ZA200807987B - Preparation of platinum(II) complexes - Google Patents
Preparation of platinum(II) complexes Download PDFInfo
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- ZA200807987B ZA200807987B ZA200807987A ZA200807987A ZA200807987B ZA 200807987 B ZA200807987 B ZA 200807987B ZA 200807987 A ZA200807987 A ZA 200807987A ZA 200807987 A ZA200807987 A ZA 200807987A ZA 200807987 B ZA200807987 B ZA 200807987B
- Authority
- ZA
- South Africa
- Prior art keywords
- oxalate
- solvent
- halogenoplatinum
- bidentate ligand
- neutral bidentate
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 7
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical class [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims description 64
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 52
- 239000003446 ligand Substances 0.000 claims description 48
- 230000007935 neutral effect Effects 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 29
- 229910052697 platinum Inorganic materials 0.000 claims description 26
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000003125 aqueous solvent Substances 0.000 claims description 17
- 150000003891 oxalate salts Chemical class 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 9
- 229960001756 oxaliplatin Drugs 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- -1 aryl ammonium compound Chemical class 0.000 claims description 6
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 claims description 5
- XNGYKPINNDWGGF-UHFFFAOYSA-L silver oxalate Chemical compound [Ag+].[Ag+].[O-]C(=O)C([O-])=O XNGYKPINNDWGGF-UHFFFAOYSA-L 0.000 claims description 4
- HEQUOWMMDQTGCX-UHFFFAOYSA-L dicesium;oxalate Chemical compound [Cs+].[Cs+].[O-]C(=O)C([O-])=O HEQUOWMMDQTGCX-UHFFFAOYSA-L 0.000 claims description 3
- RWHJHYXWZJKPAP-UHFFFAOYSA-L oxalate;tetrabutylazanium Chemical group [O-]C(=O)C([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC RWHJHYXWZJKPAP-UHFFFAOYSA-L 0.000 claims description 2
- DHLMUMIECTWLEP-UHFFFAOYSA-L oxalate;tetraphenylphosphanium Chemical compound [O-]C(=O)C([O-])=O.C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 DHLMUMIECTWLEP-UHFFFAOYSA-L 0.000 claims description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 2
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 claims description 2
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 claims description 2
- DUXDETQJUQZYEX-UHFFFAOYSA-L oxalate;rubidium(1+) Chemical compound [Rb+].[Rb+].[O-]C(=O)C([O-])=O DUXDETQJUQZYEX-UHFFFAOYSA-L 0.000 claims 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical group C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052711 selenium Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229940100890 silver compound Drugs 0.000 description 2
- 150000003379 silver compounds Chemical class 0.000 description 2
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 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 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- UJTDKNZVLGVLFT-UHFFFAOYSA-N 1,2-Bis(methylthio)ethane Chemical compound CSCCSC UJTDKNZVLGVLFT-UHFFFAOYSA-N 0.000 description 1
- ALKUAOHBBKTMKP-UHFFFAOYSA-N 1-methyl-2-(methylsulfanylmethyl)imidazole Chemical compound CSCC1=NC=CN1C ALKUAOHBBKTMKP-UHFFFAOYSA-N 0.000 description 1
- KKCQHAHBQUOKBU-UHFFFAOYSA-N 2-(1-methylsulfanylhexan-2-yl)-1h-imidazole Chemical compound CCCCC(CSC)C1=NC=CN1 KKCQHAHBQUOKBU-UHFFFAOYSA-N 0.000 description 1
- LJIZKCPUNGRRTP-UHFFFAOYSA-N 2-(1-methylsulfanylpropan-2-yl)-1h-imidazole Chemical compound CSCC(C)C1=NC=CN1 LJIZKCPUNGRRTP-UHFFFAOYSA-N 0.000 description 1
- JNGRYGVAABZSGA-UHFFFAOYSA-N 2-(2-methylsulfanylethyl)pyridine Chemical compound CSCCC1=CC=CC=N1 JNGRYGVAABZSGA-UHFFFAOYSA-N 0.000 description 1
- JAQGXZDFUNFLTD-UHFFFAOYSA-N 2-(2-methylsulfanylpropyl)pyridine Chemical compound CSC(C)CC1=CC=CC=N1 JAQGXZDFUNFLTD-UHFFFAOYSA-N 0.000 description 1
- KWXDPVBKJYKQIM-UHFFFAOYSA-N 2-(methylsulfanylmethyl)pyridine Chemical compound CSCC1=CC=CC=N1 KWXDPVBKJYKQIM-UHFFFAOYSA-N 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
© WO 2006/024897 Lo PCT/IB2005/000570 } BACKGROUND OF THE INVENTION : oo
THIS invention relates to the preparation of a platinum(ll) complexes } containing a neutral bidentate ligand, such as cis-oxalato(trans-t-1,2- : cyclohexanediamine)platinum(il) (also known as oxaliplatin), which has : become increasingly important due to its anti-cancer activity.
