JPH0449295A - New platinum complex and production of (glycolate) (3-aminopyrrolidine)platinum (ii) using the same - Google Patents
New platinum complex and production of (glycolate) (3-aminopyrrolidine)platinum (ii) using the sameInfo
- Publication number
- JPH0449295A JPH0449295A JP15622290A JP15622290A JPH0449295A JP H0449295 A JPH0449295 A JP H0449295A JP 15622290 A JP15622290 A JP 15622290A JP 15622290 A JP15622290 A JP 15622290A JP H0449295 A JPH0449295 A JP H0449295A
- Authority
- JP
- Japan
- Prior art keywords
- platinum
- aminopyrrolidine
- compound
- formula
- platinum complex
- 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.)
- Pending
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title claims description 22
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title abstract description 32
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 title abstract description 16
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 title abstract 2
- 239000003446 ligand Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 50
- 239000000203 mixture Substances 0.000 abstract description 25
- 229910001868 water Inorganic materials 0.000 abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 239000002904 solvent Substances 0.000 abstract description 12
- RUJQWQMCBPWFDO-UHFFFAOYSA-M silver;2-hydroxyacetate Chemical compound [Ag+].OCC([O-])=O RUJQWQMCBPWFDO-UHFFFAOYSA-M 0.000 abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000013078 crystal Substances 0.000 description 26
- 238000001914 filtration Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- NGXSWUFDCSEIOO-SCSAIBSYSA-N (3r)-pyrrolidin-3-amine Chemical compound N[C@@H]1CCNC1 NGXSWUFDCSEIOO-SCSAIBSYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- NGXSWUFDCSEIOO-BYPYZUCNSA-N (3s)-pyrrolidin-3-amine Chemical compound N[C@H]1CCNC1 NGXSWUFDCSEIOO-BYPYZUCNSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- QPINXQCQOKBINJ-UHFFFAOYSA-K potassium;platinum(2+);trichloride Chemical compound [Cl-].[Cl-].[Cl-].[K+].[Pt+2] QPINXQCQOKBINJ-UHFFFAOYSA-K 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 2
- 229910000367 silver sulfate Inorganic materials 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- -1 platinum (II) (3-aminopyrrolidine) Chemical compound 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- HWEXKRHYVOGVDA-UHFFFAOYSA-M sodium;3-trimethylsilylpropane-1-sulfonate Chemical compound [Na+].C[Si](C)(C)CCCS([O-])(=O)=O HWEXKRHYVOGVDA-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Abstract
Description
【発明の詳細な説明】
「産業上の利用分野」
本発明は下式［Ｉ］
で表わされる新規白金錯体、およびそれを用いる下式［
Ｉ１］
で表わされる白金錯体。Detailed Description of the Invention "Industrial Application Field" The present invention relates to a novel platinum complex represented by the following formula [I], and a novel platinum complex represented by the following formula [I] using the same.
I1] A platinum complex represented by:
（２）下式［Ｉ］
で表わされる白金錯体と塩基とを反応させることを特徴
とする下式［Ｉ１］
（式中、Ａは一０ＣＯＣＨ２０−で表わされる配位子（
式中、Ａは一０ＣＯＣＨ２０−で表わされる配位子を示
す。）
で表わされる（グリコラド）（３−アミノピロリジン）
白金（ＩＩ ）の製造方法に関する。(2) The following formula [I1] characterized by reacting a platinum complex represented by the following formula [I] with a base (wherein A is a ligand represented by 10COCH20-
In the formula, A represents a ligand represented by -COCH20-. ) (Glycorado) (3-aminopyrrolidine)
The present invention relates to a method for producing platinum (II).
「従来の技術」
特開平１−２９４６８３号には、前記式［ＩＩ ］で表
わされる（グリコラド）（３−アミノピロリジン）白金
（ＩＩ）（化合物［Ｉ１］）が制癌剤として有用であり
、この化合物は下式［ｍｌ
（式中、Ｘは塩素原子、臭素原子あるいはヨウ素原子を
示す。）
で表わされるシス−ジハロゲノ（３−アミノピロリジン
）白金（ＩＩ）から以下の２つの製造方法で製造できる
と開示されている。"Prior Art" JP-A-1-294683 discloses that (glycorado)(3-aminopyrrolidine)platinum(II) (compound [I1]) represented by the above formula [II] is useful as an anticancer agent, and that this compound can be produced from cis-dihalogeno(3-aminopyrrolidine)platinum(II) represented by the following formula [ml (wherein, X represents a chlorine atom, a bromine atom, or an iodine atom)] by the following two production methods. Disclosed.
すなわち、公知の第１の製造方法は、
ａ）化合物［ＩＩＩ ］と硝酸銀とを反応させ、シスー
ジニトラト（３−アミノピロリジン）白金（■りとする
工程、
ｂ）次いでシスージニトラト（３−アミノピロリジン）
白金（１１）を陰イオン交換樹脂で処理し、シス−ジヒ
ドロキソ（３−アミノピロリジン）白金（ＩＩ）とする
工程、
Ｃ）最後に、シス−ジヒドロキソ（３−アミノピロリジ
ン）白金（Ｉりとグリコール酸とを反応させて化合物［
Ｉ１］とし、要すればここで生成する化合物［Ｉ夏］の
幾何異性体混合物から１つの幾何異性体を単離する工程
、
の３工程より成る方法である。That is, the first known production method includes a) a step of reacting the compound [III] with silver nitrate to form cis-dinitrato(3-aminopyrrolidine) platinum (b) then preparing cis-dinitrato(3-aminopyrrolidine)platinum.
Process of treating platinum (11) with an anion exchange resin to form cis-dihydroxo(3-aminopyrrolidine)platinum(II), C) Finally, cis-dihydroxo(3-aminopyrrolidine)platinum(II) and glycol A compound [
I1] and, if necessary, isolating one geometric isomer from the geometric isomer mixture of the compound [I summer] produced here.
公知の第２の製造方法は、
ａ）化合物［Ｉｎ ］と硫酸銀と反応させ、シス−スル
ファト（３−アミノピロリジン）白金（夏りとする工程
、
ｂ）次いで、シス−スルファト（３−アミノピロリジン
）白金（ＩＩ）に水酸化バリウムを反応させ、シス−ジ
ヒドロキソ（３−アミノピロリジン）白金（ＩＩ）とす
る工程、
Ｃ）最後に、第１の方法と同様にシス−ジヒドロキソ（
３−アミノピロリジン）白金（ＩＩ ）とグリコール酸
とを反応させて化合物［Ｉ１］とし、要すればここで生
成する化合物［ＩＩ ］の幾何異性体混合物から１つの
幾何異性体を単離する工程、
の３工程より成る製造方法である。A second known production method includes a) reacting the compound [In] with silver sulfate to form cis-sulfato(3-aminopyrrolidine)platinum (b) then reacting cis-sulfato(3-aminopyrrolidine)platinum with silver sulfate; pyrrolidine)platinum(II) with barium hydroxide to give cis-dihydroxo(3-aminopyrrolidine)platinum(II); C) Finally, as in the first method, cis-dihydroxo(3-aminopyrrolidine)platinum(II).
