JPH07116146B2 - Process for producing 4-piperidinopiperidines - Google Patents
Process for producing 4-piperidinopiperidinesInfo
- Publication number
- JPH07116146B2 JPH07116146B2 JP61290121A JP29012186A JPH07116146B2 JP H07116146 B2 JPH07116146 B2 JP H07116146B2 JP 61290121 A JP61290121 A JP 61290121A JP 29012186 A JP29012186 A JP 29012186A JP H07116146 B2 JPH07116146 B2 JP H07116146B2
- Authority
- JP
- Japan
- Prior art keywords
- benzyl
- piperidinopiperidines
- general formula
- hydrogen
- present
- 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 - Fee Related
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４−ピペリジノピペリジン類の製造方法に関す
る。４−ピペリジノピペリジン類は医薬合成用の中間体
として極めて重要な化合物である。TECHNICAL FIELD The present invention relates to a method for producing 4-piperidinopiperidines. 4-Piperidinopiperidines are extremely important compounds as intermediates for pharmaceutical synthesis.
従来の技術 従来、４−ピペリジノピペリジン類の製造方法として
は、１−ベンジル−４−ピペリジノピペリジンの塩酸塩
をパラジウム／カーボンの存在下、室温で水素還元する
４−ピペリジノピペリジンの塩酸塩の製造法（J.MED.CH
EM.9（１）49〜52（1966））が知られている。2. Description of the Related Art Conventionally, as a method for producing 4-piperidinopiperidines, 4-piperidinopiperidine obtained by hydrogenating 1-benzyl-4-piperidinopiperidine hydrochloride at room temperature in the presence of palladium / carbon has been used. Of the hydrochloride salt of (J.MED.CH
EM.9 (1) 49-52 (1966)) is known.
本発明が解決しようとする問題点 この方法は82％の収率で４−ピペリジノピペリジンの塩
酸塩を得ているが、より高収率を達成しうる製造法が要
望されている。Problems to be Solved by the Present Invention This method obtains the hydrochloride of 4-piperidinopiperidine in a yield of 82%, but a production method capable of achieving a higher yield is desired.
本発明は出発原料として１−ベンジル−４−ピペリジノ
ピペリジン類を用いて、より効率よく、又高品質の４−
ピペリジノピペリジン類を製造する方法を提供するもの
である。The present invention uses 1-benzyl-4-piperidinopiperidines as a starting material to improve the efficiency and quality of 4-
The present invention provides a method for producing piperidinopiperidines.
問題点を解決するための手段 本発明者は鋭意研究を行なった結果、遊離の１−ベンジ
ル−４−ピペリジノピペリジン類（以下、単に１−ベン
ジル−４−ピペリジノピペリジン類という。）の水素還
元反応温度を100℃以上にすると、従来法に比べてそれ
以上の収率で４−ピペリジノピペリジン類を製造できる
ことを見出し本発明を完成するに至ったものである。Means for Solving the Problems As a result of intensive studies by the present inventor, free 1-benzyl-4-piperidinopiperidines (hereinafter, simply referred to as 1-benzyl-4-piperidinopiperidines) It was found that 4-piperidinopiperidines can be produced in a yield higher than that of the conventional method by setting the hydrogen reduction reaction temperature of 100 ° C. or higher to complete the present invention.
即ち、本発明は、パラジウム触媒の存在下、100℃以上
の反応温度にて一般式（１）： （式中、R1、R2及びR3はいずれも水素原子又は低級アル
キル基を意味する。）で表わされる１−ベンジル−４−
ピペリジノピペリジン類を水素で接触還元することを特
徴とする一般式（２）： （式中、R1、R2及びR3は前記と同じ。）で表わされる４
−ピペリジノピペリジン類の製造法である。That is, the present invention provides a compound represented by the general formula (1) at a reaction temperature of 100 ° C. or higher in the presence of a palladium catalyst: (In the formula, all of R 1 , R 2 and R 3 represent a hydrogen atom or a lower alkyl group.) 1-benzyl-4-
General formula (2) characterized by catalytic reduction of piperidinopiperidines with hydrogen: (In the formula, R 1 , R 2 and R 3 are the same as the above.) 4
-A method for producing piperidinopiperidines.
本発明の出発原料である一般式（１）で表わされる１−
ベンジル−４−ピペリジノピペリジン類としては、１−
ベンジル−４−ピペリジノピペリジン、１−ベンジル−
４−（２−メチルピペリジノ）ピペリジン、１−ベンジ
ル−４−（３−メチルピペリジノ）ピペリジン、１−ベ
ンジル−４−（４−メチルピペリジノ）ピペリジン、１
−ベンジル−４−（2,6−ジメチルピペリジノ）ピペリ
ジン、１−ベンジル−４−（3,5−ジメチルピペリジ
ノ）ピペリジン、１−ベンジル−４−（2,3,5−トリメ
チルピペリジノ）ピペリジン等があげられる。一般式
（１）で表わされる１−ベンジル−４−ピペリジノピペ
リジン類は、通常加圧下にパラジウム触媒を存在させ、
一般式（３）： （式中、R1,R2及びR3はいずれも水素原子又は低級アル
キル基である。）で表わされるピペリジン類と１−ベン
ジル−４−ピペリドン及び水素を反応させるだけで合成
される。又、前記一般式（３）で表わされるピペリジン
類、１−ベンジル−４−ピペリドン及び水素を反応させ
て得られた反応終了液をそのまま、前記一般式（１）で
表わされる化合物として用いることができる。1- represented by the general formula (1), which is a starting material of the present invention
Benzyl-4-piperidinopiperidines include 1-
Benzyl-4-piperidinopiperidine, 1-benzyl-
4- (2-methylpiperidino) piperidine, 1-benzyl-4- (3-methylpiperidino) piperidine, 1-benzyl-4- (4-methylpiperidino) piperidine, 1
-Benzyl-4- (2,6-dimethylpiperidino) piperidine, 1-benzyl-4- (3,5-dimethylpiperidino) piperidine, 1-benzyl-4- (2,3,5-trimethylpiperine Peridino) piperidine and the like. The 1-benzyl-4-piperidinopiperidines represented by the general formula (1) usually contain a palladium catalyst under pressure,
General formula (3): (In the formula, each of R 1 , R 2 and R 3 is a hydrogen atom or a lower alkyl group.) It is synthesized only by reacting 1-benzyl-4-piperidone and hydrogen. Further, the reaction-terminated liquid obtained by reacting the piperidine represented by the general formula (3), 1-benzyl-4-piperidone and hydrogen may be used as it is as the compound represented by the general formula (1). it can.
本発明に使用されるパラジウム触媒としては、例えばア
ルミナ、珪藻土、白土または活性炭に担持させたパラジ
ウム触媒等を挙げることができる。パラジウム触媒の使
用量としては特に制限されないが、例えば５％パラジウ
ム／カーボンなら原料の一般式（１）で表わされる１−
ベンジル−４−ピペリジノピペリジン類に対して0.1〜2
0重量％の範囲が好適である。Examples of the palladium catalyst used in the present invention include alumina, diatomaceous earth, clay and a palladium catalyst supported on activated carbon. The amount of the palladium catalyst used is not particularly limited, but for example, 5% palladium / carbon is represented by the general formula (1) of 1-
0.1-2 for benzyl-4-piperidinopiperidines
A range of 0% by weight is preferred.
本発明において、反応温度は100℃以上であれば特に限
定することはないが、100〜200℃の範囲が好適である。In the present invention, the reaction temperature is not particularly limited as long as it is 100 ° C or higher, but a range of 100 to 200 ° C is suitable.
本発明において、反応圧としては所定の温度での内容物
の蒸気圧以上であれば十分であるが、好ましくは10〜70
Kg/cm2の範囲である。所定の圧力を維持するには外部か
ら水素ガスでコントロールし、もし水素が消費されて内
圧が下がれば水素を補給して所定内圧を維持することが
出来る。In the present invention, the reaction pressure is sufficient if it is equal to or higher than the vapor pressure of the contents at a predetermined temperature, preferably 10 to 70.
It is in the range of Kg / cm 2 . In order to maintain a predetermined pressure, hydrogen gas is externally controlled, and if hydrogen is consumed and the internal pressure drops, hydrogen can be replenished to maintain the predetermined internal pressure.
本発明において、使用する溶媒はベンゼン、トルエン、
キシレン等の不活性溶媒で十分であるが、一般式（１）
で表わされる１−ベンジル−４−ピペリジノピペリジン
類を水添すると、脱ベンジル基が起きてトルエンが生成
されるので、仕込みの溶媒にはトルエンを選ぶのが好適
である。溶媒の使用量は原料の一般式（１）で表わされ
る１−ベンジル−４−ピペリジノピペリジン類の0.5〜
５倍重量が好適である。In the present invention, the solvent used is benzene, toluene,
An inert solvent such as xylene is sufficient, but the general formula (1)
When 1-benzyl-4-piperidinopiperidines represented by the formula (1) are hydrogenated, a debenzylation group occurs and toluene is produced. Therefore, it is preferable to select toluene as a solvent for charging. The amount of the solvent used is 0.5 to 0.5 of 1-benzyl-4-piperidinopiperidines represented by the general formula (1) as a raw material.
Five times the weight is preferred.
