JPS6011439A - Production of 2-arylalkylcarboxylic acid compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a non-steroidal antiinflammatory agent, with reduced number of steps, in high yield, by reacting a cyanoacetic acid ester with a halogen-substituted aromatic compound, reacting the reaction product with a lower alkyl iodide, and hydrolyzing the product. CONSTITUTION:The objective compound of formula IV (e.g. flurbiprofen) is prepared by (1) reacting the cyanoacetic acid ester of formula I (R<1> is alkyl) with the nucleus halogen-substituted aromatic compound of formula R<2>-X(R<2> is aryl; X is Br or I) in a solvent selected from hexamethylphosphoric acid triamide and N-methylpyrrolidone, in the presence of a catalyst comprising (a) a strong base and (b) copper ( I ) bromide, copper (II) bromide and /or copper ( I ) iodide, or copper and bromine and/or iodine, (2) reacting the resultant 2-aryl-2-cyanoacetic acid ester compound of formula II with lower alkyl iodide in the presence of a strong base to obtain 2-aryl-2-cyanoalkylcarboxylic acid ester compound of formula III, and (3) hydrolyzing the compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2
-Regarding a novel method for producing arylalkylcarboxylic acid compounds.

2-arylalkylecarboxylic acid compounds, such as ibuprofen and flurbiprofen, are often used as anti-inflammatory analgesics after rheumatoid arthritis or minor dental surgery.

Conventionally, many methods for producing 2-arylalkylcarboxylic acid compounds have been proposed. Among these manufacturing methods, a typical manufacturing method using an acetophenone compound as a raw material (Special Publication No. 4B-2229
No. 7 is shown in a series of reaction formulas (in the above formula, R represents a substituted or unsubstituted aryl group).

However, the production method consisting of the steps represented by the above reaction formulas has many steps as described above, and the yield is low, so it is not advantageous from an industrial standpoint.

In addition, manufacturing methods other than those described above involve many steps similar to the above manufacturing method, and cannot be said to be advantageous from a technical standpoint.

An object of the present invention is to provide a novel method for producing a 2-arylalkylcarboxylic acid compound that solves the above problems and requires fewer reaction steps and has a high yield.

The object of the present invention is to (a) hexamethylene phosphoric acid triamide and N-methoxy V;
In at least one solvent selected from pyrrolidone, a cyanoacetate represented by the general formula: (wherein, R1 represents a lower alkyl group), a strong base, and the general formula: (wherein, R1 is substituted or unsubstituted). (i) Bromination: jM (1), copper bromide (11) and iodized steel (I ), or (→at least one selected from bromine and iodine).

and by reacting in the presence of copper, a 2-aryl-2-leanoacetic acid ester compound represented by the general formula: % formula % (in the formula, R1 and R3 are the same as above) is synthesized, and The 2-ary-furey 2-cyanoacetate compound obtained in (a) is reacted with a strong base and lower alkyl iodide to form a general formula: (wherein, R1 and R'' are the same as above, R3 is lower alkyl V 2-aryl-2-cyanoalkylcarboxylic acid ester compound represented by This can be achieved by obtaining a 2-ary M alkyl I recarponic acid compound represented by the following formula (wherein R1 and R3 are the same as above).

A reaction formula of a production example for preparing rebiprofen and ibuprofen using the production method of the present invention is shown below, and (a), (h) and (C) are each of the reaction steps (a), This is an example of ibuprofen production.

That is, the present invention provides halogen (
3) is converted into a carboxylic acid-containing group represented by the general formula; The purpose is to obtain a 2-ary M alkyl calebonic acid represented by:

The production method of the present invention is an excellent industrial production method with fewer reaction steps as described above, compared to the conventional method.

(a) A halogen-substituted aromatic compound (R''-X) is a halogen-substituted aromatic compound (R''-X) in which a halogen (X'- In the present invention, the halogen refers to bromine or iodine.

Specific examples of nuclear halogen-substituted aromatic compounds include CHs OCIt+ 0 CHz CHs Hs. Bromine compounds corresponding to the iodine compounds exemplified above can also be used in the production method of the present invention.

(a) As a catalyst in the reaction step (i) Copper bromide (1), copper bromide (U) and copper iodide (1)
At least one selected from (1) or (1) at least one selected from bromine and iodine and copper are used. is 0
．． It is used in a quantitative ratio of 8 to 37V.

(3) and (b) In the reaction process, a strong base is a strong base that has the ability to remove hydrogen cations from carbon atoms to which electron-withdrawing groups (e.g., cyano groups, V-boxyl groups, etc.) are bonded and generate carbon anions. Generally, sodium hydride or sodium amide is used, and in the (a) reaction step, the cyanoacetate has a
．． 1 to 10-11: preferably in a quantitative ratio of 0.5 to 3 moles, and in the (+) reaction step, 0.1 to 1 moV of the 2-1 lyl-2-cyanoacetate compound.
It is used in a quantitative ratio of 1 to 7M, preferably 0.5 to 3 mol.

(a) and (b) As the reaction solvent in the reaction steps, the aprotic polar solvent hexamethylphosphoric acid triamide or N
- Methyflepyrrolidone is used. These aprotic polar solvents can be used alone or in combination with other aprotic polar solvents. Other aprotic polar solvents include dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane, glymes, and the like.

Since the same reaction solvent can be used in the reaction steps (a) and (b), the 2 produced after the completion of the reaction steps (a)
The reaction step (b) can be carried out directly without isolating the -aryl-2-sia/acetic acid ester M compound. Further, if necessary, after the 2-ary/L/-2-cyanoacetate compound produced in the reaction step (a) is isolated, the reaction step (b) can be carried out again.

(b) The amyl iodide used as an alkylating agent in the reaction step is the 2-ary/I/
-2-cyanoacetic acid ester compound is usually 0.
It is used in a quantitative ratio of 5 to 5 moles.

The reaction temperature in the reaction step (a) is 70 to 140°C, preferably 80 to 100°C, and the reaction time is usually within 12 hours.

The reaction temperature in the (b) reaction step is preferably 10 to 80°C, preferably 30 to 60°C, and the reaction time is usually within 3 hours.

(a) In the reaction step, a direct strong base and cyanoacetic acid nysester are first reacted to form a compound with the general formula diCHCOO.
A carbon anion represented by R+N (wherein R1 is the same as above) is generated, and then a catalyst and a nuclear halogen-substituted aromatic compound are added and reacted.

Further, in the reaction step (b), similarly to the above, a usually strong base and a 2-hour/l/-2-cyanoacetate compound are first reacted to form a compound of the general formula: (wherein R1 and R1 are the same as above). ) is generated, and then a catalyst and a lower alkyl iodide are added to carry out the reaction.

In the reaction step (C), the 2-hour/l/-2-cyanopropionic acid ester compound produced in the reaction step (b) is hydrolyzed in an acidic or alkaline aqueous solution.

Acidic aqueous solutions are acids such as hydrochloric acid and sulfuric acid diluted with water;
The alkaline aqueous solution is an alkali solution such as sodium hydroxide or potassium hydroxide diluted with water, and although the concentration is not particularly limited, it is preferable that both acid and alkaline aqueous solutions have a concentration of 5%.
~20 regulations.

The reaction temperature in the reaction step (C) is 80 to 150''C, preferably 1.10 to 100C, and the reaction time is within 15 hours.

Next, examples will be shown to illustrate the present invention in a basic manner.

Add 0.2% sodium hydride to a 20d three-necked flask equipped with 2% reflux cooling, a thermometer and a nitrogen gas inlet.
9 F (12 mmol) was added, and 12 d of hexamethyl phosphoric acid triamide was added and stirred with a magnetic stirrer.
Furthermore, ethyl cyanoacetate M1, 47 f was added to the nitrogen atmosphere.
(13m mol) was cooled and added with Shinakara.

Next, copper iodide (1) 2.29 (1 (12 mmol)
and 2-fluoro-4-iodobiphenyl 1.71f
(6ffimol) was added, heated to around 95°C, and reacted for 3 hours while stirring with a magnetic stirrer.

After the reaction was completed, the simmering mixture was poured into 5% hydrochloric acid, and the product was extracted with benzene. The extract was washed successively with an aqueous sodium sulfite solution and water, dried over sodium sulfate, and then the solvent was removed under reduced pressure. The residual aroma is recrystallized with hexane color, and 2-<2
-Fluorobiphenyl A/-4-yl)Crystals of ethyl cyanoacetate M (melting point: 47-48°0) 1.55 g (5
, 5 mmol) was obtained. The yield was 91%.

In a three flask similar to (-) above, 0.05 g (2 mmol) of sodium hydride, hexamethylene M phosphoric acid triamide 2-, and the 2-(2-7!leolobiphenyl-4-yl)cyano prepared in (a) above. Ethyl acetate 0.288
p (1 mmol) was added in order.

The mixture was then heated to 40-50°C and stirred with a magnetic stirrer for 15 minutes.

The reaction mixture was cooled to room temperature and 0.2889 methyl iodide
(2 mmol) was added and stirred for 1 hour, then heated gently and kept at 40-45°C for 16 minutes.

After the reaction was completed, the reaction mixture was poured into 5% hydrochloric acid, and the product was extracted with benzene. The extract was washed successively with an aqueous sodium sulfite solution and water, dried over sodium sulfate, and then the solvent was removed under reduced pressure. The residual aroma is recrystallized with hexane color, and 2-(2
-Fluorobiphenyl-4-yl)-2-cyanopropionate crystals 0.282F (0.95vr m
ol) was obtained. The yield was 95%.

2-(2-fluorobiphenyl- obtained in (b) above)
Ethyl 4-yl)-2-cyanopropionate 0,282
9 (0.95 mmol) with 2 d of water and 2 d of concentrated sulfuric acid
d was added and heated at 125 to 130°C for 10 hours to perform a hydrolysis reaction. Thereafter, it was cooled to room temperature and the penzesimo product was extracted. The extract was washed with water, dried, and then benzene was removed under reduced pressure, and the residue was passed through a silica gel column (20 mm + x 50 mm) using dichloromethane as an eluent.

Next, after removing dichloromethane, recrystallization was performed using hexane as a solvent to obtain 2-(2-fluorobiphenyl-4-yl).
-10 pionic acid (melting point: 118-116°C) (flurbiprofen) 0.2161 (0,885 mtool
) was obtained. The yield was 93%.

The yield of raw material 2-fluoro-4-iodobiphenyl through the above reaction steps (a), (b) and (C) is 80%.
%Met.

A 20 ml Euphro flask equipped with a reflux condenser, thermometer and nitrogen gas inlet was charged with 0.0% sodium hydride.
Next, hexamethylphosphoric acid triamide 1- was added and stirred with a magnetic stirrer, and then 0.45y (4m mol) of ethyl cyanoacetate was added under nitrogen atmosphere.
mol) of hexamethylphosphoric acid triamide (2,5q/
) solution was added dropwise. Over a period of 10 minutes, the cloudy white reaction mixture turned into a clear solution. A solution of 0.529 (2*mol) of 4-isobutyl iodobenzene in hexamethylphosphoric acid triamide (llfl!) and 0.762F (4 mmol) of copper (T) iodide were successively added to this clear solution. When heating started, the solution turned black and was kept at 90-95°C for 5 hours.

After the reaction was completed, the reaction mixture was poured into 5% hydrochloric acid, and the product was extracted with benzene. The extract was washed successively with an aqueous sodium sulfite solution and water, dried over sodium sulfate, and then the solvent was removed under reduced pressure. The residue was recrystallized from hexane to give 2-(4
-isobutyphenyl)-2-Schiff/ethyl acetate crystals 0
．． 8841 (1,56 mm01) was obtained. The yield is 7
It was 8.

2 ml of hexamethyl-dried acid triamide and 0.10 f (4 mmol) of sodium hydride were gradually added to the 2-(4-isobutyphenyl obtained in (a) above) with stirring. Next, the mixture was heated at 40 to 50°C. and kept for 30 minutes.

Then, it was cooled to room temperature, and 0.57 g of methyl iodide (4 mm
ol) was added and stirring continued for 1 hour. Then again 40
The reaction was completed by heating to ˜45° C. for 15 minutes.

After the reaction was completed, the reaction mixture was poured into 5% hydrochloric acid, and the product was extracted with benzene. The extract was washed successively with an aqueous sodium sulfite solution and water, dried over sodium sulfate, and then the solvent was removed under reduced pressure. The remaining residue was recrystallized with hexane color to obtain 2-(4
Crystals of ethyl -isobutylphenyl)-2-cyanopropionate o,aaif (1,28 mmol) were obtained. The yield was 82%.

(02-(4-isobutylphenyl)propionic acid synthesis 2-(4-isobutylphenyl) obtained in (b) above
-2-cyanopropionate ethyl 0.881F (1,2
Add 2 ml of water and 2 ql of concentrated sulfuric acid to
The mixture was heated at 25-180"C for 10 hours to carry out a hydrolysis reaction. Thereafter, it was cooled to room temperature and the product was extracted with benzene.

After washing the extract with water and drying, benzene was removed under reduced pressure, and the residue was passed through a silica gel column (20) using dichloromethane as an eluent. Next, after removing dichloromethane, hexane was added as a solvent to recrystallize the 2-(4
-isobutylphenyl)propionic acid (melting point = 75-7
7°C) (Ibuprofen) 0,25F (1,2m
mol) was obtained. Yield ki 94% TeS Tatsutatsu (a), (b) and (C) Raw materials 4 through reaction steps
The yield of -isobutyl iodobenzene was 60fo.

Each of the above products was identified by nuclear magnetic resonance analysis.

that's all Patent applicant: Daikin Industries, Ltd.

Claims (1)

[Claims] 1, <2) In at least one solvent selected from hexamethylphosphoric triamide and N-methylpyrrolidone, with the general formula: % formula % (wherein Hr represents a lower alkyl group). Cyanoacetic ester, strong base and general formula represented by
indicates bromine or iodine. ) A nuclear halogen-substituted aromatic compound represented by (i) copper bromide (+), copper bromide (1) and iodized steel (at least one selected from O, or Q selected from bromine and iodine) By reacting in the presence of at least one type of compound and copper, 2-ary-fV-2-cyanomonoacetic acid ester represented by the general formula: % formula % (wherein R1 and R'' are the same as above) (b) The 2-aryl-2-cyanoacetic acid ester compound obtained in (a) above was reacted with a strong base and lower alkyl iodide to obtain the general formula: %formula% (wherein R1 and R8 is the same as above, R3 is lower grade A V
Indicates a V group. ) 2-Aryl-2-Schif/・Aki? A general formula consisting of synthesizing Reka M ponate ester V compound and hydrolyzing it to (C) the 2-aryl-2-cyanoalkyl kyafonic acid ester compound obtained in (IJ) above: % formula % (formula A method for producing a 2-arylalkylcarboxylic acid compound represented by (where R1 and R8 are the same as above).