JP3879185B2 - Method for obtaining optically active azetidine-2-carboxylic acid - Google Patents
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- carboxylic acid
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Description
【０００１】
【発明の属する技術分野】
本発明は光学活性アゼチジン−２−カルボン酸の取得方法に関する。
【０００２】
【従来の技術】
光学活性アゼチジン−２−カルボン酸は医薬などの中間体として有用な化合物である。従来、アゼチジン−２−カルボン酸の製造方法として、二置換酪酸ベンジルエステルおよびベンズヒドリルアミンをアセトニトリル中で反応させてＮ−（ベンズヒドリル）アゼチジン−２−カルボン酸ベンジルを得、次いでこれを水添反応させる方法が知られているが［Ｊｏｕｒｎａｌ ｏｆ Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ， ６，４３５（１９６９）］、該方法で得られるアゼチジン−２−カルボン酸は光学異性体混合物であるため、さらに光学分割をして光学活性アゼチジン−２−カルボン酸とする必要があった。
【０００３】
光学分割により光学活性アゼチジン−２−カルボン酸を得る方法としては、例えばアゼチジン−２−カルボン酸の光学異性体混合物を塩化ベンジルオキシカルボニルと反応させてＮ−（ベンジルオキシカルボニル）アゼチジンカルボン酸に変換したのち、これを光学活性チロシンヒドラジドにより光学分割し、次いで水添することによって、光学活性アゼチジンカルボン酸を製造する方法［Ｊｏｕｒｎａｌ ｏｆ Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ， ６，９９３（１９６９）］、アゼチジン−２−カルボン酸の光学異性体混合物を光学活性酒石酸により光学分割した後、分解し光学活性アゼチジン−２−カルボン酸を得る方法［ＷＯ ９７０２２４１］等が知られている。
【０００４】
【発明が解決しようとする課題】
しかしながら、上記の方法は、いずれも高価な光学活性分割剤を用いる必要があり、また多段階の工程数を必要とする等の問題があった。
【０００５】
そこで本発明者らは、高価な光学分割剤を用いず１段階でアゼチジン−２−カルボン酸の光学異性体混合物から光学純度の高い光学活性アゼチジン−２−カルボン酸を取得する方法を開発するべく鋭意検討した結果、本発明に至った。
【０００６】
【課題を解決するための手段】
すなわち、本発明は、一般式（１）
で示されるアゼチジン−２−カルボン酸の光学純度が６０％〜９４％ｅｅの範囲であるアゼチジン−２−カルボン酸の光学異性体混合物を、７３．７〜８４．７重量％のメタノール水溶液又はエタノール水溶液中に溶解させて上記光学異性体混合物を含む溶液を得、次いでこの溶液を冷却して光学純度９８％ｅｅ以上の光学活性アゼチジン−２−カルボン酸を取得する方法であって、いずれか一方の光学活性アゼチジン−２−カルボン酸の種晶を、前記光学異性体混合物を含む溶液中に添加し、当該光学異性体を優先的に結晶化させることを特徴とする光学活性アゼチジン−２−カルボン酸の取得方法を提供するものである。
【０００７】
【発明の実施の形態】
以下、本発明について詳細に説明する。
本発明で用いる上式（１）で示されるアゼチジン−２−カルボン酸の光学異性体混合物（以下、単に光学異性体混合物と略する場合もある）は、Ｄ−体およびＬ−体の二種の光学異性体混合物からなるものであり、各光学異性体の混合比は、どちらか一方の光学異性体の光学純度が６０％〜９４％ｅｅの範囲である。
【０００８】
本発明において、光学異性体混合物を溶解させる溶媒としては、７３．７〜８４．７重量％のメタノール水溶液又はエタノール水溶液である。
