JP2007238576A - Method for handling mandelic acid, and stabilized composition comprising mandelic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for stably and safely handling a mandelic acid without causing the precipitation of a crystal thereof. <P>SOLUTION: The method for handling mandelic acids powder is characterized by handling the same as a form of a 1 to 4C alcohol solution wherein mandelic acid powder is dissolved. Mandelic aid powder is dissolved in the alcohol preferably in a mass ratio of 1.2/1 to 4/1 relative to the alcohol. The volume of the solution is made smaller than that of a commonly available mandelic acid powder, and hence it can be transported and stored compactly. The solution stably remains in a state of solution over a wide range of temperature, and thereby a safe handling method for mandelic acid can be provided. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a stable and safe handling method without the precipitation of mandelic acid crystals, and a stabilized mandelic acid composition.

  Mandelic acids are widely used as intermediates for the synthesis of pharmaceuticals and agricultural chemicals. In particular, optically active mandelic acid is useful as a raw material for optically active pharmaceutical synthesis.

  Mandelic acid crystals are obtained from a solution containing mandelic acid water, separated from the mother liquor by operations such as crystallization, filtration, and centrifugation, washed with water, and dried. Since the obtained crystal contains fine ones, it has a high scattering property. There is a problem that powder is scattered and difficult to handle during packing, weighing and charging into a reactor.

  Mandelic acids are strongly irritating to the skin and eyes when in acid form, so it is necessary to take protective measures against dust and dust, such as workers wearing protective equipment and providing a protective wall to shut off the outside world for safety. is not.

Also reported is a method for producing mandelic acids, in which the particle size of mandelic acids is kept within a certain range and the packing density is regulated by crystallization after partial neutralization by adding alkali to an aqueous solution containing mandelic acids and mineral acids. However, even if the particle size can be increased, there is a problem that scattering cannot be prevented because it includes fine particles. (See Patent Document 1)
In addition, a method of handling the product as a slurry or an aqueous solution can be considered, but in the case of a slurry, the product is unevenly distributed in the container, so that it is necessary to perform time-consuming treatment such as heating and dissolving or washing together during use. In the case of an aqueous solution, crystals are easily precipitated due to a change in external temperature, so that there is a problem that a large amount of water is used to form an aqueous solution.

  In addition, by using a salt such as sodium instead of the acid form, mandelic acids have improved solubility in water and can be handled as an aqueous solution. However, the mandelic acids are in acid form or in an organic solvent. For the intended use, there is a problem that operations such as desalting and dehydration are required.

JP2003-226666A

  It is an object of the present invention to find a handling method that can reduce the volume even in the form of a solution and can be applied to a wide range of temperatures in order to use it stably and safely without scattering the powdered mandelic acids. .

  Therefore, the present invention provides an economical and safe handling method of mandelic acids that can be applied to a wide range of temperature conditions and has little influence on product purity.

  As a result of various investigations on methods for solving the above problems, a solution obtained by dissolving the mandelic acids in a specific solvent (alcohol having 1 to 4 carbon atoms) having the ability to dissolve the mandelic acids at a high concentration can be handled. I found it easier. The alcohol solution of the mandelic acids obtained here can reduce the volume of the powdered mandelic acids that are usually obtained, and not only enables compact storage and transportation, but also a wide range of −20 to 60 ° C. It was found that the solution is stable even under the above temperature conditions, and handling during use becomes extremely easy, and the present invention has been completed.

  According to the present invention, it is possible to provide a handling method that can easily and safely handle mandelic acids that are easily scattered in powder form and that are highly irritating to skin in a compact and in a wide range of temperature conditions. it can.

  In the method of the present invention, powdered mandelic acids are treated as a solution in which the alcohol has 1 to 4 carbon atoms. The inventors have examined various solvents other than the alcohol, but have found that the alcohol is the best solvent that can maintain stability in a solution.

  In the present invention, the term “handling method” includes storage and transportation of mandelic acid tanks and the like, transportation by pipes including pipes, valves, nozzles, etc. and storage and transportation in small-sized plastic containers and glass bottles. Means weighing. By using the alcohol solution having 1 to 4 carbon atoms of the present invention, it is possible to prevent the powder from scattering when packing, weighing or charging the mandelic acids into the reactor, The product volume can be reduced rather than the volume, and storage and transportation can be performed in a compact manner.

