JP2965675B2 - Method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine - Google Patents
Method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidineInfo
- Publication number
- JP2965675B2 JP2965675B2 JP2320055A JP32005590A JP2965675B2 JP 2965675 B2 JP2965675 B2 JP 2965675B2 JP 2320055 A JP2320055 A JP 2320055A JP 32005590 A JP32005590 A JP 32005590A JP 2965675 B2 JP2965675 B2 JP 2965675B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- indanone
- dimethoxy
- benzyl
- methylpiperidine
- 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.)
- Expired - Lifetime
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は医薬品として有用な（−）−１−ベンジル−
４−〔（5,6−ジメトキシ−１−インダノン）−２−イ
ル〕メチルピペリジンの製造方法に関し、詳しくは不斉
水素化反応により、上記光学活性体を純粋に、かつ効率
よく製造する方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to (-)-1-benzyl- useful as a pharmaceutical.
The present invention relates to a method for producing 4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine, and more particularly, to a method for producing the above optically active compound purely and efficiently by an asymmetric hydrogenation reaction. Things.
［発明の背景および先行技術］ 生理活性のある有機化合物は、その光学異性体間で生
理活性が異なる場合がしばしば観察される。BACKGROUND OF THE INVENTION AND PRIOR ART It is often observed that biologically active organic compounds have different biological activities between their optical isomers.
このことは、本発明者らの一部が見い出したアセチル
コリンエステラーゼ阻害剤であり、アルツハイマー型老
年痴呆などの治療に有効であり、すでに特許出願した
（特開昭64−79151号）１−ベンジル−４−〔（5,6−ジ
メトキシ−１−インダノン）−２−イル〕メチルピペリ
ジンにもみられる。すなわち、上記インダノン誘導体の
光学活性体のアセチルコリンエステラーゼ阻害強度は、
左旋性化合物のIC50が4.8nM、右遷性化合物のIC50が7.7
nMとなっている。This is an acetylcholinesterase inhibitor discovered by some of the present inventors, which is effective for the treatment of Alzheimer-type senile dementia and the like, and has already been applied for a patent (Japanese Patent Application Laid-Open No. 64-79151). It is also found in 4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine. That is, the acetylcholinesterase inhibitory strength of the optically active indanone derivative is:
IC 50 of levorotatory compound 4.8 nM, IC 50 of the right遷性compound 7.7
nM.
この（−）−１−ベンジル−４−〔（5,6−ジメトキ
シ−１−インダノン）−２−イル〕メチルピペリジン
は、例えば前記した特開昭64−79151号公報に開示され
た方法によってラセミ体を合成し、これを適切な方法で
光学分割することによって得られる。方法としては、種
々考えられるが、例えば光学異性体分離用カラムを用い
る方法などがある。This (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine can be racemic, for example, by the method disclosed in the above-mentioned JP-A-64-79151. It is obtained by synthesizing the body and optically resolving it in a suitable manner. Although various methods can be considered, for example, there is a method using a column for separating optical isomers.
［発明が解決すべき課題］ しかしながら、このラセミ体の光学分割によって光学
異性体を製造する方法は、目的の光学異性体を取得する
にあたり、逆の立体配置をもつ鏡像体は不用となり、経
済性に乏しいという欠点を有する。[Problems to be Solved by the Invention] However, in the method for producing an optical isomer by optical resolution of a racemate, an enantiomer having an opposite configuration is not necessary for obtaining a desired optical isomer, and the method is economical. Has the disadvantage of being poor.
従って、（−）−１−ベンジル−４−〔（5,6−ジメ
トキシ−１−インダノン）−２−イル〕メチルピペリジ
ンのみを純粋に、効率よく製造する方法の開発が望まれ
ている。Therefore, development of a method for producing only (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine purely and efficiently is desired.
