CS199694B2 - Process for preparing 5-/phenyl substituted/-oxazolidinone and sulphur derivatives thereof - Google Patents

Abstract

Novel 5-(subst. phenyl)-oxazolidinones and their sulphur analogs of the general formula I <IMAGE> in which the substituents are defined in Claim 1, are obtained by reacting 2-amino-1(3,4-disubst. phenyl)-ethanols with a carbonic acid derivative or a thiocarbonic acid derivative in an inert solvent while heating in the presence of a basic catalyst. The novel compounds of the general formula I possess valuable pharmacological properties. They exhibit antidopaminergic, antinociceptive and anticonvulsive effects and have a depressant action on the central nervous system and thus have a certain similarity to neuroleptic agents such as chlorpromazine or haloperidol. In addition, the novel compounds possess strong phosphodiesterase-inhibiting properties and thus affect the metabolism of cyclic nucleotides. The compounds are also suitable for treating hyperproliferative diseases and diseases associated with uncontrolled cell growth.

Description

The present invention relates to a process for the preparation of the novel 5- (substituted phenyl) -oxazolidinones and their sulfur analogues of formula (I)

in which it denotes

R 1 is methyl or cyclopentyl,

R 2 is a hydrogen atom, a C 1 -C 4 alkyl group, a C 4 or C 5 cycloalkyl group, a phenyl group, a benzyl group, a pyranyl group, a C 3 -C 4 alkenyl group, and a C 3 alkynyl group,

R3 represents a hydrogen atom, an alkyl group of 2 to 3 carbon atoms, a phenyl group, an aralkyl group of 7 to 8 carbon atoms, an acetyl group, a phenyl-2 minocarbonyl group, a benzoylcarbonyl group and an ethoxycarbonyl group,

R4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

R 5 denotes a hydrogen atom, a methyl group or an ethoxycarbonyl group, and X and Y denote an oxygen or sulfur atom.

The compounds of formula I contain an asymmetric carbon atom and can therefore exist both in the form of a racemate and as optical antipodes.

The term (C 1 -C 4) -alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl. Alkenyl and alkynyl groups include, for example, 1-propenyl, 2-propenyl; 3-methyl-2-propenyl, vinyl and propargyl. The alkyl groups may also be substituted one or more times, for example by halogen, in particular fluorine, chlorine or bromine. Examples of such halogen-substituted alkyl groups are 2-chloroethyl, 3-chloropropyl, 4-bromobutyl, difluoromethyl, trifluoromethyl, 1,1,2-trifluoro-2-chloroethyl, 3,3,3-trifluoropropyl, 2,2,3,3 , 3-pentafluoropropyl, or 1,1,1,3,3,3-hexafluoro-2-propyl.

Suitable substituents for the alkyl groups are furthermore hydroxyl groups, e.g.

199894 Example of 2-hydroxypropyl or 3-hydroxypropyl, carboxy groups, for example carboxymethyl or carboxyethyl, alkoxy, wherein each alkoxy group may contain 1 to 5 carbon atoms such as ethoxymethyl, isopropoxymethyl, 2-methoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2 -isobutoxyethyl. or 3-pentoxypropyl. However, the alkoxy groups may also be ring-closed (cyclic ether residues), such as a 3-tetrahydropyranyl residue.

Lower alkyl groups may also be amino-substituted on the terminal carbon, in which the nitrogen atom is optionally substituted by alkyl groups preferably having 1 to 5 carbon atoms or is part of a four to seven membered ring. Examples of N-substituted alkyl groups include aminomethyl, 2-methylaminoethyl,

2-dimethylaminoethyl, 2-diethylaminoethyl,

3-dimethylaminopropyl, 3-ethylmethylaminopropyl, pyrrolidine, piperidine, N-methylpiperazine, hexamethylamino and the like.

C 4 -C 5 cycloalkyl groups include cyclobutyl, cyclopropylmethyl or cyclopentyl.

Suitable aryl or aralkyl groups are, in particular, phenyl and benzyl groups, which can optionally be substituted in a known manner.

As far as acyl groups are concerned, their chemical character is not critical to the properties of the compounds of the invention, and so long as the acyl group is not toxic, aliphatic and aromatic unsubstituted and substituted monobasic, dibasic and polybasic carboxylic acids, saturated or unsaturated, are suitable.

The compounds of the invention have valuable pharmacological properties. They exhibit centrally-depressive, antidopaminergic, antinociceptive and anticulsive effects and therefore have some resemblance to neuroleptics such as chlorpromazine or haloperidol. However, the compounds of the invention differ from classical neuroleptics by other modes of influencing the receptor-dependent, monoaminergic feedback mechanism (diminishing extrapyramidal side effects).

In addition, the compounds of the invention have potent phosphodiesterase-lowering properties and thus affect the metabolism of cyclic nucleotides. Since controlled cell growth is definitely regulated by cyclic nucleotides (Pastan et al. 1975) and is partially reduced in the uncontrolled proliferation network of cyclic nucleotides (Ryan and Heidrick, 1974, Voorhees et al., 197-4), the compounds are suitable for administration in hyperproliferative and uncontrolled cell growth associated diseases such aspsoriasis, polycythamia vera, neuroblastoms, immunological diseases such as bronchial asthma and thromboembolic diseases in which cyclic nucleotide metabolism disorder (Tateson JE; Trist DG, Inhibition of adenosine-3 ', 5'-cyclic monophosphate phosphodiesterase by potential antiallergic compounds; Life Sci. 18: 153-162; De Gaetano G., Pharmacology of platelet aggregation; Pharmacol. Res. Immun., 7, 301-309, 1975 ).

Based on the described effects, the compounds of the invention can be used in the form of pharmaceutical preparations for administration in the diseases mentioned. The preparation of the preparations is carried out using carriers customary for enteral or parenteral administration, such as water, alcohol, gelatin, acacia, milk sugar,. starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol and the like. The preparations may be in solid form as tablets, capsules, dragees, suppositories or in liquid form as solutions, suspensions or emulsions.

Accordingly, the present invention provides a process for the preparation of compounds of the formula I which is characterized by condensing 2-amino-1- (3,4-disubstituted phenyl) ethyl alcohol of the formula I

(II) wherein R 1, R 2, R 5, R 1 and R 5 are as defined above, with a carbonic acid or thiocarbonic acid derivative of the general formula III

X '/

(S) O = C \ Y ’(III) in which. indicates

X 'and Y' 'OR, chlorine or bromine. or an imidazole group, wherein

R represents an alkyl group of up to 4 carbon atoms, a phenyl group, an aralkyl group of 7 to 8 carbon atoms, or together may form an alkylene group of 3 or 4 carbon atoms, in an inert solvent at a temperature in the range of 60 to 200 ° C and in the presence of a basic catalyst, in particular alkaline earth carbonates, hydroxides and alcoholates and organic bases,. such as pyridine and triethylamine and optionally araliphatic. ether group reductively. it cleaves on Raney nickel the most precious metal catalyst, or the ring member oxygen and / or the oxygen of the 2-carbonyl group is exchanged for sulfur, or the obtained compound is acylated or N-alkylated to introduce substituents as R3.

The final cyclization reaction of the compounds of formula (II) may be carried out with any carbonic acid derivative (s); thiocarbon selines of formula III. The substituent R may be the same or different for X 'and Y'. Thus, for example, it may be an alkyl group having 1 to 4 carbon atoms, such as methyl or ethyl, a phenyl group, or an aryl group having 7 to 8 carbon atoms, such as benzyl. However, the substituents R may also form together an alkylene residue such as propylene or isobutylene.

Solvents which are inert to the reaction are preferably used. For example, ethers such as diethyl ether, glycol dimethyl ether or diethylene glycol dimethyl ether, aliphatic and aromatic hydrocarbons such as hexane, benzene, toluene, xylene and mesitylene, as well as alcohols such as methanol, ethanol, propyl alcohol, butyl alcohol and dimethylsulphoxide ether, and diethylene glycol monomethyl ether.

The reaction is conveniently carried out under heat. The temperature may conveniently be above room temperature and reaches the boiling point of the reaction mixture, using a temperature range of 60 to 200 ° C, preferably 100 to 160 ° C.

The cyclization reaction is carried out in the presence of basic catalysts. Suitable base catalysts are alkali metal carbonates and alkaline earth metal carbonates, and especially alkali or alkaline earth metal alcoholates such as sodium methylate and potassium carbonate. However, organic bases such as, for example, pyridine, triethylamine, alkali metal and alkaline earth metal hydroxides such as sodium hydroxide are also suitable, in particular if the group X 'or Y' is halogen. In case X 'and Y' are halogen, such as chlorine, the addition of basic catalysts may be omitted. When X 'and Y' are imidazole residues, it is preferably carried out at room temperature using dimethylformamide, tetrahydrofuran or methylene chloride as solvents. If the subsequent reductive cleavage of an aliphatic ether group, such as a benzyl group, occurs optionally with the aid of all conventional metal catalysts such as platinum, palladium, rhodium or nickel, both in pure form and also on a support material such as carbon, calcium carbonate and barium sulfate. All solvents which are inert to the reducing agents under the reaction conditions can be used as solvents. Examples include organic acids such as acetic acid and proponic acid, lower alcohols such as methyl alcohol and ethyl alcohol, esters such as ethyl acetate or aliphatic, cycloaliphatic and aromatic hydrocarbons such as hexane, cyclohexane and benzene.

Optionally, the following O-alkylation (R 2 represents a hydrogen atom) is also carried out by methods known per se. The alkylation is preferably carried out with the corresponding R 2 -halides, -methylates or -tosylates. Suitable halides are chlorides, bromides and iodides. For alkylation, for example, the hydroxy compound of formula II is dissolved in a polar solvent and heated in the presence of a base with an alkylating agent to a temperature in the range of 30 to 150 ° C. Suitable bases are, for example, sodium hydride, potassium carbonate, alkali metal alcoholates such as sodium ethylate, potassium butylate and potassium tert-butylate. Suitable solvents are dimethylformamide, dimethylacetacetamide, hexamethylphosphoric triamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran, dioxane, ketones such as acetone and methylisobutyl ketone, as well as alcohols such as ethyl alcohol, butyl alcohol and tert-butyl alcohol.

The exchange of carbonyl oxygen or ring member oxygen in the compound of formula (I) for a sulfur atom is carried out by methods known per se, such as, for example, Scheeren et al. (Synthesis 1973,149).

For example, a polysulfide such as phosphoropentasulfide in a solvent is suitable for this purpose. or a solvent mixture, in the presence of a base. The reaction can also be carried out in suspension. Suitable solvents or suspending agents are, for example, acetonitrile, tetrahydrofuran, diethyl ether, glycol dimethyl ether or pyridine. Suitable bases are sodium bicarbonate, potassium carbonate and the like. The reaction is carried out at a temperature between 30 and 120 ° C and is completed in about 3 to 24 hours.

Optionally, the following N-acylation or N-alkylation (R3 is hydrogen) is also carried out by methods known per se.

Thus, the amino compound is dissolved in a polar solvent and heated in the presence of a salt-forming agent with an alkyl halide or aryl halide, optionally acyl halide or acylanhydride, to a temperature in the range of 40 to 150 ° C.

As the polar solvent, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, as well as alcohols such as ethyl alcohol and butyl alcohol can be used. Suitable salt formers are, for example, sodium hydride, potassium carbonate, alkali metal alcoholates such as sodium ethylate, potassium tert-butylate and the like. The reaction is carried out with a haloaryl, for example iodobenzene, possibly also in the absence of a solvent, preferably in the presence of copper powder.

The following examples illustrate the invention in more detail.

199894

He did

5- (3-Benzyloxy-4-methoxyphenyl) -2-oxazolidinone

3-Benzyloxy-4-imethoxybenzaldehyde (318.6 mmol) was dissolved in ether (1200 mL). To this solution was added a solution of 558 mmol potassium cyanide in 300 mL water at room temperature. After cooling to 0 ° C, 237 mmol of 2 N sulfuric acid was added dropwise to the well stirred reaction mixture, and the reaction mixture was further stirred for 12 hours at room temperature. After separation of the aqueous phase, the ether phase is washed several times with half-saturated sodium chloride solution (50 ml each) and dried thoroughly with calcium chloride. After filtering off the desiccant and washing twice with 100 ml of ether, the combined organic phases containing crude 2- (3-benzyloxy-4-methoxyphenyl) -2-hydroxyacetonitrile are added to the next step. '

2- (3,4-Dimethoxyphenyl) -2-hydroxyacetonitrile was prepared analogously from 3,4-dimethoxybenzaldehyde and 2- (3-cyclopentyloxy-4-methoxypentyl) -2-hydroxyacetonitrile was prepared from 3-cyclopentyloxy-4-methoxybenzaldehyde.

Lithium aluminum hydride (1.3 mol) was suspended in 1000 ml of absolute ether in portions and, with good stirring and cooling, an ethereal solution of 2- (3-benzyloxy-4-methoxyphenyl) -2-hydroxyacetomtrile was added dropwise so that only a slight reflux was observed. After stirring at room temperature overnight, 400 ml of ethyl acetate were added dropwise while stirring, followed by 600 ml of water. The precipitate is filtered off with suction and the residue is washed twice with 200 ml of a mixture of ethanol and water (1; 1) each time. The combined filtrates are strongly concentrated and taken up in 300 ml of semi-concentrated hydrochloric acid. This solution is extracted twice with 200 ml of ethyl acetate each time. The acetate phase is no longer treated with a hydrochloric solution - it is cooled and made alkaline with potassium hydroxide. The eventually precipitated aluminum salt is filtered off with suction and shaken three times with 400 ml of ether each time. The combined organic phases are dried, filtered, concentrated and crystallized from ethyl acetate.

Ve. 20%. of the obtained 2-amino-1- (3-benzyloxy-4-methoxybnyl) -ethanol melts at 101-102 ° C.

Prepared in an analogous manner from 21- (3,4-dimethoxyphenyl) -2-hydroxyacetoniiril in 49% yield of 2-amino-1- (3,4-dimethoxyphenyl) -ethanol (m.p. 80-81 ° C, benzene) and from 2- (3-cyclopentyloxy-4-methoxyphenyl) -2-hydroxyacetonitrile in 70% yield of 2-amino-1- (3-cyclop (trimethyloxy-4-methoxyphenyl) -ethanol (oil)).

2-Amino-1- (3-benzyloxy-4-methoxyphenyl) -ethanol can also be prepared, for example, as follows:

mmol of 3-benzyloxy-4-methoxybenzaldehyde and 55 mmol of trimethylalyl cyanide are heated. together with 0.567 mmol of anhydrous zinc iodide po. 4 hours under a nitrogen atmosphere and at 90 ° C. The reaction mixture is then taken up in 15 ml of absolute tetrahydrofuran and this solution is added dropwise to a suspension of 60 mmol of lithium aluminum hydride. v. 35 ml of tetrahydrofuran. After heating at 60 ° C for one hour, the reaction mixture was worked up as outlined in Example 1. After recrystallization from ethyl acetate, 2-amino-1- (3-benzyloxy-4-methoxylenyl) -ethanol is isolated, m.p. 100-102 ° C in 30% yield.

mmol of 2-amino-1- (3-benzyloxy-4-methoxyphenyl) -ethanol was suspended with 50 mmol of sodium ethanolate and 91.4 mmol of diethyl carbonate in 120 ml of absolute toluene and the reaction mixture was heated for 2 hours at bath temperature 110 ° C while avoiding moisture, while distilling methanol and ethanol. Finally, toluene is distilled off in vacuo. The residue is taken up in 150 ml of chloroform and mixed with 100 ml of water. The aqueous phase is extracted twice with 150 ml of chloroform each, the combined chloroform extracts are washed with 100 ml of water, dried, filtered, concentrated and the residue is recrystallized from ethyl acetate. There was obtained 5- (3-benzyloxy-4-methoxyphenyl) -2-oxazolidinone, m.p. 132-133 ° C (yield 91%).

Example 2

In an analogous manner to that described in Example 1, the procedure was as follows. prepare the oxazolidinones from the corresponding aminoalcohols listed in Table I below, wherein R 5 is hydrogen.

recryst pressed from

Table I

Ri

R2

Rs

R4 yield (%) m.p. (° C)

-CHs —СНз —H —H 63 114 to 117 methane —CH3 —CHs /! 'AND —CH3 —H 41 132 to 134 ethanol —CH3 -Cl —H —H 45,8, 141 to 143 Ethyl acetate / ether -СНз —H —H 52 111 to 112.5 ethflzcetát /

/ ether

Example 3

2-Amino-1- (3-benyyloxy-4-methoxyphenyl) -ethanol (88.3 mmol) was dissolved in THF. 200 ml of absolute tetrahydrofuran and treated with 92.6 mmol of carbonyldiimidazole while avoiding moisture. The clear solution was stirred at room temperature overnight. After distilling off the tetrahydrofuran, the residue is taken up in 300 ml of ethyl acetate, shaken twice with 1 N hydrochloric acid and then washed with saturated sodium chloride solution until neutral, finally the reaction mixture is dried, filtered and concentrated.

Recrystallization from ethyl acetate gave 5- (3-benzyloxy-4-methoxyphenyl) -2-oxalidinone in 66% yield, mp 83-91 ° C.

Example 4

5- (3-hydroxy-4-methoxy-phenyl) -2-oxo-isoquinone

40.6 mmol of 5- (3-benzyloxy-4-methoxyphenyl) -4-2-oxazolidinone are dissolved in 700 ml of ethanol and hydrogenated in the presence of 8 g of Raney nickel at room temperature under a hydrogen pressure of 10 bar for 2 hours. 1 Уor-y. After filtering off the catalyst, the reaction mixture was evaporated and the residue was triturated with methanol. 6.74 g of S (4-hydroxy-4-methoxyphenyl) -2-oxazolidinone of melting point 157 DEG-160 DEG C. (meth) were obtained.

5- (3-Hydroxy-4-methoxyphenyl) -2-oxazolidinone (7.2 mmol) was dissolved in absolute dimethylformamide (10 mL) and stirred with sodium hydride (7.9 mmol) at 50 ° C for 1 h. After cooling, the reaction mixture was treated with 8.6 mmol of cyclopentyl bromide and then stirred for 2 hours at 80 ° C. After completion of the reaction, dimethylformamide was distilled off under vacuum at 40 ° C. The residue is taken up in 100 ml of 2 N sodium hydroxide and extracted three times with 150 ml of chloroform. The combined chloroform phase was washed with water, dried, filtered and concentrated. The residue was recrystallized from ethyl acetate / ether. There was obtained 5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxazolidinone, m.p. 11-112 ° C, in 70% yield.

Example 1 a d. 6

In the manner described in Example 5. Prepared from 54 (3-Hydroxy-4-methoxyphenyl) -2,2-oxazolidinone and the halide or tosylate of formula R2X 'of the compound of formula I shown in Table II below (R 3 = R 4 = R 5 = H).

The table indicates:

DMF (dimethylformamide) petr. - petroleum ether chlf. - chloroform tos. - tosylate

NaH - sodium hydrM

NaOEt - sodium ethanoate

Example 5

5 - ((-cyclopentyloxy) 4-methylphenyl) -24-azoylolidinone

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Example 7 '

5- (3,4-dimethoxyphenyl) -2-oxazolidinethion a

5- (3,4-dimethoxyphenyl) -2-thiazolidinone mmol of 2-amino-1- (3,4-dimethoxyphenyl) ethanol is dissolved in 65 ml of absolute dimethylsulfoxide and gradually mixed with 1.8 g of powdered potassium hydroxide. and 1.4 ml of hydrogen chloride at 10 ° C. Thereafter, the reaction mixture was stirred for 2.5 hours while avoiding moisture. After removal of the dimethylsulfoxide under vacuum, the residue is mixed with 100 ml of water and extracted three times with 100 ml of chloroform. The combined chloroform phase was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is chromatographed over 125 g of silica gel with chloroform and methanol (96: 4). After recrystallization of the corresponding methanol fraction, 5- (3,4-dimethoxyphenyl) -2-oxazolidinethione with a melting point of 177-178 ° C is obtained in 9% yield, in addition to 6% of 5- (3,4-dimethoxyphenyl) -2- m.p. 167 DEG-169 DEG C .;

Example 8

2-Amino-1- (3,4-dimethoxyphenyl) ethanol (5- (3,4-dimethoxyphenyl) -2-thiazolidinone) is dissolved in 6 ml of pyridine and treated with 11 mmol while cooling to 0 ° C. % of carbon disulfide in 10 mmol of triethylamine - (dropwise) while the temperature of the reaction mixture rises strongly. The reaction mixture was stirred for one hour at 0 ° C and then 10 mmol of benzyl chloride was added dropwise at the same temperature. After stirring overnight at 0 [deg.] C., the batch is taken up in 40 ml of 3 N sulfuric acid and extracted three times with 50 ml of chloroform each. The combined chloroform phase was washed successively with sodium bicarbonate solution and water, dried, filtered and concentrated. The spontaneously crystallizing residue is recrystallized from ethyl acetate and benzene. There was obtained a quantitative yield of [2- (3,4-dimethoxyphenyl) -2-hydroxyethyl] -dithiocarbamic acid benzyl ester, m.p. 130-132 ° C.

To 6.07 mmol of [2- (3,4-dimethoxyphenyl) -2-hydroxyethyl] -dithiocarbamic acid benzoyl ester in 50 ml of absolute ether was added dropwise 2.14 mmol of phosphfortribromide at 5 ° C. After stirring the reaction mixture for 20 hours at 5 [deg.] C., 10 ml of a mixture of methanol and water are added dropwise with cooling so that the temperature does not exceed 20 [deg.] C. The reaction mixture was then carefully mixed with 20 ml of sodium bicarbonate solution. It is extracted three times with 50 ml of chloroform each time and the combined organic phase is washed successively with 50 ml of sodium hydrogen carbonate solution and 50 ml of water, dried, filtered and concentrated. There was thus obtained 2-benzylthio-5- (3,4-dimethoxyphenyl) -1,3-thiazol-2-yne as an oil in 80% yield.

This oil was dissolved in 20 ml of ethanol, treated with 20 ml of 6 N hydrochloric acid, and refluxed for 4 hours. After concentration, the residue is taken up in 25 ml of ethanol, mixed with 19 ml of 1 N sodium hydroxide and stirred for 3 hours at room temperature. The reaction mixture is then neutralized with 2N hydrochloric acid, the ethanol is stripped off and shaken twice with 100 ml of chloroform. The chloroform phase is washed with water, dried and concentrated. The residue is chromatographed over 50 g of chloroform / methanol (96: - 4) free phase. The corresponding fraction was recrystallized from methanol to give 50% of 5- (3,4-dimethoxyphenyl) -2-thiazolidinone, m.p. 167-169 ° C. .

EXAMPLE 1- 5- (3,4-Dimethoxyphenyl) -2-oxazolidinone-3-carboxylic acid anilide

0.5 mmol of 5- (3,4-dimethoxyphenyl) -2-oxazolidinone was heated in 3 ml of phenyl isocyanate for 33 hours at - 160 ° C. After cooling, the reaction mixture was concentrated in vacuo and chromatographed over 50 g of silica gel with cyclohexane and ethyl acetate (1: 1). After recrystallization of the corresponding ethyl acetate fraction, 5- (3,4-dimethoxyphenyl) -2-oxazolidinone-3-carboxylic acid anilide, m.p. 175 DEG-182 DEG C., is obtained in 6060% yield.

Example 1 a d 10

100 mmol of 2-amino-1- (3,4-dimethoxyphenyl) -ethanol are dissolved in 100 ml of chloroform and, after cooling to 0 ° C, a solution of 100 mmol of phosgene in 100 ml of chloroform is slowly added dropwise so that the internal temperature does not exceed 5 °. C. After stirring for one hour at 5 to 10 ° C, 200 mmol of pyridine in 100 ml of chloroform are added dropwise and the reaction mixture is stirred for 3 hours, after which the organic phase is washed with a semi-concentrated sodium chloride solution and evaporated. It was obtained in 75% yield of 5- (3,4-dimethoxyphenyl) -2-oxazolidinono, m.p. 114-117 ° C.

Example 11

Dissolve 2-amino-1- (3,4-dimethoxyphenyl) ethanol (5- (3,4-dimethoxyphenyl) -2-oxazolidinone) in 5 ml of 2 N sodium hydroxide. The solution, cooled to 0 ° C, was treated dropwise with 10 mmol of ethyl chloroformate. After the addition was complete, the reaction mixture was stirred at 0 ° C for 30 minutes. The crystals formed are filtered off with suction, washed with water and dried. . Obtained in 86% yield, 2- (3,4-di-99,6'9,4) ethyl ester,

90 DEG-92 DEG C. 1S methoxyphenyl) -2-hydroxyethylcarbamine.

2- (3,4-dimethoxyphenyl) -2-hydroxyethylcarbamic acid ethyl ester was suspended with 4 mmol of sodium anolate in 12 ml of toluene and the reaction mixture was heated at a bath temperature of 110 ° C for 2 hours while avoiding moisture. In this case, methanol and ethanol are distilled off. Toluene is then distilled off in vacuo, the residue is taken up in 50 ml of chloroform and shaken with 10 ml of water. After drying, filtering and combining the organic phase, it is crystallized from methanol. 5- (3,4-O-methoxyphenyl) -2-oxazolidinone, m.p. 114 DEG-117 DEG C., is obtained in 80% yield.

Example 12

3-acytyl-5- (3,4-dimethoxyphenyl) -2-oxazolidinone

8.9 mmol of 5- (3,4-dimethoxyphenyl) -2-oxazolidinone are treated with 10 ml of acetic anhydride and -5 ml of pyridine and the reaction mixture is heated at 100 DEG C. for 5 hours. Ethyl acetate was obtained in 73% yield .alpha .- [alpha] -D- (3,4-dimethoxyphenyl) -2-oxazolidinone, m.p. 175 DEG-182 DEG.

Example 13

5- (3,4-dimethoxyphenyl) -5-propyl-2-oxazolinone mmol of 3,4-dimethoxybutyrophenone and 61.4 mmol of trimethylsilyl cyanide with the addition of 200 mg (627 mmol) of anhydrous magnesium iodide are heated for 4 hours under a nitrogen atmosphere. and to prevent moisture from reaching 90 ° C. The reaction mixture is then taken up in 15 ml of absolute tetrahydrofuran and added dropwise. was added to a suspension of 60 mol of TiCl 2 -hydrochloride in 35 ml of absolute tetrahydro-urine. The reaction mixture was heated at 60 ° C for one hour under a nitrogen atmosphere and excess lithium aluminum hydride was removed by dropwise addition of ethyl acetate and water. The precipitate is filtered off with suction over silica gel, washed well with ethyl alcohol and the mother liquor is concentrated.

The residue is taken up in ethyl acetate, acidified with 4 N hydrochloric acid and shaken. The aqueous phase is adjusted to pH 9 by addition of sodium carbonate, saturated with sodium chloride and extracted with chloroform. The chloroform phase is washed with a saturated sodium chloride solution until neutral and the solvent is distilled off after drying over sodium sulfate. Obtained in 75% yield of 5-amino-4- (3,4-dimechoxyphenyl) -4-pentanol as an oil.

17.35 mmol of 5-amino-4- (3,4-dimethoxyphenyl) -4-pentanol are dissolved in 10 ml of absolute dimethylformamide and reacted with 18> 3 mmol of 98% carbonyl-imidazole in 100 ml of absolute tetrahydrofuran for 4 days, - at room temperature and avoiding moisture. After the solvent has been removed, the residue is taken up in ethyl acetate, shaken twice with 1 N hydrochloric acid and washed with a saturated sodium chloride solution until neutral. The oily product obtained is purified over a silica gel column (350 g) in a 30: 1 chloroform / methanol system. It is obtained in 81.7% yield of 5- (3,4-dimethoxyphenyl) -5-propyl-2-oxazolindinone as an oil.

Example 14

5- (3,4-Dimethoxyphenyl) -5-methyl-2-oxazolidinone

Analogously to Example 13, 5- (3,4-dimethoxyphenyl) -5-methyl-2-oxoisothinone with a melting point of 98-101 ° C was obtained from 3,4-dimethoxyacetophenone in ~ 30% yield.

EXAMPLE 15 mmol of 5- (3,4- (4-methoxyphenyl) -2-oxazolidinone) is dissolved in 20 ml of absolute dimethylformamide and treated with 11 mmol of sodium hydroxide, followed by stirring. at 40 DEG C. After cooling, 20 mmol of methyl iodide in ml of dimethylformamide are added dropwise and after the addition is complete, the reaction mixture is stirred for a further hour at 50 DEG C. After removal of the dimethylformamide, the residue is taken up in chloroform, The residue is chromatographed over 60 g of silica gel with a chloroform / methanol (96: 4) mixture as the mobile phase. yielding 5- (3,4-dimethoxyphenyl) -3-methyl-2-oxazolidinone, m.p. 132-133 ° C, in 60% yield.

EXAMPLE 16 5- (3,4-Dimethoxyphenyl) -2-Oxazolidinone-3-carboxylic acid benzyl ester

6.25 mmol of 5- (3,4-dimethoxyphenylphenyl) -2-methyl-5-ol and 5-ololinone are dissolved in 30 ml of Oioxane and this solution is mixed with 6.25 mmol of ml (12.50 mmol) of 2N sodium hydroxide. At 4 ° C, the reaction mixture was treated with 12.5 ml of benzoxycarbonyl chloride and stirred at this temperature for 4 hours.

After mixing with 50 ml of 2N sodium hydroxide, the mixture is extracted three times with 50 ml of ethyl acetate each time. The acetate phase is washed once with 50 ml of 2N sodium hydroxide solution and twice with 50 ml of water each, dried with Sikkon®, filtered and concentrated. After distilling still present benzoxycarbonyl chloride at a temperature of 199694 x

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ture 100 ⁰ C ', and at a pressure of 133.3 Pa, the residue is recrystallized from ethyl acetate and petroleum ether to give · in 64% yield benzyl 5- (3,4-dimethoxyfenylj-2-oxazolidinone-l-carboxylic acid, m.p. Mp 124-126 ° C.

Example 17 5- (3,4-Dimethoxyphenyl) -2-oxazolidinone-3-carboxylic acid ethyl ester 5- (3,4-dimethoxyphenyl) oxazolidinone was mixed in 20 ml absolute toluene with 10 mmol trlethyleneamine at 0 ° C avoiding This mixture is further mixed with 10 mmol of ethyl chloroformate, refluxed for 4 hours and left to stand overnight. The crystallized product is after boiling still allowed to boil with 7.6 mmol of triethylamine; 6 mmol of ethyl chloroformate, the crystallized product is filtered off with suction and the combined filtrates are evaporated and the residue is chromatographed over 80 g of silica gel with cyclohexane / ethyl acetate (1: 1) as eluent to give 5- (3) ethyl ester in 43% yield. (4-dimethoxyphenyl) -2-oxazolidinone-1-carboxylic acid, m.p. 181-185 ° C.

Example 18,

Analogously to Example 15, the oxazolidinones of formula I shown in Table III are obtained from 5- (3,4-dimethoxyphenyl) -2-oxazolidinone:

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5- (3,4-dimethoxyphenyl) -4-methyl-2-oxazolidinone

2-Amino-1- (3,4-dimethoxyphenyl) -propanol (5.5 mmol) is dissolved in chloroform (50 ml) and this solution is stirred with carbonyl diimidazole (1.05 g, 6.5 mmol) for 2 hours while avoiding moisture. . The reaction mixture was then allowed to stand overnight and extracted with 50 ml of distilled water. It is then dried, filtered and concentrated. Chromatography of the residue over 50 g of mobile phase chloroform / methanol (95: 5) and recrystallization from ethyl acetate / petroleum ether gave 5- (3,4-dimethoxyphenyl) -4-methyl-2-oxazolidinone in 24% yield. mp 98-99 ° C.

The starting material 2-amino-1- (3,4-dimethoxy) propanol is obtained as follows:

To 100 mmol of 3,4-dimethoxypropiophenone in 160 methylene chloride was added dropwise 10 ml of sulfuryl chloride in 80 ml of methylene chloride at room temperature. The reaction mixture was then stirred at room temperature for 3.5 hours. After distilling off the solvent and recrystallizing the residue from a mixture of cyclohexane and petroleum ether, 2 &apos; -chloro-3,4-dimethoxyproplofenone with a melting point of 56 DEG-57 DEG C. is obtained in 89% yield.

Dissolve 43.86 mmol of 2´-chloro-3,4-dimethoxypropiophenone in 230 ml of acetone and mix this solution with 437 mg of potassium iodide and 87.72 mmol of dibenzylamine for 7 days while avoiding moisture. The reaction mixture was diluted to 1 liter with diethyl ether, filtered and concentrated. The residue is applied to silica gel and this silica gel is first stirred with chloroform, filtered off with suction and then stirred with ethanol and filtered off with suction again. The chloroform phase is chromatographed over 500 g of silica gel with chloroform as the mobile phase to give oily 2 &apos; -N, N-dibenzylamino-3,4-dimethoxypropiophenone in 49% yield.

12.39 g (31.8 mmol) of 2´-N, N-dibenzylamino-3,4-dimethoxypropiophenone are dissolved in 75 ml of isopropanol and this solution is mixed with 1.33 g (35.05 mmol) of sodium borate. After stirring at room temperature for 1 hour, the reaction mixture was refluxed for 2 hours. After cooling, the batch is filtered off with suction and the residue is boiled with ethyl acetate. After filtration from the filtrate in 59% yield of 2´- (-, Ν-dibenzylamino) -1- (3,4-dimethoxyphenyl) propanol, m.p. 151-152 ° C.

13.2 mmol of the dibenzyl compound are hydrogenated in 50 ml of absolute ethanol with 2.64 g of palladium on carbon (10%) for 3 hours at 90 ° C and at a hydrogen pressure of 10 bar. After filtering off the catalyst, the reaction mixture is concentrated and recrystallized from ethanol. Obtained in 64% yield of 2-

-amino-1- (3,4-dimethoxyphenyl) -propanol, m.p. 131-132 ° C.

Example 20 5- (3,4-Dimethoxyphenyl) -2-oxo-oxazolidine-4-carboxylic acid ethyl ester 2-amino-4- ethyl ester

The (3,4-dimethoxyphenyl) -3-hydroxypropionic acid was stirred with 12 mmol of carbonyldiimidazole in 60 ml of chloroform for 4 hours at room temperature in the absence of moisture. The reaction mixture was extracted once with 50 ml of water, dried over silica gel overnight, filtered and concentrated.

The residue is chromatographed over 130 g of silica gel using chloroform / methanol (90:10) as eluent. Recrystallization from ethyl acetate / ethanol yielded 5- (3,4-dimethoxyphenyl) -2-oxooxazolidine-4-carboxylic acid ethyl ester, m.p. 188-189 ° C, in 34% yield.

The starting material, 2-amino-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester, was prepared as follows:

44.37 mmol of 3,4-dimethoxyglycidic acid ethyl ester (prepared according to

W. Schneider et al., Arch. Pharm. 299, 817 (1966)) was boiled with dibenzylamine (97.61 mmol) in ethanol (100 ml) for 4.5 hours while preventing moisture from entering and refluxing.

The reaction mixture was allowed to stand for 3 days at room temperature, concentrated and the residue chromatographed over 400 g of silica gel using chloroform / methanol (98: 2) as eluent. Further chromatography of the appropriate fraction yielded 2-N, N-dibenzyl-4-

- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid as an oil in 89% yield.

22.2 mmol of 2-N, N-dibenzylamino-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester was hydrogenated with 4.44 g of palladium on carbon (10%) in 100 ml of undenatured ethyl alcohol for 3 hours at a temperature of 90 ° C under a hydrogen pressure of less than 1 MPa.

After removal of the catalyst, the mixture was concentrated. After recrystallization from undenatured ethyl alcohol, 2-amino-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester of m.p. 211 DEG-212 DEG C. (decomposition) is obtained in 80% yield.

Example A

The biological activity of the compounds prepared according to the invention was tested in Irvin-modified mice (Irvin, S., Psychopharmacologia (Berl.) 13, 222-251 (1968)), in which the test compounds were suspended in 10% Cremoform EL, e.g. is dissolved therein, and they are applied intraperitoneally once.

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Claims (3)

OBJECT OF THE INVENTION A process for the preparation of 5- (substituted phenyl) -oxazolidinones and theirs. The sulfur analogs of the general formula (I) in which they denote R 1 is methyl or cyclopentyl, R2 is a hydrogen atom, a (C1-C4) alkyl group, a (C4-C5) cycloalkyl group, a phenyl group, a benzyl group, a pyranyl group, a C3-C4 alkenyl group and a 3-carbon alkynyl group, R 1 represents a hydrogen atom, a C 2 -C 3 alkyl group, a phenyl group, a C 7 -C 8 aralkyl group, an acetyl group, a phenylaminocarbonyl group, a benzoylcarbonyl group and an ethoxycarbonyl group, R4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 5 denotes a hydrogen atom, a methyl and ethoxycarbonyl group and X and Y denote an oxygen or sulfur atom, characterized by condensing 2-amino-1- (3,4-disubstituted phenyl) -ethanol of the general formula II (H) in which R 1, R 2, R 3, R 1 and R 5 as defined above, with carbonic acid derivative ¹ or thiocarbonic acid derivative of the general formula III X '' Z (s O = C (III), \ Y kterém in which denotes X 'and' Y 'are -OR, chloro or bromo, or imidazole, wherein R represents an alkyl group of up to 4 carbon atoms. atoms, phenyl, 'C7 -C8 aralkyl' and together may form an alkylene group having 3 to 4 carbon atoms, in an inert solvent at a temperature in the range of 60 to 200 ° C and in the presence of a basic catalyst, in particular carbonates, hydroxides and alkali metal and organic base alcoholates such as pyridine and triethylamine, and optionally then the present araliphatic ether group is reductively cleaved onto Raney nickel or a noble metal catalyst, or the free hydroxyl group is alkylated, or oxygen is a member of the ring and / or the oxygen of the 2-carbonyl group is exchanged for sulfur, or the obtained compound is N-acylated or N-alkylated to introduce substituents R 1. 2. A process according to claim 1, wherein the compound of formula (II) in which R5 is hydrogen and R1, R2, R3 and R4 are as defined above is condensed with a compound of formula (III) in which X ' and Y 'is as defined above. 3. A process according to claim 1, wherein the compound of formula (II) wherein R @ 5 is methyl or ethoxycarbonyl and R1, R @ 2, R @ 1 and R @ 4 are as hereinbefore defined is condensed with a compound of formula (III) X 'and Y' as defined above. .