JPH01149775A - Production of optically active 2-methylpiperazine - Google Patents
Production of optically active 2-methylpiperazineInfo
- Publication number
- JPH01149775A JPH01149775A JP30885987A JP30885987A JPH01149775A JP H01149775 A JPH01149775 A JP H01149775A JP 30885987 A JP30885987 A JP 30885987A JP 30885987 A JP30885987 A JP 30885987A JP H01149775 A JPH01149775 A JP H01149775A
- Authority
- JP
- Japan
- Prior art keywords
- methylpiperazine
- optically active
- water
- tartaric acid
- organic solvent
- 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
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 title claims description 27
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 13
- 239000011975 tartaric acid Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 9
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 27
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 239000012808 vapor phase Substances 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 15
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 10
- 229960001367 tartaric acid Drugs 0.000 description 10
- JOMNTHCQHJPVAZ-RXMQYKEDSA-N (2r)-2-methylpiperazine Chemical compound C[C@@H]1CNCCN1 JOMNTHCQHJPVAZ-RXMQYKEDSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 5
- JOMNTHCQHJPVAZ-YFKPBYRVSA-N (2s)-2-methylpiperazine Chemical compound C[C@H]1CNCCN1 JOMNTHCQHJPVAZ-YFKPBYRVSA-N 0.000 description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 2
- 229960001270 d- tartaric acid Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VPZXBVLAVMBEQI-GSVOUGTGSA-N Gly-D-Ala Chemical compound [O-]C(=O)[C@@H](C)NC(=O)C[NH3+] VPZXBVLAVMBEQI-GSVOUGTGSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- -1 etc. Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上のオｌｌ１３ＪＬ
本発明は光学活性２−メチルピペラジンの製造方法に関
するものである。DETAILED DESCRIPTION OF THE INVENTION Industrial OlI13JL The present invention relates to a method for producing optically active 2-methylpiperazine.
本発明の方法により得られる光学活性２−メチルピペラ
ジンは医薬品あるいは農薬の合成原料として有用な化合
物で、今後の応用が期待されており、その工業的規模で
の製造方法が求められている。The optically active 2-methylpiperazine obtained by the method of the present invention is a compound useful as a raw material for the synthesis of pharmaceuticals or agricultural chemicals, and is expected to have future applications, and a method for producing it on an industrial scale is required.
従来の技術−
従来光学活性２−メチルピペラジンは、グリシル−（Ｓ
）−アラニンを環化して得られる（Ｓ）−３−メチル−
２，５−ピペラジノンを還元して（−）一体を得、同様
にグリシル−（Ｒ）−アラニンより（＋）一体を得る方
法が知られている（ジャーナル・オブ・ケミカル・リサ
ーチ（シップシス） 、 ４．ｉ３３，１９８０）。し
かし、この従来法は高価な原料を用いなければならず、
しがち収率が低いため、光学活性２−メチルピペラジン
の工業的な生産方法として決して満足できる方法ではな
い。Conventional technology - Conventionally, optically active 2-methylpiperazine is glycyl-(S
)-(S)-3-methyl- obtained by cyclizing alanine
It is known that 2,5-piperazinone is reduced to obtain (-) monomer, and similarly, (+) monomer is obtained from glycyl-(R)-alanine (Journal of Chemical Research (Shipsys), 4.i33, 1980). However, this conventional method requires the use of expensive raw materials,
Since the yield tends to be low, this method is by no means a satisfactory method for industrially producing optically active 2-methylpiperazine.
発明が解決しようとする問題。The problem that the invention seeks to solve.
本発明は、気相法等により安価に製造されている２−メ
チルピペラジンを出発原料として、高収率かつ簡便な光
学活性２−メチルピペラジンの工業的な製造方法を提供
することを目的とする。An object of the present invention is to provide a high-yield and simple industrial method for producing optically active 2-methylpiperazine using 2-methylpiperazine, which is produced at low cost by a gas phase method, as a starting material. .
問題７６．を解決するための手段および作用上記目的は
、本発明方法により解決される。Question 76. Means and Effects for Solving the Problems The above objects are solved by the method of the present invention.
すなわち、本発明は下記（ａ）〜（ｃ）の工程から成る
ことを特徴とする光学活性２−メチルピペラジンの製造
方法に関するものである。That is, the present invention relates to a method for producing optically active 2-methylpiperazine, which is characterized by comprising the following steps (a) to (c).
（ａ） （±）−２−メチルピペラジンと光学活性酒
石酸を溶媒中で反応させて２種のジアステレオマー塩を
生成させる工程；
（ｂ） 上記反応液中の２種のジアステレオマー塩の
溶解度差を利用して相互に分割する工程；
（ｃ） 相互に分割されたジアステレオマー塩をフリ
ー化する工程。(a) A step of reacting (±)-2-methylpiperazine and optically active tartaric acid in a solvent to produce two types of diastereomer salts; (b) A step of producing two types of diastereomer salts in the above reaction solution. (c) A step of freeing the mutually separated diastereomer salts using the difference in solubility.
本発明の出発原料となる（±）−２−メチルピペラジン
は気相法により安価に得られるものである。（±）−２
−メチルピペラジンはく＋）一体と（−）一体が当量台
まれているものに限らず、いずれか一方の光学活性体が
その対掌体に対して等量以上含まれているものでもよい
。(±)-2-Methylpiperazine, which is the starting material of the present invention, can be obtained at low cost by a gas phase method. (±)-2
-Methylpiperazine is not limited to one in which +) and (-) are contained in equivalent amounts, but may be one in which one of the optically active forms is contained in an equivalent or more amount relative to its enantiomer.
本発明において使用される光学活性酒石酸は容易に入手
が可能であり、とくに（＋）−ｄ−酒石酸は安価な光学
分割剤として各方面で利用されている。The optically active tartaric acid used in the present invention is easily available, and (+)-d-tartaric acid in particular is used in various fields as an inexpensive optical resolution agent.
本発明方法は、まず水などのようなく±）−２−メチル
ピペラジンと光学活性酒石酸の両者を溶解しやすい溶媒
に、（±）−２−メチルピペラジンと光学活性酒石酸を
混合溶解して、（±）−２−メチルピペラジンの光学活
性酒石酸との２種のジアステレオマー塩を形成させる。In the method of the present invention, first, (±)-2-methylpiperazine and optically active tartaric acid are mixed and dissolved in a solvent such as water that easily dissolves both (±)-2-methylpiperazine and optically active tartaric acid. Two diastereomeric salts of ±)-2-methylpiperazine with optically active tartaric acid are formed.
（±）−２−メチルピペラジンと光学活性酒石酸のモル
比は、（±）−２−メチルピペラジンに対し光学活性酒
石酸を２倍モル使用するのが最も効率がよく好ましい。Regarding the molar ratio of (±)-2-methylpiperazine to optically active tartaric acid, it is most efficient and preferable to use twice the mole of optically active tartaric acid to (±)-2-methylpiperazine.
次いで、形成された２種のジアステレオマー塩の溶解度
差を利用して相互に分割するには、メタノール、エタノ
ール、アセトンのような前記反応溶媒に可溶で、しかも
ジアステレオマー塩の溶解性が低い溶媒を加えた後、静
置もしくは攪拌下に結晶を析出さればよい。２種のジア
ステレオマー塩は溶解性が異なるため、１種のジアステ
レオマー塩が優先的に析出する。なお、その他の分割方
法として、あらかじめジアステレオマー塩の溶解性の低
い溶媒中でく士）−２−メチルピペラジンと光学活性酒
石酸を反応させ、生成するジアステレオマー塩を析出さ
せてもよい。Next, in order to separate the two formed diastereomeric salts from each other by utilizing the solubility difference, the diastereomeric salts are soluble in the reaction solvent such as methanol, ethanol, or acetone, and the solubility of the diastereomeric salts is After adding a solvent with a low carbon content, crystals may be precipitated by standing or stirring. Since the two types of diastereomeric salts have different solubility, one type of diastereomeric salt precipitates preferentially. As another method of separation, the diastereomeric salt may be precipitated by reacting (2-methylpiperazine) and optically active tartaric acid in a solvent in which the diastereomeric salt has low solubility, and precipitating the resulting diastereomeric salt.
分割の際に用いられる溶媒の種類、量を適宜選択するこ
とによって光学活性２−メチルピペラジンの収量、光学
純度を調整することができる。この時用いられる溶媒と
しては、メタノール、エタノール、１−プロパノール、
２−プロパノール、１−ブタノール、２−ブタノールお
よびアセトン等から選ばれる少なくとも１種の有機溶媒
またはこれらの有機溶媒と水との混合物が挙げられる。The yield and optical purity of optically active 2-methylpiperazine can be adjusted by appropriately selecting the type and amount of the solvent used during the separation. Solvents used at this time include methanol, ethanol, 1-propanol,
Examples include at least one organic solvent selected from 2-propanol, 1-butanol, 2-butanol, acetone, etc., or a mixture of these organic solvents and water.
工業的には水を主体とする混合溶媒が特に好ましい。Industrially, a mixed solvent mainly composed of water is particularly preferred.
使用する溶媒の量は特に限定されないが、例えば水−ア
セトン（３：１）の混合溶媒を用いる場合、工業的には
５〜１０倍量が好ましい。また、難溶性塩を析出させる
温度も溶媒の種類や量により、−１０〜５０℃位の範囲
で可能であるが、操作上の簡便さから室温付近が好まし
い。The amount of the solvent to be used is not particularly limited, but for example, when using a mixed solvent of water and acetone (3:1), it is preferably 5 to 10 times the amount from an industrial perspective. Further, the temperature at which the poorly soluble salt is precipitated can range from -10 to 50°C depending on the type and amount of the solvent, but is preferably around room temperature for ease of operation.
析出しな難溶性のジアステレオマー塩は濾過等の操作に
より分離し、必要に応じてこれを再結晶する。得られた
難溶性塩は水溶性の塩基で処理して分解しフリー化する
。この際用いられる塩基としては、水酸化ナトリウム、
水酸化カリウム等であり、濾別したジアステレオマー塩
に対して４倍モル程度用いればよい。The precipitated poorly soluble diastereomer salt is separated by an operation such as filtration, and recrystallized if necessary. The obtained poorly soluble salt is treated with a water-soluble base to be decomposed and freed. Bases used at this time include sodium hydroxide,
Potassium hydroxide or the like may be used in an amount of about 4 times the mole of the diastereomer salt separated by filtration.
フリー化した液は、ベンゼン、トルエン等の有機溶媒で
抽出し、次いで常圧もしくは減圧下で有機溶媒を留去し
、必要ならさらに蒸留することにより、（＋）また（−
）−２−メチルピペラジンが得られる。The freed liquid is extracted with an organic solvent such as benzene or toluene, and then the organic solvent is distilled off under normal pressure or reduced pressure. If necessary, further distillation is performed to extract (+) or (-
)-2-methylpiperazine is obtained.
一方、難溶性のジアステレオマー塩を濾別した後の濾液
は、水酸化ナトリウム等の塩基を加えて分解し、ベンゼ
ン等の有機溶媒で抽出した後溶媒を留去することにより
、難溶性のジアステレオマー塩と反対の光学活性２−メ
チルピペラジンを得ることができる。On the other hand, the filtrate after filtering off the poorly soluble diastereomer salts is decomposed by adding a base such as sodium hydroxide, extracted with an organic solvent such as benzene, and the solvent is distilled off. Optically active 2-methylpiperazine opposite the diastereomeric salt can be obtained.
得られた光学活性２−メチルピペラジンの光学純度が不
足している場合は、最初に使用した光学活性酒石酸と反
対の光学活性を有する酒石酸を使用して、同様の操作に
より最初に得られた光学活性２−メチルピペラジンと反
対の光学活性を有する２−メチルピペラジンを得ること
ができる。If the optical purity of the optically active 2-methylpiperazine obtained is insufficient, use tartaric acid having an optical activity opposite to that of the optically active tartaric acid used initially, and perform the same operation to obtain the optically active 2-methylpiperazine originally obtained. 2-Methylpiperazine having an optical activity opposite to that of active 2-methylpiperazine can be obtained.
聚施１Ｌ
水６００ｍ１にｄ−酒石酸１１７．９９ｇ （０，７８
６モル）とく±）−２−メチルピペラジン３９．３７ｇ
（０，３９３モル）を室温下溶解し、さらにアセトン２
００ｍ１を加え、攪拌しながら一晩放置した。析出した
結晶を濾取し、乾燥するとく＋）−２−メチルピペラジ
ン・ｄ−酒石酸塩（１：２）７１．０１ｇが得られた。d-tartaric acid 117.99g (0,78
6 mol) ±)-2-methylpiperazine 39.37 g
(0,393 mol) at room temperature, and then acetone 2
00ml was added and left overnight with stirring. The precipitated crystals were collected by filtration and dried to obtain 71.01 g of 2-methylpiperazine/d-tartrate (1:2).
このものの収率は４５．１％であった。この結晶に４０
％水酸化ナトリウム水溶液を加え、分離する油分をベン
ゼン５０ｍ１で２回抽出した。ベンゼン層を乾燥後、常
圧で濃縮してベンゼンを留去すると、残渣結晶として（
＋）−２−メチルピペラジンが得られ、このもの（’）
比り光度ハ［ａ ］Ｆ ＝ ＋ ４．７ （Ｃ＝ ０．
４、メタノール）であった。なお、比旋光度の測定には
日本分光■製ｒＤＩＰ−１４０型ディジタツル旋光計を
用いた。The yield of this product was 45.1%. 40 in this crystal
% aqueous sodium hydroxide solution was added, and the oil that separated was extracted twice with 50 ml of benzene. After drying the benzene layer, the benzene is distilled off by concentrating it at normal pressure, and the residual crystals (
+)-2-methylpiperazine is obtained, which (')
Comparative luminosity C[a]F = + 4.7 (C = 0.
4, methanol). Note that a digital polarimeter rDIP-140 manufactured by JASCO Corporation was used to measure the specific rotation.
先の（＋）−２−メチルピペラジン・ｄ−酒石酸塩（１
：２）を水−アセトン（１： ３）の混合溶液を溶媒と
して、常法に従って３回再結晶を繰り返した後、４０％
水酸化ナトリウム水溶液を加えて分離してくる油分をベ
ンゼン５０ｍ１で２回抽出した。ベンゼン層を乾燥し、
常圧下で濃縮してベンゼンを留去すると、残渣結晶とし
て（＋）−２−メチルピペラジンが得られ、このものの
比旋光度は［α］： ＝＋５．４ （Ｃ＝０．４、メタ
ノール）であった。この結晶をさらに数回再結晶を繰り
返しても、比旋光度は同じ値であった。(+)-2-methylpiperazine d-tartrate (1
:2) was recrystallized three times using a mixed solution of water and acetone (1:3) as a solvent according to a conventional method, and then 40%
An aqueous sodium hydroxide solution was added and the oil separated was extracted twice with 50 ml of benzene. Dry the benzene layer,
When benzene is distilled off by concentration under normal pressure, (+)-2-methylpiperazine is obtained as a residual crystal, and the specific optical rotation of this is [α]: = +5.4 (C = 0.4, methanol) Met. Even if this crystal was recrystallized several more times, the specific rotation remained the same.
実施例２
水１００ｍ１にｄ−酒石酸３０．０ｇ（０，２モル〉と
く±）−２−メチルピペラジン１０．０ｇ（０，１モル
）を室温下溶解し、さらにエタノール７０ｍ１を加え攪
拌しながら一晩放置した。析出した結晶を濾取し、乾燥
すると（＋）−２−メチルピペラジン・ｄ−酒石酸塩（
１：２）２４．９ｇが得られた。収率は６２．５％であ
った。この結晶に４０％水酸化ナトリウム水溶液を加え
て分離する油分をベンゼン５０ｍ１で２回抽出した。ベ
ンゼン層を乾燥後、常圧で濃縮してベンゼンを留去する
と、残渣結晶として（＋）−２−メチルピペラジンが得
られ、このものの比旋光度は［αＩＨ＝＋２．ｓ（Ｃ＝
０．５、メタノール）であった。また、結晶母液は濃
縮した後、４０％水酸化ナトリウム水溶液を加えて分離
する油分をベンゼン５０ｍ１で２回抽出した。ベンゼン
層を乾燥後、常圧で濃縮してベンゼンを留去すると、残
渣として（−）−２−メチルピペラジンが得られ、この
ものの比旋光度ハ［α］Ｆ ＝−５，３（Ｃ＝０．２、
メタノール）テあった。Example 2 30.0 g (0.2 mol)-2-methylpiperazine 10.0 g (0.1 mol) was dissolved in 100 ml of water at room temperature, and then 70 ml of ethanol was added and the mixture was stirred. I left it for the night. The precipitated crystals are collected by filtration and dried to give (+)-2-methylpiperazine d-tartrate (
1:2) 24.9 g was obtained. The yield was 62.5%. A 40% aqueous sodium hydroxide solution was added to the crystals, and the separated oil was extracted twice with 50 ml of benzene. After drying the benzene layer, the benzene is distilled off by concentrating at normal pressure to obtain (+)-2-methylpiperazine as a residual crystal, which has a specific optical rotation of [αIH=+2. s(C=
0.5, methanol). Further, after concentrating the crystal mother liquor, a 40% aqueous sodium hydroxide solution was added, and the separated oil was extracted twice with 50 ml of benzene. After drying the benzene layer, the benzene is distilled off by concentrating at normal pressure to obtain (-)-2-methylpiperazine as a residue, which has a specific optical rotation of [α]F = -5,3(C= 0.2,
methanol) was present.
実施例３
水５００ｍ１にｄ−酒石酸７８１ｇ（０，５２モル）と
く±）−２−メチルピペラジン２６．１ ｇ（０，２６
モル）を室温下溶解し、さらにメタノール３００ｍ１、
アセトン１００ｍ１を加え攪拌しながら一晩放置した。Example 3 781 g (0.52 mol) of d-tartaric acid and 26.1 g (0.26 mol) of -2-methylpiperazine were added to 500 ml of water.
mol) at room temperature, and further added 300 ml of methanol,
100 ml of acetone was added and left overnight with stirring.
析出した結晶を濾取し、乾燥すると（＋）−２−メチル
ピペラジン・ｄ−酒石酸塩１ ： ２）４２．８ｇが得
られた。収率は４１．１％であった。この結晶に４０％
水酸化ナトリウム水溶液を加えて分離する油分をベンゼ
ン１００ｍ１で２回抽出しな。ベンゼン層を乾燥後、常
圧下で濃縮してベンゼンを留去すると、残渣結晶として
（＋）−２−メチルピペラジンが得られ、このものの比
旋光度は［α］Ｆ ＝＋４．１ （Ｃ＝０．３、メタノ
ール）であった。また晶析母液は残渣が２５０ｇになる
まで濃縮し、そこにアセトン２００ｍ１を加えて攪拌し
ながら一晩放置した。析出した結晶を濾取し、乾燥する
と（−）−２−メチルピペラジン・ｄ−酒石酸塩（１：
２）５６．４ｇが得られた。収率は５４．２％であった
。この結晶に４０％水酸化ナトリウム水溶液を加えて分
離する油分をベンゼン１００ｍ１で２回抽出した。ベン
ゼン層を乾燥後、常圧下で濃縮してベンゼンを留去する
と、残渣として（−）−２−メチルピペラジンが得られ
、このものの比旋光度は［αＩＦ ＝−５゜０（Ｃ＝０
．４、メタノール）であった。The precipitated crystals were collected by filtration and dried to obtain 42.8 g of (+)-2-methylpiperazine/d-tartrate (1:2). The yield was 41.1%. 40% to this crystal
Add an aqueous sodium hydroxide solution and extract the oil separated twice with 100ml of benzene. After drying the benzene layer, the benzene is distilled off by concentrating it under normal pressure to obtain (+)-2-methylpiperazine as a residual crystal, and the specific optical rotation of this is [α]F = +4.1 (C= 0.3, methanol). Further, the crystallization mother liquor was concentrated until the residue amounted to 250 g, and 200 ml of acetone was added thereto and left overnight with stirring. The precipitated crystals were collected by filtration and dried to give (-)-2-methylpiperazine d-tartrate (1:
2) 56.4g was obtained. The yield was 54.2%. A 40% aqueous sodium hydroxide solution was added to the crystals, and the separated oil was extracted twice with 100 ml of benzene. After drying the benzene layer, the benzene is distilled off by concentrating under normal pressure to obtain (-)-2-methylpiperazine as a residue, and the specific optical rotation of this is [αIF = -5°0 (C = 0
．． 4, methanol).
発明の効果−
本発明方法により、気相法によって安価に得られる（±
）−２−メチルピペラジンを出発原料として、光学活性
２−メチルピペラジンが高収率かつ簡便に工業的規模で
生産できる。Effects of the invention - By the method of the present invention, it can be obtained at low cost by the gas phase method (±
)-2-Methylpiperazine as a starting material, optically active 2-methylpiperazine can be easily produced in high yield on an industrial scale.
Claims (1)
る光学活性２−メチルピペラジンの製造方法。 （ａ）（±）−２−メチルピペラジンと光学活性酒石酸
を溶媒中で反応させて２種のジアステレオマー塩を生成
させる工程； （ｂ）上記反応液中の２種のジアステレオマー塩の溶解
度差を利用して相互に分割する工程； （ｃ）相互に分割されたジアステレオマー塩をフリー化
する工程。 ２、前記工程（ｂ）において、メタノール、エタノール
、１−プロパノール、２−プロパノール、１−ブタノー
ル、２−ブタノールおよびアセトンから選ばれる少なく
とも１種の有機溶媒またはこれらの有機溶媒と水との混
合物中で２種のジアステレオマー塩を相互に分割する特
許請求の範囲第１項記載の方法。[Scope of Claims] 1. A method for producing optically active 2-methylpiperazine, which comprises the following steps (a) to (c). (a) A step of reacting (±)-2-methylpiperazine and optically active tartaric acid in a solvent to produce two types of diastereomeric salts; (b) A step of producing two types of diastereomeric salts in the above reaction solution. (c) A step of freeing the mutually separated diastereomer salts using the difference in solubility. 2. In the step (b), at least one organic solvent selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and acetone, or a mixture of these organic solvents and water. 2. The method according to claim 1, wherein two diastereomeric salts are mutually resolved.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30885987A JPH01149775A (en) | 1987-12-07 | 1987-12-07 | Production of optically active 2-methylpiperazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30885987A JPH01149775A (en) | 1987-12-07 | 1987-12-07 | Production of optically active 2-methylpiperazine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01149775A true JPH01149775A (en) | 1989-06-12 |
Family
ID=17986117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30885987A Pending JPH01149775A (en) | 1987-12-07 | 1987-12-07 | Production of optically active 2-methylpiperazine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01149775A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04128270A (en) * | 1990-05-08 | 1992-04-28 | Toray Ind Inc | Production of optically active 2-methylpiperazine |
| JP2016037495A (en) * | 2014-08-08 | 2016-03-22 | 東レ・ファインケミカル株式会社 | Method for producing optically active 2-methylpiperazine |
| JP2018507173A (en) * | 2014-12-23 | 2018-03-15 | セファロン、インク． | Method for preparing fused bicyclic 2,4-diaminopyrimidine derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4897801A (en) * | 1972-02-25 | 1973-12-13 | ||
| JPS51118711A (en) * | 1974-12-13 | 1976-10-18 | Merck & Co Inc | Dividing method and compound |
| JPS51146487A (en) * | 1975-06-06 | 1976-12-16 | Hoffmann La Roche | Optically active dibenzo *b*f* thiepines |
-
1987
- 1987-12-07 JP JP30885987A patent/JPH01149775A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4897801A (en) * | 1972-02-25 | 1973-12-13 | ||
| JPS51118711A (en) * | 1974-12-13 | 1976-10-18 | Merck & Co Inc | Dividing method and compound |
| JPS51146487A (en) * | 1975-06-06 | 1976-12-16 | Hoffmann La Roche | Optically active dibenzo *b*f* thiepines |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04128270A (en) * | 1990-05-08 | 1992-04-28 | Toray Ind Inc | Production of optically active 2-methylpiperazine |
| JP2016037495A (en) * | 2014-08-08 | 2016-03-22 | 東レ・ファインケミカル株式会社 | Method for producing optically active 2-methylpiperazine |
| KR20170039071A (en) * | 2014-08-08 | 2017-04-10 | 도오레 화인케미칼 가부시키가이샤 | Method for producing optically active 2-methylpiperazine |
| EP3178815A4 (en) * | 2014-08-08 | 2018-02-28 | Toray Fine Chemicals Co., Ltd. | Method for producing optically active 2-methylpiperazine |
| JP2018507173A (en) * | 2014-12-23 | 2018-03-15 | セファロン、インク． | Method for preparing fused bicyclic 2,4-diaminopyrimidine derivatives |
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