NO763144L - PROCEDURES FOR THE PREPARATION OF 2-NITRO-3-PHENYL-BENZOFURAN DERIVATIVES. - Google Patents

Description

Procedure for the production of 2-nitro-

'.'3- f phenylbenzofuran derivatives

The present invention relates to a group of hitherto unknown 2-nitro-3-phenylbenzofurans which are substituted in 4-, 5-, 6-

and the 7-position in the benzene ring with a. lower alkanecarboxylic acid group or an ester, an amide, acyl halide or pharmaceutically acceptable salt thereof.

The compounds in question have the character of claim 1. terizing part stated general formula.

There are known 3-phenylbenzofuranalkanecarboxylic acids and

-alkenecarboxylic acids and certain derivatives thereof, which have an anti-inflammatory effect, cf. e.g. US Patent No. 3,682,976

and 3,862,134.

The compound 2-nitro-3-phenylbenzofuran is also known, although no physiological effects have been described.

Certain neutral 2-nitrobenzofurans are also known as antibacterial agents, cf. e.g. French patent document No. 2,081,585 and several publications by Rene Royer et al. However, acidic compounds which combine the structural characteristics of the compounds in question have not been previously described. Based on the formula stated in claim 1, it can be seen that the compounds structurally combine an alkane or alkene carboxylic acid group, a benzofuran ring, as well as a 2-nitro and 3-phenyl group on the benzofuran ring. The free acids are usually white or yellowish to brown crystalline or amorphous substances after purification. They are essentially insoluble in water or aliphatic hydrocarbons and more soluble in lower alcohols, halogenated solvents, benzene, dimethylformamide, etc. The esters and amides are usually somewhat more soluble in organic solvents, while the alkali metal salts have a significant solubility in water and lower alcohols.

All the compounds in question are active against bacteria, and some are also active against other microorganisms, such as fungi and protozoa in vitro and topically. They can thus be used for disinfection and sterilization, e.g. of medical and dental equipment, as components in disinfection solutions. The compounds are particularly useful as antibacterial agents. They are generally also active in vivo in animals. The free acids are preferred for many purposes due to their generally higher antimicrobial effect in vitro, while the salts are normally used where water solubility is important.

The preferred compounds are those where R denotes methylene (-Ct 2 -) because of their high in vivo activity. Other preferred compounds due to their high antimicrobial activity are those where X denotes fluorine and/or chlorine, as well as compounds in which there is a hydrogen atom in the 4-position. The preferred compounds are antimicrobial in vitro and in vivo,

are active by oral administration and provide detectable antimicrobially active concentrations in the blood of mammals. Some of them are active against Staphylococcus aureus in concentrations below 1.0 g/ml. The particularly preferred compounds which have broad antibacterial spectra and good therapeutic ratios LD^^/ ED50 are: 2-nitro-3-phenyl-7-benzofuranacetic acid,

2-nitro-3-phenyl-6-benzofuranacetic acid, 2-nitro-3-phenyl-5-benzofuranacetic acid,

3-(4'-chlorophenyl)-2-nitro-5-benzofuranacetic acid, 3-(4<1->fluorophenyl)-2-nitro-7-benzofuranacetic acid, 3-(4<1->chlorophenyl)-2-nitro -7-benzofuranacetic acid, 2-nitro-3-phenyl1-7-benzofuranacrylic acid,

2-nitro-3-phenyl-5-benzofuranpropionic acid and 2-nitro-3-phenyl-7-benzofuranpropionic acid.

Alkali metal, alkaline earth metal, iron, aluminum and other metal and amine salts are often equivalent to the corresponding compounds in the form of free acids, but offer advantages with respect to solubility, absorption, stability, formulation, etc. The salts are of interest for topical applications, e.g. ophthalmological and dermatological. The alkali metal salts, such as the sodium and potassium salts, are preferred. The esters and amides are also useful for modifying solubility, shelf life, absorption and the like.

Among the important subclasses of the compounds in question can be mentioned those in which R denotes methylene, ethylene, methylmethylene or dimethylmethylene, X denotes methyl or methoxy, fluorine, chlorine or bromine, and compounds where n is 1, as well as where n is 2, and the one or both X denotes halogen, methyl or methoxy, as well as lower alkyl esters, hydroxyalkyl esters and N,N-dialkylaminoalkyl esters, especially the ethyl, hydroxyethyl and N,N-dimethylaminoethyl, glyceryl and methoxymethyl esters.

Compounds in which R is branched can form optically active compounds which are also covered by the invention.

The invention further relates to a method for the preparation of the compounds in question, which, as stated in the characteristic part of claim 17, are characterized by using known starting materials: A: direct nitration of 3-phenylbenzofuranalkane-d alkenecarb oxylic acids of formula II,

B: prepares an intermediate product in the form of a 2-halo-3-phenylbenzofuranalkane or alkenecarboxylic acid of formula III by either 1) carrying out a specific halogenation of the 2-position in a 3-phenylbenzofuranalkane or alkenecarboxylic acid , or 2) to hydrolyze a 2-halogeno-3-phenylbenzofuranalkane acid amide followed by a selective replacement of the 2-halogen atom with a nitro group,

C: carries out an acid hydrolysis of the corresponding 2-nitro-3-phenylbenzofuran alkane or alkene cyanide or ester with the formula IV stated in claim 17, or

D: reduces a cyano-3-phenylbenzofuran to a corresponding 3-phenylbenzofuranaldehyde followed by halogenation and nitration or direct nitration of this aldehyde to 2-nitro-3-phenylbenzofuranaldehyde which is reacted with acetic anhydride to form the corresponding 2-nitro-3-phenylbenzofuran -acrylic acid and, if desired, reduces the double bond in the side chain by catalytic hydrogenation to form the corresponding 2-nitro-3-phenylbenzofuranpropionic acid, and if desired, a free acid formed by one of the methods is transferred into an ester, an amide, an acyl halide or a salt.

The direct nitration process (process A) can be carried out with fuming nitric acid in acetic acid or acetic anhydride

or with dinitrogen tetroxide in an inert solvent such as dichloromethane. To avoid aromatic nitration, moderate temperatures of 0 - 30°C are generally used.

The halogenation step in process B 1 can be a bromination or an iodination. The bromination can be carried out with bromine water, N-bromosuccinimide or preferably bromine in a suitable solvent such as dichloromethane or acetic acid. The bromination is carried out under mild conditions, e.g. at 0 - 30°C to avoid aromatic bromination. The bromine compound can be isolated or use

des without insulation. The isolation can be carried out by extraction, precipitation by adding a solvent such as water, evaporation of volatile reaction components, etc.