［課題を解決するための手段］ そこで本発明者は、かかる課題を解決すべく種々検討
してきた結果、ルテニウム−ホスフィン錯体を使用する
不斉水素化反応によって、（−）−１−ベンジル−４−
〔（5,6−ジメトキシ−１−インダノン）−２−イル〕
メチルピペリジンが高い光学純度で得られることを見い
出し、本発明を完成した。[Means for Solving the Problems] Accordingly, the present inventors have made various studies to solve the problems, and as a result, the asymmetric hydrogenation reaction using a ruthenium-phosphine complex causes (−)-1-benzyl-4. −
[(5,6-Dimethoxy-1-indanone) -2-yl]
The present inventors have found that methylpiperidine can be obtained with high optical purity and completed the present invention.
すなわち、本発明は次式（Ｉ） で表わされる（Ｅ）−１−ベンジル−４−〔（5,6−ジ
メトキシ−１−インダノン）−２−イリデニル〕メチル
ピペリジンを、光学活性なルテニウム−ホスフィン錯体
触媒の存在下に不斉水素化することを特徴とする、次式
（II） で表わされる（−）−１−ベンジル−４−〔（5,6−ジ
メトキシ−１−インダノン）−２−イル〕メチルピペリ
ジンの製造方法を提供するものである。That is, the present invention provides the following formula (I) Asymmetric hydrogenation of (E) -1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yridenyl] methylpiperidine represented by the following formula in the presence of an optically active ruthenium-phosphine complex catalyst: The following equation (II) And a method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine represented by the formula:
本発明方法を反応式で示せば次の通りである。 The method of the present invention is represented by the following reaction formula.
本発明の原料化合物（Ｉ）は、特開昭64−79151号公
報に開示された方法によって製造されるものである。 The starting compound (I) of the present invention is produced by the method disclosed in JP-A-64-79151.
本発明において触媒として使用される光学活性なルテ
ニウム−ホスフィン錯体としては、次式（III）、（I
V）または（Ｖ）で表わされるルテニウム金属に光学活
性なホスフィン誘導体が配位した化合物が挙げられる。The optically active ruthenium-phosphine complex used as a catalyst in the present invention includes the following formulas (III) and (I)
Compounds in which an optically active phosphine derivative is coordinated to the ruthenium metal represented by V) or (V).
〔式（III）、（IV）、（Ｖ）において、Ｘはハロゲン
原子を示し、Ｙは水素原子、アミノ基、アセチルアミノ
基またはスルホン酸基を示し、R1は水素原子または直鎖
もしくは分岐鎖の低級アルキル基を示し、Ａ及びＺはそ
れぞれCIO4、PF6、BF4またはR2COO（ここでR2はアルキ
ル基、ハロゲン化低級アルキル基、低級アルキル置換基
を有していてもよいフェニル基、α−アミノアルキル基
またはα−アミノフェニルアルキル基を示す）か、ある
いはＡとＺが一緒になってアルキレンジカルボキシ基を
形成するものを示し、ｎは１または２を示す〕 式（III）、（IV）、（Ｖ）で表わされるルテニウム
−ホスフィン錯体に含まれる錯体のうち、具体的な代表
的な例を示せば次のとおりである。 [In the formulas (III), (IV) and (V), X represents a halogen atom, Y represents a hydrogen atom, an amino group, an acetylamino group or a sulfonic acid group, and R 1 represents a hydrogen atom or a linear or branched A and Z each represent CIO 4 , PF 6 , BF 4 or R 2 COO (where R 2 represents an alkyl group, a halogenated lower alkyl group, or a lower alkyl substituent) A good phenyl group, α-aminoalkyl group or α-aminophenylalkyl group) or a group in which A and Z together form an alkylenedicarboxy group, and n represents 1 or 2.] Of the complexes contained in the ruthenium-phosphine complexes represented by (III), (IV) and (V), specific representative examples are as follows.
式（III）で表わされる錯体の代表的なものを次に例
示する。Representative examples of the complex represented by the formula (III) are shown below.
