TWI293304B - Process for the preparation of bisphosphonates - Google Patents
Process for the preparation of bisphosphonates Download PDFInfo
- Publication number
- TWI293304B TWI293304B TW094137688A TW94137688A TWI293304B TW I293304 B TWI293304 B TW I293304B TW 094137688 A TW094137688 A TW 094137688A TW 94137688 A TW94137688 A TW 94137688A TW I293304 B TWI293304 B TW I293304B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- reaction
- formula
- pentylamine
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title claims description 13
- 229940122361 Bisphosphonate Drugs 0.000 title description 3
- 150000004663 bisphosphonates Chemical class 0.000 title 1
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 7
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- UOIWOHLIGKIYFE-UHFFFAOYSA-N n-methylpentan-1-amine Chemical compound CCCCCNC UOIWOHLIGKIYFE-UHFFFAOYSA-N 0.000 claims description 14
- -1 N-mercapto-N-pentyl-β-alanine oxime ester Chemical class 0.000 claims description 13
- 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 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical compound ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003849 aromatic solvent Substances 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical group CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 4
- 239000012022 methylating agents Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 3
- 229910052801 chlorine Inorganic materials 0.000 claims 3
- 239000000460 chlorine Substances 0.000 claims 3
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 2
- ADDZHRRCUWNSCS-UHFFFAOYSA-N 2-Benzofurancarboxaldehyde Chemical compound C1=CC=C2OC(C=O)=CC2=C1 ADDZHRRCUWNSCS-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 229910000831 Steel Inorganic materials 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 230000026731 phosphorylation Effects 0.000 claims 1
- 238000006366 phosphorylation reaction Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- AJIMGSCTFBEHSK-UHFFFAOYSA-M sodium;hydroxy-(1-hydroxy-1-phosphonopropyl)phosphinate Chemical compound [Na+].CCC(O)(P(O)(O)=O)P(O)([O-])=O AJIMGSCTFBEHSK-UHFFFAOYSA-M 0.000 claims 1
- 239000010959 steel Substances 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract description 4
- DRPKUPBGKFMTRM-UHFFFAOYSA-N (2-amino-1-hydroxy-1-phosphonopropyl)phosphonic acid Chemical compound CC(N)C(O)(P(O)(O)=O)P(O)(O)=O DRPKUPBGKFMTRM-UHFFFAOYSA-N 0.000 abstract 1
