JPH10109977A - Production of optically active pyridazinone derivative - Google Patents
Production of optically active pyridazinone derivativeInfo
- Publication number
- JPH10109977A JPH10109977A JP28295396A JP28295396A JPH10109977A JP H10109977 A JPH10109977 A JP H10109977A JP 28295396 A JP28295396 A JP 28295396A JP 28295396 A JP28295396 A JP 28295396A JP H10109977 A JPH10109977 A JP H10109977A
- Authority
- JP
- Japan
- Prior art keywords
- pyridazinone
- formula
- configuration
- optically active
- tartaric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明が属する技術分野】本発明は式［II］The present invention relates to a compound of the formula [II]
【化３】 で表されるＲ−配置またはＳ−配置を有する光学活性ピ
リダジノンの工業的に有用な製造方法に関する。式［I
I］で表される光学活性ピリダジノンは、例えば、ＷＯ
９６／１５１１７に記載されている優れた血小板凝集抑
制作用を有する式［III ］Embedded image An industrially useful method for producing an optically active pyridazinone having an R-configuration or an S-configuration represented by The formula [I
The optically active pyridazinone represented by I] is, for example, WO
Formula [III] having an excellent platelet aggregation inhibitory action described in US Pat.
【化４】 で表される化合物の中間体として有用である。Embedded image It is useful as an intermediate of the compound represented by
【０００２】[0002]
【従来の技術】光学活性ピリダジノンの製造法としては
一般的に光学異性体分離用カラムで分離する方法（例え
ばＥＰ２０８５１８など）が知られているが、工業的規
模には適用できない。特開平３−１６３０５０に４−
（４−アミノフェニル）−３−メチル−４−オキシブチ
ル酸から不斉還元法により合成する方法が報告されてい
るが、高温、高圧下の反応なため特殊な設備が必要とな
る。また特表平６−５０４２７５に２−プロパノール溶
媒中で、Ｌ−またはＤ−酒石酸を２〜３当量使用し光学
分割する方法が記載されている。しかし、この方法は光
学純度が１０％ｅｅ程度のピリダジノン・酒石酸塩を得
るために大量の溶媒を必要とするうえ、熟成のための時
間を多く取らねばならず、また分割効率も低い。溶媒量
を低減あるいは製造時間を短縮すると、得られる塩の光
学純度は著しく低下し、やはり工業生産には不向きであ
る。2. Description of the Related Art As a method for producing an optically active pyridazinone, a method of separating it with an optical isomer separation column (for example, EP208518) is generally known, but cannot be applied on an industrial scale. JP-A-3-163050
Although a method of synthesizing from (4-aminophenyl) -3-methyl-4-oxybutyric acid by an asymmetric reduction method has been reported, special equipment is required because of the reaction under high temperature and high pressure. JP-T-Hei 6-504275 describes a method for optical resolution using L- or D-tartaric acid in an amount of 2-3 equivalents in a 2-propanol solvent. However, this method requires a large amount of a solvent in order to obtain a pyridazinone / tartrate having an optical purity of about 10% ee, requires much time for ripening, and has a low resolution. When the amount of the solvent is reduced or the production time is shortened, the optical purity of the obtained salt is remarkably reduced, which is unsuitable for industrial production.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、式［II］で
表される光学活性ピリダジノンを工業生産に有利な方法
によって製造することを目的としている。An object of the present invention is to produce an optically active pyridazinone represented by the formula [II] by a method advantageous for industrial production.
【０００４】[0004]
【課題を解決するための手段】本発明は（１）式［Ｉ］According to the present invention, there is provided (1) the formula [I]
【化５】 で表されるピリダジノンのラセミ体（以下、（±）−ピ
リダジノンという）をＬ−またはＤ−酒石酸を分割剤と
して、低級アルコールとエステル類との混合溶媒中で分
割することを特徴とする式［II］で表されるＲ−配置ま
たはＳ−配置を有する光学活性ピリダジノンの製造方
法、（２）（±）−ピリダジノンを有機溶媒中、Ｌ−ま
たはＤ−酒石酸を１モルに対し０．３〜１．８モル使用
し、分割することを特徴とするＲ−配置またはＳ−配置
を有する光学活性ピリダジノンの製造方法及び（３）上
記（１）または（２）により分割され、不要のＲ−配置
またはＳ−配置を有する光学活性ピリダジノンまたはそ
の酒石酸塩が過剰に含まれる系を酸または塩基で処理す
ることによる（±）−ピリダジノンの回収方法である。Embedded image A racemate of pyridazinone (hereinafter referred to as (±) -pyridazinone) represented by the formula: wherein L- or D-tartaric acid is used as a resolving agent in a mixed solvent of a lower alcohol and an ester; II] A method for producing an optically active pyridazinone having an R-configuration or an S-configuration represented by (2): (2) using (±) -pyridazinone in an organic solvent, L- or D-tartaric acid in an amount of 0.3 to 1 mol. A method for producing an optically active pyridazinone having an R-configuration or an S-configuration characterized by using 1.8 moles and resolving, and (3) an unnecessary R-configuration separated by the above (1) or (2) Or a method for recovering (±) -pyridazinone by treating a system containing an optically active pyridazinone or its tartrate salt having an S-configuration in excess with an acid or a base.
