DK152047B - METHOD OF ANALOGUE FOR THE PREPARATION OF N- (2-THIENYL) -2-OXO-2,3-DIHYDRO-BENZO (B) THIOPHEN-3-CARBOXAMIDE OR SALTS THEREOF WITH BASES - Google Patents

Description

The present invention relates to an analogous process for the preparation of the novel N- (2-thienyl) -2-oxo-2,3-dihydro-benzo [b] thiophene-3-carboxamide of the formula

(I) which may also be present in the tautomeric 2-hydroxy-benzo [b] thio-phen form, or salts thereof with bases.

The process of the invention is characterized by a) reacting the compound of the formula

(II) which may also be present in the tautomeric 2-hydroxy-benzo [b] thiophene form, with a compound of the formula

(III)

wherein R represents an etherified or esterified hydroxy group OO

or an optionally substituted amino group, and R 2 represents hydrogen or wherein R 5 and R 5 together form a bond, or, b) reacting a compound of formula

(IIa) wherein means an etherified or esterified hydroxy group, with the amine of the formula

(V) or c) terminates a compound of the formula

(VI) wherein Rq is an etherified or esterified hydroxy group or an optionally substituted amino group, or a salt thereof with a base or d) in a compound of the formula

(VIII)

which may also be in the tautomeric form and wherein R

z means an optionally substituted imino group which can be hydrolytically converted to an oxo group, hydrolyzes R to oxo and, if desired, converts the free compound produced into a salt with a base or converts a formed salt with a base into a free compound or to another salt with a base.

Salts of the compound of formula I are pharmaceutically useful salts with bases, especially metal or ammonium salts. In particular, metal salts are derived from metals of the groups 1a, 1b, 11a and 11b of the periodic system, such as alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium, calcium, zinc or copper salts. Above all, ammonium salts are salts with secondary or tertiary organic bases, e.g. with morpholine, thiomorpholine, piperidine, idine, pyrrolidine, dimethyl- or diethylamine or triethylamine, but also other salts with ammonia. The salt formation with compounds of formula I is thus likely to occur from the tautomeric 2-hydroxy-benzo [b] thiophene form.

The compounds of the present invention show valuable pharmacological properties. In the foreground of the spectrum of effects are peripheral analgesic effects that can be detected on both the pheny1-p-benzoquinone-writhing test and the rat? in the vinegar-acid-writhing test analogous to that of Krupp et al.,

Switzerland, with. Wsch., Bd. 105, p. 646 (1975), described in doses of ca. 1 to approx. 10 mg / kg p.o. In addition, they show anti-inflammatory effects, such as can be demonstrated in kaolin paw edema test in rats? analogous to that of Menassé and Krupp, Toxicol, Appl. Pharmacol. Vol. 29, p. 389 (1974), described in doses of ca. 10 to approx. 100 mg / kg p.o. Furthermore, they show uricosuric effects, e.g. can be demonstrated in phenol red secretion test, analogous to that of Swingle et al., Arch. int. Pharmacodyn., Bd. 189, p. 129 (1971), described method in doses of ca. 30 to approx. 100 mg / kg p.o. The compounds are therefore used as peripheral analgesics, e.g. for the treatment of pain states of the most diverse origin, or as antiflogistics, e.g. for the treatment of arthritic inflammation, or for the influence of traumatic inflammatory and swelling conditions, as well as as uricosuric, e.g. for the treatment of arthritis.

The compounds of this invention also exhibit antithrombotic effects which can be demonstrated in rabbits by experimental pulmonary embolism, analogous to the methods described by Silver et al., Science, Vol. 183, p. 1085 (1974), at doses of ca. 0.1 to approx.

3 mg / kg p.o. In vitro, these compounds also significantly inhibit the prostaglandin synthetase system at doses of 0.1-1 µg / ml (Method White and Glassman, Prostaglandins, Vol. 7, No. 2, page 123 (1974)). also used as thrombolytics.

DE-Publication No. 2,713,584 discloses 2-oxo-2,3-dihydro-benzo [b] thiophene carboxamides having analgesic, anti-inflammatory and uricosuric effects. These known compounds may be N-substituted with a heterocyclic group, but the compounds of this invention are not disclosed in said disclosure of physical data. It has been found that the compound of formula I has an unexpectedly useful antinociceptive effect over the known compounds, which is illustrated in more detail below.