Ru2Cl4（BINAP）2N（C2H5）３ （BINAPは2,2′−ビス（ジフェニルホスフィノ）−1,
1′−ビナフチルを表わす。） Ru2Cl4（ｐ−Tol BINAP）2N（C2H5）３ （ｐ−Tol BINAPは2,2′−ビス（ジ−ｐ−トリルホスフ
ィノ）−1,1′−ビナフチルを表わす。） Ru2Cl4（ｐ−ｔ−Bu BINAP）2N（C2H5）３ （ｐ−ｔ−Bu BINAPは、2,2′−ビス（ジ−ｐ−ターシ
ャリ−ブチルフェニルホスフィノ）−1,1′−ビナフチ
ルを表わす。） Ru2Cl4（５−アセチルアミノBINAP）2N（C2H5）３ （５−アセチルアミノBINAPは、2,2′−ビス（ジフェニ
ルホスフィノ）−5,5′−ジアセチルアミノ−1,1′−ビ
ナフチルを表わす。） 式（IV）で表わされる錯体の代表的なものを次に例示
する。Ru 2 Cl 4 (BINAP) 2 N (C 2 H 5 ) 3 (BINAP is 2,2′-bis (diphenylphosphino) -1,
Represents 1'-binaphthyl. ) Ru 2 Cl 4 (p-Tol BINAP) 2 N (C 2 H 5 ) 3 (p-Tol BINAP represents 2,2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl.) Ru 2 Cl 4 (pt-Bu BINAP) 2 N (C 2 H 5 ) 3 (pt-Bu BINAP is 2,2′-bis (di-p-tert-butylphenylphenylphosphino) -1 represents 1'-binaphthyl.) Ru 2 Cl 4 (5- acetylamino BINAP) 2 N (C 2 H 5) 3 (5- acetylamino BINAP is 2,2'-bis (diphenylphosphino) -5 , 5'-Diacetylamino-1,1'-binaphthyl.) Typical examples of the complex represented by the formula (IV) are shown below.
RuHCl（BINAP）２ 式（Ｖ）で表わされる錯体の代表的なものを次に例示
する。RuHCl (BINAP) 2 Representative examples of the complex represented by the formula (V) are shown below.
Ru（BINAP）（O2CCH3）２ Ru（ｐ−Tol BINAP）（O2CCH3）２ Ru（BINAP）（O2C−ｔ−Bu）２ （ｔ−Buは、ターシャリ−ブチル基を表わす。） Ru（ｐ−Tol BINAP）（O2CCH3）２ Ru（ｐ−Tol BINAP）（O2CCF3）２ Ru（ｐ−ｔ−Bu BINAP）（O2CCH3）２ Ru（５−アセチルアミノBINAP）（O2CCH3）２ （ｉ−Prは、イソプロピル基を表わす。） 〔Ru（ｐ−Tol BINAP）〕（ClO4）２ 〔Ru（ｐ−Tol BINAP）〕（PF6）２ Ru（ｐ−Tol BINAP）（O2CCF3）２ 式（III）および（IV）で表わされる錯体は、例えば
特開昭61−63690号公報に開示された方法によって、〔R
uCl2（COD）〕ｎ（式中、CODは1,5−シクロオクタジエ
ンを示す）と、BINAP誘導体及びトリエチルアミンをト
ルンエ中、窒素雰囲気下に加えることにより得ることが
できる。また式（Ｖ）で表される錯体は、特開昭62−26
5293号公報に開示されている方法に従って、Ru2Cl
4（（＋）又は（−）−BINAP誘導体）２（Ｎ（C
2H5）３）を原料とし、これと種々のカルボン酸塩をメ
タノール、エタノール、ｔ−ブタノール等のアルコール
溶媒中で、約20〜110℃の温度で３〜15時間反応させた
後、溶媒を留去して、エーテル、エタノール等の溶媒で
目的の錯体を抽出した後、乾固すれば粗製の錯体が得ら
れる。更に酢酸エチル等で再結晶して精製品を得ること
ができる。例えば、酢酸ソーダを用いた場合は、Ru
（（＋）又は（−）−BINAP）（OCOCH3）２を得ること
ができるし、この得られたジアセテート錯体にトリフロ
ロ酢酸を塩化メチレンを溶媒として約25℃で12時間反応
せしめて、Ru（（＋）又は（−）−BINAP）（OCOCF3）
２を得ることができる。Ru (BINAP) (O 2 CCH 3 ) 2 Ru (p-Tol BINAP) (O 2 CCH 3 ) 2 Ru (BINAP) (O 2 Ct-Bu) 2 (t-Bu is a tertiary-butyl group Express.) Ru (p-Tol BINAP) (O 2 CCH 3 ) 2 Ru (p-Tol BINAP) (O 2 CCF 3 ) 2 Ru (pt-Bu BINAP) (O 2 CCH 3 ) 2 Ru (5-acetylamino BINAP) (O 2 CCH 3 ) 2 (I-Pr represents an isopropyl group.) [Ru (p-Tol BINAP)] (ClO 4 ) 2 [Ru (p-Tol BINAP)] (PF 6 ) 2 Ru (p-Tol BINAP) (O 2 CCF 3 ) 2 Complexes represented by the formulas (III) and (IV) can be prepared, for example, by the method disclosed in JP-A-61-63690.
uCl 2 (COD)] n (wherein COD represents 1,5-cyclooctadiene), a BINAP derivative and triethylamine in a toluene, under a nitrogen atmosphere. The complex represented by the formula (V) is disclosed in
According to the method disclosed in JP 5293, Ru 2 Cl
4 ((+) or (-)-BINAP derivative) 2 (N (C
2 H 5) 3) as a raw material, this with various carboxylates methanol, ethanol, an alcohol solvent such as t- butanol, After 3-15 hours at a temperature of about 20 to 110 ° C., the solvent Is distilled off, and the desired complex is extracted with a solvent such as ether or ethanol and then dried to obtain a crude complex. Further, the purified product can be obtained by recrystallization with ethyl acetate or the like. For example, when sodium acetate is used, Ru
((+) Or (−)-BINAP) (OCOCH 3 ) 2 can be obtained, and the obtained diacetate complex is reacted with trifluoroacetic acid in methylene chloride as a solvent at about 25 ° C. for 12 hours to obtain Ru. ((+) Or (−)-BINAP) (OCOCF 3 )
2 can be obtained.
本発明の反応は、式（Ｉ）で表わされる化合物に上記
ルテニウム−ホスフィン錯体を添加し、これに水素を通
じることにより実施される。これらのルテニウム−ホス
フィン錯体は、通常式（III）、（IV）または（Ｖ）で
示されるものの一つを用いるが、場合によっては、二つ
以上用いてもかまわない。The reaction of the present invention is carried out by adding the above-mentioned ruthenium-phosphine complex to the compound represented by the formula (I) and passing hydrogen therethrough. As these ruthenium-phosphine complexes, one of the compounds represented by the formulas (III), (IV) and (V) is usually used, but in some cases, two or more compounds may be used.
好ましい実施態様としては、例えばまず式（Ｉ）で表
わされる化合物とルテニウム−ホスフィン錯体の混合物
を例えば塩化メチレン等の溶媒に溶解し、オートクレー
ブ中にて水素を通じることによって行なわれる。In a preferred embodiment, for example, a mixture of the compound represented by the formula (I) and a ruthenium-phosphine complex is first dissolved in a solvent such as methylene chloride and hydrogen is passed through the autoclave.
反応条件、すなわち、水素圧、反応温度、反応時間、
使用する触媒の量は触媒の種類によって適宜決定され
る。Reaction conditions, i.e. hydrogen pressure, reaction temperature, reaction time,
The amount of the catalyst to be used is appropriately determined depending on the type of the catalyst.
