WO2011016738A1 - A process for the synthesis of 1-hydroxy-3-(n-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate - Google Patents
A process for the synthesis of 1-hydroxy-3-(n-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate Download PDFInfo
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- WO2011016738A1 WO2011016738A1 PCT/PL2010/000066 PL2010000066W WO2011016738A1 WO 2011016738 A1 WO2011016738 A1 WO 2011016738A1 PL 2010000066 W PL2010000066 W PL 2010000066W WO 2011016738 A1 WO2011016738 A1 WO 2011016738A1
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- WIPO (PCT)
- Prior art keywords
- methylpentylamino
- hydroxy
- propylidene
- monohydrate
- temperature
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 59
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 23
- 150000004682 monohydrates Chemical class 0.000 title claims abstract description 16
- LXLBEOAZMZAZND-UHFFFAOYSA-M sodium;hydroxy-[1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate Chemical compound [Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O LXLBEOAZMZAZND-UHFFFAOYSA-M 0.000 title claims abstract description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 25
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000011541 reaction mixture Substances 0.000 claims abstract description 19
- 238000002425 crystallisation Methods 0.000 claims abstract description 14
- YDWXRULMHQZBEX-UHFFFAOYSA-N 3-[methyl(pentyl)amino]propanoic acid;hydrochloride Chemical compound Cl.CCCCCN(C)CCC(O)=O YDWXRULMHQZBEX-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012296 anti-solvent Substances 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 3
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- -1 propylidene bisphosphonate monohydrate Chemical compound 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- IVFGIXMLURJXBZ-UHFFFAOYSA-N 1-phosphonopropylphosphonic acid Chemical compound CCC(P(O)(O)=O)P(O)(O)=O IVFGIXMLURJXBZ-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000002955 isolation Methods 0.000 claims description 5
- HLLNRPFJWJFNTN-UHFFFAOYSA-N CCC(OP(O)=O)OP(O)=O Chemical compound CCC(OP(O)=O)OP(O)=O HLLNRPFJWJFNTN-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- ZIZXLLSZOWGNDG-UHFFFAOYSA-N 1-phosphonopropylphosphonic acid hydrochloride Chemical compound Cl.CCC(P(O)(O)=O)P(O)(O)=O ZIZXLLSZOWGNDG-UHFFFAOYSA-N 0.000 claims description 3
- PTZBFESFWFFWAP-UHFFFAOYSA-M [Na+].CCC(P(O)(O)=O)P(O)([O-])=O Chemical compound [Na+].CCC(P(O)(O)=O)P(O)([O-])=O PTZBFESFWFFWAP-UHFFFAOYSA-M 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 230000003226 decolorizating effect Effects 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- 238000004042 decolorization Methods 0.000 claims 1
- 238000000634 powder X-ray diffraction Methods 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 239000003021 water soluble solvent Substances 0.000 claims 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 abstract description 19
- 230000000977 initiatory effect Effects 0.000 abstract 1
- 229960005236 ibandronic acid Drugs 0.000 description 19
- 239000000047 product Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 229940122361 Bisphosphonate Drugs 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- VBDRTGFACFYFCT-UHFFFAOYSA-M sodium;hydroxy-[(1r)-1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate;hydrate Chemical compound O.[Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O VBDRTGFACFYFCT-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- 150000004663 bisphosphonates Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YWSCUVIPKSJBRU-UHFFFAOYSA-N 3-[methyl(pentyl)azaniumyl]propanoate Chemical compound CCCCCN(C)CCC(O)=O YWSCUVIPKSJBRU-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920002545 silicone oil Polymers 0.000 description 3
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 3
- 230000008719 thickening Effects 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001082241 Lythrum hyssopifolia Species 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GQLYNPWQUVCODN-UHFFFAOYSA-N [1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphonic acid;hydrochloride Chemical compound Cl.CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O GQLYNPWQUVCODN-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229940028286 ibadronate Drugs 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 239000002608 ionic liquid Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 206010041569 spinal fracture Diseases 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
Definitions
- Patent application WO 2007/023342 describes a process for the synthesis of bisphosphonic acids with a high yield of approx. 75-90%, in the reaction of a hydrochloride of an appropriate aminocarboxylic acid with phosphorous acid in toluene or ethyl acetate in the presence of alkylphosphonic anhydride, such as, for example, propylphosphonic anhydride.
