JPS6348244A - Production of substituted phenylpyruvic acid - Google Patents

Abstract

PURPOSE:To economically and advantageously obtain the titled compound useful as a medicine, etc., in good yield, by reacting a substituted benzyl chloride with CO and an alkaline earth metal base in the presence of a cobalt carbonyl compound catalyst using water and a solvent sparingly soluble in the water as a solvent. CONSTITUTION:A substituted benzyl chloride, e.g. p-fluorobenzyl chloride, etc., is reacted with carbon monoxide and an alkaline earth metal base, particularly preferably calcium hydroxide in the presence of a cobalt carbonyl compound, particularly preferably dicobalt octacarbonyl to give a substituted phenylpyruvic acid, e.g. p-fluorophenylpyruvic acid, etc. In the process, water and a solvent sparingly soluble in the water, preferably a ketone, particularly methyl isobutyl ketone or acetophenone are used as a solvent. EFFECT:The catalyst is readily separated and reuse thereof can be carried out.

Description

Detailed Description of the Invention (a) Industrial Application Field The present invention provides a method for reacting substituted benzyl chloride with carbon monoxide and an alkaline earth metal base in the presence of a cobalt carbonyl compound catalyst using water as a solvent. The present invention relates to a method for producing substituted phenylbilpic acid, which is characterized in that the reaction is carried out in the presence of a poorly soluble solvent in water.

Substituted phenylbilpic acid is a substance used, for example, as a substituted phenylalanine as a medicine.

(b) Prior art The method for producing substituted phenylbilpic acid 4 by reacting substituted benzyl chloride with carbon monoxide is known, for example, as described in Japanese Patent Publication No. 56-1983. 18587 and the like.

In Japanese Patent Publication No. 56-18587, a substituted benzyl chloride and carbon monoxide are reacted in a water/alcohol mixed solvent in the presence of an alkaline earth metal base using a metal carbonyl compound, particularly a cobalt carbonyl compound, as a catalyst. A method for producing substituted phenylbilpic acid has been proposed.

(c) Problems to be solved by the invention However, in existing methods for producing substituted phenylbilpic acid, including the above-mentioned Japanese Patent Publication No. 56-18587, substituted phenylbilpic acid precipitates as a solid during the reaction. The alkali metal salt or alkaline earth metal salt of substituted phenylbirupic acid can be easily obtained by acid treatment after filtration. The carbonyl catalyst is dissolved in the reaction filtrate, and complicated steps are required to separate the by-product substituted phenylacetic acid alkali metal salt or alkaline earth metal salt from the cobalt carbonyl catalyst and to regenerate the cobalt carbonyl catalyst. .

In addition, to regenerate the cobalt carbonyl catalyst, water/alcohol solvent etc. are removed from the reaction filtrate, treated with mineral acid to recover the by-product substituted phenylacetic acid, and then the produced cobalt mineral acid salt is
For example, after processing with an alkali hydroxide or the like to form cobalt hydroxide, the cobalt hydroxide is further reacted with high-temperature, high-pressure water gas to form a cobalt carbonyl compound (7).

In addition, the method disclosed in Japanese Patent Publication No. 56-18587 uses 5 to 20
The reaction is carried out under a pressure of 0 bar; a pressure of 40 bar or more is required to obtain substituted phenylbilpic acid in a practical yield; under normal pressure, substituted phenylbilpic acid can be produced in a preferred yield. can't get it.

The present inventors have completed the present invention as a result of their earnest efforts and studies to improve these drawbacks.

(d) Means for Solving the Problems The present invention uses water as a solvent when reacting a substituted benzyl cocolide with carbon monoxide and an alkaline earth metal base in the presence of a cobalt carbonyl compound catalyst. The present invention relates to a method for producing substituted phenylbilpic acid characterized by carrying out the reaction in the presence of a poorly soluble solvent.

The substituted benzyl chloride of the present invention includes 〇-fluoropenzyl chloride, m-fluoropenzyl chloride, p-fluoropenzyl chloride,
Fluorinated penzyl chloride, 0-methylbenzyl chloride, m-methylbenzyl chloride, p-methylbenzyl chloride, o-isopropylbenzyl chloride, m-isopropylbenzyl chloride, p-isopropylbenzyl chloride, 〇-penzyl chloride, m-penzyl chloride, p-penzyl chloride, 2.4-dimethylbenzyl chloride, 3.4
-dimethylbenzyl chloride, 3゜5-dimethylbenzyl chloride, 0-methoxyhexyl chloride, m-
Methoxyhedyl chloride, p-methoxybenzyl chloride, 0-penzyloxybenzyl chloride, m-penzyloxybenzyl chloride, p-benzyloxybenzyl chloride, m, p-methylenedioxydibenzyl chloride, p-phenylbenzyl chloride , p-1-butylbenzyl chloride and the like.

Examples of the slightly water-soluble solvent in the present invention include benzene,
Aromatic hydrocarbons such as toluene, aliphatic hydrocarbons such as hexane and heptane, aliphatic and aromatic ethers such as diethyl ether, diisopropyl ether, diphenyl ether, methyl isobutyl ketone, acetophenone, diisopropyl ketone, methyl isopropyl ketone,
Aliphatic and aromatic ketones such as dibutyl ketone, diisobutyl ketone, and cyclopentanone are selected, and ketones such as methyl isobutyl ketone and acetophenone are particularly preferred.

