JPH09263578A - Production of optically active 1-benzyl-3-hydroxypyrrolidine - Google Patents
Production of optically active 1-benzyl-3-hydroxypyrrolidineInfo
- Publication number
- JPH09263578A JPH09263578A JP10396596A JP10396596A JPH09263578A JP H09263578 A JPH09263578 A JP H09263578A JP 10396596 A JP10396596 A JP 10396596A JP 10396596 A JP10396596 A JP 10396596A JP H09263578 A JPH09263578 A JP H09263578A
- Authority
- JP
- Japan
- Prior art keywords
- benzyl
- hydroxypyrrolidine
- optically active
- lactic acid
- acid
- 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.)
- Pending
Links
Landscapes
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、光学分割による光
学活性１−ベンジル−３−ヒドロキシピロリジンの製造
法に関する。光学活性１−ベンジル−３−ヒドロキシピ
ロリジンは医農薬中間体として有用な化合物である。例
えば、特開昭６１−６３６５２号公報に示された血管拡
張剤塩酸バルニジピン（Ｂａｒｎｉｄｉｐｉｎｅ）の原
料化合物として有用である。TECHNICAL FIELD The present invention relates to a method for producing optically active 1-benzyl-3-hydroxypyrrolidine by optical resolution. Optically active 1-benzyl-3-hydroxypyrrolidine is a compound useful as an intermediate for medicines and agricultural chemicals. For example, it is useful as a starting compound for the vasodilator barnidipine hydrochloride disclosed in JP-A-61-63652.
【０００２】[0002]
【従来の技術】光学活性１−ベンジル−３−ヒドロキシ
ピロリジンを製造する方法としては、（ＲＳ）−１−
ベンジル−３−ヒドロキシピロリジンを光学活性マンデ
ル酸で光学分割して光学活性１−ベンジル−３−ヒドロ
キシピロリジンを製造する方法（特開昭６１−６３６５
２号公報）、また光学分割によらない他の方法として
（ＲＳ）−１−ベンジル−３−ヒドロキシピロリジンを
先ずエステル化し、（ＲＳ）−１−ベンジル−３−アシ
ルオキシピロリジンとした後、リパーゼの一種であるＬ
ＰＬ アマノ３で加水分解し光学活性１−ベンジル−３
−ヒドロキシピロリジンを得る方法（特開平１−１４１
６００号公報）が知られている。2. Description of the Related Art As a method for producing optically active 1-benzyl-3-hydroxypyrrolidine, (RS) -1-
Method for producing optically active 1-benzyl-3-hydroxypyrrolidine by optically resolving benzyl-3-hydroxypyrrolidine with optically active mandelic acid (JP-A-61-6365)
No. 2), and as another method which does not rely on optical resolution, (RS) -1-benzyl-3-hydroxypyrrolidine is first esterified to (RS) -1-benzyl-3-acyloxypyrrolidine, which is then treated with lipase. A kind of L
Optically active 1-benzyl-3 by hydrolysis with PL Amano 3
-Method for obtaining hydroxypyrrolidine (JP-A-1-141
No. 600) is known.
【０００３】[0003]
【発明が解決しようとする課題】しかし、上記従来法
には、高価な光学活性マンデル酸を使用しなければなら
ない欠点がある。また上記の方法も先ずエステル化す
る工程が必要であり、しかも高価なリパーゼを用いなけ
ればならず経済的な製法とはいえない。本発明は、安価
な分割剤を用いて（ＲＳ）−１−ベンジル−３−ヒドロ
キシピロリジンを光学分割して、容易に光学活性１−ベ
ンジル−３−ヒドロキシピロリジンを製造する方法を提
供することを目的とする。However, the above-mentioned conventional method has a drawback that expensive optically active mandelic acid must be used. In addition, the above method also requires a step of esterification first, and requires expensive lipase, and cannot be said to be an economical production method. The present invention provides a method for easily producing optically active 1-benzyl-3-hydroxypyrrolidine by optically resolving (RS) -1-benzyl-3-hydroxypyrrolidine using an inexpensive resolving agent. To aim.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、分割剤を
種々検討した結果、光学活性乳酸を分割剤として用いれ
ば上記課題を解決し得ることを見出し、本発明を完成さ
せた。As a result of various studies on resolving agents, the present inventors have found that the above problems can be solved by using optically active lactic acid as a resolving agent, and have completed the present invention.
【０００５】即ち、本発明は、（ＲＳ）−１−ベンジル
−３−ヒドロキシピロリジンを、光学活性乳酸を分割剤
として用いて光学分割することを特徴とする光学活性１
−ベンジル−３−ヒドロキシピロリジンの製造法に関す
る。That is, the present invention is characterized by optically resolving (RS) -1-benzyl-3-hydroxypyrrolidine using optically active lactic acid as a resolving agent.
-A method for producing benzyl-3-hydroxypyrrolidine.
【０００６】[0006]
【発明の実施の形態】以下、本発明の構成を詳細に説明
する。本発明で用いる原料化合物である（ＲＳ）−１−
ベンジル−３−ヒドロキシピロリジンは、英国特許第８
３１９３４号明細書〔Ｃ．Ａ．，第５４巻 ２４８００
Ｃ（１９６０）〕で公知である。DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The configuration of the present invention will be described below in detail. The raw material compound used in the present invention is (RS) -1-
Benzyl-3-hydroxypyrrolidine is described in British Patent No. 8
31934 specification [C. A. , Volume 54, 24800
C (1960)].
【０００７】原料化合物である（ＲＳ）−１−ベンジル
−３−ヒドロキシピロリジンは、ラセミ体であっても又
はいずれか一方の光学異性体をより多く含有する混合物
であってもよい。The starting compound (RS) -1-benzyl-3-hydroxypyrrolidine may be a racemate or a mixture containing a larger amount of either one of the optical isomers.
【０００８】本発明の分割剤である光学活性乳酸は、Ｌ
−体、Ｄ−体のいずれも使用可能であり、目的に応じて
使い分ければよい。また、光学活性乳酸は、市販品をそ
のまま用いることができるが、市販品には乳酸の２量体
等のエステル成分或は酸無水物等を一部含有しているの
で、後述の参考例に示すように、これらエステル成分等
を乳酸に加水分解した後用いることも勿論可能である。
光学活性乳酸の使用量は、（ＲＳ）−１−ベンジル−３
−ヒドロキシピロリジン１モルに対して０．５〜１．５
モルが適当である。The optically active lactic acid which is the resolving agent of the present invention is L
Both the -body and the D-body can be used, and they may be used properly according to the purpose. Further, as the optically active lactic acid, a commercially available product can be used as it is. However, since the commercially available product partially contains an ester component such as a dimer of lactic acid, an acid anhydride, etc. As shown, it is of course possible to use these ester components and the like after hydrolyzing them to lactic acid.
The amount of optically active lactic acid used is (RS) -1-benzyl-3.
-0.5-1.5 per mol of hydroxypyrrolidine
Molar is appropriate.
【０００９】本発明においては、光学活性乳酸の一部を
塩酸、硫酸、リン酸等の鉱酸又は酢酸等の有機酸に置換
して光学分割を実施することも可能である。この場合、
光学活性乳酸と鉱酸又は有機酸の合計量は、（ＲＳ）−
１−ベンジル−３−ヒドロキシピロリジン１モルに対し
て０．５〜１．５モルとなるようにする。In the present invention, a part of the optically active lactic acid may be replaced with a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the like or an organic acid such as acetic acid to carry out the optical resolution. in this case,
The total amount of optically active lactic acid and mineral acid or organic acid is (RS)-
The amount is 0.5 to 1.5 mol with respect to 1 mol of 1-benzyl-3-hydroxypyrrolidine.
【００１０】本発明の方法は、通常、溶媒を用いて実施
する。用いられる溶媒は、（ＲＳ）−１−ベンジル−３
−ヒドロキシピロリジン及び光学活性乳酸と均一に混じ
り合い、両原料を変質させることのないものであり、さ
らに２種生成するジアステレオマー塩の一方の難溶性ジ
アステレオマー塩を析出させるものであれば特に限定さ
れない。このような溶媒としては、例えば、２−ブタノ
ン、アセトン、２−ブタノン−メタノール混合溶媒、２
−ブタノン−メタノール−水混合溶媒が好適に使用でき
る。溶媒の使用量は、（ＲＳ）−１−ベンジル−３−ヒ
ドロキシピロリジン１重量部に対して、通常１０重量部
以下、好ましくは２〜６重量部である。The method of the present invention is usually carried out using a solvent. The solvent used is (RS) -1-benzyl-3.
As long as it is uniformly mixed with hydroxypyrrolidine and optically active lactic acid and does not deteriorate both raw materials, and it precipitates a sparingly soluble diastereomer salt of two diastereomeric salts produced. There is no particular limitation. Examples of such a solvent include 2-butanone, acetone, 2-butanone-methanol mixed solvent, 2
A butanone-methanol-water mixed solvent can be preferably used. The amount of the solvent used is usually 10 parts by weight or less, preferably 2 to 6 parts by weight, based on 1 part by weight of (RS) -1-benzyl-3-hydroxypyrrolidine.
【００１１】本発明の実施方法の一例を示すと、（Ｒ
Ｓ）−１−ベンジル−３−ヒドロキシピロリジン及び光
学活性乳酸を溶媒中、撹拌下、４０℃程度に保つ。得ら
れた溶液を冷却及び／又は該溶液から溶媒を留去して濃
縮すると、光学活性１−ベンジル−３−ヒドロキシピロ
リジンと光学活性乳酸とにより形成されたジアステレオ
マー塩のうちの難溶性塩の結晶が析出する。析出した結
晶をろ別した後、得られた結晶を上記ジアステレオマー
塩の形成に使用した溶媒で再結晶すると、さらにジアス
テレオマー塩の光学純度を高めることができる。An example of the method of implementing the present invention is as follows (R
S) -1-Benzyl-3-hydroxypyrrolidine and optically active lactic acid are kept in a solvent at about 40 ° C. under stirring. When the obtained solution is cooled and / or the solvent is distilled off from the solution and concentrated, a sparingly soluble salt among diastereomeric salts formed by optically active 1-benzyl-3-hydroxypyrrolidine and optically active lactic acid. Crystals are precipitated. The precipitated crystals are filtered off, and the obtained crystals are recrystallized with the solvent used for forming the diastereomer salt, whereby the optical purity of the diastereomer salt can be further increased.
【００１２】上記の方法で分離したジアステレオマー塩
の塩分解を行うことにより、遊離の光学活性１−ベンジ
ル−３−ヒドロキシピロリジンを得ることができる。塩
分解は、通常行われている一般的な方法で実施すること
ができる。即ち、一例を示すと、得られたジアステレオ
マー塩を水に加え、続いてアルカリ金属の水酸化物（例
えば、水酸化ナトリウム）等のアルカリ性物質又は該ア
ルカリ性物質を含む水溶液を加えてアルカリ性にして光
学活性１−ベンジル−３−ヒドロキシピロリジンを遊離
させる。次いでジアステレオマー塩とアルカリ性物質と
の反応によって生成する乳酸のアルカリ性物質との塩が
実質的に不溶であり、且つ遊離の光学活性１−ベンジル
−３−ヒドロキシピロリジンが可溶である溶媒、例えば
シクロヘキサンを加えて遊離の光学活性１−ベンジル−
３−ヒドロキシピロリジンを抽出した後、得られたシク
ロヘキサン層を蒸留すれば目的とする遊離の光学活性１
−ベンジル−３−ヒドロキシピロリジンを単離すること
ができる。The optically active 1-benzyl-3-hydroxypyrrolidine which is free can be obtained by salt decomposition of the diastereomeric salt separated by the above method. The salt decomposition can be carried out by an ordinary method which is usually used. That is, to give an example, the obtained diastereomeric salt is added to water, and subsequently, an alkaline substance such as an alkali metal hydroxide (for example, sodium hydroxide) or an aqueous solution containing the alkaline substance is added to make it alkaline. To release optically active 1-benzyl-3-hydroxypyrrolidine. Then, a solvent in which the salt of lactic acid formed by the reaction of the diastereomer salt with the alkaline substance and the alkaline substance is substantially insoluble, and the free optically active 1-benzyl-3-hydroxypyrrolidine is soluble, for example, Free optically active 1-benzyl-
After extraction of 3-hydroxypyrrolidine, the resulting cyclohexane layer is distilled to obtain the desired free optical activity 1
-Benzyl-3-hydroxypyrrolidine can be isolated.
【００１３】[0013]
【実施例】次に実施例を示し、本発明法を説明するが、
本発明はこれらの実施例に限定されるものではない。EXAMPLES Next, the method of the present invention will be described with reference to examples.
The present invention is not limited to these examples.
【００１４】以下の実施例において、光学活性１−ベン
ジル−３−ヒドロキシピロリジンの光学純度は、光学活
性１−ベンジル−３−ヒドロキシピロリジンを予めｐ−
トルエンスルホニルクロリドで処理してトシラートとし
た後、以下の分析条件で高速液体クロマトグラフィーに
より分析した。Ｒ体の保持時間は３６．１分、Ｓ体の保
持時間は５０．２分であった。In the following examples, the optical purity of the optically active 1-benzyl-3-hydroxypyrrolidine was determined by comparing the optically active 1-benzyl-3-hydroxypyrrolidine with p-type in advance.
After treatment with toluenesulfonyl chloride to give tosylate, it was analyzed by high performance liquid chromatography under the following analysis conditions. The retention time of the R form was 36.1 minutes, and the retention time of the S form was 50.2 minutes.
【００１５】高速液体クロマトグラフィー分析条件 カラム：キラルセルＯＢ（ダイセル化学工業（株）製） ４．６ｍｍφ×２５０ｍｍ 溶離液：ヘキサン／２−プロパノール（２０／１容量
比） 流 速：１．５ｍｌ／分 検 出：ＵＶ ２２１ｎｍ 温 度：４０℃Conditions for high performance liquid chromatography analysis Column: Chiralcel OB (manufactured by Daicel Chemical Industries, Ltd.) 4.6 mmφ × 250 mm Eluent: Hexane / 2-propanol (20/1 volume ratio) Flow rate: 1.5 ml / min Detection: UV 221nm Temperature: 40 ℃
【００１６】参考例 Ｌ−乳酸の２−ブタノン溶液の調製 市販の９０％Ｌ−乳酸５０ｇ中に、撹拌下、４８％水酸
化ナトリウム水溶液４１．１ｇを滴下し、続いて６０℃
に撹拌下１時間保った。次に、２−ブタノン１６０．８
ｇを加えた後、内温を３０℃に保って、濃硫酸２５．５
ｇを滴下した。滴下終了後、２５〜３０℃に２０分間保
った後、硫酸マグネシウム６１．３ｇを加え、２５〜３
０℃に１時間撹拌下に保った。次に、無機物をろ過し、
Ｌ−乳酸の２−ブタノン溶液２１０ｇを得た。この溶液
のＬ−乳酸濃度は２０．６重量％であり、水分は３．８
重量％であった。Reference Example Preparation of 2-butanone solution of L-lactic acid To 50 g of commercially available 90% L-lactic acid, 41.1 g of 48% aqueous sodium hydroxide solution was added dropwise with stirring, and subsequently 60 ° C.
It was kept under stirring for 1 hour. Next, 2-butanone 160.8
After adding g, the internal temperature was kept at 30 ° C. and concentrated sulfuric acid 25.5
g was added dropwise. After the dropping was completed, the temperature was kept at 25 to 30 ° C. for 20 minutes, and then 61.3 g of magnesium sulfate was added to the mixture, which was added to
It was kept under stirring at 0 ° C. for 1 hour. Next, the inorganic matter is filtered,
210 g of 2-butanone solution of L-lactic acid was obtained. The L-lactic acid concentration of this solution was 20.6% by weight, and the water content was 3.8.
% By weight.
【００１７】実施例 ラセミ体である（ＲＳ）−１−ベンジル−３−ヒドロキ
シピロリジン３０．０ｇ（０．１６９モル）、メタノー
ル６ｇ及び参考例で得たＬ−乳酸の２−ブタノン溶液７
４．３ｇ（Ｌ−乳酸として０．１７０モル）を、撹拌
下、４０℃に１０分間保ち、次いで徐々に冷却して２℃
に３時間保った。その後、析出した結晶をろ別、乾燥
し、ジアステレオマー塩７．７４ｇを得た。次に、得ら
れたジアステレオマー塩の７．６９ｇをシクロヘキサン
７６．９ｇに加えた後、撹拌下、１５％水酸化ナトリウ
ム水溶液３０．８ｇを加えて混合した。静置後、シクロ
ヘキサン層を分離して炭酸カリウムで乾燥し、蒸留して
（Ｓ）−１−ベンジル−３−ヒドロキシピロリジン４．
４ｇを得た。高速液体クロマトグラフィーで分析した結
果、このＳ体の光学純度は９５％であった。比旋光度は
［α］25 D＝−３．４０°（ｃ＝５，メタノール）、
［α］25 D＝＋４．４３°（ｎｅａｔ）であった。EXAMPLE 30.0 g (0.169 mol) of racemic (RS) -1-benzyl-3-hydroxypyrrolidine, 6 g of methanol and 2-butanone solution 7 of L-lactic acid obtained in Reference Example
4.3 g (0.170 mol as L-lactic acid) was kept under stirring at 40 ° C. for 10 minutes, then gradually cooled to 2 ° C.
I kept it for 3 hours. Then, the precipitated crystals were separated by filtration and dried to obtain 7.74 g of diastereomeric salt. Next, 7.69 g of the obtained diastereomeric salt was added to 76.9 g of cyclohexane, and then 30.8 g of a 15% aqueous sodium hydroxide solution was added and mixed with stirring. After standing, the cyclohexane layer was separated, dried over potassium carbonate, and distilled (S) -1-benzyl-3-hydroxypyrrolidine.
4 g were obtained. As a result of analysis by high performance liquid chromatography, the optical purity of this S-form was 95%. The specific rotation is [α] 25 D = −3.40 ° (c = 5, methanol),
[Α] 25 D was + 4.43 ° (neat).
Claims (1)
シピロリジンを、光学活性乳酸を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１−ベンジル−３
−ヒドロキシピロリジンの製造法。1. An optically active 1-benzyl-3, characterized in that (RS) -1-benzyl-3-hydroxypyrrolidine is optically resolved by using optically active lactic acid as a resolving agent.
-Method for producing hydroxypyrrolidine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10396596A JPH09263578A (en) | 1996-03-29 | 1996-03-29 | Production of optically active 1-benzyl-3-hydroxypyrrolidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10396596A JPH09263578A (en) | 1996-03-29 | 1996-03-29 | Production of optically active 1-benzyl-3-hydroxypyrrolidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH09263578A true JPH09263578A (en) | 1997-10-07 |
Family
ID=14368086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10396596A Pending JPH09263578A (en) | 1996-03-29 | 1996-03-29 | Production of optically active 1-benzyl-3-hydroxypyrrolidine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH09263578A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6613550B2 (en) | 2000-02-29 | 2003-09-02 | Pfizer Inc. | Microbial process for preparation of optically active 3-hydroxypyrrolidine derivatives |
| WO2011010579A1 (en) * | 2009-07-21 | 2011-01-27 | 住友化学株式会社 | Process for production of optically active nipecotamide |
-
1996
- 1996-03-29 JP JP10396596A patent/JPH09263578A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6613550B2 (en) | 2000-02-29 | 2003-09-02 | Pfizer Inc. | Microbial process for preparation of optically active 3-hydroxypyrrolidine derivatives |
| WO2011010579A1 (en) * | 2009-07-21 | 2011-01-27 | 住友化学株式会社 | Process for production of optically active nipecotamide |
| CN102471267A (en) * | 2009-07-21 | 2012-05-23 | 住友化学株式会社 | Process for production of optically active nipecotamide |
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