- 238000007040 multi-step synthesis reaction Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 6
- 229940015872 ibandronate Drugs 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 229940100684 pentylamine Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010533 azeotropic distillation Methods 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000003085 diluting agent Substances 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 2
- PDLNHDSYGLTYDS-UHFFFAOYSA-N 3-aminopropanoic acid;hydrochloride Chemical compound Cl.NCCC(O)=O PDLNHDSYGLTYDS-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- ILYVXUGGBVATGA-DKWTVANSSA-N (2s)-2-aminopropanoic acid;hydrochloride Chemical compound Cl.C[C@H](N)C(O)=O ILYVXUGGBVATGA-DKWTVANSSA-N 0.000 description 1
- 208000035404 Autolysis Diseases 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- PTVDYARBVCBHSL-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu] PTVDYARBVCBHSL-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 150000002371 helium Chemical class 0.000 description 1
- UROYYJZSTVLYKU-UHFFFAOYSA-N hydrazine;prop-2-enoic acid Chemical compound [NH3+]N.[O-]C(=O)C=C UROYYJZSTVLYKU-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- NOKUWSXLHXMAOM-UHFFFAOYSA-N hydroxy(phenyl)silicon Chemical compound O[Si]C1=CC=CC=C1 NOKUWSXLHXMAOM-UHFFFAOYSA-N 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- ZWKFEVVFVAGPDE-UHFFFAOYSA-N methyl 3-[methyl(pentyl)amino]propanoate Chemical compound CCCCCN(C)CCC(=O)OC ZWKFEVVFVAGPDE-UHFFFAOYSA-N 0.000 description 1
- UZCXPYDBYUEZCV-UHFFFAOYSA-N methyl 3-aminopropanoate Chemical group COC(=O)CCN UZCXPYDBYUEZCV-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical compound COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- IKVDMBQGHZVMRN-UHFFFAOYSA-N n-methyldecan-1-amine Chemical compound CCCCCCCCCCNC IKVDMBQGHZVMRN-UHFFFAOYSA-N 0.000 description 1
- NNTVKFAXDYRERB-UHFFFAOYSA-N n-pentyl-1-phenylmethanimine Chemical compound CCCCCN=CC1=CC=CC=C1 NNTVKFAXDYRERB-UHFFFAOYSA-N 0.000 description 1
- 239000002135 nanosheet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 229920006389 polyphenyl polymer Polymers 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000028043 self proteolysis Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 239000008096 xylene Substances 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)]
-
- 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)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Physical Education & Sports Medicine (AREA)
- Molecular Biology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
1293304 九、發明說明： 【發明所屬之技術領域】 本發明係關於製備下式之單水合3_(N_甲基戊基）胺 基-1-羥丙烷-1，1-二膦酸單鈉鹽（伊班膦酸鹽）之方法：
【先前技術】 伊班膦酸鹽為直接抑制破骨細胞活性且提供用於控制高 血鈣症之有效藥理替代物之最有效抗吸收藥物中之一種。 伊班膦酸鹽在鈣化之骨骼中與羥磷灰石結合，使得其對磷 酸酶之水解溶解作用產生抗性，藉此抑制正常及異常之骨 絡吸收。此藥物增加骨㈣量且降低骨折危險，因此尤其 適用於骨路及#5代謝疾病，例如骨質疏鬆症或柏哲德氏症 (Paget’s disease)(EP-A 0252504)。 用於製備伊班膦酸鹽之下列方法在此項技術領域中係已 知的並已經過考慮。 舉例而言，EP 0402152揭示三水合4•胺基羥基亞丁 基-1-雙膦酸單鈉鹽結晶之製備法，其在三鹵化磷、亞磷酸 及甲烷磺酸存在下以一個步驟進行。此方法允許反應混合 物保持流體狀態。 WO 03/09765 5揭示雙膦酸之製備法，其包括在稀釋劑存 在下將羧酸與亞磷酸及磷醯氯組合之步驟。該稀釋劑包括 105354.doc !2933〇4 芳族烴，諸如f苯、二甲苯及苯 令A以性聚矽氧流體，諸 如聚二甲基矽虱烷及聚^基苯基矽氧烷。 入然而’在此項技術中所描述之方法在產量及純度上並不 令人滿意。 【發明内容】 因此本發明之目的係尋找以高產量低殘餘副產物方式產 生伊班膦酸鹽之新方法。 已發現該目的可由本發明之方法達成，該方法包含··
⑷將N-戊胺與苯甲I缩合以產生式〇之n_亞节基I 戊胺
(b)以甲基化劑將N-亞节基|戊胺轉化為&甲基#戊 胺； (、）以丙烯酉夂甲酿將N_甲基專戊胺轉化為式⑴之甲基· N-戊基-β-丙胺酸甲酯 CH3
III ⑷水解I甲基_N•戍基_β_丙胺酸甲醋且隨後形成氫齒化 105354.doc ?"3 1293304 物以產生式ιν之化合物 h3c
COOH
* HX 其中X為鹵素； (e)藉助於磷醯氯及亞磷酸將式IV之化合物雙磷酸化，且 在添加氫氧化鈉之後形成單水合單鈉鹽。 本务明方法之第一步驟a)包含將N-戊胺與苯甲駿縮合以 產生式II之N-亞节基-N-戊胺。 此縮合反應可在4(TC至9(TC之反應溫度下於合適溶劑（諸 如脂族醇）中進行，較佳在7(rc至75。〇下於甲醇中進行。 本發明方法之第二步驟b)包含以甲基化劑將N_亞节基_ N-戊胺轉化為N-甲基戊胺。 使用諸如曱基鹵化物或硫酸二甲醋之甲基化劑，但以硫 酸二甲酯為較佳。反應通常係在至ll〇t、較佳為9〇。〇 至l〇(TC之溫度下進行。視情況可藉由蒸汽蒸館來移除所 產生之苯甲醛且可以熟習此項技術者已知之任何方式將所 得N-甲基-N-戊胺自水相中分離，諸如藉由鹼的添加且以 合適有機溶劑（諸如脂《，較佳為二異㈣）萃取驗性溶 液產物可進-步純化，例如藉由蒸館方式進行。 在本毛月方法之第二步驟⑷中，以丙稀酸甲酯將甲 基-N-戊胺轉化為式叩之N_甲基_n_戊基-β_丙胺酸甲酯。 105354.doc 1293304 此轉化反應可在邮至65〇c之反應溫度（較佳為饥至 25°C)下於適當溶劑（諸如脂族醇、脂族醚或醚/醇混合物， 但較佳為甲醇）中進行。N_U_N•戊基_p•丙胺酸甲酿之分 離可由熟習此項技術者已知之技術（例如蒸餾法）進行。 在本發明方法之步驟（d)中，水解N_甲基_N_戊基1-丙胺 西欠甲8曰且隨後形成氫鹵化物以產生式IV之化合物。 通吊藉由在稀無機酸（但較佳為水）中回流N-甲基-戊 基-β-丙胺酸甲酯的方式進行水解，至少直至不能進一步偵 測到自曰離析物為止。隨後通常藉由添加氫氯酸水溶液的方 式形成氫齒化物，諸如氫溴酸鹽或氫氯酸鹽，較佳為氳氣 酸鹽（X=C1)。可藉由將水蒸餾且藉由在合適溶劑（諸如甲 苯/丙酮或甲基乙基酮，較佳為甲基乙基酮）中使殘餘物結 晶而分離所得N-甲基戊基-β-丙胺酸氫氣酸鹽。 本發明之步驟（e)包含藉助於磷醯氯及亞磷酸將式IV之化 合物雙磷酸化且形成單水合單鈉鹽。 N-甲基-N-戊基-β_丙胺酸氫氯酸鹽之雙磷酸化作用可在 非芳族溶劑存在下或無溶劑存在下發生。較佳使用非芳族 溶劑。 適當之非芳族溶劑為磷酸酯、膦酸酯或碳酸酯。較佳溶 劑為碳撻二乙酯。 使用填酿氣與亞磷酸之混合物作為磷酸化劑。队甲基一 Ν-戍基-β-丙胺酸氫氯酸鹽/磷醯氣/亞磷酸之莫耳比率通常 係選自 1:3:3至 1:1.4:2.4，較佳為！：ι·6:2.4至 1:1.4:2.4。 在雙罐酸化過程中反應温度適宜地保持在60°c至 105354.doc 1293304 100 C、較佳為8〇°c至90°c之範圍内。 在使用非芳族溶劑之狀況下，可获 ^ j稭由添加水且隨後共沸 蒸餾將非芳族溶劑理想地移除。 為分離單水合3-(N-甲基-N-戊基）胺基-羥丙烷_U_二 膊酸單銅鹽，在約⑽至饥範圍内之溫度下以氯氧化納 水溶液將殘餘水性反應混合物之pH值調節至約3 5至6、較 佳為4.4至4_5之pH值。 _ 如此獲得之伊班膦酸鹽可在合適溶劑中結晶，例如脂族 醇/水或脂族_ /水，較佳為乙醇/水及丙_ /水。 本發明之另一目的係提供製備式I之單水合3_(N_甲笑 N-戊基）胺基_1_羥丙烷-1，卜二膦酸單鈉鹽之方法 h3c
O' /OH p Na. · H2〇 〇^οηΓ〇η 該方法包含藉助於磷醢氯及亞填酸將式1 V之化合物雙磷 酸化 ch3 I 3
• HX 其中X為鹵素， 105354.doc -10- 1293304 且形成單水合單納鹽。 此方法之較佳實施例已在上述步驟e)中加以描述。對步 驟e)之描述以引用方式倂入本文中。 本發明之方法允許產生優越產量及品質之式I之單水合3· (N-曱基-N_戊基）胺基-1-羥丙烷-1，；1-二膦酸單鈉鹽。 【實施方式】 實例： a)製備N-亞节基-戊胺 在22C之溫度下將1〇〇 gu.b m〇1)N_戊胺添加至2〇〇如 甲醇中。添加121.8 g(l. 15 mol)苯甲醛。回流混合物且隨 後蒸餾出甲醇。殘餘之199.8 g(99 4〇/〇)N_亞苄基-戊胺用於 下一步驟中。 b)製備N-甲基-N-戊胺 在90C至lOOt之溫度下攪拌6〇 g(475 7随叫硫酸二甲 酯及67 g(382.2 mm〇i)N_亞节基_N_戊胺，且向混合物中添 加117 W純水。藉由蒸汽蒸餾將產生之苯甲醛移除。添加 "丙醚及54 ml氫氧化鈉溶液（5〇%)。分離水層。 蒸餾出二異丙趟。向殘餘物中添加33 §氣氧化納薄片以結 口殘餘之水以洛館法純化殘餘物，即粗甲基戍胺 (29.4 g ; 76%) 〇 c)製備N-甲基戊基j丙胺酸$酯 二二度其為°°C至5t之經冷卻甲醇中添加106以1·05 ΐΐ且在^戊胺。向溶液中添加108 g(1·25則1)丙烯酸 ”曰且在至溫下授掉混合物8小時。接著在真空下蒸潑出 J05354.doc 1293304 甲醇且以蒸餾法純化殘餘物以獲得188.6 giN_甲基_N_戊 基-β-丙胺酸甲酯（96.1%)。 d)製備Ν-曱基-Ν-戊基-β-丙胺酸氫氣酸鹽 藉由用138 ml水回流來水解68.8 g(367.4 mmol)N-甲基-戊基-β-丙胺酸曱酯。接著部分蒸餾出水且添加83 ml(472.7 mm〇l)氫氣酸（19%)。再次蒸餾出水並添加23〇 ml 甲基乙基酮以藉由共沸蒸餾移除殘餘之水。接著將反應混 φ 合物冷卻至24。〇。分離結晶產物並用甲基乙基酮洗滌且隨 後在真空中乾燥。獲得63.7 g(82.7%)N-甲基戊基-β-丙 胺酸氫氣酸鹽。 el)在碳酸二乙酯稀釋劑存在下製備單水合曱基 戊基）胺基-1-經丙烧-1，1-二膦酸單納鹽。 將250 g(1.19 mol)N-甲基戊基♦丙胺酸氫氯酸鹽、 233 g(2.84 mol)亞磷酸、151 ml(1.65 mol)磷醯氯及 900 ml 碳酸二乙酯逐步加熱至80°C。在持續加熱下反應2小時
春 後’將混合物冷卻至60 °C且添加1733 ml水，隨後在90 °C 至10 1 C下進行碳酸二乙酯/水之共沸蒸餾。添加358 ml 水，將混合物回流且蒸餾出水。添加3丨6 mi水且將水蒸館 出兩次。最後添加2040 ml水且將殘餘物冷卻至24〇c。在 23°C下以氫氧化鈉溶液（50%)將pH值調節至4.4。之後添加 1100 ml乙醇以開始結晶。在21°C至22°C下攪拌懸浮液8小 時。接著分離固體，用344 ml冷乙醇/純水（7/5 v/v)洗條， 隨後用344 ml丙酮/純水（5/2 V/V)洗滌並在⑼它下乾燥。獲 得315_6g(73.7%)呈無色晶體形式之標題產物。 105354.doc -12- 1293304 . I < 檢定（錯合滴定）：100.6%。 e2)製備單水合3-(N-甲基4戊基）胺基小羥丙烷_u二 膦酸單鈉鹽。 將36.3 g(m.8 mmol)N_甲基戊基_β_丙胺酸氫氯酸 鹽、33.9 g(413.2 mmol)亞磷酸、22.75 ml(248.6 mmol)磷 酿氣逐步加熱至80°C。在持續加熱下反應2小時後，將混 合物冷卻至60°C且添加25 1.7 ml水。將混合物回流並蒸餾 • 出水。添加46 ml水並將水蒸餾出兩次。添加296.5 rnkjc且 將殘餘物冷卻至24 °C。在23°C下以氫氧化鈉溶液（50%)將 pH值調節至4.5。之後添加159.7 ml乙醇以開始結晶。在 21°C至22°C下攪拌懸浮液8小時。接著分離固體，用90 ml 冷乙醇/純水（3/2 V/V)洗務，隨後用90 ml丙酮/純水（5/2 V/V)洗滌且在60°C下乾燥。獲得42.6 g(68.6%)呈無色晶體 形式之標題產物。 檢定（錯合滴定）：99.8%。
105354.doc 13-
Claims (1)
- 號專利申請案 -‘ 中文申請專利範圍替換本(96年2月) 十、申請專利範圍： 1. 一種製備式I之單水合3-(Ν-甲基-Ν-戊基）胺基_1_羥丙烷-1，1 -二膦酸單鈉鹽之方法， h3c〇 OH • 該方法包含： (a)將N-戊胺與苯曱醛縮合以產生式II之N·亞节基-N-戊胺，φ (b)以曱基化劑將N-亞节基-N-戊胺轉化為N-甲基-N- 戊胺； (c)以丙烯酸甲酯將N-甲基-N-戊胺轉化為式III之N-曱基-N-戊基-β-丙胺酸曱酯， CH. I 3S 105354-960216.doc 1293304 鹵 (d)水解N_甲基戊基♦丙胺 化物以產生式IV之化合物， 酸甲酯且隨後形成氫c〇〇H . HX 冉甲入為鹵素； ⑷藉助於義氯及亞磷酸將式Ιλ^化合物雙構㈣ 且形成單水合單鈉鹽。 明求項1之方法，其特徵為步驟a)之該縮合反應係在4 至90 C之溫度下於適當溶劑中進行。 •=求項1或2之方法’其特徵為步驟b)之該轉化反應肩 在80C至ii(TC之溫度下進行。 士 :求項1或2之方法，其特徵為步购之該轉化反應倍 以硫酸二甲酯作為甲基化劑來進行。 ^求項1或2之方法’其特徵為步驟。)之該轉化反應係 ▲ C至65t:之反應溫度下於適當溶劑中進行。 =求項1或2之方法’其特徵為步驟e)之該雙鱗酸化反 應係在非芳族溶劑存在下進行。 8 7.如：求項6之方法，其特徵為該溶劑為碳酸二乙S旨。 ，員1或2之方法’其特徵為在步驟勾之該雙磷酸化 1中1甲基|戍基}丙胺酸氫氯酸鹽/輕氯/亞填酸 之莫耳比率係選自1:3:3至1:1.4:2 4。 105354-960216.doc -2- 1293304 9·如請求項1或2之方法，其特徵為在步驟e)之該雙磷酸化 反應中反應溫度係選自6〇〇C至1〇〇。〇。 1 〇·如4求項1或2之方法，其特徵為該單水合單鈉鹽之形成 係藉由用氫氧化鈉水溶液將水性反應混合物之值調節 至約3.5至6的方式實現。 U·種製備式I之單水合3_(>^甲基_N_戊基）胺基羥丙烷_ 1，1 -二膦酸單納鹽之方法，h3ct孩方法包含藉助於磷醯氯及亞磷酸將式IV之化合物雙 磷酸化，?Η3 * HX 其中X為鹵素， 劑存在或無溶劑存在 其特徵為該雙磷酸化反應係在溶 下進行’其中該溶劑為碳酸二乙酉旨 且形成單水合單鈉鹽。 12 如請求項11之方法 其特徵為^甲基4戊基_β_丙胺 105354-960216.doc -3- Ϊ293304 耳比率係選自1:3:3至 氫氯酸鹽/磷醯氯/亞磷酸之莫 1:1.4:2.4 〇 八、试為該雙填酸化 至100°c之反應溫度下進行 14.:求項u之方法，其特徵為該單水合單鋼鹽之 :由用氯氧化鈉水溶液將水性反應混合“ ' 約3.5至6的方式實現。 值凋即至105354-960216.doc -4 -
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04105407 | 2004-10-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200621792A TW200621792A (en) | 2006-07-01 |
| TWI293304B true TWI293304B (en) | 2008-02-11 |
Family
ID=36097233
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW094137688A TWI293304B (en) | 2004-10-29 | 2005-10-27 | Process for the preparation of bisphosphonates |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US7214818B2 (zh) |
| EP (1) | EP1807090B9 (zh) |
| JP (1) | JP4560548B2 (zh) |
| KR (1) | KR100880061B1 (zh) |
| CN (1) | CN101048165B (zh) |
| AT (1) | ATE497769T1 (zh) |
| CA (1) | CA2585027C (zh) |
| DE (1) | DE602005026310D1 (zh) |
| ES (1) | ES2359415T3 (zh) |
| IL (1) | IL182690A (zh) |
| MX (1) | MX2007005114A (zh) |
| TW (1) | TWI293304B (zh) |
| WO (1) | WO2006045578A2 (zh) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2007000087A (es) * | 2004-06-23 | 2007-11-06 | Teva Pharma | Acido ibandronico solido y cristalino. |
| WO2007074475A2 (en) * | 2005-12-27 | 2007-07-05 | Natco Pharma Limited | Novel polymorphic forms of ibandronate |
| US8178712B2 (en) | 2006-06-23 | 2012-05-15 | Cipla Ltd. | Process for the synthesis of Ibandronate sodium |
| AU2007270897A1 (en) * | 2006-07-03 | 2008-01-10 | Generics [Uk] Limited | Novel process for the preparation of bisphosphonic acids |
| WO2008014510A2 (en) * | 2006-07-28 | 2008-01-31 | Dr. Reddy's Laboratories Limited | Crystalline form a of ibandronic acid and process for the preparation |
| TW200829256A (en) * | 2006-11-16 | 2008-07-16 | Teva Pharma | Crystalline forms of ibandronate sodium |
| CA2570949A1 (en) * | 2006-12-12 | 2008-06-12 | Apotex Pharmachem Inc. | Ibandronate sodium propylene glycol solvate and processes for the preparation thereof |
| US7662990B2 (en) * | 2007-04-11 | 2010-02-16 | Hoffmann-La Roche Inc. | Process for preparing ibandronate |
| EP2316841A1 (en) * | 2007-04-19 | 2011-05-04 | Dr. Reddy's Laboratories Limited | Ibandronate sodium polymorphs |
| US20090042839A1 (en) * | 2007-08-09 | 2009-02-12 | Sharon Avhar-Maydan | Crystalline forms of ibandronate sodium |
| US20090075944A1 (en) * | 2007-09-15 | 2009-03-19 | Protia, Llc | Deuterium-enriched ibandronate |
| WO2009093258A2 (en) * | 2008-01-24 | 2009-07-30 | Fleming Laboratories Limited | A new and improved process for the preparation of ibandronate sodium monohydrate |
| EP2180003A1 (en) | 2008-10-21 | 2010-04-28 | Zentiva, k.s. | Preparation of ibandronate trisodium |
| EP2192126B1 (en) | 2008-11-26 | 2013-03-27 | Synthon B.V. | Process for making zoledronic acid |
| US20100130746A1 (en) * | 2008-11-26 | 2010-05-27 | Martin Kas | Process for Making Zoledronic Acid |
| CN101863919B (zh) * | 2010-07-05 | 2011-11-23 | 武汉同源药业有限公司 | 一种化合物伊班膦酸钠的制备方法 |
| CN102093416B (zh) * | 2011-03-17 | 2013-07-24 | 南京恒生制药有限公司 | 一种合成伊班膦酸钠的方法 |
| CN103012155A (zh) * | 2012-11-29 | 2013-04-03 | 张家港市大伟助剂有限公司 | 一种n-甲基戊胺的制备方法 |
| CN103396332A (zh) * | 2013-08-19 | 2013-11-20 | 四川协力制药有限公司 | 3—[（n—甲基—n—戊基）氨基]丙酸盐酸盐的制备方法 |
| CN104628768A (zh) * | 2015-03-06 | 2015-05-20 | 江苏正大清江制药有限公司 | 一种伊班膦酸钠的制备方法 |
| CN114524925B (zh) * | 2020-11-23 | 2023-11-14 | 华润化学材料科技股份有限公司 | 钛系催化剂及其制备方法和应用 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919321A (en) * | 1966-11-08 | 1975-11-11 | Hoffmann La Roche | Halo-substituted-5H-dibenzo{8 a,d{9 cyclohepten-5-ones |
| US4220611A (en) * | 1978-06-29 | 1980-09-02 | Sandoz, Inc. | Polyoxyalkylene bridged phosphate esters |
| DE3623397A1 (de) * | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| DE3808074A1 (de) * | 1988-03-11 | 1989-09-21 | Henkel Kgaa | Verfahren zur herstellung von azacycloalkan-2,2-diphosphonsaeuren |
| DE3822650A1 (de) | 1988-07-05 | 1990-02-01 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
| US4922007A (en) | 1989-06-09 | 1990-05-01 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
| PE20011065A1 (es) | 2000-02-01 | 2001-11-21 | Procter & Gamble | Proceso para fabricar bisfosfonatos geminales |
| CN1665825A (zh) | 2002-05-17 | 2005-09-07 | 特瓦制药工业有限公司 | 用一定的稀释剂制备双膦酸 |
-
2005
- 2005-10-18 US US11/252,668 patent/US7214818B2/en active Active
- 2005-10-25 EP EP05799731A patent/EP1807090B9/en not_active Not-in-force
- 2005-10-25 DE DE602005026310T patent/DE602005026310D1/de active Active
- 2005-10-25 CA CA2585027A patent/CA2585027C/en not_active Expired - Fee Related
- 2005-10-25 AT AT05799731T patent/ATE497769T1/de active
- 2005-10-25 WO PCT/EP2005/011404 patent/WO2006045578A2/en active Application Filing
- 2005-10-25 CN CN2005800371320A patent/CN101048165B/zh not_active Expired - Fee Related
- 2005-10-25 ES ES05799731T patent/ES2359415T3/es active Active
- 2005-10-25 JP JP2007538322A patent/JP4560548B2/ja active Active
- 2005-10-25 MX MX2007005114A patent/MX2007005114A/es active IP Right Grant
- 2005-10-25 KR KR1020077011938A patent/KR100880061B1/ko not_active IP Right Cessation
- 2005-10-27 TW TW094137688A patent/TWI293304B/zh not_active IP Right Cessation
-
2007
- 2007-04-19 IL IL182690A patent/IL182690A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES2359415T3 (es) | 2011-05-23 |
| DE602005026310D1 (de) | 2011-03-24 |
| US7214818B2 (en) | 2007-05-08 |
| IL182690A0 (en) | 2007-09-20 |
| WO2006045578A2 (en) | 2006-05-04 |
| WO2006045578A3 (en) | 2006-08-17 |
| TW200621792A (en) | 2006-07-01 |
| MX2007005114A (es) | 2007-06-26 |
| JP4560548B2 (ja) | 2010-10-13 |
| IL182690A (en) | 2011-07-31 |
| KR20070070246A (ko) | 2007-07-03 |
| US20060094898A1 (en) | 2006-05-04 |
| CA2585027A1 (en) | 2006-05-04 |
| CN101048165B (zh) | 2010-12-01 |
| EP1807090A2 (en) | 2007-07-18 |
| KR100880061B1 (ko) | 2009-01-22 |
| CA2585027C (en) | 2010-05-18 |
| EP1807090B9 (en) | 2011-11-09 |
| JP2008517964A (ja) | 2008-05-29 |
| CN101048165A (zh) | 2007-10-03 |
| ATE497769T1 (de) | 2011-02-15 |
| EP1807090B1 (en) | 2011-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI293304B (en) | Process for the preparation of bisphosphonates | |
| US7528280B2 (en) | Process for the preparation of biphosphonic acids | |
| JP2008517964A5 (zh) | ||
| US7662990B2 (en) | Process for preparing ibandronate | |
| WO2009093258A2 (en) | A new and improved process for the preparation of ibandronate sodium monohydrate | |
| US8076483B2 (en) | Process for the preparation of pure risedronic acid or salts | |
| EP2038291B1 (en) | Process for the synthesis of ibandronate sodium | |
| CA2590046A1 (en) | Process for preparing a pure polymorphic form of 3-pyridyl-1-hydroxyethylidine-1,1-bisphosphonic acid sodium salt | |
| TW486483B (en) | Preparation of phosphonic acid derivatives | |
| PL208491B1 (pl) | Sposób wytwarzania kwasu [(hydroksyimino)bis(metyleno)]bisfosfonowego |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |