JPH06271593A - Production of platinum complex - Google Patents
Production of platinum complexInfo
- Publication number
- JPH06271593A JPH06271593A JP8022693A JP8022693A JPH06271593A JP H06271593 A JPH06271593 A JP H06271593A JP 8022693 A JP8022693 A JP 8022693A JP 8022693 A JP8022693 A JP 8022693A JP H06271593 A JPH06271593 A JP H06271593A
- Authority
- JP
- Japan
- Prior art keywords
- silver
- trans
- diaminocyclohexane
- chemical formula
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、制ガン剤製造の中間体
となる白金錯体（化２）の製造方法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a platinum complex (Chemical Formula 2) which is an intermediate in the production of an anticancer agent.
【０００２】[0002]
【従来の技術】従来（化２）は制ガン作用を有する白金
化合物の中間体として公知であり、（化２）の製造方法
としては、Ｋ2 Ｐｔ(II)Ｘ4 （ＸはＣｌまたはＢｒ）と
１，２−シクロヘキサンジアミン異性体とを反応させて
（化１）を生成させ、これに水を加えて沸騰溶解させた
液に、硝酸銀溶液を加えて（化１）中の塩素または臭素
を塩化銀または臭化銀として沈殿させ、濾別する方法が
用いられていた。2. Description of the Related Art Conventionally, (Chemical formula 2) is known as an intermediate of a platinum compound having an anti-cancer effect. As a method for producing (Chemical formula 2), K 2 Pt (II) X 4 (X is Cl or Br) is used. ) And a 1,2-cyclohexanediamine isomer to produce (Chemical Formula 1), and water is added to the solution to bring about boiling dissolution, and a silver nitrate solution is added to the resulting solution to give chlorine or bromine in (Chemical Formula 1). Was precipitated as silver chloride or silver bromide and then filtered off.
【０００３】ところが上記方法で製造された（化２）中
には、（化１）の未反応物や副生成物さらに未反応の銀
イオンといった多くの不純物が含まれるという製造上の
欠点がある。この混入する原因としていろいろ考えられ
るが、まず第１に（化１）の水に対する溶解度が低いこ
とがあげられる。たとえば（化１）がトランス−ｌ体塩
化物の場合、その水に対する溶解度は37℃で約0.26mg／
mlと非常に低く、沸騰溶解した場合でも約 0.5mg／mlし
か溶けない。このように（化１）の溶解度が低いため、
硝酸銀と反応させて（化１）を完全に脱塩素化するのは
物性上きわめて困難であり、上記のような不純物が混入
することになる。さらにこの反応により生じた塩化銀の
除去にも非常に問題がある。すなわち塩化銀の溶解度は
比較的低く、生成した塩化銀の大部分は除くことができ
るが、（化１）の塩化物の溶解度が低いため、この反応
には多量の水を必要とし、このように多量の水を用いた
状態では塩化銀を完全に除去するのは不可能となってく
る。以上は塩化物の場合であるが、ハロゲンが塩素より
臭素に変わると、状況はいそう悪化する。多くの白金化
合物には細胞毒性等の生理活性を有する例が多く、この
ような（化１）の未反応物や副生成物の混入は微量でさ
え、制ガン剤としての医薬品原薬としては許されない。
また混在する未反応銀イオンに関しても、重金属試験法
の中で規制されているが、従来の方法では銀イオンに関
しても満足できる数値は得られていない。However, (Chemical Formula 2) produced by the above method has a manufacturing defect that many impurities such as unreacted substances and by-products of (Chemical Formula 1) and unreacted silver ions are contained. . There are various possible causes for this contamination, but first of all, the low solubility of (Chemical Formula 1) in water can be mentioned. For example, when the chemical formula (1) is a chloride of trans-l-form, its solubility in water is about 0.26 mg / 37 ° C.
It is very low as ml and even if it dissolves by boiling, it only dissolves about 0.5 mg / ml. Since the solubility of (Chemical formula 1) is low,
It is extremely difficult in terms of physical properties to completely dechlorinate (Chemical Formula 1) by reacting it with silver nitrate, and the above impurities are mixed. Furthermore, the removal of silver chloride generated by this reaction is very problematic. That is, the solubility of silver chloride is relatively low, and most of the silver chloride produced can be removed, but since the solubility of the chloride of (Chemical Formula 1) is low, a large amount of water is required for this reaction. It becomes impossible to completely remove silver chloride when a large amount of water is used. The above is the case of chloride, but when halogen changes from chlorine to bromine, the situation worsens. Many platinum compounds often have physiological activities such as cytotoxicity, and even if a small amount of such unreacted substances and by-products is mixed in (Chemical formula 1), it is not allowed as a drug substance as a carcinostatic agent. .
