JP2999146B2 - Racemization method for aminoketone derivatives - Google Patents
Racemization method for aminoketone derivativesInfo
- Publication number
- JP2999146B2 JP2999146B2 JP7287067A JP28706795A JP2999146B2 JP 2999146 B2 JP2999146 B2 JP 2999146B2 JP 7287067 A JP7287067 A JP 7287067A JP 28706795 A JP28706795 A JP 28706795A JP 2999146 B2 JP2999146 B2 JP 2999146B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- lower alkyl
- acid
- alkyl group
- mol
- 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 - Fee Related
Links
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は中枢性の筋弛緩作用
を有する光学活性なアミノケトン誘導体の製造法に関す
る。さらに詳しくはラセミのアミノケトン誘導体を光学
分割後の不要な光学活性なアミノケトン誘導体をラセミ
化させて再利用する方法を提供するものである。The present invention relates to a method for producing an optically active aminoketone derivative having a central muscle relaxing action. More specifically, the present invention provides a method for reusing a racemic aminoketone derivative after racemizing an unnecessary optically active aminoketone derivative after optical resolution.
【０００２】[0002]
【従来の技術】アミノケトンを有する３−フェニル−５
−｛２−（ピロリジニルメチル）ブチリル｝イソオキサ
ゾール［以下、ＰＩＰと略記する］は中枢性筋弛緩作用
を有することが知られている（特開平３−１５７３７５
号公報）。とりわけその一方の光学活性なＰＩＰはラセ
ミ体に比べて、さらに顕著な中枢性筋弛緩作用を有し、
筋緊張改善剤として有効な化合物である。この光学活性
ＰＩＰの製造法としては、光学活性なＬ−カンファース
ルホン酸でジアステレオマー塩を形成させて光学分割す
る方法である（特開平５−１３８０号公報）。該光学分
割方法においてはもう一方の不要な光学活性ＰＩＰをラ
セミ化等させて再利用しなければ目的物の収率低下等の
問題点が生じ、工業的には必ずしも満足できる方法とは
いえない。光学活性なＰＩＰから１００％ラセミ化した
ＰＩＰを得る方法としては、不要な光学活性ＰＩＰと弱
酸水溶液を作用させて３−フェニル−５−｛２−エチル
−２−プロペノイル）イソオキサゾール［以下、ＰＩＥ
と略記する］を生成させ、その後にピロリジンと反応さ
せて１００％ラセミ化したＰＩＰを製造する方法を出願
したが、該方法ではＰＩＥを一旦単離させるために工程
が煩雑となるばかりでなく、新たに等モル以上のピロリ
ジンを必要とする為に工業的にも満足できる方法ではな
い。また、アミノケトン誘導体の回収方法としては、２
−メチル−１−（４−トリフルオロメチルフエニル）−
３−ピロリジノ−１−プロパノン（以下、ＭＴＰと略記
する）を光学活性な光学分割剤にて光学分割した後の濾
液にピロリジンを加えてＭＴＰを回収する方法（特開昭
６３−３１０８７８号公報）があるが、回収して得たＭ
ＴＰのラセミ化率については何ら記載あるいは示唆の記
載がなく該回収法は不要な光学活性体をラセミ化させて
回収する方法ではない。また、該方法においては回収し
た誘導体を一旦単離させるために製造工程が煩雑となる
ばかりでなく、新たに高価なピロリジンが必要となるた
めに工業的に満足できる方法ではない。BACKGROUND OF THE INVENTION 3-Phenyl-5 with aminoketone
-{2- (Pyrrolidinylmethyl) butyryl} isoxazole (hereinafter abbreviated as PIP) is known to have a central muscle relaxing action (Japanese Patent Application Laid-Open No. 3-157375).
No.). In particular, one of the optically active PIPs has a more remarkable central muscle relaxing action than the racemic body,
It is a compound effective as a muscle tone improving agent. The method for producing the optically active PIP, a method of optical resolution by forming diastereomeric salts with optically active L- camphorsulfonic scan <br/> sulfonic acid (JP-A-5-1380). In the optical resolution method, if the other unnecessary optically active PIP is not racemized and reused, there arises a problem such as a decrease in the yield of the target product, which is not always industrially satisfactory. . As a method for obtaining 100% racemized PIP from optically active PIP, 3-phenyl-5- {2-ethyl-2-propenoyl) isoxazole [hereinafter referred to as PIE]
And a reaction with pyrrolidine to produce 100% racemized PIP. However, this method not only complicates the process for once isolating PIE but also complicates the process. This method is industrially unsatisfactory since a new equimolar amount of pyrrolidine is required. In addition, as a method for recovering the aminoketone derivative, 2
-Methyl-1- (4-trifluoromethylphenyl)-
A method in which 3-pyrrolidino-1-propanone (hereinafter abbreviated as MTP) is optically resolved with an optically active optical resolving agent, and pyrrolidine is added to the filtrate to recover MTP (JP-A-63-310878). There is M
There is no description or suggestion about the racemization rate of TP, and this recovery method is not a method of recovering an unnecessary optically active substance by racemizing it. In addition, this method is not industrially satisfactory because not only the production process becomes complicated because the recovered derivative is once isolated, but also expensive pyrrolidine is newly required.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、前記した先
行技術のようにラセミなアミノケトン誘導体を光学分割
後、不要な光学活性アミノケトン誘導体をラセミ化させ
る為に、一旦中間体を生成させ単離して新たにピロリジ
ンと反応させてラセミ化させることなく、簡便に且つ安
価な方法で不要な光学活性アミノケトン誘導体を１００
％ラセミ化させることを課題とするものである。SUMMARY OF THE INVENTION According to the present invention, as described in the prior art, after an optical resolution of a racemic aminoketone derivative, an intermediate is once formed and isolated in order to racemize an unnecessary optically active aminoketone derivative. 100% of unnecessary optically active aminoketone derivatives by a simple and inexpensive method without reacting with pyrrolidine and causing racemization.
It is an object of the present invention to make the composition racem%.
