JPH0665180A - Benzoylacetonitrile derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new derivative useful as an intermediate for producing a medicine, an agrichemical and a chemical product. CONSTITUTION:A derivative of formula I {R is C(R<1>) (R<2>) R<3> [R<1> and R<2> are each H or a lower alkyl; R<3> is cyano, CON (R<4>) R<5> (R<4> and R<5> are each same as R<1>) or COOR<6> (R<6> is same as R<1>)]}, e.g. (2-chloro-5-cyanoacetyl-4- fluorophenoxy)acetamide. The compound of formula I can be obtained, e.g. by reacting a compound of formula II (X is a halogen) with a cyanidation agent such as sodium cyanide in the presence of a base such as sodium carbonate or pyridine, an acid such as hydrochloric acid or an inorganic salt such as potassium chloride or without using it in an inert solvent such as water or methanol or without using a solvent at -20 to 150 deg.C (preferably 0 to 60 deg.C) for several min to 100hr.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (I)

[Chemical 4] [In the formula, R is -C (R ¹ ) (R ² ) -R ³ (In the formula, R ¹ and R ² may be the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ is a cyano group. , -CON (R ⁴ ) R ⁵ (in the formula, R ⁴ and R ⁵ may be the same or different and represent a hydrogen atom or a lower alkyl group) or -COOR ⁶ (in the formula, R ⁶ is a hydrogen atom or A lower alkyl group is shown). ] It is related with the benzoyl acetonitrile derivative represented by these, and its manufacturing method.

[0002]

BACKGROUND OF THE INVENTION Benzoylacetonitriles are used as intermediates in the production of various pharmaceuticals, agricultural chemicals and chemicals.

[0003]

The benzoylacetonitrile derivative of the present invention is a novel compound not described in the literature and is useful as an intermediate for pharmaceuticals, agricultural chemicals, chemicals and the like.

[0004]

The method for producing the benzoylacetonitrile derivative represented by the general formula (I) of the present invention can be exemplified by the method shown below.

[Chemical 5] [In the Formula, R and X are the same as the above. Benzoyl which is a target compound by reacting the compound represented by the general formula (II) with a cyanating agent in the presence or absence of a base, an acid or an inorganic salt, or in the presence or absence of an inert solvent. Acetonitrile can be produced.

Any inert solvent can be used in this reaction so long as it does not significantly inhibit the progress of this reaction. For example, water, alcohols such as methanol, ethanol and propanol, acetonitrile and the like. Nitriles, ethers such as diethyl ether, tetrahydrofuran and dioxane, glycols such as ethylene glycol and propylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, pyridine, picoline and dimethylformamide. , Acetamide, dimethyl sulfoxide, hexamethylene tetraamide, hexamethyl phosphoramide,
N, N'-dimethyl imidazolinone etc. can be illustrated, and these inert solvents can be used individually or in mixture.

Examples of the cyanating agent used in this reaction include sodium cyanide, potassium cyanide, calcium cyanide, copper cyanide, ammonium cyanide, triethylammonium cyanide, tetrabutylammonium cyanide, acetocyanhydrin and the like. A cyanating agent can be mentioned, and the amount thereof can be selected from the range of equimolar to excess molar to the compound represented by the general formula (II), and preferably in the range of equimolar to 5-fold molar. Is.

When a base is used in this reaction, an inorganic base or an organic base can be used, and examples thereof include sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydride, and hydroxide. Inorganic bases such as sodium, potassium hydroxide, lithium carbonate, lithium hydroxide, sodium acetate, trisodium phosphate, tripotassium phosphate, sodium borate and potassium borate, and primary amines such as ethylamine and t-butylamine. , Secondary amines such as diethylamine, diisopropylamine, trimethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, N, N-diisopropylethylamine, N, N-dimethyl-n-octylamine, triethano- Luamine,
N-methylpiperidine, 1,4-diazabicyclo [2,2
2,2] tertiary amines such as octane, aniline, N,
Aromatic amines such as N-dimethylaniline, 2,6-lutidine, and pyridine can be exemplified, and the amount of these bases used is equimolar to excess with respect to the compound represented by the general formula (II). Although it can be appropriately selected and used from the molar range, a base may not be used.