【０００９】
光学異性体混合物を上記の溶媒に完全に溶解させるには、温度を６７〜８０℃の範囲で設定すればよい。
【００１０】
溶媒の使用量は、少なくとも使用する溶媒の沸点以下でアゼチジン−２−カルボン酸を溶解させる量が必要であり、また光学活性アゼチジン−２−カルボン酸の収率の観点から、溶媒の使用量はできるだけ少ない方が好ましく、６７〜８０℃の温度においてアゼチジン−２−カルボン酸の光学異性体混合物が飽和溶液となるに相当する量の１〜１．１倍の範囲がより好ましい。溶解させる温度において飽和溶液となるに相当する溶媒の量は、常法により予め決定しておけばよい。
【００１１】
アゼチジン−２−カルボン酸の光学異性体混合物を溶媒中に溶解させた後、該溶液を冷却するが、冷却速度は通常、１時間当たり１〜５０℃であり、好ましくは３〜２０℃である。また冷却速度は一定である必要はなく、連続的に変化させてもよく段階的に変化させてもよい。該溶液が冷却により到達する温度（冷却到達温度）は、−３０〜１０℃の範囲である。
【００１２】
光学異性体混合物を溶媒に溶解させた後、いずれか一方の光学活性アゼチジン−２−カルボン酸の種晶を該溶液中に添加し、当該光学異性体を優先的に結晶化させる。種晶として用いる光学活性アゼチジン−２−カルボン酸は、析出晶として取得すべき光学活性体と同種の光学活性体であるが、光学異性体混合物中にいずれか一方の光学異性体が高い比率で混合されている場合には、通常、当該光学活性体が析出晶として取得されるため、混合比率の高い光学異性体の結晶体が種晶として使用される。また、取得される光学活性アゼチジン−２−カルボン酸の光学純度の観点から、種晶として用いる光学活性アゼチジン−２−カルボン酸の光学純度は高い方が好ましく、例えば、９７％ｅｅ以上が好ましく、９８％ｅｅ以上がより好ましく、９９％ｅｅ以上が特に好ましい。
【００１３】
添加する光学活性アゼチジン−２−カルボン酸の種晶の量には特に制限はないが、通常、アゼチジン−２−カルボン酸の光学異性体混合物に対して０．０００１重量％以上、好ましくは０．００１重量％以上である。また、通常、０．１重量％以下であり、好ましくは０．０８重量％以下である。
【００１４】
光学活性アゼチジン−２−カルボン酸の結晶体を種晶として添加する場合、その添加は光学異性体混合物を溶解させた溶液の冷却前、冷却過程または冷却後等いずれの時点でもよいが、添加した種晶が添加後溶液中に完全に溶解しないようにすることが好ましく、アゼチジン−２−カルボン酸の光学異性体混合物の飽和領域または過飽和領域において添加することが好ましく、また取得される光学活性アゼチジン−２−カルボン酸の光学純度の観点から、アゼチジン−２−カルボン酸が析出する以前に種晶を添加することが好ましい。
【００１５】
したがって、種晶の添加は、通常、冷却開始直前から冷却停止直後の間のいずれかに行われるが、なかでも冷却開始時から冷却停止時の間に行うことが好ましい。種晶は、例えばアゼチジン−２−カルボン酸の光学異性体混合物の溶液を溶解させた温度よりも１〜３０℃低い温度まで一旦冷却した後添加され、種晶を添加後さらに該溶液を冷却するかまたは添加時の温度をそのまま保持することにより結晶を析出させるが、収率の観点からは、該溶液を冷却することがより好ましい。なお、種晶の添加は通常１度であるが、必要に応じて２度以上に分割してもよい。
【００１６】
かくして、光学活性アゼチジン−２−カルボン酸の結晶化物が析出してくるが、収率の観点から、該溶液をしばらく放置することがより好ましい。放置する時間は特に制限はないが、通常、２０時間程度以内、好ましくは３０分〜１０時間程度、より好ましくは１時間〜５時間程度である。このようにして得られた結晶化物は、例えば濾過操作により濾取することで、容易に溶液中の光学異性体混合物と分離することができ、光学活性アゼチジン−２−カルボン酸を取得することができる。
【００１７】
【発明の効果】
