JPH0324468B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula This invention relates to a novel compound represented by and a method for producing the same.

According to the method of the present invention, the compound represented by the general formula
React with C _1-6 alkyl in the presence of a basic catalyst,
The thus obtained 2-cyano-2-(3-phenoxy-phenyl)-acetic acid C _1-6 alkyl ester is methylated, and the obtained compound is preferably a compound suitable for introducing an amino group into the molecule. It can be produced by reacting with ammonia.

According to a preferred embodiment of the invention, m-phenoxybenzyl cyanide is prepared in an anhydrous organic solvent, preferably a lower alcohol, more preferably ethanol, with diethyl carbonate in an equimolar amount of an alkali alkoxide, preferably sodium ethoxy react in the presence of Surprisingly, carrying out this condensation consists of carrying out the synthesis by elimination of ethanol by removing by continuous azeotropic distillation the alcohol formed upon heating together with excess diethyl carbonate. A commonly used method known from the state of the art for similar reactions (Org.Synth.
Coll.Vol.IV.p.461).

According to the invention, the reaction is carried out in a homogeneous solution, thus resulting in shorter reaction times and 2-cyano-2-(3-phenoxy-phenyl)-acetic acid.
C _1-6 alkyl esters are produced in higher yield and purity. Preferably, 1 to 2.5 moles of diethyl carbonate are used per mole of m-phenoxybenzyl cyanide. 2-cyano-2- thus produced
The (3-phenoxy-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%. 2-cyano-2-(3-
When using C _1-6 alkyl phenoxy-phenyl-acetic acid ester, the starting material is dissolved in a solution of sodium ethoxide, preferably in an equimolar amount of anhydrous enol, and heated with the methylating agent. The resulting compound is isolated if desired, but preferably without isolation, preferably by reaction in solution with ammonia to form the 2-cyano-2-(3-phenoxy-phenyl)-propionic acid amide. Used in the production of

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. Reaction is 0-150
It can be carried out at a temperature range of 20 to 100°C, preferably 20 to 100°C. Compounds of the general formula containing NH ₂ as R are obtained in essentially theoretical yields 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 compounds of the present invention represented by the general formula have anti-inflammatory activity. Furthermore, the compound of the present invention is 2-(3
-phenoxy-phenyl)-propionic acid can be advantageously used.

The antirheumatic activity of 2-(3-phenoxy-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 sodium borohydride α-methyl-3-phenoxy-benzyl alcohol, and then halogenating the resulting product with phosphorus tribromide to obtain α- It was prepared by methyl-3-phenoxy-benzyl bromide and subsequent reaction with sodium cyanide in anhydrous dimethyl sulfoxide (Swiss Patent No. 527155). According to other methods α−
Methyl-α-(3-phenoxy-phenyl)-malonic acid is decarboxylated in the melt at 130-160°C. The starting material was prepared by reacting α-(3-phenoxy-phenyl)-acetic acid diethyl ester with diethyl carbonate.
(phenyl)-malonic acid diethyl ester was obtained and hydrolyzed by boiling with sodium hydroxide in an aqueous alcohol solution. 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-isobutyl-3-phenoxy-benzene (Spanish Patent No. 464352)
and those obtained by oxidizing phenoxy-phenylpropionic aldehyde with silver oxide (German Patent Publication No.
No. 2533397).

All of the above methods have one common drawback: they use expensive cresols as starting materials. According to the present invention, it has been found that 2-(3-phenoxy-phenyl)-propionic acid can be advantageously produced starting from m-phenoxybenzyl cyanide and passing through the compound represented by the general formula.

If a compound of the general formula is used as a starting material, very pure 2-(3-phenoxy-phenyl)propionic acid can be prepared in a particularly simple manner.

Another drawback of the known method is the need for further purification of the product obtained, which makes it difficult to use in industrial environments due to the very high boiling point of the product, 161-171°C/0.11 mmHg. Below, many difficulties arise. Further purification of 2-(3-phenoxy-phenyl)-propionic acid is necessary in all known processes. 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.

2-(3-phenoxy-phenyl)-propionic acid is obtained from the compound of the formula, i.e. 2-
It can be prepared from cyano-2-(3-phenoxy-phenyl)-propionic acid amide, thus 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.

To prepare 2-(3-phenoxy-phenyl)-propionic acid from the compounds of the invention, the compounds are subjected to hydrolysis and partial decarboxylation. In practice, a compound of formula or a solution containing a compound of formula, which may be isolated and purified, is preferably hydrolyzed in water or an aqueous organic solvent mixture in the presence of a base or acid. mineral acid,
For example, sulfuric or hydrochloric acid, inorganic bases such as alkalis, and alkali 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 process, the hydrolysis and partial decarboxylation of the compound of the formula can be carried out in the presence of an alkali hydroxide in an aqueous C _1-4 alcohol solution. Then 2-(3-phenoxy-phenyl)
- Propionic acid is obtained by distilling off excess alcohol and acidifying. The salts of 2-(3-phenoxy-phenyl)-propionic acid are 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 present invention will be illustrated in more detail by the following Examples, Reference Examples, and Application 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 of 1M aluminum isopropoxide in isopropyl alcohol. Distilled through the column under stirring until 100 ml. It took about 2-3 hours. 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. to the residue
500 g of ice and 550 ml of 20% aqueous hydrochloric acid solution were added. The separated oil was extracted by shaking twice with one portion each of benzene, and the benzene solution was dried over sodium sulfate. After distilling off the benzene, 195 g (97.4%) of 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 aqueous layer was shaken in 400ml 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°C under a pressure of 0.3 mmHg. 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 4 209 g of m-phenoxybenzyl cyanide and 260 g of diethyl 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 2.5 hours, 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.

Example 1 To a solution of 23 g of sodium in 500 ml of absolute alcohol were added 209 g of m-phenoxybenzyl cyanide and 260 g of diethyl carbonate.
The reaction mixture was boiled for 3 hours under stirring, 126 g of dimethyl sulfate was added dropwise with cooling, and the mixture was boiled for a further 5 hours under stirring. Most of the alcohol was distilled off and the residue was mixed with 3 water. The 2-(3-phenoxy-phenyl)-2-cyanopropionic acid ethyl ester, which was separated in the form of an oil, 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 for 90~
The temperature was kept at 100°C for 3 hours. The reaction mixture was treated as in Example 2, thus giving 220
g (92.5%) of 2-(3-phenoxy-phenyl)
-2-cyanopropionic acid amide was obtained. Melting point: 128-130℃.

Example 2 90 g of 2-(3-phenoxy-phenyl)-2-
90ml 15% of cyanopropionate ethyl ester
A solution dissolved in methanol containing ammonia was maintained at 90 to 100°C for 3 hours in a pressure tube. 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 solution, 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), 6.15ppm
(NH ₂ 2H), 6.7-7.5ppm (aromatic proton
9H) Following the method described above but using 86 g of 2-(3-phenoxy-phenyl)-2-cyanopropionic acid methyl ester, 2-(3-phenoxy-phenyl)-2-cyanopropionic acid methyl ester
Phenyl)-2-cyanopropionic acid amide was obtained. Melting point 123-125°C Example 3 Follow the same method as in Example 2, 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.

Application example 1 106.4g 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. The alcohol was then 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.

Application example 2 90 g of crude 2-(3-phenoxy-fer)propionic acid prepared according to application example 1 was added to 740 ml of
Dissolved in 0.5N sodium hydroxide solution. of solution
The pH 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 5 To a solution of 8.85 g of sodium dissolved in 175 ml of absolute alcohol were added 108.5 g of 2-(3-phenoxy-phenyl)-2-cyanoacetic acid ethyl ester in portions 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-cyanopropionic acid ethyl ester was distilled off under vacuum.

Boiling point: 155-157℃/0.05mmHg, n ²⁵ _D : 1.5490 2-(3-phenoxy-phenyl)-2-cyanopropionic acid when 103 g of m-phenoxy-phenyl-cyanoacetic acid methyl ester is used as the starting material A methyl ester was obtained. yield:
82.5%, melting point 174℃/0.1mmHg, n ²⁶ _D : 1.5520 Reference example 6 118g of 2-(3-phenoxy-phenyl)-2
- Add 226 ml of 10N to a solution of cyanopropionic acid ethyl ester in 226 ml of ethyl alcohol.
Sodium hydroxide solution was added and the reaction mixture was boiled under stirring until gas evolution ceased. The alcohol was distilled off and the residue was dissolved in water. PH of solution
was adjusted to 1 by addition of concentrated hydrochloric acid. The separated oil was extracted twice with 100 ml each of benzene. The combined benzene solutions were dried over sodium sulfate and then evaporated and the residual 2-(3-phenoxy-phenyl)-propionic acid was distilled under vacuum. Boiling point: 168-171℃/0.1mmHg.

As starting material 113 g of 2-(3-phenoxy-
When using phenyl)-2-cyanopropionic acid methyl ester, 2 with the same physical properties
-(3-phenoxy-phenyl)-propionic acid was obtained.

Reference Example 7 The reaction was carried out as described in Reference Example 5, 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 5.

Reference Example 8 209 g of m-phenoxy-benzyl cyanide and 145 g of diethyl 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 and after cooling, 126 ml
of dimethyl sulfate was added dropwise in small portions and the mixture was boiled for a further 5 hours under stirring. 500ml to reaction mixture
of 10N sodium hydroxide solution was added and the mixture was boiled under stirring until gas evolution ceased. After the reaction was completed, the alcohol was distilled off.
The residue was dissolved in water. The pH of the solution was adjusted to 1 by addition of concentrated hydrochloric acid. The separated oil was taken up in 500 ml of benzene. The benzene solution was dried over sodium sulfate and then evaporated, and the residual 2-(3-phenoxy-phenyl)-propionic acid was distilled off. Boiling point: 168-171°C/0.1mmHg. Yield: 206g (85%).

Claims (1)

[Claims] 1 formula A compound represented by 2 m-Phenoxybenzyl cyanide is converted into dicarbonate.
React with C _1-6 alkyl in the presence of a basic catalyst,
It consists of methylating the obtained 2-cyano-2-(3-phenoxy-phenyl)acetic acid C _1-6 alkyl ester and reacting the obtained compound with a compound suitable for introducing an amino group into its molecule. ,
formula A method for producing a compound represented by 3. The method according to claim 2, wherein the compound suitable for introducing an amino group is ammonia. 4. A process according to claim 2, which comprises preparing the compound of the formula without isolating any intermediate products. 3. A process according to claim 2, comprising reacting 5 m-phenoxy-benzyl cyanide with diethyl carbonate in the presence of sodium alcoholate. 6. The method according to claim 5, wherein the sodium alcoholate is sodium ethylate. 7. A process according to claim 2, comprising methylating the _C1-6 alkyl ester of 2-cyano-2-(3-phenoxy-phenyl)-acetic acid with methyl iodide or dimethyl sulfate.