JP2006036733A - Method for vaporizing hinokithiol - Google Patents
Method for vaporizing hinokithiol Download PDFInfo
- Publication number
- JP2006036733A JP2006036733A JP2004222901A JP2004222901A JP2006036733A JP 2006036733 A JP2006036733 A JP 2006036733A JP 2004222901 A JP2004222901 A JP 2004222901A JP 2004222901 A JP2004222901 A JP 2004222901A JP 2006036733 A JP2006036733 A JP 2006036733A
- Authority
- JP
- Japan
- Prior art keywords
- hinokitiol
- water
- zinc
- hinokithiol
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
ヒノキチオールは極めて低濃度で抗菌性を示し、一般細菌・真菌類に対して広い抗菌スペクトルを有する上に、耐性菌を発生し難いことが知られている。また、ヒノキチオール（ＨＴと略称することもある）は昇華性を有しており、その抗菌性は非接触的に発揮されるという特徴を有している。 Hinokitiol exhibits antibacterial properties at extremely low concentrations, has a broad antibacterial spectrum against general bacteria and fungi, and is known to be resistant to the generation of resistant bacteria. Moreover, hinokitiol (sometimes abbreviated as HT) has a sublimation property, and has the characteristic that the antibacterial property is exhibited in a non-contact manner.
近年ＨＴが植物のエチレン生成を阻害することが実証されるに至り、青果物の鮮度保持剤としてＨＴが用いられるようになった。さらに、タマネギ、ジャガイモ等の発芽抑制作用、ダニ、シロアリの防除作用、蚊の忌避作用、アレルギー疾患の症状緩和作用等の生理作用が見出されるにおよび、ＨＴを必要に応じて早急に気化させて必要な空間濃度を保つ方法が強く求められるに至った。ヒノキチオールはその微細結晶粉末の昇華性が夏期開放系においても０．６〜０．７％／日に過ぎず、上記のような用途に用いるには大量のＨＴを用いることが求められ、経済的な問題がその使用を抑えている。 In recent years, it has been demonstrated that HT inhibits plant ethylene production, and HT has been used as a freshness-preserving agent for fruits and vegetables. In addition, physiological effects such as onion and potato germination inhibitory action, mite and termite control action, mosquito repellent action, allergic disease symptom relief action, etc. are found, and HT is vaporized as needed. There has been a strong demand for a method of maintaining the required spatial density. Hinokitiol has a sublimation property of the fine crystal powder of only 0.6 to 0.7% / day even in the summer open system, and it is required to use a large amount of HT for the use as described above. Problems are limiting their use.
ヒノキチオールをそのままフィルム・紙等の包装材料に添加して抗菌あるいは鮮度保持等に用いることは望ましいことではあるが、その昇華性の故に製造過程において高温にさらすことは添加したＨＴの大部分を消失させることになる。そのため従来も種々の工夫がなされているが、決定的な成果は得られていないのが実情である。またＨＴの金属塩を添加した包装材料では直接接触した部位以外ではその効果が期待し難いこともあり、使用面での制約も無視できない。 Although it is desirable to add hinokitiol directly to packaging materials such as films and papers for antibacterial or freshness preservation, exposure to high temperatures in the manufacturing process due to its sublimation properties eliminates most of the added HT. I will let you. Therefore, various ideas have been made in the past, but the actual situation is that no definitive result has been obtained. In addition, the packaging material to which the metal salt of HT is added may not be expected to have an effect other than the part that is in direct contact, and restrictions on use cannot be ignored.
ヒノキチオールは種々の金属と錯塩を形成し易く、生成した錯塩は安定で高温に耐えるが、抗菌性は遊離のヒノキチオールのそれと大差がないため、包装材料に添加する試みもなされている。又他の化合物と反応させてヒノキチオールの錯塩からＨＴを遊離させる工夫も見られるが、遊離されたヒノキチオールはアルカリにも酸にも容易に溶解するために、ヒノキチオールを気体として蒸散させることは非常に難かしかった。 Hinokitiol tends to form complex salts with various metals, and the resulting complex salt is stable and can withstand high temperatures, but its antibacterial properties are not much different from that of free hinokitiol, so attempts have been made to add it to packaging materials. There is also a device to release HT from a complex salt of hinokitiol by reacting with other compounds, but since liberated hinokitiol is easily dissolved in both alkali and acid, it is very difficult to evaporate hinokitiol as a gas. It was difficult.
一方ポリカルボン酸のカルボキシル基に結合したトリアルキルスズやトリアリールスズ等は海水中で加水分解して防汚効果を発揮することが知られており、工業化されてすでに防汚塗料として利用されている。さきに本発明者はポリカルボン酸に銅または亜鉛原子を介してヒノキチオールを結合させる方法を発見し、水溶性のポリカルボン酸にある程度以上ヒノキチオールを結合させた化合物は、水には溶解しないが長期にわたって水と接触させると加水分解反応によってヒノキチオールを徐放することを認めた（特願２００２−３３７１１）。 On the other hand, trialkyltin and triaryltin bonded to the carboxyl group of polycarboxylic acid are known to hydrolyze in seawater and exhibit antifouling effects, and have been industrialized and already used as antifouling paints. Yes. The present inventor previously discovered a method for binding hinokitiol to polycarboxylic acid via a copper or zinc atom. A compound in which hinokitiol is bound to water-soluble polycarboxylic acid to a certain extent does not dissolve in water, but for a long time. It was confirmed that hinokitiol was released slowly by hydrolysis reaction when it was contacted with water (Japanese Patent Application No. 2002-33711).
本発明はヒノキオールを気体として蒸散させる新しい手段を開発するため、従来から鋭意研究をつづけて来たが、この研究に於いて、ポリカルボン酸に銅や亜鉛原子を介してヒノキチオールを結合させる方法に注目し、この方法を基本として更に本研究をおし進め、遂に本発明を完成するに至った。 In order to develop a new means for evaporating hinokiol as a gas, the present invention has been intensively studied so far. In this research, a method for bonding hinokitiol to a polycarboxylic acid via a copper or zinc atom. The research was further advanced based on this method, and finally the present invention was completed.
