JPH07330732A - Optically active 3-amino-1-benzylpiperidine derivative - Google Patents
Optically active 3-amino-1-benzylpiperidine derivativeInfo
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- JPH07330732A JPH07330732A JP15280894A JP15280894A JPH07330732A JP H07330732 A JPH07330732 A JP H07330732A JP 15280894 A JP15280894 A JP 15280894A JP 15280894 A JP15280894 A JP 15280894A JP H07330732 A JPH07330732 A JP H07330732A
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- Prior art keywords
- amino
- optically active
- benzylpiperidine
- derivative
- general formula
- Prior art date
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- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は医薬品等の製造中間体と
して有用な光学活性な３−アミノ−１−ベンジルピペリ
ジン誘導体およびその製造方法に関する。TECHNICAL FIELD The present invention relates to an optically active 3-amino-1-benzylpiperidine derivative useful as an intermediate for the production of pharmaceuticals and the like, and a method for producing the same.
【０００２】[0002]
【従来の技術】医薬品等産業上有用な化合物の構成成分
として３−アミノピペリジン骨格を有する多くの化合物
が知られているが、それらを製造する上での重要な原料
の一つとして３−アミノ−１−ベンジルピペリジン誘導
体が挙げられる。2. Description of the Related Art Many compounds having a 3-aminopiperidine skeleton are known as constituent components of industrially useful compounds such as pharmaceuticals, and 3-amino is one of important raw materials for producing them. -1-Benzylpiperidine derivative is mentioned.
【０００３】一般式（３） ［式中、Ｘは水素原子、ハロゲン、低級アルキルもしく
はアルコキシ基を示す］で表されるラセミ３−アミノ−
１−ベンジルピペリジン誘導体は公知であるか、または
公知の方法（J. Moragues ら、J. Chem. Soc., Perkin
Trans. 1, 938(1976)、またはA. M. Criderら、J. Med.
Chem., 23, 848 (1980))によって得られる。General formula (3) [Wherein, X represents a hydrogen atom, a halogen, a lower alkyl or an alkoxy group], and racemic 3-amino-
1-Benzylpiperidine derivatives are known or known methods (J. Moragues et al., J. Chem. Soc., Perkin.
Trans. 1, 938 (1976), or AM Crider et al., J. Med.
Chem., 23, 848 (1980)).
【０００４】[0004]
【発明が解決しようとする課題】一般式（３）で表され
る化合物は２種の光学活性体の等量混合物であって、各
々の光学活性体の製法および物理化学的性質については
全く知られていない。The compound represented by the general formula (3) is a mixture of two kinds of optically active substances in equal amounts, and the production method and physicochemical properties of each optically active substance are completely unknown. Has not been done.
【０００５】一般に、光学活性な３−アミノ−１−ベン
ジルピペリジン誘導体を製造する一つの方法として光学
活性な化合物を出発原料とし、骨格形成あるいは官能基
変換により導く方法が考えられる。例えば、光学活性な
オルニチンを原料とし、不斉合成により光学活性な３−
アミノピペリジン誘導体が得られることが知られており
（特開平３−９５１７７号公報あるいはM. Oklobdziji
ら、J. HeterocyclicChem., 20, 1329 (1983)) 、これ
を必要に応じてベンジル化すれば所望の光学活性な３−
アミノ−１−ベンジルピペリジン誘導体が得られる筈で
ある。Generally, as one method for producing an optically active 3-amino-1-benzylpiperidine derivative, a method in which an optically active compound is used as a starting material and a skeleton is formed or functional groups are converted is considered. For example, using optically active ornithine as a raw material, an optically active 3-
It is known that an aminopiperidine derivative can be obtained (JP-A-3-95177 or M. Oklobdziji).
Et al., J. Heterocyclic Chem., 20, 1329 (1983)), which can be benzylated, if desired, to give the desired optically active 3-
An amino-1-benzylpiperidine derivative should be obtained.
【０００６】しかし、このような方法は原料化合物が高
価であり、かつ、合成工程を積み重ねる必要があるた
め、工業的に有利ではない。However, such a method is not industrially advantageous because the raw material compound is expensive and it is necessary to stack the synthetic steps.