The iodination is carried out e.g. with a molecular iodine

in the presence of yellow mercuric(II) oxide in an inert solvent such as benzene. These reactions are generally carried out at 25-125°C, e.g. at the solvent reflux temperature.

The hydrolysis of the 2-halo-3-phenylbenzofuranalkanecyanides in process B 2 is carried out under strongly basic or acidic conditions, e.g. in aqueous alcoholic base at the reflux temperature or in aqueous sulfuric acid at 60 - 175°C.

In the last step in process B, the 2-halogen substituent can be replaced by selective nitrating agents, such as a strong -saltpeter acid solution, e.g. 70% aqueous nitric acid, dinitrogen tetraoxide dissolved in e.g. acetic acid or dichloromethane or a mixture of sodium nitrite and a strong acid. When using 7Q nitric acid as nitrating agent for the 2-halogen derivatives, preferably approx. 2-3 mol sodium nitrite and nitric acid per

moles of benzofuran. There are used approx. 4 - 20 ml acetic acid per g used 2-halobenzofuran derivative depending on its solubility. It is desirable to keep the 2-halobenzfuran derivative dissolved, and

the amount of acetic acid used and the reaction temperature are adjusted so that this result is easily achieved. The reaction temperature is approx. 25 - 100°C, preferably 60 - 80°C, when the halogen used is bromine.

It has been shown that a mixture of sodium nitrite, sulfuric acid and acetic acid will also nitrate the 2-halobenzofuran derivative in the 2-position. The 2-halobenzofuran derivative is dissolved in acetic acid so that it is kept dissolved (approx. 20 ml per g is required), and concentrated sulfuric acid is added in an amount of 2 - 10 ml per g. g benzofuran. Sodium nitrite is then added to the solution in an amount of 2 - 5 mol per moles of benzofuran derivative. The reaction temperature is approx. 20 - 100°C, preferably approx. 55°C. If desired, sodium nitrite can be replaced with other metal nitrites,

such as potassium nitrite.

A combination of dinitrogen tetraoxide in an inert solvent in the presence of an alkene is a preferred nitration method in process B, acetic acid and dichloromethane being the preferred solvents. As a rule, 2-5 liters of acetic acid are used per mole of benzofuran or halobenzofuran and at least 1 mole of ^2^4 ^r" ■mo"'" benzofuran. The exact amount depends on the desired reaction rate, the extent of evaporation and other physical losses, as well as the extent of a competing addition to the saturated olefin. The alkene is preferably used together with a 2-bromo-benzofuran intermediate to remove traces of BrNO2 and minimize the bromination as a side reaction. Cyclohexane is suitable for this purpose. Equimolar amounts of the alkene are preferably used and the N2^4" alkene is chosen so that it is less reactive towards ^O^ than the benzofuran, but more reactive towards BrN02 than the benzofuran.

An acidic alkene, e.g. 3-Cyclohexenecarboxylic acid is advantageous when the nitrated product is neutral. The temperature for these reactions is usually approx. 0 - 80°C, preferably 20 - 45°C at the bromine shift hinge and approx. 0 - 25°C during the iodine replacement and direct nitration. When 2-iodo-benzofurans are used, the alkene is not necessary since iodine is generally non-reactive towards the benzofuran under the reaction conditions, and only a 1/2 mol ^O^theoretic set is required there.

The 2-nitro-3-phenylbenzofuran alkane or alkene carboxylic acid esters for use in process C are prepared by nitration of the corresponding 2-halogen esters. These esters, preferably lower alkyl esters, can be easily hydrolysed by conventional acid hydrolysis.

The previously unknown 2-nitro-3-phenylbenzofuran alkane cyanides used in process C are produced a) from previously unknown bromomethyl-2-nitro-3-phenylbenzofurans by replacing bromine with cyamide in inert solvents, such as ketones, alcohols and N, N-dimethylformamide, as a rule at the solvent's reflux temperature or at approx. 100°C, or b) by replacement of halogen from 2-bromo-3-phenylbenzofuran alkane cyanides by the methods and conditions described above. Hydrolysis of the 2-nitro-3-phenylbenzofuranalkane cyanides is carried out under strongly acidic or basic conditions, e.g. in aqueous sulfuric acid at 60-175°C or in aqueous alcoholic base at the reflux temperature.

The aldehydes obtained as an intermediate in process D are hitherto unknown compounds with the formula:

in which X, Y and n have the meaning stated in the characterizing part of claim 1 and Q denotes hydrogen, bromine, iodine or nitro, are hitherto unknown and also covered by the invention. These hitherto unknown intermediates can e.g. are prepared from cyano-3-phenylbenzo-furans which are known and can be prepared in a known manner. The preparation can be carried out by reaction with aqueous formic acid in the presence of Raney nickel at moderate temperatures, such as 50 - 125<G>C.

The mentioned aldehydes can be 2-halogenated by the method according to the invention, optionally followed by replacement with a nitro group. The aldehydes' can be easily converted directly into the alkane or alkenoic acids in question. Condensation of 2-nitro-3-phenylbenzofuranaldehydes with acetic anhydride in the presence of sodium acetate enables the preparation of 2-nitro-3-phenylbenzofuranacrylic acids which can be reduced to the corresponding propionic acids by chemical hydrogenation.

The pharmaceutically acceptable salts of the acids in question can be easily prepared by reacting the acids with a suitable base and, if desired, in a suitable solvent which is evaporated to dryness. The base used to prepare the salts can be an organic base, such as sodium methoxide or an inorganic base. Furthermore, other salts which are not pharmaceutically acceptable may be useful in the synthesis of the free acids or other acceptable salts or other useful intermediates, such as pure esters. The acid halides in question can be prepared by reacting the free acid with thionyl chloride, usually in a non-reactive solvent, such as dichloromethane or benzene. The esters in question are prepared as described in connection with the use in process C. The amides are usually prepared by reacting the acyl halides with the desired amine. Finally, the free acids can also be prepared from the corresponding esters, amides and acyl halides in a manner known per se.

The antimicrobial effect of the compounds in question is assessed by a variation of the original agar plate diffusion method, cf. e.g. Vincent, J. G., and Vincent, Helen W., Proe. Soc. Exptl. Biol. With. 5_5 :162-164, 1944 , and Davis, B.D. and Mingioli, E.S., J. Bae. £6:129,-136, 1953 . In this test, the compounds in question have been shown to have a broad-spectrum activity. against gram-positive and gram-negative microorganisms. This procedure provided information on the amount of compound required to produce a complete inhibition, a partial inhibition or no inhibition at all of microbial growth on agar plates. The microbial growth on each plate is read visually, and the minimum inhibitory concentrations are determined.

