NO138695B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE TRICYCLIC COMPOUNDS - Google Patents

Description

The present invention relates to the production of tri-

cyclic compounds of the general formula

R^ means halogen, lower alkyl,

X oxygen, lower alkylimino or methylene,

m the number 0 or 1, —^

R and R^ mean hydrogen or together the group Js<*>

and salts of these compounds.

The term "lower alkyl" alone or together with other groups

means aliphatic residues with 1 to 6 carbon atoms,

which can be straight chain or branched. Examples of

such groups are methyl, ethyl, isopropyl, n-hexyl, etc.

"Halogen" is all 4 halogen atoms, i.e. fluorine, chlorine, bromine and iodine. Chlorine is preferred

It has been found that the compounds of formula I according to the invention and their salts, which are new compounds, are distinguished by strong central depressant and neuroleptic properties. They can therefore, for example, be used for the treatment of acute or chronic schizophrenia as well as also as sedatives. Particularly advantageous is that no or only weak cataleptic side effects occur, so that no or only negligible motor disturbances are felt. Formula I deals only with the hydrogenated compounds of compounds of formula IV

and their salts. Particularly preferred compounds are 3-{2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone and 3 - {2-[4-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]ethyl j- -2-oxazolidinone as well as their salts.

The compounds with the general formula I and their salts are prepared according to the invention by a method which is characterized by reacting a compound with the formula

where R-j^ has the meaning given above and Y is a leaving group with a compound of the formula where m, R2, R3 and X have the meaning given above, or that one reduces a compound of the formula

where m, R-, , R-, R and X have the above meaning,

J- £• 3

or that one reacts a compound with the formula

where R 1 has the meaning given above, with a compound of the formula

where X, Y, m, R2 and R3 have the above-mentioned meaning

ning, and if desired transfer the obtained product into a salt.

The outgoing group Y of the outgoing compounds of formula

II is preferably halogen or alkyl- or aryl-substituted sulfonyloxy. In the group Y of the starting compounds with formula II, the alkyl groups or aryl groups present are preferably lower groups, especially methyl or phenyl or tolyl; halogen atoms present are preferably chlorine or bromine.

The starting compounds of formula II are known compounds or analogues of known compounds, which can be prepared according to known methods. E.g. the group Y is introduced in its various meanings as follows: Y = halogen: The corresponding 10-hydroxy compound is reacted with a suitable halide, e.g. thionyl chloride, thionyl bromide, or with a hydrohalide in the presence of a water binding agent, such as hydrogen chloride and calcium chloride.

Y = alkyl- or aryl-substituted sulfonyloxy: The corresponding 10-hydroxy compound is reacted with an alkyl- or aryl-substituted sulfonic acid halide, e.g. the chloride.

The starting compounds of formula III can e.g. is produced according to the following reaction equation:

In the above reaction equation, X, Y, m, and R^ have

the above meanings and means a suitable protecting group, for example benzyl or a lower alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl. The condensation preferably takes place in the presence of an acid-binding agent, for example potassium carbonate or triethylamine. Finally, the protecting group, the benzyl group, is removed by hydrogenolysis, the alkoxycarbonyl group, for example, by alkaline hydro-

bright.

The reaction according to the invention of the starting compounds of the formulas II and III conveniently takes place in an inert organic solvent, e.g. in an aromatic hydrocarbon, e.g. benzene or toluene, in a chlorinated hydrocarbon, e.g. methylene chloride, trichloroethylene, chloroform, carbon tetrachloride or chlorobenzene, in an aliphatic or cyclic ether, such as diethyl ether, tetrahydrofuran or dioxane or also in dimethylformamide or dimethylsulfoxide. The temperature is suitably between approx. 30 and 200°C, whereby work is preferably done at temperatures in the region of around 100°C. If a starting compound of formula II is used, where Y is halogen or alkyl- or aryl-substituted sulfonyloxy, the reaction is preferably carried out in the presence of an acid-binding agent, preferably in the presence of an alkali carbonate, e.g. potassium carbonate, or also in the presence of an excess of the starting compound of formula

III.

The reduction according to the invention of the enamine of formula IV takes place preferably by treatment with an alkali metal borohydride in the presence of a strong acid. The alkali metal borohydride used is preferably sodium or potassium borohydride, in particular sodium borohydride. Lithium borohydride can also be used. The strong acid can be an organic as well as an inorganic acid. As organic acids, straight-chain or branched, lower mono- or dicarboxylic acids with up to 4 carbon atoms, which may be halogen-substituted, such as e.g. formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, isosmbric acid, oxalic acid and the like.

Acetic acid is preferred, oxalic acid is particularly preferred.

As inorganic acids, particularly come into consideration: Sulfuric acid, hydrohalic acid, especially hydrochloric acid or the like.

A preferred inorganic acid is concentrated sulfuric acid.

Since the enamine of formula IV is unstable in the presence of water, the reduction is conveniently carried out in the absence of water; it is appropriate to use only anhydrous acids or only

such acids, by which, if they contain any water, this

not issued, such as concentrated sulfuric acid. The reaction with an alkali metal borohydride and a strong acid is advantageously carried out in an ether, such as diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, (diglymer) or dimethoxyethane, as well as at a temperature between room temperature and the reflux temperature of the solvent. Preferably, you work under backflow conditions. The reduction according to the invention of the enamines of formula IV can also be carried out by other methods, for example by treatment with formic acid or zinc and glacial acetic acid. These reactions are also preferably carried out at a temperature between room temperature and the reflux temperature of the solvent, preferably at the reflux temperature. By reduction with zinc and glacial acetic acid, a present nitro group R^ is reduced extensively to the amino group.

The starting compounds of formula V can e.g. is prepared by reacting a compound of formula II with a mono-N-protected piperazine, e.g. N-carbethoxypiperazine, Condensation product is then saponified alkaline, e.g. using aqueous alkali.

The leaving group present in the starting compounds of formula VI has the same meaning as in the case of the starting compounds of formula II described above. The starting compounds of formula VI can e.g. is produced in such a way that a lactam of the formula is converted

where m, R2, and X have the above meanings,

to the corresponding alkali metal salt, e.g. the sodium salt. This can e.g. occur by treating the lactam of formula X with an alkali metal hydride or alkali metal amide in an aromatic hydrocarbon, such as, for example, benzene, toluene or dimethylformamide. The resulting alkali metal salt is then reacted with a compound of formula

where Hal is halogen and

Rj- is a suitable protecting group, e.g. benzyl

or 2-tetrahydropyranyl,

The shuttle group R,, in the condensation product is then cleaved hydrogenolytically or hydrolytically. The obtained hydroxy compound is reacted with a halogenating agent,

e.g. thionyl chloride, or with an alkyl- or aryl-substituted sulphonic acid halide, e.g. the chloride, and a starting compound with formula VI is then obtained.

The reaction according to the invention of the starting compounds of formulas V and VI conveniently takes place in an inert organic solvent, e.g. in an aromatic hydrocarbon, e.g. benzene or toluene, a chlorinated hydrocarbon, e.g. chloroform, an ether, e.g. dioxane or dimethoxyethane, a lower alkanol, such as methanol or ethanol, a ketone, such as acetone or methyl ethyl ketone, or also in dimethylformamide or dimethylsulfoxide. It is preferred to carry out the reaction in the presence of an acid-binding agent, e.g. in the presence of an alkali metal carbonate, e.g. sodium or potassium carbonate, or in the presence of an inert organic base, e.g. triethylamine. As an acid-binding agent, an excess of the used base of formula V also comes into question. The temperature for the reaction is preferably in the range between room temperature and the boiling point of the reaction mixture.

Obtained bases of formula I form salts both with inorganic and also with organic acids, e.g. with halogenated acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, with other mineral acids, such as sulfuric acid, phosphoric acid or nitric acid, as well as with organic acids, such as tartaric acid, citric acid, camphorsulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, ascorbic acid, maleic acid or mandelic acid, etc. Preferred salts are hydrohalides, especially the hydrochlorides and maleates. The acid addition salts are preferably prepared in a suitable solvent, such as ethanol, acetone or acetonitrile by treating free bases with the corresponding, non-aqueous acid.

The bases of formula I are partially crystalline, solid substances which are relatively well soluble in dimethylsulfoxide, dimethylformamide or in chlorinated hydrocarbons, such as e.g. chloroform, methylene chloride or also in alkanols, such as methanol or ethanol, and are relatively insoluble in water.

The acid addition salts of the bases of formula I are crystalline solids. They are well soluble in dimethylsulfoxide and dimethylformamide and in alkanols, such as methanol or ethanol, and partly also in chloroform, methylene chloride and water. They are relatively insoluble in benzene, ether and petroleum ether.

A cataleptic effect ('growth stiffness' i.e. abnormally long maintenance of a forced body position) applies to centrally depressant or neuroleptically active compounds as a disturbing side effect and exhibits motor disturbances. The products according to the invention have the advantage that they do not or only in a very small degree this has a disturbing side effect. To demonstrate this, representative representatives of the end products were administered intraperitoneally to rats. The following representatives were tested: PRODUCT A: 3-{2-[4-(2-chloro-10,11-dihydro-dibenzo[ b,f]-Thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone maleate.

PRODUCT B: 3-{1-[4-(10,11-dihydro-2-methyl-dibenzo[b,f]-thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone maleate .

As a comparison substance, chlorpromazine, a recognized central depressant or neuroleptic, was included.

The animals are considered cataleptic when the homolateral extremities remain in a crossed position for at least 10 seconds. The number of cataleptic animals is recorded every 30 minutes for 6 hours. ED^0 is the dose at which 50% of the animals show catalepsy.

Results:

The table shows that there is no or only a small cataleptic effect with A and B, in contrast to chlorpromazine.

To demonstrate the central depressant and neuroleptic properties of the final products, representative representatives were subjected to the following tests:

I. Rotating rod test

The rotating rod test examines the ability of mice to complete a coordinated motor performance. After oral administration of the test substance, mice are placed on a horizontal slowly rotating rod and the time until precipitation is measured.

ED 50 is the dose that reduces the residence time compared to that before administration of the test substance by 50%.

Product A shows a strong effect in this test

(ED 50 = 7.9 mg/kg), which is approximately equal to that of chlorpromazine (ED 50 = 5 mg/kg)

II, Determination of homovanillin acid

Rats are sprayed 2 hours before they are killed with the test substance. Homovanillic acid is extracted from the brain homogenate supernatant in butyl acetate and later in an aqueous solution and oxidized with potassium ferricyanide to a fluorescent dimer. From the increased concentration of homovanillic acid (HVS), one can conclude that the test substance acts like chlorpromazine, i.e. it increases the "turnover" of dopamine in the basal ganglia. The homovanillic acid titer in untreated rats is arbitrarily set at 100%.

In this test, A and B show an effect that almost matches that of chlorpromazine.

III. "Pole climb" test

The test provides information on behavioral reactions in rats. Rats are trained by climbing a vertical bar in the test chamber to avoid it a few seconds after an acoustic signal

(conditioned irritation) triggered electrical irritation (unconditioned irritation) via the floor grid.

The inhibition of the conditioned reaction is determined by the parameter ED 50 (mg/kg p.o.) and the inhibition of the unconditioned reaction by the parameter ED 10 (mg/kg p.o,).

The parameter ED 50 (inhibition of the conditioned reaction) gives a measure of the neuroleptic potency of the test substance. The quotient ED 10 (inhibition of the unconditioned reaction)/ ED 50 (inhibition of the conditioned reaction) gives a measure of the quality of action for the test substance, as with a rising quotient a greater selectivity of the neuroleptic effect (less neurotoxic side effect) is present

A comparison between product A and chlorpromazine gives:

In this test, A shows both a neuroleptic potency and a quality (selectivity) for the neuroleptic effect that exceeds that of chlorpromazine.

The products according to the invention can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations containing these or their salts in admixture with a pharmaceutical organic or inorganic inert carrier material suitable for enteral, e.g. oral or parenteral administration, such as water, gelatin, milk sugar, starch , magnesium stearate, talc, vegetable oil, gum arabic, poly-alkylene glycol, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules or in liquid form, e.g. as solutions , suspensions or emulsions. They may be sterilized and/or contain auxiliary substances, such as preservatives, stabilisers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

Appropriate pharmaceutical dosage form contains approx.

1 to -200 mg of a compound of formula I, respectively one of its salts. Appropriate oral dosage

areas are located at approx. 0.1 mg/kg per day to approx. 7.5 mg/kg per day. Appropriate parenteral dosing ranges - are at approx. 0.Ol mg/kg per day to approx. 0.75 mg/kg per day. However, the areas mentioned can be extended upwards or downwards according to individual needs and the professional's regulations.

In the following examples, all temperatures are given in degrees Celsius.

EXAMPLE 1

2.7 g of 1-(10,11-dihydro-2-methyldibenzo[b,f]thiepin-10-yl)-piperazine are added together with 4.3 g of powdered potassium-. carbonate, 200 mg of KJ and 90 ml of toluene to 3.2 g of N-((3-chloroethyl)oxazolidinone and heated for 24 hours under reflux. It is then poured into ice water, diluted with benzene and the organic phase is washed with saturated soda solution and water , dried with sodium sulfate and concentrated under reduced pressure. 3-[2-[4-(10,11-dihydro-2-methyl-dibenzo[b,fthiepin^10-yl)-1-piperazinyl]-ethyl]- 2-Oxazolidinone which is recrystallized from acetone-petroleum ether The maleate melts at 159-161°.

The 1-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine used as starting material can be prepared as follows: 20 g of 5-methylanthranilic acid are suspended in 200 ml of 3N hydrochloric acid at 0° . To this, a solution of 10 g of sodium nitrite and 20 ml of water is added dropwise while stirring and stirred for 25 minutes at 0°.* At 5-10°, a solution of 26.5 g of potassium iodide, 30 ml of 3N hydrochloric acid and 30 ml of water.

Stirring continues for 30 minutes at room temperature and 2 hours at reflux. It is cooled, sodium thiosulphate is added until the reaction solution is yellow (5 g) and the crystalline 2-iodo-5-methyl-benzoic acid obtained is filtered off and washed with water until neutral. The crude acid is dissolved in ether, washed well with sodium thiosulphate solution and water, dried over sodium sulphate and evaporated. Light brown crystals with m.p. 100-112°.

To a solution of 855 g of potassium hydroxide in 7 l of water, 420 g of thiophenol are added at 50° under argon and stirred for 15 min. 22.1 g of copper powder and 1 kg of 2-iodo-5-methyl-benzoic acid are then added and heated for 7 hours at reflux. After cooling, adjust to pH 3 with 600 ml of concentrated hydrochloric acid and extract with methylene chloride, wash with water, dry over sodium sulphate and concentrate to a thick crystal mass. It is then scraped off, washed with cold ethanol and low-boiling petroleum ether and dried. 3-methyl-6-(phenylthio)-benzoe-

acid with m.p. 156-157°.

650 g of 3-methyl-6-(phenylthio)-benzoic acid in 7.5 1 of absolute methanol is slowly added to 300 ml of concentrated sulfuric acid and heated for 24 hours by refluxing. The residue is concentrated and poured onto an ice-cooled sodium bicarbonate solution. The whole is extracted with ether, washed with water, dried over sodium sulphate and concentrated. 3-Methyl-6-(phenylthio)-benzoic acid methyl ester is obtained as a red-brown oil, which crystallizes on standing.

322.5 g of 3-methyl-6-(phenylthio)-benzoic acid methyl ester in 3 1 of absolute tetrahydrofuran are added dropwise under argon and under reflux to 420 ml of a 70% sodium dihydro-bis(2-methoxyethoxy)-aluminate solution in benzene (30 minutes) and cook for a further 3 hours by refluxing. Then you undress for approx. 4°, dilute with 1 liter of benzene and hydrolyze with 700 ml of 2N hydrochloric acid, then pour onto ice water and add a further 400

ml of concentrated hydrochloric acid to obtain a clear solution. The organic phase is washed with water, dried over sodium sulphate, filtered and evaporated. 3-methyl-6-(phenylthio)-benzyl alcohol is obtained as a red-brown oil.

