WO2019151299A1 - Method for producing glutaraldehyde derivative originating in natural material - Google Patents
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- WO2019151299A1 WO2019151299A1 PCT/JP2019/003098 JP2019003098W WO2019151299A1 WO 2019151299 A1 WO2019151299 A1 WO 2019151299A1 JP 2019003098 W JP2019003098 W JP 2019003098W WO 2019151299 A1 WO2019151299 A1 WO 2019151299A1
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- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
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- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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- B01J29/00—Catalysts comprising molecular sieves
- B01J29/04—Catalysts comprising molecular sieves having base-exchange properties, e.g. crystalline zeolites
- B01J29/06—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
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Definitions
- the present invention uses a naturally occurring iridoid compound as a raw material and reacts in the presence of a solid acid or a liquid acid catalyst having a pKa of 5 or less, and is added to the pyran ring in the raw iridoid compound.
- the present invention relates to a technique for producing a glutaraldehyde derivative having a structure.
- Non-Patent Document 1 oleocantal, which is one of glutaraldehyde derivatives present in olives, exhibits an anti-inflammatory analgesic effect equivalent to ibuprofen.
- Non-Patent Document 2 discloses a method for total synthesis of oleacein in 10 steps using D-ribose as a starting material.
- oleuropein which is a kind of iridoid compound abundantly contained in olive leaves, is used as a raw material and heated in the presence of 2 equivalents of chloride salt and 10 equivalents of water. Shows a method for synthesizing oleacein with a yield of 22%.
- Patent Document 1 uses 2-alkoxy-3,4-dihydro-2H-pyran as a raw material in the presence or absence of water-soluble acid in water. The method of heat treatment is shown.
- the inventor of the present invention examined the conventional synthesis method of the glutaraldehyde derivative as described above, and recognized that the following problems (1) and (2) exist.
- the present invention is based on the background of the prior art as described above and the inventor's recognition of the prior art, and uses a naturally occurring iridoid compound as a raw material and adds it to the pyran ring in the raw iridoid compound. It is an object of the present invention to provide a novel production method for producing a glutaraldehyde derivative having a substituent structure.
- the inventors generally used a naturally occurring iridoid compound having a structure represented by [Chemical Formula 2] as a raw material, and a solid acid catalyst having a pKa of 5 or less that is easily available in an organic solvent, such as zeolite, By adding silica alumina, sulfated zirconia, bentonite, polystyrene sulfonic acid or the like, or by using a liquid acid catalyst having a pKa of 5 or less as a catalyst in an organic solvent, it is added to the pyran ring in the raw material compound. It was found that a glutaraldehyde derivative having a certain substituent structure can be obtained in a relatively high yield.
- X represents sugar or hydrogen, and at least one of R 1 , R 2 , and R 3 represents a substituent containing one or more selected from alkene, carboxylic acid, ester, and alcohol.
- this application provides the following inventions.
- a method for producing a glutaraldehyde derivative having at least one substituent structure added to a pyran ring in a raw material iridoid compound using a naturally occurring iridoid compound as a raw material, and having a pKa of 5 as a catalyst A method for producing a glutaraldehyde derivative, characterized by using the following solid acid or liquid acid.
- (2) In the manufacturing method of the said glutaraldehyde derivative the manufacturing method of the derivative as described in said (1) whose water content in a reaction system is 1000 molar equivalent or less with respect to the iridoid compound used as a raw material.
- a naturally occurring iridoid compound is used as a raw material in a relatively high yield, and at least one substituent structure added to the pyran ring in the raw material is retained. It becomes possible to produce a glutaraldehyde derivative.
- the present invention is a method for producing a glutaraldehyde derivative having a substituent structure added to a pyran ring in a raw material iridoid compound using a naturally occurring iridoid compound as a raw material, and having a pKa of 5 or less as a catalyst.
- a liquid acid is used.
- the iridoid compound derived from a natural product used as a raw material is not particularly limited as long as it has the structure shown in the above [Chemical Formula 2]. Scandside and the like.
- the oleuropein is abundant in olive leaves.
- These purities are not particularly limited, and can be used as raw materials as a crude product.
- a raw material may be supplied in a water-containing state, and may be supplied through a drying process.
- the conversion reaction of the iridoid compound is usually performed in an organic solvent.
- the organic solvent to be used is not particularly limited.
- the solid acid catalyst having a pKa of 5 or less is not particularly limited.
- zeolite, silica alumina, sulfated zirconia, bentonite and polystyrene sulfonic acid are used.
- the zeolite is preferably a proton-substituted zeolite.
- Bentonite is preferably substituted with at least one ion selected from proton, titanium, and copper.
- liquid acid catalyst having a pKa of 5 or less examples include hydrochloric acid, hydrofluoric acid, bromic acid, iodic acid, sulfuric acid, phosphoric acid, nitric acid, carboxylic acid, ascorbic acid and the like.
- the amount of water in the reaction system when using a liquid acid catalyst is preferably 1000 molar equivalents or less, more preferably 100 molar equivalents or less, and even more preferably 20 molar equivalents or less with respect to the iridoid compound as a raw material.
- the amount of these catalysts used is 0.01 wt% to 1000 wt%, preferably 0.1 wt% to 400 wt%, more preferably 1 wt% to 200 wt%, based on the naturally occurring iridoid compound as a raw material. . If the amount of catalyst used is too small, the reaction will not proceed sufficiently, and if the amount of catalyst used is too large, operational problems will occur.
- the reaction method of the present invention is not particularly limited, but a method in which a solid acid catalyst or liquid acid catalyst having a pKa of 5 or less is preferably added to an organic solvent in which the raw material is dissolved, and the reaction is performed by heating is exemplified. Moreover, the method of distribute
- the reaction temperature is preferably 60 ° C. to 200 ° C., more preferably 120 ° C. to 160 ° C. When the reaction temperature is lower than this, the reaction rate becomes slow. When the reaction temperature is higher than this, the starting iridoid compound or the produced glutaraldehyde derivative is decomposed or modified.
- a glutaraldehyde derivative having a structure can be produced.
- the substituent structure in the raw material compound is not decomposed, and when a solid acid catalyst is used, the catalyst used in the reaction can be easily removed by solid-liquid separation and recovered. Since the catalyst can be reused repeatedly, various existing problems can be overcome.
- Example 1-2 In Example 1-1, Example 1 was used except that 20 mg of silica alumina (manufactured by Wako Pure Chemical Industries, SiO 2 82.3%, Al 2 O 3 12.6%) was used instead of Y-type zeolite as the solid acid. As a result of carrying out the reaction in the same manner as in -1, oleacein was obtained in a yield of 60%.
- silica alumina manufactured by Wako Pure Chemical Industries, SiO 2 82.3%, Al 2 O 3 12.6%
- Example 1-1 In Example 1-1, the reaction was conducted in the same manner as in Example 1-1 except that 20 mg of sulfated zirconia (manufactured by Wako Pure Chemical Industries, Ltd.) was used in place of Y-type zeolite as the solid acid. As a result, oleacein was recovered. Obtained at a rate of 71%.
- Example 2 ⁇ Production of oleacein with inorganic acid> Example 2-1
- 10 mg of oleuropein manufactured by Toronto Research Chemicals, purity 75%) and 10 ⁇ L (10 mol%) of a 0.14 M aqueous hydrochloric acid solution (12N hydrochloric acid is purchased from Fuji Film Wako Pure Chemical Industries, Ltd.) are added as an organic solvent.
- Add 0.5 mL of sulfoxide (Fuji Film Wako Pure Chemical Industries) containing 1.36 mg of water, 0.076 mmol, measured by Karl Fischer titration method
- the reaction was carried out for 12 hours while stirring at 350 rpm. When the solution after the reaction was confirmed by NMR, a decomposition product was confirmed.
- Example 2-2 In Example 2-1, except that 10 ⁇ L (1 mol%) of a 0.014 M hydrochloric acid aqueous solution was added, the reaction was carried out in the same manner as in Example 2-1. As a result, oleacein was obtained in a yield of 54%.
- Example 2-3 The reaction was conducted in the same manner as in Example 2-1, except that 10 ⁇ L (0.1 mol%) of a 0.0016 M aqueous hydrochloric acid solution was added. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 67%. Further, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the obtained reaction solution to carry out a liquid separation treatment.
- the ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance.
- sodium sulfate Fluji Film Wako Pure Chemical Industries
- the filtrate was concentrated to obtain an oily substance.
- silica gel column chromatography manufactured by Kanto Chemical Co., Inc.
- the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1
- 2.7 mg of oleacein (recovered) was obtained. 61%).
- Example 3 ⁇ Production of oleacein with organic acid>
- 10 mg of oleuropein (manufactured by Toronto Researchs Chemical, purity 75%) and 0.24 mg (10 mol%) of paratoluenesulfonic acid (manufactured by Kishida Chemical) were added to a glass tube with an internal volume of 2 mL, and dimethyl sulfoxide (Fuji Film Wako Pure) 0.5 mL of water (containing 1.36 mg of water, measured by Karl Fischer titration), and allowed to react for 12 hours under stirring at 350 rpm using a magnetic stirrer at 150 ° C. in an oil bath It was.
- the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 54%.
- Example 3-2 In Example 3-1, except that 24 ⁇ g (1 mol%) of p-toluenesulfonic acid (manufactured by Kishida Chemical Co., Ltd.) was added, the reaction was carried out in the same manner as in Example 2-1. As a result, oleacein was obtained in a yield of 73%. It was.
- Example 3-3 As a result of carrying out the reaction in the same manner as in Example 3-1, except that 2.4 ⁇ g (0.1 mol%) of p-toluenesulfonic acid (manufactured by Kishida Chemical Co., Ltd.) was added.
- 2.4 ⁇ g (0.1 mol%) of p-toluenesulfonic acid manufactured by Kishida Chemical Co., Ltd.
- oleacein was obtained in a yield of 77%.
- 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the obtained reaction solution to carry out a liquid separation treatment.
- the ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance.
- sodium sulfate Fluji Film Wako Pure Chemical Industries
- the filtrate was concentrated to obtain an oily substance.
