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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • 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 an improved process for the preparation of pure strontium ranelate hydrates (la-c) by using the intermediates, amino dimethyl ester of formula-ll and tetramethylester of formula-Ill, which are prepared by novel methods. And also the present invention relates to a new crystalline polymorphic form of strontium ranelate monohydrate and process for the preparation thereof.
• Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility.
• the clinical consequences of osteoporosis are vertebral and peripheral fractures. Osteoporosis is common in women after menopause and results an accelerated rate of bone loss. Thus, there is an increase in bone turnover which results decrease in bone mass and bone mineral density.
• Strontium ranelate is the only an anti-osteoporotic agent which helps in both increasing bone formation and reducing bone resorption, resulting in a rebalance of bone turnover in favour of bone formation. Therefore strontium ranelate is considered as an important medicament in bone disorder diseases and it is marketed as protelos.
• Strontium ranelate is a distrontium salt of ranelic acid and the chemical name is: distrontium 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophene carboxylic acid, represented as formula-l.
• EP0415850 provides the processes for the preparation of bivalent salts of ranelic acid, including strontium ranelate, and their therapeutic use.
• preparation of strontium ranelate hydrates like octahydrate, heptahydrate and tetrahydrate are reported but purity of the products are not mentioned.
• US Patent No.7105683 provides preparation of amino diester of formula-ll, an intermediate for the preparation of strontium ranelate, by reacting 1 ,3- acetone carboxylic acid dimethyl ester, malononitrile and sulfur in methanol medium in presence of a base - morpholine.
• US Patent No.7091364 provides process for the preparation of tetraester, methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2- thiophenecarboxylate of formul-ll l, which is another intermediate of strontium ranelate.
• the process involves reaction of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2- thiophenecarboxylate of formula-ll with methyl or ethyl bromoacetate in an organic solvent, in presence of potassium carbonate and a catalyst C 8 -Ci 0 type quaternary ammonium salt.
• US Patent No.7214805 provides the processes for the preparation of intermediates of formula-ll and formula-Ill and also strontium ranelate octahydrate.
• the intermediates, amino diester of formula-l l and tetra ester of formula-Ill are prepared by adopting the methods described in US patents, US7105683 and US7091364 respectively, whereas strontium ranelate octahydrate is prepared by heating tetraester of formula-Il l with strontium hydroxide in water medium.
• PCT Publication No.WO2010/021000 also provides the processes for the preparation of intermediates of formula-l l and formula-I ll and also strontium ranelate octahydrate.
• intermediates as well as strontium ranelate octahydrate are described and the details are as follows: amino diester of formula-ll is prepared by reacting 1 ,3-acetone dicarboxylic acid dimethyl ester, malononitrile and sulfur in methanol medium by using a different base, imidazole, in place of morpholine.
• Tetra ester of formula-Il l is prepared by reacting amino diester of formula-ll with ethyl bromoacetate in a mixture of organic solvents like acetonitrile and dimethyl sulfoxide or acetone and dimethyl sulfoxide in presence of potassium iodide and potassium carbonate.
• Strontium ranelate octahydrate is prepared via lithium salt by reacting tetra ester of formula-Il l with aqueous lithium hydroxide in tetrahydrofuran medium followed by addition of strontium chloride.
• the methodology is having certain disadvantages like usage of mixture of solvents in preparation tetraester of formula-Ill and class-ll solvent, tetrahydrofuran, in active pharmaceutical ingredient (API) formation stage.
• US Patent No.7459568 discloses the process for the preparation of alpha crystalline form of strontium ranelate, which involves refluxing strontium ranelate octahydrate in water, followed by filtration and drying to give a crystalline strontium ranelate.
• WO2010/034806 preparations of anhydrate and monohydrate forms of strontium ranelate have been described.