一般に水素圧は４〜100kg/cm2、反応温度は25〜75
℃、反応時間は24〜168時間が好ましい。Generally, the hydrogen pressure is 4-100 kg / cm 2 and the reaction temperature is 25-75.
C., and the reaction time is preferably 24-168 hours.
反応終了後、分液操作等によって触媒を除去し、減圧
濃縮、乾燥を行なえば、式（II）で表わされる目的化合
物が極めて高い光学純度で、かつ高収率で得られる。After completion of the reaction, the catalyst is removed by a liquid separation operation or the like, followed by concentration under reduced pressure and drying, whereby the target compound represented by the formula (II) can be obtained with extremely high optical purity and high yield.
［作用並びに発明の効果］ 斯くして得られる（−）−１−ベンジル−４−〔（5,
6−ジメトキシ−１−インダノン）−２−イル〕メチル
ピペリジン（II）は、アセチルコリンエステラーゼ阻害
作用に基づくアルツハイマー治療薬として有望である。[Action and Effect of the Invention] The thus obtained (-)-1-benzyl-4-[(5,
6-Dimethoxy-1-indanone) -2-yl] methylpiperidine (II) is promising as a therapeutic agent for Alzheimer based on acetylcholinesterase inhibitory action.
このように本発明方法を利用すれば、その製造工程中
に何ら光学分割等の経済的に不利な工程を経ることな
く、（−）−１−ベンジル−４−〔（5,6−ジメトキシ
−１−インダノン）−２−イル〕メチルピペリジン（I
I）を純粋に効率よく製造することができる。すなわ
ち、従来の如く光学分割する必要がないので、経済的に
極めて有利であり、本発明は工業上価値のある方法であ
る。Thus, if the method of the present invention is used, (-)-1-benzyl-4-[(5,6-dimethoxy-) can be obtained without going through any economically disadvantageous steps such as optical resolution during the production process. 1-Indanone) -2-yl] methylpiperidine (I
I) can be produced purely and efficiently. That is, since it is not necessary to perform optical division as in the prior art, it is extremely economically advantageous, and the present invention is an industrially valuable method.
［実施例］ 次に実施例を挙げて本発明を詳細に説明するが、本発
明がこれらのみに限定されることがないことはいうまで
もない。[Examples] Next, the present invention will be described in detail with reference to examples, but it goes without saying that the present invention is not limited to these.
なお、実施例は全て以下の反応式に基づくものであ
る。In addition, all Examples are based on the following reaction formula.
実施例１ あらかじめ窒素置換を行なった100ml枝付ナスフラス
コに、（Ｅ）−１−ベンジル−４−〔（5,6−ジメトキ
シ−１−インダノン）−２−イリデニル〕メチルピペリ
ジン（Ｉ）2.0g（5.3mmol）および錯体〔Ru2Cl
4（（Ｓ）−（−）−BINAP）2N（C2H5）３〕42.3mg（0.
025mmol）を秤取し、続いて塩化メチレン30mlを加えて
溶液とした。本溶液を100mlのステンレス製オートクレ
ーブに移し、水素圧（77kg/cm2）、50℃で30分撹拌した
後、室温に戻し、140時間撹拌した。塩化メチレンを減
圧下（20mmHg）に留去し、残渣に0.1N塩酸180mlを加え
塩酸塩（pH＝２）とした。酢酸エチル50mlで２回抽出に
より触媒を抽出分離し、水層に炭酸ナトリウム水溶液を
加え、pH＝９とし、水層を塩化メチレン30mlで２回抽出
し、抽出液に無水硫酸マグネシウムを加えて乾燥し、減
圧下（20mmHg）に塩化メチレンを留去し、更に高真空
（1mmHg）下に乾燥して、（−）−１−ベンジル−４−
〔（5,6−ジメトキシ−１−インダノン）−２−イル〕
メチルピペリジン（II）1.72g（収率 85.4％）を無色
の結晶として得た。高速液体クロマトグラフィ−（HPL
C）による分析の結果、化学純度は91.3％、また光学純
度は97.3％eeであった。なお、HPLCの条件は以下に示す
とおりである。 Example 1 2.0 g of (E) -1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yridenyl] methylpiperidine (I) was placed in a 100-ml branched eggplant flask which had been purged with nitrogen in advance. (5.3 mmol) and complex [Ru 2 Cl
4 ((S) - (- ) - BINAP) 2 N (C 2 H 5) 3 ] 42.3 mg (0.
