JP5501701B2 - Method for asymmetric cyanation of imine - Google Patents

Description

  The present invention relates to a method for asymmetric cyanation of imine.

There have already been many reports on methods for asymmetric cyanation of imines. For example, the following representative examples can be given.
(1) A method using an optically active thiourea type organic catalyst (Non-patent Document 1).
(2) A method using an optically active ligand derived from sugar and a catalyst prepared from gadolinium alkoxide (Non-patent Document 2).
(3) A method using a catalyst prepared from optically active amino alcohol and titanium alkoxide (Non-Patent Documents 3, 4, and 5).
(4) A method using a catalyst prepared from a partially hydrolyzed product of optically active amino alcohol and titanium alkoxide (Patent Documents 1 and 2).
(5) Mechanism of Lewis acid catalyzed reaction using imine compound as substrate (Non-patent Document 6).

International Publication No. 2008/121076 Pamphlet International Publication No. 2009/041919 Pamphlet

J. et al. Am. Chem. Soc. 124, 10012 (2002) J. et al. Am. Chem. Soc. 125, 5634 (2003) Tetrahedron Letters, 44 (2003), 3805-3808 Tetrahedron, 60, 10559 (2004) Tetrahedron, 65, 5849-5854 (2009) J. et al. Am. Chem. Soc. , 121, no. 17, p. 4284-4285 (1999)

  In the method (1), the corresponding optically active aminonitrile can be obtained with high optical purity by asymmetric cyanation of imine. However, for example, it is necessary to perform the reaction at an extremely low temperature of −78 ° C., and a long reaction time is required.

  In the method (2), the reaction temperature is, for example, about −40 ° C., the reaction temperature limit is slightly relaxed, and the reaction time is shortened. However, it is necessary to synthesize optically active ligands through more steps than sugar, and it is necessary to use gadolinium alkoxide, which is a rare earth element.

  The method (3) solves the problem of the method (2) in that a catalyst can be prepared from an optically active amino alcohol that can be synthesized more easily and an easily available titanium alkoxide. However, there is a problem that a reaction temperature of about 0 ° C. is required and the reaction time is long.

  In the method (4), high enantioselectivity is exhibited in the reaction near room temperature, and the above-mentioned problems are solved. However, as a catalyst precursor, it is necessary to react a certain amount of water with titanium alkoxide to prepare a partially hydrolyzed product, and there is a problem that the catalyst preparation process is complicated.

  As described above, there is no known method for asymmetric cyanation of imine that has industrially desirable conditions.

  An object of the present invention is to provide a novel method for asymmetric cyanation of imine. By this method, an optically active aminonitrile can be produced industrially advantageously.

The inventors of the present invention have studied to solve the above problems, and by carrying out asymmetric cyanation of imine using a cyanating agent in the presence of optically active amino alcohol, titanium alkoxide, and alcohols, As a result of finding that a high optically active aminonitrile can be obtained and further intensive studies, the present invention was completed.
That is, the present invention includes the following inventions.

[1] An optically active amino alcohol represented by the following general formula (1), a titanium alkoxide represented by the following general formula (2), and ethanol, n-propanol, n-butanol and 2,6-xylenol. the presence of that alcohol, under anhydrous conditions, and the imine represented by the following general formula (5), is reacted with a cyanating agent represented by the following general formula (6), the asymmetric cyanation the imine And producing an optically active aminonitrile .

（式中、Ｒ ^１ 〜Ｒ ^６ 、Ｒ ^９ 、Ｒ ^１０ が水素原子であり、Ｒ ^７ およびＲ ^８ の一方が水素原子、Ｒ ^７ およびＲ ^８ の他方が炭素数１〜８のアルキル基、または炭素数６〜１０のアリール基のいずれかである。）

( Wherein R ^{1 to} R ⁶ , R ⁹ and R ¹⁰ are hydrogen atoms, one of R ⁷ and R ⁸ is a hydrogen atom, the other of R ⁷ and R ⁸ is an alkyl group having 1 to 8 carbon atoms, or Any of aryl groups having 6 to 10 carbon atoms. )

（式中、Ｒ ^ａ は炭素数２以上４以下のアルキル基であり、Ｙはアセチルアセトナート基であり、ｘは２以上４以下の整数である。）

（式中、Ｒ ^１１ 及びＲ ^１２ は、独立して、水素原子、アリール基、またはイミダゾリル基、フリル基、チエニル基もしくはピリジル基であり、これらはハロゲン原子、アルキル基、アルケニル基またはアリール基を有していてもよい。また、Ｒ ^１１ 及びＲ ^１２ は異なる基である。Ｒ ^１３ は、ベンジル基、ベンズヒドリル基、アリル基、４−メトキシフェニル基、又はｔ−ブトキシカルボニル基である。）

（式中、Ｒ ^１４ 〜Ｒ ^１６ は、炭素数１〜８の直鎖状、分岐状又は環状のアルキル基である。）

(Wherein, R ^a is an alkyl group having 2 to 4 carbon atoms, Y is an acetyl acetonate group, x is 2 to 4 integer.)

(Wherein R ¹¹ and R ¹² are each independently a hydrogen atom, an aryl group, or an imidazolyl group, a furyl group, a thienyl group, or a pyridyl group, and these are a halogen atom, an alkyl group, an alkenyl group, or an aryl group. R ¹¹ and R ¹² are different groups, and R ¹³ is a benzyl group, a benzhydryl group, an allyl group, a 4-methoxyphenyl group, or a t-butoxycarbonyl group.

(Wherein R ^{14 to} R ¹⁶ are linear, branched or cyclic alkyl groups having 1 to 8 carbon atoms.)

[ 2 ] The method for producing an optically active aminonitrile according to [ 1 ], wherein the reaction temperature is room temperature.
[ 3 ] The titanium alkoxide compound is Ti (OEt) ₄ , Ti (OnPr) ₄ , Ti (OiPr) ₄ , Ti (OnBu) ₄ , or Ti (OiPr) ₂ (acac) _2. A method for producing the optically active aminonitrile according to [1] or [ 2] .
[ 4 ] The method for producing an optically active amino nitrile according to any one of [1] to [3], wherein the optically active amino alcohol is an amino alcohol having the following structure or an enantiomer thereof.

