JP2000178253A - Production of optically active pipecolic acid - Google Patents
Production of optically active pipecolic acidInfo
- Publication number
- JP2000178253A JP2000178253A JP36218798A JP36218798A JP2000178253A JP 2000178253 A JP2000178253 A JP 2000178253A JP 36218798 A JP36218798 A JP 36218798A JP 36218798 A JP36218798 A JP 36218798A JP 2000178253 A JP2000178253 A JP 2000178253A
- Authority
- JP
- Japan
- Prior art keywords
- pipecolic acid
- acid
- phenoxypropionate
- pipecolic
- optically active
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、有用な医薬品の合
成中間体として必要な光学活性ピペコリン酸の新規な製
造法を提供することにある。光学活性ピペコリン酸は
又、その官能基の化学変換によってさらに医薬品のみな
らず、光学分割剤、有機合成化学反応におけるキラルビ
ルデイングブロックや農薬、工業用製品の原材料、中間
体として利用することが可能である。[0001] The present invention is to provide a novel method for producing optically active pipecolic acid required as an intermediate for synthesizing useful pharmaceuticals. Optically active pipecolic acid can also be used as an optical resolving agent, chiral building block in organic synthetic chemical reactions, agrochemicals, raw materials for industrial products, and intermediates by chemical conversion of its functional group. is there.
【０００２】[0002]
【従来の技術】光学活性ピペコリン酸の製造法として次
のような方法が知られている。 １）光学活性化合物を出発原料として化学合成する方
法、 ２）微生物を利用して目的物を得る方法、 ３）ＲＳ−ピペコリン酸と光学分割剤を反応させジアス
テレオマー塩を得た後光学分割する方法。2. Description of the Related Art The following method is known as a method for producing optically active pipecolic acid. 1) a method of chemically synthesizing an optically active compound as a starting material, 2) a method of obtaining a target substance using a microorganism, 3) a reaction between RS-pipecolic acid and an optical resolving agent to obtain a diastereomer salt, and then optical resolution. how to.
【０００３】このうち１）の化学合成法はすでに不斉を
持つ天然アミノ酸のリジンをジアゾ化、次いでトシル
化、環化して目的物を得る方法であるが保護基の導入が
必要なため工程が長いという欠点がある。〔M. Ubukata
et al, Agric. Biol. Chem., 52, 1177 (1988),特開昭
50−５９３７７号公報〕。また、リジンから白金触媒存
在下、光化学反応で目的物を得る方法が知られているが
(特開平２−２２９１５２号公報) 、光学純度が低いた
め実用性に乏しい。２）に属する方法としては、Alcali
genes 属の微生物を利用して不要の対掌体を資化する方
法が報告されている〔 K. Mochizuki, Bio.Chem., 52,
1113(1988),WO9510604（公開）、特開昭６３−２４８３
９３号公報〕が工業的に有利な方法とはいいがたい。[0003] Among them, the chemical synthesis method 1) is a method in which lysine of a natural amino acid having asymmetry is already diazotized, then tosylated and cyclized to obtain a desired product, but the step is required since a protecting group needs to be introduced. It has the disadvantage of being long. [M. Ubukata
et al, Agric. Biol. Chem., 52 , 1177 (1988),
No. 50-59377]. Also, a method for obtaining a target substance from lysine by a photochemical reaction in the presence of a platinum catalyst is known.
(Japanese Unexamined Patent Publication No. 2-229152) is not practical because of low optical purity. As a method belonging to 2), Alcali
A method of utilizing unnecessary enantiomers using microorganisms of the gene genus has been reported [K. Mochizuki, Bio.Chem., 52 ,
1113 (1988), WO9510604 (public), JP-A-63-2483
No. 93] is not an industrially advantageous method.
【０００４】一方、３）に属するジアステレオマー法に
よる光学分割として分割剤にチロシンヒドラジド〔 D.
W. Brunwin, J. Chem. Soc. C, 3756 (1971)〕、４−メ
チルフェニルエチルアミン（野平 博之 日本化学会９
７年春季年会 2PBO80 ）によるものが知られている。し
かし、これらの分割にはいずれもアミノ基の保護が必要
である。アミノ酸の光学分割はこのように通常はその官
能基を修飾して分割した後、脱保護するのが定法であ
る。アミノ酸の光学分割に保護基を導入、脱離するため
の二工程が加わるために工業的には不利である。On the other hand, tyrosine hydrazide [D.
W. Brunwin, J. Chem. Soc. C, 3756 (1971)], 4-methylphenylethylamine (Hiroyuki Nohira, Chemical Society of Japan 9
The Spring Meeting of the 7th Annual Meeting 2PBO80) is known. However, all of these resolutions require protection of the amino group. In the optical resolution of amino acids, it is customary to modify the functional group of the amino acid and then to deprotect the amino acid. This is industrially disadvantageous because two steps for introducing and removing a protecting group are added to the optical resolution of amino acids.
