JPH1143455A - Production of halogenated alcohol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To economically and efficiently obtain the subject compound in an industrially advantageous way by reducing a specific halogenated ester with a boron hydride compound. SOLUTION: This compound expressed by the formula, Ar-R-CH2 OH is obtained by subjecting a halogenated ester (preferably, m-fluorophenyl acetate ester, etc.), expressed by the formula, Ar-R-COOR1 [Ar is a (substituted)-phenyl; R is a 1-6C alkylene; R<1> is a 1-6C alkyl, 6-12C ayl or 7-12 aralkyl] and a boron hydride compound (preferably, sodium boron hydride, etc.), to reductive reaction in a solvent (e.g. diethyl ether), preferably, in the presence of a small amount of an alcohol (preferably, methanol) at 20-150 deg.C for 5-50 hr. The preferable quantity of the reactants to be used is 0.5-2 mol for the boron hydride compound and 1-30 mol for the alcohol, based on the halogenated ester.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a halogenated alcohol. More specifically, the present invention relates to a method for producing a halogenated alcohol from a halogenated ester.

[0002]

2. Description of the Related Art As a method for producing a halogenated alcohol, for example, an m-halogenated phenethyl alcohol useful as a pharmaceutical raw material, a conventional method is to prepare m-bromochlorobenzene and magnesium by reacting a Grignard reagent with ethylene oxide. A method for producing chlorophenethyl alcohol (see French Patent No. 1552763) and a method for producing phenethyl polonate from phenethyl alcohol and boron oxide, followed by reaction with chlorine in the presence of tin chloride to produce m-chlorophenethyl alcohol (See U.S. Pat. No. 3,372,202). All of these methods have low yields. Particularly, in the method using chlorine, ortho- and para-substituted products are mainly produced, and production of the target meta-substituted product is small. Further, these methods use large amounts of explosive ethylene oxide or highly toxic chlorine, and thus are not desirable as industrial production methods.

Further, as a method for producing m-halogenated phenethyl alcohol using m-halogenated phenylacetic acid ester as a raw material, m-bromophenylacetate is produced by reducing m-bromophenylacetate by a reduction reaction using lithium aluminum hydride.
A method for producing bromophenethyl alcohol is known (Journal of American Che).
medical Society, Vol. 79, p. 37
05 (1957)). In this method, lithium aluminum hydride used as a reducing agent is unstable even in a small amount of water, and there is a risk of ignition. As a solvent, anhydrous diglyme (diethylene glycol dimethyl ether), anhydrous tetrahydrofuran, or the like is required. If the amount is large, it is not suitable for industrial use because post-treatment such as separation of diglyme is complicated. Furthermore, the yield of the obtained m-bromophenethyl alcohol is not sufficient.

[0004] In the production of halogenated alcohols, a method of reducing using a corresponding halogenated ester is useful because the raw materials are easily available. Hydrogenation reaction using copper-chromium oxide as a catalyst (e.g. Journal of
American Chemical Society
y, Vol. 54, p. 1145 (1932) etc.)
And hydrogenation reactions using Raney nickel catalysts (eg, Journal of American Chemi).
cal Society, Vol. 69, p. 3039
(See 1947)) is a general method for reducing an ester to a corresponding alcohol, and is used industrially because it is simple and inexpensive. However, when these reduction reactions were applied to the halogenated ester of the present invention, as shown in a comparative example described later, in our study, only the dehalogenation reaction of the aromatic nucleus-substituted halogen proceeded, and almost no alcohol was formed. do not do.

As described above, the conventional method for producing m-halogenated phenethyl alcohol is not always satisfactory as an industrial production method. Also,
The conventionally known method of reducing a halogenated ester proceeds with the dehalogenation reaction and cannot be said to be a practical production method.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above findings, and has as its object to produce a corresponding halogenated alcohol from a halogenated ester in a relatively simple process at a low cost and efficiently. It is an object of the present invention to provide a method for producing the same advantageously.

[0007]

Means for Solving the Problems The present inventors have studied various methods for reducing a halogenated ester to a corresponding halogenated alcohol, and as a result, completed the present invention. That is, in the gist of the present invention, in a reaction of reducing a halogenated ester represented by the following formula (1) to obtain a corresponding halogenated alcohol represented by the following formula (2), the reduction is performed using a borohydride compound. A method for producing a halogenated alcohol.