即ち、ポリカルボン酸に亜鉛を介してヒノキチオールを結合させ、茲に得た化合物にエチレンジアミンテトラ酢酸アルカリ金属塩特にはそのナトリウム塩を加えて磨砕混合した粉末は、水と接触させること、たとえば水を加えるかあるいは多湿下に吸湿させることにより、室温でヒノキチオールを遊離して気化することを発見した。さらに検討の結果、ヒノキチオールの亜鉛塩（Zn(HT)2・2H2O）も同様な方法によってＨＴを気化させることができることを発見し、ここに発明を完成した。 That is, a powder obtained by bonding hinokitiol to zinc with polycarboxylic acid and adding an alkali metal salt of ethylenediaminetetraacetate, particularly its sodium salt, to the compound obtained in the kneading mixture is brought into contact with water, for example, water It was found that hinokitiol is liberated and vaporized at room temperature by adding or absorbing moisture under high humidity. As a result of further investigation, it was discovered that zinc of hinokitiol (Zn (HT) 2 · 2H 2 O) can vaporize HT by the same method, and the present invention was completed here.
即ち本発明は
（イ）水溶性のポリカルボン酸に亜鉛を介してヒノキチオールを結合させた化合物及び／又はヒノキチオールの亜鉛塩に、エチレンジアミンテトラ酢酸アルカリ金属塩特にそのナトリウム塩を加えて磨砕混合し、
（ロ）次いで水の存在下に、たとえば多湿下において吸湿させるか、又は水を加えることにより、両者を反応させ、ヒノキチオールを遊離させるヒノキチオールの気化方法。
に係るものである。
That is, the present invention comprises (a) a compound in which hinokitiol is bound to water-soluble polycarboxylic acid via zinc and / or a zinc salt of hinokitiol, and an ethylenediaminetetraacetic acid alkali metal salt, particularly its sodium salt, is added and ground and mixed. ,
(B) Next, a method for vaporizing hinokitiol, in which moisture is absorbed in the presence of water, for example, under high humidity, or water is added to react both to release hinokitiol.
It is related to.
なお特に本発明の研究に於いて次の新しい事実が見出された。
（Ａ）エチレンジアミンテトラ酢酸トリナトリウム塩（ＥＤＴＡ・３Ｎａ）を用いたヒノキチオールとの磨砕混合物は、水を加えても両者が反応してＨＴを遊離気化させることがないこと。即ち、特にエチレンジアミンテトラ酢酸ナトリウム塩としては、モノ又はジナトリウム塩を使用して初めて、うまくＨＴを遊離出来ること。
（Ｂ）ヒノキチオールの銅塩はＥＤＴＡ・ナトリウム塩と磨砕混合して水を加えても反応しないこと。又銅を介してポリカルボン酸にＨＴを結合させた化合物はＥＤＴＡ・ナトリウム塩の保存下に水を加えると生成するヒノキチオールはヒノキチオールの銅塩として捕捉され、ＨＴを気化させることがないこと。即ち、亜鉛と銅とを使用した場では全くその挙動が異なること。
In particular, the following new facts were found in the study of the present invention.
(A) The ground mixture with hinokitiol using ethylenediaminetetraacetic acid trisodium salt (EDTA.3Na) should not cause HT to be free-vaporized even if water is added. That is, especially as ethylenediaminetetraacetic acid sodium salt, HT can be successfully released only when mono- or disodium salt is used.
(B) The copper salt of hinokitiol should not react even if EDTA / sodium salt is ground and mixed and water is added. In addition, for compounds in which HT is bonded to polycarboxylic acid via copper, the hinokitiol produced when water is added under the storage of EDTA / sodium salt is captured as the copper salt of hinokitiol and does not vaporize HT. In other words, the behavior is completely different when using zinc and copper.
本発明に於いて使用されるポリカルボン酸としては、特に好ましいものにアクリル酸、メタクリル酸、無水マレイン酸の夫々のホモポリマーやこれらの少なくとも２種のコポリマー、又は更にこれ等と他のモノマーとのコポリマーが例示出来る。この際の他のビニルモノマーとして好ましいものとして、たとえばエチレン、酢酸ビニル、スチレン等を例示出来る。 As the polycarboxylic acid used in the present invention, particularly preferred are homopolymers of acrylic acid, methacrylic acid, and maleic anhydride, at least two types of these copolymers, or these and other monomers. The copolymer of can be illustrated. Preferred examples of other vinyl monomers at this time include ethylene, vinyl acetate, styrene and the like.
また本発明に於いてポリカルボン酸としては水溶性のものが水との接触が容易でＨＴを遊離し易いとの理由で使用される。 In the present invention, a water-soluble polycarboxylic acid is used because it can easily come into contact with water and liberate HT.
本発明に於いて、上記ポリカルボン酸に亜鉛を介してヒノキチオールを結合させた化合物を製造する方法は、実質的に特願２００２−３３７１１号の方法を適用することが出来る。その代表的な方法を例示すると以下の通りである。
（Ａ）塩化亜鉛とヒノキチオールの好ましくは等モルのアルコール溶液を濃縮して可及的に塩酸を除去し、冷却してヒノキチオール１分子と亜鉛と塩素それぞれ１原子とからなる化合物の結晶を析出させ、
（Ｂ）次いでアルコール溶媒中で好ましくはテトラメチルアンモニウムハイドロオキサイドの存在下に、
（Ｃ）カルボキシル基を有するポリマー化合物と反応させて、ポリカルボン酸とヒノキチオールとを結合する方法である。
In the present invention, the method of Japanese Patent Application No. 2002-33711 can be substantially applied to the method of producing a compound in which hinokitiol is bonded to the polycarboxylic acid via zinc. The typical method is exemplified as follows.
(A) Concentrate a preferably equimolar alcohol solution of zinc chloride and hinokitiol to remove hydrochloric acid as much as possible and cool to precipitate crystals of a compound consisting of one molecule of hinokitiol and one atom each of zinc and chlorine. ,
(B) Then in an alcohol solvent, preferably in the presence of tetramethylammonium hydroxide,
(C) A method in which a polycarboxylic acid and hinokitiol are bonded by reacting with a polymer compound having a carboxyl group.
