JPS6013736A - Optical resolution of (+-)-2-chloropropionic acid - Google Patents
Optical resolution of (+-)-2-chloropropionic acidInfo
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- JPS6013736A JPS6013736A JP11813183A JP11813183A JPS6013736A JP S6013736 A JPS6013736 A JP S6013736A JP 11813183 A JP11813183 A JP 11813183A JP 11813183 A JP11813183 A JP 11813183A JP S6013736 A JPS6013736 A JP S6013736A
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- optically active
- salt
- cpa
- acid
- nea
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Abstract
Description
【発明の詳細な説明】
本発明は（±）−２−クロロゾロピオン酸の光学分割方
法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for optical resolution of (±)-2-chlorozolopionic acid.
２−クロロゾロピオン酸は２位の塩素原子の存在により
、種々の２−置換ゾロピオン酸に変換することが可能な
ため合成上重要な中間体として知られている。例えば、
加圧下においてアンモニア水溶液と作用させることによ
り容易にアラ二／に導くことができ、アルカリ水溶液で
処理することにより乳酸にすることも可能である。この
時反応は立体特異的に進行するため、光学活性な２−ク
ロロゾロピオン酸を用いれば光学活性なアラニンや乳酸
を得ることができる。光学活性な２−クロロプロピオン
酸はこの他に医薬品、農薬等の中間体としても広く用い
られている。現在光学活性２−クロロゾロピオン酸を得
る方法としては、光学活性なアラニンや乳酸からの変換
などがあげられるが、光学分割による方法はほとんど知
られていない。しかし、２−クロロゾロピオン酸のＤＬ
体が安価で入手可能なことと、光学活性体の利用方法が
多様であることなどから簡便な光学分割の方法が切望さ
れている。2-chlorozolopionic acid is known as an important synthetic intermediate because it can be converted into various 2-substituted zolopionic acids due to the presence of a chlorine atom at the 2-position. for example,
It can be easily converted into aradine by reacting with an aqueous ammonia solution under pressure, and can also be converted into lactic acid by treatment with an aqueous alkaline solution. Since the reaction proceeds stereospecifically, optically active alanine or lactic acid can be obtained by using optically active 2-chlorozolopionic acid. Optically active 2-chloropropionic acid is also widely used as an intermediate for pharmaceuticals, agricultural chemicals, and the like. Currently, methods for obtaining optically active 2-chlorozolopionic acid include conversion from optically active alanine or lactic acid, but almost no method using optical resolution is known. However, the DL of 2-chlorozolopionic acid
There is a strong need for a simple method for optical resolution, since these molecules can be obtained at low cost and optically active substances can be used in a variety of ways.
本発明者らは、これらの事実に基づき（±）−２−クロ
ロプロピオン酸の光学分割方法について種々検討を重ね
た結果、光学活性な１−（１−ナフチル）エチルアミン
を使用することにより（±）−２−クロロプロピオン酸
を高純度でしかも高収率で光学分割できることを見い出
し、本発明を完成した。Based on these facts, the present inventors conducted various studies on the optical resolution method of (±)-2-chloropropionic acid, and found that (±)-2-chloropropionic acid can be resolved by using optically active 1-(1-naphthyl)ethylamine. )-2-chloropropionic acid can be optically resolved with high purity and high yield, and the present invention has been completed.
すなわち本発明シま、（±）−２−クロロプロピオン酸
に光学活性な１−（１−ナフチル）エチルアミンを作用
させてノアステレオマ−塩を形成させ、その溶解度差を
利用して光学分割する方法である。That is, the present invention is a method in which (±)-2-chloropropionic acid is reacted with optically active 1-(1-naphthyl)ethylamine to form a noastereomer salt, and the solubility difference is utilized for optical resolution. be.
本発明の上記構成について以下に詳説する。The above configuration of the present invention will be explained in detail below.
本発明では光学活性な１−（ｌ−ナフチル）エチルアミ
ンとして、右旋性の１−（ｌ−ナフチル）エチルアミン
でも、左旋性の１−（ｌ−ナフチル）エチルアミンでも
任意に使用することができろ。In the present invention, either dextrorotatory 1-(l-naphthyl)ethylamine or levorotatory 1-(l-naphthyl)ethylamine can be used as the optically active 1-(l-naphthyl)ethylamine. .
