JP4995429B2 - Method for purifying mandelic acids - Google Patents

Description

  The present invention relates to a purification method for obtaining mandelic acids useful as pharmaceutical intermediates, liquid crystal materials and optical resolution agents with high purity.

In general, mandelic acids are converted into crude mandelic acids by hydrolysis of mandelonitriles, etc., and the crude mandelic acids are extracted with an organic solvent and then concentrated to dryness, crystallized from an organic solvent / water mixed solvent system or mixed organic solvent system. It refine | purifies by doing (patent documents 1-3). In addition, as a method of reducing the dimer of mandelic acids, which is an impurity that lowers the chemical purity of mandelic acids, a purification method by crystallization in the presence of an organic solvent that is immiscible with water and hardly soluble in mandelic acids is also known. (Patent Document 2).
However, the purification method of mandelic acids using organic solvents can produce high-purity mandelic acids that can be applied to fields such as raw materials for medical and agrochemicals, liquid crystal materials, and optical resolving agents. Therefore, it is not necessarily an industrially suitable method. Therefore, a purification method on an industrial scale using an aqueous solvent has been desired. As a purification method using an aqueous solvent, a method of recrystallizing mandelic acids from an aqueous solvent is known (Patent Document 4). However, there was no specific description of the purification conditions, and this was not a sufficient method for reducing the dimers of mandelic acids.
JP 2001-342165 A JP 2003-226666 A JP 2002-142792 A Japanese Patent Laid-Open No. 9-322797

  An object of the present invention is to provide an industrially suitable purification method for obtaining highly pure crystals of mandelic acids without using an organic solvent and containing a small amount of mandelic acid dimers.

  The present invention is directed to the purification of mandelic acids which are brought into contact with a dimer of mandelic acids and crystals containing mandelic acids and an aqueous solvent not containing an organic solvent, and are solid-liquid separated under acidic conditions at a temperature of 0 to 60 ° C. and a pH of 7.0 or less. Method.

  According to the present invention, the content of mandelic acid dimers is reduced without using an organic solvent, and high-purity mandelic acid crystals are obtained.

  In producing the mandelic acids to be used in the purification of the present invention, the precursor mandelonitriles can be produced, for example, by adding a cyanide compound to aldehydes. Examples of aldehydes include compounds represented by the following formula (I).

Examples of the Ar group of the formula (I) include phenyl, benzyl, naphthyl, pyridyl, furyl and the like. In the case of a substituted Ar group, examples of the substituent include hydroxy (optionally protected), C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, alkylthio, halogen, substituted phenyl, phenoxy, Amino or nitro is mentioned. Preferably, the Ar group is an aryl group, particularly preferably a phenyl group. They Ar group unsubstituted or _C 1 -C _{4 alkyl,} C 1 -C ₄ alkoxy, (protected may be) hydroxy, acetoxy, Cl, Br, phenyl, optionally substituted by phenoxy or fluorophenoxy Good.

Specifically, benzaldehyde, m-phenoxybenzaldehyde, p-acetoxybenzaldehyde, p-methylbenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, m-nitrobenzaldehyde, 3,4-methylenedioxybenzaldehyde Aromatic aldehydes such as 2,3-methylenedioxybenzaldehyde, furfural and pyridine-2-carbaldehyde. Preferably, benzaldehyde, m-phenoxybenzaldehyde, p-methylbenzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, p-chlorobenzaldehyde, m-nitrobenzaldehyde, 3,4-methylenedioxybenzaldehyde, 2,3-methylenedi Particularly preferred are oxybenzaldehydes, and particularly preferred are benzaldehyde, o-chlorobenzaldehyde, m-chlorobenzaldehyde, and p-chlorobenzaldehyde.
As the cyan compound to be added to these aldehyde groups, it is preferable to use hydrocyanic acid or a cyanide compound capable of generating hydrocyanic acid. Examples of the cyanide include cyanic acid, KCN, NaCN, and acetone cyanohydrin ((CH ₃ ) ₂ C (OH) CN).

Mandelonitriles are synthesized by a stereoselective addition reaction in the presence of a chemical catalyst or a biological catalyst. Examples of the chemical catalyst include cyclic dipeptides. Examples of biological catalysts include crude enzymes, purified enzymes, and immobilized enzymes containing (S) -hydroxynitrile lyase, (R) -hydroxynitrile lyase and the like derived from living organisms. These enzymes may be produced by a genetically modified microorganism incorporating a gene encoding the enzyme.
Examples of (S) -hydroxynitrile lyase include those derived from cassava (Manihot esculenta) (EC 4.1.2.37) and those derived from Hevea brasiliensis (EC 4.1) belonging to the family Euphorbiaceae. And 2.39), or those derived from Sorghum bicolor (EC 4.1.2.11).

  When aldehyde represented by the above formula (I) is used as a raw material and hydrocyanic acid is added, mandelonitriles represented by the following formula (II) are obtained.

  Examples of the mandelonitrile represented by the above formula (II) include mandelonitrile (2-hydroxy-2-phenylacetonitrile), 3-phenoxymandelonitrile (2-hydroxy-2- (3-phenoxyphenyl) acetonitrile. ), 4-acetoxymandelonitrile (2-hydroxy-2- (3-acetoxyphenyl) acetonitrile), 4-methylmandelonitrile (2-hydroxy-2- (p-tolyl) acetonitrile), 2-chloromandero Nitrile (2- (2-chlorophenyl) -2-hydroxyacetonitrile), 3-chloromandelonitrile (2- (3-chlorophenyl) -2-hydroxyacetonitrile), 4-chloromandelonitrile (2- (4-chlorophenyl) ) -2-Hydroxyacetonitrile), 3-Nito Mandelonitrile (2-hydroxy-2- (3-nitrophenyl) acetonitrile), 3,4-methylenedioxymandelonitrile (2-hydroxy-2- (3,4-methylenedioxyphenyl) acetonitrile), 2 , 3-methylenedioxymandelonitrile (2-hydroxy-2- (2,3-methylenedioxyphenyl) acetonitrile), 2- (2-furyl) -2-hydroxyacetonitrile, 2- (2-pyridyl)- And 2-aryl-2-hydroxyacetonitrile such as 2-hydroxyacetonitrile. Preferably, mandelonitrile (2-hydroxy-2-phenylacetonitrile), 3-phenoxymandelonitrile (2-hydroxy-2- (3-phenoxyphenyl) acetonitrile), 4-methylmandelonitrile (2-hydroxy- 2- (p-tolyl) acetonitrile), 2-chloromandelonitrile (2- (2-chlorophenyl) -2-hydroxyacetonitrile), 3-chloromandelonitrile (2- (3-chlorophenyl) -2-hydroxyacetonitrile) ), 4-chloromandelonitrile (2- (4-chlorophenyl) -2-hydroxyacetonitrile), 3-nitromandelonitrile (2-hydroxy-2- (3-nitrophenyl) acetonitrile), 3,4-methylene Dioxymandelonitrile (2-hydroxy-2- 3,4-methylenedioxyphenyl) acetonitrile), 2,3-methylenedioxymandelonitrile (2-hydroxy-2- (2,3-methylenedioxyphenyl) acetonitrile), particularly preferably mandero Nitrile (2-hydroxy-2-phenylacetonitrile), 2-chloromandelonitrile (2- (2-chlorophenyl) -2-hydroxyacetonitrile), 3-chloromandelonitrile (2- (3-chlorophenyl) -2- Hydroxyacetonitrile) and 4-chloromandelonitrile (2- (4-chlorophenyl) -2-hydroxyacetonitrile).

  Mandelic acids are produced by hydrolyzing the mandelonitriles obtained by the above method. Mandelic acids produced by hydrolysis are compounds represented by the following formula (III).

The mandelic acids produced by hydrolysis include dimers in which at least one pair of each hydroxyl group and carboxyl group consisting of two molecules of mandelic acids forms an ester bond between the molecules.
In order to reduce the dimer of mandelic acids contained in the mandelic acids produced by such hydrolysis, the present invention reduces the mandelic acid crystals containing the dimer produced by hydrolysis to an aqueous system containing no organic solvent. Contact with solvent. Here, the aqueous solvent means water or water containing a mineral acid and / or a mineral acid salt.
Contacting means mixing with an aqueous solvent. The mixed solution after mixing may be a solution in which mandelic acids are completely dissolved in water or a suspension mixed solution in which the mandelic acids are not completely dissolved.
In the case of a completely dissolved solution (hereinafter referred to as a uniform solution), it is preferable that the time existing as the solution (hereinafter referred to as a uniform retention time) is short in terms of a high dimer reduction effect. Therefore, the uniform holding time is preferably within 24 hours, and more preferably within 15 hours. Further, the temperature of the uniform aqueous solution may be not more than the boiling point of the solution and not less than the temperature at which the mandelic acid crystals do not precipitate, and is preferably 50 to 80 ° C. in terms of high dimer reduction effect, It is more preferable to set it as 50-65 degreeC. The pH of the homogeneous aqueous solution is preferably pH 1.5 to 14 in terms of high dimer reduction effect, and particularly preferably pH 1.8 to 14. When the pH needs to be adjusted, it is usually adjusted with an acid or a base. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, perchloric acid, citric acid, acetic acid, toluenesulfonic acid, and the like. Examples of the base include sodium hydroxide, potassium hydroxide, triethylamine, ammonia, sodium hydrogen carbonate, sodium carbonate and the like.
When it exists as a suspension mixed solution, it is only necessary to maintain a state in which crystals are precipitated, but it is preferable to comply with the following solid-liquid separation conditions.

Next, crystals of mandelic acids are collected from the homogeneous solution or suspension mixture. In the case of a suspension solution, the solution is subjected to solid-liquid separation as it is or after cooling if necessary.
Examples of the solid-liquid separation method include pressure filtration, natural filtration, heat filtration, centrifugation, and the like.
The solid-liquid separation may be performed in an inert gas atmosphere or in the air, but it is preferably performed in an inert gas atmosphere from the viewpoint of preventing coloring, and a nitrogen atmosphere is particularly preferable. The conditions may be any of normal pressure, increased pressure, or reduced pressure.
The temperature of solid-liquid separation shall be 0-60 degreeC. By making it within this range, the yield of mandelic acid crystals increases. The solid-liquid separation temperature is preferably 15 to 40 ° C, and particularly preferably 20 to 30 ° C.
Next, when using a uniform solution, after cooling to below the temperature at which it becomes a saturated solution of mandelic acids, the precipitated crystals are subjected to the solid-liquid separation described above. When cooling and crystallizing a homogeneous solution, it is preferable to set the cooling rate to 30 ° C./hour or less from the viewpoint of preventing excessive precipitation of mandelic acid dimers. The cooling rate is more preferably 20 ° C./hour or less, and particularly preferably 10 ° C./hour or less. The lower limit of the cooling rate is not particularly limited, but it is usually preferably 0.1 ° C./hour or more from the viewpoint of efficient cooling crystallization. The cooling rate is particularly preferably 0.5 ° C./hour or more.

In addition, before the solid-liquid separation, the suspension mixed solution or the suspended mixed solution in a suspended state by precipitating a part of the crystals from the homogeneous solution can be aged. The aging here means stirring or leaving the suspension mixture at a constant temperature for about 5 minutes to 200 hours, preferably for 5 minutes to 50 hours.
The aging temperature is preferably not higher than the saturation temperature of mandelic acids and not lower than the freezing point of the aqueous phase. In particular, near the saturation temperature of mandelic acids (within the upper limit of the saturation temperature, within a range of 10 ° C. from the saturation temperature, preferably within 5 ° C.) and / or near the temperature at which solid-liquid separation is performed (temperature ± 10 ° C. at which solid-liquid separation is performed) Within the range, preferably within ± 5 ° C.).
The homogeneous solution or suspension mixture may contain mineral acids and / or mineral acid salts. The concentration of the mineral acid and / or mineral acid salt is not particularly limited, but is preferably 20% by weight or less in the mixture containing the aqueous solvent and mandelic acids. By making it in this range, the dimer of mandelic acids can be reduced efficiently. The concentration of the mineral acid and / or mineral acid salt is preferably 5% by weight or less, particularly preferably 2% by weight or less.
Examples of the mineral acid contained in the homogeneous solution or suspension mixture include hydrochloric acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, perchloric acid, citric acid, acetic acid, and toluenesulfonic acid, and hydrochloric acid is preferred. Examples of the mineral acid salt include sodium salt, potassium salt, tritylethylamine salt and ammonia salt, and sodium chloride, ammonium chloride, sodium sulfate and ammonium sulfate are preferable.

Solid-liquid separation of mandelic acids from the suspension mixture is performed under acidic conditions at pH 7.0 or lower. By making it within this range, the yield of mandelic acids increases. The pH is preferably 1.0 to 2.0.
When adjusting pH as needed, an acid or a base is usually used. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, perchloric acid, citric acid, acetic acid, toluenesulfonic acid and the like. Moreover, as a base normally used here, sodium hydroxide, potassium hydroxide, a triethylamine, ammonia, sodium hydrogencarbonate, sodium carbonate etc. are mentioned, for example.

  The concentration of mandelic acids in the suspension mixture is preferably a concentration at which mandelic acids can be obtained from the suspension mixture by solid-liquid separation, for example, 1 to 80% by weight. By setting it within this range, solid-liquid separation can be efficiently performed. The concentration is more preferably 5 to 60% by weight.

  The mandelic acid crystals after solid-liquid separation are washed with a solvent or the like as necessary. In this case, the mandelic acid crystals may be washed with a solvent 1 to 5 times.

  Solvents used for the washing are polar solvents such as water, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, alcohol solvents such as methanol, ethanol, i-propanol, n-butanol, t-butanol, or diethyl ether, diisopropyl ether. , Ether solvents such as t-butyl methyl ether and tetrahydrofuran can be used. These solvents may be used alone or in combination. It is preferable to use water alone because no organic solvent is used.

Hereinafter, the present invention will be specifically described by way of examples.
In addition, the chemical purity of mandelic acids, the content ratio of the dimer of mandelic acids, and optical purity were determined on the following analysis conditions using the high performance liquid chromatography (HPLC).
<Analysis of Mandelic Acid Chemical Purity and Mandelic Acid Dimer Content>
Sample preparation method: Dissolve about 20 mg of sample in 25 mL of carrier Device: Column oven JASCO Corporation 865-CO
UV 870-UV manufactured by JASCO
Pump 880-PU manufactured by JASCO Corporation
Integrator Shimadzu Corporation C-R3A
Column: ODS-2 GL Science company carrier: acetonitrile / water (adjusted to pH 3.0 with phosphoric acid) = 30/70 (volume ratio)
Column temperature: 40 ° C
Flow rate: 1mL / min
Wavelength: 220nm
Detection limit value: Dimer content in mandelic acid crystals: 0.015% (area percentage) (when the total absorption peak area of the HPLC analysis results of mandelic acids and their dimers is 100% by area)
Retention time: 4.9 min ((S) -mandelic acid)
22.0min (Mandelic acid dimer)
The content ratio of the mandelic acid dimer was calculated from the area percentage of the absorption peak obtained by HPLC analysis, with the total area of mandelic acid and its dimer being 100 area%.

<Optical purity analysis of mandelic acids>
Sample preparation method: Dissolve about 20 mg of sample in 25 mL of carrier Device: Column oven JASCO Corporation 865-CO
UV 870-UV manufactured by JASCO
Pump 880-PU manufactured by JASCO Corporation
Integrator C-R3A manufactured by Shimadzu Corporation
Column: CHIRALCEL OJ-H (manufactured by Daicel Chemical Industries)
Carrier: Hexane / 2-propanol / trifluoroacetic acid = 90/10 / 0.1 (volume ratio)
Column temperature: 35 ° C
Flow rate: 1.0 ml / min
Wavelength: 220nm
Retention time: 16.0 min (R body), 18.2 min (S body)
The optical purity was indicated by enantiomeric excess (% ee).
The optical purity of mandelic acid was calculated by the following equation (1) from the area values of the S-form and R-form of the absorption peak obtained by HPLC analysis.
S-body optical purity (% ee)
= (S body area value-R body area value) / (S body area value + R body area value) × 100 (1)

[Preparation Example 1]
Synthesis of (S) -mandelonitrile 9.0 g of (S) -hydroxynitrile lyase enzyme (EC 4.1.2.37) aqueous solution (1072 U / mL), 50 mM sodium hydrogen phosphate / 50 mM citric acid in a 1 L flask 64.5 g of a buffer solution (pH 6.0) and 260.0 g of tertiary butyl methyl ether (manufactured by Wako Pure Chemical Industries, Ltd.) were charged. While stirring at 16 to 18 ° C., 70.6 g (2.62 mol) of hydrogen cyanide and 180.2 g (1.70 mol) of benzaldehyde (manufactured by Wako Pure Chemical Industries, Ltd.) were continuously added dropwise over 2 hours. . After completion of dropping, the mixture was stirred at 18 ° C. for 4 hours. Thereafter, substantial disappearance of benzaldehyde was confirmed by HPLC analysis. The yield and optical purity of (S) -mandelonitrile at this time were 98% and 97% ee, respectively. Subsequently, tertiary butyl methyl ether and 50 mM sodium hydrogen phosphate / 50 mM citrate buffer were distilled off with an evaporator to obtain a 90 wt% (S) -mandelonitrile aqueous solution (optical purity 97.0% ee).
[Preparation Example 2]
Synthesis of (S) -mandelic acid Into a 2 L flask was charged 275 g of 35% hydrochloric acid (2.64 mol of HCl). While stirring, 247 g (1.67 mol) of an (S) -mandelonitrile aqueous solution having an optical purity of 97% ee obtained by the method of Preparation Example 1 was dropped into this hydrochloric acid over 5 hours. Subsequently, 600 g of water was added dropwise over 2 hours with stirring at 80 ° C. to perform hydrolysis. The hydrolysis reaction solution was concentrated under reduced pressure until the concentration of (S) -mandelic acid reached 30%, and then adjusted to pH 2.0 with a 30% aqueous sodium hydroxide solution. Thereafter, the mixture was cooled to 30 ° C., and the precipitated (S) -mandelic acid was washed with 45 g of water while being centrifuged. Thereafter, the crystals adhering to the centrifuge were collected. 238 g of (S) -mandelic acid (chemical purity 91.0%, yield 85%, optical purity 98.9% ee) was obtained. This (S) -mandelic acid had a mandelic acid dimer content of 1.4% (area percentage).

[Example 1]
In a 100 mL flask, 8.6 g of (S) -mandelic acid obtained in Preparation Example 2 and 18.3 g of water were charged and heated to 60 ° C. to dissolve (S) -mandelic acid. This aqueous solution of (S) -mandelic acid that became a uniform aqueous solution (pH 2.0) was cooled from 60 ° C. to 30 ° C. at a cooling rate of 10 ° C./hour over 3 hours to precipitate crystals. The precipitated crystals were washed with 2 g of water while centrifuging. After collecting the crystals adhering to the centrifuge, 7.0 g of (S) -mandelic acid (chemical purity 99.4%, recrystallization yield 89%, optical purity 99.000) was dried under reduced pressure. 8% ee) was obtained. The content ratio of mandelic acid dimer in (S) -mandelic acid was 0.3% (area percentage).