- alkylphosphonic anhydride such as, for example, propylphosphonic anhydride.
- International patent applications WO 2006/081962 and WO 2007/127249 describe the processes for the synthesis of crystalline forms of ibandronic acid is described using silicone oil, toluene or a mixture of toluene and phosphoric acid as an additive to the reaction mixture.
- the second object of the instant invention is to be able to produce the ibandronate sodium monohydrate acid in acceptable quality.
- the first aspect of the present invention therefore discloses an improved process for the manufacture of l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid monosodium salt monohydrate. hi this process, the use of organic solvents was avoided and the reaction was carried out only in the presence of reagents. This results in homogeneous reaction medium and process costs are reduced.
- reaction mixture 70-80 0 C but preferably to about 75 0 C ,till the mass thickens.
- the heating of the reaction mixture is continued for about another hour at about 75 0 C.
- excess unreacted phosphorus trichloride is removed by methods such as concentration under reduced pressure.
- Anti-solvents are used to initiate crystallisation.
- the anti-solvents are organic solvents in which sodium ibandronate has limited solubility and they are selected preferable from a list of solvents selected from solvents such as water-miscible alcohols and ketones and preferably solvents such as methanol, ethanol, 1-propanol, 2-propanol, n-butanol, acetone and most preferably methanol or acetone.
- Acetone is added drop wise to the cooled solution of the sodium salt while maintaining the temperature in the flask in the range of about 0-5°C. The suspension is further stirred at this temperature.
- phosphorus trichloride which is used for the reaction has low boiling point, it is easier to remove it from the reaction mixture, and further its non-flammable properties are advantageous from the perspective of implementation on the industrial scale. Furthermore, phosphorous acid is the product of phosphorus trichloride hydrolysis and therefore there are no additional impurities formed during the course of the reaction.
- XRPD X-ray powder diffractogram
- FIG 2 is a diagrammatic representation of FIG 2
- the homogeneous reaction mixture was stirred at a temperature of 0-5°C for 0.5 hour.
- the mixture was then gradually heated for about 1 hour at a temperature of 73-75°C until the mass completely thickened. After thickening, the content was retained for further 1 hour at a temperature of 75 0 C.
- the precipitate of ibandronic acid monosodium salt was filtered and washed with 40.00 g of purified water and 24.00 g of methanol.
- the filtered and washed product was dried at a temperature of 50 0 C to afford 34.5 g (96%) of monosodium l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonate monohydrate as the required product.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the synthesis of 1-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate which consists in the reaction of phosphorus trichloride with an aqueous solution of 3-(N-methylpentylamino)propionic acid hydrochloride at a temperature of 0-80°C, removing excess unreacted phosphorus trichloride, hydrolysis of the reaction mixture under reflux, conversion of 1-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonic acid into its monosodium salt using sodium cation-containing alkaline substances, crystallisation using an anti-solvent. Also disclosed is a process for the synthesis of a polymorphic form of 1-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate which consists of initiating and carryout the crystallisation using acetone at a temperature of 0-5°C.
Description
A PROCESS FOR THE SYNTHESIS OF l-HYDROXY-3-(N-
METHYLPENTYLAMINO) PROPYLIDENE BISPHOSPHONIC ACID
MONOSODIUM SALT, MONOHYDRATE TECHNICAL FIELD:
This invention relates to the field of solid state chemistry of ibandronate sodium.
BACKGROUND ART Osteoporosis is a condition which is characterized by loss of the normal density of bone, resulting in brittle bones. Brittle bones are subject to fracture. The disease process can be silent (without symptoms) for several years. Post menopausal women are particularly susceptible to osteoporosis and its resulting effects. This invention relates to a process for the synthesis of l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate also known under the international non-proprietary name as ibandronate sodium.The most widely known salt of 1 -hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid is its monosodium salt monohydrate [CASRN 138926-19-9] used in the treatment of post- menopausal osteoporosis and to reduce the risk of vertebral fractures. l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid and the pharmaceutically acceptable salts thereof are disclosed in patents US 4,927,814 B and EP 252 504 B. They disclose a number of processes for the synthesis of bisphosphonates with a trialkylammonium substituent. Among others, method Ilia involves a reaction of a suitable aminocarboxylic acid with phosphorous or phosphoric acid and phosphorus trichloride.
