JPH0331238A - Optically active fluorine-containing benzoic acid derivative - Google Patents

Abstract

NEW MATERIAL:An optically active fluorine-containing benzoic acid derivative expressed by formula I (Rf is 1-2C fluoroalkyl; R is H, 1-10C alkyl or 7-10C aralkyl; mark * indicates asymmetric carbon atom). EXAMPLE:(+)-4-(1-Hydroxy-2,2,2-trifluoroethyl)benzoic acid. USE:A raw material for esters, ethers, amides, etc., useful as a ferroelectric liquid crystal, liquid crystal polymer, physiologically active substance, anticancer agent and enzyme inhibitor. PREPARATION:A compound expressed by the formula Rf-CHO is reacted with a compound expressed by formula II (R<1> is OH-protecting group) to provide a compound expressed by formula III, which is subsequently acylated to afford a compound expressed by formula IV (R<3> is alkyl or phenyl). The resultant compound expressed by formula IV is then asymmetrically hydrolyzed with an enzyme to provide an optically active substance expressed by formula V, which is subsequently etherified to afford an optically active substance expressed by formula VI (R<4> is R other than H). The primary hydroxyl group thereof is then deprotected. The obtained compound is oxidized and R<4>, as desired, is further reductively eliminated to provide the optically active substance expressed by formula 1.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to an optically active fluorine-containing benzoic acid derivative, and more specifically, it can be used as a ferroelectric liquid crystal, a liquid crystal polymer, a physiologically active substance, an anticancer agent, an enzyme inhibitor, etc. The present invention relates to optically active fluorine-containing benzoic acid derivatives useful as raw materials for esters, ethers, amides, etc. used.

[Prior art and problems to be solved by the invention] Conventionally,
Several compounds have been reported as optically active fluorine-containing alcohol derivatives that are applied to liquid crystals, pharmaceuticals, etc. Among these, optically active fluorine-containing compounds having two types of functional groups, a hydroxyl group and a carboxyl group, are found in the molecule. However, an optically active fluorine-containing compound containing two types of functional groups, a hydroxyl group and a carboxyl group, and having an aromatic ring in the molecule has not yet been reported.

[Means for Solving the Problems] The present inventors have conducted extensive research in order to develop a new optically active fluorine-containing compound as described above. In particular, various optically active alcohol derivatives having a fluoroalkyl group at the end were investigated. As a result, the inventors discovered that this type of compound with high optical purity can be obtained by asymmetric hydrolysis using an enzyme, leading to the completion of the present invention.

That is, the present invention relates to the general formula [wherein Rf represents a fluoroalkyl group having 1 or 2 carbon atoms, R represents hydrogen, an alkyl group having 1 to 10 carbon atoms, or an aralkyl group having 7 to 10 carbon atoms, and is marked with an asterisk] indicates an asymmetric carbon. ] An optically active fluorine-containing benzoic acid derivative represented by the following is provided.

There are various fluorine-containing benzoic acid derivatives represented by the general formula (1) 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 the asymmetric center. It is.

-m In formula (1), Rf has 1 carbon number as described above.
or 2 fluoroalkyl groups, such as trifluoromethyl group and difluoromethyl group.

Examples include chlorodifluoromethyl group and pentafluoroethyl group. In addition, R is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, n
-propyl group, isopropyl group, n-butyl group, isobutyl group, hexyl group.

Octyl group, nonyl group, decyl group, etc., or carbon number 7 or more
10 aralkyl groups, such as benzyl groups.

Such as phenethyl group.

By the way, the fluorine-containing benzoic acid derivative represented by the general formula (1) can be produced by various methods, but in general, the fluorine-containing benzoic acid derivative represented by the general formula (n) Rf-CIO... (II) [in the formula , Rf are the same as above. ] An aldehyde represented by the general formula (IiI) [wherein,
R' represents a hydroxyl protecting group. A Grignard reagent represented by the formula (V) is reacted with the Grignard reagent represented by the formula (V) [wherein Rf and R1 are the same as above. ] to obtain alcohol. In this step, examples of the aldehyde of general formula (11) used as a starting material include CF 3 CHO and CHF tc HO.

Examples include CCI F z CHO and Cz F s CHO.

Further, the Grignard reagent of the general formula ([[[) is prepared from a p-bromobenzyl alcohol derivative whose hydroxyl group has been protected in advance. As this hydroxyl protecting group R1, various groups can be selected from among commonly used groups as long as they do not interfere with subsequent steps, such as methoxymethyl group, 2-methoxyethoxymethyl group, etc. can be used.

