JPH08291106A - Production of optically active 2-propyloctanoic acid - Google Patents
Production of optically active 2-propyloctanoic acidInfo
- Publication number
- JPH08291106A JPH08291106A JP9832895A JP9832895A JPH08291106A JP H08291106 A JPH08291106 A JP H08291106A JP 9832895 A JP9832895 A JP 9832895A JP 9832895 A JP9832895 A JP 9832895A JP H08291106 A JPH08291106 A JP H08291106A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- acid
- salt
- propynyl
- octanoic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
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 and performing a resolution reaction after performing optical resolution. .
【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。PRIOR ART AND PROBLEMS TO BE SOLVED BY THE INVENTION The optically active 2-propyloctanoic acid (hereinafter abbreviated as target compound) produced by the present invention is a compound useful as a pharmaceutical. The racemate of the object compound of the present invention is used as a therapeutic or prophylactic agent for neurodegenerative diseases due to astrocyte dysfunction in Example 7 of Japanese Patent Application No. 6-140954.
(33). As a result of subsequent research, it was found that the R-form among the racemates was particularly active,
Therefore, various studies have been conducted on a method for efficiently obtaining the R form. Usually, to obtain an optically active form of a compound,
A method of separating the racemate by optical resolution is used. Optical resolution is carried out 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 optically resolving the salt. However, when a method of separating the target compound from the racemate was tried, as is clear from the experiments 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。The inventors of the present invention have earnestly studied, and as a result, by using 2- (2-propynyl) octanoic acid, which is a compound having a triple bond, as a starting material,
The present invention has been completed by succeeding in obtaining a high chemical yield and a high optical purity. The method of the present invention is performed by the following procedure. 1) A racemic 2- (2-propynyl) octanoic acid is used as a starting material to form a salt with an optically active amine, and 2) This salt is fractionally recrystallized and then treated with an acid. Optically active 2- (2-propynyl) octanoic acid is obtained, and 3) the target compound is obtained by reducing the obtained compound. Racemic 2- (2-propynyl) octanoic acid, which is the starting material of 1), is a known compound (Tetrahedron Lett.
ers Vol. 21, 4233, 1980), a known method, for example, the method described in the reaction formula (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) -methylpseidoephedrine (1R, 2S)-(-)-norephedrine, L-tyrosine, (-)-(cis) -benzyl- ( 2-hydroxymethylcyclohexyl) amine, (s)-(-)-1
-Methyl-2-pyrrolidinemethanol or the like is used, but (R)-(+)-1-phenethylamine and (R)-(+)-1- (4-methylphenyl) ethylamine are preferable. 2) Optical resolution is performed by fractional recrystallization, liquid column chromatography, or the like. Although a 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, and a racemic salt is dissolved in the organic solvent to gradually dissolve it. It is done by allowing it 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 mixed solvents thereof. The acid treatment may use either an inorganic acid (hydrochloric acid, nitric acid, hydrobromic acid, etc.) or an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.). The reduction of 3) may be performed by any method as long as it is a method of reducing a multiple bond into a single bond. Catalytic reduction methods are known, for example,
Inert organic solvent (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.)
0-6 using a catalyst (palladium carbon, palladium, platinum, platinum oxide, nickel, etc.) in a hydrogen atmosphere in a medium atmosphere.
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。The effects of the present invention are as follows.
It is clear that it is superior to the comparative method in chemical yield and optical purity. That is, it can be seen that the method of the present invention has a chemical yield three times better than that of the comparative example, and a product having a 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 was produced using a racemate of the target compound and an optically active amine and purification was carried out by fractional recrystallization. Yield comparison ──────────────────────────────── Chemical yield Optical purity Number of recrystallizations (ee) ── ────────────────────────────── Inventive method 27% 90.0% 5 times Comparative example 9% 82.0% 7 Time ──────────────────────────────── Note: Chemical yields are the total yields from the racemates. 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 body-S body) / (R body + S body) ratio was 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, but these 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Metallic sodium (4.60 g) was added to methanol (100 ml), the temperature was kept at 50 ° C., and dimethyl malonate (23.5 ml) was added dropwise. Hexyl bromide (28.1 ml) was slowly added to this solution, and the mixture was refluxed for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. Water (8
0 ml) was added and the mixture was extracted with n-hexane. The organic layer was washed with saturated brine, 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 =
4: 1); 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】 [Chemical 4]
【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Metallic sodium (3.60 g) was added to methanol (80 ml), the temperature was kept at 50 ° C., and the compound (32.0 g) produced in Reference Example 1 was added. Propargyl bromide (13.9 ml) was slowly added to this solution, and the mixture was refluxed for 2 hours. The reaction solution was filtered and concentrated under reduced pressure.
