JP3032447B2 - Method for producing optically active 2-propyloctanoic acid - Google Patents
Method for producing optically active 2-propyloctanoic acidInfo
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- JP3032447B2 JP3032447B2 JP7098328A JP9832895A JP3032447B2 JP 3032447 B2 JP3032447 B2 JP 3032447B2 JP 7098328 A JP7098328 A JP 7098328A JP 9832895 A JP9832895 A JP 9832895A JP 3032447 B2 JP3032447 B2 JP 3032447B2
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- JP
- Japan
- Prior art keywords
- optically active
- acid
- salt
- propynyl
- hexane
- Prior art date
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】本発明は、光学活性な２−プロピルオクタ
ン酸の製造方法に関する。さらに詳しくは、本発明は出
発原料に２−（２−プロピニル）オクタン酸を用い、光
学分割を行った後、還元反応を行なうことを特徴とする
光学活性な２−プロピルオクタン酸の製造方法に関す
る。The present invention relates to a method for producing optically active 2-propyloctanoic acid. More specifically, the present invention relates to a method for producing optically active 2-propyloctanoic acid, which comprises using 2- (2-propynyl) octanoic acid as a starting material, performing optical resolution and then performing a reduction reaction. .
【０００２】[0002]
【従来の技術および発明が解決しようとする問題点】本
発明で製造される光学活性な２−プロピルオクタン酸
（以後、目的化合物と略記する）は、医薬品として有用
な化合物である。本発明の目的化合物のラセミ体は、ア
ストロサイトの機能異常による神経変性疾患の治療また
は予防剤として特願平６−１４０９５４号中の実施例７
（３３）に記載されている。その後の研究の結果、ラセ
ミ体のうち、Ｒ体が、特に活性が強いことが見出され、
そのためＲ体を効率よく得る方法について種々検討が行
なわれた。通常、ある化合物の光学活性体を得るには、
そのラセミ体から光学分割によって分離する方法が用い
られる。光学分割は、目的化合物が酸である場合、光学
活性なアミンを用いて行なわれる。この方法は、酸と光
学活性なアミンから塩を構成させ、これを光学分割する
ことにより行なわれる。しかしながら、ラセミ体から目
的化合物を分離する方法を試みたところ、後述する実験
でも明らかなように、化学収率、光学純度ともに悪く、
実用的な方法といえるものではなかった。2. Description of the Related Art Optically active 2-propyloctanoic acid (hereinafter abbreviated as a target compound) produced by the present invention is a compound useful as a pharmaceutical. The racemic compound of the object compound of the present invention was used as an agent for treating or preventing a neurodegenerative disease caused by astrocyte dysfunction, as described in Example 7 in Japanese Patent Application No. 6-140954.
(33). As a result of the subsequent research, among the racemates, the R-form was found to have particularly strong activity,
Therefore, various studies have been made on a method for efficiently obtaining the R-form. Usually, to obtain an optically active form of a compound,
A method of separating from the racemate by optical resolution is used. Optical resolution is performed using an optically active amine when the target compound is an acid. This method is carried out by forming a salt from an acid and an optically active amine and subjecting the salt to optical resolution. However, when the method of separating the target compound from the racemate was tried, as is clear from the experiment described later, both the chemical yield and the optical purity were poor,
It was not a practical method.