Comparative experiments are performed with the compound N- (2-thienyl) -2,3-dihydro-2-oxo-3-benzo [b] thiophene carboxamide (1) prepared according to Example 1 and the comparative compound N- (2-thiazolyl) -2. 3-Dihydro-2-oxo-3-benzo [b] thiophene-carboxamide (2), cf. DE Publication No. 2,713,584, Example 3, 5th Compound.

The antinociceptive effect of the test compounds is determined by the phenyl-β-benzoquinone twist test, cf.

L. C. Hendershot and J. Forsaith, J. Pharmacol. exp. Therap.

125, 237 (1959): Albino mice (MAG cf, 18-25 g, two groups of four animals), which are not fed overnight, are injected intraperitoneally with 0.25 ml of freshly prepared O.03% suspension of phenyl-p-benzoquinone in tranganth 0.4% 55 minutes after oral administration of the test compound. Control animals are administered tragacanth 0.4% instead of the active substance.

Five minutes after the intraperitoneal injection of the irritant, the antinociceptive response is determined by counting the stretching movements over a period of 10 minutes.

The antinociceptive activity (ED5Q value) of the test compounds is determined as the dose which induces a 50% reduction in stretching movements relative to the control group. The following results are obtained: N- (2-thienyl) -2,3-dihydro-2-oxo-benzo [b] thiophene-3-carboxamide (1): ED ^ value = 0.8 mg / kg, N- (2-thiazolyl) -2,3-dihydro-2-oxo-benzo [b] thiophene-3-carboxamide (2): ED ^ value = 100 mg / kg.

It is clear from the above results that the compound of the invention has a ca. 125 times more powerful than the known compound.

In process a) the compound of formula is reacted

(II) which may also be present in the tautomeric 2-hydroxy-benzo [b] thiophene form, with a compound of the formula

(III) wherein Rq represents an etherified or esterified hydroxy group or an optionally substituted amino group, and means hydrogen, or wherein Rq and R ° together form a bond.

An etherified hydroxyl group Ryl is preferably with an optionally substituted hydrocarbon group such as lower alkyl, e.g. methyl or ethyl, or halo-lower alkyl, e.g. 2,2,2-trichloroethyl, and primarily with optionally substituted such as lower alkyl, lower alkoxy, halogenated and / or nitro-containing phenyl, etherified hydroxy lower alkoxy, such as methoxy or ethoxy, halogenlavalkoxy, e.g. 2,2,2-trichloroethoxy, or phenoxy, while an esterified hydroxyl group is preferably esterified with a strong mineral acid and primarily means halogen, especially chlorine. A substituted amino group contains one or preferably two optionally substituted hydrocarbon groups, such as lower alkyl, and / or optionally, e.g. as indicated above, phenyl is substituted as substituents and is e.g. lower alkylamino such as methylamino or ethylamino, dilavalkylamino such as dimethylamino or diethylamino, or phenylamino and preferably diphenylamino, the phenyl group being optionally substituted, e.g. with lower alkyl such as methyl, lower alkoxy, e.g. methoxy, halogen, e.g. fluorine, chlorine or bromine, and / or nitro.

However, a substituted amino group Rq may also represent the group of formula

The above reaction is usually carried out in the presence of an inorganic or organic basic agent. Speaking as inorganic bases, salt, especially alkali metal salt-forming agents such as alkali metal hydrides or amides, as well as alkali metal inorganic compounds such as correspondingly lower alkanolates, are also provided, as well as similar lower alkyl or phenyl compounds, e.g. sodium methylate, sodium ethylate, potassium tert-butylate, n-butyllithium or phenyllithium. Suitable organic bases are primarily amines such as tertiary amines, preferably trilavalkylamines, e.g. triethylamine, heterocyclic tertiary bases, especially of the pyridine type, e.g. pyridine, or quaternary bases such as tetralavalkylammonium or trilavalkyl-phenyllavalkyl-ammonium hydroxides. In the presence of the base, the starting material of formula II is reacted in anionic form, i.e. in salt form, with the starting material of formula III.

