normal sodium hydroxide solution and ethanol, distilling off the solvents to obtain the tetrasodium salt which is thereafter treated with an aqueous chloride solution of strontium dichloride.
  • Yet another process for preparing strontium ranelate disclosed in EP 0415850 includes heating the ethyl tetraester of ranelic acid at reflux in an aqueous alcoholic medium with strontium hydroxide.
  • EP 0415850 requires heating at higher temperature, which is believed to generate impurities.
  • the purity of the product doesn't meet the pharmaceutical requirements.
  • Another industrial problem is that a large amount of solvents is used in reactions and in purification processes and the 4-26 % of the organic solvents may solvate the product.
  • One of the disadvantage of the process is the high temperature of hydrolysis, because of the impurities generated in hydrolysis, the purity of the product doesn't meet the requirements of pharmaceutical industry.
  • strontium hydroxide is poorly soluble in water the product is contaminated with inorganic salts.
  • the strontium salts of the intermediers generated in hydrolysis are poorly soluble in aqueous medium as well, and so, they separate out from reaction mixture to provide a poorly miscible suspension, in addition these intermediers contaminate the product.
  • Published International Patent Application WO 2007/020527 discloses the synthesis of strontium ranelate using ranelic acid lithium salt.
  • the first example describes a process wherein the ethyl tetraester of ranelic acid is reacted with 10 % aqueous solution of lithium hydroxide in tetrahydrofuran, then strontium chloride is added to the obtained lithium salt of ranelic acid to provide strontium ranelate.
  • the ethyl tetraester of ranelic acid is reacted with aqueous lithium hydroxide again, then the reacton mixture is distilled to get oily residue to which toluene is added and further distilled to remove water traces. Then a mixture
  • Tetrahydrofuran is used as solvent. Tetrahydrofuran may be dangerous in large-scale production as it can form unstable and explosive peroxides. In addition, lithium has an effect on the central nervous system, and so, the lithium residue must be examined in the active ingredient.
  • methyl tetraester of ranelic acid is reacted with aqueous solution of sodium hydroxide without using an organic solvent at 70°C.
  • the obtained aqueous solution is mixed with ethanol and then, it is reacted with aqueous strontium chloride to get strontium ranelate.
  • methyl tetraester of ranelic acid is reacted with potassium hydroxide at 55-60 °C. Then the solution is dried at 40°C in vacuo, the residue is mixed with the mixture of methanol and ethyl-acetate then it is stirred. The obtained suspension is filtered to provide the potassium salt of ranelic acid. Then the potassium salt is reacted with strontium chloride in aquous solution of tetrahydrofuran to get strontiun ranelate.
  • strontium ranelate can be obtained in more than 99.8 % purity.
  • the properties of the used organic solvents meet the enviromental and safety requirements.
  • the process according to the present invention doesn't generate impurities because of the solvent technique.
  • the present invention relates to an industrially applicable and safe process for the preparation of stroncium ranelate in high purity.
  • ranelic acid ammoniun salt can be removed easily. Counter to previously disclosed processes, neither distillation nor precipitation by organic solvent is necessary to obtain ranelic acid salt.
  • the hydrolysis of the ranelic acid ester is carried out at room temperature and degradation products dont generate.
  • the inorganic salts used in hydrolysis are eliminated by extraction. After the removal of the ammonium salt, the product is obtained in a 99.5 % or higher purity.
  • This highly pure ammonium salt is water-soluble and the ammonium halogenides occured in the final step of the process are water-soluble as well.
  • the obtained product is not only highly pure but also free of inorganic salt impurities. Further advantage of the process according to the present invention is that crystallization of the ranelic acid ammonium salt is not necessary which decreases the cost of the process.
  • ranelic acid ester of formula (III) is reacted with alcali metal- or alcali earthmetal hydroxide in water/alcohol medium at room temperature, then after acidifying with a Bronsted-Lowry acid, the ranelic acid is extracted. The obtained solution is mixed with an organic solvent, then ranelic acid ammonium salt is removed by adding aqueous ammonia. The ammonium salt is dissolved in water and reacted with strontium halogenide to obtain strontium ranelate.
  • the starting compound of the process according to the present invention is a ranelic acid of formula (III), wherein Rj, R 2 , R 3 and R 4 represent independently H or linear branched or cyclic, saturated or unsaturated C]-C 6 alkyl group.
  • R R represent ethyl
  • Suitable solvents which can be used in the hydrolysis process according to the present invention include primary, secondary and tertiary, linear, branched or cyclic, mono- or polysubstituted Q-Q alcohols and any mixtures thereof, optionally ethanol.
  • the proportion of the water-alcohol mixture used in the hydrolysis according to the present invention may vary between 1 :20 and 20: 1, optionally 15:1.
  • the temperature applied in the hydrolysis according to the present invention may vary between 0 and 60 °C, optionally 15-30 °C.
  • any Bransted-Lowry acid can be used, optionally hydrochloric acid.
  • Suitable solvents which can be used in the extraction of ranelic acid include non or poorly water-soluble organic solvents such as chloroform, dichlormethane, dichlorethane, tetrahydrofuran, toluene, different esters, optionally ethylacetate.
  • Suitable solvents which can be used in the removal of the ammoniumsalt of ranelic acid include primary, secondary and tertiary, linear, branched or cyclic, mono- or polysubstituted C C 6 alcohols and any mixtures thereof, optionally ethanol.
  • Suitable strontium halogenides which can be used in the final step of the process according to the present invention involves strontiumchloride,-bromide,-iodide, optionally strontiumchloride.
  • the yield of the ranelic acid ammonium salt is more than 65%, typically 85%.
  • the purity of the ranelic acid ammonium salt is more than 99.5 %, typically 99.8 %.
  • the water content of the ranelic acid ammonium salt is 8.5-9.5 %.
  • the yield of strontium ranelate obtained from the ranelic acid ammonium salt is more than 70 %, typically 85 %.
  • the purity of strontium ranelate is more than 99.5%, typically 99.9 %.
  • the results of analysis (IR, DSC, TG, X-ray Power Diffraction) of strontium ranelate obtained by the process according to the present invention are identical with those described in the prior art.
  • Step size 0.0131 °2 ⁇
  • Example 1 Preparation of tetraammonium 5-[bis(2-oxido-2-oxoethyl)aniino]-4-cyano-3- (2-oxido-2-oxoethyl)thiophene-2-carboxylate
  • the characteristic IR absorption bands of the product are the following: 3462, 3050, 2203, 1571, 1397, 1352, 1301, 1235, 1176, 1003, 975, 955, 899, 810, 797, 750, 709, 656, 608 cm -1 .
  • the characteristic resonances in C solid-state NMR spectrum are the following: 179.9, 177.4, 176.4, 169.6, 164.9, 144.1, 119.1, 118.3, 117.6, 87.4, 60.5, 37.1 ppm.
  • the residue was mixed with 25 ml of ethanol, then the solution was filtered.
  • the mixture of 10 ml of ethanol and 3 ml of ammonium hydroxide was added to the obtained solution.
  • the obtained suspension was stirred at room temperature, then it was filtered and dried.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de synthèse de 5-[bis(2-oxydo-2-oxoéthyl)amino]-4-cyano-3-(2-oxydo-2-oxoéthyl)thiophène-2-carboxylate de distrontium (ranélate de strontium) de formule (I) à partir du 5-[bis(2-oxydo-2-oxoéthyl)amino]-4-cyano-3-(2-oxydo-2-oxoéthyl)thiophène-2-carboxylate de tétraammonium, le nouveau composé de formule (II) qui fait également l'objet de l'invention.
EP11703731A 2010-01-14 2011-01-14 Procédé de préparation de ranélate de strontium Withdrawn EP2523947A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU1000018A HU228820B1 (en) 2010-01-14 2010-01-14 Process for the preparation of distrontium ranelate
PCT/HU2011/000006 WO2011086399A1 (fr) 2010-01-14 2011-01-14 Procédé de préparation de ranélate de strontium