【０００５】非修飾ピペコリン酸を酒石酸で光学分割し
た例がいくつか報告されている。Beyermanらは（＋）−
ピペコリン酸を９６％アルコール中（＋）又は（−）酒
石酸で複塩をつくった後、水溶液中酢酸鉛で複分解を行
い光学活性なピペコリン酸を得ている。〔 H. C. Beyer
man, Rec.Trav. Chim.Pays-Bas, 78, 134 (1959)〕又、
Lockらはブタン酸中（±）−ピペコリン酸を酒石酸と加
熱して不要の対掌体をラセミ化しながら酒石酸で光学分
割している。〔WO96/11185〕。その他にも酒石酸で光学
分割した例がある。（ R. C. Peck and A. R. Day, J.
Heterocycl.Chem, 181 (1969)〕。There have been reported several examples of optically resolving unmodified pipecolic acid with tartaric acid. Beyerman et al. (+)-
After producing a double salt of pipecolic acid with (+) or (-) tartaric acid in 96% alcohol, it is subjected to metathesis with lead acetate in an aqueous solution to obtain optically active pipecolic acid. [HC Beyer
man, Rec.Trav.Chim.Pays-Bas, 78 , 134 (1959)]
Lock et al. Optically resolved tartaric acid while heating (±) -pipecolic acid in butanoic acid with tartaric acid to racemize unwanted enantiomers. [WO96 / 11185]. There are also other examples of optical resolution with tartaric acid. (RC Peck and AR Day, J.
Heterocycl. Chem, 181 (1969)].
【０００６】非修飾ピペコリン酸が酒石酸で光学分割さ
れる機構は明らかではないが、同様の環状アミノ酸であ
るプロリンも酒石酸で光学分割されることが知られてい
る〔S. Yamada, etal, Agric. Biol. Chem, 41, 2413
(1977) 〕。この場合はプロリン１モルに対して酒石酸
０．５モルの使用で難溶性ジアステレオマー塩が得られ
ている。ジアステレオマー塩生成時にアルデヒドを存在
させることによって高収率で光学活性２−ピペコリン酸
を得る方法も報告されている。〔T. Siraiwa, Bull. C
hem. Soc. Jpn,64, 3251 (1991) 〕。安価な天然形酒石
酸（Ｒ，Ｒ）を用いた場合得られるピペコリン酸はＲ−
ピペコリン酸であり、Ｓ−ピペコリン酸を得るために必
要な酒石酸は高価な非天然型（Ｓ、Ｓ）であり、文献に
は回収率等具体的な記載はない。また、酒石酸で光学分
割した場合、目的物を単離した母液から酒石酸を回収す
ることは困難であるので経済的ではない。Although the mechanism by which unmodified pipecolic acid is optically resolved by tartaric acid is not clear, it is known that a similar cyclic amino acid, proline, is also optically resolved by tartaric acid [S. Yamada, et al., Agric. Biol. Chem, 41 , 2413
(1977)]. In this case, a sparingly soluble diastereomer salt is obtained by using 0.5 mol of tartaric acid per 1 mol of proline. There has also been reported a method for obtaining optically active 2-pipecolic acid in high yield by allowing an aldehyde to exist during the production of diastereomeric salts. [T. Siraiwa, Bull. C
hem. Soc. Jpn, 64 , 3251 (1991)]. Pipecolic acid obtained when inexpensive natural tartaric acid (R, R) is used is R-
It is pipecolic acid, and tartaric acid necessary for obtaining S-pipecolic acid is an expensive non-natural type (S, S), and there is no specific description in the literature such as the recovery rate. Further, in the case of optical resolution with tartaric acid, it is difficult to recover tartaric acid from the mother liquor from which the target product was isolated, so that it is not economical.
【０００７】非修飾ピペコリン酸が安価で効率のよい分
割剤で直接光学分割できれば、通常の光学分割のように
官能基の保護、脱保護の二工程が省略できるので工業的
に見て利点があると考えられる。マンデル酸は非修飾中
性アミノ酸のあるものと難溶性付加物を形成するという
報告があり、付加物形成機構も論じられている〔（特公
昭５８−１１０５号公報）、日化誌, 92, 999 (197
1)〕。If unmodified pipecolic acid can be directly optically resolved with an inexpensive and efficient resolving agent, two steps of protection and deprotection of functional groups can be omitted as in ordinary optical resolution, which is industrially advantageous. it is conceivable that. It has been reported that mandelic acid forms a sparingly soluble adduct with some unmodified neutral amino acids, and the mechanism of adduct formation has also been discussed (Japanese Patent Publication No. 58-1105), Nikka Magazine, 92 , 999 (197
1)].