As the acid which can be used in this reaction, for example, mineral acids such as hydrochloric acid, sulfuric acid and the like and organic acids such as acetic acid and the like can be used, and the amount thereof is relative to the compound represented by the general formula (II). It may be selected from an equimolar to excess molar range, preferably an equimolar to 4-fold molar range, but when an excess amount of the cyanating agent used at the same time is used, one equivalent to the cyanating agent is used. It is better to use less. As the inorganic salt that can be used in this reaction, for example, calcium chloride, magnesium chloride, sodium iodide, potassium iodide, etc. can be used, and the amount thereof is the same as that of the compound represented by the general formula (II). It can be appropriately selected and used from the range of mol to excess mol. Reaction temperature is -20 ℃
It suffices that the reaction be performed by selecting from the range of 150 ° C to 150 ° C, preferably 0 ° C to 60 ° C. The reaction time is the reaction temperature,
Although it does not depend on the reaction scale and the like, it may be selected from the range of several minutes to 100 hours. After the completion of the reaction, the reaction system containing the desired product is produced as it is or after being acidified with a mineral acid such as hydrochloric acid, and isolated by a conventional method, for example, filtration, solvent extraction and the like, and purified by recrystallization or the like, if necessary. can do.

The compound represented by the general formula (II) of the present invention is
For example, it can be manufactured by the method shown below.

[Chemical 6] (In the formula, R and X are the same as above.)

The p-fluorophenol represented by the structural formula (VII) and the halides represented by the general formula (VI) are reacted to obtain a compound represented by the general formula (V), and the compound ( V) is selectively chlorinated to give a compound represented by the general formula (III), or p-fluorophenol represented by the structural formula (VII) is selectively chlorinated to obtain the general formula (IV). And reacting the compound (IV) with a halide represented by the general formula (VI) to give a compound represented by the general formula (III):
The general formula (I
The compound represented by I) can be produced.

[0011]

EXAMPLES Representative examples of the present invention will be illustrated below, but the present invention is not limited thereto. Example 1 (2-chloro-5-cyanoacetyl-4-
Fluorophenoxy) acetamide production

[Chemical 7] 5.02 g (17.9 mmol) of (2-chloro-5-chloroacetyl-4-fluorophenoxy) acetamide was added to and suspended in a solution of 2.63 g (53.7 mmol) of sodium cyanide dissolved in 25 ml of water. As a liquid, 25 ml of ethanol was added dropwise to the suspension at 30 to 40 ° C over 10 minutes, and after completion of the reaction, the reaction was carried out at 50 ° C for 1 hour. After the completion of the reaction, the reaction system was cooled, 25 ml of water was added, and 6N hydrochloric acid was added to make the mixture acidic, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the object as light brown crystals.
6 g were obtained. Physical properties m. p. 206-207 ° C Yield 95%

Example 2 Preparation of (2-chloro-5-cyanoacetyl-4-fluorophenoxy) acetonitrile 2-1

[Chemical 8] 0.5 g (1.91 mmol) of (2-chloro-5-chloroacetyl-4-fluorophenoxy) acetonitrile
Was dissolved in 5 ml of dioxane, and 5 m of water was added to the solution with stirring.
0.28 g (5.72 g) of sodium cyanide dissolved in 1
(Mmol) and added, and reacted at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water, acidified with dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 0.40 g of the desired product as light brown crystals. Physical properties m. p. 133-134 ° C, yield 82%