025 mmol) was weighed, followed by addition of 30 ml of methylene chloride to form a solution. This solution was transferred to a 100 ml stainless steel autoclave, stirred at 50 ° C. for 30 minutes under a hydrogen pressure (77 kg / cm 2 ), then returned to room temperature and stirred for 140 hours. Methylene chloride was distilled off under reduced pressure (20 mmHg), and 180 ml of 0.1N hydrochloric acid was added to the residue to form a hydrochloride (pH = 2). The catalyst was extracted and separated by extracting twice with 50 ml of ethyl acetate, an aqueous sodium carbonate solution was added to the aqueous layer to adjust the pH to 9, the aqueous layer was extracted twice with 30 ml of methylene chloride, and anhydrous magnesium sulfate was added to the extract and dried. Then, methylene chloride was distilled off under reduced pressure (20 mmHg), and further dried under high vacuum (1 mmHg) to obtain (-)-1-benzyl-4-.
[(5,6-Dimethoxy-1-indanone) -2-yl]
1.72 g (yield 85.4%) of methylpiperidine (II) was obtained as colorless crystals. High Performance Liquid Chromatography (HPL
As a result of the analysis by C), the chemical purity was 91.3% and the optical purity was 97.3% ee. The HPLC conditions are as shown below.
化学純度 カラム:YMC（Ｒ−ODS−５） 溶出液：水／アセトニトリル／過塩素酸＝600/400/5 検 出:UV254nm 流 速:1.5ml/分 光学純度 カラム:CHIRALCEL OD、4.6×250MM 溶出液：ヘキサン／イソプロピルアルコール／トリエチ
ルアミン＝700/297/31 検 出:UV270nm 流 速:0.5ml/分 実施例２ あらかじめ窒素置換を行なった100ml枝付フラスコに
原料化合物（Ｉ）2.0g（53mmol）および錯体Ru2Cl
4（（Ｓ）−（−）−BINAP）2N（C2H5）344.5mg（0.045
mmol）を秤取し、以下実施例１と同様の操作でテトラヒ
ドロフラン中で反応を行なって、目的化合物（II）1.75
g（収率87％）を得た。化学純度は98％、光学純度は96
％eeであった。Chemical purity Column: YMC (R-ODS-5) Eluent: water / acetonitrile / perchloric acid = 600/400/5 Detection: UV254nm Flow rate: 1.5ml / min Optical purity Column: CHIRALCEL OD, 4.6 × 250MM elution Liquid: hexane / isopropyl alcohol / triethylamine = 700/297/31 Detection: UV 270 nm Flow rate: 0.5 ml / min Example 2 2.0 g (53 mmol) of the starting compound (I) was placed in a 100 ml branched flask previously purged with nitrogen. Complex Ru 2 Cl
4 ((S)-(-)-BINAP) 2 N (C 2 H 5 ) 3 44.5 mg (0.045
mmol) and reacted in tetrahydrofuran in the same manner as in Example 1 to obtain 1.75 of the desired compound (II).
g (87% yield) was obtained. Chemical purity 98%, optical purity 96
% Ee.
