JP7080663B2 - Method for Producing Optically Active Cyclopentenone Derivative - Google Patents

Method for Producing Optically Active Cyclopentenone Derivative Download PDF

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JP7080663B2
JP7080663B2 JP2018024587A JP2018024587A JP7080663B2 JP 7080663 B2 JP7080663 B2 JP 7080663B2 JP 2018024587 A JP2018024587 A JP 2018024587A JP 2018024587 A JP2018024587 A JP 2018024587A JP 7080663 B2 JP7080663 B2 JP 7080663B2
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利之 野中
尭明 神島
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Genesis Research Institute Inc
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Description

本発明は、4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの光学活性体の製造方法に関する。 The present invention relates to a method for producing an optically active substance of 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one.

式(I)で表される4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの光学活性体は、プロスタグランジン(prostaglandins)、ペンテノマイシン(pentenomycin)、ベルチマイシン(vertimycin)等の医薬品原料となる有望な合成ブロックであるとされている。非特許文献1では、式(I)の光学活性体のうち、R体の合成法が示されているが、10段階の反応ステップが必要であり、全収率は約35%に留まる。また、非特許文献1では、式(I)で表される化合物の光学活性体S体の記載がない。

Figure 0007080663000001
The optically active substance of 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one represented by the formula (I) includes prostaglandins, pentenomycin, vertimycin and the like. It is said to be a promising synthetic block that can be used as a raw material for pharmaceutical products. Non-Patent Document 1 shows a method for synthesizing an R-form among the optically active substances of the formula (I), but a 10-step reaction step is required, and the total yield is only about 35%. Further, Non-Patent Document 1 does not describe the optically active S-form of the compound represented by the formula (I).
Figure 0007080663000001

一方、2-デオキシ―アルドヘキソースを出発原料とし、その水溶液を蒸発させずに加熱する工程(150℃~300℃の範囲内)における化学的変換反応により一工程で式(I)で表される4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンのラセミ体を得ることができたことが報告されている(特許文献1参照)。

Figure 0007080663000002
On the other hand, 2-deoxy-aldhexose is used as a starting material, and the aqueous solution is heated without evaporating (within the range of 150 ° C to 300 ° C) by a chemical conversion reaction, which is represented by the formula (I) in one step. It has been reported that a racemate of 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one could be obtained (see Patent Document 1).
Figure 0007080663000002

しかしながら、この方法における収率は、HPLCにおけるピーク面積を基準とした相対的な値であり、2-デオキシ―アルドヘキソースから4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンに変換する収率の向上、目的生成物である4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの精製のし易さ等の課題が存在する。 However, the yield in this method is a relative value relative to the peak area in HPLC and converts 2-deoxy-aldhexose to 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one. There are problems such as improvement in yield and ease of purification of the target product 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one.

しかも、特許文献1においても、式(I)の4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンのラセミ体のみが得られる内容にとどまっており、その光学活性体を得ることの記述がない。即ち、式(I)の光学活性体R体、S体のうち、S体の工業的な製造法の記述および化合物の記載がこれまで見当たらない。 Moreover, even in Patent Document 1, only the racemic form of 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one of the formula (I) can be obtained, and the optically active substance thereof can be obtained. There is no description. That is, among the optically active R-form and S-form of the formula (I), the description of the industrial production method of the S-form and the description of the compound have not been found so far.

特許第5776984Patent No. 5776984

J.D.Elliottら, J. Chem. Soc. Perkin Trans. I, 1782 (1981)J.D. Elliott et al., J. Chem. Soc. Perkin Trans. I, 1782 (1981)

式(I)で表される4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの4位の炭素原子は、不斉炭素原子であり、2つの光学活性体が存在する。医薬品としての有用性を高めるうえで、光学活性化合物に関する薬理活性、体内動態、安全性等の検討は重要であり、そのためには、光学活性化合物を製造する簡便な方法を開発する必要がある。 The carbon atom at the 4-position of 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one represented by the formula (I) is an asymmetric carbon atom, and there are two optically active substances. In order to enhance the usefulness as a pharmaceutical product, it is important to study the pharmacological activity, pharmacokinetics, safety, etc. of the optically active compound, and for that purpose, it is necessary to develop a simple method for producing the optically active compound.