The microorganisms used are Staphylococcus aureus, Bacillus subtil s, Pseudomonas aeruginosa, Escherichia coli and Streptococcus sp. (strains isolated from dental caries in rats or hamsters in the National Institute of Dental Health and cultured on PFY or APT agar), Aspergillus niger, Candida albicans,

Mima polymorpha, Herellea vaginicola, Klebsiella pneumoniae and Streptococcus fæcalis.

These are selected representatives of different classes of bacteria and fungi, and a confirmed activity against these indicates a broad-spectrum effect. All the compounds in question exhibit antimicrobial activity against one or more of the above-mentioned microorganisms. The compounds retain a high activity against the microorganisms both in the absence and in the presence of 10% horse serum.

The in vivo antimicrobial activity is determined against infections caused by Streptococcus pyogenes C-203 and Staphylococcus aureus (Smith) or other bacterial species. The species used is determined by the in vitro antimicrobial spectrum of the compound. Groups of 5 or 10 mice of 18 - 22 g are infected intraperitoneally with the test culture. The treatment consists of three ora-

le administrations 1, 6 and 24 hours after the infection. All mice were observed for a longer period of time, i.e. for two weeks, and the number of dead was counted at daily intervals. Control groups consisting of an infected untreated group and another infected group are used

pe who received different doses of the reference sef or compound.

The acute oral toxicity of the compounds in question is usually moderate to low, compared to the effective oral dose, and they have a good to excellent therapeutic ratio.

The compounds in question can be formulated by incorporation into conventional pharmaceutical carrier materials, either organic or inorganic, which are suitable for oral or intraperitoneal administration. For in vitro or topical application, simple aqueous solutions or suspensions are most conveniently used.-

For this purpose, concentrations of the order of 100 de-

laughing per million up to approx. 5 p.m. suitable, and the formulation is applied by dipping the object to be treated, or by local application to an infected area. The amount of compound to be used e.g. ved'oral treatment of a microbial infection will be an effective dose, which is less than the toxic amount. The amount to be administered and the method of administration to control an infection depends on the organism's species, sex, weight, physical condition, site of infection and many other factors which the person skilled in the art can easily take into account. The dose used will usually be less than 100 mg/kg per dose.

Oral treatment is suitably carried out in the form of usual pharmaceutical preparations, such as capsules, tablets, emulsions, solutions and the like. Well-known excipients, fillers, coatings etc. can be used for the production of tablets or capsules.

It is often advantageous to combine the compounds in question with other antimicrobial compounds, such as coccidiostatic agents, anthelmintic agents, antifungal agents, antibiotics, steroids or antibacterial agents, or to combine one or more of the aforementioned compounds in a single mixture. thing.

Certain of the compounds also exhibit an antiparasitic effect, as demonstrated in laboratory tests against protozoa, such as Trichomonas sp. Because of the compounds' outstanding antimicrobial action, they must also be assumed to be effective growth-promoting agents against various bird and other animal species.

The invention is illustrated in more detail by the examples below where the stated melting points are uncorrected, the temperatures are in °C and the pressures in mmHg. ■

Example 1

A mixture of 15 ml of acetic acid and 10 ml of yellow fuming nitric acid is cooled to approx. 10°C, and 4.8 g (0.019 mol) of 3-phenyl-6-benzofuranacetic acid are added there. The mixture is stirred at room temperature approx. 1 hour and poured over ice. The solid precipitate is extracted with diethyl ether, isolated and recrystallized twice from ethanol-water, and then from benzene-hexane to form a yellow powder, 2-nitro-3-phenyl-6-benzofuranacetic acid, m.p. 187 - 191°C.

Example 2

To a solution of 14.0 g (0.055 mol) 3-phenyl-7-berisofuranacetic acid (cf. column 17, line 63 in US patent no. 3,862,134) in 150 ml acetic acid, 8.9 g (0.055 mol) bromine is added drop by drop while stirring. After a precipitate begins to appear, the mixture is heated to 45°C to keep the 2-bromo-3-phenyl-7-benzofuranacetic acid dissolved. A solution of 7 ml of concentrated sulfuric acid in 50 ml of acetic acid is added to the reaction mixture and 13.8 g (0.2 mol) of solid sodium nitrite is added there while the reaction temperature is kept at approx. 55°C approx. 2 hours, after which the mixture is poured into ice water. - The precipitate is extracted with diethyl ether, isolated and recrystallized twice from benzene, then twice from ethanol. The yellow product is 2-nitro-3-phenyl-7-benzofuranacetic acid, m.p. 170 - 173°C.

Example 3

A mixture of 5.4 g (0.02 mol) 3-(4-fluorophenyl)-7-benzofuranacetic acid in 150 ml chloroform (stabilized with ethanol) is treated with 3.2 g (0.02 mol) bromine, stirred approx. 16 hours and then evaporated. The residue is extracted with petroleum ether, after which the ether is evaporated to form a white substance which is recrystallized from hexane to ethyl 2-bromo-3-(4-fluorophenyl)-7-benzofuran-acetate, m.p. 63 - 67°C.

To 3.8 g (0.0101 mol) ethyl-2-bromo-3-(4-fluorophenyl)-7-benzofuran acetate in 30 ml acetic acid, add 2 ml 70% nitric acid and then 4 g (0.0202 mol) solid sodium nitrite , and you stir while heating for 1 1/4 hours until approx. 80°C, cool and pour the mixture into water. The precipitate is extracted with diethyl ether and then isolated as an orange residue. The product is separated from the residue by chromatography on neutral aluminum oxide using a 1:1 mixture of hexane and benzene, followed by 2 portions of benzene. The eluted fractions with benzene are recrystallized from carbon tetrachloride to a white solid, ethyl 3-(4-fluoro-phenyl.)-2-nitro-7-benzofuranacetate, m.p. 103 - 104, 5°C.

