WO2007140804A1 - A process for the preparation of an oxaliplatin - Google Patents
A process for the preparation of an oxaliplatin Download PDFInfo
- Publication number
- WO2007140804A1 WO2007140804A1 PCT/EP2006/005456 EP2006005456W WO2007140804A1 WO 2007140804 A1 WO2007140804 A1 WO 2007140804A1 EP 2006005456 W EP2006005456 W EP 2006005456W WO 2007140804 A1 WO2007140804 A1 WO 2007140804A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxaliplatin
- process according
- platinum
- cyclohexanediamine
- complex
- Prior art date
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 78
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 78
- 238000000034 method Methods 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 64
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 45
- 229910052697 platinum Inorganic materials 0.000 claims description 31
- 239000007787 solid Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000000463 material Substances 0.000 claims description 21
- 229910052709 silver Inorganic materials 0.000 claims description 21
- 239000004332 silver Substances 0.000 claims description 21
- 230000002378 acidificating effect Effects 0.000 claims description 17
- 235000006408 oxalic acid Nutrition 0.000 claims description 15
- -1 silver ions Chemical class 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000012535 impurity Substances 0.000 claims description 14
- 238000000746 purification Methods 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000002091 cationic group Chemical group 0.000 claims description 9
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 9
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007790 solid phase Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- AGBXYHCHUYARJY-UHFFFAOYSA-N 2-phenylethenesulfonic acid Chemical group OS(=O)(=O)C=CC1=CC=CC=C1 AGBXYHCHUYARJY-UHFFFAOYSA-N 0.000 claims description 3
- 229920001410 Microfiber Polymers 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000003658 microfiber Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims description 3
- 229920000098 polyolefin Polymers 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 2
- 229940022682 acetone Drugs 0.000 claims 1
- 238000011275 oncology therapy Methods 0.000 abstract description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 15
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000001953 recrystallisation Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- 229910001961 silver nitrate Inorganic materials 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000004694 iodide salts Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 4
- JKNZUZCGFROMAZ-UHFFFAOYSA-L [Ag+2].[O-]S([O-])(=O)=O Chemical compound [Ag+2].[O-]S([O-])(=O)=O JKNZUZCGFROMAZ-UHFFFAOYSA-L 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000002411 adverse Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 2
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PKVULQGRLLRFPK-UHFFFAOYSA-L O[Pt+2]O Chemical compound O[Pt+2]O PKVULQGRLLRFPK-UHFFFAOYSA-L 0.000 description 1
- 229910021612 Silver iodide Inorganic materials 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- FPJNQJHCHVUNTK-UHFFFAOYSA-N platinum;dihydrate Chemical compound O.O.[Pt] FPJNQJHCHVUNTK-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 229940100890 silver compound Drugs 0.000 description 1
- 150000003379 silver compounds Chemical class 0.000 description 1
- 229940045105 silver iodide Drugs 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005406 washing Methods 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Definitions
- the present invention relates to a process for preparing oxaliplatin, to an oxaliplatin preparation of high purity and its use in the treatment of cancer.
- Oxaliplatin CAS Number [61825-94-3] is the generally used name for the (SP-4-2)-[(1 R,2R)-1 ,2-cyclohexanediamine-kN,kN ' ]- [ethanedioato(2-)-kO 1 ,kO 2 ]platinum(ll) complex of the structural formula I:
- Oxaliplatin was first reported by the Nagoya City University, Japan, in Gann, 1976, 67(6), 921-2. Oxaliplatin is frequently used in cancer therapy. A general method for preparing oxaliplatin is described in prior art, e.g. in USP 4,169,846.
- Analogous (SP-4-2)-diiodo- or dibromo- [(1 R,2R)-1 ,2-cyclohexanediamine-kN,kN ' ]platine(ll) complex can be used instead of DACHPtCI 2 in this procedure but DACHPtCI 2 is the cheapest.
- the yield of the obtained oxaliplatin is usually between 60 to 70% and the final yield is usually between 40 to 50% after re- crystallization.
- the platinum(ll)diaqua-complex described above can thus be considered as a key synthetic intermediate for oxaliplatin preparation. It has the structural formula Il and it is usually in the form of a dinitrate salt but another salts, e.g. sulphate salt, are possible:
- DACHPtCI 2 is a very low soluble in water.