本発明の反応時間は一般に0.5〜５時間程度であるが、
厳密な反応の終点は内圧の減少が無くなった時である。The reaction time of the present invention is generally about 0.5 to 5 hours,
The exact end point of the reaction is when there is no decrease in internal pressure.
上記反応で得られた一般式（２）で表わされる４−ピペ
リジノピペリジン類は一般的な単離、分離手段で得られ
る。例えば、反応液をろ過してパラジウム触媒を除去
し、ろ液を蒸留することにより、単離精製される。The 4-piperidinopiperidines represented by the general formula (2) obtained by the above reaction can be obtained by general isolation and separation means. For example, the reaction solution is filtered to remove the palladium catalyst, and the filtrate is distilled for isolation and purification.
実施例 以下に、実施例を掲げて本発明を具体的に説明するが、
本発明はこれら実施例に限定されるものではない。EXAMPLES Hereinafter, the present invention will be specifically described with reference to Examples.
The present invention is not limited to these examples.
実施例１ 3lの電磁攪はん式オートクレーブに、１−ベンジル−４
−ピペリジノピペリジン460g、トルエン1380g及び５％
パラジウム／カーボン23gを仕込み、容器内を水素置換
した後、内温140〜150℃に昇温した。次に、同温で反応
圧20Kg/cm2をたもちながら約２時間で水素39lを流入し
た。Example 1 A 3-liter electromagnetic stirring autoclave was charged with 1-benzyl-4.
-460 g piperidinopiperidine, 1380 g toluene and 5%
After charging 23 g of palladium / carbon and replacing the inside of the container with hydrogen, the internal temperature was raised to 140 to 150 ° C. Next, at the same temperature, while maintaining a reaction pressure of 20 kg / cm 2 , 39 l of hydrogen was flowed in in about 2 hours.
反応後、オートクレーブを室温に冷却し、内容物を取り
出して触媒をろ過した。ろ液をクライゼン蒸留した所、
塔頂温度112−３℃/2mmHgでG.C.純度99.5％の４−ピペ
リジノピペリジン260gを得た。前留分を合わせると、１
−ベンジル−４−ピペリジノ）ピペリジンから４−ピペ
リジノピペリジンへの収率は92.8％であった。After the reaction, the autoclave was cooled to room temperature, the contents were taken out, and the catalyst was filtered. After the Claisen distillation of the filtrate,
260 g of 4-piperidinopiperidine having a GC purity of 99.5% was obtained at a column top temperature of 112-3 ° C./2 mmHg. When the previous fractions are combined, 1
The yield from -benzyl-4-piperidino) piperidine to 4-piperidinopiperidine was 92.8%.
実施例２ １の電磁攪はん式オートクレーブに、１−ベンジル−
４−（４−メチルピペリジノ）ピペリジン162g、トルエ
ン460g及び５％パラジウム／カーボン8gを仕込んだ他
は、実施例１と同様に操作を行なった結果、４−（４−
メチルピペリジノ）ピペリジンの収率は91％であった。Example 2 The electromagnetic stirring autoclave of 1 was charged with 1-benzyl-
4- (4-Methylpiperidino) piperidine 162 g, toluene 460 g and 5% palladium / carbon 8 g were charged in the same manner as in Example 1, except that 4- (4-
The yield of methylpiperidino) piperidine was 91%.
実施例３ １−ベンジル−４−（４−メチルピペリジノ）ピペリジ
ンの代わりに、１−ベンジル−４−（3,5−ジメチルピ
ペリジノ）ピペリジンを用いたほかは実施例３と同様に
操作を行なった結果、４−（3.5−ジメチルピペリジ
ノ）ピペリジンの収率は88％であった。Example 3 The same operation as in Example 3 was carried out except that 1-benzyl-4- (3,5-dimethylpiperidino) piperidine was used instead of 1-benzyl-4- (4-methylpiperidino) piperidine. As a result, the yield of 4- (3.5-dimethylpiperidino) piperidine was 88%.
実施例４ １の電磁攪はん式オートクレーブに、１−ベンジル−
４−ピペリドン200g、ピペリジン180g及び５％パラジウ
ム／カーボン46gを仕込み、容器内を水素置換した後、
内温70〜75℃、内圧20Kg/cm2をもちながら５時間で水素
27lを流入した。その後内温100〜140℃に昇温しなが
ら、約３時間で水素22lを流入した。Example 4 The electromagnetic stirring autoclave of 1 was charged with 1-benzyl-
After charging 200 g of 4-piperidone, 180 g of piperidine and 46 g of 5% palladium / carbon, after replacing the inside of the container with hydrogen,
Hydrogen at an internal temperature of 70-75 ℃ and an internal pressure of 20Kg / cm 2 in 5 hours
Inflowed 27 l. Then, while raising the internal temperature to 100 to 140 ° C., 22 liters of hydrogen was introduced in about 3 hours.
反応液を実施例１と同様に蒸留して、G.C.純度99.3％の
４−ピペリジノピペリジンの160gを得て、１−ベンジル
−４−ピペリドンからの収率は91.1％であった。The reaction solution was distilled in the same manner as in Example 1 to obtain 160 g of 4-piperidinopiperidine having a GC purity of 99.3%, and the yield from 1-benzyl-4-piperidone was 91.1%.
比較例１ 反応を25℃で行った以外は、実施例１と同様に操作を行
った結果、４−ピペリジノピペリジンの収率は0.5％で
あった。他は未反応の１−ベンジル−４−ピペリジノピ
ペリジンを回収した。Comparative Example 1 The same operation as in Example 1 was carried out except that the reaction was carried out at 25 ° C. As a result, the yield of 4-piperidinopiperidine was 0.5%. Otherwise, 1-benzyl-4-piperidinopiperidine unreacted was recovered.
比較例２ 反応を80℃で行った以外は、実施例１と同様に操作を行
った結果、４−ピペリジノピペリジンの収率は3.5％で
あった。他は未反応の１−ベンジル−４−ピペリジノピ
ペリジンを回収した。Comparative Example 2 The result of the same operation as in Example 1 except that the reaction was carried out at 80 ° C., the yield of 4-piperidinopiperidine was 3.5%. Otherwise, 1-benzyl-4-piperidinopiperidine unreacted was recovered.
発明の効果 本発明の方法によれば、従来技術に比較し、一般式
（２）で表わされる４−ピペリジノピペリジン類の収率
が約10％向上でき、本発明は工業的に極めて有用なもの
である。Effects of the Invention According to the method of the present invention, the yield of 4-piperidinopiperidines represented by the general formula (2) can be improved by about 10% as compared with the prior art, and the present invention is industrially very useful. It is something.
Claims (2)
応温度にて一般式（１）： （式中、R1、R2及びR3はいずれも水素原子又は低級アル
キル基を意味する。）で表わされる遊離の１−ベンジル
−４−ピペリジノピペリジン類を水素で接触還元するこ
とを特徴とする一般式（２）： （式中、R1、R2及びR3は前記と同じ。）で表わされる４
−ピペリジノピペリジン類の製造法。1. A compound represented by the general formula (1) at a reaction temperature of 100 ° C. or higher in the presence of a palladium catalyst: (Wherein R 1 , R 2 and R 3 each represent a hydrogen atom or a lower alkyl group), and catalytic reduction of free 1-benzyl-4-piperidinopiperidines with hydrogen is performed. Characteristic general formula (2): (In the formula, R 1 , R 2 and R 3 are the same as the above.) 4
-Process for producing piperidinopiperidines.
囲第１項記載の方法。2. The method according to claim 1, wherein the reaction temperature is 100 to 200 ° C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61290121A JPH07116146B2 (en) | 1986-12-05 | 1986-12-05 | Process for producing 4-piperidinopiperidines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61290121A JPH07116146B2 (en) | 1986-12-05 | 1986-12-05 | Process for producing 4-piperidinopiperidines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63141964A JPS63141964A (en) | 1988-06-14 |
| JPH07116146B2 true JPH07116146B2 (en) | 1995-12-13 |
Family
ID=17752073
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61290121A Expired - Fee Related JPH07116146B2 (en) | 1986-12-05 | 1986-12-05 | Process for producing 4-piperidinopiperidines |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07116146B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10526288B2 (en) | 2016-06-09 | 2020-01-07 | Yuki Gosei Kogyo Co., Ltd. | Method for preparing 4-(piperidin-4-yl)morpholine |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07126165A (en) * | 1993-10-29 | 1995-05-16 | Masao Oguro | Therapeutic agent for tumor |
| JP2008050307A (en) * | 2006-08-25 | 2008-03-06 | Koei Chem Co Ltd | Method for producing piperidine compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5137105B2 (en) * | 1972-07-28 | 1976-10-13 | ||
| JPS5524155A (en) * | 1978-08-10 | 1980-02-21 | Yoshitomi Pharmaceut Ind Ltd | Piperidine derivative having heterocyclic ring at 4-position |
-
1986
- 1986-12-05 JP JP61290121A patent/JPH07116146B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| ＪｏｕｒｎａｌｏｆＭｅｄｉｃｉｎａｌＣｈｅｍｉｓｔｒｙ，９［１（１９６６）Ｐ．４９−５２ |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10526288B2 (en) | 2016-06-09 | 2020-01-07 | Yuki Gosei Kogyo Co., Ltd. | Method for preparing 4-(piperidin-4-yl)morpholine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63141964A (en) | 1988-06-14 |
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| JPH0522700B2 (en) |
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| LAPS | Cancellation because of no payment of annual fees |