WO2011086399A1 - Process for the preparation of strontium ranelate - Google Patents
Process for the preparation of strontium ranelate Download PDFInfo
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- WO2011086399A1 WO2011086399A1 PCT/HU2011/000006 HU2011000006W WO2011086399A1 WO 2011086399 A1 WO2011086399 A1 WO 2011086399A1 HU 2011000006 W HU2011000006 W HU 2011000006W WO 2011086399 A1 WO2011086399 A1 WO 2011086399A1
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- Prior art keywords
- acid
- carboxymethyl
- process according
- strontium
- bis
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 40
- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 title claims abstract description 27
- 229940079488 strontium ranelate Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- BGSCYLLQJSFPAG-UHFFFAOYSA-N tetraazanium;5-[bis(carboxylatomethyl)amino]-3-(carboxylatomethyl)-4-cyanothiophene-2-carboxylate Chemical compound N.N.N.N.OC(=O)CN(CC(O)=O)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N BGSCYLLQJSFPAG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 229950003464 ranelic acid Drugs 0.000 claims description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- DJSXNILVACEBLP-UHFFFAOYSA-N ranelic acid Chemical compound OC(=O)CN(CC(O)=O)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N DJSXNILVACEBLP-UHFFFAOYSA-N 0.000 claims description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 230000007062 hydrolysis Effects 0.000 claims description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- -1 dicholmethane Chemical compound 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 150000003863 ammonium salts Chemical class 0.000 claims description 10
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical group [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 229910001631 strontium chloride Inorganic materials 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229940093499 ethyl acetate Drugs 0.000 claims description 7
- 235000019439 ethyl acetate Nutrition 0.000 claims description 7
- 229910052712 strontium Inorganic materials 0.000 claims description 7
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 7
- 238000001228 spectrum Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 4
- 238000004922 13C solid-state nuclear magnetic resonance spectroscopy Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 2
- 150000004692 metal hydroxides Chemical class 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229920000728 polyester Polymers 0.000 claims 1
- UGJCNRLBGKEGEH-UHFFFAOYSA-N sodium-binding benzofuran isophthalate Chemical compound COC1=CC=2C=C(C=3C(=CC(=CC=3)C(O)=O)C(O)=O)OC=2C=C1N(CCOCC1)CCOCCOCCN1C(C(=CC=1C=2)OC)=CC=1OC=2C1=CC=C(C(O)=O)C=C1C(O)=O UGJCNRLBGKEGEH-UHFFFAOYSA-N 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 15
- 229940013553 strontium chloride Drugs 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000004482 13C cross polarization magic angle spinning Methods 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910003002 lithium salt Inorganic materials 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 159000000002 lithium salts Chemical class 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 3
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- YMVMXZLVHUNRRX-UHFFFAOYSA-N CCOC(=O)CN(CC(=O)OCC)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N Chemical compound CCOC(=O)CN(CC(=O)OCC)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N YMVMXZLVHUNRRX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 159000000008 strontium salts Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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.
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- 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
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.
Description
PROCESS FOR THE PREPARATION OF STRONTIUM RANELATE
FIELD OF THE INVENTION
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.
I II
BACKGROUND 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.
The processes disclosed in 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.
The filtration of the intermediers and products of known processes usually carried out at high temperature because the hydrolyzing agent must remain dissolved to avoid the formation of inorganic salt impurities.
Published International Patent Application WO 2004/029036 discloses a process wherein the ethyl tetraester of ranelic acid is reacted with strontium hydrixide at reflux in an aqueous medium. The purity of the obtained strontium ranelate is 98 %.
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.
Another disadvantage is that as 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.
According to the process disclosed in the second example, 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
of methanol and ethyl-acetate (1 :1) is added to the oily residue then the mixture is cooled to form a precipitate of the lithium salt. The lithium salt is reacted with strontium chloride in aqueous medium to provide strontium ranelate.
In both processes described above, 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.
In the first example of published patent application US 2009/082578, the methyl tetraester of ranelic acid is hydrolyzed with aqueous solution of sodium hydroxide in tetrahydrofuran then aqueous strontium chloride is added to the reaction mixture to provide strontium ranelate. The same process is carried out in other solvents (acetone, isopropylalcohol) and with other hydrolizing agent (potassium hydroxide) as well.
