CN101027313A - Cis-diiodo-(trans-L-1,2-cyclohexanediamine) platinum (II) complex and processes for preparing high purity oxaliplatin - Google Patents
Cis-diiodo-(trans-L-1,2-cyclohexanediamine) platinum (II) complex and processes for preparing high purity oxaliplatin Download PDFInfo
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Abstract
The present invention is related to pure cis-diiodo-(trans-L-1,2-cyclohexanediamine) Pt (II) complex, and a process of its preparation. The present invention is further related to the preparation of oxaliplatin using said cis-diiodo-(trans-L-1,2-cyclohexanediamine) Pt (II) complex.
Description
The cross reference of related application
The application requires to enjoy in the U.S. Provisional Application of application on July 12nd, 2004 number 60/586,729 and in the right of priority of the U.S. Provisional Application of application on July 27th, 2004 number 60/591,209, and their disclosed content incomes as a reference.
Background technology
Oxaliplatin, cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine)-platinum (II) title complex has following structure:
Molecular formula C
8H
14N
2O
4Pt
Molecular weight 397.3
Oxaliplatin is slightly soluble in water with 6mg/mL, the atomic methyl alcohol that is dissolved in, and be dissolved in ethanol and acetone hardly.
Oxaliplatin is with ELOXATIN
TM(injection oxaliplatin) sold, and it provides (PDR with the bottle of oxaliplatin that contains 50mg or 100mg and be used for aseptic, the preservative-free lyophilized powder form of Multiple Bonds (reconstitution); Injection oxaliplatin-complete feature article).
Oxaliplatin is a kind of antineoplastic agent that is similar to cis-platinum.It the treatment metastatic colorectal cancer in and in assisting therapy III phase (Dukes C) colorectal carcinoma with Ro 2-9757 and folinic acid administration.
US 4,169,846 claimed oxaliplatins itself and preparation method thereof, and described preparation method's yield is extremely low.After this, at for example JP 09132583, EP 0625523, EP 0801070, US 5,290,961, US 5,298, and 642, US 5,338,874 and the patent documentation of EP 0567438 in preparation trans-D-of oxaliplatin and improving one's methods of trans-L-1,2-mixture of isomers are disclosed.These methods relate to 1 of preparation formula (4), dihalo cis-platinum (II) title complex of 2-diamino-cyclohexane,
Wherein said dihalo-is on behalf of Cl, Br or I,
Be translated into cis-two hydration-1 of formula (3), the 2-diamino-cyclohexane is closed platinum (II) title complex,
Then thereby itself and oxalic acid or potassium oxalate reaction are obtained the trans-D-isomer and the trans-L-1,2-mixture of isomers of oxaliplatin.
In EP 0567438, this method is described to one kettle way, and the compound of its Chinese style (4) is converted into the compound of formula (3), and not with its separation.
Disclosed a kind of replacement synthetic route is 1 of a through type (4) in EP 0625523, and formed silver chloride is removed in dihalo cis-platinum (II) title complex of 2-diamino-cyclohexane and silver oxalate reaction subsequently, and wherein said dihalo-is on behalf of Cl or Br.
EP 0567438 further provides a kind of high purity method that obtains oxaliplatin, carries out the optical resolution that cis-oxalate (trans-D, L-1,2-cyclohexanediamine) closes the D-isomer and the L-isomer of platinum (II) by the HPLC method in this patent.
The method of another kind of acquisition oxaliplatin has been described in WO 2005/035544.This synthetic route is closed Pt (II) with two hydrations-(1, the 2-cyclohexanediamine) of tediously long step through type (3) and is carried out, and in order to obtain required oxaliplatin with high purity, it need carry out heavy processing.
Still exist preparing the method needs of oxaliplatin, these methods prepare optically pure oxaliplatin with improved and industrial method.
Summary of the invention
The cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) that one aspect of the present invention relates to isolating formula (2) closes platinum (II) title complex.
Cis-diiodo-of the present invention (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex and is characterised in that its melting range is at about 275 ℃ to about 300 ℃.Cis-diiodo-of the present invention (trans-L-1,2-1, the 2-cyclohexanediamine) it is optically pure closing platinum (II) title complex, wherein cis-diiodo-is (trans-D-1, the 2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 3%HPLC area, preferably less than about 2%HPLC area, be more preferably less than about 1%HPLC area, and most preferably less than about 0.1%HPLC area.
Another aspect of the present invention relates to optically pure cis-diiodo-(trans-L-1,2-1, the 2-cyclohexanediamine) closes platinum (II) title complex, wherein cis-diiodo-is (trans-D-1, the 2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 3%HPLC area, preferably less than about 2%HPLC area, be more preferably less than about 1%HPLC area, and most preferably less than about 0.1%HPLC area.
The further aspect of the present invention relates to a kind of by trans-L-1,2-1, and 2-cyclohexanediamine and potassium chloroplatinite and potassiumiodide react in water and prepare the method that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex.Preferably, employed trans-L-1,2-1, the 2-cyclohexanediamine is optically pure, wherein said trans-D-1, the content of 2-cyclohexanediamine isomer is less than about 3%HPLC area, preferably less than about 2%HPLC area, be more preferably less than about 1%, and most preferably less than about 0.1%HPLC area; As mentioned above, to close platinum (II) title complex also be optically pure to resulting thus cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine).
Another aspect of the present invention relates to a kind of use cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) and closes platinum (II) title complex and react the method for preparing oxaliplatin by itself and silver oxalate.Preferably, it is optically pure that employed cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, as mentioned above, therefore makes by the resulting oxaliplatin of this method it also is optically pure.
On the other hand, the present invention relates to a kind of preparation cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) that passes through and close platinum (II) title complex, preferably optically pure as mentioned above, and be translated into the method that oxaliplatin prepares oxaliplatin.
In one aspect, the method for preparing oxaliplatin that the present invention relates to may further comprise the steps: the cis-diiodo-of preparation formula (2) (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and is preferably optically pure,
With itself and AgNO
3Thereby reaction obtains cis-two hydration-1 of formula (3), and the 2-diamino-cyclohexane is closed platinum (II) title complex,
And with formula (3) thus compound and potassium oxalate reaction obtain oxaliplatin.