【０００４】[0004]
【発明を解決するための手段】本発明者等はこの課題達
成の為に光学活性アミノケトン誘導体のラセミ化方法に
ついて鋭意検討した。その結果、驚くべきことに光学活
性アミノケトン誘導体と触媒量の酸解離定数の逆数の対
数値（ｐＫａ）が２以上の弱酸を作用させると、光学活
性アミノケトン誘導体が容易にラセミ化することを発見
した。更にこのラセミ化方法により、敢えて反応中間体
を単離することなく、容易に光学活性アミノケトン誘導
体をラセミ化できることを見出し、本発明を完成するに
至った。The present inventors have intensively studied a method for racemizing an optically active aminoketone derivative in order to achieve this object. As a result, surprisingly , the pair of the optically active aminoketone derivative and the reciprocal of the acid dissociation constant
It has been discovered that when a weak acid having a numerical value (pKa) of 2 or more is applied, the optically active aminoketone derivative is easily racemized. Furthermore, they have found that the optically active aminoketone derivative can be easily racemized without intentionally isolating the reaction intermediate by this racemization method, and have completed the present invention.
【０００５】即ち、本発明は一般式（１）That is, the present invention provides a compound represented by the general formula (1):
【化３】 ［この式中Ｒ1はEmbedded image [Where R 1 is
【化４】 を表し（Ｒ5はハロゲン原子：低級アルキル基：ベンジ
ル基：ベンゾイル基：ピリジル基：低級アルキル基で置
換されていてもよいフリル基；低級アルキル基で置換さ
れていても良いチエニル基；ハロゲン原子、低級アルコ
キシ基、低級アルキル基、トリフルオロメチル基、シア
ノ基、ニトロ基、アミノ基、ジメチルアミノ基、アセト
アミド基、メタンスルホニルアミド基、アセチル基また
は低級アルコキシカルボニル基で置換されていても良い
フェニル基またはナフチル基を、Ｒ6はトリフルオロメ
チル基、低級アルキル基で置換されていても良いフェニ
ル基を、Ｚは酸素原子またはイオウ原子を表す。）、ま
たＲ2は低級アルキル基、ベンジル基、メトキシ基、フ
ェニル基、アリル基、トリフルオロメチル基もしくは低
級アルコキシ基、またはシクロプロピルメチル基を表
す。Ｒ3及びＲ4はそれぞれ独立して飽和もしくは不飽和
の低級アルキル基を表すか、Ｒ3とＲ4が環状に結合して
ピロリジン、ピペラジン、ヘキサメチレンイミン、モル
ホリン及びピぺラジンからなる群より選択された一種の
環状構造を形成しているものであっても良く、該環状構
造はメチル基、またはベンジル基で置換されていても良
い］で表される光学活性アミノケトン誘導体を有機溶媒
中にて酸解離定数の逆数の対数値（ｐＫａ）が２以上の
弱酸と作用させてラセミ化させる方法を提供するもので
ある。Embedded image (R 5 is a halogen atom: a lower alkyl group: a benzyl group: a benzoyl group: a pyridyl group: a furyl group optionally substituted with a lower alkyl group; a thienyl group optionally substituted with a lower alkyl group; a halogen atom A phenyl optionally substituted with a lower alkoxy group, a lower alkyl group, a trifluoromethyl group, a cyano group, a nitro group, an amino group, a dimethylamino group, an acetamido group, a methanesulfonylamide group, an acetyl group or a lower alkoxycarbonyl group R 6 represents a trifluoromethyl group or a phenyl group which may be substituted with a lower alkyl group; Z represents an oxygen atom or a sulfur atom; and R 2 represents a lower alkyl group or a benzyl group. Methoxy, phenyl, allyl, trifluoromethyl or lower alkoxy, Represents a cyclopropylmethyl group. R 3 and R 4 each independently represent a saturated or unsaturated lower alkyl group, or R 3 and R 4 are cyclically bonded to form a group consisting of pyrrolidine, piperazine, hexamethyleneimine, morpholine and piperazine The optically active aminoketone derivative represented by the following formula may be formed in an organic solvent: a selected cyclic structure may be formed, and the cyclic structure may be substituted with a methyl group or a benzyl group. The present invention provides a method of causing racemization by acting with a weak acid having a logarithmic value (pKa) of 2 or more of the reciprocal of the acid dissociation constant .
【０００６】本発明の方法は前記先行技術には何ら記載
あるいは示唆されておらず、従って本発明者らによって
はじめて見いだされた技術であり、医薬分野及び工業的
にも利用価値の高い光学活性アミノケトン誘導体のラセ
ミ化方法である。[0006] The method of the present invention is neither described or suggested in the above prior art, and is therefore a technique first discovered by the present inventors, and is an optically active aminoketone of high utility in the pharmaceutical field and industrially. This is a method for racemizing derivatives.
【０００７】本発明の具体的な態様は以下の通りであ
る。光学活性アミノケトン誘導体の有機溶媒溶液に酸解
離定数の逆数の対数値（ｐＫａ）が２以上の弱酸を加え
数時間作用させてラセミ化したアミノケトン誘導体を得
る。The specific embodiments of the present invention are as follows. Acid decomposition into organic solvent solution of optically active aminoketone derivative
A racemic aminoketone derivative is obtained by adding a weak acid having a logarithmic value (pKa) of 2 or more to the reciprocal of the separation constant and acting for several hours.
