JP2007238504A - 1,2-dioxetane derivative and reagent by using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new 1,2-dioxetane derivative being stable and easy for handling, and having a stable high light-emitting performance of a high quantum yield. <P>SOLUTION: The substance in a specimen is measured by using a chemiluminescent reagent containing a 1,2-dioxetane derivative expressed by general formula [I] [wherein, Ar<SB>1</SB>is an arylene or the like; A is a fluorescent pigment derivative; OY is hydroxy or the like; X is an alkylene or the like; R<SB>1</SB>, R<SB>2</SB>are each an alkylene or the like; and R<SB>3</SB>is a spacer] and generating chemiluminescence. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to 1,2-dioxetane derivatives. The 1,2-dioxetane derivative of the present invention is a compound capable of inducing chemiluminescence, and can be used as a substrate for immunoassay, for example.

  Various 1,2-dioxetane derivatives have been conventionally synthesized, and it is known that a compound having a spiroadamantyl group bonded to the 3-position is particularly useful as a chemiluminescent substrate (for example, Patent Document 1, Patent Document) 2). Moreover, various compounds are known as what the present inventors already manufactured (for example, refer patent documents 3-8). Various compounds have been synthesized (for example, see Patent Documents 9 to 11), but the stability of dioxetane itself still remains as a problem.

Japanese Patent Publication No. 5-21918 Japanese Patent Publication No. 5-45590 JP-A-8-245615 Japanese Patent Application Laid-Open No. 8-16985 JP-A-8-165287 JP-A-9-216887 JP 2002-338576 A JP 2004-002300 A Japanese Patent No. 2572171 JP-T-08-502968 Special table 2002-508654 gazette

  As described above, various studies have been made on 1,2-dioxetane derivatives, and various compounds have been created. However, the compound itself is stable and easy to handle for application in the field of clinical tests and the like, and for high sensitivity, a stable luminescence performance with a high quantum yield is required. The creation of excellent compounds has been desired.

  The inventors of the present application have made extensive studies in order to create a compound that is superior to conventional compounds under the circumstances described above, and as a result, 1,2-dioxetane derivatives having fluorescent dyes can be obtained even in protic solvents. The present invention has been completed by finding that it exhibits high luminous efficiency, and further exhibits higher luminous efficiency in the presence of a surfactant.

  That is, the present invention relates to the general formula [I]

で表されることを特徴とする、１，２−ジオキセタン誘導体（式中、Ａｒ_１はアルキル基、アリール基、ハロゲン原子、アルコキシル基、カルボキシル基、ホルミル基、アルキルエステル、アリールエステル、アルキルケトン、アリールケトン又は複素環が結合していてもよいアリーレン基であり、Ａは蛍光色素誘導体であり、ＯＹはヒドロキシル、アルキルエステル、アリールエステル、又は−ＯＳｉ（Ｒ_４Ｒ_５Ｒ_６）（ただし、Ｒ_４、Ｒ_５及びＲ_６は互いに独立にアルキル基もしくはアリール基である。）で表される基であり、Ｘはアルキレン基、アリーレン基、酸素原子、硫黄原子、カルボニル基、−（ＣＯ）−Ｏ−、−Ｏ−（ＣＯ）−、−ＮＨ−、−ＮＨ−ＣＯ−、−ＣＯ−ＮＨ−、−ＯＳｉ（Ｒ_７Ｒ_８）−（ただし、Ｒ_７及びＲ_８は互いに独立にアルキル基もしくはアリール基である。）、又は−（Ｒ_９Ｒ_１０）ＳｉＯ−（ただし、Ｒ_９及びＲ_１０は互いに独立にアルキル基もしくはアリール基である。）で表される基であり、Ｒ_１、Ｒ_２はアルキレン基、アリーレン基であり、Ｒ_３はスペーサーである。）である。

A 1,2-dioxetane derivative (wherein Ar ₁ is an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, An arylene group to which an aryl ketone or a heterocyclic ring may be bonded; A is a fluorescent dye derivative; OY is hydroxyl, an alkyl ester, an aryl ester, or —OSi (R ₄ R ₅ R ₆ ) (where R ₄ , R ₅ and R ₆ are each independently an alkyl group or an aryl group.), X is an alkylene group, an arylene group, an oxygen atom, a sulfur atom, a carbonyl group, — (CO) — O—, —O— (CO) —, —NH—, —NH—CO—, —CO—NH—, —OSi (R ₇ R ₈ ) — (where R ₇ and R ₈ are each independently an alkyl group or an aryl group.), Or — (R ₉ R ₁₀ ) SiO— (wherein R ₉ and R ₁₀ are each independently an alkyl group or an aryl group). And R ₁ and R ₂ are an alkylene group and an arylene group, and R ₃ is a spacer.

  The present invention also provides a general formula [V].

で表されることを特徴とする、１，２−ジオキセタン誘導体（式中、Ａｒ_２はアルキル基、アリール基、ハロゲン原子、アルコキシル基、カルボキシル基、ホルミル基、アルキルエステル、アリールエステル、アルキルケトン、アリールケトン又は複素環が結合していてもよいアリーレン基であり、Ａは蛍光色素誘導体であり、ＯＹはヒドロキシル、アルキルエステル、アリールエステル、又は−ＯＳｉ（Ｒ_４Ｒ_５Ｒ_６）（ただし、Ｒ_４、Ｒ_５及びＲ_６は互いに独立にアルキル基もしくはアリール基である。）で表される基であり、Ｒ_１１、Ｒ_１２はそれぞれ独立に水素原子、アルキル基、アリール基、アルキレン基又はアリーレン基である。また、Ｒ_１１、Ｒ_１２は一体となり、ジオキセタン環にスピロ結合する環式又は多環式有機環基を形成することもできる。Ｒ_１３はアルキル基、アリール基、アルキレン基又はアリーレン基であり、Ｒ_１３とＲ_１１、又はＲ_１３とＲ_１２とが一体となってジオキセタン環とヘテロ原子を含む縮合環を形成してもよい。また、Ｒ_１４はスペーサーである。）である。

A 1,2-dioxetane derivative (wherein Ar ₂ is an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, An aryl ketone or an arylene group to which a heterocycle may be bonded, A is a fluorescent dye derivative, OY is a hydroxyl, alkyl ester, aryl ester, or -OSi (R ₄ R ₅ R ₆ ) (where R ₄ , R ₅ and R ₆ are each independently an alkyl group or an aryl group. R ₁₁ and R ₁₂ are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylene group or an arylene. is a group. Further, R _11, R ₁₂ becomes integral, cyclic or polycyclic spiro bonded to the dioxetane ring It is also possible to form an organic ring group _{.R 13} is an alkyl group, an aryl group, an alkylene group or an arylene _{group, R 13} and _{R 11,} or dioxetane ring and a hetero atom and _{R 13} and _{R 12} together form And R ₁₄ is a spacer.

  The present invention also provides a chemiluminescent reagent comprising the above-described 1,2-dioxetane derivative.

  The present invention is also a luminescence method characterized by using the chemiluminescence reagent described above and decomposing a 1,2-dioxetane derivative contained therein to cause chemiluminescence.

  The present invention also provides an immunoassay reagent comprising the chemiluminescence reagent described above.

  In addition, the present invention is a measuring method characterized by measuring a substance in a sample using the above-described light emitting method. Hereinafter, the present invention will be described in detail.

  In the present specification, the “alkyl group” refers to a linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent, such as methyl, ethyl, propyl, A linear group such as butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosanyl, or the above alkyl group is appropriately branched. Refers to the group.

  Examples of the substituent that the alkyl group may have include a hydroxyl group, an alkoxyl group, and an aryl group. Examples of the alkoxyl group include straight-chain alkoxy groups having 1 to 20 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, ethoxypropoxy, and methoxyethoxyethoxy groups. Examples thereof include those in which 1 to 5 chains or branches are bonded. Examples of the aryl group include aromatic hydrocarbon groups having 6 to 20 carbon atoms such as phenyl and naphthyl groups, or 1 to 5 nitrogen atoms and oxygen in the ring such as furyl, thienyl and pyridyl groups. Examples include heteroaryl groups having an atom or a sulfur atom.

  In the present specification, the “alkylene group” refers to a divalent compound in which one arbitrary hydrogen atom is removed from the “alkyl group”.

  In the present specification, examples of the “aryl group” and “alkoxyl group” include the same aryl groups and alkoxyl groups that may be substituted with the above-described alkyl group.

  In the present specification, the “arylene group” refers to a divalent compound in which one arbitrary hydrogen atom on the aromatic ring is removed from the “aryl group”.

  In the present specification, the “polycyclic organic ring group” refers to an alkyl group having 1 to 10 carbon atoms, an alkoxyl group having 1 to 10 carbon atoms, a halogen atom, and a halogenated alkyl group having 1 to 10 carbon atoms. A polycyclic alkylene group having 6 to 30 carbon atoms optionally substituted with 1 to 10 groups independently selected from the above, for example, an adamantyl group, bicyclo [2.2.1] heptyl, etc. . In addition, a halogen atom, an alkyl group, an aryl group, a cyano group, an amide group, an alkoxyl group, or a carboxyl group may be bonded to any carbon of the polycyclic organic ring group.

  Further, in the present specification, “heterocycle” includes, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazane, pyran, pyridine, pyridazine, pyrimidine, pyrazine and the like. be able to. “Halogen atom” includes fluorine, chlorine, bromine and the like.

A is a “fluorescent dye derivative”, and examples thereof include fluorescein derivatives, benzothiazole derivatives, rhodamine derivatives, and pyrene derivatives. Although R ₃ and _{R 14} is a spacer, for example _{- (CH 2) n -,} - (CH 2) n NH -, - (CH 2) n NH- (CH 2) m -, - (CH 2) n _{CONH -, - (CH 2)} n CONH- (CH 2) m -, - (CH 2) n O-, or _- the like (n and m are _{1 - (CH 2) n O-} (CH 2) m An integer up to 20).

In the general formula [III], when R ₁₃ and R ₁₁ , or R ₁₃ and R ₁₂ are combined to form a condensed ring containing a dioxetane ring and a hetero atom, for example, a dioxetane ring and a furan ring A condensed ring or a condensed ring of a dioxetane ring and a pyran ring can be exemplified.

  Among the 1,2-dioxetane derivatives represented by the general formula [I], the formula [II]

（式中、ＯＹ及びＡは前記式［Ｉ］のＯＹ及びＡと同じであり、ｎ及びｍは１から２０までの整数である。Ｚは水素原子、アルキル基、アリール基、ハロゲン原子、アルコキシル基、カルボキシル基、ホルミル基、アルキルエステル、アリールエステル、アルキルケトン、アリールケトン又は複素環である。）で示される１，２−ジオキセタン誘導体、式［ＩＩＩ］

(In the formula, OY and A are the same as OY and A in the formula [I], and n and m are integers from 1 to 20. Z is a hydrogen atom, an alkyl group, an aryl group, a halogen atom, an alkoxyl. Group, carboxyl group, formyl group, alkyl ester, aryl ester, alkyl ketone, aryl ketone or heterocyclic ring), a 1,2-dioxetane derivative represented by the formula [III]

（式中、ＯＹ及びＡは前記式［Ｉ］のＯＹ及びＡと同じであり、ｎ及びｍは１から２０までの整数である。Ｚは前記式［ＩＩ］のＺと同じである。）で示される１，２−ジオキセタン誘導体、及び式［ＩＶ］

(In the formula, OY and A are the same as OY and A in the formula [I], and n and m are integers from 1 to 20. Z is the same as Z in the formula [II].) 1,2-dioxetane derivatives represented by the formula [IV]

（式中、ＯＹ及びＡは前記式［Ｉ］のＯＹ及びＡと同じであり、ｎは１から２０までの整数である。Ｚは前記式［ＩＩ］のＺと同じである。）で示される１，２−ジオキセタン誘導体が特に好ましいものである。

(Wherein OY and A are the same as OY and A in the formula [I], and n is an integer from 1 to 20. Z is the same as Z in the formula [II]). 1,2-dioxetane derivatives are particularly preferred.

  Among the 1,2-dioxetane derivatives represented by the general formula [V], the formula [VI]

（式中、ＯＹ及びＡは前記式［Ｖ］のＯＹ及びＡと同じであり、Ｚは水素原子、アルキル基、アリール基、ハロゲン原子、アルコキシル基、カルボキシル基、ホルミル基、アルキルエステル、アリールエステル、アルキルケトン、アリールケトン又は複素環であり、ｎは１から２０までの整数である。）で示される１，２−ジオキセタン誘導体及び式［ＶＩＩ］

(In the formula, OY and A are the same as OY and A in the formula [V], and Z is a hydrogen atom, alkyl group, aryl group, halogen atom, alkoxyl group, carboxyl group, formyl group, alkyl ester, aryl ester. , An alkyl ketone, an aryl ketone, or a heterocyclic ring, and n is an integer of 1 to 20, and a formula [VII]

（式中、ＯＹ及びＡは前記式［Ｖ］のＯＹ及びＡと同じであり、Ｚは前記式［ＶＩ］のＺと同じであり、ｎは１から２０までの整数である。）で示される１，２−ジオキセタン誘導体が特に好ましいものである。

(Wherein OY and A are the same as OY and A in the formula [V], Z is the same as Z in the formula [VI], and n is an integer from 1 to 20). 1,2-dioxetane derivatives are particularly preferred.

  Examples of the production method when the compound represented by the general formula [I] is a dihydrofuran derivative can include the following methods.

（式中、Ｒ_３及びＡは前記一般式［Ｉ］のＲ_３及びＡと同じである。Ｒ_１５〜Ｒ_２２はそれぞれ独立に水素原子、アルキル基又はアリール基である。Ｒ_２３はアルキル基である。）。

(Wherein, _{R 3} and A are the same as _{R 3} and A in the general formula _{[I] .R} 15 ~R ₂₂ independently represents a hydrogen atom, _{.R 23} is an alkyl group is an alkyl group or an aryl group .)

  The general formula (1a) can be synthesized by the production method described in JP-A-2004-2300.

(Step 1a) In this step, the compound represented by the general formula (2a) is produced by reacting the compound represented by the general formula (1a) with a compound having an R ₃ A substituent. is there. The reaction can be achieved by so-called Williamson synthesis, which is well known to those skilled in the art.

  (Step 2a) In this step, the compound represented by the general formula (3a) is produced by dehydrating the compound represented by the general formula (2a). In the reaction, thionyl chloride is allowed to act in the presence of a base such as pyridine, or an acid such as phosphoric acid or p-toluenesulfonic acid can be used as a catalyst. As the solvent, a halogenated hydrocarbon such as methylene chloride or an aromatic hydrocarbon such as toluene can be used, and it can be appropriately selected depending on the reagent to act.

  (Step 3a) In this step, the compound represented by the general formula (4a) is produced by deprotecting the compound represented by the general formula (3a). In the case of a compound represented by a methoxy group or a benzyloxy group, this reaction can be carried out by a method familiar to those skilled in the art, that is, by reacting an anion of alkylthiol or subjecting it to a hydrogenation reaction. Whether to select this reaction may be appropriately selected depending on the group to be deprotected.

  (Step 4a) In this step, the compound represented by the general formula (4a) is reacted with singlet oxygen to produce the 1,2-dioxetane derivative represented by the general formula (5a). The reaction with singlet oxygen is achieved by irradiation with visible light in an oxygen atmosphere in the presence of a photosensitizer such as methylene blue, rose bengal, tetraphenylporphine (TPP). At this time, the solvent may be a halogenated hydrocarbon such as dichloromethane, dichloroethane, or carbon tetrachloride, or an alcohol such as methanol or ethanol. The reaction is preferably performed at −80 ° C. to room temperature.

