JPS6220986B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 3-methyl-3-(substituted aryl)-
This invention relates to an improved method for producing glycidic acid esters. More specifically, the present invention provides an improved process for providing glycidic acid ester compounds in economically higher yields than conventional processes. Recently, methods have been developed to synthesize useful carboxylic acids from glycidic acid esters. For example, according to Japanese Patent Publication No. 53-35067 and Japanese Patent Publication No. 53-35068, ibuprofen, which has an anti-inflammatory effect, is produced from a compound represented by the general formula (in which Ar is a 4-lower alkyl phenyl group). The system compounds are efficiently obtained. It is already known to produce glycidic acid esters from aromatic ketones. For example, "Organic Reactions" Vol. 5, pp. 413-437,
Special Publication No. 47-24550, Publication No. 53-35067, "J.prakt.Chem." Vol. 12, pp. 110-114 (1960), "Indian J.Chem." Vol. 15B, p. 574 ( A method for synthesizing arylglycidate esters is described in literature such as (1977). However, with these methods, it is difficult to obtain glycidic acid esters in high yield (90% or more) under economic conditions.
For example, the method described in "Organic Reactions" Vol. 5, pages 413 to 437 has a yield of 70% or less and is not suitable as an industrialization method. In the method disclosed in Japanese Patent Publication No. 47-24550, the Dalzen reaction is carried out using isopropyl alcohol as a solvent and sodium isoprooxide as a base.
Such a base is difficult to make, and furthermore, the isopropyl alcohol must be distilled off after the reaction is completed.
It has the disadvantage that the operation is complicated. Tokuko Showa 53-
In the method of Publication No. 35067, the Dalzen reaction is carried out without a solvent using sodium methoxide as a base, but the yield remains at 80%. "J.
In the method described in ``Prakt. Sodium powder is dangerous and industrially undesirable. “Indian
J. Chem., Vol. 15B, pp. 574-575 (1977) uses potassium tert-butyrate in tertiary-butyl alcohol;
Butyrate is expensive, and after the completion of the reaction, the third
Butyl alcohol must be distilled off, making the operation complicated. As a result of various studies, the present inventors discovered an aryl methyl ketone represented by the general formula () Ar-COCH <sub>3</sub> () (wherein Ar represents an aryl group substituted with a substituent inert to the reaction). In the presence of economically inexpensive sodium alcoholate powder, under substantially anhydrous conditions, in a water-insoluble aprotic solvent mixture containing at least 3% by liquid volume of a dipolar aprotic organic solvent. By reacting with chloroacetate, the general formula () can be obtained in high yield. The present invention was completed by discovering that a glycidic acid ester represented by the formula (wherein Ar is as described above and R represents a lower alkyl group) can be obtained. Examples of the aryl group in the compound of general formula () above include phenyl groups and naphthyl groups substituted with one or more substituents inert to the reaction. And substituents inert to this reaction are substituents on the aryl group that interfere with the reaction in this process or are reactive with the reaction product and do not thereby reduce the yield of the reaction product. and examples of these substituents include halogen such as fluorine, alkyl groups such as t-butyl, iso-butyl, cycloalkyl groups such as cyclohexyl, alkoxy groups such as methoxy,
Examples include phenyl group, halogen-substituted phenyl group, such as fluorophenyl group, phenoxy group, and nitro group. According to the prior art level, "Compt rend" No. 268
(15), p. 1403 (1969), showed that protic solvents are superior to aprotic solvents in the Dalzene reaction, and also ``J.Org.Chem.'' No. 26
Vol. 3170 (1961) shows that potassium compounds are superior to sodium as bases in the Daltzen reaction, so the present invention is truly unexpected. Furthermore, the present invention can be applied to the synthesis of glycidic acid esters in which the phenyl group is substituted with a strong electron-donating group or an electron-withdrawing group, which has been difficult to synthesize in the past, and is extremely excellent from an economic and academic standpoint. This is a method. The dipolar aprotic solvent used in the present invention includes dimethylformamide, diethylformamide, dimethylacetamide, dimethylsulfoxide, tetramethylene sulfoxide, tetramethylene sulfone, etc., with dimethylformamide and dimethylsulfoxide being economically preferred. In terms of reaction rate, the liquid volume relative to the water-insoluble aprotic solvent is at least about 8
% of dimethylformamide or dimethyl sulfoxide. For ease of separating the glycidate ester solution from the aqueous components of the reaction mixture, dimethylformamide, diethylformamide, dimethylacetamide, tetramethylene sulfone, tetramethylene sulfoxide, or dimethyl sulfoxide may be used as the glycidate ester-forming reaction medium. Preferably, a combination with a water-insoluble aprotic organic liquid diluent is used. Although the dipolar aprotic substance can be used as the sole solvent medium for the reactants, it is preferably diluted by a water-insoluble aprotic organic liquid which accounts for the major volume proportion in the mixture. It is preferable to do so. Water-insoluble aprotic solvents include water-insoluble organic solvents such as benzene, toluene, xylene and diisopropyl ether.