【０００７】[0007]
【課題を解決するための手段】そこで工業的にも容易に
得られる一般式（３）で表されるラセミ−３−アミノ−
１−ベンジルピペリジン誘導体を、安価でかつ回収も可
能な分割剤を用いて光学分割することを鋭意研究した結
果、光学活性なジベンゾイル酒石酸を用いた光学分割に
より、光学活性な３−アミノ−１−ベンジルピペリジン
誘導体が高い光学純度で収率良く得られることを見いだ
した。Then, racemic-3-amino-represented by the general formula (3), which can be easily obtained industrially, is also provided.
As a result of diligent research on the optical resolution of the 1-benzylpiperidine derivative using a resolving agent which is inexpensive and also recoverable, the optically active 3-amino-1- It has been found that the benzylpiperidine derivative can be obtained in high yield with high optical purity.
【０００８】一般式（１） ［式中、Ｘは水素原子、ハロゲン、低級アルキルもしく
はアルコキシ基を示す］または一般式（２） ［式中、Ｘは水素原子、ハロゲン、低級アルキルもしく
はアルコキシ基を示す］で表される化合物は一般式
（３） ［式中、Ｘは水素原子、ハロゲン、低級アルキルもしく
はアルコキシ基を示す］で示される化合物と光学活性な
ジベンゾイル酒石酸を有機溶媒中熱時混合溶解し、ジア
ステレオマー塩を形成させることにより得られる。General formula (1) [In the formula, X represents a hydrogen atom, a halogen, a lower alkyl or an alkoxy group] or the general formula (2). [Wherein, X represents a hydrogen atom, a halogen, a lower alkyl or an alkoxy group] is represented by the general formula (3) A compound represented by the formula [wherein X represents a hydrogen atom, a halogen, a lower alkyl or an alkoxy group] and an optically active dibenzoyltartaric acid are mixed and dissolved in an organic solvent under heat to form a diastereomeric salt. .
【０００９】形成された２種のジアステレオマー塩は互
いに物理的および化学的性質が異なり、特に溶媒に対す
る溶解度が異なるので、２種の内１種のジアステレオマ
ー塩が優先的に析出する。この際、（＋）−ジベンゾイ
ル−Ｄ−酒石酸を用いた場合には一般式（１）に示す
（Ｒ）−（−）−３−アミノ−１−ベンジルピペリジン
との塩が優先的に析出し、（−）−ジベンゾイル−Ｌ−
酒石酸を用いた場合は一般式（２）に示す（Ｓ）−
（＋）−３−アミノ−１−ベンジルピペリジンとの塩が
優先的に析出する。The two diastereomeric salts formed have different physical and chemical properties from each other, and in particular have different solubilities in solvents, so that one of the two diastereomeric salts preferentially precipitates. At this time, when (+)-dibenzoyl-D-tartaric acid is used, a salt with (R)-(-)-3-amino-1-benzylpiperidine represented by the general formula (1) preferentially precipitates. , (-)-Dibenzoyl-L-
When tartaric acid is used, it is represented by the general formula (2) (S)-
The salt with (+)-3-amino-1-benzylpiperidine preferentially precipitates.
【００１０】この操作に用いる光学活性なジベンゾイル
酒石酸の量は一般式（３）の化合物に対して基本的には
等モル量であるが、やや過剰量を用いるのが好ましい。
溶解に用いる有機溶媒としては、好ましくはメタノー
ル、エタノール、イソプロピルアルコール等の炭素数１
〜６のアルコールであり、より好ましくはエタノールで
ある。溶媒の使用量としては一般式（３）の化合物に対
して好ましくは５〜20倍量、より好ましくは10倍量程度
である。溶解時の温度としては50℃〜使用溶媒の沸点が
好ましい。The amount of the optically active dibenzoyltartaric acid used in this operation is basically an equimolar amount with respect to the compound of the general formula (3), but it is preferable to use a slight excess amount.
The organic solvent used for dissolution preferably has 1 carbon atom such as methanol, ethanol, isopropyl alcohol, etc.
~ 6 alcohol, more preferably ethanol. The amount of the solvent used is preferably 5 to 20 times, more preferably about 10 times the amount of the compound of the general formula (3). The temperature at the time of dissolution is preferably 50 ° C. to the boiling point of the solvent used.
【００１１】次に、熱時混合溶解したジアステレオマー
塩の溶液を放置および冷却すると、主に１種類のジアス
テレオマー塩が優先的に結晶として析出する。結晶を析
出させる際の冷却温度としては好ましくは室温から−15
℃、より好ましくは室温から０℃であり、放置時間は好
ましくは１〜48時間、より好ましくは10〜20時間であ
る。析出したジアステレオマー塩は濾過によって分取
し、有機溶媒、より好ましくは少量のエタノールあるい
はアセトンで洗浄する。Next, when the solution of the diastereomer salt mixed and dissolved under heat is allowed to stand and cooled, mainly one kind of diastereomer salt preferentially precipitates as crystals. The cooling temperature when precipitating crystals is preferably room temperature to −15.
C., more preferably from room temperature to 0.degree. C., and the standing time is preferably 1 to 48 hours, more preferably 10 to 20 hours. The precipitated diastereomeric salt is separated by filtration and washed with an organic solvent, more preferably with a small amount of ethanol or acetone.
【００１２】この操作の際、ジアステレオマー塩のろ液
および洗液には逆の旋光性を持つ３−アミノ−１−ベン
ジルピペリジン誘導体が含まれているので、これを回収
して再利用すると一層有利である。ろ液および洗液を合
わせてスラリー状になるまで濃縮し、この濃縮物を塩基
で処理し、遊離する油状物を有機溶媒で抽出、乾燥後蒸
留することにより一方の光学活性体に富む３−アミノ−
１−ベンジルピペリジン誘導体を回収し、もう一種類の
ジアステレオマー塩の形成に用いることができる。ここ
で用いる塩基としては水酸化ナトリウムおよび水酸化カ
リウム等のアルカリ金属水酸化物、炭酸ナトリウムおよ
び炭酸カリウム等のアルカリ金属炭酸塩、あるいは炭酸
水素ナトリウムおよび炭酸水素カリウム等のアルカリ金
属炭酸水素塩等があげられる。これらの塩基は好ましく
は１〜20％、より好ましくは５〜10％の水溶液として用
いる。抽出溶媒としては有機溶媒、好ましくは塩化メチ
レン、酢酸エチルおよびトルエン等の非水溶媒、より好
ましくは塩化メチレンがあげられる。蒸留による精製は
減圧下、 200℃以下の加熱で行うのがよい。During this operation, the filtrate and washing solution of the diastereomeric salt contains the 3-amino-1-benzylpiperidine derivative having the opposite optical rotation, so that it should be recovered and reused. It is even more advantageous. The filtrate and washings were combined and concentrated to a slurry, the concentrate was treated with a base, and the liberated oily substance was extracted with an organic solvent, dried and distilled to enrich one of the optically active substances. Amino-
The 1-benzylpiperidine derivative can be recovered and used to form another diastereomeric salt. Examples of the base used here include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, or alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. can give. These bases are preferably used as an aqueous solution of 1 to 20%, more preferably 5 to 10%. Examples of the extraction solvent include organic solvents, preferably non-aqueous solvents such as methylene chloride, ethyl acetate and toluene, more preferably methylene chloride. Purification by distillation is preferably carried out under reduced pressure and heating at 200 ° C or lower.
【００１３】得られたジアステレオマー塩は通常の再結
晶操作により光学純度をさらに向上させることができ
る。再結晶に用いる溶媒は、有機溶媒、好ましくはメタ
ノール、エタノール、イソプロピルアルコール等の炭素
数１〜６のアルコール、より好ましくはメタノールであ
る。溶媒の使用量はジアステレオマー塩に対して好まし
くは５〜10倍量、より好ましくは５倍量である。溶解時
の温度としては50℃〜使用溶媒の沸点である。この再結
晶操作は通常１ないし２回行えば一般式（１）または一
般式（２）で表される十分な光学純度を有するジアステ
レオマー塩が得られる。The optical purity of the obtained diastereomeric salt can be further improved by a usual recrystallization operation. The solvent used for recrystallization is an organic solvent, preferably an alcohol having 1 to 6 carbon atoms such as methanol, ethanol and isopropyl alcohol, more preferably methanol. The amount of the solvent used is preferably 5 to 10 times, more preferably 5 times the amount of the diastereomer salt. The temperature at the time of dissolution is 50 ° C to the boiling point of the solvent used. This recrystallization operation is usually performed once or twice to obtain a diastereomeric salt represented by the general formula (1) or the general formula (2) having a sufficient optical purity.
