KR910002282B1 - Process for the preparation of inden acetic acid - Google Patents

Abstract

A process for preparing indene acetic acid derivs. of formula (I) comprises (a) reacting a cpd. of formula (II) with Zn powder and ethylbro-moacetate in the mixed solvent of a nonpolar solvent selected from benzene, toluene xylene, or ligroin, (b) treating (c) the reactant with H2SO4 to produce a cpd. of formula (III), and reacting (III) with a cpd. of formula (IV) in methanol or ethanol. (I) are useful as non-steroidal antipyretic analgesics.

Description

Process for preparing indene acetic acid derivative

The present invention relates to a novel process for preparing cis-5-fluoro-2-methyl-1- [para- (methylsulfinyl) benzylidene] indene-3-acetic acid represented by the following structural formula (I).

Structural formula (I) compounds can be administered orally or parenterally as nonsteroidal antipyretic analgesics with potent anti-inflammatory, antipyretic, analgesic effects.

Known methods for preparing compounds of formula (I) include Korean Patent Publication Nos. 87-127, US Patent Nos. 3647853, 3654349, 3692651, 3860659, 38,8415, 3869507, Various manufacturing methods are described in 3882239, 3897487, German Patent No. 2039426, 2039427, and the like.

However, the present invention is to prepare the target compound of formula (I) by using the starting material of the general formula (II) by using a starting material that is completely different from the above-described known methods in a high yield without a difficult reaction process. To summarize the reaction method of the present invention to the reaction scheme as follows.

In formula (III), X is a halogen atom such as chromo, bromo or a sulfonate derivative such as tosylate or methanesulfonate.

A feature of the present invention is the development of a process for preparing a cis compound which is a preferred isomer by introducing a para-methylsulfinyl substituent in the final step and a process for maximizing the yield of the reaction from the new intermediate product and simplifying the preparation process step. .

When explaining the preparation method of the present invention in detail, the compound of the general formula (III) is prepared in two ways from the compound of the general formula (II).

In the first method, metal powders such as sodium, potassium, and magnesium are heated and refluxed in a polar solvent such as alcohol, for example, methanol, ethanol, and isopropanol.

Diethyl methylmalonate was added to the solution and heated to reflux for 1 to 3 hours. To this mixture is added dropwise, for example para-fluorobenzylchloride of general formula (II), followed by heating under reflux for 1 to 3 hours to obtain dietal para-fluorobenzyl methylmalonate of general formula (III). At this time, the equivalent ratio of the compound of formula (II), diethyl methyl malonate and metal powder is preferably 1: 1.5: 2 or 1: 1.2: 1.5.

In the second method, a compound of formula (II) is reacted with diethyl malonate in the previous method to obtain diethyl para-fluorobenzylmalonate, and then the compound is dissolved in sodium, potassium, After refluxing with a metal powder such as magnesium and heating the mixture, methyl iodine is added to the mixture and refluxed at room temperature to 60 ° C. for 1 to 3 hours to obtain a new compound of general formula (III).

The method for preparing the compound of formula (IV) from the compound of formula (III) can be divided into two types.

In the first method, the compound of general formula (III) is added to an aqueous metal hydroxide solution such as potassium potassium hydroxide or sodium thorium hydroxide and heated to reflux for 1 to 3 hours. The ethanol produced by distillation under reduced pressure is blown and the aqueous solution is acidified with a strong acid such as hydrochloric acid or sulfuric acid. The compound of general formula (IV) is obtained by heating and refluxing for a long time (12-24 hours), stirring well the use liquid.

Alternatively, salt is added to dimethyl sulfoxide, heated, and then general formula (III) compound is added and stirred for 4 to 8 hours at 120 ° C. to 160 ° C. to obtain a new compound which is ethyl para-fluorobenzylmethylacetate. The compound is added to an aqueous metal hydroxy solution such as potassium hydroxide or sodium hydroxy, heated to reflux for 1 to 3 hours, and acidified with a strong acid such as hydrochloric acid or sulfuric acid to obtain a compound of formula (IV). At this time, the weight ratio of salt and general formula (III) is preferably 1 to 1.5. The theoretical invention of the second method is described in Tetrahedron Lett. No. 12, 957 (1973).

The compound of formula (IV) is added to a mixed solution with polyphosphoric acid or polyphosphoric acid and a nonpolar solvent such as benzene, xylene or toluene or in methanesulphonic acid or phosphorus pentoxide for 1 to 4 hours at 50 ° C to 150 ° C. Stirring gives the compound of general formula (V). At this time, the reaction temperature is most preferably 65 ℃ to 70 ℃.

In the process for preparing the compound of formula (VI) from the compound of formula (V), first, a zinc powder is added to a nonpolar solvent such as benzene, toluene, xylene or ligroin, or a mixture thereof, and then a catalytic amount of iodine is added. Heated to reflux.

Ethyl bromoacetate and the compound of formula (V) were added to the solution, and the mixture was heated to reflux for 1 to 4 hours, 10% to 40% of a volcanic aqueous solution was added thereto, and stirred at room temperature for 24 to 72 hours. The compound of is obtained.

At this time, the equivalent ratio of the compound of formula (V) and ethyl bromoacetate is preferably 1.5, and the weight ratio of zinc and the compound of formula (V) is about 3 is preferable. The volume ratio of benzene and ligroin, toluene and liroin, xylene and liroin in the reaction mixture is preferably 2 to 4.

The compound of formula (VII) is obtained by heating and refluxing the compound of formula (VI) in an aqueous solution of potassium hydroxy or sodium hydroxy for 1-3 hours and then acidifying with a strong acid such as sulfuric acid or hydrochloric acid.

After adding alcohols such as methanol and ethanol to metals such as sodium and potassium, add a compound of formula (III) and stir at 50 ° C to 80 ° C for 1 to 3 hours, and then add the compound of formula When added, the mixture was stirred at 50 ° C to 80 ° C for 1 to 3 hours to obtain the compound of formula (I).

Compounds of the general formula (4-) are used in the preparation of 4-methylthiobenzaldehyde in an oxidizing agent and in polar solvents such as, for example, sodium thoradic acid, meta-chloroperbenzoic acid, chlorin peroxide, hydrogen peroxide, water, acetic acid, acetone. It is obtained by stirring at time -10 degreeC-0 degreeC.

The product can be separated and purified by conventional techniques such as evaporation, filtration, extraction, recrystallization and combinations thereof. For example, when the product precipitates by cooling in the reaction mixture, it is collected by filtration. If no precipitation occurs, the reaction mixture is concentrated to dryness under reduced pressure, and the residue is concentrated between organic solvents such as ether dimethyl chloride and ethyl acetate and water. The product is obtained by shaking with the mixture and then concentrating the organic solvent. If the product contains by-products, it can be further purified by distillation under reduced pressure, recrystallization or the like.

The present invention will be described in more detail with the following examples, but the present invention is not necessarily limited to this range. Unless otherwise indicated, percentages, ratios, etc., are by weight.

Example 1

Diethyl para-fluorobenzylmethylmalonate (III)

140 ml of ethanol was slowly added dropwise to 7.72 g (0.34 mol) of natrium and heated to reflux. 47.3 g (0.27 mol) of diethyl methyl malonate was added to the solution, and the mixture was heated for 2 hours.

24.2 g (0.17 mol) of para-fluorobenzyl chloride (II, X = Cl) was slowly added dropwise to this mixture, followed by heating and stirring for 2 hours. After distillation under reduced pressure to remove ethanol, ether was added to the residue, washed with water and saturated brine in that order and dried over magnesium sulfate. The filtrate was removed after filtration, and the residue was distilled under reduced pressure (156 占 폚-57 占 폚 / 7 mmHg) to give 45.03 g (92.5% yield) of a colorless liquid product.

nmr (CDCl ₃ ) ppm: 6.76-7.25 (m, 4H), 4.18 (q, 4H), 3.17 (s, 2H), 1.29 (s, 3H), 1.18 (t, 3H)

Analyzes for C ₁₅ H ₁₉ O ₄ F

Calculated Value: C; 63.82, H; 6.78, 0; 22.67

Found: C; 63.89, H; 6.89, 0; 22.50

Example 2

Diethyl para-fluorobenzylmethylmalonate (III)

34.2 g (0.2 mol) of para-fluorobenzylbromide (II, X-Br) was reacted according to the method of Example 1 to give 51.9 g (92% yield) of a colorless liquid product.

Example 3

Diethyl para-fluorobenzylmethylmalonate (III)

) 30.8g(0.11mol)을 실시예 1의 방법에 의거 반응시키면 27.6g(89% 수율)의 무색 액체 생성물이 얻어진다.Para-fluorobenzyltosylate (II,

) 30.8 g (0.11 mol) were reacted according to the method of Example 1 to give 27.6 g (89% yield) of a colorless liquid product.

Example 4

Diethyl para-fluorobenzylmethylmalonate (III)

250 ml of ethanol was gradually added to 11.5 g (0.5 mol) of sodium, and 79.8 g (0.49 mol) of diethylmalonate was slowly added dropwise to the solution, followed by heating and stirring for 1 hour. 59.3 g (0.41 mol) of para-fluorochloride (II, X-Cl) was slowly added dropwise to the reaction mixture, followed by heating to reflux for 2 hours. The resulting ethanol is distilled off, then ether is added, washed with water, saturated brine and dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate removed to give 100 g (91% yield) of the diethyl para-fluorobenzylmalonate as a colorless liquid.

nmr (CDCl ₃ ) ppm: 6.73-7.33 (m, 4H), 4.11 (q, 4H), 3.63 (t, 2H), 3.18 (d, 1H), 1.14 (t, 6H)

100 g (0.37 mol) of diethyl para-fluorobenzyl malonate obtained was slowly added to a mixed solution of sodium 10.3 g (0.45 mol) and 250 ml of ethanol, and 105 g (0.74 mol) of methyl iodine were added thereto, followed by stirring at room temperature for 3 hours. After distilling off ethanol, ether is added, water and saturated brine are washed and dried over magnesium sulfate. Magnesium sulfate is filtered off, the filtrate is removed and the residue is distilled under reduced pressure to yield 99.1% (95% yield) of a colorless liquid product.

Example 5

Para-fluoro- alpha-methylhydroxynamic acid (IV)

Dissolve 60 g (1.30 mol) of Potassium hydroxide in 100 ml of water. 34.75 g (0.12 mol) of diethyl para-fluorobenzyl malonate (III) was added to the solution, and the mixture was heated under reflux for 3 hours. After distillation under reduced pressure, ethanol was removed and 100 ml of water was added thereto. 12N hydrochloric acid was slowly added to the above solution, and the solution was heated to reflux for 16 hours at a pH of 2 or less. After the reaction is cooled, the reaction product is extracted with ether, and the ether solution is washed with water and saturated brine and dried over magnesium sulfate. After filtration to remove the magnesium sulfate, the filtrate was distilled off, and the remaining residue was distilled under reduced pressure (135 ° C.-136 ° C./4 mmHg) to give 20.36 g (91% yield) of a colorless liquid.

nmr (CDCl ₃ ) ppm: 12.1 (s, 1H), 7.01 (m, 4H), 2.82 (m, 3H), 1.18 (d, 3H)

Example 6

Para-fluoro-alpha-methylhydrocinnamic acid (IV)

5 g of salt is added to 40 ml of dimethyl sulfoxide with water and heated to 100 ° C. while stirring. 4.06 g (0.014 mol) of diethyl para-fluoromethylmalonate (III) was added dropwise to the solution, and the mixture was heated to 160 ° C and stirred for 5 hours. After the reaction is cooled, the salt is filtered off and the organics are extracted with ethyl acetate. The ethyl acetate solution is washed with water and saturated brine and dried over magnesium sulfate. Filtration removes the magnesium sulfate and distills ethyl acetate to give 2.93 g (80% yield) of colorless liquid ethyl para-fluorobenzylmethylacetate.

nmr (CDCl ₃ ) ppm: 7.07-7.61 (m, 4H), 4.40 (q, 2H), 2.78-3.37 (m, 3H), 1.37-1.60 (m, 6H)

Analysis of C ₁₂ H ₁₅ O ₂ F

Calculated Value: C; 68.55, H; 7.19, O; 15.22

Found: C; 68.42, H; 7.22, 0; 15.40

2.10 g (1 mol) of ethyl para-fluorobenzylmethyl acetate as the above product is added to 10 ml of 10N sodium hydroxide aqueous solution, and the mixture is heated and stirred for 2 hours. After the reaction, 10 ml of water was added, and then 12N hydrochloric acid was added slowly to make the pH of the solution 2 or less, and the organics were extracted with ether. The ether solution is washed with water and saturated brine and dried over magnesium sulfate. After filtration to remove the magnesium sulfate, the filtrate was distilled to yield 1.73 g (95% yield) of a colorless liquid.

Example 7

6-Fluoro-2-methylindanone (V)

100 g of polyphosphoric acid was heated to 50 ° C., and then 10.8 g (0.059 mol) of para-fluoro-alpha-methylhydrosinamic acid (IV) was slowly added dropwise thereto. The reaction is stirred for 2 hours while maintaining the temperature of 65 ° C. 600 ml of ice water was added to the mixed solution, the mixture was stirred for 30 minutes, and the organics were extracted with ethyl acetate. The organic solution is washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated salts in this order and dried over magnesium sulfate. Filtration removes the magnesium sulfate, and the filtrate is distilled under reduced pressure to yield 9.0 g (92.8% yield) of a colorless solid.

m. p. : 33 ℃

nmr (CDCl ₃ ) ppm: 7.30 (m, 3H), 2.57-3.65 (m, 3H), 1.31 (d, 3H)

Example 8

6-fluoro-2-methylindanonone (V)

6 g of polyphosphoric acid and 10 ml of xylene were added and stirred while heating to 70 ° C. Para-fluoro-alpha-methylhydrosinamic acid (IV) was dissolved in 5 ml of xylene and slowly added dropwise to the solution. The reaction is stirred for 2 hours while maintaining the temperature at 70 ° C. Extract the product according to the method of example 7 to give a colorless solid (89% yield)

Example 9

6-fluoro-2-methylindanon (V)

40 ml of methanesulfonic acid are heated to 65 DEG C, 5 g of para-fluoro-alpha-methylhydrosinamic acid (IV) is added thereto, followed by stirring for 2 hours. Purification of the product according to the method of Example 7 after addition of 500 ml of ice water yielded a solid product (69% yield).

Example 10

6-fluoro-2-metindanonone (V)

1 g of para-fluoro-alpha-methylhydrosinamic acid (IV) was added to 15 ml of benzene and heated to reflux. 4 g of phosphorous pentoxide was added to the solution and allowed to react for 2 hours. After adding 40 ml of ice water, the product was purified according to the method of Example 7 to obtain a solid product (72% yield).

Example 11

5-Fluoro-2-methyl-indenyl acetate (VI)

45 g (0.69 mol) of zinc powder was added to 180 ml of a mixed solution of benzene and ligroin (volume ratio 3: 1), and the mixture was heated to reflux for half an hour after adding a catalytic amount of iodine. After the reaction was cooled to room temperature, 3.9 g (0.02 mol) of ethyl bromoacetate and 13 g (0.08 mol) of 6-fluoro-2-methylinnon were added thereto, followed by heating gradually with stirring. After the reaction was initiated, the remaining 19 g (0.11 mol) of ethyl bromoacetate was added dropwise. After heating to reflux for two hours, the organic solvent was washed with 100 ml of 20% sulfuric acid solution, and 300 ml of 205 sulfuric acid solution was added and stirred at room temperature for 48 hours. The organic solvent is separated, washed with water, saturated aqueous sodium bicarbonate solution and saturated brine in that order and dried over magnesium sulfate. After filtration to remove the magnesium sulfate, the filtrate was removed by forced distillation to yield 15.28 g (82.4% yield) of a white solid.

m. p. : 166-167 ℃

nmr (DMSO-d ₆ ) ppm: 6.73-7.52 (m, 3H), 3.61 (s, 2H), 3.31 (s, 2H), 2.10 (s, 3H)

Example 12

5-fluoro--2-methylindene-3-acetic acid

15.28 g (0.07 mol) of ethyl 5-fluoro-2-methyl-3-indenyl acetate (VI) was dissolved in a mixed solution of 10 ml of 2N aqueous potassium hydroxy solution and 10 ml of ethanol, and then 100 ml of 10 N aqueous potassium hydroxy solution was added thereto. After the addition, the mixture was heated to reflux for 6 hours with stirring. Distillation under reduced pressure to remove ethanol and water. The aqueous solution is washed with ether and the pH is lower than 2 with 6N hydrochloric acid solution. Filtration of the resulting solid precipitate yielded 12.2 g (90% yield) of the product.

m. p. : 166-167 ℃

nmr (DMSO-d ₆ ) ppm: 6.73-7.52 (m, 3H), 3.61 (s, 2H), 3.31 (s, 2H), 2.10 (s, 3H)

Example 13

Para-methylsulfinylbenzaldehyde

8.35 g (0.04 mol) of periodic acid are added to a mixed solution of 250 ml of water and 50 ml of acetone and cooled to -5 ° C. 5 g (0.03 mol) of para-methylthiobenzaldehyde is dissolved in a mixture of 50 ml of acetone and 250 ml of methanol and slowly added dropwise thereto. Stir for 48 hours while maintaining the reaction temperature at -5 ℃. Acetone and methanol are removed by distillation under reduced pressure, methylene chloride and water are added, and the organic layer is extracted. The organic layer was washed with water and distilled under reduced pressure to yield 4.55 g (82%) of a white solid.

m. p. : 90-91 ℃

nmr (CDCl ₃ ) ppm: 10.17 (s, 1H), 8.01 (Qq, 4H), 2.83 (s, 3H)

Example 14

Para-methylsulfinylbenzaldehyde

3.21 g (0.01 mol) of periodic acid is added to 30 ml of water and cooled to 1-2 ° C. Para-methylthiobenzaldehyde 1.4g was added to the solution, followed by stirring for 2 hours. The precipitate is filtered off and the aqueous solution is extracted with methylene chloride. The organic layer is washed with water and saturated brine in that order and dried over magnesium sulfate. Filtration removes the magnesium sulfate and the solvent is removed to yield 1.52 g (98% yield) of a white solid.

Example 15

Para-methylsulfinylbenzaldehyde

2.5 g of 30% hydrogen peroxide is added to 25 ml of acetone and cooled to -5 ° C. 1 g of para-methylthiobenzaldehyde was added to the solution, followed by stirring for 2 hours. Acetone is removed by distillation under reduced pressure and the product is extracted according to the method of Example 14 (75% yield).

Example 16

Para-methylsulfinyl benzaldehyde

10.12 g of 8% chlorine peroxide is added to 20 ml of acetic acid and cooled to -10 ° C. 1.2 g of para-methylthiobenzaldehyde was slowly added to the solution, followed by heating for 2 hours. Acetic acid is removed by distillation under reduced pressure and the product is extracted according to the method of Example 14 (69% yield).

Example 17

Cis-5-fluoro-2-methyl-l- (para-methylsulfinylbenzylidene) -3-indenylacetinic acid

25 ml of methanol was slowly added to 0.51 g (0.02 mol) of sodium thorium, and the mixture was heated and stirred for 1 hour. After the reaction solution was cooled to room temperature, 5.49 g (2.1 mmol) of 5-fluoro-2-methylindene-3-acetic acid was added thereto, followed by stirring at 60 ° C for 2 hours. Para-methylsulfinylbenzaldehyde 0.59 (3.0 mol) was added to the solution, followed by stirring at 60 ° C. for 2 hours. After the reaction is completed, methanol is removed, 200 ml of water is added, and the pH of the aqueous solution is adjusted to 2 or less with 12N hydrochloric acid. The resulting solid was filtered and recrystallized with ethyl acetate to yield 0.77 g (91% yield) of a white solid.

m. p. : 181.5 ℃ -183.5 ℃

nmr (DMSO-d ₆ ) ppm: 7.72 (q, 4H), 7.32 (s, 1H), 7.19 (t, 1H), 6.97 (d, 1H), 6,66 (t, 1H), 3.55 (s, 2H), 2.82 (s, 3H), 2.18 (s, 3H)

Claims (5)

Compound (III) is prepared from the compound of formula (II), compound (III) is prepared from the compound of formula (III), and the compound of formula (IV) is polyphosphoric acid, polyphosphoric acid, benzene, and xylene. , To react with a mixed solution of toluene or methanesulfonic acid or phosphorous pentoxide to prepare a compound of formula (V), and the compound of formula (V) in the mixed solvent of apolar solvents of benzene, toluene, xylene and ligroin Compound (VI) is prepared by reacting the powder with ethyl bromoacetate and treated with sulfuric acid to prepare a compound of formula (VI), and the compound of formula (III) and compound of formula (C) in an alcoholic solvent. A method for producing an indeneacetic acid derivative of structural formula (I) to react.

In formula (II), X is a halogen atom such as chromo, bromo or a sulfonate derivative such as tosylate, methanesulfonate. The method according to claim 1, wherein the method for preparing the compound of the general formula (III) with the compound of the general formula (II) is a reaction of the compound of the general formula (II) in the presence of an alkali metal in diethylmethylmalonate and an alcohol solvent. A method for producing the indeneacetic acid derivative of (I). The method according to claim 1, wherein the method for preparing the compound of the general formula (III) with the compound of the general formula (II) is a reaction of the compound of the general formula (II) with diethylmalonate followed by methyliodine. Method for producing an indeneacetic acid derivative of). The indenacetic acid derivative of formula (I) according to claim 1, wherein the method for preparing the compound of formula (IV) with the compound of formula (III) is heating and refluxing the compound of formula (III) in an aqueous alkali metal hydroxide solution. Manufacturing method. The process of claim 1, wherein the process for preparing the compound of formula (IV) with the compound of formula (III) is carried out by reacting the compound of formula (III) with dimethylsulfoxide and sodium chloride at 120 ° -150 ° C. A method for preparing an indeneacetic acid derivative of formula (I), which is to produce robenzene acetate and then hydrolyze it.