Example 4

A mixture of 200 ml of ethylene glycol dimethyl ether,

28.6 g (0.159 mol) ethyl-(4-hydroxyphenyl)acetate, 37.2 g (0.159 mol) 4-chloro-ct-bromoacetophenone and 28.6 g potassium carbonate are heated to the reflux temperature for 5 hours, then diluted with water and diethyl ether. The ether layer is washed with water, cold 0.5N sodium hydroxide solution and saturated sodium chloride solution and treated with active carbon and then dried. The solution is evaporated to form a residue which is recrystallised from methanol to form 24.4 g of yellow crystals of a condensation product with m.p. 87 - 92°C. This product is mixed with 165 g of polyphosphoric acid and heated to 110°C for 1-1/2 hours, poured into ice and water and extracted with diethyl ether. The ether layer is washed with water and saturated sodium chloride solution and then dried. By evaporation, 20.7 g of ethyl 3-(4-chlorophenyl)-5-benzofuranacetate are obtained. This ester is hydrolyzed in 210 ml of ethanol with 21 ml of water and 20.7 g of sodium hydroxide by heating under reflux for 2 hours. Evaporation and purification gives a solid white substance which is recrystallized twice from aqueous ethanol and then from benzene to form

of 3-(4-chlorophenyl)-5-benzofuranacetic acid, m.p. 136 - 140°C. This compound is brominated in chloroform to 2-bromo-3-(4-chlorophenyl)-5-benzofuranacetic acid, a green solid, m.p. 152 - 165°C.

The 2-bromo compound is dissolved in 106 ml of acetic acid and 56 ml of 70% nitric acid is added there. To this mixture, 4.7 g (0.068 mol) of sodium nitrite are added in small portions. The mixture is heated to 80°C within 1 hour and then poured into cold water.

The solid yellow product is recrystallized from 95% ethanol to 3-(4-chlorophenyl)-2-nitro-5-benzofuranacetic acid, m.p. 211°C (dec.).

Example 5

A solution of 3.85 g (0.0775 mol) sodium hydride in 150 ml ethylene glycol dimethyl ether and 18 g (0.0775 mol) 7-cyano-methyl-3-phenylbenzofuran is heated to the reflux temperature for approx. 1 hour. The solution is cooled in an ice bath, and 33 g (0.23 mol) methyl iodide is added there and stirred for 16 hours at approx. 21°C. To. a few ml of ethanol are added to the mixture, after which it is evaporated to

dryness. Add diethyl ether and water and mix thoroughly. The ether layer is washed with saturated sodium chloride solution, dried and evaporated to form an oil.

This oil is dissolved in 200 ml of ethanol, which is added

40 g of potassium hydroxide and the mixture is heated to the reflux temperature for approx. 16 hours. The mixture is partially evaporated, and the concentrate is extracted with a mixture of diethyl ether and hexane. It

■ organic fraction is evaporated to. formation of eholje. The oil is extracted with hexane. The extracts are evaporated to form a residue which is further hydrolysed by dissolving in 100 ml of ethylene glycol containing 10 g of 85% potassium hydroxide, and heating the mixture to 130°C for 16 hours. The product is isolated by evaporation to form a residue which is extracted with diethyl ether and hexane, after which the aqueous layer is acidified. to form a white substance which dissolves in diethyl ether, is isolated and recrystallised from a benzene-hexane mixture, and then on aqueous ethanol to form greyish-white crystals of α,α-dimethyl-3-phenyl-7-benzofuranacetic acid , m.p. 169 - 171°C.

Bromination of this compound according to the method in example 4 gives 2-bromo-α,α-dimethyl-3-phenyl-7-benzofuranacetic acid,

m.p. 183 - 186°C. Further reaction analogous to example 4 gives α,α-dimethyl-2-nitro-3-phenyl-7-benzofuranacetic acid, m.p. 256.5 - 258.5°C.

The table below shows the compounds according to examples 6-8 which can also be prepared analogously to example 4. When the 2-bromo compound formed as an intermediate is isolated, the melting point has been indicated.

Example 9

To a. stirred solution of 18.2 g (0.72 mol) 3-phenyl-5-benzofuranacetic acid in 400 ml dichloromethane, 8.2 g (0.10 mol) sodium acetate is added and then 11.5 g (0.072 mol) bromine in 25 ml dichloromethane. The solution remains under stirring for approx. 1 1/2 hours, and the mixture is washed with water, with 10% aqueous sodium hydrogen sulphite and then again with water. The dichloromethane fraction is dried over magnesium sulfate and concentrated under vacuum to 2-bromo-3-phenyl-5-benzofuranacetic acid, a white powder, m.p. 130 - 140°C. This substance is used without further purification.

To a solution of 23.8 g (0.072 mol) 2-bromo-3-phenyl-5-benzo-furanacetic acid in 250 ml acetic acid, 8.9 g (0.108 mol) cyclohexene is added and then 9.9 g (0.108 mol) dropwise dinitrogen tetraoxide in 25 ml of acetic acid. After stirring for 3 hours, the precipitate formed is collected by filtration, washed out with cold acetic acid, water and then with petroleum ether, recrystallized twice from 95% ethanol and once from isopropanol to form a yellow crystalline substance, 2-nitro-3-phenyl- 5-benzofuranacetic acid, m.p. 209 - 212°C.

Example 10

A solution of 2 g of 2-nitro-3-phenyl-5-benzofuranacetyl chloride in 75 ml of benzene is treated with gaseous ammonia. A precipitate quickly forms which is separated by filtration. Recrystallization from. 95% ethanol gives a yellow solid 2-nitro-3-phenyl-5-benzofuranacetamide, m.p. 220.5 - 222.5°C.

Example 11

Analogously to example 9, 3-phenyl-5-benzofuran-propionic acid is brominated to a light brown solid, 2-bromo-3-phenyl-5-benzo-furan-propionic acid, m.p. 70 - 80°C (unpurified). This product is reacted analogously to example 9 to yellow crystals of 2-nitro-3-phenyl-5-benzofuranpropionic acid, m.p. 174 - 178°C.

. Example 12

Analogous to example 10, 3-phenyl-7-benzofuran-propionic acid is brominated to 2-bromo-3-phenyl-7-benzofuran-propionic acid, m.p. 182-183.5°C which is further converted analogously to example 10 to a yellow solid, 2-nitro-3-phenyl-7-benzofuranpropionic acid, m.p. 217.5 - 219.5°C.

Example 13

6.5 ml of pyridine, 10.3 g (0.115 mol) of copper (I) cyanide and 22.8 g (0.1 mol) of 7-chloro-3-phenylbenzofuran are heated to 220°C for approx. 3 hours and then to 150 - 190°C for approx. 16 hours. The solution is added to 40 g of iron (II) chloride • hexahydrate in 65 ml. water and 15 ml of concentrated salt urine, heated with stirring to 90°C

about. 1 hour and filtered hot. The filtrate is cooled, and the product is separated from and extracted with a boiling mixture of benzene-toluene, and the combined organic extracts are washed with 125 ml of 6N hydrochloric acid, water, 10% sodium hydroxide and water, dried, treated. read with decolorizing carbon, and then evaporated to form crude 7-cyano-3-phenylbenzofuran, which is recrystallized from benzene-petroleum ether, m.p. 143 - 145°C.

45 g (0.0206 mol) of 7,cyano-3-phenylbenzofuran are dissolved

in formic acid (580 ml + 25 ml water) at 85°C. At this temperature and under a nitrogen atmosphere, 30 g of Raney nickel are added. The mixture is stirred. 45 minutes at this temperature. At this point a further 10 g of Raney nickel is added, and 2 hours later a further 5 g of Raney nickel. The mixture is cooled, mixed with sulfur to inactivate the catalyst and extracted with dichloromethane. The product, 3-phenyl-7-benzofurancarboxaldehyde is isolated as a gray solid. Its structural makeup is confirmed by the IR spectrum.

A stirred solution of 20 g (0.09 mol) 3-phenyl-7-benzofuranylaldehyde in 300 ml dichloromethane is cooled to 15°C, and 14.4 g (0.09 mol) bromine dissolved in 15 ml dichloromethane is added dropwise in within 15 minutes. After stirring for 5 minutes, the mixture is washed twice with saturated sodium bicarbonate solution, washed out with water and then dried over magnesium sulphate. The dichloromethane solution is filtered to remove magnesium sulfate.

The dichloromethane solution is filtered to remove magnesium sulfate and evaporated to dryness, while the temperature and the mixture are kept below 25°C. Benzene is then added, and the mixture is evaporated again under vacuum. The product is purified by column chromatography over 210 g "Florisil", eluting with 1:1 hexane-benzene and benzene.

The product from the previous step, 2-bromo-3-phenyl-7-benzofurancarboxaldehyde (29.5 g) (0.098 mol) is dissolved in 150 ml of acetic acid. The mixture is cooled to 40°C, and 15.2 g (0.12 mol) of cyclohexene are added, followed by the dropwise addition of a solution of 12.6 g (0.14 mol) of dinitrogen tetraoxide dissolved in approx. 30 ml of acetic acid. The mixture is heated to approx. 55°C for a total of 3 hours. It is cooled, and the isolated yellow precipitate after purification is 2-nitro-3-phenyl-7-benzofuranaldehyde, m.p. 174 - 176°C.

A mixture of 5.1 g (0.0191 mol) 2-nitro-3-phenyl-7-benzofuranaldehyde, 2.3 g (0.0278 mol) sodium acetate and 9.1 g acetic acid is heated to 145 - 150°C under stirring. After stirring for 16 hours, a further 10 ml of acetic acid is added, and reflux cooling is continued for 5 hours. The mixture is poured into 200 ml of water while stirring, and the residue is separated from and washed out with water, then dissolved in a solution of 30 ml of concentrated ammonium hydroxide in 400 ml of water, filtered and added to a 10% sulfuric acid solution. A gray-yellow solid is obtained which is washed with water and then with diethyl ether and recrystallized twice from acetic acid by subsequent treatment with decolorizing carbon. The product is 2-nitro-3-phenyl-7-benzofuran-acrylic acid, m.p. 281.5 - 283°C.

Example 14

To a solution of 2.97 g (10 mmol) of 2-nitro-3-phenyl-5-benzofuranacetic acid in 125 ml of methanol, 10 ml of 1.0 M sodium hydroxide solution is added. The solvent is evaporated, benzene is added and the mixture is evaporated again to form a solid residue. It is recrystallized twice from a mixture of ethanol and petroleum ether, and a pale yellow product, sodium 2-nitro-3-phenyl-5-benzofuran acetate, m.p. 270 - 273°C (decomposition).

Example 15

A mixture of 3.0 g (0.010 mol) 2-nitro-3-phenyl-5-benzofuranacetic acid, 1.8 g (0.015 mmol) thionyl chloride and 200 ml dichloromethane is heated at the reflux temperature approx. 5 hours, evaporated under vacuum to form a residue, whereupon benzene is added to the residue, and the mixture is again evaporated to dryness. This is repeated three more times. The residue is a yellow oil which is analyzed by IR spectroscopy to confirm that it is 2-nitro-3-phenyl-5-benzofuran acetyl chloride.

Example 16

A mixture of 2.6 g of 2-nitro-3-phenyl-7-benzofuranacetic acid, 2.6 g of sulfuric acid and 25 ml of ethanol is heated under reflux for approx. 16 hours. The mixture is added to 200 ml of ice water, extracted with diethyl ether, and the product is isolated as a yellow solid which is recrystallized from cyclohexane in the presence of decolorizing carbon, ethyl-2-nitro-3-phenyl-7-benzofuran acetate, m.p. 87 - 88°C.

Example 17

Equimolar amounts of 3-hydroxytoluene and α-bromoacetophenone are heated under reflux in benzene in the presence of potassium carbonate to form α-(3-methylphenoxy)acetophenone.

A mixture of 4 parts by weight of polyphosphoric acid and 1 part by weight of α-(3-methylphenoxy)acetophenone is heated to approx. 125°C for several hours, after which it is poured into an ice-water mixture. The solid product, which is a mixture (about 2:3) of 4-methyl-3-phenylbenzofuran and 6-methyl-3-phenylbenzofuran, is treated with liquid bromine in dichloromethane to form a mixture of 2-bromo-4-methyl -3-phenyl-benzofuran and 2-bromo-6-methyl-3-phenylbenzofuran which are subjected to fractional recrystallization. One fraction contains 6-isomers and 4-isomers in the ratio 1:3. This fraction is chromatographed on a silica gel column, eluting with large amounts of petroleum ether to form early fractions of approx. 85% 4-methyl isomer.

51.5 g (0.179 mol) of a mixture of 2-bromo-4-methyl-3-phenylbenzofuran and 2-bromo-6-methyl-3-phenylbenzofuran (about 15% 6-isomer), 37.7 g ( 0.178 mol) N-bromosuccinimide and approx. 0.05 g of benzoyl peroxide in 400 ml of carbon tetrachloride is heated to the reflux temperature under illumination with a sunlight lamp until the reaction is complete. The mixture is cooled, filtered to remove succinimide, and the organic layer is evaporated to dryness and suspended in petroleum ether. The solid white product is separated from by filtration in It is approx. 95% pure 2-bromo-4-bromomethyl-3-phenyl-benzofuran.. The formed 2-bromo-4-bromomethyl-3-phenylbenzofuran 44.5 g (0.122 mol) dissolved in 165 ml of acetone, 6.0 g (0.122 mol) of sodium cyanide dissolved in 30 ml of water, and 112 ml of ethanol are mixed and heated under reflux. After approx. 5 hour warm-up

ning, the mixture is left to stir at approx. 25 C for approx. 16 hours. The reaction mixture is evaporated, the residue is dissolved in diethyl ether and washed with water, and the organic layer is concentrated to form an oily brown solid, 2-bromo-4-cyano-methyl-3-phenylbenzofuran.