- Example 4 ⁇ Change in yield depending on the amount of solid acid>
- Example 4-1 A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75). %) 10 mg, bentonite (Kunimine F, Kunipia F, H + substituted type) as solid acid catalyst, 5 mg, dimethyl sulfoxide as organic solvent, 0.5 mL (containing 1.36 mg of water, measured by Karl Fischer titration method)
- the reaction was allowed to stand at 150 ° C. for 12 hours in an oil bath.
- the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 29%.
- Example 4-2 In Example 4-1, reaction was carried out in the same manner as in Example 4 except that 10 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in a yield of 69%. It was.
- bentonite Korean F, Kunipia F, H + substituted type
- Example 4-3 In Example 4-1, the reaction was carried out in the same manner as in Example 4-1, except that 20 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in a yield of 82%. It was.
- bentonite Korean F, Kunipia F, H + substituted type
- Example 4-4 The reaction was carried out in the same manner as in Example 4-1, except that 40 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in 89% yield. It was.
- Example 5 ⁇ Change in yield with reaction time> A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75). %) 10 mg, bentonite (Kunimine F, Kunipia F, H + substituted type) as solid acid catalyst, 5 mg, dimethyl sulfoxide as organic solvent, 0.5 mL (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand in an oil bath at 150 ° C. for 2, 4, 6, 8, 10, and 12 hours. The solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard. The yield of oleacein was 2% 29%, 4 hours 25%, 6 hours 35%, 8 hours 75%, 10 hours. 80%, 12 hours 82%).
- Example 6 ⁇ Change in yield due to water content> A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75). %) 10 mg, 5 mg bentonite (Kunimine F, H + substituted type manufactured by Kunimine Kogyo Co., Ltd.) as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide having a different water content as an organic solvent (using Karl Fischer titration method) Dimethyl sulfoxide containing 3, 7, 22, and 37 equivalents of water was prepared), and the mixture was allowed to stand at 150 ° C. for 12 hours in an oil bath.
- oleuropein manufactured by Toronto Research Chemicals, purity 75.
- bentonite Karl Fischer titration method
- Example 7 ⁇ Change in yield with reaction temperature> A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75). %) 10 mg, bentonite (Kunimine Industries Kunipia F, H + substituted type) 20 mg as solid acid catalyst, 0.5 mL of dimethyl sulfoxide as organic solvent (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand at 125 ° C. in an oil bath. Every 12 hours, the reaction solution was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard. As a result, oleacein was obtained in a yield (12 hours 22%, 24 hours 68%, 36 hours 76%).
- Example 8-1 A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75). %) 10 mg, bentonite (Kunimine Industries Kunipia F, H + substituted type) 20 mg as a solid acid catalyst, 0.5 mL of gamma-butyrolactone as an organic solvent (1.36 mg of water using Karl Fischer titration method) In addition, the mixture was allowed to stand at 150 ° C. for 12 hours in an oil bath.
- oleuropein manufactured by Toronto Research Chemicals, purity 75.
- bentonite Korean Industries Kunipia F, H + substituted type
- Example 8-2 In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that diethylene glycol dimethyl ether (diglyme) was added instead of gamma-butyrolactone. As a result, 1.4 mg (yield 32%) of oleacein was obtained.
- diethylene glycol dimethyl ether diglyme
- Example 8-3 In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that enmethylpyrrolidine was added instead of gamma-butyrolactone. As a result, oleacein could not be obtained.
- Example 8-4 In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that 1-octanol was added instead of gamma-butyrolactone. As a result, oleacein could not be obtained.
- Example 8-5 The reaction and post-treatment were carried out in the same manner as in Example 8-1, except that dimethyl sulfoxide was added instead of gamma-butyrolactone. As a result, 3.5 mg (yield 80%) of oleacein was obtained.
- Example 9 ⁇ Production of oleocanthal with solid acid catalyst>
- 11 mg of ligustroside 22 mg of bentonite (Kunimine Industries Kunipia F, H + substituted type) as a solid acid catalyst
- 0.5 mL of dimethyl sulfoxide as an organic solvent containing 1.36 mg of water, (Measured by Karl Fischer titration method)
- 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment.
- the ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance.
- Silica gel column chromatography manufactured by Kanto Chemical Co., Inc. was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 4.1 mg of oleocanthal (yield) 63%).
- Example 10 ⁇ Production of loganine-derived glutaraldehyde compound by solid acid catalyst> Loganin (purchased from ChengduBiopurify) 10 mg in a 2 mL glass tube, Bentonite (Kunimine Industries Kunipia F, H + substitution type) 20 mg as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide as an organic solvent (1.36 mg of water) Content, measured by Karl Fischer titration method), and allowed to stand at 150 ° C. in an oil bath. After 12 hours, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment.
- Loganin purchased from ChengduBiopurify
- Bentonite Korean Industries Kunipia F, H + substitution type
- the ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance.
- Silica gel column chromatography manufactured by Kanto Chemical was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 1.1 mg of loganine-derived glutaraldehyde compound was obtained. (Yield 25%) was obtained.
- Example 11 ⁇ Production of oleacein using oleuropein isolated from olive leaf by solid acid catalyst> To an Erlenmeyer flask with an internal volume of 100 mL, 10 g of olive leaf (purchased from Hinata Foods Co., Ltd.) and 40 mL of an 80% methanol solution were added, and the mixture was left at room temperature for extraction. After 12 hours, olive leaves were removed by filtration, and the filtrate was concentrated to obtain an oily substance.
- the ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance.
- Silica gel column chromatography (silica gel manufactured by Kanto Chemical Co., Inc.) was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 598 mg of oleacein (75% yield). %)Obtained.
- Example 3-3 the reaction was performed in the same manner as in Example 3-3 except that 1000 molar equivalents of water was added to oleuropein. No oleacein was formed, and no oleuropein residue was observed. It was. Therefore, control of the amount of moisture is important in the present invention.
- the present invention is useful for producing a corresponding glutaraldehyde derivative in high yield using a naturally occurring iridoid compound as a raw material.
- the manufactured glutaraldehyde derivative can be provided as a pharmaceutical, a pharmaceutical raw material, or a functional food.
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Abstract
Provided is a method for relatively efficiently producing a glutaraldehyde derivative using an iridoid compound occurring in nature as a starting material, said glutaraldehyde derivative holding a substituent which is attached to the pyran ring in the starting iridoid compound.
The method for producing a glutaraldehyde derivative using an iridoid compound occurring in nature as a starting material, said glutaraldehyde derivative holding at least one substituent structure which is attached to the pyran ring in the starting iridoid compound, is characterized by comprising using as a catalyst a solid acid or a liquid acid having a pKa of 5 or lower. The solid acid catalyst is at least one member selected from among silica alumina, zeolite, sulfated zirconia, bentonite and polystyrene sulfonic acid.
Description
本発明は、天然に存在するイリドイド化合物を原料として、固体酸またはｐＫａが５以下の液体酸触媒の存在下で反応させ、原料のイリドイド化合物中のピラン環に付加している少なくとも一つの置換基構造を保持したグルタルアルデヒド誘導体を製造するための技術に関する。
The present invention uses a naturally occurring iridoid compound as a raw material and reacts in the presence of a solid acid or a liquid acid catalyst having a pKa of 5 or less, and is added to the pyran ring in the raw iridoid compound. The present invention relates to a technique for producing a glutaraldehyde derivative having a structure.
天然に存在するグルタルアルデヒド誘導体は様々な薬理活性を持つことが知られている。例えば、非特許文献１には、オリーブ中に存在するグルタルアルデヒド誘導体の一つであるオレオカンタールがイブプロフェンと同等の消炎鎮痛効果を示すことが知られている。
Naturally existing glutaraldehyde derivatives are known to have various pharmacological activities. For example, it is known from Non-Patent Document 1 that oleocantal, which is one of glutaraldehyde derivatives present in olives, exhibits an anti-inflammatory analgesic effect equivalent to ibuprofen.
一方で、天然に存在するグルタルアルデヒド誘導体は化学的に不安定なものが多く、抽出以外の方法で得る方法は限られている。例えば、オリーブ中に存在するオレアセイン（［化１］参照）を合成する方法として、非特許文献２には、Ｄ－リボースを出発原料として１０段階でオレアセインを全合成する手法が示されている。また、非特許文献３には、オリーブの葉に豊富に含有されるイリドイド化合物の一種であるオレウロペインを原料として用い、２当量の塩化物塩と１０当量の水の存在下で加熱することにより一段でオレアセインを収率２２％で合成する手法が示されている。
On the other hand, many naturally occurring glutaraldehyde derivatives are chemically unstable, and the methods obtained by methods other than extraction are limited. For example, as a method for synthesizing oleacein present in olives (see [Chemical Formula 1]), Non-Patent Document 2 discloses a method for total synthesis of oleacein in 10 steps using D-ribose as a starting material. In Non-Patent Document 3, oleuropein, which is a kind of iridoid compound abundantly contained in olive leaves, is used as a raw material and heated in the presence of 2 equivalents of chloride salt and 10 equivalents of water. Shows a method for synthesizing oleacein with a yield of 22%.
他方、グルタルアルデヒドを合成する方法として、特許文献１には、２－アルコキシ－３，４－ジヒドロ－２Ｈ－ピランを原料として用い、水中にて水に可溶な酸の存在下もしくは非存在下で加熱処理する方法が示されている。
On the other hand, as a method for synthesizing glutaraldehyde, Patent Document 1 uses 2-alkoxy-3,4-dihydro-2H-pyran as a raw material in the presence or absence of water-soluble acid in water. The method of heat treatment is shown.
本発明者は、上述のような従来のグルタルアルデヒド誘導体の合成法について検討したが、次の（１）、（２）のような問題点が存在することを認識した。
（１）従来のオレアセインの合成法はいずれも収率が低いために十分な量のオレアセインを得るには実用的ではない。
（２）天然に存在する原料としてのイリドイド化合物や製造物のグルタルアルデヒド誘導体は、一般に加水分解しやすい置換基を持つため、特許文献１に記載のような、水中にて水に可溶な酸の存在下もしくは非存在下で加熱処理する手法により合成することは困難である。 The inventor of the present invention examined the conventional synthesis method of the glutaraldehyde derivative as described above, and recognized that the following problems (1) and (2) exist.
(1) None of the conventional methods for synthesizing oleacein is practical in order to obtain a sufficient amount of oleacein because the yield is low.
(2) Since an iridoid compound as a naturally occurring raw material and a glutaraldehyde derivative of a product generally have a substituent that is easily hydrolyzed, an acid that is soluble in water in water as described in Patent Document 1 It is difficult to synthesize by a method of heat treatment in the presence or absence of.
（１）従来のオレアセインの合成法はいずれも収率が低いために十分な量のオレアセインを得るには実用的ではない。
（２）天然に存在する原料としてのイリドイド化合物や製造物のグルタルアルデヒド誘導体は、一般に加水分解しやすい置換基を持つため、特許文献１に記載のような、水中にて水に可溶な酸の存在下もしくは非存在下で加熱処理する手法により合成することは困難である。 The inventor of the present invention examined the conventional synthesis method of the glutaraldehyde derivative as described above, and recognized that the following problems (1) and (2) exist.
(1) None of the conventional methods for synthesizing oleacein is practical in order to obtain a sufficient amount of oleacein because the yield is low.
(2) Since an iridoid compound as a naturally occurring raw material and a glutaraldehyde derivative of a product generally have a substituent that is easily hydrolyzed, an acid that is soluble in water in water as described in Patent Document 1 It is difficult to synthesize by a method of heat treatment in the presence or absence of.
本発明は、上述のような従来技術や該従来技術に対する本発明者の認識を背景としたものであり、天然に存在するイリドイド化合物を原料として、原料のイリドイド化合物中のピラン環に付加している置換基構造を保持したグルタルアルデヒド誘導体を製造する新規な製造法を提供することを課題とする。
The present invention is based on the background of the prior art as described above and the inventor's recognition of the prior art, and uses a naturally occurring iridoid compound as a raw material and adds it to the pyran ring in the raw iridoid compound. It is an object of the present invention to provide a novel production method for producing a glutaraldehyde derivative having a substituent structure.
最近発明者らは、一般的に［化２］に示される構造を持つ天然に存在するイリドイド化合物を原料として用い、有機溶媒中で入手の容易なｐＫａが５以下の固体酸触媒、例えばゼオライト、シリカアルミナ、硫酸化ジルコニア、ベントナイト、ポリスチレンスルホン酸等を存在させることにより、または、有機溶媒中で触媒としてｐＫａが５以下の液体酸触媒を用いることにより、原料化合物中のピラン環に付加している置換基構造を保持したグルタルアルデヒド誘導体を比較的高収率で得ることができることを見いだした。
Recently, the inventors generally used a naturally occurring iridoid compound having a structure represented by [Chemical Formula 2] as a raw material, and a solid acid catalyst having a pKa of 5 or less that is easily available in an organic solvent, such as zeolite, By adding silica alumina, sulfated zirconia, bentonite, polystyrene sulfonic acid or the like, or by using a liquid acid catalyst having a pKa of 5 or less as a catalyst in an organic solvent, it is added to the pyran ring in the raw material compound. It was found that a glutaraldehyde derivative having a certain substituent structure can be obtained in a relatively high yield.
すなわち、この出願は以下の発明を提供するものである。
（１）天然に存在するイリドイド化合物を原料として、原料イリドイド化合物中のピラン環に付加している少なくとも一つの置換基構造を保持したグルタルアルデヒド誘導体を製造する方法であって、触媒としてｐＫａが５以下の固体酸または液体酸を用いることを特徴とする、グルタルアルデヒド誘導体の製造法。
（２）前記グルタルアルデヒド誘導体の製造法において、反応系中の水分量が原料とするイリドイド化合物に対して１０００モル当量以下である、上記（１）に記載の誘導体の製造法。
（３）前記固体酸触媒がシリカアルミナ、ゼオライト、硫酸化ジルコニア、ベントナイト、ポリスチレンスルホン酸から選択される少なくとも１種類である上記（１）に記載のグルタルアルデヒド誘導体の製造法。
（４）前記ゼオライトがプロトン置換型のゼオライトである上記（３）に記載のグルタルアルデヒド誘導体の製造法。
（５）前記ベントナイトがプロトン、チタン、銅から選択される少なくとも１種類のイオンにより置換されているものである上記（３）に記載のグルタルアルデヒド誘導体の製造法。
（６）前記グルタルアルデヒド誘導体の製造法を有機溶媒中で行なう、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。
（７）前記グルタルアルデヒド誘導体の製造法を加熱条件下で行なう、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。
（８）前記イリドイド化合物がオレウロペインであり、前記グルタルアルデヒド誘導体がオレアセインである、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。
（９）前記イリドイド化合物がリグストロサイドであり、前記グルタルアルデヒド誘導体がオレオカンタールである、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。 That is, this application provides the following inventions.
(1) A method for producing a glutaraldehyde derivative having at least one substituent structure added to a pyran ring in a raw material iridoid compound using a naturally occurring iridoid compound as a raw material, and having a pKa of 5 as a catalyst A method for producing a glutaraldehyde derivative, characterized by using the following solid acid or liquid acid.
(2) In the manufacturing method of the said glutaraldehyde derivative, the manufacturing method of the derivative as described in said (1) whose water content in a reaction system is 1000 molar equivalent or less with respect to the iridoid compound used as a raw material.
(3) The method for producing a glutaraldehyde derivative according to the above (1), wherein the solid acid catalyst is at least one selected from silica alumina, zeolite, sulfated zirconia, bentonite, and polystyrene sulfonic acid.
(4) The method for producing a glutaraldehyde derivative according to the above (3), wherein the zeolite is a proton-substituted zeolite.
(5) The method for producing a glutaraldehyde derivative according to the above (3), wherein the bentonite is substituted with at least one ion selected from proton, titanium, and copper.
(6) The method for producing a glutaraldehyde derivative according to any one of (1) to (5), wherein the method for producing the glutaraldehyde derivative is performed in an organic solvent.
(7) The method for producing a glutaraldehyde derivative according to any one of (1) to (5), wherein the method for producing the glutaraldehyde derivative is performed under heating conditions.
(8) The method for producing a glutaraldehyde derivative according to any one of (1) to (5) above, wherein the iridoid compound is oleuropein and the glutaraldehyde derivative is oleacein.
(9) The method for producing a glutaraldehyde derivative according to any one of (1) to (5) above, wherein the iridoid compound is ligustroside and the glutaraldehyde derivative is oleocanthal.
（１）天然に存在するイリドイド化合物を原料として、原料イリドイド化合物中のピラン環に付加している少なくとも一つの置換基構造を保持したグルタルアルデヒド誘導体を製造する方法であって、触媒としてｐＫａが５以下の固体酸または液体酸を用いることを特徴とする、グルタルアルデヒド誘導体の製造法。
（２）前記グルタルアルデヒド誘導体の製造法において、反応系中の水分量が原料とするイリドイド化合物に対して１０００モル当量以下である、上記（１）に記載の誘導体の製造法。
（３）前記固体酸触媒がシリカアルミナ、ゼオライト、硫酸化ジルコニア、ベントナイト、ポリスチレンスルホン酸から選択される少なくとも１種類である上記（１）に記載のグルタルアルデヒド誘導体の製造法。
（４）前記ゼオライトがプロトン置換型のゼオライトである上記（３）に記載のグルタルアルデヒド誘導体の製造法。
（５）前記ベントナイトがプロトン、チタン、銅から選択される少なくとも１種類のイオンにより置換されているものである上記（３）に記載のグルタルアルデヒド誘導体の製造法。
（６）前記グルタルアルデヒド誘導体の製造法を有機溶媒中で行なう、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。
（７）前記グルタルアルデヒド誘導体の製造法を加熱条件下で行なう、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。
（８）前記イリドイド化合物がオレウロペインであり、前記グルタルアルデヒド誘導体がオレアセインである、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。
（９）前記イリドイド化合物がリグストロサイドであり、前記グルタルアルデヒド誘導体がオレオカンタールである、上記（１）から（５）のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。 That is, this application provides the following inventions.
(1) A method for producing a glutaraldehyde derivative having at least one substituent structure added to a pyran ring in a raw material iridoid compound using a naturally occurring iridoid compound as a raw material, and having a pKa of 5 as a catalyst A method for producing a glutaraldehyde derivative, characterized by using the following solid acid or liquid acid.
(2) In the manufacturing method of the said glutaraldehyde derivative, the manufacturing method of the derivative as described in said (1) whose water content in a reaction system is 1000 molar equivalent or less with respect to the iridoid compound used as a raw material.
(3) The method for producing a glutaraldehyde derivative according to the above (1), wherein the solid acid catalyst is at least one selected from silica alumina, zeolite, sulfated zirconia, bentonite, and polystyrene sulfonic acid.
(4) The method for producing a glutaraldehyde derivative according to the above (3), wherein the zeolite is a proton-substituted zeolite.
(5) The method for producing a glutaraldehyde derivative according to the above (3), wherein the bentonite is substituted with at least one ion selected from proton, titanium, and copper.
(6) The method for producing a glutaraldehyde derivative according to any one of (1) to (5), wherein the method for producing the glutaraldehyde derivative is performed in an organic solvent.
(7) The method for producing a glutaraldehyde derivative according to any one of (1) to (5), wherein the method for producing the glutaraldehyde derivative is performed under heating conditions.
(8) The method for producing a glutaraldehyde derivative according to any one of (1) to (5) above, wherein the iridoid compound is oleuropein and the glutaraldehyde derivative is oleacein.
(9) The method for producing a glutaraldehyde derivative according to any one of (1) to (5) above, wherein the iridoid compound is ligustroside and the glutaraldehyde derivative is oleocanthal.
本発明方法によれば、高価な化合物を触媒として使用することなく、天然に存在するイリドイド化合物を原料として比較的収率よく、原料中のピラン環に付加した少なくとも一つの置換基構造を保持したグルタルアルデヒド誘導体を製造することが可能になる。
According to the method of the present invention, without using an expensive compound as a catalyst, a naturally occurring iridoid compound is used as a raw material in a relatively high yield, and at least one substituent structure added to the pyran ring in the raw material is retained. It becomes possible to produce a glutaraldehyde derivative.
以下、本発明を実施するための形態について説明する。
なお、本明細書において数値範囲を示す「～」は、その前後に記載される数値を下限値および上限値として含む意味として使用される。 Hereinafter, modes for carrying out the present invention will be described.
In the present specification, “˜” indicating a numerical range is used as a meaning including numerical values described before and after the numerical value as a lower limit value and an upper limit value.
なお、本明細書において数値範囲を示す「～」は、その前後に記載される数値を下限値および上限値として含む意味として使用される。 Hereinafter, modes for carrying out the present invention will be described.
In the present specification, “˜” indicating a numerical range is used as a meaning including numerical values described before and after the numerical value as a lower limit value and an upper limit value.
本発明では、天然に存在するイリドイド化合物を原料として、原料イリドイド化合物中のピラン環に付加する置換基構造を保持したグルタルアルデヒド誘導体を製造する方法であって、触媒としてｐＫａが５以下の固体酸または液体酸を用いるものである。
The present invention is a method for producing a glutaraldehyde derivative having a substituent structure added to a pyran ring in a raw material iridoid compound using a naturally occurring iridoid compound as a raw material, and having a pKa of 5 or less as a catalyst. Alternatively, a liquid acid is used.
原料として用いる天然物由来のイリドイド化合物としては上記［化２］に示す構造であれば特に限定されないが、例えばオレウロペイン、リグストロサイド、ロガニン、ゲニポシド、アウクビン、モロニシド、ハルパコシド、デアセチルアスペルロシド、スキャンドシドなどが挙げられる。例えば、上記オレウロペインは、オリーブの葉に豊富に含有されている。これらの純度は特に制限されず、粗精製物のまま原料として用いることができる。また、原料を含水状態で供給してもよく、乾燥工程を経て供給してもよい。
The iridoid compound derived from a natural product used as a raw material is not particularly limited as long as it has the structure shown in the above [Chemical Formula 2]. Scandside and the like. For example, the oleuropein is abundant in olive leaves. These purities are not particularly limited, and can be used as raw materials as a crude product. Moreover, a raw material may be supplied in a water-containing state, and may be supplied through a drying process.
イリドイド化合物の変換反応は通常有機溶媒中で行なわれる。使用する有機溶媒は特に限定されないが、例えばジメチルスルホキシド、スルホラン、メタノール、エタノール、プロパノール、ブタノール、ペンタノール、ヘキサノール、テトラヒドロフラン、ジオキサン、ジメチルエーテル、ジエチルエーテル、ジプロピルエーテル、ジブチルエーテル、エチレングリコールジメチルエーテル、ジエチレングリコールジメチルエーテル、トリエチレングリコールジメチルエーテル、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸ブチル、ブチロラクトン、バレロラクトン、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルピロリドン、ジメチルイミダゾリジノンなどが挙げられる。
The conversion reaction of the iridoid compound is usually performed in an organic solvent. The organic solvent to be used is not particularly limited. For example, dimethyl sulfoxide, sulfolane, methanol, ethanol, propanol, butanol, pentanol, hexanol, tetrahydrofuran, dioxane, dimethyl ether, diethyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol Examples thereof include dimethyl ether, triethylene glycol dimethyl ether, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, butyrolactone, valerolactone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylimidazolidinone and the like.
ｐＫａが５以下の固体酸触媒としては、特に限定されない。好ましくはゼオライト、シリカアルミナ、硫酸化ジルコニア、ベントナイト、ポリスチレンスルホン酸が挙げられる。ゼオライトで好ましくは、プロトン置換したゼオライトである。またベントナイトで好ましくは、プロトン、チタン、銅から選択される少なくとも１種類のイオンにより置換されているものである。
The solid acid catalyst having a pKa of 5 or less is not particularly limited. Preferably, zeolite, silica alumina, sulfated zirconia, bentonite and polystyrene sulfonic acid are used. The zeolite is preferably a proton-substituted zeolite. Bentonite is preferably substituted with at least one ion selected from proton, titanium, and copper.
ｐＫａが５以下の液体酸触媒としては、塩酸、フッ酸、臭素酸、ヨウ素酸、硫酸、リン酸、硝酸、カルボン酸、アスコルビン酸等が挙げられる。
液体酸触媒を用いる場合の反応系の水分量は、原料であるイリドイド化合物に対して１０００モル当量以下であることが好ましく、より好ましくは１００モル当量以下、さらに好ましくは２０モル当量以下である。 Examples of the liquid acid catalyst having a pKa of 5 or less include hydrochloric acid, hydrofluoric acid, bromic acid, iodic acid, sulfuric acid, phosphoric acid, nitric acid, carboxylic acid, ascorbic acid and the like.
The amount of water in the reaction system when using a liquid acid catalyst is preferably 1000 molar equivalents or less, more preferably 100 molar equivalents or less, and even more preferably 20 molar equivalents or less with respect to the iridoid compound as a raw material.
液体酸触媒を用いる場合の反応系の水分量は、原料であるイリドイド化合物に対して１０００モル当量以下であることが好ましく、より好ましくは１００モル当量以下、さらに好ましくは２０モル当量以下である。 Examples of the liquid acid catalyst having a pKa of 5 or less include hydrochloric acid, hydrofluoric acid, bromic acid, iodic acid, sulfuric acid, phosphoric acid, nitric acid, carboxylic acid, ascorbic acid and the like.
The amount of water in the reaction system when using a liquid acid catalyst is preferably 1000 molar equivalents or less, more preferably 100 molar equivalents or less, and even more preferably 20 molar equivalents or less with respect to the iridoid compound as a raw material.
これらの触媒の使用量は、原料である天然に存在するイリドイド化合物に対して０.０１ｗｔ％から１０００ｗｔ％であり、好ましくは０.１ｗｔ％から４００ｗｔ％、より好ましくは１ｗｔ％から２００ｗｔ％である。触媒の使用量が少なすぎると反応が十分に進行せず、触媒の使用量が多すぎると操作上の問題が生じる。
The amount of these catalysts used is 0.01 wt% to 1000 wt%, preferably 0.1 wt% to 400 wt%, more preferably 1 wt% to 200 wt%, based on the naturally occurring iridoid compound as a raw material. . If the amount of catalyst used is too small, the reaction will not proceed sufficiently, and if the amount of catalyst used is too large, operational problems will occur.
本発明の反応方法は、特に制約されないが、好ましくは原料を溶解させた有機溶媒にｐＫａが５以下の固体酸触媒または液体酸触媒を加え、加熱反応させる方法が挙げられる。また、原料を溶解させた有機溶媒を、固体酸触媒を封入し加熱した管に流通させる方法も採用することができる。
The reaction method of the present invention is not particularly limited, but a method in which a solid acid catalyst or liquid acid catalyst having a pKa of 5 or less is preferably added to an organic solvent in which the raw material is dissolved, and the reaction is performed by heating is exemplified. Moreover, the method of distribute | circulating the organic solvent which melt | dissolved the raw material through the pipe | tube which enclosed the solid acid catalyst and was heated is also employable.
反応温度は６０℃～２００℃、中でも１２０℃～１６０℃の範囲とするのがよい。反応温度がこれより低いと反応速度が遅くなるし、また、これより高いと原料のイリドイド化合物もしくは生成したグルタルアルデヒド誘導体が分解もしくは変性する。
The reaction temperature is preferably 60 ° C. to 200 ° C., more preferably 120 ° C. to 160 ° C. When the reaction temperature is lower than this, the reaction rate becomes slow. When the reaction temperature is higher than this, the starting iridoid compound or the produced glutaraldehyde derivative is decomposed or modified.
本発明の製造法によれば、高価な化合物を触媒として使用することなく、天然に存在するイリドイド化合物を原料として一段で比較的収率よく、原料中のピラン環に付加した少なくとも一つの置換基構造を保持したグルタルアルデヒド誘導体を製造することが可能になる。
また、この製造法では、原料化合物中の置換基構造は分解せず、しかも、固体酸触媒を用いる場合には、反応に用いる触媒を固液分離により容易に除去することができ、また回収した触媒を繰り返し再利用することができるため、既往の様々な問題点を克服することができる。 According to the production method of the present invention, without using an expensive compound as a catalyst, at least one substituent added to a pyran ring in a raw material in a single step with a relatively high yield using a naturally occurring iridoid compound as a raw material. A glutaraldehyde derivative having a structure can be produced.
In this production method, the substituent structure in the raw material compound is not decomposed, and when a solid acid catalyst is used, the catalyst used in the reaction can be easily removed by solid-liquid separation and recovered. Since the catalyst can be reused repeatedly, various existing problems can be overcome.
また、この製造法では、原料化合物中の置換基構造は分解せず、しかも、固体酸触媒を用いる場合には、反応に用いる触媒を固液分離により容易に除去することができ、また回収した触媒を繰り返し再利用することができるため、既往の様々な問題点を克服することができる。 According to the production method of the present invention, without using an expensive compound as a catalyst, at least one substituent added to a pyran ring in a raw material in a single step with a relatively high yield using a naturally occurring iridoid compound as a raw material. A glutaraldehyde derivative having a structure can be produced.
In this production method, the substituent structure in the raw material compound is not decomposed, and when a solid acid catalyst is used, the catalyst used in the reaction can be easily removed by solid-liquid separation and recovered. Since the catalyst can be reused repeatedly, various existing problems can be overcome.
次に、実施例により本発明をさらに詳細に説明するが、本発明はこれら実施例により何ら限定されるものではない。
Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
（実施例１）〈固体酸触媒によるオレアセインの製造〉
（実施例１－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５％）を１０ｍｇ、固体酸触媒としてＹ型ゼオライト（東ソー製、Ｈ＋置換型、ＳｉＯ２／Ａｌ２Ｏ３＝５.５）を２０ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ加え、オイルバス中において１５０℃にて１２時間反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率７８％で得られた。 (Example 1) <Production of oleacein with solid acid catalyst>
Example 1-1
10 mg of oleuropein (manufactured by Toronto Research Chemicals, purity 75%) in a glass tube having an internal volume of 2 mL, and Y-type zeolite (manufactured by Tosoh, H + substituted, SiO 2 / Al 2 O 3 = 5.5) as a solid acid catalyst 20 mg, 0.5 mL of dimethyl sulfoxide as an organic solvent was added, and the mixture was reacted at 150 ° C. for 12 hours in an oil bath. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 78%.
（実施例１－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５％）を１０ｍｇ、固体酸触媒としてＹ型ゼオライト（東ソー製、Ｈ＋置換型、ＳｉＯ２／Ａｌ２Ｏ３＝５.５）を２０ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ加え、オイルバス中において１５０℃にて１２時間反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率７８％で得られた。 (Example 1) <Production of oleacein with solid acid catalyst>
Example 1-1
10 mg of oleuropein (manufactured by Toronto Research Chemicals, purity 75%) in a glass tube having an internal volume of 2 mL, and Y-type zeolite (manufactured by Tosoh, H + substituted, SiO 2 / Al 2 O 3 = 5.5) as a solid acid catalyst 20 mg, 0.5 mL of dimethyl sulfoxide as an organic solvent was added, and the mixture was reacted at 150 ° C. for 12 hours in an oil bath. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 78%.
（実施例１－２）
実施例１－１において、固体酸としてＹ型ゼオライトに代えてシリカアルミナ（和光純薬製、ＳｉＯ２ ８２.３％、Ａｌ２Ｏ３ １２.６％）を２０ｍｇ用いた以外は、実施例１－１と同様にして反応を行った結果、オレアセインが収率６０％で得られた。 Example 1-2
In Example 1-1, Example 1 was used except that 20 mg of silica alumina (manufactured by Wako Pure Chemical Industries, SiO 2 82.3%, Al 2 O 3 12.6%) was used instead of Y-type zeolite as the solid acid. As a result of carrying out the reaction in the same manner as in -1, oleacein was obtained in a yield of 60%.
実施例１－１において、固体酸としてＹ型ゼオライトに代えてシリカアルミナ（和光純薬製、ＳｉＯ２ ８２.３％、Ａｌ２Ｏ３ １２.６％）を２０ｍｇ用いた以外は、実施例１－１と同様にして反応を行った結果、オレアセインが収率６０％で得られた。 Example 1-2
In Example 1-1, Example 1 was used except that 20 mg of silica alumina (manufactured by Wako Pure Chemical Industries, SiO 2 82.3%, Al 2 O 3 12.6%) was used instead of Y-type zeolite as the solid acid. As a result of carrying out the reaction in the same manner as in -1, oleacein was obtained in a yield of 60%.
（実施例１－３）
実施例１－１において、固体酸としてＹ型ゼオライトに代えて硫酸化ジルコニア（和光純薬製）を２０ｍｇ用いた以外は、実施例１－１と同様にして反応を行った結果、オレアセインが収率７１％で得られた。 (Example 1-3)
In Example 1-1, the reaction was conducted in the same manner as in Example 1-1 except that 20 mg of sulfated zirconia (manufactured by Wako Pure Chemical Industries, Ltd.) was used in place of Y-type zeolite as the solid acid. As a result, oleacein was recovered. Obtained at a rate of 71%.
実施例１－１において、固体酸としてＹ型ゼオライトに代えて硫酸化ジルコニア（和光純薬製）を２０ｍｇ用いた以外は、実施例１－１と同様にして反応を行った結果、オレアセインが収率７１％で得られた。 (Example 1-3)
In Example 1-1, the reaction was conducted in the same manner as in Example 1-1 except that 20 mg of sulfated zirconia (manufactured by Wako Pure Chemical Industries, Ltd.) was used in place of Y-type zeolite as the solid acid. As a result, oleacein was recovered. Obtained at a rate of 71%.
（実施例２）＜無機酸によるオレアセインの製造＞
（実施例２－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５％）を１０ｍｇ、０.１４Ｍ塩酸水溶液（１２Ｎ塩酸は富士フィルム 和光純薬より購入）を１０μL（１０ｍｏｌ％）加え、有機溶媒としてジメチルスルホキシド(富士フィルム 和光純薬製)を０.５ｍＬ（水１.３６ｍｇ、０.０７６ｍｍｏｌ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃条件下、マグネチックスターラーを使用して３５０ｒｐｍで撹拌させながら１２時間反応させた。反応後の溶液をＮＭＲにて、確認したところ分解物を確認した。 (Example 2) <Production of oleacein with inorganic acid>
Example 2-1
To a glass tube with an internal volume of 2 mL, 10 mg of oleuropein (manufactured by Toronto Research Chemicals, purity 75%) and 10 μL (10 mol%) of a 0.14 M aqueous hydrochloric acid solution (12N hydrochloric acid is purchased from Fuji Film Wako Pure Chemical Industries, Ltd.) are added as an organic solvent. Add 0.5 mL of sulfoxide (Fuji Film Wako Pure Chemical Industries) (containing 1.36 mg of water, 0.076 mmol, measured by Karl Fischer titration method) and use a magnetic stirrer at 150 ° C. in an oil bath. The reaction was carried out for 12 hours while stirring at 350 rpm. When the solution after the reaction was confirmed by NMR, a decomposition product was confirmed.
（実施例２－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５％）を１０ｍｇ、０.１４Ｍ塩酸水溶液（１２Ｎ塩酸は富士フィルム 和光純薬より購入）を１０μL（１０ｍｏｌ％）加え、有機溶媒としてジメチルスルホキシド(富士フィルム 和光純薬製)を０.５ｍＬ（水１.３６ｍｇ、０.０７６ｍｍｏｌ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃条件下、マグネチックスターラーを使用して３５０ｒｐｍで撹拌させながら１２時間反応させた。反応後の溶液をＮＭＲにて、確認したところ分解物を確認した。 (Example 2) <Production of oleacein with inorganic acid>
Example 2-1
To a glass tube with an internal volume of 2 mL, 10 mg of oleuropein (manufactured by Toronto Research Chemicals, purity 75%) and 10 μL (10 mol%) of a 0.14 M aqueous hydrochloric acid solution (12N hydrochloric acid is purchased from Fuji Film Wako Pure Chemical Industries, Ltd.) are added as an organic solvent. Add 0.5 mL of sulfoxide (Fuji Film Wako Pure Chemical Industries) (containing 1.36 mg of water, 0.076 mmol, measured by Karl Fischer titration method) and use a magnetic stirrer at 150 ° C. in an oil bath. The reaction was carried out for 12 hours while stirring at 350 rpm. When the solution after the reaction was confirmed by NMR, a decomposition product was confirmed.
（実施例２－２）
実施例２－１において、０.０１４Ｍ塩酸水溶液を１０μL（１ｍｏｌ％）加えた以外は、実施例２－１と同様にして反応を行った結果、オレアセインが収率５４％で得られた。 (Example 2-2)
In Example 2-1, except that 10 μL (1 mol%) of a 0.014 M hydrochloric acid aqueous solution was added, the reaction was carried out in the same manner as in Example 2-1. As a result, oleacein was obtained in a yield of 54%.
実施例２－１において、０.０１４Ｍ塩酸水溶液を１０μL（１ｍｏｌ％）加えた以外は、実施例２－１と同様にして反応を行った結果、オレアセインが収率５４％で得られた。 (Example 2-2)
In Example 2-1, except that 10 μL (1 mol%) of a 0.014 M hydrochloric acid aqueous solution was added, the reaction was carried out in the same manner as in Example 2-1. As a result, oleacein was obtained in a yield of 54%.
（実施例２－３）
実施例２－１において、０.００１４Ｍ塩酸水溶液１０μL（０.１ｍｏｌ％）加えた以外は、実施例２－１と同様にして反応を行った。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率６７％で得られた。
また、得られた反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレアセインが２.７ｍｇ（収率６１％）で得られた。 (Example 2-3)
The reaction was conducted in the same manner as in Example 2-1, except that 10 μL (0.1 mol%) of a 0.0016 M aqueous hydrochloric acid solution was added. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 67%.
Further, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the obtained reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), 2.7 mg of oleacein (recovered) was obtained. 61%).
実施例２－１において、０.００１４Ｍ塩酸水溶液１０μL（０.１ｍｏｌ％）加えた以外は、実施例２－１と同様にして反応を行った。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率６７％で得られた。
また、得られた反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレアセインが２.７ｍｇ（収率６１％）で得られた。 (Example 2-3)
The reaction was conducted in the same manner as in Example 2-1, except that 10 μL (0.1 mol%) of a 0.0016 M aqueous hydrochloric acid solution was added. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 67%.
Further, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the obtained reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), 2.7 mg of oleacein (recovered) was obtained. 61%).
（実施例３）＜有機酸によるオレアセインの製造＞
（実施例３－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５％）を１０ｍｇ、パラトルエンスルホン酸（キシダ化学製）を０.２４ｍｇ（１０ｍｏｌ％）加え、有機溶媒としてジメチルスルホキシド（富士フィルム 和光純薬製）を０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃条件下、マグネチックスターラーを使用して３５０ｒｐｍで撹拌させながら１２時間反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率５４％で得られた。 (Example 3) <Production of oleacein with organic acid>
Example 3-1
10 mg of oleuropein (manufactured by Toronto Researchs Chemical, purity 75%) and 0.24 mg (10 mol%) of paratoluenesulfonic acid (manufactured by Kishida Chemical) were added to a glass tube with an internal volume of 2 mL, and dimethyl sulfoxide (Fuji Film Wako Pure) 0.5 mL of water (containing 1.36 mg of water, measured by Karl Fischer titration), and allowed to react for 12 hours under stirring at 350 rpm using a magnetic stirrer at 150 ° C. in an oil bath It was. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 54%.
（実施例３－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５％）を１０ｍｇ、パラトルエンスルホン酸（キシダ化学製）を０.２４ｍｇ（１０ｍｏｌ％）加え、有機溶媒としてジメチルスルホキシド（富士フィルム 和光純薬製）を０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃条件下、マグネチックスターラーを使用して３５０ｒｐｍで撹拌させながら１２時間反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率５４％で得られた。 (Example 3) <Production of oleacein with organic acid>
Example 3-1
10 mg of oleuropein (manufactured by Toronto Researchs Chemical, purity 75%) and 0.24 mg (10 mol%) of paratoluenesulfonic acid (manufactured by Kishida Chemical) were added to a glass tube with an internal volume of 2 mL, and dimethyl sulfoxide (Fuji Film Wako Pure) 0.5 mL of water (containing 1.36 mg of water, measured by Karl Fischer titration), and allowed to react for 12 hours under stirring at 350 rpm using a magnetic stirrer at 150 ° C. in an oil bath It was. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 54%.
（実施例３－２）
実施例３－１において、パラトルエンスルホン酸（キシダ化学製）を２４μｇ（１ｍｏｌ％）加えた以外は、実施例２-１と同様にして反応を行った結果、オレアセインが収率７３％で得られた。 (Example 3-2)
In Example 3-1, except that 24 μg (1 mol%) of p-toluenesulfonic acid (manufactured by Kishida Chemical Co., Ltd.) was added, the reaction was carried out in the same manner as in Example 2-1. As a result, oleacein was obtained in a yield of 73%. It was.
実施例３－１において、パラトルエンスルホン酸（キシダ化学製）を２４μｇ（１ｍｏｌ％）加えた以外は、実施例２-１と同様にして反応を行った結果、オレアセインが収率７３％で得られた。 (Example 3-2)
In Example 3-1, except that 24 μg (1 mol%) of p-toluenesulfonic acid (manufactured by Kishida Chemical Co., Ltd.) was added, the reaction was carried out in the same manner as in Example 2-1. As a result, oleacein was obtained in a yield of 73%. It was.
（実施例３－３）
実施例３－１において、パラトルエンスルホン酸（キシダ化学製）を２.４μｇ（０.１ｍｏｌ％）加えた以外は、実施例３－１と同様にして反応を行った結果、反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率７７％で得られた。
また、得られた反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレアセインが収率３.１ｍｇ（収率６９％）で得られた。 (Example 3-3)
As a result of carrying out the reaction in the same manner as in Example 3-1, except that 2.4 μg (0.1 mol%) of p-toluenesulfonic acid (manufactured by Kishida Chemical Co., Ltd.) was added. Was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, and oleacein was obtained in a yield of 77%.
Further, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the obtained reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (manufactured by Kanto Kagaku) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), oleacein yielded 3.1 mg. (Yield 69%).
実施例３－１において、パラトルエンスルホン酸（キシダ化学製）を２.４μｇ（０.１ｍｏｌ％）加えた以外は、実施例３－１と同様にして反応を行った結果、反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率７７％で得られた。
また、得られた反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレアセインが収率３.１ｍｇ（収率６９％）で得られた。 (Example 3-3)
As a result of carrying out the reaction in the same manner as in Example 3-1, except that 2.4 μg (0.1 mol%) of p-toluenesulfonic acid (manufactured by Kishida Chemical Co., Ltd.) was added. Was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, and oleacein was obtained in a yield of 77%.
Further, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the obtained reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (manufactured by Kanto Kagaku) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), oleacein yielded 3.1 mg. (Yield 69%).
以下の結果を表１に示す。
The following results are shown in Table 1.
（実施例４）＜固体酸量による収率の変化＞
（実施例４－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を５ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて１２時間静置反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率２９％で得られた。 (Example 4) <Change in yield depending on the amount of solid acid>
Example 4-1
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine F, Kunipia F, H + substituted type) as solid acid catalyst, 5 mg, dimethyl sulfoxide as organic solvent, 0.5 mL (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand at 150 ° C. for 12 hours in an oil bath. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 29%.
（実施例４－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を５ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて１２時間静置反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率２９％で得られた。 (Example 4) <Change in yield depending on the amount of solid acid>
Example 4-1
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine F, Kunipia F, H + substituted type) as solid acid catalyst, 5 mg, dimethyl sulfoxide as organic solvent, 0.5 mL (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand at 150 ° C. for 12 hours in an oil bath. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, oleacein was obtained in a yield of 29%.
（実施例４－２）
実施例４－１において、ベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を１０ｍｇ加えた以外は、実施例４－１と同様にして反応を行った結果、オレアセインが収率６９％で得られた。 (Example 4-2)
In Example 4-1, reaction was carried out in the same manner as in Example 4 except that 10 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in a yield of 69%. It was.
実施例４－１において、ベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を１０ｍｇ加えた以外は、実施例４－１と同様にして反応を行った結果、オレアセインが収率６９％で得られた。 (Example 4-2)
In Example 4-1, reaction was carried out in the same manner as in Example 4 except that 10 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in a yield of 69%. It was.
（実施例４－３）
実施例４－１において、ベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ加えた以外は、実施例４－１と同様にして反応を行った結果、オレアセインが収率８２％で得られた。 (Example 4-3)
In Example 4-1, the reaction was carried out in the same manner as in Example 4-1, except that 20 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in a yield of 82%. It was.
実施例４－１において、ベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ加えた以外は、実施例４－１と同様にして反応を行った結果、オレアセインが収率８２％で得られた。 (Example 4-3)
In Example 4-1, the reaction was carried out in the same manner as in Example 4-1, except that 20 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in a yield of 82%. It was.
（実施例４－４）
実施例４－１において、ベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を４０ｍｇ加えた以外は、実施例４－１と同様にして反応を行った結果、オレアセインが収率８９％で得られた。 (Example 4-4)
The reaction was carried out in the same manner as in Example 4-1, except that 40 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in 89% yield. It was.
実施例４－１において、ベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を４０ｍｇ加えた以外は、実施例４－１と同様にして反応を行った結果、オレアセインが収率８９％で得られた。 (Example 4-4)
The reaction was carried out in the same manner as in Example 4-1, except that 40 mg of bentonite (Kunimine F, Kunipia F, H + substituted type) was added. As a result, oleacein was obtained in 89% yield. It was.
以下の結果を表２に示す。
The following results are shown in Table 2.
（実施例５）＜反応時間による収率の変化＞
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を５ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて２、４、６、８、１０、１２時間静置反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率（２時間２９％、４時間２５％、６時間３５％、８時間７５％、１０時間８０％、１２時間８２％）で得られた。 (Example 5) <Change in yield with reaction time>
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine F, Kunipia F, H + substituted type) as solid acid catalyst, 5 mg, dimethyl sulfoxide as organic solvent, 0.5 mL (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand in an oil bath at 150 ° C. for 2, 4, 6, 8, 10, and 12 hours. The solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard. The yield of oleacein was 2% 29%, 4 hours 25%, 6 hours 35%, 8 hours 75%, 10 hours. 80%, 12 hours 82%).
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を５ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて２、４、６、８、１０、１２時間静置反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率（２時間２９％、４時間２５％、６時間３５％、８時間７５％、１０時間８０％、１２時間８２％）で得られた。 (Example 5) <Change in yield with reaction time>
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine F, Kunipia F, H + substituted type) as solid acid catalyst, 5 mg, dimethyl sulfoxide as organic solvent, 0.5 mL (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand in an oil bath at 150 ° C. for 2, 4, 6, 8, 10, and 12 hours. The solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard. The yield of oleacein was 2% 29%, 4 hours 25%, 6 hours 35%, 8 hours 75%, 10 hours. 80%, 12 hours 82%).
以下の結果を表３に示す。
The following results are shown in Table 3.
（実施例６）＜水分量による収量の変化＞
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を５ｍｇ、有機溶媒として水分含有量の違うジメチルスルホキシドを０.５ｍＬ（カール・フィッシャー滴定法を利用し、２、３、７、２２、３７当量の水を含んだジメチルスルホキシドをそれぞれ準備した）加え、オイルバス中において１５０℃にて１２時間静置反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率（２当量７２％、３当量８４％、７当量８２％、２２当量５９％、３７当量４８％）で得られた。 (Example 6) <Change in yield due to water content>
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, 5 mg bentonite (Kunimine F, H + substituted type manufactured by Kunimine Kogyo Co., Ltd.) as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide having a different water content as an organic solvent (using Karl Fischer titration method) Dimethyl sulfoxide containing 3, 7, 22, and 37 equivalents of water was prepared), and the mixture was allowed to stand at 150 ° C. for 12 hours in an oil bath. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, the yield of oleacein was 2% 72%, 3 equivalents 84%, 7 equivalents 82%, 22 equivalents 59%, 37 equivalents. 48%).
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を５ｍｇ、有機溶媒として水分含有量の違うジメチルスルホキシドを０.５ｍＬ（カール・フィッシャー滴定法を利用し、２、３、７、２２、３７当量の水を含んだジメチルスルホキシドをそれぞれ準備した）加え、オイルバス中において１５０℃にて１２時間静置反応させた。反応後の溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率（２当量７２％、３当量８４％、７当量８２％、２２当量５９％、３７当量４８％）で得られた。 (Example 6) <Change in yield due to water content>
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, 5 mg bentonite (Kunimine F, H + substituted type manufactured by Kunimine Kogyo Co., Ltd.) as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide having a different water content as an organic solvent (using Karl Fischer titration method) Dimethyl sulfoxide containing 3, 7, 22, and 37 equivalents of water was prepared), and the mixture was allowed to stand at 150 ° C. for 12 hours in an oil bath. When the solution after the reaction was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard, the yield of oleacein was 2% 72%, 3 equivalents 84%, 7 equivalents 82%, 22 equivalents 59%, 37 equivalents. 48%).
以下の結果を表４に示す。
The following results are shown in Table 4.
（実施例７）＜反応温度による収量の変化＞
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１２５℃にて静置反応させた。１２時間毎に、反応溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率（１２時間２２％、２４時間６８％、３６時間７６％）で得られた。 (Example 7) <Change in yield with reaction temperature>
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine Industries Kunipia F, H + substituted type) 20 mg as solid acid catalyst, 0.5 mL of dimethyl sulfoxide as organic solvent (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand at 125 ° C. in an oil bath. Every 12 hours, the reaction solution was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard. As a result, oleacein was obtained in a yield (12 hours 22%, 24 hours 68%, 36 hours 76%). .
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１２５℃にて静置反応させた。１２時間毎に、反応溶液をＮＭＲにて、テトラメチルベンゼンのメチル基を内部標準として定量したところ、オレアセインが収率（１２時間２２％、２４時間６８％、３６時間７６％）で得られた。 (Example 7) <Change in yield with reaction temperature>
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine Industries Kunipia F, H + substituted type) 20 mg as solid acid catalyst, 0.5 mL of dimethyl sulfoxide as organic solvent (containing 1.36 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand at 125 ° C. in an oil bath. Every 12 hours, the reaction solution was quantified by NMR using the methyl group of tetramethylbenzene as an internal standard. As a result, oleacein was obtained in a yield (12 hours 22%, 24 hours 68%, 36 hours 76%). .
以下の結果を表５に示す。
The following results are shown in Table 5.
（実施例８）＜溶媒の違いによる収量の変化＞
（実施例８－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ、有機溶媒としてガンマーブチロラクトンを０.５ｍＬ（カール・フィッシャー滴定法を用いて水を１.３６ｍｇ含有させた）加え、オイルバス中において１５０℃にて１２時間静置反応させた。また得られた反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレアセインが２.５ｍｇ（収率５６％）で得られた。 (Example 8) <Change in yield due to difference in solvent>
Example 8-1
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine Industries Kunipia F, H + substituted type) 20 mg as a solid acid catalyst, 0.5 mL of gamma-butyrolactone as an organic solvent (1.36 mg of water using Karl Fischer titration method) In addition, the mixture was allowed to stand at 150 ° C. for 12 hours in an oil bath. Further, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the resulting reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), 2.5 mg of oleacein (recovered) 56%).
（実施例８－１）
内容積２ｍＬのガラス管にオレウロペイン（Toronto Researchs Chemical製、純度７５
％）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ、有機溶媒としてガンマーブチロラクトンを０.５ｍＬ（カール・フィッシャー滴定法を用いて水を１.３６ｍｇ含有させた）加え、オイルバス中において１５０℃にて１２時間静置反応させた。また得られた反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレアセインが２.５ｍｇ（収率５６％）で得られた。 (Example 8) <Change in yield due to difference in solvent>
Example 8-1
A glass tube with an internal volume of 2 mL was charged with oleuropein (manufactured by Toronto Research Chemicals, purity 75).
%) 10 mg, bentonite (Kunimine Industries Kunipia F, H + substituted type) 20 mg as a solid acid catalyst, 0.5 mL of gamma-butyrolactone as an organic solvent (1.36 mg of water using Karl Fischer titration method) In addition, the mixture was allowed to stand at 150 ° C. for 12 hours in an oil bath. Further, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the resulting reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), 2.5 mg of oleacein (recovered) 56%).
（実施例８－２）
実施例８－１において、ガンマーブチロラクトンの代わりにジエチレングリコールジメチルエーテル（ジグリム）を加えたこと以外は、実施例８－１と同様にして反応と後処理を行った。その結果、オレアセインが１.４ｍｇ（収率３２％）で得られた。 (Example 8-2)
In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that diethylene glycol dimethyl ether (diglyme) was added instead of gamma-butyrolactone. As a result, 1.4 mg (yield 32%) of oleacein was obtained.
実施例８－１において、ガンマーブチロラクトンの代わりにジエチレングリコールジメチルエーテル（ジグリム）を加えたこと以外は、実施例８－１と同様にして反応と後処理を行った。その結果、オレアセインが１.４ｍｇ（収率３２％）で得られた。 (Example 8-2)
In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that diethylene glycol dimethyl ether (diglyme) was added instead of gamma-butyrolactone. As a result, 1.4 mg (yield 32%) of oleacein was obtained.
（実施例８－３）
実施例８－１において、ガンマーブチロラクトンの代わりにエヌメチルピロリジンを加えたこと以外は、実施例８－１と同様にして反応と後処理を行った。その結果、オレアセインを得ることができなかった。 (Example 8-3)
In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that enmethylpyrrolidine was added instead of gamma-butyrolactone. As a result, oleacein could not be obtained.
実施例８－１において、ガンマーブチロラクトンの代わりにエヌメチルピロリジンを加えたこと以外は、実施例８－１と同様にして反応と後処理を行った。その結果、オレアセインを得ることができなかった。 (Example 8-3)
In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that enmethylpyrrolidine was added instead of gamma-butyrolactone. As a result, oleacein could not be obtained.
（実施例８－４）
実施例８－１において、ガンマーブチロラクトンの代わり１－オクタノールを加えたこと以外は、実施例８－１と同様にして反応と後処理を行った。その結果、オレアセインを得ることができなかった。 (Example 8-4)
In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that 1-octanol was added instead of gamma-butyrolactone. As a result, oleacein could not be obtained.
実施例８－１において、ガンマーブチロラクトンの代わり１－オクタノールを加えたこと以外は、実施例８－１と同様にして反応と後処理を行った。その結果、オレアセインを得ることができなかった。 (Example 8-4)
In Example 8-1, the reaction and post-treatment were performed in the same manner as in Example 8-1, except that 1-octanol was added instead of gamma-butyrolactone. As a result, oleacein could not be obtained.
（実施例８－５）
実施例８－１において、ガンマーブチロラクトンの代わりにジメチルスルホキシドを加えたこと以外は、実施例８-１と同様にして反応と後処理を行った。その結果、オレアセインが３.５ｍｇ（収率８０％）で得られた。 (Example 8-5)
The reaction and post-treatment were carried out in the same manner as in Example 8-1, except that dimethyl sulfoxide was added instead of gamma-butyrolactone. As a result, 3.5 mg (yield 80%) of oleacein was obtained.
実施例８－１において、ガンマーブチロラクトンの代わりにジメチルスルホキシドを加えたこと以外は、実施例８-１と同様にして反応と後処理を行った。その結果、オレアセインが３.５ｍｇ（収率８０％）で得られた。 (Example 8-5)
The reaction and post-treatment were carried out in the same manner as in Example 8-1, except that dimethyl sulfoxide was added instead of gamma-butyrolactone. As a result, 3.5 mg (yield 80%) of oleacein was obtained.
以下の結果を表６に示す。
The following results are shown in Table 6.
（実施例９）＜固体酸触媒によるオレオカンタールの製造＞
内容積２ｍＬのガラス管にリグストロサイドを１１ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２２ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて静置反応させた。１２時間後、反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行い、オレオカンタールを４.１ｍｇ（収率６３％）得た。 Example 9 <Production of oleocanthal with solid acid catalyst>
In a glass tube having an internal volume of 2 mL, 11 mg of ligustroside, 22 mg of bentonite (Kunimine Industries Kunipia F, H + substituted type) as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide as an organic solvent (containing 1.36 mg of water, (Measured by Karl Fischer titration method), and allowed to stand at 150 ° C. in an oil bath. After 12 hours, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. Silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 4.1 mg of oleocanthal (yield) 63%).
内容積２ｍＬのガラス管にリグストロサイドを１１ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２２ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて静置反応させた。１２時間後、反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行い、オレオカンタールを４.１ｍｇ（収率６３％）得た。 Example 9 <Production of oleocanthal with solid acid catalyst>
In a glass tube having an internal volume of 2 mL, 11 mg of ligustroside, 22 mg of bentonite (Kunimine Industries Kunipia F, H + substituted type) as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide as an organic solvent (containing 1.36 mg of water, (Measured by Karl Fischer titration method), and allowed to stand at 150 ° C. in an oil bath. After 12 hours, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. Silica gel column chromatography (manufactured by Kanto Chemical Co., Inc.) was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 4.1 mg of oleocanthal (yield) 63%).
（実施例１０）＜固体酸触媒によるロガニン由来グルタルアルデヒド化合物の製造＞
内容積２ｍＬのガラス管にロガニン（ChengduBiopurifyより購入）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて静置反応させた。１２時間後、反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行い、ロガニン由来グルタルアルデヒド化合物が１.１ｍｇ（収率２５％）を得た。
(Example 10) <Production of loganine-derived glutaraldehyde compound by solid acid catalyst>
Loganin (purchased from ChengduBiopurify) 10 mg in a 2 mL glass tube, Bentonite (Kunimine Industries Kunipia F, H + substitution type) 20 mg as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide as an organic solvent (1.36 mg of water) Content, measured by Karl Fischer titration method), and allowed to stand at 150 ° C. in an oil bath. After 12 hours, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. Silica gel column chromatography (manufactured by Kanto Chemical) was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 1.1 mg of loganine-derived glutaraldehyde compound was obtained. (Yield 25%) was obtained.
内容積２ｍＬのガラス管にロガニン（ChengduBiopurifyより購入）を１０ｍｇ、固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を２０ｍｇ、有機溶媒としてジメチルスルホキシドを０.５ｍＬ（水を１.３６ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて静置反応させた。１２時間後、反応溶液に純水１０ｍLと酢酸エチル（キシダ化学）１０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行い、ロガニン由来グルタルアルデヒド化合物が１.１ｍｇ（収率２５％）を得た。
Loganin (purchased from ChengduBiopurify) 10 mg in a 2 mL glass tube, Bentonite (Kunimine Industries Kunipia F, H + substitution type) 20 mg as a solid acid catalyst, 0.5 mL of dimethyl sulfoxide as an organic solvent (1.36 mg of water) Content, measured by Karl Fischer titration method), and allowed to stand at 150 ° C. in an oil bath. After 12 hours, 10 mL of pure water and 10 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. Silica gel column chromatography (manufactured by Kanto Chemical) was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 1.1 mg of loganine-derived glutaraldehyde compound was obtained. (Yield 25%) was obtained.
（実施例１１）＜固体酸触媒によるオリーブ葉から単離したオレウロペインを使用したオレアセインの製造＞
内容積１００ｍLの三角フラスコにオリーブの葉（ひなた食品 晨星興産株式会社から購入）１０ｇと８０％メタノール溶液を４０ｍL加え室温で静置抽出した。１２時間後、オリーブの葉をろ過し取り除き、ろ液を濃縮し油状物質を得た。シリカゲルカラムクロマトグラフィー（シリカゲルは関東化学製）を用いてヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレウロペインを１.５３ｇ（純度８８％、ＨＰＬＣの２５４ｎｍの波長を使用し確認）得た。
得られたオレウロペイン１.５３ｇを固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を３.０６ｇ、有機溶媒としてジメチルスルホキシドを１０ｍＬ（水を１２７ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて静置反応させた。３時間後、固体触媒をろ過して回収した後、反応溶液に純水５０ｍLと酢酸エチル（キシダ化学）５０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（シリカゲルは関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行い、オレアセインを５９８ｍｇ（収率７５％）得た。 (Example 11) <Production of oleacein using oleuropein isolated from olive leaf by solid acid catalyst>
To an Erlenmeyer flask with an internal volume of 100 mL, 10 g of olive leaf (purchased from Hinata Foods Co., Ltd.) and 40 mL of an 80% methanol solution were added, and the mixture was left at room temperature for extraction. After 12 hours, olive leaves were removed by filtration, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (silica gel manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), it was found that Obtained .53 g (88% purity, confirmed using HPLC at 254 nm wavelength).
1.53 g of the obtained oleuropein was used as a solid acid catalyst, 3.06 g of bentonite (Kunimine Industries Kunipia F, H + substituted type), and 10 mL of dimethyl sulfoxide as an organic solvent (containing 127 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand at 150 ° C. in an oil bath. After 3 hours, the solid catalyst was collected by filtration, and then 50 mL of pure water and 50 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. Silica gel column chromatography (silica gel manufactured by Kanto Chemical Co., Inc.) was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 598 mg of oleacein (75% yield). %)Obtained.
内容積１００ｍLの三角フラスコにオリーブの葉（ひなた食品 晨星興産株式会社から購入）１０ｇと８０％メタノール溶液を４０ｍL加え室温で静置抽出した。１２時間後、オリーブの葉をろ過し取り除き、ろ液を濃縮し油状物質を得た。シリカゲルカラムクロマトグラフィー（シリカゲルは関東化学製）を用いてヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行った結果、オレウロペインを１.５３ｇ（純度８８％、ＨＰＬＣの２５４ｎｍの波長を使用し確認）得た。
得られたオレウロペイン１.５３ｇを固体酸触媒としてベントナイト（クニミネ工業製クニピアＦ、Ｈ＋置換型）を３.０６ｇ、有機溶媒としてジメチルスルホキシドを１０ｍＬ（水を１２７ｍｇ含有、カール・フィッシャー滴定法により測定）加え、オイルバス中において１５０℃にて静置反応させた。３時間後、固体触媒をろ過して回収した後、反応溶液に純水５０ｍLと酢酸エチル（キシダ化学）５０ｍLを加え、分液処理を行った。酢酸エチル相を回収し、乾燥剤に硫酸ナトリウム（富士フィルム 和光純薬製）を使い乾燥処理を行った後、ろ過してろ液を濃縮し、油状物質を得た。シリカゲルカラムクロマトグラフィー（シリカゲルは関東化学製）をヘキサンと酢酸エチル（１０：１から１：１にヘキサンと酢酸エチルの比率を変更した）を使用して精製を行い、オレアセインを５９８ｍｇ（収率７５％）得た。 (Example 11) <Production of oleacein using oleuropein isolated from olive leaf by solid acid catalyst>
To an Erlenmeyer flask with an internal volume of 100 mL, 10 g of olive leaf (purchased from Hinata Foods Co., Ltd.) and 40 mL of an 80% methanol solution were added, and the mixture was left at room temperature for extraction. After 12 hours, olive leaves were removed by filtration, and the filtrate was concentrated to obtain an oily substance. As a result of purification using silica gel column chromatography (silica gel manufactured by Kanto Chemical Co., Inc.) using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), it was found that Obtained .53 g (88% purity, confirmed using HPLC at 254 nm wavelength).
1.53 g of the obtained oleuropein was used as a solid acid catalyst, 3.06 g of bentonite (Kunimine Industries Kunipia F, H + substituted type), and 10 mL of dimethyl sulfoxide as an organic solvent (containing 127 mg of water, measured by Karl Fischer titration method) In addition, the reaction was allowed to stand at 150 ° C. in an oil bath. After 3 hours, the solid catalyst was collected by filtration, and then 50 mL of pure water and 50 mL of ethyl acetate (Kishida Chemical) were added to the reaction solution to carry out a liquid separation treatment. The ethyl acetate phase was recovered, dried using sodium sulfate (Fuji Film Wako Pure Chemical Industries) as the desiccant, filtered, and the filtrate was concentrated to obtain an oily substance. Silica gel column chromatography (silica gel manufactured by Kanto Chemical Co., Inc.) was purified using hexane and ethyl acetate (the ratio of hexane and ethyl acetate was changed from 10: 1 to 1: 1), and 598 mg of oleacein (75% yield). %)Obtained.
（比較例１）
実施例３－３において、水をオレウロペインに対して１０００モル当量加えたほかは実施例３－３と同様に反応を行ったところ、オレアセインの生成は認められず、またオレウロペインの残留も認められなかった。したがって、水分量の制御が本発明においては重要である。 (Comparative Example 1)
In Example 3-3, the reaction was performed in the same manner as in Example 3-3 except that 1000 molar equivalents of water was added to oleuropein. No oleacein was formed, and no oleuropein residue was observed. It was. Therefore, control of the amount of moisture is important in the present invention.
実施例３－３において、水をオレウロペインに対して１０００モル当量加えたほかは実施例３－３と同様に反応を行ったところ、オレアセインの生成は認められず、またオレウロペインの残留も認められなかった。したがって、水分量の制御が本発明においては重要である。 (Comparative Example 1)
In Example 3-3, the reaction was performed in the same manner as in Example 3-3 except that 1000 molar equivalents of water was added to oleuropein. No oleacein was formed, and no oleuropein residue was observed. It was. Therefore, control of the amount of moisture is important in the present invention.
本発明は、天然に存在するイリドイド化合物を原料として用い、対応するグルタルアルデヒド誘導体を収率よく製造するのに有用である。製造したグルタルアルデヒド誘導体は医薬品、医薬品原料、機能性食品として提供できる。
The present invention is useful for producing a corresponding glutaraldehyde derivative in high yield using a naturally occurring iridoid compound as a raw material. The manufactured glutaraldehyde derivative can be provided as a pharmaceutical, a pharmaceutical raw material, or a functional food.
Claims (9)
- 天然に存在するイリドイド化合物を原料として、原料イリドイド化合物中のピラン環に付加している少なくとも一つの置換基構造を保持したグルタルアルデヒド誘導体を製造する方法であって、触媒としてｐＫａが５以下の固体酸または液体酸を用いることを特徴とする、グルタルアルデヒド誘導体の製造法。 A method for producing a glutaraldehyde derivative having at least one substituent structure added to a pyran ring in a raw material iridoid compound using a naturally occurring iridoid compound as a raw material, and having a pKa of 5 or less as a catalyst A method for producing a glutaraldehyde derivative, characterized by using an acid or a liquid acid.
- 前記グルタルアルデヒド誘導体の製造法において、反応系中の水分量が原料とするイリドイド化合物に対して１０００モル当量以下である、請求項１に記載の誘導体の製造法。 The method for producing a derivative according to claim 1, wherein in the method for producing the glutaraldehyde derivative, the amount of water in the reaction system is 1000 molar equivalents or less with respect to the iridoid compound used as a raw material.
- 前記固体酸触媒がシリカアルミナ、ゼオライト、硫酸化ジルコニア、ベントナイト、ポリスチレンスルホン酸から選択される少なくとも１種類である請求項１に載のグルタルアルデヒド誘導体の製造法。 The method for producing a glutaraldehyde derivative according to claim 1, wherein the solid acid catalyst is at least one selected from silica alumina, zeolite, sulfated zirconia, bentonite, and polystyrenesulfonic acid.
- 前記ゼオライトがプロトン置換型のゼオライトである請求項３に記載のグルタルアルデヒド誘導体の製造法。 The method for producing a glutaraldehyde derivative according to claim 3, wherein the zeolite is a proton-substituted zeolite.
- 前記ベントナイトがプロトン、チタン、銅から選択される少なくとも１種類のイオンにより置換されているものである請求項３に記載のグルタルアルデヒド誘導体の製造法。 The method for producing a glutaraldehyde derivative according to claim 3, wherein the bentonite is substituted with at least one ion selected from proton, titanium, and copper.
- 前記グルタルアルデヒド誘導体の製造法を有機溶媒中で行なう、請求項１から５のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。 The method for producing a glutaraldehyde derivative according to any one of claims 1 to 5, wherein the method for producing the glutaraldehyde derivative is carried out in an organic solvent.
- 前記グルタルアルデヒド誘導体の製造法を加熱条件下で行なう、請求項１から５のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。 The method for producing a glutaraldehyde derivative according to any one of claims 1 to 5, wherein the method for producing the glutaraldehyde derivative is carried out under heating conditions.
- 前記イリドイド化合物がオレウロペインであり、前記グルタルアルデヒド誘導体がオレアセインである、請求項１から５のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。 The method for producing a glutaraldehyde derivative according to any one of claims 1 to 5, wherein the iridoid compound is oleuropein and the glutaraldehyde derivative is oleacein.
- 前記イリドイド化合物がリグストロサイドであり、前記グルタルアルデヒド誘導体がオレオカンタールである、請求項１から５のいずれか１項に記載のグルタルアルデヒド誘導体の製造法。
The method for producing a glutaraldehyde derivative according to any one of claims 1 to 5, wherein the iridoid compound is ligustroside and the glutaraldehyde derivative is oleocanthal.
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