この際塩化亜鉛とヒノキチオールの上記アルコール溶液のアルコールがエチルアルコールであり、またテトラメチルアンモニウムハイドロオキサイドの使用量が上記析出する化合物の等モル以下であることが好ましい。 At this time, it is preferable that the alcohol in the alcohol solution of zinc chloride and hinokitiol is ethyl alcohol, and the amount of tetramethylammonium hydroxide used is equal to or less than the equimolar amount of the precipitated compound.
この方法の詳しい手段については上記特願２００２−３３７７１号の記載の手段が全て本発明に適用出来る。 As detailed means of this method, all means described in the above Japanese Patent Application No. 2002-33771 can be applied to the present invention.
本発明に於いて使用されるヒノキチオールの亜鉛塩はＺｎ（ＨＴ）２・２Ｈ２Ｏのものを好ましいものとして例示出来る。 The zinc salt of hinokitiol used in the present invention is preferably exemplified by Zn (HT) 2 .2H 2 O.
本発明に於いて使用されるエチレンジアミンテトラ酢酸アルカリ金属塩としてはそのナトリウム塩が好ましく、特にモノ及びジナトリウム塩が好ましく使用出来、ジナトリウム塩が最も好ましい。この際トリナトリウム塩を使用することは避ける方が良い。この際のアルカリ金属としてはカリウム等を例示出来る。 The ethylenediaminetetraacetic acid alkali metal salt used in the present invention is preferably its sodium salt, particularly preferably mono- and disodium salts, and most preferably disodium salt. In this case, it is better to avoid using trisodium salt. Examples of the alkali metal at this time include potassium.
本発明に於いてはエチレンジアミンテトラ酢酸ナトリウム塩を添加するに際しては、ヒノキチオールの亜鉛化合物即ち亜鉛を介してポリカルボン酸に結合させた化合物ばかりでなく、ヒノキチオールの亜鉛塩を使用する場合も含まれる。この際の添加量は亜鉛量に対して０．１〜１０モル以上好ましくは０．５〜５モル特に好ましくは１．０〜２．０モル使用される。 In the present invention, when ethylenediaminetetraacetic acid sodium salt is added, not only a zinc compound of hinokitiol, that is, a compound bonded to polycarboxylic acid via zinc, but also a case of using a zinc salt of hinokitiol is included. The amount added is 0.1 to 10 mol or more, preferably 0.5 to 5 mol, particularly preferably 1.0 to 2.0 mol, based on the amount of zinc.
添加した後磨砕混合する。この混合物は次いで水と接触せしめてヒノキチオールを気化せしめるが、この際の水と接触せしめる手段としては、多湿下に於いて吸湿させるか、水を加える手段を好ましい手段として挙げることが出来る。 Mix after grinding. This mixture is then brought into contact with water to vaporize hinokitiol. As a means for bringing the mixture into contact with water at this time, a means for absorbing moisture under high humidity or adding water can be mentioned as a preferred means.
本発明に依ればただ単に水と接触せしめるだけで、ヒノキチオールを簡単に蒸散して気化せしめることが出来、ヒノキチオールの利用範囲が極めて広くなる。 According to the present invention, hinokitiol can be easily evaporated and vaporized by simply contacting with water, and the range of utilization of hinokitiol becomes extremely wide.
本発明の実施例及び比較例を示して本発明の特徴を説明する。但しこれ等例において使用されているヒノキチオールの金属塩は、ヒノキチオールと塩化亜鉛又は塩化銅を用いてアルコール溶媒中で合成した（以下Ｚｎ(ＨＴ)２、Ｃｕ(ＨＴ)２と略称する）。又水溶性のポリカルボン酸に金属原子を介してヒノキチオールを結合させた化合物の合成には、ポリアクリル酸（ジュリマーＡＣ−１０ＬＰ,日本純薬製）、ヒノキチオール金属塩、及び金属塩化合物を用いテトラメチルアンモニウムハイドロオキサイド{(ＣＨ３)４ＮＯＨ・５Ｈ２Ｏ}を触媒として合成した（特願２００２−３３７１１号の実施例１〜２、１２〜１３。生成物はＰＡＡ−Ｚｎ−ＨＴ、ＰＡＡ−Ｃｕ−ＨＴと略称する）。 The features of the present invention will be described with reference to examples and comparative examples of the present invention. However, the metal salt of hinokitiol used in these examples was synthesized in an alcohol solvent using hinokitiol and zinc chloride or copper chloride (hereinafter abbreviated as Zn (HT) 2 , Cu (HT) 2 ). In addition, for the synthesis of a compound in which hinokitiol is bonded to a water-soluble polycarboxylic acid through a metal atom, tetraacrylic acid (Jurimer AC-10LP, manufactured by Nippon Pure Chemical), hinokitiol metal salt, and metal salt compound are used. Methyl ammonium hydroxide {(CH 3 ) 4 NOH · 5H 2 O} was used as a catalyst (Examples 1-2 and 12-13 of Japanese Patent Application No. 2002-33711. The products were PAA-Zn-HT, PAA- Abbreviated Cu-HT).
エチレンジアミンテトラ酢酸ジナトリウム塩としてはクレワットＮ（ＥＤＴＡ・２Ｎａ・２Ｈ２Ｏ、帝国化学産業製）を用い、エチレンジアミンテトラ酢酸トリナトリウム塩として試薬（ＥＤＴＡ・３Ｎａ・ｎＨ２Ｏ、ｎ=０．１）を用いた。 Clewat N (EDTA · 2Na · 2H 2 O, manufactured by Teikoku Chemical Industry) is used as the disodium salt of ethylenediaminetetraacetic acid, and a reagent (EDTA · 3Na · nH 2 O, n = 0.1) is used as the trisodium salt of ethylenediaminetetraacetic acid. Was used.