Figure 0007080663000003
Figure 0007080663000003

本発明者らは、上記事情に鑑みて精力的に研究を重ねた。その結果、入手容易な2-デオキシ―アルドヘキソースの水溶液を蒸発させずに加圧状態で加熱することにより、1工程で式(I) で表される4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンを得たのち、本発明でキラルカラムを装着した高速液体クロマトグラフィー(以下、「HPLC」という。)装置を用いる簡易な方法により、前記の式(I)で表されるラセミ体を光学分割して、目的とする光学活性化合物を容易に製造できることを見出し、本発明を完成した。 The present inventors have energetically repeated research in view of the above circumstances. As a result, by heating the easily available aqueous solution of 2-deoxy-aldhexose under pressure without evaporating it, 4-hydroxy-2-hydroxymethyl-2-expressed by the formula (I) in one step. After obtaining cyclopentene-1-one, the racemic isomer represented by the above formula (I) by a simple method using a high performance liquid chromatography (hereinafter referred to as "HPLC") apparatus equipped with a chiral column in the present invention. The present invention was completed by finding that the desired optically active compound can be easily produced by optically dividing the mixture.

すなわち、本発明は以下の通りである。
[1]
式(I)

Figure 0007080663000004
で表される化合物を、キラルカラムを装着したHPLC装置を用いて光学分割することを含む、式(I)で表される化合物の光学活性体の製造方法。
[2]
移動相がn-ヘキサンとi-プロパノールの混合溶媒である、[1]に記載の製造方法。
[3]
式(I)で表される光学活性なシクロペンテノン化合物が99%ee以上のエナンチオマー過剰率を有する、[1]に記載の方法。
[4]
式(II)
Figure 0007080663000005
で表される光学活性体(S体)。
[5]
式(I)
Figure 0007080663000006
で表される化合物を光学分割することを含む、式(II)
Figure 0007080663000007
で表される光学活性体(S体)の製造方法。 That is, the present invention is as follows.
[1]
Equation (I)
Figure 0007080663000004
A method for producing an optically active substance of a compound represented by the formula (I), which comprises optically resolving the compound represented by the formula (I) using an HPLC apparatus equipped with a chiral column.
[2]
The production method according to [1], wherein the mobile phase is a mixed solvent of n-hexane and i-propanol.
[3]
The method according to [1], wherein the optically active cyclopentenone compound represented by the formula (I) has an enantiomeric excess of 99% ee or more.
[4]
Equation (II)
Figure 0007080663000005
Optically active substance (S-form) represented by.
[5]
Equation (I)
Figure 0007080663000006
Formulation (II), which comprises optical resolution of the compound represented by.
Figure 0007080663000007
A method for producing an optically active substance (S-form) represented by.

本発明により、目的生成物である上記の式(I)の化合物の光学活性体(R体及びS体)の新規で簡便な製造方法が提供される。即ち、式(I)で表される4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンを得たのち、本発明により、キラルカラムを装着した高速液体クロマトグラフィー(以下、「HPLC」という。)装置を用いる簡易な方法により、前記の式(I)で表されるラセミ体を光学分割して、目的とする光学活性化合物を容易に製造できた。本発明の方法は、工程数が短く、HPLCの移動相として用いた溶媒を蒸留等でリサイクルできるので、環境に比較的に優しい工業的な価値を有する。 INDUSTRIAL APPLICABILITY The present invention provides a novel and simple method for producing optically active substances (R-form and S-form) of the compound of the above formula (I), which is a target product. That is, after obtaining 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one represented by the formula (I), according to the present invention, high performance liquid chromatography equipped with a chiral column (hereinafter referred to as "HPLC"). By a simple method using an apparatus, the racemic body represented by the above formula (I) could be optically partitioned to easily produce the desired optically active compound. Since the method of the present invention has a short number of steps and the solvent used as the mobile phase of HPLC can be recycled by distillation or the like, it has an industrial value that is relatively environmentally friendly.

分取HPLCによる光学分割のHPLCチャートを示す。The HPLC chart of optical resolution by preparative HPLC is shown. 分取HPLCによる光学分割で得られたS体のHPLCチャートを示す。The HPLC chart of the S body obtained by optical resolution by preparative HPLC is shown. 分取HPLCによる光学分割で得られたR体のHPLCチャートを示す。The HPLC chart of the R body obtained by optical resolution by preparative HPLC is shown.