Publications (1)

Publication Number Publication Date
EP2523947A1 true EP2523947A1 (fr) 2012-11-21

Family

ID=89989497

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11703731A Withdrawn EP2523947A1 (fr) 2010-01-14 2011-01-14 Procédé de préparation de ranélate de strontium

Country Status (4)

Country Link
EP (1) EP2523947A1 (fr)
EA (1) EA201290592A1 (fr)
HU (1) HU228820B1 (fr)
WO (1) WO2011086399A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1398542B1 (it) * 2010-03-05 2013-03-01 Chemelectiva S R L Processo per la preparazione di un polimorfo
US8569514B1 (en) 2012-05-17 2013-10-29 Divi's Laboratories, Ltd. Process for the preparation of strontium ranelate

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2651497B1 (fr) 1989-09-01 1991-10-25 Adir Nouveaux sels de metaux bivalents de l'acide n, n-di (carboxymethyl)amino-2 cyano-3 carboxymethyl-4 carboxy-5 thiophene, leur procede de preparation et les compositions pharmaceutiques les renfermant.
FR2844795B1 (fr) 2002-09-24 2004-10-22 Servier Lab Nouveau procede de synthese industriel du ranelate de strontium et de ses hydrates
WO2007020527A2 (fr) 2005-08-19 2007-02-22 Glenmark Pharmaceuticals Limited Procede de preparation de ranelate de strontium
FR2921367B1 (fr) 2007-09-26 2009-10-30 Servier Lab Nouveau procede de synthese du ranelate de strontium et de ses hydrates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011086399A1 *

Also Published As

Publication number Publication date
WO2011086399A1 (fr) 2011-07-21
HU1000018D0 (en) 2010-03-29
HUP1000018A2 (en) 2011-10-28
EA201290592A1 (ru) 2013-05-30
HU228820B1 (en) 2013-05-28

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