JP2011105608A - Method for producing optically active cyanohydrins - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing optically active cyanohydrins, by which optically active cyanohydrins widely used as a raw material for medicines or agrochemicals can be obtained from an aliphatic aldehyde by an industrially simple method in high purity and in a high yield. <P>SOLUTION: The optically active cyanohydrins can industrially easily be obtained in high purity and in a high yield, from aliphatic aldehydes and a cyanizing agent such as inexpensive hydrogen cyanide or acetone cyanhydrin by using an organic metal complex comprising a (R, R)- or (S, S)-bisoxazolylpyridines and aluminum chloride as a catalyst. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an organometallic complex comprising (R, R)-or (S, S) -bisoxazolylpyridines and aluminum chloride using aliphatic aldehydes as hydrogen cyanide or acetone cyanohydrin as a cyanating agent. The present invention relates to a process for producing optically active cyanohydrins as asymmetric induction catalysts. Optically active cyanohydrins obtained with high yield and high optical purity by the present invention are α-hydroxy acids, α-hydroxy ketones, β-amino alcohols, α-amino acids, synthetic pyrethrenoids widely used as raw materials for pharmaceuticals and agricultural chemicals. It can be easily derived into intermediates and the like, and is very useful as a method for producing pharmaceutical and agricultural chemical intermediates.

  Optically active cyanohydrins are widely used as raw materials for pharmaceuticals and agricultural chemicals, and are particularly important for the synthesis of α-hydroxy acids, α-hydroxy ketones, β-amino alcohols, α-amino acids, synthetic pyrethrenoid intermediates and the like.

  Asymmetric selective production methods of optically active cyanohydrins are classified into (1) a production method using a biocatalyst and (2) a production method using an asymmetric organic synthesis technique. As a production method using a biocatalyst, an enzyme reaction using an enzyme possessed by a microorganism or the like is widely known. For example, oxynitrilase, lipase, hydroxynitrile lyase, amino dehydrogenase and the like can be mentioned as enzymes used for the enzyme reaction. As a method for obtaining optically active cyanohydrins from aliphatic aldehydes, a production method (Patent Document 1) in which oxynitrilase derived from Hevea brasiliensis and hydrogen cyanide is stereoselectively reacted has been reported. However, the production method using a biocatalyst is often applicable only to aldehydes having a specific substituent because the substrate application range of the enzyme is very narrow. In addition, the conditions such as temperature, pH, substrate concentration, solvent, etc. at which the enzyme used in the enzyme reaction can be used are limited. If the conditions deviate from the use conditions, the reaction activity of the enzyme is significantly reduced. Therefore, the enzyme reaction must be performed under mild conditions, and the rate of the enzyme reaction is slow, which is problematic in terms of production efficiency.

  Therefore, the production method of optically active cyanohydrins using asymmetric organic synthesis technology is currently most widely used. Catalytic asymmetric cyanation reactions using organometallic complex catalysts can be applied to a wide range of substrates, and it is easy to improve the stereoselectivity and reactivity of substrate aldehydes by changing the ligand structure. is there. For example, a method for producing optically active cyanohydrins using an organometallic complex catalyst prepared from optically active binaphthols and diethylaluminum chloride has been reported (Patent Document 2). In addition, a process for producing optically active cyanohydrins using a Schiff base ligand composed of optically active β-amino alcohols and salicylaldehydes, a titanium tetraalkoxide compound and an organometallic complex catalyst prepared from water (Patent Document 3) It has been reported. However, organometallic complex catalysts prepared from optically active binaphthols and diethylaluminum chloride are difficult to obtain due to the multi-step synthesis of the ligand, and the reaction temperature is high only at low temperatures of -40 ° C. or lower. It is difficult to use industrially such as obtaining an optical yield. An organometallic complex catalyst prepared from a Schiff base ligand, a titanium tetraalkoxide compound and water is easy to synthesize the ligand used, and has a merit that a small amount of catalyst can be used for the reaction. At the time of preparation or the water content contained in the reaction solution greatly affects the reaction results, and it is difficult to control the water content. Furthermore, trimethylsilyl cyanide is preferred as the cyanating agent, and when hydrogen cyanide, which is an inexpensive cyanating agent, is used, the progress of the reaction is not recognized, and it is difficult to use industrially. Accordingly, there has been a demand for a method for producing optically active cyanohydrins that allows the cyanation reaction of aliphatic aldehydes to proceed with high yield and high optical yield using an inexpensive and easy-to-handle organometallic complex catalyst.

