JP3721540B2 - Pyrrolidine derivatives - Google Patents
Pyrrolidine derivatives Download PDFInfo
- Publication number
- JP3721540B2 JP3721540B2 JP34110094A JP34110094A JP3721540B2 JP 3721540 B2 JP3721540 B2 JP 3721540B2 JP 34110094 A JP34110094 A JP 34110094A JP 34110094 A JP34110094 A JP 34110094A JP 3721540 B2 JP3721540 B2 JP 3721540B2
- Authority
- JP
- Japan
- Prior art keywords
- residue
- phthalimide
- formula
- ethylpyrrolidine
- succinimide
- 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
- HZWBHAJYUYKGCR-UHFFFAOYSA-N CCN1C2(CC2)CC2(CC2)C1 Chemical compound CCN1C2(CC2)CC2(CC2)C1 HZWBHAJYUYKGCR-UHFFFAOYSA-N 0.000 description 1
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
【0001】
【発明の属する技術分野】
本発明は、ピロリジン誘導体およびその製法に関する。また、本発明はこのピロリジン誘導体から、医療用医薬品としての有用性を有する化合物を合成するために使用される原料化合物、即ち、(2S,4S)−4−アミノ−2−ヒドロキシアルキル−N−エチルピロリジン(特に、(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジン)を製造する方法に関する。
【0002】
【従来の技術】
従来、(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジンは、(2S,4R)−4−アルキル(又はアリール)スルホニルオキシ−2−アルコキシカルボニル−N−エチルピロリジンをアジド化し、(2S,4S)−4−アジド−2−アルコキシカルボニル−N−エチルピロリジンに変え、次いで還元して(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジンを得るという方法によって造られていた。
【0003】
しかしながら、この方法に依る場合、途中経由するアジド化合物が爆発性を有するため、取り扱いが面倒であることに加え、常に危険性が伴っているため工業的製造にあっては避けたいところである。アミノ化合物の合成方法には既に広く知られているものとして、ハロゲン化物又はトシル化物等にフタルイミドカリウム又はコハク酸イミドカリウムを反応させて、フタルイミド誘導体又はコハク酸イミド誘導体とし、これを加水分解する方法があるが、本発明が最終的に目的としている化合物(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジンの合成においては、通常実施されている方法に依って、フタルイミド誘導体又はコハク酸イミド誘導体である式(I)で表される化合物、即ち、
【0004】
【化5】
【0005】
で示される化合物を得ることはできなかった。
【0006】
【発明が解決しようとする課題】
本発明は、医療用医薬品として有用な化合物の原料として使用される(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジンを製造するに際し、製造上の安全性を確保するために重要な役割を果たす中間体たる式(I)で表される新規化合物とその製造方法、及び該中間体から前記アミノピロリジンを製造する方法をも提供するものである。
【0007】
【課題を解決するための手段】
この発明において提供される(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジンの製造上の重要な新規中間体は以下の式(I):
【0008】
【化6】
【0009】
(式中、Bはイミド残基を、Rは低級アルキル基を示す)で表される。
この化合物の製造方法は以下に述べるとおりである。
【0010】
即ち、式(II):
【0011】
【化7】
【0012】
(式中、Xはハロゲン原子、アルキルスルホニルオキシ基またはアリールスルホニルオキシ基を、Rは低級アルキル基を示す)で示される化合物に、触媒の存在下、フタル酸イミドカリウム又はコハク酸イミドカリウムを反応させる。
【0013】
【発明の実施の形態】
本発明に使用される触媒としては、第四級アンモニウム塩、例えば、硫酸水素テトラブチルアンモニウム、硫酸水素テトラプロピルアンモニウム、硫酸水素テトラエチルアンモニウム、ベンジルトリエチルアンモニウムクロリド、ベンジルトリブチルアンモニウムクロリド、ベンジルトリエチルアンモニウムブロミドが挙げられる。
【0014】
反応に使用される溶媒としては、酢酸エチル、酢酸ブチル、ジメチルホルムアミド、ジメチルスルホキシド、クロルベンゼン、テトラヒドロフラン、ジオキサン等が挙げられ、室温及至加熱下に反応を進行させることができる。
【0015】
かくて得られた式(I)で示される化合物は還元反応に付され、更に加溶媒分解を施されることにより(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジンを与える。
【0016】
ここで還元反応のために使用される還元剤としては、水素化硼素ナトリウム、水素化アルミニウムリチウムが挙げられる。これら還元剤の使用は、ピロリジン環の4位アミノ化の準備と同時に2位におけるヒドロキシメチル化を可能とする点において特に有効である。このようにして得られた還元生成体は加溶媒分解に付されるが、当該加溶媒分解は酸又はアルカリの存在下に行われる。使用される酸としては、ベンゼンスルホン酸、p−トルエンスルホン酸、塩酸、硫酸等が挙げられ、アルカリとしてはアルコラート(メチラート、エチラート)、苛性ソーダ、苛性カリ等が挙げられる。加溶媒分解は低級アルコール、水中で都合よく行われる。アミノ基への変換とヒドロキシメチル基への変換を二段階に分けて行うことが可能であることは言うまでもない。
【0017】
【実施例】
以下、実施例を記述して本発明を具体的に詳述する。
【0018】
実施例1
(2S,4R)−4−メタンスルホニルオキシ−2−エトキシカルボニル−N−エチルピロリジン50g,フタルイミドカリウム41.9g,硫酸水素テトラ−n−ブチルアンモニウム16.0gを酢酸エチル300ml中還流下16時間撹拌した。冷却後、水150mlと48%水酸化ナトリウム5.0gとからなる水溶液を加え分液した。有機層を分取し、水洗し、塩酸溶液(濃塩酸19.65gと水100mlからなる溶液)で酸性とし、水層を分取した。当該水層を酢酸エチル150ml、炭酸カリウム26.05gと共に振盪し酢酸エチル層を分取し、10%食塩水溶液で洗浄後、減圧下濃縮し、油状物を得た。シクロヘキサンから結晶化し(2S,4S)−4−フタルイミド−2−エトキシカルボニル−N−エチルピロリジンを得た。
【0019】
得量 37.85g(収率63.3%) m.p 63〜67℃
TLC Rf0.6(トルエン:酢酸エチル 1:1)
NMRスペクトル(CDCl 3 )δ:
1.10(3H,t), 1.30(3t,t)
2.0〜4.0(7H,m), 4.23(2H,q)
4.80(1H,m), 7.83(4H,s)
【0020】
実施例2
(2S,4S)−4−フタルイミド−2−エトキシカルボニル−N−エチルピロリジン30.0gをエチルアルコール90mlに溶かし、氷冷下水素化硼素ナトリウム8.98gを加え、室温まで上げ48時間撹拌した。反応液に水90ml、塩化メチレン90mlを加えて分液し、塩化メチレン層を分取し、食塩水で洗浄した。減圧濃縮し、残渣にイソプロピルアルコール150ml、p−トルエンスルホン酸1水和物36.1gを加え1時間加熱還流した後、氷冷下一夜撹拌した。析出した結晶を濾取し、エチルアルコールで再結晶し(2S,4S)−4−アミノ−2−ヒドロキシメチル−N−エチルピロリジン・二p−トルエンスルホン酸塩を得た。
【0021】
得量 38.31g(収率82.7%) m.p 204〜205℃
NMRスペクトル(DMSO−d6)δ:
1.20(3H,t), 2.30(6H,s)
7.12(2H,d), 7.54(2H,d)
IR(neat):
3245,3078,684,569cm−1
TLC
Rf0.3(AcOEt:AcOH:H2O 3:1:1)
【0022】
比較例1
実施例1において使用した硫酸水素テトラ−n−ブチルアンモニウムを使用しないほかは実施例1と同様の操作を試みたが、目的とするフタルイミド誘導体を得ることはできず、原料回収に終わった。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pyrrolidine derivative and a method for producing the same. The present invention also provides a raw material compound used for synthesizing a compound having utility as a medical drug from this pyrrolidine derivative , that is, (2S, 4S) -4-amino-2-hydroxyalkyl-N- The present invention relates to a method for producing ethylpyrrolidine (in particular, (2S, 4S) -4-amino-2-hydroxymethyl-N-ethylpyrrolidine ).
[0002]
[Prior art]
Conventionally, (2S, 4S) -4-amino-2-hydroxymethyl-N-ethylpyrrolidine is azide of (2S, 4R) -4-alkyl (or aryl) sulfonyloxy-2-alkoxycarbonyl-N-ethylpyrrolidine. And converted to (2S, 4S) -4-azido-2-alkoxycarbonyl-N-ethylpyrrolidine and then reduced to give (2S, 4S) -4-amino-2-hydroxymethyl-N-ethylpyrrolidine. It was built by the method.
[0003]
However, when this method is used, since the azide compound that passes along the way is explosive, it is difficult to handle in addition to being troublesome to handle, and it is always dangerous. A method of hydrolyzing a phthalimide derivative or a succinimide derivative by reacting a halide or tosylate with phthalimide potassium or succinimide potassium as a widely known method for synthesizing amino compounds However, in the synthesis of the compound (2S, 4S) -4-amino-2-hydroxymethyl-N-ethylpyrrolidine which is the final object of the present invention, a phthalimide derivative is used in accordance with a commonly practiced method. Or a compound of formula (I) which is a succinimide derivative,
[0004]
[Chemical formula 5]
[0005]
It was not possible to obtain a compound represented by
[0006]
[Problems to be solved by the invention]
The present invention is used as a raw material for compounds useful as medical drugs (2S, 4S) -4- amino-2-hydroxymethyl--N- ethylpyrrolidine the manufacturing to Runisaishi, ensure safety in production The present invention also provides a novel compound represented by the formula (I), an intermediate that plays an important role in order to achieve the above, a method for producing the same, and a method for producing the aminopyrrolidine from the intermediate.
[0007]
[Means for Solving the Problems]
Ru is provided in the present invention (2S, 4S) -4- important novel intermediates in the preparation of amino-2-hydroxymethyl--N- Echirupiroriji down the following formula (I):
[0008]
[Chemical 6]
[0009]
(Wherein, B is an imide residue, R represents a lower alkyl group) represented by.
The method for producing this compound is as described below.
[0010]
That is, formula (II) :
[0011]
[Chemical 7]
[0012]
(Wherein, X represents a halogen atom , an alkylsulfonyloxy group or an arylsulfonyloxy group, and R represents a lower alkyl group) is reacted with potassium phthalimide or succinimide potassium in the presence of a catalyst. Let
[0013]
DETAILED DESCRIPTION OF THE INVENTION
The catalyst used in the present invention, quaternary ammonium salts, for example, tetrabutylammonium hydrogen sulfate, hydrogen tetrapropylammonium sulfate, hydrogen tetraethylammonium sulfate, benzyltriethylammonium chloride, benzyl tributyl ammonium chloride, benzyl triethyl ammonium bromide Can be mentioned.
[0014]
The solvent to be used in the reaction, ethyl acetate, butyl acetate, dimethylformamide, dimethyl sulfoxide, chlorobenzene, tetrahydrofuran, dioxane and the like, can make progress the reaction under heating room及至.
[0015]
The compound represented by the formula (I) thus obtained is subjected to a reduction reaction and further subjected to solvolysis to give (2S, 4S) -4-amino-2-hydroxymethyl-N-ethylpyrrolidine. give.
[0016]
Here, examples of the reducing agent used for the reduction reaction include sodium borohydride and lithium aluminum hydride. The use of these reducing agents is particularly effective in allowing hydroxymethylation at the 2-position simultaneously with preparation for 4-position amination of the pyrrolidine ring. Although thus obtained reduction product thereof is subjected to solvolysis, the solvolysis is Ru carried out in the presence of an acid or alkali. Examples of the acid used include benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, and the like. Examples of the alkali include alcoholate (methylate, ethylate), caustic soda, and caustic potash. Solvolysis is conveniently performed in lower alcohols and water . It goes without saying that conversion to an amino group and conversion to a hydroxymethyl group can be carried out in two stages.
[0017]
【Example】
Hereinafter , the present invention will be described in detail with reference to examples.
[0018]
Example 1
50 g of (2S, 4R) -4-methanesulfonyloxy-2-ethoxycarbonyl-N-ethylpyrrolidine, 41.9 g of potassium phthalimide, and 16.0 g of tetra-n-butylammonium hydrogen sulfate were stirred in 300 ml of ethyl acetate under reflux for 16 hours. did. After cooling, an aqueous solution consisting of 150 ml of water and 5.0 g of 48% sodium hydroxide was added for liquid separation. The organic layer was separated, washed with water, acidified with a hydrochloric acid solution (a solution composed of 19.65 g of concentrated hydrochloric acid and 100 ml of water), and the aqueous layer was separated. The aqueous layer was shaken with 150 ml of ethyl acetate and 26.05 g of potassium carbonate to separate the ethyl acetate layer, washed with a 10% aqueous sodium chloride solution, and concentrated under reduced pressure to obtain an oily substance. Crystallization from cyclohexane gave (2S, 4S) -4-phthalimido-2-ethoxycarbonyl-N-ethylpyrrolidine.
[0019]
Yield 37.85 g (yield 63.3%) m. p 63-67 ° C
TLC Rf 0.6 (toluene: ethyl acetate 1: 1)
NMR spectrum (CDCl 3 ) δ:
1.10 (3H, t), 1.30 (3 t, t)
2.0-4.0 (7H, m), 4.23 (2H, q)
4.80 (1H, m), 7.83 (4H, s)
[0020]
Example 2
30.0 g of (2S, 4S) -4-phthalimido-2-ethoxycarbonyl-N-ethylpyrrolidine was dissolved in 90 ml of ethyl alcohol, 8.98 g of sodium borohydride was added under ice cooling, and the mixture was warmed to room temperature and stirred for 48 hours. Water 90ml to the reaction mixture, and thereto are added methylene chloride 90ml, was separated The methylene chloride layer was washed with brine. After concentration under reduced pressure , 150 ml of isopropyl alcohol and 36.1 g of p-toluenesulfonic acid monohydrate were added to the residue, heated under reflux for 1 hour, and then stirred overnight under ice cooling. The precipitated crystals were collected by filtration and recrystallized with ethyl alcohol to obtain (2S, 4S) -4-amino-2-hydroxymethyl-N-ethylpyrrolidine · 2p-toluenesulfonate.
[0021]
Yield 38.31 g (Yield 82.7%) m. p 204-205 ° C
NMR spectrum (DMSO-d6) δ:
1.20 (3H, t), 2.30 (6H, s)
7.12 (2H, d), 7.54 (2H, d)
IR (neat):
3245, 3078, 684, 569 cm-1
TLC
Rf0.3 (AcOEt: AcOH: H2O 3: 1: 1)
[0022]
Comparative Example 1
The same operation as in Example 1 was attempted except that tetra-n-butylammonium hydrogen sulfate used in Example 1 was not used.
Claims (4)
で示されるピロリジン誘導体。Formula (I):
A pyrrolidine derivative represented by:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP34110094A JP3721540B2 (en) | 1994-12-29 | 1994-12-29 | Pyrrolidine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP34110094A JP3721540B2 (en) | 1994-12-29 | 1994-12-29 | Pyrrolidine derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH08188571A JPH08188571A (en) | 1996-07-23 |
JP3721540B2 true JP3721540B2 (en) | 2005-11-30 |
Family
ID=18343265
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP34110094A Expired - Lifetime JP3721540B2 (en) | 1994-12-29 | 1994-12-29 | Pyrrolidine derivatives |
Country Status (1)
Country | Link |
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JP (1) | JP3721540B2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007153789A (en) * | 2005-12-05 | 2007-06-21 | Mitsui Chemicals Inc | Method for producing optically active 3-aminopyrolidine derivative |
JP2008001611A (en) * | 2006-06-20 | 2008-01-10 | Mitsui Chemicals Inc | Method for producing 3r-aminopyrrolidine derivative |
-
1994
- 1994-12-29 JP JP34110094A patent/JP3721540B2/en not_active Expired - Lifetime
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Publication number | Publication date |
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JPH08188571A (en) | 1996-07-23 |
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