【０００３】[0003]
【問題を解決するための手段】本発明の発明者等は、鋭
意研究の結果、出発原料に３重結合を有する化合物であ
る２−（２−プロピニル）オクタン酸を用いることで、
高い化学収率と高い光学純度を得ることに成功し、本発
明を完成した。本発明方法は、以下の手順により行なわ
れる。 １） ラセミ体の２−（２−プロピニル）オクタン酸を
出発原料に、光学活性なアミンとの間で塩を構成させ、 ２） この塩を分別再結晶させた後、酸処理することに
よって、光学活性な２−（２−プロピニル）オクタン酸
を得、 ３） 得られた化合物を還元することにより目的化合物
を得る。 １）の出発原料であるラセミ体の２−（２−プロピニ
ル）オクタン酸は公知化合物であり（Tetrahedron Lett
ers Vol. 21, 4233, 1980参照）、公知の方法により製
造することができるが、例えば、反応工程式（Ｉ）また
は（ＩＩ）に記載の方法により製造することができる。
ここで用いられる光学活性なアミンとは、通常光学分割
に用いられるアミンであればどれでもよいが、例えば、
（Ｒ）−（＋）−１−フェネチルアミン、（Ｒ）−
（＋）−１−（４−メチルフェニル）エチルアミン、Ｌ
−アルギニン、２Ｒ−アミノブタノール、（Ｓ）−
（−）−ニコチン、ヒドロキニン、デヒドロアビエチル
アミン、（１Ｓ，２Ｓ）−メチルプセイドエフェドリン
（１Ｒ，２Ｓ）−（−）−ノルエフェドリン、Ｌ−チロ
シン、（−）−（ｃｉｓ）−ベンジル−（２−ヒドロキ
シメチルシクロヘキシル）アミン、（ｓ）−（−）−１
−メチル−２−ピロリジンメタノール等が用いられる
が、好ましくは、（Ｒ）−（＋）−１−フェネチルアミ
ン、（Ｒ）−（＋）−１−（４−メチルフェニル）エチ
ルアミンである。 ２） 光学分割は、分別再結晶、液体カラムクロマト等
により行なわれる。分別再結晶法は公知であるが、例え
ば、光学分割の対象となる化合物に対して適当な溶解度
を有する有機溶媒（単一または混合）を加熱し、これに
ラセミ体の塩を溶解させ、徐々に放冷する事により行な
われる。適当な有機溶媒としては、例えば、ｎ−ヘキサ
ン、ｎ−ペンタン、ｎ−ヘプタン、シクロヘキサン、酢
酸エチル、ＴＨＦ、テトラヒドロピラン、ジオキサン、
ジメトキシエタン、アセトン、エタノール、イソプロピ
ルアルコール、メタノール、イソプロピルエーテル、石
油エーテルおよびこれらの混合溶媒等が挙げられる。酸
処理は、無機酸（塩酸、硝酸、臭化水素酸等）、有機酸
（酢酸、トリフルオロ酢酸、メタンスルホン酸等）いず
れを用いてもよい。 ３）の還元は、多重結合を単結合に還元する方法であれ
ば、いずれの方法でもよいが、例えば、接触還元法等が
好適に用いられる。接触還元法は公知であり、例えば、
不活性な有機溶媒（酢酸エチル、ＴＨＦ、テトラヒドロ
ピラン、ジオキサン、ジメトキシエタン、ジエチルエー
テル、ビフェニルエーテル、メチルアルコール、エチル
アルコール、イソプロピルアルコール、ベンゼン、トル
エン、キシレン、アセトン、メチルエチルケトン、フェ
ニルメチルケトン、アセトニトリル、ＨＭＰＡ、ＤＭ
Ｆ、ジメチルイミダゾリジノン、これらの混合溶媒等）
中、水素雰囲気下、触媒（パラジウムカーボン、パラジ
ウム、白金、酸化白金、ニッケル等）を用いて、０−６
０℃で行なわれる。Means for Solving the Problems As a result of intensive studies, the inventors of the present invention have found that using 2- (2-propynyl) octanoic acid, which is a compound having a triple bond, as a starting material,
We succeeded in obtaining a high chemical yield and high optical purity, and completed the present invention. The method of the present invention is performed according to the following procedure. 1) Starting from racemic 2- (2-propynyl) octanoic acid as a starting material, a salt is formed between the salt and an optically active amine. 2) The salt is fractionally recrystallized, followed by acid treatment. Optically active 2- (2-propynyl) octanoic acid is obtained. 3) The target compound is obtained by reducing the obtained compound. Racemic 2- (2-propynyl) octanoic acid as a starting material of 1) is a known compound (Tetrahedron Lett
ers Vol. 21, 4233, 1980), and can be produced by a known method. For example, it can be produced by a method described in the reaction scheme (I) or (II).