The above reaction can be carried out in a solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from -18°C to room temperature.

As an alternative method to the above method, an ester represented by the general formula (■゛) RfCO,R2... (■'') [In the formula, Rf is the same as above, and R2 represents an alkyl group] and the above general formula (III) with a Grignard reagent to form the general formula (IV) [wherein Rf
and R1 are the same as above. ] The alcohol of general formula (V) can also be obtained by reducing the ketone. In this method, the fluorine-containing alkyl ester of the general formula (■゛) used as a starting material is, for example, CF3Co□CzHs.

CHF2C0□caFts, CCff1F2Co□CH
:t.

Examples include C2F and Co□CzHs.

The reaction to obtain the ketone of general formula (TV) above is carried out in the same solvent as in the above method, but preferably carried out at a lower temperature than in the above method. For the reduction of the ketone of general formula (rV),
Reducing agents commonly used to reduce carbonyl groups to hydroxyl groups can be used, such as sodium borohydride, lithium aluminum hydride, tin chloride, and the like.

The obtained alcohol of the general formula (V) is reacted with an acid chloride represented by the general formula (Vl) R3COC1,... (VI) (R' represents an alkyl group or a phenyl group) by a conventional method to form an acyl. become

Here, the acid chloride used as the acylating agent is specifically acetyl chloride, propionyl chloride, isobutyroyl chloride, octanoyl chloride, benzoyl chloride, and the like.

The resulting general formula (■) [In the formula, Rf, R' and R3 are the same as above. ] By asymmetrically hydrolyzing the acylated derivatives represented by the general formulas (■“) and (■゛) using an enzyme [in the formula, R
f, R' and R3 are the same as above. ] to obtain an optically active alcohol and ester. As the enzyme used in this reaction, various so-called hydrolytic enzymes can be used, such as lipase P, lipase MY, lipase OF, lipase P679.
Examples include cellulase and the like. Furthermore, the ester of general formula (■゛) above can be easily converted into the alcohol of general formula (V゛) and the enantiomeric alcohol by chemical hydrolysis or asymmetric hydrolysis using another enzyme. . Therefore, by adjusting the hydrolysis rate, the optical purity of both mirror specimens can be controlled to some extent.

Next, the optically active alcohol represented by the general formula (■゛) thus obtained is etherified to form a general formula (■゛).
) [In the formula, R4 represents an alkyl group having 1 to 10 carbon atoms or an aralkyl group having 7 to 10 carbon atoms, and Rf and R1 are the same as above. ] An optically active ether derivative represented by

Here, as the etherifying agent, alkyl halides such as methyl bromide, ethyl bromide, propyl bromide, butyl bromide, etc., or aralkyl halides,
For example, benzyl bromide can be used.

The primary hydroxyl group in the obtained ether m8 body of the general formula (■) is deprotected to form the general formula (IX).The obtained benzyl alcohol derivative is further oxidized to form the general formula (BI) [wherein, R4 and Rf are Same as above. ] A benzoic acid derivative represented by formula (1), that is, a compound in which R is an alkyl group or an aralkyl group, is produced. This oxidation reaction can be carried out in a conventional manner, for example, using an oxidizing agent such as permanganate.

Finally, by reductively eliminating RAM in the obtained benzoic acid derivative, a compound in which R is hydrogen in the general formula (I), that is, a compound of the general formula () [wherein R4 and Rf are as defined above] It's the same. ] benzyl alcohol derivative.

This deprotection reaction of the -class hydroxyl group may be appropriately selected depending on the type of protecting group R1.

[In the formula, Rf is the same as above. ] An optically active compound of the present invention represented by is obtained.

Particularly when R4 is a benzyl group, this debenzylation can be carried out by a conventional method. For example, debenzylation can be carried out by hydrogenation in an alcoholic solvent at normal pressure in the presence of a hydrogenation catalyst such as palladium-charcoal.

The 4-(1-hydroxyfluoroalkyl)benzoic acid thus obtained can be converted into a salt, ester, acid halide or amide by a conventional method, if necessary.

