JPH02167252A - Optically active alpha-trifluoromethyl-gamma-aminobutyric acid or ester of same compound and production thereof - Google Patents

Abstract

NEW MATERIAL:Optically active alpha-trifluoromethyl-gamma-laminobutyric acid or esters thereof represented by formula I or formula II (R is 1-10C alkyl or 7-16C aralkyl). USE:A neurergic insecticide. A medicine. A pesticide. PREPARATION:A 2-trifluoromethylpropenic ester of formula III is reacted with nitromethane to prepare an alpha-trifluoromethyl-gamma-nitrobutyric ester of formula IV and the resultant product is reduced using hydrogen. The obtained reduced compound is then subjected to an enzymatic hydrolysis, thus obtaining the objective compound of formula I.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to optically active α-trifluoromethyl-γ-aminobutyric acid or its ester, and a method for producing the same. Novel α-trifluoromethyl-T useful as selective neurogenic insecticide
-Aminobutyric acid or its ester and its efficient production method.

[Prior Art and Problems to be Solved by the Invention] Several compounds have been reported so far as optically active fluorine-containing compounds that are applied to liquid crystals, medicines, agricultural chemicals, and the like.

However, in compounds containing a trifluoromethyl group at the α-position of the carboxyl group, the acidity of the proton at the α-position is extremely high, and elimination reactions easily occur, making it difficult to control the reaction. . Furthermore, at present, compounds of this type have not been obtained with high optical purity.

Therefore, an object of the present invention is to provide a novel α-trifluoromethyl-γ-adanobutyric acid or its ester with high optical purity and an efficient method for producing the same.

[Means to solve the problem]

In particular, the present inventors investigated various optically active compounds having a trifluoromethyl group at the α-position of the carboxyl group, and found that this type of compound with high optical purity can be obtained by asymmetric hydrolysis using an enzyme. They discovered this and completed the present invention.

That is, the present invention is based on the formula Or - Monka C.F.

(In the formula, R represents an alkyl group having 1 to 10 carbon atoms or an aralkyl group having 7 to 16 carbon atoms.) Optically active α-trifluoromethyl-γ-aminobutyric acid Or it provides the ester thereof.

In addition, as a manufacturing method, 2-trifluoromethylpropenoic acid ester represented by -Moretsu is reacted with nitromethane, and α
-trifluoromethyl-γ-nitrobutyric acid ester,
The method for producing optically active α-trifluoromethyl-γ-aminobutyric acid and its esters, which is then reduced using hydrogen, and then subjected to enzymatic hydrolysis;
Alternatively, α-trifluoromethyl-T-nitrobutyric acid ester represented by the above-mentioned pattern (III) is enzymatically hydrolyzed to obtain optically active α-trifluoromethyl-y-nitrobutyric acid, and then hydrogen is removed. The optically active α-trifluoromethyl-T-
A method for producing aminobutyric acid, and further enzymatically hydrolyzing α-trifluoromethyl-T-nitrobutyric acid ester represented by the above-mentioned Monena (II[) to produce an optically active α-trifluoromethyl-γ-nitrobutyric acid ester. The present invention provides a method for producing optically active α-trifluoromethyl-γ-aminobutyric acid or an ester thereof, which comprises obtaining the following: and then reducing it using hydrogen.

α-Trifluoromethyl-T- of formula (I) according to the present invention
Aminobutyric acid is an optically active compound in which the carbon atom bonded to the trifluoromethyl group (CF, ) serves as an asymmetric center. There are various types of butyrate esters depending on the type of substituent R, but all of them are optically active compounds in which the carbon atom bonded to the trifluoromethyl group serves as an asymmetric center.

R is an alkyl group having 1 to 10 carbon atoms as described above (for example, a methyl group, ethyl group, or propyl group generally represented by 2C*Hzn++ (n=t to to).

butyl group, isobutyl group, hexyl group, octyl group, nonyl group, etc.), or an aralkyl group having 7 to 16 carbon atoms (for example, general 2CnHznP h (n = 1 to 1
0), such as a benzyl group or a phenethyl group.

By the way, this α-trifluoromethyl-T-aminobutyric acid or its ester can be produced by various methods, but it is preferably produced according to the three methods mentioned above, that is, the following three reaction formulas.

[Reaction formula l] Fs (I[I) C.F.

(Io) C.F.

(Ia) [Reaction formula 2] (III) (■゛) F3 (IV) C.F.

[Reaction formula 3] (I[I) (Ia) By each of the above reactions, the optically active α of the present invention
-Trifluoromethyl-T-aminobutyric acid or its ester can be produced.

Among these, in reaction formula 1, α-trifluoromethyl-γ-aminobutyric acid and its ester are simultaneously produced, and in reaction formula 2, α-trifluoromethyl-T-acnobutyric acid is produced, Further, in Reaction Formula 3, either α-trifluoromethyl-T-aminobutyric acid or its ester, or both can be produced simultaneously depending on the conditions in the hydrogen reduction reaction in the final step.

Next, each manufacturing process will be explained in detail.

First, 2-trifluoromethylpropenoic acid ester of general formula (U), which is a raw material, can be obtained by the following reaction.

\ / (V) \ / (Vl) (wherein, This can be carried out by a conventional method using, for example, phthalic acid chloride as a typical example.

Esterification of the acid halide of the general formula (Vl) obtained in the above step can be carried out by using an alcohol represented by -Monken (in the formula, R is the same as above) and pyridine, but α Since the reactivity at the β-position is greatly increased due to the influence of the trifluoromethyl group at the -position, side reactions such as addition of pyridine to the β-position and oligomerization occur. Therefore, the side reactions can be minimized by dropping pyridine into a methylene chloride solution of the alcohol and excess acid halide at a low temperature, for example, -20''C.

Nitromethane addition reaction The nitromethane addition reaction to the 2-trifluoromethylpropenoic acid ester of general formula (II) obtained by the above-mentioned method can be carried out under conditions such that a proton donor is present in the reaction system. For example, in a system in which a catalytic amount of an aqueous potassium carbonate solution is applied to a nitromethane solvent, fluorine is eliminated as the reaction progresses, and α-trifluoromethyl represented by the above-mentioned Ilr with nitromethane added thereto. -γ-nitrobutyric acid ester can be obtained.

Hydrogen Reduction Reaction This hydrogen reduction reaction can be carried out under almost the same conditions in each of the above reaction formulas. For example, a nitro group can be selectively reduced to an amino group by heterogeneous catalytic hydrogenation using a metal palladium catalyst on an activated carbon carrier under a hydrogen stream. As a result, in the reaction formula 1, a -trifluoromethyl-γ-aminobutyric acid ester (racemic form) of -Crimson hole (■°) can be obtained. Also, reaction formula 2
Alternatively, in Reaction Scheme 3, the final product, optically active α-trifluoromethyl-T-agonobutyric acid or its ester, can be obtained.

In enzymatic hydrolysis reaction formula 1, α-trifluoromethyl-T-a≧nobutyric acid ester of general formula (■') obtained by the above hydrogen reduction reaction, and in reaction formulas 2 and 3, hydrogen reduction Each compound with high optical purity can be obtained by asymmetrically hydrolyzing the α-trifluoromethyl-γ-nitrobutyric acid ester shown by the above-mentioned symbol (1111) with an enzyme before the reaction.

As the enzyme, various so-called hydrolytic enzymes can be used. For example, Lipase P, Lipase MY, Lipase MIO, Lipase OF, Lipase P679. Cellulase, PLE, etc. can be used.

Furthermore, as shown in reaction formulas 2 and 3, by enzymatically hydrolyzing the α-trifluoromethyl-γ-nitrobutyric acid ester of -Momona (IfI), Ni (IV) and -Momona (■
It can be divided into both mirror specimens, represented by °). The two can be easily separated by changing the pH of the aqueous phase to be extracted and the extraction solvent. By further reducing each with hydrogen, optically active α-trifluoromethyl-T-aminobutyric acid or its ester can be obtained. Particularly in some compounds where R is a benzyl group, the optically active Both mirror specimens of fluoromethyl gamma-acid #1 can be obtained.

The reactions in each step are carried out under optimal bath conditions, and the reaction time and temperature are appropriately selected depending on conditions such as the type of solvent and the amount of various auxiliaries added.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Base of optically active α-trifluoromethyl-T-aminobutyric acid 2-trifluoromethylpropenoic acid (toos remol)
and phthalic acid chloride (20d, 150 mmol) were mixed and heated at 140''C for 2 hours.

Subsequently, the product was isolated and purified by distillation to obtain 2-trifluoromethylpropenoyl chloride.

This 2-trifluoromethylpropenoyl chloride (31
, 5ξ rmol) and benzyl alcohol (3,10 rI
tl, 30a mol) was dissolved in 1/730 ml of methyl chloride under a nitrogen stream. Pyridine (2.43d, 30 mmol) was added dropwise while maintaining the reactor at -20'C, and after the reaction was completed, 1N hydrochloric acid was added.

The organic layer was dried over magnesium sulfate, the solvent was distilled off, and the organic layer was isolated and purified by distillation under reduced pressure to obtain an ester represented by the following formula.

(In the formula, Ph represents a phenyl group.) The above ester (1,456 g, 4.95 mmol) was dissolved in 5.0 d of nitromethane, and further 0.3 mol/l
1.67 ml of an aqueous potassium carbonate solution was added thereto, and the mixture was heated to reflux at 110°C. After the reaction was completed, 1N hydrochloric acid was added, and the organic layer extracted with diethyl ether was dried over magnesium sulfate, and the solvent was distilled off.

The obtained oily mixture was isolated and purified by silica gel column chromatography to obtain a compound represented by the following formula in which nitromethane was added to the above ester.

C.F.

The physical properties of the obtained α-trifluoromethyl-γ-nitrobutyric acid benzyl ester are shown below.

Note that both the proton nuclear magnetic resonance ('H-NMR) spectrum and the fluorine nuclear magnetic resonance ('F-NMR) spectrum were measured using a carbon tetrachloride solvent.

Molecule I 291 Boiling point 138°C10,60HgRf
O, 30 (hexane:ethyl acetate-5:1)"F
-NMRδ (ppm) -9,67 (d, J=7.0H
z)'H-NMRδ(ppm) 2.52(2H,q
, J=6.96Hz) 3, 32 (IH, qt, J-
7,95Hz, 7.7011z)4.36(2H,t
, J=6.39Hz) 5.25(2H,s) 7.38(5H,s) T R(neat) 1740 am-'(C=O
) Obtained T-nido r2 butyric acid ester (α-trifluoromethyl-T-nitrobutyric acid benzyl ester) 1.46
g (5,0 mol) is suspended in 50 d of distilled water,
While maintaining the temperature at 40'C, increase the hydrolase lipase P to 2.5
Added 0g. Adjust the pH of the reaction solution with 1N sodium hydroxide.
was maintained at 6 to 7 and stirred for 6 hours. Thereafter, a flocculant was added, the mixture was filtered through Celite, and unreacted ester was extracted with methylene chloride.

Furthermore, 6N hydrochloric acid was added to the aqueous phase, and the carboxylic acid was extracted with ethyl acetate at pH 2. Each organic layer was dried over magnesium sulfate, the solvent was distilled off, and then isolated and rectified by distillation to obtain an optically active ester and carboxylic acid shown in the following formula.

C.F.

CF3 0.867 g (3,0
mmol) in ethanol 6.0/d, and this was dissolved in 10% metallic palladium (activated carbon carrier) 120 mmol under a hydrogen stream.
■Dropped into. After the reaction, the reaction mixture was filtered through Celite, and the solvent was distilled off, followed by purification by silica gel column chromatography and recrystallization to obtain optically active α-trifluoromethyl-T-aminobutyric acid represented by the following formula. Ta.

C.F.

The physical properties of the obtained α-trifluoromethyl-γ-anobutyric acid are shown below. Note that all nuclear magnetic resonance spectra were measured using a heavy water solvent.

Molecule 11 171 "F-NMR δ (ppm) -9,83 (d, J=9.
4Hz) from CFsC○○H 'H-NMRδ (ppm) 2.07 (28, a+
).

2.97-3.18 (3H, m) I R()(Br) 1605cm-'(C=O)
Specific optical rotation [α] n = +3.36 (concentration in methanol, 0.42) Example 2 Using the carboxylic acid obtained in Example 1, the nitro group was reduced in the same manner as in Example 1, It was isolated and purified by fractional recrystallization to obtain optically active α-trifluoromethyl-γ-anobutyric acid represented by the following formula.

C.F.

The specific optical rotation of the obtained α-trifluoromethyl-γ-anobutyric acid is shown below.

Specific optical rotation [α]. --5,22 (concentration in methanol;
0.83) Example 3 Synthesis of optically active α-trifluoromethyl-T-aminobutyric acid methyl ester 6.732 g (42.5 mmol) of 2-trifluoromethylpropenoyl chloride prepared in the same manner as in Example 1 and 1.63 d (40.4 mmol) of methanol were dissolved in 40 d of methylene chloride, and 3.27 d of pyridine was dissolved at -20'C.
1!11 was added dropwise, and the same treatment as in Example 1 was carried out to isolate and purify the mixture to obtain an ester represented by the following formula.

The above ester (2,879 g, 18.7 mmol) was dissolved in nitromethane 20Ia1 and an additional 0.3 mol/
Add 6.6 d of potassium carbonate aqueous solution and heat to 110"C.
The mixture was heated to reflux. Thereafter, the same treatment as in Example 1 was carried out for isolation and purification to obtain a compound represented by the following formula in which nitromethane was added to the above ester.

F 3 The physical properties of the obtained α-trifluoromethyl-γ-nitrobutyric acid methyl ester are shown below.

Molecule @ 215 Boiling point 108~il1°C/8. O+ma
Hg"F-NMRδ (ppm) -10,2(d,
J=8.1Hz)'H-NMRδ(ppm) 2.
55(2)1. q, J-7,0Hz) 3.33 (LH
, qtt J-7, 6Hz, 8. ], l1z)3.
87 (3H, s) 4.52 (28, t, J=6.7Hz) T R (ne
at) 1740 c+r' (C=O) The obtained T-nitrobutyric acid ester (1,466 g 6.8 mmol) was dissolved in ethanol 7.0-, and this was dissolved in 10% metallic palladium (activated carbon carrier) under a hydrogen stream. It was dropped into 409■. After the reaction was completed, the reaction mixture was filtered through Celite, and the solvent was distilled off, followed by purification and isolation using silica gel chromatography to obtain α-trifluoromethyl-γ-aminobutyric acid methyl ester shown below.

C.F.

The physical properties of the obtained α-trifluoromethyl-T-aminobutyric acid methyl ester are shown below.

Molecular weight 185”F-NMRδ(pp+n) −7,17(d, J=8
．． 1flz)'H-NMRδ (ppm) 2.07
(2H, M) 2.77 (2H, t, J-6,0Hz)
3.27 (18, m) 3.85 (3 tl, s) 7.41 (2H, br, s) I R (neat) 1735 C1m-' (C
=O) The ester obtained above (78 μm, 0.42 mmol) was suspended in 4.2 mm of distilled water, and while maintaining the reaction temperature at 40'C, the hydrolase lipase-P was added at 0.12 mm.
g added. l Adjust the pH of the reaction solution with normal sodium hydroxide.
was maintained at 6 to 7 and stirred for 8 hours. After that, a flocculant was added thereto, filtered through Celite, and the organic layer extracted with ethyl acetate was dried over magnesium sulfate. The solvent was distilled off and isolated and purified by silica gel chromatography to obtain the optically active α- Trifluoromethyl-γ-aminobutyric acid methyl ester was obtained.

C.F.

The specific light extinction of the obtained α-trifluoromethyl-γ-adanobutyric acid methyl ester is shown below.

Specific optical density [α) 6 = +1.79 (concentration in methanol; 0.32) [Effects of the invention] As described above, the optically active α-trifluoromethyl-γ-aminobutyric acid or The ester compound has extremely high optical purity and is expected to be widely and effectively used as a compound useful as a drug or agrochemical, especially a neurogenic insecticide selective for insects, or as an intermediate thereof.

Further, according to the method of the present invention, the optically active α-trifluoromethyl-γ-anobutyric acid or its ester compound with high optical purity can be obtained without causing elimination of fluorine or the like.

Claims (4)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or general formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is an alkyl group having 1 to 10 carbon atoms or An optically active α-trifluoromethyl-γ-aminobutyric acid or an ester thereof, characterized in that it is represented by (representing an aralkyl group). (2) By reacting 2-trifluoromethylpropenoic acid ester represented by the general formula▲mathematical formula, chemical formula, table, etc.▼ (in the formula, R is the same as above) with nitromethane, the general formula▲mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R is the same as above.) Obtain α-trifluoromethyl-γ-nitrobutyric acid ester, then reduce using hydrogen, and then perform enzymatic hydrolysis. The method for producing optically active α-trifluoromethyl-γ-aminobutyric acid or its ester according to claim 1, characterized by the following. (3) By reacting 2-trifluoromethylpropenoic acid ester represented by the general formula▲mathematical formula, chemical formula, table, etc.▼ (in the formula, R is the same as above) with nitromethane, the general formula▲mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R is the same as above) α-trifluoromethyl-γ-nitrobutyric acid ester is obtained, and then enzymatic hydrolysis is performed to obtain optically active α-trifluoromethyl- 2. The method for producing optically active α-trifluoromethyl-γ-aminobutyric acid according to claim 1, characterized in that γ-nitrobutyric acid is obtained and then reduced using hydrogen. (4) By reacting 2-trifluoromethylpropenoic acid ester represented by the general formula▲mathematical formula, chemical formula, table, etc.▼ (in the formula, R is the same as above) with nitromethane, the general formula▲mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R is the same as above) α-trifluoromethyl-γ-nitrobutyric acid ester is obtained, and then enzymatic hydrolysis is performed to obtain optically active α-trifluoromethyl- The optically active α-trifluoromethyl-γ- according to claim 1, characterized in that the γ-nitrobutyric acid ester is obtained and then reduced using hydrogen.
A method for producing aminobutyric acid or its ester.