- the dissolving of DACHPtCI 2 particles is very slow and the subsequent reaction with silver salt is very quick which leads to creating platinum(ll) diaqua- complex dinitrate and the solid AgCI.
- the reaction is running in the thin liquid film on the surface of the particles of DACHPtCI 2 as a consequence of this fact and these particles are quickly covered by AgCI layer which blocks further reaction. That is why the reaction of DACHPtCI 2 with silver salt usually needs 1 to 3 days at room temperature to reach sufficient conversion according to prior art, e.g. WO 2005/035544 A1 ; WO 03/004505 A1 ; EP 1 308 454 A2. It is possible to partially reduce reaction time of DACHPtCI 2 with silver salts by increased amount of water and by increased reaction temperature but it is on account of lower yields and increased content of impurities.
- Second drawback of the above mentioned general procedure is a high content of silver in prepared oxaliplatin which is usually greater than 100 p.p.m. Any of syntetic impurities, including silver ions, may cause severe adverse effects in the therapeutic use of oxaliplatin. Their presence is to be avoided and so, the prescripted limit for silver content in oxaliplatin is less than 5 p.p.m.. Therefore, corresponding purification procedures are the subject of a great wealth of patents and patent applications.
- the technical problem underlying the present invention is therefore to provide a process for preparing oxaliplatin, which is simple and provides oxaliplatin with a high purity and simultaneously in a high yield.
- step b) purifying the acidic aqueous solution containing [(1 R,2R)-1 ,2-cyclohexanediamine-kN,kN']platinum(ll) diaquacomplex obtained in step b) with a solid poly- meric material containing cationic exchange groups to obtain a purified acidic aqueous solution and
- step d) adding oxalic acid and/or an oxalic salt to the purified acidic aqueous solution obtained in step c) to obtain purified oxaliplatin.
- One first aspect of the invention is the use a solid inert material during the reaction step a).
- the invention foresees the use of a solid inert material in step a), which is able to be brought into contact with the reactants of step a), preferably by mixing, stirring and/or agitating the reaction mixture.
- the inert material and the reaction solution of step a) form a suspension.
- the use of the inert solid material leads to a substantial reduction of reaction time, probably by an abrasion of the silver halogenid layer, e.g. AgCI layer, from the surface of DACHPtCI 2 particles.
- This reaction step takes preferably 0.5 to 5 hours at the preferred temperature range from 20 to 50 0 C instead of 1 to 3 days at room temperature according to prior art.
- a particularly preferred temperature range is from 20 to 45 0 C which leads to a complete conversion during 1 to 3 hours.
- various kinds of solid inert materials can be used, such as particulate materials, for instance powders, grain, balls, extrudates, granulates etc. These materials may for instance be materials conventionally used as inert catalyst carriers.
- silicon dioxide and/or aluminium oxide, preferably Celite can be used as a solid inert material.
- the solid inert material also improves removing of the solid AgCI after this reaction step.
- the solid inert material is prefera- bly removed after step a) and before step c), preferably in step b), preferably by centrifugation or filtration.
- a second aspect of the invention is the use of a solid polymeric material containing cationic exchange groups for purifying the acidic solution containing [(1 R,2R)-1 ,2-cyclohexanediamine- kN,kN']platinum(ll) diaqua-complex in step c).
- Solid polymeric material containing cationic exchange groups advantageously and surprisingly reduce the silver content in the purification step c) of the present process.
- the use of, in a particu- larly preferred embodiment, 5 mass.% of, in a further preferred embodiment, polyolefin microfibers containing styrene sulfonic acid groups, e.g. Smopex-101 leads to one order decrease of silver content in platinum(ll) diaqua- complex dinitrate during 1 hour at room temperature in step c).
- step c) of the present process is repeated at least once, in particular is carried out at least twice, three times or even more times.
- two purification cycles lead to the silver content in the purified acidic aqueous solution containing [(1 R,2R)-1 ,2- cyclohexanediamine-kN,kN']platinum(ll) diaquacomplex obtained in step c) below 0.1 p.p.m. and in the purified oxaliplatin obtained in step d) below 1 p.p.m..
- the similar purification effect has in a further preferred embodiment styrene-diviny I benzene co-polymers containing sulfonic acid groups, e.g. Dowex 50x8 but the amount of this ionex and the purification time should preferably be doubled in comparison with the use of polyolefin microfibers containing styrene sulfonic acid groups.
