JPH08245526A - Optically active amines, optically active imines and their production - Google Patents

Abstract

PURPOSE: To obtain optically active new amines or imines having C2 symmetry functioning as asymmetric sources of important highly selective asymmetric synthesis in synthesis of intermediates for medicines or agrochemicals. CONSTITUTION: This compound is expressed by formula I or II (R<1> and R<2> are each H, an alkyl, an alkoxy, a halogen or trifluoromethyl; * is an asymmetric carbon atom), e.g. N-(2,2,2-trifluoro-1-phenylethylidene)-2,2,2-trifluoro-1- phenylethanamine. Furthermore, the imines of formula II are obtained by reacting ketones of formula III with amines of formula IV in the presence of a catalyst such as titanium tetrachloride and the amines of formula I are obtained by reducing the imines of formula II.

Description

Detailed Description of the Invention

[0001]

The present invention relates to C which functions as a ligand for asymmetric synthesis, which is particularly useful in the fields of pharmaceutical and agricultural chemical synthesis.
_{The present invention} relates to an optically active amine having _two symmetries, an optically active imine, and a method for producing them.

[0002]

2. Description of the Related Art General formula (5) (In the formula, R represents a hydrogen atom, an alkyl group, an alkoxy group, etc.) and an optically active amine having C ₂ symmetry, and any one of the two CH ₃ groups in the general formula (5). Compounds in which one is substituted with a trifluoromethyl group are widely used as a ligand for asymmetric synthesis. The silyl enol etherification using this chiral amine amide as an asymmetric base is described in Tetrahedron Letter., 34,5105, (1
993), it is difficult to say that the optical purity is low and it is not always satisfactory.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide optically active amines having C ₂ symmetry, which are excellent as a chiral source in selective asymmetric synthesis, optically active imines, and their production. To provide the law.

[0004]

The present inventors have arrived at the present invention as a result of intensive studies to solve the above problems. That is, the present invention relates to the general formula (1) (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom or a trifluoromethyl group, and the * mark represents an asymmetric carbon atom.) Active amines, their metal salts, general formula (2) (Wherein R ¹ , R ² and * have the same meanings as described above), and an optically active imine and a method for producing the same are provided.

The present invention will be described in detail below. In the present invention, the substituents R ¹ and R ² in the general formulas (1), (2), (3) and (4) are each a hydrogen atom or C _{1 to} C _6.
Examples thereof include an alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, and a trifluoromethyl group.

The optically active imines represented by the general formula (2) of the present invention are represented by the general formula (3) (Wherein R ¹ has the same meaning as described above) and a trifluoromethyl group-containing ketone represented by the general formula (4) (In the formula, R ² has the same meaning as described above.) It is obtained by reacting with an amine having a trifluoromethyl group in the presence of a catalyst.

Examples of the catalyst used in the above production method include Lewis acids such as titanium tetrachloride, aluminum chloride and zinc chloride. Acids such as toluenesulfonic acid, methanesulfonic acid and sulfuric acid can also be used as the catalyst. . Further, in using such a catalyst, when a base is used, triethylamine and pyridine are particularly preferably used.

The amount of the catalyst used varies depending on the kind of the substrate and the combination of the catalysts and the like and cannot be specified, but
It is usually used in an amount of 0.1 equivalent or more with respect to the substrate. A solvent is usually used in the above reaction, and examples thereof include ethers such as tetrahydrofuran, diethyl ether, dichloromethane, chloroform, carbon tetrachloride, benzene and hexane, halogenated hydrocarbons, and solvents inert to the reaction. The amount used is not particularly limited.

The reaction temperature of the above reaction is usually from -70 ° C to
It is in the range of 100 ° C, preferably -30 ° C to 80 ° C.
Range. Further, the reaction time is not particularly limited.

After completion of the reaction, a usual post-treatment operation, for example,
The optically active imine (2) can be obtained by filtration, extraction, liquid separation, concentration, recrystallization, etc., and if necessary, it can be further purified by column chromatography or the like.

The optically active amines (1) can be produced by selectively hydrogenating the optically active imines (2) with a reducing agent. As the reducing agent used in this reaction, an ordinary reducing agent can be used, and examples include LiAlH ₄ and DIBA.
H, NaBH ₄ , NaBH ₃ CN, H ₂ / Pd-C, Na [AlH ₂ (OCH ₂ CH ₂ OCH
₃ )] and the like. The amount of the reducing agent used is usually 0.1 to 20 equivalent times, preferably 1 to 5 equivalent times, with respect to the optically active imine (2).

A solvent is usually used in the above reaction, and when a metal hydride is used as a reducing agent, ethers such as tetrahydrofuran and diethyl ether are preferably used. In the reduction with hydrogen using a transition metal catalyst, solvents such as alcohols such as methanol and ethanol and hydrocarbons such as hexane, toluene and chlorobenzene which are inert to the reaction are used alone or as a mixture.
The amount used is not particularly limited.

The reaction temperature is usually in the range of -78 ° C to 70 ° C, preferably 30 ° C or lower. Further, the reaction time is not particularly limited. After completion of the reaction, the optically active amines (1) can be obtained by usual post-treatment operations such as filtration, extraction, liquid separation, concentration, recrystallization and the like, and if necessary, further purified by column chromatography and the like. be able to. The obtained optically active amines (1) can be converted into a metal salt according to a conventional method,
For example, in the case of lithium, it can be converted to a lithium salt by reacting with t-butyllithium, metallic lithium, lithium hydride, n-butyllithium or the like usually in ethers such as tetrahydrofuran or diethyl ether. The amount of the raw material compound used as the metal salt is usually 1.1 to 20 with respect to the optically active amines (1).
It is used in an equivalent amount, preferably 1.5 to 7 equivalents. The amount of solvent used is not particularly limited.

[0014]

INDUSTRIAL APPLICABILITY The optically active amines (1) and their metal salts, which are the compounds of the present invention, are useful as an asymmetric source for producing an optically active substance important as an intermediate for medicines and agricultural chemicals.

[0015]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 In a 50 ml branched reactor, 1.0 g (5.74 mmo) of trifluoroacetophenone was added.
l) and (R) -trifluorophenethylamine 1.1 g
(5.75 mmol) was weighed and replaced with nitrogen. After adding methylene chloride (10 ml) and triethylamine (6.5 ml, 45.9 mmol) to the reactor, titanium tetrachloride (0.7 ml) dissolved in methylene chloride (0.5 ml) was added.
63 g, 4.02 mmol) was added dropwise with ice cooling, and the reaction solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, the generated salt was suction filtered, and the filtrate was concentrated and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the obtained concentrate was primarily purified by silica gel chromatography. The obtained crude product is recrystallized from hexane to obtain the desired N- (2,2,2-trifluoro-1-phenylethylidene) -2,2,2-
1.63 g of trifluoro-1-phenylethanamine
(Yield 86%) was obtained. Optical rotation [α] _D ²⁰ = -189 ° (c = 0.15, Et
OH), IR (CH ₂ Cl ₂ ) 1670 cm ^-1 (C
F ₃ ), ¹ H NMR δ 4.73 (q, J = 7.0H
z, 1H, CF ₃ CH), 7.0-7.6 (m, 10
H, C ₆ H ₅ ), ¹⁹ F NMR δ87.9 (d, J
= 7.5 Hz, 3F, CF ₃ ), 90.3 (s, 3F,
CF ₃ ) Elemental analysis C ₁₆ H ₁₁ F ₆ N (MW 331.26),
Calculated value: C: 58.01, H: 3.34, N: 4.2
3, analytical value: C: 58.31, H: 3.52, N: 3.
94

(Example 2) 37.8 mg (0.997 mmol) of lithium aluminum hydride was weighed in a reactor and purged with nitrogen, and then 5 ml of THF was added. -78 ° C
After cooling to N- (2,2) dissolved in 1 ml of THF.
2,2-trifluoro-1-phenylethylidene)-
300 mg (0.906 mmol) of 2,2,2-trifluoro-1-phenylethanamine was added dropwise. After the temperature was raised to room temperature, water was added to stop the reaction. The reaction mixture was suction filtered, the filtrate was concentrated and then extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was primarily purified by silica gel chromatography (chiral: meso = 3.3: 1, yield 86
%). The obtained crude product was chromatographed to separate the chiral form and the meso form, and recrystallized from hexane to obtain 217 mg of the desired di (2,2,2-trifluoro-1-phenylethyl) amine. It was Optical rotation [α] _D ²⁰ -144 ° (c = 0.15, EtO
H), IR (CH ₂ Cl ₂ ) 3550, 3000, 13
80 cm ⁻¹ , ¹ H NMR δ2.5-2.6 (br,
1H, NH), 3.92 (q, J = 7.3 Hz, 1H,
CF ₃ CH), 7.3-7.5 (m, 10H, C
₆ H ₅ ), ¹⁹ F NMR δ87.4 (d, J = 7.3
Hz, 3F, CF ₃ ), elemental analysis C ₁₆ H ₁₃ F ₆ N (MW 333.28),
Calculated value: C: 57.60, H: 3.93, N: 4.2
0, analytical value: C: 57.84, H: 3.86, N: 4.
30

Claims (4)

[Claims] 1. A general formula (1) (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom or a trifluoromethyl group, and the * mark represents an asymmetric carbon atom.) Active amines or their metal salts. 2. General formula (2) (In the formula, R ¹ , R ² and * have the same meanings as described above.) An optically active imine. 3. A general formula (3) (Wherein R ¹ has the same meaning as described above) and a trifluoromethyl group-containing ketone represented by the general formula (4) (In the formula, R ² has the same meaning as described above.) An amine having a trifluoromethyl group represented by the formula is reacted in the presence of a catalyst, and the compound is represented by the general formula (2). Method for producing optically active imines. 4. A method for producing an optically active amine represented by the general formula (1), which comprises reducing the optically active imine represented by the general formula (2).