本発明の方法によれば、高価な光学分割剤を用いず１段階でアゼチジン−２−カルボン酸の光学異性体混合物から光学活性アゼチジン−２−カルボン酸を回収することができ、さらに回収された光学活性アゼチジン−２−カルボン酸の光学純度は９９％ｅｅ以上と高いものである。
【００１８】
【実施例】
以下、実施例により本発明をさらに詳細に説明するが、本発明はこれにより限定されるものではない。
【００１９】
実施例１
アゼチジン−２−カルボン酸（８．５９ｇ；Ｌ体８６．８％ｅｅ）を水１８．０ｇ、メタノール５４．０ｇの混合溶媒（７５．０重量％水溶液）に加え７０℃で完全に溶解させた。この溶液を６０℃まで８℃／ｈｒで降温後、種晶としてＬ−アゼチジン−２−カルボン酸（０．５ｍｇ、光学純度９９．９％ｅｅ）を加え、つづいて同降温速度で−１０℃まで冷却した後、同温度で２時間保温した。得られた結晶化物を濾取してＬ−アゼチジン−２−カルボン酸（５．６４ｇ；Ｌ体＞９９．９％ｅｅ）を得た（対アゼチジン−２−カルボン酸光学異性体混合物収率６６％、対Ｌ−アゼチジン−２−カルボン酸収率７０％）。
【００２０】
実施例２
アゼチジン−２−カルボン酸（４．８１ｇ；Ｌ体８８．３％ｅｅ）を水１２．１ｇ、メタノール６２．２ｇの混合溶媒（８３．７重量％水溶液）に加え７０℃で完全に溶解させた。この溶液を６５℃まで８℃／ｈｒで降温後、種晶としてＬ−アゼチジン−２−カルボン酸（０．５ｍｇ、光学純度９９．９％ｅｅ）を加え、つづいて同降温速度で−２℃まで冷却した後、同温度で４時間保温した。得られた結晶化物を濾取してＬ−アゼチジン−２−カルボン酸（３．３３ｇ；Ｌ体＞９９．９％ｅｅ）を得た（対アゼチジン−２−カルボン酸光学異性体混合物収率６９％、対Ｌ−アゼチジン−２−カルボン酸収率７４％）。
【００２１】
実施例３
アゼチジン−２−カルボン酸（３．７６ｇ；Ｌ体９４．０％ｅｅ）を水７．３ｇ、メタノール２０．５ｇの混合溶媒（７３．７重量％水溶液）に加え７０℃で完全に溶解させた。この溶液を６５℃まで８℃／ｈｒで降温後、種晶としてＬ−アゼチジン−２−カルボン酸（０．５ｍｇ、光学純度９９．９％ｅｅ）を加え、つづいて同降温速度で−２℃まで冷却した後、同温度で４時間保温した。得られた結晶化物を濾取してＬ−アゼチジン−２−カルボン酸（２．６８ｇ；Ｌ体＞９９．９％ｅｅ）を得た（対アゼチジン−２−カルボン酸光学異性体混合物収率７１％、対Ｌ−アゼチジン−２−カルボン酸収率７３％）。
【００２２】
実施例４
アゼチジン−２−カルボン酸（９．１２ｇ；Ｌ体８９．９％ｅｅ）を水１６．６ｇ、エタノール７４．６ｇの混合溶媒（８１．８重量％水溶液）に加え８０℃で完全に溶解させた。この溶液を７０℃まで７℃／ｈｒで降温後、種晶としてＬ−アゼチジン−２−カルボン酸（１ｍｇ、光学純度９９．９％ｅｅ）を加え、つづいて同降温速度で０℃まで冷却した後、同温度で２時間保温した。得られた結晶化物を濾取してＬ−アゼチジン−２−カルボン酸（５．９５ｇ；Ｌ体＞９９．９％ｅｅ）を得た（対アゼチジン−２−カルボン酸光学異性体混合物収率６５％、対Ｌ−アゼチジン−２−カルボン酸収率６９％）。
【００２３】
実施例５
アゼチジン−２−カルボン酸（３１．６ｇ；Ｄ体７４．９％ｅｅ）を水４１．６ｇ、メタノール２３０．９ｇの混合溶媒（８４．７重量％水溶液）に加え６７℃で完全に溶解させた。この溶液を６５℃まで１０℃／ｈｒで降温後、種晶としてＤ−アゼチジン−２−カルボン酸（１ｍｇ、光学純度９９．９％ｅｅ）を加え、つづいて同降温速度で０℃まで冷却した後、同温度で２時間保温した。得られた結晶化物を濾取してＤ−アゼチジン−２−カルボン酸（１４．２ｇ；Ｄ体＞９９．９％ｅｅ）を得た（対アゼチジン−２−カルボン酸光学異性体混合物収率４５％、対Ｄ−アゼチジン−２−カルボン酸収率５１％）。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for obtaining optically active azetidine-2-carboxylic acid.