The optically active amine used here may be any amine that is usually used for optical resolution, for example,
(R)-(+)-1-phenethylamine, (R)-
(+)-1- (4-methylphenyl) ethylamine, L
-Arginine, 2R-aminobutanol, (S)-
(-)-Nicotine, hydroquinine, dehydroabiethylamine, (1S, 2S) -methylpseudoephedrine (1R, 2S)-(-)-norephedrine, L-tyrosine, (-)-(cis) -benzyl- ( 2-hydroxymethylcyclohexyl) amine, (s)-(-)-1
-Methyl-2-pyrrolidinemethanol or the like is used, and preferably (R)-(+)-1-phenethylamine and (R)-(+)-1- (4-methylphenyl) ethylamine. 2) Optical resolution is performed by fractional recrystallization, liquid column chromatography, or the like. The fractional recrystallization method is known. For example, an organic solvent (single or mixed) having an appropriate solubility for a compound to be subjected to optical resolution is heated, a racemic salt is dissolved therein, and gradually It is performed by allowing to cool. Suitable organic solvents include, for example, n-hexane, n-pentane, n-heptane, cyclohexane, ethyl acetate, THF, tetrahydropyran, dioxane,
Examples thereof include dimethoxyethane, acetone, ethanol, isopropyl alcohol, methanol, isopropyl ether, petroleum ether, and a mixed solvent thereof. For the acid treatment, any of inorganic acids (such as hydrochloric acid, nitric acid, and hydrobromic acid) and organic acids (such as acetic acid, trifluoroacetic acid, and methanesulfonic acid) may be used. The reduction in 3) may be any method as long as it reduces multiple bonds to single bonds, but, for example, a catalytic reduction method is preferably used. Catalytic reduction methods are known, for example,
Inert organic solvents (ethyl acetate, THF, tetrahydropyran, dioxane, dimethoxyethane, diethyl ether, biphenyl ether, methyl alcohol, ethyl alcohol, isopropyl alcohol, benzene, toluene, xylene, acetone, methyl ethyl ketone, phenyl methyl ketone, acetonitrile, HMPA, DM
F, dimethylimidazolidinone, a mixed solvent thereof, etc.)
Medium, hydrogen atmosphere, using a catalyst (palladium carbon, palladium, platinum, platinum oxide, nickel, etc.), 0-6
Performed at 0 ° C.
【０００４】[0004]
【化１】 Embedded image
【０００５】[0005]
【化２】 Embedded image
【０００６】[0006]
【本発明の効果】次に示されるように、本発明方法は、
化学収率および光学純度において、比較例の方法より優
れていることは明かである。即ち、本発明方法は比較例
に比べ、化学収率においては、３倍良く、また、少ない
再結晶の回数で高い光学純度の物が得られていることが
分かる。As shown below, the method of the present invention comprises:
It is clear that the chemical yield and the optical purity are superior to the method of the comparative example. That is, it can be seen that the chemical yield of the method of the present invention is three times as good as that of the comparative example, and a product of high optical purity can be obtained with a small number of recrystallizations.
【０００７】比較例は、目的化合物のラセミ体と光学活
性なアミンを用いて塩を生成させ、分別再結晶により精
製した例である。 収率の比較 ──────────────────────────────── 化学収率 光学純度 再結晶の回数 (e.e.) ──────────────────────────────── 本発明方法 ２７％ ９０．０％ ５回 比較例 ９％ ８２．０％ ７回 ──────────────────────────────── 注：化学収率は、各々、ラセミ体からの通算収率を示
す。The comparative example is an example in which a salt is produced using a racemic form of the target compound and an optically active amine, and the salt is purified by fractional recrystallization. Yield comparison ──────────────────────────────── Chemical yield Optical purity Number of recrystallizations (ee) ──方法 Method of the present invention 27% 90.0% 5 times Comparative example 9% 82.0% 7 Note: Chemical yields are the total yields from the racemates, respectively. Show.