実施例３ あらかじめ窒素置換を行なった100ml枝付フラスコに
原料化合物（Ｉ）2.0g（53mmol）および錯体〔RuCl
4（（Ｓ）−（−）−ｐ−Tol BINAP）2N（C2H5）２〕4
5.0mg（0.025mmol）を秤取し、以下実施例Ｉと同様の操
作を行なって、目的化合物（II）1.75g（収率87％）を
得た。化学純度は95.7％、光学純度は97.8％eeであっ
た。Example 3 2.0 g (53 mmol) of the starting compound (I) and a complex [RuCl
4 ((S) - (- ) - p-Tol BINAP) 2 N (C 2 H 5) 2 ] 4
5.0 mg (0.025 mmol) was weighed, and the same operation as in Example I was performed to obtain 1.75 g of the target compound (II) (yield: 87%). The chemical purity was 95.7% and the optical purity was 97.8% ee.
なお、（−）−１−ベンジル−４−〔（5,6−ジメト
キシ−１−インダノン）−２−イル〕メチルピペリジン
（II）の物性値およびスペクトルデータは次のとおりで
ある。The physical properties and spectral data of (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine (II) are as follows.
融点:104〜104.5℃ ▲〔α〕25 D▼−43゜（ｃ＝1.00、クロロホルム）1 H−NMR（400MHz,CD30D）δppm:1.24〜1.42（m,3H）,1.
54（m,1H）,1.73（m,1H）,1.75〜1.87（m,2H）,2.04
（m,2H）,2.65〜2.77（m,2H）,2.85〜2.97（m,2H）,3.2
7（dd,J＝8Hz,J＝18Hz,1H）,3.52（s,2H）,3.85（（s,3
H）,3.92（s,3H）,7.04（s,1H）,7.14（s,1H）,7.2〜7.
4（m,5H） Ms:m/e 379Mp: 104 to 104.5 ° C. ▲ [α] 25 D ▼ -43 DEG (c = 1.00, chloroform) 1 H-NMR (400MHz, CD 3 0D) δppm: 1.24~1.42 (m, 3H), 1.
54 (m, 1H), 1.73 (m, 1H), 1.75 to 1.87 (m, 2H), 2.04
(M, 2H), 2.65 to 2.77 (m, 2H), 2.85 to 2.97 (m, 2H), 3.2
7 (dd, J = 8 Hz, J = 18 Hz, 1H), 3.52 (s, 2H), 3.85 ((s, 3
H), 3.92 (s, 3H), 7.04 (s, 1H), 7.14 (s, 1H), 7.2-7.
4 (m, 5H) Ms: m / e 379
───────────────────────────────────────────────────── フロントページの続き (72)発明者 杉本 八郎 茨城県牛久市柏田町3073―13 (72)発明者 清藤 信夫 神奈川県横浜市保土ケ谷区瀬戸ケ谷町 298―46 保土ヶ谷第１香風フラット106 (72)発明者 雲林 秀徳 神奈川県茅ケ崎市中海岸１―４―39 (56)参考文献 特開 平１−79151（ＪＰ，Ａ) 特開 平２−169569（ＪＰ，Ａ) 特開 平４−21670（ＪＰ，Ａ) (58)調査した分野(Int.Cl.6，ＤＢ名) C07D 211/32 ＣＡ（ＳＴＮ)──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hachiro Sugimoto 3073-13, Kashiwada-cho, Ushiku-shi, Ibaraki (72) Inventor Nobuo Seito 298-46, Hodogaya-ku, Setagaya-cho, Hodogaya-ku, Yokohama, Kanagawa Prefecture 106 (72) ) Inventor Hidenori Unbayashi 1-4-39 Nakakaigan, Chigasaki-shi, Kanagawa (56) References JP-A-1-79151 (JP, A) JP-A-2-169569 (JP, A) JP-A-4-21670 (JP, A) (58) Field surveyed (Int. Cl. 6 , DB name) C07D 211/32 CA (STN)
Claims (2)
メトキシ−１−インダノン）−２−イリデニル〕メチル
ピペリジンを、光学活性なルテニウム−ホスフィン錯体
触媒の存在下に不斉水素化することを特徴とする、次式
（II） で表わされる（−）−１−ベンジル−４−〔（5,6−ジ
メトキシ−１−インダノン）−２−イル〕メチルピペリ
ジンの製造方法。1. The following formula (I) Asymmetric hydrogenation of (E) -1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yridenyl] methylpiperidine represented by the formula (I) in the presence of an optically active ruthenium-phosphine complex catalyst: The following equation (II) A method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine represented by the formula:
が、次式（III）、（IV）または（Ｖ）で表わされる化
合物から選択される一つまたは二つ以上である請求項１
記載の（−）−１−ベンジル−４−〔（5,6−ジメトキ
シ−１−インダノン）−２−イル〕メチルピペリジンの
製造方法。 〔式（III）、（IV）、（Ｖ）において、Ｘはハロゲン
原子を示し、Ｙは水素原子、アミノ基、アセチルアミノ
基またはスルホン酸基を示し、R1は水素原子または直鎖
