KR20090085173A - New alkyl aryl selenide derivatives and process for preparing thereof - Google Patents

Abstract

A method for manufacturing an alkyl aryl selenide derivative is provided to prepare an alkyl aryl selenide derivative with a single process without separation and refining process of intermediate from various aryl halogen compounds. An alkyl aryl selenide derivative has a structure represented by chemical formula 1. In chemical formula 1, A is CR11 or N; B is a functional group of chemical formula 1a and a functional group of chemical formula 1b; R1 is substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7) alkyl, hydroxyl, hydroxy (C1-C7) alkyl or carboxylic acid; R2 is (C1-C10) alkyl, (C6-C12) aryl, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl or (C6-C12) arylcarbonyl; R3 is (C1-C7) alkyl or (C6-C12) aryl; R11 hydrogen, halogen-substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7) alkyl, hydroxyl, hydroxy (C1-C7) alkyl or carboxylic acid; and m is an integer of 1-4.

Description

Novel alkylaryl selenide derivatives and preparation method thereof {NEW ALKYL ARYL SELENIDE DERIVATIVES AND PROCESS FOR PREPARING THEREOF}

The present invention relates to a novel alkylaryl selenide derivative and a method for preparing the same, and more particularly, the present invention relates to alkylaryl selenide derivatives represented by the following general formula (1) and various functions in organic chemistry and medicinal chemistry synthesis. A method for preparing the alkylaryl selenide derivative in a single reaction from an aryl halogen compound having an electron-donating, electron-withdrawing substituent or a hydrogen-donating substituent will be.

[Formula 1]

또는

이다.][Wherein B is

or

to be.]

Deficiency of selenium is closely related to various diseases such as arthritis, heart disease, diabetes and AIDS. In addition, taking selenium as an additional food supplement is known to prevent prostate cancer, colon cancer and lung cancer. Therefore, recently, many biomaterials based on selenium have been known, and the selenium compound chemistry of specific structure has been attracting attention, and thus, for the synthesis of stable selenium compounds that can be used as antioxidants, anticancer agents, antibacterial agents, antihypertensive agents, antiviral agents, and cytokine promoters, etc. Many studies are being done. As a result of these studies, the following diorganoselenides compounds were used as chiral ligands for the synthesis of cancer prevention substances (compounds A and B), anticancer substances (compound C), antiviral substances (D), and optical isomers. (Compound E) and the like have been reported.

The present inventors have already reported the synthesis of various sulfur compounds easily by one-pot synthesis method through substitution reaction of electrophiles and lithium aryl thiolates [Registration No. 0723828]. Based on the synthesis method of previous studies, the present invention attempted to synthesize selenium compounds. Selenium compounds in the form of ethers containing selenium have not been studied sufficiently because they pass through unstable lithium intermediates.

It is an object of the present invention to provide a novel alkylarylselenide derivative which can be an intermediate of a drug comprising selenium.

In addition, another object of the present invention is to provide a method for producing a new alkylaryl selenide derivative in a short reaction time at a low reaction time in a single reaction without the process of separating and purifying intermediates from various aryl halogen compounds. .

The present invention relates to a novel alkylaryl selenide derivative represented by the following formula (1) which plays an important role in organic chemistry and medicinal chemistry synthesis.

[Formula 1]

[Wherein A is CR ₁₁ or N;

또는

이고;B is

or

ego;

R ₁ represents (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7) alkyl, with or without halogen , Hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid;

R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl;

R ₃ is (C1-C7) alkyl or (C6-C12) aryl, wherein the alkyl of R ₃ may be further substituted with (C2-C7) alkenyl;

R ₁₁ is hydrogen, substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7 ) Alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid;

m is an integer from 1 to 4.]

The alkylaryl selenide derivative of Chemical Formula 1 is benzyl (2- (trifluoromethyl) phenyl) selan, benzyl (3- (trifluoromethyl) phenyl) selan, benzyl (4- (trifluoromethyl) phenyl) selan, benzyl (4-bromophenyl) celan, benzyl (4-biphenyl) celan, benzyl (4-methoxyphenyl) celan, t-butyl 2- (4-methoxyphenylselanyl) acetate, 1- (4-meth Methoxyphenylselanyl) -5-hexene-2ol, 4- (benzylcelanyl) phenol, (4- (benzylcelanyl) phenyl) methanol, 2- (4- (benzylcelanyl) phenyl) ethanol, t- Butyl 2- (4-hydroxyphenylselanyl) acetate, 4- (2-hydroxy-5-hexenylselanyl) phenol, 1- (4-aminophenylselanyl) -5-hexen-2-ol, It may be exemplified by 4- (benzylcelanyl) benzeneamine or 4- (benzylcelanyl) benzoic acid, but is not limited thereto.

