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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- 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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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 |
|---|---|---|---|
| EA201290592A EA201290592A1 (en) | 2010-01-14 | 2011-01-14 | METHOD OF OBTAINING STRONTIUM RANELATE |
| EP11703731A EP2523947A1 (en) | 2010-01-14 | 2011-01-14 | Process for the preparation of strontium ranelate |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP1000018 | 2010-01-14 | ||
| HU1000018A HU228820B1 (en) | 2010-01-14 | 2010-01-14 | Process for the preparation of distrontium ranelate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011086399A1 true WO2011086399A1 (en) | 2011-07-21 |
Family
ID=89989497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2011/000006 Ceased WO2011086399A1 (en) | 2010-01-14 | 2011-01-14 | Process for the preparation of strontium ranelate |
Country Status (4)
| Country | Link |
|---|---|
| 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 EP EP11703731A patent/EP2523947A1/en not_active Withdrawn
- 2011-01-14 WO PCT/HU2011/000006 patent/WO2011086399A1/en not_active Ceased
- 2011-01-14 EA EA201290592A patent/EA201290592A1/en unknown
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 |
|---|---|
| EP2523947A1 (en) | 2012-11-21 |
| HU1000018D0 (en) | 2010-03-29 |
| HU228820B1 (en) | 2013-05-28 |
| EA201290592A1 (en) | 2013-05-30 |
| HUP1000018A2 (en) | 2011-10-28 |
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