DE2813895A1 - NEW 2,4,6-TRISUBSTITUTED 2,3-DIHYDROBENZOFURANE DERIVATIVES - Google Patents

Description

Gruppo Lepetit S.p.A. Milan, Italy

New 2,4,6-trisubstituted 2, j5-dihydrobenzofuran derivatives

The invention relates to new 2,4,6-trisubstituted 2,3-dihydrobenzofuran derivatives the formula

wherein R is hydrogen or the methyl group and one of the radicals R, and Rp is the hydroxyl group, a (C, ^) AlkOXy or (C ₂ _ ^) alkanoyl radical and the other is the cyano or carboxyl group, a carbo (C, _u) alkoxy , Carbamoyl or -NR ₁₅ R ₂ , group, wherein R ^ and R ^. independently of one another hydrogen, a (C _1-2 ^) alkyl, (Cg _ ^) alkanoyl, Ca ^ o (C ₁ h) alkoxy ^ the carbobenzyloxy or carbamoyl, a mono- or di (C _{1- 2} ^) alkylamino (C _1- ^) alkyl, the benzenesulfonyl, toluenesulfonyl, 'a (C _1-2 ,) alkylsulfonyl or phenacylsulfonyl radical, and their salts with pharmaceutically acceptable acids. The compounds have anti-inflammatory, analgesic and antipyretic effects.

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2,4,6-trisubstituted 2,3-dihydrobenzofurans, their substituent is a methyl or ethyl group in the 2-position represent a new class of compounds. Some 2,4,6-trisubstituted Benzofurans (the benzofuran skeleton shows the following formula:

are known, see for example A. Wahhab, J. Prakt. Chem. 314, 213, 1972. Other benzofurans with various substituents in one or more of the possible positions are described in Bull. Sog. Chim. Fr., page 915, 1967, J. Org. Chem., 28, 398, 1963 and J. Org. Chem., 30, 1246, 1965.

The present invention relates to new 2,4,6-trisubstituted ones 2,3-Dihydrobenzofuran derivatives of the formula

where R is hydrogen or the methyl group and one of the radicals R, and Rp is the hydroxyl group, a (C-, ^) alkoxy or (Cp _-2 ,) - alkanoyl radical and the other is the cyano group, a carbo (C-, J) - alkoxy, carbamoyl or -NR- ^ R ₂ , group, in which R ₁ and R 2 ^. independently of one hydrogen, a (C _1-2 ,) alkyl-, (Cp _- J,) alkanoyl-, carbo (C _1-2 ,) alkoxy-, carbobenzyloxy-, carbamoyl-, mono- or di- (C-, _-2 ,) alkylamino- (C-, _-2 ,) alkyl-, benzenesulphonyl-, toluenesulphonyl, (C _1-2 ^) alkylsulphonyl or phenacylsulphonyl radicals, and their salts with pharmaceutically acceptable acids. The compounds have anti-inflammatory, analgesic and antipyretic effects. Under a (C _1-2 ,) alkyl radical, the methyl, ethyl, propyl, isopropyl,

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Butyl, sec-butyl and tert-butyl radicals understood. The methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy radical are denoted by a (C _{1-2) alkoxy radical.}

/ ν oxystands. The designation (CU _- J,) alkanoyl radical includes the acetyloxy, propionyloxy and butyryloxy radical. The designation (Cp j,) alkanoyl radical denotes the acetyl, propionyl and butyryl radical. Preferred compounds are those of the formula I in which R is hydrogen or methyl and one of the radicals R and Rp is the hydroxyl group or a (C _1- JIi) AlkOXy or (Cph) aliphatic-alkanoyl radical as defined above and the other is a radical of the formula - NR ^ R ₂ . represent, in which R .. and R ₂ ,, independently of one another hydrogen or a (C _1-2 ,) alkyl radical according to the above definition, and their salts with pharmaceutically acceptable acids. Most preferred are compounds of the formula I in which R is a hydrogen atom and one of the radicals R ₁ and Rp is a (C _1- J) alkoxy radical as defined above and the other is a radical of the formula -NR ^ R ₂ , in which R , and Rj, independently of one another, denote hydrogen or a (C _1- J) alkyl radical as defined above, and their salts with pharmaceutically acceptable acids.

Both organic salts are used to form therapeutically useful salts as well as inorganic acids are particularly suitable. These acids include, for example, aliphatic or aromatic Carboxylic acids such as formic acid, acetic acid, succinic acid, oxalic acid, malic acid, tartaric acid, citric acid, ascorbic acid, Benzoic acid and salicylic acid, as well as mineral acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid or perchloric acid. In the production of the invention Compounds, the first step is the formation of the 2,3-dihydrobenzofuran structure by cyclization a compound of formula II

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CH-CH = CH-R

II

wherein R has the meaning given above. For the purposes of the invention, the radical -CH ₂ -CH =CH-R must be in the 2- or 4-position. If, for example, R is hydrogen, the compound of the formula II is an o-allylphenol derivative. If R is the methyl group, the compound of the formula II is an ο-crotylphenol derivative.