Although the unreacted silver ions that are mixed are also regulated in the heavy metal test method, satisfactory values have not been obtained for silver ions by the conventional method.
【０００４】その後本発明者らは、上記従来法の欠点を
解決するため（化１）に銀イオン溶液を加えて生成した
塩化銀または臭化銀を濾別した後、該濾液にヨウ化ナト
リウムまたはヨウ化カリウムを加えて（化１）の未反応
物及び副生成物ならびに未反応銀イオンをヨード体にし
て濾別分離する方法を発明し、上記未反応物及び副生成
物並びに未反応銀イオンをかなり効率よく除去すること
に成功した。ところがこの方法を用いても依然として微
量の銀イオンが残留することはさけられず、医薬品の安
全上この残留する銀イオンをさらに少なくすることが望
まれていた。Then, in order to solve the drawbacks of the above-mentioned conventional method (Chemical formula 1), the present inventors filtered off silver chloride or silver bromide produced by adding a silver ion solution, and then added sodium iodide to the filtrate. Alternatively, the inventors have invented a method of adding potassium iodide to separate the unreacted product and by-product of (Chemical Formula 1) and the unreacted silver ion into an iodine form by filtration, and separating the unreacted product and by-product and unreacted silver. We succeeded in removing the ions quite efficiently. However, even if this method is used, a trace amount of silver ions is still unavoidable, and it has been desired to further reduce the residual silver ions for the safety of pharmaceuticals.
【０００５】[0005]
【発明が解決しようとする課題】本発明は上記従来法の
問題点を解決し、人体に有害な未反応銀イオンの混入を
さらに少なくした制ガン剤製造の中間体である（化２）
の製造方法を提供する。SUMMARY OF THE INVENTION The present invention solves the problems of the above-mentioned conventional methods and is an intermediate for the production of an anti-cancer agent (Chemical Formula 2) in which the contamination of unreacted silver ions harmful to the human body is further reduced.
A method for manufacturing the same is provided.
【０００６】[0006]
【課題を解決するための手段】本発明は（化１）に硝酸
銀溶液を加え濾過した後、該濾液のｐＨを２乃至7.3ま
で上げた後ヨウ化ナトリウムまたはヨウ化カリウムを加
え、再度濾過して液中の銀イオン並びに（化１）の未反
応物及び副生成物を分離することにより達成される。な
おｐＨを上げるときに用いる薬品としては（化２）に配
位して新たな錯体を作ることのないような薬品を用いる
ことが必要で、例えば水酸化ナトリウム、水酸化カリウ
ムなどが用いられる。According to the present invention, a silver nitrate solution is added to (Chemical formula 1) and filtered, and then the pH of the filtrate is raised to 2 to 7.3, sodium iodide or potassium iodide is added, and the mixture is filtered again. It is achieved by separating silver ions in the liquid and unreacted products and by-products of (Chemical Formula 1). Note that it is necessary to use a chemical that does not form a new complex by coordinating to (Chemical Formula 2) as the chemical used to raise the pH, and for example, sodium hydroxide, potassium hydroxide, etc. are used.
【０００７】[0007]
【作用】上記本発明の製造方法では、塩化銀または臭化
銀を濾別後、ヨウ化ナトリウムまたはヨウ化カリウムを
加えることにより、（化１）の未反応物に未反応銀イオ
ンといった不純物がヨード体に変えられるが、該ヨード
体は元来水に対する溶解度が小さく、これのｐＨを２乃
至7.3 にすることにより溶解度がさらに小さくなるため
完全に除去することができ、最終的に不純物の混入しな
い（化２）を製造することができるものである。なお、
ｐＨ上昇を２乃至7.3 にするのは、２未満では溶解度の
減少効果があまり得られず、 7.3を超えるとアルカリ性
になるため（化２）にＯＨ基が配置して別の錯体になっ
てしまうという問題があるからである。In the production method of the present invention, impurities such as unreacted silver ions are added to the unreacted product of (Chemical formula 1) by adding sodium iodide or potassium iodide after filtering out silver chloride or silver bromide. It can be changed to iodine form, but the iodine form is originally low in solubility in water, and the solubility can be further reduced by adjusting the pH to 2 to 7.3 so that it can be completely removed, and finally impurities are mixed. No (Chemical Formula 2) can be produced. In addition,
If the pH is raised to 2 to 7.3, the effect of decreasing the solubility will not be obtained if it is less than 2, and if it exceeds 7.3, it will be alkaline and the OH group will be arranged in (Chemical Formula 2) to form another complex. Because there is a problem.
【０００８】[0008]
【実施例】塩化白金酸カリウム 170ｇを水1000mlに溶解
し、トランス−ｌ−１，２−ジアミノシクロヘキサン50
ｇを水50mlに溶解した液と混合して２時間撹拌した。次
に硝酸銀 100ｇを 500mlの水に溶解させた液を加え、室
温にて反応させた。生成した塩化銀の沈殿を濾別した
後、１Ｎの水酸化ナトリウム水溶液にてｐＨを２に調整
し、ヨウ化カリウム５ｇを加えて一晩放置した。その後
沈殿を濾過することにより、濾液として（化２）の水溶
液が得られた。該水溶液を減圧濃縮で800 mlまで濃縮
し、液中の銀濃度を原子吸光分析（フレーム式）により
測定したところ、銀濃度は検出限界以下であった。EXAMPLE 170 g of potassium chloroplatinate was dissolved in 1000 ml of water, and trans-l-1,2-diaminocyclohexane 50 was added.
g was mixed with a solution dissolved in 50 ml of water and stirred for 2 hours. Next, a solution prepared by dissolving 100 g of silver nitrate in 500 ml of water was added and reacted at room temperature. After the formed silver chloride precipitate was filtered off, the pH was adjusted to 2 with a 1N aqueous sodium hydroxide solution, 5 g of potassium iodide was added, and the mixture was allowed to stand overnight. After that, the precipitate was filtered to obtain an aqueous solution of (Chemical Formula 2) as a filtrate. The aqueous solution was concentrated under reduced pressure to 800 ml, and the silver concentration in the solution was measured by atomic absorption spectrometry (frame method). The silver concentration was below the detection limit.
【０００９】[0009]
【従来例】実施例１と同様の操作により、塩化銀の沈殿
生成及び濾別まで行った。その後該濾液を減圧濃縮によ
り 800mlまで濃縮した後ヨウ化カリウム５ｇを加えて一
晩放置した。その後生成した沈殿を濾過することにより
（化２）の水溶液が得られたが、液中の銀濃度を原子吸
光分析（フレーム式）により測定したところ、銀濃度は
0.9ppm 以下であった。PRIOR ART The same procedure as in Example 1 was carried out until the precipitation of silver chloride and the filtration. Then, the filtrate was concentrated under reduced pressure to 800 ml, 5 g of potassium iodide was added, and the mixture was allowed to stand overnight. The aqueous solution of (Chemical Formula 2) was obtained by filtering the generated precipitate after that, but when the silver concentration in the liquid was measured by atomic absorption spectrometry (frame method), the silver concentration was
It was 0.9 ppm or less.
【００１０】[0010]
【発明の効果】上記のように本発明の白金錯体の製造方
法によれば、人体に有害な残留銀イオによる汚染の非常
に少ない（化２）の水溶液が得られるため、多種の制ガ
ン剤製造のための中間体の製造方法として大変有用であ
る。As described above, according to the method for producing a platinum complex of the present invention, an aqueous solution (chemical formula 2) which is extremely less contaminated by residual silver ion harmful to the human body can be obtained. Is very useful as a method for producing an intermediate.