  Examples of the production method when the compound represented by the general formula [V] is a dihydrofuran derivative include the following methods.

（式中、Ａは前記一般式［Ｖ］のＡと同じであり、Ｒ_１４は前記一般式［Ｖ］のＲ_１４と同じである。Ｒ_２４〜Ｒ_２８はそれぞれ独立に水素原子、アルキル基又はアリール基である。Ｒ_２９はアルキル基である。Ｒ_３０はアルコキシル基又はハロゲン原子である。Ｒ_３１はハロゲン原子、置換スルホニルオキシ基又はヒドロキシル基である。）。

(Wherein, A is the same as A in the general formula _{[V], R 14} is the same as _{R 14 .R} 24 _{~R 28} independently represents a hydrogen atom in the general formula [V], the alkyl group R ₂₉ is an alkyl group, R ₃₀ is an alkoxyl group or a halogen atom, and R ₃₁ is a halogen atom, a substituted sulfonyloxy group or a hydroxyl group.

  Up to step 4b to obtain the above general formula (6b) can be synthesized by the production method described in JP-A-2002-338576.

(Step 5b) In this step, the compound represented by the general formula (7b) is produced by reacting the compound represented by the general formula (6b) with a compound having an R ₁₄ A substituent. is there. The reaction can be achieved by so-called Williamson synthesis, which is well known to those skilled in the art.

  (Step 6b) In this step, the compound represented by the general formula (8b) is produced by deprotecting the compound represented by the general formula (7b). In the case of a compound represented by a methoxy group or a benzyloxy group, this reaction can be carried out by a method familiar to those skilled in the art, that is, by reacting an anion of alkylthiol or subjecting it to a hydrogenation reaction. Whether to select this reaction may be appropriately selected depending on the group to be deprotected.

  (Step 7b) In this step, the compound represented by the general formula (8b) is reacted with singlet oxygen to produce the 1,2-dioxetane derivative represented by the general formula (9b). The reaction with singlet oxygen is achieved by irradiation with visible light in an oxygen atmosphere in the presence of a photosensitizer such as methylene blue, rose bengal, tetraphenylporphine (TPP). At this time, the solvent may be a halogenated hydrocarbon such as dichloromethane, dichloroethane, or carbon tetrachloride, or an alcohol such as methanol or ethanol. The reaction is preferably performed at −80 ° C. to room temperature.

  The 1,2-dioxetane derivatives represented by the general formulas [I] and [V] of the present invention are decomposed into carbonyl compounds with chemiluminescence in the presence of fluoride ions, under alkaline conditions or in the presence of alkaline phosphatase enzymes. To do. Therefore, the 1,2-dioxetane derivative represented by the general formula [I] or [V] can be used as a chemiluminescent reagent. In particular, in order to improve the light emission quantum yield, that is, to improve the light emission yield, it is preferable to perform the above-described decomposition reaction in the presence of a surfactant. Examples of the surfactant at this time include cationic surfactants such as cetyltrimethylammonium bromide (CTAB), benzalkonium chloride, benzethonium chloride, and tri-n-butylhexadecylphosphonium bromide. And ethyltriphenylphosphonium bromide, triheptylphenylphosphonium bromide, and tetradecyltriphenylphosphonium bromide.

  The chemiluminescent reagent of the invention can be used as an immunoassay reagent in an immunoassay, and can also be used in a chemical assay method, a nucleotide probe method, and the like. Thus, the substance in a sample can be measured using the light emitting method of the present invention.

  Examples of the measurement substance in the above-described immunoassay include hormones such as hCG, TSH, and LH, cancer-related substances such as AFP and CEA, virus antigens such as HIV and HTLV-I, and antibodies and nucleic acids (DNA, RNA). Etc.

  As the above-mentioned immunoassay method, for example, alkaline phosphatase enzyme is bound in advance to a substance having specific binding property to the above-described measurement substance, and this and a sample containing the detection substance are mixed and reacted for a certain period of time. Thus, the detection substance in the sample can be bound to the substance having the binding property and the process of determining the amount of the binding substance that has been bound or not bound. The step of determining the amount of the bound or unbound substance having the binding property includes adding the 1,2-dioxetane derivative of the present invention to the reaction system, and adding the alkaline substance bound to the specific binding substance. Since the luminescence intensity increases in proportion to the amount of the phosphatase enzyme, the concentration of the substance can be determined by measuring the luminescence intensity.

  The 1,2-dioxetane derivatives [I] and [V] of the present invention can exhibit stable light emission with a high quantum yield. Therefore, it is possible to efficiently measure luminescence. For example, it is useful because highly sensitive measurement such as immunoassay is possible in the field of clinical examination.

  Hereinafter, the present invention will be described in detail by way of examples. However, the present invention is not limited only to these examples.

  Example 1

窒素雰囲気下３−ヒドロキシ−３−（２−ヒドロキシ−１，１−ジメチルエチル）−２−（３−メトキシフェニル）−４，４−ジメチルテトラヒドロフラン（化合物［１］）（８６：１４立体異性体混合物，５０２ｍｇ，１．７１ｍｍｏｌ）を脱水ＤＭＦ（６ｍＬ）に溶解し、ＮａＨ（６０％ｉｎ ＯＩＬ，１２０ｍｇ，３．００ｍｍｏｌ）脱水ＤＭＦ（３ｍＬ）懸濁液に０℃にて滴下し、室温にて３０分攪拌した。この溶液に２−（４−ブロモメチル−２−メトキシフェニル）−ベンゾチアゾール（６７０ｍｇ，２．００ｍｍｏｌ）を０℃にて加え、室温にて１時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝１：６）にて精製し、３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジロキシ］−１，１−ジメチルエチル｝−ｒ−３−ヒドロキシ−ｔ−２−（３−メトキシフェニル）−４，４−ジメチルテトラヒドロフラン（化合物［２ａ］）を微黄色油状物として得た。収量７５８ｍｇ、収率８０．９％。また異性体として３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジロキシ］−１，１−ジメチルエチル｝−ｒ−３−ヒドロキシ−ｃ−２−（３−メトキシフェニル）−４，４−ジメチルテトラヒドロフラン（化合物［２ｂ］）を微黄色油状物として得た。収量１２３ｍｇ、収率１３．１％。

3-hydroxy-3- (2-hydroxy-1,1-dimethylethyl) -2- (3-methoxyphenyl) -4,4-dimethyltetrahydrofuran (compound [1]) (86:14 stereoisomer) under nitrogen atmosphere The mixture, 502 mg, 1.71 mmol) was dissolved in dehydrated DMF (6 mL) and added dropwise to a NaH (60% in OIL, 120 mg, 3.00 mmol) dehydrated DMF (3 mL) suspension at 0 ° C. at room temperature. Stir for 30 minutes. To this solution was added 2- (4-bromomethyl-2-methoxyphenyl) -benzothiazole (670 mg, 2.00 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (ethyl acetate: hexane = 1: 6) gave 3- {2- [4- (benzothiazol-2-yl) -3-methoxybenzyloxy] -1,1-dimethylethyl}. -R-3-hydroxy-t-2- (3-methoxyphenyl) -4,4-dimethyltetrahydrofuran (compound [2a]) was obtained as a slightly yellow oil. Yield 758 mg, yield 80.9%. In addition, 3- {2- [4- (benzothiazol-2-yl) -3-methoxybenzyloxy] -1,1-dimethylethyl} -r-3-hydroxy-c-2- (3-methoxy as an isomer Phenyl) -4,4-dimethyltetrahydrofuran (compound [2b]) was obtained as a pale yellow oil. Yield 123 mg, yield 13.1%.

[2a]
¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 0.88 (roads, 3H), 1.10 (s, 3H), 1.24 (s, 3H), 1.36 (s, 3H), 2.92 (d, J = 9.0 Hz, 1H), 3.66-3.76 (m, 1H), 3.79 (s, 3H), 3.89 (d, J = 8.1 Hz, 1H), 4.07 (s, 3H), 4 .23-4.47 (m, 2H), 4.65-5.00 (m, 1H), 5.09 (br-s, 1H), 6.83 (d with fine coupling, J = 7.9 Hz, 1H), 699-7.19 (m, 4H), 7.23 (t, J = 7.9 Hz, 1H), 7.38 (dd with fine coupling, J = 7.9 and 7.1 Hz, 1H), 7.49 (dd with fine coupling, J = 8.2 and 7.1 Hz, 1H), 7.93. (D with fine coupling, J = 7.9 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H) 8.49 (d, J = 8.1 Hz, 1H) ppm.

[2b]
¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.05 (s, 3H), 1.19 (s, 3H), 1.26 (s, 3H), 1.38 (s, 3H), 2.96 (d, J = 9.3 Hz, 1H), 3.23 (d, J = 9.3 Hz, 1H), 3.46 (d, J = 7.1 Hz, 1H), 3.74 (s, 3H), 3.83 (d, J = 12.1 Hz, 1 H), 3.92 (d, J = 12.1 Hz, 1 H), 4.05 (s, 3 H), 4.13 (d, J = 7.1 Hz, 1 H), 4.68 ( br-s, 1H), 5.28, (s, 1H), 6.82-6.88 (m, 3H), 7.12 (d with fine coupling, J = 7.6 Hz, 1H), 7.18. (S with fine coupling, 1H), 7.24 (dd, J = 8.1 and 7.6 Hz, 1H), 7.37 (dd with fine fineco uping, J = 7.9 and 7.2 Hz, 1H), 7.49 (dd with fine coupling, J = 8.2, and 7.2 Hz, 1H), 7.92 (d with fine coupling, J = 7.9 Hz, 1H) , 8.08 (d with fine coupling, J = 8.2 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H) ppm.

  (Example 2)

窒素雰囲気下３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジロキシ］−１，１−ジメチルエチル｝−３−ヒドロキシ−２−（３−メトキシフェニル）−４，４−ジメチルテトラヒドロフラン（化合物［２］）（６６６ｍｇ，１．２２ｍｍｏｌ）とピリジン（１．００ｍＬ，１２．２ｍｍｏｌ）を脱水ジクロロメタン（７ｍＬ）に溶解し、ＳＯＣｌ_２（０．１１，ｍＬ，１．５ｍｍｏｌ）を０℃にて滴下し３時間攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて２回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝１：４）にて精製し、４−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジロキシ］−１，１−ジメチルエチル｝−５−（３−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３］）を微黄色油状物として得た。収量５０４ｍｇ、収率７８．３％。

3- {2- [4- (benzothiazol-2-yl) -3-methoxybenzyloxy] -1,1-dimethylethyl} -3-hydroxy-2- (3-methoxyphenyl) -4, under nitrogen atmosphere 4-Dimethyltetrahydrofuran (compound [2]) (666 mg, 1.22 mmol) and pyridine (1.00 mL, 12.2 mmol) were dissolved in dehydrated dichloromethane (7 mL), and SOCl ₂ (0.11, mL, 1.5 mmol). ) Was added dropwise at 0 ° C. and stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (ethyl acetate: hexane = 1: 4) gave 4- {2- [4- (benzothiazol-2-yl) -3-methoxybenzyloxy] -1,1-dimethylethyl}. -5- (3-Methoxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [3]) was obtained as a pale yellow oil. Yield 504 mg, Yield 78.3%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.14 (s, 6H), 1.34 (s, 6H), 3.20 (s, 2H), 3.69 (s, 3H), 3.89 (s, 2H), 4.02 (S, 3H), 4.39 (s, 2H), 6.80-6.89 (m, 2H), 6.86 (d with fine coupling, J = 7.3 Hz, 1H), 6.99 (d with fine coupling, J = 8.1 Hz, 1H), 7.06 (s, 1H), 7.15-7.21 (m, 1H), 7.37 (dd with fine coupling, J = 7.8 and 7.3 Hz, 1H), 7.49 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.93 (d with fine coupling, J = 7.8, 1H), 8.08 (d with fine coupling) ng, J = 8.1 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.2 (CH ₃ × 2), 27.4 (CH ₃ × 2), 37.0 (C), 47.0 (C), 55.1 (CH ₃ ), 55.6 (CH ₃ ), 72.1 (CH ₂ ), 79.1 (CH ₂ ), 83.1 (CH ₂ ), 110.0 (CH), 114.1 (CH), 114.9 (CH), 119.5 (CH), 121.1 (C), 121.2 (CH), 122.1 (C), 122.2 (CH), 122.7 (CH), 124.5 (CH), 125.8 ( CH), 128.8 (CH), 129.3 (CH), 136.0 (C), 136.9 (C), 143.5 (C), 151.2 (C), 152.1 (C ), 157.3 (C), 159.0 (C), 163.0 (C) ppm.

  (Example 3)

窒素雰囲気下４−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジロキシ］−１，１−ジメチルエチル｝−５−（３−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３］）（３９５ｍｇ，０．７４６ｍｍｏｌ）を脱水ＤＭＦ（４ｍＬ）に溶解し、ＭｅＳＮａ（２１５ｍｇ，３．０７ｍｍｏｌ）を加えて、１４０℃にて３時間攪拌した。反応溶液に１Ｎ−ＨＣｌ水溶液を加え、ジクロロメタンにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）にて精製し、４−｛２−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジロキシ］−１，１−ジメチルエチル｝−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［４］）を無色固体として得た。収量２３９ｍｇ、収率６３．９％。

4- {2- [4- (Benzothiazol-2-yl) -3-methoxybenzyloxy] -1,1-dimethylethyl} -5- (3-methoxyphenyl) -3,3-dimethyl- under nitrogen atmosphere 2,3-dihydrofuran (compound [3]) (395 mg, 0.746 mmol) was dissolved in dehydrated DMF (4 mL), MeSNa (215 mg, 3.07 mmol) was added, and the mixture was stirred at 140 ° C. for 3 hours. 1N-HCl aqueous solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 4: 1) gave 4- {2- [4- (benzothiazol-2-yl) -3-hydroxybenzyloxy] -1,1-dimethylethyl}. -5- (3-hydroxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [4]) was obtained as a colorless solid. Yield 239 mg, yield 63.9%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.11 (s, 6H), 1.32 (s, 6H), 3.23 (s, 2H), 3.86 (s, 2H), 4.38 (s, 2H), 5.45 (Br-s, 1H), 6.78-6.90 (m, 4H), 7.14-7.20 (m.2H), 7.42 (dd with fine coupling, J = 7.9 and 7.3 Hz, 1H), 7.52 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.91 (d with fine coupling, J = 7.9 Hz) , 1H), 8.00 (d with fine coupling, J = 8.1 Hz, 1H), 12.76 (br-s, 1H) ppm.