光学活性な１−（１−ナフチル〕エチルアミンは天然の
（＋）−酒石酸または光学活性なシス−２−ベンズアミ
ド−シクロヘキサンカルボン酸を分割剤とするノアステ
レオマ−法を用いて光学分割することによって容易（Ｃ
入手できる。（米国特許第２，９９６．’５４５号明細
書、米国特許第３，０００，９４７号明細書および特開
昭５８−２４５４５）
本発明では分割剤としての光学活性な１−（１−ナフチ
ル）エチルアミンと（±）−２−クロロプロピオン酸と
のモル比を特に限定ｆるものではないが、（±）−２−
クロロゾロピオン酸に対して分割剤を実質的に０．８〜
１，０当量使用すると（±）−２−クロロゾロピオン酸
を効率良くかつ高純度で分割できるので好ましい。Optically active 1-(1-naphthyl)ethylamine can be easily optically resolved using the norastereomer method using natural (+)-tartaric acid or optically active cis-2-benzamide-cyclohexanecarboxylic acid as a resolving agent ( C
Available. (U.S. Pat. No. 2,996.'545, U.S. Pat. No. 3,000,947, and JP-A-58-24545) In the present invention, optically active 1-(1-naphthyl) is used as a resolving agent. Although there is no particular limitation on the molar ratio of ethylamine and (±)-2-chloropropionic acid, (±)-2-
The resolving agent is substantially 0.8 to chlorozolopionic acid.
It is preferable to use 1.0 equivalent since (±)-2-chlorozolopionic acid can be efficiently and highly purified.
本発明の方法は、（±）−２−クロロス０ロビオン酸と
１−（１−ナフチル）エチルアミンを溶媒中で作用させ
ろが、その際に使用する溶媒としては水、メタノール、
エタノール、ｌ−グロノぐノール、２−７’ロバノール
、ｌ−ブタノール、アセトン、メチルエテルケトン等の
単独あるいはこれらの混合物を用いるとよく、特に２−
プロパツールを用いると高純度の光学活性２−クロロプ
ロピオン酸を得られるので好ましい。そこで溶媒として
２−ゾロ・ぐノールを使用する場合について好ましい実
施方法を下記に説明する。In the method of the present invention, (±)-2-chlororosobionic acid and 1-(1-naphthyl)ethylamine are reacted in a solvent, and the solvents used at this time include water, methanol,
Ethanol, l-gulonol, 2-7' lovanol, l-butanol, acetone, methyl ether ketone, etc. may be used alone or in mixtures thereof, especially 2-
It is preferable to use propatool because highly pure optically active 2-chloropropionic acid can be obtained. Therefore, a preferred method for using 2-zologunol as a solvent will be described below.
２−ノロパノールに（±）−２−クロロノロビオ／酸を
溶解し、これに０．８〜１．０当量の光学活性な１−（
１−ナフチル）エチルアミンの２−プロパツール溶液を
滴下し、難溶性ノアステレオマ−塩を生成させる。この
場合の塩の生成反応はＯ〜８０Ｃの間の任意の占度で行
うことが可能であるが、通常２０〜５０Ｃで行つのが好
ましい。Dissolve (±)-2-chloronorobio/acid in 2-noropanol, and add 0.8 to 1.0 equivalents of optically active 1-(
A 2-propanol solution of 1-naphthyl)ethylamine is added dropwise to form a sparingly soluble noastereomeric salt. In this case, the salt production reaction can be carried out at any temperature between 0 and 80C, but it is usually preferably carried out at 20 to 50C.