【０００５】[0005]
【発明の実施の形態】前記式［II］の化合物は下記式BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [II] is represented by the following formula:
【化６】 で表されるＲ体またはＳ体のいずれかであるが、前記式
［III ］の中間体として用いる場合は前者のＲ体が使用
される。光学分割剤として使用するＬ−またはＤ−酒石
酸は、前記式［II］のＲ体を得る場合にはＬ−酒石酸が
好適である。光学分割は、（±）−ピリダジノンおよび
Ｌ−またはＤ−酒石酸に低級アルコールとエステル類と
の混合溶媒を添加するか、または低級アルコールとエス
テル類との混合溶媒に（±）−ピリダジノンおよびＬ−
またはＤ−酒石酸を添加後、両者が溶解するまで昇温し
その温度で数分から数時間加熱する。その後冷却し、必
要に応じて光学活性ピリダジノンの酒石酸塩を接種し、
撹拌した後に析出した光学活性ピリダジノンの酒石酸塩
を濾別する。得られた塩の結晶は、実用可能な高い光学
純度を有し、再結晶等の手段によってさらに光学純度を
上げることができる。このようにして得られた光学活性
体の塩は炭酸カリウム、炭酸ナトリウム、水酸化ナトリ
ウムなどのアルカリ水溶液によりフリー化した後、再結
晶などの手法によって光学純度の高いＲまたはＳピリダ
ジノンを製造することができる。Embedded image In the case where it is used as an intermediate of the formula [III], the former R-form is used. The L- or D-tartaric acid used as the optical resolving agent is preferably L-tartaric acid when the R-form of the formula [II] is obtained. Optical resolution can be performed by adding a mixed solvent of a lower alcohol and an ester to (±) -pyridazinone and L- or D-tartaric acid, or by adding a mixed solvent of a lower alcohol and an ester to (±) -pyridazinone and L-tartaric acid.
Alternatively, after adding D-tartaric acid, the temperature is raised until both are dissolved, and the mixture is heated at that temperature for several minutes to several hours. After cooling, inoculate an optically active pyridazinone tartrate as needed,
After stirring, the precipitated tartrate salt of the optically active pyridazinone precipitated is filtered off. The obtained salt crystals have a practically high optical purity, and the optical purity can be further increased by means such as recrystallization. The salt of the optically active substance thus obtained is made free with an aqueous alkali solution such as potassium carbonate, sodium carbonate or sodium hydroxide, and then R or S pyridazinone with high optical purity is produced by a technique such as recrystallization. Can be.