The latter are carbamic acid esters, carbamic acid anhydrides, or halides, ureas and isocyanates corresponding to formula III.

The reaction is carried out in the presence or absence of a solvent or diluent and, if necessary, under cooling or heating, e.g. in a temperature range of approx. -10 to about- 120 ° C, in a closed container and / or in an inert gas, e.g. a nitrogen atmosphere.

In process b), a compound of the formula is reacted

(Ha) wherein Rq is an etherified or esterified hydroxy group, with the amine of the formula

(V)

The starting material of formula IIa can be prepared by reacting the compound of formula II with a compound of formula R form-C (= O) -R ^ (IV) wherein and R ^ independently represents an etherified or esterified hydroxy group.

3. b

Ether etherified or esterified hydroxyl groups Rq and Rq have e.g. the meanings given above for the corresponding group Rq and are e.g. lower alkoxy, such as methoxy or ethoxy, further optionally substituted phenoxy, or halogen, e.g. chloro. Suitable compounds of formula IV are e.g. dilavalkyl carbonates, e.g. diethyl carbonate, or diphenyl carbonate, phosgene or halo formic acid low alkyl esters, e.g. chlormyresyreiso-butyl ester. The reaction of the compound of formula II with a compound of formula IV is usually carried out in the presence of a base such as one of the above, e.g. an alkali metal hydride or a trilavalkylamine. Usually, an intermediate of formula IIa is not isolated but is directly reacted with the amine of formula V.

The above process steps are carried out in the absence or presence of a solvent and, if necessary, under cooling or heating, e.g. in a temperature range of approx. -10 to approx. 120 ° C, in a closed container and / or in an inert gas, e.g. a nitrogen atmosphere.

The starting materials are known or can be prepared in a manner known per se.

For example, the starting compound of formula II can be obtained by acylating an enamine derived from cyclohexanone with a cyan acetic acid ester, acylating the obtained 2-amino-4,5,6,7-tetrahydro-benzothiophene-3-carboxylic acid ester in the amino group. dehydrogenates the reaction product with sulfur and treats the obtained 2-acylamino-benzothiophene-3-carboxylic acid ester with sodium hydroxide solution or transfers a corresponding benzothiophene with butyllithium to a 2-lithium compound and oxidizes with hydrogen peroxide.

Compounds of formula III can e.g. is prepared by converting compounds of formulas Rq-C (= O) -Ro (IV) and

In process c) a compound of the formula is terminated

(VI) wherein Rq is an etherified or esterified hydroxy group or an optionally substituted amino group or a salt thereof with a base.

A salt of the starting material of formula VI is e.g. an alkali metal salt.

For example, a group R have the meaning given above and are e.g. lower alkoxy such as methoxy or ethoxy, halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, optionally substituted phenoxy or halogen, e.g. chlorine, further lower alkylamino, e.g. methylamino, dilavalkylamino, e.g. dimethylamino or diethylamino, phenylamino or diphenylamino or also the group of formula

The above cyclization reaction is carried out in a manner known per se, if necessary in the presence of a common basic condensing agent such as a salt forming agent, e.g. alkali metal salt forming agents, i.a. also an alkali metal avalkanolate, e.g. sodium methylate, sodium methylate or potassium tert-butylate. The reaction is carried out in the absence or presence of a solvent or diluent, if necessary during cooling or heating, e.g. in a temperature range of approx. 0 to approx.

150 ° C, in a closed container and / or in an inert gas, e.g. a nitrogen atmosphere.

The starting materials of formula VI 'can be prepared in a manner known per se, e.g. in the benzyl methylene group in a compound of the formula

(WE YOU)

wherein R is a group of formula

X

or a group of the formula -C (= O) -Ro, and R is hydrogen or preferably a mercapto protecting group such as hydrogenolytically cleavable α-phenyllavalkyl, e.g. benzyl, introduces a group

of the formula -C (= O) -R, respectively, reacting a compound of formula VII with a derivative of carbonic acid, such as a corresponding ester, e.g. dilavalkyl carbonate, such as diethyl carbonate, or diphenyl carbonate, dihalide, e.g. similar halogen esters, for example, halo formic acid avalanche ester, or similar urea, further corresponding isocyanate, usually in the presence of a basic agent such as an alkali metal hydride, amide or low alkanolate, or an organic base, e.g. triethylamine. A mercapto protecting group may then be cleaved in the usual manner, e.g. by treatment with catalytically activated hydrogen, thus releasing the mercapto group.