Water (70 ml) was added to the residue, and the mixture was extracted with n-hexane. The organic layer was washed with saturated brine, 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
0: 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). 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Compound produced in Reference Example 2 (5.08 g)
Lithium chloride (1.70 g) was added to a mixed solution of DMSO / water (40 ml / 0.4 ml) and 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
Purification by 4: 1) gave 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】 [Chemical 6]
【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Compound produced 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 mixture 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 brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude title compound (31.3 g) having the following physical data.
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】 [Chemical 7]
【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), and this was dissolved in heated n-hexane (8 ml). Example 2 Resolution of Optically Active Substance by Fractional Recrystallization Method Recrystallization was performed by slowly cooling the solution obtained in Example 1 to obtain crystals (2.33 g). In the same manner as above, the obtained crystals were recrystallized four times using n-hexane to obtain crystals (0.48 g). Example 3 Preparation 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 by adding 1N hydrochloric acid and then 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 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】 [Chemical 9]
【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 catalytic reduction was carried out at room temperature for 10 minutes using palladium carbon (10 mg) under a hydrogen atmosphere to give the title compound (1
13 mg) was obtained. 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 Racemate of Target Compound and Salt of Optically Active Amine (2RS) -2-Propyloctanoic Acid (20.2 g) and (R)-(+)-1-Phenylethylamine (1
A mixture of 3.0 g) was heated in n-hexane (80 m).
The salt of (2R) -2-propyloctanoic acid and (R)-(+)-1-phenylethylamine prepared separately was dissolved in 1) and added in small amounts at room temperature. This at 0 ℃ 14
By further standing for 4 hours at −20 ° C., crystals were obtained. The same operation was repeated 6 times using the obtained crystals to obtain a salt of (2R) -2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (2.47 g). It 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 obtain (2R) -2-propyloctanoic acid (1R) 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)
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 obtained by separating an optically active salt from a salt of racemic 2- (2-propynyl) octanoic acid and an optically active amine by optical resolution, and treating this salt with an acid. 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, which comprises reducing optically active 2- (2-propynyl) octanoic acid.
記載の製造方法。3. The reduction method is a catalytic reduction method.
The manufacturing method 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 characterized in that the optically active salt is separated from the salt of racemic 2- (2-propynyl) octanoic acid and the optically active amine by optical resolution and the salt is treated with an acid. 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 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 true JPH08291106A (en) | 1996-11-05 |
| JP3032447B2 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 (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999058513A1 (en) * | 1998-05-12 | 1999-11-18 | Ono Pharmaceutical Co., Ltd. | Novel intermediates and processes for the preparation of optically active octanoic acid derivatives |
