NO850561L - PROCEDURE FOR PREPARING 3-METHYL-7-FLUORO-5-NITROBENZOTYPHEN - Google Patents

Abstract

Process for the preparation of 3-methyl-7-fluoro-5-nitrobenzothiophene (I), wherein aj is transferred to 2-fluoroaniline to 7-fluoroisatin by known methods, b) nitrates 7-fluoroisatin and then the compound is oxidized to 3-fluoroisatin. 5-nitro-anthranilic acid, c) diazotizes 3-fluoro-5-nitroanthranilic acid and converts the compound with hydrochloric acid in the presence of copper () chloride to 3-fluoro-2-chloro-5-nitrobenzoic acid, d) converts 3-fluoro -2-chloro-5-nitrobenzoic acid with thionyl chloride to the corresponding acid chloride, e) converts 3-fluoro-2-chloro-5-nitrobenzoyl chloride with oxymagnesium malonic acid diethyl ester to (3-fluoro-2-chloro-5-nitrobenzoyl) -malonic acid diethyl ester, f) converts (3-fluoro-2-chloro-5-nitrobenzoyl) -malonic acid diethyl ester with propionic acid in the presence of sulfuric acid to 3-fluoro-2-chloro-5-nitroacetophenone, g) transfers 3-fluoro-2-chloro-5-nitroacetophenone with mercaptoacetic acid to (2-acetyl-6-fluoro-4-nitrophenylthioacetic acid, and. h) cyclizes the latter compound to 3-methyl-7-fluoro-5-nitrobenzothiophene (). is described.

Description

The present invention relates to a method for the production of 3-methyl-7-fluoro-5-nitrobenzothiophene as well as the intermediate products used in the production and the production thereof.

German patent application P 33 11 349.4 describes 7,8,9,1O-tetrahydrothieno[3,2-e]-pyrido[4,3-b]-indoles, a method for their preparation and the use of the compounds as pharmaceuticals. 3-Methyl-7-fluoro-5-nitrobenzothiophene constitutes a key product in the synthesis of 1-methyl-9-ethyl-4-fluoro-7,8,9,1O-tetrahydrothieno-[3,2-e]-pyrido[4 ,3-b]-indole.

The synthesis of 3-methyl-7-fluoro-5-nitrobenzothiophene stated in the aforementioned patent application involves, especially when producing larger amounts of substance, a number of difficulties. E.g. the reaction of 1,1-dimethyl-3-(3-methyl-5-nitrobenzothiophen-7-yl)-triazene with hydrofluoric acid to 3-methyl-7-fluoro-5-nitrobenzothiophene requires the use of special equipment. In the diazotization of 3-methyl-5-nitro-7-aminobenzothiophene, nitrosylsulphuric acid in concentrated sulfuric acid must be used, this means that significant amounts of inorganic salts are formed during the triazene formation; furthermore, a column chromatographic purification is required. The reduction of 3-methyl-5,7-dinitrobenzothiophene with ammonium sulphide leads to the desired 3-methyl-5-nitro-7-aminobenzothiophene, although here too a column chromatographic purification is required.

The present invention describes a method for the production of 3-methyl-7-fluoro-5-nitrobenzothiophene in which the mentioned difficulties are circumvented.

The invention relates to a method for the production of 3-methyl-7-fluoro-5-nitrobenzothiophene which consists in

