JP2003012584A - Method for producing fluorine-containing aromatic alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for easily producing a fluorine-containing aromatic alcohol useful as an intermediate for a physiologically active substance for pharmaceuticals and agrochemicals and a functional material such as electronic materials at a low cost. SOLUTION: The fluorine-containing alcohol expressed by general formula (2) [R<1> to R<4> are each independently H, a halogen atom, a (substituted) alkyl, aryl, alkoxy or aryloxy or their derivatives] is produced by reducing an oxodifluoro-1,3-cyclohexadiene such as 6-oxo-5,5-difluorocyclohexadiene of formula (1) with a dithionous acid metal salt or organic salt.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a fluorine-containing aromatic alcohol useful as an intermediate for functional materials such as pharmaceuticals, agricultural chemicals and electronic materials.

[0002]

2. Description of the Related Art As a method for producing a fluorine-containing aromatic alcohol, a method for synthesizing an aromatic alcohol corresponding to a desired fluorine-containing aromatic alcohol by directly fluorinating, for example, N-fluoro Pyridinium salt method (T. Umemoto and G. Tomizawa, J. Org. Chem.
95), 60, 6563).

Further, the corresponding aromatic alcohols are
₅ (N.Yoneda and T. Fukuhara, Chem. Lett. (2001), 22
2) and electrolytic fluorination method (JP 2001-11674A).
No.) is used to produce the desired fluorinated aromatic alcohol.

[0004]

However, the above-mentioned N-fluoropyridinium salt method (T. Umemoto and G. T.
Omizawa, J. Org. Chem. (1995), 60, 6563) produces oxodifluorocyclohexadiene as a by-product together with a target fluorine-containing aromatic alcohol. When the difluoro body is by-produced in this way, in order to selectively obtain the target fluorinated aromatic alcohols, precise separation and purification by a column or the like, or by-produced oxodifluorocyclohexadiene Is required to be converted to the desired fluorine-containing aromatic alcohol.

As an example of reducing oxodifluorocyclohexadiene to obtain a fluorine-containing aromatic alcohol, a hydrochloric acid-Zn method (JP 2001-11674 A) is used.
A) or catalytic reduction method using Pd catalyst (JHHMeur
s, DWSopher, and W. Eilenberg, Angew. Chem. (1989), 10
1 (7), 955), which is industrially disadvantageous because it requires a complicated reduction reaction after fluorination.

Further, the above-mentioned IF ₅ (N.Yoneda and T.Fu
kuhara, Chem. Lett. (2001), 222) or an electrolytic fluorination method (JP 2001-11674A) to produce a desired fluorinated aromatic alcohol by fluorination. Since cyclohexadiene is selectively produced, in this case also, in order to obtain the target fluorine-containing aromatic alcohol, it is necessary to carry out a reduction reaction again after the fluorination reaction, which is industrially disadvantageous. .

The present invention has been made to solve the above-mentioned problems of the prior art, and its purpose is to provide bioactive substances such as pharmaceuticals and agricultural chemicals and functional materials such as electronic materials. It is an object of the present invention to provide a method for producing a fluorine-containing aromatic alcohol, by which a fluorine-containing aromatic alcohol useful as an intermediate can be obtained as simply and inexpensively as possible.

[0008]

[Means for Solving the Problems]

That is, according to the present invention, oxodifluorocyclohexadiene is reduced with a metal dithionite or an organic salt to obtain a fluorine-containing aromatic alcohol.
The present invention relates to a method for producing a fluorinated aromatic alcohol.

According to the present invention, since this reaction operation is very simple, for example, fluorinating aromatic alcohols using various fluorinating agents as described above to produce fluorine-containing aromatic alcohols. In doing so, even when the oxodifluorocyclohexadiene is produced, the reduction step of the produced oxodifluorocyclohexadiene can be easily incorporated in a post-treatment operation such as ordinary extraction.

Specifically, in the post-treatment step of the reaction, the oxodifluorocyclohexadiene formed together with the target fluorinated aromatic alcohol is extracted with an organic solvent, and the extract is extracted with The reduction reaction proceeds in a step of only stirring with an aqueous solution of a metal salt of dithionate or an organic salt, and the fluorinated aromatic alcohol as a target product can be extracted from this mixed solution, so that it is substantially a step. The desired fluorine-containing aromatic alcohols can be selectively obtained without increasing the number, which is very useful.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically based on the embodiments.

More specifically, the production method according to the present invention comprises 6-oxo-5,5 represented by the following general formula (1).
It is desirable to obtain the fluorine-containing aromatic alcohols represented by the following general formula (2) by reducing -difluoro-1,3-cyclohexadiene with the metal salt of dithionite or an organic salt.