- the solid cationic polymeric material may prefera- bly be used in particulate form, for instance used in form of a suspension. It may also be used in form of a cationic ion exchange chromatography, for instance as a resin in a column.
- the solid cationic polymeric material is preferably removed after step c) and before step d), for instance by centrifugation or filtration.
- the amount of oxalic acid or oxalic salt is 0.9 to 1.1 equivalents with respect to the starting (SP-4-2)dihalogen-[(1 R,2R)-1 ,2-cyclohexanediamine- kN,kN']platinum(ll) complex in step d).
- the reaction time is 2 to 6 hours at room temperature in step d).
- the pH value in step d) is adjusted to 2.5 - 2.9, preferably 2.9, after adding of oxalic acid or oxalic salt.
- the pH value is decreased during the course of step d).
- ox- aliplatin is washed with water to remove inorganic salts and subsequently with alifatic alcohol or aceton to remove organic impurities, in particular oxalic acid, and water to improve drying procedure.
- Ox- aliplatin prepared according to the invention has prescripted pharmaceutical quality without need of re-crystallization which leads to a substantial loss of the expensive oxaliplatin.
- step a) In a preferred embodiment of the present invention (SP-4-2)dichloro- [(1 R,2R)-1 ,2-cyclohexanediamine-kN,kN']platinum(ll) complex is used as the starting (SP-4-2)dihalogen-[(1 R,2R)-1 ,2- cyclohexanediamine-kN,kN']platinum(ll) complex in step a).
- the silver salt used in step a) is silver nitrate or silver sulphate.
- the silver salt, in particular silver nitrate or silver sulphate, used in step a) is used in a stoichiometric amount in relation to the starting platinum(ll) complex, e.g. per molar equivalent of the starting platinum(ll) complex two molar equivalents of the silver nitrate or one molar equivalent of silver sulphate are used.
- a third aspect of the invention is an oxaliplatin preparation with a specific impurity profile prepared according to the invention wherein the content of silver ions in oxaliplatin is less than 1 p.p.m..
- Oxaliplatin prepared according to the invention has prescripted pharmaceutical quality without need of re-crystallization which leads to a substantial loss of the expensive oxaliplatin.
- the present invention in particular provides in a preferred embodiment the advantage that the time for preparing oxaliplatin is decreased from days to hours.
- One further preferred embodiment of the present invention solves the above-identified problem with the above-identified process, wherein such a process provides a yield of oxaliplatin, which may be comparable in comparison to the prior art methods, but wherein the reaction time is substantially decreased and the purity is improved, i.e. higher than in the prior art.
- the present invention solves the problem in another preferred embodiment, wherein the purity may be comparable in comparison to the prior art, but wherein the reaction time is substantially decreased and the yield is substantially better, i.e. higher than in the prior art.
- the present invention in particular provides in a preferred embodiment the advantage that all of its process steps can be carried out using conventional water, or, in a particularly preferred embodiment, destilled water as an aqueous medium in step a) above. According to the present invention, it is not necessary to use deoxygenated water in any of its process steps.
- the present invention therefore provides a process for preparing oxaliplatin, according to which no deoxygenated water is used.
- the process of the present invention is carried out under standard environmental conditions, in particular all and each process step of the present process is carried out in an environment, which is not using specific conditions, such as: a low oxygen atmosphere, or a vacuum, or an inert gas, or a nitrogen atmosphere, or a low oxygen atmosphere.
- the oxidizing power of spots of free oxygen present e.g. in water is negligible with respect to nitrates and/or nitric acid being present in stoichiometric amount during the preparation of the platinum (II) diaqua-complex dinitrate in step a) and/or oxaliplatin in step d).
- the present invention provides in a quick and simple manner a preparation of oxaliplatin, which is highly pure, in particular, essentially pure.
- "essentially pure" means that the oxaliplatin preparation obtained has a purity of at least 97,5%, preferably at least 98%, preferably at least 98,5%, even more preferably at least 99%, most preferably at least 99,5% (percentage values given according to the present teaching are mass %, i.e. mass/mass or weight/weight, i.e. w/w percentage determined by HPLC, if not otherwise indicated), that means other compounds except for the oxaliplatin are present only in the above identified speci- fied minor amounts.
- the degree of impurity is in overall terms most preferably at maximum 2,5%, 2,0%, or 1 ,5%, more preferably at maximum 1 ,0%, in particular 0,5%.
