JP4496770B2 - 1-halogeno-2-alkoxynaphthalene derivative and method for producing the same - Google Patents

Description

  The present invention relates to a 1-halogeno-2-alkoxynaphthalene derivative and a method for producing the same.

  1-halogeno-2-alkoxynaphthalene derivatives are useful as intermediates for the production of liquid crystal compounds and pharmaceuticals. However, depending on the type and position of the substituent, the production method is not known, and those for which the production method is known have gone through the following complicated steps. (Patent Document 1)

さらに、上記方法ではF-TEDA-BF₄（AIR PRODUCTS製）、ACCUFLOR NFSi（AlliedSignal製）等の高価格なフッ素化剤を複数回用いなければならなかった。そのため1-ハロゲノ-2-アルコキシナフタレン誘導体の簡便かつ安価な製造方法が求められていた。

Furthermore, in the above method, an expensive fluorinating agent such as F-TEDA-BF ₄ (manufactured by AIR PRODUCTS) or ACCUFLOR NFSi (manufactured by AlliedSignal) had to be used several times. Therefore, a simple and inexpensive method for producing 1-halogeno-2-alkoxynaphthalene derivatives has been demanded.

JP 2001-10995 (pages 2 and 3)

  The problem to be solved by the present invention is to provide a simple and inexpensive method for producing a 1-halogeno-2-alkoxynaphthalene derivative.

As a result of intensive studies to solve the above problems, the present inventors have found that a corresponding 1-halogeno-2-alkoxynaphthalene derivative can be obtained by allowing an alcohol derivative and a halogenating agent to act on a tetrahydronaphthalenone derivative. The present invention has been completed.
That is, the present invention relates to the general formula (1)

で表される部分構造を有する化合物に一般式（２）

A compound having a partial structure represented by the general formula (2)

（式中、R¹は芳香環を含んでいてもよい飽和炭化水素を表し、この基中に存在する1個または2個以上の水素原子はFまたはClに置換されてもよい。）で表されるアルコール誘導体およびハロゲン化剤を作用させることにより一般式（３）

Wherein R ¹ represents a saturated hydrocarbon which may contain an aromatic ring, and one or more hydrogen atoms present in this group may be substituted with F or Cl. By acting an alcohol derivative and a halogenating agent to be represented by the general formula (3)

（式中、R¹は一般式（２）と同じ意味を表し、X¹はBr、ClまたはIを表す。）で表される部分構造を有する化合物へ変換する方法を提供する。

(Wherein R ¹ represents the same meaning as in the general formula (2), and X ¹ represents Br, Cl, or I).

Furthermore, the following production methods and compounds are provided.
That is, the general formula (4)

（式中、R²はフッ素原子、塩素原子、水素原子または炭素数1〜12のアルキル基を表し、これらの基中に存在する1個のCH₂基または隣接していない2個以上のCH₂基はOおよび/またはSに置換されてもよく、またこれらの基中に存在する1個または2個以上の水素原子はFまたはClに置換されてもよく、
A¹は
(a) トランス-1,4-シクロへキシレン基(この基中に存在する1個のCH₂基または隣接していない2個のCH₂基はOおよび/またはSに置換されてもよい)
(b) 1,4-フェニレン基(この基中に存在する1個または2個以上のCH基はNに置換されてもよい)
(c) 1,4-ビシクロ[2.2.2]オクチレン基、ピペリジン-1,4-ジイル基、ナフタレン-2,6-ジイル基、デカヒドロナフタレン-2,6-ジイル基および1,2,3,4-テトラヒドロナフタレン-2,6-ジイル基
からなる群より選ばれる基であり、上記の基(a)、基(b)、基(c)はCN、FまたはClで置換されていてもよく、
Z¹は-CH₂CH₂-、-CH(CH₃)CH₂-、-CH₂CH(CH₃)-、-CH(CH₃)CH(CH₃)-、-CF₂CF₂-、-CH₂O-、-OCH₂-、-OCH(CH₃)-、-CH(CH₃)O-、-(CH₂)₄-、-(CH₂)₃O-、-O(CH₂)₃-、-CF₂O-、-OCF₂-または単結合を表し、
aは0、1、2または3を表し、
L¹ 、L²およびL³はそれぞれ独立的にフッ素原子、塩素原子または水素原子を表す。）
で表されるテトラヒドロナフタレノン誘導体に一般式（２）で表されるアルコール誘導体およびハロゲン化剤を作用させることによる一般式（５）