【００１４】光学活性な３−アミノ−１−ベンジルピペ
リジン誘導体は一般式（１）または一般式（２）で表さ
れるジアステレオマー塩を塩基で処理し、遊離する油状
物を有機溶媒で抽出、乾燥後蒸留することにより得られ
る。用いる塩基としては水酸化ナトリウムおよび水酸化
カリウム等のアルカリ金属水酸化物、炭酸ナトリウムお
よび炭酸カリウム等のアルカリ金属炭酸塩、あるいは炭
酸水素ナトリウムおよび炭酸水素カリウム等のアルカリ
金属炭酸水素塩等があげられる。これらの塩基は好まし
くは１〜20％、より好ましくは５〜10％の水溶液として
用いる。抽出溶媒としては有機溶媒、好ましくは塩化メ
チレン、酢酸エチルおよびトルエン等の非水溶媒、より
好ましくは塩化メチレンがあげられる。蒸留による精製
は減圧下、 200℃以下の加熱で行うのがよい。The optically active 3-amino-1-benzylpiperidine derivative is obtained by treating the diastereomeric salt represented by the general formula (1) or (2) with a base and extracting the liberated oil with an organic solvent. It is obtained by drying and then distilling. Examples of the base used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. . These bases are preferably used as an aqueous solution of 1 to 20%, more preferably 5 to 10%. Examples of the extraction solvent include organic solvents, preferably non-aqueous solvents such as methylene chloride, ethyl acetate and toluene, more preferably methylene chloride. Purification by distillation is preferably carried out under reduced pressure and heating at 200 ° C or lower.
【００１５】また、抽出母液に酸類を加え酸性とした
後、有機溶媒で抽出、精製することにより、光学活性な
ジベンゾイル酒石酸を回収でき、分割剤として再利用す
ることができる。Further, by adding an acid to the extraction mother liquor to make it acidic, and then extracting and purifying with an organic solvent, the optically active dibenzoyltartaric acid can be recovered and reused as a resolving agent.
【００１６】[0016]
【実施例】以下、本発明の構成と硬化を実施例により具
体的に説明するが、本発明はこれらの実施例によって限
定されるものではない。EXAMPLES The constitution and curing of the present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
【００１７】（実施例１） （Ｓ）−（＋）−３−アミノ−１−ベンジルピペリジン
・（−）−ジベンゾイル−Ｌ−酒石酸塩１水和物(Example 1) (S)-(+)-3-amino-1-benzylpiperidine. (-)-Dibenzoyl-L-tartrate monohydrate
【００１８】３−アミノ−１−ベンジルピペリジン（５
ｇ）をエタノール（50ml）に溶かし、80℃に加熱し次い
で撹拌下で（−）−ジベンゾイル−Ｌ−酒石酸１水和物
(9.9ｇ）を加えた。溶解後、５〜８℃の冷蔵庫内で１夜
放置し、析出する結晶を濾取し、エタノール（30ml）で
洗い風乾した（濾液は実施例３の原料として用いた）。
次いで得られた結晶(6.8ｇ）をメタノール（30ml）に熱
時溶解し、５〜８℃の冷蔵庫に５時間放置し再結晶を行
った。結晶を濾取し、エタノール（20ml）で洗い風乾し
て目的物 5.3ｇ（35.6％）を得た。3-amino-1-benzylpiperidine (5
g) in ethanol (50 ml), heated to 80 ° C. and then with stirring (−)-dibenzoyl-L-tartaric acid monohydrate
(9.9 g) was added. After the dissolution, the mixture was allowed to stand overnight in a refrigerator at 5 to 8 ° C., the precipitated crystals were collected by filtration, washed with ethanol (30 ml) and air-dried (the filtrate was used as the raw material of Example 3).
Then, the obtained crystals (6.8 g) were dissolved in methanol (30 ml) while being hot, and left in a refrigerator at 5-8 ° C. for 5 hours for recrystallization. The crystals were collected by filtration, washed with ethanol (20 ml) and air-dried to obtain 5.3 g (35.6%) of the desired product.