570.7 g of methyl-6-(phenylthio)-benzyl alcohol are dissolved in 1.5 l of benzene and heated at reflux. To this, 352 ml of thionyl chloride is added drop by drop over the course of 45 minutes and boiled for 90 minutes. It is then concentrated under reduced pressure and 3-methyl-6-(phenylthio)-benzyl chloride is obtained as a red-brown oil.

194 g of potassium cyanide in 250 ml of water are heated in an argon atmosphere for 17 hours by refluxing with 616.9 g of 3-methyl-8-(phenyl-thio)-benzyl chloride in 900 ml of ethanol. The ethanol is then distilled off under reduced pressure, then diluted with water and extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated. 3-Methyl-6-(phenylthio)-phenylacetonitrile is obtained as an oil.

500 g of 3-methyl-6-(phenylthio)-phenylacetonitrile, 1.2 l of ethanol, 470 g of potassium hydroxide and 500 ml of water are heated for 12 hours by refluxing. The ethanol is then evaporated under reduced pressure. Water is added to the residue until complete dissolution and the neutral parts are extracted with benzene. The aqueous solution is filtered with the addition of some dicalite and activated charcoal, cooled and adjusted with concentrated hydrochloric acid to pH 3. Extraction is then made with 3x1 liters of chloroform, washed with water, dried with calcium chloride, filtered and concentrated under reduced pressure. The crude 3-methyl-6-(phenylthio)-phenylacetic acid obtained is recrystallized from benzene-hexane. Temp. 132-135°

192 g of polyphosphoric acid are heated to 100° in a nitrogen atmosphere, 20 g of 3-methyl-6-(phenylthio)-phenylacetic acid are quickly added and stirred for 1 hour at 100-103°. The whole is then poured into ice water and extracted with ether. The extracts are washed successively with 2N caustic soda and water and dried over sodium sulphate. Upon concentration, the obtained 10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-one begins to crystallize out. Upon addition of petroleum ether and cooling, the crystallization becomes complete. Temp. 83 - 84°.

10 g of 10,11-dihydro-2-methyldibenzo[b,f]thiepin-10-one is dissolved in

lOO ml of dioxane and add 3.2 g of sodium borohydride in 5 ml of water. It is then stirred for 20 hours at room temperature. It is then concentrated under reduced pressure and the residue is distributed between ether and water. The ethereal solution is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. 10,11-dihydro-2-methyldibenzo[b,f]thiepin-10-ol is obtained as a colorless oil. 10 g of 10,11-dihydro-2-methyldibenzo[b,f]thiepin-10-ol, 100 ml of absolute benzene and 10 g of finely powdered calcium chloride are saturated at room temperature with dry hydrochloric acid gas (approx. 2 hours) and then stirred further in 20 hours. The calcium chloride is then sucked off, washed with chloroform and the filtrate concentrated under reduced pressure. 10-chloro-10,11-dihydro-2-methyl-dibenzo [b,f]thiepine is obtained as a yellow oil, which crystallizes on standing.

19.7 g of 10-chloro-10,11-dihydro-2-methyldibenz.o[b,f Jtiepine dissolved in 100 ml of chloroform are heated together with 36.5 g of 1-carbethoxypiperazine for 24 hours at reflux. It is then concentrated under reduced pressure and the residue crystallizes from acetone-hexane. One obtains 1-carbethoxy-4-(10,11-dihydro-2-methyldibenzo Lb,f]thiepin-10-yl)-piperazine with m.p. 96 - 98°.

5.4 g of 1-carbethoxy-4-(10-11,dihydro-2-methyldibenzo[b,fJthiepin-10-yl)-piperazine, 80 ml of ethylene glycol, 4.64 g of potassium hydroxide and 0.33 ml of water are heated in the of 3/4 hour to 160°. Water is then poured on, extracted with ether, the extracts are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. 1-(10,11-dihydro-2-methyldibenzo[b,fthiepin-10-yl)-piperazine is obtained as an oil.

EXAMPLE 2

7.8 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are added together with 11.6 g of powdered potassium carbonate, 0.2 g of KJ and 100 ml of toluene 8.22 g of N- ((3-chloroethyl) oxazolidinone and heated for 22 hours by refluxing. Water is then poured and the organic phase is washed with saturated soda ash solution and water, dried over sodium sulfate and concentrated under reduced pressure. Crude liquid 3 is obtained -[2-[4-(2-chloro-10, 11-dihydro-dibenzo[b,fthiepin-10-yl)-1-piperazinyl]-ethyl J-2-oxazolidinone. The maleate is produced by reaction with maleic acid in ethanol-ether $ mp 17 3 - 175°.

The 1-(2-chloro-10,11-dihydro-dibenzo[b,f Jthiepin-10-yl)-piperazine used as starting material can be prepared as follows: 100 g of 2,10-dichloro-10,11-dihydro-dibenzo [b,fJtiepine in 300 ml of chloroform is heated for 24 hours at reflux together with 18 2 g of 1-carbethoxypiperazine. Then dilute with chloroform and water. The organic phase is washed several times with water and dried over magnesium sulfate. It is then concentrated under reduced pressure and the residue crystallizes from acetone-hexane. 1-Carbethoxy-4-(2-chloro-10,11-dihydro-dibenzo[b,f jthiepin-10-yl)-piperazine is obtained; m.p. 92 - 93°.

110 g of 1-carbethoxy-4-(2-chloro-10-11,dihydro-dibenzo[_b,f jtiepin-10-yl)-piperazine, 1.5 l of ethylene glycol, 104 g of potassium hydroxide and 5.4 ml of water are heated in the course of 1 hour to 160°. Then pour on water and extract with chloroform. The organic phase is washed with water, dried over magnesium sulphate and evaporated. One obtains 1-(2-chloro-10,11-dihydro-dibenzo[b,fJthiepin-10-yl)-piperazine as an oil.

EXAMPLE 3

16.5 g of 1-[2-chloro-10,11-dihydro-dibenzo[b,fJthiepin-10-yl]-piperazine are stirred together with 9.8 g of 3-(3-chloropropyl)-2-oxazolidinone, 5.25 g of sodium carbonate and 0.75 g of sodium iodide in 100 ml of butanol for 15 hours at reflux temperature. The solvent is then evaporated under reduced pressure, and the residue is partitioned between chloroform and water. The organic phase is washed with water, dried with sodium sulphate and evaporated under reduced pressure. The remainder is decolorized in methanol with activated charcoal. From the filtered solution crystallizes on cooling 3-[3-[4-(2-chloro-10,11-dihydro-dibenzo [b,fJthiepin-10-yl)-1-piperazinyl]-propyl]-2-oxazolidinone with m.p. 136°. The maleate prepared in acetone melts at 195 - 196°.

EXAMPLE 4

50 g of 10-chloro-10,11-dihydro-2-nitro-dibenzo[b,f]thiepine and 140 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone are held for 15 minutes at 120°. After cooling, the reaction mixture is diluted with 2N sodium hydroxide and extracted with ethyl acetate. The organic phase is washed with water until the reaction is neutral and extracted with 2N aqueous methanesulfonic acid. The aqueous phase is extracted with ethyl acetate, then made alkaline and extracted again with ethyl acetate. The organic phase is washed with water until the reaction is neutral, dried over magnesium sulphate and evaporated under reduced pressure. The obtained 3-[2-[4-(10,11-dihydro-2-nitro-dibenzo[b,fJthiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone is recrystallized from acetone; m.p. 130 - 132°. By reacting the base with maleic acid, the corresponding maleate is obtained; m.p. 185 - 187°.

The 10-chloro-10,11-dihydro-2-nitro-dibenzo[b,fJ thiepine used above can be prepared as follows: A solution of 480 g of 2-chloro-5-nitro-benzaldehyde in 3.2 1 ethanol is added dropwise in a nitrogen atmosphere at 30-40° with stirring and in the course of 4 hours a solution of 320 g of thiophenol in 120 g of sodium hydroxide, 2 1 of ethanol and 440 ml of water. The reaction mixture is further stirred for 30 minutes at 60°, then cooled to 0° and filtered. Crude, crystalline 3-nitro-6-(phenylthio)-benzaldehyde with m.p. 96 -100°.

450 g of 3-nitro-6-(phenylthio)-benzaldehyde are suspended in 4 l of ethanol and 111 g of sodium borohydride are added in portions. The reaction mixture is stirred for a further 6 hours. The whole is diluted with 4 1 of water and extracted with ether. The organic solution is washed

successively with water and aqueous sodium bicarbonate solvent, dried over magnesium sulfate and evaporated under reduced pressure. The crude product is recrystallized from benzene-petroleum ether. 3-nitro-6-(phenylthio)-benzyl alcohol is obtained; $mp. 104 - 107°.

4 in < f

170.5 g of 3-nitrid-6-(phenylthio)-benzyl alcohol are suspended in 54.5 ml of pyridine and 170 ml of chloroform and titrated dropwise at a temperature below 20° and over the course of 30 minutes a solution of 78 g of thionyl chloride in 55 ml of chloroform. The whole is stirred for 30 minutes at 30° and then diluted with water. The organic phase is successively washed with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and concentrated. Crude 3-nitro-6-(phenylthio)-benzyl chloride is obtained; m.p. 58 - 60°.

230 g of 3-nitro-6-(phenylthio)-benzyl chloride, 540 ml of ethanol and 320 ml of dioxane are added to a solution of 70.5 g of potassium cyanide in 150 ml of water. Dew whole is heated for 3 hours by reflux and then concentrated under reduced pressure. The rest

diluted with water and extracted with benzene. The organic phase is washed with water and evaporated under reduced pressure. 3-nitro-6-(phenylthio)-phenylacetonitrile is obtained as a brown oil.

210.3 g 3-nitro-6-(phenylthio)-phenylacetonitrile, 210 ml water,

210 ml of concentrated sulfuric acid and 210 ml of acetic acid are heated for 20 hours by refluxing. Strip off and extract with ether. The organic phase is washed successively with water and aqueous sodium carbonate solution. The aqueous phase is made acidic with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, evaporated under reduced pressure and recrystallized from the mixture. Man.gets 3-nitro-6-(phenylthio)-phenylacetic acid; m.p. 138 -.140°.

78.4 g 3-nitro-6-(phenylthio)-phenylacetic acid pg. 400 g. polyphos-

acid is kept under stirring for 90 minutes at 105 .- 110°,

this is diluted with ice and water and extracted with benzene.

The organic phase is successively waxed with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. 10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-one is obtained; m.p. 171 - 172°.

165.3 g 10,11-dihydro-2-nitro-dibenzo [b,f]thiepine-.10-one suspension

their in 6 1 dioxane and a solution of 63 g sodium borohydride in 300 ml dioxane and 300 ml water is added. The whole is stirred overnight at room temperature, then diluted with water, in-

neutralized with sulfuric acid and extracted with ethyl acetate.

The organic phase is washed with water, dried over night

and evaporated under reduced pressure. The obtained 1,1-dihydro-2-nitro-dibenzo[b,fjtiepin-10-ol is recrystallized from ethylace-

took; m.p. 144 - 146°

124 g 10,11-dihydro-2-nitro-dibenzo[b,fJtiepin-10-ol suspension

dissolved in 69.5 ml pyridine, 615 ml benzene and 350 ml chloroform" and added dropwise while stirring at 0° 53 ml thionyl chloride. The reaction mixture is further stirred overnight at room temperature

temperature and then 30 minutes at 35 - 40°, cooled and pre-

thin with water. The organic phase is washed one after the other

with water and aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. One obtains 10-chloro-10,11-dihydro-2-nitro-dibenzo[b,fJthiepine; m.p. 74 - 77°.

The 3-[2-(1-piperazinyl)-ethyl-2-oxazolidinone used as starting material can be prepared as follows: 744 g of 1-benzylpiperazine are added together with 590 g of powdered potassium carbonate, 10 g of potassium iodide and 5 1 toluene 450 g of 3-( 2-chloroethyl)-2-oxazolidinone and heated for 21 hours at reflux. It is stripped, filtered and concentrated under reduced pressure. 3-[2-t4-benzyl-1-piperazinyl)-ethyl]-2-oxazolidinone is obtained, which boils under a pressure of 2 - 2.5 mm at 225-235°. The compound is recrystallized from ethyl acetate; m.p. 82-84. With an excess of hydrochloric acid and ethanol, the dihydrochloride is obtained; m.p. 243-245°.

291 g of 3-[2-(4-benzyl-1-piperazinyl)-ethyl]-2-oxazolidinone-dihydrochloride in 7 1 of methanol is hydrogenated in the presence of 70 g of Pd-

charcoal (5%) at 50° and 10 ato hydiogen. The reaction mixture is filtered and concentrated under reduced pressure. The rest add-

sodium hydroxide solution, extracted with chloroform, filtered through diatomaceous earth and concentrated. 3-[2-(1-pipe-razinyl)-ethyl]-2-oxazolidinone is obtained as a yellow oil. With an excess of hydrochloric acid in methanol-ether, dihydrochloride m.p. 203° (decomposition) .

EXAMPLE 5

'r

5.9 g of 1-(10,11-dihydro-2-iodo-dibenzo[b,fJthiepin-10-yl)-pipera-

in

zin is added together with 3.3 g of powdered potassium carbonate, 0.07

g of potassium iodide and 40 ml of toluene with 4.35 g of N-((?-chloroethyl)-oxazolidinone and heated for 27 hours by refluxing.

Then pour on water and dilute with chloroform. The organic phase is extracted with 2N hydrochloric acid.; The aqueous phase is made alkaline with caustic soda and extracted with chloroform. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed over aluminum oxide.

3-[2-[4-(10,11-dihydro-2-iodo-dibenzo[b,f Jthiepin-10-yl)-1-piperazinyl-ethyl]-2-oxazolidine is obtained, which by reaction with maleic acid transferred to maleatetj The maleate melts at 176 - 177°.

The starting compound 1-(10,11-dihydro-2-iodo-dibenzoTb,fthiepin-10-yl)-piperazine can be prepared as fol-

gives:

88 g of 3-nitro-6-(phenylthio)-phenylacetic acid in 880 ml of ethyl acetate are hydrogenated at 40° with hydrogen (10 ato) and 9.5 g of 5% palladium charcoal. The mixture is filtered and the filtrate is concentrated under reduced pressure. The obtained 3-amino-6-(phenylthio)-acetic

acid is recrystallized from acetone and melts at 160 - 16 2°.

50 g of 3-amino-6-(phenylthio)-acetic acid and 500 g of polyphosphoric acid are kept at 140° for 10 minutes with stirring. reaction mixture

the thing is set to neutral with caustic soda and a lot of water and ex-

treated with chloroform. The organic phase is washed with water,

dried over magnesium sulfate and evaporated under reduced pressure.

The 2-amino-10,11-dihydro-dibenzo[b,fthiepin-10-one obtained is recrystallized from benzene. Temp. 191 - 193°.

21.5 g of 2-amino-10,11-dihydro-dibenzo[b,fthiepin-10-one suspension

their at 5° in 135 ml of water and 54.5 ml of concentrated hydrochloric acid.

To this is added dropwise a solution of 9.1 g of sodium

nitrite in 32 ml of water and stir for 30 minutes at 5°. The diazonium salt solution obtained is now allowed to be added dropwise at 5°

and in the course of 30 minutes to a solution of 16.3 g of potassium

iodide in 63 ml of water and 5.5 ml of concentrated sulfuric acid. Stirring is continued for a further 2 hours at room temperature and then under reflux until the end of the iodine sublimation. reaction mixture

the mixture is cooled and extracted with ethyl acetate. The organic solution is washed successively with sodium thiosulphate solution

ning and water and dried over magnesium sulphate. The filtrate is evaporated and chromatographed on silica gel. The obtained 10,11-dihydro-2-iodo-dibenzo [b, f jtiepin-10-one is recrystallized from acetone. Temp. 129 - 131°.

12.0 g 10,11-dihydro-2-iodo-dibenzo |_b, f jtiepin-10-one suspende-

dissolve in 100 ml of ethanol and add 6 g of sodium borohydride. The whole is stirred overnight, then water is added and extracted with ether. The organic phase is washed with water until neutral

reaction, dried over magnesium sulphate and evaporated. The 10,11-dihydro-2-iodo-dibenzo[b,f]thiepin-10-ol obtained is recrystallized from ether. Temp. 131 - 133°.

A solution of 10.3 g of 10,11-dihydro-2-iodo-dibenzo[b,fJtiepine

-10-ol in 64 ml of benzene, 45 ml of chloroform and 6.3 ml of pyridine are added dropwise at -5° 5.7 ml of thionyl chloride. The whole thing is stirred for 90 minutes at room temperature and 30 minutes at 35 - 40° and

water is then added. The organic phase is washed successively with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 10-chloro-10,11-dihydro-2-iodo-dibenzo[b,fJtiepine is obtained as a brown oil.

10.1 g 10-chloro-10,11-dihydro-2-iodo-dibenzoj^,fJtiepine and 23.3

g piperazine is kept for 1 hour at 120 - 130°!. The reaction mixture is cooled, diluted with 2N sodium hydroxide and extracted with ether. The organic phase is washed with water until neutral and extracted with 500 ml of 2N hydrochloric acid. The aqueous phase is made alkaline and extracted with chloroform. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. 1-(10,11-dihydro-2-iodo-dibenzo[b,fJ thiepin-10-yl)-piperazine is obtained as a brown oil.

EXAMPLE . 6

12.5 g of 1-(2-bromo-10,11-dihydro-dibenzo[b,fJtiepin-10-yl)-piperazine are added together with 13 g of powdered potassium carbonate, 0.2 g of potassium iodide and 1 liter of toluene 13.2 g N- ((3-chloroethyl)-oxazolidinone and heated for 25 hours at reflux. Then poured onto ice water and diluted with benzene. The benzene solution is washed neutrally with water and extracted with 2N HCl. The aqueous phase is made alkaline with sodium hydroxide solution and extracted with benzene. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure.Crude 3-[2-[4-(2-bromo-10,11-dihydro-dibenzo[b,fJtiepin-10-yl)-1 is obtained -piperazinyl-ethyl]-2-oxazolidinone, which on reaction with maleic acid is converted to the maleate, m.p. 170 - 17 2°.

The starting material 1-(2-bromo-10,11-dihydro-dibenzo j_b,f jtiepin-10-yl)-piperazine can be prepared as follows: A solution of 400 g of potassium hydroxide in 3 1 of water is added at 45° in a nitrogen atmosphere 179 ml of thiophenol and stir for 15 minutes. After adding 7.1 g of copper powder and 564 g of 5-bromo-2-iodo-benzoic acid, it is heated for a full 5 hours at reflux and then filtered wet, acidified while cooling with 420 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The organic solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. This gives 3-bromo-6-(phenylthio)-benzoic acid with m.p. 171 - 17 3°.

478 g of 3-bromo-6-(phenylthio)-benzoic acid in 1.5 1 of methanol and 200 ml of concentrated sulfuric acid are heated for 8 hours under reflux. The solution is concentrated under reduced pressure, water is added and extracted with ether. The organic solution is washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. 3-Bromo-6-(phenylthio)-benzoic acid methyl ester is obtained as a yellow oil.

An undiluted solution of 65 g of lithium borohydride in 1 liter of tetrahydrofuran is added dropwise in a nitrogen atmosphere to a solution of 483 g of 3-bromo-6-(phenylthio)-benzoic acid methyl ester in 1 liter of tetrahydrofuran over the course of 120 minutes. The reaction mixture is further stirred for 4 hours at reflux. The solution is cooled to 5° and 700 ml of 3N hydrochloric acid is added dropwise over the course of 3 hours. After adding approx. 5 1 water, the mixture is extracted with ether. The organic solution is washed with water and dried over magnesium sulfate. Crude 3-bromo-6-(phenylthio)-benzyl alcohol is obtained as a yellow oil.

445 g of 3-bromo-6-(phenylthio)-benzyl alcohol are dissolved in 800 ml of benzene and heated at reflux. 165 ml of thionyl chloride are added dropwise and the whole is boiled for a further 90 minutes. After evaporation of the solvent, 3-bromo-6-(phenylthio)-benzyl chloride is obtained as a brown oil.

136.5 g of potassium cyanide in 183 ml of water are heated for 10 hours under reflux and in a nitrogen atmosphere with 470 g of 3-bromo-6-(phenylthio)-benzyl chloride in 470 ml of ethanol. The ethanol is distilled off under reduced pressure, the residue is diluted with water and extracted with ether. The extracts are washed with water, dried over magnesium sulphate and evaporated. 3-Bromo-6-(phenylthio)-phenylacetonitrile is obtained as a brown oil.

442.6 g 3-bromo-6-(phenylthio)-phenylacetonitrile, 775 ml ethanol,

37 2 g of potassium hydroxide and 290 ml of water are heated for 8 hours at

throwback dress. The ethanol is evaporated under reduced pressure. Water is added to the residue until complete dissolution and the neutral parts are extracted with toluene. The aqueous solution is cooled, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate with water and concentrated under reduced pressure. The crude 3-bromo-6-(phenylthio)-phenylacetic acid obtained is recrystallized from benzene-hexane; m.p. 118 - 120°.

J -f '■ o

2300 g of polyphosphoric acid are heated to ]?28 in a nitrogen atmosphere,

* pp

quickly add 302 g of 3-bromo-6-(phenylthio)-phenylacetic acid and stir for 8 minutes at 120 - 130°. After adding 1.5 kg of small ice cubes, the whole is extracted with benzene. The organic solution is washed successively with water and aqueous sodium bicarbonate solution and dried over magnesium sulfate. The 2-bromo-10,11-dihydro-dibenzo[b,fJtiepin-10-one obtained is distilled under reduced pressure; boiling point (0.05 mm) 170 - 175°. The compound is recrystallized from acetone-hexane; m.p. 143 - 145°.

50 g of 2-bromo-10,11-dihydro-dibenzo[b,fJtiepin-10-one are dispersed

in 250 ml of ethanol, add 9.9 g of sodium borohydride and stir

1 hour. After adding water, the whole is extracted with ether.

The organic phase is washed with water, dried over magnesium sulphate and evaporated. 2-Bromo-10,11-dihydro-dibenzo[b,f] thiepin-10-ol is obtained; m.p. 108 - 110°.

49.9 g of 2-bromo-10,11-dihydro-dibenzo[b,fJtiepin-10-ol, 250 ml of benzene and 18 g of finely powdered calcium chloride are saturated at 15°

with hydrochloric acid gas and then stirred for a further 3 hours at room temperature

trip. The precipitate is filtered off and washed with benzene. The filtrate is concentrated under reduced pressure. One obtains 2-bromo-10-chloro-10,11-dihydro-dibenzo[b,fJthiepine; m.p. 122.5 - 124°.

32.5 g of 2-bromo-10-chloro-10,11-dihydro-dibenzo[b,fjthiepine in 120

ml of chloroform is heated together with 63.3 g of 1-carbethoxypiperazine for 24 hours at reflux. It is then poured onto ice water and diluted with chloroform. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. You get yellow,

crude 1-Carbethoxy-4-(2-bromo-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine. The hydrochloride is prepared by reacting the base with ethanolic hydrochloric acid; m.p. 195°.. ~,s- ,^ r— ,j«/h

' 7B< lZi~' 0 :i& itj. b3. -CflJt.fi

47.2 g of 1-carbethoxy-4-(2-bromo-10,11-dihydr.or;dijD^10-yl)-piperazine hydrochloride, 585 ml of ethylene glycol, 32.8 g of potassium hydroxide and 1.95 ml of water is heated ( :iu~^ JjCm^ T^^^ r.,. plX f1^ 0°.

Then pour on water and extract rn\e# y& P^ fprjM i^ P$ fy~ Q£f3p-

nine spoonfuls of solution are extracted with 2N %%l%s^Y/r^-.tj§-al,t;SYre^<pp>-4b;sjil

The mixture is made alkaline, extracted with chloroform, washed

with water, dried over magnesium sulphate ;qg- k^nggntr^e^^s ^unde^

reduced pressure. One obtains crystalline iU (^^rom^lO^Ll^^^dr^

dibenzo j b, f j thiepin-10-yl)-piperazine; mp.-11 2rZ- 115 f ^

. ii. rxre-i s r-an^cf — {ol J X vas 'i)

EXAMPLE 7

9.4 g of 10-chloro-2-fluoro-10,11-dihydro-dibenzo [b, f Jtiepirr; 60 ml of chloroform and 17.1 g of 3-[2-(1-piperazinyl)-ethyl J-2-oxazoiidinone are heated for 12 hours under reflux conditions, poured there-

after on ice water and extracted with chloroform-ether. The organic phase is extracted with 2N hydrochloric acid. The aqueous phase is made alkaline with caustic soda and extracted with benzene. The organic phase is washed with water and evaporated. One obtains crude 3-[2-[4-(2-fluoro-10,11-dihydro-dibenzo[b,f jthiepin-10-yl)-1?-piperazinyl]-ethyl]-2-oxazolidinone, which after recrystallization -

tion from ethyl acetate melts at 158-159°. This base is reacted with maleic acid; the maleate thus obtained melts at 199-200°.

The 10-chloro-2-fluoro-10,11-dihydro-dibenzo [b,f]thiepine used as starting material can be prepared as follows: 160 g of 5-fluoro-anthranilic acid hydrochloride are suspended in 768 ml of water and 76.8 ml of concentrated hydrochloric acid at 0-5°. The obtained suspension is added with stirring at 0-5° over the course of 30 min.

a solution of 61.5 g of sodium nitrile in 153.5 ml of water. The obtained diazonium salt solution is stirred further for 15 minutes and then a solution of 193.5 g of potassium iodide in 41.5 nil of concentrated sulfuric acid and 400 ml of water is added dropwise at 0-2°. The reaction mixture is stirred for 3 hours under reflux conditions, then cooled and extracted with ethyl acetate.

The organic phase is washed with aqueous sodium thiosulfate solution, dried over sodium sulfate and evaporated. 5-fluoro-2-iodo-benzoic acid is obtained which melts at 142-145°.

In a nitrogen atmosphere, a solution of 150 g of potassium hydroxide in 850 ml of water at 55° is added to 47.5 ml of thiophenol. The mixture is stirred for 15 minutes and then 1.9 g of copper powder and 207 g of 5-fluoro-2-iodo-benzoic acid are added. The reaction mixture is heated for 7 hours under baking conditions, filtered while hot, evaporated and acidified with concentrated hydrochloric acid. The precipitated product is filtered off, washed with water and dried. 3-Fluoro-6-(phenylthio)-benzoic acid is obtained and melts at 146-148°. "?

144 g of 3-fluoro-6-(phenylthio)-benzoic acid in 1000 ml of tetrahydrofuran are added dropwise in a nitrogen atmosphere under reflux conditions to a 70% sodium dihydro-bis-(2-methoxyethoxy)-aluminate solution in benzene. The reaction mixture is kept for a further 2 hours under reflux conditions. After adding 400 ml of benzene, the whole is cooled to 20°, acidified

with 435 ml of 3N hydrochloric acid and then add 600 ml of concentrated hydrochloric acid. The organic phase is washed with water, dried over sodium sulphate and evaporated. 3-Fluoro-6-(phenylthio)-benzyl alcohol is obtained as a thick oil.

129 g of 3-fluoro-6-(phenylthio)-benzyl alcohol are dissolved in 385 ml

benzene and heated under reflux conditions. 73 ml of thionyl

chloride is added and it is boiled for a further 30 minutes. The reaction mixture is evaporated under reduced pressure. 3-Fluoro-6-(phenylthio)-benzyl chloride is obtained as a red-brown oil.

18.6 g of sodium cyanide in 222 ml of dimethylsulfoxide are added

once at 50° 74 g of 3-fluoro-6-(phenylthio)-benzyl chloride in 75 ml of dimethyl sulfoxide. The obtained dark reaction solution is stirred for 1 hour at 45-50°, then poured into 1500 ml of ice water and extracted with ether. The organic phase is washed three times each time with 500 ml of water, dried over sodium sulphate and evaporated. 3-Fluoro-6-(phenylthio)-phenylacetonitrile is obtained as a reddish oil. 80 g of 3-fluoro-6-(phenylthio)-phenylacetonitrile, 225 ml of ethanol, 75.5 g of potassium hydroxide and 225 ml of water are heated for 9 hours under reflux conditions. The solvent is then evaporated under reflux conditions and the residue is added to water until complete dissolution, after which the neutral solvents are treated with benzene. The aqueous solution is acidified with concentrated <;>■såltayrere^.r.fv extracted with chloroform. The organic matter is washed with TV, dried over sodium sulfate and evaporated under reduced pressure. 3-fluoro-6-(phenylthio)-phenylenedioxy is obtained ?re .which wilts at^ 80-83°.

900 g of polyphosphoric acid are heated in a nitrogen atmosphere; i.e. 128°, 80 g of 3-fluoro-6-(phenylthio)-phenylacetic acid are quickly added and stirred for 10 minutes at 120-130 (internal temperature) ... After adding ice chips, the whole is extracted with benzene.

The organic phase is washed successively with water, aqueous sodium carbonate solution and washed again with water, dried over sodium sulphate and evaporated. One obtains 2-fluoro-10,11-dihydro-dibenzo [b, f Jtiepin-10-one boiling at 118° (0.07 mm); Temp. 98-100°.

22 g of 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-one are suspended in 110 ml of ethanol and 6.1 g of sodium borohydride are added. The reaction mixture is heated for 10-15 minutes under reflux conditions, water is then added and extracted with chloroform. The organic phase is washed with water, dried over sodium sulphate and evaporated. You get 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, which melts at 110-113°.

21.2 g of 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, 110 ml of benzene and 7.9 g of finely powdered calcium chloride are saturated at 15° with hydrochloric acid gas (2 hours). The precipitate is filtered off and washed with benzene. The filtrate is evaporated under reduced pressure. 10-chloro-2-fluoro-10,11-dihydro-dibenzo[b,fjthiepine is obtained as pink-coloured crystals melting at 90-92°.

EXAMPLE 8

24.1 g of 3-[2-[4-(10,11-dihydro-2-nitro-dibenzo[b,fJthiepin-10-yl)-1-piperazinyl-ethyl]-2-oxazolidinone in 2000 ml of ethyl acetate are hydrogenated in presence of 5.7 g of 5% palladium charcoal at 70° and 10 at of hydrogen. After filtration, the filtrate is evaporated under reduced pressure. One obtains 3-[2-[4-(2-araino-10,11-dihydro-1 dibenzo[b,f]thiopin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 193-196. After chromatographic purification over aluminum oxide with acetone-hexane as eluent, a pure product is obtained which melts at 195.5-196.5°.

EXAMPLE 9

7 g of 3-[4-(2-amino-10,11-dihydro-dibenzo[b,ftythiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone, 13.1 nil£40%,ig formaldehyde and 61 ml of acetonitrile, 3.32 g of sodium borohydride are added and 1.5 ml of acetic acid is added dropwise over 10 minutes. The whole thing is stirred again for 90 minutes, then 1.5 ml of acetic acid is added dropwise and stirred for 15 minutes. The whole is now extracted with 200 ml of ether and the organic phase is washed three times with IN. aqueous potassium hydroxide solution, dried over sodium sulphate and evaporated. 3-[2-[4-(10,11-dihydro-2-dimethylamino-dibenzo[b,f Jthiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone is obtained which melts at 168-170 <*>. After recrystallization of the compound from ethanol, it melts at 171-173°. When reacted with maleic acid, the corresponding maleate is obtained which, after recrystallization from acetonitrile, melts at 143.5-144.5°.

EXAMPLE 10

8.3 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,fJtiepin-10-yl)-piperazine are added together with 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide and 80 ml of toluene with 8 .6 g of p-chloroethyl-3-methyl-2-imidazolidinone and heated for 20 hours under reflux conditions. The reaction mixture is poured onto water,

the organic phase is washed with water, dried over sodium sulphate and evaporated. One obtains 1-[2-[4-(-chloro-10,11-dihydro-dibenzo [b,fJthiepin-10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone as a brown oil. By reacting this compound with maleic acid in ethanol-ether, the corresponding maleate is obtained which melts at 186-188°.

EXAMPLE 11

11.9 g of 10-chloro-10,11-dihydro-2-(dimethylsulfamoyl)-dibenzo[b,f]-thiepine in 250 ml of chloroform is added to 20 g of 3-[2-(1-piperazinyl)-ethyl J -2-oxazolidinone and heated for 2 4 hours under reflux. race conditions. The reaction mixture is evaporated under reduced pressure and the residue is taken up in ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue is dissolved in benzene and filtered through a sieve filled with 100 g of aluminum oxide (activity level II). The eluate is evaporated and chromatographed for further purification on 75 g of silica gel (0.2-0.5 mm), whereby a 1:1 mixture of chloroform saturated with concentrated ammonia: carbon tetrachloride is used as eluent. The purified product is recrystallized from ethyl acetate-petroleum ether. One obtains 3-[2-[4-{lo,ll-dihydro-2-(dimethylsulfamoyl)-dibenzo[b,f Jthiepin-10-yl}-1-piperazinyl J-ethyl]-2-oxazolidinone which melts at 164- 165°.

The 10-chloro-10,11-dihydro-2-(dimethylsulfamoyl)-dibenzo[b,fJthiepine used as starting material can be prepared as

following:

22.9 g of 2-amino-10,11-dihydro-dibenzo[b,fJtiepin-10-one are suspended in 50 ml of concentrated hydrochloric acid and 8.6 g of sodium nitrite in 20 ml of water are added dropwise at 0° over the course of 30 minutes. The resulting suspension is stirred for 3-4 hours at 0°. The still undissolved parts are removed by filtration and the cold filtrate is immediately added to a cooled to 10-20° solution of 73 g of sulfur dioxide in 150 ml of glacial acetic acid containing 7.6 g of cupric chloride and 50 ml of benzene. The resulting mixture is heated for 5-10 minutes to 40-45° and then stirred for 3 hours at 20°. The whole is poured into ice water and extracted with benzene. The organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated. The residue is dissolved in dioxane, 50 mg of dimethylamine is added and left to stand for 15 hours at room temperature. The reaction mixture is evaporated under reduced pressure, the residue is dissolved in benzene for purification and chromatographed on silica gel (particle size 0.2-0.5 mm) with chloroform as eluent. One obtains 10,11-dihydro-2-(dimethylsulfamoyl)-dibenzo-[b,fthiepin-10-one, whose IR spectrum is in agreement with the structure.

cf

14 g of 10,11-dihydro-2-(dimethylsulfamoyl)-dibenzo[b,f Jtiepin-10-one in 200 ml of dioxane is added to 3.5 g of sodium borohydride in 15 ml of water and the mixture is stirred for 4 hours at 40°. The reaction mixture is evaporated under reduced pressure and the residue is dissolved in ethyl acetate and water. .The organic phase is washed with water, dried and evaporated. One obtains 10,11-dihydro-2-(dimethylsulfamoyl)-dibenzo[b,f Jtiepin-ao-oi.

Into a mixture of 12 g of 10,11-dihydro-2-(dimethyl-sulfamoyl)-dibenzo[b,f]thiepin-10-ol, 250 ml of benzene and 20 g of calcium chloride are introduced at 10° in the course of 2 hours of hydrochloric acid gas. The reaction mixture was then allowed to stand for 20 hours at room temperature. When nitrogen is introduced, the excess hydrochloric acid is expelled. It is all filtered off and evaporated under reduced pressure. One obtains 10-chloro-10,11-dihydro-2-(dimethylsulfamoyl)-dibenzo[b,f Jtiepine.

EXAMPLE 12

In the same way as stated in example 3, you get: •1-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl ]-2-pyrrolidinone from 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine and 1-(2-chloroethyl)-2-pyrrolidinone. The corresponding maleate is prepared in acetone and recrystallized from water; Temp. 179-180°. 3-[3-[4-(10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-propyl]-2-oxazolidinone from 1-(10,11 -dihydro-2-methyl-dibenzo[b,fthiepin-10-yl)-piperazine and 3-(3-chloropropyl)-2-oxazolidinone. Temp. 144-145°. The dimaleate prepared in acetone melts at 140-142°. 1- [2-[4-(2-chloro-10,11-dihydro-dibenzo [b,fthiepin-10-yl)-1-piperazinyl]ethyl]-2-benzimidazolinone from 1-(2-chloro-10, 11-dihydro-dibenzo[b,f jthiepin-10-yl)-piperazine and 1-(2-chloroethyl)-2-benzimidazolinone. Temp. 161-164°. The bis-(methanesulfonate) prepared in methanol and ether melts at 160-165° (decomposition). 1-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,fthiepin-10-yl)-1-piperazinyl-ethyl]-2-piperidone from 1-(2-chloro-10,11 -dihydro-dibenzo[b,fthiepin-10-yl)-piperazine and 1-(2-chloroethyl)-2-piperidone. Temp. 133°. The bis-(methanesulfonate) prepared in ethanol melts at 156-159° (decomposition).

1_[2-[4-(10,11-dihydro-2-methyl-dibenzo[b,f jthiepin-10-yl)-1-piperazinyl-ethyl}-2-pyrrolidinone from 1-(10,11-dihydro- 2-methyl-dibenzo[b,fthiepin-10-yl)-piperazine and 1-(2-chloroethyl-2-pyrrolidinone. The corresponding maleate melts at 142-144°).

EXAMPLE 13

17 g of 10-chloro-10,11-dihydro-2-trifluoromethyl-dibenzo[b,fthiepine in 90 ml of chloroform and 26.2 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone are heated for 14 hours under backflow conditions. The reaction mixture is evaporated and the residue is added to ice water, ether and 2N aqueous sodium hydroxide. After equilibration, the organic phase is washed with water and acidified with ethanolic hydrochloric acid. The resulting precipitate is filtered off and dissolved in approx. 400 ml of water? the aqueous solution is extracted with ether. The aqueous solution is added to ice, made alkaline with aqueous sodium hydroxide solution and extracted with approx. 350 ml of benzene. The benzene phase is dried over sodium sulphate, filtered and evaporated. 3-[2-[4-(10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone is obtained as an oil. 'By reaction with maleic acid, the corresponding maleate is obtained, which crystallizes from ethanol-ether;

m.p. 168-169°.

The 10-chloro-10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepine used as starting material can be prepared as follows: i ■

A solution of 6.5 g of potassium hydroxy/d in 86 ml of water is added

in a nitrogen atmosphere at 50° 10,3-,-inl thiophenol and refluxed for 30 minutes. After adding 6.5 g of copper powder and 22.5 g of 4-chloro-3-nitro-benzotrifluoride in 100 ml of ethanol, the mixture is heated for 48 hours under reflux conditions. After filtering

ir

the reaction mixture is poured onto water and extracted with ether. The ethereal phase is washed successively with aqueous sodium carbonate solution, water, aqueous cokefal solution, 2N aqueous hydrochloric acid and water, dried, f filters are filtered. 3-nitro-4-(phenylthio)-benzotrifluoride is obtained as a red oil.

26.9 g of 3-nitro-4-(phenylthio)-benzotrifluoride in 250 ml of ethanol are hydrogenated in the presence of 10 g of Raney nickel at room temperature and atmospheric pressure for 17 hours. The reaction mixture is filtered and evaporated under reduced pressure. 3-amino-4-(phenylthio)-benzotrifluoride is obtained as a red-brown oil. The compound is distilled under greatly reduced pressure and boils at 110-135° (0.1 mm; orange-coloured oil).

36 g of 3-amino-4-(phenylthio)-benzotrifluoride, 70 ml of water and

21 ml of methanesulfonic acid is heated to 90°, stirred for 20 minutes at this temperature and then cooled to 0°.

The obtained suspension is added dropwise at 0° in the course of

15 minutes a solution of 9.25 g of sodium nitrite in 33 ml of water, whereby care is taken that the temperature does not exceed 10°. The reaction mixture is stirred for approx. 1 hour at 0°, filtered and added over the course of approx. 45 minutes to a to 100° for-

heated copper cyanide suspension (prepared by adding 33.75 g of copper sulfate to 37 g of potassium cyanide in 165 ml of water).

The obtained dark reaction solution is stirred for 1 hour

100°, cool off, add 350 ml of benzene and stir overnight. The mixture is filtered through diatomaceous earth and the filter cake is washed with benzene. The organic phase is washed twice each time with 150 ml of saturated sodium chloride solution,

dried over sodium sulphate, filtered and evaporated. 2-(phenylthio)-5-trifluoromethyl-benzonitrile is obtained as a dark oil. 6 g of 2-(phenylthio)-5-trifluoromethyl-benzonitrile, 40 ml of 15% aqueous sodium hydroxide solution and 12 ml of ethanol are heated for 12 hours under reflux conditions and cooled. After adding 100 ml of water, the whole is extracted with 80 ml of benzene. The aqueous phase is cooled to 0° and acidified with concentrated hydrochloric acid. The resulting precipitate is extracted with methylene

chloride. The organic phase is washed with water until the reaction is neutral, dried over sodium sulphate, filtered and evaporated. 2-(phenylthio)-5-trifluoromethyl-benzoic acid is obtained, which melts at 140-145°.

100 g of 2-(phenylthio)-5-trifluoromethyl-benzoic acid, 750 ml of absolute methanol and 100 ml of sulfuric acid are heated for 72 hours under reflux conditions. The reaction solution is concentrated under reduced pressure and water and benzene are added. After equilibration, the organic phase is washed successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium bicarbonate solution. The benzene phase is then dried over sodium sulphate, filtered and evaporated.

2-(Phenylthio)-5-trifluoromethyl-benzoic acid methyl ester is obtained as

a yellow oil.

21.5 g of lithium borohydride are suspended in a nitrogen atmosphere in 375 ml of tetrahydrofuran and heated to reflux temperature. Under reflux conditions, this suspension is added dropwise with a solution of 130 g of 2-(phenylthio)-5-trifluoromethyl-benzoic acid methyl ester in 600 ml of tetrahydrofuran over the course of 20 minutes. The reaction mixture is stirred for 2 hours under reflux conditions and then cooled to 2°. during

After 10 minutes, 450 ml of 2N aqueous hydrochloric acid is added in such a way that the temperature does not exceed 10°. After adding 750 ml of water, the whole is extracted with 1000 ml of ether. The organic phase is washed twice, each time with 300 ml of water, dried over sodium sulphate, filtered and evaporated. 2-(phenylthio)-5-trifluoromethyl-benzyl alcohol is obtained as a pale yellow oil, which crystallizes spontaneously; m.p. 84°. 96 g of 2-(phenylthio)-5-trifluoromethyl-benzyl alcohol are dissolved in 450 ml of absolute benzene and heated to reflux temperature. The solution thus obtained is added dropwise over 20 minutes with 48 ml of thionyl chloride and is then stirred for 30 minutes. at reflux temperature. After cooling, the reaction mixture is evaporated under reduced pressure. 2-(phenylthio-5-trifluoromethyl-benzyl chloride) is obtained as a brownish-yellow oil.

11.2 g of sodium cyanide in 135 ml of dimethyl sulphoxide are heated to 40° and a solution of 87 g of 2-(phenylthio)-5-trifluoromethyl-benzyl chloride in 72 ml of dimethyl sulphoxide is added dropwise over the course of 10 minutes. The whole is stirred for 9 hours at 40°, cooled to room temperature, 200 ml of water are added and extracted with 200 ml of ether. The aqueous phase is extracted twice, each time with 100 ml of ether. The combined organic phases are now washed twice, each time with 200 ml of water, dried over sodium sulphate and evaporated under reduced pressure. 2-(phenylthio)-5-trifluoromethyl-phenylacetonitrile is obtained as a horseradish oil.

15 g of 2-(phenylthio)-5-trifluoromethyl-phenylacetonitrile, 15.1 g of sodium hydroxide, 90 ml of water and 23 ml of ethanol are heated for 12 hours under reflux conditions and then concentrated. The residue is extracted, after adding 200 ml of water, with 100 ml

benzene. The aqueous phase is then extracted with 50 ml of benzene.

The combined organic phases are extracted with 0.5N aqueous sodium hydroxide solution. The aqueous phase is acidified with hydrochloric acid and extracted with 150 ml of chloroform. The organic phase is washed with aqueous sodium chloride solution, dried and evaporated.

2-(phenylthio)-5-trifluoromethyl-phenylacetic acid is obtained as crystals melting at 102-103°.

217 g of polyphosphoric acid are heated in a nitrogen atmosphere to 110°, 21 g of 2-(phenylthio)-5-trifluoromethyl-phenylacetic acid are added and stirred for 8 minutes at 100-110°. The whole thing is cooled and 100 g of ice and 250 ml of ice water are added. The whole is extracted with 300 ml of benzene. The organic phase is successively washed twice, each time with 150 ml of water, twice, each time with 200 ml of saturated aqueous sodium carbonate solution and once with 150 ml of aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure. 10,11-dihydro-2-trifluoromethyl-dibenzo[b,fJtiepin-10-one is obtained as pale yellow crystals melting at 103-104°. 12 g of 10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-one are dissolved in 110 ml of absolute ethanol and 4 g of sodium borohydride are added. The whole is kept for 12 minutes at reflux temperature, cooled to 3o° and 350 ml of water and 100 ml of chloroform are added. After equilibration, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. 10,11-dihydro-2-trifluoromethyl-dibenzo[b,fJtiepin-10-ol is obtained as yellow crystals melting at 122-123°.

11.4 g of 10,11-dihydro-2-trifluoromethyl-dibenzo[b,fJthiepin-10-ol, 100 ml of benzene and 4 g of calcium chloride are saturated at 15° over the course of 2 hours with hydrochloric acid gas and then stirred for 3 hours at room temperature. The reaction mixture is filtered and concentrated under reduced pressure. 10-chloro-10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepine is obtained as yellow crystals.

EXAMPLE 14 (intermediate)

8.5 g of 2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-one, 30 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and 100 ml of benzene are added dropwise in an argon atmosphere at 20° 5.2 g of titanium tetrachloride in 25 ml of benzene. The reaction mixture is heated for 20 hours under reflux conditions and then poured on

a mixture of ice and aqueous sodium bicarbonate solution. The whole thing is stirred for 1 hour and filtered through diatomaceous earth. The aqueous phase is separated and washed successively with benzene and chloroform. The organic phases are concentrated and washed successively with aqueous sodium chloride solution and water, dried, filtered and evaporated under reduced pressure. 3-E.-2-[4-(2-chloro-dibenzo[b,f Jthiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone is obtained as a red-brown, viscous oil, which for purification chromatographed on 100 g of silicon dioxide (eluent ethanol: methanol: concentrated ammonia 100:50:10). A red-brown oil is obtained which is crystallized from acetone using activated charcoal. Beige-coloured crystals are obtained which, on reaction with maleic acid in acetone, are converted to the corresponding maleate (beige-coloured crystals) with a melting point of 232-233° (decomposition).

EXAMPLE 15

In an argon atmosphere, 750 mg of 3-[2-[4-(2-chloro-dibenzo[b,f Jthiepin-10-yl)-1-piperazinyl]ethyl]-2-oxazolidinone, 0.6 g of sodium borohydride and 30 ml of diglymer at 20-30° over the course of 15 minutes with 2.7 g of oxalic acid dihydrate in 15 ml of diglymer. The reaction mixture is heated for 4 hours at an internal temperature of 100° and then evaporated under reduced pressure. Chloroform and 2N sodium hydroxide solution are added to the residue. After equilibration, the aqueous phase is separated and washed twice with chloroform. The combined chloroform extracts are washed with water, dried over potassium carbonate and activated charcoal, filtered and evaporated under reduced pressure. 3-[-2-[4-(2-chloro-10,11-dihydrob-dibenzo[b,f Jthiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone is obtained as a brown oil. The maleate is produced by reaction with maleic acid in ethanol-ether; m.p. 173-175°.

Claims (1)

Analogous method for the preparation of therapeutically effective tricyclic compounds with the general formula in which X is halogen, lower alkyl, X is oxygen, lower alkylimino or methylene, m is the number 0 or 1 and R~ and R^ hydrogen or together form the group and salts of these compounds, characterized by reacting a compound with the formula where R^ has the meaning given above and Y is a leaving group with a compound with the formula where m, I^/ R-j and X have the meaning stated above, or that one reduces a compound with the formula where :m, R^, Rj» R3 and X have the meaning indicated above, or that one reacts a compound; with the formula where R, in the above-mentioned designation, with a compound Ise with the formula where X, Y, m, R 2 and R 3 have the meaning given above nothing, and, if desired, transfer the obtained product into a salt.