European Patent Application No. 0927130 JP 2001-348392 A International Publication No. 2006/041000

  In view of the above circumstances, development of a method for producing optically active cyanohydrins with high purity and high yield using a cheaper asymmetric catalyst and a cyanating agent is required. However, it is difficult to obtain optically active cyanohydrins from aliphatic aldehydes with high yields and high optical yields using asymmetric organic synthesis technology. There are few examples of obtaining optically active cyanohydrins from aliphatic aldehydes. Usually, since aliphatic aldehydes are difficult to obtain interaction due to orbital overlap with the organometallic ligand as a catalyst, the asymmetric induction effect by the organometallic complex catalyst cannot be expected so much. On the other hand, it is proposed that these catalytic asymmetric cyanation reactions have the effect of effectively increasing the optical purity of the product when a bulky cyanating agent such as trimethylsilyl cyanide is used as the cyanating agent. . However, cyanating agents such as trialkyl-substituted silylcyanides are expensive and difficult to use industrially.

  Accordingly, the present invention provides an optically active cyanohydrin that is widely used as a raw material for pharmaceuticals and agricultural chemicals, when an aliphatic aldehyde and an inexpensive hydrogen cyanide or a cyanating agent such as acetone cyanohydrin are synthesized. For obtaining high purity and high yield by using an organometallic complex consisting of (R, R)-or (S, S) -bisoxazolylpyridines and aluminum chloride as a catalyst The main purpose is to provide

  In order to industrially use an asymmetric cyanation reaction using an organometallic complex catalyst prepared from an organometallic ligand and a metal reagent, it is important that the restrictions on the reaction conditions are moderate. However, in general, 1) the catalyst is deactivated by moisture, 2) a low temperature condition of about −20 to −78 ° C. is required, and 3) the organometallic ligand used for the organometallic complex catalyst is expensive, In many cases, the synthesis requires many steps. 4) Due to factors such as the need for an expensive cyanating agent such as trimethylsilylcyanide, it is often difficult to implement industrially.

In addition, the difference in chemical yield and optical yield due to the aldehydes used as the substrate is large, and even when many of the reported organometallic complex catalysts show good results with aromatic aldehydes, aliphatic aldehydes are used as substrates. In many cases, sufficient results cannot be obtained. Therefore, it is difficult to predict the stereoselectivity of asymmetric cyanation reactions targeting aliphatic aldehydes, and the search for a catalyst in which cyanation proceeds with high selectivity to aliphatic aldehydes and the conditions for their use It is necessary to conduct a wide range of searches.

  In general, aliphatic aldehydes are different from cyanation of aromatic aldehydes, and interaction and asymmetry using orbital overlap with aromatic rings and conjugated double bonds of many asymmetric organometallic complex catalysts. Induction effect cannot be expected. Therefore, it is difficult to obtain sufficient stereoselectivity in the transition state of the reaction consisting of an organometallic complex catalyst, a cyanating agent, and aldehydes, and a sterically bulky cyanating agent such as trimethylcyanide is used. Even if it exists, the optical purity of the cyanohydrin obtained becomes low. That is, it is very difficult to use an inexpensive cyanating agent such as hydrogen cyanide having little steric hindrance for the asymmetric cyanation reaction.

