JP2015209405A - Alicyclic monoepoxy-monool compound having bis-spironorbornane structure, and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel alicyclic monoepoxy-monool compound useful as an intermediate of medicine, an intermediate material for industrial products, and an additive; and to provide a method for producing the same.SOLUTION: Problems are solved through: the synthesis and identification of an alicyclic monoepoxy-monool compound having a cycloalkanone bis-spironorbornane structure represented by the following general formula (1); the review of a production method; and the analysis of a reaction intermediate. In the formula, one of Rand Ris -OH and the other thereof is -H; Rand Rare each independently the one selected from the group consisting of a hydrogen atom, 1-10C alkyl group, and a fluorine atom; and n is an integer of 2 to 5.

Description

  The present invention relates to a novel alicyclic monoepoxy-monool compound, which is a compound useful as an intermediate raw material and additive for pharmaceutical intermediates and industrial products, and a method for producing the same.

  An alicyclic epoxy compound is used as a main component of an epoxy resin for optical applications because it becomes a raw material for an epoxy resin having high transparency (Patent Document 1). Moreover, it is used also as an additive for providing a specific function to various materials (patent documents 2 and 3). On the other hand, an alicyclic alcohol compound can be converted into an acrylic acid derivative, carbonate, or the like, and used as a raw material or additive to produce a resin with improved functionality. These resins are expected to be used as optical materials such as optical elements, optical disks, and optical fibers. For example, a polymer derived from adamantanol has excellent optical properties, moisture resistance, and heat resistance (Patent Document 4).

JP 2013-170238 A Japanese Patent Laid-Open No. 11-80317 Japanese Patent Laid-Open No. 2003-026882 JP 2003-252810 A JP 2011-162479 A

  An object of the present invention is mainly to provide an alicyclic monoepoxy-monool compound having a bisspironorbornane skeleton and a method for producing the same.

  As a result of intensive studies to achieve the above object, the present inventors have used a norbornene compound represented by the following general formula (2) as a starting material, and this is a bisspiro represented by the following general formula (3). An alicyclic monoepoxy having a bisspironorbornane structure represented by the following general formula (1) is obtained by converting into an alicyclic diepoxy compound having a norbornane structure and then selectively reducing only one side of the epoxy ring. The inventors have found that a monool compound can be produced and have completed the present invention.

（Ｒ^１、Ｒ^２のいずれか一方は−ＯＨ、他方は−Ｈであり、Ｒ^３、Ｒ^４はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基及びフッ素原子よりなる群から選択される１種を示し、ｎは２〜５の整数を示す。） That is, the first of the present invention relates to an alicyclic monoepoxy-monool compound having a bisspirononorbornane structure represented by the following general formula (1).

(One of R ¹ and R ² is —OH, the other is —H, and R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and a fluorine atom. And n represents an integer of 2 to 5.)

  That is, the second of the present invention relates to the first alicyclic monoepoxy-monool compound of the present invention, wherein n = 2 or 3 in the general formula (1).

  That is, the third of the present invention relates to the first alicyclic monoepoxy-monool compound of the present invention, wherein n = 2 in the general formula (1).

（Ｒ^１、Ｒ^２はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基及びフッ素原子よりなる群から選択される１種を示し、ｎは２〜５の整数を示す。）

（Ｒ^１、Ｒ^２はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基及びフッ素原子よりなる群から選択される１種を示し、ｎは２〜５の整数を示す。）

（Ｒ^１、Ｒ^２のいずれか一方は−ＯＨ、他方は−Ｈであり、Ｒ^３、Ｒ^４はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基及びフッ素原子よりなる群から選択される１種を示し、ｎは２〜５の整数を示す。） That is, in the fourth aspect of the present invention, an alicyclic diepoxy compound represented by the following general formula (3) is produced by epoxidizing two carbon-carbon unsaturated bonds in the following general formula (2). The present invention relates to a method for producing an alicyclic monoepoxy-monool compound represented by the general formula (1) by selectively reducing an epoxy group on one side of the compound.

(R ¹ and R ² each independently represent one selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms and a fluorine atom, and n represents an integer of 2 to 5)

(R ¹ and R ² each independently represent one selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms and a fluorine atom, and n represents an integer of 2 to 5)

(One of R ¹ and R ² is —OH, the other is —H, and R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and a fluorine atom. And n represents an integer of 2 to 5.)

  That is, the fifth of the present invention relates to the fourth method for producing an alicyclic monoepoxy-monool compound of the present invention, wherein n is 2 or 3 in the general formula (1).

