JP5748752B2 - Method for producing cyanohydrin - Google Patents

Description

  The present invention relates to a method for producing cyanohydrin.

  Cyanohydrin compounds are used for the synthesis of α-hydroxycarboxylic acid compounds, α-hydroxyketone compounds, β-aminoalcohol compounds and the like that are often used to produce physiologically active substances such as pharmaceutically active substances, vitamins, and pyrethroid compounds. It is important as an intermediate to be used.

  As the cyanohydrin compound, glycolonitrile is the most common, and as its production method, for example, methods described in Patent Documents 1 to 4 are disclosed.

  In Patent Document 1, in a formalin solution in which a catalytic amount of sodium acetate is dissolved, the pH is kept at 4.8 to 6.0 while adding acetic acid or sodium acetate at a liquid temperature of 15 to 30 ° C., if necessary. And the reaction is carried out under the same conditions.

  Patent Document 2 discloses the production of glycolonitrile characterized in that a small amount of acidic sulfite ion is present in the reaction system when formaldehyde and hydrocyanic acid are reacted in an aqueous medium to produce glycolonitrile. A method is described, and specifically, it is described that an aqueous sodium sulfite solution is appropriately supplied to a reaction vessel while adjusting the pH of the reaction solution to be 4.0 to 5.0.

  Further, in Patent Document 3, in a method for producing glycolonitrile by reacting hydrocyanic acid and formaldehyde in an aqueous medium, when T is the reaction zone temperature T (° C.) and P is the pH of the reaction solution, T and A process for producing glycolonitrile characterized in that the product of P is 155 to 240 is described. Specifically, for example, in order to lower the pH, a small amount of sulfur dioxide, sulfurous acid, sulfuric acid, etc. Is added to increase the pH, a small amount of sodium sulfite or caustic soda is added.

  Further, Patent Document 4 provides a method for preparing glycolonitrile, comprising: (a) providing a stream for supplying aqueous formaldehyde heated to a temperature of about 90 ° C. to about 150 ° C. for a measurable time; (B) contacting the heated aqueous feed stream of (a) with hydrogen cyanide at a temperature suitable for glycolonitrile synthesis, whereby glycolonitrile is produced. A method is described. It is described that the pH in the glycolonitrile synthesis reaction chamber is about 3 to about 10, preferably about 5 to about 8.

JP 62-267257 A JP-A-53-68725 JP-A-6-135923 Special table 2008-525467

  However, the methods described in Patent Documents 1 to 3 have a problem that the pH needs to be adjusted appropriately during the progress of the reaction, resulting in poor working efficiency. Moreover, in the method described in Patent Document 4, the production rate of cyanohydrin is not always high. Furthermore, in the methods described in Patent Documents 1 to 4, it is difficult to accurately control the reaction rate between formaldehyde and hydrocyanic acid.

  Therefore, the present invention can accurately control the reaction rate between the carbonyl compound and hydrocyanic acid without adjusting the pH during the reaction, and can produce cyanohydrin at a sufficiently high production rate. A method for producing cyanohydrin is provided.

  That is, the present invention provides a method for producing cyanohydrin, in which a carbonyl compound and hydrocyanic acid are reacted in a buffer solution having a pH of less than 7 to obtain cyanohydrin.

  Usually, the reaction rate between hydrocyanic acid and a carbonyl compound depends on the pH, and the pH changes as the reaction proceeds. In the conventional production method, the pH is appropriately adjusted in accordance with the change in pH. However, in such a method, it is difficult to keep the pH accurately and constant, which makes it difficult to control the reaction rate. This is considered to be a cause. In contrast, in the production method according to the present invention, the reaction proceeds in a buffer solution, and therefore the pH during the reaction is kept constant without adjusting the pH. Therefore, in the present invention, the reaction rate between the carbonyl compound and hydrocyanic acid can be controlled with high accuracy.

  Furthermore, according to the present invention, cyanohydrin can be produced with a high production rate. The reason for this is not necessarily clear, but in the present invention, since the reaction is carried out in a buffer solution, it is unlikely that the production rate is lowered due to fluctuations in pH, and a high production rate can be achieved.