  Therefore, screening of organometallic complex catalysts that can promote the cyanation reaction of aliphatic aldehydes with high yield and high optical purity even when using cheap and industrially available hydrogen cyanide or acetone cyanohydrin is conducted. It was. As a result, it was found that when a catalyst comprising bisoxazolylpyridines and aluminum chloride was used, both the chemical and optical yields of aliphatic aldehydes were good.

  Conventionally, as a method for producing optically active cyanohydrins, a method using a cyanation reaction of an aldehyde catalyzed by an organometallic complex composed of a bisoxazolylpyridine and a metal reagent includes diisopropyloxazolylpyridine by Edmunds Lukevics et al. Synthesis method of optically active mandelonitrile from benzaldehyde using aluminum chloride as organometallic complex catalyst and trimethylsilylcyanide as cyanating agent (Tetrahedron: Asymmetry, 1997, 8 (8), 1279-1285), Peter M. et al. Smith et al., A method for synthesizing optically active cyanohydrins from aldehydes using organometallic complex catalysts consisting of bisoxazolylpyridines and lanthanoids, particularly ytterbium chloride (Tetrahedron Letter, 1999, 40, 1763-1766), It was known. These methods require at least 10 mol% or more of an organometallic complex catalyst, and expensive trimethylsilyl cyanide is used as the cyanating agent. Furthermore, when an aromatic aldehyde is used as a substrate, the target cyanohydrin has been successfully obtained with a high asymmetric yield, but the aliphatic aldehyde has an optical purity of about 40% e.e. e. And is not practical for industrial use.

  However, in the presence of an organometallic complex catalyst prepared so that the molar ratio of the bisoxazolylpyridines to aluminum chloride is 1.2 to 10 according to the present invention, hydrogen cyanide or acetone cyanohydrin is used as a cyanating agent as a substrate. The method of reacting the aldehyde in a molar concentration range of 1 to 30 mol / L is a conventional aliphatic group produced by an organometallic complex catalyst comprising a bisoxazolylpyridine having a trialkyl-substituted silylcyanide as a cyanating agent and a metal reagent. Compared with the method for producing optically active cyanohydrin from aldehydes, in addition to obtaining optically active cyanohydrins with high yield and high optical purity, the reaction time usually required for 2 to 24 hours can be shortened. It has the property of Furthermore, by preparing the molar ratio of bisoxazolylpyridines to aluminum chloride to be excessive, optically active cyanohydrins can be easily obtained industrially in a short time with high yield and high optical purity. And reached the present invention.

（式中、Ｒ１は炭素数１〜９のアルキル基を表す。）

（式中、Ｒ２、Ｒ３は水素原子、炭素数１〜９のアルキル基、または炭素数６〜１４のアリール基を表す。但し、Ｒ２、Ｒ３が同じ置換基である場合を除く。）

（式中、Ｒ１は炭素数１〜９のアルキル基を表す。） That is, the present invention comprises (R, R)-or (S, S) -bisoxazolylpyridines represented by the general formula (2) and aluminum chloride, and the bisoxazolylpyridines with respect to aluminum chloride. In the presence of an organometallic complex catalyst having a molar ratio of 1.2 to 10,
An optically active cyanohydrin represented by general formula (3), characterized by reacting hydrogen cyanide or acetone cyanohydrin with an aldehyde represented by general formula (1) having a molar concentration with respect to a solvent of 1 to 30 mol / L. Manufacturing method.

(In the formula, R1 represents an alkyl group having 1 to 9 carbon atoms.)

(In the formula, R 2 and R 3 represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or an aryl group having 6 to 14 carbon atoms, except when R 2 and R 3 are the same substituent.)

(In the formula, R1 represents an alkyl group having 1 to 9 carbon atoms.)