a) transfers 2-fluoroaniline (II) to 7-fluorisatin

(III) by known methods,

b) nitrates 7-fluorisatin (III) and then oxidizes the compound to 3-fluoro-5-nitroanthranilic acid (IV), c) diazotizes 3-fluoro-5-nitroanthranilic acid (IV) and reacts the compound with hydrochloric acid in the presence of copper(I) -chloride to 3-fluoro-2-chloro-5-nitrobenzoic acid (V), d) converts 3-fluoro-2-chloro-5-nitrobenzoic acid (V) with thionyl chloride to the corresponding acid chloride (VI), e) converts 3- fluoro-2-chloro-5-nitrobenzoyl chloride (VI) with ethoxymagnesium malonic acid diethyl ester to (3-fluoro-2-chloro-5-nitrobenzoyl)-malonic acid diethyl ester (VII), f) converts (3-fluoro-2-chloro-5-nitrobenzoyl) -malonic acid diethyl ester (VII) with propionic acid in the presence of sulfuric acid to 3-fluoro-2-chloro-5-nitroacetophenone (VIII), g) transfers 3-fluoro-2-chloro-5-nitroacetophenone (VIII) with mercaptoacetic acid to (2- acetyl-6-fluoro-4-nitrophenyl-thio)acetic acid (IX), and h) ring-closes the latter to 3-methyl-7-fluoro-5-nitrobenzothiophene (I).

To illustrate the method according to the invention, reference is made to the following formula kernel:

The production of the hitherto undescribed compounds in steps (2) to (6) follows methods known per se;

but the combination of process steps (1) to (7) constitutes a significant advance in the production of 3-methyl-7-fluoro-5-nitrobenzothiophene.

Compounds of the general formula (X)

where R 1 means a carboxyl group or optionally substituted carbonyl alkyl and

R2 stands for halogen, an amino group or a thioalkyl-carboxyl group,

in particular the compounds 3-fluoro-5-nitroanthranilic acid (IV), 3-fluoro-2-chloro-5-nitrobenzoic acid (V), halides thereof (e.g. VI), (3-fluoro-2-chloro-5-nitrobenzoyl )-malonic acid diethyl ester (VII), 3-fluoro-2-chloro-5-nitroacetophenone (VIII) and (2-acetyl-6-fluoro-4-nitrophenylthio)acetic acid (IX) are new, and similarly to the procedure for their production, subject of the present invention.

The individual synthesis steps for the intermediate products used

in the method according to the invention is described in more detail below.

1st step: 7-fluorisatin (III) is known. The preparation follows from 2-fluoroaniline (II) available in technical quantities. (See: S.J. Holt and P.W. Sadler, Proe. Roy. Soc. (London) 148 B, 481-494 (1958); R.R. Smolders et al., Ing. Chim. (Brussels) 1 982 , 64 (303) , 3 -6). 2nd step: 3-fluoro-5-nitroanthranilic acid (IV). The production takes place by methods known in principle by nitration of 7-fluorisatin and oxidation with hydrogen peroxide. The nitration preferably follows with 100% nitric acid in concentrated sulfuric acid.

Other nitrating agents can also be used, such as e.g. alkali nitrates, mixed anhydrides of nitric acid or nitric acid esters, or other solvents such as e.g. glacial acetic acid or chlorinated hydrocarbons. The reaction temperatures can be varied. In general, you work at temperatures between

-20°C and 40°C, preferably at 0°C.

(See: W.C. Sumpter and W.F. Jones, J. Amer. Chem. Soc. 65,

1802 ( 1 943)) . 3rd step: 3-fluoro-2-chloro-5-nitrobenzoic acid (V). The production takes place by methods known in principle by diazotization of the corresponding anthranilic acid and reaction with hydrochloric acid in the presence of copper (I) chloride. The diazotization takes place with common reagents, such as e.g. sodium nitrite, nitrosylsulphuric acid or alkyl nitrites. As a solvent, concentrated sulfuric acid, phosphoric acid, hydrochloric acid or glacial acetic acid, or mixtures thereof, are suitable. Diazotization with nitrosylsulphuric acid in phosphoric acid-glacial vinegar mixtures is preferred. The reaction temperatures can be varied from -5°C to 30°C. The exchange of the diazonium group with chlorine follows with aqueous hydrochloric acid in the presence of a copper catalyst. Preferred catalyst is copper (I) chloride.

(See: Houben-Weyl, Vol. V/3, pp. 846 ff (1962)).

4th step: (3-fluoro-2-chloro-5-nitrobenzoyl)malonic acid diethyl ester (VII). The compound can be obtained in a known manner from the corresponding benzoic acid over the acid chloride (VI).