この操作により析出した難溶性のジアステレオマー塩な
固ン仮分離した後、必要に応じて、この難溶性ノアステ
レオマー塩を適量の２−プロパツールを用いて再結晶す
る。こうして得られ１こ精製難溶性ヅアステレオマー塩
を水酸化ナトリウム、水酸化カリウム、アンモニアなど
の塩基で処理し、エーテル、ベンゼン１工どの有機溶剤
により抽出して（＋）または（−） −１−（１−ナフ
チル）エチルアミンを回収する。更に母液を鉱酸により
酸性とし、エーテル、塩化メチレンなどの有機溶剤によ
り抽出し、乾燥、濃縮して（＋）または（−］−］２−
クロロプロピオンを得る。After the poorly soluble diastereomeric salt precipitated by this operation is temporarily separated, the poorly soluble noastereomeric salt is recrystallized using an appropriate amount of 2-propanol, if necessary. The purified poorly soluble diastereomer salt thus obtained is treated with a base such as sodium hydroxide, potassium hydroxide, or ammonia, and extracted with an organic solvent such as ether or benzene (+) or (-) -1-( 1-Naphthyl)ethylamine is recovered. The mother liquor is further acidified with mineral acid, extracted with organic solvents such as ether and methylene chloride, dried and concentrated to give (+) or (-]-]2-
Obtain chloropropion.
本発明を一層理解しやすくするために、以下に実施例を
示すが本発明は下記の実施例によって何ら制限を受ける
ものではない。EXAMPLES In order to make the present invention easier to understand, examples are shown below, but the present invention is not limited in any way by the following examples.
実施例１
２−プロパツール１２２艷に（±） −２−クロロプロ
ピオン酸（以下（±）−ＣＰＡと略記する。） ２ ｔ
、７０ ｆ （０−２ｍｏｌ ）を加え俗解した後、約
５００で加熱しなから（−）−１−（１−ナフチル）エ
チルアミン（以下（−）−ＮＥＡと略記する。） ２７
．４０ ｆ （０，１６ｍｏｌ ）の２−プロパツール
１８ゴ浴液を滴下し、別途に合成した精製（＋） −Ｃ
Ｐ Ａ・（−）−ＮＥＡ塩数■を接種した後、室温まで
ゆつくりと冷却し、約４時間放置した。析出した結晶ｕ
ｐ過し、（＋） −ｃ Ｐ Ａ ・（−） −Ｎ Ｂ
Ａ塩２７．４６ ？ （９８−２ｍｍｏｌ ）を得た。Example 1 2-proper tool 122 (±)-2-chloropropionic acid (hereinafter abbreviated as (±)-CPA) 2 t
, 70 f (0-2 mol), heated at about 500 ℃, and (-)-1-(1-naphthyl)ethylamine (hereinafter abbreviated as (-)-NEA) 27
．． 40 f (0.16 mol) of 2-propertool 18 bath solution was added dropwise to separately synthesized purified (+) -C.
After inoculating a few grams of P A (-)-NEA salt, it was slowly cooled to room temperature and left for about 4 hours. Precipitated crystal u
p passed, (+) -c P A ・(-) -N B
A salt 27.46? (98-2 mmol) was obtained.
用いた（±）−ＣＰＡ中の（十） −ＣＰ Ａに対して
の（ｃ ｉ、ｏ、ＭｅＯＨ）、ｍｐ、１３５〜１３６℃
この塩を２−プロ・ぐノールを用いて２回再７晴晶して
Ｍ製塩１６．Ｉ Ｑ ？ （５７，５ｍｍｏυを得た。(ci, o, MeOH) for (10)-CPA in (±)-CPA used, mp, 135-136 °C
This salt was re-crystallized twice using 2-pro-gnol to make M salt 16. IQ? (57.5 mmoυ was obtained.
〔α） ｇＨｏ−４−２７° （ｃ ｌ−１。[α) gHo-4-27° (cl-1.
ＭｅＯＨ） ｍｐ、１３９．５〜１４０．５℃この塩１
６−１０ ？ （５７，５ｍｍｏｌ）に３規定水酸化す
） ＩＪウム水浴液２３−を加えてエーテル抽出した。MeOH) mp, 139.5-140.5°C This salt 1
6-10? (57.5 mmol) was added with 3N hydroxide (IJum water bath solution 23-) and extracted with ether.