【００１９】融点： 127〜130 ℃ 比旋光度：［α］D 25−76.2°（Ｃ＝0.102 、エタノー
ル） 元素分析値（％）：Ｃ30Ｈ32Ｎ2 Ｏ8 ・Ｈ2 Ｏ（566.6
1）として 計算値 Ｃ 63.59 Ｈ 6.05 Ｎ 4.94 実測値 Ｃ 63.65 Ｈ 6.07 Ｎ 4.97Melting point: 127 to 130 ° C. Specific optical rotation: [α] D 25 -76.2 ° (C = 0.102, ethanol) Elemental analysis value (%): C 30 H 32 N 2 O 8 .H 2 O (566.6
1) Calculated value C 63.59 H 6.05 N 4.94 Measured value C 63.65 H 6.07 N 4.97
【００２０】（実施例２） （Ｓ）−（＋）−３−アミノ−１−ベンジルピペリジンExample 2 (S)-(+)-3-Amino-1-benzylpiperidine
【００２１】実施例１の塩(5.3ｇ）を水酸化ナトリウム
(1.5ｇ）を水（30ml）に溶かした水溶液に加え溶解し
た。分離する油状物を30mlの塩化メチレンで２回抽出し
た。塩化メチレンの抽出液を合わせ飽和食塩水で洗い、
無水硫酸ナトリウムで乾燥後、溶媒を留去した。残留物
を 170〜173 ℃／23mmHgで蒸留し、無色油状の目的物1.
55ｇ（31％）を得た。The salt of Example 1 (5.3 g) was added to sodium hydroxide.
(1.5 g) was added to an aqueous solution of water (30 ml) and dissolved. The oil which separated was extracted twice with 30 ml of methylene chloride. Combine the methylene chloride extracts and wash with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was distilled at 170-173 ℃ / 23mmHg to give the desired product as colorless oil 1.
55 g (31%) were obtained.
【００２２】比旋光度：［α］D 25＋ 12.58°（Ｃ＝9.
82、エタノール）Specific optical rotation: [α] D 25 + 12.58 ° (C = 9.
82, ethanol)
【００２３】（実施例３） （Ｒ）−（−）−３−アミノ−１−ベンジルピペリジン
・（＋）−ジベンゾイル−Ｄ−酒石酸塩１水和物(Example 3) (R)-(-)-3-amino-1-benzylpiperidine. (+)-Dibenzoyl-D-tartrate monohydrate
【００２４】実施例１の濾液を濃縮し、残留物に水酸化
ナトリウム（３ｇ）を水（50ml）に溶かした溶液を加
え、溶解した。分離する油状物を塩化メチレン（50ml）
で２回抽出した。塩化メチレンの抽出液を合わせ飽和食
塩水で洗い、無水硫酸ナトリウムで乾燥した。溶媒を留
去し得られた油状物（３ｇ）にエタノールを加え、80℃
に加熱し次いで撹拌下で（＋）−ジベンゾイル−Ｄ−酒
石酸１水和物（６ｇ）を加えて溶解した。これを５〜８
℃の冷蔵庫内で１夜放置し、析出する結晶を濾取し、エ
タノール（30ml）で洗い風乾した。次いで得られた結晶
(6.7ｇ）をメタノール（30ml）に熱時溶解し、５〜８℃
の冷蔵庫内に５時間放置し再結晶を行った。結晶を濾取
し、エタノール（20ml）で洗い風乾して目的物 5.2ｇ
（34.9％）を得た。The filtrate of Example 1 was concentrated, and the residue was dissolved by adding a solution of sodium hydroxide (3 g) in water (50 ml). Separate the oily matter with methylene chloride (50 ml)
It was extracted twice with. The methylene chloride extracts were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Ethanol was added to the oily substance (3 g) obtained by distilling off the solvent, and the temperature was adjusted to 80 ° C.
It was heated to and then under stirring (+)-dibenzoyl-D-tartaric acid monohydrate (6 g) was added and dissolved. 5 to 8
It was left overnight in a refrigerator at ℃, the precipitated crystals were collected by filtration, washed with ethanol (30 ml) and air dried. The crystals obtained then
Dissolve (6.7 g) in methanol (30 ml) when heated, 5-8 ° C
It was left in the refrigerator for 5 hours for recrystallization. The crystals were collected by filtration, washed with ethanol (20 ml) and air dried to give 5.2 g of the desired product.
(34.9%) was obtained.