The present invention also provides novel alkylarylselenide derivatives in a single reaction from aryl halogen compounds having various electron-donating, electron-withdrawing substituents or hydrogen-donating substituents. It relates to a method of manufacturing. As shown in Scheme 1 below, when the arylhalogen compound of Formula 4 has an electron-donating or electron-withdrawing substituent, halogen (C1-C4) is substituted from the aryl halogen compound (4). After substitution with an alkyllithium organometallic reagent, selenium is reacted with a compound of formula (5) or (6) continuously, or an aryl halogen compound of formula (4) is a hydrogen-judgment substituent (amino, aminoalkyl, hydroxy). , Hydroxyalkyl or carboxylic acid), the arylhalogen compound (4) reacts with the Grignard reagent (7) to protect the hydrogen-substituted substituents, and then halogen is (C1-C4) alkyllithium organic The present invention was completed by discovering that alkylaryl selenide of formula (1) was obtained by substitution of a metal reagent and subsequent reaction of selenium with a compound of formula (5) or formula (6).

Scheme 1

[Wherein A is CR ₁₁ or N;

또는

이고;B is

or

ego;

X ₁ to X ₃ are each independently halogen;

R ₁ represents (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7) alkyl, with or without halogen , Hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid;

R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl;

R ₃ is (C1-C7) alkyl or (C6-C12) aryl, wherein the alkyl of R ₃ may be further substituted with (C2-C7) alkenyl;

R ₁₁ is hydrogen, substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7 ) Alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid;

m is an integer from 1 to 4.]

That is, the present invention is a variety of the general formula (1) by reacting with the compound of formula (5) or formula (6) in a single reaction without the process of separation and purification from [step A] or [step B] from the formula (4) It is to provide a method for producing an alkylaryl selenide derivative easily and economically.

In formula, A means CR ₁₁ or a nitrogen atom contained in the aryl compound which has a resonance structure.

X ₁ and X ₂ mean a halogen atom. As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. are mentioned. Of these, bromine and iodine are particularly preferred.

X ₃ means a chlorine atom, a bromine atom, or an iodine atom as the halogen atom of the Grignard reagent.

R ₁ represents (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7) alkyl, with or without halogen , Hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid. Of each substituent R ₁ The position is a position of ortho-, meta- and para- based on the halogen atom (X ₁ ), and the number of substituents (m) means 1-4.

R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl.

R ₃ is (C 1 -C 7) alkyl or (C 6 -C 12) aryl and the alkyl of R ₃ may be further substituted with (C ₂ -C 7) alkenyl.

R ₁₁ is hydrogen, substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7 ) Alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid.

R ₂₁ is (C 1 -C 7) alkyl and represents alkyl such as methyl, ethyl, propyl, isopropyl, n -butyl, sec -butyl tert -butyl and the like.

Reaction Scheme 1 of the present invention is described in more detail as follows.

Scheme 2

[In Scheme 2, A is CR ₁₁ or N;

X ₁ and X ₂ are independently of each other halogen;

R ₁ is (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl or halogen substituted or unsubstituted;

R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl;

R ₃ is (C1-C7) alkyl or (C6-C12) aryl, wherein the alkyl of R ₃ may be further substituted with (C2-C7) alkenyl;

R ₁₁ is hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl or halogen substituted or unsubstituted;

m is an integer from 1 to 4.]

Scheme 3

[In Scheme 3, A is CR ₁₁ or N;

X ₁ to X ₃ are each independently halogen;

R ₁ is amino, amino (C ₁ -C 7) alkyl, hydroxy, hydroxy (C 1 -C 7) alkyl or carboxylic acid;

R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl;

R ₃ is (C1-C7) alkyl or (C6-C12) aryl, wherein the alkyl of R ₃ may be further substituted with (C2-C7) alkenyl;

R ₁₁ is hydrogen, substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7 ) Alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid;

R ₂₁ is (C1-C7) alkyl;

m is an integer from 1 to 4.]

In the manufacturing method of this invention, the compound of general formula (4) used as a raw material is easily available as a well-known compound.

Hereinafter, the manufacturing method of this invention is demonstrated in detail.

[Step A] Preparation of Alkylaryl Selenide Compound Represented by Chemical Formula (2) or Chemical Formula (3) Having an Electron-Container or Electron-Receiving Substituent

The alkylaryl selenide compound represented by the formula (2) is continuously reacted with the compound represented by the formula (5) after reacting the compound represented by the formula (4) with the (C1-C4) alkyl lithium organometallic reagent and selenium. Get reacted. The alkylaryl selenide compound represented by the formula (3) is continuously reacted with the compound represented by the formula (6) after reacting the compound represented by the formula (4) with the (C1-C4) alkyl lithium organometallic reagent and selenium. Get reacted to.

As the anhydrous solvent used in this step, a mixed solvent in which a single solvent such as diethyl ether, tetrahydrofuran, hexane and heptane and two or more solvents are combined is used. Among these, the most preferable solvent is a mixed solvent of diethyl ether, tetrahydrofuran, diethyl ether and tetrahydrofuran.

Examples of the alkyllithium organometallic reagent used in the halogen-metal substitution reaction include n -butyllithium, sec -butyllithium, and tert -butyllithium. The amount of the alkyllithium organometallic reagent to be used is usually 1 to 3 equivalents based on the compound of formula (4), and most preferably 1 to 1.2 equivalents for n -butyllithium and sec -butyllithium, tert -In the case of butyllithium, it is recommended to use 2 to 2.2 equivalents.

The selenium used in this process is in the form of a dark red solid powder, and the amount of selenium used is usually 1 to 3 equivalents, preferably 1 to 1.2 equivalents, relative to the compound of formula (4).

The reaction temperature may vary depending on the solvent used, but is usually -100 to 25 ° C, preferably a halogen-metal substitution reaction at -78 ° C, and a selenium introduction reaction at -20 ~ -10 ° C. , And the reaction with the compound of formula (5) or formula (6) at -10 ~ 0 ℃. Although the reaction time may vary depending on the reaction temperature and the solvent used, the reaction time is generally 30 minutes to 6 hours, preferably 1 hour or less.

[Step B] Preparation of Alkylaryl Selenide Compound Represented by Formula (2) or Formula (3) Having a Hydrogen-Current Substituent

In preparing the alkylaryl selenide compounds represented by the formula (2) or (3), the substituents of the compound represented by the formula (4) may be hydrogen-substituted substituents (amino, amino (C1-C7) alkyl, hydroxy, In the case of hydroxy (C1-C7) alkyl or carboxylic acid), the hydrogen-judgment substituent is first protected with Grignard reagent (7) and reacted with (C1-C4) alkyllithium organometallic reagent, selenium. Reaction with the compound represented by (5) or (6) yields a compound of the formula (2) or (3).

As the anhydrous solvent used in this step, a mixed solvent in which a single solvent such as diethyl ether, tetrahydrofuran, hexane and heptane and two or more solvents are combined is used. Among these, the most preferable solvent is a mixed solvent of diethyl ether, tetrahydrofuran, diethyl ether and tetrahydrofuran.

Grignard reagents protecting the hydrogen-primary substituents (amino, amino (C1-C7) alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid) include CH ₃ MgCl, CH ₃ MgBr, CH ₃ MgI , CH ₃ CH ₂ MgCl, CH ₃ CH ₂ MgBr, CH ₃ CH ₂ MgI, CH ₃ CH ₂ CH ₂ MgCl, CH ₃ CH ₂ CH ₂ MgBr, CH ₃ CH ₂ CH ₂ MgI, (CH ₃ ) ₂ CHMgCl, (CH ₃ ) ₂ CHMgBr, (CH ₃ ) ₂ CHMgI, CH ₃ CH ₂ CH ₂ CH ₂ MgCl, CH ₃ CH ₂ CH ₂ CH ₂ MgBr, CH ₃ CH ₂ CH ₂ CH ₂ MgI, C ₂ H ₅ CHCH ₃ MgCl, C ₂ H ₅ CHCH ₃ MgBr, C ₂ H ₅ CHCH ₃ MgI, (CH ₃ ) ₃ CMgCl, (CH ₃ ) ₃ CMgBr, (CH ₃ ) ₃ CMgI and the like. Of these, R ₂₁ MgCl and R ₂₁ MgBr are preferable, and more preferably (CH ₃ ) ₂ CHMgCl and CH ₃ CH ₂ CH ₂ CH ₂ MgCl. The amount of Grignard reagent used is usually 1 to 3 equivalents, most preferably 1 to 2 equivalents based on the compound of formula (4).

Examples of the alkyllithium organometallic reagent used in the halogen-metal substitution reaction include n -butyllithium, sec -butyllithium, and tert -butyllithium. The amount of the alkyllithium organometallic reagent to be used is usually 1 to 3 equivalents based on the compound of formula (4), and most preferably 1 to 1.2 equivalents for n -butyllithium and sec -butyllithium, tert -In the case of butyllithium, it is recommended to use 2 to 2.2 equivalents.

The selenium used in this process is in the form of a dark red solid powder, and the amount of selenium used is usually 1 to 3 equivalents, preferably 1 to 1.2 equivalents, relative to the compound of formula (4).

The reaction temperature may vary depending on the solvent used, but is usually -100 to 25 ° C., preferably, the hydrogen-substituted substituent protection reaction is performed at 0 to 25 ° C., and the halogen-metal substitution reaction is performed at −78 ° C., The selenium introduction reaction is carried out at -20 ~ -10 ℃, the reaction with the compound of formula (5) or formula (6) is reacted at -10 ~ 0 ℃. The reaction time may vary depending on the reaction temperature and the solvent used, but is usually reacted at 30 minutes to 6 hours, preferably 2 hours or less.

The present invention relates to an alkylaryl selenide compound of formula (2) or formula (3) thus obtained and a method for preparing the same. It is very important in the process.

As described above, the novel alkylaryl selenide derivatives of the present invention can be used as intermediates that play an important role in organic chemistry or medicinal chemical synthesis, and the method for preparing alkyl aryl selenides of the present invention is very unstable without catalyst. Short reaction time for various alkylaryl selenide derivatives that can be intermediates of selenium-containing drugs in a single reaction without using arylselenols, without separating and purifying intermediates from various aryl halogen compounds It can be produced in high yield.

Hereinafter, the method of the present invention will be described in detail with reference to Examples. However, the present invention is not limited to these examples.

[ Example  One] Of benzyl (2- (trifluoromethyl) phenyl) celan  Produce

In a nitrogen atmosphere, 272 µl (2 mmol) of 1-bromo-2- (trifluoromethyl) -benzene was added to 15 ml of anhydrous tetrahydrofuran to dissolve well and cooled to -78 ° C. 1.25 mL (1.6 M -hexane solution, 1.0 equiv) of n -butyl lithium is slowly added for 1 minute. After further stirring for 10 minutes, 158 mg (2 mmol, 1.0 equiv) of selenium powder was added at a time at -20 ° C. Stir the mixture at the same temperature for 10 minutes to completely dissolve the selenium, and then slowly add 238 μl (2 mmol, 1.0 equiv) of benzylbromide at −10 ° C. The entire mixed reaction is stirred at 0 ° C. for 20 minutes. The reaction was confirmed by TLC. After the reaction was completed, 15 ml of aqueous ammonium chloride solution was added to terminate the reaction, and the organic layer was extracted using ethyl acetate. The moisture of the organic layer is removed with magnesium sulfate, and the solvent is distilled off under reduced pressure after filtration. The residue was purified by silica gel column chromatography to obtain 466 mg (yield: 74%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.63 (d, 1H, J = 7.7 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.35-7.29 (m, 2H), 7.26-7.18 (m, 5H), 4.15 (s, 2H); HRMS (FAB) m / z calcd for C ₁₄ H ₁₁ F ₃ Se [M + H] ⁺ 315.9978, found 315.9979.

[ Example  2] Of benzyl (3- (trifluoromethyl) phenyl) celan  Produce

Same as Example 1 except that 1-bromo-2- (trifluoromethyl) -benzene was replaced with 272 μl (2 mmol) of 1-bromo-3- (trifluoromethyl) benzene After the reaction, the reaction mixture was purified to obtain 429 mg (yield: 68%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.63 (s, 1H), 7.56 (d, 1H, J = 7.8 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.29 (t, 1H, J = 7.8 Hz), 7.24-7.16 (m, 5H), 4.11 (s, 2H); HRMS (FAB) m / z calcd for C ₁₄ H ₁₁ F ₃ Se [M + H] ⁺ 315.9978, found 315.9990.

[ Example  3] Of benzyl (4- (trifluoromethyl) phenyl) celan  Produce

Same as Example 1 except for using 1-bromo-2- (trifluoromethyl) -benzene with 272 μl (2 mmol) of 1-bromo-4- (trifluoromethyl) benzene. After the reaction, the residue was purified to yield 574 mg (yield: 91%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.50 (d, 2H, J = 8.1 Hz), 7.46 (d, 2H, J = 8.1 Hz), 7.28-7.21 (m, 5H), 4.17 (s, 2H) ; HRMS (FAB) m / z calcd for C ₁₄ H ₁₁ F ₃ Se [M + H] ⁺ 315.9978, found 315.9993.