On the other hand, the present invention relates to a kind of method for preparing oxaliplatin, it prepares cis-two hydration-1 by closing platinum (II) title complex from aforesaid cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine), 2-diamino-cyclohexane platinum (II) title complex, and be translated into oxaliplatin.
Below at this detailed step is described.
Detailed Description Of The Invention
Term " polarimetry purity " is meant the amount that is present in the needed isomer in the compound of being discussed.
When this uses, about oxaliplatin, cis-diiodo-(trans-L-1,2-1, the 2-cyclohexanediamine) closes platinum (II) title complex and trans-L-1,2-1, the 2-cyclohexanediamine, term " optically pure " is meant that the content of unwanted trans-isomer(ide) is less than about 3%HPLC area, preferably, be more preferably less than about 1% area less than about 2%HPLC area, and most preferably less than about 0.1%HPLC area.Described unwanted oxaliplatin isomer is that cis-oxalate (trans-D-1,2-cyclohexanediamine) closes platinum (II) title complex.The isomer that described unwanted cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex is that cis-diiodo-(trans-D-1,2-cyclohexanediamine) closes platinum (II) title complex.Described unwanted trans-L-1,2-1, the isomer of 2-cyclohexanediamine are trans-D-1, the 2-cyclohexanediamine.The polarimetry purity of described oxaliplatin is determined with the standard method of European Pharmacopoeia.
Term " thick " is meant not the compound that is further purified by any currently known methods (for example from suitable solvent crystallization or be suspended in the suitable solvent).
The cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) that the invention provides isolating formula (2) closes platinum (II) title complex:
Cis-diiodo-of the present invention (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex and is characterised in that its melting range is at about 275 ℃ to about 300 ℃.Cis-diiodo-of the present invention (trans-L-1,2-1, the 2-cyclohexanediamine) closes platinum (II) title complex and be further characterized in that its high polarimetry purity, wherein cis-diiodo-is (trans-D-1, the 2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 3%HPLC area, preferably less than about 2%HPLC area, be more preferably less than about 1%HPLC area, and most preferably less than about 0.1%HPLC area.
It can be feature with the following NMR spectrum that is recorded on the Brucher 300MHz that cis-diiodo-of the present invention (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex:
C
13NMR，DMSO(ppm)：64.45；61.13；32.67；32.09；24.91；24.65；
H
1NMR, DMSO (δ ppm): 2.35, wide is unimodal, 2H; 1.95, dd, 2H; 1.45 wide is unimodal, 2H; 1.30 wide is unimodal, 2H; 1.00 wide is unimodal, 2H; 6.17 multiplet, (NH
2);
Pt?195?NMR，DMSO：-3543s。
The present invention further provides optically pure cis-diiodo-(trans-L-1,2-1, the 2-cyclohexanediamine) closes platinum (II) title complex, wherein cis-diiodo-is (trans-D-1, the 2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 3%HPLC area, preferably less than about 2%HPLC area, be more preferably less than about 1%HPLC area, and most preferably less than about 0.1%HPLC area.
The present invention further provides the method that the described cis-diiodo-of a kind of preparation (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex.This method comprises:
A) with the trans-L-1,2-1 of formula (5), the aqueous solution of 2-cyclohexanediamine
With M
2PtX
4With the aqueous solution of KI, thereby obtain mixture;
B) at room temperature keep described mixture; And
C) reclaim cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex.
Wherein M is Li, Na or K, and
Wherein X is I, Cl or Br.
Preferably, employed trans-L-1,2-1 in step a), the 2-cyclohexanediamine is optically pure.Use this optically pure parent material to make that formed product also is optically pure, need not tediously long encompasses processes for optical resolution, for example HPLC.Described trans-L-1,2-1, the 2-cyclohexanediamine is commercially available.
Most preferably, M is K.Most preferably, X is I.
Can reclaim described cis-diiodo-(trans-L-1,2-1 by any methods known in the art, the 2-cyclohexanediamine) closes platinum (II) title complex, for example a kind of impurity that filters described reaction solvent and all existence that comprises washs resulting material and with any ordinary method exsiccant method.In this case, in order to remove the halogen ion, resulting material can be washed in water and suspends.
At US 5,290,961 and WO 03/004505 in use KI is disclosed to generate iodine compound, this compound is removed from described reaction mixture.In the present invention, KI is used to generate cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex as the key intermediate of preparation oxaliplatin.
Close platinum (II) title complex in order to be further purified described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine), the product of step c) can be suspended in and be selected from acid amides, C
1-4In the solvent of alkyl ester, ketone, halohydrocarbon, water and composition thereof, reclaim described sublimed material with aforesaid method subsequently.
Close platinum (II) title complex in order to obtain further sublimed cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine), can repeat described purge process.
Described acid amides can be methylformamide or dimethyl formamide, preferred dimethyl formamide.Preferred C
1-4Alkyl ester is ethyl acetate and methyl acetate.Preferably, described ketone is acetone.The preferred tetracol phenixin of described halohydrocarbon, chloroform or methylene dichloride.
Most preferably, described solvent is a dimethyl formamide.
The present invention further provides a kind of preparation cis-oxalate (trans-L-1,2-1, the 2-cyclohexanediamine) close platinum (II) title complex, promptly the method for oxaliplatin relates to described cis-diiodo-(trans-L-1,2-1, the 2-cyclohexanediamine) platinum (II) title complex and silver oxalate, this method comprises:
(i) provide cis-diiodo-(trans-L-1,2-1, the 2-cyclohexanediamine) platinum (II) title complex, preferably optically pure (have less than the described cis-diiodo-of about 3%HPLC area (trans-D-1, the 2-cyclohexanediamine) platinum (II) title complex isomer), for example, by implementing the method for the described cis-diiodo-of preparation according to the present invention (trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex;
(ii) with described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus the reaction of title complex and silver oxalate obtains reaction mixture;
Thereby the sylvite that (iii) with described reaction mixture and form is KX mixes the formation oxaliplatin, and wherein KX is KCl, KBr or KI; And
(iv) reclaim described oxaliplatin.