続いてこの際の水層Ｖｃ濃硫酸４．６ ｒｎｌを加えて
塩化メチレン抽出することにより５．９３１ （５４，
７ｒｒｕｎｏｌ）の（＋） −ＣＰ Ａを得た。収率９
５．０％。用いた（±）−ＣＰＡ中の（＋） −Ｃｐ
Ａに対しての収率は５４．７％〔α］ ：：、 ＋ １
２．２° （Ｃ１，２、Ｃ山）。Subsequently, 4.6 rnl of concentrated sulfuric acid was added to the aqueous layer Vc and extracted with methylene chloride to obtain 5.931 (54,
(7rrunol) of (+)-CPA was obtained. Yield 9
5.0%. (+)-Cp in (±)-CPA used
The yield relative to A is 54.7% [α]::, + 1
2.2° (C1, 2, Mt. C).
〔α〕５８９ ＋ １２．１’ （ｎｅａｔ）。文献値
〔α］ ｓａｏ ＋ １４．６° （ｎｅａｔ） （５
−Ｊ−ＦｕｒＳ、Ｍ、Ｂｉｒｎｂａｕｍ、ａｎｄ Ｊ、
Ｐ、Ｇｒｅｅｎｓｔｅｉｎ、Ｊ。[α]589 + 12.1' (neat). Literature value [α] sao + 14.6° (neat) (5
-J-FurS, M., Birnbaum, and J.
P., Greenstein, J.
Ａｍ、 Ｃｈｅｍ、Ｓｏｃ、、７６． ６０５４ （１
９５４））から計算した光学純度は８２．９４
実施例２
（±）−ＣＰＡ２１．７Ｏｒ（０，２ｍｏｌ ）を用い
て実施例■と同様な操作で造塩し、再結晶を２回行った
。得られた（＋） −ＣＰ Ａ・（−）−ＮＢＡ塩１６
−１０ ｆ （５７，５ｍｍｏｌ ） を２−ゾロ−ぐ
ノール１１０ｍを用いてさらに再結晶を行い、精製塩１
２．６２９ （４５，１ｍｍｏｌ）を得た。〔α］ ：
：、−４，５２° （（！ ２．１ 。Am, Chem, Soc,,76. 6054 (1
The optical purity calculated from 954)) was 82.94. Example 2 Salt was prepared using (±)-CPA21.7Or (0.2 mol) in the same manner as in Example ①, and recrystallization was performed twice. Obtained (+)-CP A・(-)-NBA salt 16
-10f (57.5mmol) was further recrystallized using 110ml of 2-zolognol to obtain purified salt 1
2.629 (45.1 mmol) was obtained. [α]:
:, -4,52° ((! 2.1.
ＭｅＯＨ）ｍｐ、１４１−１４２ｃ０
この精製塩１２．６２ ？ （４５，１ｍｍｏｌ） Ｋ
３規定の水酸化ナトリウム水、浴液１８−を加えエー
テル抽出した。続いてこの際の水層に濃硫酸：ｉ６＋ｍ
を加えて塩化メチレン抽出することにより４．６５９
（４２，９ｍｍｏｌ）の（＋）−ＣＰＡを得た。収率９
５６ｏ俸、用いた（±９−ＣＰＡ中の（＋）〜ＣＰＡに
対しての収率は４２．９ ％。Ｃａ ］：：、 ＋１３
．３°（ｃ １．０゜ＣＣＡ’＜）光学純度９０．６係
。MeOH) mp, 141-142c0 This purified salt 12.62? (45.1 mmol) K
3N sodium hydroxide solution and bath solution 18- were added and extracted with ether. Next, concentrated sulfuric acid: i6+m was added to the water layer at this time.
4.659 by adding methylene chloride extraction
(42.9 mmol) of (+)-CPA was obtained. Yield 9
56 o salary, the yield for (+) ~ CPA in (±9-CPA was 42.9%.Ca]::, +13
．． 3° (c 1.0° CCA'<) Optical purity: 90.6.
