JP2002069038A - Trifluoromethyl group-bearing benzoylformic alkyls, method of producing the same and method of trifluoromethyl group-bearing phenylacetic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel trifluoromethyl group-bearing benzoylformic alkyl esters, a method of producing the same and a method of efficiently, safely and readily producing trifluoromethyl group-bearing phenylacetic acids via the benzoylformic alkyl ester in an industrial scale. SOLUTION: This invention relates to trifluoromethyl-bearing benzoylformic alkyl esters represented by the following formula (1), wherein R1 is an alkyl of 1-5 carbon atoms; n is 2 or 3, a method for producing the same and a method for producing trifluoromethyl group-bearing phenylacetic acid via the trifluoromethyl group-bearing benzoylformic alkyl ester.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel alkyl benzoylformate containing a trifluoromethyl group and a method for producing the same, and a process for producing a phenylacetic acid containing a trifluoromethyl group via the alkyl benzoylformate containing a trifluoromethyl group. It relates to a manufacturing method.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a phenylacetic acid having a plurality of trifluoromethyl groups in a molecule, a corresponding benzyl halide is reacted with sodium cyanide in alcohol to form benzyl cyanide, which is then hydrolyzed. Decomposition method (Olah, GA et al., JO
rg. Chem. 22,879 (1957)) and Will and sulfur and secondary amine in the corresponding acetophenone.
Gerodt reaction (Organic Reaction)
s 3 p. 83) to give thioacetamide, which is then hydrolyzed (Novotny, J. eta).
l. , Pharm. Sci. , 62, 910 (197
3)) is known.

However, in the conventional method, it is necessary to use sodium cyanide which is difficult to handle and treat wastewater.
In addition, there is a problem in that the process is long and it is not possible to efficiently manufacture industrially.

[0004]

SUMMARY OF THE INVENTION It is a first object of the present invention to provide novel trifluoromethyl-containing alkyl benzoylformates useful as intermediates of trifluoromethyl-containing phenylacetic acids.

[0005] A second object of the present invention is to provide a method for producing the trifluoromethyl group-containing alkyl benzoylformate.

A third object of the present invention is to industrially convert trifluoromethyl group-containing phenylacetic acids from a trifluoromethyl group-containing halobenzene via the above-mentioned trifluoromethyl group-containing alkyl benzoylformate. Another object of the present invention is to provide a manufacturing method that can efficiently, safely, and easily manufacture.

[0007]

Means for Solving the Problems The present inventors have intensively studied a method for industrially and safely producing a phenylacetic acid having a plurality of trifluoromethyl groups in a molecule. As a result, trifluoromethyl group-containing phenylmagnesium halide obtained from trifluoromethyl group-containing halobenzene easily reacts with dialkyl oxalate,
A novel compound, a trifluoromethyl group-containing alkyl benzoylformate, is hydrolyzed in an aqueous alkaline solution, then reacted with hydrazine and decomposed to obtain trifluoromethyl group-containing phenylacetic acids in high yield. Was found to be.

The present invention provides a trifluoromethyl group-containing alkyl benzoylformate represented by the following formula (1):
"Compound 1" is provided.

[0009]

Embedded image However, the symbols in the formula have the following meanings throughout this specification. R ¹ : alkyl group having 1 to 5 carbon atoms n: 2 or 3

The present invention also provides a process for producing a trifluoromethyl group-containing phenylacetic acid represented by the following formula (3) (hereinafter also referred to as “compound 3”), which is via compound 1. .

[0011]

Embedded image

Further, the present invention provides a step of reacting a trifluoromethyl group-containing phenylmagnesium halide represented by the following formula (4) (hereinafter also referred to as “compound 4”) with a dialkyl oxalate (hereinafter referred to as “step A”). ") Is provided.

[0013]

Embedded image However, the symbols in the formula have the following meanings throughout this specification. X: Cl, Br or I

The present invention also relates to a step of reacting compound 1 with hydrazine in an aqueous alkaline solution to decompose the compound (hereinafter referred to as “hydrazine”).
A process for preparing compound 3 (hereinafter referred to as "Step B").