【０００８】本発明の方法で使用する光学活性アミノケ
トン誘導体は特開平５−５１３８０号公報に記載の方法
にて製造することができる。例えば、アミノケトンを有
する（−）ＰＩＰは具体的には３−フェニル−ブチルイ
ソオキサゾールとピロリジンをメタノールに溶解した溶
液にホルマリンを加えてＰＩＰを生成させ有機溶媒にて
抽出する。抽出後有機溶媒層に光学活性なＤ−１０−カ
ンファースルホン酸を加えて光学分割操作を行い、後処
理後に（−）ＰＩＰを塩酸塩として単離する。また
（＋）ＭＴＰの製造法としては、まず特開昭６３−１１
９４２４号公報に記載の方法にてＭＴＰを生成した後
で、特開昭６３−２２５３６７号公報に記載の方法にて
光学分割し、（＋）ＭＴＰを製造する。具体的には１−
（４−α，α，α−トリフルオロメチルフェニル）−１
−プロパノン、パラホルムアルデヒド、ピロリジン塩酸
塩、イソプロピルアルコールの混合溶液に濃塩酸を加え
て加熱還流することでＭＴＰが生成する。ＭＴＰはＬ−
アセチルフェニルグリシンで光学分割操作を行った後で
（＋）ＭＴＰの塩酸塩の形で単離する。[0008] The optically active aminoketone derivative used in the method of the present invention can be produced by the method described in JP-A-5-51380. For example, (-) PIP having an aminoketone is specifically prepared by adding formalin to a solution of 3-phenyl-butylisoxazole and pyrrolidine in methanol to form PIP, and extracting the resultant with an organic solvent. Performed an optical resolution operation with addition of optically active D-10- mosquito <br/> Nfa over acid extraction after the organic solvent layer, after workup (-) isolating PIP as the hydrochloride salt. As a method for producing (+) MTP, first, JP-A-63-11 / 1988
After generating MTP by the method described in Japanese Patent No. 9424, optical separation is performed by the method described in JP-A-63-225367 to produce (+) MTP. Specifically, 1-
(4-α , α , α-trifluoromethylphenyl) -1
-MTP is generated by adding concentrated hydrochloric acid to a mixed solution of propanone, paraformaldehyde, pyrrolidine hydrochloride and isopropyl alcohol and heating to reflux. MTP is L-
After optical resolution with acetylphenylglycine, it is isolated in the form of the (+) MTP hydrochloride.
【０００９】本発明で使用する有機溶媒としては、具体
的にはジクロロメタン、クロロホルム、１，２−ジクロ
ロエタン等のハロゲン化炭化水素類、メチルプロピルケ
トン、メチルイソブチルケトン等のケトン類、酢酸エチ
ル、酢酸ブチル、酢酸プロピル、酢酸アミル等の酢酸ア
ルキルエステル類、またはベンゼン、トルエン、キシレ
ン、クロロベンゼン、ジクロロベンゼン、ニトロベンゼ
ン等の芳香族炭化水素類が好ましい。特に好ましは酢酸
エチル、酢酸ブチル等の酢酸アルキルエステル類であ
る。Examples of the organic solvent used in the present invention include halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, ketones such as methyl propyl ketone and methyl isobutyl ketone, ethyl acetate and acetic acid. Alkyl acetates such as butyl, propyl acetate and amyl acetate, or aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene and nitrobenzene are preferred. Particularly preferred are alkyl acetates such as ethyl acetate and butyl acetate.
【００１０】光学活性アミノケトン誘導体と作用させる
弱酸とは酸解離定数の逆数の対数値（以下、ｐＫａと略
する）が２以上の酸である。好ましくはｐＫａが４以上
である次亜塩素酸、ほう酸等の無機酸、酢酸、酪酸、グ
ルタル酸、コハク酸等の有機酸である。The weak acid to act on the optically active aminoketone derivative is an acid having an inverse logarithm of the acid dissociation constant (hereinafter abbreviated as pKa) of 2 or more . Preferred are inorganic acids such as hypochlorous acid and boric acid having a pKa of 4 or more, and organic acids such as acetic acid, butyric acid, glutaric acid and succinic acid.
【００１１】酸解離定数の逆数の対数値（ｐＫａ）が２
以上である弱酸の使用量はアミノケトン誘導体に対して
０．１倍モル以上であればよいが、好ましくは１．０倍
モル以上であればよい。特に好ましくは１．２倍モル以
上である。使用量の上限について特に制限はないが、あ
まり過剰に用いるのは経済的見地から好ましくない。そ
の為通常は１０倍モル以下で使用される。 The logarithm (pKa) of the reciprocal of the acid dissociation constant is 2
The amount of the above weak acid may be at least 0.1 times the mol of the aminoketone derivative, and preferably at least 1.0 times the mol. Especially preferably, it is 1.2 times or more. There is no particular upper limit to the amount used, but excessive use is not preferable from an economical point of view. Therefore, it is usually used in a molar amount of 10 times or less.
【００１２】有機溶媒中の光学活性アミノケトン誘導体
の濃度はとくに限定されるものではないが、１〜５０％
の範囲である。好ましくは１０〜３０重量％の範囲であ
る。１重量％未満では反応上特に問題点はないが、容積
効率の低下ならびに経済上の見地から好ましくはない。
一方５０重量％以上では反応混合物が粘ちょうになり反
応が充分に進行せずラセミ化率が低下することがある。The concentration of the optically active aminoketone derivative in the organic solvent is not particularly limited, but may be from 1 to 50%
Range. Preferably it is in the range of 10 to 30% by weight. If the amount is less than 1% by weight, there is no particular problem in the reaction, but it is not preferable from the viewpoint of reduction in volumetric efficiency and economical viewpoint.
On the other hand, if it is 50% by weight or more, the reaction mixture becomes viscous and the reaction does not proceed sufficiently, so that the racemization ratio may decrease.
【００１３】酸解離定数の逆数の対数値（ｐＫａ）が２
以上である弱酸と作用させる温度は−１０〜８０℃まで
許容され、好ましくは０〜６０℃の範囲である。−１０
℃未満では反応が充分進行せず収率が低下する。一方８
０℃を越えると光学活性アミノケトン誘導体の分解が起
こり易く収率が低下することがある。反応の終点はガス
クロマトグラフィーまたは液体クロマトグラフィーなど
の手段を用いて容易に知ることができる。 The logarithmic value (pKa) of the reciprocal of the acid dissociation constant is 2
The temperature at which the above-mentioned weak acid is allowed to act is allowed in the range of -10 to 80C, and preferably in the range of 0 to 60C. -10
If the temperature is lower than ℃, the reaction does not proceed sufficiently and the yield decreases. 8
When the temperature exceeds 0 ° C., the optically active aminoketone derivative is easily decomposed, and the yield may be reduced. The end point of the reaction can be easily known using a means such as gas chromatography or liquid chromatography.
