JPS609497B2 - Method for producing 5-oxo-2-(β-haloethyl)pyrrolidine derivative - Google Patents
Method for producing 5-oxo-2-(β-haloethyl)pyrrolidine derivativeInfo
- Publication number
- JPS609497B2 JPS609497B2 JP1695976A JP1695976A JPS609497B2 JP S609497 B2 JPS609497 B2 JP S609497B2 JP 1695976 A JP1695976 A JP 1695976A JP 1695976 A JP1695976 A JP 1695976A JP S609497 B2 JPS609497 B2 JP S609497B2
- Authority
- JP
- Japan
- Prior art keywords
- oxo
- haloethyl
- pyrrolidine
- producing
- chloroform
- 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
Links
Landscapes
- Pyrrole Compounds (AREA)
Description
本発明は、５ーオキソー２一（８−ハロェチル）ピロリ
ジン誘導体の製造法に関する。
更に詳しくは、５−オキソー２一ピロリジンェタノール
誘導体とハロゲン化剤とを反応せしめ５−オキソ−２−
（８ーハロェチル）ピロリジン謙導体を製造する方法に
関する。
本発明において用いられる出発原料である５ーオキソ−
２−ピロリジンェタノール譲導体は新規化合物であり、
ま０た、生成物である５−オキソー２一（８−ハロェチ
ル）ピ。リジンも新規化合物である。本発明者らは、医
薬品の中間原料として、あるいは立体化学の研究上にお
いても重要な５ーオキソー２−（３ーハロェチル）ピロ
リジン類の工業タ的に有利な製造法を見出すべく鋭意研
究した結果、５ーオキソー２一ピロリジンェタノール譲
導体とハロゲン化剤を反応せしめることにより、高収率
で５−オキソ−２−（８−ハロェチル）ピロリジン誘導
体が製造しうろことを究明し、本発明０に到達したもの
である。
即ち、本発明は下記式〔１〕
〔式中、Ｒは置換又は未置換フェニル、Ｑ−メチルベン
ジル、Ｑ−エチルベンジル、炭素数１〜４のアルキル基
を示す。
〕で表わされる５−オキソピロリジンェタノール誘導体
をハロゲン化剤と反応せしめることを特徴とする下記式
The present invention relates to a method for producing 5-oxo2-(8-haloethyl)pyrrolidine derivatives. More specifically, a 5-oxo-2-pyrrolidine ethanol derivative and a halogenating agent are reacted to form 5-oxo-2-
The present invention relates to a method for producing a (8-haloethyl)pyrrolidine conductor. 5-oxo- which is the starting material used in the present invention
2-pyrrolidineethanol derivative is a new compound,
Also, the product 5-oxo2-(8-haloethyl)pi. Lysine is also a new compound. The present inventors have conducted intensive research to find an industrially advantageous manufacturing method for 5-oxo-2-(3-haloethyl)pyrrolidines, which are important as intermediate raw materials for pharmaceuticals and in stereochemical research. - It has been discovered that 5-oxo-2-(8-haloethyl)pyrrolidine derivatives can be produced in high yield by reacting an oxo-2-pyrrolidine ethanol derivative with a halogenating agent, and the present invention 0 has been achieved. It is something. That is, the present invention provides the following formula [1] [wherein R represents substituted or unsubstituted phenyl, Q-methylbenzyl, Q-ethylbenzyl, or an alkyl group having 1 to 4 carbon atoms. The following formula is characterized in that the 5-oxopyrrolidine ethanol derivative represented by ] is reacted with a halogenating agent.
〔０〕〔式中、Ｒの定義は上記に同じ、×は塩素、臭素
、沃素原子を示す。
〕で表わされる５ーオキソー２一（８ーハロェチル）ピ
ロリジン誘導体の製造法である。
本発明方法で用いられる５ーオキソピロリジンェタノー
ル誘導体は、上記式〔１〕で表わされるものであり、こ
れらはいずれも新規化合物である。
これらの化合物は、いずれもピロリジン環の２−位の炭
素は不整炭素であって、従って、本発明方法ではそれぞ
れの化合物につき、光学活性体あるいはラヒミ体のいず
れをも使用することができる。式中、Ｒは置換又は未置
換フヱニル、Ｑーメチルベンジル、Ｑ−エチルベンジル
又は炭素数１〜４のアルキル基である。
置換フェニル基とは、例えば、ｐークロルフェニル、Ｐ
ーフロモフエニル、Ｐ−メトキシフエニル、ｐ−メチル
フエニル、ｐートリフルオロメチルフエニル、０−クロ
。
フエニル、０−ブロモフエニル、〇ーメトキシフヱニル
、０ーメチルフエニル、０−トリフルオロメチルフェニ
ル等であり、又、炭素数１〜４のアルキル基とは、例え
ば、メチル、エチル、ｎープロピル、ｌｓｏ−プロピル
、ｎーブチル、ｌｓｏ−ブチル、企てｔ−ブチル等であ
る。これらの５ーオキソピロリジンェタノール誘導体は
、相当する５−オキソ−２−ピロリジン酢酸又はそのェ
ステルを選択的に還元することにより容易に製造するこ
とができる。
本発明方法は、かかる５ーオキソピロリジンェタノール
誘導体をハロゲン化剤と反応せしめることにより行なわ
れる。
ハ。
ゲン化剤とは、５−オキソピロリジンェタ／−ル誘導体
のヒドロキシヱチル基をハロェチル基に変換しうるもの
であり、例えば、化学式で示せば、ＳＯＣ１２、ｐｈ３
ＰＣ１２（ｐｈはフェニル基を表わす。以下同じ）、ｐ
Ｃ１５、ＣＣ１４一ｐｈ３Ｐ、ＣＢｒ４−ｐｈ３Ｐ、Ｐ
Ｂｒ３、（ＣＨ３）２ＳＢｒ２、Ｃ比１一ｐｈ３Ｐ、等
をあげることができる。
反応溶媒としては、例えば、エーテル、テトラヒドロフ
ラン、ジオキサン、クロロホルム、塩化メチレン、四塩
化炭素等の不活性有機溶媒が好ましく用いられる。
反応は約５００なし、し反応溶媒の沸点までの温度にて
好ましく行なわれるが、反応溶媒の沸点近傍の温度で行
うのが特に好ましい。
本発明方法によれば、下記式〔ｍ
〔式中、Ｒの定義は上記に同じ、Ｘはハロゲン化剤より
導入されたハロゲン原子で、塩素、臭素又は沃素原子を
表わす。
〕で表わされる５ーオキソ−２−（８ーハロェチル）ピ
ロリジン譲導体が得られる。
反応混合物より、この目的物を単離するには、蒸留ある
いはクロマトグラフィーによればよい。
以下、実施例をあげ、本発明方法を詳述するが、本発明
方法はかかる実施例により、何ら限定されるものではな
い。実施例 １
ｄ１一１ーメチルー５−オキソ−２ーピロリジンエタノ
ール（１．６３夕）をクロロホルム（２０奴）に溶解し
、水浴にて約５℃に氷冷しながら塩化チオニル（１．０
の‘）を滴下した。
次で、氷格を除き２時間加熱還流を行った。反応液を氷
水（７０の【）中に注ぎクロロホルム層を分離し、水層
を２回クロロホルムで抽出し、クロロホルム層を合して
５％重曹水で３回洗浄した。クロロホルム層を無水硫酸
マグネシウムで乾燥し、得られたオイルを蒸留に付して
精製ｄｌ−１−メチル−５ーオキソ−２−８−クロロェ
チルピロリジン（１．３７夕、収率７５％）を得た。こ
の物の物理データは次の通りであり、よって目的物と同
定した。ｂ．ｐ．：７８〜８０００／０．０２側Ｈｇ、
ＩＲ（Ｎｅａｔ）２９５０・１６８０・１４５０・１３
００・１１２０狐‐ＩＮＭＲ（６０ＭＨｚ、ＣＤＣ１３
、ＴＭＳよりの６値）１．５８〜２．２８（細、複雑な
ｍ）、２．７４（汎、ｓ）、
３．５５（岬、ｍ）、
Ｎ購ｓｓ（７企ｖ、ｍ／ｅ）
１６１（Ｍ＋）、１６３（Ｍ十十２）、９８（１００％
）、実施例 ２ｄ一（十）−１ーメチル−５−オキソ−
２ーピロリジンエタ／−ル（４．０夕）をクロロホルム
（５０舷）に溶解し、約５℃に氷冷しつつ三臭化リン（
７．６多）のクロロホルム（１０の【）溶液を滴下した
。
次で氷俗を除き３時間加熱還流した。反応液を１００の
‘の氷水に注ぎ、クロロホルム層を分離し、水層はクロ
ロホルムで３回抽出し、クロロホルム層を合し５％重曹
水で３回洗浄した。無水硫酸マグネシウムで乾燥した後
、溶媒を留去して得られたオイルを蒸留に付して精製ｄ
−（十）−１ーメチルー２ーフロモエチル−５ーオキソ
ーピロリジン（３．５夕、収率６２％）を得た。この物
の物理データは次に示す通りであり、よって目的物と同
定した。ｂ．ｐ．：７４〜８０ｏ０／０．０５側Ｈｇ〔
Ｑ〕客＝十４１‐５０（Ｃ２日５〇日、Ｃ＝１）ＩＲ（
Ｎｅａｔ、弧‐１）２９５０・１６７０・１４００・１
４９０・１２６ふ１１１５、ＮＭＲ（１００ＭＨｚ、Ｃ
ＤＣ１３、ＴＭＳよりの６値）、１．６０〜２．３３（
細、複雑なｍ）、２．８２（３日、ｓ）、
３．４４（が、ｍ）、
３．７２（ＩＨ、ｍ）、
Ｎ船ｓ（７企ｖ；ｍ／ｅ）[0] [In the formula, the definition of R is the same as above, and x represents a chlorine, bromine, or iodine atom. ] This is a method for producing a 5-oxo2-(8-haloethyl)pyrrolidine derivative represented by the following formula. The 5-oxopyrrolidine ethanol derivatives used in the method of the present invention are represented by the above formula [1], and all of these are new compounds. In all of these compounds, the 2-position carbon of the pyrrolidine ring is an asymmetric carbon, and therefore, in the method of the present invention, either the optically active form or the Rahimi form of each compound can be used. In the formula, R is substituted or unsubstituted phenyl, Q-methylbenzyl, Q-ethylbenzyl, or an alkyl group having 1 to 4 carbon atoms. The substituted phenyl group is, for example, p-chlorophenyl, P
-fromophenyl, p-methoxyphenyl, p-methylphenyl, p-trifluoromethylphenyl, 0-chloro. phenyl, 0-bromophenyl, 〇-methoxyphenyl, 0-methylphenyl, 0-trifluoromethylphenyl, etc., and alkyl groups having 1 to 4 carbon atoms include, for example, methyl, ethyl, n-propyl, lso- Propyl, n-butyl, lso-butyl, tert-butyl, and the like. These 5-oxopyrrolidine ethanol derivatives can be easily produced by selectively reducing the corresponding 5-oxo-2-pyrrolidine acetic acid or its ester. The method of the present invention is carried out by reacting such a 5-oxopyrrolidine ethanol derivative with a halogenating agent. Ha. The genifying agent is one that can convert the hydroxyethyl group of the 5-oxopyrrolidine ethyl derivative into a haloethyl group, and for example, the chemical formula is SOC12, ph3
PC12 (ph represents a phenyl group. The same applies below), p
C15, CC14-ph3P, CBr4-ph3P, P
Examples include Br3, (CH3)2SBr2, C ratio 1-ph3P, and the like. As the reaction solvent, for example, inert organic solvents such as ether, tetrahydrofuran, dioxane, chloroform, methylene chloride, and carbon tetrachloride are preferably used. The reaction is preferably carried out at a temperature of about 500 ℃ up to the boiling point of the reaction solvent, and is particularly preferably carried out at a temperature near the boiling point of the reaction solvent. According to the method of the present invention, the following formula [m] [wherein the definition of R is the same as above, and X is a halogen atom introduced from a halogenating agent and represents a chlorine, bromine or iodine atom. ] A 5-oxo-2-(8-haloethyl)pyrrolidine derivative is obtained. The target product can be isolated from the reaction mixture by distillation or chromatography. Hereinafter, the method of the present invention will be described in detail with reference to Examples, but the method of the present invention is not limited in any way by these Examples. Example 1 d1-Methyl-5-oxo-2-pyrrolidine Ethanol (1.63 μm) was dissolved in chloroform (20 μg), and thionyl chloride (1.0
') was dropped. Next, the ice rack was removed and the mixture was heated under reflux for 2 hours. The reaction solution was poured into ice water (70%) to separate the chloroform layer, the aqueous layer was extracted twice with chloroform, and the chloroform layers were combined and washed three times with 5% aqueous sodium bicarbonate. The chloroform layer was dried over anhydrous magnesium sulfate, and the resulting oil was distilled to give purified dl-1-methyl-5-oxo-2-8-chloroethylpyrrolidine (1.37 pm, yield 75%). Obtained. The physical data of this object are as follows, and it was therefore identified as the target object. b. p. :78~8000/0.02 side Hg,
IR (Neat) 2950/1680/1450/13
00.1120 Fox-INMR (60MHz, CDC13
, 6 values from TMS) 1.58 to 2.28 (fine, complex m), 2.74 (wide, s), 3.55 (misaki, m), N purchase ss (7 plans, m/ e) 161 (M+), 163 (M112), 98 (100%
), Example 2d-1(10)-1-methyl-5-oxo-
Dissolve 2-pyrrolidine ethyl alcohol (4.0 m) in chloroform (50 m) and add phosphorus tribromide (2-pyrrolidine ethanol) to chloroform (50 m) while ice-cooling to approximately 5°C.
A solution of 7.6%) in chloroform (10%) was added dropwise. Next, the ice was removed and the mixture was heated under reflux for 3 hours. The reaction solution was poured into 100 ml of ice water, the chloroform layer was separated, the aqueous layer was extracted three times with chloroform, and the chloroform layers were combined and washed three times with 5% aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting oil was purified by distillation.
-(10)-1-methyl-2-furomoethyl-5-oxopyrrolidine (3.5 hours, yield 62%) was obtained. The physical data of this object are as shown below, and it was therefore identified as the target object. b. p. :74~80o0/0.05 side Hg [
Q] Customer = 141-50 (C2 50th, C = 1) IR (
Neat, arc-1) 2950・1670・1400・1
490・126fu1115, NMR (100MHz, C
DC13, 6 values from TMS), 1.60 to 2.33 (
Thin, complicated m), 2.82 (3 days, s), 3.44 (ga, m), 3.72 (IH, m), N ships (7 plans; m/e)
Claims (1)
ジル、α−エチルベンジル、炭素数１〜４のアルキル基
を示す。 〕で表わされる５−オキソピロリジンエタノール誘導体
をハロゲン化剤と反応せしめることを特徴とする下記式
〔II〕▲数式、化学式、表等があります▼ 〔式中、Ｒの定義は上記に同じ、Ｘは塩素、臭素、沃素
原子を示す。 〕で表わされる５−オキソ−２−（β−ハロエチル）ピ
ロリジン誘導体の製造法。[Claims] 1 The following formula [I] ▲ Numerical formulas, chemical formulas, tables, etc. Indicates an alkyl group. [In the formula, the definition of R is the same as above, represents chlorine, bromine, and iodine atoms. ] A method for producing a 5-oxo-2-(β-haloethyl)pyrrolidine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1695976A JPS609497B2 (en) | 1976-02-20 | 1976-02-20 | Method for producing 5-oxo-2-(β-haloethyl)pyrrolidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1695976A JPS609497B2 (en) | 1976-02-20 | 1976-02-20 | Method for producing 5-oxo-2-(β-haloethyl)pyrrolidine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS52100466A JPS52100466A (en) | 1977-08-23 |
| JPS609497B2 true JPS609497B2 (en) | 1985-03-11 |
Family
ID=11930637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1695976A Expired JPS609497B2 (en) | 1976-02-20 | 1976-02-20 | Method for producing 5-oxo-2-(β-haloethyl)pyrrolidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS609497B2 (en) |
-
1976
- 1976-02-20 JP JP1695976A patent/JPS609497B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS52100466A (en) | 1977-08-23 |
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