Dicarboxylatoplatinum(il) complexes (such as oxaliplatin) containing a neutral bidentate ligand (‘non-leaving group”) have in the past been
EE synthesized by way of a process that utilizes a silver salt to remove halide : : ions from the complex. The use of a silver compound in the process results ) in numerous contaminants, which must be removed by further processes in order to achieve purity that is suitable for anti-cancer pharmaceutical agent purposes. ” :
CONFIRMATION COPY
. -2- X
Oxaliplatin and its pharmaceutical properties were first disclosed by Kidani et al. in J Med Chem, 1978, 21, 13135 and in United States Patent No. 4,169,846. In this patent a halogenoplatinum compound is used as the s starting material. Halide ions are removed by a silver salt, whereafter an - : | oxalate is introduced, either as the free acid or a salt thereof.
EE In general, a method for the production of oxaliplatin is as set out below:
Step1.
Co mol KoPtX, + moll — PtLX; oo
X =Cl, Br, | and L = trans-£-1,2-diaminocyciohexane }
Co Step 2. © 1 mol PtLX; + 2 mol AgNO; — PtL(H.0)2" + 2AgX + 2NO5 or 1 mol PtLX, + 1 mol AgsY — PtL(H,0)% + 2AgX +.Y*
Y= SO ‘ - Step 3. _
PHL(H,0)2* + Zs(oxalate) — Ptl(oxalate) + 22° oo
Z=K' Naor H’ :
US Patent No. 5,290,961 in the name of Tanaka Kikinzoku Kogyo K.K. teaches that the abovementioned method has the disadvantage that many oo impurities are incorporated into the products. These impurities include unreacted PtLXs, AgX and Ag*. The presence of PtLX;is attributed to its generally insoluble nature in water. As a result, large quantities of water must be used in step 2 to dissolve PiLX,. This prevents the AgX, even though it is insoluble in water, from being completely removed from the solution. US patents no's. 5,338,874 and 5,420,319, also in the name of
Tanaka Kikinzoku Kogyo K.K., teach processes for the production of cis-
oo : -3- oo oxalato(trans-t-1,2-diaminocyclohexane)platinum(1l) with high optical purity : which can be used as an active pharmaceutical ingredient of a carcinostatic agent. However, these processes also follow complicated multi-step : pathways, making use of silver compounds which must also ultimately be oo removed from the process. : SUMMARY OF THE INVENTION
According to a first aspect of the invention there is provided a method for _ : the preparation of a platinum(ll) complex containing a neutral bidentate ligand, such as oxaliplatin, the method including the step of reacting a oo halogenoplatinum complex containing a neutral bidentate ligand, typically a : halogenoplatinum(ll) complex containing a neutral bidentate ligand, with an oxalate salt in a solvent, wherein more than 1 g/L of the oxalate salt is soluble in the solvent. : :
The solvent may be an aqueous solvent, a non-aqueous solvent oramixed
Ce solvent system (by mixed solvent system is meant a solvent mixture : containing a non-aqueous solvent and water). - ~ : Preferably, the halogenoplatinum(ll) complex containing a neutral bidentate : ligand is reacted with the oxalate at a molar ratio of greater than 1:1, typically between 1:1 to 1:15, preferably between 1:1 and 1:5. : “The reaction typically takes place at a temperature in the range from 40 to 100°C, preferably from 50 to 100°C, most preferably from 60 to 90°C.