Further, the present invention provides a method for producing compound 3, comprising the above-mentioned step A and step B.

A typical example of the compound 1 of the present invention is a compound represented by the following formula.

Embedded image

Among these compounds, novel alkyl 3,5-bis (trifluoromethyl) benzoylformates (hereinafter, also referred to as “compound 2”) represented by the following formula (2) are particularly useful as pharmaceutical intermediates. Important compounds 3,
Useful as an intermediate in the production of 5-bis (trifluoromethyl) phenylacetic acid.

[0018]

Embedded image X in the present invention is preferably Cl or Br, and particularly preferably Br.

Compound 4 used in step A of the present invention is
It can be obtained by a general Grignard reaction using a trifluoromethyl group-containing phenylmagnesium halide corresponding to the target compound 1. For example, 3,
5-bis (trifluoromethyl) phenylmagnesium bromide can be obtained by reacting 3,5-bis (trifluoromethyl) bromobenzene with metallic magnesium in diethyl ether (US Pat. No. 3,625,971; British Patent No. 1223945). At this time, reaction conditions such as a reaction temperature and a reaction solvent can be appropriately selected depending on the position of the substituent, the number of the substituents, and the like. As a reaction solvent, for example, diethyl ether tetrahydrofuran (THF) and the like are representative.

Representative examples of the dialkyl oxalate used in the step A include dimethyl oxalate, diethyl oxalate, dipropyl oxalate, and dibutyl oxalate.
Industrially, diethyl oxalate is particularly preferred because it is inexpensive and easy to handle.

In step A, the ratio of the trifluoromethyl group-containing phenylmagnesium halides / dialkyl oxalate to be used is preferably from 0.2 to 1.0 in terms of molar ratio, more preferably from 0.4 to 0.7.

A specific example of the step A in the present invention is as follows. 3,5-bis (trifluoromethyl)
1.0 mol per 1 mol of phenylmagnesium bromide
To 4.0 mol, preferably 1.5 to 2.5 mol of diethyl oxalate at −10 to 10 ° C., and the reaction is carried out. The desired novel compound is obtained by acid decomposition, extraction, washing with water, distillation or the like. An alkyl 5-bis (trifluoromethyl) benzoylformate is obtained. The concentration of the 3,5-bis (trifluoromethyl) phenylmagnesium bromide solution is preferably from 0.3 to 1.5 mol / L, particularly preferably from 0.5 to 1.5 mol / L.
1.2 mol / L is preferred.

As the alkaline aqueous solution used in the step B in the present invention, an aqueous potassium hydroxide solution and an aqueous sodium hydroxide solution are preferably used from the viewpoint of reactivity and ease of handling.

In this step B, the reaction temperature is 0
To 200 ° C, more preferably room temperature to 100 ° C. The pressure is preferably under reflux under pressure in order to make the reaction proceed quickly, but from the viewpoint of workability, normal pressure is preferable. In particular, step B is preferably performed under heating and reflux at normal pressure.

Further, a specific example of the step B is as follows. Ethyl 3,5-bis (trifluoromethyl) benzoylformate is suspended in an aqueous KOH solution and hydrolyzed. Then, an aqueous KOH solution and hydrazine monohydrate are added dropwise to react at room temperature to obtain a hydrazone compound. Next, the mixture is heated under reflux and cooled, and hydrochloric acid is added to obtain 3,5-bis (trifluoromethyl) phenylacetic acid as crystals. Purification such as recrystallization is performed as necessary.

The compound 1 of the present invention is useful as an intermediate of a trifluoromethyl group-containing phenylacetic acid, which is useful as a raw material for pharmaceuticals and the like, as described above, and can also be used as another new organic synthetic intermediate. . For example, it is useful as a production intermediate for liquid crystal compounds, organic electronic materials, and the like.

[0027]

EXAMPLES Examples of the present invention will be described below, but the present invention is not limited to these examples.