  Example 4

４−｛２−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジロキシ］−１，１−ジメチルエチル｝−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［４］）（５０ｍｇ，０．０９９７ｍｍｏｌ）とＴＰＰ（１．２ｍｇ）をジクロロメタン（５ｍＬ）に溶解し、酸素雰囲気下、０℃にてナトリウムランプ（９４０Ｗ）を３０分照射した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（ジクロロメタン：ジエチルエーテル＝１：１５）にて精製し、５−｛２−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジロキシ］−１，１−ジメチルエチル｝−１−（３−ヒドロキシフェニル）−４，４−ジメチル−２，６，７−トリオキサビシクロ［３．２．０］ヘプタン（化合物［５］）を無色固体として定量的に得た。

4- {2- [4- (Benzothiazol-2-yl) -3-hydroxybenzyloxy] -1,1-dimethylethyl} -5- (3-hydroxyphenyl) -3,3-dimethyl-2,3 -Dihydrofuran (compound [4]) (50 mg, 0.0997 mmol) and TPP (1.2 mg) were dissolved in dichloromethane (5 mL) and irradiated with a sodium lamp (940 W) at 0 ° C for 30 minutes in an oxygen atmosphere. . The reaction solution was concentrated under reduced pressure, further purified by silica gel chromatography (dichloromethane: diethyl ether = 1: 15), and 5- {2- [4- (benzothiazol-2-yl) -3-hydroxybenzyloxy]- 1,1-dimethylethyl} -1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [5]) as a colorless solid Obtained quantitatively.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.00 (s, 3H), 1.14 (s, 3H), 1.16 (s, 3H), 1.37 (s, 3H), 3.37 (d, J = 9.0 Hz, 1H), 3.51 (d, J = 9.0 Hz, 1H), 3.80 (d, J = 8.1 Hz, 1H), 4.44 (q _AB = 13.3 Hz, 2H), 4.57 (D, J = 8.1, 1H), 5.23 (br-s, 1H), 6.83 (d with fine coupling, J = 8.1 Hz, 1H), 6.88 (d with fine coupling, J = 8.1 Hz, 1H), 7.00 (s with fine coupling, 1H), 7.07 (s with fine coupling, 1H), 7.15 (d, J = 7.8, 1H), 7.22 (dd, J = 8.1 and 7.8 Hz, 1H), 7.42 (dd w th fine coupling, J = 7.8 and 7.3 Hz, 1 H), 7.52 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1 H), 7.65 (d, J = 8.1 Hz, 1 H), 7. 92 (d with fine coupling, J = 7.8 Hz, 1H), 8.00 (d with fine coupling, J = 8.1 Hz, 1H), 12.66 (br-s, 1H) ppm.

  (Example 5)

窒素雰囲気下４−（７−エトキシカルボニル−１，１−ジメチル−３−オキサヘプト−１−イル）−５−（３−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［６］）（１．４８ｇ，３．６６ｍｍｏｌ）を脱水ＴＨＦ（８ｍＬ）に溶解し、この溶液をＬｉＡｌＨ_４（１４４ｍｇ，３．７９ｍｍｏｌ）脱水ＴＨＦ（６ｍＬ）懸濁液に０℃にて２０分かけて滴下し、室温にて３時間攪拌した。反応溶液に１Ｎ−ＨＣｌ水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）にて精製し、４−（８−ヒドロキシ−１，１−ジメチル−３−オキサオクト−１−イル）−５−（３−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［７］）を無色油状物として得た。収量１．２４ｇ、収率９３．５％。

4- (7-Ethoxycarbonyl-1,1-dimethyl-3-oxahept-1-yl) -5- (3-methoxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [ 6]) (1.48 g, 3.66 mmol) was dissolved in dehydrated THF (8 mL), and this solution was suspended in LiAlH ₄ (144 mg, 3.79 mmol) dehydrated THF (6 mL) at 0 ° C. for 20 minutes. And then stirred at room temperature for 3 hours. 1N-HCl aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 1: 1) gave 4- (8-hydroxy-1,1-dimethyl-3-oxaoct-1-yl) -5- (3-methoxyphenyl)- 3,3-Dimethyl-2,3-dihydrofuran (compound [7]) was obtained as a colorless oil. Yield 1.24 g, 93.5% yield.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.04 (s, 6H), 1.31 (s, 6H), 1.36-1.62 (m, 6H), 3.11 (s, 2H), 3.25 (t, J = 6.3 Hz, 2H), 3.64 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.87 (s, 2H), 6.86-6.88 (m, 2H), 6.91 (d with fine coupling, J = 7.3 Hz, 1H), 7.23 (dd with fine coupling, J = 7.8 and 7.3 Hz, 1H) ppm.

  (Example 6)

窒素雰囲気下４−（８−ヒドロキシ−１，１−ジメチル−３−オキサオクト−１−イル）−５−（３−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［７］）（１６９ｍｇ，０．４６６ｍｍｏｌ）を脱水ＤＭＦ（４ｍＬ）に溶解し、この溶液をＮａＨ（６０％ｉｎ ＯＩＬ，３０．２ｍｇ，０．７５５ｍｍｏｌ）脱水ＤＭＦ（１ｍＬ）懸濁液に０℃にて滴下し、室温にて３０分攪拌した。この溶液に２−（４−ブロモメチル−２−メトキシフェニル）ベンゾチアゾール（１８０ｍｇ，０．５３９ｍｍｏｌ）を０℃にて加え室温にて更に終夜攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝１：６）にて精製し、４−｛１０−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］−１，１−ジメチル−３，９−ジオキサデカ−１−イル｝−５−（３−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［８］）を微黄色油状物として得た。収量１１５ｍｇ、収率４０．１％。

4- (8-Hydroxy-1,1-dimethyl-3-oxaoct-1-yl) -5- (3-methoxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [7] under nitrogen atmosphere ] (169 mg, 0.466 mmol) was dissolved in dehydrated DMF (4 mL), and this solution was added to a suspension of NaH (60% in OIL, 30.2 mg, 0.755 mmol) dehydrated DMF (1 mL) at 0 ° C. The solution was added dropwise and stirred at room temperature for 30 minutes. To this solution was added 2- (4-bromomethyl-2-methoxyphenyl) benzothiazole (180 mg, 0.539 mmol) at 0 ° C., and the mixture was further stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (ethyl acetate: hexane = 1: 6) gave 4- {10- [4- (benzothiazol-2-yl) -3-methoxyphenyl] -1,1-dimethyl-3, 9-Dioxadec-1-yl} -5- (3-methoxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [8]) was obtained as a slightly yellow oil. Yield 115 mg, yield 40.1%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.04 (s, 6H), 1.30 (s, 6H), 1.40-1.71 (m, 6H), 3.11 (s, 2H), 3.26 (t, J = 6.5 Hz, 2H), 3.51 (t, J = 6.6 Hz, 2H), 3.79 (s, 3H), 3.86 (s, 2H), 4.06 (s, 3H), 4 .57 (s, 2H), 6.82-6.88 (m, 2H), 6.91 (d with fine coupling, J = 7.6 Hz, 1H), 7.05-7.10 (m, 2H) , 7.22 (dd, J = 8.1 and 7.6 Hz, 1H), 7.36 (dd with fine coupling, J = 8.1 and 7.1 Hz, 1H), 7.48 (dd with fine coupling, J = 8.1 and 7 .1Hz, 1H), 7.92 (d with fine coupling) g, J = 8.1Hz, 1H), 8.08 (d, J = 8.1Hz, 1H), 8.48 (d, J = 7.8Hz, 1H) ppm.

  (Example 7)

窒素雰囲気下４−｛１０−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］−１，１−ジメチル−３，９−ジオキサデカ−１−イル｝−５−（３−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［８］）（３４６ｍｇ，０．５６２ｍｍｏｌ）をＤＭＦ（２ｍＬ）に溶解し、ＭｅＳＮａ（１２０ｍｇ，１．７１ｍｍｏｌ）を加えて、１４０℃にて２時間攪拌した。更にＭｅＳＮａ（４０．２ｍｇ，０．５７４ｍｍｏｌ）を加えて、１４０℃にて２時間攪拌した。反応溶液に１Ｎ−ＨＣｌ水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ジクロロメタン→ジクロロメタン：ジエチルエーテル＝１９：１）にて精製し、４−｛１０−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシフェニル］−１，１−ジメチル−３，９−ジオキサデカ−１−イル｝−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［９］）を微黄色油状物として得た。収量１６９ｍｇ、収率５１．２％。

4- {10- [4- (Benzothiazol-2-yl) -3-methoxyphenyl] -1,1-dimethyl-3,9-dioxadec-1-yl} -5- (3-methoxyphenyl) under nitrogen atmosphere ) -3,3-dimethyl-2,3-dihydrofuran (compound [8]) (346 mg, 0.562 mmol) was dissolved in DMF (2 mL), MeSNa (120 mg, 1.71 mmol) was added, and 140 ° C. For 2 hours. Further, MeSNa (40.2 mg, 0.574 mmol) was added and stirred at 140 ° C. for 2 hours. 1N-HCl aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (dichloromethane → dichloromethane: diethyl ether = 19: 1) gave 4- {10- [4- (benzothiazol-2-yl) -3-hydroxyphenyl] -1,1-dimethyl- 3,9-Dioxadec-1-yl} -5- (3-hydroxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [9]) was obtained as a slightly yellow oil. Yield 169 mg, 51.2% yield.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.04 (s, 6H), 1.31 (s, 6H), 1.42-1.72 (m, 6H), 3.09 (s, 2H), 3.25 (t, J = 5.9 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H), 3.87 (s, 2H), 4.55 (s, 2H), 6.79 (d with fine coupling, J = 8.1 Hz, 1H), 6.84-6.88 (m, 2H), 6.97 (d with fine coupling, J = 8.1 Hz, 1 H), 7.09 (s with fine coupling, 1 H), 7. 17 (t with fine coupling, J = 8.1 Hz, 1H), 7.41 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.51 (dd with fine coupling, J = 8. 1 and 7.3 Hz, 1 H), 7.67 (d, J = 8.1 Hz, 1 H), 7.91 (d with fine coupling, J = 8.1 Hz, 1 H), 7.99 (d with fine coupling, J = 8 .1 Hz, 1 H), 12.57 (br-s, 1 H) ppm.

  (Example 8)

４−｛１０−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシフェニル］−１，１−ジメチル−３，９−ジオキサデカ−１−イル｝−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［９］）（４６．４ｍｇ，０．０７８９ｍｍｏｌ）とＴＰＰ（１．５ｍｇ）をジクロロメタン（５ｍｌ）に溶解し、酸素雰囲気下、０℃にてナトリウムランプ（９４０Ｗ）を３０分照射した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（ジクロロメタン→ジクロロメタン：ジエチルエーテル＝１：３）にて精製し、５−｛１０−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシフェニル］−１，１−ジメチル−３，９−ジオキサデカ−１−イル｝−１−（３−ヒドロキシフェニル）−４，４−ジメチル−２，６，７−トリオキサビシクロ［３．２．０］ヘプタン（化合物［１０］）を無色固体として得た。収量４２．５ｍｇ、収率８６．９％。

4- {10- [4- (Benzothiazol-2-yl) -3-hydroxyphenyl] -1,1-dimethyl-3,9-dioxadec-1-yl} -5- (3-hydroxyphenyl) -3 , 3-Dimethyl-2,3-dihydrofuran (compound [9]) (46.4 mg, 0.0789 mmol) and TPP (1.5 mg) were dissolved in dichloromethane (5 ml), and at 0 ° C. in an oxygen atmosphere. A sodium lamp (940 W) was irradiated for 30 minutes. The reaction solution was concentrated under reduced pressure, and further purified by silica gel chromatography (dichloromethane → dichloromethane: diethyl ether = 1: 3) to give 5- {10- [4- (benzothiazol-2-yl) -3-hydroxyphenyl]. -1,1-dimethyl-3,9-dioxadec-1-yl} -1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (Compound [10]) was obtained as a colorless solid. Yield 42.5 mg, yield 86.9%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 0.91 (s, 3H), 1.10 (s, 3H), 1.14 (s, 3H), 1.37 (s, 3H), 1.34-1.68 (m, 6H) 3.24-3.38 (m, 4H), 3.50 (t, J = 6.5 Hz, 2H), 3.80 (d, J = 8.2 Hz, 1H), 4.53 (s, 2H), 4.57 (d, J = 8.2 Hz, 1H), 5.58 (br-s, 1H), 6.86 (d with fine coupling, J = 8.1, 1H), 6.95 ( d with fine coupling, J = 8.1 Hz, 1H), 7.10 (s with fine coupling, 1H), 7.14 (s with fine coupling, 1H), 7.18 (d with fine coupling, J = 7 Hz) ), 7.26 (dd, J = 8. and 7.8 Hz, 1 H), 7.42 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1 H), 7.51 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1 H), 7.68 (d , J = 8.1 Hz, 1H), 7.91 (d with fine coupling, J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 12.64 (br-s, 1H) ppm.

  Example 9

窒素雰囲気下５−［３−（ｔ−ブチルジメチルシロキシ）フェニル］−４−（１，１−ジメチル−７−スクシンイミドキシカルボニル−３−オキサヘプト−１−イル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１１］）（２１４ｍｇ，０．３７３ｍｍｏｌ）をアセトニトリル（２ｍＬ）に溶解し、２−（４−アミノメチル−２−メトキシフェニル）ベンゾチアゾール（１０６ｍｇ，０．３９２ｍｍｏｌ）を室温にて加え、５時間攪拌した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝１：２）にて精製し、４−（７−｛Ｎ−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−１−イル）−５−［３−（ｔ−ブチルジメチルシロキシ）フェニル］−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１２］）を無色油状物として得た。収量２１８ｍｇ、収率８０．２％。

5- [3- (t-butyldimethylsiloxy) phenyl] -4- (1,1-dimethyl-7-succinimidoxycarbonyl-3-oxahept-1-yl) -3,3-dimethyl-2 under nitrogen atmosphere 3-Dihydrofuran (compound [11]) (214 mg, 0.373 mmol) was dissolved in acetonitrile (2 mL), and 2- (4-aminomethyl-2-methoxyphenyl) benzothiazole (106 mg, 0.392 mmol) was dissolved at room temperature. And stirred for 5 hours. The reaction solution was concentrated under reduced pressure and further purified by silica gel chromatography (ethyl acetate: hexane = 1: 2) to give 4- (7- {N- [4- (benzothiazol-2-yl) -3-methoxybenzyl]. ] Carbamoyl} -1,1-dimethyl-3-oxahept-1-yl) -5- [3- (t-butyldimethylsiloxy) phenyl] -3,3-dimethyl-2,3-dihydrofuran (compound [12 ]) As a colorless oil. Yield 218 mg, yield 80.2%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 0.17 (s, 6H), 0.97 (s, 9H), 1.02 (s, 6H), 1.29 (s, 6H), 1.55-1.64 (m, 2H) , 1.71-1.80 (m, 2H), 2.30 (t, J = 7.6 Hz, 2H), 3.10 (s, 2H), 3.27 (t, J = 6.1 Hz, 2H), 3.84 (s, 2H), 4.02 (s, 3H), 4.49 (d, J = 5.9 Hz, 2H), 5.95 (br-s, 1H), 6.74. −6.79 (m, 2H), 6.89 (d with fine coupling, J = 7.6 Hz, 1H), 6.98 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H) 7.15 (dd, J = 7.8 and 7.6 Hz, 1H), 7.37 (dd with fine coupling, J = 8.1 and 7.1 Hz, 1H), .49 (dd with fine coupling, J = 8.1 and 7.1 Hz, 1H), 7.92 (d with fine coupling, J = 8.1 Hz, 1H), 8.07 (d with fine coupling, J = 8.1 Hz, 1H) ) 8.47 (d, J = 8.1 Hz, 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C −4.4 (CH ₃ × 2), 18.1 (C), 22.9 (CH ₂ ), 25.6 (CH ₃ × 3), 27.2 (CH ₃ × 2), 27. 4 (CH ₃ × 2), 29.0 (CH ₂ ), 36.4 (CH ₂ ), 37.0 (C), 43.3 (CH ₂ ), 47.0 (C), 55.7 ( CH ₃ ), 70.7 (CH ₂ ), 79.7 (CH ₂ ), 83.0 (CH ₂ ), 111.0 (CH), 119.8 (CH), 120.2 (CH), 121 .2 (CH), 121.4 (C), 121.7 (CH), 122.3 (C), 122.7 (CH), 123.0 (CH), 124.6 (CH), 125. 9 (CH), 128.7 (CH), 129.7 (CH), 136.0 (C), 137.1 (C), 142.8 (C), 151.0 (C), 152.1 (C) 155.0 (C), 157.3 (C), 162.8 (C), 172.9 (C) ppm.

