JPH0440337B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula hydrolyzing the compound of the formula and partially decarboxylating it and converting the compound obtained, if desired, into a salt or liberating it from the salt by methods known per se. It relates to a method for producing 2-(3-phenoxy-phenyl)-propionic acid consisting of the following.

The antirheumatic activity of 2-(3phenoxy-phenyl)-propionic acid (Fenoprofen) is known.

Several methods have been disclosed for making this compound. This compound has been prepared, for example, by hydrolyzing 2-(phenoxy-phenyl)-3-propionitrile in 50% aqueous ethanol with sodium hydroxide for 72 hours (Swiss Patent No. 527,155). The starting nitrile is obtained by methylating m-phenoxy-acetophenone, then reducing it to α-methyl-3-phenoxy-benzyl alcohol with sodium hydroxide borate, and then halogenating the resulting product with phosphorus tribromide. α-methyl-3-phenoxy-benzyl bromide,
It was then prepared by reaction with sodium cyanide in anhydrous dimethyl sulfoxide (Swiss Patent No. 527155). According to another method α-methyl-α-(3-phenoxy-phenyl)-
-) Malonic acid is decarboxylated in the melt at 130-160°C. The starting material was α-(3-phenoxy-phenyl)-acetic acid diethyl ester reacted with diethyl carbonate to obtain α-methyl-α-(3-phenoxy-phenyl)-malonic acid diethyl ester, which was dissolved in water in an aqueous alcohol solution. Produced by hydrolysis by boiling with sodium oxide. The reaction mixture in the final step was purified by washing with ether to remove the starting ester, as the hydrolysis was only partial (Swiss Patent No. 527155).

Still another method is as follows.

Reaction of phenoxy-phenylmagnesium bromide with the sodium salt of 2-bromopropionic acid in an ethereal medium (Hungarian patent no.
168376), 1-propynyl-3-(phenoxy)-benzene is reacted with thallium nitrate in the presence of alcohol (Hungarian Patent No. 173576), oxidation of 1-isobutenyl-3-phenoxy-benzene (Spanish Patent No. 464352) and one in which phenoxy-phenylpropionic aldehyde is oxidized with silver oxide (German Patent Publication No. 464352).
No. 2533397).

All of the above methods have one common drawback: they use expensive cresols as starting materials. The present invention provides an economic basis for preparing compounds of the formula from m-phenoxybenzyl cyanide as the starting material. This starting material is prepared from benzyl alcohol by halogenating it and replacing the halogen with cyano.

If a compound of the formula R is amino is used as a starting material, very pure 2-(3-phenoxy-phenyl) can be obtained in a particularly simple manner.
- Propionic acid is produced.

The known method has another drawback that the product obtained needs to be further purified,
This means that the boiling point of the product is 161-171℃/0.11mmHg
and is very high, which causes many difficulties in industrial environments. Further purification of 2-(3-phenoxy-phenyl)-propionic acid is necessary in all known methods. This is because the produced intermediate is also difficult to purify due to its high boiling point.

Also, in pharmaceutical technology, the purity of the starting materials is a fundamental requirement.

According to the invention, 2-(3-phenoxy-phenyl)-propionic acid has the formula:
is amino, ie from 2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide, thereby avoiding further purification of the product. 2-Cyano-2-(3-phenoxy-phenyl)-propionic acid amide is a solid material, which can be purified by simple crystallization if desired, so that a more or less impure starting material is also used. This makes this method economical.

The compounds of the formula used as starting materials in the process of the invention are new compounds.

The compound of formula 2 _- cyano-2-(3-phenoxy-phenyl )-acetic acid
General formula obtained by methylating C _1-6 alkyl ester It can be produced by reacting an ester compound represented by the formula in which R represents C _1-6 alkoxy with a compound suitable for introducing an amino group into the molecule, preferably ammonia, if desired.

Preferably m-phenoxybenzyl cyanide is reacted with diethyl carbonate in an anhydrous organic acid solvent, preferably a lower alcohol, more preferably ethanol, in the presence of an equimolar amount of an alkali alkoxide, preferably sodium ethoxide. .
Surprisingly, carrying out this condensation consists of carrying out the synthesis by elimination of ethanol by removing the alcohol formed by heating with excess diethyl carbonate by continuous azeotropic distillation.
Commonly used methods known from the state of the art for similar reactions (Org.Synth.Coll.Vol.IV.p.461)
It was found that better results were obtained compared to the previous method.

The reaction is carried out in homogeneous solution, thus the reaction time is shorter and 2-cyano-2-(3-phenoxy-phenyl)acetic acid C _1-6 alkyl ester is produced in higher yield and purity. Preferably, 1 to 2.5 moles of diethyl carbonate are used per mole of m-phenoxybenzyl cyanide. The thus produced 2-cyano-2-(3-phenoxy-
The (phenyl)-acetic acid C _1-6 alkyl ester is separated if desired, but is preferably treated with a methylating agent without being isolated. Dimethyl sulfate or methyl iodide is used as the methylating agent. Methylating agents are used in excess of 5-100%. When using 2-cyano-2-(3-phenoxy-phenyl)-acetic acid C _1-6 alkyl ester as the starting material, the starting material is dissolved in a solution of sodium ethoxide, preferably in an equimolar amount of absolute ethanol. and heat with methylating agent.

The ester compound is isolated if desired;
Preferably, it is converted to 2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide without isolation, preferably by reaction in solution with ammonia.

As a solvent, organic solvents such as alcohols,
In particular methanol or ethanol can be used.
The reaction of the 2-cyano-(3-phenoxy-phenyl)-propionic acid alkyl ester takes place in a solvent containing ammonia. The reaction is carried out with or without heating. The reaction is 0~
It can be carried out at a temperature range of 150°C, preferably 20 to 100°C. The compound of the above formula is obtained in substantially theoretical yield and can be easily isolated, if desired, as the product crystallizes out as colorless crystals on cooling.

If the product contains impurities, this can be easily purified by recrystallization from an aqueous alcohol solution.

The compound of the above formula or a solution containing it is preferably hydrolyzed in water or in an aqueous organic solvent mixture in the presence of a base or acid. Mineral acids such as sulfuric or hydrochloric acid, inorganic bases such as alkalis, and alkaline earth metal hydroxides or organic acids or bases can be used. The reaction is preferably accelerated by heating. The product is obtained in approximately the theoretical yield. According to a particularly preferred embodiment of the method, the hydrolysis and partial decarboxylation of the compound of the formula
It can be carried out using an aqueous C _1-4 alcohol solution in the presence of an alkali hydroxide. 2-(3-phenoxy-phenyl)-propionic acid is then obtained by distilling off the excess alcohol and acidifying.
The resulting salt of 2-(3-phenoxy-phenyl)-propionic acid can be obtained in a manner known per se.
Preference is given to producing alkali metal, alkaline earth metal and amine salts. Most preferred are the calcium salts of the compounds. If a salt of 2-(3-phenoxy-phenyl)-propionic acid is obtained during the reaction, the free acid may be liberated from the salt.

The novel compounds of the above formula have anti-inflammatory activity.

The present invention will be illustrated in more detail by the following examples and reference examples, but these examples are merely illustrative and do not limit the present invention.

Reference Example 1 Acetone is no longer detected by using 2,4-dinitro-phenyl-hydrazine in the distillation of a mixture of 189 g of m-phenoxy-benzaldehyde and 1 portion of 1M aluminum isopropoxide in isopropyl alcohol. The mixture was distilled through the column under stirring until 100 ml. Approximately 2-3
It took time. The distillation rate was adjusted so that about 200 ml of distillate could be collected during this time. Excess isopropyl alcohol was then distilled off under vacuum. 500 g of ice and 550 ml of 20% aqueous hydrochloric acid solution were added to the residue. The separated oil was extracted by shaking twice with one portion each of benzene, and the benzene solution was dried over sodium sulfate. When benzene is distilled off, 195g (97.4%)
m-phenoxybenzyl alcohol was obtained. Its purity (as determined by gas chromatography) was greater than 95%.

Reference Example 2 2 ml of pyridine was added to a solution of 200 g of m-phenoxybenzyl alcohol dissolved in 1 part of dry chloroform, and 142.8 g of thionyl chloride was dissolved in 150 g of thionyl chloride.
A solution dissolved in ml of chloroform was added dropwise while cooling with ice water. After the addition was complete, cooling was stopped and the solution was allowed to warm to room temperature under stirring and this temperature was maintained under stirring until vigorous gas evolution ceased. Then,
The mixture was boiled under stirring until gas evolution completely stopped. The solution was then poured into 2 cold water, the chloroform layer was separated and the water bath was shaken in 400 ml of chloroform. The combined chloroform solutions were washed once with water and dried over sodium sulfate. The drying agent was removed by filtration, and chloroform was distilled off to obtain 210 g (96%) of m-phenoxybenzyl chloride. It could be distilled at 128-130℃ under a pressure of 0.3mmHg. Virtually no initial residue or residue was obtained.

Reference example 3 218g of m-phenoxybenzyl chloride was
In a solution dissolved in ml 96% ethyl alcohol,
A solution of 57.8 g of sodium cyanide in 100 ml of water was added in one portion. The reaction mixture was boiled until no starting material was detected by thin layer chromatography. After the reaction was completed, the reaction mixture was poured into 1 portion of water, and the separated oil was extracted three times with 500 ml of benzene each time. Combine benzene solution,
It was washed with 1 water and dried over sodium sulfate.
Sodium sulfate was removed by filtration, and benzene was distilled off. 190 g (91%) of m-phenoxybenzyl cyanide was obtained. (>90% purity as determined by gas chromatography). Boiling point: 138
°C/0.2mmHg.

Reference Example 4 To a solution of 23 g of sodium dissolved in 500 ml of absolute alcohol were added 209 g of m-phenoxybenzyl siaide and 260 g of diethyl carbonate.
The reaction mixture was boiled for 2.5 hours with stirring, then it was poured into 3.5 ml of water and acidified with 58 ml of acetic acid. The separated oil was extracted by shaking twice with 500 ml of chloroform. The combined chloroform solutions were dried over sodium sulfate and evaporated. 2-(3-
The oily residue consisting of ethyl phenoxy-phenyl-3-cyanoacetate was distilled off under vacuum.

Boiling point: 187-192°C/ _0.2mmHg ; ^n27D ; 1.5568.

Similarly, by substituting 183 g of dimethyl carbonate for diethyl carbonate, (3-phenoxy-phenyl-cyanoacetic acid) was obtained (74%).

Boiling point: 178-182℃/ _0.2mmHg ; ^n25D ; 1.5015.

Reference Example 5 209 g of m-phenoxybenzyl cyanide and 260 g of dimethyl carbonate were added to a solution of 23 g of sodium dissolved in 500 ml of absolute alcohol.
The reaction mixture was boiled under stirring for 3 hours, 126 g of dimethyl sulfate was added portionwise while cooling, and the mixture was boiled under stirring for a further 5 hours. Most of the alcohol was distilled off and the residue was mixed with 3 water.
2-(3-phenoxy-
(phenyl)-2-cyanopropionic acid ethyl ester was extracted with three 500 ml portions of benzene. The benzene solution was dried over sodium sulfate and then evaporated under vacuum. Pour 250 ml of 15% ammonia-containing methanol into the residue and stir the mixture in a pressure tube at 90-
The temperature was kept at 100°C for 3 hours. The reaction mixture was treated as in Reference Example 6 and thus 220
g (92.5%) of 2-(3-phenoxy-phenyl)
-2-cyanopropionic acid amide was obtained. Melting point: 128-130℃.

Reference example 6 90g of 2-(3-phenoxy-phenyl)-2-
90ml 15% of cyanopropionate ethyl ester
The ammonia-containing methanol solution was kept in a pressure tube at 90-100°C for 3 hours. By this time, the starting ester was no longer detectable by thin layer chromatography. The solution was cooled and the precipitated crystals were filtered off with suction and dried. 69g (85%) of 2-
(3-phenoxy-phenyl)-2-cyanopropionic acid amide was obtained. Melting point: 128-130℃. A further 11 g of product was obtained by evaporating the mother liquor. Melting point: 123-125℃. Total yield: 98.5
%. After recrystallization from 50% aqueous alcohol, the product melts at 134-135°C.

Elemental analysis (as C ₁₆ H ₁₄ N ₂ O ₂ ): Calculated values: C% = 72.16; H% = 5.26; N% =
10.52; Experimental value: C%=71.88; H%=5.40; N%=
10.43;.

NMR (in CHU ₃ ): 1.9ppm (methyl 3H),
6.15 ppm (NH ₂ 2H), 6.7-7.5 ppm (aromatic protons) 9H) 2- (3-phenoxy-
Phenyl)-2-cyanopropionic acid amide was obtained.

Melting point: 123-125℃.

Reference Example 7 Follow the same method as in Reference Example 6, but
Instead of heating, the reaction mixture was heated at room temperature in a closed container.
It was left for 48 hours. 90g of 2-(3-phenoxy-
78 g (98%) of 2-(3-phenoxy-phenyl)-2-cyanopropionic acid ethyl ester
Phenyl)-2-cyanopropionic acid amide was obtained.

Example 1 106.4 g of 2-(3-phenoxy-phenyl)-
A mixture of 2-cyanopropionic acid amide, 200 ml of 40% aqueous sodium hydroxide solution and 400 ml of alcohol was boiled under stirring for 20 hours. Then,
The alcohol was distilled off and the residue was diluted with 200 ml of water.
The aqueous solution was acidified to PH1 by addition of concentrated hydrochloric acid.
The separated oil was extracted three times with 500 ml portions of benzene. The benzene solution was dried over sodium sulfate and then evaporated. Thus, 96 g (98.5%) of 2-
(3-Phenoxy-phenyl)-propionic acid was obtained. This product was suitable for making salts without further purification.

Example 2 90 g of crude 2-(3-phenoxy-phenyl)-2-propionic acid prepared according to Example 1 were
ml of 0.5N sodium hydroxide solution. The pH of the solution was 7-8. Treat the solution with decolorizing charcoal, add 370 ml of alcohol, and heat the mixture to 70°C.
heated to. At this temperature, 100 ml of 2M aqueous calcium chloride solution was added dropwise under stirring within 30 minutes. The solution containing the crystalline precipitate was allowed to cool to room temperature while stirring. The mixture was then left in ice water for several hours,
The white crystals were then filtered off by suction, washed twice with 100 ml of 30% aqueous alcohol solution, and air-dried.

90 g (86.5%) of the calcium salt of 2-(3-phenoxy-phenyl)propionic acid were thus obtained. Melting point: 115-120℃.

Reference Example 8 To a solution in which 8.85 g of sodium was dissolved in 175 ml of absolute alcohol, 108.5 g of 2-(3-phenoxy-phenyl)-2-cyanoacetic acid ethyl ester was added little by little and 48.7 g of dimethyl sulfate. . The reaction mixture was stirred at room temperature until the exothermic reaction was completed, then it was boiled for 5 hours. The reaction mixture was cooled and poured into 2 portions of water. The separated oil was extracted three times with 250 ml portions of chloroform. The combined chloroform solutions were washed with water and dried over sodium sulfate. Evaporate the chloroform solution 2-
The residue consisting of (3-phenoxy-phenyl)-2-cyanipropionic acid ethyl ester was distilled off under vacuum.

Melting point: 155-157℃/ _0.05mmHg , ^n25D : 1.5490.

2 when using 103 g of m-phenoxy-phenylcyanoacetic acid methyl ester as the starting material.
-(3-phenoxy-phenyl)-2-cyanoporpionic acid methyl ester was obtained. Yield: 82.5
%, melting point: ₁₇₄ ℃/0.1mmHg, ^n26D : 1.5520.

Reference Example 9 The reaction was carried out as described in Reference Example 8, except that dimethyl sulfate was replaced with 88 g of methyl iodide. The product obtained was identical to the product prepared according to Reference Example 8.

Claims (1)

[Claims] 1 formula A hydrolysis process consisting of hydrolyzing and partially decarboxylating a compound of Purity of 2-(3-phenoxy-phenyl)
- A method for producing propionic acid and its salts. 2. The method according to claim 1, wherein the reaction is carried out in water or in a mixture of water and an organic solvent. 3. The method according to claim 2, wherein the organic solvent is a C _1-4 alcohol. 4. The method according to claim 1, 2 or 3, wherein the reaction is carried out in the presence of an acid or a base. 5. The method according to claim 4, in which alkali hydroxide or sulfuric acid is used as the acid or base.