JPH08291106A - Production of optically active 2-propyloctanoic acid - Google Patents

Production of optically active 2-propyloctanoic acid

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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
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optically active
acid
salt
propynyl
octanoic acid
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JP3032447B2 (en
Inventor
Kazuo Kishimoto
Hisao Nakai
久郎 中井
一雄 岸本
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Ono Pharmaceut Co Ltd
小野薬品工業株式会社
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Abstract

PURPOSE: To provide a method for producing optically active 2-propyloctanoic acid in both higher chemical yield and optical purity than a method for separating the optical active substance from the racemic modification of the objective compound.
CONSTITUTION: A salt prepared by using (2RS)-2-(2-propenyl)octanoic acid as a racemic modification and an optically active amine is subjected to optical resolution by fractional crystallization method. The prepared crystal is treated with an acid to give optically active (2R)-2-(2-propenyl)octanoic acid, which is reduced to give optically active (2R)-2-propyloctanoic acid.
COPYRIGHT: (C)1996,JPO

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【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。 [0001] The present invention relates to a process for the preparation of optically active 2-propyl octanoate. 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。 More particularly, the present invention is used as the starting material 2- (2-propynyl) octanoic acid, after optical resolution, a process for producing an optically active 2-propyloctanoic acid and 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。 Optically active 2-propyl octanoate produced in BACKGROUND OF INVENTION It is to problems Solved] The present invention (hereinafter, abbreviated as target compound) is a compound useful as a pharmaceutical. 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 Racemic target compound of the present invention, Example 7 in Japanese Patent Application No. 6-140954 as a therapeutic or prophylactic agent for functional abnormality by neurodegenerative diseases astrocytes
(33)に記載されている。 It is described in (33). 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、 Result of subsequent research, among the racemic, R body, it is found that particularly strong activity,
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。 Various studies have been conducted on a method of obtaining good Accordingly efficiently R body. 通常、ある化合物の光学活性体を得るには、 Usually, in order to obtain the optically active form of a compound,
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。 Method for separating by optical resolution from its racemate is used. 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。 Optical resolution, when the target compound is an acid, is carried out using an optically active amine. 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。 This method causes the construction of the salt from the acid with an optically active amine, which is done by optical resolution. 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、 However, was tried a method of separating a target compound from a racemate, as evidenced in the experiments described below, chemical yield, poor in optical purity both
実用的な方法といえるものではなかった。 It was not considered a practical way.

【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、 The inventors of the present invention, in order to solve the problems] As a result of intensive studies, the use of the compounds is 2- (2-propynyl) octanoic acid having a triple bond as a starting material,
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。 It succeeded in obtaining a high chemical yield and high optical purity, and have completed the present invention. 本発明方法は、以下の手順により行なわれる。 The present invention is carried out by the following procedure. 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) racemic 2- (2-propynyl) octanoic acid as a starting material, to constitute a salt between the optically active amine, 2) After the salt was fractional recrystallization, by acid treatment, give an optically active 2- (2-propynyl) octanoic acid, 3) to obtain the desired compound by reducing the resulting compound. 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 1 2- (2-propynyl) octanoic acid racemic a starting material for) are known compounds (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。 ers Vol references. 21, 4233, 1980), can be prepared by known methods, for example, it can be prepared by methods described in Scheme (I) or (II).
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、 The optically active amine used here, but may any long usually amines used in optical resolution, for example,
(R)−(+)−1−フェネチルアミン、(R)− (R) - (+) - 1- phenethylamine, (R) -
(+)−1−(4−メチルフェニル)エチルアミン、L (+) - 1- (4-methylphenyl) ethylamine, L
−アルギニン、2R−アミノブタノール、(S)− - arginine, 2R- aminobutanol, (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 (-) - nicotine, hydroquinine, bisdehydroabietylamine, (1S, 2S) - methyl-flop Say de ephedrine (1R, 2S) - (-) - norephedrine, L- tyrosine, (-) - (cis) - benzyl - ( 2-hydroxymethyl-cyclohexyl) amine, (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。 - Although methyl-2-pyrrolidine methanol, etc. are used, preferably, (R) - 1- (4-methylphenyl) ethylamine - (+) - 1-phenethylamine, (R) - (+). 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。 2) optical resolution, fractional recrystallization is carried out by liquid column chromatography and the like. 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。 Fractional recrystallization methods are known, for example, by heating the organic solvent (single or mixed) with the appropriate solubility for the compound to be optically resolved, this dissolving the salt of the racemate, gradual It is carried out by allowing it to cool to. 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、 Suitable organic solvents include, for example, n- hexane, n- pentane, n- heptane, cyclohexane, ethyl acetate, THF, tetrahydropyran, dioxane,
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。 Dimethoxyethane, acetone, ethanol, isopropyl alcohol, methanol, isopropyl ether, petroleum ether, and mixed solvents thereof. 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。 Acid treatment, inorganic acids (hydrochloric acid, nitric acid, hydrobromic acid, etc.), organic acids (acetic acid, trifluoroacetic acid, and methanesulfonic acid) may be used either. 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。 Reduction of 3), any one of the known methods for reducing a single bond multiple bonds, but may be any method, for example, catalytic reduction method or the like is preferably used. 接触還元法は公知であり、例えば、 Catalytic reduction method is known, for example,
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 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、ジメチルイミダゾリジノン、これらの混合溶媒等) F, dimethylimidazolidinone, etc. a mixture of these solvents)
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 In using a hydrogen atmosphere, the catalyst (palladium carbon, palladium, platinum, platinum oxide, nickel, etc.), 0-6
0℃で行なわれる。 It is carried out at 0 ℃.