The formation of the acid chloride follows reaction with inorganic acid chlorides such as thionyl chloride, phosphorus (V) chloride or phosphorus (III) chloride. The reaction can be carried out in solvents such as aromatic hydrocarbons or chlorinated hydrocarbons or also in an excess of chlorinating agent at temperatures between 20°C and 100°C. Reaction in thionyl chloride at the reflux temperature is preferred.

For reaction of the acid chloride with ethoxymagnesium malonic acid diethyl ester, aromatic hydrocarbons are suitable as solvents; particularly preferred is toluene.

(See: A.P.G. Kieboom, Synthesis 1975, 327; S.R. Alpha,

J. Org. Chem. 3_8 , 3136 (1973)). 5th step: 3-fluoro-2-chloro-5-nitroacetophenone (III). The production takes place by a method known in principle by reacting (3-fluoro-2-chloro-5-nitrobenzoyl)malonic acid diethyl ester with propionic acid and sulfuric acid.

Acylated malonic ester can be converted to methyl ketone by saponification and decarboxylation. Preferred reaction conditions here are heating in propionic acid in the presence of catalytic amounts of concentrated sulfuric acid until C02 ~ evolution is complete.

(See: N.B. Chapman et al., J. Chem. Soc. (C) 1968, 518; Houben-Weyl, Vol. VII/2, pp. 1338 ff (1976)). 6th step: (2-acetyl-6-fluoro-4-nitro-phenylthio)acetic acid (IX). The compound can be prepared by a method known in principle by reaction between 3-fluoro-2-chloro-5-nitroacetophenone and mercaptoacetic acid.

The reaction is carried out in water or in organic solvents which are miscible with water (e.g. alcohols or lower ketones) in the presence of alkali (e.g. alkali bicarbonate,

-carbonate, -hydroxide or tert. amines). The use of sodium bicarbonate in aqueous isopropanol is preferred. The reaction temperature can be varied from 20°C up to boiling

the point of the solvent used; preferably between 45°C and 50°C.

(See: A. Ricci and N. Cagnoli, Ann. Chim. (Rome) 4_5, 1 72 (1955); C. Angelini, Ann. Chim. (Rome) 47, 705 (1957);

S. Middelton, Austr. J. Chem. 1_2 , 218 (1959)).

7th step: The cyclization of (2-acetyl-6-fluoro-4-nitro-phenylthio)acetic acid to 3-methyl-7-fluoro-5-nitrobenzothiophene (I) proceeds in the presence of carboxylic acids as condensing agents and optionally in the presence of interte organic solvents at temperatures between 50°C and 200°C.

The use of propionic acid has proven to be particularly advantageous. The preferred reaction temperature is here in the range from 110°C to 150°C.

(See: DE-OS 3 031 738).

The present invention shall: be described in more detail with help

of the following examples:

Example 1

a) 3-fluoro-5-nitroanthranilic acid (from 7-fluorisatin) Dissolve 33.0 g of 7-fluorisatin (0.2 mol) in 80 ml

concentrated sulfuric acid. During cooling, 8.3 ml of 100% nitric acid is added dropwise over 20 minutes at 0°C. It is stirred for 30 minutes at 0°C. The precipitate is then poured onto 400 g of ice and at 20 to 30°C the mixture is made alkaline using 45% caustic soda. At 20°C, 30 ml of 30% hydrogen peroxide is added dropwise over 10 minutes. It is stirred for 30 minutes and then the product is precipitated with concentrated hydrochloric acid until pH 2. The liquid is sucked off, the product is washed with salt

freely with water and dried in vacuum at 50°C. Yield: 34.5 g = 86.3% of theoretical yield. Freezing point: 243 to 246°C (decomposition). b) 3-fluoro-5-nitroanthranilic acid (from N-(2-fluoro-phenyl)-2-hydroxyiminoacetamide without isolation of the 7-fluoro-isatin)

a) N-(2-fluorophenyl)-2-hydroxyiminoacetamide

A mixture of 400 ml water, 110 g anhydrous

sodium sulfate and 10.7 g (0.154 mol) of hydroxylamine hydrochloride are heated to 85°C. During 60 minutes, a solution consisting of 24.8 g (0.15 mol) chloral hydrate, 15.6 g (0.14 mol) 2-fluoroaniline and 12 ml concentrated hydrochloric acid is added dropwise at 85°C in 50 ml water.