【０００６】酒石酸の量は、（±）−ピリダジノンに対
して２モル以上使用しても低級アルコール等の単独溶媒
中で分割するよりは好結果が得られるが、好ましくは
０．３〜１．８モル、特に好ましくは１．０〜１．５モ
ルである。ここで用いる低級アルコール／エステル類の
混合溶媒の低級アルコール類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、ｎ−ブ
タノール、ｉ−ブタノール等のＣ1 〜Ｃ4 のアルコール
類が好ましいが、１−プロパノール、２−プロパノール
が特に好ましい。エステル類としてはカルボン酸の低級
アルキルエステルが好ましいが、酢酸エチル、酢酸メチ
ルが特に好ましい。混合溶媒の溶媒量としては使用する
溶媒種、混合比によって異なるが、（±）−ピリダジノ
ンと酒石酸の塩が加熱還流下、溶解できる量が好まし
い。低級アルコール／エステル類の混合比は用いる溶媒
の種類によって異なるが、通常１０／９０〜９０／１
０、好ましくは３０／７０〜７０／３０である。また、
混合溶媒にかえ、１−プロパノール、２−プロパノール
等の低級アルコール等の単独溶媒でも酒石酸の量を前記
好ましい範囲に規制することにより、従来法に比べ光学
純度を向上させることができる。The use of tartaric acid in an amount of 2 mol or more with respect to (±) -pyridazinone can provide better results than resolution in a single solvent such as a lower alcohol, but is preferably 0.3 to 1. The amount is 8 mol, particularly preferably 1.0 to 1.5 mol. As the lower alcohol of the mixed solvent of lower alcohol / ester used here, C 1 to C 4 alcohols such as methanol, ethanol, 1-propanol, 2-propanol, n-butanol and i-butanol are preferable, 1-propanol and 2-propanol are particularly preferred. As the esters, lower alkyl esters of carboxylic acids are preferred, and ethyl acetate and methyl acetate are particularly preferred. The amount of the mixed solvent varies depending on the kind of the solvent used and the mixing ratio, but is preferably an amount capable of dissolving the salt of (±) -pyridazinone and tartaric acid under heating and reflux. The mixing ratio of lower alcohols / esters varies depending on the type of solvent used, but is usually 10/90 to 90/1.
0, preferably 30/70 to 70/30. Also,
By controlling the amount of tartaric acid within the above preferred range even with a single solvent such as a lower alcohol such as 1-propanol or 2-propanol instead of the mixed solvent, the optical purity can be improved as compared with the conventional method.
【０００７】上記操作により分割され不要となった光学
活性ピリダジノン・酒石酸塩は、次のようにラセミ化、
回収し、再利用することができる。光学分割濾液を濃縮
し、析出した光学活性ピリダジノン・酒石酸塩を濾別す
る。得られた光学活性ピリダジノン・酒石酸塩に水およ
び濃塩酸などの強酸を加え、５０℃から還流下で数分か
ら数時間撹拌することによってラセミ化を行う。その
後、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウム
などのアルカリ水溶液によりフリー化し、（±）−ピリ
ダジノンを濾別する。また、上記の光学活性ピリダジノ
ン・酒石酸塩に水および水酸化ナトリウム、水酸化カリ
ウムなどの強塩基を加え、５０℃から還流下で数分から
数時間撹拌することによってもラセミ化することができ
る。The optically active pyridazinone / tartrate salt that has been separated and becomes unnecessary by the above operation is racemized as follows,
Can be collected and reused. The optically resolved filtrate is concentrated, and the precipitated optically active pyridazinone / tartrate salt is filtered off. Racemization is performed by adding water and a strong acid such as concentrated hydrochloric acid to the obtained optically active pyridazinone / tartrate salt and stirring the mixture at 50 ° C. under reflux for several minutes to several hours. Then, it is made free with an aqueous alkali solution such as sodium hydroxide, potassium carbonate, sodium carbonate and the like, and (±) -pyridazinone is separated by filtration. Racemization can also be carried out by adding water and a strong base such as sodium hydroxide or potassium hydroxide to the above-mentioned optically active pyridazinone tartrate and stirring the mixture at 50 ° C. under reflux for several minutes to several hours.
【０００８】[0008]
【実施例】以下に実施例をあげて本発明をさらに詳しく
説明する。 実施例１（光学分割） （±）−ピリダジノン４．０６ｇ（２０．０ｍｍｏｌ）
とＬ−酒石酸３．６０ｇ（２４．０ｍｍｏｌ）に１−プ
ロパノール／酢酸エチル（３５／６５、体積比）１２０
ｍｌ（６．０ｌ／Ｍ）を加え、加熱溶解した。７７〜８
１℃で３０分撹拌後、ゆっくり冷却した。４０℃で結晶
が析出するが、４０〜４５℃で１時間撹拌後、２０〜２
５℃までゆっくり冷却し、さらに１時間撹拌後、結晶を
濾別した。得られた結晶は１−プロパノール／酢酸エチ
ル（３５／６５）１５ｍｌで洗浄後、乾燥しピリダジノ
ン・Ｌ−酒石酸塩４．７３ｇを得た。Ｒ−ピリダジノン
の光学純度は３１．５％ｅ．ｅ．であった。濾液中のＳ
−ピリダジノンの光学純度は５６．１％ｅ．ｅ．で、得
られた結晶の収率は計算により６４％と求められた。The present invention will be described in more detail with reference to the following examples. Example 1 (optical resolution) 4.06 g (20.0 mmol) of (±) -pyridazinone
And 1.60 g (24.0 mmol) of L-tartaric acid and 120 of 1-propanol / ethyl acetate (35/65, volume ratio)
ml (6.0 l / M) was added and dissolved by heating. 77-8
After stirring at 1 ° C. for 30 minutes, the mixture was slowly cooled. Crystals precipitate at 40 ° C, but after stirring at 40-45 ° C for 1 hour, 20-20
After slowly cooling to 5 ° C. and stirring for another 1 hour, the crystals were separated by filtration. The obtained crystals were washed with 15 ml of 1-propanol / ethyl acetate (35/65) and dried to obtain 4.73 g of pyridazinone L-tartrate. The optical purity of R-pyridazinone is 31.5% e. e. Met. S in the filtrate
-The optical purity of pyridazinone is 56.1% e. e. The yield of the obtained crystal was calculated to be 64%.