According to the description, the reaction may be carried out in diluents, such as
chlorobenzene, tetrachloroethane or dioxane. The processes disclosed in patent literature for the preparation of bisphosphonates, including ibandronic acid, are generally based on the reaction of suitable carboxylic acids with phosphorus reagents, which are a mixture of phosphorous and/or orthophosphoric acid and phosphorus halides. Ibandronic acid is prepared from 3-(N-methylpentylamino)propionic acid or its hydrochloride. Various processes for the synthesis of bisphosphonic acids known in
the art result from different approaches to the issue of stirring the dense and viscous reaction mixture, ensuring its homogeneity and, in consequence, improving heat transfer which affects process yield and quality. International patent application WO 2006/134603 discloses a reaction which may be carried out using aliphatic hydrocarbons or cyclic ethers miscible with water, such as dioxane and tetrahydrofuran.
Patent application WO 03/097655 claims that the reaction is carried out in the presence of aromatic hydrocarbons, such as toluene or silicone oils, e.g. poly
(dimethylsiloxane). The said hydrocarbons or silicone oils are diluents, because they are not miscible with the components of the reaction mixture and the process is carried out in a biphase system. According to patent application WO 2007/083240 ibandronic acid or salts thereof may be prepared in the reaction of 3-(N-methylpentylamino)propionic acid with phosphorous acid or phosphorus halides in the presence of phenol or substituted phenols.
Bisphosphonates, including ibandronic acid, may alternatively be obtained according to the process of patent application US 2007/0142636 A in which the reaction is carried out in the presence of p-cresol and according to patent US 7,361,761 B in the presence of anisole.
International patent application WO 2008/070960 discloses a process of synthesis of ibandronic acid in the reaction of 3-(N-methylpentylamino)propionic acid with phosphorous acid and phosphorus trichloride in poly(ethylene glycol) with a molecular weight of approx. 400. US patent 7,332,603 B claims ionic liquids as the reaction medium.
Patent US 7,411,087 B provides a process of synthesis of bisphosphonates, including ibandronic acid, with a high yield of about 69-76% and the reaction is carried out in sulfolane. A similar yield of sodium ibandronate monohydrate, that is, 78%, can be obtained when the reaction between the carboxylic acid and phosphorous acid and phosphorus oxychloride is carried out in the presence of diethyl carbonate. It is known from patent application WO 2005/063779 that when the process is carried out using the same reagents but without the solvent, ibandronic acid with a lower yield of about 59% may be obtained.
Patent application WO 2007/023342 describes a process for the synthesis of bisphosphonic acids with a high yield of approx. 75-90%, in the reaction of a hydrochloride of an appropriate aminocarboxylic acid with phosphorous acid in toluene or ethyl acetate in the presence of alkylphosphonic anhydride, such as, for example, propylphosphonic anhydride. The high yield and purity of the product however involves the use of an expensive reagent. International patent applications WO 2006/081962 and WO 2007/127249 describe the processes for the synthesis of crystalline forms of ibandronic acid is described using silicone oil, toluene or a mixture of toluene and phosphoric acid as an additive to the reaction mixture.
Further, it is also important to obtain the appropriate polymorphic form. Patent application WO2006/024024 discloses a polymorphic form QQ and the processes for the preparation thereof. The form is identical (Reference example 1 and Fig. 2) to form B from application WO2006/081962. Patent application WO2006/024024 discloses the processes for the synthesis of form QQ from amorphous ibandronic acid or sodium ibandronate by crystallisation at room temperature from mixtures of water and organic solvents, such as tetrahydrofuran, acetone and ethanol. In the case of water / THF and water / acetone systems, process yields were approx. 70%-80%. Owing to crystallisation from the water/ethanol system, yields of more than 90% were obtained.