【０００８】注：再結晶の回数は、光学純度（ｅ．
ｅ．）が（Ｒ体−Ｓ体）／（Ｒ体＋Ｓ体）比が８０％以
上になった時の回数を示した。Note: The number of recrystallizations depends on the optical purity (e.
e. ) Indicates the number of times when the (R-form-S-form) / (R-form + S-form) ratio became 80% or more.
【０００９】[0009]
【実施例】以下に比較例、参考例および実施例を挙げて
本発明を具体的に説明するが、これらは本発明の範囲を
限定するものではない。 参考例１ ヘキシルマロン酸ジメチルエステルの製造EXAMPLES The present invention will be specifically described below with reference to Comparative Examples, Reference Examples and Examples, which do not limit the scope of the present invention. Reference Example 1 Production of hexylmalonic acid dimethyl ester
【００１０】[0010]
【化３】 Embedded image
【００１１】メタノール（１００ｍｌ）に金属ナトリウ
ム（４．６０ｇ）を加え、５０℃に保ち、マロン酸ジメ
チル（２３．５ｍｌ）を滴下した。この溶液に臭化ヘキ
シル（２８．１ｍｌ）をゆっくり加えた後、２時間還流
した。反応液を濾過し、減圧濃縮した。残留物に水（８
０ｍｌ）を加え、ｎ−ヘキサンで抽出した。有機層を飽
和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減
圧濃縮した。残留物を蒸留により精製し、下記物性値を
有する標題化合物（３２．６ｇ）を得た。 ＴＬＣ ： Ｒｆ 0.62（ｎ−ヘキサン：酢酸エチル＝
４：１）； ＮＭＲ（CDCl3）：δ 3.74 (6H, s), 3.63 (1H, t), 1.
97-1.80 (2H, m), 1.38-1.10 (8H, m), 0.88 (3H, t)。 参考例２ ヘキシル（２−プロピニル）マロン酸ジメチルエステル
の製造[0011] Sodium metal (4.60 g) was added to methanol (100 ml), and the mixture was kept at 50 ° C and dimethyl malonate (23.5 ml) was added dropwise. Hexyl bromide (28.1 ml) was slowly added to the solution, and the mixture was refluxed for 2 hours. The reaction was filtered and concentrated under reduced pressure. Water (8
0 ml) and extracted with n-hexane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by distillation to give the title compound (32.6 g) having the following physical data. TLC: Rf 0.62 (n-hexane: ethyl acetate =
NMR (CDCl 3 ): δ 3.74 (6H, s), 3.63 (1H, t), 1.
97-1.80 (2H, m), 1.38-1.10 (8H, m), 0.88 (3H, t). Reference Example 2 Production of hexyl (2-propynyl) malonic acid dimethyl ester
【００１２】[0012]
【化４】 Embedded image
【００１３】メタノール（８０ｍｌ）に金属ナトリウム
（３．６０ｇ）を加え、５０℃に保ち、参考例１で製造
した化合物（３２．０ｇ）を加えた。この溶液にプロパ
ルギルブロミド（１３．９ｍｌ）をゆっくりと加えた
後、２時間還流した。反応液を濾過し、減圧濃縮した。
残留物に水（７０ｍｌ）を加え、ｎ−ヘキサンで抽出し
た。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウ
ムで乾燥し、減圧濃縮した。残留物を蒸留により精製し
て下記物性値を有する標題化合物（２５．５ｇ）を得
た。 ＴＬＣ ： Ｒｆ 0.79（ベンゼン：酢酸エチル＝１
０：１）； ＮＭＲ（CDCl3）：δ 3.74 (6H, s), 2.83 (2H, d), 2.