According to the fifth example, 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.
According to the sixth example, 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.
As we mentioned adove, tetrahydrofuran may be dangerous in large-scale production as it can form unstable and explosive peroxides. Yet another disadvantage is that the hydrolysis
disclosed in US 2009/082578 usually requires heating at higher temperature, which generates impurities, in our experience.
According to the above described patent applications, many processes are known for the preparation of strontium ranelate, nevertheless, they are not applicable to large-scale production. The used organic solvents are not safe enough and because of the impurities generated by the high temperature, the purity of the product isn't acceptable for pharmaceutical synthesis. Therefore, there is a need to find an industrially applicable process which is not only economical but can provide a product in a high pharmaceutically acceptable purity.
It has now been discovered that strontium ranelate can be obtained in more than 99.8 % purity. The properties of the used organic solvents meet the enviromental and safety requirements. In addition, the process according to the present invention doesn't generate impurities because of the solvent technique.
SUMMARY OF THE INVENTION
The present invention relates to an industrially applicable and safe process for the preparation of stroncium ranelate in high purity.
BRIEF DESCRIPTION OF FIGURES
Figure 1: Infrared spectrum of ammonium salt of crystalline ranelic acid
Figure 2: X-Ray Powder Diffraction pattern of ammonium salt of crystalline ranelic acid
Figure 3: 13C CP/MAS solid-state NMR spectrum of ammonium salt of crystalline ranelic acid
DETAILED DESCRIPTION OF THE INVENTION
It was surprisingly found that after hydrolyzing a ranelic acid ester with alcali metal- or alcali earth metal hydroxide at room temperature in a water/alcohol medium and then, acidifying the obtained solution of the ranelic acid salt with a Bronsted-Lowry acid ranelic acid ammonium salt can be removed by adding ammonia. After reacting the ammonium salt of ranelic acid with strontium halogenide, strontium ranelate can be obtained in high purity.
This is surprising because according to examples in the prior patent applications, the hydrolysis is usually carried out at high temperature with strotium hydroxide resulting in a badly miscible and badly soluble, contaminated product. The ranelic acid and salt intermediers are contaminated as well and recrystallization is usually necessary to obtain a pure product.
It has now been discovered that 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.
According to the process of the present invention, 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.
According to the process of the present invention, 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.
III
The starting compound of the process according to the present invention is a ranelic acid of formula (III), wherein Rj, R2, R3 and R4 represent independently H or linear branched or cyclic, saturated or unsaturated C]-C6 alkyl group.
In one embodiment of the present invention 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.
At the end of the hydrolysis, 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 C6 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.
The solid-state characteristics of the ranelic acid ammonium salt of formula (II) determined by suitable analytical techniques are disclosed below.
The most characteristic IR absorption bands of ranelic acid ammonium salt are the following:
3050, 2203, 1571, 1235, 1176, 709, 608 cm"1.
The characteristic IR spectrum is shown in Figure 1.
The most characteristic XRPD reflections are the following: 9.7, 9.8, 10.6, 16.4, 20.6, 21.1,
28.6 [°] 2Θ.
The characteristic X-ray powder diffraction pattern is shown in Figure 2.
The most characteristic resonances in 13C solid-state NMR spectrum are the following: 179.9,
176.4, 164.9, 144.1, 119.1, 37.1 ppm.
The characteristic 13C CP/MAS solid-state NMR spectrum is shown in Figure 3.