In the method for preparing oxaliplatin that relates to described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex and silver oxalate according to the present invention, step (ii) can be carried out according to the following steps:
A) with described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus title complex mixes with the alkaline aqueous solution of silver oxalate and obtains reaction mixture; And
B) described reaction mixture is heated to about 55 ℃ and arrives about 75 ℃ temperature at least 3 hours;
And step (iii) reaches (iv) and can carry out according to the following steps
C) will be from step B) described reaction mixture and form be that the sylvite of KX mixes;
D) will be from step C) described reaction mixture kept at least 4 hours; And
E) from step D) reclaim oxaliplatin in the described reaction mixture that obtains.
An embodiment that relates to the method for preparing oxaliplatin of described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex and silver oxalate according to the present invention comprises
A) with cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus the aqueous solution of title complex mixes with the basic solution of silver oxalate and obtains reaction mixture;
B) described reaction mixture is heated to about 55 ℃ to about 75 ℃, preferably approximately arrives about 60 ℃ temperature at least 3 hours for 55 ℃;
C) with step B) reaction mixture and form be that the halogenation sylvite of KX mixes;
D) described reaction mixture was kept 4 hours at least; And
E) from described reaction mixture, reclaim oxaliplatin,
Wherein form is that the sylvite of KX is KCl, KBr or KI.
In the method for preparing oxaliplatin that relates to described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex and silver oxalate, the basic solution of described silver oxalate preferably has about 4.5 to about 5.0 pH value.Preferably, by silver oxalate being dissolved in alkali metal hydroxide alkali, obtain the basic solution of silver oxalate in the solution of preferred NaOH or KOH.Preferably, described form is that the sylvite of KX is KI.
Can from the preparation process that relates to cis-diiodo-of the present invention (trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex, reclaim oxaliplatin.Preferably, in order to remove for example sedimentary silver halide compound of any impurity described reaction mixture is filtered, described sedimentary silver halide compound is obtained by silver ions that is present in described reaction mixture and halide-ions reaction.Resulting filtrate can be cooled to about 0 ℃ to 5 ℃ temperature, under this temperature, form thick oxaliplatin.Can filter, wash by any methods known in the art and dry described thick oxaliplatin.
Preferably, at the described cis-diiodo-(trans-L-1,2-1 that relates to according to the present invention, the 2-cyclohexanediamine) employed cis-diiodo-(trans-L-1,2-1 in the method for preparing oxaliplatin of platinum (II) title complex and silver oxalate, the 2-cyclohexanediamine) platinum (II) title complex has less than about 3%HPLC area, preferably less than the 2%HPLC area, be more preferably less than the 1%HPLC area, and most preferably less than the described unwanted isomer of 0.1%HPLC area, therefore and resulting oxaliplatin also comprises low levels, for example less than the 3%HPLC area, preferably less than the 2%HPLC area, be more preferably less than the 1%HPLC area and most preferably less than its corresponding unwanted isomer of 0.1%HPLC area.
Preferably by it being dissolved in water under about 70 ℃ temperature and cooling off resulting solution and come the resulting thick oxaliplatin of crystallization to about 5 ℃ temperature to about 0 ℃ at about 55 ℃.Can repeatedly repeat described crystallization in water, and from described reaction mixture, remove described residual silver ions and combine.Can preferably pass through in the aqueous solution of oxaliplatin, to add halogenation sylvite for example KI, KCl or KBr, preferred KI, thus make described unnecessary Ag
+Form silver halide precipitation and remove described silver ions with described halogen ionic reaction.Can remove formed silver halide compound from described solution by filtering, the method for any routine, for example film are used in described filtration.
Another kind is removed the method for described silver ions for passing through to use sequestrant, for example EDTA.Also has a kind of method of described silver ions of removing for passing through to use Zeo-karb.
Resulting oxaliplatin can be from being selected from acid amides, C
1-4Further recrystallization reclaims sublimed material with aforesaid method subsequently in the solvent of alkyl ester, ketone, halohydrocarbon, water and composition thereof.
Described acid amides can be methylformamide or dimethyl formamide, preferred dimethyl formamide.Preferred C
1-4Alkyl ester is ethyl acetate and methyl acetate.Preferably, described ketone is acetone.Described halohydrocarbon is preferably tetracol phenixin, chloroform or methylene dichloride.
Most preferably, described solvent is a dimethyl formamide.
The oxaliplatin that is reclaimed after aforesaid recrystallization process is optically pure, and wherein said cis-oxalate (trans-D-1,2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 3%HPLC area.Preferably, described cis-oxalate (trans-D-1,2-cyclohexanediamine) closes the content of platinum (II) title complex isomer for less than about 2%HPLC area, is more preferably less than about 1%HPLC area, and most preferably less than about 0.1%HPLC area.
Use cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex to avoid being used to cis-two hydration-1 of the formula that obtains (3), the additional step of 2-diamino-cyclohexane platinum (II) title complex as the intermediate of preparation oxaliplatin.
The present invention also provides a kind of method for preparing oxaliplatin that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex that relates to, and it comprises:
A) with the trans-L-1,2-1 of formula (5), the aqueous solution of 2-cyclohexanediamine
With M
2PtX
4Thereby obtain mixture with the aqueous solution of KI;
B) at room temperature keep described mixture;
C) reclaim cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex;
D) described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex is mixed with water, thereby and resulting solution mixed with the basic solution of silver oxalate obtain reaction mixture;
E) described reaction mixture is heated to about 55 ℃ and arrives about 75 ℃ temperature at least 3 hours;
F) be that the halogenation sylvite of KX mixes with the reaction mixture of step e) and form;
G) described reaction mixture was kept 4 hours at least; And
H) from described reaction mixture, reclaim oxaliplatin,
Wherein M is Li, Na or K,
Wherein X is I, Cl or Br, and
Wherein form is that the sylvite of KX is KCl, KBr or KI.
Preferably, employed trans-L-1,2-1 in step a), the 2-cyclohexanediamine is optically pure, it produces optically pure oxaliplatin.
Also can be via cis-two hydration-1 of formula (3), 2-diamino-cyclohexane platinum (II) title complex changes into oxaliplatin with cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex.
