JPS62103037A - Production of 2-(4-isobutylphenyl)-propionaldehyde - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for anti- inflammatory, analgesic and antipyretic agents in high yield without generating heat, by bringing 2-(4-isobutylphenyl)1,2-epoxypropane into contact with anhydrous magnesium chloride as a catalyst in the presence of a soft nucleophilic agent. CONSTITUTION:2-(4-Isobutylphenyl)1,2-epoxypropane is brought into contact with anhydrous magnesium as a catalyst, having a low acid strength and capable of giving a sufficient reaction rate and high selectivity even at a relatively low temperature in the presence of a soft nucleophilic agent, e.g. thioanisole or triphenylphosphine, to afford 2-(4-isobutylphenyl)propionaldehyde. The catalyst anhydrous magnesium chloride is preferably powder having about 100 mesh particle size and used in an amount of 0.05-1mol, preferably 0.1-0.3mol based on 1mol 2-(4-isobutylphenyl)1,2-epoxypropane.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing 2-(4-isobutylphenyl)propionaldehyde (hereinafter abbreviated as the present compound).

This compound is extremely useful as an intermediate for the synthesis of 2-(4-isobutylphenyl)propionic acid, which has excellent anti-inflammatory, analgesic and antipyretic effects.

(Prior art) Many reports have been made regarding the production method of this compound, but one method is isomerization of 2-(4-isobutylphenyl)-1,2-epoxypropane, which is easily obtained from 4-isobutylacetophenone. This method is one of the most advantageous manufacturing methods.

This isomerization reaction is usually carried out in the presence of an acid catalyst, and the following method has been published regarding the selection of an acid catalyst.

1) Method of treatment with synthetic aluminum silicate (Japanese Patent Application Laid-open No.
6-154428) 2) Method of treatment with synthetic zeolite (Special Publication No. 56-40
701) 3) A method using anhydrous zinc chloride in benzene at a temperature of 0 to 30°C (Japanese Patent Application Laid-Open No. 53-46829).

(Problems to be Solved by the Invention) All of these methods have drawbacks as industrial production methods.

That is, methods (1) and (2) are carried out at relatively high temperatures, but the raw material 2-(4-inbutyl7enyl)-
1,2-Epoxypropane is an inherently thermally unstable substance and easily converts into allyl alcohol compound (II) at high temperatures.
) and a polymer with an unknown structure, causing a decrease in purity, which was confirmed by additional tests by the present inventors.

In addition, the results of the thermal stability test of the epoxypropane obtained by the present inventors show that 2.4
%, 10°7% at 80-90°C for 5 hours, and 1
It has been confirmed that 5 hours at 10°C causes a decrease in purity of 13.7%.

Moreover, method (3) can be said to be a more improved method in that it can be carried out at a relatively low temperature. However, when the inventors conducted additional tests, they found that anhydrous zinc chloride was too acidic as a catalyst in this reaction, and they found that sulfuric acid, aluminum chloride, boron trifluoride, etc., which have been widely used in this type of reaction, were not used. As in the case where the reaction mixture was heated, heat generation was intense, the reaction mixture was colored, and a large amount of polymerized product was produced as a by-product, making it difficult to obtain the desired product in high yield. Furthermore, benzene used as a solvent in method (3) has strong mutagenicity, and therefore its industrial use is subject to strict regulations. Therefore, this method is difficult in practice.

(Means for Solving the Problem) The present inventor is not satisfied with the above-mentioned conventional technology, and has suppressed the production of by-products to produce 2-(4-isobutylphenyl)propionaldehyde with high yield and high purity. We have conducted repeated research to establish a method that can be used.

As mentioned above, when a catalyst with high acid strength is used as an isomerization reaction catalyst, not only does the formation of polymers occur competitively, but also the catalyst activity is low, so it is necessary to carry out the reaction at high temperature and for a long time. The by-product of ■ cannot be avoided.

Therefore, the present inventors focused on searching for a reaction system that uses a catalyst that has low acid strength and provides sufficient reaction rate and high selectivity even at relatively low temperatures.

As a result, using anhydrous magnesium chloride as a catalyst,
For example, it has been shown that when the reaction is carried out in the presence of a soft nucleophile such as thioanisoleyatriphenylphosphine, the desired 2-(4-isobutylphenyl)-propionaldehyde can be obtained in high yield without generating heat. discovered.

For example, 2-(4-isobutylphenyl)-1,2-
When 0.2 mol of anhydrous magnesium chloride is used per 1 mol of epoxypropane and stirred at room temperature in dichloromethane, the desired reaction hardly progresses even after 3 hours, and even after 8 hours, only a trace amount of the desired reaction occurs. Things are simply produced along with by-products. On the other hand, when the above reaction was carried out in the presence of 0.2 mol of thioanisole, in 8 hours,
At 1.0 mol, the reaction is completed in 3 hours, and the target propionaldehyde compound can be obtained in high yield without producing any by-products.

The present invention is based on this new finding, and is characterized in that 2-(4-isobutylphenyl)1,2-epoxypropane is contacted with anhydrous magnesium chloride in the presence of a soft nucleophile. This is a method for producing isobutylphenyl)propionaldehyde.

The reaction formula is shown as follows.

The reaction is generally carried out in a solvent. Any inert solvent that does not participate in the reaction can be used as the solvent.

Organic solvents that are immiscible with water, such as dichloromethane,
1. halogenated hydrocarbons such as 2-dichloroethane,
Hydrocarbons such as toluene and xylene are used,
It is also possible to use water-miscible organic solvents such as tetrahydrofuran, acetonyl, and the like.

The use of a water-immiscible solvent is advantageous because the reaction mixture can be easily recovered and reused by subjecting it to simple treatments such as washing with water and distillation. In particular, dichloroethane is preferably used because the reaction can be easily controlled under reflux and can be easily recovered.

Although it is desirable to use the solvent in an anhydrous state, commercially available products can usually be used as they are without special drying.

Dissolve 1 part by weight of epoxypropane (1) in a solvent of usually θ~10 parts by volume, preferably 2 to 5 parts by volume, add an arbitrary amount of soft nucleophile, Preferably, contact is made with 0.05 to 1.0 mol, more preferably 0.1 to 0.3 mol of anhydrous magnesium chloride. The reaction temperature is preferably 0 to 60°C, more preferably 15 to 50°C.

As soft nucleophiles, sulfides such as thioanisole and dimethyl sulfide, thiols such as ethyl mercaptan and mercaptoethanol, and phosphines such as triphenylphosphine are commonly used, but thioanisole is especially easy to handle. is preferred. It is difficult to specifically limit the amount of soft nucleophile used.

Although it may be used as a solvent in a large excess amount, it is usually 0.1 to 0 per mole of epoxypropane (1).
．． The purpose can be achieved without any problem using 2 mol.

Furthermore, since the reaction itself with anhydrous magnesium chloride is a solid-liquid heterogeneous reaction, the larger the surface area, the better the reaction efficiency, but usually, easily available 100 mesh powder is preferably used.

Although the reaction time is related to the reaction temperature and the amounts of anhydrous magnesium chloride and soft nucleophile used, the reaction is usually easily completed in one to ten-odd hours.

After the reaction, by performing normal post-treatment and purification operations,
Highly purified 2-(4-isobutylphenyl)propionaldehyde (1) can be obtained simply and inexpensively with high yield.

Example 1 38 f (0.2 mol) of 2-(4-isobutylphenyl)-1,2-epoxypropane was dissolved in dichloromethane 13
Dissolved in 0J, anhydrous magnesium chloride (100mesh
) 3.431 (0-036 moles) and Chi'+7°
The reaction was completed after stirring for 10 hours at v-h5fcO°04%/L=)e3″″”·71:.

After washing the resulting reaction mixture with dilute hydrochloric acid and then with brine,
Dichloromethane was distilled off under normal pressure. The residue is subjected to vacuum distillation and distilled at 127-130°C (8HHg)2.
-(4-isobutylphenyl)propionaldehyde 3
7.49 was obtained as a colorless oil (yield 98.5%) Purity 99% or higher f('!j:yy For DCQF-1e
,,.

Gas chromatography; Column temperature: 130 °C, flow rate: 70 ml/min)
,.

NMR (in CDCl5) ppm; C! 3 CH.

7.08 (4H, s, arom) 9.60 (IH, d, J=1 cps, -c!(o)
IR; l'c=0 1730 em (Neat) Example 2 2-(4-isobutylphenyl)-1,2-epoxypropane 38 F (0.2 mol) was dissolved in dichloromethane 13
0- dissolved in anhydrous magnesium chloride (lQQmesh
) 2.67F (0,028 mol) and Thioanilin 51 (0.04 mol) were added, and the reaction was completed by stirring for 3 hours under a stream of a.

From now on, insoluble matter was separated in a furnace, and the obtained p liquid was washed with brine, and then dichloromethane was distilled off under normal pressure.

The residue was subjected to vacuum distillation at 127-129°C (8 wag
) 36.81 of 2-(4-isobutylphenyl)propionaldehyde was obtained as a colorless oil (yield 96.8%) Purity 99% or more (effect of the invention) 2-(4-isobutylphenyl) - In the reaction to obtain 2-(4-isobutylphenyl)propionaldehyde (1) from 1,2-epoxypropane (1), by contacting it with anhydrous magnesium chloride under mild conditions in the presence of a soft nucleophile. The reaction proceeds easily without producing by-products, and highly pure 2-(4-isobutylphenyl)propionaldehyde (1) can be easily obtained in high yield.

Patent Applicant: Hamari Pharmaceutical Co., Ltd. (Voluntary) Procedural Amendment November 26, 1985 1, Case Indication: Showa Gθ Year Patent Application No. 242413 2
, Title of the invention 2 - Process for producing (4-isobutylphenyl)-propionaldehyde 3 Relationship with the case of the person making the amendment Patent applicant address 1-4 Kurishima, Higashiyodogawa-ku, Osaka-shi, Osaka Prefecture? No. t129 Name Hamarikuwahin Kogyo Co., Ltd. Representative Ministry Takami Adult 4, Agent 〒541 6 (06) 202-58
58 Address: 4-46 Mansei Building, Kitahama, Higashi-ku, Osaka Name
(6249) Propensity Table 5, Date of amendment order (voluntary) 63 Subject of amendment Column 7 of [Detailed Description of the Invention] of the specification, Contents of amendment 1 as attached, Page 114 of Specification I, Formula In the fifth line from the bottom, correct "60 to 70 degrees Celsius in the results" to "For example, 60 to 70 degrees Celsius in the results."

2. On the same page, in the 8th line from the bottom of the formula, correct "decreased purity" to "formation of allyl alcohol (III)".

3. Same, page 5, line 6 from the bottom, ``not only occurs, but has decomposition activity'' is corrected to ``occurs, and also has decomposition activity when a desolvent with low acid strength is used.''

4. Same, page 9, 3rd line from the bottom [Correct 10-odd hours J to 10-odd hours Jk:fil.

5. Same, page 9, line 4, "triphenylphosphine" and "phosphine" are corrected to "triphenylphosphine" and ")A sphine", respectively.

Amendment to the above procedure February 7, 1986 2, Title of the invention 2-(4-Isoptylpheny/L/)
-Production method of propionaldehyde 3, Relationship with the case of the person making the amendment Patent applicant address 1-4-29 Shibajima, Higashiyodogawa-ku, Osaka-shi, Osaka Prefecture Name Hamari Pharmaceutical Co., Ltd. Telephone Osaka (06) 202 -+ No. 8511 (representative) 6
, The number of inventions will increase due to the amendment. "Dichloroethane" on page 8, line 7 of the specification is corrected to "dichloromethane."

In the procedural amendment dated November 26, 1985, page 2, lines 9 and 10, "decomposition activity" is corrected to "catalytic activity."

Same, on page 2, line 1θ, "solvent" is corrected to "catalyst".

that's all

Claims (1)

[Claims] 1,2-(4-isobutylphenyl) 2-(4-isobutylphenyl) characterized by contacting 1,2-epoxypropane with anhydrous magnesium chloride in the presence of a soft nucleophile. Method for producing propionaldehyde. 2. The production method according to claim 1, wherein the soft nucleophile is a sulfide, thiol or phosphine. 3. Claim 1 in which the soft nucleophile is thioanisole, dimethyl sulfide, ethyl mercaptan, mercaptoethanol or triphenylphosphine.
Manufacturing method described in section. 4. The manufacturing method according to claim 1, wherein the anhydrous magnesium chloride is a powder of about 100 mesh. Anhydrous magnesium chloride 0.05 to 1 mole of 5,2-(4-isobutylphenyl)1,2-epoxypropane
Process according to claim 1, using 1 mol, preferably 0.1 to 0.3 mol.