Applied measuring conditions:
Parameters of Infrared spectral measurements:
Spectrometer: Thermo-Nicolet 6700 FT-IR (in KBr pellets)
Spectral resolution: 4 cm"1
Scan number: 100
Parameters of X-ray powder diffraction measurements:
Diffractometer: PANanalytical X'Pert PRO MPD
Radiation: CuKa
Accelerating voltage: 40 kV
Anode current: 40 mA
Detector: PIXcel (PW3018/00)
Scanning rate: 0.031 °20/s
Step size: 0.0131 °2Θ
Measuring range: 2-40 °2Θ
Speed of spinning: 1 revolution/s
Measuring sensitivity: ± 0.2 °2Θ
Parameters of 13C CP/MAS solid-state NMR measurements:
Instrument: Varian NMR System 600 MHz (14.1 Tesla) VnmrJ 2.2C Probe: 3.2 mm HX
Experiment: 13C CPMAS (tancpx)
Speed of spinning: 15 kHz
Rotor: 3.2 mm thin-wall zirkonia
Temperature: 25 °C
Cross-polarisation time: 3 ms (CP)
Relaxation delay: 10 s
Reference: CH2 signal of adamantane at 38.5 ppm
Number of retries: 512
EXAMPLES
The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention in any way as many variations and equivalents that are encompassed by present invention will become apparent to those skilled in the art upon reading the present disclosure.
Example 1: Preparation of tetraammonium 5-[bis(2-oxido-2-oxoethyl)aniino]-4-cyano-3- (2-oxido-2-oxoethyl)thiophene-2-carboxylate
3.5 g (0.088 mol) of sodium hydroxide was dissolved in 50 ml of distilled water then 25 ml of ethanol and 5 g (0.011 mol) of ethyl tetraester of ranelic acid were added to the solution. The reaction mixture was stirred at room temperature for 4 hours, then the ethanol was eliminated by vacuum distillation. The water phase was acidified by hydrocholir acid then it was extracted with ethyl acetate. The organic phase was washed with sodium chloride solution,
then it was distilled to the third of it. 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.
Yield: 4.1 g (83 %)
Purity (measured by HPLC): 99.76 %
Water content (measured by KF): 9.5 %
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.
Characteristic XRPD peaks are shown in Table 1 :
No. Angle 2Θ Rel. int. (%)
1 9.7 56.5
2 9.8 47.5
3 10.1 3.8
4 10.6 37.0
5 10.9 3.3
6 12.1 1.4
7 14.2 3.9
8 14.5 2.2
9 15.1 9.4
10 16.4 39.0
11 16.6 8.6
12 16.9 22.2
13 17.2 15.8
14 17.6 23.9
15 18.3 14.8
16 18.8 12.7
17 19.4 10.7
18 19.7 17.2
19 19.9 7.2
20 20.2 13.5
21 20.6 50.1
22 21.1 92.9
23 21.4 9.0
24 22.1 51.0
25 22.5 9.4
26 23.1 1.2
27 23.8 34.7
28 24.2 45.5
29 24.5 28.0
30 25.4 69.4
31 25.8 3.0
32 26.6 33.0
33 27.0 23.3
34 27.2 63.4
35 28.6 100.0
36 29.1 35.8
37 29.6 49.4
38 29.9 21.6
39 30.4 5.9
40 30.6 32.5
41 30.8 23.5
42 31 .2 36.5
43 31.5 2.1
44 31 .8 29.1
45 32.3 9.2
46 32.8 34.4
47 33.0 45.3
48 33.4 13.7
49 33.8 15.2
50 34.7 27.7
51 35.3 13.8
52 35.7 32.6
53 36.1 35.8
54 36.7 10.5
55 37.1 3.1
56 37.7 21.0
57 38.0 8.5
58 38.4 14.8
59 38.9 5.0
60 39.3 29.7
Example 2: Preparation of tetraammonium 5-[bis(2-oxido-2-oxoethyl)amino]-4-cyano-3- (2-oxido-2-oxoethyl)thiophene-2-carboxylate
4 g (8.95 mol) of ammonium salt of ranelic acid (the product of example 1) was dissolved in
40 ml of distilled water. After straining the solution mixture of 5.5 g (20.8 mol) strontium chloride and 8 ml distilled water was added to it. The reaction mixture was stirred at room temperature for 24-48 hours then the obtained product was filtered and dried.