The invention provides a kind of cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex and method for preparing oxaliplatin that cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex of relating to, it comprises:
(i) provide cis-diiodo-(trans-L-1,2-1, the 2-cyclohexanediamine) platinum (II) title complex, preferably optically pure (have less than the described cis-diiodo-of about 3%HPLC area (trans-D-1, the 2-cyclohexanediamine) platinum (II) title complex isomer), for example, by implementing the method for the described cis-diiodo-of preparation according to the present invention (trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex;
(ii) with described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus the reaction of title complex and Silver Nitrate obtains cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) in reaction mixture close platinum (II) title complex;
(iii) remove silver ions from described reaction mixture;
(iv) reclaim described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex;
(v) described cis-two hydration-(trans-L-1,2-cyclohexanediamine) closed platinum (II) title complex and be converted into oxaliplatin; And
(vi) reclaim described oxaliplatin.
At the cis-diiodo-(trans-L-1,2-1 that relates to according to the present invention, the 2-cyclohexanediamine) platinum (II) title complex and cis-two hydration-(trans-L-1,2-1, the 2-cyclohexanediamine) closes in the method for preparing oxaliplatin of platinum (II) title complex, can carry out step (ii) according to the following steps
I) with described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus title complex mixes with silver nitrate aqueous solution and obtains reaction mixture;
II) described reaction mixture is heated to about 45 ℃ to about 60 ℃, preferably approximately arrives about 55 ℃ temperature for 45 ℃, thereby the cis of obtaining-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex; And randomly further comprise
III) described suspension is cooled to about 20 ℃ and arrives about 30 ℃ temperature.
At the cis-diiodo-(trans-L-1,2-1 that relates to according to the present invention, the 2-cyclohexanediamine) platinum (II) title complex and cis-two hydration-(trans-L-1,2-1, the 2-cyclohexanediamine) close in the method for preparing oxaliplatin of platinum (II) title complex, the Silver iodide that can obtain by the interpolation by KI precipitate removes described silver ions from described reaction mixture.
At the cis-diiodo-(trans-L-1,2-1 that relates to according to the present invention, the 2-cyclohexanediamine) platinum (II) title complex and cis-two hydration-(trans-L-1,2-1, the 2-cyclohexanediamine) closes in the method for preparing oxaliplatin of platinum (II) title complex, can according to the following steps described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) be closed platinum (II) title complex and be converted into oxaliplatin: it is mixed with potassium oxalate; Described pH value is adjusted to about 4.5 to about 5.0; Thereby cooling obtains the suspension that cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex; And close platinum (II) title complex from described suspension recovery cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine).
Relate to the embodiment that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) title complex and cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) close the method for preparing oxaliplatin of platinum (II) title complex and comprise according to of the present invention:
A) cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) is closed platinum (II) thus the aqueous solution of title complex mixes with silver nitrate aqueous solution and obtains reaction mixture;
B) thus described reaction mixture is heated to about 45 ℃ to be obtained cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) and closes the suspension of platinum (II) title complex to about 60 ℃ temperature;
C) described suspension is cooled to about 20 ℃ to about 30 ℃ temperature;
D) remove described silver ions from described reaction mixture;
E) reclaim cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex; And
F) described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) closed platinum (II) title complex and be converted into oxaliplatin.
Preferably, the reaction mixture in the step b) is heated to about 45 ℃ to about 55 ℃ temperature.Preferably, make Silver iodide precipitate by adding KI, and it is removed from described reaction mixture, for example, remove described silver ions from described reaction mixture by filtering.
Preferably, employed cis-diiodo-(trans-L-1,2-1 in step a), the 2-cyclohexanediamine) it is optically pure closing platinum (II) title complex, and it also is optically pure therefore making resulting cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) close platinum (II) title complex.
Can be according to methods known in the art, for example at US 5,338, the method described in 874 is closed platinum (II) title complex with described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) and is converted into oxaliplatin.
In a preferred embodiment, according to the following steps described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) closed platinum (II) title complex and be converted into oxaliplatin: it is mixed with potassium oxalate; The aqueous solution with alkali metal hydroxide alkali is adjusted to about 4.5 to about 5.0 with described pH value; Thereby cooling obtains the suspension that cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and closes platinum (II) title complex from described suspension recovery cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine).
Preferably can prepare potassium oxalate from oxalic acid and potassium hydroxide.
The complete synthetic route of one embodiment of the invention is presented as follows:
Compare with AgBr with AgCl, the lower solubleness of AgI allows to form utmost point fine cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) and closes platinum (II) title complex.In addition, in the described method of prior art, described cis-dihalo-(trans-L-1,2-1,2-diamino-cyclohexane) closes platinum (II) title complex and AgNO
324 to 72 hours reaction times of reaction needed, wherein halogen is Br or Cl.But in the method for the invention, described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex and is converted into described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex in less than two hours.
The present invention also provides a kind of method for preparing oxaliplatin, and it comprises:
A) with the trans-L-1,2-1 of formula (5), the aqueous solution of 2-cyclohexanediamine
With M
2PtX
4Thereby obtain mixture with the aqueous solution of KI;
B) at room temperature keep described mixture;
C) reclaim cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex; And
D) described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) is closed platinum (II) title complex and is converted into oxaliplatin,
Wherein M is Li, Na or K, and
Wherein X is I, Cl or Br.
Described the present invention with reference to some preferred embodiment, from the consideration of this specification sheets, other embodiments will be tangible for those skilled in the art.Further describe the present invention with reference to the preparation of the described title complex of following detailed description and the embodiment of application method of the present invention.Under the situation that does not deviate from scope of the present invention, can implement many modifications to material and method, this will be conspicuous to those skilled in the art.
Embodiment
Embodiment 1: the preparation that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Under nitrogen atmosphere, carry out this process.
34.4 gram potassium platinochlorides are dissolved in the 275ml water.The solution of preparation 80.1 gram KI in 140ml water.Thereby two solution are mixed obtaining mixing solutions in 15 minutes, it is joined to restrain with 10 in advance then and have the trans-L-1,2 of 99.9%HPLC area polarimetry purity-1 at least, in the aqueous solution that the 2-cyclohexanediamine prepares in 30ml water.Formed thick cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) in 10 hours and close platinum (II) title complex thereby at room temperature stir this reaction soln, it is leached from described reaction soln as precipitation and with 55ml water washing 3 times.Should precipitate resuspending then in 220ml water 15 minutes and from described suspension, leach, then wash with water up to detecting less than halide-ions.Described washed precipitation was suspended in the 45ml dimethyl formamide 15 minutes.The precipitation of this suspension is leached from described suspension, with 10ml dimethyl formamide washing 3 times, thereby then with 30ml water washing 3 times and obtain cis-diiodo-(trans-L-1,2-1 for 3 times with the 20ml washing with acetone at last, the 2-cyclohexanediamine) closes platinum (II) title complex, thereby it was obtained fusing point between 275-300 ℃ in dry 12 hours under 25-30 ℃, vacuum, polarimetry purity is for 99.5%HPLC area and weight are that the 40.0 pure cis-diiodo-s (trans-L-1,2-1,2-cyclohexanediamine) that restrain close platinum (II) title complex at least.