[ 5 ] The cyanating agent is trimethylsilylcyanide, triethylsilylcyanide, tri-i-propylsilylcyanide, dimethyl (t-butyl) silylcyanide, or dimethylphenylsilylcyanide. ] The manufacturing method of the optically active aminonitrile in any one of.

  According to the present invention, an optically active aminonitrile having a high optical purity can be easily and efficiently produced as compared with a conventional production method. The optically active aminonitrile is useful as a synthetic raw material in synthetic intermediates such as pharmaceuticals and agricultural chemicals, functional materials, or other fine chemicals.

Hereinafter, the present invention will be described in detail.
(1) Optically active amino alcohol In the present invention, the reaction is carried out in the presence of an optically active amino alcohol represented by the following general formula (1).

R ^{1 to} R ¹⁰ in the general formula (1) are each independently a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, or an acyl group. , Carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro A group, a silyl group, or a siloxy group, which may have a substituent, and two or more of R ^{1 to} R ¹⁰ may be linked to each other to form a ring; The ring may have a substituent.
In the general formula (1), the case where the carbon atom bonded to R ¹ and R ² is an asymmetric carbon atom (i) type, the case where the carbon atom bonded to R ⁷ and R ⁸ is an asymmetric carbon atom Is referred to as (ii) type, or the case where the carbon atom bonded to R ⁹ and R ¹⁰ is an asymmetric carbon atom (iii).
The optical activity in the optically active amino alcohol is not particularly limited, and examples thereof include (ii) type, (iii) type (one of (ii) or (iii), or (ii) and (iii)). Both are mentioned), and the type (ii) is particularly preferable.

Although R ¹ halogen atom to R ¹⁰ is not particularly limited, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Structure of the alkyl group of R ¹ to R ¹⁰ is not particularly limited, the carbon number thereof is preferably 1 to 20, more preferably 1 to 8, may be any of linear, branched, or cyclic.
Examples of such a linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group. Is mentioned. Examples of such a branched alkyl group include i-propyl group, i-butyl group, s-butyl group, t-butyl group and the like.
Examples of such a cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

The structure of the alkenyl group of R ^{1 to} R ¹⁰ is not particularly limited, but the carbon number thereof is preferably 2 to 20, more preferably 2 to 8, and may be linear, branched or cyclic. Specific examples include a vinyl group, an allyl group, and a 1-propenyl group.

The structure of the alkynyl group of R ^{1 to} R ¹⁰ is not particularly limited, but the carbon number thereof is preferably 2 to 20, more preferably 2 to 8, and may be either linear or branched. Specific examples include ethynyl group, propargyl and the like.

Structure aryl group R ¹ to R ¹⁰ is not particularly limited, and the number of carbon atoms is preferably 6 to 20, more preferably 6 to 10. Specific examples include a phenyl group and a naphthyl group.

The structure of the aromatic heterocyclic group of R ^{1 to} R ¹⁰ is not particularly limited, but the number of molecules constituting one heterocyclic ring is preferably 5 to 20, more preferably 5 to 10. Specific examples include imidazolyl group, furyl group, thienyl group, pyridyl group and the like.

The structure of the non-aromatic heterocyclic group represented by R ^{1 to} R ¹⁰ is not particularly limited, but the number of molecules constituting one heterocyclic ring is preferably 3 to 20, more preferably 3 to 8. Specific examples include pyrrolidinyl group, piperidyl group, tetrahydrofuryl group, tetrahydropyranyl group and the like.

Although R ¹ structure of the acyl group to R ¹⁰ is not particularly limited, and the number of carbon atoms is preferably 2 to 20, more preferably 2 to 8. Specific examples include formyl group, alkylcarbonyl group such as acetyl, and arylcarbonyl group such as benzoyl group.

Although R ¹ structure alkoxycarbonyl group to R ¹⁰ is not particularly limited, and the number of carbon atoms is preferably 2 to 20, more preferably 2 to 8. Specific examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, t-butoxycarbonyl group and the like.

Although the structure of the aryloxycarbonyl group of R ^{1 to} R ¹⁰ is not particularly limited, the carbon number thereof is preferably 7 to 20, more preferably 7 to 11. Specific examples include a phenyloxycarbonyl group and a naphthyloxycarbonyl group.

Although R ¹ structure carbamoyl group to R ¹⁰ is not particularly limited, and the number of carbon atoms is preferably 2 to 20, more preferably 2 to 8. Specific examples include aminocarbonyl group, methylaminocarbonyl group, dimethylaminocarbonyl group and the like.

Although R ¹ structure of alkoxy groups to R ¹⁰ is not particularly limited, and the number of carbon atoms is preferably 2 to 20, more preferably 2 to 8. Specific examples include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, t-butoxy group and the like.

The structure of the aryloxy group of R ^{1 to} R ¹⁰ is not particularly limited, but the carbon number is preferably 6 to 20, more preferably 6 to 10. Specific examples include a phenoxy group and a naphthyloxy group.

The structure of the alkylthio group of R ^{1 to} R ¹⁰ is not particularly limited, but the carbon number is preferably 2 to 20, more preferably 2 to 8. Specific examples include a methylthio group and an ethylthio group.

The structure of the arylthio group of R ^{1 to} R ¹⁰ is not particularly limited, but the carbon number is preferably 6 to 20, more preferably 6 to 10. Specific examples include a phenylthio group and a naphthylthio group.

The structure of the alkylamino group of R ^{1 to} R ¹⁰ is not particularly limited, but the carbon number is preferably 2 to 20, more preferably 2 to 8. Specific examples include a methylamino group and a dimethylamino group.

The structure of the arylamino group of R ^{1 to} R ¹⁰ is not particularly limited, but the carbon number is preferably 6 to 20, more preferably 6 to 10. Specific examples include a phenylamino group and a naphthylamino group.

Although R ¹ structure of the silyl group to R ¹⁰ is not particularly limited, and the number of carbon atoms is preferably 1 to 20, more preferably 3 to 12. Specific examples include a trimethylsilyl group and a triethylsilyl group.

Although R ¹ structure siloxy groups to R ¹⁰ is not particularly limited, and the number of carbon atoms is preferably 1 to 20, more preferably 3 to 12. Specific examples include a trimethylsiloxy group and a triethylsiloxy group.

The type of the substituent on R ^{1 to} R ¹⁰ is not particularly limited, but a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an acyl group, a carboxyl group , Alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl Group, siloxy group and the like are mentioned as examples, and a halogen atom, an alkyl group, an alkenyl group, an aryl group and the like are preferable.

Examples of the optically active amino alcohol, ^{R 1} and ^{R 2} are hydrogen ^atoms, R 3 ^{to R 10} is a hydrogen atom, an alkyl group having 1 to 20 carbon atoms or any combination of the aryl group having 6 to 20 carbon atoms, R ¹ and R ² are each a hydrogen atom, R ^{3 to} R ⁶ are each a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms, R ^{7 to} R ¹⁰ are each a hydrogen atom, and 1 to C carbon atoms. More preferably, it is a combination of an alkyl group having 8 or an aryl group having 6 to 10 carbon atoms, and R ^{1 to} R ⁶ , R ⁹ and R ¹⁰ are any one of a hydrogen atom, R ⁷ and R ⁸ . Most preferably, one is a hydrogen atom, and any one of R ⁷ and R ⁸ is a combination of an alkyl group having 1 to 8 carbon atoms or an aryl group having 6 to 10 carbon atoms. Specific examples of the most preferable optically active amino alcohol include the following ligands (S) -L-1 to (S) -L-10, and enantiomers thereof.

(2) Titanium alkoxide compound In the present invention, a titanium alkoxide compound represented by the following general formula (2) is used.

R ^a in the general formula (2) represents a hydrogen atom, an alkyl group, an alkenyl group, or an aryl group, and these may have a substituent. Y represents a halogen atom, an alkyl acetoacetate group, or a β-diketonate group, and these may have a substituent. x is an integer and takes a value of 1 to 4.

Alkyl group R ^a, an alkenyl group and aryl group, the structure of each alkyl group of R ¹ to R ¹⁰ in the above-mentioned general formula (1), be the same structure as the structure of the alkenyl group and an aryl group it can.

  Although the halogen atom of Y is not specifically limited, A fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. are mentioned. The structure of the alkyl acetoacetate group of Y is not particularly limited, but the carbon number is preferably 5-20, more preferably 5-9. Specific examples include an ethyl acetoacetate group.

  The structure of the β-diketonate group of Y is not particularly limited, but the carbon number is preferably 5 to 20, more preferably 5 to 9. Specific examples include an acetylacetonate group, a trifluoroacetylacetonate group, and a hexafluoroacetylacetonate group.

The type of substituent on R ^a and Y is not particularly limited, but a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an acyl group, a carboxyl group, Alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl group Or a siloxy group or the like, and a halogen atom, an alkyl group, an alkenyl group, an aryl group, or the like is preferable.

  X in the general formula (2) is an integer of 1 or more and 4 or less. When x is 4, the number of Y is 0. A titanium alkoxide compound in which two or more molecules are associated with the general formula (2) as a basic unit can also be used in the present invention.

As the titanium compound, ^Ra is an alkyl group having 2 to 8 carbon atoms, Y is a chlorine atom or an acetylacetonate group, x is preferably an integer combination of 2 to 4 and ^Ra is 2 to 4 carbon atoms. More preferably, Y is an acetylacetonate group, and x is an integer combination of 2 or more and 4 or less. Specific examples of such a preferable titanium compound include Ti (OEt) ₄ , Ti (OnPr) ₄ , Ti (OiPr) ₄ , Ti (OnBu) ₄ , or Ti (acac) ₂ (OiPr) ₂ . These titanium compounds can be used alone or in combination of two or more.

(3) Alcohols In the present invention, alcohols represented by the following general formula (3) or (4) are used.

(In the formula, R ^b is a group selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, and these may have a substituent.)

R ^b in the general formula (3) is a group selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, and these may have a substituent. The structure of the alkyl group, alkenyl group, alkynyl group, and aryl group of R ^b is the same as the structure of the alkyl group, alkenyl group, alkynyl group, and aryl group of R ^{1 to} R ¹⁰ in the general formula (1). The structure can be as follows.

The type of substituent on R ^b is not particularly limited, but is a halogen atom, alkyl group, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, acyl group, carboxyl group, alkoxycarbonyl. Group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl group, or A siloxy group etc. are mentioned as an example, A halogen atom, an alkyl group, an alkenyl group, or an aryl group etc. are preferable.

As the alcohol, an alcohol of the general formula (3) in which R ^b is an alkyl group having 1 to 8 carbon atoms or an aryl group having 6 to 10 carbon atoms is preferable, and R ^b is a methyl group, an ethyl group, or n-propyl. The alcohol of the general formula (3) which is a group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group or benzyl group is more preferable. Specific examples of the most preferable alcohols include ethanol, n-propanol, and n-butanol. These alcohols can be used alone or in combination of two or more.

  Ar in the general formula (4) is an aryl group, and these may have a substituent.

The structure of the aryl group of Ar can be the same structure as the structure of the aryl group of R ^{1 to} R ¹⁰ in the general formula (1).

  The type of substituent on Ar is not particularly limited, but is a halogen atom, alkyl group, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, acyl group, carboxyl group, alkoxycarbonyl group , Aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl group, or siloxy Examples include groups such as halogen atoms, alkyl groups, alkenyl groups, and aryl groups.

  As the alcohol, Ar is preferably an alcohol of the general formula (4) in which the aryl group has 6 to 10 carbon atoms, and Ar is 2,6-dimethylphenyl group, 2,6-diethylphenyl group, 2,6-di- -N-propylphenyl group, 2,6-di-i-propylphenyl group, 2,6-di-n-butylphenyl group, 2,6-di-s-butylphenyl group, 2,6-di-i The alcohol of the general formula (4) which is a -butylphenyl group or a 2,6-di-t-butylphenyl group is more preferable. Specific examples of the most preferable alcohols include 2,6-xylenol. These alcohols can be used alone or in combination of two or more.

(4) Imine In the present invention, imine is used as a raw material for optically active aminonitrile.
Although the structure of the imine according to the present invention is not particularly limited, for example, it can be represented by the following general formula (5).