以下、本発明の実施形態について説明する。本実施形態は本発明を実施する一例であって、本発明は本実施形態に限定されるものではない。 Hereinafter, embodiments of the present invention will be described. The present embodiment is an example of carrying out the present invention, and the present invention is not limited to the present embodiment.

以下、本発明に係る構造式(I)で表されるシクロペンテノン誘導体の光学活性体の製造方法について説明する。 Hereinafter, a method for producing an optically active substance of a cyclopentenone derivative represented by the structural formula (I) according to the present invention will be described.

(出発原料)
出発原料である4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンのラセミ体は、非特許文献1、特許文献1等の公知の方法により製造することができる。
(Starting raw material)
The racemic mixture of 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one, which is a starting material, can be produced by known methods such as Non-Patent Document 1 and Patent Document 1.

本発明にかかる光学活性化合物の製造法は、ラセミ化合物の「光学分割」操作を含む方法であり、当該「光学分割」操作は、キラルカラムを装着したHPLCを使用するものである。前記の「キラルカラム」とは、キラル順相カラム、キラル逆相カラムまたはキラルイオン交換カラムを示し、どのカラムを採用するかは、光学分割操作に供する化合物の種類やその他の諸条件により異なり、特に限定はされない。 The method for producing an optically active compound according to the present invention is a method including an "optical resolution" operation of a racemic compound, and the "optical resolution" operation uses HPLC equipped with a chiral column. The above-mentioned "chiral column" refers to a chiral normal phase column, a chiral reverse phase column or a chiral ion exchange column, and which column is adopted depends on the type of compound to be subjected to the optical resolution operation and other conditions, and in particular. There is no limitation.

前記の「光学分割」操作において使用する移動相は、使用するHPLCの機種、使用するカラムの種類、光学分割に供する化合物、流速等により異なり、特に限定はされないが、キラル順相カラムを用いた場合、移動相の好適な例としては、n-ヘキサンとi-プロパノールの混合溶媒やn-ヘキサンとエタノールの混合溶媒、n-ヘプタンとi-プロパノールの混合溶媒等が挙げられる。 The mobile phase used in the above-mentioned "optical division" operation varies depending on the type of HPLC used, the type of column used, the compound used for optical division, the flow velocity, etc., and is not particularly limited, but a chiral normal phase column is used. In this case, suitable examples of the mobile phase include a mixed solvent of n-hexane and i-propanol, a mixed solvent of n-hexane and ethanol, a mixed solvent of n-heptane and i-propanol, and the like.

また、移動相における溶媒の混合比は、使用するカラム、光学分割に供する化合物及びHPLCの移動相の流量等により異なることは言うまでもなく、特に限定されないが、好適な例を挙げると、n-ヘキサンとi-プロパノールの混合溶媒で体積比(混合前の体積比。以下の記述における体積比もすべて混合前の体積比を意味する)6/4から4/6の範囲であり、より好適には体積比5/5である。n-ヘキサンとi-プロパノールの混合溶媒で体積比2/6になると、移動相の溶媒の極性が高くなるため、光学活性体それぞれのピークが接近して光学分割しにくくなる。逆に、n-ヘキサンとi-プロパノールの混合溶媒で体積比6/2となると、光学分割は行えるが、キラルカラム内でゾーン(帯)状に濃縮された光学活性体それぞれが析出し、固体状の光学活性体となってキラルカラム内を閉塞させる場合がある。即ち、式(I)のシクロペンテノ誘導体(ラセミ体)が移動相中に溶解し続けるために、移動相である混合溶媒は極性があることが好ましい。 It goes without saying that the mixing ratio of the solvent in the mobile phase varies depending on the column used, the compound to be subjected to optical division, the flow rate of the mobile phase of HPLC, and the like, and is not particularly limited. The volume ratio of the mixed solvent of i-propanol and i-propanol (volume ratio before mixing. The volume ratios in the following description also mean the volume ratio before mixing) are in the range of 6/4 to 4/6, more preferably. The volume ratio is 5/5. When the volume ratio of the mixed solvent of n-hexane and i-propanol is 2/6, the polarity of the solvent of the mobile phase becomes high, so that the peaks of the optically active substances approach each other and it becomes difficult to perform optical resolution. On the contrary, when the volume ratio is 6/2 with a mixed solvent of n-hexane and i-propanol, optical resolution can be performed, but each optically active substance concentrated in a zone shape is precipitated in the chiral column and is in a solid state. It may become an optically active substance of the chiral column and block the inside of the chiral column. That is, in order for the cyclopenteno derivative (racemic mixture) of the formula (I) to continue to dissolve in the mobile phase, it is preferable that the mixed solvent as the mobile phase has polarity.

(エナンチオマー過剰率(%ee))
用語「エナンチオマー過剰率(%ee)」は、当業者によく知られている。エナンチオマー過剰率は、2種のエナンチオマーのうちの一方の、他方に対する過剰率であり、百分率で表される。当該の化合物ABがエナンチオマーAとエナンチオマーBからなる場合に言い換えれば、当該の化合物AB中にエナンチオマーAとエナンチオマーBが含まれる場合に、エナンチオマー過剰率は、当該の化合物AB中のエナンチオマーAのモル数とエナンチオマーBのモル数から計算することができる。即ち、エナンチオマー過剰率は、AB→A+Bの分割について、下記のように定義される:
エナンチオマー過剰率(%ee)=[(エナンチオマーAのモル数)-(エナンチオマーBのモル数)]/[(エナンチオマーAのモル数)+(エナンチオマーBのモル数)]×100
ただし、エナンチオマーAが過剰のエナンチオマーである。
(Enantiomeric excess (% ee))
The term "enantiomeric excess (% ee)" is well known to those of skill in the art. The enantiomeric excess is the excess of one of the two enantiomerics with respect to the other, and is expressed as a percentage. In other words, when the compound AB consists of enantiomeric A and enantiomeric B, when the compound AB contains enantiomeric excess and enantiomeric B, the enantiomeric excess is the number of moles of enantiomeric excess in the compound AB. And can be calculated from the number of moles of enantiomeric B. That is, the enantiomeric excess is defined as follows for the AB → A + B division:
Enantiomeric excess (% ee) = [(Mole number of Enantiomeric A)-(Mole number of Enantiomeric B)] / [(Mole number of Enantiomeric A) + (Mole number of Enantiomeric B)] × 100
However, the enantiomer A is an excessive enantiomer.

エナンチオマー過剰率は、光学分割と同じキラルカラムを用いて、HPLC分析により測定される。本発明では、エナンチオマー過剰率の測定におけるHPLC分析条件としては、光学分割と同じHPLC分析条件が用いられる。HPLCのチャートにおける、エナンチオマーAとエナンチオマーBそれぞれのピーク面積の値からエナンチオマー過剰率の値が算出できる。他の方法として、エナンチオマー過剰率は、キラルシフト試薬を用いるH-NMR分析によっても決定できる。 The enantiomeric excess is measured by HPLC analysis using the same chiral column as the optical resolution. In the present invention, the same HPLC analysis conditions as those for optical resolution are used as the HPLC analysis conditions for measuring the enantiomeric excess. The value of the enantiomeric excess can be calculated from the value of the peak area of each of the enantiomeric A and the enantiomeric B in the HPLC chart. Alternatively, the enantiomeric excess can also be determined by 1 H-NMR analysis using a chiral shift reagent.

本発明の光学分割におけるエナンチオマー過剰率は、好ましくは95%ee以上、特に好ましくは99%ee以上の範囲を例示できる。 The enantiomeric excess in the optical resolution of the present invention can be exemplified in a range of preferably 95% ee or more, particularly preferably 99% ee or more.

(旋光性)
旋光性の値の測定には、旋光計またはHPLC分析が用いられる。旋光計が示す正負の値から、式(I)で表される化合物の光学活性体のうち、R体、S体が判別できる。
(Optical rotation)
Optical rotation meter or HPLC analysis is used to measure the optical rotation value. From the positive and negative values indicated by the polarimeter, the R-form and S-form can be discriminated from among the optically active compounds of the compound represented by the formula (I).

以下、実施例により本発明を更に詳細に説明するが、本発明は、これら実施例によって何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

光学活性な4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの製造(光学分割条件)
HPLC装置:LC-Forte/R (YMC社製、分取HPLC)
カラム:CHIRAL ART Cellulose-SC (粒径5μm、φ30.0mm I.D.、長さ250mm、YMC社製)
カラム温度:室温
移動相:n-ヘキサン/i-プロパノール(=50:50<v/v>)
流量:13mL/min
紫外線可視分光器検出波長:220nm
Production of optically active 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one (optical resolution conditions)
HPLC device: LC-Forte / R (YMC, preparative HPLC)
Column: CHIRAL ART Cellulose-SC (particle size 5 μm, φ30.0 mm ID, length 250 mm, manufactured by YMC)
Column temperature: Room temperature mobile phase: n-hexane / i-propanol (= 50: 50 <v / v>)
Flow rate: 13 mL / min
Ultraviolet visible spectroscope detection wavelength: 220 nm

注入量:4.5mL (1610mg/L in Eluent:4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンのラセミ体32.2mgを混合溶媒(n-ヘキサン10mL、i-プロパノール 10mL)に溶かして調整) Injection volume: 4.5 mL (1610 mg / L in Eluent: 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one racemic 32.2 mg dissolved in a mixed solvent (n-hexane 10 mL, i-propanol 10 mL) Adjustment)

図1で表されるように、シクロペンテノン誘導体の光学活性体として、 R体、S体がそれぞれのピークに分かれている。それぞれのピークを分取し、光学分割できる。なお、旋光度測定には、旋光計(POLAX-2L、ATAGO社、等)を用いた。 As shown in FIG. 1, the R-form and the S-form are divided into peaks as optically active substances of the cyclopentenone derivative. Each peak can be separated and optically resolved. An optical rotation meter (POLAX-2L, ATAGO, etc.) was used for optical rotation measurement.

光学活性な4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの製造(光学分割条件)
HPLCの条件は、実施例1と同じである。ラセミ体の注入量を増やした。
Production of optically active 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one (optical resolution conditions)
The HPLC conditions are the same as in Example 1. Increased the amount of racemic injection.

注入量:2~3mL (約40000mg/L in Eluent:例えば、4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンのラセミ体(特許文献2の方法を用いて製造)2.69gを混合溶媒(n-ヘキサン30mL、i-プロパノール30mL)に溶かして調整) Injection amount: 2 to 3 mL (about 40,000 mg / L in Eluent: for example, a racemic mixture of 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one (manufactured by the method of Patent Document 2) 2.69 g is mixed. Prepared by dissolving in a solvent (30 mL of n-hexane, 30 mL of i-propanol)

HPLCチャートのR体、S体のピークを観察しながら手動で、それぞれの光学活性体を分取した。ラセミ体の注入量が約100mg/回に増えると、R体、S体それぞれのピークの裾が重なってくるため、 R体、S体それぞれの回収液に他方の微量な混入(数パーセント)がみられた。 Each optically active substance was manually separated while observing the peaks of the R-form and S-form on the HPLC chart. When the injection amount of racemic mixture is increased to about 100 mg / dose, the tails of the peaks of R-form and S-form overlap, so a small amount (several percent) of the other is mixed in the recovery solution of R-form and S-form. It was seen.

光学活性な4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの製造(光学分割条件)
HPLCの条件は、実施例1と同じである。実施例2で得られたR体(数パーセントのS体含む)、S体(数パーセントのR体含む)をそれぞれ、もう一度HPLCで光学分割した。
Production of optically active 4-hydroxy-2-hydroxymethyl-2-cyclopentene-1-one (optical resolution conditions)
The HPLC conditions are the same as in Example 1. The R-form (including a few percent of S-form) and the S-form (including a few percent of R-form) obtained in Example 2 were optically resolved by HPLC once again.

(実施例2で得られたS体(数パーセントのR体含む)の光学分割)
試料溶液の注入量約2mL (約40000mg/L in Eluent:実施例2で得られたS体(数パーセントのR体を含む)1.27gを混合溶媒(n-ヘキサン16mL、i-プロパノール16mL)に溶かして調整)である。
(Optical resolution of S-form (including several percent R-form) obtained in Example 2)
Injection amount of sample solution about 2 mL (about 40,000 mg / L in Eluent: 1.27 g of S-form (including several percent R-form) obtained in Example 2) was added to a mixed solvent (n-hexane 16 mL, i-propanol 16 mL). Melt and adjust).

(実施例2で得られたR体(数パーセントのS体含む)の光学分割)
試料溶液の注入量3mL (約40000mg/L in Eluent:実施例2で得られたR体(数パーセントのS体を含む)1.07gを混合溶媒(n-ヘキサン14mL、i-プロパノール 14mL)に溶かして調整)である。
(Optical resolution of R-form (including several percent S-form) obtained in Example 2)
Injection volume of sample solution 3 mL (about 40,000 mg / L in Eluent: 1.07 g of R-form (including several percent S-form) obtained in Example 2) was dissolved in a mixed solvent (n-hexane 14 mL, i-propanol 14 mL). Adjustment).

図2、図3に光学分割で得られたS体、R体のHPLCチャートを示す。99%ee以上の光学純度でR体、S体が得られることが分かった。 2 and 3 show HPLC charts of S-form and R-form obtained by optical resolution. It was found that R-form and S-form can be obtained with an optical purity of 99% ee or higher.

99%ee以上の光学活性体(R体)及び(S体)の比旋光度([α]D)を測定した。それぞれの[α]D値は以下であった。
(R体):[α]D=+33.0°(C=1.0 in EtOH)、(S体):[α]D=-31.9°(C=1.0 in EtOH)
The specific rotations ([α] D ) of the optically active substances (R-form) and (S-form) of 99% ee or more were measured. Each [α] D value was as follows.
(R body): [α] D = + 33.0 ° (C = 1.0 in EtOH), (S body): [α] D = -31.9 ° (C = 1.0 in EtOH)

本発明により、目的生成物である上記式(I)の化合物の光学活性体の新規で簡便な製造方法が提供される。式(I)で表される4-ヒドロキシ-2-ヒドロキシメチル-2-シクロペンテン-1-オンの光学活性体はプロスタグランジン、ペンテノマイシン(pentenomycin)及びベルチマイシン(vertimycin)等の医薬品原料となる有望な合成ブロックであるとされている。

INDUSTRIAL APPLICABILITY The present invention provides a novel and simple method for producing an optically active substance of the compound of the above formula (I), which is a target product. The optically active substance of 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one represented by the formula (I) can be used as a raw material for pharmaceutical products such as prostaglandin, pentenomycin and vertimycin. It is said to be a promising synthetic block.

Claims (5)

式(I)
Figure 0007080663000008
で表される化合物を、キラルカラムを装着した高速液体クロマトグラフィー(以下、「HPLC」という)装置を用いて光学分割することを含み、移動相がn-ヘキサンとi-プロパノールの混合溶媒であり、n-ヘキサンとi-プロパノールの混合溶媒の体積比が6:4~4:6である、式(I)で表される化合物の光学活性体の製造方法。
Equation (I)
Figure 0007080663000008
The compound represented by is optically partitioned using a high performance liquid chromatography (hereinafter referred to as “HPLC”) apparatus equipped with a chiral column, and the mobile phase is a mixed solvent of n-hexane and i-propanol. A method for producing an optically active compound of a compound represented by the formula (I), wherein the volume ratio of the mixed solvent of n-hexane and i-propanol is 6: 4 to 4: 6 .
式(I)で表される光学活性なシクロペンテノン化合物が99%ee以上のエナンチオマー過剰率を有する、請求項1に記載の製造方法。 The production method according to claim 1, wherein the optically active cyclopentenone compound represented by the formula (I) has an enantiomeric excess of 99% ee or more. 式(II)
Figure 0007080663000009
で表される光学活性体(S体)。
Equation (II)
Figure 0007080663000009
Optically active substance (S-form) represented by.
式(I)
Figure 0007080663000010
で表される化合物を光学分割することを含み、移動相がn-ヘキサンとi-プロパノールの混合溶媒であり、n-ヘキサンとi-プロパノールの混合溶媒の体積比が6:4~4:6である、式(II)
Figure 0007080663000011
で表される光学活性体(S体)の製造方法。
Equation (I)
Figure 0007080663000010
Including optical resolution of the compound represented by, the mobile phase is a mixed solvent of n-hexane and i-propanol, and the volume ratio of the mixed solvent of n-hexane and i-propanol is 6: 4 to 4: 6. , Equation (II)
Figure 0007080663000011
A method for producing an optically active substance (S-form) represented by.
式(II)で表される光学活性体(S体)が99%ee以上のエナンチオマー過剰率を有する、請求項4に記載の製造方法 The production method according to claim 4, wherein the optically active substance (S-form) represented by the formula (II) has an enantiomeric excess of 99% ee or more .
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US4683341A (en) * 1984-12-19 1987-07-28 Daicel Chemical Industries, Ltd. Optical resolution of oxycyclopentenone
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