Embodiment 2: the preparation that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Under 15-25 ℃, be dissolved in the 100g potassium platinochloride in the 1000mL water and stirred 20 minutes, then the B of this solution by band filter paper filtered.In an independent flask, at room temperature pack into 80.0g KI and 150mL water; Then with solution and the K of described KI
2PtCl
4Mix and be incorporated in 20-30 ℃ of following the stirring 20 minutes.Slowly add trans-L-1,2-1 to resulting solution, 2-cyclohexanediamine (DACH) (29.5g) with the mixture of water (70mL).Stirred this reaction mixture 3 hours down at 20-30 ℃.Under vacuum, leach described solid product and wash (3 * 300mL) with water with B.With described product in vacuum drying oven 65 ℃ of following dryings at least 12 hours.This cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex product and has the polarimetry purity of 99.5%HPLC area at least.
Embodiment 3: the preparation that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Under nitrogen atmosphere, carry out this process.
The inferior potassium platinate of 34.4 gram tetrachloros is dissolved in the 275ml water.The solution of preparation 80.1 gram KI in 140ml water.Thereby two solution are mixed obtaining mixing solutions in 15 minutes, it is joined to restrain with 10 in advance then and have the trans-L-1,2 of 99.9%HPLC area polarimetry purity-1 at least, in the aqueous solution that the 2-cyclohexanediamine prepares in 30ml water.Formed thick cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) in 10 hours and close platinum (II) title complex thereby at room temperature stir this reaction soln, it is leached from described reaction soln as precipitation and with 55ml water washing 3 times.Should precipitate resuspending then in 220ml water 15 minutes and from described suspension, leach, then wash with water up to detecting less than halide-ions.Described washed precipitation is suspended in 45 milliliters in advance with in the solution of 50% dimethyl formamide and 50% water preparation 15 minutes.The precipitation of described suspension is leached from described suspension, wash 3 times with 50% dimethyl formamide/aqueous solution 10ml, thereby then with 30ml water washing 3 times and obtain cis-diiodo-(trans-L-1,2-1 for 3 times with the 20ml washing with acetone at last, the 2-cyclohexanediamine) closes platinum (II) title complex, thereby it was obtained pure cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) in dry 12 hours close platinum (II) title complex under 25-30 ℃, vacuum.Resulting pure cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex and has fusing point between 275-300 ℃, the polarimetry purity of 99.5%HPLC area and the weight of 37.0 grams at least.
Embodiment 4: the preparation that cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
The 100g platinum cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) of packing under 20-30 ℃ closes platinum (II) title complex and 400mL water and stirred 20 minutes.In above-mentioned solution, add and use AgNO
3(69.3g) with the mixture of water (100-130mL) preparation.Under 20-30 ℃, this mixture was stirred 60 minutes, be heated to 45-55 ℃ and stirred 10 minutes then.Then stirred this suspension 20 minutes at 20-30 ℃ of 8g KI that cools off this suspension down and be added in the 20ml water then.Under vacuum, leach resulting Silver iodide and wash (2 * 100mL) with water.Preserving resulting solution in the dark, preparation is used in the next step.
Embodiment 5: the preparation of potassium oxalate
Under agitation, 35.66g potassium hydroxide is dissolved among the 300mL MeOH and at room temperature 36.45g oxalic acid is joined in this solution.Stirred this mixture 3 hours.The described solvent of distillation is 100mL up to cumulative volume under normal pressure.Under vacuum, leach described salt, with MeOH (3 * 20mL) washings and drying 12h at least under room temperature, vacuum.
Embodiment 6: the preparation that cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Because it is light sensitive that described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex,, described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) under nitrogen atmosphere and in faint light, carries out so closing the preparation process of platinum (II) title complex.
10 gram cis-diiodo-s (trans-L-1,2-1,2-cyclohexanediamine) are closed platinum (II) title complex (2) to be dissolved in the 800ml water.Then 5.4 gram silver oxalates are joined in this solution and also the pH value is adjusted to 4.5-5.0 with 0.1N NaOH solution.This reaction soln 55-60 ℃ of down heating 3 hours, and is added 0.05 gram KI and stirred 4 hours under uniform temp.Add 0.1 gram gac then and it is filtered with AgI down with 0.2 μ m film at 55-60 ℃.Thereby with described filtrate the volume that under 55-60 ℃, is concentrated to 70ml under the vacuum and 0-5 ℃ down cooling form thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) more than 30 minutes and close platinum (II) complex structure (1).Leaching described thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) from this solution closes platinum (II) complex structure (1) and uses twice of 10ml cold water washing.Dry described washed cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closed platinum (II) complex structure (1) 12 hour under 25-30 ℃, vacuum then.Obtain 5.6 gram crude products (1).By it is dissolved under 55-60 ℃ in the 450ml water, under this temperature, adds 0.05 gram gac and pass through 0.2 μ m membrane filtration; Thereby then described filtrate is concentrated under 55-60 ℃, vacuum 40ml volume and 0-5 ℃ down cooling formed precipitation in 30 minutes and described thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closed platinum (II) title complex product (1) crystallization.Leach described precipitation and with 5.0ml water washing 3 times.It is dry more than 24 hours described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) to be closed platinum (II) title complex product (1) under 45-50 ℃, vacuum.By under 55-60 ℃ with described cis-oxalate (trans-L-1,2-1, the 2-cyclohexanediamine) closing platinum (II) title complex product (1) is dissolved in the 450ml water again, and thereby adding 0.05 restrains KI and stirs the silver ions of removing any tracer level in 4 hours and come the described cis-oxalate of purifying (trans-L-1,2-1,2-cyclohexanediamine) to close platinum (II) title complex product (1) under uniform temp.After adding 0.05 gram gac and going out by 0.2 μ m membrane filtration, under 55-60 ℃, vacuum, described filtrate is concentrated to the final volume of 40ml, thereby and 0-5 ℃ down cooling formed precipitation in 30 minutes.Leach described precipitation and with 5.0ml water washing 3 times.It is dry more than 12 hours described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) to be closed platinum (II) title complex product (1) under 25-30 ℃, vacuum.Described dry cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) of crossing is closed platinum (II) title complex product (1) be suspended in the 30ml dimethyl formamide, stirred 15 minutes, leach and wash 3 times with the 5.0ml dimethyl formamide from this suspension.At last, at room temperature described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) is closed platinum (II) title complex product (1) resuspending in 20ml water 15 minutes, thereby from this suspension, leach and remove dimethyl formamide 3 times with the 5.0ml cold water washing.Under 45-50 ℃, vacuum, described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) was closed platinum (II) title complex product (1) dry 20 hours.Obtaining weight is that 5.0 grams and polarimetry purity are that the pure cis-oxalate of 99.9%HPLC area (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex (1) crystal at least.
