JP2594826B2 - Method for producing p- or m-hydroxyphenethyl alcohol - Google Patents

Description

The present invention relates to a method for producing p- or m-hydroxyphenethyl alcohol, which is useful as an agricultural chemical intermediate or a liquid crystal polymer raw material.

Prior Art p-Hydroxyphenethyl alcohol is called tyrosol and is obtained by fermentation of tyrosine. To obtain hydroxyphenethyl alcohol industrially, it can be produced by reduction of hydroxyphenylacetic acid obtained from cyanomethylphenol or hydroxymandelic acid, its ester form, acetoxy form, etc., but the purity of the raw material is low, so it must be further purified. Must.

DISCLOSURE OF THE INVENTION The present invention provides a method for producing industrially inexpensive and high-purity p- or m-hydroxyphenethyl alcohol by improving the above-mentioned drawbacks of the conventional method for producing p-hydroxyphenethyl alcohol. Is what you do.

B) Constitution of the Invention Means for Solving the Problems The present inventors have made intensive efforts to solve the above problems, and as a result, have found an advantageous industrial production method of p- or m-hydroxyphenethyl alcohol. Reached. That is, the gist of the first invention is as follows: Reacting any one of hydrochloric acid, hydrogen chloride and sulfuric acid with p- or m-tert-butoxyphenethyl alcohol represented by the formula: In the method for producing p- or m-hydroxyphenethyl alcohol.

The gist of the second aspect of the present invention is as follows: One of p-toluenesulfonic acid, methanesulfonic acid and a strongly acidic ion exchange resin is added to p- or m-tert-butoxyphenethyl alcohol represented by the formula below, and isobutylene is distilled out of the system under reduced pressure. Expression characterized by leaving In the method for producing p- or m-hydroxyphenethyl alcohol.

The method for producing the p- or m-hydroxyphenethyl alcohol of the present invention is shown by the following reaction formula. However, hydrochloric acid, hydrogen chloride, and sulfuric acid (hereinafter referred to as “de-tert-butylating agent”), p-toluenesulfonic acid, methanesulfonic acid, and a strongly acidic ion exchange resin (hereinafter, referred to as “de-tert-butylating agent”)
The product derived from the tert-butyl group to be eliminated differs depending on the type of rt-butylation catalyst) and the method of use.

Hereinafter, the production method of the compound of the present invention will be described in more detail.

First, the starting compound of the present invention, p- or m-tert
-Butoxy-phenethyl alcohol [formula (II)] is a novel compound. Then, by introducing p- or m-tert-butoxyhalogenobenzene to the Grignard reagent and reacting it with ethylene oxide, a highly pure product of the corresponding p- or m-tert-butoxyphenethyl alcohol can be easily obtained. (JP-A-1-156939). The production examples of the compound of the formula (II) are referred to as Reference Production Examples 1 to
3 is shown.

Method (A) When hydrochloric acid is allowed to act on tert-butoxyphenethyl alcohol as a tert-butoxylating agent, the desired hydroxyphenethyl alcohol and tert-butyl chloride are by-produced.

The hydrochloric acid used in this reaction may be 10% hydrochloric acid, concentrated hydrochloric acid or hydrogen chloride, and the amount used is 2% of the theoretical amount.
An appropriate amount is about 3 to 3 times the molar amount.

In this reaction, tert-butoxyphenethyl alcohol is not necessarily diluted with a solvent, but aromatic solvents such as benzene, toluene, and xylene, aliphatic solvents such as hexane, pentane, and owatane, dichloromethane, and chloroform are used. And a solvent such as dichloroethane, an ether solvent such as diethyl ether and tetrahydrofuran, and an alcohol solvent such as methanol, ethanol and propanol.

The reaction temperature is desirably set to a low temperature because the tert-butyl chloride eliminated at a high temperature acts as a Friedel-Crafts reactant and by-produces a core tert-butyl compound.
Usually, it is appropriate to carry out in the range of 0 ° C to 30 ° C.