A solution of 37 g of 2-bromo-4-cyanomethyl-3-phenyl-benzofuran in 235 ml of absolute ethanol is treated with 15 g of potassium hydroxide in 15 ml of water, and the mixture is heated under reflux for approx. 2 days, and concentrated by evaporation, after which water is added, and the mixture is extracted with diethyl ether. The aqueous layer is acidified with hydrochloric acid, after which the mixture is extracted with dichloromethane. The extracts are dried and evaporated to form a brown residue which is treated with diethyl ether to form a solid which is separated by filtration and washed with isopropanol. The product is 2-bromo-3-phenyl-4-benzofuranacetic acid, m.p. 131 - 133°C.

A solution of 2-bromo-3-phenyl-4-benzofuranacetic acid and cyclohexene in chloroform is reacted with dinitrogen tetraoxide analogously to example 9 to a pale yellow solid 2-nitro-3-phenyl-4-benzofuranacetic acid, m.p. 187.5 - 189.5°C.

Example 18

Analogous to example 17, 5,7-dimethyl-3-phenylbenzofuran is obtained from 2,4-dimethyl-phenol and α-bromoacetophenone, which are cyclized at 50 - 60°C.

To a solution of 5 g (0.0225 mol) of 5,7-dimethyl-3-phenylbenzofuran in 30 ml of carbon tetrachloride and 8.0 g (0.045 mol) of N-bromosuccinimide in 30 ml of carbon tetrachloride, 0.01 g of benzoyl peroxide is added. The mixture is kept at the reflux temperature under irradiation with a solar lamp approx. 30 minutes, cool and filter. The filtrate is evaporated to an oily residue, of which 2/3 consists of the desired 2-bromo-5-bromomethyl-7-methyl-3-phenyl-benzofuran according to NMR spectral analysis. The mixture is dissolved in 34 ml of acetone, and 1.3 g of sodium cyanide in 6 ml of ether is added there. The mixture is added to 25 ml of ethanol, heated to the reflux temperature approx. 40 hours, and then evaporated. The residue is treated with water and diethyl ether, and the resulting ether layer is separated, dried and evaporated. The brown oily residue is purified on a silica gel column to form 3.9 g of a yellow oil which is essentially 2-bromo-5-cyanomethyl-7-methyl-3-phenylbenzofuran which is hydrolysed analogously to example 17 to 0.89 g of a white substance 2-bromo-7-methyl-3-phenyl-5-benzofuranacetic acid, m.p. 183.5 - 189°C. A solution of 0.89 g (0.0027 mol) 2-bromo-7-methyl-3-phenyl-5-benzofuranacetic acid in 50 ml chloroform and 0.43 g cyclohexene is reacted with 0.57 g dinitrogen tetraoxyd approx. 16 hours as described in Example 17 to a yellow solid, 7-methyl^2-nitro-3-phenyl-5-benzofuranacetic acid, m.p. 189 - 191.5°C.

Example 19

Analogous to example 17, from 4-hydroxytoluene and α-bromoacetophenone, α-(4-methylphenoxy)acetophenone is obtained.

Analogous to example 17, α-.(4-methylphenoxy)-acetophenone is cyclized with polyphosphoric acid at 60°C to 5-methyl-3-phenylbenzofuran, m.p. 144.5 - 146°C.

112 g (0.538 mol) of 5-methyl-3-phenylbenzofuran dissolved in 500 ml of carbon tetrachloride are treated with 192 g (1.076 mol) of N-bromosuccinimide. 0.1 g of benzoyl peroxide is added, and the mixture is stirred and heated to the reflux temperature under irradiation with a sunlight lamp. After approx. After 1 hour, 0.5 g of tert-butyl hydroxide and 0.5 g of cobalt stearate are added. The mixture is refluxed for 2 hours after filtration, and the concentrate is concentrated and washed with petroleum ether. The crude product is 2-bromo-5-bromomethyl-3-phenylbenzofuran, m.p. 99 - 108°C.

A solution of 49.4 g (0.135 mol) of 2-bromo-5-bromomethyl-3-phenylbenzofuran in 1100 ml of acetic acid is heated to 55°C with 25.4 g (0.202 mol) of cyclohexene-4-carboxylic acid. To this solution, 18.6 g (0.202 mol) of dinitrogen tetraoxide in 40 ml of acetic acid are added dropwise over approx. 2 hours. The precipitated product is collected by filtration, washed with cold acetic acid, water and petroleum ether. The yellow crystals of 5-bromomethyl-2-nitro-3-phen-,ylbenzofuran are dried to m.p. 172 - 180°C.

5 g (0.015 mol) of 5-bromomethyl-2-nitro-3-phenylbenzofuran in 95 ml of acetone is treated with 20 ml of ethanol and refluxed, and there 0.015 mol of sodium cyanide in 9 ml of water is added and refluxed approx. 2 hours. The mixture is evaporated, after which dichloromethane and water are added to the residue. The organic layer is separated, washed with water and dried, after which it is evaporated. The residue is purified by elution twice with benzene over a column of silica gel, followed by refluxing in 30 ml of diethyl ether. Recrystallization twice from benzene gives 5-cyanomethyl-2-nitro-3-phenylbenzofuran, m.p. 166 - 168°C. 1 ml of 50% sulfuric acid and 0.1 g of 5-cyanomethyl-2-nitro-3-phenylbenzofuran are slowly heated for 1 hour in an oil bath at approx.

160°C (bath temperature), after which it is heated at this temperature for a further 1 1/2 hours, allowed to cool, and poured into water. The un-

This mixture is extracted twice with dichloromethane, and the organic extracts are washed with water, dried and evaporated to form 2-nitro-3-phenylbenzofuran-5-acetic acid, identical to the product obtained in example 9.

Example 20

Step 1: 50 g (0.175 mol) 4-phenyl-α-bromoacetophenone, 30.6 g

(0.17 mol) ethyl-4-hydroxyphenylacetate and 36 g (0.26

mol) of potassium carbonate in 500 ml of benzene is heated under reflux for approx. 16 hours during removal of water through a Dean-Stark trap. The mixture is filtered, washed with water and saturated sodium chloride. solution and dried over calcium sulfate. Evaporation and recrystallization give white plates of ethyl 4-(4-phenylbenzoylmethoxy)-phenylacetate.