15-1.98 (3H, m), 1.46-1.04 (8H, m), 1.02-0.84 (3H,
m)。 参考例３ ２−（２−プロピニル）オクタン酸メチルの製造To methanol (80 ml) was added sodium metal (3.60 g), and the mixture was kept at 50 ° C. and the compound prepared in Reference Example 1 (32.0 g) was added. Propargyl bromide (13.9 ml) was slowly added to the solution, and the mixture was refluxed for 2 hours. The reaction was filtered and concentrated under reduced pressure.
Water (70 ml) was added to the residue, and extracted with n-hexane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by distillation to give the title compound (25.5 g) having the following physical data. TLC: Rf 0.79 (benzene: ethyl acetate = 1)
NMR (CDCl 3 ): δ 3.74 (6H, s), 2.83 (2H, d), 2.
15-1.98 (3H, m), 1.46-1.04 (8H, m), 1.02-0.84 (3H, m
m). Reference Example 3 Production of methyl 2- (2-propynyl) octanoate
【００１４】[0014]
【化５】 Embedded image
【００１５】参考例２で製造した化合物（５．０８ｇ）
のＤＭＳＯ／水（４０ｍｌ／０．４ｍｌ）の混合溶液に
塩化リチウム（１．７０ｇ）を加え、９０分間還流し
た。反応液を放冷し、水に注ぎ、ｎ−ヘキサンで抽出し
た。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネ
シウムで乾燥し、減圧濃縮した。残留物をシリカゲルカ
ラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル＝
４：１）で精製し、下記物性値を有する標題化合物
（３．１５ｇ）を得た。 ＴＬＣ ： Ｒｆ 0.78（ｎ−ヘキサン：酢酸エチル＝
４：１）； ＮＭＲ（CDCl3）：δ 3.61 (3H, s), 2.68-2.38 (3H,
m), 2.00 (1H, t), 1.77-1.52 (2H, m), 1.42 (8H, m),
0.97-0.82 (3H, m)。 参考例４ ２−（２−プロピニル）オクタン酸The compound prepared in Reference Example 2 (5.08 g)
To a mixed solution of DMSO / water (40 ml / 0.4 ml) was added lithium chloride (1.70 g), and the mixture was refluxed for 90 minutes. The reaction solution was allowed to cool, poured into water, and extracted with n-hexane. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
4: 1) to give the title compound (3.15 g) having the following physical data. TLC: Rf 0.78 (n-hexane: ethyl acetate =
4: 1); NMR (CDCl 3 ): δ 3.61 (3H, s), 2.68-2.38 (3H,
m), 2.00 (1H, t), 1.77-1.52 (2H, m), 1.42 (8H, m),
0.97-0.82 (3H, m). Reference Example 4 2- (2-propynyl) octanoic acid
【００１６】[0016]
【化６】 Embedded image
【００１７】参考例３で製造した化合物（３７．５ｇ）
をメチルアルコール（４００ｍｌ）に溶解し、これに２
Ｎ水酸化ナトリウム水溶液を加えて室温で終夜撹拌し
た。反応液を減圧濃縮し、残留物を２Ｎ塩酸で酸性とし
た後、酢酸エチルで抽出した。有機層を水、飽和食塩水
で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮
し、下記の物性値を有する粗標題化合物（３１．３ｇ）
を得た。 ＴＬＣ ： Ｒｆ 0.41（ｎ−ヘキサン：酢酸エチル＝
５：１）； ＮＭＲ(CDCl3) ： δ 10.5-9.2 (1H, br), 2.60-2.3
0 (3H, m), 1.95 (1H, t), 1.80-1.40 (2H, m), 1.40-
1.00 (8H, m), 0.89 (3H, t)。 実施例１ （２ＲＳ）−２−（２−プロピニル）オクタン酸と
（Ｒ）−（＋）−１−フェニルエチルアミンの塩の製造The compound prepared in Reference Example 3 (37.5 g)
Is dissolved in methyl alcohol (400 ml), and 2
An aqueous solution of N sodium hydroxide was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude title compound having the following physical data (31.3 g).