  The present invention also includes adding a hydrocyanic acid to the buffer solution while maintaining a buffer solution containing a carbonyl compound and having a pH of less than 7 within a predetermined temperature range, and the carbonyl compound and the hydrocyanic acid in the buffer solution. The present invention provides a method for producing cyanohydrin in which cyanohydrin is obtained by reacting with. According to such a production method, the reaction rate between the carbonyl compound and hydrocyanic acid can be accurately controlled without adjusting the pH, and cyanohydrin can be produced with a high production rate.

  In the present invention, the buffer solution preferably contains a weak acid and a salt of the weak acid. The buffer solution preferably contains an organic acid and a salt of the organic acid. According to such a buffer solution, fluctuations in pH in the reaction between the carbonyl compound and hydrocyanic acid can be further suppressed. Therefore, the effect of the present invention is more reliably achieved.

  The organic acid is preferably an α-hydroxycarboxylic acid of the same type as the α-hydroxycarboxylic acid produced when cyanohydrin is hydrolyzed. By using such an organic acid, purification is facilitated when the produced cyanohydrin is further hydrolyzed to obtain an α-hydroxycarboxylic acid. In addition, the production rate of cyanohydrin is further improved.

  The organic acid is preferably glycolic acid. According to the buffer solution containing glycolic acid and a salt of glycolic acid, it is possible to further suppress pH fluctuations and to further improve the production rate of cyanohydrin.

  The carbonyl compound is preferably an aldehyde, and more preferably formaldehyde. Cyanohydrins obtained from such carbonyl compounds are very useful as intermediates for producing physiologically active substances such as pharmaceutically active substances, vitamins or pyrethroid compounds.

  According to the present invention, the reaction rate between the carbonyl compound and hydrocyanic acid can be accurately controlled without adjusting the pH during the reaction, and cyanohydrin can be produced at a sufficiently high production rate. In addition, a method for producing cyanohydrin can be provided.

  A preferred embodiment of the method for producing cyanohydrin of the present invention will be described below.

  In the method for producing cyanohydrin according to this embodiment, a carbonyl compound and hydrocyanic acid are reacted in a buffer solution having a pH of less than 7 to obtain cyanohydrin.

  Here, the carbonyl compound is a compound having a carbonyl group, and examples thereof include a compound represented by the following formula (1).

In the formula, R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an alkylaryl group having 7 to 9 carbon atoms.

  Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. These alkyl groups may be linear, branched, or form a ring.

  Examples of the aryl group having 6 to 14 carbon atoms include phenyl group, tolyl group, xylyl group, naphthyl group, biphenyl group, and anthryl group.

  Examples of the alkylaryl group having 7 to 9 carbon atoms include benzyl group, ethylphenyl group, cinnamyl group and the like.

Specific examples of the carbonyl compound include acetone (a compound in which R ¹ and R ² are both methyl groups), methyl ethyl ketone (a compound in which ^one of R ¹ and R ² is a methyl group, and the other is an ethyl group), isobutylmethyl Ketones such as ketones (compounds in which ^one of R ¹ and R ² is a methyl group and the other is an isobutyl group); formaldehyde (a compound in which both R ¹ and R ² are hydrogen atoms), acetaldehyde (R ¹ and R ² In which one of them is a hydrogen atom and the other is a methyl group), propionaldehyde (a compound in which ^one of R ¹ and R ² is a hydrogen atom and the other is an ethyl group), benzaldehyde ( ^one of R ¹ and R ² is a hydrogen atom) , Aldehydes such as a compound in which the other is a phenyl group;

In the formula (1), compounds in which R ¹ and R ² are not hydrogen atoms are ketones, and compounds in which at least one of R ¹ and R ² is a hydrogen atom are aldehydes.