Next, a specific operation example of the reaction using hydrochloric acid as the tert-butylating agent will be described. First, tert-butoxyphenethyl alcohol is used alone or diluted in a solvent, and concentrated hydrochloric acid of 2 to 3 moles is added dropwise at a temperature of 30 ° C. or lower, and stirring is continued for 1 to 2 hours. The conversion of the reaction at this point is
%. When an aromatic or aliphatic solvent is used, the generated hydroxyphenethyl alcohol is precipitated as a crystal, and can be separated as a crude crystal by a filtration operation or the like. When a solvent such as dichloromethane is used, hydroxyphenethyl alcohol is dissolved in the solvent.Therefore, the organic layer is separated, washed with water, and the like. A crude crystal of phenethyl alcohol is obtained. The hydroxyphenethyl alcohol thus obtained is
It can be purified by reconstitution or distillation.

Method (B) When sulfuric acid is allowed to act on tert-butoxyphenethyl alcohol as a tert-butylating agent, the desired hydroxyphenethyl alcohol and tert-butyl alcohol are by-produced.

In this reaction, the concentration of sulfuric acid to be used is important.
50% concentration is a practical use range. That is, when the concentration is low, the reaction rate is low, and when the concentration is high, the by-products in which the tert-butyl group is substituted on the benzene ring of the hydroxyphenethyl alcohol formed increase. In the above-mentioned sulfuric acid concentration range, sulfuric acid acts as a catalyst, and the amount used is one-quarter.
It is sufficient that the molar ratio is about or more, and after the reaction, tert-butyl alcohol is recovered in good yield.

The reaction temperature is suitably about 0 to 30 ° C. to prevent side reactions.

A reaction solvent is not particularly required, but an inert solvent as shown in the method (A) may be used.

Method (C) The reaction for elimination of the tert-butyl group of tert-butoxyphenethyl alcohol as isobutylene is a reverse reaction of tert-butylation. It proceeds by distilling out of the reaction system. Actually, there can be used the above-mentioned tert-butylating agent, but generally, p-toluenesulfonic acid, methanesulfonic acid, a strongly acidic ion exchange resin or the like is added as a non-volatile acid, and the pressure is reduced. It is effective to distill off the isobutylene formed under the conditions out of the reaction system.
Even in this reaction, side reactions are involved at high temperatures, so 40 to 50
° C is the allowable upper limit.

Effect of the Invention In the production method of the present invention, the reaction operation is easier than in the conventional synthesis method, and p- or m-hydroxyphenethyl alcohol can be obtained with high purity. Further, the tert-butyl group used as a protecting agent for the phenolic hydroxyl group is recovered and can be reused. Therefore, the method of the present invention is advantageous as an industrial method.

Next, the production method of the present invention will be described more specifically by showing examples of the present invention.

Example 1 Method for producing p-hydroxyphenethyl alcohol In a 1-volume flask equipped with a stirrer, 97.1 g (0.5 mol) of p-tert-butoxyphenethyl alcohol and 300 ml of dichloromethane were added, and 150 g of concentrated hydrochloric acid was added dropwise at 25 to 30 ° C. Then, stirring was continued for 2 hours.

After the reaction, the mixture was neutralized with an aqueous sodium carbonate solution to separate a dichloromethane layer, and the solvent was distilled off to obtain a crude crystal of p-hydroxyphenethyl alcohol. Then, by vacuum distillation,
64.4 g of a fraction having a boiling point of 140 ° C./3 mmHg (gas chromatography purity 100%, yield 93.2%) was obtained. Melting point of target substance is 91-9
At 2 ° C., the infrared absorption spectrum was completely consistent with the standard.

(1) NMR spectrum ^{δ2.72 (2H, t, H d} ) δ6.70 (2H, d, H b) δ3.40 (1H, s, H f) δ7.04 (2H, d, H c) δ3.70 (2H, ^{t, H e) δ8.10 (1H} , s, H a) (2) of 300ml capacity equipped with a infrared absorption spectrum 3350 cm ^-1 OH stretching 1100 cm ^-1 example 2 p-hydroxy pheneticillin chill alcohol production method stirrer 97.1 g (0.5 mol) of p-tert-butoxyphenethyl alcohol was placed in the flask,
100 g of 40% sulfuric acid was added dropwise at 25-30 ° C, and stirring was continued for 2 hours.

After the reaction, the mixture was neutralized with an aqueous sodium carbonate solution and extracted with 300 ml of dichloromethane, and the solvent was distilled off to obtain crude crystals of p-hydroxyphenethyl alcohol.

Then, by vacuum distillation, a fraction having a boiling point of 140 ° C./3 mmHg 63.
6g (gas chromatography purity 99.9%, yield 91.1%)
I got The melting point of the target product was 91 to 92 ° C, and the infrared absorption spectrum was completely consistent with the standard.

Example 3 Method for producing m-hydroxyphenethyl alcohol In a 300 ml flask equipped with a stirrer, 97.1 g (0.5 mol) of m-tert-butoxyphenethyl alcohol was placed, and 25-
Hydrogen chloride gas was blown in at 30 ° C., and stirring was continued for 2 hours.

After the reaction, the mixture was neutralized with an aqueous sodium carbonate solution and extracted with 300 ml of dichloromethane, and the solvent was distilled off to obtain crude crystals of m-hydroxyphenethyl alcohol. Then, 63.4 g of a fraction having a boiling point of 168 ° C./4 mmHg (gas chromatography purity 99.9%, yield 91.7%) was obtained by vacuum distillation. The melting point of the target product was 89 to 91 ° C., and the infrared absorption spectrum was completely consistent with that of the standard m-hydroxyphenethyl alcohol.

(1) NMR spectrum ^{δ2.75 (2H, t, H f} ) δ3.80 (2H, t, H g) δ3.40 (1H, s, H h) δ6.60~7.20 (4H, m, H b -
^{H e) δ8.10 (1H, s} , H a) (2) m-tert infrared absorption spectrum 3350 cm ^-1 OH stretching 1140 cm ^-1 eggplant type flask preparation 300ml capacity of Example 4 m-hydroxy phenethyl alcohol 97.1 g (0.5 mol) of butoxyphenethyl alcohol and p-
5 g of toluenesulfonic acid was added, and the temperature of the hot water bath was increased while stirring with a magnetic stirrer under reduced pressure (25 mmHg) using an aspirator, and the resulting isobutylene gas was distilled off by maintaining the temperature at 40 ° C. for 2 hours.

After the reaction, the resultant was dissolved in 300 ml of dichloromethane, washed with water, and the solvent was distilled off to obtain crude crystals of m-hydroxyphenethyl alcohol.

Then 62.6 g of a fraction having a boiling point of 168 ° C./4 mmHg by vacuum distillation
(Gas chromatography purity 99.9%, yield 90.5%). The melting point of the target product was 89 to 91 ° C., and the infrared absorption spectrum was completely consistent with the standard.

Reference Production Example 1 Method for Producing p-tert-butoxyphenethyl Alcohol Attached to a stirrer and a reflux condenser, purged with nitrogen, and placed 29.2 g (1.2 mol) of shaved metal magnesium in a dry, one-volume, four-diameter flask. To this were added 50 ml of anhydrous tetrahydrofuran and 2 ml of ethyl bromide. After confirming the start of foaming and reaction on the metal magnesium surface,
A solution of 184.6 g (1.0 mol) of p-tert-butoxychlorobenzene dissolved in 500 ml of anhydrous tetrahydrofuran was added dropwise at reflux temperature over about 2 hours, and stirring was further continued for 5 hours to add p-tert-butoxyphenylmagnesium chloride. Obtained.

When a portion of the sample was separated, injected and decomposed, and analyzed by gas chromatography, the conversion of the Grignard reagent was 99.8%.

Subsequently, ethylene oxide 48.4 g (1.1 mol) is added at 20-30 ° C.
, And the stirring was continued for 2 hours at the same temperature. Then, the reaction solution is poured into 500 ml of a saturated ammonium chloride aqueous solution to be treated, and the organic layer is separated by further adding 500 ml of toluene, washed with water, dehydrated with anhydrous sodium sulfate, distilled off the solvent, and distilled under reduced pressure to give a boiling point. P-tert-Butoxyphenethyl alcohol as a fraction at 117-121 ° C./3 mmHg
5.4 g (90.3% yield) were obtained. The analytical purity by gas chromatography was 99.8%. The analysis values and physical properties were as follows.