【0004】 [0004]

【化1】 [Formula 1]

【0005】 [0005]

【化2】 ## STR2 ##

【0006】 [0006]

【本発明の効果】次に示されるように、本発明方法は、 As [Effect of the invention] as shown below, the present method,
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。 In the chemical yield and optical purity, it is apparent that the superior method of Comparative Example. 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。 That is, the method the present invention compared with the comparative example, in the chemical yield, 3-fold better, also, it can be seen that those of high optical purity by the number of times of recrystallization is obtained little.

【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。 [0007] comparative example, to produce a salt using racemic and optically active amine of the target compound is an example purification by fractional recrystallization. 収率の比較 ──────────────────────────────── 化学収率 光学純度 再結晶の回数 (ee) ──────────────────────────────── 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。 Number of comparisons ──────────────────────────────── chemical yield optical purity recrystallization yield (ee) ── ────────────────────────────── present invention a method 27% 90.0% 5 times Comparative example 9% 82.0% 7 times ──────────────────────────────── Note: the chemical yield, respectively, the overall yield from racemic show.

【0008】注:再結晶の回数は、光学純度(e. [0008] Note: The number of times of recrystallization, the optical purity (e.
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。 ) Is (R body -S body) / (R body + S form) ratio showed the number of time became more than 80%.

【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。 EXAMPLES Comparative Example below is a description of specifics of the present invention by way of Reference Examples and Examples, which are not intended to limit the scope of the present invention. 参考例1 ヘキシルマロン酸ジメチルエステルの製造 Preparation of Reference Example 1-hexyl dimethyl malonate

【0010】 [0010]

【化3】 [Formula 3]

【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。 [0011] Methanol (100ml) in sodium metal (4.60 g) was added, maintaining the 50 ° C., was added dropwise dimethyl malonate (23.5 ml). 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。 It was slowly added hexyl bromide (28.1 ml) to the solution, and refluxed for 2 hours. 反応液を濾過し、減圧濃縮した。 The reaction was filtered and concentrated under reduced pressure. 残留物に水(8 To the residue water (8
0ml)を加え、n−ヘキサンで抽出した。 0 ml) was added and extracted with n- hexane. 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。 The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 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。 The residue was purified by distillation to give the title compound having the following physical data (32.6 g). TLC : Rf 0.62(n−ヘキサン:酢酸エチル= TLC: Rf 0.62 (n-hexane: ethyl acetate =
4:1); NMR(CDCl 3 ):δ 3.74 (6H, s), 3.63 (1H, t), 1. 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)。 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 Preparation of Reference Example 2-hexyl (2-propynyl) malonic acid dimethyl ester

【0012】 [0012]

【化4】 [Of 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。 [0013] Methanol (80 ml) to sodium metal (3.60 g) was added, maintaining the 50 ° C., the compound prepared in reference example 1 (32.0 g) was added. 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。 After the slow addition of propargyl bromide (13.9 ml) to the solution, and refluxed for 2 hours. 反応液を濾過し、減圧濃縮した。 The reaction was filtered and concentrated under reduced pressure.
残留物に水(70ml)を加え、n−ヘキサンで抽出した。 Water (70 ml) was added to the residue and extracted with n- hexane. 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。 The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 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。 The residue to give the title compound having the following physical data was purified by distillation (25.5 g). TLC : Rf 0.79(ベンゼン:酢酸エチル=1 TLC: Rf 0.79 (benzene: ethyl acetate = 1
0:1); NMR(CDCl 3 ):δ 3.74 (6H, s), 2.83 (2H, d), 2. 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, 15-1.98 (3H, m), 1.46-1.04 (8H, m), 1.02-0.84 (3H,
m)。 m). 参考例3 2−(2−プロピニル)オクタン酸メチルの製造 Preparation of Reference Example 3 2- (2-propynyl) methyl octanoate