In process d), R is hydrolyzed in a compound of the z formula

(VIII)

which may also be in the tautomeric form and wherein R

z means an optionally substituted imino group which can be hydrolytically converted to an oxo group into oxo.

In a substituted imino group R 1, a substituent e.g. an optionally substituted hydrocarbon group such as low alkyl, e.g. methyl or ethyl, or phenyl, or a carboxylic acid or a half-ester of carbonic acid derived acyl group, e.g. lower alkanoyl such as acetyl or benzoyl or lower alkoxycarbonyl such as methoxy or ethoxycarbonyl.

The starting material of formula VIII is converted by hydrolysis, preferably by treatment with water in the presence of a basic or acidic agent such as an inorganic base, e.g. an alkali metal hydroxide, or a mineral acid, e.g. salt or sulfuric acid, to the desired compound of formula I.

The reaction is carried out in the presence or absence of a solvent or diluent and, if necessary, under cooling or heating, e.g. in a temperature range of approx. -10 to approx. 120 ° C, in a closed container and / or in an inert gas, e.g. a nitrogen atmosphere.

The starting material of formula VIII can be prepared in a manner known per se, e.g. translates a compound of formula

(IX) wherein R is preferably an unsubstituted imino group and the z group -R -H is therefore primarily a primary amino group, z e.g. with phosgene or a chloro formic acid low alkyl ester, and reacting a compound of the formula thus obtained

(X) optionally after introducing a substituent into a hydrogen-containing imino group R, e.g. by treatment with a low Z;

alkyl halide in the presence of an alkali metal compound-forming reagent, with the amine of formula (V) and, if desired, in a starting material of formula VIII wherein R

z is an unsubstituted imino group, or in a tautomer thereof, wherein -R-H is an unsubstituted amino group, substituting this imino or amino group, e.g. by low alkylation or acylation, the latter e.g. by treatment with a suitable symmetrical, mixed or internal anhydride of a carboxylic acid.

The compound of formula I may preferably be used in the form of pharmaceutical preparations for enteral, such as oral, rectal or parenteral administration or for topical or topical use in warm blooded animals. The compositions contain the pharmacologically active substance alone or together with a pharmaceutically useful carrier. The dosage of the active substance depends on the nature, age and individual condition of the warm-blooded animal as well as the mode of application.

The pharmaceutical compositions contain from ca. 10 to approx. 95%, preferably from ca. 20 to approx. 90%, of the active substance. For example, pharmaceutical compositions are those in elixir, aerosol or spray form or in dosage unit form such as dragees, tablets, capsules, suppositories or ampoules.

The pharmaceutical compositions are prepared in a manner known per se, e.g. by conventional mixing, granulation, coating, dissolution or lyophilization methods.

The daily dose, which primarily depends on the patient's condition and / or the indication, represents a warm-blooded animal of approx.

70 kg from approx. 300 mg to approx. 1 g.

The process according to the invention is further illustrated by the following examples.

Exanple1.

To a suspension of 2.4 g of a 50% sodium hydride mineral oil dispersion in 100 ml of hexamethylphosphoric triamide is added dropwise with cooling a solution of 7.5 g of 2,3-dihydro-2-oxo-benzo [b]. thiophene in 50 ml of hexamethylphosphoric triamide, keeping the temperature below 15 ° C. After half an hour of stirring at room temperature, 52 g of N- (2-thienyl) -carbamic acid phenyl ester dissolved in 50 ml of hexamethylphosphoric acid triamide are added dropwise under external cooling. Stir for an additional 16 hours at room temperature and pour the reaction mixture into a mixture of 200 ml of 2N hydrochloric acid and 1000 ml of ice water. An oil which crystallizes after approx. 2 hours. The crystalline product containing the solvent is dissolved in 2N sodium hydroxide solution and the solution is washed four times with ethyl acetate. The organic phase is washed with water, the aqueous phases are collected and adjusted to pH = 1, and the crude product is suctioned off and recrystallized from tetrahydrofuran / ether. N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophenecarboxamide is obtained, m.p. 142-144 ° C (dec.).

Example 2.

0.8 g of N- (2-thienyl) -2-acetamino-benzo [b] thiophene-3-carboxamide is suspended in 5 ml of ethanol, 2.5 ml of water and 2.5 ml of concentrated hydrochloric acid and heated in 7 1/2 For one hour at reflux, the mixture leaves for 16 hours at room temperature and evaporates the ethanol under reduced pressure. The evaporation residue is taken up with water, isolated by suction filtration and then washed with water. The residue is taken up in dilute sodium hydroxide solution and the insoluble components are filtered off, the aqueous phase is acidified and the precipitated N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene carboxamide is filtered off. with m.p. 142-144 ° C (dec.).

The starting material can be prepared as follows: Into a sulfonation flask are added 3 g of magnesium shavings and 3D ml of anhydrous tetrahydrofuran, and to make ethyl magnesium bromide 13.5 g of ethyl bromide are added. After dissolving the magnesium, 6.1 g of 2-aminothiophene dissolved in 60 ml of absolute tetrahydrofuran are added dropwise, stirring for 1 hour at room temperature and then heated for another 15 minutes to reflux. Then 8 g of 2-acetamido-benzo [b] thiophene-3-carboxylic acid ester, dissolved in 100 ml of absolute tetrahydrofuran, is added dropwise at room temperature. It is then heated to reflux for 15 minutes, stirred for another 15 minutes at room temperature, evaporated in vacuo, added dilute hydrochloric acid to the evaporation residue and extracted twice with chloroform. The chloroform extracts are collected, dried over sodium sulfate and evaporated in vacuo to dryness. There is obtained crude N- (2-thienyl) -2-acetamino-benzo [b] thiophene-3-carboxamide, which can be used without further purification.

Example 3

11.4 g o-mercapto-phenylmalonic acid N- (2-thienyl) -amide is heated in 50 ml of dimethylformamide and 1 ml of concentrated hydrochloric acid for 2 hours at 100 ° C. The mixture is allowed to cool, to which 100 ml of water is added, the precipitate is sucked off and taken up in 100 ml of diethyl ether. The organic phases are obtained after washing, first with 1N sodium hydroxide solution and then with water, drying with sodium sulfate, evaporation, chromatography and crystallization from ether N- (2-thienyl) -2-oxo-2,3-dihydro-hydroxide. benzo [b] thiophene-3-carboxamide, m.p. 142-144 ° C (dec.).

For example, the starting material can be prepared as follows:

Through a solution of 9.4 g of o-mercaptophenylacetic acid in 56 ml of 1 N sodium hydroxide solution, a strong air flow is conducted for 8 hours with stirring. The reaction mixture is evaporated on a rotary evaporator to dryness. To the residue is added twice 50 ml of toluene and evaporated to dryness each time. The residue is then dried for 90 minutes in high vacuum at 50 ° C and suspended in 180 ml of dimethylformamide and 7 g of dimethyl sulfate are added with stirring over 3 minutes. The reaction mixture is heated to 110 ° C for 1 hour with stirring, then cooled and poured on ice. The resulting suspension is extracted with ethyl acetate and the organic phases are combined and washed with water, dried over sodium sulfate and evaporated. The residue (18 g) is dissolved in 200 ml of dimethylformamide and dripped to a suspension of 4.8 g of 50% sodium hydride in 200 ml of dimethylformamide. With gentle heating, stirring is continued until the end of hydrogen evolution. Then a solution of 15 g of 2-thienyl isocyanate in 100 ml of dimethylformamide is slowly added dropwise at 0 ° C. The solution is stirred for an additional 24 hours at room temperature and added; then ice and dilute hydrochloric acid. The separated product is extracted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. There is obtained o, o'-bis- [α-methoxycarbonyl-N- (2-thienyl) carbamylmethyl] diphenyl disulfide which can be used without purification.