  Hydrogen cyanide or acetone cyanide in the presence of a catalyst prepared such that the molar ratio of (R, R)-or (S, S) -bisoxazolylpyridines of the present invention to aluminum chloride is 1.2-10 In the method of producing optically active cyanohydrins from aliphatic aldehydes using hydrin as a cyanating agent, asymmetric induction is difficult when an organometallic complex catalyst is used, and usually 40 to 50% e from aliphatic aldehydes. . e. The optical purity of optically active cyanohydrins obtained as an optical purity of about 75% e. e. And is easily manufactured industrially with a high yield.

When hydrogen cyanide or acetone cyanohydrin is used as the cyanating agent, optically active cyanohydrins can be obtained in high yield and high optical purity in a short time, and cyanating agents such as trialkyl-substituted silyl cyanides are used. The amount of catalyst can be greatly reduced compared to the case.

In addition, it was found that the amount of catalyst required for the reaction can be further reduced by setting the molar concentration of the aliphatic aldehyde as a substrate in the range of 1 to 30 mol / L. After the cyanating agent was added, the reaction could be completed in a short time.
In addition, since optically active cyanohydrins with high optical purity can be obtained by combining techniques such as optical resolution, optically active cyanohydrins can be obtained more efficiently than in the case of racemic optical isomer resolution. This is an economically advantageous process for producing an optically active cyanohydrin that is industrially inexpensive.

  In the method of the present invention, aldehydes that can be used as a starting material are not particularly limited, but representative examples include propionaldehyde, butyraldehyde, valeraldehyde, isovaleraldehyde, hexaaldehyde, heptaldehyde, octylaldehyde, Isobutyraldehyde, 2-methylbutyraldehyde, 2-ethylbutyraldehyde, 2-ethylhexanal, pivalaldehyde, 2,2-dimethylpentanal, cyclopropanecarbaldehyde, cyclohexanecarbaldehyde, crotonaldehyde, 3-methylcrotonaldehyde, Methacrolein or trans-2-hexenal, especially butyraldehyde, isobutyraldehyde, valeraldehyde, pivalaldehyde, propionaldehyde, Cyclohexane carboxaldehyde is preferably used.

  Further, examples of the cyanating agent used in the reaction of the present invention include hydrogen cyanide or acetone cyanohydrin. In particular, when hydrogen cyanide is used, the reaction time is shortened and the optical yield is remarkably improved.

（Ｒ２，Ｒ３は水素原子、炭素数１〜９のアルキル基、または炭素数６〜１４のアリール基を表す。但し、Ｒ２、Ｒ３が同じ置換基である場合を除く。）で示される（Ｒ，Ｒ）−、または（Ｓ，Ｓ）−ビスオキサゾリルピリジン類のアルミニウム錯体を触媒とすることを特徴とする。 In the reaction of these aliphatic aldehydes with a cyanating agent, the method of the present invention is represented by the general formula (2)

(R2 and R3 represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or an aryl group having 6 to 14 carbon atoms, except when R2 and R3 are the same substituent). , R)-or (S, S) -bisoxazolylpyridines as a catalyst.

  As the substituent of the oxazoline ring, any substituent can be used as long as it has a structure represented by the general formula (2). For example, an isobutyl group, an isopropyl group, an n-butyl group, an n-propyl group, Examples thereof include a tert-butyl group, a phenyl group, and a naphthyl group. Aluminum chloride is preferably used as the aluminum compound.

アルデヒド類にシアノ化剤を作用させる際に、一般式（２）で示される触媒を用いて光学活性シアノヒドリン類を製造する方法である。 That is, in the method of the present invention, as in the general formula (A) (wherein R1 is the same as described above, the sign of * represents an asymmetric carbon atom),

This is a method for producing optically active cyanohydrins using a catalyst represented by the general formula (2) when a cyanating agent is allowed to act on aldehydes.

  The asymmetric cyanation catalyst used in the reaction of the present invention is prepared so that the molar ratio of (R, R)-or (S, S) -bisoxazolylpyridines to aluminum chloride is 1.2-10. It is desirable to do. When the molar ratio of the bisoxazolylpyridines to aluminum chloride is less than 1.2, the reactivity is lowered and the optical purity is remarkably lowered. On the other hand, there is no particular problem when the molar ratio of the bisoxazolylpyridines to aluminum chloride is greater than 10, but using a large amount of the bisoxazolylpyridines is expensive and impractical.

  Specifically, the asymmetric cyanation catalyst was prepared by adding 1 millimole to 0.001 ml of aluminum chloride in a nitrogen stream with respect to 100 mL of the solvent used in carrying out the reaction of the present invention as described below. 59 mol, preferably 2 mmol to 0.2 mol are suspended, and then (R, R)-or (S, S) -bisoxazolylpyridines are added in an amount of 1.2 mmol to 5.9 mol, preferably Is obtained by adding 2.4 mmol to 2 mol and stirring at a temperature of -30 to 50 ° C, preferably -10 to 30 ° C for 0.5 to 12 hours. The reaction of the present invention may be further carried out by adding a reactant to this solution, and may be used after the catalyst is isolated.

  In the reaction of the present invention, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, and chlorobenzene, ethyl acetate, butyl acetate, 1,4-dioxane, toluene, benzene, and the like are used as solvents. Halogenated hydrocarbons such as methylene, 1,2-dichloroethane, chlorobenzene and chloroform are preferred.

  The solvent should be used in an amount of 0.034 to 1 mL (molar concentration is 1 to 30 mol / L), preferably 0.1 to 1 mL (molar concentration is 1 to 10 mol / L) per 1 mmol of aldehydes. Is preferred. When the molar concentration of the substrate aldehyde is larger than 30 mol / L, the effect of stabilizing the catalyst by the solvent cannot be obtained, so that the reactivity is lowered and the optical purity of the produced cyanohydrin is lowered. On the other hand, when the molar concentration of the substrate aldehyde is less than 1 mol / L, the yield of cyanohydrin and optical purity are decreased, and further, the oxidation reaction of the substrate aldehyde is preferentially performed and the corresponding carboxylic acid by-product is recognized. Absent.

  In the reaction of the present invention, 1 to 3 mol, preferably 1.2 to 2.5 mol of cyanating agent is used per 1 mol of aldehydes.

  That is, the catalyst is used in an amount of 0.001 to 0.5 mol, preferably 0.02 to 0.1 mol, per 1 mol of aldehydes.

  In the reaction of the present invention, these aldehydes and cyanating agent are continuously added to the catalyst solution, and the reaction is performed by stirring at -20 to 40 ° C, preferably -10 to 30 ° C for 0.1 to 24 hours. Can be implemented.

  Thus, by using the method of the present invention, optically active cyanohydrins can be easily obtained industrially from aliphatic aldehydes with high purity and high yield. For example, as raw materials for pharmaceuticals and agricultural chemicals. Widely used α-hydroxy acids, α-hydroxy ketones, β-amino alcohols, α-amino acids, synthetic pyrethrenoid intermediates, etc. with high purity and high yield, without requiring special equipment and efficiently It was also possible to manufacture economically.

  The present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to these examples. In the following examples, the optical purity of cyanohydrin was determined by GC analysis. The following conditions were used for the analysis.

Column; β-Dex325 (30 m × 0.25 mm × 0.25 μm thickness, manufactured by SUPELCO)
Carrier gas; helium detection; FID
Detection temperature: 230 ° C
Injection temperature: 180 ° C
Column temperature: 120 ° C

Example 1
Under a nitrogen atmosphere, (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4)

1.13 g (3.8 mmol) was dissolved in 50 mL of methylene chloride, 0.34 g (2.5 mmol) of aluminum chloride was further added, and the mixture was stirred at room temperature for 1 hour. To this solution was added 4.33 g (50 mmol) of pivalaldehyde, the solution was cooled to 0 ° C., 1.6 g (60 mmol) of hydrogen cyanide was added, and the mixture was allowed to react for 10 minutes, followed by GC analysis. As a result, the conversion of the substrate was 99.8%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 75.7% e.e. e. Met.