【００２５】融点： 127〜130 ℃ 比旋光度：［α］D 25＋77.0°（Ｃ＝0.103 、エタノー
ル） 元素分析値（％）：Ｃ30Ｈ32Ｎ2 Ｏ8 ・Ｈ2 Ｏ（566.6
1）として 計算値 Ｃ 63.59 Ｈ 6.05 Ｎ 4.94 実測値 Ｃ 63.30 Ｈ 5.97 Ｎ 4.99Melting point: 127-130 ° C. Specific rotation: [α] D 25 + 77.0 ° (C = 0.103, ethanol) Elemental analysis value (%): C 30 H 32 N 2 O 8 .H 2 O (566.6
1) Calculated value C 63.59 H 6.05 N 4.94 Measured value C 63.30 H 5.97 N 4.99
【００２６】（実施例４） （Ｒ）−（−）−３−アミノ−１−ベンジルピペリジン(Example 4) (R)-(-)-3-amino-1-benzylpiperidine
【００２７】実施例３の塩(5.2ｇ）を水酸化ナトリウム
(1.5ｇ）を水（30ml）に溶かした水溶液に加え溶解し
た。分離する油状物を30mlの塩化メチレンで２回抽出し
た。塩化メチレンの抽出液を合わせ飽和食塩水で洗い、
無水硫酸ナトリウムで乾燥後、溶媒を留去した。残留物
を 170〜172 ℃／23mmHgで蒸留し、無色油状の目的物1.
50ｇ（30％）を得た。The salt of Example 3 (5.2 g) was added to sodium hydroxide.
(1.5 g) was added to an aqueous solution of water (30 ml) and dissolved. The oil which separated was extracted twice with 30 ml of methylene chloride. Combine the methylene chloride extracts and wash with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was distilled at 170-172 ° C / 23mmHg to give the desired product as a colorless oil 1.
Obtained 50 g (30%).
【００２８】比旋光度：［α］D 25− 12.75°（Ｃ＝9.
76、エタノール）[0028] Specific rotation: [α] D 25 - 12.75 ° (C = 9.
76, ethanol)
【００２９】（実施例５） （Ｒ）−（−）−３−アミノ−１−ベンジルピペリジン
・（＋）−ジベンゾイル−Ｄ−酒石酸塩１水和物(Example 5) (R)-(-)-3-amino-1-benzylpiperidine. (+)-Dibenzoyl-D-tartrate monohydrate
【００３０】実施例１において、（−）−ジベンゾイル
−Ｌ−酒石酸１水和物のかわりに（＋）−ジベンゾイル
−Ｄ−酒石酸１水和物を用いて目的物 5.2ｇ（34.9％）
を得た。In Example 1, (+)-dibenzoyl-D-tartaric acid monohydrate was used instead of (-)-dibenzoyl-L-tartaric acid monohydrate, and 5.2 g (34.9%) of the desired product was used.
Got
【００３１】融点： 127〜130 ℃ 比旋光度：［α］D 25＋75.5°（Ｃ＝0.101 、エタノー
ル） 元素分析値（％）：Ｃ30Ｈ32Ｎ2 Ｏ8 ・Ｈ2 Ｏ（566.6
1）として 計算値 Ｃ 63.59 Ｈ 6.05 Ｎ 4.94 実測値 Ｃ 63.32 Ｈ 5.98 Ｎ 5.03Melting point: 127 to 130 ° C. Specific rotation: [α] D 25 + 75.5 ° (C = 0.101, ethanol) Elemental analysis value (%): C 30 H 32 N 2 O 8 .H 2 O (566.6
1) Calculated value C 63.59 H 6.05 N 4.94 Measured value C 63.32 H 5.98 N 5.03
【００３２】（実施例６） （Ｒ）−（−）−３−アミノ−１−ベンジルピペリジン(Example 6) (R)-(-)-3-amino-1-benzylpiperidine
【００３３】実施例５の塩(5.2ｇ）を用いて、実施例２
と同様にして目的物1.50ｇ（30％）を得た。Example 2 using the salt of Example 5 (5.2 g)
In the same manner as in 1., 1.50 g (30%) of the desired product was obtained.
【００３４】沸点： 169〜173 ℃／23mmHg 比旋光度：［α］D 25− 12.88°（Ｃ＝9.70、エタノー
ル）The boiling point: 169~173 ℃ / 23mmHg Specific rotation: [α] D 25 - 12.88 ° (C = 9.70, ethanol)
【００３５】（実施例７） （Ｓ）−（＋）−３−アミノ−１−ベンジルピペリジン
・（−）−ジベンゾイル−Ｌ−酒石酸塩１水和物Example 7 (S)-(+)-3-Amino-1-benzylpiperidine. (-)-Dibenzoyl-L-tartrate monohydrate
【００３６】実施例５で得られる濾液を用いて、実施例
３と同様にして目的物 5.2ｇ（34.9％）を得た。Using the filtrate obtained in Example 5, 5.2 g (34.9%) of the desired product was obtained in the same manner as in Example 3.