[Example 2]
In a 100 mL flask, 7.5 g of (R) -mandelic acid containing 0.8% of mandelic acid dimer and 22.5 g of water were charged and heated to 60 ° C. to dissolve (R) -mandelic acid. This aqueous solution of (R) -mandelic acid, which became a uniform aqueous solution (pH 1.8), was cooled from 60 ° C. to 25 ° C. over 3 hours and 30 minutes at a cooling rate of 5 ° C./hour to precipitate crystals. After centrifuging the precipitated crystals, the crystals adhering to the centrifuge are recovered, and the crystals are dried under reduced pressure to obtain 5.7 g of (R) -mandelic acid (chemical purity 99.3%, recrystallization yield). The ratio was 76% and the optical purity was 99.8% ee). The content ratio of mandelic acid dimer in (R) -mandelic acid was 0.03% (area percentage).

[Example 3]
(S) -mandelic acid 10.5 g containing mandelic acid dimer 1.1% in a 100 mL flask, sodium chloride 0.39 g, ammonium chloride 0.12 g, ammonium sulfate 0.21 g, and water 18.7 g were charged. The (S) -mandelic acid was dissolved by heating to ° C. This (S) -mandelic acid aqueous solution, which became a uniform aqueous solution (pH 1.8), was cooled from 60 ° C. to 15 ° C. at a cooling rate of 5 ° C./hour over 4 hours and 30 minutes to precipitate crystals. The precipitated crystals were washed with 2 g of water while centrifuging. After recovering the crystals adhering to the centrifuge, 10.3 g of (S) -mandelic acid (chemical purity 99.5%, recrystallization yield 97.8%, optical purity) was dried under reduced pressure. 99.8% ee) was obtained. The content ratio of mandelic acid dimer in (S) -mandelic acid was 0.76% (area percentage).

[Example 4]
In a 100 mL flask, 12 g of (S) -mandelic acid containing 1.1% of mandelic acid dimer and 18 g of water were charged, and (S) -mandelic acid was suspended in water and stirred at 30 ° C. for 3 hours. This (S) -mandelic acid suspension mixture, which became a suspension mixture (pH 1.9), was washed with 2 g of water while centrifuging. After collecting the crystals adhering to the centrifuge, the crystals are dried under reduced pressure to obtain 10.3 g of (S) -mandelic acid (chemical purity 99.5%, recovery rate 72.6%, optical purity 99.8). % Ee) was obtained. The mandelic acid dimer content in (S) -mandelic acid was 0.05% (area percentage).

[Example 5]
In a 100 mL flask, 11.54 g of (S) -mandelic acid obtained in Example 1 and 18.46 g of water were charged, and (S) -mandelic acid was suspended in water and stirred at 30 ° C. for 3 hours. This (S) -mandelic acid suspension mixture, which became a suspension mixture (pH 2.0), was washed with 2 g of water while centrifuging. After collecting the crystals adhering to the centrifuge, 9.87 g of (S) -mandelic acid (chemical purity 99.5%, recovery rate 93.5%, optical purity 99.8) was dried under reduced pressure. % Ee) was obtained. The content ratio of mandelic acid dimer in (S) -mandelic acid was 0.35% (area percentage).

Claims (2)

Mandelic acid, 2-chloromandelic acid, 3-chloromandelic acid or 4-chloromandelic acid dimer as mandelic acid dimer and mandelic acid as mandelic acid, 2-chloromandelic acid, 3-chloromandelic acid or After the crystal containing 4-chloromandelic acid is dissolved in water at 50 to 80 ° C. or water containing a mineral acid and / or a mineral salt, the aqueous solution is cooled to 15 to 40 ° C. at a cooling rate of 20 ° C./hour. A method for purifying mandelic acids which is cooled and solid-liquid separated under an acidity of pH 1.0 to 2.0 or less. The mandelic acid dimer and the crystals containing mandelic acid are dissolved in water at 50 to 80 ° C. or water containing a mineral acid and / or a mineral salt, and then the aqueous solution is cooled at a cooling rate of 20 ° C./hour. A method for purifying mandelic acid, which is cooled to ˜40 ° C. and solid-liquid separated under an acidic pH of 1.0 to 2.0.