Depending on the position of the allyl or crotyl radical in the benzene ring the cyclization to 2,3-dihydrobenzofuran takes place by thermal or acid-induced ring closure according to one of the following schemes:

Scheme A

COOCH

Scheme B

COOCH ₀ HBr / AgOH

t. O

OCH,

HOOC

CH ₂ -CH = CH R

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In the practical implementation, the cyclization of 2-allyl or 2-crotyl-3-hydroxy-5-methoxyt> enzoic acid methyl ester carried out according to scheme A by placing the starting material in an inert atmosphere, for example in nitrogen or carbon dioxide, heated to a temperature of about 200 to about 280 ° C for about 2 to 4 hours. The cyclized The compound is then worked up according to the usual method by placing the cooled reaction mass in an aqueous alkali solution dissolves, extracted with a water-immiscible organic solvent, the organic phase is concentrated and the product is purified by vacuum distillation or column chromatography. The reaction can also be in a neutral or basic high-boiling organic solvents are carried out, in which case the reaction mixture Heated to reflux temperature for 2 to 6 hours. The solvent is then evaporated off and the cyclization product worked up as described above.

According to scheme B, the acid-induced cyclization of the 4-allyte or ^ -Crotyl - ^ - hydroxy-S-methoxybenzoic acid methyl ester takes place, by dissolving the starting material in acetic acid and then adding hydrobromic acid.

. The reaction can take place at room temperature. However, in general, the reaction mixture is preferably heated or heated to reflux to speed the reaction, which can be complete in 1 to 4 hours. Separation and cleaning of the 2, ^ - dihydrobenzofuran obtained are carried out by customary methods, taking into account that the acidic reaction conditions enable the hydrolysis of the carboromethoxy group. It has also been found that if the reaction time is extended to 7 to 10 hours, the hydrolysis of the methoxy group leads to Hydroxy group takes place.

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The starting materials of the formula II can easily by Claisen rearrangement of allylphenyl ethers of the formula III

COOCH,

III

in which R is hydrogen or methyl, are obtained using the method of Tarbell, Organic Reactions, Vol. II, New York, 1944, that is, with heating of the allyl phenyl ether in the absence of a solvent to a temperature between 180 or 220 ⁰ C, or by heating a solution of a compound of the formula III in a basic or neutral high-boiling organic solvent under reflux. Suitable solvents are Ν, Ν-dimethylaniline, Ν, Ν-diethylaniline, paraffin oil, tetralin or kerosene. The rearrangement is preferably carried out in an inert atmosphere. The isomers are worked up by customary processes, making use of the various solubilities of the carboxylic acids obtained by alkaline hydrolysis in aqueous solutions.

The two isomers can also be precipitated as a mixture and separated from one another by column chromatography. The desired products of the formula II are then obtained by customary esterifications.

The process of schemes A and B gives compounds of the formula I in which R is hydrogen or methyl and one of the radicals R, and Rg a methoxy radical and the other mean a carboxyl or carbomethoxy group.

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If other compounds of the formula I are sought, the corresponding radicals must be introduced by obvious chemical reactions that are familiar to the average person skilled in the art. For example, the alkaline hydrolysis of the carbomethoxy substituent in the 4-position leads to the corresponding carboxyl group, which in turn, like the carboxyl group in the 6-position formed in the acid-induced cyclization, with a (.C-, u ) alkanol in the presence of a strongly acidic medium can be implemented, giving the desired 4- or 6-carbo (C-, ^) alkoxy derivatives.

The carboxyl group in the 4- or 6-position can be subjected to further chemical modifications. For reasons of expediency, it is first converted into the more reactive group -COHaI, in which Hal is a halogen atom, preferably chlorine or bromine, which in turn can be converted into the radical -CON by reaction with nitrium nitrite. Furthermore, the group -COHaI can be converted into the amide by ammonolysis, which can be dehydrated to give compounds of the formula I in which R ₁ . or R _{2 is} the cyano group.

The benzofurans with a -CON ^ group in the 4- or 6-position are intermediates for the preparation of other compounds that fall within the scope of the general formula.

The thermal decomposition of the -CON ·, group leads to compounds of the formula I in which R ₁ or Rp denote the amino group, that is to say the radical -NR- ^ r ^, in which R ^ and R ₁ denote hydrogen. If the decomposition takes place in the presence of a (C-, η ) alkanol or benzyl alcohol, compounds of the formula I are obtained in which R ₁ or R _{0 is} a carbo (C) -

1-4 are alkoxyamino or carbobenzyloxyamino radicals.

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_{The compounds in which R 1} or R _{2 is} the methylamino group are easily prepared from these compounds in a simple reductive step. Most preferred among the reducing agents is lithium aluminum hydride.

