JP2001131148A - Method for depositing diastereomer crystal - Google Patents
Method for depositing diastereomer crystalInfo
- Publication number
- JP2001131148A JP2001131148A JP35639599A JP35639599A JP2001131148A JP 2001131148 A JP2001131148 A JP 2001131148A JP 35639599 A JP35639599 A JP 35639599A JP 35639599 A JP35639599 A JP 35639599A JP 2001131148 A JP2001131148 A JP 2001131148A
- Authority
- JP
- Japan
- Prior art keywords
- diastereomer
- acetone
- hydroxymethyl
- water
- trans
- 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.)
- Granted
Links
Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は医薬品の合成中間体
として有用なラセミ−トランス−３−ヒドロキシメチル
−４−Ｒ１−ピペリジン類（Ｒ１は置換されていても良
いフェニル基を表す）由来のジアステレオマ−酸塩結晶
の析出方法に関わる。特に抗鬱剤またはパ−キンソン病
治療剤パロキセチンの中間体として有用なラセミ−トラ
ンス−３−ヒドロキシメチル−４−（４−フルオロフェ
ニル）−ピペリジン由来のジアステレオマ−酸塩結晶の
析出方法に関わる。The present invention relates to racemic-trans-3-hydroxymethyl-4-R 1 -piperidines (R 1 represents a phenyl group which may be substituted) useful as a synthetic intermediate for pharmaceuticals. The present invention relates to a method for precipitating diastereomerate crystals. In particular, the present invention relates to a method for precipitating diastereomeric acid salt crystals derived from racemic-trans-3-hydroxymethyl-4- (4-fluorophenyl) -piperidine, which is useful as an intermediate of an antidepressant or a paroxetine agent for treating Parkinson's disease.
【０００２】[0002]
【従来の技術および発明が解決しようとする課題】従来
ラセミ−トランス−３−ヒドロキシメチル−４−Ｒ１−
ピペリジン類（Ｒ１は置換されていても良いフェニル基
を表す）を光学分割するにあたり、このラセミ−トラン
ス体と、（２Ｒ、３Ｒ）−ｏ−クロロタ−トラニル酸の
ような光学活性な有機酸とを反応させてｄ体の該有機酸
塩であるジアステレオマ−とｌ体の該有機酸塩であるジ
アステレオマ−とを生成させ、いずれかのジアステレマ
−を結晶として析出させる方法は公知である（特開平１
０−２９１９７５号公報）。公知方法では水溶媒中でジ
アステレオマ−を生成させ、次いでこの反応水溶から目
的のジアステレオマ−を結晶析出させているが、水溶液
中で結晶析出させると析出結晶に不純物が混入し精製に
手間取る問題があった。特に、４−Ｒ１−５−Ｒ２ＯＯ
Ｃ−ピペリジン−２−オン類（Ｒ１は前述のとおりであ
り、Ｒ２ＯＯＣは還元されてヒドロキシメチルになるエ
ステル基を表す）を水素化リチウムアルミニウム等の還
元剤で還元して得たラセミ−トランス−３−ヒドロキシ
メチル−４−Ｒ１−ピペリジン類を十分精製することな
く原料として用い光学分割したときに本問題は顕著に現
れる。BACKGROUND OF INVENTION Problems to be Solved] Conventional racemic - trans-3-hydroxymethyl--4-R 1 -
When optically resolving a piperidine (R 1 represents a phenyl group which may be substituted), the racemic-trans form and an optically active organic acid such as (2R, 3R) -o-chlorota-tranylic acid are used. To form a diastereomer, which is the organic acid salt of the d-form, and a diastereomer, which is the organic acid salt of the l-form, to precipitate any of the diastereomers as crystals. Kaiping 1
0-291975). In the known method, a diastereomer is formed in an aqueous solvent, and then the desired diastereomer is precipitated from the aqueous solution of the reaction. Was. In particular, 4-R 1 -5-R 2 OO
Racemic compounds obtained by reducing C-piperidin-2-ones (R 1 is as described above and R 2 OOC represents an ester group reduced to hydroxymethyl) with a reducing agent such as lithium aluminum hydride; This problem becomes conspicuous when -trans-3-hydroxymethyl-4-R 1 -piperidine is used as a raw material without sufficient purification and subjected to optical resolution.
【０００３】[0003]
【課題を解決するための手段】本発明者らは前記公知方
法においてジアステレオマ−の析出段階において水溶媒
に代えてアセトン−水溶媒を用いることにより不純物の
混入のない純度のよいジアステレオマ−が析出し濾過洗
浄するだけで純度のよい結晶が単離取得できることを見
出し本発明を完成した。本発明は以下の各項に要約する
ことができる。The inventors of the present invention have found that a diastereomer having a high purity without impurities is deposited by using acetone-water solvent in place of the aqueous solvent in the diastereomer precipitation step in the known method. The present inventors have found that crystals having high purity can be isolated and obtained only by filtration and washing, and completed the present invention. The present invention can be summarized in the following sections.
【０００４】（１）ラセミ−トランス−３−ヒドロキシ
メチル−４−Ｒ１−ピペリジン類（ここでＲ１は置換基
を有していてもよいフェニル基を表す）と光学活性な有
機酸とを反応させてｄ体由来のジアステレオマ−とｌ体
由来のジアステレオマ−とを生成させ、いずれかのジア
ステレマ−を結晶として析出せしめる方法において、ア
セトン−水溶媒中でジアステレオマ−結晶を析出させる
ことを特徴とするラセミ−トランス−３−ヒドロキシメ
チル−４−Ｒ１−ピペリジン類（ここでＲ１は前述のと
おりである）由来のジアステレオマ−結晶の析出方法。(1) Racemic-trans-3-hydroxymethyl-4-R 1 -piperidines (where R 1 represents a phenyl group which may have a substituent) and an optically active organic acid Reacting to form a diastereomer derived from the d-isomer and a diastereomer derived from the l-isomer, and precipitating any of the diastereomers as crystals, wherein the diastereomer crystals are precipitated in an acetone-water solvent. A method for depositing diastereomeric crystals derived from the following racemic-trans-3-hydroxymethyl-4-R 1 -piperidines (where R 1 is as described above).