Yield: 5.0 g (85 %)
Purity (measured by HPLC): 99.91 %
Example 3: Preparation of tetraammoni m 5-[bis(2-oxido-2-oxoethyl)amino]-4-cyano-3- (2-oxido-2-oxoethyl)thiophene-2-carboxylate
1.9 g (0.048 mol) of sodium hydroxide was dissolved in 50 ml of distilled water then, 25 ml of ethanol and 5 g (0.012 mol) of 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyano-3-(2-oxido-2- oxoethyl)thiophene-2-carboxylic acid were added to the solution. The reaction mixture was stirred at room temperature for 4 hours then the ethanol was eliminated by vacuum distillation. The water phase was acidified by hydrochloric acid, then it was extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, then it was distilled to the third of it. 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.
Yield: 4.0 g (71 %)
Purity (measured by HPLC): 99.6 %
Water content (measured by KF): 8.5 %
Example 4: Preparation of tetraammonium 5-[bis(2-oxido-2-oxoethyl)amino]-4-cyano-3- (2-oxido-2-oxoethyl)thiophene-2-carboxylate
12.66 g (0.316 mol) of sodium hydroxide was dissolved in 180 ml of distilled water, then 90 ml of ethanol and 18 g (0.0396 mol) of ethyl tetraester of ranelic acid were added to the solution. The reaction mixture was stirred at room temperature for 4 hours then the ethanol was eliminated by vacuum distillation. The water phase was acidified by hydrochloric acid then it was extracted with ethyl acetate. The organic phase was extracted with ammonia solution, then the obtained water phase was mixed with 126 ml of ethanol. The obtained suspension was stirred at room temperature, then it was filtered and dried.
Yield: 11.9 g (67 %)
Purity (measured by HPLC): 99.8 %
Claims
1. 5 -[Bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid tetraammonium salt (ranelic acid tetraammonium salt) of formula (II).
2. 5 -[Bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid tetraammonium salt according to claim 1, characterized in that having characteristic X-ray powder diffractions at about 9.7, 9.8, 10.6, 16.4, 20.6, 21.1, 28.6 °2Θ.
3. 5 -[Bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid tetraammonium salt according to any of claims 1-2, characterized in that it has an X- ray powder diffraction pattern substantially in accordance with Figure 2.
4. 5 -[Bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid tetraammonium salt according to claim 1, characterized in that having a 13C solid-state NMR spectrum comprising characteristic resonances at about 179.9, 176.4, 164.9, 144.1, 1 19.1, 37.1 ppm.
5. 5 -[Bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid tetraammonium salt according to any of claims 1-2, characterized in that it has a 13C solid-state NMR spectrum substantially in accordance with Figure 3.
6. A process for the synthesis of strontium ranelate of formula (I): characterized in that a mono- or polyester of ranelic acid of compound of formula (III): wherein Rl9 R2, R and R4 independently represent linear, branched or cyclic, saturated or unsaturated CrC6 alkyl group, is hydrolyzed in water-ethanol solution at 15-30 °C with alcali metal or alcali earthmetal hydroxide, then ranelic acid is extracted in the presence of a Bransted-Lowry acid, the obtained solution is mixed with an organic solvent then with liquid ammonia to yield compound of formula (II), which is reacted with strontium halogenide in aqueous medium.
7. The process according to claim 6, wherein Rl5 R2, R3 and R4 represent ethyl.
8. The process according to any of claims 6-7, wherein the solvent of the hydrolysis is ethanol.
9. The process according to any of claims 6-8, wherein the ratio of watenethanol used in hydrolysis is 2:1.
10. The process according to any of claims 6-9, wherein the ratio of ranelic acid esther: solvent in hydrolysis is 15 : 1.
11. The process according to any of claims 6-10, wherein the hydro lizing agent is alcali metal hydroxide.
12. The process according to any of claims 6-11, wherein the hydrolysis is carried out at room temperature.
13. The process according to any of claims 6-12, wherein the Bransted-Lowry acid used in the hydrolysis is hydrochloric acid.
14. The process according to any of claims 6-13, wherein the poorly water-soluble organic solvent used in extraction is selected from: chloroform, dicholmethane, dichlorethane, tetrahydrofuran, toluene, esters or ethylacetate.
15. The process according to any of claims 6-14, wherein the solvent used in the removal of the ammonium salt of ranelic acid is selected from primary, secondary, tertiary, mono-or polysubstituted, linear, branched or cyclic Q-Q alcihol and any mixtures thereof.