- the amount of oxalic acid (reaction component) in the oxaliplatin preparation is at maximum 0,2%, in particular at maximum 0,1%, more preferably at maximum 0,05%.
- the amount of platinum(ll) diaqua-complex (synthetic intermediate II) in the oxaliplatin preparation is in a preferred embodiment at maximum 0,10%.
- the amount of dihydroxy platinum IV-complex (product of oxidation of oxaliplatin) in the oxaliplatin preparation is in a preferred embodi- ment at maximum 0,05%.
- the total amount of the above-identified mentioned three impurities, oxalic acid, platinum (II) diaqua complex and the dihydroxy platinum (IV) complex in the oxaliplatin preparation is at maximum 0,30%.
- the amount of the reverse S,S-enantiomer of oxaliplatin is in a preferred embodiment at maximum 0,10%.
- the amount of hydroxo-bridge platinum-complex dimer and other detectable impurities in the oxaliplatin preparation is in a preferred embodiment at maximum 0,10%.
- the amount of silver in the oxaliplatin preparation is in a preferred embodiment less than 1 p.p.m.
- the total content of oxaliplatin-related impurities in the product according to the invention is less than 0,30%.
- the total yield of the final product is at least 60%, preferably at least 65%, and most preferred at least 70% (w/w), based on the starting DACHPtCI 2 .
- the subject-matter of this invention is a very quick, simple and effective method for the preparation of oxaliplatin of the structural formula I :
- the precipitated silver compounds in particular the precipitated silver compounds, purification of the acidic aqueous solution containing the corresponding platinum(ll) diaqua-complex (structural formula II) with a solid polymeric material containing cationic exchange groups, adding oxalic acid or its salts to the purified acidic aqueous solution, wherein, in a preferred embodiment the pH-value is adjusted to 2.8 to 2.9, after adding oxalic acid or its salts and the resulting ox- aliplatin is separated in a high purity and yield.
- Oxaliplatin prepared according to the invention has a high purity and needs no additional re-crystallization steps from water.
- the silver salt used in step a) is silver nitrate (AgNO 3 ) or silver sulphate (Ag 2 SO 4 ).
- the content of Ag + in oxaliplatin is less than 1 p.p.m. .
- step c) that means for the purification of the acidic aqueous solution to obtain a purified acidic aqueous solution 2 or 3 purification steps are conducted without substantial loss of the product.
- the process of the present invention can, in a preferred embodiment of the present invention, be conducted in water in the absence of light, in particular visible light.
- the present invention also foresees a pharmaceutical composition
- a pharmaceutical composition comprising an oxaliplatin preparation of the present invention together with at least one pharmaceutically acceptable carrier and optionally further additives.
- the present invention provides the use of an oxaliplatin preparation according to the present invention for the preparation of a pharmaceutical composition for the treatment of cancer.
- the yield of oxaliplatin was 2.80 g (70.5% based on starting DACHPtCI 2 ).
- the appearance of the product was white.
- the content of silver was less than 0.00005 mass %, i.e. 0.5 p.p.m., the content of oxalic acid was 0.04%, the content of platinum(ll) diaqua-complex was 0.08%, and the total content of related impurities was 0.22% (by HPLC method).
- the appearance of the product was white.
- the content of silver was 0.0001 mass %, i.e. 1 p.p.m.
- the content of oxalic acid was 0,04%
- the content of platinum(ll) diaqua-complex was 0.09%
- the total content of related impurities was 0.25% (by HPLC method).
- the crude acidic filtrate had the content of silver ions 0.2500 mass.%, i.e. 2500 p.p.m.
- the yield of oxaliplatin was 2.60 g (65.5% based on starting DACHPtCI 2 ). The appearance of the product was white. The content of silver was 0.0220 mass %, i.e. 220 p.p.m.
- Example 4 (comparative, according to prior art) All procedures were made at room temperature in the absence of light.
- the purified solution was filtered through an ultrafilter with the porosity 0.22 ⁇ m. 1.27 g oxalic acid dihydrate 99.5% (10 mmol) was added to the purified solution, the mixture was stirred 4 hours at room temperature and the resulting suspension was cooled to 3 0 C. The final solid ox- aliplatin was separated by filtration, washed four times with 5 ml ice water and four times with 5 ml ethanol. Oxaliplatin was dried under nitrogen flow at 4O 0 C to the constant weight.
- the yield of oxaliplatin was 2,51 g (63.2% based on starting DACHPtCI 2 ).
- the content of silver was 0.0004 mass %, i.e. 4 p.p.m.. but the appearance of the product was light yellow.
- the light yellow oxaliplatin was re-crystallized from hot water (1 mass part of oxaliplatin and 42 mass part of water).
- the hot solution was ultrafiltered, cooled to 3 0 C, the solid product was separated by filtration and washed three times with 5 ml of ice water.
- the oxaliplatin was dried under nitrogen flow at 4O 0 C to the constant weight.
- the yield was 1 ,60 g (40.3% based on the starting DACHPtCI 2 ).
- the appearance of the product was white.
- the content of silver was 0.0002 mass %, i.e. 2 p.p.m., the content of oxalic acid was 0.03%, the content of platinum(ll) diaqua-complex was 0.10%, and the total content of related impurities was 0.21% (by HPLC method).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Inorganic Compounds Of Heavy Metals (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT06754208T ATE487730T1 (en) | 2006-06-08 | 2006-06-08 | METHOD FOR PRODUCING AN OXALIPLATIN |
EP06754208A EP2029615B8 (en) | 2006-06-08 | 2006-06-08 | A process for the preparation of an oxaliplatin |
ES06754208T ES2353531T3 (en) | 2006-06-08 | 2006-06-08 | PROCEDURE FOR THE PREPARATION OF AN OXALIPLATIN. |
DE602006018205T DE602006018205D1 (en) | 2006-06-08 | 2006-06-08 | METHOD FOR PRODUCING AN OXALIPLATIN |
PCT/EP2006/005456 WO2007140804A1 (en) | 2006-06-08 | 2006-06-08 | A process for the preparation of an oxaliplatin |
CA002652641A CA2652641A1 (en) | 2006-06-08 | 2006-06-08 | A process for the preparation of an oxaliplatin |
AU2006344273A AU2006344273A1 (en) | 2006-06-08 | 2006-06-08 | A process for the preparation of an oxaliplatin |
US12/303,587 US7872150B2 (en) | 2006-06-08 | 2006-06-08 | Process for the preparation of an oxaliplatin |
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PCT/EP2006/005456 WO2007140804A1 (en) | 2006-06-08 | 2006-06-08 | A process for the preparation of an oxaliplatin |
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WO2007140804A1 true WO2007140804A1 (en) | 2007-12-13 |
WO2007140804A8 WO2007140804A8 (en) | 2008-03-27 |
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PCT/EP2006/005456 WO2007140804A1 (en) | 2006-06-08 | 2006-06-08 | A process for the preparation of an oxaliplatin |
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US (1) | US7872150B2 (en) |
EP (1) | EP2029615B8 (en) |
AT (1) | ATE487730T1 (en) |
AU (1) | AU2006344273A1 (en) |
CA (1) | CA2652641A1 (en) |
DE (1) | DE602006018205D1 (en) |
ES (1) | ES2353531T3 (en) |
WO (1) | WO2007140804A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2208731A1 (en) * | 2009-06-26 | 2010-07-21 | Umicore AG & Co. KG | Process for preparation of 1,2-diamino-cyclohexane-platinum(II) complexes |
WO2010081924A1 (en) * | 2009-01-13 | 2010-07-22 | Capital, Business Y Gestión De Finanzas, S.L. | Process for preparing pharmaceutical-grade neutral platinum (ii) antineoplastic derivatives having low silver content |
CN101891771A (en) * | 2010-07-30 | 2010-11-24 | 重庆泰濠制药有限公司 | Method for preparing oxaliplatin |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1404689A1 (en) * | 2001-07-02 | 2004-04-07 | Debiopharm S.A. | Oxaliplatin active substance with a very low content of oxalic acid |
CZ302618B6 (en) | 2009-09-10 | 2011-08-03 | Univerzita Palackého | Platinum cyclobutane-1,1-dicarboxylate complexes with N6-benzyladenine derivatives, process of their preparation and use of these complexes as medicaments in antitumor therapy |
CN102643308B (en) * | 2012-05-11 | 2014-05-07 | 海南锦瑞制药股份有限公司 | Oxaliplatin crystal compound and freeze-dried powder injection |
