JP2003221354A - 1-(tert-BUTOXYPHENYL)-omega-HALOALKANE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To develop a raw material from which a hydroxyphenylhaloalkane used as a synthetic intermediate in the fields of medicines, agrichemicals, liquid crystals, and the like, can be easily produced. <P>SOLUTION: This 1-(tert-butoxyphenyl)-ω-haloalkane is represented by formula (1) (wherein X is Cl or Br; and (n) is an integer of 3 or 5-10). <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 1- (te
rt-butoxyphenyl) -ω-haloalkane. More specifically, in the fields of medicine, agricultural chemicals, liquid crystals, etc., novel 1- (te, which is a raw material for the synthesis of hydroxyphenylhaloalkane, which is said to be useful as a synthetic intermediate.
rt-Butoxyphenyl) -ω-haloalkane.

[0002]

2. Description of the Related Art Conventionally, hydroxyphenylhaloalkanes having a hydroxyphenyl group have been useful as synthetic intermediates in the fields of medicine, agricultural chemicals, liquid crystals and the like. As a raw material for synthesizing hydroxyphenylhaloalkane, for example, alkoxyphenethyl chloride is mentioned, and it is known that it can be obtained by a reaction of producing a corresponding alkoxyphenethyl alcohol and then chlorinating a hydroxyl group site.

Chlorination of alkoxyphenethyl alcohol is easily carried out by chlorination with a chlorinating agent such as phosphorus oxychloride or thionyl chloride. However, as a method for producing alkoxyphenethyl chloride, there are problems as an industrial production method such as a reaction in two steps including an alcohol production step and a decrease in total yield.

On the other hand, 1- (p-chlorophenyl) -ω-
As a method for producing bromoalkane, a method of reacting p-chlorophenylmagnesium halide and dibromoalkane in the presence of a copper compound and a lithium compound is disclosed in JP-A-200-200.
No. 0-159702. But p
It is very difficult to substitute chloro in the -chlorophenyl form with a hydroxyl group to give hydroxyphenyl haloalkane, which is said to be useful as a synthetic intermediate in the fields of medicine, agricultural chemicals, liquid crystals and the like.

Further, as a raw material for the synthesis of hydroxyphenylhaloalkane, 1- (p-methoxyphenyl) -4 in which a hydroxy group is protected by a methoxy group which is an alkoxy group.
-Specific examples include chlorobutane. To dealkylate these aliphatic alkoxyphenyl chloroalkanes to hydroxyphenyl chloroalkanes,
It is necessary to perform treatment under a strong acidic condition using hydrobromic acid, hydroiodic acid, trifluoroacetic acid, or the like, and a problem is that the yield and purity of hydroxychloroalkane obtained are low.

[0006]

Therefore, it is desired to develop a raw material capable of easily producing hydroxyphenylhaloalkane.

The present invention has been made to solve the above problems, and is a synthetic raw material for obtaining a hydroxyphenyl haloalkane, which is said to be useful as a synthetic intermediate in the fields of medicine, agricultural chemicals, liquid crystals, etc., in high yield. It is an object to provide 1- (tert-butoxyphenyl) -ω-haloalkane used as

[0008]

Means for Solving the Problems The inventors of the present invention have made extensive studies to solve the above problems. As a result, 1-having a tert-butyl group as a hydroxy protecting group
It has been found that (tert-butoxyphenyl) -ω-haloalkane is useful as a raw material for producing hydroxyphenylhaloalkane. Further, as an industrially advantageous method for producing 1- (tert-butoxyphenyl) -ω-haloalkane, a Grignard reaction of tert-butoxyphenyl magnesium halide and dihaloalkane is carried out in the presence of a specific compound to obtain the desired compound. The inventors have found that the compound can be obtained with high selectivity and high yield, and have completed the present invention.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION 1- (tert-
The method for producing butoxyphenyl) -ω-haloalkane will be described in detail.

The synthetic route of 1- (tert-butoxyphenyl) -ω-haloalkane in the present invention is as follows.