The substituents R 1 and R k other than hydrogen are also introduced by known methods by reacting the corresponding 4- or 6-unsubstituted amino derivatives with suitable reaction partners. For example, reaction with an alkylating agent such as a (C-, _ ^) alkyl halide or (C ₁ _ ^) alkyl sulfate yields compounds in which R ^ and / or R ^ are (C _1- ^) alkyl groups. Compounds in which IU and / or Rh denote a (Cp_2,) - alkanoyl radical are obtained by reacting the corresponding compounds in which R ^, and / or R ^ represent hydrogen, with halides or anhydrides of aliphatic acids with 2 to 4 carbon atoms. Carbo (C-, ^) -alkoxy and carbobenzyloxy-amino groups are obtained by reaction with corresponding (C-, _2j.) Alkyl and benzyl carbonates. For their part, as described above, they can be converted into 4- or 6-methylamino derivatives. The benzenesulfonyl, toluenesulfonyl, (C _1- ^) alkylsulfonyl and phenacylsulfonyl groups are conveniently obtained by reaction with benzenesulfonyl, toluenesulfonyl, (C _1- ^) alkylsulfonyl and phenacylsulfonyl halides, while the carbamoyl group can be introduced by the unsubstituted amino derivative in an acidic medium, reacts with an alkali isocyanate.

A convenient route to compounds in which R and R ₂ denote a ( ^C 2--2 alkylamino group is to reduce the (Cp-2-) acyl substituents of the amino group.

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Finally, the methoxy groups in the 4- or 6-position can also be converted into another radical as defined above by known chemical reactions. Demethylation can be carried out by refluxing the compound with HBr / AcOH mixtures, or by refluxing a solution of the compound in carbon disulfide or nitrobenzene with anhydrous aluminum chloride and decomposing the resulting aluminum complex with water. The reaction of the hydroxy derivative obtained in this way with (Cp j,) - alkyl sulfates in a strongly alkaline medium leads to the corresponding (Cp_N) alkoxy derivatives, while the (Cp ^) - alkanoyloxy groups in the 4- or 6-position by reaction with the appropriate acyl halide or Anhydride in acidic medium "can be obtained.

Also other methods that are used to convert an existing remainder into another remainder according to the above meaning can be used for the respective substituents, are considered to fall within the scope of the invention even without a detailed description.

As already mentioned, the compounds according to the invention have anti-inflammatory, analgesic and antipyretic effects. They are of low toxicity since the oral LDp- ₀ values are never below 1000 mg / kg in mice and above 2000 mg / kg orally in rats. The toxicities were determined according to Lichtfield and Wilcoxon, Jaurn., Pharm. Expt. Ther., 96, _ 99, 1949.

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The anti-inflammatory effect was determined after several test procedures. One method is to determine the ability of the compounds to reduce edema caused by injection of carrageenin into the rat paw. The test was carried out according to CA. Winter et al., Proc. Soc. Exptl. Biol. Med. 111, 544, 1962. Another method is to determine the extent to which the test compounds reduce the weight of a granuloma which forms on a cotton ball implanted subcutaneously in the rat, see Meier et al., Experientia 6 ^ _ 469, 1950.

Representative experiments have shown that the compound of Example 11, that is to say 2,5-dihydro-6-methoxy-N, 2-dimethyl-4-benzofuranamine, causes a reduction in edema induced by carrageenin of about 70% when administered an absolute safe dose, ie about 1/5 of the LD ₁ -Q * En granuloma test, the same compound ■ reduces the granuloma weight by more than 40 % .

The most important pharmacological aspect of the compounds according to the invention lies in the effectiveness in the rat test in the case of arthritis induced by adjuvants. This test is absolutely meaningful because the arthritis caused by an adjuvant is one of the best pharmacological parameters that the pharmacologist can use to research possible anti-inflammatory effects, due to the parallels between it and some joint diseases observed in humans (compare Pearson, CM, Arthritis and allied conditions, p. 119 "Lead and Febiger Publ., 1967, and Pearson CM., J. Chronic Diseases, 16, 863, 1963).

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The adjuvant-induced arthritis test was performed as described by BB Newbould, Brit. Jour. Pharmacol. 21, 127 * (1963). The degree of effectiveness of the compounds in this test is given by their ability to reduce the volume of the hind paws of laboratory animals. In another representative experiment, the compound of Example 11 was found to be significantly more active in this arthritis test than acetylsalicylic acid, which is one of the most effective and widely used anti-inflammatory drugs. The results summarized in the following table were obtained with doses corresponding to I / 5 of the LDj- _n :

link

LD ₅₀ mg / kg rat po

Dose mg / kg rat p.o.

% Volume reduction of the hind paws

2,3-dihydro-6-methoxy-N, 2-dimethyl - ^ - benzofuran-

amine 2800

Acetylsalicylic acid

200

200

36 25

These beneficial properties are associated with interesting analgesic and antipyretic properties, which according to the methods of Randall et al., Arch. Int. Pharmacodyn. 111, 4-09 (Ϊ957) and Builler et al., J. Pharm. Pharmacol. 9 ^ _ 128 (1957). Finally, it should be mentioned that the new 2,3-dihydrobenzofuran derivatives according to the invention have a very low ulcerogenic effect compared to other known and therapeutically used anti-inflammatory agents. The uleerogenic effect was determined according to Thuillier et al., Chim.Ther. 3.51 (1968).

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example 1

2,3-Dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid methyl ester

2-Allyl-3-hydroxy-5-methoxybenzoic acid methyl ester is heated ^{to 260 ° C. for about 3 hours in a nitrogen atmosphere.} After cooling, the reaction mass is dissolved in a little 20% potassium hydroxide solution and the aqueous-alkaline solution is extracted with ethyl ether. The organic phase is concentrated and the crude residue gives the title compound in 45% yield; Kp _n , = 136 - I38 ⁰ C.

Example 2
2,3 ~ Dihydro-4-methoxy-2-methyl-6-benzofurancarboxylic acid

1 g of methyl 4-allyl-3-hydroxy-5-methoxybenzoate in 5 ml of glacial acetic acid and 1.5 ml of 48% hydrobromic acid is refluxed for 3 hours. Then the mixture is concentrated to dryness and the crude residue is dissolved in an aqueous alkali solution. 0.3 g of dimethyl sulfate are added to the resulting solution, and the mixture is then refluxed for a further 2 hours. When the cooled reaction mixture is acidified, the title compound separates out and is recrystallized from ethyl ether / petroleum ether. Yield 60 %, P. 180 to 182 ° C.

Example 3

2,3-Dihydro-4-hydroxy-2-methy1-6-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% hydrobromic acid

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Heated to reflux for 8 hours. The reaction mixture is then concentrated to dryness and the residue is crystallized from ethyl ether / petroleum ether after trituration with water and filtration. The product is obtained in a yield of 19.9 g (71 %), mp 181 to 184 ^° C.

Example 4

2, ^ - Dihydro-6-hydroxy-2-methyl- ⁱ i · - benzofurancarboxylic acid

To a solution of 55 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid methyl ester (for preparation see Example 1) in 160 ml of acetic acid, βθ ml of 48% hydrobromic acid are added and the resulting mixture is stirred for 16 hours Heated to reflux. The reaction mixture is then concentrated to dryness and the residue is dissolved in concentrated sodium hydroxide solution. The resulting solution is heated in a water bath for 2 hours, then cooled, acidified with concentrated hydrochloric acid and extracted with ether. When the ether extract is concentrated, a crude residue is obtained which is purified by column chromatography with a mixture of chloroform / methanol as the eluting system (with a gradual increase in the proportion of methanol). The title compound is obtained from the last fractions (CHCl 3 + _75% MeOH) is crystallized from ethyl ether / petroleum ether to yield 14.2 g (47%), mp 225-227 ⁰ C.

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

6.9 g of the compound from Example 4 are dissolved in 25 ml of 22% sodium hydroxide solution and the solution is ^{heated to} 30.degree

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held while 9 ml of diethyl sulfate are added dropwise. The mixture is then refluxed for 2 hours. After adding 2 ml of concentrated sodium hydroxide solution, the mixture is heated for a further 2 hours. The reaction mixture is then cooled, acidified with concentrated hydrochloric acid and filtered. The solid is dissolved in ethyl ether and the solution is dried over sodium sulfate and concentrated to a small volume. The pesticide which separates out when petroleum ether is added is recrystallized from Sthyläfeher, 5.9 g (75 %) of 6-ethoxy-2,3-dihydro-2-methyl-4-benzofurancarboxylic acid with a temperature of 155 to 157 ° C are obtained « ,

Example 6

Ethoxy-2,3-dihydro-2-methyl-4-benzofuranyl (6 ~ ethoxy-2,3-dihydro-2-methyl-benzofuranyl) carbarnic acid ethyl ester

a) A solution of 5 * 7 S 6-ethoxy-2,3-dihydro-2-methyl-4-benzofurancarboxylic acid (For preparation, see Example 5), 3 * 7 ml of thionyl chloride, a few drops of N, N- «dimethyl

formamide and 60 ral anhydrous benzene is 4 hours mild heated to reflux. Then the reaction mixture is concentrated to dryness and the residue is dissolved in 65 ml of acetone solved. The solution is cooled to 5 ° C., while slowly stirring a solution of 2.8 g of sodium azide in 8 ml Adding water. After the addition has ended, the mixture is stirred for a further hour, then the reaction mixture is poured into ice water poured and extracted with ether. When the organic phase is concentrated, an oily residue is obtained from the azide the starting acid.

b) This residue is dissolved in βθ ml of anhydrous xylene and the solution is slowly heated to 120 ⁰ C and held J30 min. at this temperature. Then 10 ml of ethanol

added dropwise, whereupon the mixture is refluxed for 3 hours.

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The residue obtained after the solvent has evaporated is finally crystallized from ethyl ether, 5.3 g (93 %) of the title compound of P. 6K ⁰ C are obtained.

Example 7

6-ethoxy-2,3-dihydro-N, 2-dimethyl - ^ - benzofuranamine hydrochloride

A solution of 4.1 g of the compound obtained according to Example 6 in 30 ml of anhydrous benzene is slowly added to a suspension of 1 g of lithium aluminum hydride in 35 ml of anhydrous diethyl ether. The reaction mixture is. Heated 6 hours at reflux and then cooled, the aluminum complex was decomposed by the addition of 3 ^m l of water "After half an hour's stirring at room temperature the inorganic salts are filtered off and the filtrate is concentrated. Hydrogen chloride is passed into a solution of the residue thus obtained in ethyl ether. The precipitate which forms is filtered off and recrystallized from ethyl alcohol / ethyl ether to give 3 S (80%) of the title compound from P. 173-175 ⁰ C..

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

To a mixture of 158 g of 2,3-dihydro-6-methoxy-2-methyl— * J— Benzofurancarbonsäuremethylester and 88.5 S sodium hydroxide flakes in 320 ml of water is ethanol slowly with stirring added until a fine clear solution is obtained. The reaction mixture is left to stand at room temperature for about 5 hours, then the solvent is evaporated off under reduced pressure,

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the residue is taken up in water and acidified ⁷³¹¹ dilute hydrochloric acid and extracted with Ä'ther. Beim- concentrating the organic phase to dryness and crystallization of the residue from ethyl ether with the addition of petroleum ether obtained 106 g (71.6%) of the title compound from P. 155-155 ⁰ C.

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

70 ml of thionyl chloride at room temperature with stirring in a mixture of 2 g 1O6,8; 5-dihydro-6-methoxy-2-methyl ~ ^t - dripped benzofurancarboxylic acid and 840 ml of anhydrous benzene!. After the addition has ended, the reaction mixture is ^{heated to 80 °} C. for 5 hours and then concentrated to dryness. The residue obtained from the chloride of the starting acid is purified by crystallization from ethyl ether / petroleum ether and then dissolved in 1370 ml of anhydrous acetone. To the resulting solution, which is cooled to 5 ° C. with stirring, 6 l, 6 g of sodium: azide in 180 ml of water are slowly added. The temperature is maintained for a further 1 hour, then the reaction mixture is poured into 4600 ml of distilled cold water. After extraction with ethyl ether and concentration of the organic phase, the crude azide of the starting acid is obtained, which is purified by crystallization from ethyl ether.

A solution of this intermediate product in 100 ml of ethyl ether is slowly added, with stirring, to 600 ml of ethylene glycol, which is heated to 85 ° C. in an oil bath. After the addition has ended, the temperature is ^{increased to 220 °} C. for 5 minutes, then the reaction mixture is made alkaline by adding a solution of 98 g of potassium hydroxide flakes in ethylene glycol. Afterward

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is heated to reflux for 20 min. After cooling, the reaction mixture is poured into 1200 ml of distilled, ice-cold water, then stirred for 10 minutes and acidified with concentrated hydrochloric acid. After 15 minutes, the mixture is made basic again with concentrated sodium hydroxide solution. Extraction with ethyl ether, concentration of the organic extract and crystallization of the residue from petroleum ether gives 8l g of the title compound from P. 59 to 6l C; Yield, calculated on the starting acid, 88.6 %.

Example 10

(2, J5-Dihydro-6-methoxy-2-methyl-4-benzofuranyl) carbamic acid ethyl ester

55 * 75 g of ethyl chlorocarbonate in 100 ml of anhydrous benzene are slowly added at 5 ⁰ C under stirring to a solution of 8l g of 2,3 ~ dihydro-6-methoxy-2-methyl-4-benzofuranamine in 46 ml of triethylamine and 700 ml of anhydrous benzene admitted. When the addition is complete, the reaction mixture is warmed up gently, then stirred at room temperature for another ^ hours. Subsequently, the reaction mixture is 2 hours. Heated at reflux abgekühlt-, washed with water, dried and concentrated over sodium sulfate to dryness to give 95 * 8l g (83.5%) of the title compound, bp _Q ^ S 172 ° C.

Example 11

2,3> -Dihydro-6-methoxy-N, 2-dimethyl-4-benzofuranamine

95.8l g (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl) carbamic acid ethyl ester (For preparation see example 10) are in 385 ml Dissolved anhydrous ethyl ether and the resulting solution

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is added dropwise with stirring to a suspension of 21.01 g of lithium aluminum hydride in 600 ml of anhydrous ethyl ether, which is cooled to 0 ⁰ C. The reaction mixture is refluxed for 5 hours. After cooling, "63 ml of cold distilled water are added and the depositing the inorganic salts are filtered off The Piltrat is concentrated dried over sodium sulfate and to an oily residue which after purification by vacuum distillation ~ j> K the title compound g front Kp _n - ^. = 137 ° C. This compound, which solidifies slightly, melts at 53 ° C. (from ethyl ether / petroleum ether). The hydrochloride melts at 147 ° C.

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

The title compound is obtained according to the procedure of Example, by reacting the 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine with propionyl chloride instead of ethyl chlorocarbonate.
P. 101 to 102 ⁰ C (from ethyl ether), yield 44 g (75 %).

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

A solution of J>, 2 g of N- (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl) propanamide (Preparation sjäie Example 12) in 30 ml of anhydrous benzene is gradually added to a suspension of 1.1 g of lithium aluminum hydride in 30 ml of anhydrous ethyl ether at 0 C are added and the resulting reaction mixture is heated to reflux temperature for 6 hours.