  The mandelic acids in the present invention are crystalline powders at room temperature and do not form a salt.

  Examples of such mandelic acids include derivatives thereof in addition to mandelic acid, for example, those having a substituent on the benzene ring of mandelic acid.

  Specific examples of the substituent include, for example, a linear or branched alkyl group having 1 to 5 carbon atoms such as a methyl group and an ethyl group, a methoxy group, a methylthio group, a nitro group, a cyano group, or chlorine, bromine, fluorine And the like.

  The mandelic acids used in the present invention may be any of R-form, S-form or racemic form, but either R-form or S-form optical is used as a raw material for synthesizing optically active medicines and agricultural chemicals. The purity is preferably 98% or more.

  The alcohol used in the present invention has 1 to 4 carbon atoms, preferably 1 to 2, and more preferably 1. Alcohols having 1 to 4 carbon atoms do not cause precipitation over a wide range of temperatures and are excellent in handling.

  Specific examples of the alcohol include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butanol.

  A suitable mass ratio between the mandelic acids and the alcohol is 1.2 / 1 to 4/1, and more preferably 1.5 to 3/1. This is because in the range of 1.2 / 1 to 4/1, a solution without crystal precipitation is obtained. This is because 1.5 to 3/1 can be easily prepared into a solution by mixing. In addition, although the volume of the said alcohol solution obtained by suitable mass ratio becomes smaller than the volume of the original powder, this is compared with the volume obtained at 25 degreeC.

  The volume of the powder used in the present invention is determined by the tap method defined in JIS K5101.

  The method for preparing the alcohol solution of mandelic acids may be obtained by dissolving powdered mandelic acids. For example, a method of gradually adding powdered mandelic acids into stirred alcohol, alcohol and powdered mandelic acids A method of mixing by heating and stirring can be performed.

  The alcohol solution of mandelic acids can be handled at a temperature of -20 to 60 ° C. Within this temperature, it can be handled stably. A more preferable temperature is -20 to 50 ° C. This is because, at -20 to 50 ° C., volume expansion can be suppressed and negative caustic to the storage container can be reduced.

  Furthermore, the solution in which the mass ratio of mandelic acids and methanol is 1.2 / 1 to 4/1 is stable with no precipitation of crystals or the like even if it is put in a freezer at −20 ° C. and stored for one week. there were.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, the scope of the present invention is not limited only to these Examples.

(Measurement of sample volume)
It calculated | required by the tap method prescribed | regulated to JISK5101. Specifically, about 100 mL of the powder was placed on a sieve having an opening of 0.5 mm and sieved. 100 mL of the sample that passed through the sieve was gradually put into a 100 mL graduated cylinder, and the mass was measured. Next, a rubber stopper was attached to the graduated cylinder, and a tap was dropped 50 times on a rubber plate from a height of 5 cm. The sample volume in the graduated cylinder after tapping was measured.

(Stability test)
A mandelic acid composition is prepared by dissolving mandelic acid in methanol. The appearance of the composition is visually observed for the presence of crystal powder, transparency, and fluidity. Thereafter, the mandelic acid composition is put in a freezer at −20 ° C. and stored for one week, the appearance of the composition is observed, and the transparency, crystal precipitation and fluidity are evaluated.

Example 1
The volume of the powder of R-2-chloromandelic acid crystals was determined by the method described above. As a result, the volume of this sample was 78.5 mL and the mass was 48.4 g. This sample is added with 32.3 g of 2-propanol (R-2-chloromandelic acid concentration 60% by mass), heated and mixed to dissolve the powder, and is a transparent liquid with no visual turbidity. It was confirmed. The volume at this time was 77.5 mL at 25 ° C.

(Example 2)
The volume of the powder of R-2-chloromandelic acid crystals was determined by the method described above. As a result, the volume of this sample was 78.5 mL and the mass was 48.4 g. 16.1 g of methanol (R-2-chloromandelic acid concentration: 75% by mass) was added to this sample and mixed to dissolve the powder, which was visually confirmed to be a transparent liquid with no cloudiness. The volume at this time was 53.6 mL at 25 ° C. This solution was put into a freezer at −20 ° C. and left for 1 week. Observation of the state after standing revealed that the original transparent liquid had no crystal precipitation and had fluidity.