[0002]
[Prior art]
Optically active azetidine-2-carboxylic acid is a compound useful as an intermediate for pharmaceuticals and the like. Conventionally, as a method for producing azetidine-2-carboxylic acid, di-substituted butyric acid benzyl ester and benzhydrylamine are reacted in acetonitrile to obtain benzyl N- (benzhydryl) azetidine-2-carboxylate, which is then hydrogenated. [Journal of Heterocyclic Chemistry, 6, 435 (1969)], but the azetidine-2-carboxylic acid obtained by this method is a mixture of optical isomers. It was necessary to use azetidine-2-carboxylic acid.
[0003]
As a method for obtaining optically active azetidine-2-carboxylic acid by optical resolution, for example, a mixture of optical isomers of azetidine-2-carboxylic acid is reacted with benzyloxycarbonyl chloride to form N- (benzyloxycarbonyl) azetidinecarboxylic acid. After the conversion, this is optically resolved with an optically active tyrosine hydrazide and then hydrogenated to produce an optically active azetidinecarboxylic acid [Journal of Heterocyclic Chemistry, 6,993 (1969)], azetidine-2- A method [WO 9970241] and the like are known in which an optically active mixture of optical isomers of carboxylic acid is optically resolved with optically active tartaric acid and then decomposed to obtain optically active azetidine-2-carboxylic acid.
[0004]
[Problems to be solved by the invention]
However, each of the above methods has a problem that it is necessary to use an expensive optically active resolving agent and requires a multi-step number of steps.
[0005]
Therefore, the present inventors have developed a method for obtaining optically active azetidine-2-carboxylic acid having high optical purity from a mixture of optical isomers of azetidine-2-carboxylic acid in one step without using an expensive optical resolution agent. As a result of intensive studies, the present invention has been achieved.
[0006]
[Means for Solving the Problems]
That is, the present invention relates to the general formula (1)
An optical isomer mixture of azetidine-2-carboxylic acid having an optical purity of azetidine-2-carboxylic acid represented by the formula of 60% to 94% ee is mixed with 73.7 to 84.7% by weight methanol aqueous solution or ethanol. dissolved in an aqueous solution to obtain a solution containing the optical isomer mixture, and then a method for obtaining an optically active azetidine-2-carboxylic acid or ee optical purity of 98% by cooling the solution, either one An optically active azetidine-2-carboxylic acid seed crystal is added to a solution containing the optical isomer mixture and the optical isomer is preferentially crystallized. A method for obtaining an acid is provided.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail.
The optical isomer mixture of azetidine-2-carboxylic acid represented by the above formula (1) used in the present invention (hereinafter sometimes simply referred to as optical isomer mixture) is classified into two types, D-form and L-form. The mixture ratio of each optical isomer is such that the optical purity of one of the optical isomers is in the range of 60% to 94% ee.