実施例３
実施例１′Ｉｃて得られた造塩母液を減圧下に乾固しく
理論量酸ＣＰＡとして１０１．８ ｍｍｏｌ）３規定の
水酸化ナトリウム水溶ｉ ４０．７ ｒｎｌ、を加え、
エーテル抽出した。続いてこの際の水層に濃硫酸８．１
−を加えて塩化メチレン抽出することにより、１０−８
８９ （Ｉ Ｏ０，３ｍｒｎｏｌ）の（−Ｊ−ＣＰＡを
得た。〔α〕３１−５・９５゜（ｃｌ・１． Ｃα、）
光学純度４０．６係。Example 3 The salt-forming mother liquor obtained in Example 1'Ic was dried under reduced pressure, and a theoretical amount of acid CPA (101.8 mmol) was added with 40.7 rnl of 3N sodium hydroxide aqueous solution.
Extracted with ether. Subsequently, 8.1% of concentrated sulfuric acid was added to the water layer at this time.
- and extracted with methylene chloride, 10-8
(-J-CPA of 89 (IO0,3 mrnol) was obtained. [α] 31-5·95° (cl·1. Cα,)
Optical purity: 40.6.
実施例４
実施例３で得た光学純度４０．６％の（−）−ＣＰ Ａ
Ｉ ０．８２９ （９９，７ｍｍｏｌ）を２−プロパ
ツール１０−に俗解した後約５０℃で加熱しながら（＋
）−ＮＥＡ ｌ ７．０８ Ｆ （９９，７ｍｍｏｌ）
の２−プロパツール１０ｍ７！浴欣を滴下し、室温で約
２時間放置した。析出した結晶を濾過し、２−プロノぞ
ノール約１０−で洗浄１−ることにより、（−）−ｃｐ
Ａ・（＋） −Ｎ ＥＡｌ蔦２１．４３ ｆ （７６−
６ｍｎ＋ｏｌ）を得た。Example 4 (-)-CP A with optical purity of 40.6% obtained in Example 3
I 0.829 (99.7 mmol) was dissolved in 2-propatool 10- and then heated at about 50°C (+
)-NEA l 7.08 F (99.7 mmol)
2-Proper tool 10m7! Bath soap was added dropwise and left at room temperature for about 2 hours. The precipitated crystals were filtered and washed with about 10% of 2-pronozonol to give (-)-cp.
A・(+) −N EAL ivy 21.43 f (76−
6 mn+ol) was obtained.
〔α〕” ＋４．＋３２° （ｃ Ｏ，９７、ＭｅＯＨ
）ｍｐ、１ ３ ８〜１３９℃
この塩を２−ゾロ・ぐノールがら再結晶を行い、精製塩
１５．７５ｇを得た。〔α〕２６＋４．７５° （ｃ
２．０ 、 ＭｅＯＨ） 。ｍｐ、’ １３８．５〜１
４０℃
この精製塩１５．７５ ｇ （５６，３ｍｍｏｌ）に３
規定の水酸ナトリウム水溶液２２．５ ｍｌ を加えて
エーテル抽出した。続いてこの際の水層に濃硫酸４．５
ｍｌを加えて塩化メチレン抽出して５．４６ ｇ （
５０，３ｍｍｏｌ）の（−） −ＣＰＡを得た。収率８
９４％。用いたＣＰＡ中の（−）−ＣＰＡＫ対する収率
は６９．６％。〔α〕、８゜−１０，６３° （ｃｌ、
ｏ、Ｃα４ ）光学純度７２４％。[α]” +4.+32° (c O,97, MeOH
) mp, 1 3 8-139°C This salt was recrystallized from 2-zolo-gnol to obtain 15.75 g of purified salt. [α]26+4.75° (c
2.0, MeOH). mp,' 138.5~1
40℃ 15.75 g (56.3 mmol) of this purified salt
22.5 ml of a specified aqueous sodium hydroxide solution was added and extracted with ether. Subsequently, 4.5% of concentrated sulfuric acid was added to the water layer at this time.
ml and extracted with methylene chloride to obtain 5.46 g (
50.3 mmol) of (-)-CPA was obtained. Yield 8
94%. The yield based on (-)-CPAK in the CPA used was 69.6%. [α], 8°-10,63° (cl,
o, Cα4) optical purity 724%.