20/0 g of crude o, o1-bis [α-methoxycarbonyl-N- (2-thienyl) carbamylmethyl] diphenyl disulfide are suspended in 300 ml of ethanol and stirring is added portionwise with 7 g of sodium borohydride. The mixture is stirred for 4 hours at room temperature and evaporated, then water and then hydrochloric acid are added to just congo acidic reaction and extracted with ethyl acetate. Evaporation gives crude o-mercapto-phenylmalonic acid N- (2-thienyl) -amide, which can be cyclized without further purification.

Example 4

To a stirred suspension of -2.32 g of sodium hydride suspension (50% in mineral oil) in 60 ml of tetrahydrofuran is added dropwise 7.3 g of 2,3-dihydro-2-oxo-benzo [b] thiophene in 50 ml. '· tetrahydrofuran. The mixture is stirred for 30 minutes, then 5 ml of pyridine is added and then 7.8 g of N- (2-thienyl) carbamyl chloride is added dropwise in 20 ml of tetrahydrofuran, then the mixture is stirred for 1 hour at room temperature and for 2 hours at 60 ° C. ° C. The mixture is then poured into 750 ml of ice water, then acidified with 2N hydrochloric acid, and the precipitate is suctioned off and recrystallized from acetone / hexane.

N- (2-thienyl) -2,3-dihydro-2-oxo-benzo [b] thiophein-3-carboxamide is obtained, m.p. 142-144 ° C (dec.).

Example 5

To a suspension of 6.5 g of sodium hydride suspension (5% of mineral oil) in 100 ml of hexamethylphosphoric triamide is added dropwise with cooling to 10 ° C a solution of 20.2 g of 2,3-dihydro-2-oxo-benzo [b] thiophene. The mixture is stirred for 1 hour at room temperature, then a solution of 38.2 g of N- (2-thienyl) urea in 100 ml of hexamethylphosphoric acid triamide is added dropwise. The mixture is stirred for 10 hours at room temperature and then for 22 hours at 60 ° C, then added to a mixture of 100 ml of 2 N hydrochloric acid and 1000 g of ice. The resulting mixture is extracted with three times 250 ml of diethyl ether, the ether phases are dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from diethyl ether to give N- (2-thienyl) -2,3-dihydro-2-oxo-benzo [b] thiophene-3-carboxamide, m.p. 142-144 ° C (dec.).

Example 6

To a cooled suspension of 8.7 g of 50% sodium hydride suspension in paraffin oil in 250 ml of hexamethylphosphoric triamide is added dropwise a solution of 27.5 g of 2,3-dihydro-2-oxo-benzo [b] thiophene in 100 ml of hexamethylphosphoric triamide. . The mixture is stirred for 1 hour at room temperature, then cooled again to 0 ° C and 31.3 g of N- (2-thienyl) carbamic acid ethyl ester dissolved in 50 ml of hexamethylphosphoric acid triamide are added dropwise. The mixture is stirred for 20 hours at room temperature, then poured into a mixture of 1500 g of ice and 200 ml of 2N hydrochloric acid. The mixture is extracted twice with 300 ml of diethyl ether and the ether extracts are washed with water for neutral reaction and evaporated to dryness. As the residue, N- (2-thienyl) -2-oxo-2,3-dihydro-benzo [b] thiophene-3-carboxamide is obtained, m.p. 142-144 ° C (dec.).

Example 7 Dissolve 16.9 g of 2,3-dihydro-3-oxo-benzo [b] thiophene in 200 ml of hexamethylphosphoric triamide. The solution is cooled to 0 ° C, then a solution of 3.2 g of butyl lithium in 20 ml of n-hexane is added dropwise under nitrogen. The mixture is allowed to warm to room temperature, to which is added portionwise 31 g of N- (2-thienyl) -carbamic acid (2,2,2-trichloro) ethyl ester, after which the mixture is stirred for 2 hours at 0 ° C and then for 20 hours. at room temperature. The mixture is poured into 1000 g of ice and extracted with three times 100 ml of diethyl ether, the ether phases are dried over sodium sulfate, evaporated to dryness and the residue is recrystallized from hexane / diethyl ether (1: 5). N- (2-thienyl) -2,3-dihydro-2-oxo-benzo [b] thiophene-3-carboxamide is obtained, m.p. 142-144 ° C (dec.).

Example 8.

To a solution of 1 g of N- (2-thienyl) -2-formamino-benzo [b] thiophene-3-carboxamide in 5 ml of ethanol and 5 ml of water is added 3 ml of hydrochloric acid and the mixture is heated to ca. 10 hours of reflux. After removing the alcohol, the residue is washed with water, taken up in dilute sodium hydroxide solution and isolated by suction filtration. The aqueous phase is acidified and the precipitated N- (2-thienyl) -2-oxo-2,3-dihydro-benzo [b] thiophene = 3 "carboxamide is recrystallized from ether, mp 142-144 ° C (dec. ).

The starting material is prepared as follows:

To prepare the organometal compound, 10.9 g of ethyl bromide are added dropwise to a mixture of 4 g of magnesium shavings and absolute tetrahydrofuran under cooling. To the reaction product is added portionwise a solution of 9.9 g of 2-amino-thiophene in absolute tetrahydrofuran and the solution is heated briefly under reflux. Then 7.5 g of 2-formamino-benzo [b] thiophene-3-carboxylic acid ethyl ester, dissolved in 100 ml of absolute tetrahydrofuran, is added dropwise at room temperature. Then, the mixture is heated at reflux for 15 minutes, then the mixture is stirred for 15 minutes at room temperature. The solvent is distilled off and the residue is hydrolyzed with dilute hydrochloric acid. Then, small portions of methylene chloride are extracted, the organic phase is dried over sodium sulfate, the solvent is distilled off, and the resulting N- (2-thienyl) -2-formamino-benzo [b] thiophen-3-carboxamide is used directly for further reaction. .

Example 9

20 g of N- (2-thienyl) -2-OXO-2,3-dihydro-3-benzo [b] thiophene carboxamide are suspended in 250 ml of acetone and 66 ml of 1 N sodium hydroxide solution are added and a solution is formed. The solution is evaporated to dryness, the residue is first stirred with toluene and then with diethyl ether, isolated by suction filtration and dried. The sodium salt of N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophenecarboxamide is obtained, m.p. > 280 ° C.

/ '

Example 10.

470 mg of 2-oxo-2,3-dihydro-3-benzo [b] thiophenecarboxylic acid ethyl ester (2.11 mmol) and 218 mg of 2-aminothiophene (2.22 mmol) are refluxed in 3 ml of xylene for 5 hours. After cooling, the product is precipitated by the addition of 3 ml of hexane. After further dilution with 5 ml of ether and stirring, the crystalline N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene carboxamide is isolated and extracted with m.p. 142-144 ° C (dec.).

Example 11.

4.0 g of o-mercaptophenylmalonic acid phenyl ester N- (2-thienyl) amide is suspended in 100 ml of ethanol, then 0.2 ml of 5 N sodium hydroxide solution is added and stirred for 2 hours. The mixture is evaporated to dryness, the residue is taken up in ether, washed twice with water, the solution is evaporated to begin crystallization, then pentane is added and cooled to -15 ° C.

and filtered. Crystalline N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene carboxamide is obtained, m.p. 142-144 ° C.

The starting material can be prepared by reacting o-mercapto-phenylmalonic acid N- (2-thienyl) -amide with phenol in benzene solution in the presence of the approx. equimolar amount of N, N-dicyclohexylcarbodiimide.

Example 12.

30.0 g of bis-o - [(α-methoxycarbonyl) -N- (2-thienyl) -carbamylmethyl] diphenyl sulfide are suspended in 300 ml of ethanol, and 7.0 g of sodium borohydride are added portionwise with stirring. The mixture is stirred for 4 hours at room temperature, then heated for a further 1 hour at reflux. Then the mixture which is added to water is evaporated, acidified with hydrochloric acid for just conguric acid reaction and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in ether and the solution is filtered over silica gel. The filtrate is evaporated to begin crystallization, an equal amount of petroleum ether is added and the crystalline product is isolated. N- (2-thienyl) -2-oxo-2,3-dihydro-3-benzo [b] thiophene carboxamide is obtained, m.p. 142-144 ° C.