A step of reacting platinum (II) (3-aminopyrrolidine) with glycolic acid to form compound [I1] and, if necessary, isolating one geometric isomer from the geometric isomer mixture of compound [II] produced here. This manufacturing method consists of the following three steps.
上記の各公知の製造方法は共に、化合物ｃ ｎｒ ］か
ら目的とする化合物［ＩＩ ］まで３工程を要し、化合
物［ＩＩ ’Ｊの収率が充分でないので改良の余地が有
る。Each of the above-mentioned known production methods requires three steps from compound c nr ] to the target compound [II ], and the yield of compound [II'J is not sufficient, so there is room for improvement.
「発明が解決しようとする課題」
本発明者等は、工程および収率の改善された化合物［Ｉ
Ｉ ］の製造方法について検討した。本発明の目的は、
化合物［ｎ］を製造するために有用な製造用中間体およ
びそれを用いる化合物［Ｉ１］の工業的に有利な製造方
法を提供することにある。“Problems to be Solved by the Invention” The present inventors have developed a compound [I
We investigated the manufacturing method of [I]. The purpose of the present invention is to
The object of the present invention is to provide a manufacturing intermediate useful for manufacturing compound [n] and an industrially advantageous manufacturing method of compound [I1] using the same.
「課題を解決するための手段」
種々検討の結果、本発明者等は下式［Ｉ］で表わされる
シス−ビス（グリコラド）（３−アミノピロリジン）白
金（ＩＩ）（本発明の白金錯体［■］）が化合物［Ｉ１
］を製造する上で重要な中間体となること、そしてこの
中間体を経由する化合物［ＩＩ ］の製造方法は、工程
が簡単で収率が高いことを見出し、本発明を完成した。"Means for Solving the Problems" As a result of various studies, the present inventors have discovered that the platinum complex of the present invention [ ■]) is a compound [I1
The present invention was completed based on the discovery that compound [II] is an important intermediate in the production of compound [II], and that the process for producing compound [II] via this intermediate is simple and has a high yield.
本発明の白金錯体［Ｉ］は、３−アミノピロリジンの環
上アミノ基の立体配置により一対の光学異性体が存在し
得るが、本発明はこれらの異性体およびその混合物を包
含する。The platinum complex [I] of the present invention may have a pair of optical isomers depending on the configuration of the amino group on the ring of 3-aminopyrrolidine, and the present invention includes these isomers and mixtures thereof.
これら立体異性体は下記の通りである。These stereoisomers are as follows.
・シス−ビス（グリコラド）［（ＲＳ）−３−アミノピ
ロリジン］白金（ＩＩ） ・・・異性体Ｉ−ａと呼ぶ
・シス−ビス（グリコラド）、［（Ｒ）−３−アミノピ
ロリジン］白金（ＩＩ ）・・・異性体１−ｂと呼ぶ
・シス−ビス（グリコラド）［（Ｓ）−３−アミノピロ
リジン］白金（ＩＩ ） ・・・異性体Ｉ−Ｃと呼ぶ
また、本発明の方法で製造される化合物［Ｉ１］は、特
開平１−２９４８８３号に記載されている通り、配位子
であるグリコラド基（ＯＣＯＣＨ２０−）の配位方向に
より幾何異性体が、そして３−アミノピロリジンの環状
のアミノ基の立体配置により光学異性体も存在し得る。・Cis-bis(glycorado) [(RS)-3-aminopyrrolidine]platinum(II) ...called isomer I-a ・cis-bis(glycorado), [(R)-3-aminopyrrolidine]platinum (II)...referred to as isomer 1-b cis-bis(glycorado)[(S)-3-aminopyrrolidine]platinum(II)...referred to as isomer I-C Also, the method of the present invention As described in JP-A No. 1-294883, the compound [I1] produced by [I1] has geometric isomers depending on the coordination direction of the glycolad group (OCOCH20-) which is a ligand, and a geometric isomer of 3-aminopyrrolidine. Optical isomers may also exist depending on the configuration of the cyclic amino group.
特開平１−２９４６８３号には、化合物［Ｉ１］の幾何
異性体について、その１３Ｃ−ＮＭＲスペクトル（測定
溶媒、Ｄ２０ ）に於いて、グリコラド基のカルボニル
に基づくピークが低磁場に出現する幾何異性体にαの記
号、高磁場に出現する幾何異性体にβの記号を付して表
示されているが、本願明細書では、化合物［ＩＩ ］の
Ｘ線結晶解析結果をもとにＩＵＰＡＣ無機化学命名法委
員会で定められた規則により、命名する。JP-A-1-294683 describes a geometric isomer of compound [I1] in which a peak based on the carbonyl of the glycolade group appears in a low magnetic field in its 13C-NMR spectrum (measurement solvent: D20). The geometric isomer that appears in a high magnetic field is indicated with the symbol α, and the geometric isomer that appears in a high magnetic field is indicated with the symbol β. Named according to rules established by the Law Commission.
従って、特開平１−２９４６８３号に記載された化合物
［ＩＩ ］の名称と本願明細書に記載する名称は以下の
通り対応する。Therefore, the name of compound [II] described in JP-A-1-294683 and the name described in the present specification correspond as follows.