16. The process according to any of claims 6-15, wherein the strontium halogenide used in the synthesis of strontium ranelate is strontium chloride.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11703731A EP2523947A1 (en) | 2010-01-14 | 2011-01-14 | Process for the preparation of strontium ranelate |
| EA201290592A EA201290592A1 (en) | 2010-01-14 | 2011-01-14 | METHOD OF OBTAINING STRONTIUM RANELATE |
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 |
| HUP1000018 | 2010-01-14 |
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| Publication Number | Publication Date |
|---|---|
| WO2011086399A1 true WO2011086399A1 (en) | 2011-07-21 |
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ID=89989497
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2011/000006 WO2011086399A1 (en) | 2010-01-14 | 2011-01-14 | Process for the preparation of strontium ranelate |
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|---|---|
| EP (1) | EP2523947A1 (en) |
| EA (1) | EA201290592A1 (en) |
| HU (1) | HU228820B1 (en) |
| WO (1) | WO2011086399A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2542546A1 (en) * | 2010-03-05 | 2013-01-09 | Chemelectiva Srl. | Process for the preparation of a polymorph of strontium ranelate |
| US8569514B1 (en) | 2012-05-17 | 2013-10-29 | Divi's Laboratories, Ltd. | Process for the preparation of strontium ranelate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0415850A1 (en) | 1989-09-01 | 1991-03-06 | Adir Et Compagnie | Bivalent metal salts of 2-N,N-di(carboxymethyl)amino,3-cyano,4-carboxymethyl,5-carboxy-thiophene-acid, process for their preparation and pharmaceutical compositions containing them |
| WO2004029036A1 (en) | 2002-09-24 | 2004-04-08 | Les Laboratoires Servier | Novel method for the industrial synthesis of strontium ranelate and the hydrates thereof |
| WO2007020527A2 (en) | 2005-08-19 | 2007-02-22 | Glenmark Pharmaceuticals Limited | Process for the preparation of strontium ranelate |
| US20090082578A1 (en) | 2007-09-26 | 2009-03-26 | Les Laboratoires Servier | Process for the synthesis of strontium ranelate and its hydrates |
-
2010
- 2010-01-14 HU HU1000018A patent/HU228820B1/en unknown
-
2011
- 2011-01-14 EA EA201290592A patent/EA201290592A1/en unknown
- 2011-01-14 EP EP11703731A patent/EP2523947A1/en not_active Withdrawn
- 2011-01-14 WO PCT/HU2011/000006 patent/WO2011086399A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0415850A1 (en) | 1989-09-01 | 1991-03-06 | Adir Et Compagnie | Bivalent metal salts of 2-N,N-di(carboxymethyl)amino,3-cyano,4-carboxymethyl,5-carboxy-thiophene-acid, process for their preparation and pharmaceutical compositions containing them |
| US5128367A (en) | 1989-09-01 | 1992-07-07 | Adir Et Compagnie | Divalent metal salts of 2-[N-N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid |
| WO2004029036A1 (en) | 2002-09-24 | 2004-04-08 | Les Laboratoires Servier | Novel method for the industrial synthesis of strontium ranelate and the hydrates thereof |
| WO2007020527A2 (en) | 2005-08-19 | 2007-02-22 | Glenmark Pharmaceuticals Limited | Process for the preparation of strontium ranelate |
| US20090082578A1 (en) | 2007-09-26 | 2009-03-26 | Les Laboratoires Servier | Process for the synthesis of strontium ranelate and its hydrates |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2542546A1 (en) * | 2010-03-05 | 2013-01-09 | Chemelectiva Srl. | Process for the preparation of a polymorph of strontium ranelate |
| US8569514B1 (en) | 2012-05-17 | 2013-10-29 | Divi's Laboratories, Ltd. | Process for the preparation of strontium ranelate |
Also Published As
| Publication number | Publication date |
|---|---|
| HU228820B1 (en) | 2013-05-28 |
| EA201290592A1 (en) | 2013-05-30 |
| HUP1000018A2 (en) | 2011-10-28 |
| HU1000018D0 (en) | 2010-03-29 |
| EP2523947A1 (en) | 2012-11-21 |
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