| WO2001051449A1 (en) * | 2000-01-13 | 2001-07-19 | Heinz Nau | Method for producing enantiomer-pure analogs of valproic acid |
| EP1153910A1 (en) * | 1999-02-18 | 2001-11-14 | Ono Pharmaceutical Co., Ltd. | Process for the preparation of (2r)-2-propyloctanoic acid |
| WO2005032536A1 (en) * | 2003-10-03 | 2005-04-14 | Ono Pharmaceutical Co., Ltd. | Drug containing (2r)-2-propyloctanoic acid as the active ingredient |
| WO2005105722A1 (en) * | 2004-04-28 | 2005-11-10 | Ono Pharmaceutical Co., Ltd. | Crystal comprising (2r)-2-propyloctoic acid and amine |
| US7282605B2 (en) | 2003-04-18 | 2007-10-16 | Kaneka Corporation | Optically active 2-allylcarboxylic acid derivative and process for producing the same |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPWO2006098292A1 (en) | 2005-03-15 | 2008-08-21 | 小野薬品工業株式会社 | Eye disease treatment |
| 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 |
-
1995
- 1995-04-24 JP JP7098328A patent/JP3032447B2/en not_active Expired - Fee Related
Cited By (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6392073B1 (en) | 1998-05-12 | 2002-05-21 | Ono Pharmaceutical Co., Ltd. | Intermediates and processes for the preparation of optically active octanoic acid derivatives |
| WO1999058513A1 (en) * | 1998-05-12 | 1999-11-18 | Ono Pharmaceutical Co., Ltd. | Novel intermediates and processes for the preparation of optically active octanoic acid derivatives |
| AU748360B2 (en) * | 1998-05-12 | 2002-06-06 | Ono Pharmaceutical Co. Ltd. | Novel intermediates and processes for the preparation of optically active octanoic acid derivatives |
| US6333415B1 (en) | 1998-05-12 | 2001-12-25 | Ono Pharmaceutical Co., Ltd. | Intermediates and processes for the preparation of optically active octanoic acid derivatives |
| JP2010248198A (en) * | 1999-02-18 | 2010-11-04 | Ono Pharmaceut Co Ltd | Process for preparation of (2r)-2-propyloctanoic acid |
| CN100430364C (en) * | 1999-02-18 | 2008-11-05 | 小野药品工业株式会社 | Process for preparation of (2R)-2-propyloctanoic acid |
| EP1153910A4 (en) * | 1999-02-18 | 2002-08-07 | Ono Pharmaceutical Co | Process for the preparation of (2r)-2-propyloctanoic acid |
| US6608221B1 (en) | 1999-02-18 | 2003-08-19 | Ono Pharmaceutical Co., Ltd. | Process for the preparation of (2R)-2-propyloctanoic acid |
| JP4752989B2 (en) * | 1999-02-18 | 2011-08-17 | 小野薬品工業株式会社 | Method for producing (2R) -2-propyloctanoic acid |
| EP1153910A1 (en) * | 1999-02-18 | 2001-11-14 | Ono Pharmaceutical Co., Ltd. | Process for the preparation of (2r)-2-propyloctanoic acid |
| EP1714956A1 (en) * | 1999-02-18 | 2006-10-25 | Ono Pharmaceutical Co., Ltd. | Process for the preparation of (2R)-2-Propyloctanoic acid |
| EP1721882A1 (en) * | 1999-02-18 | 2006-11-15 | Ono Pharmaceutical Co., Ltd. | Process for the preparation of (2R)-2-Propyloctanoic acid |
| WO2001051449A1 (en) * | 2000-01-13 | 2001-07-19 | Heinz Nau | Method for producing enantiomer-pure analogs of valproic acid |
| US7282605B2 (en) | 2003-04-18 | 2007-10-16 | Kaneka Corporation | Optically active 2-allylcarboxylic acid derivative and process for producing the same |
| JP4715515B2 (en) * | 2003-10-03 | 2011-07-06 | 小野薬品工業株式会社 | Drugs containing (2R) -2-propyloctanoic acid as an active ingredient |
| US8053599B2 (en) | 2003-10-03 | 2011-11-08 | Ono Pharmaceutical Co., Ltd. | Drug containing (2R)-2-propyloctanoic acid as the active ingredient |
| JPWO2005032536A1 (en) * | 2003-10-03 | 2006-12-14 | 小野薬品工業株式会社 | Drugs containing (2R) -2-propyloctanoic acid as an active ingredient |
| AU2004277826B2 (en) * | 2003-10-03 | 2010-05-27 | Ono Pharmaceutical Co., Ltd. | Drug containing (2R)-2-propyloctanoic acid as the active ingredient |
| WO2005032536A1 (en) * | 2003-10-03 | 2005-04-14 | Ono Pharmaceutical Co., Ltd. | Drug containing (2r)-2-propyloctanoic acid as the active ingredient |
| WO2005105722A1 (en) * | 2004-04-28 | 2005-11-10 | Ono Pharmaceutical Co., Ltd. | Crystal comprising (2r)-2-propyloctoic acid and amine |