It is stirred for 60 minutes at 85°C and then cooled to 30°C. The precipitate is stirred out with 200 ml of dichloromethane. The organic phase is separated, reacted with 70 ml of water and adjusted to pH 12 using caustic soda. After 30 min. stirring, the pH is adjusted to 10.5 with dilute hydrochloric acid. The aqueous phase is carefully separated and the product is precipitated at 20 - 25°C by adding hydrochloric acid until pH 7. The liquid phase is suctioned off, the product is washed with water and dried in a vacuum at 50°C.

Yield: 15.5 g = 60.8% of theoretical yield. Freezing point: 113 - 115°C.

3) 3-fluoro-5-nitroanthranilic acid

In 150 ml concentrated sulfuric acid is introduced during 20 min. at 80 - 85°C 50 g (0.274 mol) N-(2-fluorophenyl)-2-hydroxyiminiacetamide. Then stir for a further 40 min. at 80 - 85°C. The precipitate is cooled to 0°C. Within 30 min. at 0°C, 13 ml of 100% nitric acid are added dropwise, then stirred for a further 30 min. at 0°C. The precipitate is poured onto ice and adjusted with caustic soda to pH 12. After adding 50 ml of 30% hydrogen peroxide, stir for 30 min. at 20°C. The product is then precipitated by the addition of hydrochloric acid until pH 2, the liquid phase is sucked off, and the product is washed salt-free with water and dried in a vacuum at 50°C.

Yield: 31.8 g = 58.0% of theoretical yield. Freezing point: 237 - 239°C (decomposition).

Example 2

3- fluoro- 2- chloro- 5- nitrobenzoic acid

A suspension of 100.5 g of 3-fluoro-5-nitroanthranilic acid (0.5 mol) in 400 ml of 85% phosphoric acid and 200 ml of glacial acetic acid is diazotized at 0°C with nitrosylsulphuric acid consisting of 35.2 sodium nitrite (0.51 mol ) and 250 ml of concentrated sulfuric acid. It is stirred for 2 hours at 0°C. The diazonium salt solution is stirred at 20 - 25°C into a mixture consisting of 65 g of copper (I) chloride and 600 ml of concentrated hydrochloric acid. It is stirred further

15 min. at 25°C, then briefly heated to 70°C and cooled again to room temperature. The precipitate is sucked off and washed with water. The mother liquor is extracted with 1000 ml of diisopropyl ether. The precipitate is dissolved in ether extract; it is filtered over diatomaceous earth. After distilling off the solvent, the residue is vacuum-recrystallized from 250 ml of toluene, the liquid is sucked off and the product is dried in a vacuum at 50°C.

Yield: 69.4 g = 62.4% of theoretical yield.

Freezing point: 155 - 157°C.

Example 3

(3-fluoro-2-chloro-5-nitrobenzoyl) malonic acid diethyl ester 40.0 g of 3-fluoro-2-chloro-5-nitrobenzoic acid (0.18 mol) is heated under reflux in 150 ml of thionyl chloride with 1 ml of diethyl formamide until complete gas evolution (approx. 2 hours). The excess of thionyl chloride is distilled off and the acid chloride formed is distilled in vacuum.

Yield: 40.0 g = 93.0% of theoretical yield.

Boiling point: 98 to 101°C/0.1 torr.

To a solution of 0.25 mol of ethoxymagnesium malonic acid diethyl ester in 140 ml of absolute toluene is added dropwise at room temperature the solution of 40.0 g of 3-fluoro-2-chloro-5-nitrobenzoyl chloride (0.168 mol) in 190 ml of absolute toluene, it is stirred for 15 my. and the precipitate is poured over a mixture consisting of 170 g of ice and 30 ml of concentrated sulfuric acid.

The organic phase is separated, washed with water until neutrality is achieved and the toluene is distilled off under vacuum. The residue is brought to crystallisation by adding 100 ml of naphtha (40/60). The liquid is sucked off, the product is waxed with kerosene and dried in a vacuum at room temperature.

Yield: 4 7.7 g = 78.5% of theoretical yield.

Freezing point: 59°C.

Example 4

3- fluoro- 2- chloro- 5- nitroacetophenone

47.7 g of (3-fluoro-2-chloro-5-nitrobenzoyl)malonic acid diethyl ester (0.132 mol) is heated to boiling under reflux for 2 hours in 55 ml of propionic acid with the addition of 0.5 ml of concentrated sulfuric acid. The propionic acid is then distilled off under vacuum at up to 100°C. The residue is dissolved in 100 ml of methylene chloride, washed neutrally with water and filtered over an A^O-j layer. The solvent is distilled off in a vacuum

and the residue is brought to crystallization by the addition of 100 ml of naphtha (40/60). The liquid is sucked off, the product is washed with kerosene and dried in a vacuum at 30°C.

Yield: 25.2 g = 87.8% of theoretical yield.

Freezing point: 6 7°C.

Example 5

(2-acetyl-6-fluoro-4-nitro-phenylthio)acetic acid 25.0 g of 3-fluoro-2-chloro-5-nitroacetophenone (0.115 mol) and 21.0 g of sodium bicarbonate (0.25 mol) are suspended in a mixture consisting of 90 ml of isopropanol and 30 ml of water.

Within 10 min. at 45 to 50°C, 11.1 g of freshly distilled mercaptoacetic acid (0.12 mol) are added dropwise, and the mixture is stirred for 1 hour at this temperature. After dilution with 250 ml of ice water, the product is precipitated by the dropwise addition of 20 ml of concentrated hydrochloric acid, the liquid is sucked off, the product is washed with water and dried in a vacuum at 50°C.

Yield: 29.0 g = 92.3% of theoretical yield.

Freezing point: 110 to 115°C.

Example 6

3- methyl 1- 7- fluoro- 5- nitrobenzothiophene

10.0 g of (2-acetyl-6-fluoro-4-nitro-phenylthio)acetic acid (0.0366 mol) is heated under reflux in 40 ml of propionic acid until CG 2 development is complete (approx. 1.5 hours). The propionic acid is then distilled off under vacuum, the residue is dissolved in 50 ml of methylene chloride and filtered over silica gel. The solvent is then distilled off under vacuum and the residue that remains is recrystallized from 40 ml of isopropanol. The liquid is sucked off, the product is washed with isopropanol and dried in a vacuum at 45°C.

Yield: 5.1 g = 66.0% of theoretical yield.

Freezing point: 111°C.

The 3-methyl-7-fluoro-5-nitrobenzothiophene produced according to the invention serves for the production of 7,8,9,10-tetrahydrothieno [3,2-e]pyrido [4,3-b]indoles of general formula (XI)

where R stands for hydrogen or alkyl.

The new substituted 7,8,9,1O-tetrahydrothieno-[3,2-e]pyrido [4,3-b]indole derivatives of formula (XI), which are not re-

state of the present invention, shows a better central-nervous vibration spectrum, especially also a better therapeutically usable in-vivo activity than the compounds known according to the state of the art, and mentioned in European patent no. 12 347. The compounds of formula (XI) as well as their pharmaceutical use thus constitute an enrichment of pharmacy.

The compounds of formula (XI) can be processed into pharmaceutical preparations which, in addition to non-toxic, inert, pharmaceutically suitable carriers, may contain one or more of the compounds (XI) or salts thereof.