【００１４】ラセミ化反応終了後は炭酸水素ナトリウ
ム、炭酸ナトリウム等のアルカリ水溶液で該溶媒層を中
和洗浄後、必要に応じて副生した中間体は等モルのピロ
リジン等のアミン類を加えてラセミ化したアミノケトン
誘導体にすればよい。引き続き該溶媒層を水洗浄し無水
硫酸ナトリウム等で乾燥した後で光学活性な１０−カン
ファースルホン酸、アセチルフェニルグリシン等の光学
分割剤を加えて光学分割すればよい。After completion of the racemization reaction, the solvent layer is neutralized and washed with an aqueous alkali solution such as sodium hydrogencarbonate or sodium carbonate, and if necessary, an intermediate by-produced by adding an equimolar amine such as pyrrolidine. It may be a racemized aminoketone derivative. Subsequently the solvent layer optically active after drying with water washed over anhydrous sodium sulfate or the like 10 cans <br/> files over acid may be optically resolved by adding an optical resolution agent such as acetyl phenylglycine.
【００１５】[0015]
【実施例】以下、実施例によって本発明の方法を詳細に
説明する。 参考例１ 〔３−フェニル−５−ブチリルイソオキサゾール〕ベン
ズアルドキシム１０ｇ（０．０８２モル）および１−ヘ
キシン−３−オール９ｇ（０．０９２モル）をジクロロ
メタン５０ｍｌに溶解した。反応液を氷冷し、１２％次
亜塩素酸ナトリウム水溶液５８ｇ（０．１モル）を内温
１５〜２５℃に保ちながら滴下した。滴下終了後、内温
１５〜２５℃に保ちながら３時間撹拌した。この反応液
に１２％次亜塩素酸ナトリウム水溶液４９ｇ（０．０７
９モル）を滴下した。反応液の内温を１０℃に冷却し、
ピリジン塩酸塩水溶液（６Ｎ塩酸２．８ｍｌとピリジン
１．３ｍｌで調製）を２０分間かけて滴下した。その後
１２％次亜塩素酸ナトリウム水溶液とピリジン塩酸塩
水溶液を交互に３回ずつ滴下反応した。反応液を分液し
て得られたジクロロメタン層に５％亜硫酸水素ナトリウ
ム水溶液１００ｍｌを加えて３０分間撹拌した。ジクロ
ロメタン層を水、塩酸水の順に洗浄した後ジクロロメタ
ンを留去した。残渣をエタノール４０ｍｌから再結晶し
て目的化合物１０．６ｇを得た。融点８９〜９０℃EXAMPLES The method of the present invention will be described below in detail with reference to examples. Reference Example 1 [3-Phenyl-5-butyrylisoxazole] 10 g (0.082 mol) of benzaldoxime and 9 g (0.092 mol) of 1-hexyn-3-ol were dissolved in 50 ml of dichloromethane. The reaction solution was ice-cooled, and 58 g (0.1 mol) of a 12% aqueous solution of sodium hypochlorite was added dropwise while maintaining the internal temperature at 15 to 25 ° C. After completion of the dropwise addition, the mixture was stirred for 3 hours while maintaining the internal temperature at 15 to 25 ° C. 49 g of a 12% aqueous sodium hypochlorite solution (0.07
9 mol) was added dropwise. Cool the internal temperature of the reaction solution to 10 ° C,
An aqueous solution of pyridine hydrochloride (prepared with 2.8 ml of 6N hydrochloric acid and 1.3 ml of pyridine) was added dropwise over 20 minutes. Thereafter, a 12% aqueous sodium hypochlorite solution and a pyridine hydrochloride aqueous solution were alternately and dropwisely added three times. 100 ml of a 5% aqueous sodium bisulfite solution was added to the dichloromethane layer obtained by separating the reaction solution, and the mixture was stirred for 30 minutes. The dichloromethane layer was washed with water and aqueous hydrochloric acid in that order, and then dichloromethane was distilled off. The residue was recrystallized from 40 ml of ethanol to obtain 10.6 g of the desired compound. 89-90 ° C
【００１６】参考例２ 〔３−フェニル−５−（２−ピロリジノメチルブチリ
ル）イソオキサゾール塩酸塩〕３−フェニル−５−ブチ
リルイソオキサゾール２０ｇ（０．０９３モル）及びピ
ロリジン７．９３ｇ（０．１１１モル）をメタノール６
２ｇに加えた。反応液を撹拌し、内温を２０〜３０℃に
保ちながら３７％ホルマリン水溶液９．０４ｇ（０．１
１１モル）を滴下した。滴下終了後、２０〜３０℃に保
ち、１時間撹拌した。反応液に酢酸エチル１７８ｇを加
えた。さらに水１５０ｇを加え分液抽出して有機層を得
た。得られた有機層を氷冷し、２Ｎ塩酸水溶液１７８ｇ
を加えて分液抽出した。得られた水層をクロロホルム１
８０ｇで抽出した。水層を再びクロロホルムで抽出し、
得られたクロロホルム層を合わせて無水硫酸ナトリウム
で乾燥した。硫酸ナトリウムを濾別して得られたクロロ
ホルム溶液に酢酸エチル２９４ｇを撹拌下、滴下した。
溶液を氷冷して析出した結晶を濾取して酢酸エチルで洗
浄し、減圧下乾燥して無色の目的化合物を２０．８ｇ得
た。融点１５１〜１５３℃Reference Example 2 [3-phenyl-5- (2-pyrrolidinomethylbutyryl) isoxazole hydrochloride] 3-phenyl-5-butyrylisoxazole 20 g (0.093 mol) and pyrrolidine 7.93 g ( 0.111 mol) in methanol 6
2 g. The reaction solution was stirred, and 9.04 g (0.1%) of a 37% aqueous formalin solution was maintained while maintaining the internal temperature at 20 to 30 ° C.