  That is, the sixth of the present invention relates to the fourth method for producing an alicyclic monoepoxy-monool compound of the present invention, wherein n is 2 in the general formula (1).

  According to the present invention, an alicyclic monoepoxy-monool compound having a bisspironorbornane structure and a method for producing the same are provided. The compound is useful as an intermediate material and additive for pharmaceutical intermediates and industrial products.

2 is a chart showing an IR spectrum of an alicyclic diepoxy compound represented by the chemical formula (6) obtained in Example 1. FIG. 2 is a chart showing a ¹ H-NMR (CDCl ₃ ) spectrum of an alicyclic diepoxy compound represented by the chemical formula (6) obtained in Example 1. FIG. 2 is a chart showing a ¹³ C-NMR (CDCl ₃ ) spectrum of an alicyclic diepoxy compound represented by the chemical formula (6) obtained in Example 1. FIG. 2 is a chart showing an FD-MS spectrum of an alicyclic diepoxy compound represented by the chemical formula (6) obtained in Example 1. FIG. 2 is a chart showing an IR spectrum of an alicyclic monoepoxy-monool compound represented by chemical formula (7) obtained in Example 1. FIG. 2 is a chart showing a ¹ H-NMR (CDCl ₃ ) spectrum of an alicyclic monoepoxy-monool compound represented by chemical formula (7) obtained in Example 1. FIG. 2 is a chart showing a ¹³ C-NMR (CDCl ₃ ) spectrum of an alicyclic monoepoxy-monool compound represented by chemical formula (7) obtained in Example 1. FIG. 3 is a chart showing an FD-MS spectrum of an alicyclic monoepoxy-monool compound represented by chemical formula (7) obtained in Example 1. FIG.

(Structure of the alicyclic monoepoxy-monool compound of the present invention)
The alicyclic monoepoxy-monool compound according to the present invention is an alicyclic monoepoxy-monool compound having a bisspironorbornane skeleton represented by the following general formula (1).

（Ｒ^１、Ｒ^２のいずれか一方は−ＯＨ、他方は−Ｈであり、Ｒ^３、Ｒ^４はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基及びフッ素原子よりなる群から選択される１種を示し、ｎは２〜５の整数を示す。）

(One of R ¹ and R ² is —OH, the other is —H, and R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and a fluorine atom. And n represents an integer of 2 to 5.)

  The alicyclic monoepoxy-monool compound according to the present invention has a norbornane ring at the symmetrical position of the cycloalkanone, has a strong symmetry, and does not have a freely rotatable carbon-carbon bond. As a basic structure. To date, no production examples of alicyclic monoepoxy-monool compounds having the basic structure are known.

  The general formula (1) collectively represents a plurality of isomers generated from the conformational relationship between a cycloalkanone ring and a norbornane ring, a norbornane ring and an epoxide ring, and a norbornane ring and a hydroxy group. .

（Ｒ^１、Ｒ^２はそれぞれ独立に、水素原子、炭素数１〜１０のアルキル基及びフッ素原子よりなる群から選択される１種を示し、ｎは２〜５の整数を示す。） In the production of the alicyclic monoepoxy-monool compound according to the present invention, a bisspironorbornene compound having a structure corresponding to these, that is, a bisspirononorbornene compound represented by the following general formula (2) is used as a raw material, It is preferable to produce it through chemical modification of the unsaturated bond in the compound. The manufacturing method of the following general formula (2) is disclosed in Patent Document 5 (paragraphs [0119] to [0132]) by the present applicant.

(R ¹ and R ² each independently represent one selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms and a fluorine atom, and n represents an integer of 2 to 5)

The compound having a bisspirornorbornene structure produced by the production method disclosed in Patent Document 5 (see also the examples described later) is not isolated, and the reaction mixture can be used as it is, or isolated and purified. Then, it may be used for subsequent reactions.
A compound having a bisspirononorbornene structure having cycloheptanone or cyclooctanone as a skeleton can be synthesized in the same manner as described above.

  Hereinafter, a method for producing the alicyclic monoepoxy-monool compound according to the present invention from the bisspironorbornene compound will be described.

  When producing the alicyclic monoepoxy-monool compound according to the present invention, using the corresponding bisspirononorbornene compound as a raw material, an alicyclic diepoxy compound is obtained by epoxidation, and then only the epoxide ring on one side is obtained. It is preferably obtained by selective reduction.

(Method for producing alicyclic diepoxy compound)
In order to produce an alicyclic diepoxy compound, which is an intermediate for producing an alicyclic monoepoxy-monool compound according to the present invention, from the bisspironorbornene compound, it is preferable to epoxidize a carbon-carbon double bond. This can be done using known methods. Among these, a combination of a heteropolyacid catalyst and a peracid is simple and preferable.

