JPH0645572B2 - Process for producing 2-hydroxy-3-butenoic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a 2-hydroxy-3-butenoic acid derivative.

According to the invention, the general formula A glycidic acid ester derivative represented by the formula (wherein R represents a lower alkyl group) is treated with magnesium chloride to give a compound of the general formula A compound represented by the formula (wherein R represents a lower alkyl group) is obtained in good yield.

The amount of magnesium chloride used in the method of the present invention is about 0.5 to 3 times the mol of the raw material compound, but when the amount of 1.0 to 1.2 mol is used per 1 mol of the raw material in operation, the desired product is obtained in an extremely high yield. Obtainable. The reaction should be carried out in the substantial absence of water, but anhydrous solvents may be used, for example dioxane, ethers such as dibutyl ether, acetic acid esters such as butyl acetate, toluene, Examples thereof include aromatic hydrocarbons such as xylene, halogenated carbons such as 1,1,2-trichloroethane, tetrachloroethylene and tetrochlorethane, and solvents such as amides such as dimethylformamide, dimethylacetamide and formamide. The reaction temperature may be 60 to 150 ° C. without any problem, but 80 to 120 ° C. is convenient. The reaction time is 30 minutes to 20 hours, but the reaction can be substantially completed in about 2 to 4 hours. As magnesium chloride, a commercially available anhydrous product can be used as it is.

The product of the process of the invention thus obtained is useful as an intermediate for the known anti-inflammatory agent known as naproxen. That is, the obtained 2-hydroxy-3-butenoic acid derivative of the formula (II) is treated with, for example, sodium methylate in methanol, and then hydrolyzed to give the compound of the formula Of keto acid and then treated with hydrogen peroxide in alkali 2- (6-Methoxy-2-naphthyl) -propionic acid can be obtained.

The compound represented by the formula (I) used as a raw material in the method of the present invention has, for example, the formula It can be produced by reacting the compound of (1) with chloroacetic acid ester, and this reaction is preferably carried out under the conditions of the dulzene condensation, that is, under the anhydrous condition in the presence of a base condensing agent under an inert gas. As the condensing agent, sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium isopropoxide, potassium tertiary butoxide and the like can be used.

Next, examples of the method of the present invention will be described. However, the present invention is not limited to these.

Example 1 2-hydroxy-3- (6-methoxy-2-
Naphthyl) -3-butenoic acid methyl 6-methoxy-2-acetylnaphthalene 120 g and methyl chromate acetate 120 g are dissolved in toluene 1200 ml, and potassium tertiary butyrate 120 g is stirred.
Was gradually added in a nitrogen stream at 3 to 5 ° C. over 2 hours.
After stirring for 1 hour at 5-7 ° C, water and ethyl acetate were added and stirred well. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The crude crystal obtained by distilling off the organic solvent under reduced pressure was recrystallized from benzene to give 3-methyl-
123 g of methyl 3- (6-methoxy-2-naphthyl) -glycidate was obtained. Yield 75.3% (theoretical value). Melting point 120.5
~ 124.1 ° C. The elemental analysis results for C ₁₆ H ₁₆ O _{4 are} as follows.

83 g of methyl 3-methyl-3- (6-methoxy-2-naphthyl) glycidate prepared as described above was dissolved in 500 ml of toluene to obtain 31.9 g of magnesium chloride.
The mixture was added at 0 ° C, stirred at 90-100 ° C for 3 hours, and the reaction solution was poured into dilute hydrochloric acid. The organic layer was separated, washed successively with water, an aqueous solution of sodium bicarbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure, and the residue was recrystallized from benzene-hexane to give 2-hydroxy-
78 g of methyl 3- (6-methoxy-2-naphthyl) -3-butenoate was obtained. Yield 93.9% (theoretical value). Melting point 90.2〜
92.3 ° C. The elemental analysis results for C ₁₆ H ₁₆ O _{4 are} as follows.

Example 2 2-hydroxy-3- (6-methoxy-2-
Naphthyl) -3-butenoic acid tert-butyl 6-methoxy-2-acetylnaphthalene (5.5 g) and chloroacetic acid tert-butyl (8.3 g) were dissolved in 60 ml of toluene, and potassium tertiary butylate (6.2 g) was stirred to 0.
Gradually added at ~ 5 ° C over 40 minutes. 1 at 0-5 ° C
After stirring for an hour, water and ethyl acetate were added and stirred well. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to obtain 9.1 g of semi-crystalline tertiary butyl 3-methyl-3- (6-methoxy-2-naphthyl) -glycidate. The yield was quantitative. The elemental analysis results for C ₁₉ H ₂₂ O _{4 are} as follows.

3.6 g of tert-butyl 3-methyl-3- (6-methoxy-2-naphthyl) -glycidate, prepared as described above, was added to n.
-Dissolved in 20 ml of butyl ether, magnesium chloride
1.6 g was added and stirred at 95-100 ° C. for 3 hours, and the reaction solution was poured into dilute hydrochloric acid. Extraction was performed with n-butyl ether, and the extract was washed with water, an aqueous solution of sodium bicarbonate, water and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from benzene-hexane to give 2-hydroxy-3- (6-methoxy-2).
3.5 g of tert-butyl-3-naphthyl) -3-butenoate were obtained. Melting point 85.7-86.5 ° C. Yield 97.5% (theoretical value). C ₁₉
The elemental analysis results for H ₂₂ O _{4 are} as follows.

Example 3 2-Hydroxy-3- (6-methoxy-2-
Naphthyl) -3-butenoic acid tert-butyl 6.3-methyl-3- (6-methoxy-2-naphthyl) -glycidic acid tert-butyl 6.3 g is dissolved in butyl acetate 70 ml, and magnesium chloride 2.0 g is added to 90 Stirred at ~ 100 ° C for 3 hours. Dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with butyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Butyl acetate was distilled off under reduced pressure to give 2-hydroxy-3- (6-methoxy-
6.0 g of tert-butyl 2-naphthyl) -3-butenoate were obtained. Melting point 85.5-86.5 ° C. Yield 95.2% (theoretical value).

Example 4 2-Hydroxy-3- (6-methoxy-2-
Methyl naphthyl) -3-butenoate Methyl 3-methyl-3- (6-methoxy-2-naphthyl) -glycidate 27.2 g of tetrachloroethylene 300 ml
, 10 g of magnesium chloride and 90
Stirred at ~ 100 ° C for 3 hours. After adding dilute hydrochloric acid, the mixture was extracted with tetrachloroethylene. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 26.8 g of methyl 2-hydroxy-3- (6-methoxy-2-naphthyl) -3-butenoate. Melting point 91.0-92.7 ° C. Yield 99.0% (theoretical value).

Example 5 2-Hydroxy-3- (6-methoxy-2-
Naphthyl) -3-butenoic acid tert-butyl 3-methyl-3- (6-methoxy-2-naphthyl) -glycidic acid tert-butyl 31.4 g was dissolved in toluene 1000 ml, magnesium chloride 10 g was added and 90 ~
The mixture was stirred at 100 ° C for 4 hours. Dilute hydrochloric acid was added to the reaction solution, and toluene extraction was performed. The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from benzene-hexane to obtain 28.9 g of tert-butyl 2-hydroxy-3- (6-methoxy-2-naphthyl) -3-butenoate. Melting point 85.9-86.5 ° C. Yield 92.0% (theoretical value).

Example 6 2-Hydroxy-3- (6-methoxy-2-
Methyl naphthyl) -3-butenoate Methyl 3-methyl-3- (6-methoxy-2-naphthyl) -glycidate 12.6 g was added to 100 ml of dimethylformamide.
And add 4.4 g of magnesium chloride to 90-1
The mixture was stirred at 00 ° C for 3 hours. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. 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 11.5 g of methyl 2-hydroxy-3- (6-methoxy-2-naphthyl) -3-butenoate. Melting point 90.8〜
92.1 ° C. Yield 90.7% (theoretical value).

Example 7 2- (6-Methoxy-2-naphthyl) -propionic acid 120 g of 6-methoxy-2-acetylnaphthalene and 120 g of methyl chloroacetate are dissolved in 1200 ml of toluene, and 120 g of potassium tertiary butyrate with stirring.
Was gradually added at 3-5 ° C over 2 hours. After stirring at 5 to 7 ° C for 1 hour, water and ethyl acetate were added and thoroughly stirred. The organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was distilled off under reduced pressure to obtain 166.3 g of crude crystals of glycidic acid ester.

64 g of magnesium chloride was added to a solution of 166.3 g of the above crude crystals in 600 ml of xylene, and the mixture was stirred at 90 to 100 ° C. for 4 hours. After cooling, 65 ml of 35% hydrochloric acid was added to 500 ml of water.
What was diluted with was dripped in 1 hour. After completion of dropping, the mixture was stirred for 15 minutes and the organic layer was separated. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 161.2 g of crude hydroxybutenoic acid ester crystals.

The above crude crystals (161.2 g) were dissolved in xylene (1000 ml), and 28% sodium methylate methanol solution (180 ml) was diluted with methanol (90 ml) and added.
The mixture was stirred at 6 ° C for 1 hour. Then water 600 at 50-55 ℃
ml was added and stirred for 30 minutes. The reaction solution was cooled to 15 to 20 ° C., and while stirring, 90 ml of 35% hydrogen peroxide solution was added to 30 mL.
It took a minute to add dropwise. After completion of dropping, the mixture was stirred at 15 to 20 ° C for 1 hour, and the aqueous layer was separated. 35% hydrochloric acid 9% in this aqueous solution
It was acidified by adding 0 ml and then extracted with ethyl acetate.
The extract was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from isopropyl alcohol to give 2-
(6-methoxy-2-naphthyl) -propionic acid 90 g
Got Melting point 152.5-154.7 ° C. Yield 65.1% (theoretical yield from 6-methoxy-2-acetylnaphthalene). C ₁₄
The elemental analysis results for H ₁₄ O _{3 are} as follows.

Next, in order to show the specific action and effect of the magnesium chloride used in the present invention, the results of similar experiments using other compounds such as Lewis acid will be given as comparative examples.

Comparative Example 0.5 g of methyl 3-methyl-3- (6-methoxy-2-naphthyl) glycidate was dissolved in a solvent of 10 to 20 ml, 0.5 g of various catalysts were added to this solution, and the results are shown in the table while stirring. The reaction was carried out under the conditions.

After the reaction was completed, the reaction solution was poured into hydrochloric acid, and experiment Nos. 4, 5, and 7 were performed.
For ~ 9, ether extraction was performed. In other experimental examples, the reaction solution was poured into hydrochloric acid to separate the organic layer. The ether extract and the organic layer solution were washed with water, sodium bicarbonate water, water and saturated saline solution, dried over anhydrous NaSO ₄ , and then concentrated. The residue was quantified by thin layer chromatography (TCL), and the yield was determined. I asked. The TCL conditions are as follows.

Thin layer: Silica gel (Merck) Developing solvent: Benzene: AcOEt = 9: 1 Color development: 50% sulfuric acid spray, 120 ° C, 5 minutes

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Claims (1)

[Claims] 1. A general formula A general formula, characterized in that a glycidic acid ester derivative of the formula (wherein R represents a lower alkyl group) is treated with magnesium chloride. (Wherein R represents a lower alkyl group) 2-hydroxy-
Process for producing 3-butenoic acid derivative.