Embodiment 7: the preparation that cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Because it is light sensitive that described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex,, described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) under nitrogen atmosphere and in faint light, carries out so closing the preparation process of platinum (II) title complex.
10 gram cis-diiodo-s (trans-L-1,2-1,2-cyclohexanediamine) are closed platinum (II) title complex (2) to be dissolved in the 800ml water.Then 5.4 gram silver oxalates are joined this solution and with 0.1N NaOH solution the pH value are adjusted to 4.5-5.0 when needs (only when).With this reaction mixture 55-60 ℃ of down heating 3 hours and add 0.05 gram KI and under uniform temp, stirred 4 hours.Add 0.1 gram gac then and it is filtered with AgI down with 0.2 μ m film at 55-60 ℃.Thereby with described filtrate under 55-60 ℃, vacuum, be concentrated to 70ml volume and 0-5 ℃ down cooling form thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) more than 30 minutes and close platinum (II) title complex (1).Described thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closed that platinum (II) title complex (1) leaches and with twice of 10ml cold water washing from described solution.Under 25-30 ℃, vacuum, washed cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) was closed platinum (II) title complex (1) dry 12 hours then.Obtain the thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) of 5.6 grams and close platinum (II) title complex product (1).By it is dissolved under 55-60 ℃ in the 450ml water, under this temperature, adds 0.05 gram gac and pass through 0.2 μ m membrane filtration; Thereby then described filtrate is concentrated under 55-60 ℃, vacuum 40ml volume and 0-5 ℃ down cooling formed precipitation in 30 minutes and described thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closed platinum (II) title complex product (1) crystallization.Leach described precipitation and with 5.0ml water washing 3 times.It is dry more than 24 hours described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) to be closed platinum (II) title complex product (1) under 45-50 ℃, vacuum.By under 55-60 ℃ with described cis-oxalate (trans-L-1,2-1, the 2-cyclohexanediamine) closing platinum (II) title complex product (1) is dissolved in the 450ml water again, thereby and under uniform temp, add 0.05 gram KI and stir and removed any tracer level silver ions in 4 hours and come the described cis-oxalate of purifying (trans-L-1,2-1,2-cyclohexanediamine) to close platinum (II) title complex product (1).After adding 0.05 gram gac and going out by 0.2 μ m membrane filtration, under 55-60 ℃, vacuum, described filtrate is concentrated to the final volume of 40ml, thereby and 0-5 ℃ down cooling formed precipitation in 30 minutes.Leach this precipitation and with 5.0ml water washing 3 times.It is dry more than 12 hours described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) to be closed platinum (II) title complex product (1) under 25-30 ℃, vacuum.Cis-oxalate (trans-L-1,2-1 that drying is crossed, the 2-cyclohexanediamine) closes in the solution that platinum (II) title complex product (1) is suspended in 50% dimethyl formamide of 30ml and 50% water, stirred 15 minutes, and leached and wash 3 times with 50% dimethyl formamide/aqueous solution 5.0ml from described suspension.At last, at room temperature described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) is closed platinum (II) title complex product (1) resuspending in 20ml water 15 minutes, thereby from described suspension, leach and remove dimethyl formamide 3 times with the 5.0ml cold water washing.Under 45-50 ℃, vacuum, described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) was closed platinum (II) title complex product (1) dry 20 hours.Obtaining weight is that 5.4 grams and polarimetry purity are that the pure cis-oxalate of 99.9%HPLC area (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex (1) crystal at least.
Embodiment 8: the preparation that cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Because described cis-oxalate (trans-L-1,2-1, the 2-cyclohexanediamine) it is light sensitive closing platinum (II) title complex (1), so closing the preparation process of platinum (II) title complex (1), described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) should under nitrogen atmosphere and in faint light, carry out.
10 gram cis-diiodo-s (trans-L-1,2-1,2-cyclohexanediamine) are closed platinum (II) title complex (2) to be dissolved in the 800ml water.Then 5.4 gram silver oxalates are joined this solution and with 0.1N NaOH solution the pH value are adjusted to 4.5-5.0 when needs (only when).With this reaction soln 70-75 ℃ of down heating 3 hours and add 0.05 gram KI and under uniform temp, stirred 4 hours.Add 0.1 gram gac then and it is filtered with AgI down with 0.2 μ m film at 70-75 ℃.Thereby under 70-75 ℃, vacuum, described filtrate is concentrated to 70ml volume and 0-5 ℃ down cooling form thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) more than 30 minutes and close platinum (II) title complex (1).Described thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closed that platinum (II) title complex (1) leaches and with twice of 10ml cold water washing from described solution.Under 25-30 ℃, vacuum, washed cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) was closed platinum (II) title complex (1) dry 12 hours then.Obtain the thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) of 5.6 grams and close platinum (II) title complex product (1).By under 70-75 ℃, it being dissolved in the 450ml water, under this temperature, adding 0.05 gram gac and pass through 0.2 μ m membrane filtration; Thereby under 70-75 ℃, vacuum, described filtrate is concentrated to then 40ml volume and 0-5 ℃ down cooling formed precipitation in 30 minutes and described thick cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closed platinum (II) title complex product (1) crystallization.Leach described precipitation and with 5.0ml water washing 3 times.It is dry more than 24 hours described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) to be closed platinum (II) title complex product (1) under 45-50 ℃, vacuum.By under 70-75 ℃ with described cis-oxalate (trans-L-1,2-1, the 2-cyclohexanediamine) closing platinum (II) title complex product (1) is dissolved in the 450ml water again, thereby and under uniform temp, add 0.05 gram KI and stir and removed any tracer level silver ions in 4 hours and come the described cis-oxalate of purifying (trans-L-1,2-1,2-cyclohexanediamine) to close platinum (II) title complex product (1).After adding 0.05 gram gac and going out by 0.2 μ m membrane filtration, under 70-75 ℃, vacuum, described filtrate is concentrated to the final volume of 40ml, thereby and 0-5 ℃ down cooling formed precipitation in 30 minutes.Leach this precipitation and with 5.0ml water washing 3 times.It is dry more than 12 hours described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) to be closed platinum (II) title complex product (1) under 25-30 ℃, vacuum.Cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) that drying is crossed closes platinum (II) title complex product (1) and is suspended in the 30ml dimethyl formamide, stirs 15 minutes, leaches and with 5.0ml dimethyl formamide washing 3 times from described suspension.At last, at room temperature described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) is closed platinum (II) title complex product (1) resuspending in 20ml water 15 minutes, thereby leach and remove dimethyl formamide 3 times with the 5.0ml cold water washing from described suspended matter.Under 45-50 ℃, vacuum, described cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) was closed platinum (II) title complex product (1) dry 20 hours.Obtaining weight is that 5.0 grams and polarimetry purity are that the pure cis-oxalate of 99.9%HPLC area (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex (1) crystal at least.
Embodiment 9: the preparation that cis-oxalate (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Close to cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) and add about 54g potassium oxalate in the solution of platinum (II) title complex and the pH value is adjusted to 4.5-5.0 with 0.1M KOH.This mixture was stirred 2.5 hours at least.This reaction mixture is cooled between 5-10 ℃, and resulting suspension is leached and (9: 1v/v) Zhi Bei cold mixt washs described solid with alcohol-water with 100mL.Then will this moistening product be suspended in the water (7.0L) and heat up up to dissolving fully.In order to remove described insoluble impurities, under vacuum by the described hot solution of 0.2mm membrane filtration, and with hot water (100mL) washed twice.Under 60 ℃, vacuum, remove anhydrate up to the final volume of 2L and under vacuum, leach formed precipitation and with 100mL with alcohol-water (9: the 1v/v) cold mixt of preparation washing, then 5 ℃ down with absolute ethanol (100mL) washing, at 5 ℃ down with 50ml DMF washed twice and with 50ml washing with alcohol three times.The described precipitation of vacuum-drying 60 minutes on funnel then.At room temperature, arrive about 100mL by the 0.2mm filter paper filtering and with described solution concentration with described product 4.8L water dissolution; Then with this solution at 30 minutes internal cooling to 0-5 ℃.This suspended matter is leached and under 5 ℃, uses 9: 1 volumes of 50ml: volume of ethanol: the mixture washed twice of water, use twice of 50ml washing with alcohol down with 30ml DMF washing three times and at 0-5 ℃.With described solid under vacuum dry 12 hours.
Embodiment 10: the sign that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex
Levy cis-diiodo-of the present invention (trans-L-1,2-1,2-cyclohexanediamine) by the following NMR stave that is recorded on the Brucher 300MHz and close platinum (II) title complex:
C
13NMR，DMSO(ppm)：64.45；61.13；32.67；32.09；24.91；24.65
H
1NMR, DMSO (δ ppm): 2.35, wide is unimodal, 2H; 1.95, dd, 2H; 1.45 wide is unimodal, 2H; 1.30 wide is unimodal, 2H; 1.00 wide is unimodal, 2H; 6.17 multiplet, (NH
2)
Pt?195?NMR，DMSO：-3543s。
In described NMR spectrum, can't see the peak that significantly can belong to impurity.
Claims (33)
1. the cis-diiodo-of isolating formula (2) (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex.
2. the cis-diiodo-of claim 1 (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and it has from about 275 ℃ of fusing points to about 300 ℃ of scopes.
3. the cis-diiodo-of claim 1 (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and wherein said cis-diiodo-(trans-D-1,2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 3%HPLC area.
4. cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and wherein said cis-diiodo-(trans-D-1,2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 3%HPLC area.
5. each cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex in the claim 3 and 4, and wherein said cis-diiodo-(trans-D-1,2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 2%HPLC area.
6. the cis-diiodo-of claim 5 (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and wherein said cis-diiodo-(trans-D-1,2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 1%HPLC area.
7. the cis-diiodo-of claim 5 (trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and wherein said cis-diiodo-(trans-D-1,2-cyclohexanediamine) closes the content of platinum (II) title complex isomer less than about 0.1%HPLC area.
8. one kind prepares the method that cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) closes platinum (II) title complex, and it comprises:
A) with the trans-L-1,2-1 of formula (5), the 2-cyclohexanediamine
With M
2PtX
4Thereby mixing obtains mixture with KI;
B) described mixture is kept at room temperature; And
C) reclaim cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex,
Wherein M is Li, Na or K, and
Wherein X is I, Cl or Br.
9. the method for claim 8, the described trans-L-1,2-1 in step a) wherein, 2-cyclohexanediamine have less than the about described trans-D-1 of 3%HPLC area, 2-cyclohexanediamine isomer.
10. the method for claim 9, wherein said cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) are closed platinum (II) title complex and are had less than the about described cis-diiodo-(trans-D-1,2-cyclohexanediamine) of 3%HPLC area and close platinum (II) title complex isomer.
11. the method for claim 8, wherein M is K.
12. the method for claim 8, wherein X is I.
13. the method for claim 8 further comprises by it is suspended in being selected from acid amides, C
1-4Described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) with step c) in the solvent of alkyl ester, ketone, halohydrocarbon, water and composition thereof closes platinum (II) title complex purifying.
14. the method for claim 13, wherein said solvent is selected from methylformamide, dimethyl formamide, ethyl acetate, methyl acetate, acetone, tetracol phenixin, chloroform and methylene dichloride.
15. the method for claim 14, wherein said organic solvent is a dimethyl formamide.