R ¹¹ and R ¹² in the general formula (5) are independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group. A hydrogen atom or an aryl group such as an aryl group and an aromatic heterocyclic group is particularly preferable. These may have a substituent, and these two groups may be connected to each other to form a ring. R ¹¹ and R ¹² are different groups, and either one is preferably a hydrogen atom.
The structure of the alkyl group of R ¹¹ and R ¹² is not particularly limited, but the carbon number thereof is preferably 1-20, more preferably 1-8, and may be any of linear, branched or cyclic. Examples of such a linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group. Is mentioned. Examples of such a branched alkyl group include i-propyl group, i-butyl group, s-butyl group, t-butyl group and the like. Examples of such a cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
The structure of the alkenyl group of R ¹¹ and R ¹² is not particularly limited, but the carbon number thereof is preferably 2-20, more preferably 2-8, and may be any of linear, branched or cyclic. Specific examples include a vinyl group, an allyl group, and a 1-propenyl group.
The structure of the alkynyl group of R ¹¹ and R ¹² is not particularly limited, but the carbon number is preferably 2 to 20, more preferably 2 to 8, and may be either linear or branched. Specific examples include ethynyl group, propargyl and the like.
The structure of the aryl group of R ¹¹ and R ¹² is not particularly limited, but the carbon number thereof is preferably 6-20, more preferably 6-10. Specific examples include a phenyl group and a naphthyl group.
The structure of the aromatic heterocyclic group of R ¹¹ and R ¹² is not particularly limited, but the number of atoms constituting one heterocyclic ring is preferably 5 to 20, more preferably 5 to 10. Specific examples include imidazolyl group, furyl group, thienyl group, pyridyl group and the like.
The structure of the non-aromatic heterocyclic group represented by R ¹¹ and R ¹² is not particularly limited, but the number of atoms constituting one heterocyclic ring is preferably 3-20, more preferably 3-8. Specific examples include pyrrolidinyl group, piperidyl group, tetrahydrofuryl group, tetrahydropyranyl group and the like.
The type of substituent on R ¹¹ and R ¹² is not particularly limited, but is a halogen atom, alkyl group, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, acyl group, carboxyl group , Alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl Group, siloxy group and the like are mentioned as examples, and a halogen atom, an alkyl group, an alkenyl group, an aryl group and the like are preferable.

The structure of R ^{13 in} the general formula (5) is not particularly limited, but a hydrogen atom, alkyl group, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, acyl group, alkoxycarbonyl Group, silyl group, phosphine oxide group, sulfinyl group or sulfoxy group are preferable, and alkyl group, alkenyl group, aryl group or alkoxycarbonyl group is particularly preferable. These may have a substituent and may be linked to R ¹¹ or R ¹² to form a ring.
The structure of the alkyl group of R ¹³ is not particularly limited, but the carbon number thereof is preferably 1-20, more preferably 1-8, and may be any of linear, branched or cyclic. Examples of such a linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group. Is mentioned. Examples of such a branched alkyl group include i-propyl group, i-butyl group, s-butyl group, t-butyl group and the like. Examples of such a cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
The structure of the alkenyl group of R ¹³ is not particularly limited, but the carbon number thereof is preferably 2 to 20, more preferably 2 to 8, and may be any of linear, branched or cyclic. Specific examples include a vinyl group, an allyl group, and a 1-propenyl group.
The structure of the alkynyl group of R ¹³ is not particularly limited, but the carbon number thereof is preferably 2 to 20, more preferably 2 to 8, and may be either linear or branched. Specific examples include ethynyl group, propargyl and the like.
The structure of the aryl group of R ¹³ is not particularly limited, but the carbon number is preferably 6-20, more preferably 6-10. Specific examples include a phenyl group and a naphthyl group.
The structure of the aromatic heterocyclic group for R ¹³ is not particularly limited, but the number of molecules constituting one heterocyclic ring is preferably 5 to 20, and more preferably 5 to 10. Specific examples include imidazolyl group, furyl group, thienyl group, pyridyl group and the like.
The structure of the non-aromatic heterocyclic group of R ¹³ is not particularly limited, but the number of molecules constituting one heterocyclic ring is preferably 3-20, more preferably 3-8. Specific examples include pyrrolidinyl group, piperidyl group, tetrahydrofuryl group, tetrahydropyranyl group and the like.
The structure of the acyl group of R ¹³ is not particularly limited, but the carbon number is preferably 2-20, more preferably 2-8. Specific examples include formyl group, alkylcarbonyl group such as acetyl, and arylcarbonyl group such as benzoyl group.
Structure alkoxycarbonyl group R ¹³ is not particularly limited, and the number of carbon atoms is preferably 2 to 20, more preferably 2 to 8. Specific examples include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, t-butoxycarbonyl group and the like.
The structure of the silyl group of R ¹³ is not particularly limited, but the carbon number is preferably 1-20, more preferably 3-12. Specific examples include a trimethylsilyl group and a triethylsilyl group.
The structure of the phosphine oxide group of R ¹³ is not particularly limited, but the carbon number is preferably 2-20, more preferably 2-12. Specific examples include a diphenylphosphine oxide group.
The structure of the sulfinyl group of R ¹³ is not particularly limited, but the carbon number is preferably 1-20, more preferably 1-10. Specific examples include a methylsulfinyl group, phenylsulfinyl and the like.
The structure of the sulfoxy group of R ¹³ is not particularly limited, but the carbon number is preferably 1-20, more preferably 1-10. Specific examples include a methylsulfonyl group and phenylsulfonyl.

The type of substituent on R ¹³ is not particularly limited, but a halogen atom, alkyl group, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, acyl group, carboxyl group, alkoxycarbonyl Group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl group, or A siloxy group etc. are mentioned as an example, A halogen atom, an alkyl group, an alkenyl group, or an aryl group etc. are preferable.

Specific examples of such preferable R ¹³ include a benzyl group, a benzhydryl group, an allyl group, a 4-methoxyphenyl group, and a t-butoxycarbonyl group.

Specific examples of the imine of the present invention include the following examples.

R ^{11 to} R ¹³ are chiral or achiral groups. When R ^{11 to} R ¹³ are a chiral group, the optical purity of the carbonyl compound is not particularly limited, but is preferably 80% ee or more, more preferably 95% ee or more, and even more preferably 97% ee or more. When the optical purity of the carbonyl compound is high, it is excellent in that the diastereo ratio of the optically active alcohol to be produced is increased.

(5) Cyanating Agent The cyanating agent according to the present invention is not particularly limited as long as it contains a cyano group and can introduce a cyano group by reaction with imine, but hydrogen cyanide and the following general formula The cyanating agent represented by (6) is preferred, and a mixture thereof can also be preferably used. Furthermore, a cyanating agent represented by the following general formula (6) is more preferable.

R ^{14 to} R ¹⁶ in the general formula (6) are independently a hydrogen atom, an alkyl group, or an aryl group, and these may have a substituent, and these two groups are linked to each other. To form a ring.
The structure of the alkyl group of R ^{14 to} R ¹⁶ is not particularly limited, but the carbon number thereof is preferably 1 to 20, more preferably 1 to 8, and may be linear, branched or cyclic.
Examples of such a linear alkyl group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group. Is mentioned. Examples of such a branched alkyl group include i-propyl group, i-butyl group, s-butyl group, t-butyl group and the like.
Examples of such a cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
The structure of the aryl group of R ^{14 to} R ¹⁶ is not particularly limited, but the carbon number is preferably 6 to 20, and more preferably 6 to 10. Specific examples include a phenyl group and a naphthyl group.

Although R ¹⁴ kinds of substituents on to R ¹⁶ is not particularly limited, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, non-aromatic heterocyclic group, an acyl group, a carboxyl group , Alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl Group, siloxy group and the like are mentioned as examples, and a halogen atom, an alkyl group, an alkenyl group, an aryl group and the like are preferable.

  Specific examples of the cyanating agent include trimethylsilyl cyanide, triethylsilyl cyanide, tri-i-propylsilyl cyanide, dimethyl (t-butyl) silyl cyanide, and dimethylphenylsilyl cyanide. Particularly preferred.

(6) Catalyst preparation In the present invention, an effective catalyst for the asymmetric cyanation reaction of imine is prepared from the above optically active amino alcohol and the above titanium alkoxide.

  The optically active amino alcohol and the titanium alkoxide compound are preferably mixed in the presence of a solvent to obtain a solution containing the catalyst. The obtained solution can be used as a catalyst solution for the asymmetric cyanation reaction of the present invention. In the catalyst solution, it is presumed that the optically active amino alcohol is coordinated to titanium of the titanium alkoxide to form an optically active titanium complex.

  The amount of optically active amino alcohol added to 1 mole of titanium in the titanium alkoxide compound is not particularly limited, but is preferably 0.1 to 3.0 moles, more preferably 0.2 to 2.0 moles, and even more preferably. Is 0.5 to 1.5 mol (hereinafter, “to” represents that an upper limit value and a lower limit value are included unless otherwise specified).

  The solvent used in preparing the catalyst solution is not particularly limited, but an aprotic solvent is preferable. Specifically, halogenated hydrocarbon solvents such as dichloromethane, chloroform, fluorobenzene, trifluoromethylbenzene, aromatic hydrocarbon solvents such as toluene and xylene, ester solvents such as ethyl acetate, tetrahydrofuran, dioxane, diethyl Ether solvents such as ether and dimethoxyethane, and nitrile solvents such as acetonitrile and propionitrile are preferred. Among these, a halogen-based solvent or an aromatic hydrocarbon-based solvent is particularly preferable. Furthermore, these can be used alone or as a mixed solvent. Although the usage-amount of a solvent is not specifically limited, Usually, it is 1-5000 ml with respect to 1 mmol of titanium atoms, Preferably it is about 10-500 ml. At this time, although reaction temperature is not specifically limited, Usually, it can prepare by stirring at about room temperature, for example, 15-30 degreeC for about 5 minutes-1 hour.

  The catalyst solution is preferably prepared in a dry inert gas atmosphere. Examples of the inert gas include nitrogen, argon, helium and the like.

  The catalyst solution prepared as described above can be used as it is for the asymmetric cyanation reaction of the imine of the present invention without any special purification operation.

(7) Cyanation reaction In the present invention, an optically active aminonitrile is obtained by asymmetric cyanation of the imine with a cyanating agent in the presence of the catalyst and alcohol.
For example, J. et al. Am. Chem. Soc. , 121, no. 17, 4284-4285 (1999), such as Scheme 1, shows a basic reaction mechanism for the addition reaction of CN ions to an imine double bond. The cyanation reaction mechanism of the present invention is presumed to follow the mechanism of Lewis acid catalyzed reaction using such a general imine compound as a substrate.

  Although the usage-amount of the catalyst used in this invention is not specifically limited, Preferably it is 0.01-30 mol% as a titanium atom with respect to 100 mol% of imines, More preferably, it is 0.1-10 mol%.

  Although the usage-amount of the alcohol used in this invention is not specifically limited, Preferably it is 50-200 mol% as a hydroxyl equivalent with respect to 100 mol% of cyanating agents, More preferably, it is 90-150 mol%.

  The amount of the cyanating agent used in the method of the present invention is not particularly limited, but is preferably 50 to 300 mol%, more preferably 90 mol% to 200 mol% with respect to 100 mol% of imine.

  In the cyanation reaction of the present invention, it is preferable to use a solvent. Although it may be the same as or different from the solvent used in preparing the catalyst solution, it is usually preferable to use the same solvent. Although the kind of solvent is not specifically limited, an aprotic solvent is preferable. Specific preferred examples include solvents that can be used when preparing the catalyst solution. Furthermore, these can be used alone or as a mixed solvent. The above catalyst solution can be used as it is as a solvent for the cyanation reaction. In addition, the alcohol, imine, and cyanating agent can be dissolved in a solvent used for the reaction and added to the reaction system as a solution. The total amount of the solvent used is preferably 0.1 to 50 ml, more preferably about 0.2 to 25 ml per 1 mmol of the substrate carbonyl compound.

  The order of adding each component of the catalyst, alcohol, imine, cyanating agent and solvent used in the present invention is not particularly limited. For example, the imine, cyanating agent, Alcohol and solvent are added sequentially.