The processes of synthesis of form B of sodium ibandronate monohydrate is disclosed in application WO2006/081962 which resulted in yields of approx. 80%. The claimed crystallisation process of l-hydroxy-3-(N-methylpentylamino)propylidene bisphosphonic acid monosodium salt, monohydrate (form B) is conducted in a polar solvent (water) at a temperature of 10-45°C and crystallisation is initiated by adding a polar aprotic solvent (acetone, THF). Sodium ibandronate crystallised in this way may contain some amount of form A besides polymorphic form B. Manufacturing process of polymorphic form QQ is disclosed in patent application WO2006/024024 in example 39, wherein, 3 g of sodium ibandronate is dissolved in 18 mL of water at room temperature. 40 mL of THF is added in one portion to the resulting solution. The resulting suspension is stirred for 16 h at room temperature. The precipitate is filtered off, washed with 2x20 mL of THF and dried in the vacuum dryer at a temperature of 500C for 18 h. 2.42 g of sodium ibandronate form QQ is obtained, (fig 18 ) and fig. 2 in this patent application).
The X-ray powder diffractogram (XRPD) of the resulting compound is shown in Fig. 2 in this patent application. Given the propensity of a large section of the female population to being affected by conditions such as osteoporosis, there is a constant need to evolve improved methods to be able to synthesize drugs using cheaper and cost effective methods.
SUMMARY OF THE INVENTION
A major disadvantage of the aforementioned processes is, the addition of an additional agent to the reaction mixture by way solvents or diluents. The addition of solvents/diluents does not always ensure homogeneity of the reaction mixture and further, they frequently become the source of additional unwanted impurities. The process, time and resources needed to remove these additional unwanted impurities from the required product can substantially increase the cost of the final drug.
An aspect of the present invention, is a process for the synthesis of l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonic acid monosodium salt, monohydrate, the process comprising; a) reaction of a solution of 3-(N-methylpentylamino) propionic acid hydrochloride in water with phosphorus trichloride; b) removal of unreacted phosphorus trichloride; c) addition of water to the reaction mixture and carrying out hydrolysis; d) optionally decolourising the aqueous solution of l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid, hydrochloride; e) conversion of 1 -hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid into its monosodium salt in solution;
f) precipitation of monosodium l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonate monohydrate from the solution using at least one anti-solvent; g) isolation of monosodium l-hydroxy-3-(N-methylpentylamino)propylidene
sbisphosphonate monohydrate.
According to the second aspect of the invention is the crystallization of a particular polymorphic form of ibadronate sodium with the following XRPD pattern., wherein,
the XRPD pattern of the polymorphic form is characterized by the values of about : 9.73; 12.26; 14.39; 16.77; 17.20; 20.02; 25.81 +/- 0.02 [ °2Th.
and the steps involved in the crystallization are ; a) dissolution of sodium ibandronate in water; b) concentration of the solution; c) cooling the residue; d) addition of acetone to initiate the crystallisation of monosodium 1 -hydroxy-3- (N-methylpentylamino) propylidene bisphosphonate, monohydrate at a temperature
. of 0-50C e) isolation, washing and drying of monosodium l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonate, monohydrate.
This invention provides a process for the synthesis of l-hydroxy-3-(N- methylpentylamino) propylidene, bisphosphonic acid, monosodium salt, monohydrate which is not only cost effective but also affords the desired product in acceptable quality and yields.
DISCLOSURE OF INVENTION
One object of the instant invention is to reduce costs of production of ibandronate sodium monohydrate.
The second object of the instant invention is to be able to produce the ibandronate sodium monohydrate acid in acceptable quality.
The third object of the instant invention is to have a method of synthesis of ibandronate sodium monohydrate that in addition to the above also affords the product in good yield.
The first aspect of the present invention therefore discloses an improved process for the manufacture of l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid monosodium salt monohydrate. hi this process, the use of organic solvents was avoided and the reaction was carried out only in the presence of reagents. This results in homogeneous reaction medium and process costs are reduced.
The process for the synthesis according to the invention consists of the following general steps:
In one embodiment of this invention, 3-(N-methylpentylamino) propionic acid hydrochloride is added drop wise to a reaction vessel which contains phosphorus trichloride, cooled to a temperature range of approx. 0-80°C and preferably at 0-50C . The resulting reaction mixture is allowed to react while gradually heating to a temperature range to approx.