[ Example  4] Of benzyl (4-bromophenyl) celan  Produce

Purification after the reaction in the same manner as in Example 1, except that 1-bromo-2- (trifluoromethyl) -benzene was replaced with 1,4-dibromobenzene 472 mg (2 mmol). To give 548 mg (yield: 84%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.33 (d, 2H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.4 Hz), 7.24-7.17 (m, 5H), 4.07 (s, 2H) ; HRMS (FAB) m / z calcd for C ₁₃ H ₁₁ BrSe [M + H] ⁺ 325.9209, found 325.9193.

[ Example  5] Of benzyl (4-biphenyl) celan  Produce

The reaction was carried out in the same manner as in Example 1, except that 1-bromo-2- (trifluoromethyl) -benzene was replaced with 466 mg (2 mmol) of 4-bromobiphenyl, and the title compound was purified. 563 mg (yield 87%) were obtained.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.57-7.19 (m, 14H), 4.14 (s, 2H); HRMS (FAB) m / z calcd for C ₁₉ H ₁₆ Se [M + H] ⁺ 324.0417, found 324.0415.

[ Example  6] Of benzyl (4-methoxyphenyl) celan  Produce

The reaction was carried out in the same manner as in Example 1, except that 1-bromo-2- (trifluoromethyl) -benzene was replaced with 250 μl (2 mmol) of 1-bromo-4-methoxybenzene. Purification gave 482 mg (yield: 87%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.35 (d, 2H, J = 8.5 Hz), 7.25-7.18 (m, 3H), 7.12 (d, 2H, J = 7.3 Hz), 6.77 (d, 2H, J = 8.6 Hz), 4.00 (s, 2H), 3.78 (s, 3H); HRMS (FAB) m / z calcd for C ₁₄ H ₁₄ OSe [M + H] ⁺ 278.0210, found 278.0244.

[ Example  7] t-butyl 2- (4- Methoxyphenylselanyl Manufacture of Acetate

250 μl (2 mmol) of 1-bromo-2- (trifluoromethyl) -benzene and 295 μl (2 mmol of tert-butyl 2-bromoacetate with benzylbromide , 1.0 equivalent), except that the reaction mixture was used in the same manner as in Example 1, and then purified to obtain 512 mg (yield: 85%) of the title compound.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.52 (d, 2H, J = 10.5 Hz), 6.81 (d, 2H, J = 10.5 Hz), 3.76 (s, 3H), 3.31 (s, 2H), 1.38 (s, 9H); MS (ESI) m / z 302.90 ([M + H] ⁺ ).

[ Example  8] 1- (4- Methoxyphenylselanyl ) -5- Hexene Preparation of 2-ol

250 μl (2 mmol) of 1-bromo-2- (trifluoromethyl) -benzene and 226 μl of 2- (3-butenyl) oxysilane in benzylbromide (2 mmol) mmol, 1.0 equivalent), except that the reaction was carried out in the same manner as in Example 1, and purified to obtain 428 mg (yield: 75%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.48 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 5.77 (m, 1H), 4.96 (m, 2H), 3.77 (s, 3H), 3.64 (m, 1H), 3.01 (dd, 1H, J = 12.7, 3.6 Hz), 2.79 (dd, 1H, J = 12.6, 8.7 Hz), 2.64 (brs, 1H), 2.19 ( td, 1H, J = 14.5, 7.1 Hz), 2.09 (td, 1H, J = 14.7, 7.3 Hz), 1.59 (q, 2H, J = 7.2 Hz); HRMS (FAB) m / z calcd for C ₁₃ H ₁₈ O ₂ Se [M + H] ⁺ 286.0472, found 286.0444.

[ Example  9] 4- ( Benzyl selanyl Production of Phenol

In a nitrogen atmosphere, 346 mg (2 mmol) of 4-bromophenol was added to 15 ml of anhydrous tetrahydrofuran to dissolve well, and the temperature was lowered to 0 ° C. At the same temperature 1.0 ml (2 mmol, 2.0 M -ether solution, 1.0 equiv) of isopropylmagnesium chloride are slowly added. After the reaction for 10 minutes, the reaction was cooled to −78 ° C., and 2.4 ml (4 mmol, 1.7 M -pentane solution, 2.0 equiv) of tert -butyllithium were slowly added for 1 minute. After further stirring for 30 minutes, 158 mg (2 mmol, 1.0 equiv) of selenium powder was added at a time at -20 ° C. Stir the mixture at the same temperature for 10 minutes to completely dissolve the selenium, and then slowly add 238 μl (2 mmol, 1.0 equiv) of benzylbromide at −10 ° C. The entire mixed reaction is stirred at 0 ° C. for 20 minutes. The reaction was confirmed by TLC. After the reaction was completed, 15 ml of aqueous ammonium chloride solution was added to terminate the reaction, acidified with ethyl acetate and 5% aqueous hydrochloric acid solution, and the organic layer was extracted. The moisture of the organic layer is removed with magnesium sulfate, and the solvent is distilled off under reduced pressure after filtration. The residue was purified by silica gel column chromatography to obtain 453 mg (yield: 86%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.30 (d, 2H, J = 8.5 Hz), 7.25-7.16 (m, 3H), 7.11 (d, 2H, J = 7.2 Hz), 6.69 (d, 2H, J = 8.5 Hz), 4.88 (s, 1 H), 3.99 (s, 2 H); HRMS (FAB) m / z calcd for C ₁₃ H ₁₂ OSe [M + H] ⁺ 264.0053, found 264.0042.

[ Example  10] (4- ( Benzyl selanyl ) Phenyl Methanol Production

The reaction was carried out in the same manner as in Example 9, except that 4-bromophenol was replaced with 374 mg (2 mmol) of (4-bromophenyl) methanol, and the residue was purified to yield 449 mg of the title compound (yield: 81%). )

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.42 (d, 2H, J = 8.0 Hz), 7.25-7.17 (m, 7H), 4.62 (s, 2H), 4.08 (s, 2H), 2.00 (brs, 1H) HRMS (FAB) m / z calcd for C ₁₄ H ₁₄ OSe [M + H] ⁺ 278.0210, found 278.0222.

[ Example  11] 2- (4- ( Benzyl selanyl ) Phenyl Production of Ethanol

The reaction was carried out in the same manner as in Example 9, except that 4-bromophenol was replaced with 280 μl (2 mmol) of (4-bromophenyl) ethanol, and the residue was purified to give 489 mg of the title compound (yield: 84% )

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.38 (d, 2H, J = 8.0 Hz), 7.24-7.17 (m, 5H), 7.09 (d, 2H, J = 7.9 Hz), 4.06 (s, 2H) , 3.80 (t, 2H, J = 6.6 Hz), 2.81 (t, 2H, J = 6.6 Hz), 1.68 (brs, 1H) HRMS (FAB) m / z calcd for C ₁₅ H ₁₆ OSe [M + H] ⁺ 292.0366, found 292.0370.

[ Example  12] t-butyl 2- (4- Hydroxyphenylselanyl Manufacture of Acetate

The reaction was carried out in the same manner as in Example 9, except that benzylbromide was replaced by 295 μl (2 mmol) of tert-butyl 2-bromoacetate to obtain 465 mg (yield: 81%) of the title compound. .

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.46 (d, 2H, J = 8.5 Hz), 6.67 (d, 2H, J = 8.5 Hz), 3.31 (s, 2H), 1.42 (s, 9H); HRMS (FAB) m / z calcd for C ₁₂ H ₁₆ O ₃ Se [M + H] ⁺ 288.0265, found 288.0294.

[ Example  13] 4- (2-hydroxy-5- Hexenyl selanyl Production of Phenol

The reaction was carried out in the same manner as in Example 9, except that benzylbromide was used by replacing 226 μl (2 mmol) of 2- (3-butenyl) oxirane and purified to give 423 mg of the title compound (yield: 78%). Got.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.42 (d, 2H, J = 8.5 Hz), 6.72 (d, 2H, J = 8.5 Hz), 5.76 (m, 1H), 4.96 (m, 2H), 3.67 (m, 1H), 3.05 (dd, 1H, J = 12.8, 3.6 Hz), 2.80 (dd, 1H, J = 12.8, 8.7 Hz), 2.67 (brs, 1H), 2.13 (m, 2H), 1.82 ( brs, 1 H), 1.62 (m, 2 H); HRMS (FAB) m / z calcd for C ₁₂ H ₁₆ O ₂ Se [M + H] ⁺ 272.0316, found 272.0358.

[ Example  14] 1- (4- Aminophenylselanyl ) -5- Hexene Preparation of 2-ol

Replace 4-bromophenol with 438 mg (2 mmol) of 4-iodobenzeneamine, use 2.0 ml (4 mmol, 2.0 M-ether solution, 2.0 equiv) of isopropylmagnesium chloride, and add benzylbromide. The reaction was carried out in the same manner as in Example 9, except that 226 μl (2 mmol) of 2- (3-butenyl) oxirane was used to obtain 411 mg (yield: 76%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.35 (d, 2H, J = 8.4 Hz), 6.57 (d, 2H, J = 8.4 Hz), 5.77 (m, 1H), 4.96 (m, 2H), 3.61 (m, 1H), 2.98 (dd, 1H, J = 12.6, 3.5 Hz), 2.73 (dd, 1H, J = 12.6, 8.8 Hz), 2.13 (m, 2H), 1.59 (m, 2H); HRMS (FAB) m / z calcd for C ₁₂ H ₁₇ NOSe [M + H] ⁺ 271.0475, found 271.0465.

[ Example  15] 4- ( Benzyl selanyl ) Benzeneamine  Produce

435 mg (yield: 83%) of the title compound was purified after reaction in the same manner as in Example 14, except that 2-238- (3-butenyl) oxirane was replaced with 238 μl (2 mmol) of benzyl bromide. Got.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.41 (d, 2H, J = 8.7 Hz), 7.25-7.16 (m, 3H), 7.12 (d, 2H, J = 7.2 Hz), 6.47 (d, 2H, J = 8.7 Hz), 3.95 (s, 2 H); HRMS (FAB) m / z calcd for C ₁₃ H ₁₃ NSe [M + H] ⁺ 263.0213, found 263.0261.

[ Example  16] 4- ( Benzyl selanyl Production of benzoic acid

The reaction was carried out in the same manner as in Example 9, except that 4-bromophenol was used by replacing 402 mg (2 mmol) of 4-bromobenzoic acid to obtain 478 mg (yield: 82%) of the title compound. .

¹ H NMR (600 MHz, DMSO- d ₆ ) δ 12.86 (s, 1H), 7.81 (d, 2H, J = 8.0 Hz), 7.55 (d, 2H, J = 7.9 Hz), 7.35 (d, 2H, J = 7.4 Hz), 7.28 (t, 2H, J = 7.5 Hz), 7.21 (t, 1H, J = 7.3 Hz), 4.34 (s, 2H); HRMS (FAB) m / z calcd for C ₁₄ H ₁₂ O ₂ Se [M + H] ⁺ 292.0003, found 291.9997.

Claims (8)

An alkylaryl selenide derivative represented by the following formula (1). [Formula 1]

[Wherein A is CR ₁₁ or N; B is

or

ego; R ₁ represents (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7) alkyl, with or without halogen , Hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid; R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl; R ₃ is (C1-C7) alkyl or (C6-C12) aryl, wherein the alkyl of R ₃ may be further substituted with (C2-C7) alkenyl; R ₁₁ is hydrogen, substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7 ) Alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid; m is an integer from 1 to 4.] The method of claim 1, Alkylaryl selenide derivatives selected from the following compounds. Benzyl (2- (trifluoromethyl) phenyl) celan Benzyl (3- (trifluoromethyl) phenyl) celan Benzyl (4- (trifluoromethyl) phenyl) celan Benzyl (4-bromophenyl) celan Benzyl (4-biphenyl) celan Benzyl (4-methoxyphenyl) celan t-butyl 2- (4-methoxyphenylselanyl) acetate 1- (4-methoxyphenylselanyl) -5-hexene-2ol 4- (benzylcelanyl) phenol (4- (benzylcelanyl) phenyl) methanol 2- (4- (benzylcelanyl) phenyl) ethanol t-butyl 2- (4-hydroxyphenylselanyl) acetate 4- (2-hydroxy-5-hexenylcelanyl) phenol 1- (4-aminophenylselanyl) -5-hexen-2-ol 4- (benzylcelanyl) benzeneamine 4- (benzylcelanyl) benzoic acid To react the aryl halogen compound of Formula 4 with (C1-C4) alkyllithium to replace the halogen of the aryl halogen compound of Formula 4 with lithium, and then to continuously react the selenium and the compound of Formula 5 Method for producing alkyl aryl selenides. [Formula 2]

[Formula 4]

[Formula 5]

[Wherein A is CR ₁₁ or N; X ₁ and X ₂ are independently of each other halogen; R ₁ is (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl or halogen substituted or unsubstituted; R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl; R ₁₁ is hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl or halogen substituted or unsubstituted; m is an integer from 1 to 4.] To react the aryl halogen compound of Formula 4 and (C1-C4) alkyllithium to replace the halogen of the aryl halogen compound of Formula 4 with lithium, and then to continuously react the selenium and the compound of Formula 6 Method for producing alkyl aryl selenides. [Formula 3]

[Formula 4]

[Formula 6]

[Wherein A is CR ₁₁ or N; X ₁ is halogen; R ₁ is (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl or halogen substituted or unsubstituted; R ₃ is (C1-C7) alkyl or (C6-C12) aryl, wherein the alkyl of R ₃ may be further substituted with (C2-C7) alkenyl; R ₁₁ is hydrogen, (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl or halogen substituted or unsubstituted; m is an integer from 1 to 4.] After reacting an aryl halogen compound of Formula 4 with a Greennard reagent of Formula 7 to protect the hydrogen-primer substituent, (C1-C4) alkyllithium is added to replace halogen with lithium, and selenium and formula Method for producing an alkylaryl selenide of formula 2 characterized in that the compound of 5 to continuously react. [Formula 2]

[Formula 4]

[Formula 5]

[Formula 7]

[Wherein A is CR ₁₁ or N; X ₁ to X ₃ are each independently halogen; R ₁ is amino, amino (C ₁ -C 7) alkyl, hydroxy, hydroxy (C 1 -C 7) alkyl or carboxylic acid; R ₂ is (C 1 -C 10) alkyl, (C 6 -C 12) aryl, (C 1 -C 10) alkoxycarbonyl, (C 1 -C 10) alkylcarbonyl or (C 6 -C 12) arylcarbonyl; R ₁₁ is hydrogen, substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7 ) Alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid; R ₂₁ is (C1-C7) alkyl; m is an integer from 1 to 4.] After reacting an aryl halogen compound of Formula 4 with a Greennard reagent of Formula 7 to protect the hydrogen-primer substituent, (C1-C4) alkyllithium is added to replace halogen with lithium, and selenium and formula Method for producing an alkylaryl selenide of formula 3 characterized in that the compound of 6 to continuously react. [Formula 3]

[Formula 4]

[Formula 6]

[Formula 7]

[Wherein A is CR ₁₁ or N; X ₁ and X ₃ are independently of each other halogen; R ₁ is amino, amino (C ₁ -C 7) alkyl, hydroxy, hydroxy (C 1 -C 7) alkyl or carboxylic acid; R ₃ is (C1-C7) alkyl or (C6-C12) aryl, wherein the alkyl of R ₃ may be further substituted with (C2-C7) alkenyl; R ₁₁ is hydrogen, substituted or unsubstituted (C1-C7) alkyl, (C1-C7) alkoxy, (C1-C7) alkylthio, (C6-C12) aryl, halogen, amino, amino (C1-C7 ) Alkyl, hydroxy, hydroxy (C1-C7) alkyl or carboxylic acid; R ₂₁ is (C1-C7) alkyl; m is an integer from 1 to 4.] The method according to any one of claims 3 to 6, The alkyllithium used is n -butyllithium, sec -butyllithium, tert -butyllithium, and the amount thereof is 1 to 3 equivalents based on the aryl halogen compound of the formula (4). The method according to claim 5 or 6, The Grignard reagent is CH ₃ MgCl, CH ₃ MgBr, CH ₃ MgI, CH ₃ CH ₂ MgCl, CH ₃ CH ₂ MgBr, CH ₃ CH ₂ MgI, CH ₃ CH ₂ CH ₂ MgCl, CH ₃ CH ₂ CH ₂ MgBr , CH ₃ CH ₂ CH ₂ MgI, (CH ₃ ) ₂ CHMgCl, (CH ₃ ) ₂ CHMgBr, (CH ₃ ) ₂ CHMgI, CH ₃ CH ₂ CH ₂ CH ₂ MgCl, CH ₃ CH ₂ CH ₂ CH ₂ MgBr, CH ₃ CH ₂ CH ₂ CH ₂ MgI, C ₂ H ₅ CHCH ₃ MgCl, C ₂ H ₅ CHCH ₃ MgBr, C ₂ H ₅ CHCH ₃ MgI, (CH ₃ ) ₃ CMgCl, (CH ₃ ) ₃ CMgBr, (CH ₃ ) A method for producing an alkylaryl selenide, characterized in that one selected from the group consisting of ₃ CMgI.