【００３７】融点： 127〜130 ℃ 比旋光度：［α］D 25−75.2°（Ｃ＝0.106 、エタノー
ル）Melting point: 127 to 130 ° C. Specific optical rotation: [α] D 25 -75.2 ° (C = 0.106, ethanol)
【００３８】（実施例８）（Ｓ）−（＋）−３−アミノ
−１−ベンジルピペリジンExample 8 (S)-(+)-3-Amino-1-benzylpiperidine
【００３９】実施例７の塩(5.2ｇ）を用いて実施例２と
同様にして目的物1.52ｇ（30.4％）を得た。Using the salt of Example 7 (5.2 g) and in the same manner as in Example 2, 1.52 g (30.4%) of the desired product was obtained.
【００４０】沸点： 168〜172 ℃／23mmHg 比旋光度：［α］D 25＋ 12.54°（Ｃ＝9.70、エタノー
ル）Boiling point: 168 to 172 ° C./23 mmHg Specific rotation: [α] D 25 + 12.54 ° (C = 9.70, ethanol)
【００４１】[0041]
【発明の効果】本発明はかって明らかでなかった３−ア
ミノ−１−ベンジルピペリジン誘導体の光学活性体の製
造に関するものであり、安価な光学分割剤を用い、再結
晶という容易な操作で連続的に効率よく、しかも高い光
学純度で光学活性体を得ることが可能であり、さらにこ
の分割剤の回収、再使用も可能であることから工業的に
極めて有用な知見と方法を提供するものである。さらに
本発明による光学活性な３−アミノ−１−ベンジルピペ
リジン誘導体は、特願平５−２５４９８３号に記載する
抗痴呆薬として有用な光学活性イミダゾリジノン誘導体
を経済的有利に製造するための原料として使用すること
ができる。INDUSTRIAL APPLICABILITY The present invention relates to the production of an optically active substance of a 3-amino-1-benzylpiperidine derivative, which has never been clarified, and uses an inexpensive optical resolving agent to continuously perform recrystallization by an easy operation. It is possible to obtain an optically active substance with high efficiency and high optical purity, and further, it is possible to recover and re-use this resolving agent, which provides industrially extremely useful knowledge and method. . Further, the optically active 3-amino-1-benzylpiperidine derivative according to the present invention is a raw material for economically and advantageously producing an optically active imidazolidinone derivative useful as an anti-dementia drug described in Japanese Patent Application No. 5-254983. Can be used as
Claims (6)
はアルコキシ基を示す］で表される（Ｒ）−（−）−３
−アミノ−１−ベンジルピペリジン誘導体と（＋）−ジ
ベンゾイル−Ｄ−酒石酸とからなる塩またはその水和
物。1. The general formula (1) [In the formula, X represents a hydrogen atom, a halogen, a lower alkyl or an alkoxy group] (R)-(-)-3
A salt consisting of an amino-1-benzylpiperidine derivative and (+)-dibenzoyl-D-tartaric acid or a hydrate thereof.
ある請求項１に記載の塩またはその水和物。2. The salt or its hydrate according to claim 1, wherein in the general formula (1), X is a hydrogen atom.
はアルコキシ基を示す］で表される（Ｓ）−（＋）−３
−アミノ−１−ベンジルピペリジン誘導体と（−）−ジ
ベンゾイル−Ｌ−酒石酸とからなる塩またはその水和
物。3. The general formula (2) [In the formula, X represents a hydrogen atom, a halogen, a lower alkyl or an alkoxy group] (S)-(+)-3
-A salt of an amino-1-benzylpiperidine derivative and (-)-dibenzoyl-L-tartaric acid or a hydrate thereof.
ある請求項３に記載の塩またはその水和物。4. The salt or hydrate thereof according to claim 3, wherein in the general formula (2), X is a hydrogen atom.