【０００８】[0008]
【発明が解決しようとする課題】上記の従来法には、ア
ミノ基を保護するための保護基の導入や脱離が必要であ
るので工程が複雑である、得られる目的生成物の光学純
度が低く実用性に乏しい、目的物の収率が低い、光学分
割剤の回収効率が悪いなど多くの問題点があった。本発
明は非修飾ピペコリン酸を直接光学分割できれば上記の
ような諸問題を解決できるという立場から鋭意研究を進
めて本発明に到達したもので、既にその製造方法等を提
案している、光学活性２−フェノキシプロピオン酸の光
学分割剤としての利用に着目した。現在まで本発明者ら
は光学活性２−フェノキシプロピオン酸の工業的製法及
びこの分割剤を用いたアミン類の光学分割法を特許申請
した。（特開平９−２６８１８１号、１０−４５６８９
号、１０−１７５９１３号、１０−２７９５２１号各公
報）。すなわち、本発明は、光学活性２−フェノキシプ
ロピオン酸を用いて非修飾ピペコリン酸を光学分割する
ことにより医薬品等の合成中間体として有用な光学純度
の高い光学活性ピペコリン酸を高収率で経済的有利に製
造し、分割剤である光学活性２−フェノキシプロピオン
酸を効率よく回収し、再使用することを目的とする。The above-mentioned conventional method requires the introduction and elimination of a protecting group for protecting the amino group, so that the process is complicated and the optical purity of the obtained target product is low. There are many problems such as low and poor practicality, low yield of the target substance, and poor recovery efficiency of the optical resolving agent. The present invention has reached the present invention by conducting intensive studies from the standpoint that the above-mentioned problems can be solved if unmodified pipecolic acid can be directly optically resolved, and the present invention has already been proposed. We focused on the use of 2-phenoxypropionic acid as an optical resolving agent. To date, the present inventors have applied for a patent for an industrial method for producing optically active 2-phenoxypropionic acid and an optical resolution method for amines using this resolving agent. (JP-A-9-268181, 10-45689
Nos. 10-175913 and 10-279521). That is, the present invention optically resolves unmodified pipecolic acid using optically active 2-phenoxypropionic acid to produce optically active pipecolic acid having high optical purity useful as a synthetic intermediate for pharmaceuticals and the like in high yield and economical. An object of the present invention is to advantageously produce and efficiently recover an optically active 2-phenoxypropionic acid, which is a resolving agent, and reuse it.
【０００９】[0009]
【課題を解決するための手段】本発明は（１）（±）−
ピペコリン酸（ＲＳ−１）を水、低級アルコール、又は
それらの任意の割合の混合物からなる媒体中で、好まし
くは０．２５〜３モル当量の光学活性２−フェノキシプ
ロピオン酸（Ｒ−２又はＳ−２）と反応させ、難溶性ジ
アステレオマー塩として生ずる新規なＳ−（−）−ピペ
コリン酸・Ｓ−（−）−２−フェノキシプロピオン酸塩
(3)及びＲ−（＋）−ピペコリン酸・Ｒ（＋）−２−フ
ェノキシプロピオン酸 (5)塩の製造方法、The present invention provides (1) (±) −
Pipecolic acid (RS-1) is preferably dissolved in a medium consisting of water, a lower alcohol, or a mixture thereof in any proportion thereof, preferably in an amount of 0.25 to 3 molar equivalents of optically active 2-phenoxypropionic acid (R-2 or S-2). -S-(-)-Pipecolic acid.S-(-)-2-phenoxypropionate, which is reacted with -2) to form a sparingly soluble diastereomer salt
(3) and a method for producing R-(+)-pipecolic acid-R (+)-2-phenoxypropionic acid (5) salt,
【００１０】（２）（±）−ピペコリン酸（ＲＳ−１）
を水、低級アルコール、又はそれらの任意の割合の混合
物からなる媒体中で、好ましくは、０．２５〜３モル当
量の光学活性２−フェノキシプロピオン酸（Ｒ又はＳ−
２）と反応させ、難溶性ジアステレオマー塩として生ず
る新規なＳ−（−）−ピペコリン酸・Ｓ−（−）−２−
フェノキシプロピオン酸塩(3) 又はＲ−（＋）−ピペコ
リン酸・Ｒ（＋）−２−フェノキシプロピオン酸塩(5)
を得、次いで得られたＳ−（−）ピペコリン酸・Ｓ−
（−）−２−フェノキシプロピオン酸塩(3) 又はＲ−
（＋）−ピペコリン酸・Ｒ（＋）−２−フェノキシプロ
ピオン酸塩(5) を水に溶解又は懸濁したものに当量又は
過剰の酸を加えて複分解し光学的に純粋なＳ−（−）−
ピペコリン酸（Ｓ−１）又はＲ−（＋）−ピペコリン酸
（Ｒ−１）を製造する方法。(2) (±) -Pipecolic acid (RS-1)
In a medium consisting of water, a lower alcohol or a mixture thereof in any proportion, preferably from 0.25 to 3 molar equivalents of optically active 2-phenoxypropionic acid (R or S-
New S-(-)-pipecolic acid S-(-)-2-reacted with 2) to form a sparingly soluble diastereomer salt
Phenoxypropionate (3) or R-(+)-pipecolic acid R (+)-2-phenoxypropionate (5)
And then the obtained S-(-) pipecolic acid · S-
(-)-2-phenoxypropionate (3) or R-
(+)-Pipecolic acid.R (+)-2-phenoxypropionate (5) is dissolved or suspended in water, and an equivalent or excess acid is added thereto to decompose to give optically pure S-(- )-
A method for producing pipecolic acid (S-1) or R-(+)-pipecolic acid (R-1).
