JPH1059895A - Production of mandelic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To safely obtain the subject compound in a high yield and in a high purity in one process by dropping an acid to an aldehyde derivative in the presence of a cyano compound and subsequently hydrolyzing the reaction product with a mineral acid. SOLUTION: This method for producing a mandelic acid derivative comprises dropping an acid (A) to an aldehyde derivative of the formula (R<1> -R<3> are each H, a halogen, a 1-5C alkyl, a 1-5C alkoxy, hydroxyl group, phenyl which may be substituted) in the presence of (B) a cyano compound in a solvent and subsequently hydrolyzing the obtained corresponding mandelonitrile derivative with a mineral acid. The solvent is especially preferably ethyl acetate, and is used in an amount of 0.5-5 weight times that of the component A. The component B includes sodium cyanate and potassium cyanate, and is used in an amount of 1-4 moles, preferably 1.1-1.3 moles, per mole of the component A. Thereby, the mandelic acid derivative useful as a synthetic intermediate for medicines can safely be obtained in a high yield and in a high purity in only one process.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a mandelic acid derivative. Mandelic acid derivatives are useful as synthetic intermediates for pharmaceuticals.

[0002]

2. Description of the Related Art Various production methods have been proposed for mandelic acid derivatives. As a typical example, Org. S
ynth., Coll. Vol., I, 336 (1941) (method 1), Org.
Synth., Coll. Vol., III, 538 (1955) (method 2),
The method described in A. Merz, Synthesis, 724 (1974) (method 3) is known. However, the method 1 has many steps and is complicated, and the method 2 uses inexpensive raw materials. However, the method is complicated and the purity of the product is low, and the method 3 is short but has low yield and low odor. , Etc. Other methods are also known, but have similar problems, and none of them are industrially advantageous.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a simple and industrially advantageous method for producing a mandelic acid derivative.

[0004]

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, the present inventors added hydrocyanic acid to an aldehyde derivative by dropping an acid in the presence of a cyanide compound. To produce a mandelonitrile derivative, which can be hydrolyzed with a mineral acid without isolation to produce a mandelic acid derivative in high yield, high purity, and safely in only one step compared to the aldehyde derivative. Was found. In particular, even when substituted with a phenyl group, which was considered to have low yield and purity in the conventional method, such as 4-phenylmandelic acid, the yield was extremely high and the purity was high. The present invention has been completed based on such findings.

That is, the gist of the present invention is as follows: (1) The general formula (I)

[0006]

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(Wherein R ¹ , R ² and R ³ may be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, A hydroxyl group or a phenyl group which may have a substituent) is added to the aldehyde derivative represented by the formula (II) in the presence of a cyanide compound in a solvent.

[0008]

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(Wherein R ¹ , R ² and R ³ have the same meanings as R ¹ , R ² and R ³ in the general formula (I)). Having the general formula (III) characterized in that it is hydrolyzed by a mineral acid without isolation.

[0010]

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(Wherein R ¹ , R ² and R ³ have the same meanings as R ¹ , R ² and R ³ in formula (I)), (2) The method according to (1), wherein the solvent is an organic solvent such as ethyl acetate, toluene, tetrahydrofuran, acetic acid, methanol, ethanol, propanol, water or a mixed solvent thereof, (3). (4) The method according to the above (1) or (2), wherein the solvent is distilled off by heating during the hydrolysis.
The method according to any one of (1) to (3), wherein acetic acid is added together with the mineral acid added during the hydrolysis, and (5) the mandelic acid derivative represented by the general formula (III) is -Phenyl mandelic acid, the production method according to any one of the above (1) to (4).

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. In the present invention, a hydrocyanic acid is added to an aldehyde derivative represented by the general formula (II) by adding an acid dropwise to the aldehyde derivative represented by the general formula (I) in a solvent in the presence of a cyanide compound. This produces a delonitrile derivative.

Examples of the process include a method of dropping an aqueous solution of a cyanide compound and an acid onto an aldehyde derivative in a solvent, and a method of dropping an acid on an aldehyde derivative and a cyanide compound in a solvent. In
A method in which an acid is added dropwise to an aldehyde derivative and a cyanide compound in a solvent is preferable.

The aldehyde derivative used as a raw material of the present invention is
It is represented by the general formula (I). Wherein R ¹ , R ² and R ³
May be the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a hydroxyl group, or a phenyl group which may have a substituent. . Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t
Examples thereof include an tert-butyl group and a pentyl group. Examples of the alkoxy group having 1 to 5 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and a pentyloxy group. Examples of the substituent which may be substituted on the phenyl group include a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, and a hydroxyl group.

Specifically, benzaldehyde, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde,
4-bromobenzaldehyde, 4-methylbenzaldehyde, 4-ethylbenzaldehyde, 4-propylbenzaldehyde, 4-butylbenzaldehyde, 4-pentylbenzaldehyde, 4-methoxybenzaldehyde, 4-ethoxybenzaldehyde, 4-propoxybenzaldehyde, 4-butoxybenzaldehyde, 4-
Examples include pentyloxybenzaldehyde, 4-hydroxybenzaldehyde, and 4-phenylbenzaldehyde. These can use a commercial item as it is.

The solvent used in the present invention includes:
An organic solvent such as ethyl acetate, toluene, tetrahydrofuran, acetic acid, methanol, ethanol, and propanol, water or a mixed solvent thereof is used, and ethyl acetate is particularly preferable. The amount of the aldehyde derivative is preferably 0.5 to 5 times the weight of the aldehyde derivative.

The cyan compound used in the present invention includes sodium cyanide, potassium cyanide and the like. The amount of the aldehyde derivative to be used is 1 to 4 mol, preferably 1.1 to 1.3 mol, per 1 mol of the aldehyde derivative.

As the acid used in the present invention, mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as methanesulfonic acid and the like are used, and mineral acids are preferable, and hydrochloric acid is particularly preferable. The amount is preferably 1 to 3 mol per 1 mol of the aldehyde derivative.

The reaction temperature is usually from 0 to 30 ° C., and the reaction time may be short, since almost no unreacted aldehyde derivative remains after dropping the acid. It is preferred to add the acid dropwise.

The mandelonitrile derivative thus obtained is represented by the general formula (II). Wherein R ¹ , R ²
And R ³ have the same meanings as R ¹ , R ² and R ³ in formula (I). Specifically, mandelonitrile, 4-fluoromandelonitrile, 4-chloromandelonitrile, 4-bromomandelonitrile,
-Methyl mandelonitrile, 4-ethyl mandelonitrile, 4-propyl mandelonitrile, 4-butyl mandelonitrile, 4-pentyl mandelonitrile, 4-methoxy mandelonitrile, 4-ethoxy mandelonitrile, 4- Examples thereof include propoxymandelonitrile, 4-butoxymandelonitrile, 4-pentyloxymandelonitrile, 4-hydroxymandelonitrile, and 4-phenylmandelonitrile.

The produced mandelonitrile derivative represented by the general formula (II) has poor stability and unreacted hydrocyanic acid remains. Therefore, in the present invention, mineral acid alone or isolated without isolation. Hydrolysis in the presence of a mineral acid and further acetic acid gives a mandelic acid derivative represented by the general formula (III).

Thus, in the present invention, the cyanide compound is used. However, since the cyanide compound is used in a closed vessel and the resulting mandelonitrile is hydrolyzed by adding a mineral acid or the like as it is without isolation, it is safe. A mandelic acid derivative represented by the general formula (III) can be obtained.

The hydrolysis is usually carried out by adding a mineral acid at a temperature of 0 to 30 ° C. and then heating to 50 to 110 ° C. The reaction time varies depending on the reaction temperature, but is usually 2 to
It takes about 10 hours. In the present invention, the solvent may be distilled off during heating.

Examples of the mineral acid for hydrolysis include hydrochloric acid and sulfuric acid, and hydrochloric acid is particularly preferred. Further, the amount of the aldehyde derivative used is preferably 1 to 15 mol, particularly 2 to 8 mol, per 1 mol of the aldehyde derivative. In the present invention, hydrolysis can be promoted by further adding acetic acid soluble in both water and an organic solvent such as ethyl acetate. The amount used is preferably 1 to 3 times the weight of the aldehyde derivative.

The resulting mandelic acid derivative is filtered, washed,
It is extracted by a usual operation such as extraction with an organic solvent and crystallization.

The mandelic acid derivative thus obtained is represented by the general formula (III). Wherein each represent the same meaning as R ^1, R ² and R ³ R ^1, R ² and R ³ in the general formula (I). Specifically, mandelic acid,
4-fluoromandelic acid, 4-chloromandelic acid, 4-
Bromomandelic acid, 4-methyl mandelic acid, 4-ethyl mandelic acid, 4-propyl mandelic acid, 4-butyl mandelic acid, 4-pentyl mandelic acid, 4-methoxy mandelic acid, 4-ethoxy mandelic acid, 4-propoxy mandelic Examples thereof include acid, 4-butoxymandelic acid, 4-pentyloxymandelic acid, 4-hydroxymandelic acid, and 4-phenylmandelic acid. The mandelic acid derivative obtained by the production method of the present invention is useful as a synthetic intermediate of a pharmaceutical.

[0027]

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 In a 100 ml flask, 20 ml (18 g) of ethyl acetate and 10 g (55 mmol) of 4-phenylbenzaldehyde were added.
And 4 g (61.4 mmol) of potassium cyanide were charged, and 6.3 g (60.5 mmol) of concentrated hydrochloric acid was added dropwise at 15 to 20 ° C. over 70 minutes. After stirring at the same temperature for 1 hour, 60 g (0.58 mol) of concentrated hydrochloric acid was added dropwise to 85 to 9
Ethyl acetate was distilled off by heating to 0 ° C. Heat for 2 hours,
Cool to room temperature, filter, wash with water and dry to obtain 1
2 g of 4-phenylmandelic acid were obtained. (Yield 96.1
%, HPLC purity = 96%) Elemental analysis actual value Carbon 73.4% Hydrogen 5.5% Calculated value (C ₁₄ H ₁₂ O ₃ ) Carbon 73.4% Hydrogen 5.3%

Example 2 In a 100 ml flask, 20 ml (18 g) of ethyl acetate and 10 g (55 mmol) of 4-phenylbenzaldehyde were added.
And 4 g (61.4 mmol) of potassium cyanide were added, and 6.3 g (60.5 mmol) of concentrated hydrochloric acid was added dropwise at 10 to 15 ° C. over 45 minutes. Then, 45 ml (0.25 mol) of a 20% by weight aqueous hydrochloric acid solution was injected, and the mixture was heated at 85 to 90 ° C.
And ethyl acetate was distilled off. The mixture was heated at 85 ° C. for 2 hours, cooled to room temperature, filtered, washed with water, and dried to obtain 12.2 g of 4-phenylmandelic acid. (Yield 96.5%, HPLC purity = 95.1%)

Example 3 10 ml (8.7 g) of toluene and 10 g (55 mmol) of 4-phenylbenzaldehyde were placed in a 100 ml flask.
And potassium cyanide at 15 to 20 ° C.
A solution of 4 g (83 mmol) dissolved in 10 ml of water and then 11.4 ml (0.13 mol) of concentrated hydrochloric acid were added dropwise over 90 minutes. 60 ml (0.69 mol) of concentrated hydrochloric acid was injected, and the mixture was heated to 75 to 80 ° C. and stirred for 5 hours. The mixture was cooled to room temperature, filtered, washed with water and dried to obtain 12.4 g of 4-phenylmandelic acid. (Yield 99.3%, HPLC purity = 93.5%)

Example 4 400 ml (360 g) of ethyl acetate and 4
-200 g (1.098 mol) of phenylbenzaldehyde and 86 g (1.32 mol) of potassium cyanide were charged, and 137 g (1.32 mol) of concentrated hydrochloric acid was added dropwise at 20 to 25 ° C over 3 hours. After stirring for 2 hours, 1132 ml (6.2 mol) of a 20% by weight aqueous hydrochloric acid solution was injected, and 90 to 9
Ethyl acetate was distilled off by heating to 5 ° C. 95-100 ° C
For 5 hours, cooled to room temperature, filtered, washed with water and dried to obtain 250 g of 4-phenylmandelic acid. (Yield 99.9%, HPLC purity = 99.2%)

Example 5 1200 ml (1080 g) of ethyl acetate, 600 g (3.29 mol) of 4-phenylbenzaldehyde and 258 g (3.96 mol) of potassium cyanide were charged, and 16 to 2
At 6 ° C., 413 g (3.96 mol) of concentrated hydrochloric acid was added dropwise over 3 hours. After stirring for 2 hours, 1200 ml of acetic acid (1080
g) and 810 ml (9.3 mol) of concentrated hydrochloric acid.
The mixture was heated to １００100 ° C. to distill off ethyl acetate. Water 150
Add 0 ml, heat at 98-106 ° C for 5 hours, cool to room temperature, filter, wash with water and dry, 725 g
Of 4-phenylmandelic acid was obtained. (96.5% yield,
HPLC purity = 99%)

Example 6 In a slurry of 20 ml (20 g) of water and 10 g (55 mmol) of 4-phenylbenzaldehyde, 7.2 g (0.198 mol) of potassium cyanide dissolved in 20 ml of water and 11.4 g of concentrated hydrochloric acid ( 0.11 mol) at 8-15 ° C
For 2 hours. Then, 60 ml of concentrated hydrochloric acid (0.
69 mol) and heated to 68-70 ° C for 10 hours. The mixture was cooled to room temperature, filtered, washed with water and dried to obtain 6.12 g of 4-phenylmandelic acid. (Yield 96.7%, HPLC purity = 96%)

Example 7 600 g (3.29 mol) of 4-phenylbenzaldehyde was added to 1200 ml (1080 g) of ethyl acetate and dissolved, and 258 g (3.95 mol) of potassium cyanide was added.
Was dissolved in 720 ml of water, and the mixture was cooled to about 15 ° C. Next, 413 g (3.95 mol) of concentrated hydrochloric acid was added dropwise at 10 to 30 ° C over 3 hours, and the mixture was stirred for 1 hour. Acetic acid 12
58 g and 948 g (9.08 mol) of concentrated hydrochloric acid were injected, and 8
After heating to 5-90 ° C and refluxing for 5 hours, 90-100
Ethyl acetate was distilled off at ℃, and 780 g of water was added.
The temperature was raised to 05 ° C. After stirring for 2 hours, the mixture was cooled to room temperature, filtered, washed with water and dried to obtain 724 g of 4-phenylmandelic acid. (Yield 96.3%, HPLC purity = 99.3%)

Example 8 100 g (0.549 mol) of 4-phenylbenzaldehyde was dissolved in 200 ml (180 g) of ethyl acetate, and 43 g (0.66 mol) of potassium cyanide was added to 120 ml of water.
Was mixed with the solution dissolved in Subsequently, 72.6 g (0.7 mol) of concentrated hydrochloric acid was added dropwise at 15 to 25 ° C over 2 hours, and 1
Stirred for hours. 215 g of acetic acid and 360 g of concentrated hydrochloric acid (3.5 g)
Mol), and the mixture was heated to 80 to 85 ° C and refluxed for 4 hours. Then, ethyl acetate was distilled off at 85 to 95 ° C and cooled to 25 ° C. The crystallized crystals were filtered, washed with water and dried to obtain 120.7 g of 4-phenylmandelic acid.
(Yield 96.4%, HPLC purity = 98.6%)

[0036]

According to the production method of the present invention, a mandelic acid derivative can be obtained with high yield, high purity and safely.

Claims (5)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ , R ² and R ³ may be the same or different, and each is a hydrogen atom, a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a hydroxyl group, or An acid is added dropwise to an aldehyde derivative represented by the formula (II) in a solvent in the presence of a cyanide compound to represent a phenyl group which may have a substituent. Wherein R ¹ , R ² and R ³ have the same meanings as R ¹ , R ² and R ³ in formula (I), respectively, and isolated. General formula (III) characterized in that hydrolysis is carried out with a mineral acid without performing (Wherein R ¹ , R ² and R ³ have the same meanings as R ¹ , R ² and R ³ in formula (I), respectively). 2. The method according to claim 1, wherein the solvent is an organic solvent such as ethyl acetate, toluene, tetrahydrofuran, acetic acid, methanol, ethanol, propanol, water or a mixed solvent thereof. 3. The method according to claim 1, wherein the solvent is distilled off by heating during the hydrolysis. 4. A mineral acid to be added during hydrolysis,
4. The method according to claim 1, wherein acetic acid is added. 5. The method according to claim 1, wherein the mandelic acid derivative represented by the general formula (III) is 4-phenylmandelic acid.