  Although reaction temperature is not specifically limited, Usually, it is the range of -80 degreeC-the boiling point of a solvent, and the range of -20 degreeC-50 degreeC is more preferable. More preferably, it is the range of 0 degreeC-40 degreeC, Most preferably, it is 15 degreeC-35 degreeC. In particular, when the compound of the general formula (4) is added as an alcohol, a reaction temperature of room temperature (15 ° C. to 35 ° C.) is preferable. Although reaction time is not specifically limited, The range of 5 minutes-24 hours is preferable, and the range of 30 minutes-8 hours is more preferable. The reaction of the present invention can be performed at room temperature (15 ° C. to 35 ° C.), for example, as shown in the Examples. At this time, the reaction of the present invention can be performed, for example, with a reaction time of 15 minutes to 2 hours.

  The reaction of the present invention can be carried out without stirring or with stirring. From the viewpoint of performing the reaction uniformly with good reproducibility, it is preferable to carry out the reaction with stirring. About the method of stirring a reaction solution, the well-known method which is not specifically limited can be used.

  The optically active aminonitrile obtained by the present invention can be purified and isolated by a known method. Examples of the purification method include recrystallization, distillation, column chromatography and the like.

  The optically active aminonitrile obtained according to the present invention can be derivatized using a known method. For example, it can be derived into an α-amino acid by hydrolyzing a nitrile group by a known method and converting it to a carboxyl group. At this time, the isolated optically active aminonitrile after purification by a known method may be derivatized, or derivatized by adding the operation to a mixed solution containing unpurified optically active aminonitrile. You can also.

  After the reaction of the present invention, the optically active amino alcohol can be separated and reused by a known method. Examples of the separation method include recrystallization and column chromatography.

  Such an optically active aminonitrile according to the present invention is useful as a synthetic raw material for synthetic intermediates such as pharmaceuticals and agricultural chemicals, functional materials, or other fine chemicals.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.

The identification of the amino nitrile produced in this example is based on comparison of the ¹ H NMR spectrum (using Bruker 400 manufactured by Bruker) in a deuterated chloroform solvent (manufactured by Merck) containing TMS as a standard substance with previously reported values. It was done by doing. The conversion rate and asymmetric yield of asymmetric cyanation were measured using ¹ H NMR spectrum and high performance liquid chromatography (Waters Model 2695). At this time, CHIRALPAK OJ-H (manufactured by Daicel Chemical Industries) was used as the optically active column. The absolute configuration of the optically active aminonitrile was determined by comparing the reported values for the retention time of high performance liquid chromatography.

In the examples, toluene (hereinafter referred to as “anhydrous toluene”) as a solvent was manufactured by KANTO CHEMICAL CO., INC. Ti (OnBu) ₄ , Ti (acac) ₂ (OiPr) ₂ , TiCl (OiPr) ₃ , TiCl ₂ (OiPr) ₂ , N-benzylidenebenzylamine, n-butanol, n-propanol, i-propanol, 2,6 -Dimethylphenol, the above compound was used without purification of a reagent manufactured by Sigma-Aldrich Pte Ltd. Trimethylsilylcyanide was used after being purified by distillation from Wako Pure Chemical Industries, Ltd. (Wako Pure Chemical Industries, Ltd.). The optically active amino alcohol (formula (S) -L-8) used in the examples was synthesized from salicylaldehyde and (S) -t-leucinol according to a known method (described in Non-Patent Document 4). All reactions were performed under a nitrogen atmosphere. The equipment used for the reaction was a sufficiently dry one.

Example 1
In a test tube with a lid, 2.3 mg (0.010 mmol) of an optically active amino alcohol (the above formula (S) -L-8) was weighed, and 0.50 mL of anhydrous toluene was added to prepare a solution of Ti (OnBu). ₄ ) 0.20 mL (0.010 mmol) of an anhydrous toluene solution (0.050 mol / L) was added, and the mixture was stirred at 23 ° C. for 30 minutes. 39 mg (0.20 mmol) of N-benzylidenebenzylamine, 30 mg (0.30 mmol) of trimethylsilylcyanide and 15 mg (0.20 mmol) of n-butanol were sequentially added to the solution thus obtained at 23 ° C. After stirring at 23 ° C. for 15 minutes, a small amount of reaction solution is taken to measure the conversion rate of the raw material and the asymmetric yield of the product, and a low-boiling compound such as a solvent and unreacted trimethylsilylcyanide with a vacuum pump Was removed to obtain N-benzylamino-2-phenylacetonitrile with an excess of (S) form. The conversion rate of the raw material was 99%, and the asymmetric yield of the product was 87%.

(Example 2)
In a test tube with a lid, 2.3 mg (0.010 mmol) of optically active amino alcohol (formula (S) -L-8) is weighed and dissolved in 0.50 mL of anhydrous toluene, and anhydrous toluene of Ti (OnBu) ₄ The solution (0.050 mol / L) 0.20mL (0.010mmol) was added, and it stirred at 23 degreeC for 30 minutes. The resulting solution was transferred to a 2 mL volumetric flask and anhydrous toluene was added until the total volume was 2 mL. 0.20 mL of the solution thus prepared was weighed into another test tube with a lid, diluted by adding 0.50 mL of anhydrous toluene, and 39 mg (0.20 mmol) of N-benzylidenebenzylamine and 30 mg (0.30 mmol) of trimethylsilylcyanide. , 15 mg (0.20 mmol) of n-butanol were sequentially added at 23 ° C.

  After stirring at 23 ° C. for 2 hours, a small amount of reaction solution is taken to measure the conversion rate of raw materials and the asymmetric yield of the product, and a low-boiling compound such as a solvent and unreacted trimethylsilylcyanide with a vacuum pump Was removed to obtain N-benzylamino-2-phenylacetonitrile with an excess of (S) form. The conversion rate of the raw material was 99%, and the asymmetric yield of the product was 84%.

(Example 3)
Instead of 2.3 mg of optically active amino alcohol (formula (S) -L-8) (0.010 mmol), 4.6 mg of optically active amino alcohol (formula (S) -L-8) (0. 020 mmol) was used, and the same operation as in Example 1 was performed to obtain N-benzylamino-2-phenylacetonitrile with an excess of (S) form. The conversion rate of the raw material was 73%, and the asymmetric yield of the product was 86%.

(Example 4)
The same operation as in Example 1 except that 0.20 mL (0.010 mmol) of an anhydrous toluene solution (0.050 mol / L) of TiCl ₂ (OiPr) ₂ was used instead of the anhydrous toluene solution of Ti (OnBu) ₄ To obtain N-benzylamino-2-phenylacetonitrile in which the (S) form was excessive. The conversion rate of the raw material was 65%, and the asymmetric yield of the product was 60%.