Preferably, the reaction takes place in a non-aqueous solvent or a mixed a solvent system.
The non-aqueous solvent is preferably an organic liquid, typically an amide - such as dimethyiformamide (dmf).
. | -4- :
The neutral bidentate ligand in the halogenoplatinum complex may be an amine such as 1,2-diaminocyclohexane, or the neutral bidentate ligand may oo contain donor atoms other than N, or N together with a donor atom other than N, typically S or Se, for example: . « neutral bidentate heterocyclic amines with an S donor atom (for
Lo ‘example thioetherial groups), such as: : : - 1-alkyl/aryl-2-alkylthioalkyl/ary} heterocyclic amines, particularly imidazoles oo or pyridines, for example: - Ligand (i) 1-methyl-2-methylthiomethyl-imidazole a.
Ligand (ii) 1-methyl-2-methylthioethyl-imidazole
Ligand (ii) 1-methyl-2-methyithiopropyl-imidazole : : : Ligand (iv) 1-butyl-2-methyithiomethyl-imidazole a. - | Ligand (v) 1-butyl-2-methylthioethyl-imidazole oo
Ligand (vi) 2-methylthiomethyl-pyridine : Ligand (vii) 2-methylthioethyl-pyridine Co : Ligand (viii) ' 2-methylthiopropyl-pyridine; ’ : « aminoalkylthioalkyl/aryl compounds for example: . oo
Ligand (ix) 1-amino-2-thiomethyl-ethane -
Ligand (x) {-amino-2-thicethyl-ethane; B . dithioethers for example:
Ligand (xi) 2,5-dithiahexane; « diselenoethers for example: ~
Ligand (xii) 2,5-diselenchexane; etc.
The halogen in the halogenoplatinum(ll) complex may be Cl, Br or |,
R preferably Cl. ‘New halogenoplatinum(lf) complexes containing S or Se donor atoms which may be used in the method of the invention include:
Complex (xi) - bis-chloro-(1-methyl-2-methyithiomethyl-imidazole)platinum(ll)
Complex (xi) bis-chloro-(1-methyl-2-methylthioethyl-imidazole)platinumil) : Complex (xiii) bis-chloro-(1-methyl-2-methylthiopropyl-imidazole)platinum(H!)
Complex (xiv) bis-chloro-(1-butyl-2-methylthiomethyl-imidazole)platinumil)
Complex (xv) bis-chloro-(1-butyl-2-methylthioethyl-imidazole)platinum(l}).
Advantageously, the halogenoplatinum(il) complex containing a neutral : bidentate ligand is optically pure.
The oxalate may be a metal oxalate other than silver oxalate or an organic : oxalate salt. E
In a first preferred embodiment of the invention, the oxalate is a metal oxalate other than silver oxalate, typically an alkali metal oxalate such as rubidium or cesium oxalate, preferably cesium oxalate, and the solvent is a } mixed solvent system. : The mixed solvent system is preferably a mixture of an amide e.g.
Co dimethylformamide (dmf) and water, preferably at a ratio of dmf to water of oo 60:40 by volume to 90:10 by volume, most preferably 70:30 by volume to 90:10 by volume. - : : Preferably, the solubility of the metal oxalate in the solvent is greater than 2 oo : : g/L, most preferably greater than 3 g/L, typically about 5 g/L. : } . a Preferably, the halogenoplatinum(ll) complex containing a neutral bidentate ligand is dissolved in the organic liquid such as dmf and thereafter water is added to provide a solvent which is a mixture of organic liquid and water.
The metal oxalate may be dissolved in a mixture of organic liquid and water and added, typically drop-wise, to a solvent containing the halogenoplatinum(il) complex containing a neutral bidentate ligand.
The reaction typically takes place at a temperature in the range of 40 to : 100°C, preferably 80 to 100°C, most preferably 90°C. Co
The halogenoplatinum(il) complex is preferably bis-chioro-(trans-{-1 ,2- diaminocyclohexane)platinum(il), most preferably cis-bis-chloro-(frans-t- 1,2-diaminocyclohexane)platinum(li).
: oo In the second preferred embodiment of the invention, the oxalate is an ; oxalate salt such as a tetraalkyl or arylammonium compound, forexample a : : tetraethylammonium, tetrapropylammonium, tetrabutylammonium or oo tetraphenylphosphonium oxalate, preferably tetrabutylammonium oxalate, and the solvent is a mixed solvent system or a purely non-aqueous solvent system.
Co The mixed solvent system may be a mixture of a non-aqueous solvent such as dmf, and water, preferably at a ratio of dmf to water of 90:10 by volume to 95:5 by volume. .
Preferably, the organic oxalate salt has a solubility in the solvent of greater } than 2 g/L, more preferably greater than 10 g/L, more preferably greater than 50 g/L, most preferably more than 100 g/L, and may be about 300 g/L.
Preferably, the halogenoplatinum(il) complex containing a neutral bidentate ’ : : ligand is dissolved in an organic liquid and the organic oxalate salt is . dissolved in an organic liquid and added, typically drop-wise, to the solvent ’ containing the halogenoplatinum(ll) complex containing a neutral bidentate LL ligand. :
Water may be added to the organic liquid after the cis-bis-halogeno(trans-t- 1,2-diaminocyclohexane)platinum(ll) has been dissolved in the organic oo liquid. : The reaction typically takes place at a temperature in the range of 30°C to. 90°C, preferably 50°C to 70°C, most preferably 60°C.
The halogenoplatinum(li) complex is preferably bis-chloro-(trans-t-1,2- diaminocyclohexane)platinum(ll), most preferably cis-bis-chloro(trans-¢-1,2- , diaminocyclohexane)platinum(li). : ~The invention also relates to a method for the preparation of an oxalatoplatinum(ll) complex containing a neutral bidentate ligand, such as oo oxaliplatin, the method including the step of reacting a halogenoplatinum : complex containing a neutral bidentate ligand, typically a halogenoplatinum : : (I) complex containing a neutral bidentate ligand, with a metal oxalate - other than silver oxalate, in a mixed solvent system. So :
The invention further relates to a method for the preparation of an oxalatoplatinum(ll) complex containing a neutral bidentate ligand, such as - : : oxaliplatin, the method including the step of reacting a halogenoplatinum complex containing a neutral bidentate ligand, typically a : halogenoplatinum(ll) complex containing a neutral bidentate ligand, with an oo organic oxalate salt.
New halogenoplatinum(l) complexes having neutral bidentate ligands : : : containing S or Se donor atoms include: - : oo - Complex (xi) bis-chloro-(1-methyl-2-methylthiomethyl- imidazole)platinum(1) :
Complex (xii) bis-chloro-(1-methyl-2-methylthioethyl-imidazole)platinum(li) : Po Complex (xiii) bis-chloro-(1-methyl-2-methylthiopropyl- imidazole)platinum(ll) : B : : Complex (xiv) bis-chloro-(1-butyl-2-methylthiomethyl-imidazole)platinum(ll) : : : Complex (xv) bis-chloro-(1-butyl-2-methylthioethyl-imidazole)platinum(il).