The concentration of the substituted benzyl chloride in the reaction solvent is not particularly limited, but it is generally 1 to 50% by weight based on the slightly water-soluble solvent.

The amount of water is generally 10 to 200% of the solvent that is poorly soluble in water.
Heavy view% use weight.

The alkaline earth metal base used in the present invention is generally selected from alkaline earth metal hydroxides, alkaline earth metal oxides and alkaline earth metal carbonates, but in particular alkaline earth metal hydroxides are used. Among them, calcium hydroxide is preferred.

The amount of the alkaline earth metal base used generally needs to be at least 1 mol per mol of substituted benzyl chloride, and is preferably small (1.0 to 2.5 mol per mol of substituted benzyl chloride).

As the catalyst, cobalt carbonyl compounds, especially dicobalt octacarbonyl, are preferred.

The cobalt carbonyl compound/benzyl chloride (mole ratio) of the catalyst is generally used in a range of 1/1 to 1/1000, but a range of 1/30 to j/200 is particularly preferred.

Carbon monoxide does not need to be of high purity, and water gas or the like can also be used. Carbon monoxide pressure generally ranges from normal pressure to 200+
A range of r/ca is adopted.

The reaction temperature is preferably 20 to 150°C, preferably 40 to 100°C.
°C is good.

Generally, the reaction is carried out until absorption of carbon monoxide stops;
The reaction solution is treated as follows in order to recover the target product, substituted phenylbilpic acid, by-products, substituted phenylacetic acid, and cobalt carbonyl catalyst.

That is, by filtering the reaction solution, a solid portion consisting of the alkaline earth metal salt of substituted phenylbilpic acid precipitated as a solid during the reaction, an aqueous layer portion containing the alkaline earth metal salt of substituted phenylacetic acid, and cobalt. It can be separated into a slightly water-soluble solvent layer containing a carbonyl catalyst.

Subsequently, the alkaline earth metal salt of substituted phenylbilpic acid separated by filtration is made acidic with an aqueous mineral acid solution, for example, a dilute aqueous hydrochloric acid solution, and the resulting aqueous solution is extracted with a suitable organic solvent, such as diethyl ether. Thereafter, substituted phenylbilpic acid can be obtained by removing the organic solvent. Similarly, the aqueous layer portion containing the alkaline earth metal salt of substituted phenylacetic acid is made acidic with a mineral acid aqueous solution, for example, dilute hydrochloric acid aqueous solution, and the resulting aqueous solution is extracted with a suitable organic solvent, such as diethyl ether. By-product substituted phenylacetic acid can be recovered by removing the solvent.

Further, the portion of the solvent layer containing the cobalt carbonyl catalyst that is sparingly soluble in water can be recycled to the reaction system as it is without any treatment and can be reused.

(e) Effects of the invention According to the present invention, the substituted phenylbilpine acid oxidation rate is high (,
The alkaline earth metal salt of the by-product substituted phenylacetic acid and the cobalt carbonyl catalyst can be easily separated from each other, and the cobalt carbonyl catalyst can be recycled to the reaction system as it is for reuse.

Therefore, it has become possible to economically produce substituted phenylbilpic acid.

The present invention will be described in detail below with reference to Examples, but the present invention is not limited thereto.

(F) Examples Example 1 In a 500 m# stainless steel autoclave, 100 mA of methyl isobutyl ketone, 50 ml of water, 9.3 g (0,126 mol) of calcium hydroxide, and 8.8 g of p-penzyl fluoride chloride ( 0.0, OEi 1 mole), and dicobalt octacarbonyl 1.2 g (0.0035
Mol) was prepared.

Clean the inside of the autoclave with carbon monoxide, raise the temperature without stirring under carbon monoxide pressure, and then reduce the carbon monoxide pressure to 1 kg/c.
The reaction was carried out at a temperature of 50° C. for 10 hours until absorption of carbon monoxide stopped.

After the reaction, the reaction mixture was separated from the autoclave into a solid, an organic layer, and an aqueous layer through a pressure filter using carbon monoxide pressure.

The obtained solid was transferred to a 500 mf flask, and 270 mj! of 10% aqueous hydrochloric acid solution was added. and diethyl ether 150mj!
was added and stirred until the solid was completely dissolved. After separating the diethyl ether layer, the aqueous layer was further diluted with 100% diethyl ether.
Extracted twice with mj2. These diethyl ether layers were combined, washed with water, and then dried over sodium sulfate. After drying, diethyl ether was distilled off to obtain 8.1 g of p-fluorinated phenylbilpic acid, with a yield of 73.0%.

The aqueous layer of the reaction filtrate was treated with 70mj of 10% aqueous hydrochloric acid solution! Make it acidic and diethyl ether 100m7! Extracted three times. These diethyl ether layers were combined, dried over sodium sulfate, and then the diethyl ether was distilled off to obtain 1.0 g of p-fluorinated phenylacetic acid, with a yield of 10.7%.

A cobalt carbonyl catalyst was present in the organic layer of the reaction filtrate.

Example 2 The reaction and treatment were carried out in the same manner as in Example 1, except that acetophenone was used as a poorly water-soluble solvent. The yield of p-fluorinated phenylbilpic acid was 72.0%, and the yield of p-fluorinated phenylacetic acid was 10.5%.

Example 3 While blowing carbon monoxide under normal pressure, the reaction temperature was set at 50°C.
The reaction and treatment were carried out in the same manner as in Example 1, except that the reaction time was 20 hours. The yield of p-fluorinated phenylbilpic acid was 71.5%, and the yield of p-fluorinated phenylacetic acid was 9.2%.
Met.

Example 4 100 m# of methyl isobutyl ketone, 50 m of water, 9.3 g (0,126 mol) of calcium hydroxide, 8.8 g (0,061 mol) of 〇-fluorinated penzyl chloride
, and dicobalt octacarbonyl 1.2 g (0,00
35 mol), and the reaction and treatment were carried out in the same manner as in Example 1. 〇-Yield of fluorinated phenylvirpic acid is 68.0
%, the yield of 0-fluorinated phenylacetic acid was 5.9%.

Example 5 Methyl isobutyl ketone 100m4. 50 ml of water, 9.3 g (0,126 mol) of calcium hydroxide, 8.8 g (0,061 mol) of m-penzyl fluoride, and 1.2 g (0,0035 mol) of dicobalt octacarbonyl.
mol), and the reaction and treatment were carried out in the same manner as in Example 1. The yield of m-fluorinated phenylbilpic acid was 71.4%,
The yield of m-fluorinated phenylacetic acid was 3.5%.

Example 6 100 nl of methyl isobutyl ketone, 50 ml of water, hydroxylation power)Li',i'')L9.3 g (0,126 mol), p-penzyl chloride 9.8 g (0,0
61 mol), and 1.2 g of dicobalt octacarbonyl
(0,0035 mol) was charged, and the reaction and treatment were carried out in the same manner as in Example 1. The yield of p-chlorinated phenylvirupic acid is 77.4%, and the yield of p-chlorinated phenylbilpic acid is 2.
．． It was 4%.

Example 7 Methyl isobutyl ketone 100mI! , water 50 mp1 calcium hydroxide 9', 3 g (0,126 mol), p
-penzyl chloride 9.8 g (0', 061
mole), and dicobalt octacarbonyl 1.2 g (0
,0035 mol), and the reaction and treatment were carried out in the same manner as in Example 1. The yield of p-phenylvirpic acid chloride is 7
The yield of p-chlorophenylacetic acid was 10.3%.

Example 8 Methyl isobutyl ketone 100mji! , water 50m11
Calcium hydroxide 9.3g (0,126 mol), 2.4
-dimethylbenzylchloride)'9.4 g (0°0
61 mol), and dicobalt octacarbonyl 1.2
g (0,0035 mol) was charged, and the reaction and treatment were carried out in the same manner as in Example 1. The yield of 2,4-dimethylphenylbilpic acid was 81.0%, and the yield of 2,4-dimethylphenylacetic acid was 1.7%.

Example 9 Methyl isobutyl ketone 100 mβ, water 50 ml, calcium hydroxide 9.3 g (0,126 mol), 3,4-dimethylbenzyl chloride 9.4 g (0°061 mol)
, and dicobalt octacarbonyl 1.2 g (0,
0035 mol), and the reaction and treatment were carried out in the same manner as in Example 1. The yield of 3,4-dimethylphenylbilpic acid was 73.5%, and the yield of 3,4-dimethylphenylacetic acid was 2.0%.

Example 10 100 m# of methyl isobutyl ketone, 50 liters of water, 9.3 g (0,126 mol) of calcium hydroxide, 10.3 g (0,061 mol) of p-isopropylbenzyl chloride, and 1.2 g (0,061 mol) of dicobalt octacarbonyl. g (0
,0035 mol), and the reaction and treatment were carried out in the same manner as in Example 1. The yield of p-isopropylphenylbilpic acid was 72.1%, and the yield of p-isopropylphenylacetic acid was 6.8%.

Claims (1)

[Claims] 1. When reacting substituted benzyl chloride with carbon monoxide and an alkaline earth metal base in the presence of a cobalt carbonyl compound catalyst, the reaction is performed in the presence of water as a solvent and a solvent that is sparingly soluble in water. A method for producing substituted phenylbilpic acid, characterized by: 2. The manufacturing method according to claim 1, wherein the solvent that is poorly soluble in water is a ketone. 3. The manufacturing method according to claim 1, wherein the ketone is methyl isobutyl ketone or acetophenone. 4. The production method according to claim 1, wherein the alkaline earth metal base is calcium hydroxide. 5. The manufacturing method according to claim 1, wherein the cobalt carbonyl compound is dicobalt octacarbonyl. 6. The manufacturing method according to claim 1, wherein the carbon monoxide pressure is normal pressure to 100 kg/cm^2.