(Example 5)
The same operation as in Example 1 was conducted except that 0.20 mL (0.010 mmol) of an anhydrous toluene solution (0.050 mol / L) of TiCl (OiPr) ₃ was used instead of the anhydrous toluene solution of Ti (OnBu) _4. This was performed to obtain N-benzylamino-2-phenylacetonitrile with an excess of (S) form. The conversion rate of the raw material was 65%, and the asymmetric yield of the product was 60%.

(Example 6)
Example 1 except that 0.20 mL (0.010 mmol) of an anhydrous toluene solution (0.050 mol / L) of Ti (acac) ₂ (OiPr) ₂ was used instead of the anhydrous toluene solution of Ti (OnBu) ₄ The same operation was performed to obtain N-benzylamino-2-phenylacetonitrile with an excess of (S) form. The conversion rate of the raw material was 99%, and the asymmetric yield of the product was 88%.

(Example 7)
The same operation as in Example 1 was carried out except that 12 mg (0.20 mmol) of n-propanol was used instead of n-butanol, to obtain N-benzylamino-2-phenylacetonitrile with an excess of (S) form. . The conversion rate of the raw material was 99%, and the asymmetric yield of the product was 87%.

(Example 8)
The same operation as in Example 1 was carried out except that 24 mg (0.20 mmol) of 2,6-xylenol was used instead of n-butanol, and (S) the excess N-benzylamino-2-phenylacetonitrile was obtained. Obtained. The conversion rate of the raw material was 77%, and the asymmetric yield of the product was 90%.

（式中、Ｒ ^１ 〜Ｒ ^１０ は、それぞれ独立に水素原子、ハロゲン原子、アルキル基、アルケニル基、アルキニル基、アリール基、芳香族複素環基、非芳香族複素環基、アシル基、カルボキシル基、アルコキシカルボニル基、アリールオキシカルボニル基、カルバモイル基、ヒドロキシル基、アルコキシ基、アリールオキシ基、チオール基、アルキルチオ基、アリールチオ基、アミノ基、アルキルアミノ基、アリールアミノ基、シアノ基、ニトロ基、シリル基、又はシロキシ基であり、これらは置換基を有していてもよく、Ｒ ^１ 〜Ｒ ^１０ のうちの２個以上が、相互に連結して環を形成していてもよく、環は置換基を有していてもよい。）

（式中、Ｒ ^ａ は、水素原子、アルキル基、アルケニル基、又はアリール基を示し、これらは置換基を有していてもよい。Ｙは、ハロゲン原子、アルキルアセトアセテート基、又はβ−ジケトナート基を示し、これらは置換基を有していてもよい。ｘは整数で、１から４の値をとる。）

（式中、Ｒ ^ｂ は、水素原子、アルキル基、アルケニル基、アルキニル基、又はアリール基から選ばれた基であり、これらは置換基を有していてもよい。）
２．下記一般式（１）で表される光学活性アミノアルコール、下記一般式（２）で表されるチタンアルコキシド、及び下記一般式（４）で表されるアルコールの存在下、イミンとシアノ化剤とを反応させることを特徴とする、イミンの不斉シアノ化方法。

（式中、Ｒ ^１ 〜Ｒ ^１０ は、それぞれ独立に水素原子、ハロゲン原子、アルキル基、アルケニル基、アルキニル基、アリール基、芳香族複素環基、非芳香族複素環基、アシル基、カルボキシル基、アルコキシカルボニル基、アリールオキシカルボニル基、カルバモイル基、ヒドロキシル基、アルコキシ基、アリールオキシ基、チオール基、アルキルチオ基、アリールチオ基、アミノ基、アルキルアミノ基、アリールアミノ基、シアノ基、ニトロ基、シリル基、又はシロキシ基であり、これらは置換基を有していてもよく、Ｒ ^１ 〜Ｒ ^１０ のうちの２個以上が、相互に連結して環を形成していてもよく、環は置換基を有していてもよい。）

（式中、Ｒ ^ａ は、水素原子、アルキル基、アルケニル基、又はアリール基を示し、これらは置換基を有していてもよい。Ｙは、ハロゲン原子、アルキルアセトアセテート基、又はβ−ジケトナート基を示し、これらは置換基を有していてもよい。ｘは整数で、１から４の値をとる。）

（式中、Ａｒは、アリール基であり、置換基を有していてもよい。）
３．反応温度が、室温である、２に記載のイミンの不斉シアノ化方法。
４．前記チタンアルコキシド化合物が、Ｔｉ（ＯＥｔ） _４ 、Ｔｉ（ＯｎＰｒ） _４ 、Ｔｉ（ＯｉＰｒ） _４ 、Ｔｉ（ＯｎＢｕ） _４ 、又はＴｉ（ＯｉＰｒ） _２ （ａｃａｃ） _２ であることを特徴とする、１から３のいずれかに記載のイミンの不斉シアノ化方法。
５．前記イミンが、下記一般式（５）で表されることを特徴とする、１から４のいずれかに記載のイミンの不斉シアノ化方法。

（式中、Ｒ ^１１ 及びＲ ^１２ は、独立して、水素原子、アルキル基、アルケニル基、アルキニル基、アリール基、芳香族複素環基、又は非芳香族複素環基であり、これらは置換基を有していてもよく、これら二つの基が相互に連結して環を形成してもよい。またＲ ^１１ 及びＲ ^１２ は異なる基である。Ｒ ^１３ は、水素原子、アルキル基、アルケニル基、アルキニル基、アリール基、芳香族複素環基、非芳香族複素環基、アシル基、アルコキシカルボニル基、シリル基、ホスフィンオキシド基、スルフィニル基、又はスルホキシ基であり、これらは置換基を有していてもよい。また、Ｒ ^１３ はＲ ^１１ 又はＲ ^１２ と連結して環を形成することもできる。）
６．前記シアノ化剤が、下記一般式（６）で表されることを特徴とする、１から５のいずれかに記載のイミンの不斉シアノ化方法。