70-800C but preferably to about 750C ,till the mass thickens. The heating of the reaction mixture is continued for about another hour at about 750C. In one embodiment of this invention, excess unreacted phosphorus trichloride is removed by methods such as concentration under reduced pressure.
The residue is cooled and purified water is added drop wise to obtain a homogeneous solution. This is followed by hydrolysis. The cooled reaction mixture is filtered to afford
l-hydroxy-3-(N-methylpentylamino) propylidene] bisphosphonic acid, hydrochloride which is then converted to the corresponding monosodium salt using cooled aqueous solutions of base such as those selected from sodium hydroxide, sodium bicarbonate, sodium carbonate etc are added into the reaction medium while taking care that the pH remains in the range of approximately 4.4 and 4.5.
Anti-solvents are used to initiate crystallisation. The anti-solvents are organic solvents in which sodium ibandronate has limited solubility and they are selected preferable from a list of solvents selected from solvents such as water-miscible alcohols and ketones and preferably solvents such as methanol, ethanol, 1-propanol, 2-propanol, n-butanol, acetone and most preferably methanol or acetone.
The cooled suspension is filtered and dried and sodium ibandronate monohydrate is obtained.
While carrying out the above reaction, the molar ratio of 3-(N-methylpentylamino) propionic acid hydrochloride to phosphorus trichloride and water is 1 :6:6;
According to the second aspect of the present invention is the synthesis of a polymorphic form of sodium ibandronate monohydrate.
In one embodiment of this invention the said polymeric form is obtained by suspension of ibandronic acid sodium salt in water. Then the suspension is heated with stirring (until the sodium salt dissolves). Subsequently, the solution is concentrated by distillation under reduced pressure and the residue is cooled to a temperature of about 00C.
Acetone is added drop wise to the cooled solution of the sodium salt while maintaining the temperature in the flask in the range of about 0-5°C. The suspension is further stirred at this temperature.
The reaction mixture is filtered and the residue is washed with water - acetone mixture (1 :2). The residue is then dried to afford the expected polymorphic form (Fig. 1) of monosodium l-hydroxy-3-(N-methylpentylamino)propylidene bisphosphonate monohydrate in 95% yield.
The instant invention considerably reduces the costs of production of the ibandronic acid by using the above method. Firstly by following the above procedure, the use of the solvent and cost of removal of excess solvent after the completion of the reaction is eliminated.
Secondly, the cost of purification of the product from the unwanted residues
/impurities is eliminated and the entire process can be carried out in one pot starting from the synthesis of ibandronic acid till the isolation of its monosodium salt.
Thirdly, since phosphorus trichloride which is used for the reaction has low boiling point, it is easier to remove it from the reaction mixture, and further its non-flammable properties are advantageous from the perspective of implementation on the industrial scale. Furthermore, phosphorous acid is the product of phosphorus trichloride hydrolysis and therefore there are no additional impurities formed during the course of the reaction.
Further, it was observed that by the above mentioned procedure, the thickening of the reaction mass in the final phase of phosphonation and during phosphorus trichloride distillation does not affect product quality and yield. Sufficient care is taken that the reaction vessel is heated with a mild heating medium, such as heated water. Even though stirring conditions are less favourable or even stirring stops altogether, heat transfer is sufficient for the reaction and to distil off excess phosphorus trichloride. Until the step involving hydrolysis, the reaction vessel is heated gently using heated water, which prevents overheating of the thickening mass and generation of unwanted impurities.
Importantly, by using the above mentioned process, ibandronic acid does not have to be isolated from the reaction mixture and purified. During the step of conversion of 1 -hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid hydrochloride into its monosodium salt, the appropriate pH conditions are maintained . Also during the crystallisation of the monosodium salt, by the addition of a suitable anti-solvent the desired product i.e. sodium ibandronate monohydrate can be obtained in a high yield of approx. 85-96%.
BRIEF DESCRIPTION OF DRAWINGS
FIG:1:
The X-ray powder diffractogram (XRPD) of the polymorphic ibandronate sodium as synthesised as part of the instant invention.
FIG 2:
The X-ray powder diffractogram (XRPD) of the polymorphic ibandronate sodium described in WO2006/024024, Example 39, (figure -18)
BEST MODE FOR CARRYING OUT THE INVENTION
The following non limiting examples are further illustrated for reference .