Example 1 2.43 g of magnesium slices in a 200-ml four-necked flask equipped with a stirrer, thermometer, dropping funnel, and condenser under a nitrogen stream.
(0.10 mol), and dry dimethyl ether 3m
l covered the surface. Next, 29.3 g (0.10 mol) of 3,5-bis (trifluoromethyl) bromobenzene
117 ml of diethyl ether solution was added a little, and after the exothermic reaction was confirmed, the remainder was added dropwise over 1 hour under gentle reflux. After aging for 30 minutes, the mixture was cooled to prepare a solution of 3,5-bis (trifluoromethyl) phenylmagnesium bromide in diethyl ether.

Next, 18 ml of diethyl ether and 36.8 g (0.25 mol) of diethyl oxalate were added to a 300-ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel, and a condenser. Under a nitrogen stream, a diethyl ether solution of 3,5-bis (trifluoromethyl) phenylmagnesium bromide obtained above was added dropwise at -5 ° C or lower over 90 minutes.

After aging for 30 minutes, the reaction mixture was treated with hydrochloric acid (15 m
1) and pour into ice water (150 ml) and separate the organic phase
did. The organic phase was washed twice with 50 ml of 5% saline, and then washed with Mg.
SO _FourAnd dried. After distilling off diethyl ether, the remaining liquid was
Distilled to 3,5-bis (trifluoromethyl) benzo
25.8 g (82% yield) of ethyl ilmate was obtained.

B. p. 101 to 105 ° C./2 mmHg n _D ²⁵ 1.427 IR (neat): 1738 cm ⁻¹ (C ＝ O), 170
^{7cm -1 (C = O),} 1618cm -1 ( benzene ring),
1281 cm ^-1 (CF) ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.46
(3H, t, J = 7, 1 Hz), 4.50 (2H, q,
J = 7.1 Hz), 8.15 (1H, s), 8.54
(2H, s) MS (EI) m / e (%): 296 (2%), 295
(12%), 241 (100%), 225 (30%),
214 (10%), 163 (6%), 144 (2%),
75 (4%)

Example 2 In the same manner as in Example 1, 2.74 g (0.113 mol) of magnesium and anhydrous THF12
In 0 ml, 29.3 g (0.10 mol) of 3,5-bis (trifluoromethyl) bromobenzene was added dropwise at 30 to 35 ° C. for 1 hour under a nitrogen stream while confirming heat generation.
After aging for 0 minutes, the mixture was cooled to prepare a THF solution of 3,5-bis (trifluoromethyl) phenylmagnesium bromide.

Next, TH was placed in a 300 ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel, and a condenser.
F18 ml and diethyl oxalate 36.8 g (0.25 m
ol), and a THF solution of 3,5-bis (trifluoromethyl) phenylmagnesium bromide obtained above was added dropwise at 90 ° C. or lower over 90 minutes under a nitrogen stream, and 3
Aged for 0 minutes.

After aging, hydrochloric acid (9.6 ml) was added to the reaction mixture.
And water (44 ml) were added dropwise, and after decomposition, the organic phase was separated. The aqueous phase was extracted with 50 ml of ethyl acetate, and the organic phase was combined with the previously obtained organic phase, washed twice with 50 ml of 5% brine, and dried over MgSO ₄ . After THF was distilled off, the remaining liquid was distilled, whereby 26.4 g (yield 84%) of ethyl 3,5-bis (trifluoromethyl) benzoylformate was obtained.

Example 3 In the same manner as in Example 1, under a nitrogen stream,
105m of 1M ethylmagnesium bromide in THF
1 (0.105 mol) at 20-30 ° C, 3,5
-Bis (trifluoromethyl) bromobenzene 29.3
g (0.10 mol) in THF (10 ml) was added dropwise over 1 hour, aged for 30 minutes, and cooled to prepare a THF solution of 3,5-bis (trifluoromethyl) phenylmagnesium bromide. Thereafter, the reaction and treatment were carried out in the same manner as in Example 2 to obtain 24.3 g (yield 77.5%) of ethyl 3,5-bis (trifluoromethyl) benzoylformate.

Example 4 3,5 was placed in a 100 ml four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser.
-Ethyl bis (trifluoromethyl) benzoylformate 1
0 g (31.8 mmol) and 23.3 ml of water were charged, and 4.37 g (36.6 m) of a 47% aqueous KOH solution was added at room temperature.
mol) was added dropwise. The suspension was allowed to react for 1 hour at room temperature,
Hydrolysis was performed. Then, a 47% KOH aqueous solution 4.18
g (35.0 mmol) and hydrazine monohydrate3.
34 g (66.8 mmol) was added dropwise and reacted at room temperature for 1 hour to obtain a hydrazone compound. The mixture was refluxed at 99 to 103 ° C. for 8 hours while distilling off low boiling point substances. After cooling, add hydrochloric acid 1
When 4.8 g was added, crystals precipitated. The crystals were separated by filtration, washed twice with 20 ml of ice water, and dried under reduced pressure to obtain 8.17 g of pale yellow crystals. When this was recrystallized from toluene, 6.47 g (yield: 74.7%) of 3,5-bis (trifluoromethyl) phenylacetic acid was obtained as white crystals. mp: 121-123 ° C ¹ H-NMR (CDCl ₃ ) σ (ppm): 3.81
(2H, s), 7.75 (2H, s), 7.82 (1
H, s)

[0037]

The compound 1 of the present invention is a novel compound useful as an intermediate of phenylacetic acid having a trifluoromethyl group.

According to the method of the present invention, the novel alkyl benzoylformate containing a trifluoromethyl group can be produced.

Further, according to the method of the present invention, a trifluoromethyl group is used in a molecule by using a trifluoromethyl group-containing halobenzene as a starting material and the trifluoromethyl group-containing alkyl benzoylformate as an intermediate. A plurality of phenylacetic acids having high purity and stable quality can be produced industrially efficiently, safely and easily.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Junko Tokuda 3-2-1-10 Chigasaki, Chigasaki-shi, Kanagawa F-term in Seimi Chemical Co., Ltd. 4H006 AA01 AB84 AC44 BA02 BA06 BA29 BA32 BB31 BB45 BE10 BE11 BE12 BE13 BE27 BJ50 BM10 BM71 BR30 BS10 KA31

Claims (6)

[Claims] 1. A trifluoromethyl group-containing alkyl benzoylformate represented by the following formula (1). Embedded image However, the symbols in the formula have the following meanings. R ¹ : alkyl group having 1 to 5 carbon atoms n: 2 or 3 2. The trifluoromethyl group-containing alkyl benzoylformate according to claim 1, which is represented by the following formula (2). Embedded image However, the symbols in the formula have the following meanings. R ¹ : alkyl group having 1 to 5 carbon atoms 3. A process for producing a trifluoromethyl group-containing phenylacetic acid represented by the following formula (3), which comprises passing through the trifluoromethyl group-containing alkyl benzoylformate according to claim 1 or 2. Embedded image However, the symbols in the formula have the following meanings. n: 2 or 3 4. The method of claim 1 or 2, further comprising the step of reacting a trifluoromethyl group-containing phenylmagnesium halide represented by the following formula (4) with a dialkyl oxalate. Production method. Embedded image However, the symbols in the formula have the following meanings. X: Cl, Br or In: 2 or 3 5. A trifluoromethyl group-containing benzoyl formate according to claim 1 or 2, which is reacted with hydrazine in an aqueous alkaline solution to decompose the benzoyl formate. A method for producing phenylacetic acid. Embedded image However, the symbols in the formula have the following meanings. n: 2 or 3 6. A step of reacting a trifluoromethyl group-containing phenylmagnesium halide represented by the following formula (4) with a dialkyl oxalate to obtain a trifluoromethyl group-containing alkyl benzoylformate; Reacting an alkyl benzoylformate with hydrazine in an aqueous alkali solution to decompose the benzoyl formate, and producing the trifluoromethyl group-containing phenylacetic acid represented by the following formula (3). Embedded image