[0008]

Ar—R—COOR ¹ (1) Ar—R—CH ₂ OH (2)

Wherein Ar is a halogen-substituted phenyl group, R is an alkylene group having 1 to 6 carbon atoms which may have a branch, R ¹ is an alkyl group having 1 to 6 carbon atoms, and 6 to 6 carbon atoms. 1
2 represents an aryl group or an aralkyl group having 7 to 12 carbon atoms. Further, the gist of the present invention is a method for producing a halogenated alcohol, wherein an alcohol is added at the time of the reduction reaction. The method for producing a halogenated alcohol, wherein the alcohol is methanol, , Wherein the halogenated alcohol is m-halogenated phenethyl alcohol. Hereinafter, the method for producing a halogenated alcohol of the present invention will be described in detail.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION

(Raw Materials) Examples of the raw material halogenated ester represented by the formula (1) used in the present invention include halogenated phenylacetic acid esters, 3- (halogenated phenyl) propionic acid esters, and 2- (halogenated phenyl) propionic acid. Ester, 4- (halogenated phenyl) butanoic acid ester, 3- (halogenated phenyl) butanoic acid ester, 2- (halogenated phenyl) butanoic acid ester, 5
-(Halogenated phenyl) pentanoic acid ester, 4-
(Halogenated phenyl) pentanoic acid esters, 3- (halogenated phenyl) pentanoic acid esters, 2- (halogenated phenyl) pentanoic acid esters, and the like. The halogen atom-substituted phenyl group means a phenyl group in which a benzene nucleus is substituted with a chloro group, a bromo group, an iodine group, or a fluoro group, and the number of substitution of these halogen atoms is 1 to 5
When there are a plurality of substitution numbers, they may be the same or different. In the formula (1), R ¹ is an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms or an aralkyl group having 7 to 12 carbon atoms, such as a methyl group, an ethyl group, a propyl group, and a butyl group. Pentyl, hexyl, cyclohexyl, phenyl, tolyl, xylyl, naphthyl, benzyl and the like. Preferred specific examples of such a halogenated ester include m-fluorophenyl acetate, m-bromophenyl acetate, o-bromophenyl acetate, p-bromophenyl acetate, m-chlorophenyl acetate and m-iodophenylacetic acid. Esters are mentioned. Also, as a particularly preferred specific example,
m-chlorophenyl acetate and m-bromophenyl acetate. These can be easily prepared by a known method in which acetophenone is subjected to nuclear chlorination or bromination, then treated with monophorin and sulfur to form m-chloro or m-bromophenylacetic acid, and then esterified by reaction with an alcohol under acidic conditions. Manufacturable.

(Reduction reaction) In the reduction reaction, the halogenated ester represented by the above formula (1) is reduced using a borohydride compound as a reducing agent. As the borohydride compound of the reducing agent used in the production method of the present invention, sodium borohydride, lithium borohydride, calcium borohydride, zinc borohydride, magnesium borohydride,
Potassium borohydride, beryllium borohydride, barium borohydride and the like can be used, but sodium borohydride, lithium borohydride, calcium borohydride and the like are preferred mainly from an economic viewpoint.
Sodium borohydride can be easily produced from a borate ester and sodium hydride, but a commercially available product may be used as it is. Other borohydride compounds are obtained by reacting sodium borohydride with the corresponding halide, for example, calcium borohydride is obtained by reacting sodium borohydride with calcium chloride. These borohydride compounds may be prepared in advance and added during the reduction reaction, but may be prepared in a reaction vessel and used as it is. The amount of the borohydride compound to be used relative to the starting halogenated ester is usually 0.3 to 10 mol, preferably 0.5 to 5 mol, particularly preferably 0.5 to 2 mol.

[0012] More preferable results are obtained when a small amount of alcohol is present in the present reduction reaction system. That is, a complex of the alcohol and the borohydride compound is formed, and the reduction reaction proceeds more rapidly. Examples of the alcohol used include aliphatic alcohols such as methanol, ethanol, propanol and butanol, and aromatic alcohols such as phenol and benzyl alcohol. Aliphatic alcohols such as methanol, ethanol, propanol and butanol are preferred, and methanol is particularly preferred. This is because high reactivity and selectivity can be obtained by the presence of methanol. The alcohol used is in the range of 0.1 to 50 mol, preferably 1 to 30 mol, based on the starting halogenated ester. If it is smaller than 0.1 in terms of improving the reaction rate, a sufficient effect cannot be obtained,
On the other hand, when it is larger than 50, the reaction speed does not increase so much and it is not economical. These alcohols may be used by being mixed with the reaction solvent in advance, or may be added to the reaction system during the reaction and used. It is more preferable to sequentially add the target halogenated alcohol to the reaction system because the target halogenated alcohol can be obtained in high yield. This is because, by successive addition, a proton source required for reduction is effectively supplied.