Example 2
Under a nitrogen atmosphere, 450 mg (1.5 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 50 mL of methylene chloride. 136 mg (1 mmol) of aluminum chloride was added and stirred at room temperature for 1 hour. To this solution was added 4.33 g (50 mmol) of pivalaldehyde, the solution was cooled to 0 ° C., 1.6 g (60 mmol) of hydrogen cyanide was added, and the mixture was reacted by stirring for 4 hours, followed by GC analysis. As a result, the conversion rate of the substrate was 82.7%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 65.8% e.e. e. Met.

Example 3
Under a nitrogen atmosphere, 604 mg (2.04 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 2 mL of methylene chloride, and 223 mg (1.7 mmol) of aluminum chloride was added, and the mixture was stirred at room temperature for 1 hour. To this solution, 1.44 g (16.6 mmol) of pivalaldehyde and 1.68 g (20 mmol) of acetone cyanohydrin were added and reacted by stirring at room temperature for 1 hour, and GC analysis was performed. The substrate conversion was 99.8%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 67.1% e.e. e. Met.

Comparative Example 1
The reaction was performed in the same manner as in Example 3 except that the amount of the solvent was 100 mL. Analysis was conducted 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the substrate conversion rate was 64.2% and only pivalic acid was produced.

Example 4
Under a nitrogen atmosphere, 181 mg (0.6 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 2 mL of methylene chloride, and 67 mg (0.5 mmol) of aluminum chloride was added and stirred at room temperature for 1 hour. To this solution, 216 mg (2.5 mmol) of pivalaldehyde and 234 mg (2.8 mmol) of acetone cyanohydrin were added and reacted by stirring at room temperature for 2 hours. The conversion was 97.7%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 66.4% e.e. e. Met.

Comparative Example 2
The reaction was conducted in the same manner as in Example 4 except that the cyanating agent was 295 mg (2.8 mmol) of trimethylsilylcyanide. The analysis was conducted 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the conversion rate of the substrate was 88.4%, and after removal of the siloxy group, the 2-hydroxy-3,3-dimethylbutanenitrile produced Has an optical purity of 38.6% e.e. e. Met.

Comparative Example 3
Under a nitrogen atmosphere, 151 mg (0.5 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 2 mL of methylene chloride, and 67 mg (0.5 mmol) of aluminum chloride was added and stirred at room temperature for 2 hours. To this solution, 216 mg (2.5 mmol) of pivalaldehyde and 298 mg (3.5 mmol) of acetone cyanohydrin were added and reacted by stirring at room temperature for 2 hours. The conversion was 10% and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 53.8% e.e. e. Met.

Example 5
Under a nitrogen atmosphere, 1.51 g (5 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 25 mL of methylene chloride. 0.34 g (2.5 mmol) of aluminum chloride was added and stirred at room temperature for 1 hour. To this solution was added 2.15 g (25 mmol) of pivalaldehyde, the solution was cooled to 0 ° C., 1.01 g (38 mmol) of hydrogen cyanide was added, and the mixture was allowed to react with stirring for 2 hours for GC analysis. However, the conversion of the substrate was 92.3%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 70.3% e.e. e. Met.

Comparative Example 4
The same as Example 5 except that the amount of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) used was changed to 760 mg (2.5 mmol). The reaction was performed. Analysis was conducted 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the conversion of the substrate was 52.1%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 50.8% e. . e. Met.

Example 6
Under a nitrogen atmosphere, 151 mg (0.51 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 1.5 mL of methylene chloride. Further, 22 mg (0.17 mmol) of aluminum chloride was added, and the mixture was stirred at room temperature for 1 hour. When 144 mg (1.66 mmol) of pivalaldehyde and 168 mg (2 mmol) of acetone cyanohydrin were added to this solution and reacted by stirring at room temperature for 1 hour, GC analysis was conducted. Was 98.8%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 69.8% e.e. e. Met.

Comparative Example 5
Under a nitrogen atmosphere, (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) (101 mg, 0.34 mmol) was dissolved in methylene chloride (2 mL). 22 mg (0.17 mmol) of aluminum chloride was added and stirred at room temperature for 1 hour. When 144 mg (1.66 mmol) of pivalaldehyde and 168 mg (2 mmol) of trimethylsilylcyanide were added to this solution and stirred for 22 hours at room temperature, GC analysis was performed. After removing the siloxy group at 78.2%, the optical purity of the resulting 2-hydroxy-3,3-dimethylbutanenitrile is 42.0% e.e. e. Met.

Example 7
Under a nitrogen atmosphere, 76 mg (0.23 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 1 mL of methylene chloride, and 22 mg (0.17 mmol) of aluminum chloride was added and stirred at room temperature for 1 hour. When 288 mg (3.32 mmol) of pivalaldehyde and 336 mg (4 mmol) of acetone cyanohydrin were added to this solution and reacted with stirring at room temperature for 2 hours, GC analysis was conducted. Is 95.4%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile is 68.3% e.e. e. Met.

Comparative Example 6
The reaction was performed in the same manner as in Example 7 except that the amount of the solvent was 0.1 mL. Analysis was performed 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the substrate conversion was 52.1%, and the chemical yield of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 24.7%. The optical purity is 41.1% e.e. e. Met.

Example 8
Under a nitrogen atmosphere, 60 mg (0.2 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 1 mL of methylene chloride. 22 mg (0.17 mmol) of aluminum chloride was added and stirred at room temperature for 1 hour. To this solution, 120 mg (1.66 mmol) of isobutyraldehyde and 168 mg (2 mmol) of acetone cyanohydrin were added and reacted by stirring at room temperature for 2 hours. When GC analysis was performed, the conversion rate of the substrate was as follows. 98.4%, The optical purity of the produced 2-hydroxy-3-methylbutanenitrile is 67.6% e.e. e. Met.

Example 9
The reaction was conducted in the same manner as in Example 8 except that 96 mg (1.66 mmol) of propionaldehyde was used. Analysis was conducted 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the conversion of the substrate was 99.1%, and the optical purity of the produced 2-hydroxybutanenitrile was 68.5% e.e. e. Met.

Example 10
Under a nitrogen atmosphere, 1.13 g (3.8 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was added to 50 mL of 1,2-dichloroethane. In addition, 0.34 g (2.5 mmol) of aluminum chloride was added, and the mixture was stirred at room temperature for 1 hour. To this solution was added 4.33 g (50 mmol) of pivalaldehyde, the solution was cooled to 0 ° C., 1.6 g (60 mmol) of hydrogen cyanide was added, and the mixture was allowed to react for 10 minutes, followed by GC analysis. As a result, the conversion rate of the substrate was 100%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 76.4% e.e. e. Met.

Example 11
The reaction was conducted in the same manner as in Example 10 except that 50 mL of 1,4-dioxane was used as the solvent. Analysis was conducted 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the conversion of the substrate was 92.9%, and the optical purity of the produced 2-hydroxybutanenitrile was 71.7% e.e. e. Met.

Example 12
The reaction was performed in the same manner as in Example 10 except that the solvent was 50 mL of toluene. Analysis was conducted 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the conversion of the substrate was 95.8%, and the optical purity of the produced 2-hydroxybutanenitrile was 65.8% e.e. e. Met.

Example 13
The reaction was performed in the same manner as in Example 10 except that the solvent was 50 mL of chlorobenzene. Analysis was conducted 2 hours after the start of stirring of the asymmetric cyanation reaction. As a result, the conversion of the substrate was 97.5%, and the optical purity of the produced 2-hydroxybutanenitrile was 72.6% e.e. e. Met.

Comparative Example 7
Under a nitrogen atmosphere, 112 mg (0.37 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 5 mL of acetonitrile, and further chlorinated. 102 mg (0.37 mmol) of ytterbium was added, and the mixture was stirred at room temperature for 1 hour. At 0 ° C., 320 mg (3.7 mmol) of pivalaldehyde and 376 mg (4.4 mmol) of acetone cyanohydrin were added to this solution, and the mixture was reacted by stirring at 0 ° C. for 2 hours for GC analysis. However, the substrate conversion was 0%.

Comparative Example 8
Under a nitrogen atmosphere, 198 mg (0.66 mmol) of (R, R) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (4) was dissolved in 10 mL of acetonitrile, and further chlorinated. 183 mg (0.66 mmol) of ytterbium was added, and the mixture was stirred at room temperature for 1 hour. When 570 mg (6.57 mmol) of pivalaldehyde and 987 mg (7.88 mmol) of trimethylsilylcyanide were added to this solution at 0 ° C., the mixture was stirred at 0 ° C. for 2 hours to perform a GC analysis. The substrate conversion was 95.4%, and after removal of the siloxy group, the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 13.4% e.e. e. Met.

Example 14
Under a nitrogen atmosphere, (R, R) -2,6-bis (4-phenyl-2-oxazolin-2-yl) pyridine (5)

1.0 g (2.71 mmol) was dissolved in 35 mL of methylene chloride, and 0.25 g (1.96 mmol) of aluminum chloride was further added, followed by stirring at room temperature for 1 hour. To this solution was added 3.57 g (41.4 mmol) of pivalaldehyde, the solution was cooled to 0 ° C., 1.96 g (72.5 mmol) of hydrogen cyanide was added, and stirred for 4 hours to react. As a result of GC analysis, the conversion of the substrate was 93.2%, and the optical purity of the produced 2-hydroxy-3,3-dimethylbutanenitrile was 56.4% e.e. e. Met.

  Useful in the fields of medicine and agricultural chemicals. Special equipment is also required for α-hydroxy acids, α-hydroxy ketones, β-amino alcohols, α-amino acids, synthetic pyrethrenoid intermediates, etc. that are widely used as raw materials for pharmaceuticals and agricultural chemicals, with high purity and high yield. It is possible to manufacture efficiently and economically.

Claims (5)

It comprises (R, R)-or (S, S) -bisoxazolylpyridines represented by the general formula (2) and aluminum chloride, and the molar ratio of the bisoxazolylpyridines to aluminum chloride is 1.2. In the presence of an organometallic complex catalyst of
An optically active cyanohydrin represented by general formula (3), characterized by reacting hydrogen cyanide or acetone cyanohydrin with an aldehyde represented by general formula (1) having a molar concentration with respect to a solvent of 1 to 30 mol / L. Manufacturing method.

(In the formula, R1 represents an alkyl group having 1 to 9 carbon atoms.)

(In the formula, R 2 and R 3 represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or an aryl group having 6 to 14 carbon atoms, except when R 2 and R 3 are the same substituent.)

(In the formula, R1 represents an alkyl group having 1 to 9 carbon atoms.) The substituents R2 and R3 of the (R, R)-or (S, S) -bisoxazolylpyridines are hydrogen atom, isobutyl group, sec-butyl group, isopropyl group, n-butyl group, n-propyl group. The method for producing optically active cyanohydrins according to claim 1, wherein the substituent is selected from the group consisting of tert-butyl group, phenyl group, and naphthyl group. The substituent R1 of the aldehyde represented by the general formula (1) is an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, an ethyl group, or a cyclohexyl group. A process for producing the optically active cyanohydrins described in 1. 4. The solvent according to claim 1, wherein the solvent is selected from the group consisting of methylene chloride, 1,2-dichloroethane, chloroform, chlorobenzene, benzene, toluene, ethyl acetate, butyl acetate, and 1,4-dioxane. A method for producing optically active cyanohydrins. 5. The process for producing an optically active cyanohydrin according to claim 1, wherein the reaction temperature is −20 ° C. to 40 ° C.