[0014]

[Chemical 3] [However, in the general formula (1) and the general formula (2), R ^{1 to} R ⁴ may be the same or different, and a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, And an aryl group which may have a substituent, an alkoxy group which may have a substituent, an aryloxy group which may have a substituent and derivatives thereof. In addition, at least one set of R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ may be integrated to form a part of a cyclic structure, and the cyclic structure may be unsubstituted. Alternatively, it may be an aromatic ring having a substituent. ]

Further, 6- represented by the following general formula (3)
Oxo-3,3-difluoro-1,4-cyclohexadiene is reduced with the metal dithionite salt or organic salt to obtain a fluorine-containing aromatic alcohol represented by the following general formula (4). Is desirable.

[0016]

[Chemical 4] [However, in the general formula (3) and the general formula (4), R ^{5 to} R ⁸ may be the same or different, and a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, And an aryl group which may have a substituent, an alkoxy group which may have a substituent, an aryloxy group which may have a substituent and derivatives thereof. In addition, at least one set of R ⁵ and R ⁶ , R ⁷ and R ⁸ may be integrated to form a part of a cyclic structure, and the cyclic structure may be an unsubstituted or substituted aromatic ring. May be ]

More specifically, in the presence of a solvent capable of dissolving the oxodifluorocyclohexadiene, the metal salt of dithionite or an organic salt is dissolved or suspended in water or an organic solvent, and a two-layer system. Alternatively, it is preferable to carry out the reaction in a homogeneous system.

According to the production method of the present invention, since this reaction operation is very simple, when fluorinating aromatic alcohols using various fluorinating agents to produce fluorinated aromatic alcohols, for example. When the oxodifluorocyclohexadiene is produced, the reduction step of the produced oxodifluorocyclohexadiene can be easily incorporated in a post-treatment operation such as ordinary extraction.

For example, in the post-treatment step of the reaction, the oxodifluorocyclohexadiene is extracted with an organic solvent,
The reduction reaction proceeds in a step of only stirring the extract with the aqueous solution of the metal dithionite or the organic salt, and the fluorine-containing aromatic alcohol as a target can be extracted from this mixture. Therefore, the desired fluorine-containing aromatic alcohol can be selectively obtained without substantially increasing the number of steps, which is very useful.

Examples of the metal salt of the dithionous acid metal salt include lithium salt, sodium salt, potassium salt, cesium salt, magnesium salt, calcium salt, barium salt and the like. Among these, sodium dithionite or dithionite Preference is given to using potassium.

Examples of the organic salt of dithionous acid organic salt include ammonium salts such as ammonium salt, methylammonium salt, tetramethylammonium salt, tetraethylammonium salt, tetrabutylammonium salt, octyltriethylammonium salt and benzyltrimethylammonium salt. Can be mentioned.

It is also possible to carry out the reaction by adding a catalytic amount to an equivalent amount of a phase transfer catalyst to the metal salt of dithionite or the organic salt. The phase transfer catalyst, for example, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium fluoride, tetraethylammonium iodide, tetramethylammonium bromide, Examples thereof include quaternary ammonium salts such as methyltrioctylammonium bromide, methyltrioctylammonium chloride, phenyltrimethylammonium bromide and phenyltrimethylammonium chloride.

The solvent that can be used in the method for producing a fluorine-containing aromatic alcohol according to the present invention is not particularly limited as long as it can dissolve the oxocyclohexadiene as a raw material, and ethers and esters. , Aryl hydrocarbons, alkyl hydrocarbons, halogenated hydrocarbons, water and the like. Also,
Among these solvents, any two or more kinds of solvents may be mixed and used.

The equivalent number of the metal salt of dithionite or the organic salt to the oxocyclohexadiene used as a raw material is preferably 0.5 to 50 times, preferably 0.5 to 25 times. A double mole is more preferable. If it is less than this range, the reaction may be incomplete, and if it is more than this range, the metal dithionite or organic salt is unnecessarily consumed.

The reaction temperature may be appropriately set depending on the reactivity of the raw materials used and the solvent used, but it is 0 ° C to 100 ° C.
The range is preferably selected, and more preferably 5 ° C to 70 ° C.

In the present invention, the above general formula (1),
The alkyl group represented by (2), (3) and (4) may have a linear or branched structure, and may have a cyclic structure, and preferably has 1 to 20 carbon atoms, and more preferably has 1 to 20 carbon atoms. It means an alkyl group having 1 to 10 carbon atoms. Further, the alkyl group may be a halogen atom, a hydroxyl group, a cyano group, an aryl group, an alkoxy group, an aryloxy group,
It may be substituted with a substituent such as an amino group.

The aryl group shown in each of the above general formulas is preferably an aromatic group having 6 to 20 carbon atoms, more preferably 1 to 14 carbon atoms, and the aryl group is also the alkyl group. Similar to the group, it may be substituted with a substituent such as an alkyl group, a halogen atom, a hydroxyl group, a cyano group, an alkoxy group, an aryloxy group and an amino group.

The alkoxy group preferably has 1 carbon atom.
To 20, more preferably an alkoxy group having 1 to 10 carbon atoms, and the alkoxy group may be substituted with the same substituent as in the case of the above alkyl group.

The aryloxy group means an alkoxy group having preferably 6 to 20 carbon atoms, more preferably 6 to 14 carbon atoms, and the aryloxy group is the same substituent as in the case of the above aryl group. May be replaced by

Further, examples of the halogen atom include fluorine, chlorine, bromine and iodine.

Fluorine-containing aromatic alcohols which are the target substances of the present invention are useful as intermediates for functional materials such as pharmaceuticals, agricultural chemicals and electronic materials.

[0032]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 (Synthesis of 2-fluoro-1-naphthol)

[Chemical 5]

721 mg (5 mmol) of 1-naphthol
In 15 ml of dichloromethane solution of N-fluoro-5-
(Trifluoromethyl) pyridinium-2-sulfonate (1.84 g, 7.5 mmol) was added, and the mixture was heated under reflux for 26 hours. After cooling, the reaction mixture was poured into water and extracted with 30 ml of diethyl ether. To this extract was added 1 mmol of fluorobenzene as a standard substance, and ¹⁹ F-NMR was measured to find that 2-fluoro-1-naphthol 2.4 mm.
ol (48%) and 2,2-difluoro-1-oxo-
1,2-dihydronaphthalene 1.09 mmol (22
%) Was produced (both combined, 3.49 mmol).

Here, sodium dithionite Na ₂ S ₂
When 30 g of an aqueous solution of 2.0 g (11 mmol) of O ₄ was added and the mixture was stirred at room temperature for 1 hour, ¹⁹ F-NMR was measured again, the reduction reaction proceeded quantitatively and 2,2-difluoro-1-oxo- 1,2-Dihydronaphthalene disappeared, and 3.43 mmol-equivalent (yield 69%) of 2-fluoro-1-naphthol was obtained. In addition, 2-fluoro-
1-naphthol and 2,2-difluoro-1-oxo-
The compound data of 1,2-dihydronaphthalene is based on literature values (S. Stavber and M. Zupan, J. Org. Chem. (1985), 50, 3609-
3612).

Example 2 (6-Fluoro-2,4-di-
Synthesis of t-butylphenol)

[Chemical 6]

2,4-di-t-butylphenol 256
1.16 g (3.7 mm) of N-fluoro-4,6-bis (tofluoromethyl) pyridinium-2-sulfonate in a dichloromethane (6 ml) solution of mg (1.24 mmol).
ol) was added and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into water, the organic layer was extracted, and the extract was concentrated under reduced pressure. The concentrated residue was dissolved in 1,2-dimethoxyethane 10 ml, fluorobenzene 1mmol added as a standard substance, ¹⁹ F
When -NMR was measured, 6-fluoro-2,4-di-t-butylphenol 0.34 mmol (27%) and 1,3-di-t-butyl-5,5-difluoro-6-oxo-1, 3-cyclohexadiene 0.25 mmol
(20%) was generated (0.59 mmo for both)
l).

Here, 870 mg of Na ₂ S ₂ O ₄ (5 mm
ol) in 10 ml of water was added (the reaction solution was in a substantially uniform state except for a trace amount of insoluble matter), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, extracted with dichloromethane, the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the desiccant was removed from the oven, and the mixture was concentrated under reduced pressure. It was dissolved concentrated residue in a small amount of dichloromethane, after addition of p- fluorobenzene 0.3mmol again as a standard, again ¹⁹
When F-NMR was measured, the reduction reaction proceeded quantitatively, and 1,3-di-t-butyl-5,5-difluoro-6 was obtained.
-Oxo-1,3-cyclohexadiene disappeared and
59 mmol equivalent (47% yield) of 6-fluoro-2,
4-Di-t-butylphenol was obtained.