はアルコキシ基を示す］で表される（±）−３−アミノ
−１−ベンジルピペリジン誘導体を光学活性なジベンゾ
イル酒石酸を光学分割剤として用いて光学分割すること
を特徴とする光学活性な３−アミノ−１−ベンジルピペ
リジン誘導体の製造方法。5. The general formula (3) [Wherein, X represents a hydrogen atom, a halogen, a lower alkyl or an alkoxy group], and (±) -3-amino-1-benzylpiperidine derivative is used as an optical resolving agent using optically active dibenzoyltartaric acid. A method for producing an optically active 3-amino-1-benzylpiperidine derivative, which comprises resolving.
ある請求項５に記載の光学活性な３−アミノ−１−ベン
ジルピペリジン誘導体の製造方法。6. The method for producing an optically active 3-amino-1-benzylpiperidine derivative according to claim 5, wherein in the general formula (3), X is a hydrogen atom.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15280894A JPH07330732A (en) | 1994-06-10 | 1994-06-10 | Optically active 3-amino-1-benzylpiperidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15280894A JPH07330732A (en) | 1994-06-10 | 1994-06-10 | Optically active 3-amino-1-benzylpiperidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07330732A true JPH07330732A (en) | 1995-12-19 |
Family
ID=15548613
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15280894A Pending JPH07330732A (en) | 1994-06-10 | 1994-06-10 | Optically active 3-amino-1-benzylpiperidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07330732A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002096909A1 (en) * | 2001-05-31 | 2002-12-05 | Pfizer Products Inc. | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| JP2007252238A (en) * | 2006-03-22 | 2007-10-04 | Koei Chem Co Ltd | Method for producing optically active nitrogen-containing cyclic compound |
| WO2008102720A1 (en) | 2007-02-19 | 2008-08-28 | Kaneka Corporation | Method for producing optically active 3-aminopiperidine or salt thereof |
| JP2009541231A (en) * | 2006-06-19 | 2009-11-26 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Polymorphs and methods |
| USRE41783E1 (en) | 1999-12-10 | 2010-09-28 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine compounds |
| JP2011057619A (en) * | 2009-09-10 | 2011-03-24 | Tokai Univ | Method for producing optically active amine compound, and diastereomer salt and method for producing the same |
-
1994
- 1994-06-10 JP JP15280894A patent/JPH07330732A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE41783E1 (en) | 1999-12-10 | 2010-09-28 | Pfizer Inc. | Pyrrolo[2,3-D]pyrimidine compounds |
| AU2002304401B2 (en) * | 2001-05-31 | 2008-04-17 | Pfizer Products Inc. | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| WO2002096909A1 (en) * | 2001-05-31 | 2002-12-05 | Pfizer Products Inc. | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| AU2002304401C1 (en) * | 2001-05-31 | 2009-03-05 | Pfizer Products Inc. | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| KR100926875B1 (en) * | 2001-05-31 | 2009-11-16 | 화이자 프로덕츠 인코포레이티드 | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| EA012666B1 (en) * | 2001-05-31 | 2009-12-30 | Пфайзер Продактс Инк. | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| EP1609781A1 (en) * | 2001-05-31 | 2005-12-28 | Pfizer Products Incorporated | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine |
| HRP20030943B1 (en) * | 2001-05-31 | 2011-11-30 | Pfizer Products Inc. | Optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors |
| CZ304366B6 (en) * | 2001-05-31 | 2014-04-02 | Pfizer Products Inc. | 3-{(3R, 4R)-4-Methyl-3-[methyl-(7h-pyrrolo [2,3-d] pyrimidin-4-yl )amino] piperidin-1-yl) }-3-oxo propionitrile, pharmaceutical composition containing thereof and its use |
| JP2007252238A (en) * | 2006-03-22 | 2007-10-04 | Koei Chem Co Ltd | Method for producing optically active nitrogen-containing cyclic compound |
| JP2009541231A (en) * | 2006-06-19 | 2009-11-26 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | Polymorphs and methods |
| WO2008102720A1 (en) | 2007-02-19 | 2008-08-28 | Kaneka Corporation | Method for producing optically active 3-aminopiperidine or salt thereof |
| US8338142B2 (en) | 2007-02-19 | 2012-12-25 | Kaneka Corporation | Method for producing optically active 3-aminopiperidine or salt thereof |
| JP2011057619A (en) * | 2009-09-10 | 2011-03-24 | Tokai Univ | Method for producing optically active amine compound, and diastereomer salt and method for producing the same |
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