【００１１】（３）Ｓ−（−）−ピペコリン酸・Ｓ−
（−）−２−フェノキシプロピオン酸塩(3) 又はＲ−
（＋）−ピペコリン酸・Ｒ（＋）−２−フェノキシプロ
ピオン酸塩(5) を水に溶解又は懸濁したものに当量又は
過剰の酸を加えて複分解し光学的に純粋なＳ−（−）−
ピペコリン酸（Ｓ−１）又はＲ−（＋）−ピペコリン酸
を製造する方法を提供するものであり、分割剤である光
学活性２−フェノキシプロピオン酸は酸性条件下でラセ
ミ化することなく容易に有機溶媒で抽出でき、再使用で
きる。(3) S-(-)-Pipecolic acid / S-
(-)-2-phenoxypropionate (3) or R-
(+)-Pipecolic acid.R (+)-2-phenoxypropionate (5) is dissolved or suspended in water, and an equivalent or excess acid is added thereto to decompose to give optically pure S-(- )-
An object of the present invention is to provide a method for producing pipecolic acid (S-1) or R-(+)-pipecolic acid, wherein an optically active 2-phenoxypropionic acid as a resolving agent can be easily prepared without racemization under acidic conditions. Can be extracted with organic solvents and reused.
【００１２】[0012]
【発明の実施の形態】本発明は下記反応式に示すよう
に、（±）−ピペコリン酸（ＲＳ−１）と光学活性２−
フェノキシプロピオン酸（Ｓ−２又はＲ−２）とを反応
させてジアステレオマー塩（3、４又は5、6 ） を形成
させ、各々の塩の溶解度差を利用して光学活性ピペコリ
ン酸（Ｓ−１又はＲ−１）を得る方法である〔化学式
１、２〕。BEST MODE FOR CARRYING OUT THE INVENTION According to the present invention, (±) -pipecolic acid (RS-1) and optically active
Reaction with phenoxypropionic acid (S-2 or R-2) to form diastereomeric salts (3, 4, or 5, 6), and utilizing the difference in solubility of each salt, the optically active pipecolic acid (S -1 or R-1) [Chemical formulas 1 and 2].
【００１３】[0013]
【化１】 Embedded image
【００１４】[0014]
【化２】 Embedded image
【００１５】このプロセスはジアステレオマー塩合成反
応、光学活性体単離工程の二工程よりなる。ピペコリン
酸ジアステレオマー塩合成反応をにおいて、分割剤をラ
セミ体の好ましくは０．２５〜２.０当量、更に好まし
くは０．３〜１．０当量混合し、これらを適当な溶媒と
混合する。使用する溶媒は出発物質をある程度溶解する
もので、反応に関与しないものであれば任意のものを用
いることができる。好ましくはエーテル類、ケトン類、
アルコール類、水またはこれらの混合溶媒である。これ
らのうち水が最も適当である。混合液を攪拌して、０℃
〜還流温度、好ましくは６０〜８０℃に加熱して内容物
を溶解する。内容物が溶解したら徐々に冷却し、１０〜
３０℃付近でジアステレオマー塩の分離を行う。必要な
らば種晶を加えてジアステレオマー塩を析出しやすくす
る。得られたジアステレオマー塩は常法にしたがい再結
晶により精製することができる。This process comprises two steps of a diastereomer salt synthesis reaction and an optically active isomer isolation step. In the pipecolic acid diastereomer salt synthesis reaction, the resolving agent is preferably mixed in a racemic form with 0.25 to 2.0 equivalents, more preferably 0.3 to 1.0 equivalent, and these are mixed with an appropriate solvent. . The solvent used dissolves the starting material to some extent, and any solvent can be used as long as it does not participate in the reaction. Preferably ethers, ketones,
Alcohols, water or a mixed solvent thereof. Of these, water is the most suitable. Stir the mixture at 0 ° C
To the reflux temperature, preferably 60 to 80 ° C. to dissolve the contents. When the contents are dissolved, slowly cool,
Separation of diastereomeric salts is carried out at around 30 ° C. If necessary, seed crystals are added to facilitate precipitation of diastereomeric salts. The obtained diastereomer salt can be purified by recrystallization according to a conventional method.
【００１６】次に光学活性体の単離工程は以下のように
して行う。ジアステレオマー塩を水に懸濁または溶解さ
せさ、これに強酸（塩酸、硝酸、硫酸等）を添加し、さ
らに反応に関与しない非水溶性溶媒（トルエン、クロロ
ホルム、１、２−ジクロロエタン等）を加えて、分割剤
を抽出、回収する。一方、水層には塩基を加える。例え
ば、炭酸バリウム、炭酸カルシウム等を硫酸に対して当
量添加し、生じた塩をろ別し、水を留去して目的物の光
学活性体を得る。得られた光学活性ピペコリン酸は常法
に従い再結晶等により精製できる。また、この他にも適
当なイオン交換樹脂を用いて分割剤と分離したのち、溶
媒を留去して目的物を得ることもできる。Next, the step of isolating the optically active substance is performed as follows. A diastereomer salt is suspended or dissolved in water, a strong acid (hydrochloric acid, nitric acid, sulfuric acid, etc.) is added thereto, and a water-insoluble solvent not involved in the reaction (toluene, chloroform, 1,2-dichloroethane, etc.) To extract and collect the resolving agent. On the other hand, a base is added to the aqueous layer. For example, barium carbonate, calcium carbonate, or the like is added in an equivalent amount to sulfuric acid, the resulting salt is filtered off, and water is distilled off to obtain the desired optically active substance. The obtained optically active pipecolic acid can be purified by recrystallization or the like according to a conventional method. In addition, after separation from the resolving agent using a suitable ion exchange resin, the solvent can be distilled off to obtain the desired product.
【００１７】（参考例）本参考例はＳ−ピペコリン酸の
光学純度の測定法を示すものである。ここに示される測
定法はＳ−ピペコリン酸をメトキシ-トリフルオロ-フェ
ニル酢酸(MTPA)誘導体へ導くモッシャー法〔 J. A. Dal
e, D. L. Dull, H. S. Mosher, "J. Org. Chem.", 34,
2543(1969)〕によりジアステレオマーに誘導し、1H-NMR
測定により光学純度を決定するものである。すなわち、
Ｓ−ピペコリン酸（Ｓ−１）0.5g (4mmol) をベンゼン-
メタノール＝5：1の溶液12mｌに溶解し、2ＭのTMS-ジア
ゾメタンヘキサン溶液0.5g (4mmol)を滴下した。滴下終
了後室温で1時間撹拌した。反応終了後溶媒を減圧下に
留去し、Ｓ−ピペコリ酸メチルエステルを定量的に得
た。次に得られたエステル70mg(0.4mmol)を5mlのジクロ
ロメタンに溶かし、0.03mlのピリジンを加え、S-MTPA-
クロリド0.1g (0.4mmol)を滴下した。この溶液を室温で
1時間撹拌し、反応終了を確認後減圧下で濃縮した。得
られた生成物をシリカゲルによるクロマトグラフィーで
精製し（ヘキサン-酢酸エチル=5：1）、Ｓ−ピペコリン
酸メチルエステルのMTPAアミドを得た。得られたアミド
の1H-NMRを測定し2位水素のシグナルＳ−体ではδ5.56
(CDCl3),Ｒ−体ではδ5.40(CDCl3) の積分値から光学純
度を求めた。同様にR-ピペコリン酸についても光学純度
を測定した。Reference Example This reference example shows a method for measuring the optical purity of S-pipecolic acid. The measurement method described here is based on the Mosher method for introducing S-pipecolic acid into a methoxy-trifluoro-phenylacetic acid (MTPA) derivative [JA Dal
e, DL Dull, HS Mosher, "J. Org. Chem.", 34 ,
2543 (1969)] to give a diastereomer, 1H-NMR
The optical purity is determined by measurement. That is,
0.5 g (4 mmol) of S-pipecolic acid (S-1) was added to benzene-
The solution was dissolved in 12 ml of a 5: 1 methanol solution, and 0.5 g (4 mmol) of a 2M TMS-diazomethanehexane solution was added dropwise. After the addition, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure to quantitatively obtain S-pipecolic acid methyl ester. Next, 70 mg (0.4 mmol) of the obtained ester was dissolved in 5 ml of dichloromethane, 0.03 ml of pyridine was added, and S-MTPA-
0.1 g (0.4 mmol) of chloride was added dropwise. This solution at room temperature
The mixture was stirred for 1 hour, and after confirming the completion of the reaction, concentrated under reduced pressure. The obtained product was purified by chromatography on silica gel (hexane-ethyl acetate = 5: 1) to obtain MTPA amide of S-pipecolic acid methyl ester. 1H-NMR of the obtained amide was measured, and the signal S-form of hydrogen at position 2 was δ5.56.
The optical purity was determined from the integrated value of δ5.40 (CDCl 3 ) for (CDCl 3 ) and R-form. Similarly, the optical purity of R-pipecolic acid was measured.