  (Example 10)

窒素雰囲気下４−（７−｛Ｎ−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−１−イル）−５−［３−（ｔ−ブチルジメチルシロキシ）フェニル］−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１２］）（１６３ｍｇ，０．２２４ｍｍｏｌ）を脱水ＤＭＦ（２５ｍＬ）に溶解し、塩化リチウム（１０２ｍｇ，２．４１ｍｍｏｌ）を室温にて加え、１６０℃にて７時間３０分、１７５℃にて終夜攪拌し、更に塩化リチウム（９０ｍｇ，２．１２ｍｍｏｌ）を加え１７５℃にて４時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝２：１）にて精製し４−（７−｛Ｎ−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−１−イル）−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１３］）を無色固体として得た。収量７９．１ｍｇ、収率５８．９％。

4- (7- {N- [4- (Benzothiazol-2-yl) -3-methoxybenzyl] carbamoyl} -1,1-dimethyl-3-oxahept-1-yl) -5- [3 under nitrogen atmosphere -(T-Butyldimethylsiloxy) phenyl] -3,3-dimethyl-2,3-dihydrofuran (compound [12]) (163 mg, 0.224 mmol) was dissolved in dehydrated DMF (25 mL), and lithium chloride (102 mg , 2.41 mmol) was added at room temperature, and the mixture was stirred at 160 ° C. for 7 hours 30 minutes and at 175 ° C. overnight. Further lithium chloride (90 mg, 2.12 mmol) was added, and the mixture was stirred at 175 ° C. for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (ethyl acetate: hexane = 2: 1) gave 4- (7- {N- [4- (benzothiazol-2-yl) -3-hydroxybenzyl] carbamoyl} -1,1- Dimethyl-3-oxahept-1-yl) -5- (3-hydroxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [13]) was obtained as a colorless solid. Yield 79.1 mg, Yield 58.9%.

¹ H-NMR (500 MHz, CDCl ₃ ):
δ _H 1.01 (s, 6H), 1.29 (s, 6H), 1.57-1.64 (m, 2H), 1.77-1.90 (m, 2H), 2.35 ( t, J = 7.2 Hz, 2H), 3.10 (s, 2H), 3.29 (t, J = 5.7 Hz, 2H), 3.85 (s, 2H), 4.50 (d, J = 5.8 Hz, 2H), 5.91 (br-s, 1H), 6.79 (d with fine coupling, J = 7.6 Hz, 1H), 6.83 (d with fine coupling, J = 8.1 Hz) , 1H), 6.90 (d, J = 8.0 Hz, 1H), 7.00 (s with fine coupling, 1H), 7.03 (s with fine coupling, 1H), 7.16 (dd, J = 8 .1 and 7.6 Hz, 1 H), 7.42 (dd with inecoupling, J = 8.1 and 7.1 Hz, 1H), 7.51 (dd with fine coupling, J = 8.1 and 7.1 Hz, 1H), 7.66, (d, J = 8.0 Hz, 1H), 7. 91 (d, J = 8.1 Hz, 1H), 7.9 (d, J = 8.1 Hz, 1H), 8.32 (s, 1H), 12.60 (brs, 1H) ppm.

  (Example 11)

４−（７−｛Ｎ−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−１−イル）−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１３］）（４３．４ｍｇ，０．０７２２ｍｍｏｌ）とＴＰＰ（１．３ｍｇ）をジクロロメタン（５ｍｌ）に溶解し、酸素雰囲気下０℃にてナトリウムランプ（９４０Ｗ）を３０分照射した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（ジクロロメタン→ジクロロメタン：ジエチルエーテル＝１：３）にて精製し、５−（７−｛Ｎ−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−１−イル）−１−（３−ヒドロキシフェニル）−４，４−ジメチル−２，６，７−トリオキサビシクロ［３．２．０］ヘプタン（化合物［１４］）を無色固体として得た。収量４５．１ｍｇ、収率９８．７％。

4- (7- {N- [4- (Benzothiazol-2-yl) -3-hydroxybenzyl] carbamoyl} -1,1-dimethyl-3-oxahept-1-yl) -5- (3-hydroxyphenyl ) -3,3-dimethyl-2,3-dihydrofuran (compound [13]) (43.4 mg, 0.0722 mmol) and TPP (1.3 mg) were dissolved in dichloromethane (5 ml) and dissolved at 0 ° C. in an oxygen atmosphere. Was irradiated with a sodium lamp (940 W) for 30 minutes. The reaction solution was concentrated under reduced pressure, and further purified by silica gel chromatography (dichloromethane → dichloromethane: diethyl ether = 1: 3) to give 5- (7- {N- [4- (benzothiazol-2-yl) -3- Hydroxybenzyl] carbamoyl} -1,1-dimethyl-3-oxahept-1-yl) -1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2. 0] heptane (compound [14]) was obtained as a colorless solid. Yield 45.1 mg, yield 98.7%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 0.87, (s, 3H), 1.04 (s, 3H), 1.12 (s, 3H), 1.35 (s, 3H), 1.50-1.82 (m, 4H) ), 2.27-2.43 (m, 2H), 3.23 (d, J = 9.3 Hz, 1H), 3.29-3.42 (m, 2H), 3.5 (d, J = 9.3 Hz, 1H), 3.80 (d, J = 8.0 Hz, 1H), 4.50 (q _ABd , J = 15.0 and 5.8 Hz, 2H), 4.54 (d, J = 8 0.0 Hz, 1H), 6.35 (t, J = 5.8 Hz, 1H), 6.89 (d with fine coupling, J = 8.1 Hz, 1H), 6.96 (d with fine coupling, J = 8. 1 Hz, 1H), 7.06-7.10 (m, 2H), 7.22-7.28 (m, 2H), 7.41 (dd wit) fine coupling, J = 7.9 and 7.3 Hz, 1H), 7.51 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.90. (D with fine coupling, J = 7.9 Hz, 1H), 7.9, (d with fine coupling, J = 8.1 Hz, 1H), 12.72 (brs, 1H) ppm.

  (Example 12)

窒素雰囲気下５−［３−（ｔ−ブチルジメチルシロキシ）フェニル］−４−（７−カルボキシ−１，１−ジメチル−３−オキサヘプト−１−イル）−３，３−ジメチル−２，３−ジヒドロキシフラン（化合物［１５］）（１０８ｍｇ，０．２２７ｍｍｏｌ）を脱水ジクロロメタン（１ｍＬ）に溶解し、室温にてＳＯＣｌ_２（０．０２ｍＬ，０．２７４ｍｍｏｌ）を加えて３時間攪拌した。反応溶液を減圧濃縮し、窒素雰囲気下にて脱水ＴＨＦ（１ｍＬ）にて溶解した。この溶液に［３’，６’−ジ（ｔ−ブチルジメチルシロキシ）−３−オキソスピロ［イソベンゾフラン−１（３Ｈ），９’−（９Ｈ）キサンテン］−５−イル］アミン（１３５ｍｇ，０．２３４ｍｍｏｌ）とピリジン（０．０２ｍＬ，０．２４７ｍｍｏｌ）を加え終夜攪拌した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝３：１）にて精製し、５−［３−（ｔ−ブチルジメチルシロキシ）フェニル］−４−（７−｛Ｎ−［３’，６’−ジヒドロキシ−３−オキソスピロ（イソベンゾフラン−１（３Ｈ），９’−（９Ｈ）キサンテン）−５−イル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−７−イル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１６］）を橙色固体として得た。収量１３０ｍｇ、収率７１．２％。

5- [3- (t-Butyldimethylsiloxy) phenyl] -4- (7-carboxy-1,1-dimethyl-3-oxahept-1-yl) -3,3-dimethyl-2,3- under nitrogen atmosphere Dihydroxyfuran (compound [15]) (108 mg, 0.227 mmol) was dissolved in dehydrated dichloromethane (1 mL), and SOCl ₂ (0.02 mL, 0.274 mmol) was added at room temperature, followed by stirring for 3 hours. The reaction solution was concentrated under reduced pressure and dissolved in dehydrated THF (1 mL) under a nitrogen atmosphere. To this solution was added [3 ′, 6′-di (t-butyldimethylsiloxy) -3-oxospiro [isobenzofuran-1 (3H), 9 ′-(9H) xanthen] -5-yl] amine (135 mg,. 234 mmol) and pyridine (0.02 mL, 0.247 mmol) were added and stirred overnight. The reaction solution was concentrated under reduced pressure and further purified by silica gel chromatography (ethyl acetate: hexane = 3: 1) to give 5- [3- (t-butyldimethylsiloxy) phenyl] -4- (7- {N- [ 3 ′, 6′-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9 ′-(9H) xanthen) -5-yl] carbamoyl} -1,1-dimethyl-3-oxahept-7-yl) -3,3-dimethyl-2,3-dihydrofuran (compound [16]) was obtained as an orange solid. Yield 130 mg, 71.2% yield.

¹ H-NMR (500 MHz, CD ₃ OD):
δ _H 0.19 (s, 6H), 0.98 (s, 9H), 1.05 (s, 6H), 1.31 (s, 6H), 1.61-1.69 (m, 2H) 1.76-1.845 (m, 2H), 2.46 (t, J = 7.3 Hz, 2H), 3.14 (s, 2H), 3.28-3.35 (m, 2H) 3.83 (s, 2H), 6.51-6.58 (m, 4H), 6.60-6.70 (m, 4H), 6.75 (s with fine coupling, 1H), 6.81. (D with fine coupling, J = 8.2 Hz, 1H), 6.89 (d with fine coupling, J = 7.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.20 ( dd, J = 8.2 and 7.6 Hz, 1H), 7.83-7.90 (m, 1H), 8.29 ( br-s, 1H) ppm.

  (Example 13)

窒素雰囲気下５−［３−（ｔ−ブチルジメチルシロキシ）フェニル］−４−（７−｛Ｎ−［３’，６’−ジヒドロキシ−３−オキソスピロ（イソベンゾフラン−１（３Ｈ），９’−（９Ｈ）キサンテン）−５−イル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−７−イル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１６］）（９３．１ｍｇ，０．１１６ｍｍｏｌ）を脱水ＴＨＦ（０．５ｍＬ）に溶解し、室温にてテトラブチルアンモニウムフルオライド（１Ｍ ＴＨＦ溶液０．４０ｍＬ，０．４０ｍｍｏｌ）を加え１時間攪拌した。反応溶液に１Ｎ−ＨＣｌ水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝９：１）にて精製し、４−（７−｛Ｎ−［３’，６’−ジヒドロキシ−３−オキソスピロ（イソベンゾフラン−１（３Ｈ），９’−（９Ｈ）キサンテン）−５−イル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−１−イル）−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１７］）を橙色固体として得た。収量５６．６ｍｇ、収率７０．８％。

5- [3- (t-butyldimethylsiloxy) phenyl] -4- (7- {N- [3 ′, 6′-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9′-) under nitrogen atmosphere (9H) Xanthen) -5-yl] carbamoyl} -1,1-dimethyl-3-oxahept-7-yl) -3,3-dimethyl-2,3-dihydrofuran (compound [16]) (93.1 mg , 0.116 mmol) was dissolved in dehydrated THF (0.5 mL), tetrabutylammonium fluoride (1 M THF solution 0.40 mL, 0.40 mmol) was added at room temperature, and the mixture was stirred for 1 hour. 1N-HCl aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (ethyl acetate: hexane = 9: 1) gave 4- (7- {N- [3 ′, 6′-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9 ′). -(9H) xanthen) -5-yl] carbamoyl} -1,1-dimethyl-3-oxahept-1-yl) -5- (3-hydroxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (Compound [17]) was obtained as an orange solid. Yield 56.6 mg, Yield 70.8%.

¹ H-NMR (500 MHz, CD ₃ OD):
δ _H 1.06 (s, 6H), 1.30 (s, 6H), 1.60-1.70 (m, 2H), 1.76-1.84 (m, 2H), 2.46 ( t, J = 7.4 Hz, 2H), 3.13 (s, 2H), 3.27-3.32 (m, 2H), 3.82 (s, 2H), 6.53 (dd, J = 8.7 and 2.3 Hz, 2H), 6.63 (br-d, J = 8.7 Hz, 2H), 6.66 (d, J = 2.3 Hz, 2H), 6.71-6.76 (m) 3H), 7.11-7.16 (m, 2H), 7.86 (d, J = 8.5 Hz, 1H), 8.31 (br-s, 1H) ppm.

  (Example 14)

４−（７−｛Ｎ−［３’，６’−ジヒドロキシ−３−オキソスピロ（イソベンゾフラン−１（３Ｈ），９’−（９Ｈ）キサンテン）−５−イル］カルバモイル｝−１，１−ジメチル−３−オキサヘプト−１−イル）−５−（３−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１７］）（４９．４ｍｇ，０．０７１４ｍｍｏｌ）とＴＰＰ（１．０ｍｇ）をジクロロメタン（５ｍｌ）とＣＨ_３ＯＨ（５ｍＬ）に溶解し、酸素雰囲気下０℃にてナトリウムランプ（９４０Ｗ）を３時間照射した。反応溶液を減圧濃縮し、更にジクロロメタンとクロロホルムにてリンスし、５−（７−｛Ｎ−［３’，６’−ジヒドロキシ−３−オキソスピロ（イソベンゾフラン−１（３Ｈ），９’−（９Ｈ）キサンテン）−５−イル］−カルバモイル｝−１，１−ジメチル−３−オキサヘプト−８−イル）−１−（３−ヒドロキシフェニル）−４，４−ジメチル−２，６，７−トリオキサビシクロ［３．２．０］ヘプタン（化合物［１８］）を橙色固体として得た。収量２６．８ｍｇ、収率５１．９％。

4- (7- {N- [3 ', 6'-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9'-(9H) xanthen) -5-yl] carbamoyl} -1,1-dimethyl -3-oxahept-1-yl) -5- (3-hydroxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [17]) (49.4 mg, 0.0714 mmol) and TPP (1 0.0 mg) was dissolved in dichloromethane (5 ml) and CH ₃ OH (5 mL), and irradiated with a sodium lamp (940 W) at 0 ° C. under an oxygen atmosphere for 3 hours. The reaction solution was concentrated under reduced pressure and further rinsed with dichloromethane and chloroform to give 5- (7- {N- [3 ′, 6′-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9 ′-(9H ) Xanthen) -5-yl] -carbamoyl} -1,1-dimethyl-3-oxahept-8-yl) -1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxa Bicyclo [3.2.0] heptane (compound [18]) was obtained as an orange solid. Yield 26.8 mg, Yield 51.9%.

¹ H-NMR (400 MHz, CD ₃ OD):
δ _H 0.87 (s, 3H), 1.13 (s, 3H), 1.17 (s, 3H), 1.39 (s, 3H), 1.56-1.66 (m, 2H) , 1.71-1.82 (m, 2H), 2.45 (t, J = 7.1 Hz, 2H), 3.24 (d, J = 9.1 Hz, 1H), 3.33-3. 41 (m, 3H), 3.79 (d, J = 8.1 Hz, 1H), 4.47 (d, J = 8.1 Hz, 1H), 6.55 (d with fine coupling, J = 8.7 Hz) , 2H), 6.62-6.74 (m, 4H), 6.82 (d with fine coupling, J = 8.0 Hz, 1H), 7.03-7.08 (m, 2H), 7.15. (D, J = 8.5 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.83-7.92 (m, 1H), 8.29 ( r-s, 1H) ppm.

  (Example 15)

窒素雰囲気下、４−ｔ−ブチル−５−（３−ヒドロキシ−５−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［１９］）（５００ｍｇ，１．８１ｍｍｏｌ）を脱水ＤＭＦ（３ｍＬ）に溶解し、ＮａＨ（６０％ｉｎ ＯＩＬ，８０ｍｇ，２．０ｍｍｏｌ）の脱水ＤＭＦ（２ｍＬ）懸濁液に滴下し、室温にて４０分攪拌した。この溶液に４−（ベンゾチアゾール−２−イル）−３−メトキシベンジルブロミド（６３５ｍｇ，１．９０ｍｍｏｌ）を加え、室温にて更に１時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：ジクロロメタン＝１：２）にて精製し、４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジロキシ］−５−メトキシフェニル｝−３，３−ジメチル−２，３−ジヒドロフラン（化合物［２０］）を無色アモルファス状固体として得た。収量８０．７ｍｇ、収率８４．０％。

4-t-butyl-5- (3-hydroxy-5-methoxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [19]) (500 mg, 1.81 mmol) was dehydrated under a nitrogen atmosphere. It melt | dissolved in DMF (3 mL), it was dripped at the dehydrated DMF (2 mL) suspension of NaH (60% in OIL, 80 mg, 2.0 mmol), and it stirred at room temperature for 40 minutes. 4- (Benzothiazol-2-yl) -3-methoxybenzyl bromide (635 mg, 1.90 mmol) was added to this solution, and the mixture was further stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: dichloromethane = 1: 2) gave 4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-methoxybenzyloxy] -5- Methoxyphenyl} -3,3-dimethyl-2,3-dihydrofuran (compound [20]) was obtained as a colorless amorphous solid. Yield 80.7 mg, Yield 84.0%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.04 (s, 9H), 1.32 (s, 6H), 3.79 (s, 3H), 3.87 (s, 2H), 4.06 (s, 3H), 5.12 (S, 2H), 6.49 (s with fine coupling, 1H), 6.53 (s with fine coupling, 1H), 6.55 (s with fine coupling, 1H), 7.15 (s, 1H), 7. 16 (d, J = 8.5 Hz, 1H), 7.37 (dd with fine coupling, J = 8.1 and 7.1 Hz, 1 H), 7.49 (dd with fine coupling, J = 8.3 and 7.1 Hz, 1 H) 7.93 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.4 (CH ₃ × 2), 32.3 (CH ₃ × 3), 32.4 (C), 47.1 (C), 55.4 (CH ₃ ), 55.7 (CH ₃ ), 69.6 (CH ₂ ), 83.1 (CH ₂ ), 101.4 (CH), 108.4 (CH), 108.9 (CH), 110.3 (CH), 119.7 ( CH), 121.2 (CH), 121.8 (C), 122.7 (CH), 124.5 (CH), 125.4 (C), 125.9 (CH), 129.7 (CH) ), 136.1 (C), 138.1 (C), 141.1 (C), 149.6 (C), 152.1 (C), 157.4 (C), 159.1 (C) , 160.3 (C), 162.8 (C) ppm
Mass (m / z,%):
530 (M ^{+ +1,} 11), 529 (M ⁺ , 29), 516 (13), 515 (38), 514 (100), 257 (12), 256 (12), 255 (46), 254 (93 ).

  (Example 16)

窒素雰囲気下４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジロキシ］−５−メトキシフェニル｝−３，３−ジメチル−２，３−ジヒドロフラン（化合物［２０］）（３００ｍｇ，０．５６６ｍｍｏｌ）を脱水ＤＭＦ（３ｍＬ）に溶解し、ＭｅＳＮａ（１５８ｍｇ，２．２５ｍｍｏｌ）を加えて、１４０℃にて２時間攪拌した。反応溶液に１Ｎ−ＨＣｌ水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝６：１）にて精製し、４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジロキシ］−５−ヒドロキシフェニル｝−３，３−ジメチル−２，３−ジヒドロフラン（化合物［２１］）を無色アモルファス状固体として得た。収量１９９ｍｇ、収率７０．０％。

4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-methoxybenzyloxy] -5-methoxyphenyl} -3,3-dimethyl-2,3-dihydro under nitrogen atmosphere Furan (compound [20]) (300 mg, 0.566 mmol) was dissolved in dehydrated DMF (3 mL), MeSNa (158 mg, 2.25 mmol) was added, and the mixture was stirred at 140 ° C. for 2 hr. 1N-HCl aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 6: 1) gave 4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyloxy] -5. -Hydroxyphenyl} -3,3-dimethyl-2,3-dihydrofuran (compound [21]) was obtained as a colorless amorphous solid. Yield 199 mg, yield 70.0%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.04 (s, 9H), 1.31 (s, 6H), 3.86 (s, 2H), 4.89 (br-s, 1H), 5.06 (s, 2H), 6 .41 (s with fine coupling, 1H), 6.44 (s with fine coupling, 1H), 6.52 (s with fine coupling, 1H), 7.00 (d, J = 8.1 Hz, 1H), 7.15 (S with fine coupling, 1H), 7.41 (dd with fine coupling, J = 8.1 and 7.1 Hz, 1H), 7.51 (dd with fine coupling, J = 8.3 and 7.1 Hz, 1H), 7.68 ( d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 1 2.56 (br-s, 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.3 (CH ₃ × 2), 32.3 (CH ₃ × 3), 32.4 (C), 47.1 (C), 69.2 (CH ₂ ), 83.0 (CH ₂ ), 102.6 (CH), 108.9 (CH), 110.3 (CH), 116.0 (CH), 116.1 (C), 118.0 (CH), 121.4 (CH) , 122.1 (CH), 125.5 (CH), 125.8 (C), 126.6 (CH), 128.5 (CH), 132.5 (C), 137.9 (C), 142.2 (C), 149.2 (C), 151.7 (C), 156.4 (C), 157.8 (C), 159.2 (C), 169.0 (C) ppm
Mass (m / z,%):
502 (M ^{+ +1,} 12), 501 (M ⁺ , 31), 488 (10), 487 (32), 486 (100), 256 (20), 241 (32), 240 (44), 213 (15 ), 212 (98).

  (Example 17)

４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジロキシ］−５−ヒドロキシフェニル｝−３，３−ジメチル−２，３−ジヒドロフラン（化合物［２１］）（１００ｍｇ，０．１９９ｍｍｏｌ）とＴＰＰ（１ｍｇ）をジクロロメタン（１０ｍＬ）に溶解し、酸素雰囲気下、０℃にてナトリウムランプ（９４０Ｗ）を３０分照射した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（ジクロロメタン：ジエチルエーテル＝５０：１）にて精製し、５−ｔ−ブチル−１−｛３−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジロキシ］−５−ヒドロキシフェニル｝−４，４−ジメチル−２，６，７−トリオキサビシクロ［３．２．０］ヘプタン（化合物［２２］）を無色固体として得た。収量１０６ｍｇ、収率９９．６％。

4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyloxy] -5-hydroxyphenyl} -3,3-dimethyl-2,3-dihydrofuran (compound [21]) (100 mg, 0.199 mmol) and TPP (1 mg) were dissolved in dichloromethane (10 mL), and irradiated with a sodium lamp (940 W) at 0 ° C. for 30 minutes in an oxygen atmosphere. The reaction solution was concentrated under reduced pressure and further purified by silica gel chromatography (dichloromethane: diethyl ether = 50: 1) to give 5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3. -Hydroxybenzyloxy] -5-hydroxyphenyl} -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [22]) was obtained as a colorless solid. Yield 106 mg, yield 99.6%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 0.96 (s, 9H), 1.12 (s, 3H), 1.32 (s, 3H), 3.79 (d, J = 8.2 Hz, 1H), 4.55 (d, J = 8.2 Hz, 1H), 5.05 (br-s, 1H), 5.09 (q _AB , J = 12.7 Hz, 2H), 6.52 (s with fine coupling, 1H), 6.74. (S, 1H), 6.80 (s, 1H), 7.00 (d with fine coupling, J = 8.1 Hz, 1H), 7.16 (s with fine coupling, 1H), 7.42 (dd with fine coupling) , J = 7.8 and 7.2 Hz1H), 7.52 (dd with fine coupling, J = 8.3 and 7.2 Hz1H), 7.68 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 12.56 (br-s, 1 H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 18.4 (CH ₃ ), 24.9 (CH ₃ ), 26.9 (CH ₃ × 3), 36.7 (C), 45.5 (C), 69.3 (CH ₂ ), 80.2 (CH ₂ ), 103.8 (CH), 105.2 (C), 107.5 (CH), 108.7 (CH), 116.1 (CH), 116.2 (C), 116.4 (C), 118.0 (CH), 121.5 (CH), 122.1 (CH), 125.5 (CH), 126.7 (CH), 128.6 (CH), 132 .5 (C), 138.3 (C), 142.1 (C), 151.7 (C), 156.5 (C), 157.9 (C), 159.3 (C), 168. 9 (C) ppm
Mass (m / z,%):
534 (M ^{+ +1,} 12), 533 (M ⁺ , 33), 376 (23), 241 (28), 240 (100), 213 (12), 212 (71).

  (Example 18)

窒素雰囲気下、５−（３−ブロモ−５−メトキシフェニル）−４−ｔ−ブチル−３，３−ジメチル−２，３−ジヒドロフラン（化合物［２３］）（５００ｍｇ，１．４７ｍｍｏｌ）を脱水ＴＨＦ（３ｍＬ）に溶解し、−７８℃にてｎ−ブチルリチウム（１．６２Ｍ，１．０ｍＬ，１．６２ｍｍｏｌ）を滴下し１０分攪拌した。この溶液に４−（ベンゾチアゾール−２−イル）−３−メトキシベンズアルデヒド（４１４ｍｇ，１．５４ｍｍｏｌ）の脱水ＴＨＦ（２ｍＬ）溶液を滴下し、更に１時間攪拌した。反応溶液に水を加えてクエンチし、更に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）にて精製し、４−ｔ−ブチル−５−（３−｛１−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］−１−ヒドロキシメチル｝−５−メトキシフェニル）−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２４］）を無色アモルファス状固体として得た。収量５９０ｍｇ、収率７５．６％。

Under a nitrogen atmosphere, 5- (3-bromo-5-methoxyphenyl) -4-tert-butyl-3,3-dimethyl-2,3-dihydrofuran (compound [23]) (500 mg, 1.47 mmol) was dehydrated. It melt | dissolved in THF (3 mL), n-butyllithium (1.62M, 1.0 mL, 1.62 mmol) was dripped at -78 degreeC, and it stirred for 10 minutes. To this solution was added dropwise a solution of 4- (benzothiazol-2-yl) -3-methoxybenzaldehyde (414 mg, 1.54 mmol) in dehydrated THF (2 mL), and the mixture was further stirred for 1 hour. Water was added to the reaction solution for quenching, and a saturated aqueous ammonium chloride solution was further added, followed by extraction with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 9: 1) gave 4-t-butyl-5- (3- {1- [4- (benzothiazol-2-yl) -3-methoxyphenyl]. -1-Hydroxymethyl} -5-methoxyphenyl) -3,3-dimethyl 1-2,3-dihydrofuran (compound [24]) was obtained as a colorless amorphous solid. Yield 590 mg, yield 75.6%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.02 (s, 9H), 1.32 (s, 6H), 2.48 (br-d, J = 3.2 Hz, 1H) 3.79 (s, 3H), 3.86 (s , 2H), 4.01 (s, 3H), 5.84 (d, J = 2.8 Hz, 1H), 6.77 (s with fine coupling, 1H), 6.90 (s with fine coupling, 1H), 6.94 (s, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 7.36 (dd with fine coupling, J = 7.8 and 7.3 Hz, 1H ), 7.48 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H) , 8.45 (d, J = 8.3 Hz, 1 ) Ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.4 (CH ₃ × 2), 32.4 (C), 32.4 (CH ₃ × 3), 47.1 (C), 55.3 (CH ₃ ), 55.6 (CH ₃ ), 75.5 (CH), 83.1 (CH ₂ ), 109.6 (CH), 112.2 (CH), 114.5 (CH), 119.4 (CH), 120.8 (CH ), 121.1 (CH), 121.2 (C), 122.6 (CH), 124.5 (CH), 125.8 (C), 125.9 (CH), 129.4 (CH) 135.9 (C), 137.5 (C), 144.5 (C), 147.8 (C), 149.5 (C), 152.0 (C), 157.2 (C), 159.4 (C), 163.1 (C) ppm
Mass (m / z,%):
529 (M ⁺ , 13), 527 (21), 515 (21), 514 (64), 513 (52), 512 (100), 498 (24), 268 (16).

  (Example 19)

窒素雰囲気下４−ｔ−ブチル−５−（３−｛１−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］−１−ヒドロキシメチル｝−５−メトキシフェニル）−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２４］）（８００ｍｇ，１．５１ｍｍｏｌ）を脱水ジクロロメタン（８ｍＬ）に溶解し、０℃にてＳＯＣｌ_２（０．１３ｍＬ，１．７８ｍｍｏｌ）を滴下し１時間３０分攪拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝６：１）にて精製し、４−ｔ−ブチル−５−（３−｛１−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］−１−クロロメチル｝−５−メトキシフェニル）−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２５］）を無色アモルファス状固体として得た。収量７６４ｍｇ、収率９２．３％。

4-t-butyl-5- (3- {1- [4- (benzothiazol-2-yl) -3-methoxyphenyl] -1-hydroxymethyl} -5-methoxyphenyl) -3,3 under nitrogen atmosphere -Dimethyl l-2,3-dihydrofuran (compound [24]) (800 mg, 1.51 mmol) was dissolved in dehydrated dichloromethane (8 mL), and SOCl ₂ (0.13 mL, 1.78 mmol) was added dropwise at 0 ° C. And stirred for 1 hour 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 6: 1) gave 4-t-butyl-5- (3- {1- [4- (benzothiazol-2-yl) -3-methoxyphenyl]. -1-Chloromethyl} -5-methoxyphenyl) -3,3-dimethyl 1-2,3-dihydrofuran (compound [25]) was obtained as a colorless amorphous solid. Yield 764 mg, yield 92.3%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.03 (s, 9H), 1.32 (s, 3H), 132 (s, 3H), 3.80 (s, 3H), 3.87 (s, 2H), 4.03 (s 3H), 6.12 (s, 1H), 6.79 (s with fine coupling, 1H), 6.94 (s with fine coupling, 1H), 6.96 (s, 1H), 7.10 (d, J = 1.6 Hz, 1 H), 7.14 (dd, J = 8.1 and 1.6 Hz, 1 H), 7.38 (dd with fine coupling, J = 7.8 and 7.3 Hz, 1 H), 7.49 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 8.49 (d, J = 8.1Hz, 1H) pp .