10.0 g (38.2 mmol) of 2-2 (2-chloro-5-chloroacetyl-4-fluorophenoxy) acetonitrile was suspended in 60 ml of dioxane, and 2.24 g of sodium cyanide was suspended in the suspension. (45.7 mmol) and sodium carbonate 4.04 g (38.2 mmol) in water 30
Add the solution dissolved in ml dropwise, and at the end of the addition,
The reaction was carried out over time. After completion of the reaction, the reaction solvent was distilled off from the reaction system under reduced pressure of 50 ml, and then brine 50 ml, then 6N
Hydrochloric acid (15 ml) was added and the precipitated crystals were collected by filtration and dried under reduced pressure to give the desired product as yellow crystals, 9.10
g was obtained. Physical properties m. p. 133-134 ° C Yield 94%

Example 3 Preparation of (2-chloro-5-cyanoacetyl-4-fluorophenoxy) acetamide

[Chemical 9] 3-1 (2-chloro-5-chloroacetyl-4-fluorophenoxy) acetamide 10.0 g (35.7 mmol)
Was suspended in 50 ml of dioxane, and 2.63 g (53.6 mmol) of sodium cyanide and 3.87 g (35.7 mmol) of sodium carbonate were added to 50 ml of water.
The solution dissolved in was dropped, and after completion of the dropping, reaction was carried out at 50 ° C. for 45 minutes. After completion of the reaction, add 5 reaction solvents from the reaction system.
After distilling off under reduced pressure of 0 ml, brine (50 ml) and then 6N hydrochloric acid (15 ml) were added, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the target product as light brown crystals (9.73).
g was obtained. Physical properties m. p. 206-207 ° C 100% yield

3-2 Sodium cyanide (1.3 g, 26.5 mmol) was dissolved in 25 ml of water, and 1.8 g (17.
8 mmol), (2-chloro-5-chloroacetyl-4)
-Fluorophenoxy) acetamide 5.0 g (17.
8 mmol) and 25 ml of ethanol were added, and the reaction was carried out at 45 ° C. for 1 hour with stirring. After the reaction was completed, 25 ml of the reaction solvent was distilled off from the reaction system under reduced pressure, and 25 ml of water and 6N were added.
10 ml of hydrochloric acid was added, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the object as light brown crystals 4.4.
g was obtained. Physical properties m. p. 206-207 ° C Yield 91%

3-3 Sodium cyanide (1.1 g, 21.4 mmol) was dissolved in 10 ml of water, 10 ml of ethanol was added, and 0.74 g (7.1 mmol) of concentrated hydrochloric acid was added dropwise to the solution. Stir for 5 minutes and then add (2-chloro-5-chloroacetyl-4
-Fluorophenoxy) acetamide 2.0 g (7.1
(Mmol) and reacted at room temperature for 5 hours. After the reaction was completed, 10 ml of water was added to the reaction system, and then the crystals precipitated by acidification with 10% hydrochloric acid were collected by filtration and dried under reduced pressure to obtain 1.7 g of the desired product as light brown crystals. Physical properties m. p. 206-207 ° C Yield 88%

1.0 g (3.57 mmol) of 3-4 (2-chloro-5-chloroacetyl-4-fluorophenoxy) acetamide was added to a mixed solvent of 5 ml of water and 10 ml of ethanol. Acetone cyanohydrin (0.46 g, 5.3 mmol) and triethylamine (0.90 g, 8.93 mmol) were added and the reaction was carried out at 45 ° C. for 1 hour with stirring. After the reaction was completed, 5 ml of water was added to the reaction system, and then 10
1.7 g of a target substance as a light brown crystal by filtering the crystals precipitated by acidification with% hydrochloric acid and drying under reduced pressure.
Obtained. Physical properties m. p. 206-207 ° C Yield 88%

Example 4 Preparation of ethyl 2-chloro-5-cyanoacetyl-4-fluorophenoxyacetate

[Chemical 10] 4-1 Sodium cyanide (0.48 g, 9.7 mmol) was dissolved in acetamide (10 ml) at 30 ° C., and triethylamine (0.33 g, 3.2 mmol) was added to the solution, followed by 2-chloro-5-chloroacetyl. 30 g of ethyl 4-fluorophenoxyacetate (1 g, 3.2 mmol) was added.
The reaction was carried out at 30 ° C. for 30 minutes with stirring. After completion of the reaction, 10 ml of water was added to the reaction solution to obtain the desired product with ethyl acetate (10 ml).
It was extracted with × 3), the extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product as brown crystals. Physical properties m. p. 96.5-97.0 ° C Yield 73%

4-2 0.98 g (19.9 mmol) of sodium cyanide was dissolved in 10 ml of water, 10 ml of ethanol was added to the solution, and then 2-chloro-5-chloroacetyl-4-fluorophenoxyacetic acid. 2 g (6.5 mmol) of ethyl was added and the reaction was carried out at 50 ° C. for 30 minutes with stirring. After completion of the reaction, 50 ml of water was added to the reaction solution, the desired product was extracted with ethyl acetate (20 ml × 3), the extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The product was obtained as brown crystals. Physical properties m. p. 96.5-97.0 ° C. Yield 59% 2-chloro-5-cyanoacetyl-4-fluoroacetic acid was also obtained as crystals in addition to the desired product. Physical properties m. p. 189-191 ° C Yield 25%

Example 5 Preparation of 2-chloro-5-cyanoacetyl-4-fluorophenoxyacetic acid

[Chemical 11] 0.26 g (5.3 mmol) of sodium cyanide was dissolved in 5 ml of water at 30 ° C., and 0.5 g of 2-chloro-5-chloroacetyl-4-fluorophenoxyacetic acid was added to the solution.
(1.8 mmol) and sodium carbonate 0.19 g
A solution prepared by dissolving (1.8 mmol) in 20 ml of water was added and the reaction was carried out for 30 minutes with stirring. After the reaction was completed, 10 ml of water was added to the reaction solution, and 2 ml of 6N-hydrochloric acid was added to acidify it. The precipitated crystals were methylene chloride (10 ml × 3).
The extract was washed with water, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product as brown crystals. Physical properties m. p. 189-191 ° C Yield 70%

Example 6 Preparation of 2-chloro-5-cyanoacetyl-4-fluorophenoxyisopropyl acetate

[Chemical 12] 2.27 g (46.4 mmol) of sodium cyanide was dissolved in 12.5 ml of water, and 12.5 of ethanol was added to the solution.
ml, then 2-chloro-5-chloroacetyl-
5 g (16 mmol) of isopropyl 4-fluorophenoxyacetate was added, and the reaction was carried out at 40 ° C. for 30 minutes with stirring. After completion of the reaction, 50 ml of water was added to the reaction solution, the target product was extracted with methylene chloride (25 ml × 3), the extract solution was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The product was obtained as brown crystals. Physical properties m. p. 87-88 ° C yield 55%

Claims (2)

[Claims] 1. The general formula (I) [In the formula, R is -C (R ¹ ) (R ² ) -R ³ (In the formula, R ¹ and R ² may be the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ is a cyano group. , -CON (R ⁴ ) R ⁵ (in the formula, R ⁴ and R ⁵ may be the same or different and represent a hydrogen atom or a lower alkyl group) or -COOR ⁶ (in the formula, R ⁶ is a hydrogen atom or A lower alkyl group is shown). ] The benzoyl acetonitrile derivative represented by these. 2. The general formula (II) [In the formula, R is -C (R ¹ ) (R ² ) -R ³ (In the formula, R ¹ and R ² may be the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ is a cyano group. , -CON (R ⁴ ) R ⁵ (in the formula, R ⁴ and R ⁵ may be the same or different and represent a hydrogen atom or a lower alkyl group) or -COOR ⁶ (in the formula, R ⁶ is a hydrogen atom or A lower alkyl group) and X represents a halogen atom.] Is reacted with a cyanating agent in the presence or absence of a base, an acid or an inorganic salt. General formula (I) [In formula, R is the same as the above. ] The manufacturing method of the benzoyl acetonitrile derivative represented by these.