For example, the starting material can be prepared as follows:

Through a solution of 9.4 g of o-mercaptophenylacetic acid in 56 ml of 1 N sodium hydroxide solution, a vigorous flow of air is conducted for 8 hours with stirring. The reaction mixture is evaporated to dryness on a rotary evaporator. To the residue is added 50 ml of toluene and evaporated to dryness. This is repeated. Then, the residue is dried for 90 minutes in high vacuum at 50 ° C, then suspended in 180 ml of dimethylformamide and then stirred over 3 minutes to add 7 g of dimethyl sulfate. The reaction mixture is heated for 1 hour with stirring to 110 ° C, then cooled and poured onto ice =

The resulting suspension is extracted with ethyl acetate, the organic phases are combined and washed with water, dried over sodium sulfate and evaporated. The residue (18 g) is dissolved in 200 ml of dimethylformamide and added dropwise to a suspension of 4.8 g of 50% sodium hydride in 200 ml of dimethylformamide. Stirring is continued under gentle heating until hydrogen evolution has ceased. Then, slowly, at 0 ° C, a solution of 15 g of 2-thienyl isocyanate in 100 ml of dimethylformamide is added dropwise. The solution is stirred for an additional 24 hours at room temperature, then ice and dilute hydrochloric acid are added. The separated bis-o - [(α-methoxycarbonyl) -N- (2-thienyl) carbamylmethyl] diphenyl disulfide is extracted with ethyl acetate, the solution is washed with water, dried over sodium sulfate and evaporated. The starting material can be used directly without further purification.

Example 13

Dissolve 1 g of N- (2-thienyl) -2-benzoylamino-benzo [b] thiophene-3-carboxamide in 10 ml of ethanol and add 2.5 ml of water in 3 ml of concentrated hydrochloric acid and heat the solution reflux o The solution is evaporated and the residue is dissolved / 1

Claims (8)

An analogous process for the preparation of N- (2-thienyl) -2-oxo-2,3-dihydro-benzo [b] thiophene-3-carboxamide of the formula (I) which may also be present in the tautomeric 2-hydroxy-benzo [b] thio-phen form, or salts thereof with bases, characterized in that a) the compound of the formula is reacted (II) which may also be present in the tautomeric 2-hydroxy-benzo [b] thiophene form, with a compound of the formula (III) wherein Rq represents an etherified or esterified hydroxy group or an optionally substituted amino group and R ° means hydrogen or wherein Rq and R4 together form a bond, or b) translates a compound of the formula (IIa) wherein means an etherified or esterified hydroxy group, with the amine of the formula or c) ring ends a compound of the formula (VI) wherein Rq is an etherified or esterified hydroxy group or an optionally substituted amino group, or a salt thereof with base or d) in a compound of the formula (VIII) which may also be in the tautomeric form and wherein R represents an optionally substituted imino group which can be hydrolytically converted to an oxo group, hydrolyzes R to oxor and, if desired, converts the produced free compound into a salt with a base or convert a formed salt with a base to a free compound or to another salt with a base ot 'i Process according to claim 1, characterized in that a carbamic acid ester, a carbamic acid halide or the isocyanate are used as compounds of formula III. Process according to claim 1, characterized in that Rq in formulas III or VI means halogen or C 1-4 alkoxy. Process according to claims 1-3, characterized in that the reaction of the compound of formula II with a compound of formula III is carried out in the presence of a base. Process according to claim 4, characterized in that an alkali metal hydride, amide, -C 1-4 alkanolate, a tri-C 1-4 alkylamine, pyridine, a tetra-C or a tri-C 1-4 alkylphenyl-C 1-4 -alkylammonium hydroxide. Process according to claim 1, characterized in that Rq in the formula IIa means halogen or C 1-4 alkoxy. Process according to claims 1 and 3, characterized in that the cyclization is carried out in the presence of a base. Process according to claim 1, characterized in that R 2 in the formula VIII means C 1-4 alkanoyl, C 2-5 alkoxy-carbonyl or benzoylimino.