As the carbonyl compound, aldehydes are preferable. That is, in Formula (1), it is preferable that at least one of R ¹ and R ² is a hydrogen atom. Aldehydes easily react with hydrocyanic acid more efficiently than ketones, and can produce cyanohydrin at a higher production rate. Of the aldehydes, formaldehyde is preferable from the viewpoint of producing glycolonitrile useful as a production intermediate for glycine, hydantoin, and the like.

  The carbonyl compound can be subjected to the reaction as an aqueous solution, for example. That is, when the carbonyl compound is formaldehyde, it can be subjected to the reaction as an aqueous formaldehyde solution.

  Cyanic acid can be subjected to the reaction in any form such as gas, liquid or aqueous solution, and is preferably provided as a liquid or aqueous solution.

  From the viewpoint of improving the production rate of cyanohydrin, the amount of hydrocyanic acid used for the reaction is preferably 1 to 1.2 times, more preferably 1 to 1.1 times in terms of moles, relative to the total amount of carbonyl compound.

  Cyanohydrin obtained by the reaction of a carbonyl compound and hydrocyanic acid is, for example, a compound represented by the following formula (2).

Wherein, ^{R 1} and ^{R 2} have the same meanings as ^{R 1} and ^{R 2} in the formula (1).

Specifically, for example, formaldehyde is glycolonitrile (also known as hydroxyacetonitrile, a compound in which R ¹ and R ² in formula (2) are both hydrogen atoms), and acetone is acetone cyanohydrin (also known as α-hydroxy). Isobutyronitrile, a compound in which R ¹ and R ² in formula (2) are both methyl groups), and benzaldehyde from mandelonitrile ( ^one of R ¹ and R ² in formula (2) is a hydrogen atom and the other is Each compound is a phenyl group.

  The reaction between the carbonyl compound and hydrocyanic acid is preferably carried out in the presence of a catalyst. Examples of the catalyst include sodium cyanide and potassium cyanide.

  The amount of catalyst used is preferably 0.01 to 0.5 mol%, more preferably 0.05 to 0.1 mol%, based on the total amount of carbonyl compounds to be subjected to the reaction.

  The buffer solution means a solution having a buffering action, that is, a solution whose change in pH is small even when a predetermined amount of acid or base is added. The buffer is preferably an aqueous solution containing a weak acid and a weak acid salt, and more preferably an aqueous solution containing an organic acid and an organic acid salt.

  Examples of the weak acid include organic acids such as acetic acid, formic acid, glycolic acid, citric acid, tartaric acid, mandelic acid, glutaric acid, malic acid, malonic acid, phthalic acid, and succinic acid; inorganic acids such as phosphoric acid and boric acid; Of these, organic acids are preferred.

  Examples of the weak acid salts include alkali metal salts such as sodium salts and potassium salts of the above weak acids; alkaline earth metal salts such as magnesium salts and barium salts.

  Moreover, as said weak acid, alpha-hydroxycarboxylic acid is preferable. According to the buffer containing α-hydroxycarboxylic acid and a salt of α-hydroxycarboxylic acid, cyanohydrin can be obtained at a higher production rate.

  As alpha-hydroxycarboxylic acid, the compound represented by following formula (3) is mentioned, for example.

In the formula, R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an alkylaryl group having 7 to 9 carbon atoms. Moreover, as a C1-C6 alkyl group, a C6-C14 aryl group, and a C7-C9 alkylaryl group, the group similar to the above is illustrated, respectively.

  By the way, cyanohydrin produces | generates (alpha) -hydroxycarboxylic acid, for example by the hydrolysis reaction using microorganisms. The α-hydroxycarboxylic acid thus produced is often used and useful for producing a physiologically active substance such as a pharmaceutically active substance, a vitamin or a pyrethroid compound.

  Therefore, when the α-hydroxycarboxylic acid of the same kind as the α-hydroxycarboxylic acid produced when hydrolyzing the produced cyanohydrin is used as the weak acid, the above-mentioned hydrolysis can be performed without purifying the cyanohydrin after the reaction. It can be subjected to a decomposition reaction. At this time, the presence of the α-hydroxycarboxylic acid does not inhibit the hydrolysis reaction using the microorganism, and it is the same as the α-hydroxycarboxylic acid produced by the hydrolysis reaction, and therefore does not inhibit the purification operation. From such a viewpoint, it is preferable to use the same kind of α-hydroxycarboxylic acid as the α-hydroxycarboxylic acid produced when the produced cyanohydrin is hydrolyzed as the weak acid. Such α-hydroxycarboxylic acid can be represented by the following formula (4).

In the formula, R ¹ and R ² are the same groups as R ¹ and R ² in formula (1).

  That is, for example, when formaldehyde is used as the carbonyl compound according to the present embodiment, a buffer solution containing glycolic acid and a salt of glycolic acid is preferable as the buffer solution.

  The pH of the buffer solution is less than 7, and from the viewpoint of improving the production rate of cyanohydrin, it is preferably 1 to 6, and more preferably 3 to 5. If the pH is too high, the reverse reaction from cyanohydrin to the carbonyl compound proceeds, and sudden abnormal reactions are likely to occur, and the production rate of cyanohydrin tends to decrease. On the other hand, if the pH is too low, the reaction itself is stable but the reaction rate is slow.

  The reaction rate of the reaction between the carbonyl compound and hydrocyanic acid can be accurately controlled by appropriately changing the pH of the buffer solution. The pH of the buffer solution can be adjusted as appropriate by changing the molar ratio of the weak acid to the salt of the weak acid. For example, when glycolic acid is used as the weak acid and sodium glycolate is used as the salt of the weak acid, glycolic acid (GA) and sodium glycolate (GANa) are estimated from the acid dissociation constant of glycolic acid (3.63 [25 ° C.]). When the molar ratio of (GA / GANa) is 0.43, a buffer solution having a pH of 4 can be prepared.

For example, when the acid dissociation constant of a weak acid is Ka, in order to prepare a buffer solution having a pH of X, the molar ratio Y of weak acid to weak acid salt (mol number of weak acid / mol of weak acid salt) The number may be a value represented by the following formula (i).
Y = 10 ^(pKa-x) (i)

  The buffer is preferably prepared such that the difference between the pH at the start of the reaction of the carbonyl compound and hydrocyanic acid and the pH at the completion of the reaction is 0 to 1, It is more preferable that it is prepared as follows. By suppressing the change width of the pH as described above, the production rate of cyanohydrin is further remarkably improved. In addition, the reaction rate can be controlled with higher accuracy.

  In the production method according to the present embodiment, by adjusting the content of the weak acid and the salt of the weak acid in the buffer solution, the pH change range can be suppressed within the above range. Specifically, the content of the weak acid is 0.02 to 0.24 mol% and the content of the salt of the weak acid is 0.04 to 0.52 mol% with respect to the total amount of the carbonyl compound subjected to the reaction. Thus, the change width of the pH can be suppressed within the above range.

  In the method for producing cyanohydrin according to the present embodiment, for example, a buffer solution containing a carbonyl compound and having a pH of less than 7 is maintained in a predetermined temperature range, while adding hydrocyanic acid to the buffer solution, the buffer solution It can be carried out by reacting a carbonyl compound and hydrocyanic acid in the reaction.

  Said predetermined temperature range is 10-90 degreeC normally from a viewpoint from which the production | generation rate of cyanohydrin becomes favorable, Preferably it is 20-80 degreeC, More preferably, it is 30-60 degreeC. If the temperature is too high, the reverse reaction from cyanohydrin to the carbonyl compound proceeds, and sudden abnormal reactions are likely to occur, and the production rate of cyanohydrin tends to decrease. On the other hand, if the temperature is too low, the reaction itself is stable but the reaction rate is slow.

  The reaction of the carbonyl compound and hydrocyanic acid is preferably carried out while adding hydrocyanic acid to the buffer solution containing the carbonyl compound and temperature-controlled as described above. The addition rate is preferably 0.05 to 10 mol% / min, more preferably 0.1 to 5 mol% / min, based on the total amount of the carbonyl compound. If the addition rate is too fast, there may be abrupt pH fluctuation, and if the addition rate is too slow, the process time becomes longer and the working efficiency decreases. The temperature of the buffer solution is preferably adjusted so as to maintain the above-mentioned predetermined temperature range during the addition of hydrocyanic acid, and after the addition of hydrocyanic acid is completed until the reaction is completed. It is preferable to adjust the temperature range.