The solvent used in the reaction of the present invention may be any solvent which dissolves the starting halogenated ester and does not hinder the reduction reaction. Specific examples thereof include ethers such as diethyl ether, tetrahydrofuran and dioxane; And aromatic carbons such as benzene, toluene and xylene. These solvents can be used as they are without pre-treatment such as dehydration.

Although the reaction is sufficient even at room temperature or lower,
In order to further improve the reaction rate, the reaction is usually performed under heating. The reaction temperature is 0 to 200 ° C, preferably 20 to 150 ° C.
It is in the range of ° C. The reaction may be carried out in air or under an atmosphere of an inert gas such as nitrogen or argon. The reaction time depends on the reaction temperature, but is usually 0.1.
It is in the range of 1 to 200 hours, preferably 0.5 to 50 hours. When the alcohol is sequentially added, the starting halogenated ester and the borohydride compound are dissolved in a solvent, and after reaching a desired reaction temperature, a predetermined device such as a dropping funnel or a microfeeder is used for the sequential addition. It is desirable to complete the addition in about 1/2 to 2/3 of the reaction time. According to this production method, since the reduction reaction proceeds rapidly, the addition time is generally about 0.5 to 10 hours. After completion of the reduction reaction, hydrochloric acid, sulfuric acid,
After adding a mineral acid aqueous solution such as nitric acid to neutralize and decompose unreacted borohydride compounds, the solvent is concentrated and removed as necessary,
The objective halogenated alcohol is isolated by a general method such as extraction, distillation, crystallization and the like.

The reaction product obtained by the production method of the present invention is the target halogenated alcohol represented by the above formula (2) in which the starting halogenated ester is reduced,
Almost no other by-products such as dehalogenated products are produced.

[0016]

Next, the present invention will be described more specifically with reference to examples. The product was quantitatively analyzed by gas chromatography using an internal standard method using diglyme as an internal standard substance, and the conversion and selectivity were determined by the following equations.

Example 1 A stir bar and 620 mg of methyl m-bromophenylacetate were placed in a 30 ml three-necked flask equipped with a condenser and a thermometer.
(2.71 mmol), 10.8 m of tetrahydrofuran
l and diglyme 70m as internal standard substance for analysis
g was charged and made uniform. After adding 204.7 mg (5.41 mmol) of sodium borohydride, the internal temperature was raised to 66 ° C. After starting reflux, methanol 171 was added.
6 mg (53.6 mmol) was added over 1.5 hours using a microfeeder. After the addition, the reaction was continued under reflux for another 1 hour. After cooling the reactor, 5.7 ml of 1.2N hydrochloric acid was added to neutralize and decompose unreacted sodium borohydride. As a result of quantitative analysis of the obtained solution by gas chromatography, 3 mg (0.013 mmol) of unreacted methyl m-bromophenylacetate and 523 mg (2.45 mmol of m-bromophenethyl alcohol) were obtained.
l) had been generated. The conversion of methyl m-bromophenylacetate was 99.5%, and the selectivity for m-bromophenethyl alcohol was 96%. The reaction was concentrated to dryness and the residue was solid-liquid extracted three times with 10 ml of dichloromethane.
The dichloromethane was removed from the obtained extract using an evaporator, and m-bromophenethyl alcohol was removed from the extract.
2 mg (2.42 mmol; yield 83%) was obtained.

Example 2 A stir bar and 680 mg of methyl m-chlorophenylacetate were placed in a 30 ml three-necked flask equipped with a condenser and a thermometer.
(3.68 mmol), tetrahydrofuran 15.5 m
l and diglyme 88m as internal standard substance for analysis
g was charged and made uniform. After adding 250.6 mg (6.62 mmol) of sodium borohydride thereto, the internal temperature was raised to 66 ° C. After the start of reflux, methanol 247
6 mg (77.3 mmol) was added over 2 hours using a microfeeder. After the addition, the reaction was continued under reflux for another 1 hour. After cooling the reactor, 1N hydrochloric acid 8ml
Was added to neutralize and decompose unreacted sodium borohydride. As a result of quantitative analysis of the obtained solution by gas chromatography, no unreacted methyl m-chlorophenylacetate remained. Also, 541.7 mg (3.46 mmol) of m-chlorophenethyl alcohol was produced. The conversion of methyl m-chlorophenylacetate is 10
0%, selectivity for m-chlorophenethyl alcohol is 94
%Met. The reaction solution was concentrated to dryness, and the residue was subjected to solid-liquid extraction five times with 20 ml of ethyl acetate. Ethyl acetate was removed from the obtained extract using an evaporator, and 518.7 mg of m-chlorophenethyl alcohol (3.32 m
mol; yield 90%).