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.4 (CH ₃ ), 27.4 (CH ₃ ), 32.4 (C), 32.5 (CH ₃ × 3), 47.2 (C), 55.4 (CH ₃ ), 55.7 (CH ₃ ), 63.4 (CH), 83.2 (CH ₂ ), 111.1 (CH), 113.7 (CH), 114.9 (CH), 120.6 (CH) , 121.2 (CH), 122.0 (CH), 122.1 (C), 122.8 (CH), 124.7 (CH), 125.9 (CH), 126.0 (C), 129.6 (CH), 136.1 (C), 137.7 (C), 141.4 (C), 144.5 (C), 149.2 (C), 152.1 (C), 157 .2 (C), 159.3 (C), 162.4 (C) ppm
Mass (m / z,%):
549 (M ⁺ +2, 1), 547 (M ⁺ , 3), 532 (14), 527 (19), 514 (17), 513 (47), 512 (100), 499 (25), 498 (68 ), 268 (12).

  (Example 20)

窒素雰囲気下４−ｔ−ブチル−５−（３−｛１−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］−１−クロロメチル｝−５−メトキシフェニル）−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２５］）（６００ｍｇ，１．０９ｍｍｏｌ）をＭｅＯＨ（６ｍＬ）に溶解し、室温にて炭酸カリウム（１．２１ｇ，８．７５ｍｍｏｌ）と１０％Ｐｄ−Ｃ（１２０ｍｇ）を加えた。続いて反応系を水素雰囲気下として２時間攪拌した。反応溶液をセライト濾過し、濾液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝６：１）にて精製し、４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジル］−５−メトキシフェニル｝−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２６］）を無色アモルファス状固体として得た。収量３９２ｍｇ、収率６９．７％。

4-t-butyl-5- (3- {1- [4- (benzothiazol-2-yl) -3-methoxyphenyl] -1-chloromethyl} -5-methoxyphenyl) -3,3 under nitrogen atmosphere -Dimethyl l-2,3-dihydrofuran (compound [25]) (600 mg, 1.09 mmol) was dissolved in MeOH (6 mL), and potassium carbonate (1.21 g, 8.75 mmol) and 10% Pd were dissolved at room temperature. -C (120 mg) was added. Subsequently, the reaction system was placed in a hydrogen atmosphere and stirred for 2 hours. The reaction solution was filtered through Celite, saturated aqueous ammonium chloride solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 6: 1) gave 4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-methoxybenzyl] -5- Methoxyphenyl} -3,3-dimethyl l-2,3-dihydrofuran (compound [26]) was obtained as a colorless amorphous solid. Yield 392 mg, 69.7% yield.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.04 (s, 9H), 1.32 (s, 6H), 3.78 (s, 3H), 3.86 (s, 2H), 3.97 (s, 3H), 4.01 (S, 2H), 6.69-6.72 (m, 2H), 6.77 (s, 1H), 6.82 (s with fine coupling, 1H), 6.97 (d with fine coupling, J = 8 .1 Hz, 1 H), 7.35 (dd with fine coupling, J = 8.0 and 7.1 Hz, 1 H), 7.47 (dd with fine coupling, J = 8.3 and 7.1 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 8.43 (d, J = 8.1 Hz, 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.4 (CH ₃ × 2), 32.4 (C), 32.4 (CH ₃ × 3), 41.9 (CH ₂ ), 47.1 (C), 55.3 (CH ₃ ), 55.6 (CH ₃ ), 83.1 (CH ₂ ), 112.2 (CH), 113.0 (CH), 114.9 (CH), 120.3 (C), 121.1 ( CH), 121.9 (CH), 122.6 (CH), 123.2 (CH), 124.4 (CH), 125.5 (C), 125.8 (CH), 129.5 (CH ), 136.0 (C), 137.5 (C), 141.2 (C), 145.3 (C), 149.7 (C), 152.2 (C), 157.3 (C) , 159.4 (C), 163.1 (C) ppm
Mass (m / z,%):
^{513 (M +, 23),} 500 (13), 499 (39), 498 (100).

  (Example 21)

窒素雰囲気下４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−メトキシベンジル］−５−メトキシフェニル｝−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２６］）（２２０ｍｇ，０．４２８ｍｍｏｌ）を脱水ＤＭＦ（２ｍＬ）に溶解し、ＭｅＳＮａ（１２６ｍｇ，１．８０ｍｍｏｌ）を加えて、１４０℃にて２時間３０分攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）にて精製し、４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジル］−５−ヒドロキシフェニル｝−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２７］）を無色固体として得た。収量１５８ｍｇ、収率７５．９％。

4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-methoxybenzyl] -5-methoxyphenyl} -3,3-dimethyl l-2,3-dihydro under nitrogen atmosphere Furan (compound [26]) (220 mg, 0.428 mmol) was dissolved in dehydrated DMF (2 mL), MeSNa (126 mg, 1.80 mmol) was added, and the mixture was stirred at 140 ° C. for 2 hr 30 min. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 4: 1) gave 4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyl] -5- Hydroxyphenyl} -3,3-dimethyl l-2,3-dihydrofuran (compound [27]) was obtained as a colorless solid. Yield 158 mg, Yield 75.9%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.05 (s, 9H), 1.31 (s, 6H), 3.85 (s, 2H), 3.92 (s, 2H), 4.83 (br-s, 1H), 6 .61 (s with fine coupling, 1H), 6.64 (s with fine coupling, 1H), 6.73 to 6.78 (m, 2H), 6.93 (s with fine coupling, 1H), 7.40 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.50 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7. 89 (d with fine coupling, J = 8.1 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 12.48 (br-s, 1H) p pm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.3 (CH ₃ × 2), 32.4 (C), 32.4 (CH ₃ × 3), 41.6 (CH ₂ ), 47.1 (C), 83.0 (CH ₂ ), 114.8 (C), 115.1 (CH), 115.9 (CH), 118.0 (CH), 120.4 (CH), 121.4 (CH), 122.0 (CH) , 123.1 (CH), 125.3 (CH), 125.8 (C), 126.6 (CH), 128.4 (CH), 132.4 (C), 137.4 (C), 141.2 (C), 146.3 (C), 149.3 (C), 151.8 (C), 155.4 (C), 157.8 (C), 169.2 (C) ppm
Mass (m / z,%):
485 (M ⁺ , 24), 472 (11), 471 (35), 470 (100), 212 (32), 57 (31).

  (Example 22)

４−ｔ−ブチル−５−｛３−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジル］−５−ヒドロキシフェニル｝−３，３−ジメチルｌ−２，３−ジヒドロフラン（化合物［２７］）（１００ｍｇ，０．２０６ｍｍｏｌ）とＴＰＰ（１ｍｇ）をジクロロメタン（１０ｍＬ）に溶解し、酸素雰囲気下０℃にてナトリウムランプ（９４０Ｗ）を３０分照射した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（ジクロロメタン：ジエチルエーテル＝１００：１）にて精製し、５−ｔ−ブチル−１−｛３−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシベンジル］−５−ヒドロキシフェニル｝−４，４−ジメチル−２，６，７−トリオキサビシクロ［３．２．０］ヘプタン（化合物［２８］）を無色固体として得た。収量９５．５ｍｇ、収率８９．６％。

4-t-butyl-5- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyl] -5-hydroxyphenyl} -3,3-dimethyll-2,3-dihydrofuran (compound [27]) (100 mg, 0.206 mmol) and TPP (1 mg) were dissolved in dichloromethane (10 mL), and irradiated with a sodium lamp (940 W) at 0 ° C. for 30 minutes in an oxygen atmosphere. The reaction solution was concentrated under reduced pressure and further purified by silica gel chromatography (dichloromethane: diethyl ether = 100: 1) to give 5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3. -Hydroxybenzyl] -5-hydroxyphenyl} -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [28]) was obtained as a colorless solid. Yield 95.5 mg, Yield 89.6%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 0.99 (s, 9H), 1.13 (s, 3H), 1.34 (s, 3H), 3.80 (d, J = 8.1 Hz, 1H), 3.96 (s, 2H), 4.56 (d, J = 8.1 Hz, 1H), 4.86 (br-s, 1H), 6.70 (s, 1H), 6.75 (dd, J = 7.8and1. 7 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 6.98 (s, 1H), 7.09 (s, 1H), 7.40 (dd with fine coupling, J = 7. 8 and 7.3 Hz, 1 H), 7.50 (dd with fine coupling, J = 7.8 and 7.3 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.89 (d, J = 7 .8 Hz, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 12.47 (br-s, 1 H) pm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 18.4 (CH ₃ ), 25.0 (CH ₃ ), 26.8 (CH ₃ × 3), 36.7 (C), 41.7 (CH ₂ ), 45.5 (C), 80.1 (CH ₂ ), 105.1 (C), 113.6 (CH), 114.9 (C), 116.5 (C), 117.2 (CH), 117.9 (CH), 120.4 (CH), 121.4 (CH), 121.5 (CH), 122.0 (CH), 125.4 (CH), 126.6 (CH), 128.4 (CH), 132 .4 (C), 137.6 (C), 141.5 (C), 146.1 (C), 1151.8 (C), 155.6 (C), 157.8 (C), 169. 2 (C) ppm
Mass (m / z,%):
518 (M ^{+ +1,} 17), 517 (M ⁺ , 52), 461 (12), 432 (14), 417 (17), 377 (27), 361 (30), 360 (100), 334 (14 ), 333 (56), 332 (19), 331 (13).

  (Example 23)

窒素雰囲気下５−（３−ブロモ−５−メトキシフェニル）−４−ｔ−ブチル−３，３−ジメチル−２，３−ジヒドロフラン（化合物［２９］）（５００ｍｇ，１．４７ｍｍｏｌ）を脱水ＴＨＦ（５ｍＬ）に溶解し、−７８℃にてｎ−ブチルリチウム（１．６１Ｍ，１．０ｍＬ，１．６１ｍｍｏｌ）を滴下し１０分攪拌した。この溶液にＮ−メチルホルムアニリド（０．２１ｍＬ，１．７０ｍｍｏｌ）を加え、更に１時間攪拌した。反応溶液に水を加えてクエンチし、更に１Ｎ−塩酸水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９：１）にて精製し、５−（３−ホルミル−５−メトキシフェニル）−４−ｔ−ブチル−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３０］）を無色油状物として得た。収量４０４ｍｇ、収率９５．１％。

5- (3-Bromo-5-methoxyphenyl) -4-tert-butyl-3,3-dimethyl-2,3-dihydrofuran (compound [29]) (500 mg, 1.47 mmol) was dehydrated in a nitrogen atmosphere. (5 mL), n-butyllithium (1.61 M, 1.0 mL, 1.61 mmol) was added dropwise at −78 ° C., and the mixture was stirred for 10 minutes. N-methylformanilide (0.21 mL, 1.70 mmol) was added to this solution, and the mixture was further stirred for 1 hour. Water was added to the reaction solution for quenching, and a 1N aqueous hydrochloric acid solution was further added, followed by extraction with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 9: 1), and 5- (3-formyl-5-methoxyphenyl) -4-tert-butyl-3,3-dimethyl-2,3-dihydrofuran. (Compound [30]) was obtained as a colorless oil. Yield 404 mg, yield 95.1%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.06 (s, 9H), 1.35 (s, 6H), 3.87 (s, 3H), 3.89 (s, 2H), 7.11 (s with fine coupling, 1H), 7 .35 (s with fine coupling, 1H), 7.41 (s, 1H), 9.96 (s, 1H) ppm
¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.3 (CH ₃ × 2), 32.4 (C), 32.5 (CH ₃ × 3), 47.3 (C), 55.6 (CH ₃ ), 83.2 (CH ₂ ), 111.9 (CH), 122.8 (CH), 125.2 (CH), 126.8 (C), 137.4 (C), 138.4 (C), 148.2 (C) , 159.7 (C), 191.7 (CH) ppm
Mass (m / z,%):
288 (M ⁺ , 24), 274 (19), 273 (100), 217 (14), 163 (32), 57 (10).

  (Example 24)

窒素雰囲気下４−（ベンゾチアゾール−２−イル）−３−メトキシ−ベンジルトリフェニルホスフォニウムブロミド（５００ｍｇ，１．４７ｍｍｏｌ）を脱水ＴＨＦ（６ｍＬ）に溶解し、−７８℃にてｎ−ブチルリチウム（１．６１Ｍ，０．７５ｍＬ，１．２１ｍｍｏｌ）を滴下し、０℃にて３０分攪拌した。５−（３−ホルミル−５−メトキシフェニル）−４−ｔ−ブチル−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３０］）（３２０ｍｇ，１．１１ｍｍｏｌ）脱水ＴＨＦ（３ｍＬ）溶液を−７８℃にて滴下し、室温にて１時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１２：１）にて精製し、（Ｚ）−４−ｔ−ブチル−５−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］ビニル｝−５−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３１］Ｚ体）を無色アモルファス状固体として得た。収量４６８ｍｇ、収率８０．２％。また、異性体として（Ｅ）−４−ｔ−ブチル−５−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］ビニル｝−５−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３１］Ｅ体）を無色アモルファス状固体として得た。収量９３．９ｍｇ、収率１６．１％。

4- (Benzothiazol-2-yl) -3-methoxy-benzyltriphenylphosphonium bromide (500 mg, 1.47 mmol) was dissolved in dehydrated THF (6 mL) under a nitrogen atmosphere, and n-butyl was dissolved at -78 ° C. Lithium (1.61 M, 0.75 mL, 1.21 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes. 5- (3-Formyl-5-methoxyphenyl) -4-tert-butyl-3,3-dimethyl-2,3-dihydrofuran (compound [30]) (320 mg, 1.11 mmol) dehydrated THF (3 mL) solution Was added dropwise at −78 ° C. and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 12: 1) gave (Z) -4-t-butyl-5- (3- {2- [4- (benzothiazol-2-yl) -3. -Methoxyphenyl] vinyl} -5-methoxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [31] Z form) was obtained as a colorless amorphous solid. Yield 468 mg, yield 80.2%. In addition, (E) -4-t-butyl-5- (3- {2- [4- (benzothiazol-2-yl) -3-methoxyphenyl] vinyl} -5-methoxyphenyl) -3 as an isomer , 3-Dimethyl-2,3-dihydrofuran (compound [31] E form) was obtained as a colorless amorphous solid. Yield 93.9 mg, Yield 16.1%.

Compound [31] Z Form
¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.01 (s, 9H), 1.28 (s, 6H), 3.68 (s, 3H), 3.82 (s, 5H), 6.63 (d, J = 12.2 Hz, 1H), 6.69 (d, J = 12.2 Hz, 1H), 6.71 (s with fine coupling, 1H), 6.80 (s with fine coupling, 1H), 6.83 (s, 1H), 6 96 (s, 1H), 7.02 (dd, J = 8.1 and 1.2 Hz, 1 H), 7.36 (dd with fine coupling, J = 7.8 and 7.1 Hz, 1 H), 7.48 (dd with) fine coupling, J = 8.3 and 7.1 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 8.1Hz, 1H) pp .

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.3 (CH ₃ × 2), 32.3 (C), 32.4 (CH ₃ × 3), 47.1 (C), 55.2 (CH ₃ ), 55.4 (CH ₃ ), 83.0 (CH ₂ ), 112.0 (CH), 114.0 (CH), 114.6 (CH), 121.1 (C), 121.1 (CH), 122.2 (CH ), 122.7 (CH), 123.0 (CH), 124.4 (CH), 125.6 (C), 125.8 (CH), 129.3 (CH), 129.9 (CH) , 131.5 (CH), 136.0 (C), 137.8 (C), 138.0 (C), 140.6 (C), 149.4 (C), 152.2 (C), 156.8 (C), 159.0 (C), 162.8 (C) ppm
Mass (m / z,%):
525 (M ⁺ , 20), 512 (38), 511 (39), 510 (100), 454 (9).