Citations (2)
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EP0801070A2 (en) * | 1996-04-10 | 1997-10-15 | Tanaka Kikinzoku Kogyo K.K. | Process of preparing platinum compound |
WO2005035544A1 (en) * | 2003-10-17 | 2005-04-21 | Pliva-Lachema A.S. | Oxaliplatin with a low content of accompanying impurities and a method for preparation thereof |
Family Cites Families (5)
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JPS6041077B2 (en) | 1976-09-06 | 1985-09-13 | 喜徳 喜谷 | Cis platinum(2) complex of 1,2-diaminocyclohexane isomer |
JPH0776230B2 (en) * | 1992-01-13 | 1995-08-16 | 田中貴金属工業株式会社 | Method for producing platinum compound |
JP3025602B2 (en) | 1993-05-21 | 2000-03-27 | デビオファーム エス.アー. | Method for producing optically high purity cis-oxalate (trans-l-l, 2-cyclohexanediamine) platinum (II) complex |
JPH09278785A (en) | 1996-04-10 | 1997-10-28 | Tanaka Kikinzoku Kogyo Kk | Production of platinum compound |
EP1404689A1 (en) | 2001-07-02 | 2004-04-07 | Debiopharm S.A. | Oxaliplatin active substance with a very low content of oxalic acid |
-
2006
- 2006-06-08 AT AT06754208T patent/ATE487730T1/en not_active IP Right Cessation
- 2006-06-08 AU AU2006344273A patent/AU2006344273A1/en not_active Abandoned
- 2006-06-08 WO PCT/EP2006/005456 patent/WO2007140804A1/en active Application Filing
- 2006-06-08 CA CA002652641A patent/CA2652641A1/en active Pending
- 2006-06-08 DE DE602006018205T patent/DE602006018205D1/en active Active
- 2006-06-08 US US12/303,587 patent/US7872150B2/en not_active Expired - Fee Related
- 2006-06-08 ES ES06754208T patent/ES2353531T3/en active Active
- 2006-06-08 EP EP06754208A patent/EP2029615B8/en not_active Not-in-force
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0801070A2 (en) * | 1996-04-10 | 1997-10-15 | Tanaka Kikinzoku Kogyo K.K. | Process of preparing platinum compound |
WO2005035544A1 (en) * | 2003-10-17 | 2005-04-21 | Pliva-Lachema A.S. | Oxaliplatin with a low content of accompanying impurities and a method for preparation thereof |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010081924A1 (en) * | 2009-01-13 | 2010-07-22 | Capital, Business Y Gestión De Finanzas, S.L. | Process for preparing pharmaceutical-grade neutral platinum (ii) antineoplastic derivatives having low silver content |
EP2208731A1 (en) * | 2009-06-26 | 2010-07-21 | Umicore AG & Co. KG | Process for preparation of 1,2-diamino-cyclohexane-platinum(II) complexes |
WO2010149337A1 (en) | 2009-06-26 | 2010-12-29 | Umicore Ag & Co. Kg | Process for preparation of 1,2-diamino-cyclohexane-platinum (ii) complexes |
CN102803279A (en) * | 2009-06-26 | 2012-11-28 | 尤米科尔股份公司及两合公司 | Process for preparation of 1,2-diamino-cyclohexane-platinum (ii) complexes |
JP2012530737A (en) * | 2009-06-26 | 2012-12-06 | ユミコア・アクチエンゲゼルシャフト・ウント・コムパニー・コマンディットゲゼルシャフト | Process for producing 1,2-diamino-cyclohexane-platinum (II) complex |
US8637692B2 (en) | 2009-06-26 | 2014-01-28 | Umicore Ag & Co. Kg | Process for preparation of 1,2-diamino-cyclohexane-platinum (II) complexes |
CN101891771A (en) * | 2010-07-30 | 2010-11-24 | 重庆泰濠制药有限公司 | Method for preparing oxaliplatin |
Also Published As
Publication number | Publication date |
---|---|
EP2029615A1 (en) | 2009-03-04 |
AU2006344273A1 (en) | 2007-12-13 |
CA2652641A1 (en) | 2007-12-13 |
ATE487730T1 (en) | 2010-11-15 |
EP2029615B1 (en) | 2010-11-10 |
US20100174102A1 (en) | 2010-07-08 |
EP2029615B8 (en) | 2011-02-02 |
DE602006018205D1 (en) | 2010-12-23 |
WO2007140804A8 (en) | 2008-03-27 |
US7872150B2 (en) | 2011-01-18 |
ES2353531T3 (en) | 2011-03-02 |
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