・α−グリコラド−（３ＲＳ）−３−アミノピロリジン
白金（ＩＩ ） ・・・・ ａｂ −［グリコラド（２
−） −０，Ｏ’ ］ −ｃｄ −［（ＲＳ） −３−
アミノピロリジン］白金（ＩＩ）（異性体１１−ａと呼
ぶ）
・β−グリコラド−（３Ｒ３）−３−アミノピロリジン
白金（ＩＩ） ・・・・ ａｂ −［グリコラド（２
−） −ｏ、 Ｏ’ ］ −ｄｃ −［（ＲＳ） −３
−アミノピロリジン］白金（ＩＩ）（異性体１１ｂと呼
ぶ〕
・α−グリコラド−（３Ｒ）−３−アミノピロリジン白
金（ＩＩ）・・・・ ８ｂ−［グリコラド（２−）−０
，Ｏ°］ −ｃｄ −［（Ｒ） −３−アミノピロリジ
ン］白金（ＩＩ）（異性体１１−ｃと呼ぶ〕
・β−グリコラド−（３Ｒ）−３−アミノピロリジン白
金（ＩＩ）・・・・ ａｂ −［グリコラド（２−）−
０，Ｏ°］ −ｄｃ−［（Ｒ） −３−アミノピロリジ
ン］白金（ＩＩ）（異性体１１ｄと呼ぶ）
・α−グリコラド−（３Ｓ）−３−アミノピロリジン白
金（ＩＩ）・・・・ ａｂ −［グリコラド（２−）−
０，Ｏ°］ −ｃｄ −［（Ｓ） −３−アミノピロリ
ジン］白金（ＩＩ）［異性体１１−ｅと呼ぶ］
・β−グリコラド−（３Ｓ）−３−アミノピロリジン白
金（ＩＩ）・・・・ ａｂ −［グリコラド（２−）−
０，０’ ］ −ｄｃ−［（Ｓ）−３−アミノピロリジ
ン］白金（ＩＩ）（異性体１１−ｆと呼ぶ〕
本発明の白金錯体［Ｉ１の製造方法およびこれを用いる
化合物［夏！］の製造方法を以下に説明する。・α-Glycorado-(3RS)-3-aminopyrrolidine platinum(II) ...ab-[Glycorado(2
-) -0,O' ] -cd -[(RS) -3-
aminopyrrolidine] platinum(II) (referred to as isomer 11-a) ・β-Glycorado-(3R3)-3-aminopyrrolidineplatinum(II) ...ab-[glycorado(2
-) -o, O' ] -dc -[(RS) -3
-Aminopyrrolidine] Platinum(II) (referred to as isomer 11b) - α-Glycorado-(3R)-3-aminopyrrolidineplatinum(II)... 8b-[Glycorado(2-)-0
,O°] -cd-[(R)-3-aminopyrrolidine]platinum(II) (referred to as isomer 11-c) ・β-Glycorado-(3R)-3-aminopyrrolidineplatinum(II)...・ ab -[glycolad(2-)-
0,O°] -dc-[(R) -3-aminopyrrolidine]platinum(II) (referred to as isomer 11d) ・α-Glycorado-(3S)-3-aminopyrrolidineplatinum(II)... ab -[glycolad(2-)-
0,O°] -cd -[(S)-3-aminopyrrolidine]platinum(II) [referred to as isomer 11-e] ・β-Glycorado-(3S)-3-aminopyrrolidineplatinum(II)...・・ ab -[glycolad(2-)-
0,0'] -dc-[(S)-3-aminopyrrolidine]platinum(II) (referred to as isomer 11-f) Platinum complex of the present invention [Production method of I1 and compound using the same [Summer!] The manufacturing method will be explained below.
本発明の白金錯体［］の製造方法を反応式で示すと下記
の通りである。The reaction formula of the method for producing the platinum complex [] of the present invention is as follows.
は、カラムクロマトグラフィー、再結晶などの通常の精
製手段で精製することができる。can be purified by conventional purification methods such as column chromatography and recrystallization.
本発明の白金錯体［ＩＩを用いる化合物［ＩＩ ］の製
造方法は下記の反応式で示される。The method for producing compound [II] using platinum complex [II] of the present invention is shown by the following reaction formula.
（式中、Ｘは前記の通りである。）
すなわち、化合物［ｍ］とグリコール酸銀とを反応させ
ることにより本発明の白金錯体［ＩＩを製造することが
できる。(In the formula, X is as described above.) That is, the platinum complex [II of the present invention] can be produced by reacting the compound [m] with silver glycolate.
反応は、通常、水またはＤＭＦを溶媒とし、遮光下室温
〜１００℃で３０分間〜４日−間行う。The reaction is usually carried out using water or DMF as a solvent at room temperature to 100° C. in the dark for 30 minutes to 4 days.
グリコール酸銀の使用量は、化合物［ＩＩＩ ］に対し
て１．８〜２．５倍モル、好ましくは２．０〜２．２倍
モルである。The amount of silver glycolate used is 1.8 to 2.5 times the mole of compound [III], preferably 2.0 to 2.2 times the mole.
上記反応で生成する本発明の白金錯体［ＩＩ（式中、Ａ
は前記の通りである。）
すなわち、本発明の白金錯体［ＩＩと塩基とを水溶媒中
で反応させることにより、化合物［！■］を製造するこ
とが出来る。The platinum complex [II (in the formula, A
is as described above. ) That is, by reacting the platinum complex [II of the present invention with a base in an aqueous solvent, the compound [! ■] can be manufactured.
反応は０〜１００℃、好ましくは２０〜８０℃の範囲で
１０分間〜２時間行う。The reaction is carried out at a temperature of 0 to 100°C, preferably 20 to 80°C, for 10 minutes to 2 hours.
塩基には水酸化ナトリウム、水酸化カリウム等の無機塩
基、トリエチルアミン等の３級アミンが使用される。こ
れら塩基の化合物［ＩＩに対する使用量は、１．０〜１
．５倍モルである。As the base, inorganic bases such as sodium hydroxide and potassium hydroxide, and tertiary amines such as triethylamine are used. The amount of these bases used for compound [II is 1.0 to 1
．． It is 5 times the mole.
上記製造方法で生成する化合物［Ｉ１］は、例えば、カ
ラムクロマトグラフィーまたは／および再結晶により精
製することができる。Compound [I1] produced by the above production method can be purified, for example, by column chromatography and/or recrystallization.
この製造方法によると、特開平１−２９４６８３号に記
載された製造方法の場合と同様、グリコラド基の配位方
向に基く一対の幾何異性体の混合物が生成するが、生成
物を例えばメタノール−水の混合溶媒から再結晶するか
、あるいは反応液にメタノールを加えて幾何異性体のう
ちで水に対して溶解度の低い幾何異性体のみを析出させ
ることができる。また、この母液から水に対して溶解度
の低い幾何異性体をさらに得ることも出来る。すなわち
、母液中に含有される他方の幾何異性体を加熱によって
水に対して溶解度の低い幾何異性体に転移させ、これを
例えばメタノール−水の混合溶媒から析出させて得るこ
とができる。According to this production method, as in the case of the production method described in JP-A-1-294683, a mixture of a pair of geometric isomers based on the coordination direction of the glycolad group is produced; Among the geometric isomers, only the geometric isomer with low solubility in water can be precipitated by recrystallizing from a mixed solvent of , or by adding methanol to the reaction solution. Further, geometric isomers with low solubility in water can also be obtained from this mother liquor. That is, it can be obtained by converting the other geometric isomer contained in the mother liquor into a geometric isomer with low solubility in water by heating, and precipitating this from a mixed solvent of methanol and water, for example.
「発明の効果」
本発明の白金錯体［ＩＩから、制癌剤として有用な化合
物［Ｉ１］を収率良く容易に製造することができるので
、本発明の白金錯体［Ｉ］は化合物［ＩＩ ］の有用な
製造中間体となり得る。"Effects of the Invention" Since the compound [I1] useful as an anticancer agent can be easily produced with good yield from the platinum complex [II] of the present invention, the platinum complex [I] of the present invention is useful as a compound [II]. It can be used as a production intermediate.
しかも、本発明の白金錯体［ＩＩは化合物［ｍ］から１
工程で容易に製造し得るので、本発明の白金錯体［ＩＩ
を経由することによって、従来、化合物［ＩＩＩ ］か
ら３工程で製造されていた化合物［ＩＩ ］を２工程で
収率よく製造できるようになった。Moreover, the platinum complex [II of the present invention is 1 from the compound [m]
The platinum complex [II] of the present invention can be easily produced by a process.
Compound [II], which was conventionally produced from compound [III] in three steps, can now be produced in good yield in two steps.
すなわち、本発明の白金錯体［ＩＩを使用する本発明の
製造方法によって、従来に比べ、化合物［Ｉｆ ］が工
業的に有利に製造可能となった。That is, by the production method of the present invention using the platinum complex [II of the present invention], the compound [If 2 ] can be produced industrially more advantageously than in the past.
「実施例」 次に実施例を挙げて本発明を説明する。"Example" Next, the present invention will be explained with reference to Examples.
なお、実施例中に示した’ Ｈ−ＮＭＲスペクトルの化
学シフトδ（ｐｐｍ）は、重水（０２０）を溶媒とし、
２．２−ジメチル−２−シラペンタン−５−スルホン酸
ナトリウムを内部標準として３００ＭＨｚで測定した値
である。In addition, the chemical shift δ (ppm) of the 'H-NMR spectrum shown in the examples is calculated using heavy water (020) as a solvent.
This is a value measured at 300 MHz using sodium 2.2-dimethyl-2-silapentane-5-sulfonate as an internal standard.
実施例１
シス−ジクロロ［（Ｒ３） −３−アミノピロリジン〕
白金（ＩＩ）（特開平１−２９４６８３号参照） １．
００ｇを水１０ｍ１に懸濁し、この懸濁液にグリコール
酸ｇ１．ｒ）４ｇを加え、遮光下室温で２日間攪拌し、
不溶物を濾過により除去した。次いで０．５％塩化ナト
リウム水溶液を、濾液に白濁が生じなくなるまで加え、
生成した沈殿を濾過して除いた。得られた水溶液を減圧
下に濃縮し、残渣にメタノール１５Ｅｌｌｌを加え、室
温で１２時間放置した。析出した結晶を濾取し、無色結
晶として標記化合物１．１０ｇ（収率８９．８％）を得
た。Example 1 cis-dichloro[(R3)-3-aminopyrrolidine]
Platinum (II) (see JP-A-1-294683) 1.
00 g in 10 ml of water, and to this suspension was added 1.0 g of glycolic acid. Add 4 g of r) and stir at room temperature for 2 days in the dark,
Insoluble matter was removed by filtration. Next, 0.5% aqueous sodium chloride solution was added until the filtrate no longer became cloudy.
The formed precipitate was removed by filtration. The resulting aqueous solution was concentrated under reduced pressure, 15Ell of methanol was added to the residue, and the mixture was left at room temperature for 12 hours. The precipitated crystals were collected by filtration to obtain 1.10 g (yield: 89.8%) of the title compound as colorless crystals.
融点：１７５〜１９０℃（着色分解）
Ｉ Ｒ（ＫＢｒ）ｃｍ−’： ３３９０，３１９２，１
６３２，１５９２，１４０３゜１３０５．１０８６
’ １１−ＮＭＲ（Ｃ２０） δ： １．８９〜２．
１２（２）１．ｍ）、 ２．２５〜２．５０（ＩＨ，ｍ
）、２．８５ 〜３．３５（３Ｈ，ｍ）、 ３．７１
〜３．９７（１）１．ｍ）、４．００（２Ｈ，ｓ）、４
．０８（２）１．ｓ）、 ４．９０〜５．２５（ＩＨ，
ｍ） 、５．２５〜５．７０ （ＩＨ，ｍ） 、６．７
０ （ＩＨ，ｂｓ） 。Melting point: 175-190°C (color decomposition) IR (KBr) cm-': 3390,3192,1
632,1592,1403°1305.1086' 11-NMR (C20) δ: 1.89-2.
12(2)1. m), 2.25-2.50 (IH, m
), 2.85 ~ 3.35 (3H, m), 3.71
~3.97(1)1. m), 4.00 (2H, s), 4
．． 08(2)1. s), 4.90-5.25 (IH,
m), 5.25-5.70 (IH, m), 6.7
0 (IH, bs).
元素分析値（Ｃ８Ｈ＋ａＮ２０ａ Ｐ ｔとして）二計
算値（％） Ｃ，２２，２Ｂ、Ｈ，３，７４，Ｎ、６
．５０実測値（％） Ｃ，２２，１Ｂ；Ｈ，３，７７
：Ｎ、６．３９実施倶２
性体Ｉ−ｂ）
シス−ジクロロ［（Ｒ）−３−アミノピロリジン〕白金
（ＩＩ）（特開平１−２９４６８３号参照） １３．９
４ｇを水１５０！Ｄｉに懸濁し、この懸濁液にグリコー
ル酸銀１４．４８ ｇを加え、遮光下室温で４日間攪拌
し、不溶物を濾過により除去した。次いで０．５％塩化
ナトリウム水溶液を、濾液に白濁が生じなくなるまで加
え、生成した沈殿を濾過して除いた。Elemental analysis value (as C8H+aN20a Pt) 2 calculated value (%) C, 22, 2B, H, 3, 74, N, 6
．． 50 Actual value (%) C, 22, 1B; H, 3,77
:N, 6.39 Example 2 I-b) Cis-dichloro[(R)-3-aminopyrrolidine]platinum(II) (see JP-A-1-294683) 13.9
4g of water for 150 yen! 14.48 g of silver glycolate was added to this suspension, stirred at room temperature for 4 days in the dark, and insoluble materials were removed by filtration. Next, a 0.5% aqueous sodium chloride solution was added until the filtrate no longer became cloudy, and the formed precipitate was removed by filtration.