  Peracids include, for example, inorganic acids such as aqueous hydrogen peroxide, performic acid, peracetic acid, perpropionic acid, permaleic acid, perbenzoic acid, m-chloroperbenzoic acid, organic peracids such as perphthalic acid, and , And their acid anhydrides. Among these, it is preferable to use hydrogen peroxide water.

  A commercially available hydrogen peroxide solution can be used as it is. The amount of hydrogen peroxide used is preferably in the range of 2.0 to 5.0 moles relative to the carbon-carbon unsaturated bond in the bisspirononorbornene compound of the starting compound, 2.2 to 3.0 More preferably, it is in the range of double mole. When the amount is less than 2.0 times mole, the reaction does not proceed sufficiently. When the amount exceeds 5.0 times mole, side reactions such as oxidative decomposition of the epoxy ring of the produced alicyclic diepoxy compound proceed and the yield. Tends to decrease.

  The reaction temperature is preferably in the range of 30 to 80 ° C. When the temperature is lower than 30 ° C, the reaction rate is extremely low and the reaction efficiency is poor. When the temperature exceeds 80 ° C, the raw materials and the product may be decomposed.

  The molar ratio of the heteropolyacid and the hydrogen peroxide solution is preferably in the range of 1: 100 to 1: 400 with respect to hydrogen peroxide, and considering the reaction efficiency, the molar ratio is 1: 150 to 1: 250. A range is more preferable.

  As a method for opening only the epoxide on one side of the diepoxide, a method in which a lithium-naphthalene complex is used as a reducing agent and then water is added can be used. When a known reducing agent is used, the ring-opening reaction does not proceed, or not only the opening of the epoxide but also the carbonyl group of the cycloalkanone ring is reduced, and the target product cannot be obtained.

  An alicyclic monoepoxy-monool compound according to the present invention and a method for producing the same are provided. The compound is useful as an intermediate material and additive for pharmaceutical intermediates and industrial products.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated more concretely, this invention is not limited to a following example.

  In addition, in the following, identification of the molecular structure of the compound obtained in each Example is performed using an IR spectrophotometer (manufactured by JASCO Corporation, trade names: FT / IR-460, FT / IR-4100), NMR spectroscopy. IR machine (product name: UNITY INOVA-600 and JEOL Ltd. JNM-Lambda500) and FD-MS mass spectrometer (product of JEOL Ltd., product name: JMS-700V) , NMR, and FD-MS spectra were measured.

(Synthesis of raw material "cyclopentanone type bisspirocyclonorbornene")
(Synthesis Example 1)
<First step>
First, 30.86 g (378.5 mmol) of dimethylamine hydrochloride was added to a 1 L three-necked flask. Next, 12.3 g (385 mmol) of paraformaldehyde, 23.9 g (385 mmol) of ethylene glycol, and 12.95 g (154 mmol) of cyclopentanone were further added to the three-necked flask. Next, after adding 16.2 g (165 mmol) of methylcyclohexane to the three-necked flask, 0.4 g of 35 mass% hydrochloric acid (HCl: 3.85 mmol) was added to obtain a first mixed solution. The acid (HCl) content in the first mixed solution is 0.025 molar equivalent (3.85 [mol amount of HCl] / 154 [cyclopentanone] based on the ketone group in cyclopentanone. Molar amount] = 0.025).

で表されるマンニッヒ塩基を含有する反応液を得た。 Next, the inside of the three-necked flask was purged with nitrogen, the temperature in the three-necked flask was set at 85 ° C. at normal pressure (0.1 MPa), and the first mixed solution was heated and stirred for 8 hours to obtain the following chemical formula (5) :

The reaction liquid containing the Mannich base represented by this was obtained.

<Second step>
Next, after cooling the reaction solution in the three-necked flask to 50 ° C., methanol (250 ml) and 4.17 g of a 50 mass% dimethylamine aqueous solution (dimethylamine: 46) with respect to the reaction solution in the three-necked flask. 0.2 mmol) and 30.5 g (461.5 mmol) of cyclopentadiene were added to obtain a second mixed solution. Next, the inside of the three-necked flask is replaced with nitrogen, the temperature in the three-necked flask is set to 65 ° C. at normal pressure (0.1 MPa), and the second mixed solution is heated and stirred at 65 ° C. for 5 hours to form a compound. I let you.

  Next, the second mixed liquid in the three-necked flask was concentrated by azeotropic distillation of methylcyclohexane and methanol, and 100 mL of the liquid was removed from the second mixed liquid. By removing 100 mL of such liquid, most of methylcyclohexane (75% by mass with respect to the total amount of methylcyclohexane in the second mixed solution before concentration) was removed from the second mixed solution. Next, after the said 2nd liquid mixture after methylcyclohexane removal was cooled on -20 degreeC temperature conditions for 12 hours, the crystal | crystallization was deposited, Then, it filtered under reduced pressure and the crystal | crystallization was obtained. The crystal thus obtained was washed three times with 20 mL of -20 ° C. methanol, and then evaporated to remove the methanol to obtain 17.4 g (yield 47) of the product. %)Obtained.

で表される５−ノルボルネン−２−スピロ−２’−シクロペンタノン−５’−スピロ−２’’−５’’−ノルボルネンであることが確認された。 In order to confirm the structure of the compound thus obtained, IR and NMR ( ¹ H-NMR and ¹³ C-NMR) measurements were performed. The following chemical formula (5):

It was confirmed that it was 5-norbornene-2-spiro-2′-cyclopentanone-5′-spiro-2 ″ -5 ″ -norbornene represented by

Example 1
(Synthesis of alicyclic diepoxy compounds)
A 1 L two-necked flask equipped with a reflux tube was charged with cetylpyridinium chloride (467 mg, 1.37 mmol) and 5-norbornene-2-spiro-2′-cyclopentanone-5′-spiro-2 ″ -5 ″. -Norbornene (10.0 g, 41.6 mmol) and 400 mL of chloroform were added and stirred at room temperature. In addition, H3PW12O40 (1.32 g, 0.458 mmol) and hydrogen peroxide (concentration 30 wt%, 21.1 g, 94.0 mmol) were added to a 200 mL eggplant flask equipped with a reflux tube, heated to 60 ° C., and heated to 30 ° C. Stir for minutes and cool to room temperature to give a yellow solution. This solution was added to a 1 L two-neck eggplant flask and stirred while heating to 40 ° C. In order to confirm the progress of the reaction, a part of the reaction solution was collected on the way, and ¹ H-NMR was measured. As a result, it was confirmed that the intermediate monoepoxide and the product diepoxide were formed, and the reaction was continued. After 4.5 hours from the start of heating, the completion of the reaction could be confirmed, so stirring was stopped and the mixture was allowed to cool to room temperature. The solution was transferred to a separatory funnel, and a liquid separation operation was performed to remove the aqueous layer. Next, 50 mL of a sodium thiosulfate aqueous solution having a concentration of 10 wt% was prepared. This was added to the organic layer, and a liquid separation operation was performed to remove the aqueous layer. Next, 50 mL of a sodium carbonate aqueous solution having a concentration of 5 wt% was prepared. This was added to the organic layer for liquid separation, and the aqueous layer was discarded. Next, 100 mL of pure water was added to the organic layer to perform a liquid separation operation, and the aqueous layer was discarded. The organic layer was transferred to a 1 L Erlenmeyer flask, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a pale yellow powdery crude product. This was purified by recrystallization operation (the solvent used was methanol) to obtain 7.38 g of a white product (yield 65.1%).

In order to confirm the structure of the compound thus obtained, IR, NMR ( ¹ H-NMR and ¹³ C-NMR) and MS measurements were performed. The IR spectrum and ¹ H-NMR (CDCl ₃ ) spectrum of the compound thus obtained were measured, and the FD-MS spectrum was measured to identify the compound. From the results, it was confirmed that the obtained compound was a compound represented by the following chemical formula (6).

(Synthesis of lithium naphthalene complex)
The following operations were performed in a glove box under an argon atmosphere. Naphthalene (12.8 g, 99.8 mmol) and dehydrated THF (50 mL) were added to a 100 mL eggplant flask to make a uniform solution. Next, metallic lithium (granular, 578.5 mg) was added little by little and stirred at room temperature. At this time, it was confirmed that the lithium metal was gradually dissolved to become a dark green solution.
Since it is an unstable compound, confirmation by instrumental analysis such as NMR is impossible. This compound is known.

（Ｒ^１、Ｒ^２のいずれか一方は−ＯＨ、他方は−Ｈである。） (Synthesis of alicyclic monoepoxide-monool)
The raw material epoxy compound (200 mg, 0.734 mmol) was placed in a 50 mL eggplant flask and purged with nitrogen. While flowing nitrogen, dehydrated THF (5.1 mL) was added to obtain a homogeneous solution. This solution was cooled to −78 ° C. (using a dry ice / acetone refrigerant), a lithium-naphthalene complex solution (5.9 mL) was added, and the mixture was stirred at −78 ° C. for 3 hours. Thereafter, degassed pure water (2 mL) was added, and stirring was continued for 6 hours while gradually returning to room temperature. Next, the solution was transferred to a 100 mL separatory funnel, and water (10 mL) and ethyl acetate (5 mL) were added for liquid separation, and the aqueous layer was removed. 5% hydrochloric acid (10 mL) was added to the organic layer to perform a liquid separation operation, and the aqueous layer was removed. The organic layer was transferred to a 100 mL Erlenmeyer flask, and dried by adding anhydrous sodium sulfate. Filtration was performed, and the filtrate was concentrated to obtain a crude product. This was purified by column chromatography (stationary phase: silica gel manufactured by Fuji Silysia, mobile phase: hexane / ethyl acetate = 1/2) to obtain the desired product. When IR (see FIG. 1), ¹ H-NMR (see FIG. 2), ¹³ C-NMR (see FIG. 3) and FD-MS measurement (see FIG. 4) of the target product were carried out, only one epoxide ring was observed. Was confirmed to be a compound represented by the following general formula (7).

(One of R ¹ and R ² is —OH, and the other is —H.)

(Synthesis of cyclohexanone type bisspironorbornene):
It was synthesized according to Example 2 described in Patent Document 7 (paragraphs [0126] to [0132]) (yield 56%).

(Synthesis of alicyclic monoepoxy-monool compound):
An alicyclic diepoxide having a cyclohexanone type bisspironorbornane structure is synthesized using the cyclohexanone type bisspironorbornene as a raw material in the same manner as described above. From IR, ¹ H-NMR, ¹³ C-NMR, and MS spectrum, it can be confirmed that the product has a cyclohexanone type alicyclic diepoxy compound structure represented by the following chemical formula (8).

A cyclohexanone type alicyclic monoepoxy-monool compound represented by the following chemical formula (9) is obtained by selectively reducing only one epoxy ring of the cyclohexanone type alicyclic diepoxy compound. It can be confirmed by IR, ¹ H-NMR, ¹³ C-NMR, and MS spectrum that the product has an alicyclic monoepoxy-monool structure represented by the following chemical formula (8).

（Ｒ^１、Ｒ^２のいずれかは−ＯＨ、他方は−Ｈである。）

(One of R ¹ and R ² is —OH, and the other is —H.)

(Synthesis of other alicyclic monoepoxy-monool compounds):
In the general formula (1), when n = 4 (cycloheptanone) and 5 (cyclooctanone) on the cycloalkanone ring, the cycloheptanone type and cyclooctanone type bis are formed in the same manner as the above method. The corresponding alicyclic monoepoxy-monool compound is synthesized through each alicyclic diepoxy compound using a compound having a spironobornane structure.

  The alicyclic monoepoxy-monool compounds according to the present invention are useful as intermediates and additives for pharmaceutical intermediates and industrial products.

Claims (6)

An alicyclic monoepoxy-monool compound represented by the following general formula (1).

(One of R ¹ and R ² is —OH, the other is —H, and R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and a fluorine atom. And n represents an integer of 2 to 5.)   The alicyclic monoepoxy-monool compound according to claim 1, wherein n = 2 or 3 in the general formula (1).   The alicyclic monoepoxy-monool compound according to claim 1, wherein n = 2 in the general formula (1). A norbornene compound represented by the following general formula (2) is used as a raw material, and two carbon-carbon unsaturated bonds in the compound are epoxidized to produce an alicyclic diepoxy compound represented by the following general formula (3). Then, an alicyclic monoepoxy-monool compound represented by the following general formula (1) is produced by selectively reducing an epoxy group on one side of the compound. The manufacturing method of the alicyclic monoepoxy-monool compound represented by General formula (1).

(R ¹ and R ² each independently represent one selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms and a fluorine atom, and n represents an integer of 2 to 5)

(R ¹ and R ² each independently represent one selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms and a fluorine atom, and n represents an integer of 2 to 5)

(One of R ¹ and R ² is —OH, the other is —H, and R ³ and R ⁴ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, and a fluorine atom. And n represents an integer of 2 to 5.)   In the said General formula (1), it is n = 2 or 3, The manufacturing method of the alicyclic monoepoxy-monool compound of Claim 4 characterized by the above-mentioned.   In the said General formula (1), it is n = 2, The manufacturing method of the alicyclic monoepoxy-monool compound of Claim 4 characterized by the above-mentioned.

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