(In the formula, R ² represents a fluorine atom, a chlorine atom, a hydrogen atom or an alkyl group having 1 to 12 carbon atoms, and one CH ₂ group present in these groups or two or more adjacent CHs. _Two groups may be substituted with O and / or S, and one or more hydrogen atoms present in these groups may be substituted with F or Cl,
A ¹ is
(a) trans-1,4-cyclohexylene group (the two CH ₂ groups not one CH ₂ group or adjacent present in group may be substituted with O and / or S)
(b) 1,4-phenylene group (one or more CH groups present in this group may be substituted with N)
(c) 1,4-bicyclo [2.2.2] octylene group, piperidine-1,4-diyl group, naphthalene-2,6-diyl group, decahydronaphthalene-2,6-diyl group and 1,2,3 , 4-tetrahydronaphthalene-2,6-diyl group selected from the group consisting of the group (a), the group (b) and the group (c) may be substituted with CN, F or Cl. Often,
Z ¹ is -CH ₂ CH _2- , -CH (CH ₃ ) CH _2- , -CH ₂ CH (CH ₃ )-, -CH (CH ₃ ) CH (CH ₃ )-, -CF ₂ CF _2- , -CH ₂ O-, -OCH _2- , -OCH (CH ₃ )-, -CH (CH ₃ ) O-,-(CH ₂ ) ₄ -,-(CH ₂ ) ₃ O-, -O (CH ₂ ) _3- , -CF ₂ O-, -OCF ₂ -or a single bond,
a represents 0, 1, 2 or 3,
L ¹ , L ² and L ³ each independently represent a fluorine atom, a chlorine atom or a hydrogen atom. )
General formula (5) obtained by allowing an alcohol derivative represented by general formula (2) and a halogenating agent to act on a tetrahydronaphthalenone derivative represented by general formula (5)

（式中、R¹、A¹、Z¹、L¹、L²、L³およびaはそれぞれ独立的に一般式(４)と同じ意味を表し、R²は請求項１における一般式(２)と同じ意味を表し、X¹はBr、ClまたはIを表す。）で表される1-ハロゲノ-2-アルコキシナフタレン誘導体の製造方法および一般式（５）で表される1-ハロゲノ-2-アルコキシナフタレン誘導体を提供する。

(Wherein R ¹ , A ¹ , Z ¹ , L ¹ , L ² , L ³ and a each independently represent the same meaning as in the general formula (4), and R ² represents the general formula (2 And X ¹ represents Br, Cl or I.) A method for producing a 1-halogeno-2-alkoxynaphthalene derivative represented by formula (1) and a 1-halogeno-2 represented by formula (5): An alkoxynaphthalene derivative is provided.

  According to the present invention, a 1-halogeno-2-alkoxynaphthalene derivative, which has so far been complicated in production process and required the use of an expensive fluorinating agent, can be produced simply and inexpensively.

  As the halogenating agent in this production method, bromine, chlorine, iodine, N-chlorosuccinimide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, etc. can be used. Bromine is preferred.

  This production method preferably uses a solvent, and as the solvent, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane Chlorinated hydrocarbons such as pentane, hexane, cyclohexane, heptane, octane, decahydronaphthalene, etc., diethyl ether, methyl-t-butyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, etc. Ether solvents, aromatic compounds such as benzene, toluene, xylene, chlorobenzene and the like can be used alone or in combination. Among them, chlorinated hydrocarbons are preferable, and dichloromethane or 1,2-dichloroethane is particularly preferable.

  Although the reaction temperature can be carried out from the freezing point of the solvent to the solvent reflux temperature, it is preferably from -20 ° C to 40 ° C, more preferably from 0 ° C to 30 ° C.

  The compounds represented by general formula (2), general formula (4) and general formula (5) include many compounds, but the following compounds are preferred.