〔Example〕

Next, the present invention will be explained in more detail 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 (lifluoroethyl)benzyl ether (a) 70 d of a solution of 6.9 g (30 mmol) of methoxymethyl p-bromobenzyl ether in tetrahydrofuran was slowly added dropwise to 0.73 g (30 mmol) of magnesium under an argon stream. , Grignard reagent was prepared. After the exotherm subsided, the reaction mixture was kept at -70°C, trifluoroacetaldehyde prepared from 3.5d (30 mmol) of trifluoroacetaldehyde ethyl hemiacetal was added dropwise thereto, and the mixture was heated at -70°C for 24 hours.
Allowed time to react. Thereafter, the temperature was returned to room temperature, and a saturated ammonium chloride aqueous solution was added to terminate the reaction. After extraction with diethyl ether, washing with saturated brine, and drying over anhydrous magnesium sulfate, the solvent was distilled off, and the product was isolated by vacuum distillation to obtain methoxymethyl 4-(1-hydroxy-2,2
,2-)lifluoroethyl)benzyl ether 2.25
g (9.0 mmol) was obtained. The physical properties of the obtained compound are shown below.

"F-NMR (CCf4): δppn+ -0,33(d, J=6.6Hz)'H
-NMR (CCf, ): δppm3.30<3H,s), 4.33 (IH.

d, J=4.5Hz), 4.50 (2H,s)
, 4.60 (2H, s), 4.60-4.93
(I H, m).

7.23-7.50 (4H, m) I R (neat) (cm-'): 3400 (OH
) (b) A solution of 9.96 g (70 mmol) of ethyl trifluoroacetate in 80 I of tetrahydrofuran! dl (a)
80 d of a solution of 70 mmol of Grignard reagent in tetrahydrofuran prepared in the same manner as above was added to
It was slowly added dropwise at 0°C.

After stirring for 20 hours, a saturated aqueous ammonium chloride solution was added to terminate the reaction. After extraction with diethyl ether, washing with saturated brine and drying, the solvent was distilled off and the product was isolated by distillation, yielding 11.5 g (46.3 mmol) of methoxymethyl 4-(1oxo-2, 2,2-)lifluoroethyl)benzyl ether was obtained. The physical properties of the obtained compound are shown below.

19F-NMR (CCffi, ): δppm -5,
67(S)'H-NMR (CCI2.): δppn+ 3.40 (3H,s), 4.70 (
4H.

m), 7.50-8.23 (4H, m)I R
(neat) (cm-'): 1710 (C=O)
Next, 0.36 g of lithium aluminum hydride (9,4
6.8 g (27.4 mmol) of the ketone obtained above was added to a solution of 9 mmol) suspended in 10 ml of diethyl ether.
A diethyl ether solution of 40% 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, drying over anhydrous magnesium sulfate, distilling off the solvent, and isolating the product by distillation, 5.67 g (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 A solution of 12.5 g (50 mmol) of methoxymethyl 4-(1-hydroxy-2,2,2-1-trifluoroethyl)benzyl ether in 50 d of methylene chloride Pyridine 4.
8 ml (60 mmol) and isobutyryl chloride5.
8d (55 mmol) was added and incubated at room temperature under a nitrogen stream for 24 hours.
Stir for hours. The reaction was terminated by adding a saturated aqueous ammonium chloride solution, extracted with methylene chloride, and the extract was washed successively with water and saturated brine, dried, and the solvent was distilled off.

The product was purified by silica gel column chromatography to yield 13.2 g (41 mmol) of methoxymethyl 4-(
1-isobutyryloxy-2,2,2-trifluoroethyl) pendyl ether was obtained.

The physical properties of the obtained compound are shown below.

"F NMR (CCla>: δppm -2,33 (d, J=7.2Hz) IH
-NMR (CC14): δppa+ 1.21 (3H, d, J=7.2 cells).

1.17 (3)1. d, J=7.27), 2.67(
L H, sev, J=7.2Hz), 3.35
(3H, s).

4.58 (2H, s), 4.65 (2H, s).

6.17 (1) (, q, J=7.27), 7.33~
7.63 (4H, m) I R (neat) (cm-Re: 1760 (C=0)
(3)(+)-Methoxymethyl 4-(1-hydroxy-
Synthesis of 2,2,2-trifluoroethyl)benzyl ether Methoxymethyl 4-(1-isobutyryloxy) 2.2.
2-)Lifluoroethyl)benzyl ether 23.7g
(74 mmol) and Lipase P37g (manufactured by Amano Pharmaceutical ■)
was suspended in 800 ml of distilled water and stirred at 40°C. After reacting for 8.5 hours while maintaining the pH at 6 to 7 with an IN sodium hydroxide aqueous solution, ethyl acetate was added and the enzyme was removed by filtration through Celite. After separating the oil layer,
After washing successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, drying, and distilling off the solvent, the alcohol compound, which is a hydrolysis product, and the unreacted acylated compound were separated and purified using silica gel column chromatography. The hydrolysis rate was 45%, and 7.96 g (31.8 mmol) of alcohol and 11.3 g (35.2 mmol) of acylated product were obtained. The optically active alcohol obtained [
The specific optical rotation of methoxymethyl 4-(1-hydroxy-2,2,2-trifluoroethyl)benzyl ether was as follows.

[α) o=+28.3 (cm1.02.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 3 Od of tetrahydrofuran and (+)methoxymethyl 4-(1-hydroxy-2,2°2-trifluoroethyl) 30 d of a solution of 6.0 g (24 mmol) of fluoroethyl benzyl ether in tetrahydrofuran was added dropwise at 0° C. under a nitrogen stream. After stirring for 1 hour, 3.7 d of benzyl bromide
(30.5 mmol) was added dropwise, a catalytic amount of tetrabutylammonium iodide was added, and 400
Time reacted. The reaction was terminated by adding a saturated aqueous ammonium chloride solution, extracted with diethyl ether, the extract was washed with saturated brine, dried, the solvent was distilled off, and purified by silica gel column chromatography to give 6.45 g (19
, 0 mmol) of methoxymethyl 4-(l-benzyloxy-2,2,2-trifluoroethyl)benzyl ether was obtained. The physical properties of this substance were as follows.

19F NMRCCC1a): δppm -2,17(d, J=6.6t(z)I
H-NMRCC14): δppm 3.33 (3H, s), 4.33-4.
80 (7H, m), 7.10-7.63 (9H, m)
(5) Synthesis of 4-(1-benzyloxy-2,2,2-trifluoroethyl)benzyl alcohol methanol 2
Methoxymethyl 4-(1benzyloxy-2,
2,2-1-lifluoroethyl)benzyl ether6.
A catalytic amount of p-)luenesulfonic acid was added to a solution of 47 g (19 mmol) and refluxed for 38 hours. After the reaction was completed, diethyl ether was added, washed sequentially with a saturated aqueous sodium bicarbonate solution, water and saturated brine, dried, the solvent was distilled off, and purified by silica gel column chromatography to give 5.20 g (17,5 mmol) of 4-(1-'
Benzyloxy-2,2,2-trifluoroethyl)benzyl alcohol was obtained. The physical properties of this compound were as follows.

1"F-NMR (CCj24): δppm -2,33(d, J-6,6Hz)'H
-NMR (CCL): δppm 3.43 (IH,s), 4.30-4
．． 77 (5H, m), 7.20-7.57 (9H, m
)I R(neat) (cm-'):3350 (O
H)(6)(+)-4-(1-benzyloxy-2,2
Synthesis of ゜2-trifluoroethyl)benzoic acid 4-(1-
5.2 g (17.5 mmol) of benzyloxy-2,2,2-)lifluoroethyl)benzyl alcohol was dissolved in a mixed solvent of 60 d of acetone and 20 d of distilled water, and the solution was heated to 0°
At C. 4.1 g (25.9 mmol) of potassium permanganate were slowly added. After reacting for 20 hours at O''C, celite filtration was performed to remove manganese dioxide, the filtrate was made alkaline by adding an aqueous potassium hydroxide solution, the oil layer was separated, and 6N hydrochloric acid was added to remove the aqueous layer. The pH was adjusted to 2. The resulting precipitate was filtered and dried to give 4.21 g (
13.5 mmol) of (+)-4-(1-benzyloxy-2,2,2-)lifluoroethyl)benzoic acid was obtained. The physical properties of this compound were as follows.

Specific optical rotation [α) D = +85.98 (cm1.11. methanol) 19F-NMRCC1', ): δppm -2,67 (d, J = 6.6Hz) IH
-NMR (C(1,): δppm 4.37-5.00 (3H, m), 7.
33 (5H, s), 7.508.27 (4H, m)
+9.50~10.2 (IH, bs) I R (KBr) (cm-'): 1680 (C=
O).