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Then the temperature is lowered to 0 ° C and the aluminum complex is decomposed by adding ~ 5.5 ml of water. After stirring for half an hour at room temperature, the inorganic salts are filtered off and the piltrate is dried over sodium sulfate and concentrated to dryness. Vacuum distillation of the residue obtained in this way gives 2.8 g (93 %) of the title compound from K ^ ₀ = I ² ^ O bis

ι ο P '

142 C. The hydrofluoride obtained by treating the free bass with HCl melts at 110 to 111 ⁰ C.

Example 14
N-Ethyl ^^ - dihydro-e-methoxy ^ -methyl - ^ - 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 mixed with 5 ml of ethyl bromide and traces of potassium iodide in a steel vessel. The reaction vessel is closed and heated to 100 ° C. in an oil bath for 15 hours. After this reaction time the mixture is allowed to cool and filtered. The filtrate is concentrated to dryness to give an oily residue, which upon distillation under reduced pressure 1.1 g of the desired product, bp _nf - receives ⁼⁼ 135 ° C.

Example 15

N, N-Diethyl-2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine

The alkylation reaction is as in the previous example carried out and the work-up is carried out as described, up to the second filtration. Then to isolate the Diethylamino derivative discarded the benzene filtrate containing the monoethylamino derivative, while the remaining

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Solid is taken up in water / water. The solution is cooled, made basic with 50% sodium hydroxide solution and carefully extracted with ethyl ether. The oily residue obtained when the organic phase is concentrated is distilled under reduced pressure, 1.2 g of N, N-diethyl-2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine having a boiling point of _Q , - = 131 ⁰ C.

Example 16
N- (2,3 ~ Dihydro-6-methoxy-2-methyl-4-benzofuranyl) acetamide

This compound is prepared by following the procedure of Example 10 by adding 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine Reacts with acetyl chloride. The compound melts at 104 ° C (from isopropyl ether / ethyl alcohol).

Example 17

N- (2,3-Dihydro-6-methoxy-2-methyl-1- benzofuranyl) diacetamide

A reaction mixture of 2.4 g of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine, 10 ml of acetic anhydride and 1 drop of pyridine is heated for 90 min. At I30 to l40 ⁰ C. After cooling and evaporation of excess acetic anhydride, the residue is distilled under reduced pressure to give 2.4 g (69%) of the Ti te lver bond, bp = _Q ^ l'6O ° C. The distillate, which solidifies, is crystallized from ethyl ether / petroleum ether, mp 56 to 57 ° C.

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Example l8

(2 _i 3-dihydro-6-methoxy-2-methyl-4-benzofuranyl) phenylacetamide

The title compound is prepared according to the procedure of Example IO prepared from 2,; ^{5-dihydro-6-methoxy-2-methyl-i} · f -benzofuranamin and benzoyl chloride, P. 148 ⁰ C (from isopropyl ether / ethyl alcohol).

Example 19

N, N-diethyl-N ^l - (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl) -1,2-ethanediamine dihydrochloride

2.8o g of 2-diethylaniinoethyl chloride and traces of potassium iodide become a solution of 5 g of 2, 3-dihydro-6-methoxy-2-methyl-4-benzofuranamine and 2.02 g of triethylamine in 50 ml of anhydrous toluene are added and the resulting mixture is left for 16 hours. heated to reflux. After cooling and washing with water, the toluene phase is dried over sodium sulfate and then concentrated to dryness. Hydrochloric acid becomes an ethereal solution of the resulting oily residue added until a pesticide precipitates, then the mixture becomes cooled down. The precipitate is filtered off and recrystallized from ethanol with the addition of ethyl ether. The yield of title compound is 3.55 g, P. 158 to 159 ° C.

Example 20

N- (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl / phenacylsulfonamide

To a solution of 15 * 5 S 2,3-dihydro-6-methoxy-2-methyl-4-

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benzofuranamine and 10.5 S anhydrous pyridine in 100 ml of methylene chloride, which is cooled to 0 to 5 ⁰ C, a solution of 24.5 g in 80 ml Phenacylsulfonylchlorid ■ methylene chloride. After the dropwise addition has ended, the reaction mixture is warmed to room temperature and stirred for 5 hours. The solution is then washed with water, dried over sodium sulfate and concentrated to dryness. When the resulting thick oil crystallizes from ethyl alcohol / ethyl ether, 16 g of the title compound are obtained with a melting point of 14.5 ° C. to 110 ° 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 are dissolved in 16 ml of 0.1 η hydrochloric acid, then 1.1 g of sodium cyanate is gradually added, whereupon a white crystalline solid precipitates. The reaction mixture is heated on a water bath, cooled after 90 minutes and filtered. Recrystallization of the resulting precipitate from ethyl alcohol to g (6l%) of the title compound, P. 204 to 206 ⁰ C. receives 1.9

Example 22

(2,3-Dihydro-6-methoxy-2-methyl-4-benzofuranyl) carbamic acid phenylme thyIe s ter

0.65 g of phenyl methyl chlorocarbonate are poured into a mixture of 0.7 g of 2,2-dihydro-6-methoxy-2-methyl » ² l · benzofuranamine hydrochloride, 5 ml of 2N sodium hydroxide solution and 10 ml of chloroform was added dropwise. After the addition is complete

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Vigorously stirred for another 1 hour at the same temperature and 2 hours at room temperature. The organic phase is then separated off, washed with water / water, dried over sodium sulfate and concentrated to dryness. The residue obtained is crystallized twice from ethyl ether / petroleum ether, 0.9 g (88 %) - (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl) carbamic acid phenylmethyl ester of P. 82 to 8.degree can be obtained.

Example 23

N- (2,3-Dihydro-6-methoxy-2-methyl-4-benzofuranyl) -N-methylpropanamide

The reaction is carried out according to the procedure of Example 10, propionyl chloride being added dropwise to a benzene solution of 2, ^ - dihydro-ö-methoxy-N ^ -dimethyl - ^ - benzofuranamine and triethylamine. The crude product is isolated by cooling the reaction mixture, which had previously been refluxed for 2 hours, then the precipitate formed is filtered off, triturated with benzene, filtered off and discarded. The benzene filtrate is concentrated to dryness and the residue is distilled under reduced pressure. This gives 2 g. (90 %) of the pure connection from Kp ₀ ψ = 140 to 142 ⁰ G.

Example 24

(2,5-Dihydro-4-methoxy-2-methyl-6-benzofuranyl) carbamic acid ethyl ester

A solution of 4.5 ml of thionyl chloride in 10 ml of anhydrous benzene is benzo ydro-4-methoxy-2-methyl-6 to 6.5 g of 2,5 ~ di ⁿ

809842/0710

281389S

furancarboxylic acid (for preparation see Example 2) in 65 ml of anhydrous benzene and a few drops of N, N-dimethylformamide were added dropwise. The reaction mixture is heated to 70 to 80 ° C. and stirred for 4 hours at the same temperature. The solvent is then evaporated off and the thick oil thus obtained is dissolved in 65 ml of acetone. J5> 9 g of sodium azicL in 15 ml of water are added to the resulting solution, which has cooled to about 5 ° C., and the mixture is then stirred for a further hour at the same temperature. 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 concentrated and the residue is redissolved in 150 ml of ethyl ether, the solution is dried over sodium sulfate and concentrated to a small volume. The separating out after addition of petroleum ether a solid is dissolved in 60 ml of anhydrous xylene and the solution is heated with stirring to 120 ⁰ C. After 30 minutes at this temperature, 10 ml of anhydrous ethanol are added and the mixture is heated to Γ30 ° C. in an oil bath for 3 hours. Thereafter, the reaction mixture is concentrated to dryness and the resulting residue is distilled under reduced pressure to give the 0.4 mm Hg and I70 to I80 ⁰ C boiling fraction is collected. Crystallization of the solidified distillate from ethyl ether / petroleum ether 5 g (78%) of the title compound, melting at 93-94 ⁰ C.

Example 25

2, j5-dihydro-4-methoxy-N, 2-dimethyl-6-benzofuranamine

The ". ^" Compound is made by following the procedure of Example 11, starting from (2,3-dihydro-4-methoxy-2-methyl-6-benzofuranyl) carbamic acid ethyl ester. You get them in

809842/07 1 0

O,

94 ^ iger yield, Κρ _{Λ ο} = IjJO C. The corresponding hydrochloride melts after crystallization from ethanol / ethyl ether at 157 to 158 ⁰ C.

Example 26

2, ^ -Dihydro-6-hydroxy-N, 2- dimethyl-4-benzofuranamine

5 ml of 48% hydrobromic acid are 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 off and, after treatment with sodium bicarbonate, the residue is carefully extracted with ether. The organic phase is concentrated and dried over sodium sulfate to give a crude product which gives, upon crystallization from ethyl ether / petroleum ether 3 g (77%) of the title compound, P. 126 to 128 ⁰ C.

Example 27

6-acetoxy-2,3-dihydro-N, 2-dimethyl-4-benzofuranamine hydrochloride

1.7 g of the compound according to Example 26 are added to 20 ml of ethanol containing 0.8 g of hydrobromic acid. After concentration, a tarry residue is obtained which is carefully dried in vacuo over phosphorus pentoxide will. The residue is dissolved in 20 ml of trifluoroacetic acid and 1.4 g of acetyl bromide is gradually added to the solution. After stirring for an hour, a few drops will appear Water is added and the reaction mixture is concentrated to dryness under reduced pressure with gentle warming. Of the

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The residue is dissolved in a little cold water and the solution is made basic with sodium bicarbonate and then carefully extracted with ethyl ether. When the ether phase is concentrated and the resulting residue is purified by column chromatography with chloroform and 1 % acetone as the elution system, 6-acetoxy-2, J-dihydro-N, 2-dimethyl-4-benzofuramine is obtained, the hydrochloride of which after crystallization from ethanol / Ether melts at 159 to 160 C. The yield is 57 % of theory.

Typical 2,4,6-trisubstituted 2,3-dihydrobenzofurans, the can be prepared by the methods of the above examples include the following:

-N

CH ₃ O

-N

-N '

^ COCH, CH

COCH

CH ₃ O

OH

-N. / CH, 'CH "

^ CH,

CH ₃ O

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CH ₃ O

-N

-NH-SO

CH ₃ O

'CH,

CN

CH ₃ O

CH ₃ O

Production of the raw material:

^ -Allyl ^ -hydroxy-S-methoxy-benzoic acid and 2-allyl-3- ⁿ ydroxy-5-methoxy-benzoic acid

Of 3-hydroxy-5-methoxybenzoic acid methyl ester is obtained by reaction with allyl bromide to the 3-allyloxy-5-methoxyfeenzoesäuremethylester from Kp _Q u _ 128 to 130 ⁰ C. This compound is subjected to an allyl rearrangement by placing them in N, N- Dimethylaniline heated to reflux for about 6 hours in a nitrogen atmosphere. After cooling, the solvent is evaporated, the residue is taken up with ether, washed with cold dilute hydrochloric acid and then carefully extracted with 20% aqueous sodium hydroxide solution. 4-Allyl- and 2-allyl-3-hydroxy-5-methoxy-benzoic acid are separated by acidification and subsequent fractional crystallization.

For: Gruppo Lepetit S.p.A, Milan, Italy

Dr HJWolff 8098 42/0710 Lawyer

Claims (1)

BEIL, WOUFF & BEIL 3 March 0, 1978 LAWYERS ADELONSTRASSE 58 * O I v) Q 3 FRANKFURT AM MAIN 80 Claims 1. 2, ^, 6-Trisubstituted 2,3-Dihydrobenzofuran Derivatives following formula 2 7 wherein R is hydrogen or the methyl group, one of the "radicals R ₁ and R _{2 is} the hydroxyl group, a (C ^^ ) alkoxy or (C ₂ _] i) alkanoyloxy radical and the other is the cyano _y carboxyl, a carbo (C -, ^) alkoxy, carbamoyl or -NR-ZR ₂ , group, in which R, and R ^ are independently hydrogen, a (C-, u) alkyl, () alkanoyl, carbo (C- , ^) alkoxy- ^ den carbobenzyloxy, carbamoyl, a mono- or di (: C, ^ alkylamino-fC-, J alkyl, the benzenesulfonyl, toluenesulfonyl, a (C, 2i.) ^A l ^k yl ^su l ^{i> on} yl ~ or the phenylsulfonyl radical, and their salts with pharmaceutically acceptable acids. 2. A compound according to claim 1, characterized in that R is hydrogen or the methyl group and one of the radicals R and R _{2 is} the hydroxyl group, a (C -, _ h) alkoxy or (Cp_2,) aliphatic alkanoyloxy radical and the other is a radical of the formula -NR-, R ₂ , represent, wherein R, and R _2,; independently of one another hydrogen or (C-, h Xn-I ₁₀ , ι mean, and their salts with pharmaceutically acceptable acids. 809842/0710 ORIGINAL INSPECTED Compound according to claim 1, characterized in that R is a hydrogen atom and one of the radicals R-. and Rp represents a (C-, j,) alkoxy radical and the other represents a radical of the formula -NR- ^ Rj, wherein R_ ^ and R _2,. independently of one another are hydrogen or (C-, u ) alkyl radicals, and their salts with pharmaceutically acceptable acids. -N _i 2-dimethyl-4-benzofuranamine <. Process for the preparation of 2,4,6-trisubstituted 2,3-dihydrobenzofuran derivatives represented by the following formula wherein R is hydrogen or the methyl group, one of the radicals R-. and Rp is the hydroxyl group, a (C, j,) alkoxy or (Cp_j,) alkanoyl radical and the other is the cyano, carboxyl, a carbo (C, ^) alkoxy, carbamoyl or -NR ^ Rji group represent wherein R ^ and Rj ,, independently of one another. Hydrogen, a (C-, u) alkyl-, (Cp j,) -alkanoyl-, Ca ^ o (C _1- J,) alkoxy-, the carbobenzyloxy-, carbamoyl-, a mono- or di (C-, u ) alkylamino- (C-, ^ ) -alkyl-, the benzenesulfonyl-, toluenesulfonyl-, a bed.eu "ben" (C _1- ^) alkylsulfonyl or the phenacylsulfonyl radical / and their salts with pharmaceutically acceptable acids, characterized in that a compound of the formula _{{ COOCFL} M.
6th 3 2 CH-CH = CH-R 80984 2/0710 wherein R has the meaning given above and the radical -CHp-CH = CH-R is in the 2- or 4-position of the phenyl ring can be subjected to thermal or acid-induced cyclization Formation of a compound of the formula I in which R is hydrogen or the methyl group and one of the radicals R, and Rp a methoxy radical and the other a carboxyl or carbomethoxy group, and this compound in a known manner into the desired derivative of Formula I transferred. 6. The method of claim 5 * characterized in that one carries out the thermal cyclization at a temperature of about 200 to about 28o C ^0. 7. The method according to claim 5 *, characterized in that the acid induced cyclization in the presence of a mixture of acetic acid and hydrobromic acid executes. 809842/0710