【００１８】[0018]
【実施例】（実施例１）本実施例は上記化学式１の工程
に従って行った。（±）−ピペコリン酸（ＲＳ−１）５
２ｇ（０．４０ｍｏｌ）、Ｓ−２−フェノキシプロピオ
ン酸（Ｓ−２）３４ｇ（０．２０ｍｏｌ）、水１４０ｍ
ｌを混合し、これを加熱、内容物を溶解させ、室温まで
12時間かけ冷却した。生じた結晶を分離し、７０〜７５
℃で減圧乾燥し粗ジアステレオマー塩(3) を得た。収量
４６．４ｇ（収率７８．８％）、旋光度〔α〕D −２
６．６（Ｃ．０．５２５℃ ＭｅＯＨ）得られたジアス
テレオマー塩を水１４０ｍｌで温度80℃に加熱溶解さ
せ、12時間で室温まで冷却放置し、生じた結晶を分離、
乾燥して精製ジアステレオマー塩(3) を得た。 収量３２．５ｇ（収率 ５５．２％）、旋光度〔α〕D
−２９．４（Ｃ．０．５ ２５℃ ＭｅＯＨ） 得られたジアステレオマー塩(3) ５ｇ（１７ｍｍｏ
ｌ）、硫酸０．８３ｇ（８．５ｍｍｏｌ）及び水２０ｍ
ｌを混合した。これに１，２−ジクロロエタン２０ｍｌ
を加え分液した。水層に水酸化カルシウム０．８５ｇ
（８．５ｍｍｏｌ）を加え不溶分をろ別、水を減圧留去
した後メタノール２００ｍｌを加え残渣を溶解した。不
溶分をセライトろ過し、メタノールを減圧留去してＳ−
ピペコリン酸（Ｓ−１）を得た。 収量１．６ｇ（ジアステレオマー塩からの収率７２．７
％）、旋光度〔α〕D−２５．７（Ｃ．０．５ ２５℃
Ｈ2Ｏ）、融点２６５℃光学純度95%ee以上 一方、有機層は水１０ｍｌで洗浄し硫酸ナトリウムで乾
燥、溶媒を留去し、分割剤（Ｓ−２）を回収した。
（２．４ｇ、回収率８３．８％）。回収された分割剤に
は、ＨＰＬＣ（ダイセル社製Chiralcel ODカラム）分析
の結果ラセミ化は認められなかった。(Example 1) This example was performed according to the process of the above-mentioned chemical formula 1. (±) -Pipecolic acid (RS-1) 5
2 g (0.40 mol), 34 g (0.20 mol) of S-2-phenoxypropionic acid (S-2), 140 m of water
and heat it to dissolve the contents and bring to room temperature
Cooled for 12 hours. The resulting crystals are separated and 70-75
The crystals were dried under reduced pressure to obtain a crude diastereomer salt (3). Yield 46.4 g (yield 78.8%), optical rotation [α] D -2.
6.6 (C. 0.525 ° C. MeOH) The obtained diastereomer salt was dissolved by heating to a temperature of 80 ° C. with 140 ml of water, allowed to cool to room temperature for 12 hours, and the resulting crystals were separated.
After drying, a purified diastereomer salt (3) was obtained. Yield 32.5 g (55.2% yield), optical rotation [α] D
−29.4 (C.0.5 25 ° C. MeOH) 5 g of the obtained diastereomer salt (3) (17 mmol)
l), sulfuric acid 0.83 g (8.5 mmol) and water 20m
1 were mixed. 20 ml of 1,2-dichloroethane
Was added and liquid separation was performed. 0.85 g of calcium hydroxide in the water layer
(8.5 mmol) was added, insolubles were filtered off, water was distilled off under reduced pressure, and then 200 ml of methanol was added to dissolve the residue. The insoluble matter was filtered through celite, methanol was distilled off under reduced pressure, and S-
Pipecolic acid (S-1) was obtained. Yield 1.6 g (72.7 yield from diastereomeric salt)
%), Optical rotation [α] D- 25.7 (C. 0.5 25 ° C)
H 2 O), melting point: 265 ° C., optical purity: 95% ee or more On the other hand, the organic layer was washed with 10 ml of water, dried over sodium sulfate, and the solvent was distilled off to recover the resolving agent (S-2).
(2.4 g, 83.8% recovery). Racemization was not observed in the collected resolving agent as a result of HPLC (Chiralcel OD column manufactured by Daicel).
【００１９】（実施例２）本実施例は上記化学式２の工
程に従って行った。（±）−ピペコリン酸（ＲＳ−１）
５２ｇ（０．４０ｍｏｌ），Ｒ−２−フェノキシプロピ
オン酸（Ｒ−２）３４ｇ（０．２０ｍｏｌ），水１４０
ｍｌを混合し、以下実施例１と同じ操作を行い精製ジア
ステレオマー塩(5) を得た。 収量３４．２ｇ（収率 ５８．５％）、旋光度〔α〕D
＋２９．８（Ｃ．０.５ ２５℃ ＭｅＯＨ） 光学純
度95%ee以上 得られたジアステレオマー塩 (5)５ｇ（１７ｍｍｏ
ｌ）、硫酸０．８３ｇ（８．５ｍｍｏｌ）及び水２０ｍ
ｌを混合した。これに１，２−ジクロロエタン２０ｍｌ
を加え分液した。以下実施例１と同様な操作を行いＲ−
ピペコリン酸（Ｒ−１）を得た。 収量１．５ｇ（ジアステレオマー塩からの収率６８．１
％）、旋光度〔α〕D＋２５．６（Ｃ．０．５ ２５℃
Ｈ2 Ｏ） 融点２６３℃ 光学純度95%ee以上 一方、有機層は水１０ｍｌで洗浄し硫酸ナトリウムで乾
燥、溶媒を留去し、分割剤（Ｒ−２）を回収した。
（２．５ｇ、回収率８７．３％）。回収された分割剤に
は、ＨＰＬＣ（ダイセル社製Chiralcel ODカラム) 分析
の結果ラセミ化は認められなかった。Example 2 This example was performed according to the process of the above-mentioned chemical formula 2. (±) -Pipecolic acid (RS-1)
52 g (0.40 mol), 34 g (0.20 mol) of R-2-phenoxypropionic acid (R-2), water 140
Then, the same operation as in Example 1 was performed to obtain a purified diastereomer salt (5). Yield: 34.2 g (58.5% yield), optical rotation [α] D
+29.8 (C.0.5 25 ° C. MeOH) Optical purity 95% ee or more Diastereomer salt obtained (5) 5 g (17 mmo)
l), sulfuric acid 0.83 g (8.5 mmol) and water 20m
1 were mixed. 20 ml of 1,2-dichloroethane
Was added and liquid separation was performed. Thereafter, the same operation as in Example 1 was performed to perform R-
Pipecolic acid (R-1) was obtained. Yield 1.5 g (68.1 yield from diastereomer salt)
%), Optical rotation [α] D +25.6 (C. 0.5 25 ° C.