16. the method for claim 13 wherein repeats described purification step.
17. a method for preparing oxaliplatin, it comprises:
(i) method of enforcement claim 8;
(ii) the cis-diiodo-that will in step c), obtain (trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus the reaction of title complex and silver oxalate obtains reaction mixture;
Form oxaliplatin thereby (iii) described reaction mixture is mixed with KX, wherein KX is KCl, KBr or KI; And
(iv) reclaim described oxaliplatin.
18. the method for claim 17, wherein step is (ii) carried out according to the following steps
D) the described cis-diiodo-that will in step c), obtain-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus title complex mixes with the alkaline aqueous solution of silver oxalate and obtains reaction mixture; And
E) described reaction mixture is heated to about 55 ℃ and arrives about 75 ℃ temperature at least 3 hours;
Wherein step (iii) and is (iv) carried out according to the following steps
F) will mix with KX from the described reaction mixture of step e), wherein KX is KCl, KBr or KI;
G) will keep at least 4 hours from the described reaction mixture of step f); And
H) the described reaction mixture that obtains from step g) reclaims oxaliplatin.
19. the method for claim 18, wherein the basic solution of the silver oxalate of step d) has about 4.5 to about 5.0 pH value.
20. the method for claim 18, wherein will the described reaction mixture in step e) be heated to about 55 ℃ to about 60 ℃ temperature.
21. the method for claim 18, wherein said form are the sylvite of KX is KI.
22. described cis-oxalate (trans-D-1,2-cyclohexanediamine) that the method for claim 18, wherein said oxaliplatin have less than about 3%HPLC area closes platinum (II) title complex isomer.
23. the method for claim 18 further comprises by with step h) in the oxaliplatin that obtains be dissolved in the water, from described reaction mixture remove residual silver ions and with the oxaliplatin crystallization with step h) the oxaliplatin purifying that obtains.
24. the method for claim 23 further comprises: after with described oxaliplatin crystallization, be selected from acid amides, C
1-4The described oxaliplatin of crystallization in the organic solvent of alkyl ester, ketone, halohydrocarbon.
25. the method for claim 24, wherein said organic solvent is a dimethyl formamide.
26. the method for claim 23 is wherein removed described silver ions by being selected from following method: precipitate silver halide, use sequestrant and use cation exchange resin by in the aqueous solution of described oxaliplatin, adding halogenation sylvite.
27. a method for preparing oxaliplatin, it comprises:
(i) method of enforcement claim 8;
(ii) the cis-diiodo-that will in step c), obtain (trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus the reaction of title complex and Silver Nitrate obtains cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) in reaction mixture close platinum (II) title complex;
(iii) from described reaction mixture, remove silver ions;
(iv) reclaim described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex;
(v) described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) closed platinum (II) title complex and be converted into oxaliplatin; And
(vi) reclaim described oxaliplatin.
28. the method for claim 27, wherein step is (ii) carried out according to the following steps
D) with described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) platinum (II) thus the aqueous solution of title complex and Silver Nitrate obtains reaction mixture;
E) thus described reaction mixture is heated to about 45 ℃ to be obtained cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) to about 60 ℃ temperature and closes the suspension of platinum (II) title complex; And
F) described suspension is cooled to about 20 ℃ and arrives about 30 ℃ temperature.
29. the method for claim 28, wherein will the described reaction mixture in step e) be heated to about 45 ℃ to about 55 ℃ temperature.
30. the method for claim 27 is wherein removed described silver ions by the precipitation Silver iodide from described reaction mixture, the precipitation of described Silver iodide obtains by adding KI.
31. the method for claim 27 is wherein closed platinum (II) title complex with described cis-two hydration-(trans-L-1,2-1,2-cyclohexanediamine) according to the following steps and is converted into oxaliplatin: it is mixed with potassium oxalate; Described pH value is adjusted to about 4.5 to about 5.0; Thereby cooling obtains cis-oxalate-(trans-L-1,2-1,2-cyclohexanediamine) and closes the suspension of platinum (II) title complex; And from described suspension recovery cis-oxalate close-(trans-L-1,2-1,2-cyclohexanediamine) close platinum (II) title complex.
32. described cis-oxalate (trans-D-1,2-cyclohexanediamine) that the method for claim 27, wherein said oxaliplatin have less than about 3%HPLC area closes platinum (II) title complex isomer.
33. a method for preparing oxaliplatin, it may further comprise the steps:
A) with the trans-L-1,2-1 of formula (5), the aqueous solution of 2-cyclohexanediamine
With M
2PtX
4Thereby obtain mixture with the aqueous solution of KI;
B) described mixture is kept at room temperature;
C) reclaim cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) and close platinum (II) title complex; And
D) described cis-diiodo-(trans-L-1,2-1,2-cyclohexanediamine) is closed platinum (II) title complex and is converted into oxaliplatin,
Wherein M is Li, Na or K, and
Wherein X is I, Cl or Br.
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| US58672904P | 2004-07-12 | 2004-07-12 | |
| US60/586,729 | 2004-07-12 | ||
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891771A (en) * | 2010-07-30 | 2010-11-24 | 重庆泰濠制药有限公司 | Method for preparing oxaliplatin |
| CN102643308A (en) * | 2012-05-11 | 2012-08-22 | 海南锦瑞制药股份有限公司 | Oxaliplatin crystal compound and freeze-dried powder injection |
| CN101723982B (en) * | 2008-10-31 | 2013-01-02 | 齐鲁制药有限公司 | Platinum complex compound with antitumor activity and synthesis method thereof |
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2005
- 2005-07-12 CN CN 200580023237 patent/CN101027313A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723982B (en) * | 2008-10-31 | 2013-01-02 | 齐鲁制药有限公司 | Platinum complex compound with antitumor activity and synthesis method thereof |
| CN101891771A (en) * | 2010-07-30 | 2010-11-24 | 重庆泰濠制药有限公司 | Method for preparing oxaliplatin |
| CN101891771B (en) * | 2010-07-30 | 2012-12-12 | 重庆泰濠制药有限公司 | Method for preparing oxaliplatin |
| CN102643308A (en) * | 2012-05-11 | 2012-08-22 | 海南锦瑞制药股份有限公司 | Oxaliplatin crystal compound and freeze-dried powder injection |
| 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 |
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