11 mol) was added dropwise. After completion of the dropwise addition, the mixture was kept at 20 to 30 ° C and stirred for 1 hour. 178 g of ethyl acetate was added to the reaction solution. Further, 150 g of water was added, and the mixture was separated and extracted to obtain an organic layer. The obtained organic layer was ice-cooled, and 178 g of a 2N hydrochloric acid aqueous solution was obtained.
Was added for liquid separation and extraction. The resulting aqueous layer was washed with chloroform 1
Extracted with 80 g. The aqueous layer was extracted again with chloroform,
The obtained chloroform layers were combined and dried over anhydrous sodium sulfate. 294 g of ethyl acetate was added dropwise to a chloroform solution obtained by filtering off sodium sulfate while stirring.
The solution was cooled on ice, and the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain 20.8 g of a colorless target compound. 151-153 ° C
【００１７】参考例３ 〔（−）−３−フェニル−５−（２−ピロリジノメチル
ブチリル）イソオキサゾール塩酸塩〕 ＰＩＰ１０ｇ（０．０３３３モル）を酢酸エチル２００
ｍｌに溶解した。この溶液にＤ−１０カンファースルホ
ン酸１１．５ｇを加えて３０分間撹拌し、溶解させた。
この溶液を氷冷下２時間撹拌して析出した結晶を濾取し
た。得られた結晶を酢酸エチルで洗浄後乾燥して（−）
ＰＩＰ・Ｄ−１０カンファースルホン酸塩１１．８ｇを
得た。（−）ＰＩＰ・Ｄ−カンファースルホン酸塩７．
０ｇを水４０ｍｌと酢酸エチル４０ｍｌの混合液に溶解
し、１０％炭酸ナトリウム水溶液２２ｍｌを加え、１０
分間撹拌した。反応液を分液し、得られた有機層を１０
％炭酸ナトリウム水溶液１１ｍｌで洗浄した。ついで、
この有機層を２Ｎ塩酸水１７ｍｌで２回抽出して、水層
を合わせた。この水溶液からクロロホルム１２ｍｌで２
回抽出してクロロホルム層を合わせた。得られたクロロ
ホルム溶液を無水硫酸ナトリウムで乾燥した。硫酸ナト
リウムを濾別して得たクロロホルム溶液に酢酸エチル７
２ｍｌを滴下して１時間室温で撹拌した後、氷冷下、１
時間撹拌した。析出した結晶を濾取して（−）ＰＩＰ塩
酸塩２．５ｇを得た。融点１４５〜１４６℃ 光学純度
９９．８５％以上Reference Example 3 [(-)-3-phenyl-5- (2-pyrrolidinomethylbutyryl) isoxazole hydrochloride] 10 g (0.0333 mol) of PIP was added to 200 ml of ethyl acetate.
Dissolved in ml. This solution was added to D-10 camphor <br/> phosphate 11.5g was stirred for 30 minutes to dissolve.
The solution was stirred for 2 hours under ice cooling, and the precipitated crystals were collected by filtration. The obtained crystals were washed with ethyl acetate and then dried (-).
To obtain a PIP · D-10 camphorsulfonate 11.8g. (-) PIP · D- camphorsulfonate 7.
0 g was dissolved in a mixture of 40 ml of water and 40 ml of ethyl acetate, and 22 ml of a 10% aqueous sodium carbonate solution was added.
Stirred for minutes. The reaction solution was separated, and the obtained organic layer was separated into 10
Washed with 11 ml of a 10% aqueous sodium carbonate solution. Then
The organic layer was extracted twice with 17 ml of 2N aqueous hydrochloric acid, and the aqueous layers were combined. From this aqueous solution, add 2 ml of chloroform
It was extracted twice and the chloroform layers were combined. The obtained chloroform solution was dried over anhydrous sodium sulfate. Ethyl acetate 7 was added to the chloroform solution obtained by filtering off sodium sulfate.
2 ml was added dropwise, and the mixture was stirred at room temperature for 1 hour.
Stirred for hours. The precipitated crystals were collected by filtration to obtain 2.5 g of (-) PIP hydrochloride. Melting point 145-146 ° C Optical purity 99.85% or more
【００１８】実施例１ 酢酸ブチル５００ｇに（−）ＰＩＰ塩酸塩１１２．２ｇ
（０．３３５モル）と５％炭酸ナトリウム水溶液７４
１．９ｇ（０．３５０モル）を加えて脱塩した。有機溶
媒層を分液して５００ｇの水で洗浄し、無水硫酸ナトリ
ウム１５ｇにて乾燥した。乾燥剤除去後に酢酸１０ｇ
（０．１６８モル）を加え２０〜３０℃の温度で１５時
間撹拌してラセミ化反応させた。反応終了後に有機溶媒
層を５％炭酸ナトリウム水溶液４００ｇで洗浄し、無水
硫酸ナトリウム２０ｇにて乾燥した。乾燥剤除去後キラ
ルカラムによる液体クロマトグラフィー分析にて該有機
溶媒層のＰＩＰの（＋）体と（−）体の比率を調べた結
果５０：５０であった。該有機溶媒層にＬ−１０−カン
ファースルホン酸１５５ｇ（０．６７モル）を加えて２
種類のジアステレオマー塩を形成させ、難溶性のジアス
テレオマー塩を晶析させて固体を分離し、乾燥して
（＋）ＰＩＰ・Ｌ−１０−カンファースルホン酸塩を得
た。 収量 １１５．０ｇ（０．１５１モル） 収率 ４５．１モル％〔対（−）ＰＩＰ塩酸塩〕 光学純度 ９９．５％ｅｅExample 1 112.2 g of (-) PIP hydrochloride was added to 500 g of butyl acetate.
(0.335 mol) and 5% aqueous solution of sodium carbonate 74
1.9 g (0.350 mol) was added and desalted. The organic solvent layer was separated, washed with 500 g of water, and dried with 15 g of anhydrous sodium sulfate. Acetic acid 10g after desiccant removal
(0.168 mol) and stirred at a temperature of 20 to 30 ° C. for 15 hours to cause a racemization reaction. After completion of the reaction, the organic solvent layer was washed with 400 g of a 5% aqueous sodium carbonate solution and dried with 20 g of anhydrous sodium sulfate. After the desiccant was removed, the ratio of the (+) form and the (-) form of PIP in the organic solvent layer was determined by liquid chromatography analysis using a chiral column, and the result was 50:50. 155 g (0.67 mol) of L-10-camphorsulfonic acid was added to the organic solvent layer to give 2
Different diastereomeric salts were formed, the poorly soluble diastereomer salt was crystallized, and the solid was separated and dried to obtain (+) PIP · L-10-camphorsulfonate. Yield 115.0 g (0.151 mol) Yield 45.1 mol% [vs. (-) PIP hydrochloride] Optical purity 99.5% ee
【００１９】実施例２ 酢酸ブチル５００ｇに（−）ＰＩＰ塩酸塩１１２．２ｇ
（０．３３５モル）と５％炭酸ナトリウム水溶液７４
１．９ｇ（０．３５０モル）を加えて脱塩した。有機溶
媒層を分液して５００ｇの水で洗浄し、無水硫酸ナトリ
ウム１５ｇにて乾燥した。乾燥後に酢酸２０ｇ（０．３
３３モル）を加え２０〜３０℃の温度で１５時間撹拌し
てラセミ化反応させた。反応終了後に有機溶媒層を５％
炭酸ナトリウム水溶液４００ｇで洗浄し、無水硫酸ナト
リウム２０ｇにて乾燥した。乾燥剤除去後キラルカラム
による液体クロマトグラフィー分析にて該反応液中のＰ
ＩＰの（＋）体と（−）体の比率を調べた結果５０：５
０であった。該有機溶媒層にＬ−１０−カンファースル
ホン酸１５５ｇ（０．６７モル）を加えて２種類のジア
ステレオマー塩を形成させ、難溶性のジアステレオマー
塩を晶析させて固体を分離し、乾燥して（＋）ＰＩＰ・
Ｌ−１０−カンファースルホン酸塩を得た。 収量 １０９．９ｇ（０．１４４モル） 収率 ４３．０モル％〔対（−）ＰＩＰ塩酸塩〕 光学純度 ９９．５％ｅｅEXAMPLE 2 112.2 g of (-) PIP hydrochloride was added to 500 g of butyl acetate.
(0.335 mol) and 5% aqueous solution of sodium carbonate 74
1.9 g (0.350 mol) was added and desalted. The organic solvent layer was separated, washed with 500 g of water, and dried with 15 g of anhydrous sodium sulfate. After drying, 20 g of acetic acid (0.3 g
33 mol) and stirred at a temperature of 20 to 30 ° C. for 15 hours to cause a racemization reaction. After the reaction, 5% of organic solvent layer
It was washed with 400 g of an aqueous sodium carbonate solution and dried with 20 g of anhydrous sodium sulfate. After removing the desiccant, P in the reaction solution was determined by liquid chromatography analysis using a chiral column.
The result of examining the ratio of the (+) form and the (-) form of IP was 50: 5.
It was 0. 155 g (0.67 mol) of L-10-camphorsulfonic acid was added to the organic solvent layer to form two kinds of diastereomeric salts, and a hardly soluble diastereomer salt was crystallized to separate a solid. Dry (+) PIP ・
L-10-Camphorsulfonate was obtained. Yield 109.9 g (0.144 mol) Yield 43.0 mol% [vs. (-) PIP hydrochloride] Optical purity 99.5% ee
【００２０】参考例４ ２−メチル−１−（４−トリフルオロメチルフェニル）
−３−ピロリジノ−１−プロパノン １−（４−α，α，α−トリフルオロメチルフェニル）
−１−プロパノン２．５ｇ、パラホルムアルデヒド１．
１１ｇ、ピロリジン塩酸塩１．６ｇ及びイソプロピルア
ルコール２０ｍｌとの混合液に濃塩酸０．１ｍｌを加え
１６時間加熱還流する。反応終了後、反応液を減圧下に
濃縮しイソプロピルアルコールを留去する。得られた残
渣に水を加え酢酸エチルで洗浄する。その水層をアンモ
ニア水でアルカリ性とし、酢酸エチルで抽出する。この
酢酸エチル層を無水硫酸マグネシウムで乾燥し、乾燥剤
除去後濃縮して油状物の目的化合物１．５８ｇを得た。Reference Example 4 2-methyl-1- (4-trifluoromethylphenyl)
-3-Pyrrolidino-1-propanone 1- (4-α, α, α-trifluoromethylphenyl)
2.5 g of -1-propanone, paraformaldehyde 1.
0.1 ml of concentrated hydrochloric acid is added to a mixture of 11 g, 1.6 g of pyrrolidine hydrochloride and 20 ml of isopropyl alcohol, and the mixture is refluxed for 16 hours. After completion of the reaction, the reaction solution is concentrated under reduced pressure, and isopropyl alcohol is distilled off. Water is added to the obtained residue and the mixture is washed with ethyl acetate. The aqueous layer is made alkaline with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated after removing the desiccant to give 1.58 g of the target compound as an oil.
【００２１】参考例５ （＋）−２−メチル−１−（４−トリフルオロメチルフ
ェニル）−３−ピロリジノ−１−プロパノン塩酸塩 ＭＴＰ３０６ｇ（１．０７モル）及びｄ−アセチルフェ
ニルグリシン（〔α〕 20 D−２１２．８°，ｃ＝１．
０，メタノール）２１０ｇ（１．０８モル）を酢酸エチ
ル１４００ｍｌに溶解し、塩を生成させた後、室温で一
晩放置ついで約５℃で３時間撹拌する。析出した結晶を
濾過し、減圧乾燥するとＭＴＰ・Ｌ−アセチルフェニル
グリシン塩２１９ｇを得る。濾液からも１７５ｇの２次
晶を得る。結晶３９４ｇに１０％食塩水６３０ｍｌ、酢
酸エチル９５０ｍｌ、及び２８％アンモニア水６０ｍｌ
を加えて溶解後、有機層を食塩水で洗浄し、無水硫酸マ
グネシウムで乾燥する。乾燥剤除去後酢酸エチル溶液中
に冷却下塩化水素ガス２９ｇを徐々に導入後、内温約５
℃で２時間撹拌する。析出した結晶を濾過し、酢酸エチ
ルで洗浄後減圧乾燥すると（＋）ＭＴＰ塩酸塩２１７ｇ
を得る。Reference Example 5 (+)-2-Methyl-1- (4-trifluoromethylphenyl)
Enyl) -3-pyrrolidino-1-propanone hydrochloride MTP (306 g, 1.07 mol) and d-acetylphene
Nylglycine ([α] 20 D−212.8 °, c = 1.
210 g (1.08 mol) of ethyl acetate
Dissolved in 1400 ml of toluene to form a salt,
Stir overnight then stir at about 5 ° C. for 3 hours. The precipitated crystals
After filtration and drying under reduced pressure, MTP ・ L-acetylphenyl
219 g of the glycine salt are obtained. 175g secondary from filtrate
Obtain crystals. 394 g of crystals, 630 ml of 10% saline, vinegar
Ethyl acid 950ml and 28% ammonia water 60ml
The organic layer was washed with brine and dried over anhydrous
Dry with gnesium. After removing the desiccant, in ethyl acetate solution
After gradually introducing 29 g of hydrogen chloride gas under cooling, the internal temperature was reduced to approx.
Stir for 2 hours at ° C. The precipitated crystals are filtered, and ethyl acetate is added.
After washing with water and drying under reduced pressure, (+) MTP hydrochloride 217 g
Get.
【００２２】実施例３ 酢酸ブチル５００ｇに（＋）ＭＴＰ塩酸塩１０７．９６
ｇ（０．３３５モル）と５％アンモニア水１１９．０ｇ
（０．３５０モル）を加えて脱塩した。脱塩後に分液し
て溶媒層を水５００ｇで洗浄し、酢酸１０ｇ（０．１６
８モル）を加え２０〜３０℃の温度で２５時間撹拌して
ラセミ化反応させた。反応終了後に有機溶媒層を５％炭
酸ナトリウム水溶液４００ｇで洗浄した。洗浄後に無水
硫酸マグネシウム２０ｇにて２０時間乾燥した。乾燥剤
除去後減圧乾燥下にて濃縮することにより、油状のＭＴ
Ｐ９３．６７ｇ（０．３１８モル）を得た。収率は
（＋）ＭＴＰ塩酸塩に対して９８モル％であった。また
ＭＴＰをキラルカラムによる液体クロマトグラフィー分
析を行った結果、（＋）体：（−）体の比は５０：５０
であった。EXAMPLE 3 (+) MTP hydrochloride 107.96 in 500 g of butyl acetate
g (0.335 mol) and 119.0 g of 5% aqueous ammonia
(0.350 mol) and desalted. After desalting, liquid separation was performed, and the solvent layer was washed with 500 g of water and 10 g of acetic acid (0.16 g).
8 mol) and stirred at a temperature of 20 to 30 ° C. for 25 hours to cause a racemization reaction. After the completion of the reaction, the organic solvent layer was washed with 400 g of a 5% aqueous sodium carbonate solution. After washing, it was dried with 20 g of anhydrous magnesium sulfate for 20 hours. After removing the desiccant, the mixture is concentrated under reduced pressure to give an oily MT.
93.67 g (0.318 mol) of P were obtained. The yield was 98 mol% based on (+) MTP hydrochloride. Further, as a result of performing liquid chromatography analysis of MTP using a chiral column, the ratio of (+)-form: (-)-form was 50:50.
Met.
【００２３】[0023]
【発明の効果】本発明の方法によれば、不要な光学活性
アミノケトン誘導体をラセミ化させる為に、一旦中間体
を生成させ単離して新たにピロリジン等のアミンと反応
させてラセミ化させることなく、簡便に且つ安価な方法
で不要な光学活性アミノケトン誘導体を１００％ラセミ
化させることが可能となり工業的に価値の高い方法であ
る。According to the method of the present invention, in order to racemize an unnecessary optically active aminoketone derivative, an intermediate is once generated, isolated, and reacted with an amine such as pyrrolidine to be newly racemized. In addition, it is possible to racemize an unnecessary optically active aminoketone derivative by 100% by a simple and inexpensive method, which is an industrially valuable method.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ Ａ６１Ｋ 31/42 Ａ６１Ｋ 31/42 31/425 31/425 Ｃ０７Ｂ 55/00 Ｃ０７Ｂ 55/00 Ａ (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 221/00 C07C 225/06 C07D 261/08 C07D 275/02 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. 7 Identification code FI A61K 31/42 A61K 31/42 31/425 31/425 C07B 55/00 C07B 55/00 A (58) Fields surveyed (Int. Cl. 7, DB name) C07C 221/00 C07C 225/06 C07D 261/08 C07D 275/02 CA (STN) REGISTRY (STN)
Claims (4)
ル基：ベンゾイル基：ピリジル基：低級アルキル基で置
換されていてもよいフリル基；低級アルキル基で置換さ
れていても良いチエニル基；ハロゲン原子、低級アルコ
キシ基、低級アルキル基、トリフルオロメチル基、シア
ノ基、ニトロ基、アミノ基、ジメチルアミノ基、アセト
アミド基、メタンスルホニルアミド基、アセチル基また
は低級アルコキシカルボニル基で置換されていても良い
フェニル基またはナフチル基を、Ｒ6はトリフルオロメ
チル基、低級アルキル基で置換されていても良いフェニ
ル基を、Ｚは酸素原子またはイオウ原子を表す。）、ま
たＲ2は低級アルキル基、ベンジル基、メトキシ基、フ
ェニル基、アリル基、トリフルオロメチル基もしくは低
級アルコキシ基、またはシクロプロピルメチル基を表
す。Ｒ3及びＲ4はそれぞれ独立して飽和もしくは不飽和
の低級アルキル基を表すか、Ｒ3とＲ4が環状に結合して
ピロリジン、ピペラジン、ヘキサメチレンイミン、モル
ホリン及びピぺラジンからなる群より選択された一種の
環状構造を形成しているものであっても良く、該環状構
造はメチル基、またはベンジル基で置換されていても良
い］で表される光学活性アミノケトン誘導体を有機溶媒
中にて酸解離定数の逆数の対数値（ ｐＫａ）が２以上の
弱酸と作用させてラセミ化させる方法。1. A compound of the general formula (1) [Wherein R 1 is (R 5 is a halogen atom: a lower alkyl group: a benzyl group: a benzoyl group: a pyridyl group: a furyl group optionally substituted with a lower alkyl group; a thienyl group optionally substituted with a lower alkyl group; a halogen atom A phenyl optionally substituted with a lower alkoxy group, a lower alkyl group, a trifluoromethyl group, a cyano group, a nitro group, an amino group, a dimethylamino group, an acetamido group, a methanesulfonylamide group, an acetyl group or a lower alkoxycarbonyl group R 6 represents a trifluoromethyl group or a phenyl group which may be substituted with a lower alkyl group; Z represents an oxygen atom or a sulfur atom; and R 2 represents a lower alkyl group or a benzyl group. Methoxy, phenyl, allyl, trifluoromethyl or lower alkoxy, Represents a cyclopropylmethyl group. R 3 and R 4 each independently represent a saturated or unsaturated lower alkyl group, or R 3 and R 4 are cyclically bonded to form a group consisting of pyrrolidine, piperazine, hexamethyleneimine, morpholine and piperazine The optically active aminoketone derivative represented by the following formula may be formed in an organic solvent: a selected cyclic structure may be formed, and the cyclic structure may be substituted with a methyl group or a benzyl group. A method of causing a logarithmic value ( pKa) of the reciprocal of the acid dissociation constant to act on a weak acid having 2 or more to cause racemization.
アルキルエステル類、ケトン類、芳香族炭化水素類であ
る請求項１に記載の方法。2. The method according to claim 1, wherein the organic solvent is a halogenated hydrocarbon, an alkyl acetate, a ketone, or an aromatic hydrocarbon.
２以上の弱酸が有機酸である請求項１記載の方法。3. The method according to claim 1, wherein the weak acid having a logarithm (pKa) of the reciprocal of the acid dissociation constant of 2 or more is an organic acid.
２以上の弱酸と作用させる温度が−５〜８０℃である請
求項１記載の方法。4. The logarithmic value (pKa) of the reciprocal of the acid dissociation constant is
The method according to claim 1, wherein the temperature at which the reaction with two or more weak acids is carried out is -5 to 80C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7287067A JP2999146B2 (en) | 1994-11-11 | 1995-11-06 | Racemization method for aminoketone derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6-277370 | 1994-11-11 | ||
| JP27737094 | 1994-11-11 | ||
| JP7287067A JP2999146B2 (en) | 1994-11-11 | 1995-11-06 | Racemization method for aminoketone derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08208572A JPH08208572A (en) | 1996-08-13 |
| JP2999146B2 true JP2999146B2 (en) | 2000-01-17 |
Family
ID=26552361
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7287067A Expired - Fee Related JP2999146B2 (en) | 1994-11-11 | 1995-11-06 | Racemization method for aminoketone derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2999146B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4834333B2 (en) * | 2005-06-27 | 2011-12-14 | アルプス薬品工業株式会社 | Method for producing optically active benzylamine derivative |
| CN112375005A (en) * | 2019-08-16 | 2021-02-19 | 国药集团工业有限公司 | Racemization method of ketamine, its derivative or its salt |
-
1995
- 1995-11-06 JP JP7287067A patent/JP2999146B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08208572A (en) | 1996-08-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4118946B2 (en) | Process for the production of levobupivacaine and its analogues | |
| JPH10507464A (en) | Crystallization of levobupivacaine and its analogs | |
| KR102236806B1 (en) | Process for the preparation of enantiomerically enriched 3-aminopiperidine | |
| JP2999146B2 (en) | Racemization method for aminoketone derivatives | |
| JP2912570B2 (en) | Racemization method for aminoketone derivatives | |
| JP2871556B2 (en) | Propenone derivative and method for producing the same | |
| NO772745L (en) | PROCEDURES FOR THE PREPARATION OF N-SUBSTITUTED PYRROLIDINES | |
| EP0973737A4 (en) | Efficient synthesis of a chiral mediator | |
| JP2005509011A (en) | Recovery and reuse of chiral tartaric acid resolving agent | |
| JPH1036327A (en) | Production of optically active isomer of 1-(3-methoxyphenyl)ethylamine | |
| US20190127315A1 (en) | Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester | |
| JP3157118B2 (en) | Optical resolution method of piperidine derivative using acylamino acid | |
| US20040073057A1 (en) | Racemization of optically active 2-substituted phenyl glycine esters | |
| JP3304419B2 (en) | Method for producing optically active 1- (4-halogenophenyl) ethylamine | |
| JP3552260B2 (en) | Optical resolution of 1-amino-2-indanols | |
| JP2004315535A (en) | Method for preparing hexahydropyridazine-3-carboxylic acid derivative | |
| JP3284608B2 (en) | Method for producing optically active 1-phenylethylamine derivative | |
| JP4441260B2 (en) | Process for producing 4-amino-4-phenylpiperidines | |
| EP0990637A1 (en) | Process for producing ketoprofen and 5-benzoyl-3-methyl-2-indolinone | |
| SU1198065A1 (en) | Method of producing benzoic ether of 2,5-dimethylpiperidol-4 alpha-isomer | |
| JP2004143170A (en) | Method for obtaining enantio-concentrated 3-aminopentanenitrile or its salt | |
| JPS63310878A (en) | Recovery of propanone derivative | |
| JP2005075754A (en) | Method for optical resolution of trans-1,2-bis(3,5-dimethylphenyl)-1,2-ethanediamine | |
| JP2001064275A (en) | Optical resolution of isocoumarin derivative | |
| JP2001288171A (en) | Method for producing optically active tetrahydroisoquinoline derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |