JP4933743B2 - Method for producing mandelic acids - Google Patents

Description

  The present invention relates to a method for producing mandelic acids useful as raw materials for medicines and agricultural chemicals, liquid crystal materials and optical resolution agents.

  As a method for producing mandelic acids, a production method is known in which mandelonitriles are obtained by addition reaction of an aldehyde compound and cyanide, and then the obtained mandelonitriles are acid-hydrolyzed (Patent Document 1). . In the above addition reaction, a method using a chemical catalyst (Non-Patent Document 1) or a method using a biological catalyst (Non-Patent Document 2, Non-Patent Document 3) is known. In addition, methods for collecting mandelic acids after acid hydrolysis include extracting mandelic acids with an organic solvent, then concentrating and drying the organic solvent, and extracting mandelic acids with a mixed solvent of an organic solvent and water. Then, a method for crystallization is known (Patent Document 3, Patent Document 4, Patent Document 5). However, it has been a problem that a dimer of mandelic acids is generated during the collection process, and the chemical purity of the mandelic acids is reduced (Patent Document 5). Furthermore, when mandelonitriles are hydrolyzed to produce mandelic acids, it is necessary to use a large amount of an aqueous acid solution. However, in this case, coloring of the produced mandelic acids and post-treatment steps become complicated. In addition, the waste treatment of the acid aqueous solution causes a problem of environmental pollution, and therefore an industrially effective production method has been desired.

JP 10-59895 A JP 2001-348356 A JP 2001-342165 A JP 2003-206255 A JP 2003-226666 A Inoue, S. et al., J. Org. Chem., 55, 181-185 (1990) Effenberger, F. et al., Angew. Chem. Int. Ed. Engl., 33, 1555-1564 (1994) Effenberger, F. et al., Tetrahedron Lett., 31, 1249-1252 (1990)

  An object of the present invention is to provide a method for producing high-purity mandelic acids having a low environmental burden and a high recovery rate.

The present invention is as follows.
The manufacturing method of mandelic acids including the process of the following (1)-(4).
(1) A step of hydrolyzing mandelonitriles.
(2) A step of crystallizing and solid-liquid separating the mandelic acids obtained in step (1).
(3) A step of recrystallizing the mandelic acid crystals solid-liquid separated in the step (2).
(4) A step of circulating and using the mother liquor obtained in step (3) in any one of steps (1) to (3).
As well as
The manufacturing method of mandelic acids including the process of the following (1)-(4).
(1) A step of hydrolyzing mandelonitriles.
(2) A step of crystallizing and solid-liquid separating the mandelic acids obtained in step (1).
(3) A step of recrystallizing the mandelic acid crystals solid-liquid separated in the step (2).
(4) A step of circulating and using the mother liquor obtained in step (2) in step (1).

  According to the present invention, it is possible to produce highly pure mandelic acids with a low environmental load and a high recovery rate.

The first invention of the present application will be described in detail in the order of steps.
In step (1), mandelonitriles are hydrolyzed. Mandelonitriles used in the present invention can be prepared, for example, by adding hydrocyanic acid to aldehydes represented by the formula (I).

Ar groups of formula I include, for example, 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.

  In the synthesis of mandelonitriles, it is possible to carry out the addition reaction stereoselectively in the presence of a chemical catalyst or a biological catalyst. Chemical catalysts 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. In addition, these enzymes may be produced by a genetically modified microorganism incorporating a gene encoding these enzymes.

  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).

  The mandelonitriles may be racemic or optically active. When used in the production of optically active mandelic acids, the mandelonitriles are preferably 60% ee or more, more preferably 85 to 100% ee, and particularly preferably, in the subsequent hydrolysis reaction. 90-100% ee. Here, ee represents an enantiomeric excess (ee).

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

  Mandelonitriles used for hydrolysis can be purified by a known method such as extraction, distillation, column chromatography, crystallization or activated carbon treatment, and used for the hydrolysis reaction. Further, without any particular purification, a mineral acid or the like is added to the reaction solution to stabilize mandelonitriles, the solvent of the reaction solution is distilled off under normal pressure or reduced pressure, and concentrated, followed by a hydrolysis reaction. Can be used for The solvent is distilled off from the reaction solution, and the content of the mandelonitriles in the concentrated solution containing the mandelonitriles is preferably 80% by weight or more, and 90% by weight or more. Particularly preferred.

The hydrolysis of mandelonitriles in the concentrate is preferably carried out using a mineral acid. Examples of the mineral acid used here include hydrochloric acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, perchloric acid, and the like, preferably hydrochloric acid.
The use amount of the mineral acid is preferably 0.5 to 20 equivalents based on the mandelonitrile to be subjected to hydrolysis. The amount used is more preferably 0.9 to 10 equivalents, and particularly preferably 1 to 5 equivalents.

  The solvent used in the hydrolysis step is usually water, but if necessary, polar solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, hydrocarbon solvents such as toluene, hexane, heptane, 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.

The method of adding mandelonitriles, mineral acids and solvents in the hydrolysis step is preferably a method of adding the solvents after adding the mandelonitriles into the mineral acids from the viewpoint of improving the reaction efficiency. As a method for adding the solvent, the solvent may be added to the mineral acid and the mandelonitrile solution, or the mineral acid and the mandelonitrile solution may be added to the solvent.
The amount of the solvent added is preferably 0.5 to 20 times by weight with respect to the mandelonitriles. The addition amount is more preferably 1 to 10 times, and particularly preferably 1 to 5 times. The amount of water at this time does not include water in mineral acid.
If a large amount of mineral acid is used, it is not always necessary to add a solvent, but the wastewater load due to an increase in the acidic waste liquid is greatly increased. In addition, the precipitation of by-products such as ammonium salts, mandelic acids or mandelamides may make stirring difficult, so the amount of mineral acid used can be reduced and at the same time the reaction efficiency can be improved. Thus, a method of adding water is preferred.

  The concentration of mandelonitriles in the mineral acid is not particularly limited, but is preferably 1 to 70% by weight. 5 to 60% by weight is more preferable, and 10 to 50% by weight is particularly preferable.

The reaction temperature in the hydrolysis step is preferably -5 ° C to the boiling point of the solvent, and more preferably in the range of 10 to 90 ° C. Impurities can be reduced within this temperature range.
In the hydrolysis step, the reaction temperature when mandelonitriles are added to the mineral acid and the reaction temperature when adding the solvent to the reaction solution may be the same or different. For example, the reaction temperature when mandelonitriles are produced by enzymatic reaction and the mandelonitriles obtained by distilling off the solvent are added to the mineral acid is preferably -5 ° C to the boiling point temperature of the solvent. The temperature is particularly preferably 10 to 40 ° C. The reaction temperature when the solvent is added to the reaction solution is preferably 10 ° C. to the boiling point of the solvent, particularly preferably 30 to 90 ° C.

  The hydrolysis reaction may be performed under an inert gas atmosphere or in the air. An inert gas atmosphere is preferable from the viewpoint of preventing coloring. Moreover, any conditions may be sufficient under normal pressure, pressurization, or pressure reduction. It is preferable to set the pressure under normal pressure from the viewpoint that impurities are reduced and the process is simplified.

  Next, in the step (2), the produced mandelic acid crystals are precipitated and subjected to solid-liquid separation. Examples of the method for precipitating mandelic acid crystals include a method of cooling the hydrolysis reaction solution.

  The cooling rate of the hydrolysis reaction solution is preferably 0.3 to 30 ° C./hour, for example. The cooling rate is more preferably 0.4 to 20 ° C./hour, and particularly preferably 0.5 to 10 ° C./hour. Examples of methods other than cooling include a precipitation method by adding an inorganic salt and utilizing the salting-out effect, or a precipitation method by concentration. The inorganic salt is not particularly limited as long as the salting-out effect can be expected, and examples thereof include sodium chloride, ammonium sulfate, and ammonium chloride. These addition amounts are not particularly limited as long as mandelic acids are precipitated. It is also possible to utilize the salting out effect by adding a base and generating an inorganic salt with a mineral acid. In the case of concentration, the amount of the hydrolysis reaction solution to be concentrated is not particularly limited as long as the amount of mandelic acids is precipitated, and may be concentrated under reduced pressure or normal pressure.

  The mandelic acids precipitated by the above method are preferably left or stirred (hereinafter referred to as an aging step) while the crystals are precipitated before solid-liquid separation. By this aging step, dimers of mandelic acids generated as impurities in the hydrolysis step can be reduced. The dimer of mandelic acids is composed of two molecules of mandelic acids, and at least one pair of each hydroxyl group and carboxyl group forms an ester bond between the molecules.

  The aging step is preferably performed at 0 to 90 ° C. under an inert gas atmosphere for 5 minutes to 20 hours and with stirring or standing. The temperature is more preferably 10 to 70 ° C, and particularly preferably 15 to 60 ° C.

  Next, the precipitated crystals are recovered by solid-liquid separation. As a method of solid-liquid separation, any method can be used as long as the precipitated mandelic acids can be separated and the mandelic acids can be recovered. For example, the solid-liquid separation method by pressure filtration, natural filtration, heat filtration, or centrifugation is mentioned. The separation temperature is preferably 5 ° C. to aging temperature. Within this range, the dimer of mandelic acids can be reduced, and this is preferable because the recovery rate of mandelic acids is high. The separation temperature is more preferably 5 to 45 ° C, and particularly preferably 10 to 40 ° C. The separation temperature means the temperature of the slurry liquid containing mandelic acids.

The separation operation may be performed under an inert gas atmosphere or in the air. In view of preventing coloring, it is preferable to use an inert gas atmosphere.
Further, if necessary, the mandelic acids after separation can be washed. Solvents used for washing are water, polar solvents such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, alcohol solvents such as methanol, ethanol, i-propanol, n-butanol, t-butanol, or diethyl ether, diisopropyl ether, t -Ether solvents such as butyl methyl ether and tetrahydrofuran can be used. These solvents may be used alone or in combination.

Furthermore, when the mandelic acids are colored, they can be redissolved and treated with activated carbon.
The solvent used for the activated carbon treatment is not particularly limited as long as it can dissolve mandelic acids. For example, 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, t-butyl methyl ether, Ether solvents such as tetrahydrofuran can be used. These solvents may be used alone or in combination.

  When the activated carbon treatment is performed, the concentration of mandelic acids is preferably 1 to 80% by weight. By making it within this range, production efficiency is improved. The concentration is more preferably 5 to 60% by weight, and particularly preferably 10 to 50% by weight. Here, the concentration of mandelic acids represents the weight% of mandelic acids contained in the solvent, and the weight of mandelic acids includes those that are precipitated and those that are dissolved without precipitating. The amount of activated carbon used is preferably 0.01 to 10% by weight based on the weight of the solution containing mandelic acids. The amount used is preferably 0.05 to 5% by weight, particularly preferably 0.1 to 3% by weight.

  The treatment temperature of the activated carbon is preferably 5 ° C. to the boiling point of the solvent. By making it within this range, coloring can be reduced significantly. The treatment temperature is more preferably 10 to 90 ° C, particularly preferably 20 to 80 ° C. When the activated carbon treatment is performed, the pH range may be a range in which coloring can be reduced. This pH adjustment can be adjusted with an acidic compound or a basic compound.

The method for adding mandelic acids, activated carbon, acidic compound or basic compound and solvent in the activated carbon treatment is not particularly limited. A method of adding mandelic acids, activated carbon and an acidic compound or a basic compound to the solvent is preferred.
The activated carbon treatment conditions may be in an inert gas atmosphere or in the air. From the viewpoint of preventing coloring, an inert gas atmosphere is preferable, and a nitrogen atmosphere is particularly preferable.

  The method for separating the activated carbon after the activated carbon treatment is not particularly limited as long as it is a method capable of separating a solution in which activated carbon and mandelic acids are dissolved and recovering the solution. Examples thereof include a solid-liquid separation method by pressure filtration, natural filtration, heat filtration, or centrifugation.

The separation temperature in activated carbon separation means the temperature of a slurry containing a solution in which activated carbon and mandelic acids are dissolved. The separation temperature is preferably a temperature at which mandelic acids are dissolved. The separation temperature is more preferably 5 ° C. to the boiling point of the solvent, more preferably 10 to 90 ° C., and particularly preferably 15 to 80 ° C. After the activated carbon separation, a solution in which mandelic acids are dissolved is collected. If necessary, the separated activated carbon may be washed 1 to 5 times.
The solution containing mandelic acids after the activated carbon treatment is subjected to solid-liquid separation again by precipitating crystals according to the above-described method.

  Next, in the step (3), the solid-liquid separated mandelic acid crystals are recrystallized. Solvents used for recrystallization are polar solvents such as water, dimethyl sulfoxide, dimethylformamide and dimethylacetamide, alcohol solvents such as methanol, ethanol, i-propanol, n-butanol and t-butanol, or diethyl ether, diisopropyl ether, Ether solvents such as t-butyl methyl ether and tetrahydrofuran may be used. These solvents may be used alone or in combination.

  The pH range of the recrystallization mother liquor is not particularly limited. The pH when adjusting the pH as required is preferably acidic. The pH is more preferably 3.5 or less, and particularly preferably 2.5 or less. When adjusting the pH, 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 to be used usually, sodium hydroxide, potassium hydroxide, triethylamine, ammonia, sodium hydrogen carbonate, sodium carbonate and the like can be mentioned.

  The concentration of the mandelic acid solution to be recrystallized is preferably 1 to 80% by weight. Within this range, production efficiency is improved. The concentration is more preferably 5 to 60% by weight, and particularly preferably 10 to 50% by weight. Here, the weight% represents mandelic acids contained in the solvent, and the weight includes both mandelic acids precipitated and dissolved in the solvent.

  The maximum recrystallization temperature is preferably 20 ° C. to the boiling point of the solvent. By making it within this range, mandelic acids are highly purified and production efficiency is good. The maximum temperature is particularly preferably 30 to 90 ° C. The minimum temperature is preferably from the melting point of the solvent to 60 ° C, particularly preferably from 5 to 50 ° C.

  The cooling rate for precipitating the mandelic acids is preferably 0.3 to 30 ° C./hour because the dimer of mandelic acids contained in the separated mother liquor can be prevented from precipitating. The cooling rate is more preferably 0.4 to 20 ° C./hour, and particularly preferably 0.5 to 10 ° C./hour.

  Moreover, the amount of precipitation of mandelic acids from the recrystallization solvent is adjusted as necessary. Examples of means for adjusting the amount of precipitated mandelic acids include a method of cooling the recrystallization solution, a method of concentrating a part thereof, a method of utilizing a salting out effect, and the like. Any one of these methods may be performed, or may be performed simultaneously. A method by cooling is more preferred.

The recrystallization operation may be performed under an inert gas atmosphere or in the air. From the viewpoint of preventing coloring, an inert gas atmosphere is preferable, and a nitrogen atmosphere is particularly preferable. In addition, any condition may be used under normal pressure, increased pressure, or reduced pressure. More preferably, the pressure is reduced to normal pressure from the viewpoint of reducing impurities and simplifying the process.
After recrystallization, mandelic acids can be obtained according to the solid-liquid separation described in the step (2). After solid-liquid separation, the crystals may be washed as necessary. The washing operation can also be performed according to the step (2).

Next, in the step (4), the separated mother liquor obtained in the step (3) is circulated and used in any one of the steps (1) to (3). By performing this operation, mandelic acids contained in the separated mother liquor can be recovered, and further, the waste water load due to the acidic waste liquid can be reduced.
In the step (3), the separated mother liquor includes a separated mother liquor after solid-liquid separation and a washed mother liquor by a washing operation following the recrystallization operation. The recrystallization operation, solid-liquid separation, and washing can be repeated a plurality of times, and the recrystallization solvent can be recycled. These mother liquors do not need to be adjusted at all and are reused in the step (3). However, it is preferable to adjust the pH from the viewpoint that the dimers of mandelic acids contained in the mother liquor can be decomposed. . The pH range is preferably 2.0 to 14.0 as required. The pH is more preferably 6.0 to 14.0, and particularly preferably 10.0 to 14.0. Usually, a base is used to adjust the pH. Examples of the base include sodium hydroxide, potassium hydroxide, triethylamine, ammonia, sodium bicarbonate, sodium carbonate and the like.