【0014】 [0014]

【化5】 [Of 5]

【0015】参考例2で製造した化合物(5.08g) [0015] The compound prepared in Reference Example 2 (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。 Mixed solution of lithium chloride (1.70 g) was added in DMSO / water (40ml / 0.4ml), was refluxed for 90 minutes. 反応液を放冷し、水に注ぎ、n−ヘキサンで抽出した。 The reaction mixture was allowed to cool, poured into water and extracted with n- hexane. 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。 The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 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= The residue was purified by silica gel column chromatography (n- hexane: ethyl acetate =
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。 4: 1) to give the title compound having the following physical data (3.15 g). TLC : Rf 0.78(n−ヘキサン:酢酸エチル= TLC: Rf 0.78 (n-hexane: ethyl acetate =
4:1); NMR(CDCl 3 ):δ 3.61 (3H, s), 2.68-2.38 (3H, 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), m), 2.00 (1H, t), 1.77-1.52 (2H, m), 1.42 (8H, m),
0.97-0.82 (3H, m)。 0.97-0.82 (3H, m). 参考例4 2−(2−プロピニル)オクタン酸 Reference Example 4 2- (2-propynyl) octanoic acid

【0016】 [0016]

【化6】 [Omitted]

【0017】参考例3で製造した化合物(37.5g) [0017] The compound prepared in Reference Example 3 (37.5g)
をメチルアルコール(400ml)に溶解し、これに2 It was dissolved in methyl alcohol (400 ml), thereto 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。 It was stirred overnight at room temperature by the addition of N aqueous sodium hydroxide. 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。 The reaction mixture was concentrated under reduced pressure, after which the residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. 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) The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, the crude title compound having the following physical data (31.3 g)
を得た。 It was obtained. TLC : Rf 0.41(n−ヘキサン:酢酸エチル= TLC: Rf 0.41 (n-hexane: ethyl acetate =
5:1); NMR(CDCl 3 ) : δ 10.5-9.2 (1H, br), 2.60-2.3 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- 0 (3H, m), 1.95 (1H, t), 1.80-1.40 (2H, m), 1.40-
1.00 (8H, m), 0.89 (3H, t)。 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 Example 1 (2RS) -2- (2- propynyl) octanoic acid (R) - (+) - preparation of a salt of 1-phenylethylamine

【0018】 [0018]

【化7】 [Omitted]

【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 [0019] (2RS)-2-(2-propynyl) octanoic acid (prepared in Reference Example 4; 2.32 g; 12.7 m
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。 M) to (R) - (+) - 1- phenylethylamine and (1.22 g) was added and dissolved thereto a heated n- hexane (8 ml). 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。 It performs recrystallization by cooling slowly the solution obtained in dividing a first embodiment of the optically active substance according to Example 2 fractional recrystallization, to give crystals (2.33 g). 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。 Similarly using the obtained crystals below performs further four times recrystallized from n- hexane to obtain crystals (0.48 g). 実施例3 (2S)−2−(2−プロピニル)オクタン酸の製造 Preparation of Example 3 (2S) -2- (2- propynyl) octanoic acid

【0020】 [0020]

【化8】 [Of 8]

【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、 [0021] After the 1N hydrochloric acid was added acidic crystals obtained in Example 2 (267 mg), and extracted with n- hexane,
有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。 The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 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: The residue was dissolved in n- hexane, silica gel column chromatography (n- hexane: ethyl acetate = 2:
1)で精製し、無色油状物質(160mg)を得た。 1) to give a colorless oil (160 mg). 実施例4 (2R)−2−プロピルオクタン酸の製造 Preparation of Example 4 (2R) -2- propyl octanoate

【0022】 [0022]

【化9】 [Omitted]

【0023】実施例3で得られた化合物(114mg) The compound obtained in Example 3 (114 mg)
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 Was dissolved in ethyl acetate (2 ml), under an atmosphere of hydrogen, using a palladium on carbon (10 mg), subjected to 10 min catalytic reduction at room temperature, the title compound having the following physical data (1
13mg)を得た。 13mg) was obtained. TLC:Rf 0.34(n−ヘキサン:酢酸エチル= TLC: Rf 0.34 (n-hexane: ethyl acetate =
4:1); NMR(CDCl3):δ 2.46-2.27 (1H, m), 1.75-1.12 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 (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, CHCl 3 ) 光学純度:90.0% e. . 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. 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 (Gas chromatography) Optical resolution using a salt of racemic and optically active amine of Comparative Example object compound (2RS)-2-propyl octanoate (20.2 g) and (R) - (+) - 1-phenylethylamine (1
3.0g)の混合物を加熱したn−ヘキサン(80m The mixture was heated for 3.0 g) n-hexane (80 m
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。 Was dissolved in l), were prepared separately (2R) -2-propyloctanoic acid (R) - (+) - as a seed to a salt of 1-phenylethylamine was added in small portions at room temperature. これを0℃で14 This at 0 ℃ 14
時間さらに−20℃で4時間静置する事により、結晶を得た。 By 4 hours to stand at the time still -20 ° C., to obtain crystals. 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。 Using the obtained crystals, similar operation by repeating the further six, (2R) -2-propyloctanoic acid (R) - (+) - give 1-phenylethylamine salt (2.47 g) It was. 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 The resulting crystals were washed with dissolved 1N hydrochloric acid n- hexane, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, having the following physical (2R)-2-propyl octanoate (1 .49
g;通算収率9%)を得た。 g; yield the total yield 9%). 旋光度:[α] D −3.91(c=0.985, CHCl 3 ) 光学純度:82.0% e. Optical rotation: [α] D -3.91 (c = 0.985, CHCl 3) Optical purity: 82.0% e. e. e. (ガスクロマトグラフィー) (Gas chromatography)

Claims (6)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】 ラセミ体の2−(2−プロピニル)オク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. A by optical resolution from a salt of racemic 2- (2-propynyl) octanoic acid and an optically active amine to separate an optically active salt, the salt acid treatment, an obtained optically active 2 - (2-propynyl) process for producing an optically active 2-propyloctanoic acid, which comprises reducing the octanoic acid.
  2. 【請求項2】 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。 2. A process for producing an optically active 2-propyloctanoic acid, which comprises reducing an optically active 2- (2-propynyl) octanoic acid.
  3. 【請求項3】 還元方法が、接触還元法である請求項2 3. A reduction method is a catalytic reduction method according to claim 2
    記載の製造方法。 The method according.
  4. 【請求項4】 ラセミ体の2−(2−プロピニル)オク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. A separating an optically active salt by optical resolution from a salt of racemic 2- (2-propynyl) octanoic acid with an optically active amine, optically active, characterized in that acid treatment of this salt 2- (2-propynyl) fabrication method of octanoic acid.
  5. 【請求項5】 光学活性なアミンが、フェニルエチルアミンである請求項4記載の製造方法。 5. The optically active amine is The process of claim 4, wherein phenylethylamine.
  6. 【請求項6】 光学分割が分別再結晶法である請求項4 6. The method of claim 4 optical resolution is fractional recrystallization
    記載の製造方法。 The method according.
JP7098328A 1995-04-24 1995-04-24 Method for producing an optically active 2-propyl octanoate Expired - Fee Related JP3032447B2 (en)

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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
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
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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
US6333415B1 (en) 1998-05-12 2001-12-25 Ono Pharmaceutical Co., Ltd. Intermediates and processes for the preparation of optically active octanoic acid derivatives
US6392073B1 (en) 1998-05-12 2002-05-21 Ono Pharmaceutical Co., Ltd. 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
EP1153910A1 (en) * 1999-02-18 2001-11-14 Ono Pharmaceutical Co., Ltd. Process for the 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
JP2010248198A (en) * 1999-02-18 2010-11-04 Ono Pharmaceut Co Ltd Process for 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
US7282605B2 (en) 2003-04-18 2007-10-16 Kaneka Corporation Optically active 2-allylcarboxylic acid derivative and process for producing the same
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
US8053599B2 (en) 2003-10-03 2011-11-08 Ono Pharmaceutical Co., Ltd. Drug containing (2R)-2-propyloctanoic acid as the 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
US7820715B2 (en) 2004-04-28 2010-10-26 Ono Pharmaceutical Co., Ltd. Crystal comprising (2R)-2-propyloctanoic acid and amine
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
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

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