もしくは分岐鎖の低級アルキル基を示し、Ａ及びＺはそ
れぞれCIO4、PF6、BF4またはR2COO（ここでR2はアルキ
ル基、ハロゲン化低級アルキル基、低級アルキル置換基
を有していてもよいフェニル基、α−アミノアルキル基
またはα−アミノフェニルアルキル基を示す）か、ある
いはＡとＺが一緒になってアルキレンジカルボキシ基を
形成するものを示し、ｎは１または２を示す〕2. An optically active ruthenium-phosphine complex is one or more selected from compounds represented by the following formulas (III), (IV) or (V).
A method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine as described. [In the formulas (III), (IV) and (V), X represents a halogen atom, Y represents a hydrogen atom, an amino group, an acetylamino group or a sulfonic acid group, and R 1 represents a hydrogen atom or a linear or branched A and Z each represent CIO 4 , PF 6 , BF 4 or R 2 COO (where R 2 represents an alkyl group, a halogenated lower alkyl group, or a lower alkyl substituent) A good phenyl group, an α-aminoalkyl group or an α-aminophenylalkyl group), or a compound in which A and Z together form an alkylenedicarboxy group, and n represents 1 or 2]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2320055A JP2965675B2 (en) | 1990-11-21 | 1990-11-21 | Method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2320055A JP2965675B2 (en) | 1990-11-21 | 1990-11-21 | Method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04187674A JPH04187674A (en) | 1992-07-06 |
| JP2965675B2 true JP2965675B2 (en) | 1999-10-18 |
Family
ID=18117221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2320055A Expired - Lifetime JP2965675B2 (en) | 1990-11-21 | 1990-11-21 | Method for producing (-)-1-benzyl-4-[(5,6-dimethoxy-1-indanone) -2-yl] methylpiperidine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2965675B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007043440A1 (en) | 2005-10-14 | 2007-04-19 | Eisai R & D Management Co., Ltd. | Process for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine or hydrochloride thereof |
| US7795438B2 (en) | 2004-04-28 | 2010-09-14 | Eisai R&D Management Co., Ltd | Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride |
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1990
- 1990-11-21 JP JP2320055A patent/JP2965675B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7795438B2 (en) | 2004-04-28 | 2010-09-14 | Eisai R&D Management Co., Ltd | Processes for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine and hydrochloride |
| WO2007043440A1 (en) | 2005-10-14 | 2007-04-19 | Eisai R & D Management Co., Ltd. | Process for producing 1-benzyl-4-[(5,6-dimethoxy-1indanon)-2-yl]methylpiperidine or hydrochloride thereof |
| US7332606B2 (en) | 2005-10-14 | 2008-02-19 | Eisai R&D Management Co., Ltd. | Process for producing 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine or hydrochloride thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04187674A (en) | 1992-07-06 |
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