COMPARATIVE EXAMPLE 1 A 30 ml 3 tube equipped with a cooling pipe, a dropping funnel and a thermometer was used.
Under a nitrogen atmosphere, a stirring bar, 163 mg (4.30 mmol) of lithium aluminum hydride, 7.5 ml of tetrahydrofuran and 67 mg of diglyme as an internal standard substance for analysis were charged into a neck flask and kept at 0 ° C under ice cooling. After 492 mg (2.15 mmol) of methyl m-bromophenylacetate dissolved in 3 ml of tetrahydrofuran was added dropwise, the internal temperature was raised to 66 ° C. After the start of reflux, 1360 mg (42.5 mmol) of methanol was added over 1.5 hours using a micro feeder. After the addition, the reaction was continued under reflux for another 1 hour. After cooling the reactor, 7 ml of 1.2N hydrochloric acid was added to neutralize. As a result of quantitative analysis of the obtained solution by gas chromatography, methyl m-bromophenylacetate did not remain. Further, 351 mg of m-bromophenethyl alcohol was used.
(1.74 mmol) and m-bromophenylacetic acid 1
3.9 mg (0.06 mmol) had been produced. m-
The conversion of methyl bromophenylacetate was 100%, and the selectivity for m-bromophenethyl alcohol was 81%.

Comparative Example 2 In a stainless steel autoclave having an internal volume of 30 ml, 597.5 mg (2.61 mm) of methyl m-bromophenylacetate was placed.
ol), 15 ml of dioxane and 75 mg of toluene as an internal standard substance for analysis were charged and homogenized. After adding 428 mg (1.11 mmol) of BaCuCr ₂ O ₅ thereto, 175 atm of hydrogen was introduced, and 25 mL of water was introduced using a stirrer.
The mixture was stirred and mixed at 0 ° C. for 3 hours. The reactor was cooled and opened to obtain a reaction solution. As a result of quantitative analysis of the product by gas chromatography, 294.7 mg (1.09 mmol) of unreacted methyl methyl-bromophenylacetate, 184.7 mg (1.23 mmol) of methyl phenylacetate, 7.4 mg of m-bromophenethyl alcohol (0.037mm
ol). The conversion of methyl m-bromophenylacetate was 51%, and the selectivity for m-bromophenethyl alcohol was 3%.

Comparative Example 3 1169 mg (5.10 mmol) of methyl m-bromophenylacetate was placed in a 30 ml stainless steel autoclave.
l), 10 ml of dry ethanol and 81 mg of toluene as an internal standard substance for analysis were charged and homogenized. After adding 2.5 g of W4 type Raney nickel thereto, 30 atm of hydrogen was introduced, and the mixture was stirred and mixed at 50 ° C. for 3 hours using a stirrer. The reactor was cooled and opened to obtain a reaction solution. As a result of quantitative analysis of the product by gas chromatography, 629.8 mg of unreacted methyl m-bromophenylacetate was obtained.
(2.75 mmol), methyl phenylacetate 141.2
mg (0.94 mmol), ethyl phenylacetate 200
mg (1.22 mmol) and 4.7 mg (0.024 mmol) of m-bromophenethyl alcohol. The conversion of methyl m-bromophenylacetate is 46%,
The selectivity for m-bromophenethyl alcohol was 1%.

[0022]

According to the present invention, it is possible to provide a method for producing a halogenated alcohol from a halogenated ester in a relatively simple process at a low cost, efficiently, and industrially advantageously.

Claims (4)

[Claims] In a reaction for reducing a halogenated ester represented by the following formula (1) to obtain a corresponding halogenated alcohol represented by the following formula (2), the reduction is carried out using a borohydride compound. A method for producing a halogenated alcohol. Ar—R—COOR ¹ (1) Ar—R—CH ₂ OH (2) (wherein, Ar is a halogen-substituted phenyl group, and R is a C 1-6 carbon atom) An alkylene group which may have a branch, R ¹ represents an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 12 carbon atoms.) 2. The method for producing a halogenated alcohol according to claim 1, wherein the alcohol is added during the reduction reaction. 3. The method for producing a halogenated alcohol according to claim 2, wherein the alcohol is methanol. 4. The method for producing a halogenated alcohol according to claim 1, wherein the halogenated alcohol is m-halogenated phenethyl alcohol.