• This publication provides process for the preparation of an anhydrate/amorphous and monohydrate form of strontium ranelate, which involves suspending a known hydrate - tetrahydrate or octahydrate form of strontium ranelate in an organic solvent, heating the suspension under reflux, cooling the suspension, recovering the solid and drying the solid to obtain crystalline strontium ranelate, and optionally converting the crystalline form into an amorphous form of strontium ranelate.
• the water content of the resulting hydrates is measured by loss on drying (LOD) analysis and the crystalline and amorphous forms are identified by X-ray powder diffraction measurements.
• LOD loss on drying
• the present invention relates to the process for preparation of a new crystalline strontium ranelate monohydrate form obtained by careful dehydration of octahydrate of strontium ranelate.
• the dehydration process carried out by heating the strontium ranelate octahydrate at about 80-120°C and more specifically at 90-100°C under vacuum in a rotocone dryer to provide a crystalline strontium ranelate monohydrate.
• the strontium ranelate monohydrate obtained in the present invention is an high purity product with less hygroscopicity and excellent stability. Therefore the obtained product by the present invention can advantageously be used in pharmaceutical compositions due to its high quality factors.
• the strontium ranelate monohydrate obtained in the present invention is found to be a new crystalline polymorphic form of monohydrate of strontium ranelate.
• This new crystalline polymorph is characterized by X-ray powder diffraction pattern (XRD) and thermo gravimetric analysis (TGA).
• XRD pattern of strontium ranelate monohydrate obtained by the present invention is different from that of mentioned in the prior art, disclosed in PCT Publication No.WO2010/034806. Therefore the crystalline form of present invention is considered as a new polymorph of strontium ranelate monohydrate, designated as Polymorph-F, which is represented by formula-lc.
• One aspect of the present invention provides a novel process for the preparation of amino diester of formula-ll by using an alternative, cheap and commercially available base- triethyl amine.
• Another aspect of the present invention provides an economical process for the preparation of tetra ester of formula-Ill by using a cheap and commercially available catalyst- cetrimide.
• the octahydrate of strontium ranelate theoretically has a water content of 21 .90 wt.%, the tetrahydrate of 12.29 wt.% and the monohydrate of 3.38 wt.% and all these forms are presented in this invention.
• Another important aspect of the present invention provides processes for preparation of high quality active pharmaceutical ingredients (APIs), strontium ranelate octahydrate represented by the formula-la, tetrahydrate represented by the formula-lb and monohydrate represented by the formula-lc.
• APIs active pharmaceutical ingredients
• strontium ranelate octahydrate represented by the formula-la tetrahydrate represented by the formula-lb
• monohydrate represented by the formula-lc The APIs obtained by the present process is excellent in chemical purity, more than 99.80% by HPLC, and with substantially free from impurities.
• the present invention provides processes to obtain a very pure APIs which are matching all the quality attributes as per the pharmaceutical and ICH guidelines.
• the octahydrate is by weight of water from about 21 .0 wt. % to about 23.50 wt.%, more preferably from about 22.0 wt.% to about 23.0 wt.% and most preferably from about 21 .50 wt.% to about 22.50 wt.%
• strontium ranelate tetrahydrate is by weight of water from about 1 1 .0 wt.% to about 13.0 wt.%, more preferably from about 1 1 .50 wt.% to about 12.50 wt.% and most preferably from about 12.0 wt.% to about 12.50 wt.%
• strontium ranelate monohydrate is by weight of water from about 2.50 wt.% to about 5.0 wt.%, more preferably from about 3.0 wt.% to about 4.0 wt.% and most preferably from about 3.20 wt.%
• Another aspect of the present invention provides a process for the preparation of crystalline strontium ranelate monohydrate Form-F with a water content of about 3.2 wt.% to 3.8 wt.%, which is related to a monohydrate.
• Another aspect of the present invention provides strontium ranelate monohydrate Form-F having purity more than 99.85% as measured by HPLC
• the present invention further provides strontium ranelate hydrates obtained by the processes herein described are having negligible residual organic solvents or organic volatile impurities, which are below than limits recommended for active pharmaceutical ingredients as set forth in ICH guidelines.
• Figure-1 depicts X-ray powder pattern diffractogram (XRPD) of crystalline strontium ranelate octahydrate.
• Figure-2 depicts X-ray powder pattern diffractogram (XRPD) of crystalline strontium ranelate tetrahydrate.
• Figure-3 depicts X-ray powder pattern diffractogram (XRPD) of Form-F of crystalline strontium ranelate monohydrate.
• Figure-4 depicts thermogram of (TGA) of Form-F of crystalline strontium ranelate monohydrate.
• Powder XRD of the samples were determined by using X-ray Difractometer, PANanytical, X'pert PRO, X'celerator, X-ray tube with Cu target anode, Divergence slits 15, Receiving slit 0.10mm, Scatter slit 1 °, Power: 45 KV, 40 mA, Scanning speed: 2.122 deg/min,Wave length: 1.5406A.
• TGA of the samples were determined by using Instrument: TA Instruments,
• the present invention provides an improved and a cost effective industrial process for the preparation of high pure strontium ranelate hydrates like strontium ranelate octahydrate (la), strontium ranelate tetrahydrate (lb) and strontium ranelate monohydrate (lc).
• the present invention provides strontium ranelate octahydrate and other hydrates obtained by the described process are having purity greater than 99.50% and more preferably greater than 99.80% as measured by HPLC.
• the present invention provides a process to obtain strontium ranelate octahydrate and other hydrates having very less process related impurities, the individual impurities lower than 0.2 % and more preferably lower than 0.1 % , and total impurities lower than 0.5% and more preferably lower than 0.2% as measured by HPLC.
• the present invention provides a process to obtain strontium ranelate octahydrate and other hydrates having very negligible residual solvent impurities or organic volatile impurities which are lower than ICH norms.
• the present invention provides an improved process for the preparation of amino diester of formula-ll, which comprises,
• step b) heating the reaction mixture obtained in step a) to form triethylamine complex of formula-VI I in situ.
• Yet another embodiment of the present invention wherein the organic solvent is used in reaction of dimethyl 3-oxoglutarate, malononitrile and triethylamine is selected from a C C 4 alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone and mixtures thereof, preferably methanol.
• a C C 4 alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone and mixtures thereof, preferably methanol.
• Yet another embodiment of the present invention further involves compound of complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine formed in situ is reacted with sulfur without isolating the triethylamine complex to provide an amino diester of formula-ll.
• Another embodiment of the present invention provides process for the preparation of the tetra methyl ester of formula-Ill, which comprises,
• step a) of reaction of compound of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate with methyl bromoacetate is carried out in an organic solvent in presence of an inorganic base and a catalyst-cetrimide, a C-
• the reaction is carried out at reflux temperature, about 80-82°C followed by isolation of a compound of formula-Ill,
• organic solvent used in the reaction of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate and methyl bromoacetate is selected from a C C 4 alcohol, such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone and the nitriles such as acetonitrile and the mixtures thereof, preferably acetonitrile.
• a C C 4 alcohol such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone
• Yet another embodiment of the present invention wherein the inorganic base used in reaction of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate and methyl bromoacetate is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably potassium carbonate.
• In one embodiment of the present invention provides preparation of strontium ranelate octahydrate of formula-la by hydrolyzing the tetraester of formula-lll.
• Another embodiment of present invention provides process for the preparation of strontium ranelate, octahydrate of formula-la, which comprises: a) addition of tetraester of formula-lll to the strontium hydroxide in an aqueous medium,
• step b) heating the reaction mass obtained in step a) about 100 -102°C,
• Yet another embodiment of the present invention provides process for preparation of strontium ranelate tetrahydrate of formula-lb, which comprises: a) addition of strontium ranelate octahydrate of formula-la into the isopropanol, b) heating the reaction mass obtained in step a) at about 80 - 85°C,
• Yet another embodiment of the present invention provides process for the preparation of strontium ranelate monohydrate of formula-lc, polymorph form, which comprises; a) charging of strontium ranelate octahydrate in to a rotocone vacuum dryer, b) heating the product preferably at 95 -100°C under vacuum,
• One embodiment of the present invention provides a process to obtain a new polymorphic Form-F of crystalline strontium ranelate monohydrate in well defined crystalline form which can be reproduced.
• Another embodiment of the present invention relates to strontium ranelate octahydrate characterized by a water content of about 22.50 wt.% measured by LOD.
• the octahydrate of strontium ranelate has a water content of about 21.0 wt.% to about 23.50 wt.%.
• Another embodiment of the present invention relates to strontium ranelate tetrahydrate characterized by a water content of about 12.21 wt.% measured by LOD.
• the tetrahydrate of strontium ranelate has a water content of about 11 .0 wt.% to about 13.0 wt.%.
• Another embodiment of the present invention relates to a new crystalline Form-F of strontium ranelate monohydrate characterized by a water content of 3.65 wt.% measured by TGA.
• the monohydrate of strontium ranelate has a water content of about 2.50 wt. % to about 5.0 wt.%.
• Another embodiment of the present invention relates to a new crystalline Form-F of strontium ranelate monohydrate characterized by a water content of 3.68 wt.% measured by LOD.
• the monohydrate of strontium ranelate has a water content of about 2.5% to about 5.0 wt.%.
• the crystalline strontium ranelate octahydrate of the present invention having characteristic X-ray powder diffraction pattern is shown in Figure-1 and peak values are shown in table-l.
• the crystalline Form-F of strontium ranelate monohydrate of the present invention having characteristic X-ray powder diffraction pattern, shown in Figure-3, having peaks with the following characteristic peak values (2 ⁇ ): 26.82, 25.59, 27.29, 9.29, 16.34, 10.48, 13.32, 17.41 , 18.54, 24.74, 29.08, 29.59, 33.00, 35.12 and 13.77 ⁇ 0.2.
• the crystalline Form-F of strontium ranelate monohydrate has an X-ray powder diffraction pattern corresponding to Figure-3 the diffraction angles and the relative intensities are given in the table-Ill.
• Example-1 Process for the preparation of methyl 5-amino-4-cvano-3-(2-methoxy-2- oxoethyl)-2-thiophenecarboxylate of formula-ll:
• Example-2 Process for the preparation of methyl 5-fbis(2-methoxy-2- oxoethyl) amino1-4-cvano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-Ill:
• Acetonitrile (700 ml), potassium carbonate (95.13 g), compound of formula-ll (100 g), cetrimide (4.0 g) and methyl bromoacetate (132.24 g) were charged in to a round bottom flask and heated at 80-82°C for 4 hours. Later reaction mass was cooled to 25-30°C and filtered the inorganic salts, the filtrate was concentrated to give crude product, which was crystallized from methanol, filtered and dried to furnish pure title compound.
• Strontium hydroxide (153.50 g), DM water (3500 ml) and the compound of formula-Ill (100 g) were charged in to a round bottom flask and heated at 100°C-102°C for 12 hours. Reaction mass was cooled and filtered the product. The product was taken in to aqueous isopropanol, heated for 2 hours, filtered and dried to obtain pure title product
• Example-4 Process for the preparation of strontium ranelate tetrahvdrate of formula-
• Strontium ranelate octahydrate (100 g) and isopropanol (600 ml) were charged in to a round bottom flask and heated at 80-85°C for 2 hours. Cooled the reaction mass to room temperature, filtered the material and dried at 60-65°C for 4 hours to give title compound of formula lb.
• Example-5 Process for the preparation of strontium ranelate monohydrate, Form-F of formula-lc:
• Strontium ranelate octahydrate 150 g was charged into a rotocone vacuum dryer and heated at 95°C-100°C for 25 hours under vacuum. Then dryer is cooled to room temperature and material is collected.

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• 2012
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