The above new complexes may be used in methods of treating cancer in : patients, and in methods of manufacturing medicaments for treating cancer
So in patients. :
Optically pure trans-{-1,2-diaminocyclohexane is used to prepare an optically pure halogenoplatinum complex containing a neutral bidentate ligand in the form of cis-bis-halogeno(trans-t-1,2- diaminocyclohexane)platinum(lf), from K,PtXs where X=Cl|, Br, |, preferably
X=Cl,
© WO 2006/024897 . . PCT/IB2005/000570 g The optically pure trans--1,2-diaminocyclohexane may be ‘prepared by oo dissolving trans-1,2-diaminocyclohexane in water and adding {tartaric acid to the solution by stirring continuously at 90°C. When all the tartaric acid is : ; dissolved, glacial acetic acid is added drop-wise while stirring. The mixture : is heated for 1 hour at 90°C whereafter it is cooled to room temperature. : The resultant white £-1,2-diaminocyclohexane-t-tartrate is filtered and : washed and oven dried. The salt is then crystallized out of the hot water Co and cooled. The recrystallized £-1,2-diaminocyclohexane-t-tartrate is added : : Co to sodium hydroxide and dissolved in water. Once the amine has dissolved a it is extracted with dichloromethane. The extracted dichloromethane a portions are added together and dried with anhydrous sodium sulphate. : Most of the solvent is removed by vacuum distillation. The last portion of oo solvent may be removed at atmospheric pressure to avoid the amine from distilling under vacuum, using an air condenser. ’
The optically pure trans-{-1,2-diaminocyclohexane is then reacted with a a platinum(ll) compound such as K;PtX, where X is a halide such Cl, Brorl, - . typically KoPtCly, to form cis-bis-halogeno(trans-{-1,2- : : oo : diaminocyclohexane)platinum(ll), typically ~~ cis-bis-chloro-(frans-t-1,2- : Co a ~ diaminocyclohexane)platinum(ll). This method is described in Inorganica :
Chimica Acta (1985) 108 : pp 63-66 (the content of which is incorporated herein by reference). : The optically pure cis-bis-halogeno(trans-£-1,2- diaminocyclohexane)platinum(ll), typically cis-bis-chloro-(trans-£-1,2- diaminocyclohexane)platinum(ll), is then reacted with a oxalate salt in a : solvent. In prior art methods, such as those discussed in the background to the invention, silver ions are used in the production of oxaliplatin. Such reactions take place in an aqueous solution and silver chloride (AgCl) is : formed as a by-product of the reaction. Less than 1 g/L of the cis-bis- . chloro-(trans-£-1,2-diaminocyclohexane)platinum(ll) is soluble in the : : aqueous solution, and the driving force of the reaction is the insolubility of the AgCl (which must be removed from the solution by filtration). According to an aspect of the invention, the inventor has found that it is advantageous
Claims (43)
1. A method for the preparation of an oxalatoplatinum(ll) complex containing a neutral bidentate ligand, the method including the step of reacting a halogenoplatinum complex containing a neutral bidentate ligand with a water soluble metal oxalate other than silver oxalate, wherein the neutral bidentate ligand is reacted with the oxalate at a molar ratio of greater than 1:1.
2. The method according to claim 1, wherein the oxalate is a metal . oxalate selected from rubidium oxalate or cesium oxalate.
3. The method according to claim 1 or claim 2, wherein the halogenoplatinum complex containing a neutral bidentate ligand is reacted with the oxalate at a molar ratio of between 1:1 and 1:15.
4. The method according to claim 3, wherein the halogenoplatinum complex containing a neutral bidentate ligand is reacted with oxalate at a molar ratio of between 1:1 and 1:5.
5. The method according to any one of claims 1 to 4, wherein the solvent is a mixed solvent system.
6. The method according to claim 5, wherein the mixed solvent system is a mixture of an amide and water.
7. The method according to claim 6, wherein the amide is dimethylformamide (dmf).
8. The method according to claim 7, wherein the ratio of dmf to water is 60:40 to 90:10 by volume.
9. The method according to claim 8, wherein the ratio of dmf to water is 70:30 by volume to 90:10 by volume.
10. The method according to any one of claims 1 to 9, wherein the solubility of the metal oxalate in the solvent is greater than 2 g/L.
11. The method according to claim 10, wherein the solubility of the metal oxalate in the solvent is greater than 3 g/L.
12. The method according to claim 11, wherein the solubility of the metal oxalate in the solvent is about 5 g/L
13. The method according to any one of claims 1 to 12, wherein the bis- halogenoplatinum(ll) complex containing a neutral bidentate ligand is dissolved in a non-aqueous solvent and thereafter water is added to provide a solvent which is a mixture of non-aqueous solvent and water.
14. The method according to any one of claims 1 to 13, wherein the metal oxalate is dissolved in a mixture of non-aqueous solvent and water and added to a solvent containing the halogenoplatinum(ll) complex containing a neutral bidentate ligand.