（式中、Ｒ ^１４ 〜Ｒ ^１６ は、独立して、水素原子、アルキル基、又はアリール基であり、これらは置換基を有していてもよく、これら二つの基が相互に連結して環を形成してもよい。）
(Comparative example)
The same operation as in Example 1 was carried out except that 12 mg (0.20 mmol) of i-propanol was used in place of n-butanol, to obtain N-benzylamino-2-phenylacetonitrile having an excessive (S) form. . The raw material conversion was only 49%, and the asymmetric yield of the product was 86%.
Hereinafter, examples of the reference form will be added.
1. In the presence of an optically active amino alcohol represented by the following general formula (1), a titanium alkoxide represented by the following general formula (2), and an alcohol represented by the following general formula (3), an imine, a cyanating agent, A method for asymmetric cyanation of imine, which comprises reacting

(Wherein R ^{1 to} R ¹⁰ are each independently a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an acyl group, or a carboxyl group. , Alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl Or a siloxy group, which may have a substituent, and two or more of R ^{1 to} R ¹⁰ may be connected to each other to form a ring, and the ring is substituted. It may have a group.)

(In the formula, R ^a represents a hydrogen atom, an alkyl group, an alkenyl group, or an aryl group, which may have a substituent. Y represents a halogen atom, an alkyl acetoacetate group, or a β-diketonate. And these may have a substituent, x is an integer and takes a value of 1 to 4.)

(In the formula, R ^b is a group selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, or an aryl group, and these may have a substituent.)
2. In the presence of an optically active amino alcohol represented by the following general formula (1), a titanium alkoxide represented by the following general formula (2), and an alcohol represented by the following general formula (4), an imine, a cyanating agent, A method for asymmetric cyanation of imine, which comprises reacting

(Wherein R ^{1 to} R ¹⁰ are each independently a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an acyl group, or a carboxyl group. , Alkoxycarbonyl group, aryloxycarbonyl group, carbamoyl group, hydroxyl group, alkoxy group, aryloxy group, thiol group, alkylthio group, arylthio group, amino group, alkylamino group, arylamino group, cyano group, nitro group, silyl Or a siloxy group, which may have a substituent, and two or more of R ^{1 to} R ¹⁰ may be connected to each other to form a ring, and the ring is substituted. It may have a group.)

(In the formula, R ^a represents a hydrogen atom, an alkyl group, an alkenyl group, or an aryl group, which may have a substituent. Y represents a halogen atom, an alkyl acetoacetate group, or a β-diketonate. And these may have a substituent, x is an integer and takes a value of 1 to 4.)

(In the formula, Ar is an aryl group and may have a substituent.)
3. 3. The method for asymmetric cyanation of imine according to 2, wherein the reaction temperature is room temperature.
4). The titanium alkoxide _compound, characterized in that it is a _{Ti (OEt) 4, Ti (} OnPr) 4, Ti (OiPr) 4, Ti (OnBu) 4, or _{Ti (OiPr) 2 (acac)} 2, from 1 4. The method for asymmetric cyanation of imine according to any one of 3 above.
5). 5. The method for asymmetric cyanation of imine according to any one of 1 to 4, wherein the imine is represented by the following general formula (5).

(Wherein R ¹¹ and R ¹² are independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aromatic heterocyclic group, or a non-aromatic heterocyclic group, and these are substituents. And these two groups may be linked to each other to form a ring, and R ¹¹ and R ¹² are different groups, and R ¹³ represents a hydrogen atom, an alkyl group, or an alkenyl group. An alkynyl group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, an acyl group, an alkoxycarbonyl group, a silyl group, a phosphine oxide group, a sulfinyl group, or a sulfoxy group, which have a substituent. R ¹³ can also be linked to R ¹¹ or R ¹² to form a ring.)
6). 6. The method for asymmetric cyanation of imine according to any one of 1 to 5, wherein the cyanating agent is represented by the following general formula (6).

(In the formula, R ^{14 to} R ¹⁶ are each independently a hydrogen atom, an alkyl group, or an aryl group, which may have a substituent, and these two groups are linked to each other to form a ring. May be formed.)

Claims (5)

An optically active amino alcohol represented by the following general formula (1), a titanium alkoxide represented by the following general formula (2), and an alcohol selected from ethanol, n-propanol, n-butanol and 2,6-xylenol presence, under anhydrous conditions, and the imine represented by the following general formula (5), is reacted with a cyanating agent represented by the following general formula (6), the imine asymmetrically cyanation, optical A process for producing active aminonitrile .

( Wherein R ^{1 to} R ⁶ , R ⁹ and R ¹⁰ are hydrogen atoms, one of R ⁷ and R ⁸ is a hydrogen atom, the other of R ⁷ and R ⁸ is an alkyl group having 1 to 8 carbon atoms, or Any of aryl groups having 6 to 10 carbon atoms. )

(Wherein, R ^a is an alkyl group having 2 to 4 carbon atoms, Y is an acetyl acetonate group, x is 2 to 4 integer.)

(Wherein R ¹¹ and R ¹² are each independently a hydrogen atom, an aryl group, or an imidazolyl group, a furyl group, a thienyl group, or a pyridyl group, and these are a halogen atom, an alkyl group, an alkenyl group, or an aryl group. R ¹¹ and R ¹² are different groups, and R ¹³ is a benzyl group, a benzhydryl group, an allyl group, a 4-methoxyphenyl group, or a t-butoxycarbonyl group.

(Wherein R ^{14 to} R ¹⁶ are linear, branched or cyclic alkyl groups having 1 to 8 carbon atoms.) The reaction temperature is room temperature, a method for producing an optically active amino nitrile of claim 1. The titanium alkoxide compound is Ti (OEt) ₄ , Ti (OnPr) ₄ , Ti (OiPr) ₄ , Ti (OnBu) ₄ , or Ti (OiPr) ₂ (acac) _2. A method for producing the optically active aminonitrile according to 1 or 2 .   The method for producing an optically active amino nitrile according to any one of claims 1 to 3, wherein the optically active amino alcohol is an amino alcohol having the following structure or an enantiomer thereof.

  5. The method according to claim 1, wherein the cyanating agent is trimethylsilylcyanide, triethylsilylcyanide, tri-i-propylsilylcyanide, dimethyl (t-butyl) silylcyanide, or dimethylphenylsilylcyanide. A method for producing the optically active aminonitrile according to item.