EXAMPLE- 1.
Synthesis of [l-hydroxy-3-(N-methylpentylamino) propylidene] bisphosphonic acid monosodium salt monohydrate.
21.0O g [0.10 mol] of 3-(N-methylpentylamino) propionic acid hydrochloride in 10.8 g [0.60 mol] of water was added drop wise (over a period of 0.5-1.5 hours) to 82.40 g [0.60 mol] of phosphorus trichloride, previously cooled to a temperature of 0 to 50C .The rate of addition was such that the temperature of the reaction mixture did not exceed 5°C.
Subsequently, the homogeneous reaction mixture was stirred at a temperature of 0-5°C for 0.5 hour. The mixture was then gradually heated for about 1 hour at a temperature of 73-75°C until the mass completely thickened. After thickening, the content was retained for further 1 hour at a temperature of 750C.
Subsequently, excess phosphorus trichloride was distilled off from the reaction mixture under reduced pressure while maintaining the temperature of the heating medium at 75°C.
The distillation residue was cooled and 100.00 g of purified water was added drop wise for 0.5 hour to obtain a homogeneous solution. Subsequently, the content was heated to a temperature of 100-1040C and maintained at the same temperature (boiling) for 6 hours. After the end of hydrolysis, the aqueous solution containing l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonic acid hydrochloride was cooled to a temperature below 90°C .
The decolouration was achieved by adding 1.00 g of activated carbon and 1.00 g of diatomaceous earth (Hyflo super cell) to the reaction flask. The content was heated to boiling and maintained under reflux for 0.5 hour. The reaction mixture was then cooled to a temperature below 90°C and filtered. The residue containing the activated carbon and the diatomaceous earth was discarded. In order to convert l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid hydrochloride into its monosodium salt, a 45% sodium hydroxide solution was added to the clear filtrate at a temperature of 55-60°C while maintaining the pH at 4.4-4.5.
Subsequently, 120.00 g of methanol (anti solvent) was added to the solution at a temperature of 55-600C for 0.25 hour and the product precipitated. The suspension was cooled to a temperature of 18-200C and stirred in these conditions for 2 hours.
The precipitate of ibandronic acid monosodium salt was filtered and washed with 40.00 g of purified water and 24.00 g of methanol. The filtered and washed product was dried at a temperature of 500C to afford 34.5 g (96%) of monosodium l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonate monohydrate as the required product.
1H NMR (D2O): δ=3.56 ppm (m, IH); 3.33 (m, IH); 3.22 (m, IH); 3.06 (m, IH); 2.85 (s, 3H); 2.36 (m, 2H); 1.73 (m, 2H); 1.35 (m, 4H); 0.89 (t, J=6.4 Hz, 3H)
31P(1HJ NMR (D2O): δ=20.54 ppm (d, JP,P=30.0 Hz); 20.62 (d, JP,P=30.0 Hz)
13C NMR (D2O): 6=74.9 ppm (t, JC,P=135 Hz); 59.1 ; 55.7 (t, JC,F=7 HZ); 42.1 ; 30.5; 30.5; 26.0; 24.2; 15.8
XRPD: 9.74; 12.27; 14.37; 16.78; 17.17; 20.03. 25.78 +/- 0.02 [ °2Th.]
EXAMPLE- 2.
Synthesis of [l-hydroxy-3-(N-methylpentylamino)propylidene]bisphosphonic acid monosodium salt monohydrate.
The same procedure as described for example 1 was used to react 82.40 g [0.60 mol] of phosphorus trichloride with 21.00 g [0.10 mol] of 3-(N-methylpentylamino) propionic acid hydrochloride in 10.8 g [0.60 mol] of water. All the steps were done as described for example- 1, till the l-hydroxy-3-(N-methylpentylamino) proylidene, bisphosphonic acid, monosodium salt was obtained.
Subsequently, 160.00 g of acetone (anti solvent) was added to the solution at a temperature of 55-60°C for 0.25 hour and the product was precipitated. The suspension was then cooled to a temperature of 18-20°C and stirred in these conditions for 2 hours.
The precipitate of ibandronic acid monosodium salt was filtered and washed with 40.00 g of purified water and 24.00 g of acetone. The filtered and washed product was dried at a temperature of 500C to afford 30.5 g (85%) of monosodium l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonate, monohydrate as the required product.
1H NMR (D2O): δ=3.56 ppm (m, IH); 3.33 (m, IH); 3.22 (m, IH); 3.06 (m, IH); 2.85 (s, 3H);
2.36 (m, 2H); 1.73 (m, 2H); 1.35 (m, 4H); 0.89 (t, J=6.4 Hz, 3H)
31P (1H) NMR (D2O): δ=20.54 ppm (d, JP,P=30.0 Hz); 20.62 (d, JP,P=30.0 Hz)
13C NMR (D2O): δ=74.9 ppm (t, JC,P=135 Hz); 59.1; 55.7 (t, JCiP=7 Hz); 42.1; 30.5; 30.5; 26.0; 24.2; 15.8
XRPD: 9.73; 12.26; 14.39; 16.77; 17.20; 20.02; 25.81 +/- 0.02 [ °2Th.]
EXAMPLE-3
Synthesis of polymorphic form of l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid, monosodium salt, monohydrate.
150 mL of water and 33.35 g (0.9 mol) of ibandronic acid monosodium salt were added to a round-bottom flask. The suspension was heated to 800C with stirring for 30 min (until the sodium salt dissolves). Subsequently, the solution was concentrated to a volume of 100 mL by distillation under reduced pressure and the residue was cooled to a temperature of 00C.
200 mL of acetone was then added drop wise to the cooled solution of the sodium salt for 30 min maintaining the temperature in the flask in the range of 0-50C. The suspension was further stirred at this temperature for 4 hours.
The reaction mixture was filtered and the residue was washed twice with 2 x 27 mL portions of water - acetone mixture (1 :2). The residue was then dried at a temperature of 9O0C for 17 hours to afford 31.6 g (0.088 mol) of the required polymorphic form (Fig. 1) of monosodium l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonate, monohydrate in 95% yeild.
1H NMR (D2O): δ=3.56 ppm (m, IH); 3.33 (m, IH); 3.22 (m, IH); 3.06 (m, IH); 2.85 (s, 3H); 2.36 (m, 2H); 1.73 (m, 2H); 1.35 (m, 4H); 0.89 (t, J=6.4 Hz, 3H)
31P(1H) NMR (D2O): δ=20.54 ppm (d, JP;P=30.0 Hz); 20.62 (d, JP;P=30.0 Hz)
13C NMR (D2O): 5=74.9 ppm (t, Jc,p=135 Hz); 59.1; 55.7 (t, JC,P=7 Hz); 42.1 ; 30.5; 30.5; 26.0; 24.2; 15.8
XRPD: 9.73; 12.26; 14.39; 16.77; 17.20; 20.02; 25.81 +/- 0.02 [ °2Th.]
ABBREVIATION:
XRPD : X-ray powder diffractogram .