| US20100331414A1 (en) * | 2004-04-28 | 2010-12-30 | Ono Pharmaceutical Co., Ltd | Crystal comprising (2r)-2-propyloctanoic acid and amine |
| JP4730303B2 (en) * | 2004-04-28 | 2011-07-20 | 小野薬品工業株式会社 | Crystal composed of (2R) -2-propyloctanoic acid and amine |
| US7820715B2 (en) | 2004-04-28 | 2010-10-26 | Ono Pharmaceutical Co., Ltd. | Crystal comprising (2R)-2-propyloctanoic acid and amine |
| JPWO2005105722A1 (en) * | 2004-04-28 | 2008-03-13 | 小野薬品工業株式会社 | Crystal composed of (2R) -2-propyloctanoic acid and amine |
| US8273916B2 (en) | 2004-04-28 | 2012-09-25 | Ono Pharmaceutical Co., Ltd. | Crystal comprising (2R)-2-propyloctanoic acid and amine |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3032447B2 (en) | 2000-04-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101454571B1 (en) | Synthesis of intermediate for treprostinil production | |
| JP4147516B2 (en) | Novel intermediate compound and method for producing optically active octanoic acid derivative | |
| JP3032447B2 (en) | Method for producing optically active 2-propyloctanoic acid | |
| JPH09502459A (en) | Method for producing (+)-(1R) -cis-3-oxo-2-pentyl-1-cyclopentaneacetic acid | |
| JPS59196839A (en) | Phenylacetic acid derivative | |
| MX2008012393A (en) | Improved crystalline material. | |
| WO2012167413A1 (en) | Method for preparing optically pure (-)-clausenamide compound | |
| JP2018087184A (en) | (E)-3-methyl-2-cycloalkenone compound, 3-halo-3-methylcycloalkanone compound and method for producing (R)-3-methylcycloalkanone compound | |
| JP2007503445A (en) | Cycloalkylamino acid compounds, methods for their production and use | |
| JP2008239602A (en) | Preparation of organic compound bearing trifluoromethyl group on quaternary carbon | |
| US20030187296A1 (en) | Cyclic ketones, their preparation and their use in the synthesis of amino acids | |
| JP2005298334A (en) | Novel intermediate compound and method for manufacturing compound by using the same | |
| JPH04308550A (en) | Method of stereoselectively converting diol into alcohol | |
| JP2009242357A (en) | Method for producing dicyclohexane derivative | |
| JP2008214262A (en) | Method for producing optically active sulfonylimine compound | |
| CH636868A5 (en) | PROCESS FOR THE PREPARATION OF AN OPTICALLY ACTIVE ALPHA-CYANE ALCOHOL ETHER. | |
| JP2016169166A (en) | Production method of 1-amino-3,5-dimethyladamantane hydrochloride | |
| JPH0417938B2 (en) | ||
| JP2003137835A (en) | Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid | |
| JP3134786B2 (en) | 2-Azabicyclo [3.3.0] octane derivatives, their production and optical resolution of diols or amino alcohols | |
| JP4643566B2 (en) | Method for allylation of N-acylhydrazone | |
| EP0531700A2 (en) | Pure diastereomere intermediates and their use in the preparation of (R)- or (S)-ketoprofen | |
| DE102005012408A1 (en) | Preparation of optically active 3-phenylpropionic acid derivative, useful to prepare halo-phenyl compound, comprises hydrogenating cis-isomer mixture of phenyl compound; crystallizing the enantiomer mixture and isolating the solid material | |
| JP3083383B2 (en) | Isomer separation method | |
| JP2762106B2 (en) | Method for producing 3-hydroxypyrrolidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20080210 Year of fee payment: 8 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Year of fee payment: 9 Free format text: PAYMENT UNTIL: 20090210 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Year of fee payment: 10 Free format text: PAYMENT UNTIL: 20100210 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Year of fee payment: 10 Free format text: PAYMENT UNTIL: 20100210 |
|
| FPAY | Renewal fee payment (prs date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20100210 Year of fee payment: 10 |
|
| LAPS | Cancellation because of no payment of annual fees |