Such preparations also include pharmaceutical preparations in dosage units. This means that the preparations are available in the form of individual parts, i.e. tablets, dragées, capsules, pills, suppositories and ampoules, where the content of the active

as substance constitutes a fraction or multiple of a single dose. The dosing units can e.g. 1,2,3 or 4 single-

doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active substance that is prescribed for an application, and which usually corresponds to a full, half, a third or a quarter of the daily

dose.

Non-toxic, inert, pharmaceutically suitable carriers are understood to mean solid, semi-solid or liquid diluents, fillers and auxiliary substances of any type.

Tablets, dragées, capsules, pills, granules, suppositories, solutions, suspensions and emulsions can be mentioned as preferred pharmaceutical preparations.

Tablets, dragées, capsules, pills and granules may contain the active substance(s) in addition to the usual carrier substances, such as e.g. (a) fillers and delay agents, e.g. starch, milk sugar, cane sugar, glucose, mannitol and silicic acid, (b) binder, e.g. carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, (c) agents that retain moisture, e.g. glycerin, (d) explosive, e.g. agar-agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g. kerosene, and (f) resorption accelerators,

e.g. quaternary ammonium compounds, (g) wetting agent,

e.g. cetyl alcohol, glycerin monostearate, (h) adsorbent, e.g. kaolin and bentonite, and (i) lubricant, e.g. talc, calcium and magnesium stearate and solid polyethylene glycol or mixtures of the substances listed under (a) to (i).

The tablets, dragées, capsules, pills and granules can be equipped with coatings or envelopes that possibly contain opalizing agents, and can also be composed in such a way that they release the active substance exclusively or preferentially in a specific part of the intestinal tract, possibly with delayed release , whereby it can be used as embedding compounds, e.g. polymer compounds and waxes.

The active substance or substances may optionally also be present in micro-encapsulated form with one or more of the carrier substances listed above.

The suppositories can next to it, or they, active

substance contain the usual water-soluble or water-insoluble carrier substances, e.g. polyethylene glycol, fat, e.g. cocoa butter, and higher esters (e.g. C^-alcohol with C-|g fatty acid) or mixtures of these substances.

Solutions and emulsions can, in addition to the active substance(s), contain common carrier substances such as solvents, solubilizers and emulsifiers, e.g. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn kernel oil, olive oil, castor oil and sesame oil, glycerin, glycerin informal, tetrahydrofur -furyl alcohol, polyethylene glycol and fatty acid esters of sorbitans or mixtures of these substances.

For parenteral use, the solutions and emulsions can

also available in sterile and blood isotonic form.

In addition to the active substance(s), the suspensions may contain normal carriers, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The aforementioned preparation forms can also contain coloring agents, preservatives as well as odor and taste-improving additives, e.g. peppermint oil and eucalyptus oil and sweetener, e.g. saccharin.

The therapeutically active compounds are preferably present in the above-mentioned pharmaceutical preparations in a concentration of approx. 0.1 to 99.5, preferably 0.5 to 95% by weight of the total mixture.

The above-mentioned pharmaceutical preparations can by side

of compounds of formula (XI) and/or the compounds' salts also contain other pharmaceutical active substances.

The production of the above-mentioned pharmaceutical preparations takes place according to known methods, e.g. by mixing the active substance or substances with the carrier substances.

The active substances of formula (XI) or the pharmaceutical preparations can be used orally, parenterally and/or rectally, preferably orally and parenterally, especially orally and intravenously.

It has generally proven advantageous to administer the active substance or substances by parenteral (i.v. or i.rn.) application in amounts of approx. 0.01 to approx. 10, preferably 0.1 to 1 mg/kg body weight every 24 hours, and when used orally in amounts of approx. 0.05 to approx. 100, preferably 0.1 to 10 mg/kg body weight every 24 hours, possibly in the form of several single administrations to achieve the desired result. A single administration contains the active substance, or substances, preferably in amounts of approx. 0.01 to approx. 30, especially 0.03 to 3 mg/kg body weight.