Step 2: 15 g of the product from step 1 and 150 g of polyphosphoric acid are heated to approx. 130°C approx. 45 minutes, pour in 1 liter of water and stir. A solid yellow substance is obtained which is recrystallised to form ethyl 3-(4-biphenylyl)-5-benzofuran acetate.

Step 3: 6.5 g of the ester product obtained in step 2, 150 ml

ethanol and 150 ml of 10% sodium hydroxide solution are heated on a steam bath for approx. 1 1/2 hours and then filtered hot.'

The filtrate is heated on a steam bath for 30 minutes, and remains

then acidified to form 3-(4-biphenylyl)-5-benzofuranacetic acid, m.p. 230 - 233°C.

Step 4: A mixture of 1.5 g (4.6 mmol) of 3-(4-biphenylyl)-5-benzofuranacetic acid in 250 ml of dichloromethane is treated

with 0.5 g (5 mmol) dinitrogen tetraoxide, and the mixture is stirred for approx.

16 hours. The mixture is evaporated, and the residue is recrystallised to form 2-nitro-3-(4-biphenylyl)-5-benzofuranacetic acid.

sum. -7i,^0r.

Example 21

Analogously to example 20, 3-(3-methoxyphenyl)-2-nitro-5-benzofuranacetic acid is obtained from α-bromo-3-methoxy-acetophenone and ethyl-4-hydroxyphenylacetate, m.p. 153 - 156°C.

Example 22

From 4-bromo-a-bromoacetophenone and 4-hydroxyphenylacetic acid analogously to example 2, steps 1 and 2, ethyl 3-(4-bromophenyl)-5-benzofuran acetate is obtained.

A mixture of 20 g (0.056 mol) ethyl 3-(4-bromophenyl)-5-benzofuran acetate, 6.0 g (0.067 mol) copper(I) cyanide and 5 ml pyridine is stirred under a nitrogen atmosphere while heating on oil-

bath at 150 - 160°C for 18 hours, after which 18 g of iron(III) chloride, 10 ml of concentrated hydrochloric acid and 50 ml of water are poured in. The mixture is heated on a steam bath for 1 1/2 hours, extracted with diethyl ether,

after which the extracts are washed with 6N hydrochloric acid, 10% sodium hydroxide and saturated sodium chloride solution. The dried solution is filtered off, evaporated to approx. 25 ml, and hexane is added there. The product is collected, dissolved in diisopropyl ether and treated with decolorizing carbon. The hydrate is evaporated to 50 ml, and the precipitate, ethyl 3-(4-cyanophenyl)-5-benzofuran acetate, is collected.

To a solution of 2.5 g (8.2 mmol) of the ester i

75 ml of methanol is added to 0.48 g (8.2 mmol) of 85% potassium hydroxide,

and the mixture is stirred for approx. 16 hours. The solution is diluted with

75 ml of water and then acidified with hydrochloric acid. The precipitate is separated

from, dissolve in boiling chloroform and dry. Hexane is added to the solution until the product, 3-(4-cyanophenyl)-5-benzo-furanacetic acid precipitates.

A solution of 1.0 g of 3-(4-cyanophenyl)-5-benzofuran-acetic acid and 1 g of dinitrogen tetraoxide in 200 ml of dichloromethane is stirred

travel approx. 16 hours. Evaporation of the reaction mixture leaves a residue which is dissolved in chloroform. The solution is placed in a 50 g silica gel column for chromatography. Elution with chloro-

form gives the desired product as a yellow crystalline substance, 3-(4-cyanophenyl)-2-nitro-5-benzofuranacetic acid, m.p. 220-222°C..

The compounds in the following table are prepared ana-

logged with the synthesis method described in example 20, starting from 4-hydroxyphenylacetic acid and the suitably known substitution

pea a-bromo-acetophenone..

Example 30

Thionyl chloride is reacted with 2-nitro-3-phenylbenzofuran-5-acetic acid to 2-nitro-3-phenyl-5-benzofuran acetyl chloride. 3 g of 2-nitro-3-phenyl-5-benzofuran acetyl chloride and 30 ml of ethylene glycol in 130 ml of chloroform are heated for 3 1/2 hours. Upon isolation and purification, 2-hydroxyethyl-2-nitro-3-phenyl-5-benzofuran acetate is obtained, m.p. 104 - 107°C.

Example 31

2.59 g of 2-nitro-3-phenyl-5-benzofuran acetyl chloride in 35 ml of benzene is treated with 1.46 g (16.4 mmol) of N,N-dimethylaminoethanol approx. 64 hours. The mixture is washed twice with water, and the organic layer is evaporated. The residue is dissolved in chloroform and chromatographed on silica gel. IR and NMR spectral analysis is consistent with the desired product, N,N-dimethylaminoethyl-2-nitro-3-phenyl-5-benzofuranacetate, which is reacted with perchloric acid in diethyl ether to form the perchloric acid salt.

Example 3 2

To 2.08 g (8.25 mmol) of 3-phenyl-7-benzofuranacetic acid

in 10 ml of benzene at 60°C, yellow mercury(II) oxide (1.45 g, 6.7 mmol) and 2.9 g (8.25 mmol) of iodine are added slowly in small portions. After 2 hours, the mixture is filtered, after which the filtrate is evaporated to form 2-iodo-3-phenyl-7-benzofuranacetic acid.

To 2.2 g (5.8 mmol) 2-iodo-3-phenyl-7-benzofuranacetic acid, 1.8 g (12 mmol) cyclohexene and 175 ml chloroform is added 0.9 g (10 mmol) dinitrogen tetraoxyd in 15 ml of chloroform. The mixture is stirred for 20 hours, washed with water and made basic with sodium hydroxide. The chloroform layer is acidified with hydrochloric acid, washed twice with water and dried, after which it is evaporated to form 2-nitro-3-phenyl-7-benzofuranacetic acid, identical to the product prepared in example 2.

Analogous to example 20, the following acids are prepared as an intermediate, and the final products with formula 1 are prepared from known substituted acetophenones or acetophenones prepared in a known manner, as well as ethyl-4-hydroxyphenylacetate. The aceto-phenones are treated with equivalent bromine in methylene chloride to obtain the desired phenacyl bromides.