(1) Elemental analysis value CH calculated value 74.2% 9.3% Actual value 74.3% 9.3% (2) NMR spectrum ^{δ1.30 (9H, s, H a} ) δ2.74 (2H, t, H b) δ3.10 (1H, s, H f) δ2.68 (2H, t, H e) δ6.88 (2H, ^{d, H b) δ7.18 (2H} , d, H c) (2) infrared absorption spectrum 3350 cm ^-1 OH stretching 1100 cm ^-1 reference example 2 p-tert-butoxy pheneticillin chill alcohol preparation stirrer and reflux condenser Was replaced with nitrogen, and 24.3 g (1.0 mol) of scraped metal magnesium was placed in a 1-volume dried 4-diameter flask, and 10 ml of anhydrous diethyl ether and 2 ml of ethyl bromide were added thereto. After confirming the start of foaming and reaction on the metal magnesium surface, p
-Tert-butoxybromobenzene 114.6 g (0.5 mol)
Was dissolved in 400 ml of anhydrous diethyl ether dropwise at reflux temperature over about 1 hour, and stirring was continued for another 5 hours to obtain p-tert-butoxyphenyl magnesium bromide. When a part of the sample was separated, decomposed with water and analyzed by gas chromatography, the conversion of the Grignard reagent was 99.9%.

Subsequently, 24.2 g (0.55 mol) of ethylene oxide was added for 20 to 30
The mixture was blown in at 1 ° C. for 1 hour and further stirred at the same temperature for 2 hours to synthesize p-tert-butoxyphenethyl alcohol. Next, the reaction solution was poured into 250 ml of a saturated aqueous solution of ammonium chloride for treatment, and 250 ml of toluene was added to separate the organic layer. Then, after washing with water, the solvent is distilled off by dehydration with anhydrous sodium sulfate and distilled under reduced pressure to give a boiling point of 117 to 1
As a fraction at 21 ° C./3 mmHg, 82.9 g (yield: 85.3%) of p-tert-butoxyphenethyl alcohol was obtained. The analytical purity by gas chromatography was 99.5%.

Reference Production Example 3 Production Method of m-tert-butoxyphenethyl Alcohol Attached to a stirrer and a reflux condenser, purged with nitrogen, and put 29.2 g (1.2 mol) of shaved metal magnesium in a dry, one-volume, four-diameter flask. To this were added 50 ml of anhydrous tetrahydrofuran and 2 ml of ethyl bromide. After confirming the start of foaming and reaction on the metal magnesium surface,
A solution prepared by dissolving 184.6 g (1.0 mol) of m-tert-butoxychlorobenzene in 500 ml of anhydrous tetrahydrofuran was added dropwise at reflux temperature over about 2 hours, and stirring was further continued for 5 hours to obtain m-tert-butoxyphenylmagnesium chloride. Obtained.

When a part of the sample was separated and hydrolyzed, and analyzed by gas chromatography, the conversion of the Grignard reagent was 99.9%. Then 48.4 g of ethylene oxide
(1.1 mol) was blown at 20-30 ° C. over 1 hour, and stirring was continued at the same temperature for 2 hours.

Then, the reaction solution is poured into 500 ml of a saturated aqueous solution of ammonium chloride for hydrolysis, and the organic layer is separated by adding 500 ml of toluene, washed with water, dehydrated with anhydrous sodium sulfate, distilled off the solvent, and rectified under reduced pressure. Then, with a fraction having a boiling point of 129 to 130 ° C./4 mmHg, m-tert-butoxyphenethyl alcohol 176.2 g
(90.7% yield). The analytical purity by gas chromatography was 99.9%. The analysis values and physical properties were as follows.

(1) Elemental analysis value CH calculated value 74.2% 9.3% Actual value 74.2% 9.2% (2) NMR spectrum δ 1.30 (9H, s, H ^a ) δ 2.75 (2H, t, H ^f ) δ 3.40 (1H, b, H ^f ) δ 3.65 (2 H, t, H ^g ) δ 6.60-7.20 ( ^{4H, m, H b -H e} ) (2) infrared absorption spectrum 3350 cm ^-1 OH stretching 1140 cm ^-1

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07C 37/055 9155-4H C07C 37/055 // C07B 61/00 300 C07B 61/00 300

Claims (2)

(57) [Claims] (1) Expression Reacting any one of hydrochloric acid, hydrogen chloride and sulfuric acid with p- or m-tert-butoxyphenethyl alcohol represented by the formula: A method for producing p- or m-hydroxyphenethyl alcohol represented by the formula: (2) One of p-toluenesulfonic acid, methanesulfonic acid and a strongly acidic ion exchange resin is added to p- or m-tert-butoxyphenethyl alcohol represented by the formula below, and isobutylene is distilled out of the system under reduced pressure. Expression characterized by leaving A method for producing p- or m-hydroxyphenethyl alcohol represented by the formula: