JPH11279159A - Production of optically active piperazinecarboxlic acid ester - Google Patents
Production of optically active piperazinecarboxlic acid esterInfo
- Publication number
- JPH11279159A JPH11279159A JP10095385A JP9538598A JPH11279159A JP H11279159 A JPH11279159 A JP H11279159A JP 10095385 A JP10095385 A JP 10095385A JP 9538598 A JP9538598 A JP 9538598A JP H11279159 A JPH11279159 A JP H11279159A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- represented
- bis
- phenylmethyl
- menthyl
- 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.)
- Withdrawn
Links
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は式（III)で示される
光学活性の（Ｒ）−１，４−ビス（フェニルメチル）−
２−ピペラジンカルボン酸−Ｌ−メンチルエステルの工
業的に有用な製造方法に関するものである。式（Ｖ）で
示される（Ｒ）−４−（３−ホスホノ−２−プロペニ
ル）−２−ピペラジンカルボン酸は、スイスサンド社で
開発された優れた抗欝病、抗アルツハイマー病薬（特開
昭６３−２０３６９１）であり、式（III)で表される化
合物は（Ｖ）の中間体として有用である。The present invention relates to an optically active (R) -1,4-bis (phenylmethyl) -formula represented by the formula (III):
The present invention relates to an industrially useful method for producing 2-piperazinecarboxylic acid-L-menthyl ester. (R) -4- (3-Phosphono-2-propenyl) -2-piperazinecarboxylic acid represented by the formula (V) is an excellent antidepressant and anti-Alzheimer's disease drug developed by Swiss Sands Co., Ltd. The compound represented by formula (III) is useful as an intermediate of (V).
【０００２】[0002]
【化５】 Embedded image
【０００３】[0003]
【化６】 Embedded image
【０００４】[0004]
【従来の技術】従来、式（III)で表される（Ｒ）−１，
４−ビス（フェニルメチル）−２−ピペラジンカルボン
酸−Ｌ−メンチルエステル（Ｒ体）の合成法は、１，４
−ビス（フェニルメチル）−２−ピペラジンカルボン酸
低級アルキルエステルとＬ−メントールとのエステル交
換反応を行わせた後、得られたジアステレオマー化合物
の溶解度差により、ジアステレオマーを分割し、Ｒ体
（III)を得ていた。その際、母液の主成分である式
（Ｉ）で表される（Ｓ）−１，４−ビス（フェニルメチ
ル）−２−ピペラジンカルボン酸−Ｌ−メンチルエステ
ル（Ｓ体）は不要となり、収率も低かった（特開昭６３
−２０３６９１）。2. Description of the Related Art Conventionally, (R) -1,
The synthesis method of 4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L-menthyl ester (R-form) is described in 1,4.
After a transesterification reaction of -bis (phenylmethyl) -2-piperazinecarboxylic acid lower alkyl ester and L-menthol, diastereomers are separated by the difference in solubility of the resulting diastereomeric compound, and R Body (III). At that time, (S) -1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L-menthyl ester (S-form) represented by the formula (I), which is a main component of the mother liquor, becomes unnecessary, and the yield is reduced. The rate was also low (Japanese
-203691).
【０００５】[0005]
【化７】 Embedded image
【０００６】[0006]
【発明が解決しようとする課題】以上のことから、不要
となったＳ体（Ｉ）を再利用する方法の開発が望まれて
いた。本発明は不要なＳ体（Ｉ）をラセミ化させ、Ｒ，
Ｓ混合物とし、さらにその混合物からＲ体（III)を取り
出し、収率の向上を計る事を目的とするものである。From the above, it has been desired to develop a method of reusing the S-form (I) that is no longer needed. The present invention racemizes the unnecessary S-isomer (I),
The object is to obtain an S mixture, and further extract the R-form (III) from the mixture to improve the yield.
【０００７】[0007]
【課題を解決するための手段】本発明者らは上記の課題
について検討した結果、本発明を完成するに至った。Means for Solving the Problems The present inventors have studied the above problems and as a result have completed the present invention.
【０００８】即ち本発明はＳ体またはＳ体を主成分とす
る溶液を塩基存在下、加熱し、Ｒ，Ｓ混合物（II）とし
た後、光学分割することを特徴とするＲ体（III)の製造
方法である。That is, the present invention provides an R-form (III) characterized in that an S-form or a solution containing an S-form as a main component is heated in the presence of a base to obtain an R, S mixture (II) and then optically resolved. It is a manufacturing method of.
【０００９】[0009]
【化８】 Embedded image
【００１０】本発明の塩基存在下の塩基とは、有機塩基
及び無機塩基であり、好ましくは無機塩基類で、例えば
ソジウムハイドライド、ソジウムメチラート、ｔ−ブト
キシカリウムが挙げられる。The base in the presence of the base of the present invention is an organic base or an inorganic base, preferably an inorganic base, such as sodium hydride, sodium methylate and potassium t-butoxide.
【００１１】本発明の塩基の使用量は、Ｓ体（Ｉ）に対
して、理論的には等モルであるが、触媒量でも反応が進
行し、例えば、（Ｉ）に対して１０〜２０ｍｏｌ％でも
よい。The amount of the base used in the present invention is theoretically equimolar to the S-form (I), but the reaction proceeds even with a catalytic amount, for example, 10 to 20 mol based on (I). % May be used.
【００１２】本発明の溶媒については反応に不活性な溶
媒が好ましく、例えばベンゼンやトルエンである。The solvent of the present invention is preferably a solvent inert to the reaction, for example, benzene or toluene.
【００１３】本発明の反応温度については温度を加えた
方が良く、好ましくは、１１０〜１２０℃で反応する。As for the reaction temperature of the present invention, it is better to add a temperature, and the reaction is preferably performed at 110 to 120 ° C.
【００１４】本発明の反応時間については短時間で進行
するが、好ましくは２〜３時間反応する。Although the reaction time of the present invention proceeds in a short time, it is preferable to carry out the reaction for 2 to 3 hours.
【００１５】本発明の晶析条件は、塩酸水溶液に有機溶
剤を加えて、晶析することを、何度か繰り返す。これに
よって、より純度のよいＲ体（III)を得る事ができる。In the crystallization conditions of the present invention, the crystallization by adding an organic solvent to an aqueous hydrochloric acid solution is repeated several times. As a result, R-form (III) with higher purity can be obtained.
【００１６】本発明の晶析条件の有機溶剤とは極性溶媒
であり、例えばエーテルやエタノールである。The organic solvent under the crystallization conditions of the present invention is a polar solvent, for example, ether or ethanol.
【００１７】本発明のＳ体（Ｉ）をラセミ化させ、Ｒ体
（III)を得る方法は、何度でもリサイクル可能である。The method of the present invention for obtaining the R-form (III) by racemizing the S-form (I) can be recycled any number of times.
【００１８】本発明の製造方法を工業的に行なうために
は次の２つの方法が可能である。In order to carry out the production method of the present invention industrially, the following two methods are possible.
【００１９】（１）Ｓ体（Ｉ）またはＳ体（Ｉ）を主成
分とする溶液を式（IV）で表されるＮ，Ｎ′−ジベンジ
ルピペラジン−２−カルボン酸低級アルキルエステルと
Ｌ−メントールとの反応液に加え、エステル交換反応を
行なわせながらラセミ化させた後、光学分割を行なう。(1) The S-form (I) or a solution containing the S-form (I) as a main component is prepared by mixing N, N'-dibenzylpiperazine-2-carboxylic acid lower alkyl ester represented by the formula (IV) with L Addition to a reaction solution with menthol, followed by racemization while performing a transesterification reaction, followed by optical resolution.
【００２０】（２）Ｓ体（Ｉ）を加熱し、ラセミ化した
後、この溶液を式（IV）で表される化合物とＬ−メント
ールとを反応させて得られたジアステレオマー化合物溶
液に加え同時に光学分割を行なう。(2) After heating and racemizing the S-form (I), this solution is added to a diastereomer compound solution obtained by reacting the compound represented by the formula (IV) with L-menthol. At the same time, optical division is performed.
【００２１】以上いずれの方法を採用した場合でも、前
記述べたとおり、何度でもリサイクル可能である。In any of the above methods, as described above, the material can be recycled any number of times.
【００２２】以下に実施例を挙げ本発明を詳細に説明す
る。Hereinafter, the present invention will be described in detail with reference to examples.
【００２３】[0023]
【実施例】（Ｒ）−１，４−ビス（フェニルメチル）−
２−ピペラジンカルボン酸−Ｌ−メンチルエステルの合
成：Ｎ，Ｎ′−ジベンジルピペラジン−２−カルボン酸
メチルエステル３６．７ｇ（１１４ｍｍｏｌ）をトルエ
ン１００ｍｌを溶媒として用いて撹拌し、室温でＬ−メ
ントール２６．１ｇ（１６７ｍｍｏｌ）を加え、ディー
ンスタークトラップを用いて３０分加熱還流を行い、ト
ルエンを脱水した。反応液を冷却後、ＮａＨ（分散物、
５５〜６０％）１ｇ（２６ｍｍｏｌ）を添加し、３時間
加熱還流を行った。この時、６０ｍｌのトルエンを留去
し、新しいトルエン６０ｍｌを加えるという方法で、脱
メタノールを行った。反応液を冷却した後、２Ｎ ＨＣ
ｌ ６０ｍｌ、エーテル１５０ｍｌを加え、２０〜２５
℃で１時間、撹拌をすると結晶が析出し、その結晶をろ
取し、乾燥することにより、（Ｒ）−１，４−ビス（フ
ェニルメチル）−２−ピペラジンカルボン酸−Ｌ−メン
チルエステル−塩酸塩−水和物３２．４ｇ（ジアステレ
オマー純度６５．８％ｄ．ｅ．）を得た。EXAMPLES (R) -1,4-bis (phenylmethyl)-
Synthesis of 2-piperazinecarboxylic acid-L-menthyl ester: N, N'-dibenzylpiperazine-2-carboxylic acid methyl ester 36.7 g (114 mmol) was stirred using 100 ml of toluene as a solvent, and L-menthol was added at room temperature. 26.1 g (167 mmol) was added, and the mixture was heated under reflux for 30 minutes using a Dean-Stark trap to dehydrate toluene. After cooling the reaction solution, NaH (dispersion,
(55-60%) 1 g (26 mmol) was added, and the mixture was heated under reflux for 3 hours. At this time, methanol removal was carried out by distilling off 60 ml of toluene and adding 60 ml of fresh toluene. After cooling the reaction solution, 2N HC
l Add 60 ml and ether 150 ml and add 20-25
After stirring at 1 ° C. for 1 hour, crystals were precipitated. The crystals were collected by filtration and dried to give (R) -1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L-menthyl ester- 32.4 g of hydrochloride-hydrate (diastereomer purity 65.8% de) were obtained.
【００２４】さらにこの混合物を０．２Ｎ ＨＣｌ ６
０ｍｌ、ＥｔＯＨ １００ｍｌで再結晶を行い、最終的
に（Ｒ）−１，４−ビス（フェニルメチル）−２−ピペ
ラジンカルボン酸−Ｌ−メンチルエステル−塩酸塩−水
和物２０．２ｇ（収率３５％、ジアステレオマー純度９
８．８％ｄ．ｅ．）を得た。The mixture was further treated with 0.2N HCl 6
Recrystallization was performed with 0 ml and EtOH 100 ml, and finally (R) -1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L-menthyl ester-hydrochloride-hydrate 20.2 g (yield) 35%, diastereomer purity 9
8.8% d. e. ) Got.
【００２５】この時、得られた２回分のろ液に２８％Ｎ
ａＯＨを適量加え、ｐＨ１２としてトルエン３０ｍｌで
３回抽出した。有機層は硫酸マグネシウムで乾燥し、濃
縮乾固し、オイル３８．７ｇ（Ｒ／Ｓ＝２／７）を得
た。このオイルにトルエン１００ｍｌを加え、ディーン
スタークを用いて３０分加熱還流を行い、トルエンを脱
水した。反応液を冷却後、ＮａＨ（分散物、５５〜６０
％）１ｇ（２６ｍｍｏｌ）を添加し、３時間加熱還流を
行った。（この時、反応液をチェックすると、（Ｒ／Ｓ
＝１／１）にラセミ化していた。）反応液を冷却した
後、２Ｎ ＨＣｌ６０ｍｌ、エーテル１５０ｍｌを加
え、２０〜２５℃で１時間、撹拌すると結晶が析出し、
その結晶をろ取し、乾燥することにより、（Ｒ）−１，
４−ビス（フェニルメチル）−２−ピペラジンカルボン
酸−Ｌ−メンチルエステル−塩酸塩−水和物１７．６ｇ
（ジアステレオマー純度７５．０％ｄ．ｅ．）を得た。At this time, 28% N was added to the obtained two filtrates.
An appropriate amount of aOH was added to adjust the pH to 12, followed by extraction with 30 ml of toluene three times. The organic layer was dried over magnesium sulfate and concentrated to dryness to obtain 38.7 g of oil (R / S = 2/7). 100 ml of toluene was added to this oil, and the mixture was heated under reflux for 30 minutes using a Dean Stark to dehydrate the toluene. After cooling the reaction solution, NaH (dispersion, 55-60
%) Of 1 g (26 mmol) was added, and the mixture was heated under reflux for 3 hours. (At this time, when the reaction solution is checked, (R / S
= 1/1). After cooling the reaction solution, 2N HCl (60 ml) and ether (150 ml) were added, and the mixture was stirred at 20 to 25 ° C. for 1 hour to precipitate crystals.
The crystals are collected by filtration and dried to give (R) -1,
17.6 g of 4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L-menthyl ester-hydrochloride-hydrate
(Diastereomer purity 75.0% de) was obtained.
【００２６】さらにこの混合物を０．２Ｎ ＨＣｌ ６
０ｍｌ、ＥｔＯＨ １００ｍｌで再結晶を行い、最終的
に（Ｒ）−１，４−ビス（フェニルメチル）−２−ピペ
ラジンカルボン酸−Ｌ−メンチルエステル−塩酸塩−水
和物１２．０ｇ（収率２１％、ジアステレオマー純度９
６．１％ｄ．ｅ．）を得た。この結果、ラセミ化リサイ
クル１回を加えたトータル収率はＹ＝５６．２％（３
２．２ｇ）と向上した。Further, the mixture was mixed with 0.2N HCl 6
Recrystallization was performed with 0 ml and EtOH 100 ml, and finally (R) -1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L-menthyl ester-hydrochloride-hydrate 12.0 g (yield) 21%, diastereomer purity 9
6.1% d. e. ) Got. As a result, the total yield obtained by adding one racemization recycling was Y = 56.2% (3
2.2 g).
【００２７】[0027]
【発明の効果】本発明の製造法は優れた抗欝病、抗アル
ツハイマー病薬（特開平７−２３３８７）の医薬品の中
間体として有用な光学活性な（Ｒ）−１，４−ビス（フ
ェニルメチル）−２−ピペラジンカルボン酸−Ｌ−メン
チルエステルを効率良く製造できる工業的に優れた製造
方法である。Industrial Applicability The production method of the present invention provides an optically active (R) -1,4-bis (phenyl) which is useful as an intermediate of an excellent drug for antidepressant and anti-Alzheimer's disease (JP-A-7-23387). This is an industrially superior production method capable of efficiently producing (methyl) -2-piperazinecarboxylic acid-L-menthyl ester.
Claims (3)
ス（フェニルメチル）−２−ピペラジンカルボン酸−Ｌ
−メンチルエステルまたは該エステルを主成分とする溶
液を塩基存在下加熱し、式（II）で表される（Ｒ）−と
（Ｓ）−１，４−ビス（フェニルメチル）−２−ピペラ
ジンカルボン酸−Ｌ−メンチルエステル混合物とした
後、光学分割することを特徴とする式（III)で表される
（Ｒ）−１，４−ビス（フェニルメチル）−２−ピペラ
ジンカルボン酸−Ｌ−メンチルエステルの製造方法。 【化１】 【化２】 【化３】 (1) (S) -1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L represented by the formula (I)
-Menthyl ester or a solution containing the ester as a main component is heated in the presence of a base to give (R)-and (S) -1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid represented by the formula (II). (R) -1,4-bis (phenylmethyl) -2-piperazinecarboxylic acid-L-menthyl carboxylate represented by the formula (III), which is obtained by preparing an acid-L-menthyl ester mixture and then performing optical resolution. Method for producing ester. Embedded image Embedded image Embedded image
物を主成分とする溶液を式（IV）で表されるＮ，Ｎ′−
ジベンジルピペラジン−２−カルボン酸低級アルキルエ
ステルとＬ−メントールとの反応液に加え、エステル交
換反応を行ないながら式（II）で表される化合物とし、
化学分割を行う請求項１記載の製造方法。2. A method according to claim 1, wherein the compound represented by the formula (I) or a solution containing the compound as a main component is N, N'-
The compound represented by the formula (II) is added to a reaction solution of dibenzylpiperazine-2-carboxylic acid lower alkyl ester and L-menthol to carry out a transesterification reaction,
The method according to claim 1, wherein the chemical resolution is performed.
物を主成分とする溶液を塩基存在下加熱し、式（II）で
表される化合物とした後、式（IV）で表される化合物と
Ｌ−メントールとのエステル交換反応を行なわせた反応
液に加え、同時に光学分割する請求項１記載の製造方
法。 【化４】 （式中、Ｒは低級アルキル基を示す。）3. A compound represented by the formula (I) or a solution containing the compound as a main component is heated in the presence of a base to obtain a compound represented by the formula (II), and then the compound represented by the formula (IV) 2. The method according to claim 1, wherein the compound is added to a reaction solution in which a transesterification reaction between the compound and L-menthol has been carried out, and is simultaneously subjected to optical resolution. Embedded image (In the formula, R represents a lower alkyl group.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10095385A JPH11279159A (en) | 1998-03-24 | 1998-03-24 | Production of optically active piperazinecarboxlic acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10095385A JPH11279159A (en) | 1998-03-24 | 1998-03-24 | Production of optically active piperazinecarboxlic acid ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11279159A true JPH11279159A (en) | 1999-10-12 |
Family
ID=14136191
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10095385A Withdrawn JPH11279159A (en) | 1998-03-24 | 1998-03-24 | Production of optically active piperazinecarboxlic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11279159A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002040457A1 (en) * | 2000-11-20 | 2002-05-23 | Biovitrum Ab | Piperazinylpyrazines compounds as antagonists of serotonin 5-ht2 receptor |
| US6756377B2 (en) | 2000-11-20 | 2004-06-29 | Biovitrum Ab | Compounds and their use |
| JP2010529187A (en) * | 2007-06-11 | 2010-08-26 | ハンミ ファーム． シーオー．， エルティーディー． | Method for producing bepotastine and intermediate used therefor |
-
1998
- 1998-03-24 JP JP10095385A patent/JPH11279159A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002040457A1 (en) * | 2000-11-20 | 2002-05-23 | Biovitrum Ab | Piperazinylpyrazines compounds as antagonists of serotonin 5-ht2 receptor |
| US6756377B2 (en) | 2000-11-20 | 2004-06-29 | Biovitrum Ab | Compounds and their use |
| JP2010529187A (en) * | 2007-06-11 | 2010-08-26 | ハンミ ファーム． シーオー．， エルティーディー． | Method for producing bepotastine and intermediate used therefor |
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