JPS62242641A - Production of alpha-phenylpropionic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound advantageously, by carbonylating an alpha-phenylethyl alcohol derivative in the presence of a rhodium catalyst, etc., adding the prepared reaction solution to water in the presence of zinc iodide, separating the mixture into two phases and repeatedly using the catalyst. CONSTITUTION:A compound shown by formula I (R is H, alkyl, alkenyl or aryl) is reacted with carbon monoxide in the presence of a rhodium catalyst and an iodine compound to give a reaction solution containing the aimed compound shown by the formula II. Water is added to the reaction solution in the presence of zinc iodide, the reaction solution is separated into two phases of a reaction product phase and a hydrous phase. The catalyst in the hydrous phase is repeatedly used to give the aimed compound useful as analgesic, etc., industrially advantageously. Since the zinc iodide prevents insoluble rhodium from precipitating, makes operation of the phase separation easy and has no bad influence on carbonylation activity of the catalyst at all, the separated catalyst can be returned to the reaction state directly in the state of the mixture with zinc iodide and circulated and used efficiently.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an industrial method for producing α-phenylpropionic acid derivatives.

α-Phenylpropionic acid derivatives have pharmacological effects such as analgesia, anti-inflammatory, and antipyretic properties, and are useful as pharmaceuticals.

[Conventional technology and problems]

The present inventors have separately developed an industrially advantageous method for obtaining α-phenylpropionic acid derivatives in good yield by reacting α-phenylethyl alcohol derivatives with carbon monoxide in the presence of a rhodium catalyst and an iodine compound. A patent application was filed under the heading.

However, since this production method uses an extremely expensive rhodium catalyst, in actual applications it is essential to establish a method for efficiently separating the rhodium catalyst from the product and recycling it by returning it to the reaction system. .

Conventionally, two methods have been used to separate and reuse this type of homogeneous catalyst: a distillation separation method and a phase separation method.

The distillation separation method is a method in which a reaction product or a portion of the reaction solvent is distilled off from a reaction liquid extracted from a reactor, and the distillation residue containing the catalyst is circulated to the reactor as a catalyst liquid. When this method is applied to the production of α-phenylpropionic acid derivatives by carbonylation of α-phenylethyl alcohol derivatives, the product α-phenylpropionic acid derivatives have a high boiling point, and its distillation requires high vacuum and high temperature. As a result, there is a problem in that the catalyst is easily deactivated, such as rhodium metalation, and a polymer of styrene derivative, which is the main by-product of this reaction, gradually accumulates in the catalyst solution.

On the other hand, the phase separation method involves adding a polar solvent such as water and, in some cases, a non-polar solvent such as paraffin to the reaction solution to separate two phases: a phase containing the reaction product and a phase containing the catalyst. The catalyst is separated and recycled by returning the separated catalyst to the reaction system. When this method is applied to the production of α-phenylpropionic acid derivatives using a rhodium catalyst, the rhodium complex in the reaction solution is extremely unstable, so if water is added to the reaction solution even under a nitrogen atmosphere, , the phase separation operation was difficult because the decomposition of the rhodium complex was accelerated and insoluble rhodium compounds were precipitated.

[Means for solving problems]

When carrying out the above phase separation method, the present inventors added compounds that can serve as stabilizing ligands for rhodium complexes, such as various iodide salts or phosphines, in order to prevent the precipitation of insoluble rhodium compounds. However, although they all have the effect of preventing the precipitation of insoluble rhodium compounds, they also reduce the catalytic activity of rhodium in the carbonylation reaction of α-phenylethyl alcohol derivatives. Even if the recovered rhodium was directly returned to the reaction system, the desired catalytic activity could not be obtained.

However, the present inventors found that when zinc iodide was added, the precipitation of insoluble rhodium compounds during phase separation was prevented, and the phase separation operation was not only facilitated, but zinc iodide was also added to the rhodium catalyst. It was discovered that the separated rhodium catalyst could be returned to the reaction system as a mixture with zinc iodide and recycled efficiently since it had no adverse effect on carbonylation activity, and α-phenylpropionic acid derivatives were produced. The present invention was completed by establishing an industrially advantageous method.

That is, the present invention provides an α-phenylethyl alcohol derivative represented by the general formula (wherein P represents hydrogen, an alkyl group, an alkenyl group, or an aryl group) in the presence of a rhodium catalyst and an iodine compound. , -To a reaction solution containing an α-phenylpropionic acid derivative represented by the general formula (wherein P has the same meaning as above) obtained by reacting with carbon oxide, water was added in the coexistence of zinc iodide. The present invention relates to a method for producing α-phenylpropionic acid derivatives, which is characterized in that the addition of the compound results in two-phase separation into a reaction product and a water-containing phase, and the rhodium catalyst in the water-containing phase is repeatedly used.

The present invention will be explained in detail below. 1 (a) Catalyst As the rhodium catalyst, rhodium compounds such as rhodium halide, rhodium carbonyl, and rhodium acetate are generally used. Even if the rhodium catalyst is charged together with the raw materials at the time of the reaction, the rhodium catalyst can be used under pressure of -carbon oxide and hydrogen under pressure of 10
A carbonyl complex formed at 0°C to 200°C may be used.

(b) Iodine compound (co-catalyst) As a co-catalyst, use an iodine compound such as I2, ■, alkyl iodide, etc. in a ratio of 0.5 to 6 iodine atoms to rhodium atoms.
It is necessary to add it at a rate of approximately gram equivalent. When using rhodium iodide or a rhodium catalyst recovered from the reaction solution as the rhodium catalyst, it is not necessarily necessary to add an iodine compound as a co-catalyst.