Claims (1)
は、シス、トランス−ｄまたはトランス−ｌ体であり、
ＸはＣｌまたはＢｒである）は硝酸銀溶液を加える一般
式 【化２】 （式中、１，２−ジアミノシクロヘキサン立体配位は、
シス、トランス−ｄまたはトランス−ｌ体である。）で
示される白金錯体の製造方法において、（化１）に硝酸
銀溶液を加えて濾過した後、該濾液のｐＨを 2.0乃至
7.3まで上げた後、ヨウ化ナトリウムまたはヨウ化カリ
ウムを加え、再度濾過して液中の銀イオン並びに（化
１）の未反応物及び副生成物を分離することを特徴とす
る、白金錯体の製造方法。1. A general formula: (In the formula, the configuration of 1,2-diaminocyclohexane is cis, trans-d or trans-l,
X is Cl or Br) is a general formula of adding a silver nitrate solution. (In the formula, the configuration of 1,2-diaminocyclohexane is
It is a cis, trans-d or trans-1 form. In the method for producing a platinum complex represented by the formula (1), after adding a silver nitrate solution to (Chemical Formula 1) and filtering, the pH of the filtrate is 2.0 to
After raising the temperature to 7.3, sodium iodide or potassium iodide is added, and the mixture is filtered again to separate silver ions in the liquid and unreacted products and by-products of (Chemical formula 1). Production method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5080226A JP3044512B2 (en) | 1993-03-15 | 1993-03-15 | Method for producing platinum complex |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5080226A JP3044512B2 (en) | 1993-03-15 | 1993-03-15 | Method for producing platinum complex |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06271593A true JPH06271593A (en) | 1994-09-27 |
| JP3044512B2 JP3044512B2 (en) | 2000-05-22 |
Family
ID=13712449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5080226A Expired - Lifetime JP3044512B2 (en) | 1993-03-15 | 1993-03-15 | Method for producing platinum complex |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3044512B2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1308454A3 (en) * | 1996-04-10 | 2003-05-14 | Debiopharm S.A. | Process of preparing platinum compound |
| WO2005056641A1 (en) * | 2003-12-10 | 2005-06-23 | Toudai Tlo, Ltd. | Coordination complex of diaminocyclohexaneplatinum(ii) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same |
| WO2006098496A1 (en) * | 2005-03-18 | 2006-09-21 | The University Of Tokyo | Coordination compound composed of diaminocyclohexane platinum (ii) and block copolymer and anti-cancer agent comprising the same |
| WO2009157561A1 (en) * | 2008-06-26 | 2009-12-30 | 独立行政法人科学技術振興機構 | Polymer/metal complex composite having mri contrast ability and mri contrasting and/or antitumor composition using the same |
| CN114378298A (en) * | 2021-12-21 | 2022-04-22 | 上海铂生金属材料有限公司 | Preparation method of superfine platinum powder |
-
1993
- 1993-03-15 JP JP5080226A patent/JP3044512B2/en not_active Expired - Lifetime
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1308454A3 (en) * | 1996-04-10 | 2003-05-14 | Debiopharm S.A. | Process of preparing platinum compound |
| WO2005056641A1 (en) * | 2003-12-10 | 2005-06-23 | Toudai Tlo, Ltd. | Coordination complex of diaminocyclohexaneplatinum(ii) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same |
| AU2004297126B2 (en) * | 2003-12-10 | 2010-11-25 | Toudai Tlo, Ltd. | Coordination complex of diaminocyclohexaneplatinum(II) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same |
| US8012463B2 (en) | 2003-12-10 | 2011-09-06 | Toudai Tlo, Ltd. | Coordination complex of diaminocyclohexaneplatinum(II) with block copolymer containing poly(carboxylic acid) segment and antitumor agent comprising the same |
| WO2006098496A1 (en) * | 2005-03-18 | 2006-09-21 | The University Of Tokyo | Coordination compound composed of diaminocyclohexane platinum (ii) and block copolymer and anti-cancer agent comprising the same |
| JP4992089B2 (en) * | 2005-03-18 | 2012-08-08 | 国立大学法人 東京大学 | Coordination compound of diaminocyclohexaneplatinum (II) and block copolymer and anticancer agent containing the same |
| WO2009157561A1 (en) * | 2008-06-26 | 2009-12-30 | 独立行政法人科学技術振興機構 | Polymer/metal complex composite having mri contrast ability and mri contrasting and/or antitumor composition using the same |
| JP5651468B2 (en) * | 2008-06-26 | 2015-01-14 | 独立行政法人科学技術振興機構 | Polymer-metal complex composite having MRI contrast capability, and composition for MRI contrast and / or antitumor using the same |
| US8961949B2 (en) | 2008-06-26 | 2015-02-24 | Japan Science And Technology Agency | Polymer-metal complex composite having MRI contrast ability and MRI contrasting and/or antitumor composition using the same |
| CN114378298A (en) * | 2021-12-21 | 2022-04-22 | 上海铂生金属材料有限公司 | Preparation method of superfine platinum powder |
| CN114378298B (en) * | 2021-12-21 | 2024-04-02 | 上海铂生金属材料有限公司 | Preparation method of superfine platinum powder |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3044512B2 (en) | 2000-05-22 |
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