JPH0931010A - Production of aryl cyclopropyl ketone compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially obtain in high yield the subject compound important as a raw material for producing medicines and agrochemicals (esp. medicines). SOLUTION: An arylacetic acid of the formula R<1> CH2 COOH (I) [R<1> is (alkyl- or halogen-substituted) phenyl or 2-thienyl] is reacted with a haloalkylmagnesium of the formula R<2> MgX (II) (R is an alkyl; X is a halogen atom) in an organic solvent followed by reaction with a cyclopropanecarboxylic ester of the formula R<3> COOR<4> (III) [R<3> is a (alkyl- or fluorine-substituted) cyclopropyl group; R<4> is an alkyl] to obtain the objective aryl cyclopropyl ketone of the formula R<1> CH2 COR<3> (IV). In this case, 2.5-5mol equivalent of the Grignard reagent (II) based on the arylacetic acid (I) is used.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing arylcyclopropyl ketones in high yield. Arylcyclopropylketones are also called 2-aryl-1-cyclopropylethanones and are important compounds for the production of pharmaceuticals, agricultural chemicals, etc., especially as a raw material for the production of pharmaceuticals (JP-A-6-41139).

[0002]

2. Description of the Related Art As a conventional method for producing aryl cyclopropyl ketones, a method of reacting sodium phenylacetate with an acid chloride in the presence of isopropylmagnesium chloride (Bull.
c. Chim. France 51, 1331, 1932), a method of reacting sodium phenylacetate with an equimolar amount of isopropylmagnesium chloride and then reacting with cyclopropanecarboxylic acid esters (Revue Roumaine
de Chemie 29, 719, 1984), a method of reacting benzyl Grignards with cyclopropyl cyanide (Liebigs Ann. Chem 697, 100, 100,
1966, JP-A-6-41139), a method of reacting benzyl Grignards with cyclopropylcarbonyl chloride (Eur. J. Med. Chem.-Chi
m. Ther., 10 pages, 112 pages, 1975, JP-A-6-4113.
9), a method for reacting cyclopropyl Grignards with benzyl cyanides (Eur. J. Med. Chem.-Chim. The
r., vol. 10, p. 112, 1975), a method of reacting phenylacetic acid chlorides with trimethylsilylcyclopropane (Revue Roumaine de Chemi
e 29, p. 719, 1984) was known.

The reaction yield of the method (1) is 50 to 70%, but 10 to 25% of β-hydroxyglutaric acid is by-produced. In this method, the conversion rate of phenylacetic acid is less than 50% and the yield is about 80%, so the substantial yield is 40%.
The yield was extremely low and the method was not industrially satisfactory. In the methods (1) and (2), benzyl Grignards are stable only in a diethyl ether solvent which is difficult to use industrially, and are industrially difficult to implement. According to the method, the production of cyclopropyl Grignards must be carried out at a low temperature, the stability thereof is low, and the production of halogenated cyclopropane as a raw material is difficult, so that industrialization is extremely difficult. This method is low in yield, is extremely difficult to produce trimethylsilylcyclopropane as a raw material, and is expensive. As described above, the conventional method is not industrially satisfactory.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for producing arylcyclopropyl ketones in high yield as an industrial production method.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides an arylacetic acid represented by the general formula (I) and an alkylmagnesium halide represented by the general formula (II) in an organic solvent as shown in the following reaction formula. Is a method for producing an arylcyclopropylketone (IV), which comprises reacting a cyclopropanecarboxylic acid ester represented by the general formula (III) with a group (hereinafter referred to as Grignard reagent). The method is characterized by using 2.5 to 5 molar equivalents of Grignard reagent (II) with respect to acetic acid (I).

[0006]

Embedded image

(In the formula, R ¹ represents a phenyl group or a 2-thienyl group which may be substituted with alkyl or halogen having 1 to 4 carbon atoms, and R ² represents an alkyl group having 1 to 8 carbon atoms. In the formula, X represents a halogen atom, R ³ represents an alkyl having 1 to 4 carbon atoms or a cyclopropyl group which may be substituted with fluorine, and R ⁴ represents 1 to 1 carbon atoms.
4 represents an alkyl group)

The inventors of the present invention have diligently studied the fundamental causes of low conversion and low yield in the method of the above-mentioned literature for the purpose of producing arylcyclopropylketones (IV), and as a result,
Grignard reagent for starting arylacetic acids (II)
It was found that the amount of is an important factor, and the present invention has been completed. It was also found that the aryl acetic acid itself can be used without using salts such as sodium aryl acetate as a raw material.

That is, in the present invention, the Grignard reagent (II) is added to the starting arylacetic acid (I) in an amount of 2.5 to 5
By using an equivalent amount, the target product can be obtained in a high yield, which greatly exceeds the conventional yield shown in the comparative example, and the yield based on the aryl acetic acid can be obtained as well as the yield based on the aryl acetic acid based on the conventional yield. It greatly exceeds the rate.

The arylacetic acids (I) used in the production method of the present invention include phenylacetic acid, methylphenylacetic acid (each isomer), chlorophenylacetic acid (each isomer), fluorophenylacetic acid (each isomer), ethyl. Aryl acetic acids containing a substituent that does not react with the Grignard reagent, such as phenylacetic acid (each isomer) and 2-thienylacetic acid, can be used.

As the Grignard reagent (II), methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, n-propyl magnesium chloride,
Examples thereof include n-propylmagnesium bromide, i-propylmagnesium chloride, i-propylmagnesium bromide, n-butylmagnesium chloride, i-butylmagnesium chloride and i-butylmagnesium bromide, but especially i-propylmagnesium chloride, i. Secondary alkylmagnesium halides such as -propylmagnesium bromide, i-butylmagnesium chloride and i-butylmagnesium bromide are excellent, and among them, i-propylmagnesium bromide and i-propylmagnesium bromide are particularly excellent.

As the reaction solvent, ether solvents such as ether, tetrahydrofuran, dioxane, dibutyl ether, etc., particularly tetrahydrofuran suitable for industrial use are preferable. Considering operations such as extraction after the reaction, tetrahydrofuran, benzene, toluene, etc. A mixed solvent of and is a better solvent.

Cyclopropanecarboxylic acids include cyclopropanecarboxylic acid, 1-methylcyclopropanecarboxylic acid, 2-methylcyclopropanecarboxylic acid and 1-methylcyclopropanecarboxylic acid.
Ethylcyclopropanecarboxylic acid, 2-ethylcyclopropanecarboxylic acid, cis or trans-1,2-dimethylcyclopropanecarboxylic acid, cis or trans-1,
2-diethylcyclopropanecarboxylic acid, cis or trans-2,3-dimethylcyclopropanecarboxylic acid, cis or trans-2,3-diethylcyclopropanecarboxylic acid, 1-propylcyclopropanecarboxylic acid, 2-
Propylcyclopropanecarboxylic acid, 2-fluorocyclopropanecarboxylic acid and the like,

Examples of these cyclopropanecarboxylic acid esters (III) include alkyl esters having 1 to 4 carbon atoms such as methyl, ethyl, propyl (including isomers) and butyl (including each isomer). Any kind can be used.

The molar ratio of the compounds to be used is 1 mol of arylacetic acid (I) to Grignard reagent (II).
Is in the range of 2.5 to 5 moles, preferably 3 to 4 moles, and outside this range, the yield of the desired product decreases. The cyclopropanecarboxylic acid ester (III) is in the range of 0.5 to 2 mol, preferably 0.9 to 1.5 mol, based on 1 mol of the arylacetic acid (I).

The reaction temperature is the Grignard reagent (I
The reaction between I) and the aryl acetic acid (I) is performed at 40 ° C. or lower, preferably 0 to 35 ° C. for 0.5 to 5 hours to generate an alkane, and then further reacted at 65 ° C. or higher for 1 to 5 hours. To complete. Then, the cyclopropanecarboxylic acid ester (III) is reacted in the range of -30 to 100 ° C, preferably -10 to 75 ° C for 0.5 to 5 hours. After that, it is preferable to heat to 30 to 100 ° C. to complete the reaction.

After the completion of the reaction, the product is decomposed with acid to obtain the desired product in the organic layer. Acids used for decomposition include hydrochloric acid, sulfuric acid,
Mineral acids such as phosphoric acid are preferred.

The target substance is usually obtained by concentrating the obtained organic layer,
It can be isolated by distillation under reduced pressure.

Further, particularly when a mixed solvent of tetrahydrofuran and benzene, toluene or the like is used as the reaction solvent, the addition of tri-lower alkylamine such as triethylamine improves the reaction yield. The amount of tri-lower alkylamine added is in the range of 0.1 to 2 mol, preferably 0.5 to 2 mol, based on the aryl acetic acid used.

The aryl cyclopropyl ketones (IV) thus obtained include 2- (2-chlorophenyl) -1-cyclopropylethanone, 2- (3-chlorophenyl) -1-cyclopropylethanone, 2- (4-
Chlorophenyl) -1-cyclopropylethanone, 2-
(2-Fluorophenyl) -1-cyclopropylethanone, 2- (3-fluorophenyl) -1-cyclopropylethanone, 2- (4-fluorophenyl) -1-cyclopropylethanone, 2- (2 -Bromophenyl) -1
-Cyclopropylethanone, 2- (3-bromophenyl) -1-cyclopropylethanone, 2- (4-bromophenyl) -1-cyclopropylethanone, 2- (2-
Methylphenyl) -1-cyclopropylethanone, 2-
(3-methylphenyl) -1-cyclopropylethanone,

2- (4-methylphenyl) -1-cyclopropylethanone, 2- (2-chlorophenyl) -1-
(1-Methylcyclopropyl) ethanone, 2- (2-chlorophenyl) -1- (1-ethylcyclopropyl) ethanone, 2- (2-fluorophenyl) -1- (1-methylcyclopropyl) ethanone, 2- (2-Fluorophenyl) -1- (1-ethylcyclopropyl) ethanone, 2- (2-chlorophenyl) -1- (2-methylcyclopropyl) ethanone, 2- (2-chlorophenyl)
-1- (2-ethylcyclopropyl) ethanone, 2-
(2-Fluorophenyl) -1- (2-methylcyclopropyl) ethanone, 2- (2-fluorophenyl) -1
-(2-ethylcyclopropyl) ethanone, 2- (2-
Thienyl) -1-cyclopropylethanone, 2- (3-
Thienyl) -1-cyclopropylethanone and the like.

[0022]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 To a tetrahydrofuran solution (15 ml, 30 mmol) of 2M isopropyl magnesium chloride, a tetrahydrofuran solution of 4-chlorophenylacetic acid (1.17 g, 10 mmol) was added under ice-cooling so that the internal temperature was 20 ° C. or lower. It was dripped over a period of minutes. After completion of dropping, the mixture was reacted at reflux temperature for 3 hours. The obtained solution was cooled to 10 ° C. or lower, 3 ml of a tetrahydrofuran solution of methyl cyclopropanecarboxylate (0.95 g, 9.5 mmol) was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the mixture was ice-cooled, 10 ml of water was added, the mixture was neutralized with 2N hydrochloric acid (15 ml), and extracted with ethyl acetate. The layers were separated, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (eluent;
Ethyl acetate: hexane = 1: 5), 1.58 g (8.1
(mmol) of 2- (4-chlorophenyl) -1-cyclopropylethanone was obtained. Yield 85% based on methyl cyclopropanecarboxylate. NMR (CDCl ₃ z, 400MHz); 0.99-1.05 (2H, m), 1.09-1.99 (1
H, m), 3.79 (2H, s), 7.13 (2H, dt, J = 8.5Hz), 7.28 (2H,
dt, J = 8.5Hz, 1.7Hz) MS (CI, m / z): 195 (m ⁺ +1), 125, 89, 69

Example 2 2-Fluorophenylacetic acid (9.25 g, 60 mmol) and triethylamine (100 ml, 210 mmol) in a tetrahydrofuran-benzene (2: 1 volume) mixed solution of isopropylmagnesium chloride at a concentration of 2.1 mol / l were added. 60 mg, 0.6 mmol) in tetrahydrofuran (4.6
A liquid dissolved in a mixed solution of 3 g) and benzene (2.31 g) was added dropwise at 35 ° C. over 1 hour. After completion of dropping, the mixture was reacted at reflux temperature for 2 hours. The resulting solution is 45-55 ° C.
Cooled to methyl cyclopropanecarboxylate (5.71).
g, 57 mmol) in a mixed solution of tetrahydrofuran (3.60 g) and benzene (2.31 g) was added dropwise at the same temperature for 20 minutes. Then, the mixture was heated under reflux for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and 18% hydrochloric acid 46.0 g
Was added and the layers were separated. The obtained organic layer was washed twice with 20 ml of a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and then concentrated. Analysis by liquid chromatography revealed that 9.1 g of 2- (2-fluorophenyl) -1-cyclopropylethanone was obtained.
Yield based on methyl cyclopropanecarboxylate is 90.2
%Met.

Example 3 2- (2-Fluorophenyl)-was reacted in the same manner as in Example 1 except that 1.54 g (10 mmol) of 2-fluorophenylacetic acid was used instead of 4-chlorophenylacetic acid.
1-Cyclopropylethanone was obtained with a methyl cyclopropanecarboxylate yield of 91%. Boiling point; 110-112 ° C / 4 mmHg NMR (CDCl ₃ , 400 MHz); 0.82-0.98 (2H, m), 1.03-1.17 (2
H, m), 1.92-2.06 (1H, m), 3.86 (2H, s), 7.10-7.30 (4H,
m) MS (CI, m / z): 179 (m ⁺ +1)

Example 4 Example 1 was repeated except that 1.50 g (10 mmol) of 4-methylphenylacetic acid was used instead of 4-chlorophenylacetic acid.
2- (4-methylphenyl) -1-
Cyclopropylethanone was obtained with a yield of 64% based on methyl cyclopropanecarboxylate. NMR (CDCl ₃ , 400MHz); 0.79-0.86 (2H, m), 0.97-1.05 (2
H, m), 1.91-2.06 (1H, m), 2.33 (3H, s), 3.77 (2H, s),
7.12 (4H, d, J = 1.8Hz) MS (CI, m / z): 175 (m ⁺ +1), 105, 69

Example 5 2-Thienylacetic acid in place of 4-chlorophenylacetic acid
The reaction was performed in the same manner as in Example 1 except that 55 g (10 mmol) was used to obtain 2- (4-thienyl) -1-cyclopropylethanone in a methyl cyclopropanecarboxylate standard yield of 91%. NMR (CDCl ₃ , 400MHz); 0.86-0.93 (2H, m), 1.04-1.10 (2
H, m), 1.97-2.06 (1H, m), 4.02 (2H, s), 6.90 (1H, dd,
J = 3.7, 1.2Hz), 6.97 (1H, dd, J = 5.5, 3.7Hz), 7.22 (2H,
dd, J = 5.6, 1.2Hz) MS (CI, m / z): 167 (m ⁺ +1), 97, 69

Example 6 1.54 g (10 mmol) of 2-fluorophenylacetic acid and 1.08 g (10 mmol) of methyl 1-methylcyclopropanecarboxylate were used instead of 4-chlorophenylacetic acid and methyl cyclopropanecarboxylate, respectively. Other than the above, the reaction was performed in the same manner as in Example 1 to obtain 2- (2-fluorophenyl) -1- (1-methylcyclopropyl) ethanone as a colorless oily matter in a methyl cyclopropanecarboxylate reference yield of 84%. NMR (CDCl ₃ , 400MHz); 0.77 (2H, dd, J = 6.6, 3.7Hz), 1.
33 (2H, dd, J = 6.6, 3.7Hz), 1.42 (3H, s), 3.74 (2H,
s), 7.00-7.25 (4H, m) MS (CI, m / z): 193 (m ⁺ +1), 149, 109, 83

Example 7 Instead of 4-chlorophenylacetic acid and methyl cyclopropanecarboxylate, 1.54 g (10 mmol) of 2-fluorophenylacetic acid and 1.08 g (10 mmol) of methyl 2-methylcyclopropanecarboxylate were used, respectively. Other than that, the reaction was performed in the same manner as in Example 1 to obtain 2- (2-fluorophenyl) -1- (2-methylcyclopropyl) ethanone as a colorless oily substance with a methyl cyclopropanecarboxylate reference yield of 77%. NMR (CDCl ₃ , 400MHz); 0.68-0.75 (1H, m), 1.06 (3H, d,
J = 6.1Hz), 1.25-1.32 (1H, m), 1.36-1.43 (1H, m), 1.68
-1.74 (1H, m), 3.83 (2H, s), 7.02-7.28 (4H, m) MS (CI, m / z): 193 (m ⁺ +1), 1
09, 83

EXAMPLE 8 2-Fluorophenylacetic acid (9.25 g, 60 mmol) and triethylamine were added to a mixed solution of isopropylmagnesium chloride at a concentration of 2.1 mol / l in tetrahydrofuran-benzene (2: 1 by volume) (71 ml, 150 mmol). A solution obtained by dissolving (60 mg, 0.6 mmol) in a mixed solution of tetrahydrofuran (4.63 g) and benzene (2.31 g) was added dropwise at 35 ° C over 1 hour. After completion of dropping, the mixture was reacted at reflux temperature for 2 hours. 5 ° C
Cooled to methyl cyclopropanecarboxylate (5.71).
g, 57 mmol) dissolved in a mixed solution of tetrahydrofuran (3.60 g) and benzene (1.80 g) was added dropwise at the same temperature for 20 minutes. Then, the mixture was heated under reflux for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and 18% hydrochloric acid 46.0 g
Was added and the layers were separated. The obtained organic layer was washed twice with 20 ml of a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and then concentrated. Analysis by liquid chromatography revealed that 5.9 g of 2- (2-fluorophenyl) -1-cyclopropylethanone was obtained.
The yield based on methyl cyclopropanecarboxylate was 59%.

Example 9 A solution of 2-fluorophenylacetic acid in an isopropylmagnesium bromide solution prepared from 30.7 g (250 mmol) of 2-bromopropane, 6.08 g of magnesium (0.25 gram atom) and 125 ml of tetrahydrofuran.
A solution of 3 g (100 mmol) in 75 ml of tetrahydrofuran was added dropwise over 1 hour. After completion of dropping, the reaction temperature was raised from room temperature to the reflux temperature and the reaction was carried out for 6 hours. The solution was cooled to 5 ° C and 10.8 g (9% ethyl cyclopropanecarboxylate)
A solution of 5 mmol of tetrahydrofuran in 20 ml was added dropwise.
After completion of the dropping, the reaction temperature was again raised to reflux and the reaction was carried out at the same temperature for 3 hours. After cooling to room temperature, 12 ml of water and 125 ml of 2N hydrochloric acid were added for neutralization. The organic layer was separated and the aqueous layer was extracted twice with 50 ml of methylene chloride. The combined methylene chloride layers were washed with 50 ml of saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. After concentration under reduced pressure, the residue is distilled under reduced pressure and 2
9.5 g (53 mmol) of-(2-fluorophenyl) -1-cyclopropylethanone was obtained. The yield based on 2-fluorophenylacetic acid was 53%, and the yield based on ethyl cyclopropanecarboxylate was 56%.

Comparative Example 1 2- (2-fluorophenyl) -was carried out in the same manner as in Example 8 except that triethylamine was not added.
3.6 g of 1-cyclopropylethanone was obtained. The yield based on methyl cyclopropanecarboxylate was 20%.

Comparative Example 2 Ethyl cyclopropanecarboxylate (158 g, 1 mol) was dissolved in 4 volumes of anhydrous ether and the resulting ether solution was stirred with sodium 4-methylphenylacetate (38 g, 0. 21 mol) in ether.
After completion of the dropping, the mixture was refluxed for 3 hours to react. The resulting reaction solution was slowly poured into cooled hydrochloric acid. The ether layer and the aqueous layer were separated, and the aqueous layer was extracted twice with anhydrous ether. The combined ether layers were dried over anhydrous magnesium sulfate, and the ether layers were concentrated under reduced pressure. The obtained oily residue was heated at 100 ° C. for 10 to 15 minutes to dissolve the ether layer, and washed with a saturated aqueous sodium hydrogen carbonate solution and water in this order. The washed ether solution was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated. 2- (4-Methylphenyl) -1-cyclopropylethanone (16.5 g, 0.11 mol) was obtained from the third fraction among the obtained first fraction, second fraction and third fraction. The yield based on ethyl cyclopropanecarboxylate is 45.
%Met.

Comparative Example 3 2- (4-chlorophenyl) -1 was reacted in the same manner as in Comparative Example 2 except that sodium 4-chlorophenylacetate (38 g, 0.3 mol) was used in place of sodium 4-methylphenylacetate. -Cyclopropylethanone (21.3
g, 0.11 mol) was obtained. The yield based on ethyl cyclopropanecarboxylate was 37%.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kikuo Ataka 5 1978, Ogushi, Ube City, Yamaguchi Prefecture 5 1978, Ube Research Co., Ltd. Ube Laboratory (72) Inventor Yoichi Hashimoto 2111, 2111 Okami Hiratsuka, Kanagawa Prefecture (72) Inventor Tadano 26 Takamura, Hiratsuka City, Kanagawa Prefecture Takamura housing complex 38-101 (72) Inventor Masayuki Umeno 521, Chigasaki, Chigasaki City, Kanagawa Prefecture

Claims (6)

[Claims] 1. In an organic solvent, a compound represented by the general formula (I) R ¹ CH ₂ COOH (wherein R ¹ is a phenyl group which may be substituted with alkyl having 1 to 4 carbon atoms or halogen or 2-thienyl). Group) and an arylacetic acid represented by the general formula (II) R ² MgX (wherein R ² represents an alkyl group having 1 to 8 carbon atoms,
X represents a halogen atom), and then is reacted with a halogenated alkylmagnesium compound represented by the general formula (III) R ³ COOR ⁴ (wherein R ³ is alkyl having 1 to 4 carbon atoms or fluorine). R ⁴ represents an optionally substituted cyclopropyl group.
Represents an alkyl group having 1 to 4 carbon atoms) and is reacted with a cyclopropanecarboxylic acid ester represented by the general formula (IV) R ¹ CH ₂ COR ³ (wherein R ¹ and R ³ are as described above). In the method for producing arylcyclopropylketones represented by the same)
2.5 to 5 molar equivalents of the halogenated alkylmagnesiums are used. 2. The production method according to claim 1, wherein the alkyl magnesium halide represented by the general formula (II) is isopropyl magnesium chloride or isopropyl magnesium bromide. 3. The production method according to claim 1, wherein the aryl acetic acid represented by the general formula (I) is 4-chlorophenylacetic acid, 2-fluorophenylacetic acid, 4-methylphenylacetic acid or 2-thienylacetic acid. . 4. The cyclopropanecarboxylic acid ester represented by the general formula (III) is methyl cyclopropanecarboxylate, ethyl cyclopropanecarboxylate, methyl 1-methylcyclopropanecarboxylate or 2-methylcyclopropanecarboxylic acid. The method according to claim 1, which is methyl. 5. The production method according to claim 1, wherein tri-lower alkylamine is added and reacted. 6. The production method according to claim 5, wherein the organic solvent is a mixed organic solvent of tetrahydrofuran and benzene.