Example 40

Analogous to example 17, 3-bromo-4-hydroxytoluene and α-bromo-acetophenone are reacted to α-(2-bromo-4-methylphenoxy)acetophenone, which is cyclized as in example 17 to 7-bromo-5-methyl-3-phenylbenzofuran in form of a brown oil. This oil is treated with bromine as described in Example 11 to form 2,7-dibromo-5-methyl-3-phenyl-benzofuran as an oil which is crystallized from hexane. This oil is reacted with N-bromosuccinimide as described in example 17 to form solid 5-bromomethyl-2,7-dibromo-3-phenylbenzofuran. Again, analogously to example 17, this substance is reacted with sodium cyanide to form 5-cyanomethyl-2,7-dibromo-3-phenylbenzofuran as a solid white substance.

11.1 g (0.028 mol) 5-cyanomethyl-2,7-dibromo-3-phenyl-benzofuran, 10.7 g (0.11 mol) dinitrogen tetraoxide, 13.9 g (0.11 mol) cyclohexene-4- carboxylic acid and 1 g of iodine in 500 ml of chloroform are stirred at 23°C for 16 hours. A further 13.9 g of cyclohexene-4-carboxylic acid and 10.7 g of dinitrogen tetraoxide are added and stirring is continued for 16 hours. The reaction mixture is then treated with 500 ml of 10% sodium thiosulphate. The organic phase is washed three times with 250 ml portions of saturated sodium bicarbonate, once with .250 ml of 3N hydrochloric acid and dried. Evaporation gives 7-bromo-5-cyanomethyl-2-nitro-3-phenylbenzofuran as a yellow solid which is recrystallized from ethyl acetate-hexane.

2.0 g of 7-bromo-5-cyanomethyl-2-nitro-3-phenylbenzofuran and 30 ml of 1:1 sulfuric acid and water are stirred and heated to 150°C for 1 1/2 hours, after which the mixture is poured into 200 ml of water. The solid is recrystallized from ethanol to form yellow crystals of 7-bromo-2-nitro-3-phenyl-5-benzofuranacetic acid, m.p. 125 - 127°C.

Example 41

Analogously to example 17, 2-hydroxy-4-methoxy-toluene and α-bromo-2-fluoroacetophenone are converted to 2-fluoro-α-(2-methyl-5-methoxyphenoxy)-acetophenone, m.p. 57 - 58°C (purified), where cyclization in polyphosphoric acid gives 3-(2-fluorophenyl)-7-methyl-4-methoxy-benzofuran as a brown oil.

Analogous to example 17, 3-(2-fluorophenyl)-7-methyl-4-methoxybenzofuran is brominated with N-bromosuccinimide to 2-bromo-7-bromomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran in the form of an oil.

Analogous to example 17, 2-bromo-7-bromomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran is reacted with sodium cyanide to 2-bromo-7-cyanomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran.

2-bromo-7-cyanomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran is heated under reflux in ethanolic sodium hydroxide for 6 hours. Extraction with diethyl ether gives 2-bromo-3-(2-fluorophenyl)-4-methoxy-7-benzofuranacetic acid, m.p. 188-191.5°C (purified) .

Analogously to example 17, 2-bromo-3-(2-fluoro-phenyl)-4-methoxy-7-benzofuranacetic acid is reacted with dinitrogen tetraoxide to 3-(2-fluorophenyl)-4-methoxy-2-nitr6-7-benzofuranacetic acid. Recrystallization from benzene gives yellow crystals, m.p. 185-195°C.

Claims (17)

1. Substituted 2-nitro-3-phenylbenzofurans, characterized in that they have the general formula: wherein X denotes halogen, C-^ - alkyl, C-^ - C, alkoxy, nitro, phenyl, cyano or trifluoromethyl, n is 0, 1 or 2, R denotes the straight chain or branched C-^ - C^ .alkylene or C2 - alkenylene, and Y denotes methyl, methoxy, halogen or hydrogen, or esters, amides, acyl halides or pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, characterized in that R is methylene. 3. Compound according to claim 1, characterized in that each X is fluorine and/or chlorine. 4. Compound according to claim 1, characterized in that the 4-position in the benzofuran part is unsubstituted. 5. Compound according to claim 1, characterized in that it is an alkali metal salt." 6. Compound according to claim 1, characterized in that n is 0. 7.. Compound according to claim 6, characterized in that it is 2-nitro-3-phenyl-7-benzofuranacetic acid. 8.. Compound according to claim 6, characterized in that it is 2-nitro-3-phenyl-6-benzofuranacetic acid. 9. Compound according to claim 6, characterized in that it is 2-nitro-3-phenyl-5-benzofuranacetic acid. 10. Compound according to claim 6, characterized in that it is 2-nitro-3-phenyl.1-7-benzofuran acrylic acid. 11. Compound according to claim 6, characterized in that it is 2-nitro-3-phenyl-5-benzofuranpropionic acid. 12. Compound according to claim 6, characterized in that it is 2-nitro-3-phenyl-7-benzofuranpropionic acid. 13. Compound according to claim 1, where n is 1. 14. Compound according to claim 13, characterized in that it is 3-(4'-chlorophenyl)-2-nitro-5-benzofuranacetic acid. 15. Compound according to claim 13, characterized in that it is 3-(4'-fluorophenyl)-2-nitro-7-benzofuranacetic acid. 16. Compound according to claim 13, characterized in that it is 3-(4 <1-> chlorophenyl)-2-nitro-7-benzofuranacetic acid. 17. Process for the preparation of compounds according to any of the preceding claims with the general formula: wherein X denotes halogen, C 1 - C 4 alkyl, - C 4 alkoxy, nitro, phenyl, cyano or trifluoromethyl, n is 0, 1 or 2, R denotes straight chain or branched C 1 - C 4 alkylene or C 2 - C 4 alkenylene, and Y denotes methyl, methoxy, halogen or hydrogen or esters, amides, acyl halides or salts thereof, characterized in that manA. directly nitrites the 2-position in a compound of the formula B. produces an intermediate with the formula wherein Q is bromine or iodo, followed by a selective replacement of the 2-halogen atom with a nitro group, C. performs an acid hydrolysis of a corresponding compound with the formula wherein A is cyano or a carboxylic acid ester group, orD. reduces a compound with the formula to the corresponding 3-phenylbenzofuranaldehyde followed by halogenation and nitration or direct nitration of the aldehyde to the corresponding 2-nitro-3-phenylbenzofuranaldehyde which is reacted with acetic anhydride to form the corresponding 2-nitro-3-phenyl-benzofuran acrylic acid and, if desired, reduces the double bond in the side chain by catalytic hydrogenation to the corresponding 2-nitro-3-phenylbenzofuranpropionic acid, in which formulas X, n, R and Y have the meaning given above, and if desired, a formed free acid transfers into an ester, an amide, an acyl halide or a salt.