Claims
CLAIMS:
1) A process for the synthesis of l-hydroxy-3-(N-methylpentylamino) propylidene
bisphosphonic acid monosodium salt, monohydrate, the process comprising: a) reaction of a solution of 3-(N-methylpentylamino) propionic acid hydrochloride in water with phosphorus trichloride; b) removal of unreacted phosphorus trichloride; c) addition of water to the reaction mixture and carrying out hydrolysis; d) optionally decolourising the aqueous solution of l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid, hydrochloride; e) conversion of l-hydroxy-3-(N-methylpentylamino) propylidene bisphosphonic acid into its monosodium salt in solution; f) precipitation of monosodium l-hydroxy-3-(N-methylpentylamino) propylidene
bisphosphonate monohydrate from the solution using at least one anti-solvent; g) isolation of monosodium l-hydroxy-3-(N-rnethylpentylamino) propylidene
bisphosphonate monohydrate. 2) The process as claimed in claim 1 wherein in step (a), the molar ratio of 3-(N- methylpentylamino) propionic acid hydrochloride to phosphorus trichloride and water is 1 :6:6;
3) The process, as claimed in claims 1 to 2, wherein in step (a), the reaction of 3-(N- methylpentylamino) propionic acid hydrochloride with phosphorus trichloride of step (a) is carried out at a temperature of 0-800C, and more preferably first at a temperature of 0-50C and subsequently at a temperature of 70-800C, and more preferably at 750C;
4) The process as claimed in claims 1 to 3, wherein in step (b), the unreacted phospohorous trichloride is removed by methods such as under reduced pressure with slow heating; 5) The process as claimed in claims 1 to 4, wherein in step (c), the hydrolysis is carried out at a temperature of 100-1050C, and preferably under reflux;
6) The process as claimed in claims 1 to 5, wherein in step (d), activated carbon is used as an agent for decolourisation of the solution;
7) The process, as claimed in claims 1 to 6, wherein in step (e), l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonic acid hydrochloride is converted into its monosodium salt at an acidic pH and preferably at a pH of 4.4-4.5; 8) The process as claimed in claims 1 to 7, wherein in step (e), the monosodium salt of l-hydroxy-3-(N-methylpentylamino) propylidene, bisphosphonic acid is synthesized using sodium cation-containing alkaline substances, selected from a group comprising of sodium hydroxide, sodium carbonate, sodium bicarbonate and the like; 9) The process as claimed in claims 1 to 8, wherein in step (f), the anti-solvents used are water soluble solvents selected from the group comprising of water soluble methanol, ethanol, 1-propanol, 2-propanol, n-butanol, and water soluble ketones such as acetone and combinations thereof; 10) A process of obtaining a crystalline form of l-hydroxy-3-(N-methylpentylamino) propylidene, bisphosphonic acid monosodium salt monohydrate, wherein the XRPD pattern of the polymorphic form is about,
9.73; 12.26; 14.39; 16.77; 17.20; 20.02; 25.81 +/- 0.02 [ °2Th.]
and the steps involved in crystallization are ; f) dissolution of sodium ibandronate in water; g) concentration of the solution;
h) cooling the residue; i) addition of acetone to initiate the crystallisation of monosodium l-hydroxy-3- (N-methylpentylamino) propylidene, bisphosphonate monohydrate at a temperature of 0-50C j) isolation, washing and drying of monosodium l-hydroxy-3-(N- methylpentylamino) propylidene bisphosphonate, monohydrate. 11) The process as claimed in claim 10, wherein in step (a), the weight ratio of sodium ibandronate to water is 1 :4 to 1 :5, and preferably 1 : 4.5.
12) The process as claimed in claims 10 to 11, wherein in step (b), the aqueous solution of sodium ibandronate is concentrated to 2/3 of its original volume.
13) The process as claimed in claims 10 to 12, , wherein in step (c), the concentrated solution is cooled to a temperature below 50C, and preferably 0-5°C;
14) The process as claimed in claims 10 to 13,, wherein in step (d) , acetone is added to the solution and crystallisation is carried out at a temperature of 0-50C.
15) The process as claimed in claims 10 to 14, wherein in step (d) , the volume ratio of the sodium ibandronate solution to acetone is 1 :2.
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| PLP-388725 | 2009-08-05 | ||
| PL388725A PL388725A1 (en) | 2009-08-05 | 2009-08-05 | Process for the preparation of monohydrate of monosodium salt of [1-hydroxy-3-(N-menthylpentylamino) propylidene] bisphosphonic acid |
| PLP-391423 | 2010-06-08 | ||
| PL391423A PL391423A1 (en) | 2010-06-08 | 2010-06-08 | Process for the preparation of polymorphic form of monohydrate of monosodium salt of [1-hydroxy-3-(N-menthylpentylamino) propylidene] bisphosphonic acid |
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| CN103030661A (en) * | 2012-11-16 | 2013-04-10 | 湖南方盛制药股份有限公司 | Method for preparing sodium ibandronate |
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| WO2009093258A2 (en) * | 2008-01-24 | 2009-07-30 | Fleming Laboratories Limited | A new and improved process for the preparation of ibandronate sodium monohydrate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103030661A (en) * | 2012-11-16 | 2013-04-10 | 湖南方盛制药股份有限公司 | Method for preparing sodium ibandronate |
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| Publication number | Publication date |
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| WO2011016738A8 (en) | 2011-11-24 |
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