特許出願人 野 平 博 之Patent applicant Hiroyuki Nohei
Claims (1)
−ナフチル）エチルアミンを作用させ、それらの塩の溶
解度の差を利用して温媒によって（＋）−２−クロロプ
ロピオン酸塩と、（−）−２−クロロノロピオン酸塩を
分離し、さらに各基に塩基性物質を作用させることによ
って（＋）−２−クロロゾロピオン酸と（−）−２−ク
ロロプロピオン酸を遊離させることを特徴とする（±）
−２−クロロゾロピオン酸の光学分割法。(±)-2-chloropropionic acid with optically active 1-(1
-Naphthyl)ethylamine is applied, and (+)-2-chloropropionate and (-)-2-chloropropionate are separated by a hot medium using the difference in solubility of these salts, and then It is characterized by liberating (+)-2-chlorozolopionic acid and (-)-2-chloropropionic acid by acting a basic substance on each group (±)
Optical resolution method of -2-chlorozolopionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11813183A JPS6013736A (en) | 1983-07-01 | 1983-07-01 | Optical resolution of (+-)-2-chloropropionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11813183A JPS6013736A (en) | 1983-07-01 | 1983-07-01 | Optical resolution of (+-)-2-chloropropionic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6013736A true JPS6013736A (en) | 1985-01-24 |
Family
ID=14728806
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11813183A Pending JPS6013736A (en) | 1983-07-01 | 1983-07-01 | Optical resolution of (+-)-2-chloropropionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6013736A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63162526A (en) * | 1986-12-25 | 1988-07-06 | Daiitsushi:Kk | Spherical salt and method for granulating spherical salt |
| JPS63301816A (en) * | 1987-01-29 | 1988-12-08 | Takeda Chem Ind Ltd | Core-containing granule and production thereof |
| JPH02138147A (en) * | 1988-11-17 | 1990-05-28 | Ube Ind Ltd | Optical resolution of 2-chlorobutanoic acid |
| JPH0395138A (en) * | 1989-09-07 | 1991-04-19 | Nissan Chem Ind Ltd | Optical resolution of 3-methylheptanoic acid |
| WO2008004044A1 (en) * | 2006-07-04 | 2008-01-10 | Laboratorio Chimico Internazionale S.P.A. | Process for the preparation of (r)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates |
| CN102344355A (en) * | 2011-08-25 | 2012-02-08 | 上海科利生物医药有限公司 | Method for preparing chiral (S)-2-propionic acid |
-
1983
- 1983-07-01 JP JP11813183A patent/JPS6013736A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63162526A (en) * | 1986-12-25 | 1988-07-06 | Daiitsushi:Kk | Spherical salt and method for granulating spherical salt |
| JPH0449486B2 (en) * | 1986-12-25 | 1992-08-11 | Daiitsushi Jugen | |
| JPS63301816A (en) * | 1987-01-29 | 1988-12-08 | Takeda Chem Ind Ltd | Core-containing granule and production thereof |
| JPH0832625B2 (en) * | 1987-01-29 | 1996-03-29 | 武田薬品工業株式会社 | Nucleated granule and method for producing the same |
| JPH02138147A (en) * | 1988-11-17 | 1990-05-28 | Ube Ind Ltd | Optical resolution of 2-chlorobutanoic acid |
| JPH0395138A (en) * | 1989-09-07 | 1991-04-19 | Nissan Chem Ind Ltd | Optical resolution of 3-methylheptanoic acid |
| WO2008004044A1 (en) * | 2006-07-04 | 2008-01-10 | Laboratorio Chimico Internazionale S.P.A. | Process for the preparation of (r)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates |
| JP2009542615A (en) * | 2006-07-04 | 2009-12-03 | ラボラトリオ キミコ インテルナツィオナーレ ソチエタ ペル アツィオーニ | (R)-(−)-3- (Carbamoylmethyl) -5-methylhexanoic acid, pregabalin, and synthetic intermediate production method |
| CN102344355A (en) * | 2011-08-25 | 2012-02-08 | 上海科利生物医药有限公司 | Method for preparing chiral (S)-2-propionic acid |
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