JP2002255912A - Method for producing optically active alpha- aminoketones - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply and industrially advantageously producing optically active α-amino ketones. SOLUTION: This method for producing the optically active α-amino ketones represented by general formula (I) is characterized by reacting a compound represented by general formula (II) with a base in the presence of an optically active phase transfer catalyst represented by general formula (IV) and a lower alcohol and then treating with an acid (wherein, R<1> and R<2> denote each H, an alkyl or an aryl, a heteroaryl or an aralkyl which may have a substituent; R<3> denotes a leaving group; R<a> , R<b> and R<c> denote each H, a halogen, hydroxy, an alkyl, an alkoxy or the like; X denotes an anion atom or an anionic group; and * means having an axial asymmetry).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an optically active .alpha.-aminoketone useful as an intermediate for producing agricultural chemicals and a method for producing the same.

[0002]

2. Description of the Related Art Optically active α-aminoketones are useful as precursors of optically active β-aminoalcohols. As a practical method for synthesizing conventional α-aminoketones, an optically active α-amino acid is converted to an α-aminoketone such as α-phthalimidic acid.
Derivation of the acid halide of the (protected amino) acid, which is
A method for converting optically active α-aminoketones by an iedel-Crafts reaction is known (J. Org.
Chem. , 50 , 3481 (1985), EP-30.
No. 4,018).

However, according to the above method, expensive optically active α-amino acids must be used, and unnatural α-amino acids are often difficult to obtain. Further, F
A protecting group that is stable in the riedel-Crafts reaction and can be efficiently deprotected under acidic conditions is required, and the operation of protection / deprotection itself is complicated. As described above, α-aminoketones are unstable under conditions other than acidic conditions, and it is often difficult to obtain starting materials. Therefore, industrially advantageous production methods have not been known.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and has as its object to provide a simple and industrially advantageous method for producing optically active α-aminoketones.

[0005]

Means for Solving the Problems The present inventor has proposed an optically active α
-As a result of intensive studies on the advantageous production method of aminoketones, oxime ethers are treated with acid in the presence of an optically active phase transfer catalyst and a lower alcohol, and then treated with an acid. The inventors have found that α-aminoketones can be obtained, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula (II):

[0007]

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(Wherein R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent or Represents an aralkyl group which may have a substituent,
R ³ represents a leaving group. A) reacting a compound represented by the formula (I) with a base in the presence of an optically active phase transfer catalyst and a lower alcohol, followed by treatment with an acid.

[0009]

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(Wherein, R ¹ and R ² have the same meanings as described above, and C * represents an optically active carbon atom.) A process for producing an optically active α-aminoketone represented by the formula:

In the present invention, the optically active phase transfer catalyst is represented by the general formula (IV):

[0012]

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[0013] (wherein, R ^a, R ^b and R ^c are each independently hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkyl group, optionally having a substituent An alkoxy group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent,
X represents an aralkyl group which may have a substituent or an aralkyloxy group which may have a substituent, X represents an anion atom or an anionic group, and * represents axial asymmetry. . It is preferable to use the compound represented by the formula:

In the present invention, the optically active phase transfer catalyst is represented by the general formula (V):

[0015]

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(Wherein, R ^a , R ^b , R ^c , X and * have the same meanings as described above). In the present invention, the optically active phase transfer catalyst is represented by the general formula (VI):

[0017]

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(Wherein ^Ra and * have the same meanings as described above).

In the present invention, as the optically active phase transfer catalyst, a compound represented by the general formula (VIIa) or (VIIb)

[0020]

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(Wherein ^Ra is a hydrogen atom, a phenyl group,
Represents a 3,4,5-trifluorophenyl group or a β-naphthyl group. It is more preferable to use the compound represented by the formula:

According to the present invention, there is provided a simple and industrially advantageous method for producing optically active α-aminoketones.
The present invention uses an oxime ether compound represented by the general formula (II), which is easily available, as a starting material, and thus has a wide range of applications. Therefore, according to the present invention, α-aminoketones having various substituents, which were conventionally difficult to synthesize, can be easily produced.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the general formulas (I) and (II), R ¹ and R ² are
Each independently represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent,
Represents a heteroaryl group which may have a substituent or an aralkyl group which may have a substituent.

