JP2683809B2 - Process for producing 1-benzyl-3-benzylaminopyrrolidines - Google Patents
Process for producing 1-benzyl-3-benzylaminopyrrolidinesInfo
- Publication number
- JP2683809B2 JP2683809B2 JP63132346A JP13234688A JP2683809B2 JP 2683809 B2 JP2683809 B2 JP 2683809B2 JP 63132346 A JP63132346 A JP 63132346A JP 13234688 A JP13234688 A JP 13234688A JP 2683809 B2 JP2683809 B2 JP 2683809B2
- Authority
- JP
- Japan
- Prior art keywords
- benzyl
- present
- pyrrolidone
- benzylaminopyrrolidines
- hydrogen
- 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
Landscapes
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は１−ベンジル−３−ベンジルアミノピロリジ
ン類の製造法に関する。１−ベンジル−３−ベンジルア
ミノピロ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 1-benzyl-3-benzylaminopyrrolidines. 1-Benzyl-3-benzylaminopyrrolidines are extremely important compounds as intermediates for pharmaceutical synthesis.
従来技術 従来、１−ベンジル−３−ベンジルアミノピロリジン
の製造法としては、1,2,4−トリ置換−ブタン（置換基
はハロゲン原子又はOR′（Ｒ′はアルカンスルホニル基
あるいは芳香族スルホニル基を示す））にベンジルアミ
ンを反応させる方法が知られている（特開昭62−8756
5）。PRIOR ART Conventionally, as a method for producing 1-benzyl-3-benzylaminopyrrolidine, 1,2,4-trisubstituted-butane (substituent is a halogen atom or OR '(R' is an alkanesulfonyl group or an aromatic sulfonyl group Is shown)) with benzylamine (JP-A-62-8756).
Five).
本発明が解決しようとする課題 この従来方法では、次の様な欠点があり、工業的製造
法としては十分なものとはいいがたい。Problems to be Solved by the Present Invention This conventional method has the following drawbacks and cannot be said to be sufficient as an industrial manufacturing method.
原料として1,2,4−トリハロゲノブタンを用いた場
合、このハロゲンによる腐食のために、安価な鉄製製造
装置を使用して１−ベンジルアミノピロリジンを製造し
がたく、製造装置に対する材質上の制限がある。さら
に、精製１−ベンジル−３−ベンジルアミノピロリジン
は反応液を抽出、濃縮、蒸留を行ない、次いで留出した
粗製品を再蒸留することによって得られる。このように
精製１−ベンジル−３−ベンジルアミノピロリジンを得
るには、かなり繁雑な処理を必要とする。When 1,2,4-trihalogenobutane is used as a raw material, it is difficult to produce 1-benzylaminopyrrolidine using an inexpensive iron manufacturing device due to the corrosion due to the halogen, There is a limit. Furthermore, purified 1-benzyl-3-benzylaminopyrrolidine can be obtained by extracting, concentrating and distilling the reaction solution, and then redistilling the distilled crude product. Thus, obtaining a purified 1-benzyl-3-benzylaminopyrrolidine requires a rather complicated process.
置換基がOR′、又はOR′とハロゲン原子である1,2,4
−トリ置換−ブタンを原料として用いた場合、精製１−
ベンジル−３−ベンジルアミノピロリジンを得るには、
1,2,4−トリハロゲノブタンの場合よりも一層繁雑な処
理を必要とする。すなわち、反応液を抽出、濃縮、蒸留
し、さらに得られた油状物を塩酸処理し、次いで抽出、
蒸留して精製１−ベンジル−３−ベンジルアミノピロリ
ジンを得ている。Substituents are OR 'or OR' and halogen atom 1,2,4
-When tri-substituted-butane is used as a raw material, purification 1-
To obtain benzyl-3-benzylaminopyrrolidine,
It requires a more intensive treatment than is the case with 1,2,4-trihalogenobutane. That is, the reaction solution was extracted, concentrated, and distilled, and the obtained oily substance was treated with hydrochloric acid, and then extracted,
Distillation gives purified 1-benzyl-3-benzylaminopyrrolidine.
本発明の目的は、かかる欠点を克服した１−ベンジル
−３−ベンジルアミノピロリジン類の新規な製造法を提
供することにある。An object of the present invention is to provide a novel method for producing 1-benzyl-3-benzylaminopyrrolidines which overcomes such drawbacks.
問題を解決すための手段 本発明者は鋭意研究を行なった結果、パラジウム触媒
の存在下に、１−ベンジル−３−ピロリドン類とベンジ
ルアミン及び水素を反応させると、反応液から触媒をろ
別後、単蒸留を行なうのみで、高純度の１−ベンジル−
３−ベンジルアミノピロリジン類を高収率で製造できる
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 Problem As a result of earnest studies by the present inventor, when 1-benzyl-3-pyrrolidones were reacted with benzylamine and hydrogen in the presence of a palladium catalyst, the catalyst was filtered off from the reaction solution. After that, simple distillation is performed, and high-purity 1-benzyl-
The inventors have found that 3-benzylaminopyrrolidines can be produced in high yield, and have completed the present invention.
すなわち、本発明はパラジウム触媒の存在下、一般式
（１）： （式中、Ｒは水素原子又は低級アルキル基を示す）で示
される１−ベンジル−３−ピロリドン類、ベンジルアミ
ン、及び水素を反応させることを特徴とする一般式
（２）： （式中、Ｒは前記と同じ）で示される１−ベンジル−３
−ベンジルアミノピロリジン類の製造法である。That is, the present invention provides a compound of the general formula (1): (Wherein R represents a hydrogen atom or a lower alkyl group), 1-benzyl-3-pyrrolidone, benzylamine, and hydrogen are reacted with each other, and a general formula (2): (In the formula, R is the same as above) 1-benzyl-3
-A method for producing benzylaminopyrrolidines.
本発明の一般式（１）及び（２）におけるＲは低級ア
ルキル基を示し、具体的にはメチル基、エチル基、プロ
ピル基、ブチル基、tert−ブチル基などの炭素数１〜４
のアルキル基が挙げられる。R in the general formulas (1) and (2) of the present invention represents a lower alkyl group, specifically, a methyl group, an ethyl group, a propyl group, a butyl group, a tert-butyl group and the like having 1 to 4 carbon atoms.
Alkyl group.
本発明の一般式（１）で示される１−ベンジル−３−
ピロリドン類としては、例えば１−ベンジル−３−ピロ
リドン、１−ベンジル−２−メチル−３−ピロリドン、
１−ベンジル−４−メチル−３−ピロリドン、１−ベン
ジル−４−エチル−３−ピロリドン、１−ベンジル−４
−ブチル−３−ピロリドンなどが挙げられる。1-benzyl-3-represented by the general formula (1) of the present invention
Examples of pyrrolidones include 1-benzyl-3-pyrrolidone, 1-benzyl-2-methyl-3-pyrrolidone,
1-benzyl-4-methyl-3-pyrrolidone, 1-benzyl-4-ethyl-3-pyrrolidone, 1-benzyl-4
-Butyl-3-pyrrolidone and the like can be mentioned.
本発明において、例えば出発原料の一つである１−ベ
ンジル−３−ピロリドンは一般にＮ−ベンジル−Ｎ−カ
ルボキシメチル−β−アラニン・ジアルキルエステルを
金属アルコキシドの存在下で環化し、次いで酸性条件下
で脱炭酸反応を行ない好収率で製造できる。In the present invention, for example, 1-benzyl-3-pyrrolidone, which is one of the starting materials, is generally cyclized from N-benzyl-N-carboxymethyl-β-alanine dialkyl ester in the presence of a metal alkoxide and then under acidic conditions. The decarboxylation reaction is carried out with and the product can be produced in good yield.
本発明で用いられるベンジルアミンの使用量は、一般
式（１）で表わされる１−ベンジル−３−ピロリドン類
に対して等モル以上あれば十分であるが、好ましくは１
〜５倍モルの範囲である。The amount of benzylamine used in the present invention is sufficient if it is equimolar or more to 1-benzyl-3-pyrrolidone represented by the general formula (1), but preferably 1
˜5 times the molar range.
本発明において、触媒としてパラジウム触媒を用いる
ことが重要である。他の水素化触媒として、例えばラネ
ーニッケルを用いると、パラジウム触媒に比べて本発明
の目的物を極めて低い収率でしか得ることができない。In the present invention, it is important to use a palladium catalyst as the catalyst. When Raney nickel, for example, is used as another hydrogenation catalyst, the target compound of the present invention can be obtained only in an extremely low yield as compared with the palladium catalyst.
本発明で用いられるパラジウム触媒は、工業的に市販
されているアルミナ、珪藻土、白土又は活性炭等に担持
させたものが挙げられる。又、パラジウム触媒にはニッ
ケル等の他の金属を含有してもよい。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１−ベンジル−３−ピロリド
ン類に対して0.1％〜20重量パーセントの範囲が好適で
ある。Examples of the palladium catalyst used in the present invention include those supported on industrially commercially available alumina, diatomaceous earth, clay or activated carbon. Further, the palladium catalyst may contain other metal such as nickel. The amount of the palladium catalyst used is not particularly limited, but for example, in the case of 5% palladium / carbon, the range of 0.1% to 20% by weight is preferable with respect to the starting 1-benzyl-3-pyrrolidones.
本発明において、反応温度は特に限定されないが、20
〜100℃の範囲が好適である。反応温度が20℃より低い
と反応速度が著しく遅くなり、工業的には不利となる。
又、反応温度は100℃より高いと反応速度は速いが高沸
点の副生成物ができ、収率が低下する。In the present invention, the reaction temperature is not particularly limited, but may be 20
A range of up to 100 ° C is preferred. When the reaction temperature is lower than 20 ° C, the reaction rate becomes remarkably slow, which is industrially disadvantageous.
On the other hand, if the reaction temperature is higher than 100 ° C, the reaction rate is fast, but a high boiling point by-product is formed, and the yield is lowered.
本発明は通常加圧下で反応を行ない、水素の分圧とし
ては0.5〜100kg/cm2の範囲が好ましい。所定の圧力を維
持するには外から供給する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できる。In the present invention, the reaction is usually carried out under pressure, and the partial pressure of hydrogen is preferably in the range of 0.5 to 100 kg / cm 2 . To maintain the prescribed pressure, control with hydrogen gas supplied from the outside,
If hydrogen is consumed and the internal pressure drops, replenish it with hydrogen,
A predetermined internal pressure can be maintained.
本発明の方法は反応溶媒を用いなくても実施できる
が、反応溶媒としてベンゼン、トルエン、キシレン等の
不活性溶媒の使用は、本発明の目的物の収率が向上し、
好ましい。The method of the present invention can be carried out without using a reaction solvent, but the use of an inert solvent such as benzene, toluene or xylene as a reaction solvent improves the yield of the object of the present invention,
preferable.
本発明において、反応時間は通常18時間程度で十分で
ある。In the present invention, a reaction time of about 18 hours is usually sufficient.
このようにして生成された１−ベンジル−３−ベンジ
ルアミノピロリジン類は、一般的な分離手段で容易に単
離精製できる。例えば、反応液をろ過してパラジウム触
媒を除去し、ろ液を単蒸留することにより単離精製され
る。The 1-benzyl-3-benzylaminopyrrolidines thus produced can be easily isolated and purified by a general separation means. For example, the reaction solution is filtered to remove the palladium catalyst, and the filtrate is subjected to simple distillation for isolation and purification.
実施例 以下に、実施例を挙げて本発明を具体的に説明する
が、本発明はこれらの実施例に限定されるものではな
い。Examples The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
実施例１ １リットルの電磁攪はん式オートクレーブに、１−ベ
ンジル−３−ピロリドン120g、ベンジルアミン220g及び
５％パラジウム／カーボン3gを仕込み、容器内を水素置
換した後、内温を50℃に昇温した。次に、同温で反応圧
20kg/cm2を保ちながら、８時間で水素18リットルを流入
した。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別した。ろ液を単蒸留したとこ
ろ、塔頂温度192〜193℃/1.0mmHgでGC純度99.3％の１−
ベンジル−３−ベンジルアミノピロリジン144gを得た。
この前後の留分を合わせると、１−ベンジル−３−ベン
ジルアミノピロリジンの収率は88％であった。Example 1 A 1-liter electromagnetic stirring type autoclave was charged with 120 g of 1-benzyl-3-pyrrolidone, 220 g of benzylamine and 3 g of 5% palladium / carbon, and after replacing the inside of the vessel with hydrogen, the internal temperature was raised to 50 ° C. The temperature was raised. Next, at the same temperature, reaction pressure
While maintaining 20 kg / cm 2 , 18 liters of hydrogen was introduced in 8 hours. After the reaction, the autoclave was cooled to room temperature, the contents were taken out, and the catalyst was filtered off. When the filtrate was subjected to simple distillation, the column top temperature was 192-193 ° C / 1.0 mmHg and the GC purity was 99.3%.
144 g of benzyl-3-benzylaminopyrrolidine were obtained.
When the fractions before and after this were combined, the yield of 1-benzyl-3-benzylaminopyrrolidine was 88%.
実施例２ 実施例１と同じ反応器に１−ベンジル−３−ピロリド
ン120g、ベンジルアミン220g、トルエン240g及び５％パ
ラジウム／カーボン3gを仕込み、容器内を水素置換した
後、内温50℃、内圧40kg/cm2を保ちながら水素18リット
ルを４時間で流入した。反応液を実施例１と同様に処理
して、GC純度99.5％の１−ベンジル−３−ベンジルアミ
ノピロリジン170gを得て、その前後の留分を合わせると
１−ベンジル−３−ベンジルアミノピロリジンの収率は
95.0％となった。Example 2 The same reactor as in Example 1 was charged with 120 g of 1-benzyl-3-pyrrolidone, 220 g of benzylamine, 240 g of toluene and 3 g of 5% palladium / carbon, and after the inside of the vessel was replaced with hydrogen, the internal temperature was 50 ° C. and the internal pressure was 50 ° C. While maintaining 40 kg / cm 2 , 18 liters of hydrogen were flowed in in 4 hours. The reaction mixture was treated in the same manner as in Example 1 to obtain 170 g of 1-benzyl-3-benzylaminopyrrolidine having a GC purity of 99.5%, and the fractions before and after it were combined to give 1-benzyl-3-benzylaminopyrrolidine. The yield is
It was 95.0%.
実施例３ １−ベンジル−３−ピロリドンの代わりに、１−ベン
ジル−４−メチル−３−ピロリドン129gを使用した他
は、実施例１と同様に操作し、GC純度99.0％の１−ベン
ジル−４−メチル−３−ベンジルアミノピロリジン153g
（収率80％）を得た。Example 3 1-benzyl-3-pyrrolidone 1-benzyl-3-methyl-3-pyrrolidone was used instead of 1-benzyl-3-pyrrolidone in the same manner as in Example 1 except that 129 g of 1-benzyl-4-methyl-3-pyrrolidone was used. 153 g of 4-methyl-3-benzylaminopyrrolidine
(80% yield).
発明の効果 本発明の方法によれば、従来技術に比べて極めて簡単
な分離精製手段で、高純度１−ベンジル−３−ベンジル
アミノピロリジン類が高収率で得ることができ、又、従
来技術のように出発原料にハロゲン化物を用いないの
で、製造装置の材質的制限がなく、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, highly pure 1-benzyl-3-benzylaminopyrrolidines can be obtained in high yield by a very simple separation and purification means as compared with the prior art. As described above, since a halide is not used as a starting material, there is no limitation on the material of the manufacturing apparatus, and the present invention is industrially very useful.
Claims (1)
される１−ベンジル−３−ピロリドン類、ベンジルアミ
ン及び水素を反応させることを特徴とする一般式
（２）： （式中、Ｒは前記と同じ）で示される１−ベンジル−３
−ベンジルアミノピロリジン類の製造法。1. A compound represented by the general formula (1) in the presence of a palladium catalyst: (Wherein R represents a hydrogen atom or a lower alkyl group), 1-benzyl-3-pyrrolidone, benzylamine and hydrogen are reacted with each other. (In the formula, R is the same as above) 1-benzyl-3
-A method for producing benzylaminopyrrolidines.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63132346A JP2683809B2 (en) | 1988-05-30 | 1988-05-30 | Process for producing 1-benzyl-3-benzylaminopyrrolidines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63132346A JP2683809B2 (en) | 1988-05-30 | 1988-05-30 | Process for producing 1-benzyl-3-benzylaminopyrrolidines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01301655A JPH01301655A (en) | 1989-12-05 |
| JP2683809B2 true JP2683809B2 (en) | 1997-12-03 |
Family
ID=15079197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63132346A Expired - Lifetime JP2683809B2 (en) | 1988-05-30 | 1988-05-30 | Process for producing 1-benzyl-3-benzylaminopyrrolidines |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2683809B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008050307A (en) * | 2006-08-25 | 2008-03-06 | Koei Chem Co Ltd | Method for producing piperidine compound |
-
1988
- 1988-05-30 JP JP63132346A patent/JP2683809B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01301655A (en) | 1989-12-05 |
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