得られた水溶液を減圧下に濃縮し、残漬にメタノール１
５ｍ１を加え、室温で１時間放置した。析出した結晶を
濾取し、無色結晶として標記化合物１４．９５ ｇ （
収率８７．６％）を得た。The resulting aqueous solution was concentrated under reduced pressure, and 1 1/2 methanol was added to the residue.
5ml was added and left at room temperature for 1 hour. The precipitated crystals were collected by filtration to give 14.95 g of the title compound as colorless crystals (
A yield of 87.6%) was obtained.
融点：１９０〜２１０℃（着色分解）
［α コ ２０ ＋ｓ、ａ ° （Ｃ−０，
５，Ｈ２０）ｒ Ｒ（ＫＢｒ）ｃｍ−’： ３４６６．
３３１２，３２００，３１０８，１５３９゜１６Ｎ、２
３９４，１３０１．Ｉ［Ｉ９１ｉ、２０１１３’ Ｈ−
ＮＭＲ（Ｃ２０） δ： １．８９〜２．１２（２Ｈ
，ｍ）、 ２．２５〜２．５０（１Ｂ、ａ＋）、２．８
５ 〜３．３５（３Ｈ，ｌ１１）、３．７１〜３．９７
（１）１．ｍ）、４．００（２Ｈ，ｓ）、４．０７ （
２）１．ｓ）、４．９０〜５．２５（ＩＨ，ｍ）、５．
２５ 〜５．７０（ＩＨ，ｍ）、８．７０（ＩＨ，ｂｓ
）。Melting point: 190-210°C (color decomposition) [α ko 20 +s, a ° (C-0,
5,H20)rR(KBr)cm-': 3466.
3312, 3200, 3108, 1539°16N, 2
394,1301. I[I91i, 20113' H-
NMR (C20) δ: 1.89-2.12 (2H
, m), 2.25-2.50 (1B, a+), 2.8
5 ~ 3.35 (3H, l11), 3.71 ~ 3.97
(1)1. m), 4.00 (2H, s), 4.07 (
2)1. s), 4.90-5.25 (IH, m), 5.
25 ~ 5.70 (IH, m), 8.70 (IH, bs
).
元素分析値（Ｃａ Ｈ１６Ｎ２０Ｓ Ｐ ｔとして）：
計算値（％） Ｃ，２２，２８；Ｈ，３，７４，Ｎ、
６．５０実測値（％） Ｃ，２２，１５，Ｈ，３，５
６，Ｎ、６．４７実施例３
過して除いた。得られた水溶液を減圧下に濃縮し、残渣
にメタノール１０■ｌを加え、室温で１５時間放置した
。析出した結晶を濾取し、無色結晶として標記化合物７
０８ｍｇ （収率８７．８％）を得た。ここで得られ
た化合物の物性分析値は実施例２で得られたシス−ビス
（グリコラド）［（Ｒ）−３−アミノピロリジン］白金
（ＩＩ ）のそれに一致した。Elemental analysis value (as Ca H16N20S Pt):
Calculated value (%) C, 22, 28; H, 3, 74, N,
6.50 Actual value (%) C, 22, 15, H, 3, 5
6,N, 6.47 Example 3 Removed by filtration. The resulting aqueous solution was concentrated under reduced pressure, 10 liters of methanol was added to the residue, and the mixture was allowed to stand at room temperature for 15 hours. The precipitated crystals were collected by filtration and the title compound 7 was obtained as colorless crystals.
08 mg (yield 87.8%) was obtained. The physical property analysis values of the compound obtained here corresponded to those of cis-bis(glycorado)[(R)-3-aminopyrrolidine]platinum(II) obtained in Example 2.
実施例４
シス−ショート［（Ｒ）−３−アミノピロリジン］白金
（ＩＩ）［水を溶媒として（Ｒ）−３−アミノピロリジ
ン、塩化第一白金酸カリウムおよびヨウ化カリウムを反
応させ合成した］ １．ＯｇをＮ、Ｎ−ジメチルホルム
アミド５ｍｌに溶解し、この溶液にグリコール酸銀ＢＢ
４ｍｇを加え、遮光下室温で１時間攪拌した。反応液に
水１５ｍ１を加え、室温で更に２０分間攪拌した。不溶
物を濾過により除去した後、０．５％塩化ナトリウム水
溶液を、濾液に白濁が生じなくなるまで加え、生成した
沈殿を濾性体１−ｃ）
シス−ショート［（Ｓ）−３−アミノピロリジン］白金
（ＩＩ）（水を溶媒として（Ｓ）−３−アミノピロリジ
ン、塩化第一白金酸カリウムおよびヨウ化カリウムを反
応させて合成した） １．０ ｇをＮ、Ｎ−ジメチルホ
ルムアミド５ｍｌに溶解し、この溶液にグリコール酸銀
６８４ｍｇを加え、遮光下室温で１時間攪拌した。反応
液に水１５鱈を加え、室温でさらに２０分間攪拌した。Example 4 Cis-short [(R)-3-aminopyrrolidine]platinum(II) [Synthesized by reacting (R)-3-aminopyrrolidine, potassium chloride platinum, and potassium iodide using water as a solvent] 1. Dissolve Og in 5 ml of N,N-dimethylformamide, and add silver glycolate BB to this solution.
4 mg was added, and the mixture was stirred at room temperature for 1 hour in the dark. 15 ml of water was added to the reaction solution, and the mixture was further stirred at room temperature for 20 minutes. After removing insoluble materials by filtration, 0.5% aqueous sodium chloride solution was added until the filtrate no longer became cloudy, and the resulting precipitate was collected as filter material 1-c) cis-short [(S)-3-aminopyrrolidine] ] Platinum (II) (synthesized by reacting (S)-3-aminopyrrolidine, potassium chloride platinum, and potassium iodide using water as a solvent) 1.0 g was dissolved in 5 ml of N,N-dimethylformamide. Then, 684 mg of silver glycolate was added to this solution, and the mixture was stirred at room temperature for 1 hour in the dark. 15 pieces of water were added to the reaction solution, and the mixture was further stirred at room temperature for 20 minutes.
不溶物を濾過により除去した後、０．５％塩化ナトリウ
ム水溶液を、濾液に白濁が生じなくなるまで加え、生成
した沈殿を濾過して除いた。得られた水溶液を減圧下に
濃縮し、残漬にメタノール１０１１１を加え、室温で１
５時間放置した。析出した結晶を濾取し、無色結晶とし
て標記化合物６８５ｍｇ （収率８５．０％）を得た
。After removing insoluble matter by filtration, a 0.5% aqueous sodium chloride solution was added until the filtrate no longer became cloudy, and the formed precipitate was removed by filtration. The resulting aqueous solution was concentrated under reduced pressure, and methanol 10111 was added to the residue, and the solution was evaporated at room temperature.
It was left for 5 hours. The precipitated crystals were collected by filtration to obtain 685 mg (yield: 85.0%) of the title compound as colorless crystals.
融点：１９０〜２１３℃（着色分解）
［α］ ” −８，８” （Ｃ−０，５，）１２０）
Ｉ Ｒ（ＫＢｒ）ｃｍ−’： ３４６２，３３１６，３
２００，３１０８，１６３８゜１６１３．１３９４，１
３０２．１０９６．１０８４’Ｈ−ＮＭＲ（０２０）
δ： １．８９〜２．１２（２Ｈ，ｍ）、 ２．２５
〜２．５０（ＩＨ，ｍ）、２．８５〜３．３５（３８，
ｍ）、 ３．７１〜３．９７（ＩＨ，ｍ）、４．００（
２Ｂ、Ｓ）、４．０８（２Ｈ，Ｓ）、 ４．９０〜５．
２５（ＩＨ，ｍ）、５．２５〜５．７０（ＩＨ，ｍ）、
６．７０（ＩＨ，、ｂＳ）。Melting point: 190-213℃ (color decomposition) [α] "-8,8" (C-0,5,)120)
IR(KBr)cm-': 3462,3316,3
200,3108,1638゜1613.1394,1
302.1096.1084'H-NMR (020)
δ: 1.89-2.12 (2H, m), 2.25
~2.50 (IH, m), 2.85 ~ 3.35 (38,
m), 3.71-3.97 (IH, m), 4.00 (
2B, S), 4.08 (2H, S), 4.90-5.
25 (IH, m), 5.25 to 5.70 (IH, m),
6.70 (IH,, bS).
元素分析値（Ｃａ Ｈ１６Ｎ２０６ Ｐ ｔとして）：
計算イＬ！ （％ ） Ｃ，２２，２８：Ｈ，
３，７４：Ｎ、６．５０実測値（％） Ｃ，２２，１
８；Ｈ，３，７３；Ｎ、６．４７実施例５
ａｂ−［グリコラド（２−） −〇、Ｏ’ ］ｃｄ−（
Ｒ３）−３−アミノピロリジン 全実施例１のシス−
ビス（グリコラド）［（Ｒ５）−３−アミノピロリジン
］白金（ＩＩ）１．１０ｇを水２ｍｌに懸濁し、この懸
濁液にＩＮの水酸化ナトリウム水溶液２．５５ｍ１を加
え、室温で１時間攪拌した。反応液（異性体１１−ａと
異性体１１−ｂが生成している）を濾過し、濾液にメタ
ノール５０ｍ１を加え、５℃で４日間放置した。析出し
た結晶を濾取し、無色結晶として標記化合物４８８Ｂ
（収率５３．９％）を得た。Elemental analysis value (as Ca H16N206 Pt):
Calculation L! (%) C, 22, 28:H,
3,74:N, 6.50 actual value (%) C, 22,1
8; H, 3,73; N, 6.47 Example 5 ab-[glycolad(2-)-〇,O']cd-(
R3)-3-Aminopyrrolidine Cis- of all Examples 1
1.10 g of bis(glycorado)[(R5)-3-aminopyrrolidine]platinum(II) was suspended in 2 ml of water, 2.55 ml of IN aqueous sodium hydroxide solution was added to this suspension, and the mixture was stirred at room temperature for 1 hour. did. The reaction solution (in which isomer 11-a and isomer 11-b were produced) was filtered, 50 ml of methanol was added to the filtrate, and the mixture was left at 5° C. for 4 days. The precipitated crystals were collected by filtration and the title compound 488B was obtained as colorless crystals.
(yield 53.9%).
融点：１９２℃付近で灰色に着色し始め２０７℃付近で
黒色化して分解
ＩＲ（にＢｒ）ｃｍ−’ ＋ ３４４８．３１２８．２
９９２．２８８０゜２８１２、１６６８．１３４０．１
２９８゜’Ｈ−ＮＭＲ（０２０）δ： １．８８〜２．
０７ （２Ｈ，ｍ） 、 ２．４３ （１）１゜ｄｃｌ
、Ｊ−１０）１ｚ、１）１ｚ）、 ３．０５（ＩＨ，ｄ
、Ｊ−１０Ｈｚ）、 ３．１８（１８，ｄ、Ｊ−４）１
ｚ） 、 ３．２１〜３．３４ （１）１．ｍ） 、
３．７１〜３．８０（ＩＨ，ｍ）、 ３．９８（２）１
．ｓ）。Melting point: Begins to turn gray around 192°C, turns black around 207°C and decomposes IR (Br) cm-' + 3448.3128.2
992.2880°2812, 1668.1340.1
298°'H-NMR (020) δ: 1.88-2.
07 (2H, m), 2.43 (1) 1°dcl
, J-10)1z, 1)1z), 3.05(IH,d
, J-10Hz), 3.18 (18, d, J-4) 1
z), 3.21-3.34 (1)1. m),
3.71-3.80 (IH, m), 3.98 (2) 1
．． s).
元素分析値（Ｃ８ＨＩ２Ｎ２０３ Ｐ ｔとして）計算
値（％） Ｃ，２０，２９，Ｈ，３，４０，Ｎ、７．
８９実測値（％） Ｃ，２Ｄ、３７．Ｈ，３，２８，
Ｎ、７．９６実施例６
実施例２のシス−ビス（グリコラド）［（Ｒ）−３−ア
ミノピロリジン〕白金（ＩＩ ） １２．６２ ｇを水
１０ｍ１に懸濁し、この懸濁液にＩＮの水酸化ナトリウ
ム水溶液２９．３＋＋＋１を加え、室温で１時間攪拌し
た。反応液（異性体１１−ｃと異性体１１ｄが生成して
いる）を濾通し、濾液にメタノール４００１を加え、５
℃で４日間放置した。析出した結晶な濾取し、無色結晶
として標記化合物４．７２ｇ （収率４５．４％）を得
た。Elemental analysis value (as C8HI2N203 P t) Calculated value (%) C, 20, 29, H, 3, 40, N, 7.
89 Actual value (%) C, 2D, 37. H,3,28,
N, 7.96 Example 6 12.62 g of cis-bis(glycorado)[(R)-3-aminopyrrolidine]platinum(II) from Example 2 was suspended in 10 ml of water, and this suspension was added with IN. 29.3++1 of a sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution (isomer 11-c and isomer 11d are produced) was filtered, methanol 4001 was added to the filtrate, and 5
It was left at ℃ for 4 days. The precipitated crystals were collected by filtration to obtain 4.72 g (yield: 45.4%) of the title compound as colorless crystals.