H 2 O) Melting point: 263 ° C. Optical purity: 95% ee or more On the other hand, the organic layer was washed with 10 ml of water, dried over sodium sulfate, and the solvent was distilled off to recover the resolving agent (R-2).
(2.5 g, 87.3% recovery). Racemization was not observed in the collected resolving agent as a result of HPLC (Chiralcel OD column, manufactured by Daicel).
【００２０】[0020]
【発明の効果】本発明によると、光学分割剤として回収
性の良好な光学活性２−フェノキシプロピオン酸を分割
剤として用い、非修飾ピペコリン酸と付加物を生成させ
ることにより工業的有利に光学分割を行うことができる
ので、医薬品のみならず、光学分割剤、有機合成化学反
応におけるキラルビルディングブロックや農薬、工業用
製品の原材料、中間体として利用することが可能な光学
活性ピペコリン酸を経済的に製造することができる。Industrial Applicability According to the present invention, optically active 2-phenoxypropionic acid having good recoverability is used as an optical resolving agent as a resolving agent, and an unmodified pipecolic acid and an adduct are formed to produce an optically resolving solution in an industrially advantageous manner. Of optically active pipecolic acid, which can be used not only as pharmaceuticals, but also as optical resolving agents, chiral building blocks in organic synthetic chemical reactions, agricultural chemicals, raw materials for industrial products, and intermediates. Can be manufactured.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 洪 南基 神奈川神奈川県平塚市須賀2700番地 大東 化学株式会社研究所内 Ｆターム(参考） 4C054 AA02 CC01 DD32 EE01 FF01 4H006 AA02 AC83 AD30 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Hong Nan Ki 2700, Suga, Hiratsuka-shi, Kanagawa, Japan Daito Chemical Research Laboratory F-term (reference) 4C054 AA02 CC01 DD32 EE01 FF01 4H006 AA02 AC83 AD30
Claims (3)
ル、又はそれらの任意の割合の混合物からなる媒体中
で、光学活性２−フェノキシプロピオン酸と反応させ、
難溶性ジアステレオマー塩として生ずるＳ−（−）−ピ
ペコリン酸・Ｓ−（−）−２−フェノキシプロピオン酸
塩又はＲ−（＋）−ピペコリン酸・Ｒ（＋）−２−フェ
ノキシプロピオン酸塩の製造方法。(1) reacting (±) pipecolic acid with optically active 2-phenoxypropionic acid in a medium consisting of water, a lower alcohol, or a mixture thereof in any ratio;
S-(-)-Pipecolic acid.S-(-)-2-phenoxypropionate or R-(+)-Pipecolic acid.R (+)-2-phenoxypropionate, which is formed as a sparingly soluble diastereomer salt Manufacturing method.
ル、又はそれらの任意の割合の混合物からなる媒体中
で、光学活性２−フェノキシプロピオン酸と反応させ、
難溶性ジアステレオマー塩として生ずるＳ−（−）ピペ
コリン酸・Ｓ−（−）−２−フェノキシプロピオン酸塩
又はＲ−（＋）−ピペコリン酸・Ｒ（＋）−２−フェノ
キシプロピオン酸塩を得、次いで得られたＳ−（−）ピ
ペコリン酸・Ｓ−（−）−２−フェノキシプロピオン酸
塩又はＲ−（＋）−ピペコリン酸・Ｒ（＋）−２−フェ
ノキシプロピオン酸塩を水に溶解又は懸濁したものに当
量又は過剰の酸を加えて複分解し光学的に純粋なＳ−
（−）−ピペコリン酸又はＲ−（＋）−ピペコリン酸を
製造する方法。(2) reacting (±) -pipecolic acid with optically active 2-phenoxypropionic acid in a medium consisting of water, a lower alcohol or a mixture thereof in any proportion;
S-(-) pipecolic acid.S-(-)-2-phenoxypropionate or R-(+)-pipecolic acid.R (+)-2-phenoxypropionate, which is generated as a sparingly soluble diastereomer salt, Then, the obtained S-(-) pipecolic acid.S-(-)-2-phenoxypropionate or R-(+)-pipecolic acid.R (+)-2-phenoxypropionate is added to water. An optically pure S-
A method for producing (-)-pipecolic acid or R-(+)-pipecolic acid.
２−フェノキシプロピオン酸塩又はＲ−（＋）−ピペコ
リン酸・Ｒ−（＋）−２−フェノキシプロピオン酸塩を
水に溶解又は懸濁したものに当量又は過剰の酸を加えて
複分解し、光学的に純粋なＳ−（−）−ピペコリン酸
（Ｓ−１）又はＲ−（＋）−ピペコリン酸を製造する方
法。3. S-(-)-Pipecolic acid.S-(-)-
2-phenoxypropionate or R-(+)-pipecolic acid-R-(+)-2-phenoxypropionate dissolved or suspended in water is added with an equivalent or excess acid to cause double decomposition, and A method for producing highly pure S-(-)-pipecolic acid (S-1) or R-(+)-pipecolic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36218798A JP4397987B2 (en) | 1998-12-21 | 1998-12-21 | Process for producing optically active pipecolic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP36218798A JP4397987B2 (en) | 1998-12-21 | 1998-12-21 | Process for producing optically active pipecolic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000178253A true JP2000178253A (en) | 2000-06-27 |
| JP4397987B2 JP4397987B2 (en) | 2010-01-13 |
Family
ID=18476208
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP36218798A Expired - Fee Related JP4397987B2 (en) | 1998-12-21 | 1998-12-21 | Process for producing optically active pipecolic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4397987B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002316952A (en) * | 2001-04-18 | 2002-10-31 | Daito Kagaku Kk | Method for optical purification of optically active 2- phenoxypropionic acid |
| JP2006169158A (en) * | 2004-12-15 | 2006-06-29 | Daito Kagaku Kk | Method for producing optically active amino acids |
| US7683175B2 (en) | 2005-06-06 | 2010-03-23 | Navinta, Llc | Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom |
| CN108752253A (en) * | 2018-06-27 | 2018-11-06 | 深圳市茵诺圣生物科技有限公司 | A kind of polynary aza-cyclic Non-natural chiral amino acid and its synthetic method |
-
1998
- 1998-12-21 JP JP36218798A patent/JP4397987B2/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002316952A (en) * | 2001-04-18 | 2002-10-31 | Daito Kagaku Kk | Method for optical purification of optically active 2- phenoxypropionic acid |
| JP2006169158A (en) * | 2004-12-15 | 2006-06-29 | Daito Kagaku Kk | Method for producing optically active amino acids |
| JP4728636B2 (en) * | 2004-12-15 | 2011-07-20 | 大東化学株式会社 | Process for producing optically active amino acids |
| US7683175B2 (en) | 2005-06-06 | 2010-03-23 | Navinta, Llc | Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom |
| CN108752253A (en) * | 2018-06-27 | 2018-11-06 | 深圳市茵诺圣生物科技有限公司 | A kind of polynary aza-cyclic Non-natural chiral amino acid and its synthetic method |
| CN108752253B (en) * | 2018-06-27 | 2020-11-24 | 深圳市茵诺圣生物科技有限公司 | Multi-nitrogen heterocyclic non-natural chiral amino acid and synthesis method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4397987B2 (en) | 2010-01-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4170990B2 (en) | Process for producing optically active serine derivatives | |
| EP0441160B1 (en) | Process for preparing levo and dextro fenfluramine | |
| US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
| JP4397987B2 (en) | Process for producing optically active pipecolic acid | |
| JPH083120A (en) | Acylamino acid-alpha-arylamine adduct salt and method for optically revolving alpha-arylamine | |
| HU204247B (en) | Process for optical resolving raceme compositions of alpha-naphtyl-propionic acid derivatives | |
| JP3088777B2 (en) | Novel optical resolving agent and method for producing optically active amine using the same | |
| JP2002521469A (en) | Preparation of R-(-)-carnitine | |
| JP4093608B2 (en) | Process for producing optically active 2-phenoxypropionic acid | |
| JPH02243663A (en) | Method for synthesizing optically active amino acid | |
| JPH04308550A (en) | Method of stereoselectively converting diol into alcohol | |
| JP2002537394A (en) | Method for producing paroxetine | |
| JP4005168B2 (en) | Process for producing optically active 2-aryloxypropionic acid | |
| JP2825608B2 (en) | Optically active threo-3-amino-2-hydroxypentanoic acid and process for producing the same | |
| JP3005669B2 (en) | Method for producing asymmetric fluorinated primary amines | |
| JP3911302B2 (en) | Process for producing optically active 2-methylpiperazine | |
| JPH11322665A (en) | Purification of optically active alpha-trifluoromethyl lactic acid | |
| JP4126921B2 (en) | Process for producing optically active β-phenylalanine derivative | |
| JP3432880B2 (en) | Preparation of optically active azaspiro compounds | |
| JP3201998B2 (en) | Method for producing (S) -benzoxazine derivative and method for racemizing (R) -benzoxazine derivative | |
| JP3288109B2 (en) | Optical isomer separation method | |
| JP3284607B2 (en) | Method for producing optically active 1-phenylethylamine | |
| JP2003137835A (en) | Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid | |
| JPH10237013A (en) | Production of optically active 2-benzylsuccinic acid | |
| WO1991003453A1 (en) | Optically active 2-(alkyl-substituted phenyl)-propionic acid derivative and optical resolution of (±)-1-methyl-3-phenylpropylamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20051219 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20060216 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060302 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20070927 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090707 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090907 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20091014 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20091022 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20121030 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20131030 Year of fee payment: 4 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |