WO2013175270A1 - Procédé amélioré pour la préparation d'hydrates de ranélate de strontium et nouvelle forme polymorphe monohydratée - Google Patents
Procédé amélioré pour la préparation d'hydrates de ranélate de strontium et nouvelle forme polymorphe monohydratée Download PDFInfo
- Publication number
- WO2013175270A1 WO2013175270A1 PCT/IB2012/052645 IB2012052645W WO2013175270A1 WO 2013175270 A1 WO2013175270 A1 WO 2013175270A1 IB 2012052645 W IB2012052645 W IB 2012052645W WO 2013175270 A1 WO2013175270 A1 WO 2013175270A1
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- WIPO (PCT)
- Prior art keywords
- strontium ranelate
- formula
- monohydrate
- preparation
- octahydrate
- Prior art date
Links
- 229940079488 strontium ranelate Drugs 0.000 title claims abstract description 89
- -1 strontium ranelate hydrates Chemical class 0.000 title claims abstract description 73
- 238000000034 method Methods 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 150000004682 monohydrates Chemical class 0.000 title description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 41
- ZHEZAQJNZMLYBA-UHFFFAOYSA-J distrontium;5-[bis(carboxylatomethyl)amino]-3-(carboxylatomethyl)-4-cyanothiophene-2-carboxylate;octahydrate Chemical compound O.O.O.O.O.O.O.O.[Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N ZHEZAQJNZMLYBA-UHFFFAOYSA-J 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 15
- 238000002411 thermogravimetry Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 11
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- RNJOKCPFLQMDEC-UHFFFAOYSA-N 4(R),8-dimethyl-trans-2-nonenoyl-CoA Chemical compound COC(=O)CC(=O)CC(=O)OC RNJOKCPFLQMDEC-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- BLYLWUDQKYBGJD-UHFFFAOYSA-N methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate Chemical compound COC(=O)CC1=C(C(=O)OC)SC(N)=C1C#N BLYLWUDQKYBGJD-UHFFFAOYSA-N 0.000 claims description 7
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 229960002798 cetrimide Drugs 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- UUCCCPNEFXQJEL-UHFFFAOYSA-L strontium dihydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 claims description 5
- 229910001866 strontium hydroxide Inorganic materials 0.000 claims description 5
- IXLRCPSVPMSMMM-UHFFFAOYSA-N methyl 3-(dicyanomethylidene)-5-hydroxy-5-methoxypent-4-enoate Chemical compound COC(=O)CC(=C(C#N)C#N)C=C(O)OC IXLRCPSVPMSMMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 claims description 2
- 239000012736 aqueous medium Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 238000001757 thermogravimetry curve Methods 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 8
- WJKLKWHUBHCSFS-UHFFFAOYSA-N 5-[bis(carboxymethyl)amino]-3-(carboxymethyl)-4-cyanothiophene-2-carboxylic acid;strontium Chemical compound [Sr].[Sr].OC(=O)CN(CC(O)=O)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N WJKLKWHUBHCSFS-UHFFFAOYSA-N 0.000 description 27
- 239000003960 organic solvent Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 229940086542 triethylamine Drugs 0.000 description 11
- 239000008186 active pharmaceutical agent Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000004689 octahydrates Chemical class 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- 229960004592 isopropanol Drugs 0.000 description 6
- 210000000988 bone and bone Anatomy 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000004685 tetrahydrates Chemical class 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- AYCCQDIBOMUCEW-UHFFFAOYSA-N methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate Chemical compound COC(=O)CN(CC(=O)OC)C=1SC(C(=O)OC)=C(CC(=O)OC)C=1C#N AYCCQDIBOMUCEW-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000008416 bone turnover Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 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 description 2
- 229950003464 ranelic acid Drugs 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 0 C*C(CN(CC(O)=O)c([s]c(C(*)=O)c1CC(*)=O)c1C#N)=O Chemical compound C*C(CN(CC(O)=O)c([s]c(C(*)=O)c1CC(*)=O)c1C#N)=O 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 102100025490 Slit homolog 1 protein Human genes 0.000 description 1
- 101710123186 Slit homolog 1 protein Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- JIUIIWVYHWSFAZ-UHFFFAOYSA-N ac1o0v2m Chemical compound O.O.O.O.O JIUIIWVYHWSFAZ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229910001631 strontium chloride Inorganic materials 0.000 description 1
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 description 1
- 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 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 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
-
- 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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Abstract
La présente invention concerne un procédé amélioré pour la préparation d'hydrates de ranélate de strontium purs (Ia-c) en utilisant les intermédiaires, amino diméthyl ester (II) et tétraméthyl ester (III), qui sont préparés par de nouveaux procédés. La présente invention concerne également une nouvelle forme polymorphe cristalline de la forme monohydratée de ranélate de strontium F, et un procédé pour sa préparation. Formules (Ia-c) : Ia- ranélate de strontium octahydraté : n = 8 Ib- ranélate de strontium tétrahydraté : n = 4 Ic- ranélate de strontium monohydraté : n = 1 formule (II) et formule (III).
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Citations (3)
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WO2004029036A1 (fr) * | 2002-09-24 | 2004-04-08 | Les Laboratoires Servier | Nouveau procede de synthese industriel du ranelate de strontium et de ses hydrates |
WO2010021000A2 (fr) * | 2008-08-22 | 2010-02-25 | Glenmark Generics Limited | Procédé de préparation de ranélate de strontium |
WO2010034806A1 (fr) * | 2008-09-29 | 2010-04-01 | Ratiopharm Gmbh | Formes anhydrates et hydrates de ranélate de strontium |
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WO2004029036A1 (fr) * | 2002-09-24 | 2004-04-08 | Les Laboratoires Servier | Nouveau procede de synthese industriel du ranelate de strontium et de ses hydrates |
WO2010021000A2 (fr) * | 2008-08-22 | 2010-02-25 | Glenmark Generics Limited | Procédé de préparation de ranélate de strontium |
WO2010034806A1 (fr) * | 2008-09-29 | 2010-04-01 | Ratiopharm Gmbh | Formes anhydrates et hydrates de ranélate de strontium |
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