融点：１９６℃付近で灰色に着色し始め２１４℃付近で
黒色化して分解
［α コ ” ＋１２．２ ° （Ｃ−０，５
，Ｈ２Ｏ）ロ
ー Ｒ（ＫＢｒ）ｃｍ−’ ： ３４４２．３１１Ｂ、
２９９２．２Ｂ９０゜２８１６、１６６９．１６５７
．１３４７．１３１０’Ｈ−ＮＭＲ（０２０）δ：
１．８８〜２．０７（２Ｈ，＋ａ）、２．４３（ＩＨ。Melting point: It begins to turn gray around 196°C, turns black around 214°C, and decomposes [α +12.2° (C-0,5
, H2O) rho R(KBr) cm-': 3442.311B,
2992.2B90°2816, 1669.1657
．． 1347.1310′H-NMR(020)δ:
1.88-2.07 (2H, +a), 2.43 (IH.
ｄｄ、Ｊ＝１０Ｈｚ、ＩＨｚ）、３．０５（ＩＨ，ｄ、
Ｊ−１０）１ｚ）、３．１８（ＩＨ，ｄ、Ｊ−４Ｈｚ）
、３．２１〜３．３４（ＩＨ，ｍ）、３．７１〜３．８
０ （１）１．＋ｅ） 、 ３．９８ （２Ｈ，ｓ）
。dd, J=10Hz, IHz), 3.05(IH, d,
J-10) 1z), 3.18 (IH, d, J-4Hz)
, 3.21-3.34 (IH, m), 3.71-3.8
0 (1)1. +e), 3.98 (2H,s)
.
元素分析値（Ｃ６Ｈ１２Ｎ２０ｓ Ｐ ｔとして）：計
算値（％） Ｃ，２０，２９，Ｈ，３，４Ｄ、Ｎ、７
．８９実測値（％） Ｃ，２０，１９；Ｈ，３，２１
：Ｎ、７．８５実施例７
実施例２のシス−ビス（グリコラド）［（Ｒ）−３−ア
ミノピロリジン］白金（ＩＩ）１．０（Ｉｇを水２ｍｌ
に懸濁し、この懸濁液にトリエチルアミン０．２３ｇを
加え、室温で４０分間攪拌した。反応液（異性体１１−
ｃと異性体１１−ｄが生成している）を濾過し、濾液に
メタノール２０ｍ１を加え、５℃で４日間放置した。析
出した結晶を濾取し、無色結晶として標記化合物３８９
＋ａｇ （収率４７．２％）を得た。Elemental analysis value (as C6H12N20s P t): Calculated value (%) C, 20, 29, H, 3, 4D, N, 7
．． 89 Actual value (%) C, 20, 19; H, 3, 21
:N, 7.85 Example 7 cis-bis(glycorado)[(R)-3-aminopyrrolidine]platinum(II) of Example 2 (1.0 (Ig) in 2 ml of water
0.23 g of triethylamine was added to this suspension, and the mixture was stirred at room temperature for 40 minutes. Reaction solution (isomer 11-
c and isomer 11-d) were filtered, 20 ml of methanol was added to the filtrate, and the mixture was left at 5° C. for 4 days. The precipitated crystals were collected by filtration, and the title compound 389 was obtained as colorless crystals.
+ag (yield 47.2%) was obtained.
ここで得られた化合物の物性分析値は実施例６で得られ
たａｂ−［グリコラド（２−） −〇。The physical property analysis values of the compound obtained here are ab-[glycolad(2-)-〇 obtained in Example 6.
０°］−ｃｄ −［（Ｒ）−３−アミノピロリジン］白
金（ＩＩ）（異性体１ｌ−ｃ）のそれに一致した。0°]-cd-[(R)-3-aminopyrrolidine]platinum(II) (isomer 11-c).
実施例８
の混合物
実施例２のシス−ビス（グリコラド）［（Ｒ）−３−ア
ミノピロリジン］白金（ＩＩ ） ５００ｍｇを水１ｍ
ｌに懸濁し、この懸濁液にＩＮの水酸化ナトリウム水溶
液１．１６ｍ１を加え、室温で１時間攪拌した。反応液
（異性体１１−ｃと異性体１１ｄが生成している）を減
圧下に濃縮し、残漬をシリカゲルカラムクロマトグラフ
ィー［展開溶媒：メタノール−水（１０：１）］により
精製した。溶出液を薄層クロマトグラフィー［薄層板：
Ｋｉｅｓｅｌｇｅｌ ［ｉ［ＩＦ２５４、メルク社製
、展開溶媒：メタノール−水（１０：１） ］ テモニ
ターし、Ｒｆ値約０．２ ＋７）化合物を含む両分を集
めた。溶媒を減圧下留去し、残漬に少量のメタノールを
加え結晶を濾取し、無色結晶としてａｂ−［グリコラド
（２−）−０，Ｏ’ ］−ｃｄ −［（Ｒ）−３−アミ
ノピロリジン〕白金（ｎ）（異性体１ｌ−ｅ）とａｂ−
［グリコラド（２−）−０，Ｏ’ ］ −ｄｃ−［（Ｒ
）−３−アミノピロリジン］白金（ＩＩ）（異性体１ｌ
−ｄ）との約７：３の混合物３３７＋ａｇ（収率８１．
８％）を得た。Mixture of Example 8 500 mg of cis-bis(glycorado)[(R)-3-aminopyrrolidine]platinum(II) of Example 2 was added to 1 ml of water.
1.16 ml of IN aqueous sodium hydroxide solution was added to this suspension, and the mixture was stirred at room temperature for 1 hour. The reaction solution (in which isomer 11-c and isomer 11d were produced) was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [developing solvent: methanol-water (10:1)]. The eluate was subjected to thin layer chromatography [thin layer plate:
Kieselgel [i[IF254, manufactured by Merck & Co., Ltd., developing solvent: methanol-water (10:1)] was monitored, and both fractions containing the compound (Rf value about 0.2 +7) were collected. The solvent was distilled off under reduced pressure, a small amount of methanol was added to the residue, and the crystals were collected by filtration to give ab-[glycolad(2-)-0,O']-cd-[(R)-3-amino as colorless crystals. pyrrolidine] platinum (n) (isomers 1l-e) and ab-
[Glycolade(2-)-0,O']-dc-[(R
)-3-aminopyrrolidine] platinum(II) (isomer 1l
-d) in an approximately 7:3 mixture 337+ag (yield 81.