[0008]
In the present invention, the solvent for dissolving the optical isomer mixture is a 73.7 to 84.7% by weight methanol aqueous solution or an ethanol aqueous solution .
[0009]
What is necessary is just to set temperature in the range of 67-80 degreeC in order to dissolve an optical isomer mixture completely in said solvent.
[0010]
The amount of solvent used is required to dissolve at least the azetidine-2-carboxylic acid at the boiling point of the solvent used, and from the viewpoint of the yield of optically active azetidine-2-carboxylic acid, the amount of solvent used is The amount is preferably as small as possible, and more preferably in the range of 1 to 1.1 times the amount corresponding to the azetidine-2-carboxylic acid optical isomer mixture becoming a saturated solution at a temperature of 67 to 80 ° C. The amount of the solvent corresponding to a saturated solution at the dissolving temperature may be determined in advance by a conventional method.
[0011]
After the optical isomer mixture of azetidine-2-carboxylic acid is dissolved in a solvent, the solution is cooled, and the cooling rate is usually 1 to 50 ° C. per hour, preferably 3 to 20 ° C. . The cooling rate does not have to be constant, and may be changed continuously or stepwise. The temperature that the solution reaches upon cooling (cooling arrival temperature) is in the range of −30 to 10 ° C.
[0012]
After the optical isomer mixture is dissolved in a solvent, one of the optically active azetidine-2-carboxylic acid seed crystals is added to the solution to preferentially crystallize the optical isomer. The optically active azetidine-2-carboxylic acid used as a seed crystal is the same optically active substance as the optically active substance to be obtained as a precipitated crystal, but either one of the optical isomers is present in a high ratio in the optical isomer mixture. In the case of being mixed, since the optically active substance is usually obtained as a precipitated crystal, an optical isomer crystal having a high mixing ratio is used as a seed crystal. In addition, from the viewpoint of the optical purity of the optically active azetidine-2-carboxylic acid obtained, the optical purity of the optically active azetidine-2-carboxylic acid used as a seed crystal is preferably higher, for example, 97% ee or more is preferable. 98% ee or more is more preferable, and 99% ee or more is particularly preferable.
[0013]
The amount of the seed crystal of optically active azetidine-2-carboxylic acid to be added is not particularly limited, but is usually 0.0001% by weight or more, preferably 0.8%, based on the optical isomer mixture of azetidine-2-carboxylic acid. 001% by weight or more. Moreover, it is 0.1 weight% or less normally, Preferably it is 0.08 weight% or less.
[0014]
When a crystal of optically active azetidine-2-carboxylic acid is added as a seed crystal, the addition may be performed at any time, such as before, during or after cooling of the solution in which the optical isomer mixture is dissolved. It is preferable to prevent the seed crystal from being completely dissolved in the solution after the addition, and it is preferable to add it in the saturated region or the supersaturated region of the optical isomer mixture of azetidine-2-carboxylic acid, and the obtained optically active azetidine From the viewpoint of the optical purity of -2-carboxylic acid, it is preferable to add a seed crystal before azetidine-2-carboxylic acid is precipitated.
[0015]
Therefore, the seed crystal is usually added either immediately before the start of cooling or immediately after the stop of cooling. In particular, it is preferably performed between the start of cooling and the stop of cooling. For example, the seed crystal is added after being cooled to a temperature lower by 1 to 30 ° C. than the temperature at which the solution of the optical isomer mixture of azetidine-2-carboxylic acid is dissolved, and the solution is further cooled after the seed crystal is added. Alternatively, crystals are precipitated by maintaining the temperature at the time of addition as it is, but it is more preferable to cool the solution from the viewpoint of yield. The seed crystal is usually added once, but may be divided into two or more if necessary.
[0016]
Thus, although a crystallized product of optically active azetidine-2-carboxylic acid is precipitated, it is more preferable to leave the solution for a while from the viewpoint of yield. The time for leaving is not particularly limited, but is usually within about 20 hours, preferably about 30 minutes to 10 hours, more preferably about 1 hour to 5 hours. The crystallized product thus obtained can be easily separated from the optical isomer mixture in the solution by, for example, filtration by filtration, and optically active azetidine-2-carboxylic acid can be obtained. it can.