Compound [31] E form
¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.10 (s, 9H), 1.36 (s, 6H), 3.86 (s, 3H), 3.90 (s, 2H), 4.12 (s, 3H), 7.04 (S with fine coupling, 1H), 7.11 (s, 1H), 7.12 (d, J = 16.4 Hz, 1H), 7.17 (s, 1H), 7.19 (d, J = 16 .4 Hz, 1 H), 7.30 (d with fine coupling, J = 8.1 Hz, 1 H), 7.37 (dd, J = 8.1 and 7.1 Hz, 1 H), 7.49 (dd with fine coupling, J = 8.1 and 7.1 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 8.53 (d, J = 8.1 Hz) , 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.4 (CH ₃ × 2), 32.5 (C), 32.5 (CH ₃ × 3), 47.2 (C), 55.4 (CH ₃ ), 55.7 (CH ₃ ), 83.2 (CH ₂ ), 109.5 (CH), 111.9 (CH), 115.2 (CH), 119.4 (CH), 121.1 (CH), 121.1 (CH ), 121.6 (C), 122.7 (CH), 124.5 (CH), 125.8 (C), 125.9 (CH), 128.3 (CH), 129.7 (CH) , 130.1 (CH), 136.1 (C), 137.8 (C), 137.9 (C), 140.8 (C), 149.5 (C), 152.2 (C), 157.4 (C), 159.5 (C), 162.8 (C) ppm
Mass (m / z,%):
526 (M ^{+ +1,} 17), 525 (M ⁺ , 40), 512 (14), 511 (39), 510 (100), 454 (24).

  (Example 25)

窒素雰囲気下（Ｚ）−４−ｔ−ブチル−５−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］ビニル｝−５−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３１］Ｚ体）（５００ｍｇ，０．９５１ｍｍｏｌ）をＭｅＯＨ（３ｍＬ）と酢酸エチル（２ｍＬ）に溶解し、室温にて１０％Ｐｄ−Ｃ（１００ｍｇ）を加えた。続いて反応系を水素雰囲気下として６時間３０分攪拌した。反応溶液をセライト濾過し減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝１５：１）にて精製し、４−ｔ−ブチル−５−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］エチル｝−５−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３２］）を無色アモルファス状固体として得た。収量４４２ｍｇ、収率８８．１％。

(Z) -4-t-butyl-5- (3- {2- [4- (benzothiazol-2-yl) -3-methoxyphenyl] vinyl} -5-methoxyphenyl) -3,3 under nitrogen atmosphere -Dimethyl-2,3-dihydrofuran (compound [31] Z form) (500 mg, 0.951 mmol) was dissolved in MeOH (3 mL) and ethyl acetate (2 mL), and 10% Pd-C (100 mg) at room temperature. Was added. Subsequently, the reaction system was placed in a hydrogen atmosphere and stirred for 6 hours and 30 minutes. The reaction solution was filtered through celite and concentrated under reduced pressure. Further, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 15: 1) to give 4-t-butyl-5- (3- {2- [4- (benzothiazol-2-yl) -3-methoxyphenyl]. Ethyl} -5-methoxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [32]) was obtained as a colorless amorphous solid. Yield 442 mg, Yield 88.1%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.03 (s, 9H), 1.32 (s, 6H), 2.91-3.02 (m, 4H), 3.77 (s, 3H), 3.86 (s, 2H) , 4.00 (s, 3H), 6.66 (s with fine coupling, 1H), 6.68 (s with fine coupling, 1H), 6.74 (s, 1H), 6.79 (s, 1H), 6.96 (dd, J = 8.1 and 1.2 Hz, 1H), 7.35 (dd with fine coupling, J = 7.8 and 7.3 Hz, 1 H), 7.48 (dd with fine coupling, J = 8.1 and 7. 3 Hz, 1 H), 7.91 (d, J = 7.8 Hz, 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 8.42 (d, J = 8.1 Hz, 1 H) ppm .

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.4 (CH ₃ × 2), 32.4 (C), 32.4 (CH ₃ × 3), 37.4 (CH ₂ ), 37.9 (CH ₂ ), 47.1 (C ), 55.2 (CH ₃ ), 55.6 (CH ₃ ), 83.1 (CH ₂ ), 112.0 (CH), 112.8 (CH), 114.3 (CH), 120.1 (C), 121.1 (CH), 121.4 (CH), 122.6 (CH × 2), 124.3 (CH), 125.4 (C), 125.8 (CH), 129. 4 (CH), 136.0 (C), 137.4 (C), 142.3 (C), 146.1 (C), 149.9 (C), 152.2 (C), 157.1 (C), 159.1 (C), 163.2 (C) ppm
Mass (m / z,%):
527 (M ⁺ , 15), 514 (13), 513 (39), 512 (100), 255 (16).

  (Example 26)

窒素雰囲気下４−ｔ−ブチル−５−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−メトキシフェニル］エチル｝−５−メトキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３２］）（４８０ｍｇ，０．９１０ｍｍｏｌ）を脱水ＤＭＦ（４．５ｍＬ）に溶解し、ＭｅＳＮａ（３２０ｍｇ，４．５７ｍｍｏｌ）を加えて、１４０℃にて２時間３０分攪拌した。反応溶液に１Ｎ−塩酸水溶液を加え、酢酸エチルにて抽出した。有機層は飽和食塩水にて３回洗浄し、無水硫酸マグネシウムにて乾燥し、減圧下にて濃縮した。更にシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）にて精製し、４−ｔ−ブチル−５−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシフェニル］エチル｝−５−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３３］）を無色固体として得た。収量４３９ｍｇ、収率９６．５％。

4-t-butyl-5- (3- {2- [4- (benzothiazol-2-yl) -3-methoxyphenyl] ethyl} -5-methoxyphenyl) -3,3-dimethyl-2 under nitrogen atmosphere , 3-dihydrofuran (compound [32]) (480 mg, 0.910 mmol) was dissolved in dehydrated DMF (4.5 mL), MeSNa (320 mg, 4.57 mmol) was added, and 140 ° C. for 2 hours 30 minutes. Stir. A 1N hydrochloric acid aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Further purification by silica gel chromatography (hexane: ethyl acetate = 3: 1) gave 4-t-butyl-5- (3- {2- [4- (benzothiazol-2-yl) -3-hydroxyphenyl]. Ethyl} -5-hydroxyphenyl) -3,3-dimethyl-2,3-dihydrofuran (compound [33]) was obtained as a colorless solid. Yield 439 mg, yield 96.5%.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 1.03 (s, 9H), 1.31 (s, 6H), 2.85 to 2.96 (m, 4H), 3.85 (s, 2H), 4.65 (s, 1H) , 6.61 (s, 1H), 6.62 (s, 1H), 6.72 (s, 1H), 6.74 (dd, J = 8.1 and 1.4 Hz, 1H), 6.93 (d , J = 14 Hz, 1 H), 7.40 (dd, J = 7.8 and 7.3 Hz, 1 H), 7.50 (dd, J = 8.1 and 7.3 Hz, 1 H), 7.57 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 12.45 (s, 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 27.3 (CH ₃ × 2), 32.4 (C), 32.4 (CH ₃ × 3), 36.9 (CH ₂ ), 37.5 (CH ₂ ), 47.1 (C ), 83.0 (CH ₂ ), 114.7 (CH), 114.8 (C), 115.3 (CH), 117.4 (CH), 120.1 (CH), 121.4 (CH ), 122.0 (CH), 122.5 (CH), 125.3 (CH), 125.7 (C), 126.6 (CH), 128.3 (CH), 132.4 (C) , 137.3 (C), 142.6 (C), 147.3 (C), 149.4 (C), 151.8 (C), 155.2 (C), 157.8 (C), 169.3 (C) ppm
Mass (m / z,%):
500 (M ^{+ +1,} 11), 499 (M ⁺ , 26), 485 (43), 484 (100), 442 (10), 428 (17), 374 (12), 242 (13), 241 (26 ), 212 (17).

  (Example 27)

４−ｔ−ブチル−５−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシフェニル］エチル｝−５−ヒドロキシフェニル）−３，３−ジメチル−２，３−ジヒドロフラン（化合物［３３］）（１００ｍｇ，０．２００ｍｍｏｌ）とＴＰＰ（１ｍｇ）をジクロロメタン（１０ｍＬ）に溶解し、酸素雰囲気下０℃にてナトリウムランプ（９４０Ｗ）を３０分照射した。反応溶液を減圧濃縮し、更にシリカゲルクロマトグラフィー（ジクロロメタン：ジエチルエーテル＝３０：１）にて精製し、５−ｔ−ブチル−１−（３−｛２−［４−（ベンゾチアゾール−２−イル）−３−ヒドロキシフェニル］エチル｝−５−ヒドロキシフェニル｝−４，４−ジメチル−２，６，７−トリオキサビシクロ［３．２．０］ヘプタン（化合物［３４］）を無色固体として定量的に得た。

4-t-butyl-5- (3- {2- [4- (benzothiazol-2-yl) -3-hydroxyphenyl] ethyl} -5-hydroxyphenyl) -3,3-dimethyl-2,3- Dihydrofuran (compound [33]) (100 mg, 0.200 mmol) and TPP (1 mg) were dissolved in dichloromethane (10 mL), and irradiated with a sodium lamp (940 W) at 0 ° C. for 30 minutes in an oxygen atmosphere. The reaction solution was concentrated under reduced pressure and further purified by silica gel chromatography (dichloromethane: diethyl ether = 30: 1) to give 5-t-butyl-1- (3- {2- [4- (benzothiazol-2-yl). ) -3-Hydroxyphenyl] ethyl} -5-hydroxyphenyl} -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [34]) as a colorless solid Obtained.

¹ H-NMR (400 MHz, CDCl ₃ ):
δ _H 0.98 (s, 9H), 1.13 (s, 3H), 1.34 (s, 3H), 2.88-3.00 (m, 4H), 3.79 (d, J = 8.1 Hz, 1H), 4.56 (d, J = 8.1 Hz, 1H), 4.76 (s with fine coupling, 1H), 6.69 (s with fine coupling, 1H), 6.76 (dd, J = 8.1 and 1.5 Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 6.95 (s with fine coupling, 1H), 7.05 (s, 1H), 7.40 ( dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.50 (dd with fine coupling, J = 8.1 and 7.3 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), .90 (d, J = 8.1Hz, 1H), 7.98 (d, J = 8.1Hz, 1H), 12.45 (s, 1H) ppm.

¹³ C-NMR (125 MHz, CDCl ₃ ):
δ _C 18.4 (CH ₃ ), 25.0 (CH ₃ ), 26.8 (CH ₃ × 3), 36.7 (C), 36.8 (CH ₂ ), 37.4 (CH ₂ ) , 45.5 (C), 80.1 (CH ₂ ), 105.0 (C), 113.3 (CH), 114.8 (C), 116.5 (C), 116.7 (CH) , 117.4 (CH), 120.1 (CH), 120.8 (CH), 121.4 (CH), 122.0 (CH), 125.3 (CH), 126.6 (CH), 128.3 (CH), 132.4 (C), 137.5 (C), 142.8 (C), 147.0 (C), 151.8 (C), 155.3 (C), 157 .8 (C), 169.2 (C) ppm
Mass (m / z,%):
532 (M ^{+ +1,} 20), 531 (M ⁺ , 62), 484 (13), 475 (11), 446 (16), 391 (16), 375 (25), 374 (100), 372 (12 ), 347 (34), 346 (12), 345 (12), 318 (18), 241 (13), 240 (17), 212 (42), 187 (15).

(Example 28)
5- {2- [4- (Benzothiazol-2-yl) -3-hydroxybenzyloxy] -1,1-dimethylethyl} -1- (3-hydroxyphenyl) -4, obtained in Example 4. 1 mL of a 1.00 × 10 ⁻⁵ M acetonitrile solution of 4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [5]) was added to 1.00 of tetrabutylammonium fluoride. It added to 25 mL of * 10 ^<-2> M acetonitrile solution at 25 degreeC, and the light emission at that time was measured with the fluorescence spectrometer. At this time, the emission quantum yield was estimated to be 0.24, the half-life of light emission was 14 seconds, and λ _max was 470 nm.

(Example 29)
5- {10- [4- (Benzothiazol-2-yl) -3-hydroxyphenyl] -1,1-dimethyl-3,9-dioxadec-1-yl} -1- (obtained in Example 8 3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [10]) in 1 mL of a 1.00 × 10 ⁻⁵ M acetonitrile solution was added to tetra It added to 25 mL of 1.00 * 10 ^<-2> M acetonitrile solution of butylammonium fluoride at 25 degreeC, and the light emission at that time was measured with the fluorescence spectrometer. The light emission quantum yield at this time was estimated to be 0.18, the half life of light emission was 21 seconds, and λ _max was 468 nm.

(Example 30)
5- (7- {N- [4- (Benzothiazol-2-yl) -3-hydroxybenzyl] carbamoyl} -1,1-dimethyl-3-oxahept-1-yl)-obtained in Example 11- 1 mL of 1.00 × 10 ⁻⁵ M acetonitrile solution of 1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [14]) Was added to 2 mL of a 1.00 × 10 ⁻² M acetonitrile solution of tetrabutylammonium fluoride at 25 ° C., and the luminescence at that time was measured with a fluorescence analyzer. The luminescence quantum yield at this time was estimated to be 0.20, the half-life of luminescence was 26 seconds, and λ _max was 469 nm.

(Example 31)
5- (7- {N- [3 ', 6'-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9'-(9H) xanthen) -5-yl]-obtained in Example 14 Carbamoyl} -1,1-dimethyl-3-oxahept-8-yl) -1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane 1 mL of a 5.90 × 10 ⁻⁵ M acetonitrile solution of (Compound [18]) was added to 2 mL of a 1.00 × 10 ⁻² M acetonitrile solution of tetrabutylammonium fluoride at 25 ° C., and luminescence at that time was analyzed by fluorescence analysis Measured with a meter. The light emission quantum yield at this time was estimated to be 0.18, the half life of light emission was 141 seconds, and λ _max was 535 nm.

(Example 32)
5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyloxy] -5-hydroxyphenyl} -4,4-dimethyl-2 obtained in Example 17 , 6,7-Trioxabicyclo [3.2.0] heptane (compound [22]) in 1 mL of a 1.00 × 10 ⁻⁵ M acetonitrile solution was added to tetrabutylammonium fluoride in 1.00 × 10 ⁻² M. It added to acetonitrile solution 2mL at 25 degreeC, and the light emission at that time was measured with the fluorescence spectrometer. The light emission quantum yield at this time was estimated to be 0.23, the half life of light emission was 16 seconds, and λ _max was 469 nm.

(Example 33)
5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyl] -5-hydroxyphenyl} -4,4-dimethyl-2, obtained in Example 22. 1 mL of a 1.00 × 10 ⁻⁵ M acetonitrile solution of 6,7-trioxabicyclo [3.2.0] heptane (compound [28]) was added to 1.00 × 10 ⁻² M acetonitrile of tetrabutylammonium fluoride. It added at 25 degreeC to 2 mL of solutions, and the light emission at that time was measured with the fluorescence spectrometer. The light emission quantum yield at this time was estimated to be 0.21, the light emission half-life was 5.4 seconds, and λ _max was 471 nm.

(Example 34)
5-t-butyl-1- (3- {2- [4- (benzothiazol-2-yl) -3-hydroxyphenyl] ethyl} -5-hydroxyphenyl} -4,4 obtained in Example 27 -1 mL of a 1.00 × 10 ⁻⁵ M acetonitrile solution of dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [34]) was added to 1.00 × tetrabutylammonium fluoride. The luminescence at that time was measured with a fluorescence analyzer at 2 ° C. in 2 mL of 10 ⁻² M acetonitrile solution, and the luminescence quantum yield at this time was estimated to be 0.21, and the luminescence half-life was 4.1 seconds. , Λ _max was 470 nm.

(Example 35)
5- {2- [4- (Benzothiazol-2-yl) -3-hydroxybenzyloxy] -1,1-dimethylethyl} -1- (3-hydroxyphenyl) -4, obtained in Example 4. 0.1 mL of a 1.00 × 10 ⁻³ M acetonitrile solution of 4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [5]) was added to 0.69 M sodium hydroxide. It added to 2.9 mL of aqueous solution at 25 degreeC, and the light emission at that time was measured with the fluorescence analyzer. The light emission quantum yield at this time was estimated to be 6.5 × 10 ⁻⁴ , the light emission half-life was 320 seconds, and λ _max was 469 nm.

(Example 36)
5- {10- [4- (Benzothiazol-2-yl) -3-hydroxyphenyl] -1,1-dimethyl-3,9-dioxadec-1-yl} -1- (obtained in Example 8 3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [10]) at 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mL of the mixed solution was added to 2 mL of a 0.1 M aqueous solution of sodium hydroxide at 25 ° C., and the luminescence at that time was measured with a fluorescence analyzer. The light emission quantum yield at this time was estimated to be 5.5 × 10 ⁻⁴ , the light emission half-life was 500 seconds, and λ _max was 468 nm.

(Example 37)
5- (7- {N- [4- (Benzothiazol-2-yl) -3-hydroxybenzyl] carbamoyl} -1,1-dimethyl-3-oxahept-1-yl)-obtained in Example 11- 1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [14]) at 1.00 × 10 ⁻⁴ M water: acetonitrile = 1 mL of a 90:10 mixed solution was added to 2 mL of a 0.1 M aqueous solution of sodium hydroxide at 25 ° C, and the luminescence at that time was measured with a fluorescence analyzer. The light emission quantum yield at this time was estimated to be 3.4 × 10 ⁻⁴ , the light emission half-life was 540 seconds, and λ _max was 468 nm.

(Example 38)
5- (7- {N- [3 ', 6'-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9'-(9H) xanthen) -5-yl]-obtained in Example 14 Carbamoyl} -1,1-dimethyl-3-oxahept-8-yl) -1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane 1 mL of a 5.90 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mixed solution of (Compound [18]) was added to 2 mL of a 0.1 M aqueous solution of sodium hydroxide at 25 ° C., and the luminescence at that time was measured with a fluorescence analyzer. Measured with The light emission quantum yield at this time was estimated to be 5.6 × 10 ⁻³ , the light emission half-life was 540 seconds, and λ _max was 525 nm.

(Example 39)
5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyloxy] -5-hydroxyphenyl} -4,4-dimethyl-2 obtained in Example 17 , 6,7-Trioxabicyclo [3.2.0] heptane (compound [22]) 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 1 mL of a mixed solution was added to 0.1 M sodium hydroxide. It added to 2 mL of aqueous solution at 25 degreeC, and the light emission at that time was measured with the fluorescence spectrometer. The light emission quantum yield at this time was estimated to be 9.2 × 10 ⁻³ , the half life of light emission was 1450 seconds, and λ _max was 470 nm.

(Example 40)
5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyl] -5-hydroxyphenyl} -4,4-dimethyl-2, obtained in Example 22. 1 mL of a 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mixed solution of 6,7-trioxabicyclo [3.2.0] heptane (compound [28]) was added to a 0.1 M aqueous solution of sodium hydroxide. It added to 2 mL at 25 degreeC, and the light emission at that time was measured with the fluorescence spectrometer. The light emission quantum yield at this time was estimated to be 3.1 × 10 ⁻³ , the light emission half-life was 430 seconds, and λ _max was 469 nm.

(Example 41)
5-t-butyl-1- (3- {2- [4- (benzothiazol-2-yl) -3-hydroxyphenyl] ethyl} -5-hydroxyphenyl} -4,4 obtained in Example 27 -1 mL of a 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mixed solution of dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [34]) was added to sodium hydroxide. Was added to 2 mL of 0.1 M aqueous solution at 25 ° C., and the luminescence at that time was measured with a fluorescence analyzer, where the luminescence quantum yield was estimated to be 2.7 × 10 ⁻³ and the luminescence half-life was 300. Second, λ _max was 469 nm.

(Example 42)
5- {2- [4- (Benzothiazol-2-yl) -3-hydroxybenzyloxy] -1,1-dimethylethyl} -1- (3-hydroxyphenyl) -4, obtained in Example 4. 0.1 mL of a 1.00 × 10 ⁻³ M acetonitrile solution of 4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [5]) was added to 0.69 M sodium hydroxide. , 2.9 mL of a mixed aqueous solution of tri-n-butylhexadecylphosphonium bromide 2.9 × 10 ⁻⁵ M at 25 ° C., and the luminescence at that time was measured with a fluorescence analyzer. The light emission quantum yield at this time was estimated to be 5.3 × 10 ⁻² , the half life of light emission was 3020 seconds, and λ _max was 475 nm.

(Example 43)
5- {10- [4- (Benzothiazol-2-yl) -3-hydroxyphenyl] -1,1-dimethyl-3,9-dioxadec-1-yl} -1- (obtained in Example 8 3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [10]) at 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mL of the mixed solution was added to 0.1 mL of sodium hydroxide and 2 mL of a 1.1 × 10 ⁻⁴ M mixed aqueous solution of tri-n-butylhexadecylphosphonium bromide at 25 ° C., and the luminescence at that time was measured with a fluorescence analyzer. Measured with The light emission quantum yield at this time was estimated to be 4.6 × 10 ⁻² , the light emission half-life was 870 seconds, and λ _max was 475 nm.

(Example 44)
5- (7- {N- [4- (Benzothiazol-2-yl) -3-hydroxybenzyl] carbamoyl} -1,1-dimethyl-3-oxahept-1-yl)-obtained in Example 11- 1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [14]) at 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 1 mL of the mixed solution was added to 0.1 mL of sodium hydroxide and 2 mL of a 1.1 × 10 ⁻⁴ M mixed aqueous solution of tri-n-butylhexadecylphosphonium bromide at 25 ° C. Measured with a fluorescence analyzer. The light emission quantum yield at this time was estimated to be 4.5 × 10 ⁻² , the half life of light emission was 1580 seconds, and λ _max was 473 nm.

(Example 45)
5- (7- {N- [3 ', 6'-dihydroxy-3-oxospiro (isobenzofuran-1 (3H), 9'-(9H) xanthen) -5-yl]-obtained in Example 14 Carbamoyl} -1,1-dimethyl-3-oxahept-8-yl) -1- (3-hydroxyphenyl) -4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane 1 mL of a 5.90 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mixed solution of (Compound [18]) was added to 0.1 M sodium hydroxide, 1.1 × tri-n-butylhexadecylphosphonium bromide. 10 was added at 25 ° C. to ^-4 M mixed aqueous solution 2 mL, and luminescence was measured at that time in a fluorescent spectrometer. The light emission quantum yield at this time was estimated to be 4.4 × 10 ⁻³ , the light emission half-life was 1420 seconds, and λ _max was 534 nm.

(Example 46)
5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyloxy] -5-hydroxyphenyl} -4,4-dimethyl-2 obtained in Example 17 , 6,7-Trioxabicyclo [3.2.0] heptane (compound [22]) 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 1 mL of a mixed solution was added to 0.1M sodium hydroxide. , Tri-n-butylhexadecylphosphonium bromide was added to 2 mL of a mixed aqueous solution of 1.00 × 10 ⁻⁴ M at 25 ° C., and luminescence at that time was measured with a fluorescence analyzer. The light emission quantum yield at this time was estimated to be 5.9 × 10 ⁻² , the light emission half-life was 1350 seconds, and λ _max was 473 nm.

(Example 47)
5-t-butyl-1- {3- [4- (benzothiazol-2-yl) -3-hydroxybenzyl] -5-hydroxyphenyl} -4,4-dimethyl-2, obtained in Example 22. 1 mL of a 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mixed solution of 6,7-trioxabicyclo [3.2.0] heptane (compound [28]) was added to 0.1M sodium hydroxide, The mixture was added to 2 mL of a 1.00 × 10 ⁻⁴ M mixed aqueous solution of tri-n-butylhexadecylphosphonium bromide at 25 ° C., and the emission at that time was measured with a fluorescence analyzer. The light emission quantum yield at this time was estimated to be 3.6 × 10 ⁻² , the light emission half-life was 950 seconds, and λ _max was 474 nm.

(Example 48)
5-t-butyl-1- (3- {2- [4- (benzothiazol-2-yl) -3-hydroxyphenyl] ethyl} -5-hydroxyphenyl} -4,4 obtained in Example 27 1 mL of a 1.00 × 10 ⁻⁴ M water: acetonitrile = 90: 10 mixed solution of dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [34]) was added to sodium hydroxide. Was added to 2 mL of a 1.00 × 10 ⁻⁴ M mixed aqueous solution of 0.1 M of tri-n-butylhexadecylphosphonium bromide at 25 ° C., and luminescence at that time was measured with a fluorescence spectrometer. The yield was estimated to be 3.6 × 10 ⁻² , the luminescence half-life was 1110 seconds, and λ _max was 473 nm.

(Comparative Example 1)
5-t-butyl-1- (3-hydroxy) phenyl-4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound) described in JP-A-9-216887 [35])

の１．００×１０^−５Ｍアセトニトリル溶液１ｍＬを、テトラブチルアンモニウムフルオライドの１．００×１０^−２Ｍアセトニトリル溶液２ｍＬに２５℃で加え、そのときの発光を蛍光分析計で測定した。このときの発光量子収率は０．１１と見積もられ、発光の半減期は２５秒、λ_ｍａｘは４６７ｎｍであった。

1 mL of 1.00 × 10 ⁻⁵ M acetonitrile solution was added to 2 mL of 1.00 × 10 ⁻² M acetonitrile solution of tetrabutylammonium fluoride at 25 ° C., and the luminescence at that time was measured with a fluorescence spectrometer. The light emission quantum yield at this time was estimated to be 0.11, the light emission half-life was 25 seconds, and λ _max was 467 nm.

(Comparative Example 2)
1.00 × 10 5 of 5-t-butyl-1- (3-hydroxy) phenyl-4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [35]) ⁴ mL of ^-4 M water: acetonitrile = 90: 10 mixed solution was added to 2 mL of a 0.1 M aqueous solution of sodium hydroxide at 25 ° C., and luminescence at that time was measured with a fluorescence spectrometer. The light emission quantum yield at this time was estimated to be 1.1 × 10 ⁻⁵ , the light emission half-life was 810 seconds, and λ _max was 467 nm.

(Comparative Example 3)
1.00 × 10 5 of 5-t-butyl-1- (3-hydroxy) phenyl-4,4-dimethyl-2,6,7-trioxabicyclo [3.2.0] heptane (compound [35]) ^-4 M water: acetonitrile = 1 mL of a mixed solution of 90:10 was added at 25 ° C. to 0.1 mL of sodium hydroxide and 2 mL of a 1.00 × 10 ⁻⁴ M mixed aqueous solution of tri-n-butylhexadecylphosphonium bromide. The luminescence at that time was measured with a fluorescence analyzer. The light emission quantum yield at this time was estimated to be 2.3 × 10 ⁻⁴ , the light emission half-life was 1930 seconds, and λ _max was 473 nm.

Claims (12)

Formula [I]

A 1,2-dioxetane derivative (wherein Ar ₁ is an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, An arylene group to which an aryl ketone or a heterocyclic ring may be bonded; A is a fluorescent dye derivative; OY is hydroxyl, an alkyl ester, an aryl ester, or —OSi (R ₄ R ₅ R ₆ ) (where R ₄ , R ₅ and R ₆ are each independently an alkyl group or an aryl group.), X is an alkylene group, an arylene group, an oxygen atom, a sulfur atom, a carbonyl group, — (CO) — O—, —O— (CO) —, —NH—, —NH—CO—, —CO—NH—, —OSi (R ₇ R ₈ ) — (where R ₇ and R ₈ are each independently an alkyl group or an aryl group.), Or — (R ₉ R ₁₀ ) SiO— (wherein R ₉ and R ₁₀ are each independently an alkyl group or an aryl group). And R ₁ and R ₂ are an alkylene group and an arylene group, and R ₃ is a spacer.) The 1,2-dioxetane derivative according to claim 1, wherein the compound of formula [II]

(Wherein OY and A are the same as OY and A in the formula [I], n and m are integers from 1 to 20, Z is a hydrogen atom, An alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, an aryl ketone, or a heterocyclic ring). The 1,2-dioxetane derivative according to claim 1, wherein the compound of formula [III]

(Wherein OY and A are the same as OY and A in the formula [I], n and m are integers from 1 to 20, Z is a hydrogen atom, An alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, an aryl ketone, or a heterocyclic ring). The 1,2-dioxetane derivative of claim 1, wherein the compound of formula [IV]

(Wherein, OY and A are the same as OY and A in the formula [I], and n is an integer from 1 to 20. Z is a hydrogen atom or an alkyl group) An aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, an aryl ketone, or a heterocyclic ring. General formula [V]

A 1,2-dioxetane derivative (wherein Ar ₂ is an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, An aryl ketone or an arylene group to which a heterocycle may be bonded, A is a fluorescent dye derivative, OY is a hydroxyl, alkyl ester, aryl ester, or -OSi (R ₄ R ₅ R ₆ ) (where R ₄ , R ₅ and R ₆ are each independently an alkyl group or an aryl group. R ₁₁ and R ₁₂ are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylene group or an arylene. is a group. Further, R _11, R ₁₂ becomes integral, cyclic or polycyclic spiro bonded to the dioxetane ring It is also possible to form an organic ring group _{.R 13} is an alkyl group, an aryl group, an alkylene group or an arylene _{group, R 13} and _{R 11,} or dioxetane ring and a hetero atom and _{R 13} and _{R 12} together form And R ₁₄ is a spacer. 6. The 1,2-dioxetane derivative according to claim 5, wherein the compound of formula [VI]

(Wherein, OY and A are the same as OY and A in the formula [V], and Z is a hydrogen atom, an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, A group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, an aryl ketone, or a heterocyclic ring, and n is an integer of 1 to 20.). 6. The 1,2-dioxetane derivative according to claim 5, wherein the formula [VII]

(Wherein, OY and A are the same as OY and A in the formula [V], and Z is a hydrogen atom, an alkyl group, an aryl group, a halogen atom, an alkoxyl group, a carboxyl group, A group, a formyl group, an alkyl ester, an aryl ester, an alkyl ketone, an aryl ketone, or a heterocyclic ring, and n is an integer of 1 to 20.). A chemiluminescent reagent comprising the 1,2-dioxetane derivative according to any one of claims 1 to 7. The chemiluminescent reagent according to claim 8, further comprising a surfactant. A luminescence method characterized by using the chemiluminescence reagent according to claim 8 or 9 and decomposing a 1,2-dioxetane derivative contained therein to cause chemiluminescence. An immunoassay reagent comprising the chemiluminescent reagent according to claim 8 or 9. A method for measuring a substance in a sample using the light emitting method according to claim 10.