The alkyl group of the alkyl group which may have a substituent includes, for example, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, t
An alkyl group having 1 to 20 carbon atoms such as -butyl, n-pentyl, n-hexyl, n-octyl, n-nonyl, n-decyl, eicosanyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, etc. A cycloalkyl group having 3 to 8 carbon atoms;

Examples of the aryl group of the aryl group which may have a substituent include a phenyl group, a 1-naphthyl group and a 2-naphthyl group. Examples of the heteroaryl group of the heteroaryl group which may have a substituent include, for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl Group, 3-pyrazolyl group, 4
-Pyrazolyl group, 5-pyrazolyl group, 2-indolyl group, 3-indolyl group, quinolyl group; and the like.
Examples of the aralkyl group of the aralkyl group which may have a substituent include, for example, a benzyl group, a phenyl group, a 3-phenylpropyl group, a diphenylmethyl group and the like.

The alkyl group, aryl group, heteroaryl group and aralkyl group may have 1 to 3 identical or different substituents. Examples of such a substituent include halogen atoms such as fluorine, chlorine, bromine and iodine;
C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl groups; methoxy, ethoxy, n-propoxy, isopropoxy, C1-C6 alkoxy groups such as n-butoxy, isobutoxy, t-butoxy and n-pentoxy groups; and the like.

R ³ is, for example, an alkylcarbonyl group having 1 to 8 carbon atoms, an alkenylcarbonyl group having 1 to 8 carbon atoms, an aralkylcarbonyl having 7 to 13 carbon atoms, or an aralkylenylcarbonyl group having 7 to 13 carbon atoms. Elimination of an optionally substituted arylcarbonyl group, an alkylsulfonyl group having 1 to 18 carbon atoms, an aralkylsulfonyl group having 7 to 12 carbon atoms, and an arylsulfonyl group optionally having a substituent Represents a group.

The alkylcarbonyl group having 1 to 8 carbon atoms or the alkenylcarbonyl group having 1 to 8 carbon atoms includes
Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, octanoyl, cyclohexanecarbonyl, acryloyl, propioyl, methacryloyl, crotonoyl and the like. Examples of the aralkylcarbonyl group having 7 to 13 carbon atoms or the aralkylenyl carbonyl group having 7 to 13 carbon atoms include phenylacetyl, β-phenylpropionyl, cinnamyl, and 2- (1-naphthyl) propionyl group. . Examples of the arylcarbonyl of the arylcarbonyl group which may have a substituent include a benzoyl, 1-naphthoyl, 2-naphthoyl group and the like.

Examples of the alkylsulfonyl group having 1 to 18 carbon atoms include methylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, cyclohexylsulfonyl, n-octadecylsulfonyl and the like. Examples of the aralkylsulfonyl group having 7 to 12 carbon atoms include α-benzylsulfonyl, 2- (1-naphthyl) ethylsulfonyl, and the like. Examples of the optionally substituted arylsulfonyl group include benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.

The optionally substituted arylsulfonyl group and the optionally substituted arylcarbonyl group may each have 1 to 3 identical or different substituents. Examples of such a substituent include halogen atoms such as fluorine, chlorine, bromine and iodine; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
an alkyl group having 1 to 6 carbon atoms such as an n-hexyl group; methoxy, ethoxy, n-propoxy, isopropoxy, n-
Alkoxy groups having 1 to 6 carbon atoms such as butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy and n-hexyloxy groups;

The compound represented by the general formula (II) is described, for example, in Synthesis. 946 (1982), and can be easily obtained by reacting the corresponding ketoxime with an acid halide or an acid anhydride.