[0017]
【The invention's effect】
According to the method of the present invention, optically active azetidine-2-carboxylic acid can be recovered from the optical isomer mixture of azetidine-2-carboxylic acid in one step without using an expensive optical resolving agent, and further recovered. The optical purity of optically active azetidine-2-carboxylic acid is as high as 99% ee or higher.
[0018]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by this.
[0019]
Example 1
Azetidine-2-carboxylic acid (8.59 g; L-form 86.8% ee) was added to a mixed solvent ( 75.0 wt% aqueous solution) of 18.0 g of water and 54.0 g of methanol and completely dissolved at 70 ° C. . After the temperature of this solution was lowered to 60 ° C. at 8 ° C./hr, L-azetidine-2-carboxylic acid (0.5 mg, optical purity 99.9% ee) was added as a seed crystal, followed by −10 ° C. at the same temperature reduction rate. And cooled to the same temperature for 2 hours. The obtained crystallized product was collected by filtration to give L-azetidine-2-carboxylic acid (5.64 g; L-form> 99.9% ee) (vs. azetidine-2-carboxylic acid optical isomer mixture yield 66). %, Yield of L-azetidine-2-carboxylic acid 70%).
[0020]
Example 2
Azetidine-2-carboxylic acid (4.81 g; L-form 88.3% ee) was added to a mixed solvent ( 83.7 wt% aqueous solution) of water 12.1 g and methanol 62.2 g and completely dissolved at 70 ° C. . This solution was cooled to 65 ° C. at 8 ° C./hr, L-azetidine-2-carboxylic acid (0.5 mg, optical purity 99.9% ee) was added as a seed crystal, and then −2 ° C. at the same rate of temperature decrease. After cooling to the same temperature, the mixture was kept at the same temperature for 4 hours. The resulting crystallized product was collected by filtration to obtain L-azetidine-2-carboxylic acid (3.33 g; L-form> 99.9% ee) (vs. azetidine-2-carboxylic acid optical isomer mixture yield 69). %, 74% yield of L-azetidine-2-carboxylic acid).
[0021]
Example 3
Azetidine-2-carboxylic acid (3.76 g; L-form 94.0% ee) was added to a mixed solvent (73.7 wt% aqueous solution) of 7.3 g of water and 20.5 g of methanol and completely dissolved at 70 ° C. . This solution was cooled to 65 ° C. at 8 ° C./hr, L-azetidine-2-carboxylic acid (0.5 mg, optical purity 99.9% ee) was added as a seed crystal, and then −2 ° C. at the same rate of temperature decrease. After cooling to the same temperature, the mixture was kept at the same temperature for 4 hours. The obtained crystallized product was collected by filtration to obtain L-azetidine-2-carboxylic acid (2.68 g; L-form> 99.9% ee) (vs. azetidine-2-carboxylic acid optical isomer mixture yield 71). %, 73% yield of L-azetidine-2-carboxylic acid).
[0022]
Example 4
Azetidine-2-carboxylic acid (9.12 g; L-form 89.9% ee) was added to a mixed solvent ( 81.8 wt% aqueous solution) of 16.6 g of water and 74.6 g of ethanol and completely dissolved at 80 ° C. . After the temperature was lowered to 70 ° C. at 7 ° C./hr, L-azetidine-2-carboxylic acid (1 mg, optical purity 99.9% ee) was added as a seed crystal, followed by cooling to 0 ° C. at the same temperature reduction rate. Then, it was kept at the same temperature for 2 hours. The obtained crystallized product was collected by filtration to obtain L-azetidine-2-carboxylic acid (5.95 g; L-form> 99.9% ee) (vs. azetidine-2-carboxylic acid optical isomer mixture yield 65) %, 69% yield of L-azetidine-2-carboxylic acid).