I got TLC: Rf 0.41 (n-hexane: ethyl acetate =
5: 1); NMR (CDCl 3 ): δ 10.5-9.2 (1H, br), 2.60-2.3
0 (3H, m), 1.95 (1H, t), 1.80-1.40 (2H, m), 1.40-
1.00 (8H, m), 0.89 (3H, t). Example 1 Preparation of salt of (2RS) -2- (2-propynyl) octanoic acid and (R)-(+)-1-phenylethylamine
【００１８】[0018]
【化７】 Embedded image
【００１９】（２ＲＳ）−２−（２−プロピニル）オク
タン酸（参考例４で製造した；２．３２ｇ；１２．７ｍ
Ｍ）に（Ｒ）−（＋）−１−フェニルエチルアミン
（１．２２ｇ）を加え、これを加熱したｎ−ヘキサン
（８ｍｌ）に溶解させた。 実施例２ 分別再結晶法による光学活性体の分割 実施例１で得られた溶液をゆっくり冷却することで再結
晶化を行ない、結晶（２．３３ｇ）を得た。得られた結
晶を用いて以下同様に、ｎ−ヘキサンを用いて再結晶を
さらに４回行ない、結晶（０．４８ｇ）を得た。 実施例３ （２Ｓ）−２−（２−プロピニル）オクタン酸の製造(2RS) -2- (2-propynyl) octanoic acid (prepared in Reference Example 4; 2.32 g; 12.7 m)
(R)-(+)-1-Phenylethylamine (1.22 g) was added to M), which was dissolved in heated n-hexane (8 ml). Example 2 Resolution of Optically Active Substance by Fractional Recrystallization Method The solution obtained in Example 1 was recrystallized by slowly cooling to obtain crystals (2.33 g). The obtained crystals were recrystallized four times using n-hexane in the same manner as above to obtain crystals (0.48 g). Example 3 Production of (2S) -2- (2-propynyl) octanoic acid
【００２０】[0020]
【化８】 Embedded image
【００２１】実施例２で得られた結晶（２６７ｍｇ）に
１Ｎ塩酸を加え酸性とした後、ｎ−ヘキサンで抽出し、
有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮し
た。残留物をｎ−ヘキサンに溶解し、シリカゲルカラム
クロマトグラフィー（ｎ−ヘキサン：酢酸エチル＝２：
１）で精製し、無色油状物質（１６０ｍｇ）を得た。 実施例４ （２Ｒ）−２−プロピルオクタン酸の製造The crystals (267 mg) obtained in Example 2 were acidified with 1N hydrochloric acid, and extracted with n-hexane.
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in n-hexane and subjected to silica gel column chromatography (n-hexane: ethyl acetate = 2:
Purification in 1) gave a colorless oil (160 mg). Example 4 Production of (2R) -2-propyloctanoic acid
【００２２】[0022]
【化９】 Embedded image
【００２３】実施例３で得られた化合物（１１４ｍｇ）
を酢酸エチル（２ｍｌ）に溶解し、水素雰囲気下、パラ
ジウムカーボン（１０ｍｇ）を用いて、室温で１０分間
接触還元を行ない、下記物性値を有する標題化合物（１
１３ｍｇ）を得た。 ＴＬＣ：Ｒｆ ０．３４（ｎ−ヘキサン：酢酸エチル＝
４：１）； ＮＭＲ（CDCl3）：δ 2.46-2.27 (1H, m), 1.75-1.12
(14H, m), 0.96-0.75 (6H, m)； ＩＲ（neat）：ν 2959, 2932, 2860, 1708, 1466, 141
9, 1380, 1290, 1255, 1217, 1112, 944 cm-1. 旋光度：［α］D -4.80 (c=2.87, CHCl3) 光学純度：９０．０％ ｅ．ｅ．（ガスクロマトグラフ
ィー） 比較例 目的化合物のラセミ体と光学活性アミンの塩を用いた光
学分割 （２ＲＳ）−２−プロピルオクタン酸（２０．２ｇ）お
よび（Ｒ）−（＋）−１−フェニルエチルアミン（１
３．０ｇ）の混合物を加熱したｎ−ヘキサン（８０ｍ
ｌ）に溶解し、別に用意した（２Ｒ）−２−プロピルオ
クタン酸と（Ｒ）−（＋）−１−フェニルエチルアミン
の塩を種として、室温で少量加えた。これを０℃で１４
時間さらに−２０℃で４時間静置する事により、結晶を
得た。得られた結晶を用いて、同様の操作をさらに６回
繰り返すことにより、（２Ｒ）−２−プロピルオクタン
酸と（Ｒ）−（＋）−１−フェニルエチルアミンの塩
（２．４７ｇ）を得た。得られた結晶をｎ−ヘキサンに
溶解し１Ｎ塩酸で洗浄し、有機層を無水硫酸マグネシウ
ムで乾燥し、減圧濃縮することにより、下記の物性値を
有する（２Ｒ）−２−プロピルオクタン酸（１．４９
ｇ；通算収率９％）を得た。 旋光度：［α］D −３．９１(c=0.985, CHCl3) 光学純度：８２．０％ ｅ．ｅ．（ガスクロマトグラフ
ィー）The compound obtained in Example 3 (114 mg)
Was dissolved in ethyl acetate (2 ml), and subjected to catalytic reduction under hydrogen atmosphere using palladium carbon (10 mg) at room temperature for 10 minutes to give the title compound (1) having the following physical data.
13 mg). TLC: Rf 0.34 (n-hexane: ethyl acetate =
4: 1); NMR (CDCl3): δ 2.46-2.27 (1H, m), 1.75-1.12
(14H, m), 0.96-0.75 (6H, m); IR (neat): ν 2959, 2932, 2860, 1708, 1466, 141
9, 1380, 1290, 1255, 1217, 1112, 944 cm -1 . Optical rotation: [α] D -4.80 (c = 2.87, CHCl 3 ) Optical purity: 90.0% e. e. (Gas Chromatography) Comparative Example Optical Resolution Using Racemic Form of Target Compound and Optically Active Amine Salt (2RS) -2-propyloctanoic acid (20.2 g) and (R)-(+)-1-phenylethylamine (1
3.0 g) of the mixture was heated to n-hexane (80 m
l) and a small amount of (2R) -2-propyloctanoic acid and a separately prepared salt of (R)-(+)-1-phenylethylamine were added at room temperature. This is added at 0 ° C for 14
The crystals were obtained by allowing to stand at −20 ° C. for further 4 hours. The same operation was further repeated six times using the obtained crystals to obtain a salt (2.47 g) of (2R) -2-propyloctanoic acid and (R)-(+)-1-phenylethylamine. Was. The obtained crystals were dissolved in n-hexane, washed with 1N hydrochloric acid, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2R) -2-propyloctanoic acid (1) having the following physical properties. .49
g; total yield 9%). Optical rotation: [α] D -3.91 (c = 0.985, CHCl 3 ) Optical purity: 82.0% e. e. (Gas chromatography)
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 平２−91041（ＪＰ，Ａ) 特開 昭61−134344（ＪＰ，Ａ) 特開 平４−230225（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 57/18 B01J 23/40 C07B 57/00 346 C07C 51/43 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-91041 (JP, A) JP-A-61-134344 (JP, A) JP-A-4-230225 (JP, A) (58) Field (Int.Cl. 7 , DB name) C07C 57/18 B01J 23/40 C07B 57/00 346 C07C 51/43
Claims (6)
タン酸と光学活性なアミンの塩から光学分割により光学
活性な塩を分離し、この塩を酸処理し、得られた光学活
性な２−（２−プロピニル）オクタン酸を還元すること
を特徴とする光学活性な２−プロピルオクタン酸の製造
方法。1. An optically active salt is separated from a salt of racemic 2- (2-propynyl) octanoic acid and an optically active amine by optical resolution, and this salt is treated with an acid to obtain the obtained optically active salt. -A method for producing optically active 2-propyloctanoic acid, which comprises reducing (2-propynyl) octanoic acid.
タン酸を還元することを特徴とする光学活性な２−プロ
ピルオクタン酸の製造方法。2. A method for producing optically active 2-propyloctanoic acid, comprising reducing optically active 2- (2-propynyl) octanoic acid.
記載の製造方法。3. The method according to claim 2, wherein the reduction method is a catalytic reduction method.
The manufacturing method as described.
タン酸と光学活性なアミンの塩から光学分割により光学
活性な塩を分離し、この塩を酸処理することを特徴とす
る光学活性な２−（２−プロピニル）オクタン酸の製造
方法。4. An optically active salt comprising separating an optically active salt from a salt of racemic 2- (2-propynyl) octanoic acid and an optically active amine by optical resolution, and subjecting this salt to acid treatment. A method for producing 2- (2-propynyl) octanoic acid.
ミンである請求項４記載の製造方法。5. The method according to claim 4, wherein the optically active amine is phenylethylamine.
記載の製造方法。6. The method according to claim 4, wherein the optical resolution is a fractional recrystallization method.
The manufacturing method as described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7098328A JP3032447B2 (en) | 1995-04-24 | 1995-04-24 | Method for producing optically active 2-propyloctanoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7098328A JP3032447B2 (en) | 1995-04-24 | 1995-04-24 | Method for producing optically active 2-propyloctanoic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08291106A JPH08291106A (en) | 1996-11-05 |
| JP3032447B2 true JP3032447B2 (en) | 2000-04-17 |
Family
ID=14216846
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7098328A Expired - Fee Related JP3032447B2 (en) | 1995-04-24 | 1995-04-24 | Method for producing optically active 2-propyloctanoic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3032447B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2266559A1 (en) | 2005-03-15 | 2010-12-29 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for ophthalmic disease |
| CN102517460B (en) * | 2011-12-31 | 2014-02-05 | 宁波江丰电子材料有限公司 | Method for purifying tantalum powder and tantalum target |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW509672B (en) * | 1998-05-12 | 2002-11-11 | Ono Pharmaceutical Co | Novel intermediate compounds and processes for the production of optical active octanoic acid derivatives |
| TWI268921B (en) * | 1999-02-18 | 2006-12-21 | Ono Pharmaceutical Co | A process for preparing (2R)-2-propyloctanoic acid |
| DE10002945A1 (en) * | 2000-01-13 | 2001-07-26 | Heinz Nau | Enantio- or diastereo-selective preparation of valproic acid or valproic acid amide analogs for use as antiepileptic agents, by 4- or 5-stage process using (+)- or (-)-camphor-sultam as chiral auxiliary |
| US7282605B2 (en) | 2003-04-18 | 2007-10-16 | Kaneka Corporation | Optically active 2-allylcarboxylic acid derivative and process for producing the same |
| BRPI0415001A (en) * | 2003-10-03 | 2006-11-07 | Ono Pharmaceutical Co | (2r) -2-propyloctanoic acid containing drug as active ingredient |
| EP1741697B1 (en) * | 2004-04-28 | 2012-12-19 | Ono Pharmaceutical Co., Ltd. | Crystal comprising (2r)-2-propyloctanoic acid and dibenzylamine |
-
1995
- 1995-04-24 JP JP7098328A patent/JP3032447B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2266559A1 (en) | 2005-03-15 | 2010-12-29 | Ono Pharmaceutical Co., Ltd. | Therapeutic agent for ophthalmic disease |
| CN102517460B (en) * | 2011-12-31 | 2014-02-05 | 宁波江丰电子材料有限公司 | Method for purifying tantalum powder and tantalum target |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08291106A (en) | 1996-11-05 |
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