【０００９】実施例２（光学分割） （±）−ピリダジノン９０．０ｇ（０．４４３ｍｏｌ）
とＬ−酒石酸７９．８ｇ（０．５３１ｍｏｌ）に酢酸エ
チル１７３０ｍｌ、２−プロパノール９３０ｍｌを加
え、加熱溶解した。７５℃で３０分撹拌後、ゆっくり冷
却した。５２℃で結晶が析出するが、５０〜５５℃で１
時間撹拌後、２０〜２５℃までゆっくり冷却し、さらに
１時間撹拌後、結晶を濾別した。得られた結晶は２−プ
ロパノール／酢酸エチル（３５／６５）２００ｍｌで洗
浄後、乾燥しピリダジノン・Ｌ−酒石酸塩１２８．１ｇ
を得た。Ｒ−ピリダジノンの光学純度は３３．５％ｅ．
ｅ．であった。濾液中のＳ−ピリダジノンの光学純度は
５６．１％ｅ．ｅ．で、得られた結晶の収率は計算によ
り６９％と求められた。Example 2 (optical resolution) 90.0 g (0.443 mol) of (±) -pyridazinone
Then, 1730 ml of ethyl acetate and 930 ml of 2-propanol were added to 79.8 g (0.531 mol) of L-tartaric acid and dissolved by heating. After stirring at 75 ° C. for 30 minutes, the mixture was slowly cooled. Crystals precipitate at 52 ° C, but 1 to 50-55 ° C.
After stirring for 20 hours, the mixture was slowly cooled to 20 to 25 ° C., and further stirred for 1 hour. The obtained crystals were washed with 200 ml of 2-propanol / ethyl acetate (35/65), dried and dried, and pyridazinone / L-tartrate salt (128.1 g) was obtained.
I got The optical purity of R-pyridazinone is 33.5% e.
e. Met. The optical purity of S-pyridazinone in the filtrate was 56.1% e. e. The yield of the obtained crystals was calculated to be 69%.
【００１０】実施例３（光学分割） （±）−ピリダジノン１．１３ｇ（５．５６ｍｍｏｌ）
とＬ−酒石酸１．２０ｇ（８．０ｍｍｏｌ）にエタノー
ル／酢酸エチル（５０／５０）２５ｍｌ（４．５ｌ／
Ｍ）を加え、加熱溶解した。６８℃で３０分撹拌後、ゆ
っくり冷却した。３０℃で結晶が析出するが、そのまま
２０〜２５℃までゆっくり冷却し、さらに１時間撹拌
後、結晶を濾別した。得られた結晶を乾燥しピリダジノ
ン・Ｌ−酒石酸塩１．２８ｇを得た。Ｒ−ピリダジノン
の光学純度は２０．５％ｅ．ｅ．、得られた結晶の収率
は６２％であった。Example 3 (optical resolution) 1.13 g (5.56 mmol) of (±) -pyridazinone
And 1.20 g (8.0 mmol) of L-tartaric acid in 25 ml of ethanol / ethyl acetate (50/50) (4.5 l /
M) was added and dissolved by heating. After stirring at 68 ° C. for 30 minutes, the mixture was slowly cooled. Crystals precipitate at 30 ° C., but the mixture is slowly cooled to 20 to 25 ° C., stirred for 1 hour, and then filtered. The obtained crystals were dried to obtain 1.28 g of pyridazinone L-tartrate. The optical purity of R-pyridazinone is 20.5% e. e. The yield of the obtained crystals was 62%.
【００１１】実施例４（光学分割） （±）−ピリダジノン３．００ｇ（１４．７６ｍｍｏ
ｌ）とＬ−酒石酸２．６６ｇ（１７．７１ｍｍｏｌ）に
ｎ−ブタノール／酢酸エチル（３５／６５）１０２ｍｌ
（６．９ｌ／Ｍ）を加え、加熱溶解した。８６℃で３０
分撹拌後、ゆっくり冷却した。５１℃で結晶が析出する
が、４９〜５１℃で１時間撹拌後、そのまま２０〜２５
℃までゆっくり冷却し、さらに３時間撹拌後、結晶を濾
別した。得られた結晶はｎ−ブタノール／酢酸エチル
（３５／６５）１０ｍｌで洗浄後、乾燥しピリダジノン
・Ｌ−酒石酸塩３．５３ｇを得た。Ｒ−ピリダジノンの
光学純度は２２．６％ｅ．ｅ．、濾液中のＳ−ピリダジ
ノンの光学純度は６４．８％ｅ．ｅ．で、得られた結晶
の収率は計算により７４％と求められた。Example 4 (optical resolution) 3.00 g of (±) -pyridazinone (14.76 mmol)
l) and 2.66 g (17.71 mmol) of L-tartaric acid in 102 ml of n-butanol / ethyl acetate (35/65)
(6.9 l / M) and dissolved by heating. 30 at 86 ° C
After stirring for minutes, the mixture was slowly cooled. Crystals precipitate at 51 ° C, but after stirring at 49-51 ° C for 1 hour,
After slowly cooling to ℃ and stirring for further 3 hours, the crystals were filtered off. The obtained crystals were washed with 10 ml of n-butanol / ethyl acetate (35/65) and dried to obtain 3.53 g of pyridazinone L-tartrate. The optical purity of R-pyridazinone is 22.6% e. e. The optical purity of S-pyridazinone in the filtrate was 64.8% e. e. The yield of the obtained crystals was calculated to be 74%.
【００１２】比較例１（光学分割） （±）−ピリダジノン３．００ｇ（１４．７６ｍｍｏ
ｌ）とＬ−酒石酸４．４３ｇ（２９．５３ｍｍｏｌ）に
２−プロパノール８９ｍｌ（６．０ｌ／ｍｏｌ）を加
え、加熱溶解した。８２℃で３０分撹拌後、ゆっくり冷
却した。６５℃で結晶が析出するが、６０〜６５℃で１
時間撹拌後、２０〜２５℃までゆっくり冷却し、さらに
１時間撹拌後、結晶を濾別した。得られた結晶は２−プ
ロパノール９ｍｌで洗浄後、乾燥しピリダジノン・Ｌ−
酒石酸塩４．７２ｇを得た。Ｒ−ピリダジノンの光学純
度は４．０％ｅ．ｅ．であった。濾液中のＳ−ピリダジ
ノンの光学純度は８２．５％ｅ．ｅ．で、得られた結晶
の収率は計算により９５％と求められた。Comparative Example 1 (optical resolution) (±) -pyridazinone 3.00 g (14.76 mmol)
To 1) and 4.43 g (29.53 mmol) of L-tartaric acid, 89 ml (6.0 l / mol) of 2-propanol was added and dissolved by heating. After stirring at 82 ° C. for 30 minutes, the mixture was slowly cooled. Crystals are precipitated at 65 ° C.
After stirring for 20 hours, the mixture was slowly cooled to 20 to 25 ° C., and further stirred for 1 hour. The resulting crystals were washed with 9 ml of 2-propanol, dried and dried with pyridazinone L-.
4.72 g of tartrate were obtained. The optical purity of R-pyridazinone is 4.0% e. e. Met. The optical purity of S-pyridazinone in the filtrate was 82.5% e. e. The yield of the obtained crystals was calculated to be 95%.
【００１３】実施例５（精製） 実施例２で得たピリダジノン・Ｌ−酒石酸塩１２８．１
ｇに酢酸エチル１２１０ｍｌ、２−プロパノール６５０
ｍｌを加え、加熱溶解した。７５℃で３０分撹拌後、ゆ
っくり冷却した。４３℃で結晶が析出するが、４５℃付
近で１時間撹拌後、２０〜２５℃までゆっくり冷却し、
さらに１時間撹拌後、結晶を濾別、乾燥した。得られた
結晶は２−プロパノール／酢酸エチル（３５／６５）１
４０ｍｌで洗浄後、乾燥しピリダジノン・Ｌ−酒石酸塩
収量８４．１ｇを得た。Ｒ−ピリダジノンの光学純度は
６３．０％ｅ．ｅ．で、濾液中のＳ−ピリダジノンの光
学純度は２５．５％ｅ．ｅ．であった。得られたピリダ
ジノン・Ｌ−酒石酸塩８４．１ｇに水７３３ｍｌを加え
た。１０℃以下に氷冷し、飽和炭酸ナトリウム水溶液を
３０分かけて滴下し（温度４〜１０℃）、ｐＨ８に調整
した。５０分撹拌後、結晶を濾別した。得られた結晶は
水１００ｍｌで洗浄後、乾燥し、光学純度６２．７％
ｅ．ｅ．（Ｒ）のピリダジノン３７．４ｇを得た。この
ピリダジノンにジオキサン３６８ｍｌを加え、１００℃
に加熱した。３０分撹拌後、ゆっくり冷却した。２０〜
２５℃で１時間撹拌後、結晶を濾別した。得られた結晶
はジオキサン１８ｍｌで洗浄した。洗浄液を含めた濾液
４１５．２ｇを濃縮乾固しイソプロピルエーテル２３０
ｍｌを加え、撹拌後、結晶を濾別した。得られた結晶を
乾燥しＲ−ピリダジノン２３．３ｇを得た。光学純度９
８．９％ｅ．ｅ．、収率２６％（対（±）−ピリダジノ
ン）であった。Example 5 (Purification) Pyridazinone L-tartrate salt obtained in Example 2 128.1
g in ethyl acetate, 1210 ml, 2-propanol 650
Then, the mixture was heated and dissolved. After stirring at 75 ° C. for 30 minutes, the mixture was slowly cooled. Crystals precipitate at 43 ° C, but after stirring for 1 hour at around 45 ° C, slowly cool to 20 to 25 ° C,
After stirring for an additional hour, the crystals were separated by filtration and dried. The obtained crystals were 2-propanol / ethyl acetate (35/65) 1
After washing with 40 ml, it was dried to obtain 84.1 g of pyridazinone L-tartrate. The optical purity of R-pyridazinone is 63.0% e. e. The optical purity of S-pyridazinone in the filtrate was 25.5% e. e. Met. 733 ml of water was added to 84.1 g of the obtained pyridazinone L-tartrate. The mixture was ice-cooled to 10 ° C. or lower, and a saturated aqueous solution of sodium carbonate was added dropwise over 30 minutes (temperature: 4 to 10 ° C.) to adjust the pH to 8. After stirring for 50 minutes, the crystals were separated by filtration. The obtained crystals were washed with 100 ml of water, dried, and had an optical purity of 62.7%.
e. e. 37.4 g of pyridazinone of (R) were obtained. 368 ml of dioxane is added to this pyridazinone,
Heated. After stirring for 30 minutes, the mixture was slowly cooled. 20 ~
After stirring at 25 ° C. for 1 hour, the crystals were separated by filtration. The obtained crystals were washed with 18 ml of dioxane. 415.2 g of the filtrate containing the washing solution was concentrated to dryness, and isopropyl ether 230 was removed.
After stirring, the crystals were separated by filtration. The obtained crystals were dried to obtain 23.3 g of R-pyridazinone. Optical purity 9
8.9% e. e. And the yield was 26% (vs. (±) -pyridazinone).
【００１４】実施例６（ラセミ化回収） 実施例２および５と同様に光学分割を行って得た濾液を
あわせた後（全量８００ｇ、ピリタジノン濃度１．２３
ｗｔ％）濃縮し、ピリダジノン・Ｌ−酒石酸塩を濾別、
乾燥した。得たピリダジノン・Ｌ−酒石酸塩９．３４ｇ
（ピリダジノン含有率４５．７ｗｔ％，光学純度５１．
５％ｅｅ（Ｓ））に水７６ｍｌ、濃塩酸４．３８ｇを加
え、２時間加熱還流しラセミ化した。２５〜３０℃まで
冷却し、酢酸エチル１０ｍｌ添加後、２８％水酸化ナト
リウム水溶液１２．３ｇを滴下、ｐＨ７．８に調整し
た。０〜５℃まで冷却し、３０分撹拌後、濾別した。得
られた結晶は水１１ｍｌ、酢酸エチル３ｍｌで洗浄後、
乾燥し（±）−ピリダジノン３．６５ｇを得た。化学純
度９８．０ｗｔ％、光学純度はラセミ体であった。ピリ
ダジノン・Ｌ−酒石酸塩に対する収率は８４％であっ
た。Example 6 (racemic recovery) The filtrates obtained by optical resolution in the same manner as in Examples 2 and 5 were combined (total amount: 800 g, pyritadinone concentration: 1.23).
wt%), and concentrate the pyridazinone L-tartrate by filtration.
Dried. 9.34 g of the obtained pyridazinone L-tartrate
(Pyridazinone content 45.7 wt%, optical purity 51.
To 5% ee (S)), 76 ml of water and 4.38 g of concentrated hydrochloric acid were added, and the mixture was heated under reflux for 2 hours to be racemized. After cooling to 25 to 30 ° C. and adding 10 ml of ethyl acetate, 12.3 g of a 28% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 7.8. After cooling to 0 to 5 ° C and stirring for 30 minutes, the mixture was filtered off. The obtained crystals were washed with 11 ml of water and 3 ml of ethyl acetate.
Drying yielded 3.65 g of (±) -pyridazinone. The chemical purity was 98.0 wt%, and the optical purity was a racemic form. The yield based on pyridazinone L-tartrate was 84%.
【００１５】実施例７（ラセミ化回収したピリダジノン
での光学分割） 実施例６で回収したピリダジノン３．０ｇ（化学純度９
８．０ｗｔ％，１４．５ｍｍｏｌ）に２−プロパノール
／酢酸エチル（３５／６５、体積比）８７ｍｌ（６．０
ｌ／Ｍ）、Ｌ−酒石酸２．６１ｇ（１７．４ｍｍｏｌ）
を加え、加熱溶解した。７５℃で１時間撹拌後、ゆっく
り冷却した。４８℃で結晶が析出するが、４５〜５０℃
で１時間撹拌後、２０〜２５℃までゆっくり冷却し、さ
らに１時間撹拌後、結晶を濾別した。得られた結晶は２
−プロパノール／酢酸エチル（３５／６５）７ｍｌで洗
浄後、乾燥しピリダジノン・Ｌ−酒石酸塩４．４１ｇを
得た。ピリダジノン・Ｌ−酒石酸塩のピリダジノン含有
率は４６．９ｗｔ％、Ｒ−ピリダジノンの光学純度は２
９．５％ｅ．ｅ．であった。得られた結晶の収率は計算
により７０％と求められた。ピリダジノンの光学純度
は、光学異性体分離用カラムを用いたＨＰＬＣ法によっ
て測定した。測定条件は次の通りである。 カラム：ＣＨＩＲＡＬＰＡＫ ＡＳ ４．６ｍｍφ×２
５０ｍｍ（ダイセル化学工業株式会社） 溶離液：ｎ−ヘキサン／エタノール＝１／１（Ｖ／Ｖ） 流速 ：１．０ｍｌ／ｍｉｎ． 検出器：ＵＶ２５４ｎｍ カラム温度：４０℃Example 7 (optical resolution using racemized recovered pyridazinone) Pyridazinone 3.0 g recovered in Example 6 (chemical purity 9)
8.0 wt%, 14.5 mmol) and 87 ml of 2-propanol / ethyl acetate (35/65, volume ratio).
1 / M), 2.61 g (17.4 mmol) of L-tartaric acid
Was added and dissolved by heating. After stirring at 75 ° C. for 1 hour, the mixture was slowly cooled. Crystals precipitate at 48 ° C, but 45-50 ° C
After stirring for 1 hour, the mixture was slowly cooled to 20 to 25 ° C., and further stirred for 1 hour. The obtained crystal is 2
-Washed with 7 ml of propanol / ethyl acetate (35/65) and dried to obtain 4.41 g of pyridazinone L-tartrate. The pyridazinone content of pyridazinone L-tartrate is 46.9 wt%, and the optical purity of R-pyridazinone is 2
9.5% e. e. Met. The yield of the obtained crystals was calculated to be 70%. The optical purity of pyridazinone was measured by an HPLC method using a column for separating optical isomers. The measurement conditions are as follows. Column: CHIRALPAK AS 4.6mmφ × 2
Eluent: n-hexane / ethanol = 1/1 (V / V) Flow rate: 1.0 ml / min. Detector: UV254nm Column temperature: 40 ° C
【００１６】[0016]
【発明の効果】本発明は、医薬品の中間体として有用な
光学活性ピリダジノンの製造、対掌体のラセミ化回収を
行い、工業的に有利な方法で安価に光学活性体を提供で
きる。具体的には従来法に比較し、高い光学純度、溶媒
量の大幅な低減、製造時間の大幅な短縮などを提供でき
る。Industrial Applicability According to the present invention, an optically active pyridazinone useful as an intermediate of a pharmaceutical can be produced, and the enantiomer can be racemized and recovered, and an optically active substance can be provided at low cost by an industrially advantageous method. Specifically, compared to the conventional method, high optical purity, a large reduction in the amount of solvent, a significant reduction in the production time, and the like can be provided.
Claims (4)
石酸を分割剤として低級アルコールとエステル類との混
合溶媒中で、光学分割することを特徴とする式［II］ 【化２】 で表されるＲ−配置またはＳ−配置を有する光学活性ピ
リダジノンの製造方法。1. A compound of the formula [I] Wherein the racemic pyridazinone represented by the formula is optically resolved in a mixed solvent of a lower alcohol and an ester using L- or D-tartaric acid as a resolving agent. A method for producing an optically active pyridazinone having an R-configuration or an S-configuration represented by the formula:
ミ体を有機溶媒中、Ｌ−またはＤ−酒石酸をピリダジノ
ンのラセミ体１モルに対し０．３〜１．８モル使用し分
割することを特徴とする式［II］で表されるＲ−配置ま
たはＳ−配置を有する光学活性ピリダジノンの製造方
法。2. A method for resolving a racemic pyridazinone represented by the formula [I] in an organic solvent, wherein L- or D-tartaric acid is used in an amount of 0.3 to 1.8 mol per mol of racemic pyridazinone. A method for producing an optically active pyridazinone having an R-configuration or an S-configuration represented by the formula [II], characterized by the following:
ラセミ体を低級アルコールとエステル類との混合溶媒中
で、Ｌ−またはＤ−酒石酸をピリダジノンのラセミ体１
モルに対し０．３〜１．８モル使用し分割することを特
徴とする式［II］で表されるＲ−配置またはＳ−配置を
有する光学活性ピリダジノンの製造方法。3. A racemic pyridazinone represented by the formula [I], wherein L- or D-tartaric acid is racemic pyridazinone 1 in a mixed solvent of a lower alcohol and an ester.
A method for producing an optically active pyridazinone having an R-configuration or an S-configuration represented by the formula [II], characterized by using 0.3 to 1.8 moles per mole and dividing.
Ｒ−配置またはＳ−配置を有する光学活性ピリダジノン
もしくはその酒石酸塩が過剰に含まれている系を酸また
は塩基の存在下、ラセミ化することを特徴とする式
［Ｉ］で表されるピリダジノンのラセミ体の回収方法。4. A system containing an optically active pyridazinone having an R-configuration or an S-configuration represented by the formula [II], which is optically resolved and unnecessary, or a tartrate salt thereof is excessively contained in the presence of an acid or a base. A method for recovering a racemic pyridazinone represented by the formula [I], which comprises racemizing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28295396A JPH10109977A (en) | 1996-10-04 | 1996-10-04 | Production of optically active pyridazinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28295396A JPH10109977A (en) | 1996-10-04 | 1996-10-04 | Production of optically active pyridazinone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH10109977A true JPH10109977A (en) | 1998-04-28 |
Family
ID=17659268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28295396A Withdrawn JPH10109977A (en) | 1996-10-04 | 1996-10-04 | Production of optically active pyridazinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH10109977A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011007123A1 (en) | 2009-07-14 | 2011-01-20 | Cipla Limited | Process for preparing levosimendan and intermediates for use in the process |
| CN103554032A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Preparation method of high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone |
-
1996
- 1996-10-04 JP JP28295396A patent/JPH10109977A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011007123A1 (en) | 2009-07-14 | 2011-01-20 | Cipla Limited | Process for preparing levosimendan and intermediates for use in the process |
| US9000158B2 (en) | 2009-07-14 | 2015-04-07 | Cipla Limited | Process for preparing levosimendan and intermediates for use in the process |
| CN103554032A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Preparation method of high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone |
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