(C) Zinc Iodide Zinc iodide may be added to the reaction solution or added water after the carbonylation reaction and prior to the phase separation operation, or may be added together with the raw materials prior to the carbonylation reaction. The amount added is usually in the range of 1:1 to 1:6 in Rh:Zn atomic ratio. Furthermore, when using a rhodium catalyst recovered by phase separation, it is not necessarily necessary to add zinc iodide.

(d) Solvent Although the carbonylation reaction itself proceeds without a solvent, it is preferable to use a solvent in order to suppress side reactions and operate phase separation. Examples of solvents include ethers such as 1,4-dioxane, aromatic hydrocarbons such as benzene and toluene, aliphatic hydrocarbons such as hexane and heptane, carboxylic acids such as acetic acid, ketones such as acetone, or Mixtures thereof are preferably used. Further, when a solvent is used, the raw alcohol concentration is usually about 1 to 50% by weight.

(e) In the α-phenylethyl alcohol derivative serving as a raw material represented by raw alcohol, the substituent R represents hydrogen, an alkyl group, an alkenyl group, or an aryol group. Examples of the alkyl group and alkenyl group include chain, branched, or cyclic groups, such as methyl group, ethyl group, propyl group, isobutyl group, isoprenyl group, and cyclohexyl group. Examples of the aryl group include phenyl group, tolyl group, xylyl group, and naphthyl group.

(f) Adding water to the reaction solution after the water reaction. The amount of water added varies depending on the reaction solvent, but when using 1,4-dioxane as the solvent,
Usually, it is in the range of 175 to 1/l (volume ratio) of the reaction solution.

(g) - Carbon oxide Carbon monoxide may be pure or may contain an inert gas such as nitrogen, or hydrogen. The reaction proceeds at either normal pressure or high pressure, but from the viewpoint of reaction rate and economy, a range of normal pressure to 100 kg/cm'' is preferable.

In addition, if hydrogen is included, its partial pressure is between normal pressure and 5 kg/ca+
``If the pressure is higher than that, it is preferable in the sense that it helps the dissolution of the rhodium compound, but if the pressure is higher than that, hydrogenation by-products will increase, which is disadvantageous.

(h) Reaction temperature The reaction temperature is usually 30 to 130°C, but preferably 60 to 100°C from the economic point of view and suppression of side reactions.

〔Example〕

Hereinafter, methods for separating, recovering, and reusing a rhodium catalyst will be specifically explained using examples. Incidentally, in the Examples, an example using a batch method is shown, but it goes without saying that continuous reaction and continuous extraction are also possible by applying known techniques.

Example 1 α-(
9.0 g of 4-isobutylphenyl)ethyl alcohol,
Add 1.5 g of rhodium iodide, 2.0 g of zinc iodide, and 100- of dioxane as a solvent, and set the hydrogen pressure to 1 at+.
s, - carbon oxide pressure 6 kg/cm", reaction temperature 85
The reaction was allowed to proceed at ℃ for 3 hours with stirring.

After cooling, 100% of water was added to 100% of the cooled reaction solution under nitrogen, and after stirring for several minutes, the mixture was allowed to stand and was separated into two layers.

The components in each layer were analyzed by NMR and atomic absorption, and Table 1
The results shown are obtained.

Table 1 Separate the lower layer from the upper layer and heat at 30°C under 20m+*Hg vacuum.
Water and dioxane were distilled off. The obtained residue was again put into the autoclave together with 8.0 g of α-(4-isobutylphenyl)ethyl alcohol and 90 mZ of dioxane, and the reaction was carried out in the same manner as the first time, and almost the same catalytic activity as the first time was obtained.

Thereafter, the rhodium catalyst was similarly reused five more times, and the results shown in Table 2 were obtained.

From the results in Table 2, it is clear that the catalytic activity is maintained even when the rhodium catalyst is used repeatedly.

Table 2 Comparative Example 1 α-
(4-isobutylphenyl)ethyl alcohol 9.0g
, 1.5 g of rhodium iodide and 1 dioxane as solvent
00 ml and hydrogen pressure latm.

-The reaction was carried out at a carbon oxide pressure of 6 kg/cn+'' and a reaction temperature of 85° C. for 3 hours with stirring.

After cooling, add 4° of water to 100 mZ of the reaction solution under nitrogen atmosphere.
was added and stirred for several minutes, then allowed to stand, but due to the precipitation of the insoluble rhodium compound, it became a suspension and no liquid separation occurred.

Comparative Example 2 α-(4-isobutylphenyl)ethyl alcohol 9.
0g, rhodium iodide 1.5g, potassium iodide 1.0
g and dioxane 100 as a solvent, hydrogen pressure 1at11, carbon oxide pressure 6kg7cm'', reaction temperature 85℃ for 3 hours with stirring.The reaction rate was lower than when zinc iodide was added. was less than 1/10, and the amount of ibuprofen produced was also a trace amount.

Claims (1)

[Claims] 1. An α-phenylethyl alcohol derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents hydrogen, an alkyl group, an alkenyl group, or an aryl group) , α-phenylpropylene, which is obtained by reacting with carbon monoxide in the presence of a rhodium catalyst and an iodine compound, is represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R has the same meaning as above) By adding water to the reaction solution containing the ionic acid derivative in the presence of zinc iodide, the reaction product phase and the water-containing phase are separated into two phases, and the rhodium catalyst in the water-containing phase can be repeatedly used. A method for producing a characterized α-phenylpropionic acid derivative.