ポリアクリル酸にＺｎを介してヒノキチオールを結合させた化合物、例えばＰＡＡ−Ｚｎ−ＨＴ（ＬｏｔＮｏ．３、ＨＴ１９．０３％、Ｚｎ７．５４％）は含有しているＨＴとＺｎのモル比はぼ１対１であって、理論的にはアクリル酸単位１００個に対して−ＺｎＨＴ基が１１個程度が結合しているのみで、遊離のカルボキシル基を相当数残していると考えられる。 A compound in which hinokitiol is bonded to polyacrylic acid via Zn, for example, PAA-Zn-HT (Lot No. 3, HT 19.03%, Zn 7.54%) contains a molar ratio of HT to Zn of about 1. In theory, it is theoretically considered that only about 11 —ZnHT groups are bonded to 100 acrylic acid units, and a considerable number of free carboxyl groups remain.
なおこの化合物は水には不溶であるが、多湿下におくと吸水してヒノキチオール臭を発することを知った。 It was found that this compound is insoluble in water, but it absorbs water and emits a hinokitiol odor when placed under high humidity.
そこでＰＡＡ−Ｚｎ−ＨＴ（ＬｏｔＮｏ．３）４００ｍｇにクレワットＮ（ＥＤＴＡ２Ｎａ・２Ｈ２Ｏ）２６６ｍｇ（０．５６３ミリモル）を加えて磨砕混合し、これに水２００ｍｇを加えて密栓して室温に１週間放置した。これにクロロホルム２０ｍｌを加えて１時間攪拌抽出し、クロロホルム溶液２９．０１ｇを分取した。残渣はエタノール２０ｍｌを加え攪拌抽出し、残留物を減圧乾燥して白色粉末３９０ｍｇをえた。 Therefore, 266 mg (0.563 mmol) of Clewat N (EDTA2Na · 2H 2 O) was added to 400 mg of PAA-Zn-HT (Lot No. 3), and the mixture was ground and mixed. Left for a week. To this, 20 ml of chloroform was added, followed by stirring and extraction for 1 hour, and 29.01 g of a chloroform solution was collected. The residue was extracted by stirring with 20 ml of ethanol, and the residue was dried under reduced pressure to give 390 mg of white powder.
分析の結果、クロロホルム溶液はＨＴ５２．２ｍｇ（０．３２ミリモル）を含有するが、Ｚｎをほとんど含有せず、白色粉末はＺｎ２２．３ｍｇ（０．３４ミリモル）を含有するが、ＨＴの存在は認められず、かつ水には容易に溶解することを知った。 As a result of the analysis, the chloroform solution contains 52.2 mg (0.32 mmol) of HT, but hardly contains Zn, and the white powder contains 22.3 mg (0.34 mmol) of Zn, but the presence of HT is recognized. And was found to dissolve easily in water.
従って水及びクロロホルムに不溶のＰＡＡ−Ｚｎ−ＨＴが加水分解を受けてＨＴを遊離し、これとほぼ当量の亜鉛がＥＤＴＡ・２Ｎａに捕捉されたものと考えられ、Ｚｎを介して結合されたヒノキチオールは水を加えることによってヒノキチオールを遊離することを確信するに至った。 Therefore, it is considered that PAA-Zn-HT insoluble in water and chloroform is hydrolyzed to liberate HT, and zinc equivalent to this is captured by EDTA · 2Na, and hinokitiol bound via Zn. Came to be convinced that liberating hinokitiol by adding water.
ＰＡＡ−Ｚｎ−ＨＴ（ＬｏｔＮｏ．３、ＨＴ１９．０３％、Ｚｎ７．５４％、ＨＴ／Ｚｎ=１．０／１．０モル／モル）２４４ｍｇをクレワットＮ１２７ｍｇ（０．３４ミリモル）と磨砕混合し、硝子製シャーレに拡げる。 244 mg of PAA-Zn-HT (Lot No. 3, HT 19.03%, Zn 7.54%, HT / Zn = 1.0 / 1.0 mol / mol) was ground and mixed with 127 mg (0.34 mmol) of Clewat N. Expand to a glass petri dish.
これを底部に水５０ｍｌを入れた２ｌビーカー中に保持し、ポリエチレンフィルムで密封して室温に放置する。ほぼ直線的に吸水増量して３週間で１６６ｍｇの増量が認められた。 This is held in a 2 l beaker with 50 ml of water at the bottom, sealed with a polyethylene film and left at room temperature. The water absorption increased almost linearly, and an increase of 166 mg was observed in 3 weeks.
３週間後シャーレ内容物をクロロホルムで攪拌抽出してクロロホルム溶液と白色残渣に分離し、それぞれＨＴとＺｎの含量を測定すると、クロロホルム溶液中にはＨＴ３４．５２ｍｇ（回収率９３．７％）、Ｚｎ０．５４ｍｇが、又白色残渣中にはＨＴ３．８ｍｇ、Ｚｎ１７．２ｍｇ（回収率９３．７％）が検出された。即ち本実験条件ではＰＡＡ−Ｚｎ−ＨＴの９３．７％が加水分解されてＨＴを遊離すると共に、ＺｎはクレワットＮと共にポリアクリル酸に固定されて水溶性の白色残渣となったものと考えられる。 After 3 weeks, the petri dish contents were extracted by stirring with chloroform and separated into a chloroform solution and a white residue. When the contents of HT and Zn were measured, respectively, HT34.52 mg (recovery rate 93.7%), Zn0 .54 mg, and HT 3.8 mg and Zn 17.2 mg (recovery rate 93.7%) were detected in the white residue. That is, under this experimental condition, 93.7% of PAA-Zn-HT is hydrolyzed to liberate HT, and Zn is fixed to polyacrylic acid together with crewat N to form a water-soluble white residue. .
ヒノキチオールの亜鉛塩は水に対して極めて安定な化合物である。例えばＺｎ（ＨＴ）２・２Ｈ２Ｏ（ＬｏｔＮｏ．１１、水分１０．４７％、ＨＴ７３．３２％、Ｚｎ１４．８２％）９０７ｍｇを、イオン交換水２０ｍｌに懸濁して1週間室温に放置した後濾過水洗乾燥すると、ヒノキチオールの亜鉛塩はそのまま回収される。収量８７０ｍｇ（Ｚｎ含量１５．３８％、Ｚｎとしての回収率１００．６％）であった。 The zinc salt of hinokitiol is a very stable compound against water. For example, 907 mg of Zn (HT) 2 · 2H 2 O (Lot No. 11, moisture 10.47%, HT 73.32%, Zn 14.82%) is suspended in 20 ml of ion-exchanged water and left at room temperature for 1 week, followed by filtration. When washed with water and dried, the zinc salt of hinokitiol is recovered as it is. The yield was 870 mg (Zn content: 15.38%, recovery rate as Zn: 100.6%).
しかし、Ｚｎ（ＨＴ）２・２Ｈ２Ｏ（ＬｏｔＮｏ．１１）１０３ｍｇ（０．２４ミリモル）をクレワットＮ１１．５ｍｇ（０．３０ミリモル）と共に水５ｍｌに懸濁して１５分間激しく攪拌した後、濾過水洗乾燥してえられる白色沈殿は、収量８６ｍｇ（Ｚｎ含量１５．４％）であった。又濾洗液を合して濃縮してえられた乾固物にはＺｎ２．５ｍｇが検出された。これはクレワットＮと共に水に溶解したＺｎ（ＨＴ）２・２Ｈ２Ｏ１７ｍｇの亜鉛含量２．５ｍｇと完全に一致する。 However, 103 mg (0.24 mmol) of Zn (HT) 2 .2H 2 O (Lot No. 11) was suspended in 5 ml of water together with 11.5 mg (0.30 mmol) of Clewat N and stirred vigorously for 15 minutes, followed by washing with filtered water. The white precipitate obtained by drying was a yield of 86 mg (Zn content 15.4%). In addition, 2.5 mg of Zn was detected in the dried product obtained by concentrating the filtrate with the filtrate. This is in complete agreement with the zinc content of 2.5 mg of 17 mg Zn (HT) 2 .2H 2 O dissolved in water with Clewat N.
従ってヒノキチオールの亜鉛塩もクレワットＮの共存下においては徐々に水と反応してヒノキチオールを遊離することを確信した。 Therefore, it was convinced that the zinc salt of hinokitiol also gradually reacted with water to release hinokitiol in the presence of crewat N.
Ｚｎ（ＨＴ）２・２Ｈ２Ｏ（ＬｏｔＮｏ．１１、水分１０．４７％、ＨＴ７３．３２％、Ｚｎ１４．８２％）２２２ｍｇにクレワットＮ（ＥＤＴＡ・２Ｎａ・２Ｈ２Ｏ）１９８ｍｇを加えて磨砕混合する（Ｚｎ／ＥＤＴＡ・２Ｎａ=１．００／１．０６モル／モル）。 Add 198 mg of Clewat N (EDTA · 2Na · 2H 2 O) to 222 mg of Zn (HT) 2 · 2H 2 O (Lot No. 11, moisture 10.47%, HT 73.32%, Zn 14.82%) and mix by grinding (Zn / EDTA · 2Na = 1.00 / 1.06 mol / mol).
この粉末に水５０ｍｇを加え、密栓して室温に1週間放置した後クロロホルム１０ｍｌで可溶物を抽出し、さらに少量のクロロホルムで洗浄し、クロロホルム溶液１８．２６ｇと不溶残渣２５３ｍｇを分取した。分析の結果、クロロホルム溶液はＺｎ０．４５ｍｇ、ＨＴ１２７．８ｍｇ（回収率７８．６％）、不溶残渣はＺｎ２５．７ｍｇ（回収率７８．１％）を含有することが判った。 50 mg of water was added to this powder, sealed and allowed to stand at room temperature for 1 week, and then the soluble material was extracted with 10 ml of chloroform, washed with a small amount of chloroform, and 18.26 g of chloroform solution and 253 mg of insoluble residue were separated. As a result of analysis, it was found that the chloroform solution contained 0.45 mg Zn, HT 127.8 mg (recovery rate 78.6%), and the insoluble residue contained 25.7 mg Zn (recovery rate 78.1%).
従ってＺｎ（ＨＴ）２・２Ｈ２ＯはＥＤＴＡ・２Ｎａ・２Ｈ２Ｏの共存下に加水分解してヒノキチオールを遊離する。 Accordingly, Zn (HT) 2 .2H 2 O is hydrolyzed in the presence of EDTA.2Na.2H 2 O to release hinokitiol.
Ｚｎ（ＨＴ）２・２Ｈ２Ｏ（ＬｏｔＮｏ．１２、Ｈ２Ｏ８．６３％、ＨＴ７６．３８％、Ｚｎ１５．５６％）９０３ｍｇ（Ｚｎとして２．１ミリモル）と、クレワットＮ（ＥＤＴＡ・２Ｎａ・２Ｈ２Ｏ）７７０ｍｇ（２．１ミリモル）を磨砕混合してシャーレ上に拡げる。これを室温で３週間放置すると、重量１３ｍｇが減少するのみで殆ど何の変化も見られない。そこでこれを実施例２と同じ装置を用いて吸湿させ、次にこれを室内にもどしてＨＴを気化させる。この操作を図１に示すような日程で反覆する。開始より２５日目に内容物を混合均一化した後分析に供した。なお２回目以降の吸湿は図１に示すように同一日中５時間で行った。各吸湿気化の前後における重量変化を示したものが図１である。 Zn (HT) 2 · 2H 2 O (LotNo.12, H 2 O8.63%, HT76.38%, Zn15.56%) and (2.1 mmol as Zn) 903 mg, Kurewatto N (EDTA · 2Na · 2H 2 O) 770 mg of (2.1 mmol) were mulled spread on petri dish. If this is left at room temperature for 3 weeks, the weight is only reduced by 13 mg and almost no change is observed. Then, this is made to absorb moisture using the same apparatus as Example 2, and this is then returned indoors and HT is vaporized. This operation is repeated on the schedule as shown in FIG. On the 25th day from the start, the contents were mixed and homogenized and subjected to analysis. The second and subsequent moisture absorptions were performed in the same day for 5 hours as shown in FIG. FIG. 1 shows the weight change before and after each moisture absorption.
最終残留物１４４０ｍｇ中のヒノキチオール含量は分析の結果４４２ｍｇと得られたから、２４日間のＨＴの減量は２２７ｍｇであって、同期間中の重量減２４８ｍｇと略等しいことが判った。 Since the hinokitiol content in the final residue of 1440 mg was 442 mg as a result of the analysis, it was found that the decrease in HT for 24 days was 227 mg, which was almost equal to the weight loss of 248 mg during the same period.
又各気化段階の終りの重量が大体直線的に減少していることから、Ｚｎ（ＨＴ）２・２Ｈ２ＯはＥＤＴＡ・２Ｎａ・２Ｈ２Ｏの共存下に水と反応してヒノキチオールを遊離し、このものは水と共に気化して散逸するものと考えられる。 In addition, since the weight at the end of each vaporization step is almost linearly reduced, Zn (HT) 2 · 2H 2 O reacts with water in the presence of EDTA · 2Na · 2H 2 O to release hinokitiol. This material is considered to vaporize and dissipate with water.
因みに気化速度は
２４７ｍｇ／１６日=１５．４ｍｇ／日=２．２４％／日
であって、ヒノキチオール微結晶粉末の昇華速度０．６〜０．７％／日の３倍以上に達する。
Incidentally, the vaporization rate is 247 mg / 16 days = 15.4 mg / day = 2.24% / day, and the sublimation rate of the hinokitiol fine crystal powder is 0.6 to 0.7% / day, which is three times or more.
即ちヒノキチオールの亜鉛塩を当量以上のＥＤＴＡ・２Ｎａ・２Ｈ２Ｏを加えて磨砕混合した粉末は、必要に応じて水を加えるか、あるいは吸湿させるとヒノキチオールを気化して必要な空間を必要なヒノキチオールの蒸気で満たすことができることを示している。 In other words, powder obtained by grinding and mixing hinokitiol zinc salt with EDTA · 2Na · 2H 2 O in an amount equal to or greater than the equivalent amount needs water to vaporize hinokitiol when necessary or to absorb moisture. It shows that it can be filled with hinokitiol vapor.
ＰＡＡ−Ｃｕ−ＨＴ（ＬｏｔＮｏ．２０、Ｃｕ５．８４％）ＨＴ１３．６９％、Ｃｕ／ＨＴ１．１／１．０モル／モル）１１００ｍｇと、クレワットＮ（ＥＤＴＡ・２Ｎａ・２Ｈ２Ｏ）４２０ｍｇ（１．１３ミリモル）を磨砕混合し、水３１０ｍｇを加えて密栓して室温に１週間放置した後クロロホルム２０ｍｌを加えて１時間撹拌抽出する。さらにクロロホルム５ｍｌを加えて同様に抽出してクロロホルム層計３７．９３ｇを分取した。残渣は減圧乾固して青色固体１．５１ｇをえた。分析の結果、クロロホルム抽出物はＣｕ２８．４５ｍｇ（０．４４７ミリモル）、ＨＴ１４７．９ｍｇ（０．９０７ミリモル）を含有し、抽出残渣にはヒノキチオールは検出されないが、銅３４．４ｍｇ（０．５４ミリモル）が存在することが判った。 PAA-Cu-HT (Lot No. 20, Cu 5.84%) HT 13.69%, Cu / HT1.1 / 1.0 mol / mol) 1100 mg and Crewat N (EDTA · 2Na · 2H 2 O) 420 mg (1 .13 mmol) is triturated and mixed, 310 mg of water is added and sealed, left at room temperature for 1 week, and then 20 ml of chloroform is added and extracted with stirring for 1 hour. Further, 5 ml of chloroform was added and extracted in the same manner to obtain a total of 37.93 g of chloroform layer. The residue was dried under reduced pressure to obtain 1.51 g of a blue solid. As a result of the analysis, the chloroform extract contained 28.45 mg (0.447 mmol) of Cu and 147.9 mg (0.907 mmol) of HT, and no hinokitiol was detected in the extraction residue, but 34.4 mg (0.54 mmol) of copper. ) Existed.
抽出物及び残渣中のＣｕ及びＨＴの回収率合計がそれぞれ９７．７％及び９８．６％であり、クロロホルム抽出物に含有されるＣｕ／ＨＴ=１．０／２．０モル／モルであることから、ＰＡＡ−Ｃｕ−ＨＴは加水分解によって生じたＣｕの１／２はＣｕ（ＨＴ）２としてクロロホルムに抽出され、残りの１／２のＣｕはＥＤＴＡに捕捉されてＰＡＡと共に抽出残渣中に存在するものと考えられる。 The total recoveries of Cu and HT in the extract and residue are 97.7% and 98.6%, respectively, and Cu / HT = 1.0 / 2.0 mol / mol contained in the chloroform extract. Therefore, in PAA-Cu-HT, 1/2 of Cu produced by hydrolysis is extracted into chloroform as Cu (HT) 2 , and the remaining 1/2 of Cu is captured by EDTA in the extraction residue together with PAA. It is considered to exist.
Ｃｕ（ＨＴ）２（ｍｐ１７３．５〜１７４．５℃）３９０ｍｇ（１．０ミリモル）とクレワットＮ（ＥＤＴＡ・２Ｎａ・２Ｈ２Ｏ）４０９ｍｇ（１．１ミリモル）を磨砕混合してえられる粉末は、多湿下に1週間放置しても吸湿増量することがない。そこで水２０ｍｌを加えて1夜放置した後濾過水洗乾燥して青色結晶３６０ｍｇをえた。このものはｍｐ１７４．５〜１７５℃でＩＲスペットル測定の結果元のＣｕ（ＨＴ）２であることが確かめられた（回収率９２．３％）。 Powder obtained by grinding and mixing 390 mg (1.0 mmol) of Cu (HT) 2 (mp 173.5 to 174.5 ° C.) and 409 mg (1.1 mmol) of Clewat N (EDTA · 2Na · 2H 2 O) Does not increase the moisture absorption even when left under high humidity for 1 week. Therefore, 20 ml of water was added and left overnight, then washed with filtered water and dried to give 360 mg of blue crystals. This product was confirmed to be the original Cu (HT) 2 as a result of IR spettle measurement at mp 174.5 to 175 ° C. (recovery rate 92.3%).
この事実はＣｕ（ＨＴ）２は水の存在においてもＥＤＴＡ・２Ｎａ・２Ｈ２Ｏと反応しないことを示すもので、比較例１の結果を裏書きするものである。 This fact indicates that Cu (HT) 2 does not react with EDTA · 2Na · 2H 2 O even in the presence of water, and the results of Comparative Example 1 are endorsed.
Ｚｎ（ＨＴ）２（水分１０．４７％、ＨＴ７３．３２％、Ｚｎ１４．８２％ＨＴ／Ｚｎ=１．９８／１．００モル／モル）６００ｍｇ（１．３７ミリモル）をＥＤＴＡ・３Ｎａ４９０ｍｇ（１．３７ミリモル）と磨砕混合する。このもの１０９０ｍｇを室温で密閉容器（容量２ｌ、水５０ｍｌを底部に保持）中に放置する。３８日後内容物は吸水増量し、泥状物１６９０ｍｇを残した（吸水量６００ｍｇ、給水率５５．０％）。 Zn (HT) 2 (moisture 10.47%, HT 73.32%, Zn 14.82% HT / Zn = 1.98 / 1.00 mol / mol) 600 mg (1.37 mmol) was added to EDTA · 3Na 490 mg (1. 37 mmol). 1090 mg of this is left at room temperature in a closed container (2 l capacity, 50 ml water held at the bottom). After 38 days, the content increased in water absorption, leaving 1690 mg of mud (water absorption 600 mg, water supply rate 55.0%).
このものの一部６２０ｍｇを秤取し、１０ｍｌの水で２回抽出し、水可溶物２００ｍｇと水不溶物１８５ｍｇを分離した。水可溶物はＦｅＣｌ３によるヒノキチオールの呈色反応を全く示さず、系中のヒノキチオールはすべて水不溶物中に含有されると考えられる。水不溶物は分析の結果ＨＴ７４．７８％、Ｚｎ１５．０１％を含有し、ＨＴとＺｎとのモル比は０．４５８／０．２３７=１．９９／１．００モル／モルであった。これはＺｎ（ＨＴ）２が収率８５％で回収されたことを示している。従ってＺｎ（ＨＴ）２とＥＤＴＡ・３Ｎａと水の存在下においても反応せず、加水分解は起こらないものと理解される。 A portion of 620 mg was weighed and extracted twice with 10 ml of water to separate 200 mg of water soluble material and 185 mg of water insoluble material. The water-soluble material does not show any color reaction of hinokitiol by FeCl 3, and all hinokitiol in the system is considered to be contained in the water-insoluble material. As a result of analysis, the water-insoluble matter contained HT 74.78% and Zn 15.01%, and the molar ratio of HT to Zn was 0.458 / 0.237 = 1.99 / 1.00 mol / mol. This indicates that Zn (HT) 2 was recovered with a yield of 85%. Therefore, it is understood that the reaction does not occur even in the presence of Zn (HT) 2 , EDTA · 3Na and water, and hydrolysis does not occur.
Claims (3)
（ロ）次いで水と接触させて両者を反応させ、ヒノキチオールを遊離させることを特徴とするヒノキチオールの気化方法 (I) A compound in which hinokitiol is bonded to polycarboxylic acid via zinc and / or zinc salt of hinokitiol, and ethylenediaminetetraacetic acid alkali metal salt is added and ground and mixed.
(B) A method for vaporizing hinokitiol, wherein the hinokitiol is liberated by bringing it into contact with water and allowing them to react.
The vaporization method according to claim 1, wherein an equimolar amount or more of EDAT · 2Na is used with respect to the zinc content of the hinokitiol zinc compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004222901A JP4868197B2 (en) | 2004-07-30 | 2004-07-30 | Method for vaporizing hinokitiol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004222901A JP4868197B2 (en) | 2004-07-30 | 2004-07-30 | Method for vaporizing hinokitiol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006036733A true JP2006036733A (en) | 2006-02-09 |
| JP4868197B2 JP4868197B2 (en) | 2012-02-01 |
Family
ID=35902112
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004222901A Expired - Fee Related JP4868197B2 (en) | 2004-07-30 | 2004-07-30 | Method for vaporizing hinokitiol |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4868197B2 (en) |
Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63211218A (en) * | 1987-02-27 | 1988-09-02 | Nippon Zeora Kk | Composition for oral cavity application |
| JPH0377801A (en) * | 1989-08-21 | 1991-04-03 | Matsushita Electric Works Ltd | Antimicrobial agent |
| JPH0769873A (en) * | 1993-09-01 | 1995-03-14 | Yuki Gosei Kogyo Co Ltd | Sterilizing and disinfecting agent for pseudomonas aeruginosa |
| JPH07126111A (en) * | 1993-11-05 | 1995-05-16 | Japan Tobacco Inc | Herbicide |
| JPH07173053A (en) * | 1993-12-20 | 1995-07-11 | Otsuka Pharmaceut Co Ltd | Antimicrobial agent |
| JPH09175916A (en) * | 1995-12-25 | 1997-07-08 | Mitsubishi Gas Chem Co Inc | Antiseptic for wood |
| JPH1060288A (en) * | 1996-05-17 | 1998-03-03 | Mitsubishi Gas Chem Co Inc | Antibacterial and antifungal resin composition |
| JP2000119115A (en) * | 1998-10-06 | 2000-04-25 | Osaka Organic Chem Ind Ltd | Hinokitiol-formulated composition |
| JP2001072505A (en) * | 1999-09-03 | 2001-03-21 | Tatsuhiko Oe | Germicidal composition |
| JP2001278704A (en) * | 2000-03-29 | 2001-10-10 | Asahi Kasei Corp | Aqueous emulsion containing hinokitiol |
| JP2001302980A (en) * | 2000-04-19 | 2001-10-31 | Asahi Kasei Corp | Hinokitiol-containing coating |
| JP2001323218A (en) * | 2000-05-17 | 2001-11-22 | Asahi Kasei Corp | Water-based coating material containing antimicrobial agent |
| JP2003089606A (en) * | 2001-07-12 | 2003-03-28 | Kanae Toryo Kk | Hinokitiol sustained release agent |
| JP2003137702A (en) * | 2001-11-05 | 2003-05-14 | Asahi Kasei Corp | Colloidal solution of metal complex |
| JP2004043327A (en) * | 2002-07-09 | 2004-02-12 | Asahi Kasei Chemicals Corp | Wood treating agent |
| JP2004244468A (en) * | 2003-02-12 | 2004-09-02 | Naoichi Sakota | Method for combining polycarboxylic acid with hinokitiol |
-
2004
- 2004-07-30 JP JP2004222901A patent/JP4868197B2/en not_active Expired - Fee Related
