JPH11100348A - Production of halogenated phenylpropionic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a halogenated phenylpropionic acid in high yield by catalytically reducing a halogenated cinnamic acid in the presence of ruthenium. SOLUTION: One hundred parts by weight of a halogenated cinnamic acid of formula I (X is a halogen; R is H, methyl or the like) is catalytically hydrogenated in the presence of a catalyst, preferably 0.12-0.5 pts.wt. of ruthenium, preferably at 10-60C for 8-20 hours to give the objective compound. The above- stated reduction process is preferably carried out in a lower alcohol as methanol or a mixed solvent comprising 100 pts.wt. of a lower alcohol and 0-50 pts.wt. of water as of 2-propanol-water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a halogenated phenylpropionic acid compound. More specifically, the present invention relates to a method for producing a halogenated phenylpropionic acid compound which is an important intermediate of a therapeutic agent which is very effective for hyperparathyroidism.

[0002]

2. Description of the Related Art Conventionally, a catalyst containing palladium or platinum as a component has been used for catalytic reduction of a halogenated cinnamic acid compound. However, when a catalytic reduction of a halogenated cinnamic acid compound is performed using such a catalyst, a dehalogenated product is produced at a production rate of 2.5 to 15%, and a halogenated phenylpropionic acid compound can be obtained efficiently. Can not.

[0003]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and provides an efficient, simple, and industrially advantageous method for producing a halogenated phenylpropionic acid compound. Aim.

[0004]

The gist of the present invention is to provide (1)
General formula (I):

[0005]

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(Wherein, X represents a halogen atom, R represents a hydrogen atom, a methyl group, an ethyl group or an isopropyl group)
Wherein the halogenated cinnamic acid compound represented by the general formula (II) is catalytically reduced in the presence of ruthenium as a catalyst:

[0007]

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Wherein X and R are the same as defined above, and (2) a method for preparing a halogenated cinnamic acid compound represented by the general formula (I) in a lower alcohol Alternatively, the method for producing a halogenated phenylpropionic acid compound according to the above (1), which is carried out by catalytic reduction in a mixed solvent of a lower alcohol and water, and (3) reacting the halogenated cinnamate compound represented by the general formula (I) The present invention relates to the method for producing a halogenated phenylpropionic acid compound according to the above (1) or (2), wherein the catalytic reduction is carried out at a temperature of 20 to 30 ° C.

[0009]

According to the method for producing a halogenated phenylpropionic acid compound of the present invention, as described above,
General formula (I):

[0010]

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(Wherein, X represents a halogen atom, R represents a hydrogen atom, a methyl group, an ethyl group or an isopropyl group)
By catalytic reduction of a halogenated cinnamic acid compound represented by the formula in the presence of ruthenium as a catalyst:

[0012]

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(Wherein X and R are the same as described above), thereby obtaining a halogenated phenylpropionic acid compound represented by the formula:

In the halogenated cinnamic acid compound represented by the general formula (I), X represents a halogen atom, and R represents a hydrogen atom, a methyl group, an ethyl group or an isopropyl group.

As the halogen atom, a fluorine atom,
Chlorine, bromine and iodine atoms.

Specific examples of the halogenated cinnamic acid compound represented by the general formula (I) include, for example, o-chlorocinnamic acid, methyl o-chlorocinnamate and the like.

As described above, the catalytic reduction of the halogenated cinnamic acid compound represented by the general formula (I) is carried out in the presence of ruthenium as a catalyst, but is preferably carried out in a solvent. It can be performed according to the following method.

That is, by adding a solvent to the halogenated cinnamic acid compound represented by the general formula (I) and shaking or stirring the solution under a hydrogen atmosphere in the presence of ruthenium as a catalyst, or By blowing hydrogen gas into the solution, hydrogen can be dissolved in the solution.

The ruthenium used as a catalyst can be used, for example, as a carrier in which ruthenium is supported on a carrier generally known in catalytic chemistry such as carbon and alumina, and ruthenium oxide.

The amount of ruthenium used is determined by the general formula (I)
Is preferably about 0.125 to 0.5 part by weight based on 100 parts by weight of the halogenated cinnamic acid compound represented by the formula:

As the solvent, for example, methanol,
One or more of lower alcohols having 1 to 5 carbon atoms such as ethanol and 2-propanol, and a mixed solvent thereof with water are exemplified. Among these, a mixed solvent of 2-propanol and water and methanol are preferred. The mixing ratio of the lower alcohol and water is preferably about 0 to 50 parts by weight of water with respect to 100 parts by weight of the lower alcohol.

The amount of the solvent used is not particularly limited. For example, when a lower alcohol is used, the amount used is 600 parts by weight based on 100 parts by weight of the halogenated cinnamic acid compound represented by the general formula (I). When a mixed solvent of a lower alcohol and water is used, the amount of the solvent is 800 parts by weight based on 100 parts by weight of the halogenated cinnamic acid compound represented by the general formula (I). ~ 1
It is preferably about 000 parts by weight.

In the catalytic reduction, for example, activated carbon or the like may be appropriately used in order to suppress poisoning of the catalyst.

The reaction temperature at the time of the catalytic reduction is desirably 10 ° C. or higher, preferably 20 ° C. or higher from the viewpoint of the reaction rate, and is 60 ° C. or lower, preferably, from the viewpoint of suppressing the formation of dehalogenated products. Is desirably 30 ° C. or less.

The reaction time cannot be determined in general because it varies depending on conditions such as the amount of the catalyst used. However, it is sufficient that the reaction time is such that the catalytic reduction is completed.
It may be about 0 hours. When shaking or stirring a solution in which the halogenated cinnamic acid compound is dissolved in a solvent under a hydrogen atmosphere, the pressure of the hydrogen gas is 3 to 18 kg.
f / cm ² may be sufficient.

The completion of the catalytic reduction can be confirmed, for example, by esterifying the raw material and the product and then examining the conversion using gas chromatography.

After completion of the reaction, the obtained halogenated phenylpropionic acid compound represented by the general formula (II) is isolated by ordinary separation operations such as crystallization, filtration, concentration, washing, and extraction. be able to.

According to the manufacturing method of the present invention described above,
Since the generation rate of by-product dehalogenated products such as phenylpropionic acid and its derivatives is very small, usually about 0.5% or less, halogenated phenylpropione represented by the general formula (II) can be efficiently used. An acid compound can be obtained. The production rate of the dehalogenated compound can be measured by using high performance liquid chromatography (HPLC).

[0029]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Example 1 A 1 liter Teflon beaker was charged with methanol 240
g, o-chlorocinnamic acid 30 g, 5% ruthenium carbon (5
(0% water content) and 6 g of powdered activated carbon were charged and subjected to catalytic reduction at about 25 ° C. while stirring. Catalytic reduction is carried out by injecting hydrogen gas at a pressure of 3 to 5 kgf / cm ^2.
Time went on. After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of an 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C for 30 minutes. After 225 g of methanol was distilled off under normal pressure, 120 g of 10% hydrochloric acid was obtained.
Was added dropwise at 20-30 ° C. After stirring at 0 to 5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain 28 g of o-chlorophenylpropionic acid (93% yield, HPLC purity 9%).
9.8%, dechloro form 0.2%, conversion 99.8%).

Example 2 A 1 liter Teflon beaker was charged with methanol 240
g, o-chlorocinnamic acid 30 g, 5% ruthenium carbon (5
(0% water content) 1.5 g and powdered activated carbon 2.4 g were charged and subjected to catalytic reduction at about 25 to 29 ° C. while stirring. The catalytic reduction is performed by reducing hydrogen gas to 17 to 18 kgf / cm ^2.
For 8 hours. After the completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of an 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C for 30 minutes. After 225 g of methanol was distilled off under normal pressure, 1
120 g of 0% hydrochloric acid was added dropwise at 20 to 30 ° C. 0-5 ° C
After stirring for 1 hour at room temperature, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution, and dried to obtain o-
27 g of chlorophenylpropionic acid were obtained (yield 90
%, HPLC purity 99.8%, dechloro form 0.1%, conversion rate 98.7%).

Example 3 A 1-liter Teflon beaker was charged with 216 g of 2-propanol, 24 g of water, 30 g of o-chlorocinnamic acid, 1.5 g of 5% ruthenium carbon (containing 50% water) and 2.4 g of powdered activated carbon. The catalytic reduction was carried out at about 25 to 29 ° C. while stirring. Catalytic reduction reduces hydrogen gas to 16-18k
This was performed for 15 hours while press-fitting at gf / cm ² . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of an 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C for 30 minutes. 200 g of 2-propanol
Was distilled off at normal pressure, and 120 g of 10% hydrochloric acid was added at 20 to 30 ° C.
Was dropped. After stirring at 0-5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain o-chlorophenylpropionic acid 28.
g was obtained (93% yield, 99.8% HPLC purity, 0.2% dechloro product, 99.8% conversion).

Example 4 In a 200 ml Teflon beaker, methanol 60 was added.
g, 10 g of methyl o-chlorocinnamate, 0.5 g of 5% ruthenium carbon (containing 50% water) and 0.2 g of powdered activated carbon were charged and subjected to catalytic reduction at about 20 ° C. with stirring.
The catalytic reduction was performed for 8 hours while pressurizing hydrogen gas at 3 to 5 kgf / cm ² . After completion of the catalytic reduction, the catalyst was filtered, washed, and the filtrate and the washing solution were combined. Then, 20 g of a 14% aqueous sodium hydroxide solution was added thereto, and the mixture was hydrolyzed at 80 ° C.
The methanol was distilled off under reduced pressure. After extraction by adding 29 g of 10% hydrochloric acid and 54 g of toluene, the solvent was distilled off under reduced pressure to obtain 8.5 g of o-chlorophenylpropionic acid (yield 85%, HPLC purity 99.8%, dechloro form). 0.2%, 98.0% conversion).

Comparative Example 1 In a 1-liter Teflon beaker, methanol 240 was added.
g, 30 g of o-chlorocinnamic acid, 1.5 g of 5% M-type palladium carbon (containing 50% water) and 1.2 g of powdered activated carbon, and the mixture was subjected to catalytic reduction at about 27 to 32 ° C. with stirring. The catalytic reduction was performed for 15 minutes while pressurizing hydrogen gas at 3 to 4 kgf / cm ² . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of an 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C for 30 minutes. After 225 g of methanol was distilled off under normal pressure, 10
120 g of 20% hydrochloric acid was added dropwise at 20 to 30 ° C. After stirring at 0-5 ° C. for 1 hour, the crystals were filtered, washed with 10 g of a 10% aqueous methanol solution and dried to obtain 28 g of o-chlorophenylpropionic acid (yield 93%,
HPLC purity 92.0%, dechloro form 8.0%, conversion 100%).

Comparative Example 2 2-propanol 9 was placed in a 300 ml four-necked flask.
0 g, 10 g of water, 10 g of o-chlorocinnamic acid, 0.5 g of 5% platinum carbon (containing 50% water) and 0.5 g of powdered activated carbon were charged and subjected to catalytic reduction at about 40 ° C. while stirring.
The catalytic reduction was performed for 6 hours while injecting hydrogen gas at normal pressure. After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined.
g was added and stirred at 55 ° C. for 30 minutes. After 85 g of 2-propanol was distilled off under normal pressure, 40 g of 10% hydrochloric acid was added to the mixture for 20 to 20 hours.
It was added dropwise at 30 ° C. After stirring at 0-5 ° C. for 1 hour, the crystals were filtered and washed with 10 g of a 10% aqueous methanol solution.
By drying, 27 g of o-chlorophenylpropionic acid was obtained (yield 90%, HPLC purity 87.9).
%, Dechloro product 12.1%, conversion 99.5%).

Comparative Example 3 In a 1-liter Teflon beaker, methanol 240 was added.
g, 30 g of o-chlorocinnamic acid, 6 g of 5% M-type palladium carbon (containing 50% water), and 1.2 g of powdered activated carbon, were subjected to catalytic reduction at about 30 ° C. while stirring. The catalytic reduction was performed for 8 hours while pressurizing hydrogen gas at 3 to 5 kgf / cm ² . After completion of the catalytic reduction, the catalyst was filtered and washed, and the filtrate and the washing solution were combined. Then, 120 g of an 8% aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C for 30 minutes.
After 225 g of methanol was distilled off under normal pressure, 10% hydrochloric acid 12
0 g was added dropwise at 20-30 ° C. After stirring at 0-5 ° C. for 1 hour, the crystals were filtered and 10% aqueous methanol solution 10 g.
And 22 g of phenylpropionic acid, which is a dechloro form of o-chlorophenylpropionic acid, was obtained (yield 91%, HPLC purity 99%).

From the above results, in comparison with Comparative Examples 1 to 3 in which palladium carbon and platinum carbon were used as the catalyst, in Examples 1 to 4, ruthenium carbon was used, and thus the catalyst was a by-product. It can be seen that the production rate of the dehalogenated product is very low, and the halogenated phenylpropionic acid compound can be obtained efficiently, conveniently and industrially advantageously.

[0038]

According to the production method of the present invention, by using ruthenium as a catalyst for the catalytic reduction of a halogenated cinnamic acid compound, halogenated phenylpropionine can be efficiently, conveniently and industrially advantageously obtained. Acids can be produced.

Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 61/00 300 C07B 61/00 300

Claims (3)

[Claims] 1. A compound of the general formula (I): (Where X is a halogen atom, R is a hydrogen atom, a methyl group,
Wherein the halogenated cinnamic acid compound represented by ethyl group or isopropyl group is catalytically reduced in the presence of ruthenium as a catalyst. (Wherein, X and R are the same as described above). 2. The production of a halogenated phenylpropionic acid compound according to claim 1, wherein the halogenated cinnamic acid compound represented by the general formula (I) is catalytically reduced in a lower alcohol or a mixed solvent of a lower alcohol and water. Method. 3. The process for producing a halogenated phenylpropionic acid compound according to claim 1, wherein the halogenated cinnamic acid compound represented by the general formula (I) is catalytically reduced at a reaction temperature of 20 to 30 ° C.