Identification data of 6-fluoro-2,4-di-t-butylphenol; ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.28 (9H, s), 1.41 (9H, s), 5.21 (1
H, br.d, J = 7Hz), 6.96 (1H, dd, J = 12Hz, 2Hz), 7.04 (1H, t, J = 2
¹⁹ F-NMR (CDCl ₃ , ppm): -143.7 (dd, J = 12Hz, 7Hz) .Mass spectrum m / e: 224 (M ⁺ ), 209 (M ⁺ -CH ₃ ) High-resolution mass spectrum m / e (M ⁺ ): Calculated value: C
₁₄ H ₂₁ FO: 224.15764. Found: 224.15819.

Identification data of 1,3-di-t-butyl-5,5-difluoro-6-oxo-1,3-cyclohexadiene; ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.17 (9H, 9H, s), 1.27 (9H, s), 5.99 (1
H, td, J = 6Hz, 2Hz), 6.85 (1H, d, J = 2Hz). ¹⁹ F-NMR (CDCl ₃ , ppm): -105.5 (d, J = 6Hz). Mass spectrum m / e: 242 (M ⁺ ), 227 (M ⁺ -CH ₃ ) High-resolution mass spectrum m / e (M ⁺ ): Calculated value: C
₁₄ H ₂₀ F ₂ O: 242.14822. Found: 242.114715.

[0041]

As is clear from the above, according to the present invention, since this reaction operation is very simple, the aromatic alcohols are fluorinated using various fluorinating agents as described above. When the oxodifluorocyclohexadiene is produced during the production of the fluorinated aromatic alcohol, the reduction step of the produced oxodifluorocyclohexadiene can be easily incorporated into a post-treatment operation such as ordinary extraction. it can.

Specifically, in the post-treatment step of the reaction, a step of only extracting the oxodifluorocyclohexadiene with an organic solvent and stirring the extract with an aqueous solution of the metal dithionite or the organic salt. Thus, the reduction reaction proceeds, and the fluorinated aromatic alcohol as a target can be extracted from this mixed solution, so that the fluorinated aromatic alcohol of interest can be selected without substantially increasing the number of steps. It is very useful.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kenji Adachi             Daikin, 3 Miyukigaoka, Tsukuba City, Ibaraki Prefecture             Industry Co., Ltd. F term (reference) 4H006 AA02 AC24 AC41 BA51 BB12                       BC10 BC31 BE90 FC52 FC54                       FE13 FE73 FE74                 4H039 CA41 CA60 CB20 CG20

Claims (5)

[Claims] 1. A method for producing a fluorine-containing aromatic alcohol, which comprises reducing an oxodifluorocyclohexadiene with a metal dithionite or an organic salt to obtain a fluorine-containing aromatic alcohol. 2. A 6-oxo-5,5-difluoro-1,3-cyclohexadiene represented by the following general formula (1) is reduced with the metal dithionite salt or an organic salt to obtain the following general formula: The method for producing a fluorine-containing aromatic alcohol according to claim 1, wherein the fluorine-containing aromatic alcohol represented by the formula (2) is obtained. [Chemical 1] [However, in the general formula (1) and the general formula (2), R ^{1 to} R ⁴ may be the same or different, and a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, And an aryl group which may have a substituent, an alkoxy group which may have a substituent, an aryloxy group which may have a substituent and derivatives thereof. In addition, at least one set of R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ may be integrated to form a part of a cyclic structure, and the cyclic structure may be unsubstituted. Alternatively, it may be an aromatic ring having a substituent. ] 3. A 6-oxo-3,3-difluoro-1,4-cyclohexadiene represented by the following general formula (3) is reduced with the metal salt of dithionite or an organic salt to obtain the following general formula: The method for producing a fluorine-containing aromatic alcohol according to claim 1, wherein the fluorine-containing aromatic alcohol represented by the formula (4) is obtained. [Chemical 2] [However, in the general formula (3) and the general formula (4), R ^{5 to} R ⁸ may be the same or different, and a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, And an aryl group which may have a substituent, an alkoxy group which may have a substituent, an aryloxy group which may have a substituent, and derivatives thereof. In addition, at least one set of R ⁵ and R ⁶ , R ⁷ and R ⁸ may be integrated to form a part of a cyclic structure, and the cyclic structure may be an unsubstituted or substituted aromatic ring. May be ] 4. The method for producing a fluorinated aromatic alcohol according to claim 1, wherein the metal salt of dithionite is sodium dithionite or potassium dithionite. 5. The method for producing a fluorine-containing aromatic alcohol according to claim 1, wherein the metal dithionite or organic salt is reacted by adding a phase transfer catalyst in a catalytic amount to an equivalent amount.