In the general formula (2), R ¹ is preferably a saturated hydrocarbon having 1 to 7 carbon atoms (one or two or more hydrogen atoms may be substituted with fluorine), a methyl group, an ethyl group, a propyl group, A butyl group, a pentyl group, a trifluoromethyl group, a difluoromethyl group, and a fluoromethyl group are more preferable.

In the general formulas (4) and (5), R ² preferably represents a fluorine atom, a chlorine atom or a hydrogen atom when a is 0, but otherwise represents an alkyl group having 1 to 12 carbon atoms. Or it is preferable to represent a C1-C12 alkoxyl group, and a C1-C7 alkyl group or a C1-C7 alkoxyl group is more preferable.

A ¹ is preferably a trans-1,4-cyclohexylene group, a 1,4-phenylene group, a fluorine-substituted 1,4-phenylene group or a 1,4-bicyclo [2.2.2] octylene group.

Z ¹ is -CH ₂ CH _2- , -CH (CH ₃ ) CH _2- , -CH ₂ CH (CH ₃ )-, -CH (CH ₃ ) CH (CH ₃ )-, -CF ₂ CF ₂ -or It preferably represents a single bond, more preferably —CH ₂ CH ₂ — or a single bond.

  a preferably represents 0, 1 or 2, and more preferably 0.

  More specifically, examples of the compound suitable for production according to the present invention include the following compounds among the compounds of the general formula (5).

EXAMPLES Hereinafter, although an Example is given and this invention is further explained in full detail, this invention is not limited to these Examples. The structure of the compound was confirmed by nuclear magnetic resonance spectrum (NMR), mass spectrum (MS) and the like.
Example 1 Synthesis of 1-bromo-2-methoxy-5,6,7-trifluoronaphthalene

10 g of 5,6,7-trifluoro-1,2,3,4-tetrahydronaphthalen-2-one was dissolved in 40 mL of dichloromethane, and 2.4 g of methanol was added and cooled with ice. Bromine 5.2 mL was dripped there over 30 minutes, and also it stirred for 30 minutes. The reaction solution was poured into a solution of sodium bisulfite (10 g) in water (100 mL) and stirred for a while. The organic layer was separated, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 14.5 g of a brown solid. This was purified by column chromatography (silica gel 70 g / toluene) and recrystallization (ethanol 40 mL) to obtain 8.0 g of 1-bromo-2-methoxy-5,6,7-trifluoronaphthalene as almost colorless crystals. Rate 55%).
MS m / z
290, 292 (M ⁺ )
Melting point
122.5 123 ° C
¹ H-NMR (400 MHz, CDCl ₃ ) δ:
4.05 (s, 3 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.75 7.85 (m, 1 H), 8.02 (d, J = 9.2 Hz, 1 H)
Comparative Example 1 Synthesis of 1-bromo-2-methoxy-5,6,7-trifluoronaphthalene

(1) Synthesis of 1,1-difluoro-6-methoxy-1H-naphthalen-2-one
F-TEDA-BF ₄ (1-chloromethyl-4-fluoro-1,4-diazonium bicyclo [2,2,2] octanebis (tetrafluoroborate), AIR at room temperature in 6-methoxy-2-naphthol in acetonitrile PRODUCTS) was added in 3 portions every 15 minutes. After stirring at room temperature for 5 hours, the reaction mixture was added to ice water, neutralized with 10% aqueous sodium hydroxide solution, and extracted with toluene. After washing the organic layer with water, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography to obtain 1,1-difluoro-6-methoxy-1H-naphthalen-2-one.

(2) Synthesis of 6-methoxy-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene
DAST (diethylamino boron trifluoride) was added to a THF (tetrahydrofuran) solution of 1,1-difluoro-6-methoxy-1H-naphthalen-2-one and stirred at 50 ° C. for 2 hours. The reaction mixture was added to ice water, neutralized with 10% aqueous sodium hydrogen carbonate solution, and extracted with hexane. After washing the organic layer with water, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography to obtain 6-methoxy-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene. Got.

(3) Synthesis of 6-methoxy-1,1,2,2-tetrafluoro-1,2,3,4-tetrahydronaphthalene
Add 6-methoxy-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene in ethyl acetate to the autoclave, add 5% palladium on carbon (50% water), triethylamine, and silica gel, and add hydrogen pressure 0.4 MPa. For 3 hours. The reaction mixture was filtered through Celite, and the crude product obtained by distilling off the solvent from the filtrate under reduced pressure was purified by column chromatography to give 6-methoxy-1,1,2,2-tetrafluoro-1,2 1,3,4-tetrahydronaphthalene was obtained.

(4) Synthesis of 1,2-difluoro-6-methoxynaphthalene
To the THF solution of 6-methoxy-1,1,2,2-tetrafluoro-1,2,3,4-tetrahydronaphthalene was added ice-cooled potassium-t-butoxide, and the temperature was raised. Stir. The reaction mixture was added to ice water, neutralized with 10% aqueous sodium hydrogen carbonate solution, and extracted with hexane. After the organic layer was washed with water, the crude product obtained by distilling off the solvent was purified by column chromatography to obtain 1,2-difluoro-6-methoxynaphthalene.

(5) Synthesis of 6-methoxy-1,2,3-trifluoronaphthalene
1,2-Difluoro-6-methoxynaphthalene was dissolved in a THF / toluene mixed solvent, cooled to −40 ° C., and butyl lithium (1.5 M hexane solution) was slowly added dropwise. After stirring at −40 ° C. for 1 hour, ACCUFLOR NFSi (N-fluorobenzenesulfinimide, manufactured by AlliedSignal) was added, and the mixture was gradually warmed to room temperature and stirred at room temperature for 8 hours. The reaction mixture was added to ice water and extracted with hexane. After washing the organic layer with water, the solvent was distilled off and the resulting crude product was purified by column chromatography to obtain 6-methoxy-1,2,3-trifluoronaphthalene.

(6) Synthesis of 1-bromo-2-methoxy-5,6,7-trifluoronaphthalene
6-Methoxy-1,2,3-trifluoronaphthalene was dissolved in 1,2-dichloroethane, and iron powder was added and cooled with ice. Thereto was added dropwise a 1,2-dichloroethane solution of bromine over 30 minutes, and the mixture was further stirred for 1 hour. The reaction mixture was poured into 10% hydrochloric acid and stirred for 30 minutes, sodium hydrogen sulfite was added, and the mixture was further stirred for 30 minutes. The organic layer was separated, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was purified by column chromatography to obtain 1-bromo-2-methoxy-5,6,7-trifluoronaphthalene.

In Comparative Example 1, which is a production method described in Patent Document 1, the number of steps is very long, and a high-cost fluorinating agent such as F-TEDA-BF ₄ or ACCUFLOR NFSi must be used. On the other hand, in Example 1, which is the production method of the present invention, a 1-halogeno-2-alkoxynaphthalene derivative can be produced in one step, and the reactant used is also inexpensive.

(Example 2) Synthesis of 1-bromo-2-methoxy-7,8-difluoronaphthalene Under the same conditions as in Example 1, 5,6,7-trifluoro-1,2,3,4-tetrahydronaphthalene- By using 7,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-one instead of 2-one, 1-bromo-2-methoxy-7,8-difluoronaphthalene was obtained.

The present invention is very useful as a method for producing intermediates for liquid crystal compounds and medicines.

Claims (10)

General formula (4)

(In the formula, R ² represents a fluorine atom, a chlorine atom, a hydrogen atom or an alkyl group having 1 to 12 carbon atoms, and one CH ₂ group present in these groups or two or more adjacent CHs. _Two groups may be substituted with O and / or S, and one or more hydrogen atoms present in these groups may be substituted with F or Cl,
A ¹ is
(a) trans-1,4-cyclohexylene group (the two CH ₂ groups not one CH ₂ group or adjacent present in group may be substituted with O and / or S)
(b) 1,4-phenylene group (one or more CH groups present in this group may be substituted with N)
(c) 1,4-bicyclo [2.2.2] octylene group, naphthalene-2,6-diyl group, decahydronaphthalene-2,6-diyl group and 1,2,3,4-tetrahydronaphthalene-2,6 A group selected from the group consisting of a -diyl group, the group (a), the group (b), the group (c) may be substituted with CN, F or Cl,
Z ¹ is -CH ₂ CH _2- , -CH (CH ₃ ) CH _2- , -CH ₂ CH (CH ₃ )-, -CH (CH ₃ ) CH (CH ₃ )-, -CF ₂ CF _2- , -CH ₂ O-, -OCH _2- , -OCH (CH ₃ )-, -CH (CH ₃ ) O-,-(CH ₂ ) ₄ -,-(CH ₂ ) ₃ O-, -O (CH ₂ ) _3- , -CF ₂ O-, -OCF ₂ -or a single bond,
a represents 0, 1, 2 or 3,
L ¹ , L ² and L ³ each independently represent a fluorine atom, a chlorine atom or a hydrogen atom. )
The tetrahydronaphthalenone derivative represented by general formula (2)

(Wherein R ¹ represents a saturated hydrocarbon, and one or more hydrogen atoms present in this group may be substituted with F or Cl) and a halogenating agent represented by General formula (5)

(Wherein R ² , A ¹ , Z ¹ , L ¹ , L ² , L ³ and a each independently represent the same meaning as in general formula (4), and R ¹ has the same meaning as in general formula (2) Wherein X ¹ represents Br, Cl or I). In General Formula (2), General Formula (4), and General Formula (5), R ¹ is an alkyl group having 1 to 7 carbon atoms, and R ² is a fluorine atom, a chlorine atom, a hydrogen atom, or 1 to 7 carbon atoms. An alkyl group in which one CH ₂ group present in this group may be substituted with O, and one or more hydrogen atoms present in this group may be substituted with F or Cl A ¹ is trans-1,4-cyclohexylene group, 1,4-bicyclo [2.2.2] octylene group or 1,4-phenylene group (which may be substituted with F or Cl). ), A is 0, 1 or 2, Z ¹ is —CH ₂ CH ₂ —, —CF ₂ CF ₂ —, —CH ₂ O—, —OCH ₂ —, —CF ₂ O—, — The production method according to claim 1, wherein the production method is OCF ₂ — or a single bond, and X ¹ is Br. In General Formula (2), General Formula (4), and General Formula (5), R ¹ is an alkyl group having 1 to 7 carbon atoms, R ² is a fluorine atom, a chlorine atom, or a hydrogen atom, and a is 0 The production method according to claim ¹ , wherein X ¹ is Br. The production method according to any one of claims 1 to 3, wherein bromine is used as the halogenating agent, and X ¹ is Br in the general formula (5). The amount of the solvent used when the alcohol derivative represented by the general formula (2) and the halogenating agent are allowed to act on the tetrahydronaphthalenone derivative represented by the general formula (4) is represented by the general formula (4). The production method according to claim 1, which is 1 to 50 times the mass of the compound. A dichloromethane or 1,2-dichloroethane is used as a solvent used when the alcohol derivative represented by the general formula (2) and the halogenating agent are allowed to act on the tetrahydronaphthalenone derivative represented by the general formula (4). The manufacturing method in any one of 1-3. The process according to any one of claims 1 to 3, wherein the reaction temperature is -20 ° C to 40 ° C. The production method according to any one of claims 1 to 3, wherein the amount of the halogenating agent used is 0.5 to 5 molar equivalents of the compound represented by the general formula (4). The production method according to any one of claims 1 to 3, wherein the amount of the compound represented by the general formula (2) to be used is 0.5 to 10 molar equivalents of the compound represented by the general formula (4). General formula (5)

(Wherein R ² represents a fluorine atom, a chlorine atom or a hydrogen atom, a represents 0, L ¹ and L ² both represent a fluorine atom and L ³ represents a hydrogen atom, or L ² and L ³ represent Both are fluorine atoms and L ¹ represents a hydrogen atom, R ¹ represents an alkyl group having 1 to 7 carbon atoms, and X ¹ represents Br.) 1-halogeno-2-alkoxynaphthalene derivatives represented by: