JP2667911B2 - Optically active fluorine-containing benzoic acid derivative - Google Patents

Description

The present invention relates to an optically active fluorinated benzoic acid derivative,
Specifically, ferroelectric liquid crystals, liquid crystal polymers, bioactive substances,
Esters used as anticancer agents and enzyme inhibitors,
The present invention relates to an optically active fluorine-containing benzoic acid derivative useful as a raw material for ethers, amides and the like.

[Problems to be solved by conventional technology and invention]

Heretofore, some compounds have been reported as optically active fluorine-containing alcohol derivatives applied to liquid crystals and pharmaceuticals. Among these, optically active fluorine-containing compounds having two kinds of functional groups of a hydroxyl group and a carboxyl group in the molecule are found. However, an optically active fluorine-containing compound containing two types of functional groups, a hydroxyl group and a carboxyl group, in the molecule and having an aromatic ring has not yet been reported.

[Means for solving the problem]

The present inventors have intensively studied to develop a novel optically active fluorine-containing compound as described above. Among them,
Various optically active alcohol derivatives having a fluoroalkyl group at the terminal were investigated. As a result, they have found that this type of compound having high optical purity can be obtained by asymmetric hydrolysis using an enzyme, and have completed the present invention.

That is, the present invention relates to the general formula [In the formula, Rf represents a fluoroalkyl group having 1 or 2 carbon atoms, and R represents hydrogen, an alkyl group having 1 to 10 carbon atoms or 7 carbon atoms.
~ 10 aralkyl groups are shown, and * indicates an asymmetric carbon. ] It is intended to provide an optically active fluorine-containing benzoic acid derivative represented by the following formula:

There are various fluorine-containing benzoic acid derivatives represented by the general formula (I) according to the present invention, depending on the type of Rf, but all of them are optically active compounds in which the carbon atom bonded to the fluoroalkyl group is an asymmetric center. It is.

In the general formula (I), Rf has 1 carbon as described above.
Or 2 fluoroalkyl groups such as a trifluoromethyl group, a difluoromethyl group, a chlorodifluoromethyl group, and a pentafluoroethyl group. R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a hexyl group, an octyl group, a nonyl group, and a decyl group. Etc. or carbon number 7-10
Are aralkyl groups such as benzyl group and phenethyl group.

By the way, the fluorine-containing benzoic acid derivative represented by the general formula (I) can be produced by various methods, but generally, first, the general formula (II) Rf-CHO (II) , Rf are the same as above. And an aldehyde represented by the general formula (III) [Wherein, R ¹ represents a protecting group for a hydroxyl group. And reacting the Grignard reagent represented by the general formula (V) [Wherein, Rf and R ¹ are the same as described above. To obtain the alcohol represented by the formula In this step, examples of the aldehyde of the general formula (II) used as a starting material include CF ₃ CHO, CHF ₂ CHO, CCIF ₂ CHO, and C ₂ F ₅ CHO. The Grignard reagent of the general formula (III)
It is prepared from a p-bromobenzyl alcohol derivative having a hydroxyl group protected in advance. This hydroxyl protecting group
As R ¹ , various ones can be selected as long as they do not interfere with the subsequent steps from those which can be used usually, and for example, a methoxymethyl group, a 2-methoxyethoxymethyl group or the like can be used. Can be.

The above reaction can be carried out in a solvent such as diethyl ether or tetrahydrofuran at -78 ° C to ordinary temperature.

As an alternative to the above method, general formula (II ′) RfCO ₂ R ² ... (II ′) wherein Rf is the same as above, and R ² represents an alkyl group. Is reacted with the Grignard reagent of the above general formula (III) to give a compound of the general formula (IV) [Wherein, Rf and R ¹ are the same as described above. And then reducing the ketone to give the alcohol of the above general formula (V).
In this method, the general formula (I
Examples of the fluorine-containing alkyl ester of I ′) include CF ₃
CO ₂ C ₂ H ₅ , CHF ₂ CO ₂ C ₂ H ₅ , CClF ₂ CO ₂ CH ₃ , C ₂ F ₅ CO ₂ C ₂ H _{5 and the} like.

The reaction for obtaining the ketone of the general formula (IV) is carried out in the same solvent as in the above method, but is preferably carried out at a lower temperature than the above method. In the reduction of the ketone of the general formula (IV), a reducing agent usually used for reducing a carbonyl group to a hydroxyl group, for example, sodium borohydride, lithium aluminum hydride, stannic chloride and the like can be used.

The obtained alcohol of the general formula (V) is converted to a general formula (VI) R ³ COCl... (VI) [R ³ represents an alkyl group or a phenyl group. ] It reacts with the acid chloride represented by these, and it acylates. Here, specific examples of the acid chloride used as the acylating agent include acetyl chloride, propionyl chloride, isobutyroyl chloride, octanoyl chloride, benzoyl chloride and the like.

General formula (VII) obtained [In the formula, Rf, R ¹ and R ³ are the same as defined above. Asymmetric hydrolysis of an acylated derivative represented by the formula (V ′) or (VII ′) [In the formula, Rf, R ¹ and R ³ are the same as defined above. To obtain an optically active alcohol and ester represented by the formula: As the enzyme used in this reaction, various enzymes can be used as long as they are so-called hydrolases, and examples thereof include lipase P, lipase MY, lipase OF, lipase P679, and cellulase. The ester of the general formula (VII ') can be easily converted into the alcohol of the general formula (V') and the enantiomer by chemical hydrolysis or asymmetric hydrolysis by another enzyme. . Therefore,
The optical purity of both enantiomers can be controlled to some extent by adjusting the hydrolysis rate.

Next, the optically active alcohol represented by the general formula (V ') thus obtained is etherified to form a compound of the general formula (VIII) [In the formula, R ⁴ is an alkyl group having 1 to 10 carbon atoms or 7 to
Indicates 10 aralkyl group, Rf and R ¹ are as defined above. ] An optically active ether derivative represented by the formula: Here, as the etherifying agent, an alkyl halide such as methyl bromide, ethyl bromide, propyl bromide or butyl bromide, or an aralkyl halide such as benzyl bromide can be used.

The primary hydroxyl group in the obtained ether derivative of the general formula (VIII) is deprotected to give the general formula (IX) Wherein R ⁴ and Rf are the same as above. ] The benzyl alcohol derivative represented by these. The deprotection reaction of the primary hydroxyl group may be appropriately selected depending on the kind of the protecting group R ^1.

The obtained benzyl alcohol derivative is further oxidized to obtain the compound of the general formula (I ′) Wherein R ₄ and Rf are the same as above. ] A benzoic acid derivative represented by the following formula, that is, the general formula (I)
Wherein R is an alkyl group or an aralkyl group. This oxidation reaction can be performed by a conventional method, for example, using an oxidizing agent such as permanganate.

Finally, the compound in which R is hydrogen in the general formula (I), that is, the general formula (I ″) is obtained by reductively removing the R ⁴ group in the obtained benzoic acid derivative. Wherein Rf is the same as above. ] The optically active compound of this invention represented by this is obtained. Especially R ⁴
Is a benzyl group, this debenzylation can be carried out by a conventional method. For example, debenzylation can be carried out by hydrogenation at normal pressure in an alcoholic solvent in the presence of a hydrogenation catalyst such as palladium-charcoal.

〔Example〕

Next, the present invention will be described more specifically based on examples, but the present invention is not limited thereto.

Example 1 Synthesis of (+)-4- (1-hydroxy-2,2,2-trifluoroethyl) benzoic acid (1) Methoxymethyl 4- (1-hydroxy-2,2,2-
Synthesis of trifluoroethyl) benzyl ether (a) 6.9 g of methoxymethyl p-bromobenzyl ether was added to 0.73 g (30 mmol) of magnesium under an argon stream.
(30 mmol) of a tetrahydrofuran solution (70 ml) was slowly added dropwise to prepare a Grignard reagent. After the exotherm had subsided, the reaction mixture was kept at -70 ° C and added to 3.5 ml of trifluoroacetaldehyde ethyl hemiacetal (3 ml).
Trifluoroacetaldehyde prepared from (0 mmol) was added dropwise and reacted at -70 ° C for 24 hours. Thereafter, the temperature was returned to room temperature, and a saturated ammonium chloride aqueous solution was added to terminate the reaction. The mixture was extracted with diethyl ether, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off.
The product was isolated by distillation under reduced pressure to give methoxymethyl 4-
2.25 g (9.0 mmol) of (1-hydroxy-2,2,2-trifluoroethyl) benzyl ether were obtained. The physical properties of the obtained compound are shown below. ¹⁹ F-NMR (CCl ₄ ): δ ppm-0.33 (d, J = 6.6 Hz) ¹ H-NMR (CCl ₄ ): δ ppm 3.30 (3H, s), 4.33 (1H, d, J =
4.5Hz), 4.50 (2H, s), 4.60 (2H, s), 4.60 ~ 4.93 (1H,
m), 7.23 to 7.50 (4H, m) IR (neat) (cm ^-1 ): 3400 (OH) (b) A solution of 9.96 g (70 mmol) of ethyl trifluoroacetate in 80 ml of tetrahydrofuran was prepared in the same manner as in (a). Eighty milliliters of the prepared Grignard reagent (70 mmol) in tetrahydrofuran was slowly added dropwise at -70 ° C under an argon stream. After stirring for 20 hours, a saturated aqueous ammonium chloride solution was added to terminate the reaction. Extract with diethyl ether,
After washing with saturated saline and drying, the solvent was distilled off, the product was isolated by distillation, and 11.5 g (46.3 mmol) of methoxymethyl 4- (1-oxo-2,2,2-trifluoroethyl) was obtained. Benzyl ether was obtained. The physical properties of the obtained compound are shown below. ¹⁹ F-NMR (CCl ₄ ): δppm-5.67 (s) ¹ H-NMR (CCl ₄ ): δppm 3.40 (3H, s), 4.70 (4H, m), 7.
50 to 8.23 (4H, m) IR (neat) (cm ^-1 ): 1710 (C = O) Next, a solution of 0.36 g (9.49 mmol) of lithium aluminum hydride suspended in 10 ml of diethyl ether was added as described above. 40 ml of a diethyl ether solution of 6.8 g (27.4 mmol) of the obtained ketone was added dropwise at 0 ° C. under a nitrogen stream. After stirring at room temperature for 3 hours, the reaction was terminated with an aqueous sodium sulfate solution. After decantation, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was isolated by distillation.
(22.7 mmol) of methoxymethyl 4- (1-hydroxy-2,2,2-trifluoroethyl) benzyl ether was obtained.

(2) methoxymethyl 4- (1-isobutyryloxy-
Synthesis of 2,2,2-trifluoroethyl) benzyl ether Pyridine was added to a solution of 12.5 g (50 mmol) of methoxymethyl 4- (1-hydroxy-2,2,2-trifluoroethyl) benzyl ether in 50 ml of methylene chloride. 4.8 ml (60 mmol) and 5.8 ml (55 mmol) of isobutyl chloride were added, and the mixture was stirred at room temperature for 24 hours under a nitrogen stream. A saturated aqueous ammonium chloride solution was added to terminate the reaction, and the mixture was extracted with methylene chloride. The extract was washed with water and saturated saline sequentially, dried, and the solvent was distilled off. The product was purified by silica gel column chromatography, and 13.2 g (41 mmol)
Of methoxymethyl 4- (1-isobutyryloxy-2,2,
2-trifluoroethyl) benzyl ether was obtained. The physical properties of the obtained compound are shown below. ¹⁹ F-NMR (CCl ₄ ): δ ppm-2.33 (d, J = 7.2 Hz) ¹ H-NMR (CCl ₄ ): δ ppm 1.21 (3 H, d, J = 7.2 Hz), 1.17
(3H, d, J = 7.2Hz), 2.67 (1H, sev, J = 7.2Hz), 3.35 (3
H, s), 4.58 (2H, s), 4.65 (2H, s), 6.17 (1H, q, J = 7.2H
z), 7.33 to 7.63 (4H, m) IR (neat) (cm ^-1 ): 1760 (C = O) (3) (+)-methoxymethyl 4- (1-hydroxy-
Synthesis of 2,2,2-trifluoroethyl) benzyl ether Methoxymethyl 4- (1-isobutyryloxy-2,2,
23.7 g (74 mmol) of 2-trifluoroethyl) benzyl ether and 37 g of lipase P (manufactured by Amano Pharmaceutical Co., Ltd.) in distilled water
It was suspended in 800 ml and stirred at 40 ° C. After a reaction was performed for 8.5 hours while maintaining the pH at 6 to 7 with a 1N aqueous sodium hydroxide solution, ethyl acetate was added, and the mixture was filtered through celite to remove the enzyme. After separating the oil layer, the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried, and the solvent was distilled off. The alcohol product as a hydrolysis product and the unreacted acylated product were then purified by silica gel column chromatography. Were separated and purified. The hydrolysis was 45%, and 7.96 g (31.8 mmol) of the alcohol and 11.3 g (35.2 mmol) of the acylated product were obtained. The specific rotation of the obtained optically active alcohol compound [methoxyethyl 4- (1-hydroxy-2,2,2-trifluoroethyl) benzyl ether] was as follows.

[Α] _D = + 28.3 (c = 1.02, methanol) (4) Methoxymethyl 4- (1-benzyloxy-2,2,
Synthesis of 2-trifluoroethyl) benzyl ether 0.72 g (30 mmol) of sodium hydride was suspended in 30 ml of tetrahydrofuran, and (+)-methoxymethyl 4
A solution of 6.0 g (24 mmol) of-(1-hydroxy-2,2,2-trifluoroethyl) benzyl ether in 30 ml of tetrahydrofuran was added dropwise at 0 ° C under a nitrogen stream. After stirring for 1 hour, 3.7 ml (30.5 mmol) of benzyl bromide was added dropwise, and a catalytic amount of tetrabutylammonium iodide was added, followed by reaction at room temperature for 40 hours. The reaction was terminated by adding a saturated aqueous solution of ammonium chloride, the mixture was extracted with diethyl ether, the extract was washed with saturated saline and dried,
The solvent was distilled off and the residue was purified by silica gel column chromatography to give 6.45 g (19.0 mmol) of methoxymethyl 4-
(1-benzyloxy-2,2,2-trifluoroethyl)
Benzyl ether was obtained. The physical properties of this substance were as follows. ¹⁹ F-NMR (CCl ₄ ): δ ppm -2.17 (d, J = 6.6 Hz) ¹ H-NMR (CCl ₄ ): δ ppm 3.33 (3H, s), 4.33 to 4.80 (7H,
m), 7.10-7.63 (9H, m) (5) Synthesis of 4- (1-benzyloxy-2,2,2-trifluoroethyl) benzyl alcohol Methoxymethyl 4- (1-benzyloxy-) in 20 ml of methanol A catalytic amount of p-toluenesulfonic acid was added to a solution of 6.47 g (19 mmol) of 2,2,2-trifluoroethyl) benzyl ether, and the mixture was refluxed for 38 hours. After completion of the reaction, diethyl ether was added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried, evaporated, and purified by silica gel column chromatography to give 5.20 g (17.5 mmol) of silica gel. 4- (1-Benzyloxy-2,2,2-trifluoroethyl) benzyl alcohol was obtained. Physical properties of this compound were as described below. ¹⁹ F-NMR (CCl ₄ ): δppm−2.33 (d, J = 6.6 Hz) ¹ H-NMR (CCl ₄ ): δppm 3.43 (1H, s), 4.30-4.77 (5H,
m), 7.20 to 7.57 (9H, m) IR (neat) (cm ^-1 ): 3350 (OH) (6) (+)-4- (1-benzyloxy-2,2,2-trifluoroethyl) Synthesis of benzoic acid Dissolve 5.2 g (17.5 mmol) of 4- (1-benzyloxy-2,2,2-trifluoroethyl) benzyl alcohol in a mixed solvent of 60 ml of acetone and 20 ml of distilled water. 4.1 g (25.9 mmol) of potassium was gradually added. After reacting at 0 ° C. for 20 hours, the mixture was filtered through celite to remove manganese dioxide, and the filtrate was made alkaline by adding an aqueous solution of potassium hydroxide.
The pH of the aqueous layer was adjusted to 2 by adding hydrochloric acid. The resulting precipitate was filtered and dried to give 4.21 g (13.5 mmol) of (+)-4-
(1-benzyloxy-2,2,2-trifluoroethyl)
Benzoic acid was obtained. The physical properties of this compound were as follows.

Specific rotation [α] _D = + 85.98 (c = 1.11, methanol) ¹⁹ F-NMR (CCl ₄ ): δ ppm-2.67 (d, J = 6.6 Hz) ¹ H-NMR (CCl ₄ ): δ ppm 4.37 ~ 5.00 (3H, m), 7.33 (5H, m
s), 7.50 to 8.27 (4H, m), 9.50 to 10.2 (1H, bs) IR (KBr) (cm ^-1 ): 1680 (C = O), 2950 (OH) (7) (+)-4- Synthesis of (1-hydroxy-2,2,2-trifluoroethyl) benzoic acid (+)-4- (1-benzyloxy-2,2,2-trifluoroethyl) benzoic acid 1.02 g (3.3 mmol) Dissolved in 10 ml of ethanol, 10% palladium charcoal 0.12 g
Was added and the mixture was stirred at room temperature for 80 hours under a hydrogen stream. After filtration, the solvent was distilled off, the residue was purified by silica gel column chromatography, and further recrystallized from hexane to give 0.52 g (2.32 mmol) of (+)-4- (1-hydroxy-2,2,2- Trifluoroethyl) benzoic acid was obtained.
Physical properties of this compound were as described below. ¹⁹ F-NMR (CCl ₄ ): δ ppm-1.33 (d, J = 7.2 Hz) ¹ H-NMR (CCl ₄ ): δ ppm 5.10 (1 H, q, J = 7.2 Hz), 6.43-
7.00 (1H, bs), 7.47 to 8.33 (4H, m), 8.33 to 10.0 (1H, b
s) IR (KBr) (cm ^-1 ): 1700 (C = O), 3000 (OH), 3500
(OH) [α] _D = + 76.09 (c = 1.01, methanol) Example 2 Synthesis of (−)-4- (1-benzyloxy-2,2,2-trifluoroethyl) benzoic acid Example 1 11.2 g (35 mmol) of optically active methoxymethyl 4- (1-isobutyryloxy-2,2,2-trifluoroethyl) benzyl ether obtained in (3) is added to 70 ml of acetone and 35 ml of a 2N aqueous sodium hydroxide solution. And the mixture was stirred at room temperature for 20 hours. After extraction with diethyl ether, the oil layer was successively washed with water, a saturated aqueous solution of ammonium chloride and saturated saline, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the product was isolated and purified by distillation to obtain 6.69.
g (26.7 mmol) of (−)-methoxymethyl 4- (1
-Hydroxy-2,2,2-trifluoroethyl) benzyl ether was obtained. The specific rotation of this product was as follows.

[Α] _D = −20.9 (c = 1.01, methanol) Subsequently, benzylation, removal of a methoxymethyl group and oxidation were carried out in the same manner as in (4), (5) and (6) of Example 1. 4.71 g (15.2 mmol) of (-)-4- (1-benzyloxy-2,2,2-trifluoroethyl) benzoic acid were obtained. This compound showed the same physical properties as the product of Example 1, (6).

Specific rotation [α] _D = −76.31 (c = 1.04, methanol) Example 3 Synthesis of optically active 4- (1-benzyloxy-2,2,2-trifluoroethyl) benzoic acid Example 1 (2) The methoxymethyl 4- (1-
1.46 g (4.56 mmol) of isobutyryloxy-2,2,2-trifluoroethyl) benzyl ether and lipase MY1.2
5 g (manufactured by Meito Sangyo Co., Ltd.) is suspended in 50 ml of distilled water, the temperature is maintained at 40 ° C., and the pH is adjusted to 6 to 7 with a 1N aqueous sodium hydroxide solution.
For 8 hours. Then, ethyl acetate was added and the mixture was filtered through Celite to remove the enzyme. The oil layer was separated, washed successively with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried and evaporated, and then subjected to silica gel column chromatography for unreacted acylation with the alcohol product as a hydrolysis product. The body was separated and purified. With a hydrolysis rate of 42%, 0.43 g (1.73 mmol) of alcohol form
And 0.73 g (2.26 mmol) of the acylated product were obtained. The specific rotation of the obtained optically active alcohol compound was as follows.

[Α] _D = −17.89 (c = 1.02, methanol) Subsequently, benzylation, removal of a methoxymethyl group and oxidation were carried out in the same manner as in (4), (5) and (6) of Example 1. Optically active 4- (1-benzyloxy-2,2,2-
Trifluoroethyl) benzoic acid was obtained. This compound
The product showed the same physical properties as the product (6) of Example 1.

〔The invention's effect〕

The fluorine-containing benzoic acid derivative of the present invention is a novel optically active compound, and is used as a raw material for synthesizing esters, ethers, amides and the like used as ferroelectric liquid crystals, liquid crystal polymers, physiologically active substances, anticancer agents and enzyme inhibitors. Useful.

Claims (1)

(57) [Claims] (1) General formula [In the formula, Rf represents a fluoroalkyl group having 1 or 2 carbon atoms, and R represents hydrogen, an alkyl group having 1 to 10 carbon atoms or 7 carbon atoms.
~ 10 aralkyl groups are shown, and * indicates an asymmetric carbon. ] An optically active fluorine-containing benzoic acid derivative represented by