NO781127L - NEW 2,4,6-TRISUBSTITUATED-2,3-DIHYDRO-BENZOFURAN DERIVATIVES, AND PROCEDURES FOR THEIR PREPARATION - Google Patents

Description

New 2,4,6-trisubstituted-2,3-dihydrobenzofuran derivatives and process for their preparation.

The present invention relates to new 2,4,6-trisubstituted-2,3-dihydrobenzofurans, as well as a process for their production. These compounds in which the substituent in the 2-position is a methyl or an ethyl group represent a new class of compounds. Some examples of 2,4,6-trisubstituted-benzofurans are known (the benzofuran nucleus has the general formula:

see e.g. A. Wahhab, J. Prakt. Chem. 314, 213, 1972. Other benzofurans which are variously substituted at one or more possible positions are described in Bull. Soc. Chim. Fr., page 915, 1967å J. Org. Chem., 28, 398, 1963 and J. Org. Chem., 30, 1246, 1965.

The new 2,4,6-trisubstituted-2,3-dihydrobenzofuran derivatives covered by the present invention have the general formula:

where R is hydrogen or methyl; one of R 1 and R 2 is hydroxy, (C 1-4 ) alkoxy or (C 2-4 )alkanoyloxy, and the other is selected from cyano, carbo(C 1-4 ) alkoxy, carbamoyl and a -NR^R^ group,

where R_ and R^ are independently hydrogen, (C^_4)alkyl, (C2_4)alkanoyl, carbo(C-^_4) alkoxy, carbobenzyloxy, carbamoyl, mono- and di-(C^_^)-alkylamino-(C -L_4) alkyl, benzenesulfonyl, toluenesulfonyl, alkylsulfonyl or phenacylsulfonyl; and salts thereof with pharmaceutically acceptable acids.

The compounds have anti-inflammatory, analgesic and antipyretic effects.

The term "(C 1-4 )alkyl" includes alkyl radicals selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl; the term "(C 1-4 ) alkoxy" includes alkoxy groups

selected from methoxy, . ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy; the term "(C2_4)alkanoyloxy" includes alkanoyloxy groups selected from acetyloxy, propionyl-

oxy and butyryloxy; the term "lower (C 2-4 )alkanoyl" includes alkanoyl radicals selected from acetyl, propionyl and butyryl. A preferred group of compounds comprises those compounds of formula I where R is hydrogen or methyl, one of R₁ and R₂ is hydroxy, (C₁₄) alkoxy, as defined above, or (C₂₄) aliphatic alkanoyloxy, as defined above, and the second is the group -NR^R^ wherein R^ and R^ are independently hydrogen or a (C 1 -4 )alkyl group, as defined above; and salts thereof with pharmaceutically acceptable acids.

The most preferred group of compounds comprises those compounds of formula I where R is a hydrogen atom, one of R 2

and R 2 is a (C 1-4 ) alkoxy group and the other is the group -NR 2 R 2 , where R 2 and R 2 are each independently hydrogen or (C 4 ) alkyl,

as well as salts thereof with pharmaceutically acceptable acids.

Acids which are particularly suitable for the formation of therapeutically useful salts are both organic and inorganic acids. Such acids are e.g. aliphatic or aromatic carboxylic acids,

e.g. formic acid, acetic acid, succinic acid, oxalic acid, malic acid,

tartaric acid, citric acid, ascorbic acid, benzoic acid and salicylic acid, and mineral acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid. The compounds of formula I

is set by means of methods which, as a first step, comprise the formation of the basic 2,3-dihydrobenzofuran nucleus, by cyclization of a compound of the formula:

where R has the meaning given above. For the purposes of the invention, the radical -CH2_CH=CH-R must be either in the 2-position or in the 4-position. Thus, when R is hydrogen, the compound of formula II is an o-allylphenol derivative; and when R is methyl, the compound of formula II is an o-crotylphenyl derivative.

Depending on the position of the allyl or crotyl group

in the benzene ring, cyclization to 2,3-dihydrobenzofurans is achieved by thermal or acid-induced cyclization according to the reaction schemes below:

In practice, the cyclization of 2-allyl or 2-crotyl-3-hydroxy-5-methoxybenzoic acid methyl esters according to scheme A is carried out by heating the starting material in an inert atmosphere, e.g. nitrogen or carbon dioxide, to a temperature varying from approx. 200° to approx. 280°C for about 2-4 hours. The ring-closed compound is then recovered using conventional methods which include dissolving the cooled reaction mass in an aqueous alkaline solution, extraction with a water-miscible organic solvent, evaporation of the organic phase and purification of the product by vacuum distillation or column chromatography. This reaction can alternatively be carried out in a neutral or basic high-boiling organic solution batch, heating the reaction mixture to the reflux temperature for 2-6 hours. At the end of this time, the solvent is evaporated and the cyclization product is recovered as described above.

According to scheme B, the acid-induced ring closure is carried out

of 4-allyl or 4-crotyl-3-hydroxy-5-methoxybenzoic acid methyl esters by dissolving the starting material in acetic acid and then adding hydrobromic acid.

The reaction can be carried out at room temperature, but it is however usually preferred to heat or even reflux the obtained reaction mixture in order to increase the speed of the reaction which can be completed within 1-4 hours. Separation and purification of the 2,3-dihydrobenzofurans obtained is carried out in the usual way, taking into account that the acidic reaction conditions promote hydrolysis of the carbomethoxy group.

It has also been found that when the reaction time is extended up to 7-10 hours, hydrolysis of the methoxy group to a hydroxy group can take place.

The starting materials of formula II can be easily prepared

by Claisen rearrangement of allyl phenyl ethers with the formula:

where R is hydrogen or methyl, carried out as described by Tarbell in Organic Reactions, vol. II, New York, 1944, i.e. by heating the allyl phenyl ether in the absence of solvent to a temperature between 180 and 220°C, or refluxing a solution of a compound of formula III in a basic or neutral high-boiling organic solvent.

Suitable solvents that can be used are N,N-dimethylaniline, N,N-diethylaniline, paraffin oil, tetralin and kerosene. The redeposition is preferably carried out in an inert atmosphere. Recovery of the obtained isomers is achieved using usual methods, taking into account the different solubilities of the corresponding carboxylic acids, obtained by alkaline hydrolysis, in aqueous solutions.

The two isomers can alternatively be precipitated as a mixture and separated by column chromatography. Conventional esterification methods give the desired products of formula II.

According to the methods outlined in schemes A and B, compounds of formula I are obtained where R is hydrogen or methyl,

one of R 1 and R 2 is a methoxy radical and the other is a carboxy or carbomethoxy group.

When other compounds of formula I are desired, the corresponding groups must be introduced by means of obvious chemical modifications which are quite common in the art. Thus, alkaline hydrolysis of the carbomethoxy substituent in the 4-position leads to the corresponding carboxy group which in turn, which also applies to the carboxy group in the 6-position formed by the acid-induced ring closure, can be reacted with a (C^_^)alkanol in the presence of a strongly acidic medium for formation of the desired 4- or 6-crabo (C-j__4) alkoxy derivatives.

The carboxy group in the 4- or 6-position can undergo other chemical modifications. For convenience, it is first converted to the more reactive COhal group, where hal is a halogen atom, preferably chlorine or bromine, which can in turn be converted to the corresponding -CON^ group by reaction with NaN^.

The -COhal group is alternatively converted by ammonolysis

to the corresponding amide which can be dehydrated and thus give compounds of formula I where R^ or R ? is cyano.

The benzofuran compounds having the -CON^ group in the 4-

or 6-position, prepared as indicated above, are intermediates for the preparation of other compounds covered by the general formula.

Thus, thermal decomposition of the -CON^ group gives compounds of formula I where R^ or R2 is amino, i.e. the group

-NR^R^ in which R^ and R^ are hydrogen, whereas, on the other hand, if the decomposition takes place in the presence of a (C^-4)alkanol or benzyl alcohol, compounds of the formula I are obtained in which R^ or R^ are carbo(C 1-4 ) alkoxyamino or carbobenzyloxyamino radical. From these compounds one can easily by means of a simple reductive

step, prepare compounds where R, or R2 is methylamino. Among the reducing agents, lithium aluminum hydride is preferred.

The substituents R^ and R^ other than hydrogen are also introduced using known methods by reacting the corresponding 4- or 6-unsubstituted amino derivatives with suitable reactants.

Thus gives e.g. reaction with an alkylating agent, such as (C^_4)alkyl halides or (C^_4)alkyl sulfates, compounds where R^or R^or both are (C^_^)alkyl groups. Compounds in which R^ or/and R^ is a (C2-4)alkanoyl radical are obtained by reacting the corresponding compounds in which R^ or/and R^ is hydrogen, with halides or anhydrides of (C2-4)aliphatic acids. Carbo(C^_^) alkoxy and carbobenzyloxy amino groups are obtained by reaction with corresponding (C^_4) alkyl-

and benzyl carbonates. They can further be converted to the 4- or 6-methylamino derivatives as discussed above. The benzenesulfonyl, toluenesulfonyl, (C^_^)alkylsulfonyl and phenacylsulfonyl groups are conveniently introduced by reaction with benzenesulfonyl, toluenesulfonyl, (C^_^)alkylsulfonyl and phenacylsulfonyl halides, respectively, while the carbamoyl group can is introduced, by reacting the unsubstituted amino derivative with an alkali isocyanate in an acidic medium.