[0011]

[Chemical 2]

The Grignard reagent (the compound represented by the general formula (2) (hereinafter, referred to as the compound represented by the general formula (1)) which is a raw material of the compound represented by the general formula (1) (hereinafter, also referred to as "compound (1)")
Also referred to as "compound (2)". )) X'is a halogen atom, and examples thereof include iodine, chlorine and bromine. Also,
The position of the tert-butoxy group may correspond to the desired compound (1), and any of the ortho position, the meta position, and the para position can be used. The compound (2) is a known compound and can be prepared by a conventional method, for example, JP-A-4-17.
It can be easily obtained by the method described in Japanese Patent No. 3756.

(Regarding the compound of the general formula (3)) The dihaloalkane represented by the general formula (3) is a known compound, in which X and Y may be the same or different, and a chlorine atom. Or represents a bromine atom. When X and Y are different, X is a chlorine atom and Y is a bromine atom. Further, n in the formula represents 3, 5 to 10, preferably 3,
5 and 6. General formula (3) used in the present invention
The dihaloalkane represented by is shown in Table 1.

[0014]

[Table 1]

The above dihaloalkane is easily obtained as a commercial product and can be used.

Production Method (of Compound of General Formula (1)) The present invention is carried out as follows. That is, tert-butoxyphenyl magnesium halide represented by the following general formula (2)

[Chemical 3] (Wherein X ′ represents a halogen atom), a dihaloalkane represented by the following general formula (3)

[Chemical 4] (X and Y may be the same or different and are a chlorine atom or a bromine atom, and when they are different, X is a chlorine atom, Y
Is a bromine atom, and n is an integer of 3, 5 to 10)
Is reacted in the presence of a copper compound to obtain the desired 1- (tert-butoxyphenyl) -ω-haloalkane represented by the following general formula (1).

[Chemical 5]

The amount of the dihaloalkane used as the starting material for synthesizing the compound of the general formula (1) of the present invention is 0.5 to 2 in molar ratio with respect to the other starting material, the compound (2) which is a Grignard reagent. It is preferably in the range of double, particularly 0.6
It is preferably in the range of 6 to 1.0 times.

The copper compound used in this reaction is a monovalent or divalent copper compound as a catalyst, specifically, copper oxide, copper fluoride, copper chloride, copper bromide, copper iodide, copper sulfate. , Inorganic carbonates such as copper carbonate and copper nitrate; organic acid copper salts such as copper formate, copper acetate, copper benzoate and copper octadecanoate; acetylacetonato copper (I) or (II); carbon monoxide, nitriles , A complex compound in which amines, phosphines, olefins, etc. are coordinated with copper, specifically, carbonyl (diethylenetriamine) copper tetraphenylborate, tetrakis (acetonitrile) copper hexafluorophosphate,
Tetrachlorocopper tetraethylammonium salt, tetrachlorotetrakis (triphenylphosphine) tetracopper, etc .;
In addition, a mixture of such compounds with copper that forms a complex compound in the reaction system, and the like; Among these copper compounds, monovalent or divalent copper chloride, copper bromide and copper iodide are preferable, and monovalent salts are particularly preferable. These are all available.

The amount of the copper compound used in the present invention is
The molar ratio is preferably 0.001 to 1 times, and particularly preferably 0.01 to 0.5 times that of the compound (2).

The reaction procedure for obtaining the compound (1) using the above raw materials will be described below.

A solvent is added to the compound (2) which is a Grignard reagent and a copper compound and mixed. Examples of the solvent used at this time include ethers such as THF (tetrahydrofuran), diethyl ether and dibutyl ether.

To the above mixture, a dihaloalkane of the general formula (3) dissolved in a solvent such as THF, diethyl ether or dibutyl ether is added dropwise at 0 to 70 ° C. over 1 to 4 hours, and the reaction is carried out at the required temperature. The reaction is continued for a certain period of time to obtain the target compound (1). Reaction temperature is 0
Although the temperature is not higher than 0 ° C, it is usually carried out at 0 ° C or higher in order to further improve the reaction rate. 0 to 200 ° C is preferable,
Furthermore, 20-150 degreeC is preferable. The reaction time varies depending on the reaction temperature and the target product obtained, but is usually 0.1 to
200 hours, preferably 0.5 to 50 hours.

The reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

After completion of the reaction, water, hydrochloric acid, sulfuric acid,
An aqueous solution of a mineral acid such as nitric acid; or an organic acid such as formic acid, acetic acid, triphenylacetic acid and p-toluenesulfonic acid is added to decompose and neutralize the unreacted Grignard reagent (compound (2)), and then as necessary. Then, the solvent is concentrated and removed, and the desired 1- (tert-butoxyphenyl) -ω-haloalkane (Compound (1)) can be isolated by a general method such as extraction crystallization.

The 1- (te obtained as described above
Specific examples of rt-butoxyphenyl) -ω-haloalkane are shown in Tables 2 to 4.

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Table 4]

By the production method of the present invention, 1- (tert-butoxyphenyl) -ω-haloalkane can be obtained from compound (2) in high yield and high purity.

Further, as described in Reference Production Example 1, the tert-butyl group of 1- (tert-butoxyphenyl) -ω-haloalkane can be easily deprotected under mild conditions. A hydroxyphenylhaloalkane useful as an intermediate in the field of liquid crystals and the like can be easily obtained in high yield and high purity.

The hydroxyphenyl haloalkane is useful in the field of liquid crystals, and specifically, it is used as an intermediate of a biphenyl type liquid crystal compound represented by the following general formula (6) (JP-A-2-131451). ).

[Chemical 6] (In the formula, m represents an integer of 1 to 10, and R ₁ and R ₂ are C 1
To 18 alkyl groups, and X ₁ and X ₂ represent hydrogen atom, chlorine atom, and fluorine atom. )

[0032]

EXAMPLES Example 1 A 500 ml four-necked flask equipped with a stirrer and a reflux condenser, purged with nitrogen, was placed in a dry p-tert- flask.
160 ml (260 mmol) of a tetrahydrofuran solution of butoxyphenyl magnesium chloride was added, and subsequently, 0.05 g (0.51 mmol) of copper (I) chloride was added. Then, 25.0 g (158 mmol) of 1-bromo-3-chloropropane dissolved in 25 ml of tetrahydrofuran was added dropwise thereto at a temperature of 60 to 70 ° C., and the mixture was continuously stirred for 4 hours. 1 in the resulting reaction mixture
The reaction was terminated by adding 100 ml of 0% sulfuric acid aqueous solution, and the upper layer of the separated liquid was 25 ml of 10% sodium hydroxide aqueous solution.
Washed with. The obtained organic layer is concentrated with a vacuum evaporator and distilled under reduced pressure to give a boiling point of 138 ° C./0.6 mmH.
As a fraction of 1- (p-tert-butoxyphenyl) -3-chloropropane, 19.1 g (purity 99.2)
%, Yield 53.1%).

The physical properties of the obtained compound are as follows. Mass: m / e 226 (m ⁺ ), 211, 170,
107

A stirrer and a reflux condenser were attached, the atmosphere was replaced with nitrogen, and 127 ml of a tetrahydrofuran solution of p-tert-butoxyphenyl magnesium chloride was added to a dry 500 ml four-necked flask (208 mmo).
1), followed by 0.04 g (0.41) of copper (I) chloride.
mmol) was added. Then, 25.3 g (136 mmol) of 1-bromo-5-chloropentane dissolved in 25 ml of tetrahydrofuran under the temperature condition of 40 to 55 ° C.
Was added dropwise, and the mixture was continuously stirred for 3 hours. The reaction was terminated by adding 100 ml of a 10% aqueous sulfuric acid solution to the obtained reaction mixture, and the upper layer of the liquid separation was washed with 25 ml of a 10% aqueous sodium hydroxide solution. The obtained organic layer was concentrated with a vacuum evaporator and distilled under reduced pressure to give a boiling point of 121 ° C.
As a fraction of 0.1 mmHg, 23.4 g of 1- (p-tert-butoxyphenyl) -5-chloropentane (purity 99.2%, yield 67.2%) was obtained.

The physical properties of the obtained compound are as follows. Mass: m / e 254 (m ⁺ ), 239, 198,
107

Example 3 A 500 ml four-necked flask, equipped with a stirrer and a reflux condenser, purged with nitrogen, was placed in a p-tert-dried flask.
140 ml (205 mmol) of a solution of butoxyphenyl magnesium chloride in tetrahydrofuran was added, and then 0.04 g (0.41 mmol) of copper (I) chloride was added. Then, 25.0 g (125 mmol) of 1-bromo-6-chlorohexane dissolved in 25 ml of tetrahydrofuran was added dropwise thereto at a temperature of 40 to 50 ° C., and the mixture was continuously stirred for 3 hours. 1 in the resulting reaction mixture
The reaction was terminated by adding 100 ml of 0% sulfuric acid aqueous solution, and the upper layer of the separated liquid was 25 ml of 10% sodium hydroxide aqueous solution.
Washed with. The obtained organic layer is concentrated with a vacuum evaporator and distilled under reduced pressure to give a boiling point of 158 ° C./0.6 mmH.
25.2 g of 1- (p-tert-butoxyphenyl) -6-chlorohexane as a fraction of g (purity 98.2)
%, Yield 73.6%).

The physical properties of the obtained compound are as follows. Mass: m / e 268 (m ⁺ ), 253, 212,
107

Reference Production Example 1- (pt) was added to a 500 ml volumetric flask equipped with a stirrer.
ert-butoxyphenyl) -3-chloropropane 11
Add 3 g (0.5 mol), and add concentrated hydrochloric acid 1 at 20 to 30 ° C.
50 g (1.5 mol) was added dropwise and stirring was continued for 5 hours.

After the reaction, this was neutralized with 5% sodium carbonate water, extracted with 300 ml of toluene, and the solvent was distilled off to obtain 77 g of the desired 1- (p-hydroxyphenyl) -3-chloropropane (yield. 90%) as an oil.

The physical properties of the obtained compound are as follows. Mass (CI): m / e 171 (m ⁺ +1), 13
On the other hand, 18.5 g (0.1 mol) of 1- (p-methoxyphenyl) -3-chloropropane and 30 g of concentrated hydrochloric acid.
(0.3 mol) was placed in a 100 ml flask and placed at 25-
The stirring was continued for 5 hours at 30 ° C., but no change was observed. Further, there was no change even if stirring was continued for 10 hours at the reflux temperature.

[0041]

INDUSTRIAL APPLICABILITY According to the present invention, 1- (t) which is a raw material for the synthesis of hydroxyphenylhaloalkane, which is said to be useful as a synthetic intermediate in the fields of medicine, agricultural chemicals, liquid crystals, etc.
The ert-butoxyphenyl) -ω-haloalkane can be easily produced. Then, from 1- (tert-butoxyphenyl) -ω-haloalkane, hydroxyphenylhaloalkane having a hydroxyphenyl group can be easily obtained with high yield and high purity.

Claims (4)

[Claims] 1. The following general formula (1): (In the formula, X is a chlorine atom or a bromine atom, and n is
An integer of 3, 5 to 10 is shown. ), 1- (te
rt-Butoxyphenyl) -ω-haloalkane. 2. A tert on the benzene ring of the general formula (1).
1- (t) according to claim 1, characterized in that the -butoxy group is substituted in the para position of the ω-haloalkyl group.
ert-Butoxyphenyl) -ω-haloalkane. 3. A tert on the benzene ring of the general formula (1).
1- (t) according to claim 1, characterized in that the -butoxy group is substituted in the meta position of the ω-haloalkyl group.
ert-Butoxyphenyl) -ω-haloalkane. 4. The 1- (tert-butoxyphenyl) -ω according to claim 1, 2 or 3, characterized in that n in the general formula (1) is 3, 5, or 6. -Haloalkane.