(Example 3)
About 50 g of S-mandelic acid crystal powder was placed on a 0.5 mm sieve and sieved. Thereafter, the same operation as in Example 1 was performed, and the volume was measured.
As a result of the measurement, the volume of this sample was 77.8 mL and the mass was 49 g. The powder was dissolved by adding 26.4 g of methanol (S-mandelic acid concentration: 65% by mass) to this powder and mixing, and it was confirmed that the powder was a clear liquid without white turbidity. The volume at this time was 73.5 mL at 25 ° C. This solution was put into a freezer at −20 ° C. and left for 1 week. Observation of the state after standing revealed that the original transparent liquid had no crystal precipitation and had fluidity.

Example 4
About 50 g of S-2-chloromandelic acid crystal powder was placed on a 0.5 mm sieve and sieved. Thereafter, the same operation as in Example 1 was performed, and the volume was measured.
As a result of the measurement, the volume of this sample was 74.9 mL and the mass was 48.7 g. The powder was dissolved by adding and mixing 20.9 g of methanol (S-2-chloromandelic acid concentration 70% by mass) to this powder, and it was confirmed that it was a transparent liquid with no turbidity by visual observation. The volume at this time was 60.9 mL at 25 ° C. Furthermore, this solution was put into a -20 ° C freezer and left for one week. Observation of the state after standing revealed that the original transparent liquid had no crystal precipitation and had fluidity.

(Example 5)
The amount of methanol in Example 2 was changed to 32.3 g (R-2-chloromandelic acid concentration 60% by mass) and added and mixed to dissolve the powder, which is a transparent liquid with no visual turbidity. It was confirmed. The volume at this time was 77.0 mL at 25 ° C. Furthermore, this solution was put into a -20 ° C freezer and left for one week. Observation of the state after standing revealed that the original transparent liquid had no crystal precipitation and had fluidity.

(Comparative Example 1)
Instead of the methanol in Example 1, 32.3 g of ion-exchanged water (R-2-chloromandelic acid concentration 60% by mass) was added and mixed to dissolve the powder. When it was heated to 50 ° C. because it was cloudy, it became a transparent liquid. At 40 ° C. or lower, crystals precipitated and became cloudy. At 25 ° C., a large amount of crystals precipitated and the fluidity was lost.

(Comparative Example 2)
About 100 g of S-2-chloromandelic acid crystal powder was placed on a 0.5 mm sieve and sieved. Thereafter, the same operation as in Example 1 was performed, and the volume was measured.
As a result of the measurement, the volume of this sample was 74.9 mL and the mass was 48.7 g. To this powder, 39.8 g of t-butyl methyl ether (S-2-chloromandelic acid concentration 55% by mass) was added and mixed to dissolve the powder. Since the powder was not melted and became cloudy, when heated to 50 ° C., it melted and showed fluidity. At 25 ° C., a large amount of crystals precipitated and the fluidity was lost.

According to the method for handling mandelic acids of the present invention, powdered mandelic acids can be used safely and efficiently at room temperature which is easy to scatter and is irritating. Furthermore, the volume can be made smaller than the powder state, and storage and transportation in a space-saving manner are possible.

Claims (6)

A method for handling mandelic acids, characterized in that the mandelic acids in powder form are treated as a solution in which alcohols having 1 to 4 carbon atoms are dissolved. The method according to claim 1, wherein the mass ratio of mandelic acids to the alcohol is 1.2 / 1 to 4/1. 3. The method according to claim 1, wherein the volume of the mandelic acid alcohol solution obtained at 25 ° C. is smaller than the volume of the mandelic acid powder. The method according to any one of claims 1 to 3, wherein the alcohol solution of the mandelic acids is handled at a temperature of -20 to 60 ° C. The method according to claim 1, wherein the alcohol is methanol. A stabilized mandelic acid composition, wherein the mass ratio of mandelic acid and methanol is 1.2 / 1 to 4/1, and crystals do not precipitate in the following stability test.
Stability test: The mandelic acid composition is placed in a freezer at -20 ° C and stored for 1 week.