The reaction temperature may be a temperature at which the organic solvent can be kept in a liquid state, but it is preferable to carry out the reaction at -5°C to 5°C. Although the reaction time depends on the amount of dipolar aprotic solvent and the reaction temperature, the reaction can be completed within about 10 hours. As the sodium alcoholate, sodium methylate powder or sodium ethylate powder is economically preferred. Chloroacetic ester and sodium alcoholate each per mole of aryl methyl ketone.
It is preferred to use a molar ratio of 2.0 to 3.0. The glycidic acid ester obtained as described above has high purity and can be used as it is as a reaction intermediate. Table 1 shows data on infrared absorption spectra and nuclear magnetic resonance spectra of representative examples of glycidic acid esters obtained according to the present invention.

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[Table] Next, examples according to the present invention are listed. However, the present invention is not limited thereto. Example 1 Methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate 100 g of 6-methoxy-2-acetylnaphthalene
(0.50 mol) and methyl chloroacetate 119.3 g
(1.10 mol) was dissolved in 1000 ml of benzene, added with 50 ml of dimethyl sulfoxide, and then heated at 0-3℃.
Sodium methylate powder takes 1.5 hours
59.4g (1.10mol) was added. 0~ after addition
The mixture was stirred at 3° C. for 30 minutes, and the reaction solution was poured into water. 800 ml of ethyl acetate was added to perform extraction. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 136 g of crystals of methyl 3-methyl-3-(6-methoxy-2-naphthyl)-glycidate (trans-cis mixture). The yield was quantitative. Elemental analysis (as C ₁₆ H ₁₆ O ₄ ) C H actual value: 70.69% 6.05% Calculated value: 70.57% 5.92% Example 2 3-Methyl-3-(4-isobutylphenyl)
-Ethyl glycidate 4-isobutylacetophenone 8.8g (0.05 mol) and ethyl chloroacetate 12.3g (0.1 mol)
Dissolve in 90ml of toluene and add diethylformamide.
10ml and at 0-3°C 6.8g (0.1 mol) of sodium ethylate powder were added over 30 minutes at -2-3°C. After stirring at the same temperature for 30 minutes, the reaction solution was poured into water, and then extracted with toluene.
The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Toluene was distilled off under reduced pressure to obtain 13.0 g of oily ethyl 3-methyl-3-(4-isobutylphenyl)-glycidate. yield
99.2% (theoretical value). Elemental analysis (as C ₁₆ H ₂₂ O ₃ ) C H actual value: 73.40% 8.35% Calculated value: 73.25% 8.45% Example 3 3-Methyl-3-(4-tertiary butylphenyl)-ethyl glycidate 4- Tertiary butylacetophenone 8.8g (0.05
12.3 g (0.1 mol) of ethyl chloroacetate, 90 ml of xylene, 7 ml of tetramethylene sulfoxide and 6.8 g (0.1 mol) of sodium ethylate powder
From 3-methyl-
13.1 g of ethyl 3-(4-tert-butylphenyl)-glycidate was obtained. The yield was quantitative. Elemental analysis (as C ₁₆ H ₂₂ O ₃ ) C H actual value: 73.19% 8.50% Calculated value: 73.25% 8.45% Example 4 Methyl 3-methyl-3-(4-nitrophenyl)-glycidate 4-nitroacetophene 10 g (0.185 mol) of sodium methylate powder was added over 1 hour at -2 to 1°C in a stirred mixture of 13.9 g (0.0843 mol) of sodium chloride, 20 g (0.185 mol) of methyl chloroacetate, 15 ml of dimethyl sulfoxide and 150 ml of benzene. Added gradually. After the addition was complete, the mixture was stirred for 30 minutes at 0-3°C and water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to obtain 18.2 g (91.2%) of oily methyl 3-methyl-3-(4-nitrophenyl)-glycidate. Elemental analysis (as C ₁₁ H ₁₁ NO ₅ ) C H N actual value: 55.80% 4.56% 6.01% calculated value: 55.69% 4.67% 5.91% Example 5 Methyl 3-methyl-3-(3-nitrophenyl)-glycidate 3-nitroacetophenone 7.0g, sodium methylate powder 5.0g, methyl chloroacetate 10.0g
g, benzene 95 ml and dimethylformamide 5
ml, perform the same operation as in Example 4 to obtain an oily 3-
9.5 g of methyl-3-(3-nitrophenyl)-glycidate was obtained. Yield 94.5% (theoretical value). Elemental analysis (as C ₁₁ H ₁₁ NO ₅ ) C H N actual value: 55.56% 4.54% 5.80% calculated value: 55.59% 4.67% 5.91% Example 6 Methyl 3-methyl-3-(2-nitrophenyl)-glycidate 2-nitroacetophenone 5.0g, sodium methylate powder 3.6g, methyl chloroacetate 7.2g,
100ml benzene and 5ml dimethyl sulfoxide
The same operation as in Example 4 was performed to obtain 6.7 g of oily methyl 3-methyl-3-(2-nitrophenyl)-glycidate. Yield 93.3% (theoretical value). Elemental analysis (as C ₁₁ H ₁₁ NO ₅ ) C H N actual value: 55.51% 4.60% 6.02% calculated value: 55.69% 4.67% 5.91% Example 7 3-Methyl-3-(4-cyclohexylphenyl)-glyside Methyl acid 4-cyclohexylacetophenone 10.1g, methyl chloroacetate 10.9g, dimethyl sulfoxide 10
ml and in a stirred mixture of 100 ml of toluene.
At 1° C., 5.4 g of sodium methylate powder was gradually added over a period of 1 hour. 30 at 0-3℃ after addition
Stir for a minute and pour into water. Perform toluene extraction, wash the extract sequentially with water and saturated saline,
It was then dried with anhydrous sodium sulfate. Toluene was distilled off under reduced pressure to obtain oily 3-methyl-3-(4
-cyclohexylphenyl)-methyl glycidate
13.1g was obtained. Yield 95.5% (theoretical value). Elemental analysis (as C ₁₇ H ₂₂ O ₃ ) C H actual value: 74.26% 7.99% Calculated value: 74.42% 8.08% Example 8 Methyl 3-methyl-3-(4'-fluoro-4-biphenylyl)-glycidate 4'-Fluoro-4-acetylbiphenyl 21.4
10.8 g of sodium methylate powder was gradually added over 1 hour at -2 to 2° C. to a stirred mixture of 21.7 g of methyl chloroacetate, 200 ml of benzene and 20 ml of dimethyl sulfoxide. After addition -1~
Stir for 30 minutes at 2°C and then pour into water. Benzene extraction was performed, and the extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Benzene is distilled off under reduced pressure to obtain powdered 3-methyl-3.
27.1 g of methyl -(4'-fluoro-4-biphenylyl)-glycidate was obtained. Yield 94.6% (theoretical value). Melting point 68.6-70.2℃. Elemental analysis (as C ₁₇ H ₁₅ FO ₃ ) C H actual value: 71.16% 5.11% Calculated value: 71.32% 5.28% Example 9 Methyl 3-methyl-3-(2-fluoro-4-biphenylyl)-glycidate 2 -Fluoro-4-acetylbiphenyl10.7
g, 10.8 g of methyl chloroacetate, 5.4 g of sodium methylate powder, 10 ml of dimethyl sulfoxide and 100 ml of benzene to obtain 3-methyl-3-(2-fluoro-4-biphenylyl)-glycidic acid. 13.6 g of methyl was obtained. Yield 94.8g (theoretical value). Elemental analysis (as C ₁₇ H ₁₅ FO ₃ ) C H actual value: 71.40% 5.41% Calculated value: 71.32% 5.28% Example 10 Methyl 3-methyl-3-(4-biphenylyl)-glycidate 4-acetylbiphenyl 19.6g, methyl chloroacetate 21.7g, sodium methylate powder 10.8g,
20ml dimethyl sulfoxide and 200ml benzene
Then, the same operation as in Example 8 was performed to obtain powdered 3-
25.8 g of methyl-3-(4-biphenylyl)-glycidate was obtained. Yield 96.1% (theoretical value). Melting point 74.7-77.0°C Elemental analysis (as C ₁₇ H ₁₆ O ₃ ) C H actual value: 75.95% 5.89% Calculated value: 76.10% 6.01% Example 11 3-Methyl-3-(4-methoxyphenyl)-
Methyl glycidate -2° to 2% in a stirred mixture of 7.5 g of 4-methoxyacetophenone, 16.3 g of methyl chloroacetate, 16 g of tetramethylene sulfone, and 100 ml of benzene.
8.1 g of sodium methylate powder was slowly added over a period of 1 hour. -2° to 0°C after addition
Stir for 30 minutes and then pour into water. Benzene extraction was performed, and the extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure to obtain oily 3-methyl-3-(4-
10.4 g of methyl (methoxyphenyl)-glycidate was obtained. Yield 93.7% (theoretical value). Elemental analysis (as C ₁₂ H ₁₄ O ₄ ) C H actual value: 64.69% 6.26% Calculated value: 64.85% 6.35% Example 12 3-Methyl-3-(3-phenoxyphenyl)
-Methyl glycidate 3-phenoxyacetophenone 21.2g, methyl chloroacetate 32.6g, sodium methylate powder
Oily 3-methyl-3-(3-phenoxyphenyl) was obtained by carrying out the same operation as in Example 11 from 16.2 g, dimethyl sulfoxide 20 ml and benzene 200 ml.
-27.0g of methyl glycidate was obtained. Yield 95.2%
(Theoretical value). Elemental analysis (as C ₁₇ H ₁₆ O ₄ ) C H actual value: 71.71% 5.80% Calculated value: 71.82% 5.67% Example 13 3-Methyl-3-(4-isobutylphenyl)
-Methyl glycidate In a stirred mixture of 17.6 g of 4-isobutylacetophenone, 21.7 g of methyl chloroacetate, 10 ml of dimethyl sulfoxide and 100 ml of xylene at -2 to 2°C
Then, 10.8 g of sodium methylate powder was gradually added over a period of 1 hour. After the addition was completed, the mixture was stirred at -2 to 2°C for 30 minutes, and the reaction solution was poured into water. Extraction was performed with xylene, and the extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Xylene was distilled off under reduced pressure to obtain oily 3-methyl-3-(4-
isobutylphenyl)-methyl glycidate 23.9g
I got it. Yield 96.2% (theoretical value). Elemental analysis (as C ₁₅ H ₂₀ O ₃ ) C H actual value: 72.41% 8.01% Calculated value: 72.55% 8.12%

Claims (1)

[Claims] 1 Aryl methyl ketone represented by the general formula () Ar-COCH ₃ () (in the formula, Ar represents an aryl group substituted with a substituent inert to the reaction) in the presence of sodium alcoholate powder under substantially anhydrous conditions with a chloroacetic ester in a water-insoluble aprotic solvent mixture containing at least 3% by liquid volume of a dipolar aprotic organic solvent; General formula () (In the formula, Ar represents an aryl group substituted with a substituent inert to the reaction, and R represents a lower alkyl group.) Manufacturing method.