15. The method according to any one of claims 1 to 14, wherein the reaction takes place at a temperature in the range of 40 to 100°C.
16. The method according to claim 15, wherein the reaction takes place at a temperature in the range of 80 to 100°C.
17. The method according to claim 16, wherein the reaction takes place at a temperature of 90°C.
18. The method according to any one of claims 1 to 17, wherein halogenoplatinum(ll) complex is bis-chloro-(trans-£-1,2- diamonocyclohexane)platinum(ll).
19. The method according to claim 18, wherein halogenoplatinum(ll) complex is cis-bis-chloro-(trans-£-1,2- diaminocyclohexane)platinum(ll).
20. A method for the preparation of an oxalatoplatinum(ll) complex containing a neutral bidentate ligand, the method including the step of reacting a halogenoplatinum complex containing a neutral bidentate ligand with an organic oxalate salt.
21. The method according to claim 20, wherein the halogenoplatinum complex containing a neutral bidentate ligand is reacted with the oxalate at a molar ratio of greater than 1:1.
22. The method according to claim 21, wherein the halogenoplatinum complex containing a neutral bidentate ligand is reacted with the oxalate at a molar ratio of between 1:1 and 1:15.
23. The method according to claim 22, wherein the halogenoplatinum complex containing a neutral bidentate ligand is reacted with oxalate at a molar ratio of between 1:1 and 1:5.
24. The method according to any one of claims 20 to 23, wherein the organic oxalate salt is a tetra-alkyl or aryl ammonium compound.
25. The method according to claim 24, wherein the organic oxalate salt is a tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium or tetraphenylphosphonium oxalate.
26. The method according to claim 25, wherein the organic oxalate salt is tetrabutylammonium oxalate.
27. The method according to any one of claims 20 to 26, wherein the solvent is a mixed solvent system or a non-aqueous solvent.
28. The method according to claim 27, wherein the solvent is a mixture of a non-aqueous solvent and water.
29. The method according to claim 28, wherein the non-aqueous solvent is an amide.
30. The method according to claim 29, wherein the amide is dimethylformamide (dmf).
31. The method of claim 30, wherein the dmf and water are at a ratio of 90:10 by volume to 95:5 by volume.
32. The method according to claim 27, wherein the solvent is a non- aqueous solvent.
33. The method according to claim 32, wherein the non-aqueous solvent is an amide.
34. The method according to claim 33, wherein the amide is dimethylformamide (dmf).
35. The method according to any one of claims 20 to 34, wherein the organic oxalate salt has a solubility in the solvent of greater than 2 g/L.
36. The method according to claim 35, wherein the organic oxalate salt has a solubility in the solvent of greater than 10 g/L.
37. The method according to claim 35, wherein the organic oxalate salt has a solubility in the solvent of greater than 50 g/L.
38. The method according to claim 37, wherein the organic oxalate salt has a solubility of greater than 100 g/L.
39. The method according to claim 20, wherein the halogenoplatinum(l!) complex containing a neutral bidentate ligand is dissolved an non- aqueous solvent and the organic oxalate salt is dissolved in a non- aqueous solvent and added to the solvent containing the halogenoplatinum(ll) complex containing a neutral bidentate ligand.
-27 = . a
40. The method according to any one of claims 20 to 39, wherein the reaction takes place at a temperature of 50 to 70°C. :
41. The method according to claim 40, wherein the reaction takes place at a temperature of 60°C. ©
42. The method according to claim 41, wherein water is added to oo solvent after the cis-bis-halogeno(trans-£-1,2- - ~ diaminocyclohexane)platinum(ll) has been dissolved in the organic : a © liquid. co | :
43." The method according to any one of claims 1 to 42, wherein the oxalatoplatinum(ll) complex containing a neutral bidentate ligand is Co oxaliplatin. : DATED THIS 17TH DAY OF SEPTEMBER 2008 : a . "SPOOR & FISHER APPLICANT'S PATENT ATTORNEYS :
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| US60611904P | 2004-09-01 | 2004-09-01 |
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| ZA200807987A ZA200807987B (en) | 2004-09-01 | 2008-09-17 | Preparation of platinum(II) complexes |
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