Patent Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63211218A (en) * | 1987-02-27 | 1988-09-02 | Nippon Zeora Kk | Composition for oral cavity application |
| JPH0377801A (en) * | 1989-08-21 | 1991-04-03 | Matsushita Electric Works Ltd | Antimicrobial agent |
| JPH0769873A (en) * | 1993-09-01 | 1995-03-14 | Yuki Gosei Kogyo Co Ltd | Sterilizing and disinfecting agent for pseudomonas aeruginosa |
| JPH07126111A (en) * | 1993-11-05 | 1995-05-16 | Japan Tobacco Inc | Herbicide |
| JPH07173053A (en) * | 1993-12-20 | 1995-07-11 | Otsuka Pharmaceut Co Ltd | Antimicrobial agent |
| JPH09175916A (en) * | 1995-12-25 | 1997-07-08 | Mitsubishi Gas Chem Co Inc | Antiseptic for wood |
| JPH1060288A (en) * | 1996-05-17 | 1998-03-03 | Mitsubishi Gas Chem Co Inc | Antibacterial and antifungal resin composition |
| JP2000119115A (en) * | 1998-10-06 | 2000-04-25 | Osaka Organic Chem Ind Ltd | Hinokitiol-formulated composition |
| JP2001072505A (en) * | 1999-09-03 | 2001-03-21 | Tatsuhiko Oe | Germicidal composition |
| JP2001278704A (en) * | 2000-03-29 | 2001-10-10 | Asahi Kasei Corp | Aqueous emulsion containing hinokitiol |
| JP2001302980A (en) * | 2000-04-19 | 2001-10-31 | Asahi Kasei Corp | Hinokitiol-containing coating |
| JP2001323218A (en) * | 2000-05-17 | 2001-11-22 | Asahi Kasei Corp | Water-based coating material containing antimicrobial agent |
| JP2003089606A (en) * | 2001-07-12 | 2003-03-28 | Kanae Toryo Kk | Hinokitiol sustained release agent |
| JP2003137702A (en) * | 2001-11-05 | 2003-05-14 | Asahi Kasei Corp | Colloidal solution of metal complex |
| JP2004043327A (en) * | 2002-07-09 | 2004-02-12 | Asahi Kasei Chemicals Corp | Wood treating agent |
| JP2004244468A (en) * | 2003-02-12 | 2004-09-02 | Naoichi Sakota | Method for combining polycarboxylic acid with hinokitiol |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4868197B2 (en) | 2012-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ZA200502875B (en) | Active bromide containing biocidal compositions and their preparation. | |
| SE436282B (en) | PROCEDURE FOR THE PREPARATION OF N-PHOSPHONOMETHYL Glycine SALTS | |
| Ohshita et al. | Synthesis and optical properties of dithienostiboles | |
| JP4868197B2 (en) | Method for vaporizing hinokitiol | |
| TW201741234A (en) | Surface-modified sodium hypochlorite pentahydrate crystal, and method for producing same | |
| US8318974B2 (en) | Drying agent and method for forming the same | |
| Badea et al. | Some new acrylate complexes as a criterion in their selection for further co-polymerization reaction | |
| JPH03199114A (en) | Stabilized particles and method for production thereof and vermin control | |
| EP4232442A1 (en) | A process for the preparation of chlorantraniliprole | |
| JP2004315332A (en) | Method of manufacturing inorganic iodine compound | |
| Inagaki et al. | Organometallic ionic liquids from half-sandwich Ru (II) complexes with various chelating ligands | |
| JP2016067999A (en) | Composite catalyst for the production of methanol and method for producing the same, and method for producing methanol | |
| US2583559A (en) | Tetraglycine dihydroheptiodide and methods of making the same | |
| RU2507195C1 (en) | Method of obtaining asymmetric ethylene diamine-n,n-dipropionic acid | |
| IL27118A (en) | Tris(omega-carboxypolymethylene)tin chlorides | |
| Ferenc et al. | Complexes of some transition metal ions with selected dichlorophenoxyacetic acid: Thermal, spectral and magnetic properties | |
| EP0268616B1 (en) | Composition of matter containing potassium acetylsalicylate and useful for producing solutions of potassium acetylsalicylate, and process for preparation | |
| US2388496A (en) | Method of preparing copper arsenicals | |
| CN105949237B (en) | A kind of preparation method of glyphosate dimethylamine salt raw medicine | |
| US10087197B2 (en) | Selective extraction of anions from solution | |
| CN113797225A (en) | Free radical trapping agent and application thereof | |
| JP5761713B2 (en) | New metal complex ionic liquid | |
| JP3790880B2 (en) | Novel trilithium salt or tripotassium salt hydrate of 2,4,6-trimercapto-1,3,5-triazine, and method for producing hydrate and anhydride | |
| JP2004244468A (en) | Method for combining polycarboxylic acid with hinokitiol | |
| WO2024062200A1 (en) | Method for synthesizing eco-friendly mofs, in particular flexible mofs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20070625 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20100818 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20101207 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20110128 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20111011 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20111102 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20141125 Year of fee payment: 3 |
|
| LAPS | Cancellation because of no payment of annual fees |