  The reaction time of the reaction between the carbonyl compound and hydrocyanic acid is usually about 1 to 10 hours. As described above, since the reaction rate is adjusted by changing the pH of the buffer solution, the reaction time can be appropriately adjusted in accordance with the reaction rate.

  In the reaction between the carbonyl compound and hydrocyanic acid, the pressure in the reaction zone may be normal pressure or under pressure. In addition, the production method according to this embodiment can be preferably carried out by either a batch method or a continuous method. When the continuous method is adopted, it is preferable to divide the reaction zone into two or more and carry out the reaction in multiple stages.

  After the reaction between the carbonyl compound and hydrocyanic acid is completed, the reaction solution containing cyanohydrin is preferably adjusted to a pH of preferably 2 or less, more preferably 1.5 or less by adding an acid such as sulfuric acid. . By adjusting the pH of the reaction solution in this manner, the reverse reaction from cyanohydrin to the carbonyl compound is suppressed, and the storage stability of cyanohydrin in the reaction solution is improved.

  Then, for example, cyanohydrin can be obtained by removing the solvent and residual hydrocyanic acid under reduced pressure and concentrating the reaction solution whose pH has been adjusted as described above. The temperature during concentration is preferably 50 ° C. or lower. If the temperature during concentration is higher than 50 ° C., cyanohydrin may be decomposed.

  The preferred embodiment of the present invention has been described above, but the present invention is not limited to the above embodiment.

  Next, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples, and can be appropriately modified and implemented without departing from the scope of the present invention.

Example 1
In the reactor, 79.54 parts by mass of a 37% by mass aqueous formaldehyde solution, 0.17 parts by mass of glycolic acid (purity 97% by mass), 0.50 parts by mass of sodium glycolate (purity 97% by mass), and 60 parts by mass of water were added. The temperature was raised to 45 ° C. while weighing, stirring and dissolving. The pH of this mixed solution at 45 ° C. was 3.9.

  In this mixed solution, 27.81 parts by mass of liquid hydrocyanic acid was added dropwise over 30 minutes. The pH of the reaction solution immediately after dropping all of the liquid hydrocyanic acid was 4.1. Then, it stirred at 45 degreeC for further 1 hour. The pH of the reaction solution at the completion of the reaction was 4.1, and the glycolonitrile production rate was 96% (formaldehyde basis).

(Example 2)
In a reactor, 79.54 parts by mass of a 37% by mass aqueous formaldehyde solution, 0.02 parts by mass of glycolic acid (purity 97% by mass), 0.05 parts by mass of sodium glycolate (purity 97% by mass), and 60 parts by mass of water were added. The temperature was raised to 45 ° C. while weighing, stirring and dissolving. The pH of this mixed solution at 45 ° C. was 3.6.

  In this mixed solution, 27.81 parts by mass of liquid hydrocyanic acid was added dropwise over 30 minutes. The pH of the reaction solution immediately after dropping all of the liquid hydrocyanic acid was 3.7. Thereafter, the mixture was further stirred at 45 ° C. for 1.5 hours. The pH of the reaction solution at the completion of the reaction was 3.8, and the glycolonitrile production rate was 96% (formaldehyde standard).

(Example 3)
In the reactor, 79.54 parts by mass of a 37% by mass aqueous formaldehyde solution, 0.33 parts by mass of glycolic acid (purity 97% by mass), 0.99 parts by mass of sodium glycolate (purity 97% by mass), and 60 parts by mass of water were added. The temperature was raised to 45 ° C. while weighing, stirring and dissolving. The pH of this mixed solution at 45 ° C. was 4.0.

  In this mixed solution, 27.81 parts by mass of liquid hydrocyanic acid was added dropwise over 30 minutes. The pH of the reaction solution immediately after dropping all of the liquid hydrocyanic acid was 4.2. Then, it stirred at 45 degreeC for further 1 hour. When the reaction was completed, the pH of the reaction solution was 4.2, and the glycolonitrile production rate was 97% (formaldehyde standard).

Example 4
In a reactor, 57.32 parts by mass of acetaldehyde, 0.30 parts by mass of lactic acid (purity 90% by mass), 0.81 parts by mass of sodium lactate (purity 90% by mass), and 24.05 parts by mass of water are weighed and stirred. , Dissolved and cooled to 7 ° C. The pH of this mixed solution at 7 ° C. was 5.3.

  In this mixed solution, 36.90 mass parts of liquid hydrocyanic acid was dripped over 1 hour. The pH of the reaction solution immediately after dropping all of the liquid hydrocyanic acid was 4.5. Then, it heated up at 20 degreeC and stirred for further 2 hours. The pH of the reaction liquid at the completion of the reaction was 4.3, and the lactonitrile production rate was 99% (based on acetaldehyde).

(Comparative Example 1)
In the reactor, 79.54 parts by mass of 37% by mass aqueous formaldehyde solution and 60 parts by mass of water were weighed and heated to 45 ° C. while stirring. The pH of this solution at 45 ° C. was 4.4.

  To this solution, 0.06 part by mass of a 0.5% by mass sulfuric acid aqueous solution and 0.13 part by mass of a 0.1% by mass caustic soda aqueous solution were added to adjust the pH to 4.1. When 27.03 parts by mass of liquid hydrocyanic acid was added dropwise to this solution over 30 minutes, the pH of the reaction solution gradually decreased, and the pH of the reaction solution immediately after adding all of the liquid hydrocyanic acid was 2.7. . Then, it stirred at 45 degreeC for further 1 hour. The pH of the reaction solution after stirring for 1 hour was 2.7, and the glycolonitrile production rate was 86% (formaldehyde reference).

  From the above results, when a carbonyl compound and hydrocyanic acid are reacted in a solution in which the pH is simply adjusted with an acid and a base, the pH fluctuates with the progress of the reaction, and the production rate of cyanohydrin does not increase so much. I understand that. In contrast, when a carbonyl compound and hydrocyanic acid are reacted in a buffer adjusted to an acidic pH, the pH does not fluctuate greatly, so the reaction rate is stabilized within an appropriate range, and the rate of cyanohydrin production is high. I understand that

Claims (8)

  Reacting a carbonyl compound with hydrocyanic acid in the absence of a catalyst or in the presence of a catalyst selected from the group consisting of sodium cyanide and potassium cyanide in a buffer having a pH of less than 7 to obtain a cyanohydrin. Production method. While holding a buffer solution containing a carbonyl compound and having a pH of less than 7 at 10 to 90 ° C. , hydrocyanic acid is added to the buffer solution, and the carbonyl compound and the hydrocyanic acid are reacted in the buffer solution. And obtaining a cyanohydrin
The method for producing cyanohydrin, wherein the reaction of the carbonyl compound and the hydrocyanic acid is carried out in the absence of a catalyst or in the presence of a catalyst selected from the group consisting of sodium cyanide and potassium cyanide.   The method for producing cyanohydrin according to claim 1 or 2, wherein the buffer contains a weak acid and a salt of the weak acid.   The method for producing cyanohydrin according to any one of claims 1 to 3, wherein the buffer solution contains an organic acid and a salt of the organic acid.   The said organic acid is a manufacturing method of the cyanohydrin of Claim 4 which is the same kind of alpha-hydroxycarboxylic acid as the alpha-hydroxycarboxylic acid produced | generated when the said cyanohydrin is hydrolyzed.   The method for producing cyanohydrin according to claim 4, wherein the organic acid is glycolic acid.   The method for producing cyanohydrin according to any one of claims 1 to 6, wherein the carbonyl compound is an aldehyde.   The method for producing cyanohydrin according to any one of claims 1 to 7, wherein the carbonyl compound is formaldehyde.