A convenient method for obtaining the compounds wherein

one of R 1 and R 2 is a (C 2 - 4 )alkylamino group, is reduction of the (C 2 - 4 ) acyl substituents on the amino group.

The methoxy group in the 4- or 6-position can also be converted by means of chemical reactions into another group which is covered by the meanings for the said substituent: demethylation can be carried out by refluxing the compound with HBr/AcOH mixtures or alternatively by refluxing a CS,> -or nitrobenzene solution of the compound with anhydrous AlCl^ and decomposition of the aluminum complex obtained with water. Reaction of the thus obtained hydroxy derivative with (C2_^)-alkyl sulphates in a strongly alkaline medium gives the corresponding (C2_4) alkoxy derivatives, while on the other hand the (C2_^)alkanoyloxy group in the 4- or 6-position can be obtained by reaction with a suitable (C2_^ )aliphatic acyl halide or anhydride under acidic conditions.

It should be understood that alternative methods which can be suitably used for the conversion of a pre-existing radical into another which is covered by the given definitions, are covered by the present invention even if they are not specifically described.

As indicated above, the compounds of formula I have anti-inflammatory, analgesic and antipyretic action. They also have low toxicity since LD,. The Q values are never lower than 1000 mg/kg orally in mice and higher than 2000 mg/kg orally in rats. The toxicities were determined according to Lichtfield and Cilcoxon, Journ. Pharm. Expt. Ther. , _96, 99, 1949.

The anti-inflammatory activity was determined using several methods; "and by one method the ability of the compounds to reduce edema induced in the paw of the rat by injection of carrageenan was evaluated and determined and the experiment was carried out according to the method attempted by CA. Winter et al. in Proe. Soc. Exptl. Biol. Med . 111, 544, (1962). According to another method, the effect of the compounds in reducing the weight of granuloma formed on a cotton pellet implanted subcutaneously in a rat, using the method described by Meier et al. in Experientia 6, 469, (1950).

Representative experiments have shown that the compounds set forth in Example 11, namely 2,3-dihydro-6-methoxy-N,2-dimethyl-4-benzofuranamine caused a reduction of the carrageenan-induced edema of about 70% above the controls even when administered -tion in an absolutely safe dose, i.e. around 1/5 of its LDj-q value. In the experiment with the granuloma cotton pellet, the same compound in the same dosage reduces the weight of said granuloma by more than 40% over the controls.

However, the most important pharmacological property of the compounds is that they are also effective in the adjuvant-induced arthritis experiment in rats. This experiment is certainly relevant since adjuvant arthritis is one of the best pharmacological parameters with which a pharmacologist can examine compounds with regard to their possible anti-inflammatory activity, due to the parallelism of effects that exists between said arthritis and some joint diseases that have been observed in humans (see S.M. Pearson, Arthritis and allied conditions, page 119, Lea and Febinger Publ., 1967 and CM. Pearson, J. Chronic Diseases, 16, 863 , 1963).

The experiment regarding adjuvant-induced arthritis was carried out as described by B.B. Newbould in Brit»Jour. Pharmacol., 21, 127, (1963). The measure of effectiveness of the compounds in this experiment is given by their ability to reduce the volume of the hind paws in laboratory animals. In another representative experiment, the compounds in example 11 proved to be significantly more active in the experiment with adjuvant-induced arthritis than acetylsalicylic acid, which is one of the most effective and widely used anti-rheumatic drugs. The results obtained, which are indicated in the table below, were obtained by testing the compounds in a dosage corresponding to 1/5 of their LD^^ value.

These beneficial properties are also associated with interesting analgesic and antipyretic properties which were investigated using the methods described by Randall et. eel. in Arch. Int. Pharmacodyn. 111, 409, (1957) and by Builler et al. in J. Pharm. Pharmacol. 9, 128, (1957), respectively. It should also be pointed out

that the new 2,3-dihydrobenzofuran derivatives exhibit a very low ulcerogenic activity which is several times less than that observed with known and therapeutically useful anti-inflammatory substances. The ulcerogenic effect was determined according to Thuillier et.al. Chim. Ther. 3, 51, (1968).

The following examples illustrate the invention.

Example 1: 2,3-dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid<y>leste<r>

2-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester is heated in a nitrogen atmosphere to 260°C for about 3 hours. On cooling, the reaction mass is dissolved in a small amount of 20% KOH and the aqueous alkaline solution is then extracted with ethyl ether. The organic phase is evaporated and the impure residue gives the above compound in a yield of 45%. Kp/0.3mmHg 136-138°C.

Example 2: 2,3-dihydro-4-methoxy-2-methyl-6-benzofurancarboxylic acid

1 g of 4-allyl-3-hydroxy-5-methoxybenzoic acid methyl ester i

5 ml of glacial acetic acid and 1.5 ml of 48% HBr are boiled under reflux in 3

hours. The mixture is then concentrated to dryness and the impure residue is dissolved in an aqueous alkaline solution. 0.3 g of dimethyl sulphate is added to the resulting solution which is refluxed for a further 2 hours. The desired compound which is precipitated by acidification of the cooled reaction mixture is recrystallized from ethyl ether-petroleum ether. Yield 60%, m.p. 180-182°C.

Example 3: 2,3-dihydro-4-hydroxy-2-methyl-6-benzofurancarboxylic acid

A mixture of 30 g of 4-allyl-3-hydroxy-5-methoxybenzoic acid, 150 ml of glacial acetic acid and 45 ml of 48% HBr is heated to reflux temperature for 8 hours. The reaction mixture is then concentrated to dryness and the residue obtained, ground with water and filtered, crystallized from ethyl ether-petroleum ether. The product is obtained in a yield of 19.9 g (71% of the theoretical yield) and has a melting point of 181-184°C.

Example 4: 2,3-dihydro-6-hydroxy-2-methyl-4-benzofurancarboxylic acid

To a solution of 35 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid methyl ester, prepared in example 1, in 160 ml of acetic acid, 60 ml of 48% HBr is added and the resulting mixture is refluxed for 16 hours. The reaction mixture is then concentrated to dryness and the residue is dissolved in concentrated NaOH. The resulting solution, which is heated in a water bath for 2 hours, is cooled, acidified with concentrated HCl and extracted with ether. Evaporation of the ether extract gives an impure residue which is purified by column chromatography using a mixture of CHCl 2 and MeOH as eluent, the percentage of MeOH being gradually increased. The desired compound, which is recovered from the last fractions (CHCl^ + 3% MeOH), is crystallized from ethyl ether-petroleum ether. Yield 14.2 g (47% of the theoretical yield), m.p. 225-227°C.

Example 5: 6-ethoxy-2,3-dihydro-2-methyl-4-benzofurancarboxylic acid

6.9 g of the compound prepared in example 4 are dissolved in

25 ml of 22% NaOH and the resulting solution is kept at 30°C

during the dropwise addition of 9 ml of diethyl sulphate, after which reflux is carried out for 2 hours. After adding 2 ml of concentrated NaOH, heating is continued for a further 2 hours. The mixture is then cooled, acidified with concentrated HCl and filtered. The solid substance recovered on the filter is dissolved in ethyl ether and the resulting solution is dried over Na 2 SO 3 and then concentrated to a small volume. The solid which is precipitated by the addition of petroleum ether is recrystallized from ethyl ether and gives 5.9 g (75% of the theoretical yield) of 6-ethoxy-2,3-dihydro-2-methyl-4-benzofurancarboxylic acid which melts with 155- 157°C.

Example 6: (6-ethoxy-2,3-dihydro-2-methyl-4-benzofuranyl)carbamic acid ethyl ester

a) A solution consisting of 5.7 g of 6-ethoxy-2,3-dihydro-2-methyl-4-benzofurancarboxylic acid, prepared as indicated in Example

5, 3.7 ml of SOC^, a few drops of N,N-dimethylformamide and 60 ml of water

free benzene, boil gently under reflux for 4 hours. After this time, the reaction mixture is concentrated to dryness and the residue obtained, dissolved in 65 ml of acetone, is cooled to 5°C, while a solution of 2.8 g of sodium azide in 8 ml of water is gradually added with stirring. Stirring at the same temperature is continued for a further 1 hour, after which the reaction mixture is poured into ice water and extracted with ether. Evaporation of the organic phase gives an oily residue which is the azide of the starting carboxylic acid compound.

b) This oily residue, dissolved in 60 ml of anhydrous xylene, is gradually heated to 120°C and kept at this temperature for

30 minutes. 10 ml of EtOH are then added dropwise to the reaction mixture, which is then boiled under reflux for 3 hours. The residue obtained by evaporation of the solvent is crystallized from ethyl ether and this gives 5.3 g (93% of the theoretical yield) of the desired compound indicated above, m.p. 64°C. Example 7: 6-ethoxy-2,3-dihydro-N,2-dimethyl-4-benzofuranamine hydrochloride

A solution of 4.1 g of the compound prepared in

example 6, in 30 ml of anhydrous benzene is gradually added to a suspension of LiAlH^ (1 g) in anhydrous ethyl ether (35 ml). The obtained reaction mixture is refluxed for 6 hours and

is then cooled and the aluminum complex is decomposed by the addition of 3 ml of water. After stirring at room temperature for 30

minutes, the inorganic salts are discarded by filtration, the filtrate is evaporated and HCl is bubbled into a solution of the obtained residue in ethyl ether. The precipitate that forms is collected on the filter and recrystallized from ethyl alcohol-ethyl ether and this gives 3 g (80% of the theoretical yield) of the above-mentioned desired compound which melts at 173-175°C.

Example 8: 2,3-dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid

To a stirred mixture of 158 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid methyl ester and 88.5 g of sodium hydroxide flakes in 320 ml of water, ethanol is added gradually until a clear solution is obtained. The reaction mixture is left at room temperature for about 5 hours, after which the solvent is evaporated under reduced pressure and the residue obtained, taken up in water and acidified with dilute HCl, is extracted with ether. Concentration of the organic phase to dryness and crystallization of the residue from ethyl ether by addition of petroleum ether gives 106 g (71.6% of the theoretical yield) of the desired compound stated above, m.p. 153-155°C.

Example 9: 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine

70 ml of SOCI2 are dropped at room temperature into a stirred solution of 106.8 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuran-carboxylic acid in 840 ml of anhydrous benzene. After the addition is complete, the reaction mixture is heated to 80°C for 5 hours and then concentrated to dryness. The residue thus obtained, consisting of the acyl chloride of the starting acid, is purified by crystallization from ethyl ether-petroleum ether and dissolved in 1370 ml of anhydrous acetone. To the resulting solution cooled with stirring to +5°C, 61.6 g of NaN 2 dissolved in 180 ml of water are gradually added. The latter temperature is maintained for a further 1 hour, after which the reaction mixture is poured into 4600 ml of cold distilled water. Extraction with ethyl ether and evaporation of the organic phase gives the impure azide of the starting carboxylic acid compound which is purified by crystallization from ethyl ether.

A solution of this intermediate product in 100 ml of ethyl ether is gradually added with stirring to 600 ml of ethylene glycol heated in an oil bath to 85°C. When the addition is finished, the temperature is increased to 220°C for 5 minutes, after which the reaction mixture is made alkaline with an ethylene glycol solution of 98 g of KOH flakes and refluxed for 20 minutes. After cooling, the reaction mixture is poured into 1200 ml of distilled ice water, stirred in 10 minutes is acidified with concentrated HCl and after 15 minutes the whole is made basic again with concentrated NaOH. By extraction with ethyl ether, evaporation of this organic extract and crystallization of the resulting residue from petroleum ether, 81 g of the desired compound are obtained. Temp. 59-61°C. Total yield calculated for the starting carboxylic acid compound is 88.6%.

Example 10: (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-carbamic acid ethyl ester

55.75 g of ethyl chlorocarbonate in 100 ml of anhydrous benzene is added gradually at 5°C to a stirred solution of 81 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 46 ml of triethylamine in 700 ml of anhydrous benzene. After the addition is complete, the reaction mixture is gently heated and stirring is continued at room temperature for 3 hours. The reaction mixture is then boiled under reflux in

2 hours, cooled, washed with water, dried over Na 2 SO 4 and concentrated to dryness to give 95.81 g (83.5' of the theoretical yield) of the desired compound, kp/0.4 mmHg 172°C. Example 11: 2,3-dihydro-6-methoxy-N,2-dimethyl-4-benzofuranamine

95.81 g of (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-carbamic acid ethyl ester prepared as indicated in Example 10 is dissolved in 385 ml of anhydrous ethyl ether and the resulting solution is added dropwise to a stirred suspension of 21.01 g of LiAlH^ in 600 ml of anhydrous ethyl ether cooled to 0°C, after which the obtained reaction mixture is refluxed for 5 hours. After cooling, 63 ml of cold, distilled water is added to the reaction mixture and the inorganic salts that precipitate are passed by filtration. The filtrate, dried over Na^SO^, is evaporated and this gives an oily residue which, purified by vacuum distillation, gives 34 g of the desired compound, kp/0.3 mmHg 137°C. This compound, which solidifies easily, melts at 53°C (from ethyl ether petroleum ether). The corresponding hydrochloride melts at 147°C.

Example 12: N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-propanamide

This compound is prepared according to the method described in example 10 by reacting the 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine starting compound with propionyl chloride instead of ethyl chlorocarbonate. Temp. 101-102°C (from ethyl

ether), yield 44 g (75% of theoretical).

Example 13: 2,3-dihydro-6-methoxy-2-methyl-N-propyl-4-benzofuranamine

A solution of 3.2 g of N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)propanamide, prepared as indicated in the previous example, in 30 ml of anhydrous benzene is gradually added to a suspension of 1.1 g LiAlH^ in 30 ml of anhydrous ethyl ether at 0°C

and the resulting reaction mixture is heated to reflux temperature for 6 hours. The temperature is then lowered to 0°C and the aluminum complex is decomposed by adding 3.3 ml of water. After stirring for 30 minutes at room temperature, the inorganic salts are discarded by filtration and the filtrate, dried over Na2SO4, is concentrated to dryness. Distillation in vacuum of

the obtained residue gives 2.8 g (93% of the theoretical yield) of the desired compound, kp/0.2 mmHg 140-142°C. The corresponding hydrochloride prepared by treating the free base with HCl melts at 110-111°C.

Example 14: N-ethyl-2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine

3 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 2.02 g of triethylamine in 30 ml of anhydrous benzene are poured into a steel reaction vessel and 5 ml of ethyl bromide and traces are added of potassium iodide. The reaction container is closed and heated in an oil bath to 100°C for 15 hours. The reaction mixture is then allowed to cool and is filtered. The filtrate is concentrated to dryness and this gives an oily residue which on distillation under reduced pressure gives 1.1 g of the desired product, kp/0.5 mmHg 13 5°C. Example 15: N,N-diethyl-2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine

The alkylation reaction is carried out exactly as in the previous example and the same methods are followed up to the second filtration. Then, to recover the desired diethylamino derivative,

the benzene filtrate containing the monoethylamino derivative is discarded, while the remaining solid substance is taken up in water. The solution obtained is cooled, made basic by the addition of 50% NaOH and extracted thoroughly with ethyl ether. The oily residue obtained by evaporation of the organic phase is distilled under reduced pressure and this yields 1.2 g of N,N-diethyl-2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine, bp/0, 5 mmHg = 131°C.

Example 16: N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-acetamide

This compound is prepared according to the methods in example 10 by reacting 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine with acetyl chloride. Temp. 104°C (from isopropyl ether/ethyl alcohol).

Example 17: N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-diacetamide

A reaction mixture consisting of 2.4 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine, 10 ml of acetic anhydride and a drop of pyridine is heated to 130-140°C for 90 minutes. After cooling and evaporation of excess acetic anhydride, the residue is distilled under reduced pressure and this yields 2.4 g (69%

of the theoretical yield) of the desired compound, kp/0.4 mmHg 160°C. The distillate which solidifies is crystallized from ethyl ether-petroleum ether, m.p. 56-57°C.

Example 18: (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-phenylacetamide

This compound is prepared according to the methods indicated in example 10 by starting from 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and benzoyl chloride. Temp. 148°C, (from isopropyl ether-ethyl alcohol).

Example 19: N,N-diethyl-N'-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-1,2-ethanediamine dihydrochloride

2.80 g of 2-diethylaminoethyl chloride and traces of potassium iodide are added to a solution of 3 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 2.02 g of triethylamine in 50 ml of anhydrous toluene and the resulting reaction mixture boil under reflux for 16 hours. After cooling and washing with water, the toluene phase is dried over Na2SC>4 and then concentrated to dryness. Hydrochloric acid is added to an ether solution of the resulting oily residue until a solid precipitates, after which cooling is carried out. The precipitate is collected on the filter and recrystallized from ethanol by the addition of ethyl ether, and this gives 3.55 g of the desired compound. Temp. 158-159°C.

Example 20: N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-phenacylsulfonamide

A solution of 24, 5 g of phenacylsulfonyl chloride in 80 ml of methylene chloride. After the instillation has ended, the reaction mixture is heated to room temperature and stirred for 5 hours. The solution is then washed with water, dried over sodium sulfate and concentrated to dryness. Crystallization of the resulting thick oil from ethyl alcohol-ethyl ether gives 16 g of the desired compound melting at 143-145°C.

Example 21: N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-urea

2.5 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine is dissolved in 16 ml of 0.1N HCl and by gradual addition of 1.1 g of sodium cyanate to the resulting solution a white crystalline solid is precipitated. The reaction mixture is then heated in a water bath and after 90 minutes cooling and filtration are carried out. By recrystallization of the obtained precipitate from ethyl alcohol, 1.9 g (61% of the theoretical yield) of the desired compound is obtained, m.p. 204-206°C.

Example 22: (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-carbamic acid phenylmethyl ester

0.65 g of phenylmethylchlorocarbonate is added dropwise. at 5°C in a stirred mixture containing 0.7 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine hydrochloride, 5 ml of 2N NaOH and 10 ml of chloroform. When the addition is finished, vigorous stirring is continued for one hour at the same temperature and for 2 hours at room temperature. The organic phase is then separated, washed with water, dried over Na 2 SO 4 and concentrated to dryness. The residue obtained is crystallized twice from ethyl ether-petroleum ether and this gives 0.9 g (88% of the theoretical yield) of (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)carbamic acid phenylmethyl ester, m.p. . 82-83°C.

Example 23: N-(2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)-N-methylpropanamide

The reaction is carried out as indicated in example 10 by dripping propionyl chloride into a benzene solution of 2,3-dihydro-6-methoxy-N-2-dimethyl-4-benzofuranamine and triethylamine. Recovery of the impure end product is achieved by cooling the reaction mixture, which has previously been refluxed for 2 hours, separating the resulting precipitate which, ground with benzene and filtered, is then discarded and finally concentrating the benzene filtrate to dryness. Distillation under reduced pressure of the resulting residue gives 2 g (90% of the theoretical yield) pure

connection. Kp/0.4 mmHg 140-142°C.

Example 24: (2,3-dihydro-4-methoxy-2-methyl-6-benzofuranyl)-carbamic acid ethyl ester

A solution of 4.5 ml of SOC^ in 10 ml of anhydrous benzene is added dropwise to 6.5 g of 2,3-dihydro-4-methoxy-2-methyl-6-benzofurancarboxylic acid, prepared in Example 2, suspended in 65 ml of anhydrous benzene and a few drops of N,N-dimethylformamide. The reaction mixture is gradually heated to 70-80°C and stirred at this temperature for 4 hours. The solvent is then evaporated and the thick oil obtained is dissolved in 65 ml of acetone. 3.9 g of NaN^ in 15 ml of water is added to the resulting solution cooled to approx. 5 C and stirring is continued at this temperature for a further 1 hour.

The reaction mixture is then poured into 400 ml of ice water and extracted twice with 100 ml of ethyl ether. The organic phase is evaporated and the residue, which is redissolved in 150 ml of ethyl ether and dried over Na^SO^, is concentrated to a small volume. The solid which is precipitated by the addition of petroleum ether is dissolved in 60 ml of anhydrous xylene and heated with stirring up to 12 0 oC. After 30 minutes at this temperature, 10 ml of anhydrous ethanol are added and the mixture is then heated in an oil bath to 130°C for 3 hours. The reaction mixture is then concentrated to dryness and the resulting residue is distilled under reduced pressure whereby the fraction boiling at 170-180°C at 0.4 mm Hg is collected, and crystallization from ethyl ether/petroleum ether of the solidified distillate gives 5 g ( 78% of the theoretical yield) of the desired compound, m.p. 93-94°C. Example 25: 2,3-dihydro-4-methoxy-N,2-dimethyl-6-benzofuranamine

This compound is prepared according to the methods stated in example 11, but by starting from (2,3-dihydro-4-methoxy-2-methyl-6-benzofuranyl)carbamic acid ethyl ester. Kp/0.2 mmHg 130°C, yield 94%.

The corresponding hydrochloride, crystallized from ethanol/ethyl ether, melts at 157-158°C.

Example 26: 2,3-dihydro-6-hydroxy-N,2-dimethyl-4-benzofuranamine

5 ml of 48% HBr is added to a solution of 5 g of 2,3-dihydro-6-methoxy-N,2-dimethyl-4-benzofuranamine hydrochloride in 20 ml of acetic acid and the resulting mixture is refluxed for 16 hours. The solvent is then evaporated and the residue, taken up in sodium bicarbonate, is thoroughly extracted with ether. Evaporation of this organic phase, which is previously dried over. Na 2 SO 4 gives an impure residue which is crystallized from ethyl ether-petroleum ether and this gives 3 g of the desired end product. Yield 77% of the theoretical, m.p. 126-128°C.

Example 27: 6-acetoxy-2,3-dihydro-N,2-dimethyl-4-benzofuran-amine hydrochloride

1.7 g of the compound prepared in the previous example is added to 20 ml of ethanol containing 0.8 g of HBr. By evaporation, a tar-like residue is obtained which is carefully dried in vacuum over P2°5- The residue is then dissolved in 20 ml of CF^COOH and 1.4 g of CH^COBr is gradually added to the resulting solution.

After stirring for 1 hour, a few drops of water are added and the reaction mixture is concentrated to dryness under reduced pressure by gentle heating. The residue obtained is dissolved in a small amount of cold water and the solution, which has been made basic by the addition of NaHCO-j, is thoroughly extracted with ethyl ether. Evaporation of the ether phase and purification of the resulting residue by column chromatography using CHCl^+ 1% acetone as eluent gives 6-acetoxy-2,3-dihydro-N,2-dimethyl-4-benzofuranamine, the hydrochloride of which crystallized from ethanol/

ether melts at 159-160°C. Yield 57% of the theoretical.

Typical 2,4,6-trisubstituted-2,3-dihydrobenzofurans

which can be produced using the methods described in the examples, are the following:

Preparation of the starting material: 4-allyl-3-hydroxy-5-methoxybenzoic acid and

2-allyl-3-hydroxy-5-methoxybenzoic acid.

Starting from 3-hydroxy-5-methoxybenzoic acid methyl ester by reaction with allyl bromide, 3-allyloxy-5-methoxybenzoic acid methyl ester is obtained. Kp 128-130°C/0.4 mmHg. This compound is subjected to allyl rearrangement which is carried out by refluxing in N,N-dimethylaniline in a nitrogen atmosphere for about 6

hours. After cooling, the solvent is evaporated and the residue, taken up in ether, washed with cold, dilute HCl and then thoroughly extracted with aqueous 20% NaOH. Separation of 4-allyl-

and the 2-allyl-3-hydroxy-5-methoxy-benzo acids are obtained by fractional crystallization by acidification.

Claims (7)

1. 2,4,6-trisubstituted-2,3-dihydrobenzofuran derivatives, characterized in that they have the general formula: where R is hydrogen or methyl, one of R^ and R^ is hydroxy, (C^ _4 ) alkoxy or (C 2 _4 )alkanoyloxy, and the other is cyano, carboxy, carbo(C^ _4 ) alkoxy, carbamoyl or a - NR^ R^ -group, where R^ and R^ are independently hydrogen, (C^ _4 )alkyl, (C2 _4 )alkanoyl, carbo(C^ _^ )alkoxy, carbobenzyloxy, carbamoyl, mono- and di-(C 4)-alkylamino-(C 4 ) alkyl., benzenesulfonyl, toluenesulfonyl, - alkylsulfonyl or phenasylsulfonyl; and salts thereof with pharmaceutically acceptable acids. .2. Compound according to claim 1, characterized in that R is hydrogen or methyl, one of R^ and R2 is hydroxy, (C^ _4 ) alkoxy or (C2 _^ ) aliphatic alkanoyloxy and the other is the group -NR^ R^ where R^ and R 1 is each independently hydrogen or a (C 1 -4 )alkyl group; and salts thereof with pharmaceutically acceptable acids. 3. Compound according to claim 1, characterized in that R is a hydrogen atom, one of R^ and R2 is a (C 1-4 ) alkoxy group and the other is the group -NR^ R^ where R^ and R^ are each independently hydrogen or (C 1 -4 )alkyl; and salts thereof with pharmaceutically acceptable acids. 4. Compound according to claim 1, characterized in that it consists of 2,3-dihydro-6-methoxy-N,2-dimethyl-4-benzofuranamine. 5. Process for the preparation of 2,4,6-trisubstituted-2,3-dihydrobenzofuran derivatives with the general formula: where R is hydrogen or methyl, one of <v> R^ and R 2 is hydroxy, ^ C 1-^~ alkoxy or (C 2 _4 )alkanoyloxy, and the other is cyano, carboxy, carbo(C 4 -C 4 ) alkoxy, carbamoyl or a -NR^ R^ -group, where R^ and R^ are independently hydrogen, (C^_4 )alkyl, (C2_4 )alkanoyl, carbo(C-L_4 ) alkoxy, carbobenzyloxy, carbamoyl, mono- and di-(C 4 ) alkylamino-(C 4 ) alkyl, benzenesulfonyl, toluenesulfonyl, (C 4 ) alkylsulfonyl or phenacylsulfonyl; and salts thereof with pharmaceutically acceptable acids, characterized in that a compound of the general formula: where R has the meaning given above and the group -CH2 =CH=CH-R can be in the 2- or 4-position in the phenyl ring, is subjected to thermal or acid-induced ring closure whereby a compound of formula I is obtained, where R is hydrogen or methyl, one of R 1 and R 2 is a methoxy radical and the other is a carboxy or a carbomethoxy group, which compound is further converted into the other compounds covered by formula I by means of methods known per se. 6. Method according to claim 5, characterized in that the thermal ring closure is carried out at a temperature varying from approx. 200 to approx. 280°C. 7. Method according to claim 5, characterized in that the acid-induced ring closure is carried out in the presence of mixtures of acetic acid and hydrobromic acid.