It may be necessary to deviate from the dosage stated above, this depends on the species and body weight of the organism being treated, the type and degree of the disease, the type of preparation and use of the medicine, as well as the time period or interval where the treatment is to take place. IN

in some cases it may be sufficient to use less than the amount of active substance stated above, while in other cases the amount stated above must be exceeded. The determination of the necessary optimal dosage and type of application of the active substance can be easily determined by the person skilled in the art.

The active substances of formula (XI) can also be present in pharmaceuticals which, in addition to compounds of formula (XI), contain other active substances. The following can preferably be mentioned: 3-receptor blockers, parasympatholytics, anxiolytics, neuroleptics, hypnotics and sedatives.

The preparation of compounds of formula (XI) will be described in the following by means of the following examples.

Example 7

1- methyl- 9- ethyl- 4- fluoro- 7, 8, 9, 1O- tetrahydrothieno [3,2-e]-pyrido[4,3-b]undole

0.1 mol of 3-methyl-7-fluoro-5-hydrazinobenzothiophene hydrochloride and 0.11 mol of 1-ethylpiperidone were dissolved in 300 ml of isopropanol at reduced temperature. The solution was brought to boiling and reacted with 100 ml of HCl-saturated isopropanol during 10 min. in hot condition. After boiling for 1 hour, cool to 0°C and: the crystals (which occur) are sucked off. For purification, the crude product is reacted with 300 ml of 10% caustic soda, the base is taken up in methylene chloride and, after washing with water, the organic base is dried over sodium sulfate After filtering and evaporating the solvent, the base is obtained in crystalline form from isopropyl ether.

Yield: 75% of theoretical yield; freezing point 182 -183°C

after recrystallization from acetic acid ethyl ester. Lactate: 0.05 mol of base is dissolved in 700 ml of acetone and reacted with 15 g of L(+)-lactic acid. Colorless crystals. Yield: 95% of theoretical yield;

freezing point: 203 - 205°C.

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3- methyl - 7- fluoro- 5- hydrazinobenzothiophene hydrochloride

A suspension of 0.1 mol of 3-methyl-7-fluoro-5-aminobenzothiophene hydrochloride is formed in 100 ml of water and 100 ml of concentrated hydrochloric acid, the suspension is reacted between -5°C and 0°C dropwise with a solution of 0.11 mol sodium nitrite in 50 ml of water. The diazonium salt solution is dripped into a mixture of 0.21 mol SnCl2.2H20 and 200 ml concentrated hydrochloric acid at 0 C. After heating to room temperature, add 60 ml isopropanol, the crystal mass is sucked off and recrystallized from isopropanol.

Yield: 88% of theoretical yield; freezing point 2 05 -210°C (decomposition).

3- methyl- 7- fluoro- 5- aminobenzothiophene hydrochloride

(Procedure a)

0.01 mol of 3-methyl-7-fluoro-5-nitrobenzothiophene is hydrated in 300 ml of methanol in the presence of 1 g of palladium charcoal at 25°C. After filtering off the catalyst, the filtrate is compressed to approx. 100 ml, an ether-HCl solution is added and the hydrochloride is sucked off.

Yield: 92% of theoretical yield; freezing point 273 - 275°C (decomposition).

(Procedure b)

0.09 mol of 3-methyl-7-fluoro-5-nitrobenzothiophene is heated to boiling in 220 ml of methanol together with 2 g of palladium charcoal. 0.35 mol of hydrazine hydrate is then added dropwise over the course of 30 min. After 2 hours of boiling, it is filtered, the filtrate is compressed, the residue is dissolved in ether and washed with water. The hydrochloride is precipitated from the ether solution.

Yield: 97% of theoretical yield;' freezing point 273 - 275°C (decomposition).

3- methyl- 7- fluoro- 5- nitrobenzothiophene

(Description of the preparation according to the invention, see above).

Claims (15)

1. Process for the production of 3-methyl-7-fluoro-5-nitrobenzothiophene (I), characterized in that a) transfers 2-fluoroaniline (II) to 7-fluorisatin (III) by known methods, b) nitrates 7-fluorisatin (III) and then oxidizes the compound to 3-fluoro-5-nitroanthranilic acid (IV), c) diazotizes 3-fluoro-5-nitroanthranilic acid (IV) and converts the compound with hydrochloric acid in the presence of copper (I) chloride to 3-fluoro-2-chloro-5-nitrobenzoic acid (V), d) converts 3-fluoro-2-chloro-5-nitrobenzoic acid (V) with thionyl chloride to the corresponding acid chloride (VI), e) converts 3-fluoro-2-chloro-5-nitrobenzoyl chloride (VI) with ethoxymagnesium malonic acid diethyl ester to (3-fluoro-2-chloro-5-nitrobenzoyl)-malonic acid diethyl ester (VII), f) reacts (3-fluoro-2-chloro-5-nitrobenzoyl)-malonic acid diethyl ester (VII) with propionic acid in the presence of sulfuric acid to 3-fluoro-2-chloro-5-nitroacetophenone (VIII), g) transfers 3-fluoro-2-chloro-5-nitroacetophenone (VIII) with mercaptoacetic acid to (2-acetyl-6-fluoro-4-nitrophenylthio)acetic acid (IX), and h) ring-closes the latter compound to 3-methyl-7-fluoro-5-nitrobenzothiophene (I). 2. Process for the production of 3-fluoro-5-nitroanthranilic acid (IV), characterized by dissolving 7-fluorisatin (III) in sulfuric acid, nitrating with nitric acid and oxidizing with an oxidizing agent. 3. Compound, characterized in that it consists of 3-fluoro-5-nitroanthranilic acid (IV). 4. Process for the production of 3-fluoro-2-chloro-5-nitrobenzoic acid (V), characterized by diazotizing 3-fluoro-5-nitroanthranilic acid (IV) and reacting the compound with hydrochloric acid in the presence of copper (I) chloride . 5. Compound, characterized in that it consists of 3-fluoro-2-chloro-5-nitrobenzoic acid (V). 6. Process for the production of 3-fluoro-2-chloro-5-nitrobenzoic acid chloride (VI), characterized by reacting 3-fluoro-2-chloro-5-nitrobenzoic acid (V) with thionyl chloride or with another suitable chloride. 7. Compound, characterized in that it consists of 3-fluoro-2-chloro-5-nitrobenzoic acid chloride (VI). 8. Process for the production of (3-fluoro-2-chloro-5-nitrobenoyl)-malonic acid diethyl ester (VII), characterized by reacting 3-fluoro-2-chloro-5-nitrobenzoic acid chloride (VI) with ethoxymagnesium malonic acid diethyl ester. 9. Compound, characterized in that it consists of (3-fluoro-2-chloro-5-nitrobenzoyl)-malonic acid diethyl ester (VII) . 10. Process for the production of 3-fluoro-2-chloro-5-nitroacetophenone (VIII), characterized by reacting (3-fluoro-2-chloro-5-nitrobenzoyl)-malonic acid diethyl ester (VII) with propionic acid in the presence of sulfuric acid. 11. Compound, characterized in that it consists of 3-fluoro-2-chloro-5-nitroacetophenone (VIII ). 12. Process for the production of (2-acetyl-6-fluoro-4-nitrophenylthio)acetic acid (IX), characterized by reacting 3-fluoro-2-chloro-5-nitroacetophenone (VIII) with mercaptoacetic acid. 13. Compound, characterized in that it consists of (2-acetyl-6-fluoro-4-nitrophenylthio)acetic acid (IX) . 14. Process for the production of 3-methyl-7-fluoro-5-nitrobenzothiophene, characterized by closing the ring with (2-acetyl-6-fluoro-4-nitrophenylthio)acetic acid (IX). 15. Compounds of general formula (X) where R-j stands for a carboxyl group or optionally substituted carbonylalkyl, and R2 stands for halogen, an amino group or a thioalkyl- carboxyl group.