[0023]
Example 5
Azetidine-2-carboxylic acid (31.6 g; D-form 74.9% ee) was added to a mixed solvent ( 84.7 wt% aqueous solution) of 41.6 g of water and 230.9 g of methanol and completely dissolved at 67 ° C. . This solution was cooled to 65 ° C. at 10 ° C./hr, D-azetidine-2-carboxylic acid (1 mg, optical purity 99.9% ee) was added as a seed crystal, and then cooled to 0 ° C. at the same rate of temperature decrease. Then, it was kept at the same temperature for 2 hours. The obtained crystallized product was collected by filtration to obtain D-azetidine-2-carboxylic acid (14.2 g; D-form> 99.9% ee) (vs. azetidine-2-carboxylic acid optical isomer mixture yield 45). %, 51% yield of D-azetidine-2-carboxylic acid).
Claims (2)
で示されるアゼチジン−２−カルボン酸の光学純度が６０％〜９４％ｅｅの範囲であるアゼチジン−２−カルボン酸の光学異性体混合物を、７３．７〜８４．７重量％のメタノール水溶液又はエタノール水溶液中に溶解させて上記光学異性体混合物を含む溶液を得、次いでこの溶液を冷却して光学純度９８％ｅｅ以上の光学活性アゼチジン−２−カルボン酸を取得する方法であって、いずれか一方の光学活性アゼチジン−２−カルボン酸の種晶を、前記光学異性体混合物を含む溶液中に添加し、当該光学異性体を優先的に結晶化させることを特徴とする光学活性アゼチジン−２−カルボン酸の取得方法。General formula (1)
A mixture of optical isomers of azetidine-2-carboxylic acid having an optical purity of azetidine-2-carboxylic acid represented by the formula of 60 to 94% ee of 73.7 to 84.7% by weight of methanol aqueous solution or ethanol dissolved in an aqueous solution to obtain a solution containing the optical isomer mixture, and then a method for obtaining an optically active azetidine-2-carboxylic acid or ee optical purity of 98% by cooling the solution, either one An optically active azetidine-2-carboxylic acid seed crystal is added to a solution containing the optical isomer mixture and the optical isomer is preferentially crystallized. How to get acid.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18636397A JP3879185B2 (en) | 1997-07-11 | 1997-07-11 | Method for obtaining optically active azetidine-2-carboxylic acid |
| EP98101085A EP0855446B1 (en) | 1997-01-24 | 1998-01-22 | Process for producing optically active azetidine-2-carboxylic acid derivative |
| DE69813053T DE69813053T2 (en) | 1997-01-24 | 1998-01-22 | Process for the preparation of optically active azetidine-2-carboxylic acid derivatives |
| DE69834276T DE69834276T2 (en) | 1997-01-24 | 1998-01-22 | Process for improving the optical purity of azetidine-2-carboxylic acid |
| EP03001297A EP1308519B1 (en) | 1997-01-24 | 1998-01-22 | Process for improving optical purity of azetidine-2-carboxylic acid |
| US09/012,227 US6162621A (en) | 1997-01-24 | 1998-01-23 | Process for producing optically active azetidine-2-carboxylic acid derivative |
| US09/619,386 US6410279B1 (en) | 1997-01-24 | 2000-07-19 | Process for producing optically active azetidine-2-carboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18636397A JP3879185B2 (en) | 1997-07-11 | 1997-07-11 | Method for obtaining optically active azetidine-2-carboxylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH1129552A JPH1129552A (en) | 1999-02-02 |
| JP3879185B2 true JP3879185B2 (en) | 2007-02-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18636397A Expired - Fee Related JP3879185B2 (en) | 1997-01-24 | 1997-07-11 | Method for obtaining optically active azetidine-2-carboxylic acid |
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| Country | Link |
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| JP (1) | JP3879185B2 (en) |
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| JPH1129552A (en) | 1999-02-02 |
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