8%).
’Ｈ−ＮＭＲ（Ｄ２０）６ ： １．８８〜２．０７（
２Ｈ，ｍ）、２．３９（０，３Ｈ、ｄｄ） 、２．４３
（０，７Ｈ，ｄｄ） 、３．０５ （０，７Ｈ，ｄ）
、３．０８ （０，３Ｈ，ｄ）、３．１７〜３．３４
（２Ｈ，ｍ）、３．７０〜３．８０（ＩＨ。'H-NMR (D20) 6: 1.88-2.07 (
2H, m), 2.39 (0,3H, dd), 2.43
(0,7H, dd) , 3.05 (0,7H, d)
, 3.08 (0,3H,d), 3.17-3.34
(2H, m), 3.70-3.80 (IH.
ｍ） 、３．９８ （１，４Ｈ，Ｓ） 、４．０４ （
０，６Ｈ，Ｓ） 。m), 3.98 (1,4H,S), 4.04 (
0,6H,S).
実施例９
−３−アミノピロリジン
白金（ＩＩ）（異性体
１１−ｄ との約３ニアの混合物
シス−ビス（グリコラド）［（Ｒ）−３−アミノピロリ
ジン］白金（ＴＩ）（実施例２と同様にして合成した）
２．０ｇを水２ｍｌに懸濁し、この懸濁液にＩＮの水
酸化ナトリウム水溶液４６４ｍ１を加え、室温で１時間
攪拌した。反応液（異性体１１−ｃと異性体Ｉｉｄが生
成している）を濾過し、濾液にメタノール５ｈｌを加え
、５℃で３日間放置した。析出物を濾取し、無色結晶Ａ
７１１ｍｇを得た。Example 9 -3-Aminopyrrolidine Platinum (II) (approximately 3 nia mixture with isomer 11-d cis-bis(glycorado)[(R)-3-aminopyrrolidine]platinum (TI) (as in Example 2) (Synthesized in the same way)
2.0 g was suspended in 2 ml of water, 464 ml of IN aqueous sodium hydroxide solution was added to this suspension, and the mixture was stirred at room temperature for 1 hour. The reaction solution (in which isomer 11-c and isomer Iid were produced) was filtered, 5 hl of methanol was added to the filtrate, and the mixture was left at 5° C. for 3 days. Collect the precipitate by filtration to obtain colorless crystals A.
711 mg was obtained.
結晶Ａの母液を減圧下に濃縮し、残漬をシリカゲルカラ
ムクロマトグラフィー［展開溶媒：メタノール−水（１
ｏ：１）］により精製した。溶出液を薄層クロマトグラ
フィー［薄層板： Ｋｉｅｓｅ１ｇｅ１６０Ｆ２Ｓ４、
メルク社製、展開溶媒：メタノール−水（１０：１）］
でモニターし、Ｒｆ値約０．２の化合物を含む画分を集
めた。溶媒を減圧下留去し、残漬を水２ｍｌに溶解し６
０℃で４時間攪拌の後、メタノール２０１を加え、５℃
で１晩放置した。析出物を濾取し無色結晶８２２４ｍｇ
を得た。The mother liquor of crystal A was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [developing solvent: methanol-water (1
o:1)]. The eluate was subjected to thin layer chromatography [thin layer plate: Kiese1ge160F2S4,
Manufactured by Merck & Co., developing solvent: methanol-water (10:1)]
The fractions containing the compound with an Rf value of about 0.2 were collected. The solvent was distilled off under reduced pressure, and the residue was dissolved in 2 ml of water.
After stirring at 0°C for 4 hours, methanol 201 was added and the mixture was heated to 5°C.
It was left overnight. The precipitate was collected by filtration and 8224 mg of colorless crystals were obtained.
I got it.
さらに、結晶Ｂの母液を６０℃で７時間攪拌した後、５
℃で１晩放置し析出物を濾取し無色結晶Ｃ３３ｍｇを得
た。Furthermore, after stirring the mother liquor of crystal B at 60°C for 7 hours,
The mixture was left to stand overnight at °C, and the precipitate was collected by filtration to obtain 33 mg of colorless crystals C.
上記結晶Ａ％ＢおよびＣのＮＭＲスペクトルは、実施例
６で得られた異性体！Ｉ−ｃのそれに一致し、結晶Ａ％
ＢおよびＣは異性体１１−ｃであることが確認された（
収率５Ｂ、８ｋ）。The NMR spectra of the above crystals A%B and C are the isomers obtained in Example 6! Consistent with that of I-c, crystal A%
B and C were confirmed to be isomer 11-c (
Yield 5B, 8k).
さらに結晶Ｃの母液を減圧下に濃縮乾固し、残漬をエタ
ノール３ｍｌで洗浄し無色結晶２９８ｍｇ（収率１８．
１ｋ）を得た。ＮＭＲスペクトルからこの結晶は、異性
体１１−ｃと異性体１１−ｄとの約３ニアの混合物であ
ることが確認された。Further, the mother liquor of crystal C was concentrated to dryness under reduced pressure, and the residue was washed with 3 ml of ethanol to obtain 298 mg of colorless crystals (yield: 18.
1k) was obtained. It was confirmed from the NMR spectrum that this crystal was a mixture of about 3 Nia of isomer 11-c and isomer 11-d.
Claims (2)
とする下式［II］ ▲数式、化学式、表等があります▼［II］ （式中、Ａは−ＯＣＯＣＨ＿２Ｏ−で表わされる配位子
を示す。） で表わされる白金錯体の製造方法。(2) The following formula [I] ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ The following formula [II] characterized by reacting the platinum complex represented by [I] with a base ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼[II] (In the formula, A represents a ligand represented by -OCOCH_2O-.) A method for producing a platinum complex represented by the following.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15622290A JPH0449295A (en) | 1990-06-14 | 1990-06-14 | New platinum complex and production of (glycolate) (3-aminopyrrolidine)platinum (ii) using the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15622290A JPH0449295A (en) | 1990-06-14 | 1990-06-14 | New platinum complex and production of (glycolate) (3-aminopyrrolidine)platinum (ii) using the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0449295A true JPH0449295A (en) | 1992-02-18 |
Family
ID=15623028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15622290A Pending JPH0449295A (en) | 1990-06-14 | 1990-06-14 | New platinum complex and production of (glycolate) (3-aminopyrrolidine)platinum (ii) using the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0449295A (en) |
-
1990
- 1990-06-14 JP JP15622290A patent/JPH0449295A/en active Pending
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