The optically active phase transfer catalyst used in the present invention is not limited as long as it is an optically active quaternary ammonium salt.

[0033]

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[0034] (wherein, R ^a and R ^b are each independently,
A hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an aryl group which may have a substituent,
A heteroaryl group which may have a substituent, an aralkyl group which may have a substituent or an aralkyloxy group which may have a substituent, X represents an anion atom or an anionic group Represents It is preferable to use the compound represented by the formula (1).

[0035] R ^a, R ^b and R ^c in the general formula (IV),
Each independently a hydrogen atom; a halogen atom such as fluorine, chlorine, bromine or iodine; a hydroxyl group; an alkyl group which may have a substituent; an alkoxy group which may have a substituent; An aryl group which may have a substituent; a heteroaryl group which may have a substituent; an aralkyl group which may have a substituent; or an aralkyloxy group which may have a substituent.

As the alkyl group of the alkyl group which may have a substituent, for example, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, t
An alkyl group having 1 to 20 carbon atoms such as -butyl, n-pentyl, n-hexyl, n-octyl, n-nonyl, n-decyl, eicosanyl group; and a carbon number such as cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl group. 3
To 8 cycloalkyl groups;

Examples of the alkoxy group of the alkoxy group which may have a substituent include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy, t-butoxy, n-pentyloxy, n
An alkoxy group having 1 to 6 carbon atoms such as a hexyloxy group;
A cycloalkyloxy group having 3 to 6 carbon atoms, such as cyclopentyloxy and cyclohexyloxy;

Examples of the aryl group of the aryl group which may have a substituent include a phenyl group, a 1-naphthyl group and a 2-naphthyl group. Examples of the heteroaryl group of the heteroaryl group which may have a substituent include, for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group Group, 3-pyrazolyl group, 4
-Pyrazolyl group, 5-pyrazolyl group, 2-indolyl group, 3-indolyl group, quinolyl group and the like. Examples of the aralkyl group of the aralkyl group which may have a substituent include, for example, a benzyl group, a phenyl group,
Examples include a phenylpropyl group and a diphenylmethyl group. The aralkyloxy group of the aralkyloxy group which may have a substituent includes, for example, a benzyloxy group, a phenylyloxy group, a 3-phenylpropyloxy group, a diphenylmethoxy group and the like.

The alkyl group, alkoxy group, aryl group, heteroaryl group, aralkyl group and aralkyloxy group may have 1 to 3 identical or different substituents. Such substituents include, for example, fluorine,
Halogen atoms such as chlorine, bromine and iodine; alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl groups; methoxy , Ethoxy, n-
1 to 1 carbon atoms such as propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and n-pentoxy groups
6 alkoxy groups; chloromethyl, trichloromethyl,
Haloalkyl groups such as trifluoromethyl and 1,1,1, -trifluoroethyl; phenyl, 2-naphthyl, 2
An aryl group or a heteroaryl group such as -thiophenyl, 2-pyridyl, or 4-pyridyl group;

X represents an anion atom or an anionic group. Specific examples thereof include halogen anion atoms such as fluorine, chlorine, bromine and iodine; hydroxyl, alkoxy, acetoxy, HCO ₂ , HSO ₄ and Cl
Examples include an anionic group such as an O ₄ group.

In the present invention, among the compounds represented by the general formula (IV), from the viewpoints of availability, production cost and the like, the compound represented by the general formula (V)

[0042]

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(Wherein R ^a , R ^b , R ^c , X and * have the same meanings as described above), and more preferably a compound represented by the general formula (VI):

[0044]

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(Wherein ^Ra and * have the same meanings as described above), and more preferably a compound represented by formula (VIIa) or (VIIb):

[0046]

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(Wherein ^Ra is a hydrogen atom, a phenyl group,
Represents a 3,4,5-trifluorophenyl group or a β-naphthyl group. It is more preferable to use the compound represented by the formula:

The amount of the optically active phase transfer catalyst used is 0.0001 to 1 with respect to the compound represented by the general formula (II).
Equivalent, preferably in the range of 0.001 to 0.1 equivalent.

The optically active phase transfer catalyst (IV) is described, for example, in J. Am. Am. Chem. , Soc. , 121 , 651
9 (1999).

The base used in the present invention has the general formula (III)

[0051]

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(Where R⁴Is a hydrogen atom; or methyl,
Ethyl, n-propyl, isopropyl, n-butyl, i
Sobutyl, t-butyl, n-pentyl, n-hexyl groups
Etc. C _1-6Represents an alkyl group, and M represents lithium, nato
Lithium, potassium, cesium and other alkali metal atoms or
Alkaline earth metal atoms such as magnesium and calcium
Represent. )).

The compound represented by the general formula (I) can be produced as follows. First, a compound represented by the general formula (II), an optically active phase transfer catalyst and
A solution of a lower alcohol in an inert solvent;
The reaction mixture obtained by mixing the base represented by I) with a solid or a solvent solution is reacted in a temperature range of 5 ° C. to the boiling point, preferably 10 to 60 ° C. for 1 to 48 hours, preferably 4 to Stir for 18 hours.

Next, the obtained reaction mixture is reacted with an acid, water is added to the reaction mixture, and the solution obtained by liquid separation is reacted with an acid.
The target compound can be obtained by any method of reacting the solution obtained by liquid separation with an acid. Said ~
Is carried out in a temperature range from -20 ° C to the boiling point, preferably 5 to 40 ° C, with stirring for 1 to 48 hours, preferably 4 to 18 hours. In addition, an inert solvent solution of a lower alcohol, a phase transfer catalyst, and a base is prepared in advance,
Thereafter, the compound represented by the general formula (II) can be added and reacted.

As the lower alcohol, alcohols having 1 to 6 carbon atoms such as methanol, ethanol and propanol are preferable. The amount used is 1 to 10 equivalents, preferably 2 to 5 equivalents to the compound represented by the general formula (II).
The range of equivalents.

Examples of the inert solvent include aromatic hydrocarbon solvents such as benzene and toluene; hydrocarbon solvents such as hexane and Isopar E; chlorine solvents such as chloroform and chlorobenzene; diethyl ether and t-butyl methyl ether. And the like.

Examples of the base represented by the general formula (III) include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; calcium hydroxide;
Hydroxides of alkaline earth metals such as cesium hydroxide; carbonates of alkali metals such as sodium carbonate and potassium carbonate;
Alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide;
Metal alkoxides such as cesium methoxide and magnesium ethoxide; and the like.

These bases can be used in a range of 2 to 10 equivalents, preferably 3 to 5 equivalents, based on the compound represented by the formula (II). The base can be used as a powder in a solid state, but it can be used after being dissolved in methanol, ethanol, water or the like. When used as a solution, it is preferable to use an aqueous solution of a hydroxide, the concentration of which is usually in the range of 30% to the saturated concentration of the base.

The acid used in the present invention is not particularly limited as long as it is a common acid such as acetic acid, hydrogen chloride and sulfuric acid.
Although aqueous solutions thereof can be used as appropriate, hydrochloric acid is preferred from the viewpoint of versatility and handleability. The amount of the acid used is usually in the range of 1 to 2 equivalents to the base used. When the acid is used in a solution, its concentration is usually in the range of 5% to the saturation concentration of the acid.

[0060]

Next, the present invention will be described in more detail by reference examples and examples. Note that the present invention is not limited to these.

Example 1 Optically active 2-amino-1,2-diphenylaminoethane
Preparation of -1-one anti-deoxybenzoin oxime (where "a
"anti" means that an imino group substituted with a hydroxy group is located on the opposite side of the carbon where the amino group is generated) 63
mg (0.3 mmol), p-toluenesulfonic acid chloride 69 mg (0.36 mmol), optically active phase transfer catalyst (VIIa: Ra = β-naphthyl) 13.5 mg
(0.015 mmol), a mixed solution of 123 ml of methanol and 3 ml of toluene at 0 ° C. under strong stirring at 50%
1 ml of an aqueous potassium hydroxide solution was slowly added dropwise. After completion of the dropwise addition, the mixture was further stirred for 4 hours and then separated. Concentrated hydrochloric acid (0.3 ml) was added to the organic layer, followed by vigorous stirring. 2 at 0 ° C
After further stirring for an hour, the precipitated crystals were filtered and dried, and 40 mg of the title compound was obtained (yield 53%, 0.159 mmol).
1) was obtained.

This salt was dissolved in 1 ml of pyridine, and 35 ml (0.3 mmol) of benzoyl chloride was added.
Stirred for hours. Pyridine was distilled off from the reaction solution under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: diethyl ether: dichloromethane: n-hexane = 1: 1).
4:10), optically active 2-benzoylamino-1,2-diphenylaminoethan-1-one was quantitatively obtained. When the optical purity of this product was measured by high performance liquid chromatography (Chiralpak AD, isopropyl alcohol: n-hexane = 1: 2), the optical purity was 30% ee.

The ¹ H-NMR data of this product is shown below. ¹ H-NMR (300 MHz, CDCl ₃ , δpp
m): 8.01-8.06 (m, 2H), 7.83-
7.88 (m, 2H), 7.75 (d, J = 7.2H)
z, 1H), 7.40-7.58 (m, 8H), 7.2
3-7.37 (m, 3H), 6.76 (d, J = 7.2
Hz, 1H)

[0064]

As described above, according to the present invention,
A simple and industrially advantageous process for producing optically active α-aminoketones is provided. In addition, the present invention uses an easily available oxime ether compound represented by the general formula (II) as a starting material, and therefore has a wide range of applications. Therefore, according to the present invention, α-aminoketones having various substituents can be easily produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 225/22 C07C 225/22 // C07B 61/00 300 C07B 61/00 300

Claims (5)

[Claims] 1. A compound of the general formula (II) (Wherein R ¹ and R ² are each independently a hydrogen atom,
Represents an alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or an aralkyl group which may have a substituent, and R ³ represents a leaving group . The compound represented by the general formula (I), wherein a base is allowed to act on the compound represented by the formula (1) in the presence of an optically active phase transfer catalyst and a lower alcohol, followed by treatment with an acid. (Wherein R ¹ and R ² have the same meanings as described above, and C * represents an optically active carbon atom). 2. The optically active phase transfer catalyst according to the general formula (IV): ## STR3 ## (Wherein, R ^a , R ^b and R ^c each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group optionally having a substituent, an alkoxy group optionally having a substituent, Group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an aralkyl group which may have a substituent or an aralkyloxy which may have a substituent X represents an anion atom or an anionic group, and * represents that the compound has axial asymmetry.) The method for producing α-aminoketones according to claim 1, wherein the compound is represented by the following formula: 3. The optically active phase transfer catalyst according to the general formula (V): 3. The method for producing α-aminoketones according to claim 1 or 2, wherein a compound represented by the formula: wherein R ^a , R ^b , R ^c , X and * have the same meanings as described above. 4. The optically active phase transfer catalyst according to the general formula (VI): (Wherein ^Ra and * represent the same meaning as described above).
-A method for producing amino ketones. 5. The compound of the general formula (VIIa) or (VIIb) as the optically active phase transfer catalyst. (Wherein ^Ra is a hydrogen atom, a phenyl group, 3,4,5-
Represents a trifluorophenyl group or a β-naphthyl group. The method for producing α-aminoketones according to any one of claims 1 to 4, wherein the compound represented by formula (1) is used.