  For example, the separated mother liquor can be used as a solvent in the hydrolysis reaction in step (1). In this case, if the separation mother liquor contains water, it is not necessary to add water again, so that the solvent to be used can be reduced. In the step (2), it can be used as a solvent for washing the crystal after solid-liquid separation. It can also be used as a solvent for dissolving mandelic acid crystals during the activated carbon treatment. In step (3), it is used in the same manner as in step (2).

  In particular, when water is used as a washing solution for crystal washing, since mandelic acids are more soluble in the recrystallization mother liquor than the mandelic acid dimer, the mandelic acids are predominantly eluted and the separated mandelic acids are separated. To lose. However, by using the above-described separation mother liquor, mandelic acids eluted in the cleaning liquid are reduced, and mandelic acid dimers are easily dissolved in the cleaning liquid. Therefore, the cleaning efficiency can be improved, and as a result, high-purity mandelic acids can be produced.

Next, the second invention of the present application will be described.
The second invention differs from the first invention in that the separated mother liquor obtained in the step (2) is circulated and used. The reaction conditions, operation conditions, and the like in steps (1) to (3) can be carried out in the same manner as in the first invention described above. In step (4), the separation mother liquor, the method of use, and the like that are to be used for circulation can be implemented in the same manner as described above.
With the above production method, the recovery rate of mandelic acids can be improved, and the wastewater load due to the acidic waste liquid can be reduced.

  Hereinafter, the present invention will be described in more detail with reference to examples. The purity, yield, mandelic acid dimer content, and optical purity of the mandelic acids in the examples were determined by high performance liquid chromatography.

<Chemical purity of mandelic acids, yield and dimer content in mandelic acid crystals>
Sample preparation method: Dissolve 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 Carrier manufactured by GL Sciences: Acetonitrile: Water = 3/7 (adjusted to pH 3.0 with phosphoric acid)
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 result of mandelic acid and its dimer is 100 area%)

<Optical purity of mandelic acids>
Sample preparation method: Dissolve 20 mg of sample in 25 mL of carrier

Apparatus: Column oven 865-CO manufactured by JASCO Corporation

UV 870-UV manufactured by JASCO

Pump 880-PU manufactured by JASCO Corporation

Integrator Shimadzu Corporation C-R3A

Column: CHIRALCEL OJ-H (4.6 mm × 250 mm) manufactured by Daicel Chemical Industries, Ltd.

Carrier: Hexane / IPA / trifluoroacetic acid = 90/10 / 0.1

Column temperature: 35 ° C

Flow rate: 1.0 mL / min

Wavelength: 220nm

Detection limit value: 99.9% ee

[Example 1]
(1) Preparation of (S) -mandelic acid 275 g of 35% hydrochloric acid (2.64 mol) of HCl was charged in a 2 L flask, and 222 g (1.67 mol) of (S) -mandelonitrile having an optical purity of 97% ee was added thereto. Was added. Then, after stirring for 5 hours at 30 ° C., 600 g of water was added. Subsequently, it hydrolyzed at 80 degreeC for 2 hours, stirring. Thereafter, the hydrolysis reaction solution was concentrated under reduced pressure until the concentration of (S) -mandelic acid reached 30%. Subsequently, the concentrate was adjusted to pH 2.0 with 30% sodium hydroxide and cooled to 30 ° C. to precipitate (S) -mandelic acid. The precipitated (S) -mandelic acid was washed with 45 g of water while centrifuging. Next, the crystals attached to the centrifuge were collected. The mandelic acid dimer content ratio of the obtained (S) -mandelic acid crystals 238 g (chemical purity 91.0%, yield 85%, optical purity 98.9% ee) is 1.4% (area percentage). there were.

(2) Preparation of recrystallization mother liquor 8.6 g of (S) -mandelic acid crystal obtained in (1) of Example 1 and 18.3 g of water were charged into a 1 L flask. This was heated to 60 ° C. to dissolve (S) -mandelic acid crystals. Next, the solution was cooled from 60 ° C. to 30 ° C. at a cooling rate of 10 ° C./hour to precipitate crystals. The precipitated (S) -mandelic acid was washed with 2 g of water while centrifuging. Next, the crystals adhering to the centrifuge were collected, and the crystals were dried under reduced pressure. Recrystallization mother liquid 20g which combined 7.0 g (chemical purity 99.4%, recrystallization yield 89%, optical purity 99.8% ee) and (S) -mandelic acid and the washing | cleaning liquid was obtained. The mandelic acid dimer content ratio of the obtained (S) -mandelic acid crystal was 0.3% (area percentage).

(3) Activated carbon treatment of recrystallized mother liquor 172.8 g of (S) -mandelic acid crystals obtained in (1) of Example 1, 320 g of water, and 2 g of activated carbon were charged into a 1 L flask. This was stirred at 60 ° C. for 1 hour. The activated carbon was removed from the solution by heating filtration, and the activated carbon was washed with 48 g of water. The combined solution of the filtrate and the activated carbon cleaning solution was cooled from 60 ° C. to 30 ° C. at a cooling rate of 10 ° C./hour to precipitate crystals. The precipitated (S) -mandelic acid crystals were washed with 32 g of water while centrifuging. Next, the crystals adhering to the centrifuge were collected, and the crystals were dried under reduced pressure. 136 g (chemical purity 99.5%, recrystallization yield 86%, optical purity 99.8% ee) of (S) -mandelic acid crystals and a washing solution were combined to obtain 398 g of a recrystallization mother liquor. The mandelic acid dimer content ratio of the obtained (S) -mandelic acid crystal was 0.3% (area percentage).

[Example 2]
In a 100 mL flask, 12.5 g of 35% hydrochloric acid (HCl 0.120 mol) was charged. To this, 10.1 g (0.076 mol) of (S) -mandelonitrile having an optical purity of 97% ee was added and stirred at 30 ° C. for 5 hours. 27.3 g of the recrystallization mother liquor obtained in (3) of Example 1 was added and hydrolyzed while stirring at 80 ° C. for 2 hours. Under reduced pressure, the hydrolysis reaction solution was concentrated until the concentration of (S) -mandelic acid was 30% by weight. The concentrate was adjusted to pH 2.0 with 30% sodium hydroxide and cooled to 30 ° C. to precipitate crystals. The precipitated (S) -mandelic acid crystals were washed with 2 g of water while centrifuging. Next, the crystals attached to the centrifuge were collected. The mandelic acid dimer content of 11.2 g (chemical purity 93.0%, yield 90%, optical purity 99.3% ee) of the obtained (S) -mandelic acid crystals was 1.0% (area percentage). )Met.

[Example 3]
The same procedure as in Example 2 was performed, except that the water used for washing was changed to the recrystallization mother liquor obtained in (1) of Example 1. The mandelic acid dimer content ratio of the obtained (S) -mandelic acid crystals 11.3 g (chemical purity 94.0%, recrystallization yield 92%, optical purity 99.4% ee) was 0.8% ( Area percentage).

[Example 4]
In a 100 mL flask, 10.8 g of (S) -mandelic acid crystals obtained in (1) of Example 1 and 22.9 g of recrystallization mother liquor obtained in (3) of Example 1 were charged. This was heated to 60 ° C. to dissolve (S) -mandelic acid crystals. Next, the crystal was precipitated by cooling from 60 ° C. to 30 ° C. at a cooling rate of 10 ° C./hour. The precipitated (S) -mandelic acid crystals were washed with 2 g of water while centrifuging. Next, the crystals adhering to the centrifuge were collected, and the crystals were dried under reduced pressure. 9.2 g of (S) -mandelic acid crystals (chemical purity 99.6%, recrystallization yield 93%, optical purity 99.8% ee) were obtained. The content of mandelic acid dimer in the crystal was 0.1% (area percentage).

[Example 5]
In a 100 mL flask, 10.8 g of (S) -mandelic acid crystals obtained in (1) of Example 1, 20 g of recrystallization mother liquor obtained in (3) of Example 1, and 0.2 g of activated carbon were charged. Subsequently, it stirred at 60 degreeC for 1 hour. The activated carbon was removed from the solution by heating filtration, and the activated carbon was washed with 3 g of water. The combined solution of the filtrate and the activated carbon cleaning solution was cooled from 60 ° C. to 30 ° C. at a cooling rate of 10 ° C./hour to precipitate crystals. The precipitated (S) -mandelic acid was washed with 2 g of water while centrifuging. Next, the crystals adhering to the centrifuge were collected, and the crystals were dried under reduced pressure. 9.0 g of (S) -mandelic acid crystals (chemical purity 99.7%, recrystallization yield 91%, optical purity 99.9% ee) were obtained. The content of mandelic acid dimer in the crystal was 0.1% (area percentage).

[Example 6]
This was carried out in the same manner as in Example 5 except that the water used for washing after centrifugation in Example 1 (3) was changed to the recrystallization mother liquor obtained in Example 1 (3). 9.2 g of (S) -mandelic acid (chemical purity 99.8%, recrystallization yield 93%, optical purity 99.9% ee) was obtained. The content of crystalline mandelic acid dimer was 0.1%.

[Example 7]
Into a 100 mL flask was charged 25.0 g of 35% hydrochloric acid (HCl 0.240 mol), and 20.2 g (0.152 mol) of (S) -mandelonitrile having an optical purity of 97% ee was added thereto. Subsequently, after stirring this at 30 degreeC for 5 hours, 54.5 g of recrystallization mother liquid obtained by (3) of Example 1 was added. This was hydrolyzed with stirring at 80 ° C. for 2 hours. The hydrolysis reaction liquid was cooled and stirred at 55 ° C. for 3 hours while precipitating a part of (S) -mandelic acid crystals. Further, this was aged at 50 ° C. for 3 hours while stirring. It concentrated until the density | concentration of (S) -mandelic acid became 30 weight% under pressure reduction. The concentrate was adjusted to pH 2.0 with 30% sodium hydroxide and cooled to 30 ° C. to precipitate crystals. The precipitated (S) -mandelic acid crystals were washed with 4 g of water while centrifuging. Next, the crystals attached to the centrifuge were collected. The mandelic acid dimer content of the obtained (S) -mandelic acid crystal 22.4 g (chemical purity 96.0%, yield 92%, optical purity 99.5% ee) was 0.08% (area percentage). )Met.

[Example 8]
The recrystallization mother liquid obtained in (3) of Example 1 was adjusted to pH 12.0 with 30% sodium hydroxide. Then, it left still at room temperature for 3 hours. The same procedure as in Example 7 was performed, except that the recrystallization mother liquor obtained in (3) of Example 1 was changed to 54.5 g of the recrystallization mother liquor (pH 12.0). The mandelic acid dimer content of the obtained (S) -mandelic acid crystals 22.6 g (chemical purity 96.1%, yield 93%, optical purity 99.5% ee) was 0.07% (area percentage). )Met.

It was possible to produce high-purity mandelic acids even if the recrystallized mother liquor and / or the crystallization mother liquor separated into solid and liquid were recycled.

Claims (2)

The manufacturing method of mandelic acids including the process of the following (1)-(4).
(1) Step of hydrolyzing mandelonitriles with mineral acid in aqueous solvent (2) Step of crystallizing and solid-liquid separating the mandelic acids obtained in step (1) (3) Solid state in step (2) Step (4) of recrystallizing liquid-separated mandelic acid crystals at a cooling rate of 0.3 to 30 ° C./hour in an aqueous solvent, and any of steps (1) to (3) as the mother liquor obtained in step (3) A process that is used in a single cycle. The manufacturing method of mandelic acids including the process of the following (1)-(4).
(1) Step of hydrolyzing mandelonitriles with mineral acid in aqueous solvent (2) Step of crystallizing and solid-liquid separating the mandelic acids obtained in step (1) (3) Solid state in step (2) Step (4) of recrystallizing liquid-separated mandelic acid crystals in a water solvent at a cooling rate of 0.3 to 30 ° C./hour A step of circulating and using the mother liquor obtained in Step (2) in Step (1).