Synthesis of (+)-4-(1-
1.02 g (3.3 mmol) of benzyloxy-2,22-trifluoroethyl)benzoic acid was added to 1 OI of ethanol.
10% palladium charcoal dissolved in nIl 0.1
2 g was added thereto, and the mixture was stirred at room temperature for 80 hours under a hydrogen stream.

After filtration, the solvent was distilled off, purified by silica gel column chromatography, and further recrystallized from hexane to obtain 0.52 g (2.32 mmol) of (+)
-4-(1-hydroxy-2,2,2-trifluoroethyl)benzoic acid was obtained. The physical properties of this compound were as follows.

"F-NMR (C(u4): δppm -1,33(d, J=7.2Hz)'H
-NMR (CCj!4): δppm 5.10 (I H, Q, J = 7.2
1(z).

6.43-7.00 (IH, bs), 7.47-8.
33 (4H, m), 8.33-10.0 (LH, bs
)IR (KBr) (cm-'): 1700 (C=O
).

3000 (OH), 3500 (OH) [α]. =+
76.09 (cm1.01, methanol) Example 2 Synthesis of (-)-4-(1-benzyloxy-2,2,2-trifluoroethyl)benzoic acid Example 1 Optical properties obtained in (3) 11.2 g (35 mmol) of active methoxymethyl 4-(1-isobutyryloxy-2,2゜2-trifluoroethyl)hensyl ether was dissolved in 70 d 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 washed successively with water, saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, it is isolated and purified by distillation to obtain 6
．． 69 g (26.7 mmol) of (=)-methoxymethyl 4-(1-hydroxy 2.2.2-trifluoroethyl)hensyl ether were obtained. The specific rotation of this substance is
It was as follows.

[α) o-20,9 (cm 1.01, methanol) Subsequently, benzylation, removal of methoxymethyl group, and oxidation were performed in the same manner as in (4), (5), and (6) of Example 1. and 4.71 g (15.2 mmol) of (-)-4-
(1-benzyloxy-2,2,2-trifluoroethyl)benzoic acid was obtained. This compound is Example 1 (6)
It showed physical properties similar to those of the product.

Specific optical rotation [α), = -76,31 (c = 1.04.methanol) Example 3 Synthesis of optically active 4-(1-benzyloxy-2,2゜2-trifluoroethyl)benzoic acid Methoxymethyl 4-(1-isobutyryloxy-) obtained in Example 1 (2)
1.46 g (4.56 mmol) of 2,2,2-1-lifluoroethyl)benzyl ether and 1.2 of lipase MY
5g (manufactured by Meito Sangyo ■) was suspended in 50d of distilled water, the temperature was maintained at 40°C, and p
) The reaction was carried out for 8 hours while maintaining the temperature between 16 and 7. Thereafter, ethyl acetate was added and the mixture was filtered through Celite to remove the enzyme. The oil layer was separated, washed sequentially with water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried, and the solvent was distilled off. After that, silica gel column chromatography was performed to remove the hydrolysis product alcohol and unreacted acylation. The body was separated and purified. Hydrolysis rate: 42%, alcohol content: 0.43
g (1,73 mmol) and 0.73 g (2
, 26 mmol) was obtained. The specific rotation of the optically active alcohol obtained was as follows.

[α) o = 17.89 (c = 1.02. methanol) Subsequently, benzylation, removal of methoxymethyl group, and oxidation were performed in the same manner as in (4), (5), and (6) of Example 1. The optically active 4-(l-hensyloxy-2,2,
2-)Lifluoroethyl)benzoic acid was obtained. This compound exhibited physical properties similar to those of the product of Example 1 (6).

〔Effect of the invention〕

The fluorine-containing benzoic acid derivative of the present invention is a novel optically active compound, and is an ester used as a ferroelectric liquid crystal, a liquid crystal polymer, a physiologically active substance, an anticancer agent, and an enzyme inhibitor.
It is useful as a raw material for the synthesis of ethers, amides, etc.

Claims (2)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, Rf represents a fluoroalkyl group having 1 or 2 carbon atoms, R is hydrogen, an alkyl group having 1 to 10 carbon atoms, or a 7 to 10 carbon number represents an aralkyl group, and the * mark represents an asymmetric carbon. ] An optically active fluorine-containing benzoic acid derivative represented by (2) A fluorine-containing benzoic acid derivative which is a salt, ester, acid halide or amide of the fluorine-containing benzoic acid derivative according to claim 1.