【０００５】（２）Ｒ１が４−フルオロフェニル基であ
る（１）に記載の析出方法。(2) The method according to (1), wherein R 1 is a 4-fluorophenyl group.
【０００６】（３）ラセミ−トランス−３−ヒドロキシ
メチル−４−Ｒ１−ピペリジン類がラセミ−トランス−
３−ヒドロキシメチル−４−（４−フルオロフェニル）
−ピペリジンである（１）または（２）のいずれかに記
載の析出方法。(3) Racemic-trans-3-hydroxymethyl-4-R 1 -piperidine is racemic-trans-
3-hydroxymethyl-4- (4-fluorophenyl)
-The precipitation method according to any one of (1) and (2), which is piperidine.
【０００７】（４）光学活性な有機酸が光学活性なｏ−
クロロタ−トラニル酸（ｏ−ｃｈｌｏｒｏ−ｔａｒｔｒ
ａｎｉｌｉｃ−ａｃｉｄ）である（１）〜（３）のいず
れかに記載の析出方法。 （５）光学活性なｏ−クロロタ−トラニル酸が（２Ｒ、
３Ｒ）−ｏ−クロロタ−トラニル酸である（４）に記載
の析出方法。(4) An optically active organic acid is an optically active o-
O-chloro-tartric acid
(1) to (3), which is an anionic-acid). (5) The optically active o-chlorota-tranylic acid is (2R,
The precipitation method according to (4), which is 3R) -o-chlorota-tranylic acid.
【０００８】（６）結晶として析出するジアステレオマ
−が（３Ｓ、４Ｒ）−３−ヒドロキシメチル−４−（４
−フルオロフェニル）−ピペリジン、（２Ｒ、３Ｒ）−
ｏ−クロロタ−トラニル酸塩、一水和物である（１）に
記載の析出方法。(6) The diastereomer precipitated as crystals is (3S, 4R) -3-hydroxymethyl-4- (4
-Fluorophenyl) -piperidine, (2R, 3R)-
The precipitation method according to (1), which is o-chlorota-tranilate or monohydrate.
【０００９】（７）アセトン：水＝０．１〜０．５：１
（Ｖ／Ｖ）であるアセトン−水を用いる（１）〜（６）
のいずれかに記載の析出方法。(7) acetone: water = 0.1-0.5: 1
(1) to (6) using (V / V) acetone-water
The precipitation method according to any one of the above.
【００１０】（８）アセトン：水＝０．２：１（Ｖ／
Ｖ）であるアセトン−水を用いる（８）に記載の析出方
法。(8) Acetone: water = 0.2: 1 (V /
(8) The precipitation method according to (8), wherein acetone-water is used.
【００１１】（９）ラセミ−トランス−３−ヒドロキシ
メチル−４−Ｒ１−ピペリジン類（ここでＲ１は置換基
を有していてもよいフェニル基を表す）と光学活性な有
機酸とを水溶媒中で反応させてｄ体の該有機酸由来であ
る酸塩であるジアステレオマ−とｌ体の該有機酸由来で
ある酸塩であるジアステレオマ−とを生成させ次いで、
この反応水溶液にアセトンを添加しアセトン−水溶液と
し冷却し、いずれかのジアステレオマ−を結晶析出させ
る（１）〜（８）のいずれかに記載の析出方法。(9) racemic-trans-3-hydroxymethyl-4-R 1 -piperidines (where R 1 represents a phenyl group which may have a substituent) and an optically active organic acid Reacting in an aqueous solvent to form a diastereomer, an acid salt derived from the organic acid in d form, and a diastereomer, an acid salt derived from the organic acid in 1 form,
Acetone is added to the reaction aqueous solution to form an acetone-water solution, followed by cooling to precipitate any diastereomer.
【００１２】[0012]
【００１３】本発明の製造法の一例は次ぎのように図示
できる。An example of the production method of the present invention can be illustrated as follows.
【化１】 Embedded image
【００１４】（上式中、Ｒ１は置換されていても良いフ
ェニル基を表し、Ｒ２は水素原子、低級アルキル基、ア
ルアルキル基等反応を妨げない置換基を表し、またＲ＊
ＣＯＯＨは（２Ｒ、３Ｒ）−ｏ−クロロタートラニル酸
等の光学活性なカルボン酸を表す）[0014] (In the formula, R 1 represents a phenyl group which may be substituted, R 2 represents a hydrogen atom, a lower alkyl group, do not interfere with the aralkyl group or the like reactive substituents, also R *
COOH represents an optically active carboxylic acid such as (2R, 3R) -o-chlorotartranilic acid
【００１５】以下、本発明の方法を詳しく説明する。本
発明ではまずラセミ−トランス−３−ヒドロキシメチル
−４−Ｒ１−ピペリジン類（ここでＲ１は置換基を有し
ていてもよいフェニル基を表す）と光学活性な有機酸と
を反応させて光学活性な有機酸とｄ体−３−ヒドロキシ
メチル−４−Ｒ１−ピペリジン類との塩であるジアステ
レオマ−、および光学活性な有機酸とｌ体−３−ヒドロ
キシメチル−４−Ｒ１−ピペリジン類との塩であるジア
ステレオマ−を生成させる。ここでラセミ−トランス−
３−ヒドロキシメチル−４−Ｒ１−ピペリジン類として
は、特開平９−２７８７５４号公報の一般式（２）で表
されるようなピペリジンカルビノ−ル類、特開平１０−
２９１９７５号公報の式（１）の一部に含まれるような
ピペリジン誘導体を言い、上述の公開公報に記載される
ように、トランス−４−Ｒ１−５−Ｒ３ＯＯＣ−ピペリ
ジン２−オン類（Ｒ１は置換されていても良いフェニル
基を表し、 Ｒ３ＯＯＣは還元されてヒドロキシメチル
になるエステル基を表す）と還元剤とを反応させること
により得られる。Hereinafter, the method of the present invention will be described in detail. In the present invention, first, a racemic-trans-3-hydroxymethyl-4-R 1 -piperidine (where R 1 represents a phenyl group which may have a substituent) is reacted with an optically active organic acid. Diastereomer which is a salt of an optically active organic acid and d-form-3-hydroxymethyl-4-R 1 -piperidine, and an optically active organic acid and 1-form-3-hydroxymethyl-4-R 1- Diastereomers which are salts with piperidines are formed. Where racemic-trans-
Examples of 3-hydroxymethyl-4-R 1 -piperidines include piperidine carbinols represented by the general formula (2) in JP-A-9-278754, and
291975 refers to a piperidine derivative included in a part of the formula (1), and as described in the above-mentioned publication, trans-4-R 1 -5-R 3 OOC-piperidin-2-ones (R 1 represents an optionally substituted phenyl group, and R 3 OOC represents an ester group that is reduced to hydroxymethyl) and a reducing agent.
【００１６】すなわち「類」とはピペリジンにおいて特
に指摘した位置以外、例えばＮ１位が無置換であっても
良いし、また反応を妨げない置換基（例えば前記特許公
開公報開示の低級アルキル基、アルアルキル基等が例示
される）を有していてよいことを意味する。また４位
Ｒ１の置換されていても良いフェニル基は前記特許公
開公報に開示されるようなものを言い、無置換のフェニ
ル基またはフッ素等のハロゲン原子、メトキシ、エトキ
シ等のアルコキシル基、その他、反応を妨げない置換基
を有するフェニル基を言う。That is, the “class” may be unsubstituted at a position other than the position indicated particularly in piperidine, for example, at the N1 position, or may be a substituent that does not hinder the reaction (for example, a lower alkyl group, an alky! Alkyl group or the like). Also 4th
The optionally substituted phenyl group for R 1 is as disclosed in the above-mentioned patent publication, and is an unsubstituted phenyl group or a halogen atom such as fluorine, an alkoxyl group such as methoxy and ethoxy, and other reactions. Refers to a phenyl group having a substituent that does not interfere.
【００１７】光学活性な有機酸としては、酒石酸、クロ
ロタ−トラニル酸等の不斉炭素を有し光学活性を示す有
機酸、特に有機カルボン酸が例示される。光学活性なｏ
−クロロタ−トラニル酸、特にＬ体すなわち（２Ｒ、３
Ｒ）体はパロキセチンの重要中間体である（３Ｓ、４
Ｒ）−３−ヒドロキシメチル−４−（４−フルオロフェ
ニル）−ピペリジンと析出良好かつ純度の良いジアステ
レオマ−を生成する。Examples of the optically active organic acid include organic acids having an asymmetric carbon atom and having optical activity, such as tartaric acid and chlorota-tranylic acid, particularly organic carboxylic acids. Optically active o
-Chlorota-tranylic acid, especially the L-form, ie (2R, 3
The R) form is an important intermediate of paroxetine (3S, 4
R) -3-Hydroxymethyl-4- (4-fluorophenyl) -piperidine and a diastereomer with good precipitation and good purity are produced.
【００１８】反応はラセミ−トランス体と有機酸を適当
な溶媒中でで混合し、生成する二種のジアステレオマ−
が溶解する温度以上にまで昇温する。溶媒としては水、
アセトンまたはアセトン−水が挙げられるが、水が経済
上望ましい。水溶媒では通常、７０℃以上に昇温し溶解
反応させる。好ましく、溶解性、化合物の熱安定性等を
考慮し８０〜９０℃である。本有機酸塩形成反応ではセ
ライト等の不純物吸着剤を加えて反応させても良い。In the reaction, the racemic-trans form and the organic acid are mixed in a suitable solvent, and the resulting two diastereomers are formed.
The temperature is raised to a temperature at which the is dissolved. Water as the solvent,
Acetone or acetone-water may be mentioned, but water is economically desirable. In the case of an aqueous solvent, the temperature is usually raised to 70 ° C. or higher to cause a dissolution reaction. It is preferably 80 to 90 ° C. in consideration of solubility, thermal stability of the compound, and the like. In the present organic acid salt forming reaction, the reaction may be carried out by adding an impurity adsorbent such as celite.
【００１９】反応終了後、不純物吸着剤や不溶の不純物
があれば、加熱下、加温下に不溶物を濾過去する。次い
でこの反応溶液を冷却し、ｄ体からなるジアステレオマ
−、ｌ体からなるジアステレオマ−のいずれかを結晶析
出させるが、本発明ではこの結晶析出をアセトン−水溶
媒で行う。結晶析出には冷却過程で、必要に応じ予め入
手している目的結晶を種晶として添加して目的結晶の析
出を促進することができる。After the reaction, if there is an impurity adsorbent or an insoluble impurity, the insoluble matter is filtered off under heating and heating. Then, the reaction solution is cooled to crystallize either a diastereomer composed of the d-form or a diastereomer composed of the l-form. In the present invention, the crystallization is performed with an acetone-water solvent. For crystal precipitation, a target crystal obtained in advance can be added as a seed crystal as needed in the cooling step to promote the precipitation of the target crystal.
【００２０】結晶析出のためのアセトン−水溶媒につい
ては塩形成反応を水溶媒で行ったときは反応終了後の反
応液にアセトンを添加し、アセトン溶媒で行ったときは
反応終了後の反応液に水を添加しアセトン−水溶液を調
整する。１形成反応を水溶媒で行ったときは反応終了後
の反応液がアセトンの沸点（５６℃）以下になったとこ
ろでアセトンの添加を行う。通常４５〜５５℃で行い、
その後、再昇温しアセトンを還流させジアステレオマ−
が溶解していることを確かめる。As for the acetone-water solvent for crystal precipitation, acetone is added to the reaction solution after the completion of the reaction when the salt formation reaction is carried out with the aqueous solvent, and the reaction solution after the reaction is completed when the reaction is carried out with the acetone solvent. Water to prepare an acetone-water solution. (1) When the formation reaction is carried out with an aqueous solvent, acetone is added when the reaction solution after the reaction has dropped below the boiling point of acetone (56 ° C.). Usually performed at 45-55 ° C,
Thereafter, the temperature was raised again, and the acetone was refluxed to give a diastereomer.
Make sure that is dissolved.
【００２１】次いで常法に従い冷却し、目的のジアステ
レオマ−結晶を析出させるが、この際、５０℃程になっ
たところで、別途目的結晶の微量を種晶として接種し目
的結晶を効率良く取得してもよい。添加するアセトンは
通常、水１に対し０．１〜０．５（Ｖ／Ｖ）を加える。
特に光学純度の良い析出晶を収率を与える点で０．１５
〜０．２５（Ｖ／Ｖ）が好ましく、更には０．２（Ｖ／
Ｖ）程度が好ましい。Then, the mixture is cooled according to a conventional method to precipitate the desired diastereomer crystals. At this time, when the temperature reaches about 50 ° C., a small amount of the desired crystals is separately inoculated as seed crystals to obtain the desired crystals efficiently. Is also good. The amount of acetone to be added is usually 0.1 to 0.5 (V / V) per 1 part of water.
In particular, 0.15 in terms of giving a precipitated crystal having good optical purity to give a yield.
To 0.25 (V / V), more preferably 0.2 (V / V).
V) is preferred.
【００２２】アセトン−水溶媒は原料ラセミ−トランス
体に対して通常１０〜５０Ｖ／Ｗとなるように使用する
が、収率の点から１５〜２０Ｖ／Ｗ程度となるように使
用する。パロキセチンの重要中間体である（３Ｓ、４
Ｒ）−３−ヒドロキシメチル−４−（４−フルオロフェ
ニル）−ピペリジン、Ｌ−ｏ−クロロタ−トラニル酸塩
は一水和物として析出するが、その収率はアセトン：水
＝０．２：１程度になるように水、アセトンを使用し、
総計容量が原料ラセミ−トランス体に対して１５Ｖ／Ｗ
程度になるよう使用したとき最も良好であった。The acetone-water solvent is usually used at a rate of 10 to 50 V / W with respect to the raw material racemic-trans form, but is used at a rate of about 15 to 20 V / W from the viewpoint of yield. An important intermediate of paroxetine (3S, 4
R) -3-Hydroxymethyl-4- (4-fluorophenyl) -piperidine and Lo-chlorota-tranilate are precipitated as monohydrate, and the yield is acetone: water = 0.2: Use water and acetone to make it about 1.
Total capacity is 15V / W for raw material racemic-trans
It was the best when it was used to the extent.
【００２３】２）塩形成反応でアセトンを溶媒として使
用したときは、反応終了後のアセトン反応液に水を加え
結晶析出をさせるが、水の量は結晶析出に十分な量であ
れば良い。例えば、結晶として析出するジアステレオマ
−が（３Ｓ、４Ｒ）−３−ヒドロキシメチル−４−（４
−フルオロフェニル）−ピペリジン、（２Ｒ、３Ｒ）−
ｏ−クロロタ−トラニル酸塩であるときは、その酸塩は
一水和物として析出するが、一水和物を形成する水の量
以上であれば良い。しかし好ましい水の量は、前述１）
の塩形成反応で水を溶媒として使用して得た反応液にア
セトンを加えたときの、アセトン、水の割合に準じ、前
述の通りである。2) When acetone is used as a solvent in the salt formation reaction, water is added to the acetone reaction solution after the reaction to precipitate crystals, and the amount of water may be any amount sufficient for crystal precipitation. For example, a diastereomer that precipitates as a crystal is (3S, 4R) -3-hydroxymethyl-4- (4
-Fluorophenyl) -piperidine, (2R, 3R)-
When it is an o-chlorota-tranilate, the acid salt precipitates as a monohydrate, but it may be any amount as long as it is equal to or more than the amount of water forming the monohydrate. However, the preferred amount of water is 1) described above.
As described above, according to the ratio of acetone and water when acetone is added to a reaction solution obtained by using water as a solvent in the salt formation reaction of the above.
【００２４】以上のようにして析出させて得たジアステ
レオマ−結晶は不純物を含まない純度の良いものであっ
て、濾過し水で洗浄し乾燥するだけで品質的に十分であ
り、更に精製する必要はない。また更に精製するにして
も再結晶回数を大幅に減らせる等、精製操作を大幅に削
減できる。The diastereomer crystals obtained by precipitation as described above have a high purity without impurities, and are sufficient in quality only by filtration, washing with water and drying. There is no. Further, even if the product is further purified, the number of times of recrystallization can be greatly reduced, and the purification operation can be greatly reduced.
【００２５】このようにして得たジアステレオマ−結晶
は水酸化ナトリウム水溶液等を用いた常法で加水分解し
て光学活性な有機酸との塩結合を解き、光学純度の高い
光学活性なトランス−３−ヒドロキシメチル−４−Ｒ１
−ピペリジン類を得ることができる。また、このような
加水分解はジアステレマ−結晶を取得した直後に独立し
て行うことなく次工程以降のいずれかの反応段階におい
て、行うこともできる。The diastereomer crystals thus obtained are hydrolyzed by a conventional method using an aqueous solution of sodium hydroxide or the like to dissolve a salt bond with an optically active organic acid, thereby obtaining an optically active trans-3 having a high optical purity. -Hydroxymethyl-4-R 1
-Piperidines can be obtained. In addition, such hydrolysis can be carried out in any of the reaction steps after the next step without being carried out independently immediately after obtaining the diasteremer crystal.
【００２６】[0026]
【実施例】次に、本発明を実施例に基づいてさらに詳細
に説明するが、本発明はかかる実施例のみに限定される
ものではない。Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to only these examples.
【００２７】参考例 ラセミ−トランス−３−ヒドロキ
シメチル−４−（４−フルオロフェニル）−ピペリジン
の製造例 ラセミ−シス、トランス−４−（４−フルオロフェニ
ル）−５−メトキシカルボニルピペリジン−２−オン３
７．６９ｇ（０．１５モル）、トルエン１８８ｍｌ、２
８％ナトリウムメトキシドメタノ−ル溶液２．８９ｇ
（０．０１５モル）を加え、昇温溶解後、３℃まで徐冷
し、析出した結晶がラセミ−トランス−４−（４−フル
オロフェニル）−５−メトキシカルボニルピペリジン−
２−オンであることをＨＰＬＣで確認した。Reference Example Racemic-trans-3-hydroxy
Cimethyl-4- (4-fluorophenyl) -piperidine
Preparation racemic - cis, trans-4- (4-fluorophenyl) -5-methoxycarbonyl-2-one 3
7.69 g (0.15 mol), toluene 188 ml, 2
2.89 g of an 8% sodium methoxide methanol solution
(0.015 mol), and after heating and dissolving, the mixture was gradually cooled to 3 ° C., and the precipitated crystals were separated from racemic-trans-4- (4-fluorophenyl) -5-methoxycarbonylpiperidine-
It was confirmed by HPLC that it was 2-one.
【００２８】その後、このスラリ−液に２０％塩化水素
メタノ−ル溶液４．１０ｇを添加して酸性とし、シスへ
の再異性化を止め、濃縮してメタノ−ルを除去し、テト
ラヒドロフラン（ＴＨＦ） ７５ｍｌで希釈してラセミ
−トランス−４−（４−フルオロフェニル）−５−メト
キシカルボニルピペリジン−２−オンのＴＨＦ−トルエ
ンスラリ−溶液を得た。別途、水素化リチウムアルミニ
ウム１０．５３ｇ（０．２７８モル）をＴＨＦ１８８ｍ
ｌに溶解させた液を調製し、この中にｏ−ジクロロベン
ゼン４．４１ｇ（０．０３モル）を添加した後、先程の
スラリ−溶液を２０〜４０℃で滴下した。４０〜４５℃
で１時間１０分熟成後、還流下で２時間反応させ、室温
まで冷却した。Thereafter, 4.10 g of a 20% hydrogen chloride methanol solution was added to the slurry to make it acidic, the re-isomerization to cis was stopped, the methanol was removed by concentration, and tetrahydrofuran (THF) was added. ) Dilute with 75 ml to obtain a THF-toluene slurry solution of racemic-trans-4- (4-fluorophenyl) -5-methoxycarbonylpiperidin-2-one. Separately, 10.53 g (0.278 mol) of lithium aluminum hydride was added to THF188m
A solution was prepared by dissolving the solution in 1 l, and 4.41 g (0.03 mol) of o-dichlorobenzene was added thereto, and the slurry solution was added dropwise at 20 to 40 ° C. 40-45 ° C
After 1 hour and 10 minutes aging, the mixture was reacted under reflux for 2 hours and cooled to room temperature.
【００２９】別途、水７６０ｍｌに９９％水酸化ナトリ
ウム１１２．１２ｇ（１．３９モル）を溶解した液を調
整し、この中に反応液を５４〜５６℃にて滴下・水解
し、分液した。次ぎに有機層にセライト１．８８ｇを添
加し、濾過して得られた母洗液を常圧留去し、２８０ｍ
ｌ留出したところでトルエン１５０ｍｌを追加し、更に
１４７ｍｌを留去した。留去終了後、室温まで徐冷して
析出した結晶を濾過し、トルエン２８ｍｌで洗浄し、乾
燥してラセミ−トランス−３−ヒドロキシメチル−４−
（４−フルオロフェニル）−ピペリジン２５．６６ｇ
（０．１２３モル）を得た（収率はラセミ−シス、トラ
ンス−４−（４−フルオロフェニル）−５−メトキシカ
ルボニルピペリジン−２−オンに対して８２％であっ
た）。Separately, a solution prepared by dissolving 112.12 g (1.39 mol) of 99% sodium hydroxide in 760 ml of water was prepared, and the reaction solution was added dropwise at 54 to 56 ° C., hydrolyzed, and separated. . Next, 1.88 g of celite was added to the organic layer, and the mother wash obtained by filtration was distilled off under normal pressure.
At the end of distillation, 150 ml of toluene was added, and 147 ml was distilled off. After completion of the distillation, the mixture was gradually cooled to room temperature, and the precipitated crystals were collected by filtration, washed with 28 ml of toluene, and dried to obtain racemic-trans-3-hydroxymethyl-4-.
25.66 g of (4-fluorophenyl) -piperidine
(0.123 mol) was obtained (the yield was 82% based on racemic-cis, trans-4- (4-fluorophenyl) -5-methoxycarbonylpiperidin-2-one).
【００３０】実施例１（−）−（３Ｓ、４Ｒ）−３−ヒドロキシメチル−４−
（４−フルオロフェニル）−ピペリジン、（２Ｒ、３
Ｒ）−ｏ−クロロタ−トラニル酸塩、一水和物の製法 水２３０ｍｌ、ラセミ（３ＳＲ、４ＲＳ）−トランス−
３−ヒドロキシメチル−４−（４−フルオロフェニル）
−ピペリジン２０．０ｇ（９５．６ｍｍｏｌ）、Ｌ（２
Ｒ、３Ｒ）−ｏ−クロロタ−トラニル酸２６．１ｇ（１
００．４ｍｍｏｌ）、セライト０．４ｇを混合し、８５
℃まで昇温し、濾過して熱水２０ｍｌで洗い込んだ。母
洗液を５５℃まで冷却した後、アセトン５０ｍｌを加
え、５０℃で接種して４０〜５０℃で３０分間攪拌した
後、２８〜３２℃まで冷却し、１〜２４時間熟成した
後、濾過し水４０ｍｌで洗浄し、乾燥して表題化合物を
得た。尚、熟成時間と収率および品質の関係は下表の通
りであった。Example 1 (-)-(3S, 4R) -3-hydroxymethyl-4-
(4-fluorophenyl) -piperidine, (2R, 3
R) -O-chlorota-tranilate, production method of monohydrate 230 ml of water, racemic (3SR, 4RS) -trans-
3-hydroxymethyl-4- (4-fluorophenyl)
-Piperidine 20.0 g (95.6 mmol), L (2
R, 3R) -o-chlorota-tranylic acid 26.1 g (1
00.4 mmol) and 0.4 g of celite, and 85
The temperature was raised to ℃, filtered and washed with 20 ml of hot water. After cooling the mother wash to 55 ° C, 50 ml of acetone was added, inoculated at 50 ° C, stirred at 40 to 50 ° C for 30 minutes, cooled to 28 to 32 ° C, aged for 1 to 24 hours, and filtered. Washed with 40 ml of water and dried to obtain the title compound. The relationship between aging time, yield and quality was as shown in the table below.
【表１】 [Table 1]
【００３１】実施例２（３Ｓ、４Ｒ）−トランス−３−ヒドロキシメチル−４
−（４−フルオロフェニル）−ピペリジン、Ｌ−ｏ−ク
ロロタ−トラニル酸塩．一水和物の合成 水２４０ｍｌ、ラセミ−トランス−３−ヒドロキシメチ
ル−４−（４−フルオロフェニル）−ピペリジン２０．
０ｇ（９５．６ｍｍｏｌ）、Ｌ−ｏ−クロロタ−トラニ
ル酸２６．１ｇ（１００．４ｍｍｏｌ）、セライト０．
４ｇを混合し、８５℃まで昇温し、濾過して熱水２０ｍ
ｌで洗い込んだ。母洗液を５５℃まで冷却した後、アセ
トン４０ｍｌを加え、５５℃で接種して４５〜５５℃で
３０分間攪拌した後、３３〜３７℃まで冷却し、１〜２
４時間熟成した後、濾過し、水４０ｍｌで洗浄し、乾燥
して表題化合物を得た。尚、熟成時間と収率および品質
の関係は下表の通りであった。Example 2 (3S, 4R) -trans-3-hydroxymethyl-4
-(4-fluorophenyl) -piperidine, Lo-c
Lorota-tranilate. Synthetic water of monohydrate 240 ml, racemic-trans-3-hydroxymethyl-4- (4-fluorophenyl) -piperidine 20.
0 g (95.6 mmol), 26.1 g (100.4 mmol) of L-o-chlorota-tranylic acid, 0.1 g of celite.
4 g, heated to 85 ° C., filtered and 20 m of hot water
Washed with l. After cooling the mother wash to 55 ° C, 40 ml of acetone was added, inoculated at 55 ° C, stirred at 45 to 55 ° C for 30 minutes, cooled to 33 to 37 ° C, and
After aging for 4 hours, the mixture was filtered, washed with 40 ml of water and dried to obtain the title compound. The relationship between aging time, yield and quality was as shown in the table below.
【表２】 [Table 2]
【００３２】実施例（３Ｓ、４Ｒ）−トランス−３−ヒドロキシメチル−４
−（４−フルオロフェニル）−ピペリジン、Ｌ−ｏ−ク
ロロタ−トラニル酸塩、一水和物の合成 水２６０ｍｌ、（３ＳＲ、４ＲＳ）−トランス−３−ヒ
ドロキシメチル−４−（４−フルオロフェニル）−ピペ
リジン２０．０ｇ（９５．６ｍｍｏｌ）、Ｌ−ｏ−クロ
ロタ−トラニル酸２６．１ｇ（１００．４ｍｍｏｌ）、
セライト０．４ｇを混合し、８６℃まで昇温し、濾過し
て熱水２０ｍｌで洗い込んだ。母洗液を５５℃まで冷却
した後、アセトン２０ｍｌを加え、６５℃で接種して６
０〜６５℃で３０分間攪拌した後、３４〜３７℃まで冷
却し、１時間熟成した後、濾過し、水４０ｍｌで洗浄
し、乾燥して表題化合物１９．５ｇ（収率４１．８％）
を得た。尚、品質は（３Ｓ、４Ｒ）体／（３Ｒ、４Ｓ）
体＝９９．５％／０．５％であった。Example (3S, 4R) -trans-3-hydroxymethyl-4
-(4-fluorophenyl) -piperidine, Lo-c
Lorota-tranilate, synthetic water of monohydrate 260 ml, (3SR, 4RS) -trans-3-hydroxymethyl-4- (4-fluorophenyl) -piperidine 20.0 g (95.6 mmol), Lo -Chlorota-tranylic acid 26.1 g (100.4 mmol),
0.4 g of celite was mixed, heated to 86 ° C., filtered and washed with 20 ml of hot water. After cooling the mother wash to 55 ° C., 20 ml of acetone was added, and the mixture was inoculated at 65 ° C. for 6 hours.
After stirring at 0 to 65 ° C for 30 minutes, the mixture was cooled to 34 to 37 ° C, aged for 1 hour, filtered, washed with 40 ml of water, and dried to obtain 19.5 g of the title compound (yield: 41.8%).
I got The quality is (3S, 4S) / (3R, 4S)
Body = 99.5% / 0.5%.
【００３３】実施例４（３Ｓ、４Ｒ）−トランス−３−ヒドロキシメチル−４
−（４−フルオロフェニル）−ピペリジン、Ｌ−ｏ−ク
ロロタ−トラニル酸塩、一水和物の合成 水１８０ｍｌ、（３ＳＲ、４ＲＳ）−トランス−３−ヒ
ドロキシメチル−４−（４−フルオロフェニル）−ピペ
リジン２０．０ｇ（９５．６ｍｍｏｌ）、Ｌ−ｏ−クロ
ロタ−トラニル酸２６．１ｇ（１００．４ｍｍｏｌ）、
セライト０．４ｇを混合し、８７℃まで昇温し、濾過し
て熱水２０ｍｌで洗い込んだ。母洗液を５５℃まで冷却
した後、アセトン１００ｍｌを加え、４０℃で接種して
３０〜３４℃で３０分間攪拌した後、３〜５℃まで冷却
し、２４時間熟成した後、濾過し水４０ｍｌで洗浄し、
乾燥して表題化合物２０．７ｇ（収率４４．４％）を得
た。尚、品質は（３Ｓ、４Ｒ）／（３Ｒ、４Ｓ）体＝９
９．０％／１．０％であった。Example 4 (3S, 4R) -trans-3-hydroxymethyl-4
-(4-fluorophenyl) -piperidine, Lo-c
Lorota-tranilate, 180 ml of synthesized water of monohydrate , (3SR, 4RS) -trans-3-hydroxymethyl-4- (4-fluorophenyl) -piperidine 20.0 g (95.6 mmol), Lo -Chlorota-tranylic acid 26.1 g (100.4 mmol),
0.4 g of celite was mixed, heated to 87 ° C., filtered and washed with 20 ml of hot water. After cooling the mother wash solution to 55 ° C, 100 ml of acetone was added, inoculated at 40 ° C, stirred at 30 to 34 ° C for 30 minutes, cooled to 3 to 5 ° C, aged for 24 hours, filtered and filtered. Wash with 40ml,
Drying afforded 20.7 g (44.4% yield) of the title compound. The quality is (3S, 4R) / (3R, 4S) = 9
It was 9.0% / 1.0%.
【００３４】実施例５（３Ｓ、４Ｒ）−トランス−３−ヒドロキシメチル−４
−（４−フルオロフェニル）−ピペリジン、Ｌ−ｏ−ク
ロロタ−トラニル酸塩、一水和物の合成 アセトン９０ｍｌ、ラセミ−トランス−４−（４−フル
オロフェニル）−３−ヒドロキシメチルピペリジン１
０．０ｇ（４７．８ｍｍｏｌ）、Ｌ−ｏ−クロロタ−ト
ラニル酸１３．０ｇ（５０．１ｍｍｏｌ）、セライト
０．２ｇを混合し、４３℃まで昇温し、濾過してアセト
ン１０ｍｌで洗い込んだ。母洗液を２７℃まで冷却し、
接種したが晶析しなかった為、２０℃で水０．８６ｇ
（４７．８ｍｍｏｌ）を加えたところ、晶析した。再度
５７℃まで昇温溶解した後、２８〜３２℃まで冷却し、
１時間熟成した後、濾過し、アセトン２０ｍｌで洗浄
し、乾燥して表題化合物７．６０ｇ（収率３２．７％）
を得た。尚、品質は（３Ｓ、４Ｒ）体／（３Ｒ、４Ｓ）
体＝９６．８％／３．２％であった。Example 5 (3S, 4R) -trans-3-hydroxymethyl-4
-(4-fluorophenyl) -piperidine, Lo-c
Lorota-tranilate, synthesis of monohydrate 90 ml of acetone, racemic-trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine 1
A mixture of 0.0 g (47.8 mmol), 13.0 g (50.1 mmol) of Lo-chlorota-tranylic acid, and 0.2 g of celite was heated to 43 ° C., filtered and washed with 10 ml of acetone. . Cool the mother wash to 27 ° C,
Inoculated but not crystallized, so 0.86 g of water at 20 ° C
When (47.8 mmol) was added, it crystallized. After heating again to 57 ° C., it was cooled to 28 to 32 ° C.,
After aging for 1 hour, the mixture was filtered, washed with 20 ml of acetone, and dried, and 7.60 g (yield 32.7%) of the title compound was obtained.
I got The quality is (3S, 4S) / (3R, 4S)
Body = 96.8% / 3.2%.
【００３５】（３Ｓ、４Ｒ）−トランス−３−ヒドロキ
シメチル−４−（４−フルオロフェニル）−ピペリジ
ン、Ｌ−ｏ−クロロタ−トラニル酸塩、一水和物の物性 旋光度［α］２０ Ｄ＋４２．６°、 融点 １３３．９
℃ 得られた表題化合物を２％水酸化ナトリウム水溶液中で
脱塩して、乾燥して（３Ｓ、４Ｒ）−トランス−３−ヒ
ドロキシメチル−４−（４−フルオロフェニル）−ピペ
リジンを得た（収率８３％）。（３Ｓ、４Ｒ）−トランス−３−ヒドロキシメチル−４
−（４−フルオロフェニル）−ピペリジンの物性値 旋光度［α］２０ Ｄ−３８．１°、 融点９１．９℃ (3S, 4R) -trans-3-hydroxy
Cimethyl-4- (4-fluorophenyl) -piperidi
, Lo-chlorota-tranilate, physical rotation of monohydrate [α] 20 D + 42.6 °, melting point 133.9
C. The obtained title compound was desalted in 2% aqueous sodium hydroxide and dried to give (3S, 4R) -trans-3-hydroxymethyl-4- (4-fluorophenyl) -piperidine ( Yield 83%). (3S, 4R) -trans-3-hydroxymethyl-4
Physical Properties of- (4-Fluorophenyl) -piperidine Optical rotation [α] 20 D −38.1 °, melting point 91.9 ° C.
【００３６】比較例１ （３Ｓ、４Ｒ）−トランス−３−ヒドロキシメチル−４
−（４−フルオロフェニル）−ピペリジン、Ｌ−ｏ−ク
ロロタ−トラニル酸塩、一水和物の合成 水１５０ｍｌ、ラセミ−トランス−３−ヒドロキシメチ
ル−４−（４−フルオロフェニル）−ピペリジン１０．
０ｇ（４７．８ｍｍｏｌ）、Ｌ−ｏ−クロロタ−トラニ
ル酸１３．０ｇ（５０．２ｍｍｏｌ）、７０℃まで昇温
し、接種して５８〜６５℃で３０分間攪拌した後、３５
〜５５℃まで冷却し、１５時間熟成した後、濾過し水２
０ｍｌで洗浄し、乾燥して表題化合物を得た。尚、熟成
温度・熟成時間と収率および品質の関係は下表の通りで
あった。Comparative Example 1 (3S, 4R) -trans-3-hydroxymethyl-4
- (4-Furuorofe sulfonyl) - piperidine, L-o-click
9. Lorotranthranilate, synthetic water of monohydrate 150 ml, racemic-trans-3-hydroxymethyl-4- (4-fluorophenyl) -piperidine
0 g (47.8 mmol), 13.0 g (50.2 mmol) of Lo-chlorota-tranylic acid, heated to 70 ° C., inoculated, stirred at 58 to 65 ° C. for 30 minutes, and then cooled to 35 ° C.
After cooling to ~ 55 ° C and aging for 15 hours,
Wash with 0 ml and dry to give the title compound. The relationship between the aging temperature / aging time, yield and quality was as shown in the table below.
【００３７】なお得られた表題化合物には若干の樹脂状
成分が認められた。従って、本比較例のような方法では
原料化合物ラセミ−トランス−３−ヒドロキシメチル−
４−（４−フルオロフェニル）−ピペリジンは高純度に
精製したものを使用しなければならない。In the obtained title compound, some resinous components were observed. Therefore, in the method as in this comparative example, the starting compound racemic-trans-3-hydroxymethyl-
4- (4-fluorophenyl) -piperidine must be used in a highly purified form.
【００３８】[0038]
【表３】 [Table 3]
【発明の効果】本発明のよればパロキセチン等の医薬中
間体として有用なジアステレマ−結晶が高純度、高収率
で得られる。According to the present invention, diasteremer crystals useful as pharmaceutical intermediates such as paroxetine can be obtained with high purity and high yield.
Claims (9)
ル−４−Ｒ１−ピペリジン類（ここでＲ１は置換基を有
していてもよいフェニル基を表す）と光学活性な有機酸
とを反応させてｄ体由来のジアステレオマ−とｌ体由来
のジアステレオマ−とを生成させ、いずれかのジアステ
レマ−を結晶として析出せしめる方法において、アセト
ン−水溶媒中でジアステレオマ−結晶を析出させること
を特徴とするラセミ−トランス−３−ヒドロキシメチル
−４−Ｒ１−ピペリジン類（ここでＲ１は前述のとおり
である）由来のジアステレオマ−結晶の析出方法。1. A reaction between a racemic-trans-3-hydroxymethyl-4-R 1 -piperidine (where R 1 represents a phenyl group which may have a substituent) and an optically active organic acid. A diastereomer derived from the d-isomer and a diastereomer derived from the l-isomer are formed, and one of the diastereomers is precipitated as a crystal, wherein the diastereomer crystals are precipitated in an acetone-water solvent. A method for depositing diastereomeric crystals derived from racemic-trans-3-hydroxymethyl-4-R 1 -piperidines (where R 1 is as described above).
求項１に記載の析出方法。2. The method according to claim 1, wherein R 1 is a 4-fluorophenyl group.
ル−４−Ｒ１−ピペリジン類がラセミ−トランス−３−
ヒドロキシメチル−４−（４−フルオロフェニル）−ピ
ペリジンである請求項１または２のいずれかに記載の析
出方法。3. The racemic-trans-3-hydroxymethyl-4-R 1 -piperidine is racemic-trans-3-
The method according to claim 1, wherein the method is hydroxymethyl-4- (4-fluorophenyl) -piperidine.
ロタ−トラニル酸である請求項１〜３のいずれかに記載
の析出方法。4. The method according to claim 1, wherein the optically active organic acid is optically active o-chlorota-tranilic acid.
（２Ｒ、３Ｒ）−ｏ−クロロタ−トラニル酸である請求
項４に記載の析出方法。5. The method according to claim 4, wherein the optically active o-chlorota-tolanic acid is (2R, 3R) -o-chlorota-tolanic acid.
（３Ｓ、４Ｒ）−３−ヒドロキシメチル−４−（４−フ
ルオロフェニル）−ピペリジン、（２Ｒ、３Ｒ）−ｏ−
クロロタ−トラニル酸塩、一水和物である請求項１に記
載の析出方法。6. A diastereomer which precipitates as crystals is (3S, 4R) -3-hydroxymethyl-4- (4-fluorophenyl) -piperidine, (2R, 3R) -o-
The precipitation method according to claim 1, wherein the precipitation method is chlorotatranilate or a monohydrate.
／Ｖ）のアセトン−水を用いる請求項１〜６のいずれか
に記載の析出方法。7. Acetone: water = 0.1-0.5: 1 (V
The precipitation method according to any one of claims 1 to 6, wherein (V) acetone-water is used.
アセトン−水を用いる請求項７に記載の析出方法。8. The deposition method according to claim 7, wherein acetone-water of acetone: water = 0.2: 1 (V / V) is used.
ル−４−Ｒ１−ピペリジン類（ここでＲ１は置換基を有
していてもよいフェニル基を表す）と光学活性な有機酸
とを水溶媒中で反応させてｄ体由来のジアステレオマ−
とｌ体由来のジアステレオマ−とを生成させ、次いで、
この反応水溶液にアセトンを添加しアセトン−水溶液と
し冷却し、いずれかのジアステレオマ−を結晶析出させ
る請求項１〜８のいずれかに記載の析出方法。9. A racemic-trans-3-hydroxymethyl-4-R 1 -piperidine (where R 1 represents a phenyl group which may have a substituent) and an optically active organic acid are mixed with water. Diastereomers derived from d-form by reacting in a solvent
And a diastereomer derived from 1-isomer,
The precipitation method according to any one of claims 1 to 8, wherein acetone is added to the reaction aqueous solution to form an acetone-water solution, followed by cooling to precipitate any diastereomer.
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|---|---|---|---|
| JP35639599A JP3780787B2 (en) | 1999-11-09 | 1999-11-09 | Method for precipitation of diastereomeric crystals |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP35639599A JP3780787B2 (en) | 1999-11-09 | 1999-11-09 | Method for precipitation of diastereomeric crystals |
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| Publication Number | Publication Date |
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| JP3780787B2 JP3780787B2 (en) | 2006-05-31 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006282607A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Purification method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate |
| JP2006282605A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Preparation method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate and method for recovering optical resoluting agent |
| JP2006282606A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Method of crystallizing (3s,4r)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine(+)-2'-chlorotartranyl acid monohydrate |
| WO2011024691A1 (en) * | 2009-08-25 | 2011-03-03 | 住友化学株式会社 | Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate |
-
1999
- 1999-11-09 JP JP35639599A patent/JP3780787B2/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006282607A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Purification method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate |
| JP2006282605A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Preparation method of (3s, 4r)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine (+)-2'-chlorotartranyl acid monohydrate and method for recovering optical resoluting agent |
| JP2006282606A (en) * | 2005-04-01 | 2006-10-19 | Sumitomo Chemical Co Ltd | Method of crystallizing (3s,4r)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine(+)-2'-chlorotartranyl acid monohydrate |
| WO2011024691A1 (en) * | 2009-08-25 | 2011-03-03 | 住友化学株式会社 | Process for preparation of optically active ethyl 1-amino-2-ethenylcyclopropanecarboxylate |
| JP2011046613A (en) * | 2009-08-25 | 2011-03-10 | Sumitomo Chemical Co Ltd | Method for producing optically active ethyl 1-amino-2-ethenylcyclopropane-1-carboxylate or acid addition salt thereof, and intermediate used for the production method |
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| Publication number | Publication date |
|---|---|
| JP3780787B2 (en) | 2006-05-31 |
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