CH635578A5 - Process for preparing novel 5-(subst. phenyl)-oxazolidinones and their sulphur analogs - Google Patents

Description

The invention relates to a process for the preparation of new 5- (Subst. Phenyl) oxazolidinones and their sulfur analogs of the general formula I.

0R2

1 °

(I), where X

R, lower alkyl or cycloalkyl,

R2 is hydrogen, optionally substituted lower alkyl, cycloalkyl, aryl, aralkyl, alkenyl, heterocyclic radicals having a heteroatom, this heteroatom being oxygen or nitrogen, alkynyl and cycloalkylalkyl,

R3 is hydrogen, lower alkyl, alkenyl, alkynyl, aryl, aralkyl or acyl,

R4 is hydrogen or lower alkyl and R5 is lower alkyl, lower alkoxycarbonyl and hydrogen and

X! and X2 independently of one another denote oxygen or sulfur.

The compounds of general formula I have an asymmetric carbon atom and can therefore be present both as racemates and as optical antipodes.

Lower alkyl means alkyl groups with up to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-methylbutyl, 2,2-dimethylpropyl and hexyl. Alkenyl and alkynyl groups are e.g. 1-propenyl, 2-propenyl, 3-methyl-2-propenyl, vinyl and propargyl. The lower alkyl groups can also be substituted one or more times, for example by halogen, in particular fluorine, chlorine and bromine. Examples of halogen-substituted alkyl groups are 2-chloroethyl, 3-chloropropyl, 4-bromobutyl, difluoromethyl, trifluoromethyl, l, l, 2-trifluoro-2-chloroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3 -Pentafluoropropyl, 1,1,1,3,3,3-hexafluoro-2-propyl. Also suitable as substituents of the alkyl groups are hydroxyl groups, for example as 2-hydroxyethyl or 3-hydroxypropyl, carboxy groups for example as carboxymethyl or carboxyethyl, alkoxy groups, where each alkoxy group can contain 1 to 5 C atoms, for example as ethoxymethyl, Isopropoxy methyl, 2-methoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 3-pentoxypropyl. The alkoxy groups can also be closed (cyclic ether radicals), such as. B. the 3-tetrahydropyranyl radical.

The lower alkyl groups can also be terminally substituted with amino groups in which the nitrogen can optionally be mono- or disubstituted by alkyl groups having preferably 1 to 5 carbon atoms or is part of a 4- to 7-membered ring. Examples of N-substituted alkyl groups are aminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 3-dimethylaminopropyl, 3-ethylmethylaminopropyl, pyrrolidino, piperidino, N-methylpiperazino, hexamethyleneimino, etc.

Cycloalkyl or cycloalkyl-alkyl groups preferably contain 3 to 7 carbon atoms. The cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl groups are preferred.

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

All residues of physiologically compatible carboxylic acids are suitable as acyl. Preferred are those derived from alkanoyl acids having 1 to 18 carbon atoms, preferably 2 to 8 carbon atoms, such as e.g. monobasic alkanoyl acids such as formic acid, vinegar, propion, butter, isobutter, a-ethyl butter, pivaline, valerian, isovalerian, a-ethyl valerian, trimethyl acetic, 2-methyl butter, 3-ethyl butter -, Capronic acid, triethyl acetic acid, enanthic or caprylic acid, or cyclic acids, preferably cycloaliphatic acids, such as cyclo-propylidene acetic acid, cyclobutyl carbonate, cyclopentyl carbonate, cyclopentyl acetic acid, β-cyclopentyl propionic acid, cyclohexyl carbonate or cyclohexyl carbonate or also carbocyclic aryl or aralkyl acids such as benzoin, 2-, 3- or 4-methylbenzoic acid.

Since the chemical character of the acyl group is not critical for the properties of the novel compounds which can be prepared according to the invention, as long as the acyl group is not toxic, other aliphatic and aromatic unsubstituted and substituted, mono-, di- and polybasic carboxylic acids, saturated and unsaturated aliphatic, araliphatic and aromatic carboxylic acids having up to 18 carbon atoms, preferably up to 8 carbon atoms.

Examples include undecyl, dodecane, tetradecane, hexadecane, octadecane, palmitic, stearic and β-cyclohexylpropionic acid, 2,3-, 2,4-, 2,6-, 3,4- and 3 , 5-dimethylbenzoic, ethylbenzoic, naphthoeic, 3-methyl-a-naphthoeic, ß-phenylpropionic, diphenylacetic and a-naphthylacetic acid or carbamic acids such as carbamic, phenylcarbamic, n-butylcarbamic, dimethylcarbamine -, Diethylcarbamin- and allophanoic acid or heterocyclic acids such as the ß-furylcarbon-, pyrrolcarbon-, ß-pyrrolidinopropion-, N-methylpyrrolidino-2-carbon-, 6-hydroxy-in-dolyl-3-vinegar, N- Methylmorpholino-2-carbon and pyrrole-2-carboxylic acid. The acyl radicals can also be substituted one or more times. The following radicals may be mentioned as substituents: hydroxy, halo, alkoxy, aralkoxy, acyloxy, sulfonyloxy, amido, sulfato, nitro, mercapto and cyano, such as e.g. in the acyl residues of glycolic, lactic, citric, tartaric, maleic, glyceric, mannonic, gluconic and salicylic acid or acyl residues of amino acids such as glycine, aminopropionic, diglycolamino and triglycolamino acid, methylglycine, dimethylglycine, diethylglycine. The acyl residues of p-aminosalicyl, p-aminobenzoic, ethyl mercaptoacetic, benzylmercaptoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, thioglycol, m-nitrobenzoic, 2,3,4-trimethoxybenzo may also be mentioned, for example -, Phenoxyacetic and a-naphthyloxyacetic acid. The alkoxylated and aralkoxylated acyl residues of formic acid such as e.g. Carbethoxy and carbobenzyloxy.

The novel compounds of the general formula I which can be prepared according to the invention have valuable pharmacological properties. They show central depressive, antidopa-minergic, antinociceptive and anticonvulsive effects and thus have a certain similarity to neuroleptics such as chlorpromazine or haloperidol. However, the new compounds that can be produced according to the invention differ from the classical neuroleptics by differently influencing receptor-dependent, monoaminergic re4

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coupling mechanisms (reduction of extrapyramidal side effects).

In addition, the compounds which can be prepared according to the invention have strong phosphodiesterase inhibiting properties and thus influence the metabolism of cyclic nucleotides. Since controlled cell growth is crucially regulated by cyclic nucleotides (Pastan et al "1975) and cyclic nucleotides in some cases in uncontrolled proliferating tissue. are reduced (Ryan and Heidrick, 1974, Voorhees et al., 1974), the compounds are suitable for the treatment of hyperproliferative diseases associated with uncontrolled cell growth such as psoriasis, polycythemia vera, neuroblastoma, immunological diseases such as bronchial asthma and thromboembolic Diseases in which there is a disturbance in the metabolism of cyclic nucleotides (Tate-son, JE; Trist, DG, Inhibition of adenosine-3 ', 5'-cyclic monophosphate Phosphodiesterase by potential antiallergic Compounds; Life Sei. 18, 153-162; De Gaetano, G., Phar-macology of platelet aggregation; Pharmacol. Res. Commun. 7, 301-309, 1975).

Because of the effects described, the novel compounds which can be prepared according to the invention can be used in the form of pharmaceutical preparations for the treatment of the abovementioned diseases. The preparations are made with the usual carriers for enteral or parenteral administration, such as water, alcohol, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol, etc. The preparations can be in solid form as tablets, capsules, dragées, suppositories or in liquid form as solutions, suspensions or emulsions.

The process according to the invention for the preparation of compounds of the formula I is characterized in that 2-amino-l (3,4-disubst. Phenyl) ethanol of the general formula II

OR.

0

1

Rj_5 have the meaning given above, with a carbonic acid or thiocarbonic acid derivative of the general formula III

/ X '

X = C (III), wherein

No where

X for oxygen or sulfur,

X 'and Y are OR, chlorine, bromine or imidazole, with R being alkyl, aryl, aralkyl and together as alkylene, or if X is sulfur, X' and Y may also together be sulfur, in an inert Reacts solvent in the heat in the presence of a basic catalyst, and optionally subsequently reductively cleaves an araliphatic ether group present with Raney nickel or with a noble metal catalyst, or alkylates a free hydroxy group, or the

635 578

Exchanging ring oxygen and / or oxygen of the 2-carbonyl group for sulfur, or, if R3 is hydrogen, N-acylated or N-alkylated.

The ring closure reaction for compounds of the formula II can be carried out per se with all carbonic acid or thiocarbonic acid derivatives of the general formula III. R can be the same or different. So it preferably means lower alkyl or aralkyl such. B. methyl, ethyl and benzyl. R can also be an alkylene radical, e.g. Propylene or iso-butylene.

The solvents used are expediently inert towards the reactants. Examples include ethers such as diethyl ether, glycol dimethyl ether or di-ethylene glycol dimethyl ether, aliphatic and aromatic hydrocarbons such as hexane, benzene, toluene, xylene and mesitylene, but also alcohols such as methanol, ethanol, propanol, butanol and dimethyl sulfoxide, glycol monomethyl ethyl ether.

The reaction is carried out in the heat. The temperature should be above room temperature and generally extends to the boiling point of the reaction mixture, the temperature range 60 to 200 ° C., preferably 100 to 160 ° C. being used.

The cyclization reaction is carried out in the presence of a basic catalyst. Suitable basic catalysts are alkali metal and alkaline earth metal carbonates and especially alcoholates such as sodium methylate and potassium carbonate. However, organic bases such as pyridine, triethylamine, alkali metal and alkaline earth metal hydroxides such as sodium hydroxide are also suitable, in particular in the case where X or Y is halogen. In the event that X and Y are halogen, e.g. Chlorine, the addition of a basic catalyst can also be omitted. If X and Y are imidazole residues, it is preferably carried out at room temperature, dimethylformamide, tetrahydrofuran and methylene chloride being suitable as solvents. The optionally subsequent reductive cleavage of an araliphatic ether group, such as the benzyl group, is usually carried out per se with all common metal catalysts, such as e.g. Platinum, palladium, rhodium or nickel, both in pure form and on carrier materials such as coal, calcium carbonate and barium sulfate. All those which are inert to the reducing agents under the conditions according to the invention can be used as solvents. Examples include organic acids such as acetic acid and propionic acid, lower alcohols such as methanol and ethanol, esters such as ethyl acetate, aliphatic, cycloaliphatic and aromatic hydrocarbons such as hexane, cyclohexane and benzene.

The subsequent O-alkylation (R2 means hydrogen) is normally also carried out according to methods known per se. The alkylation is preferably carried out with the corresponding R 2 halide, mesylate or tosylate. Chlorides, bromides and iodides are suitable as halides. For the alkylation, the hydroxy compound of the formula II is dissolved, for example, in a polar solvent and heated to temperatures between 30 and 150 ° C. in the presence of a base with the alkylating agent. Examples of suitable bases are sodium hydride, potassium carbonate, alkali alcoholates, such as sodium ethylate, potassium butoxide and potassium tert-butoxide. Examples of suitable solvents are dimethylformamide, dimethylacetamide, hexamethylphosphoric acid tri-amide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, dioxane, ketones, such as acetone and methyl isobutyl ketone, and alcohols, such as ethanol, butanol and tert-butanol.

The exchange of the carbonyl oxygen or the ring oxygen in compounds of the formula I for sulfur

5

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635 578

can according to known methods such. B. Scheeren et al. Synthesis 1973, 149 are run.

For example, a polysulfide such as phosphorus pentasulfide in a solvent or solvent mixture in the presence of a base is suitable for this purpose. The reaction can also be carried out in a suspension. Suitable solvents or suspending agents are, for example, acetonitrile, tetrahydrofuran, diethyl ether, glycol dimethyl ether and pyridine. Sodium hydrogen carbonate, potassium carbonate, etc. are suitable as bases. The reaction is complete at 30 to 120 ° C after about 3 to 24 hours.

The subsequent N-acylation or N-alkylation (R3 = H) is usually also carried out according to methods known per se. For example, the amino compound is preferably dissolved in a polar solvent and heated to 40 to 150 ° C. in the presence of a salt former with an alkyl or aryl or acyl halide or acyl anhydride. Dimethyl-formamide, dimethylacetamide, tetrahydrofuran, dioxane and alcohols such as ethanol and butanol can be used as polar solvents. Suitable salt formers are, for example, sodium hydride, potassium carbonate, alkali alcoholates, such as sodium ethylate, potassium tert-butoxide, etc. The reaction with halogenaryl, for example iodobenzene, can also be carried out without a solvent, preferably in the presence of copper powder.

The following examples are intended to explain the invention.

example 1

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

318.6 mmol of 3-benzyloxy-4-methoxybenzaldehyde are dissolved in 1200 ml of ether. A solution of 558 mmol potassium cyanide in 300 ml water is added at room temperature. After cooling to 0 ° C., 237 mmol of 2N sulfuric acid are added dropwise to the well-stirred mixture and the reaction mixture is stirred at room temperature for 12 hours. After separating the aqueous phase, the ether is washed several times with 50 ml of semi-saturated saline and dried over calcium chloride. After filtering off the drying agent and washing again with twice 100 ml of ether, the combined organic phases, which contain the crude 2- (3-benzyloxy-4-methoxyphenyl) -2-hydroxyaceto-nitrile, are used for the next step.

In an analogous manner, the 2- (3,4-dimethoxyphenyl) -2-hydroxyacetonitrile was converted from 3,4-dimethoxybenzaldehyde and the 2- (3-cyclopentyloxy-4-methoxyphenyl) -2- from 3-cyclopentyloxy-4-methoxybenzaldehyde. hydroxyacetonitrile produced.

1.3 moles of lithium aluminum hydride are suspended in portions in 1 liter of absolute ether and the ether solution of 2- (3-benzyl-oxy-4-methoxyphenyl) -2-hydroxyacetonitrile is added dropwise with cooling and good stirring so that only a slight reflux occurs. After stirring

At room temperature overnight, 400 ml of ethyl acetate and then 600 ml of water are added dropwise with cooling. The resulting precipitate is then filtered off with suction and the residue is washed twice with 200 ml each time of ethanol (1: 1) 5. The collected 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. The ethyl acetate phase is discarded, and the hydrochloric acid solution is cooled and made alkaline with potassium hydroxide solution - any aluminum salts which may precipitate are filtered off and shaken out three times with 400 ml of ether each time. The combined organic phases are dried, concentrated after filtration and recrystallized from ethyl acetate.

The 2-amino-1- (3-i5 benzyloxy-4-methoxyphenyl) ethanol obtained in 20% yield melts at 101 to 102 ° C.

In an analogous manner, 2- (3,4-dimethoxyphenyl) -2-hydroxyacetonitrile in 49% yield yields 2-amino-1- (3,4-dimethoxyphenyl) ethanol (mp. 80 to 81 ° C, benzene) and 20 prepared from 2- (3-cyclopentyloxy-4-methoxyphenyl) -2-hydroxyaceto-nitrile in 70% yield 2-amino-l- (3-cyclopentyloxy-4-methoxyphenyl) ethanol (oil).

2-Amino-l- (3-benzyloxy-4-methoxyphenyl) ethanol can also be prepared as follows:

25 50 mmol of 3-benzyloxy-4-methoxybenzaldehyde and 55 mmol of trimethylalyl cyanide are heated together with 0.567 mmol of anhydrous zinc iodide for 4 hours at 90 ° C. under nitrogen and with exclusion of moisture. It 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 in 35 ml of tetrahydrofuran. After heating for one hour at 60 ° C., working up is carried out as described in Example 1. After recrystallization from ethyl acetate, 2-amino-1- (3-benzyloxy-4-35 methoxyphenyl) ethanol with a melting point of 100 to 102 ° C. is isolated in 30% yield.

36 mmol of 2-amino-l- (3-benzyloxy-4-methoxyphenyl) ethanol are doped with 50 mmol of sodium methylate and 91.4 mmol of diethyl carbonate in 120 ml of absolute toluene suspen-40 and heated to 110 ° C. bath temperature with exclusion of moisture for 2 hours, distilling over methanol and ethanol. The toluene is then distilled off, finally in an oil pump vacuum. The residue is taken up in 150 ml of chloroform and distributed against 100 ml of water. The water phase is extracted twice with 150 ml of chloroform each time, the combined chloroform extracts are washed with 100 ml of water, dried, filtered, concentrated and recrystallized from ethyl acetate. 5- (3-Benzyloxy-4-methoxyphenyl) -2-oxazolidinone with a melting point of 132 to 133 ° C. (91% yield) is obtained.

Example 2

Analogously to Example 1, the 55 oxazolidinones listed in the following table are prepared from the corresponding amino alcohols, where R5 is hydrogen.

Ri R2 R3 R4 Yield (%) Mp. (° C) Recrystallized from

-CH3 -CH3 -H -H 63 114-117 methanol

-CH3 -CH3 -CH3 -H 41 132-134 ethanol

-CH3 <] -H -H 45.8 141-143 ethyl acetate / ether

<\ -CH3 -H -H 52 111-112.5 ethyl acetate / ether

7

635 578

Example 3

88.3 mmol of 2-amino-1- (3-benzyloxy-4-methoxyphenyl) ethanol are dissolved in 200 ml of absolute tetrahydrofuran and 92.6 mmol of carbonyl-diimidazole are added with the exclusion of moisture. The clear solution is stirred at room temperature overnight. After the tetra-hydrofuran has been distilled off, the mixture is taken up in 300 ml of ethyl acetate, shaken twice with in hydrochloric acid and then washed neutral with saturated sodium chloride solution, dried, filtered and concentrated.

After recrystallization from ethyl acetate, 5- (3-benzyloxy-4-methoxyphenyl) -2-oxazolidinone of melting point 83 to 91 ° C. is obtained in 66% yield.

Example 4

5- (3-Hydroxy-4-methoxyphenyl) -2-oxazolidinone 40.6 mmol 5- (3-Benzyloxy-4-methoxyphenyl) -2-oxazolino-dinone are dissolved in 700 ml of ethanol and in the presence of 8 g of Raney Nickel (B 113, Degussa, Frankfurt) at room temperature under a hydrogen pressure of 100 atm. Hydrogenated for 2.2 hours. After filtering off the catalyst, the mixture is evaporated and the residue is recrystallized from methanol. 6.74 g of 5- (3-hydroxy-4-methoxyphenyl) -2-oxazolidinone with a melting point of 157 ° to 160 ° C. (methanol) are obtained.

Example 5

5- (3-Cyclopentyloxy-4-methoxyphenyl) -2-oxazolidinone 7.2 mmol 5- (3-Hydroxy-4-methoxyphenyl) -2-oxazolidinone are dissolved in 10 ml of absolute dimethylformamide 30

and stirred with 7.9 mmol sodium hydride for 1 hour at 50 ° C. After cooling, 8.6 mmol of cyclopentyl bromide are added and the mixture is then stirred at 80 ° C. for 2 hours. When the reaction has ended, the dimethylform-5 amide is stripped off in vacuo at 40.degree. The residue is taken up in 100 ml of 2N sodium hydroxide solution and extracted three times with 150 ml of chloroform.

The combined chloroform phases are washed with water 10, dried, filtered and concentrated. The residue is recrystallized from ethyl acetate / ether. 5- (3-Cyclopentyloxy-4-methoxy-phenyl) -2-oxazolidinone of melting point 111 to 112 ° C. is obtained in 70% yield.

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Example 6

According to the procedure given in Example 5, 5- (3-hydroxy-4-methoxyphenyl) -2-oxazolidinone and the halide or tosylate R2X "are used to prepare the compounds indicated in the following Table 20 (R3 = R4 = R5 - H ).

It means DMF = dimethylformamide petr. = Petroleum ether 25 Chlf. = Chloroform

Tos. = Tosylate NaH = sodium hydride NaOEt = sodium ethylate

table

solvent

R2

Ri

X "

Yield (%)

Mp (° C)

Recrystallized in

Temperature / time

-ch3 -ch3

J

Br

60 64

114-117 98-100

Methanol ethyl acetate

60 ° C / 2 h 80 ° C / 2 h

-ch3

Br

34

107-110

Ethyl acetate

80 ° C / 3 h

1

Oh dear

w

Br

20th

106-107

Ethyl acetate

60 ° C / 20 h

-ch3 -ch3 -ch3

Br Br Br

43 70 80

74-75 87-88 146-147

Ethyl acetate

Ethyl acetate / petr.

Ethyl acetate / petr.

90 ° C / 4.5 h 60 ° C / 3 h 60 ° C / 3 h

-ch3

Cl

47

oil

Chromatography Chlf./Methanol (9: 1)

50 ° C / 3 h

-ch3

Phi, Cl

26

108-109

Chromatography 70 ° C / 6 h Chlf./Methanol & ethyl acetate / Petr.

-ch3

Tos.

37

86-88

Ethyl acetate

90 ° C / 3 h

DMF / NaH DMF / NaH

DMF / NaH

DMF / NaH DMF / NaH DMF / NaH

DMF / NaH

Ethanol / NaOEt

DMF / NaH

-CH3

- (CH2) 2-CH3

DMF / NaH -CH2-CH:

/

CH3

^ CH,

(CH2) 3-CH3

-ch2-ch = ch2

-CH2-CeeCH

^ ch2 xch3

-CH2-C

<D

<3

Example 7

5- (3,4-Dimethoxyphenyl) -2-oxazolidinthione and 5- (3,4-Dimethoxyphenyl) -2-thiazolidinone 45 mmol 2-amino-l- (3,4-dimethoxyphenyl) ethanol are dissolved in 65 ml absolute dimethyl sulfoxide dissolved and successively with 1.8 g of powdered potassium hydroxide and

1.4 ml of carbon disulfide are added at 10 ° C. The reaction mixture is then stirred for 2.5 hours with the exclusion of moisture. After the dimethyl sulfoxide has been stripped off under vacuum, the residue is mixed with 100 ml of water and extracted three times with 100 ml of chloroform. The combined chloroform phases are over anhydrous

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Magnesium sulfate dried, filtered and concentrated. The residue is chromatographed over 125 g of silica gel with chloroformic methanol (96: 4). After recrystallization of the corresponding fractions from methanol, 5- (3,4-dimethoxyphenyl) -2-oxazolidinthione with a melting point of 177 to 178 ° C. in addition to 6% of 5- (3,4-dimethoxyphenyl) -2-thiazolidinone are obtained in 9% yield obtained from melting point 167 to 169 ° C.

Example 8

5- (3,4-dimethoxyphenyl) -2-thiazolidinone

10 mmol of 2-amino-l- (3,4-dimethoxyphenyl) ethanol are dissolved in 6 ml of pyridine and, while cooling to 0 ° C., 11 mmol of carbon disulfide in 10 mmol of triethylamine are added dropwise, the temperature rising sharply. The mixture is stirred at 0 ° C. for 1 hour and 10 mmol of benzyl chloride are then added dropwise at the same temperature. After stirring overnight at 0 ° C., the mixture is taken up in 40 ml of 3N sulfuric acid and extracted three times with 50 ml of chloroform each. The combined chloroform phases are washed successively with sodium hydrogen carbonate and water, dried, filtered and concentrated. The spontaneously crystallizing residue is recrystallized from benzene and ethyl acetate. It is obtained in quantitative yield [2- (3,4-dimethoxyphenyl) -2-hydroxyethyl] -dithiocarbamic acid benzyl ester of melting point 130 to 132 ° C.

To 6.07 mmol [2- (3,4-dimethoxyphenyl) -2-hydroxy-ethyl] -dithiocarbamic acid benzyl ester in 50 ml absolute ether, 2.14 mmol phosphorus tribromide are added dropwise at +5 ° C. After the mixture has been stirred at 5 ° C. for 20 hours, 10 ml of methanol / water are added dropwise with cooling in such a way that the temperature does not rise above 20 ° C. The reaction mixture is then carefully stirred into 20 ml of sodium hydrogen carbonate solution. It is extracted three times with 50 ml of chloroform each time and the combined organic phases are washed in succession with 50 ml of sodium hydrogen carbonate solution and 50 ml of water, dried, filtered and concentrated.

2-Benzylthio-5- (3,4-dimethoxyphenyl-l, 3-thi-azol-2-yne is obtained as an oil in 80% yield.

This oil is dissolved in 20 ml of ethanol, mixed with 20 ml of 6N hydrochloric acid and refluxed for 4 hours. After concentration, the residue is taken up in 25 ml of ethanol, mixed with 19 ml of an sodium hydroxide solution and stirred for 3 hours at room temperature. Then the reaction mixture is neutralized with 2N hydrochloric acid, the ethanol is stripped off and extracted three times with 100 ml of chloroform. The chloroform phase is washed with water, dried and concentrated. The residue is chromatographed over 50 g of silica gel using the eluent chloroform / methanol (96: 4). The corresponding fractions are recrystallized from methanol, giving 50% of 5- (3,4-dimethoxyphenyl) -2-thiazolidinone with a melting point of 167 to 169 ° C.

Example 9

5- (3,4-Dimethoxyphenyl) -2-oxazolidinone-3-carboxylic acid ani-

lid

0.5 mmol of 5- (3,4-dimethoxyphenyl) -2-oxazolidinone are heated in 3 ml of phenyl isocyanate at 160 ° C. for 3 hours. After cooling, the reaction mixture is concentrated in vacuo and chromatographed over 50 g of silica gel with cyclohexane / ethyl acetate (1: 1). After recrystallization of the corresponding fractions from ethyl acetate, 5- (3,4-dimethoxyphenyl) -2-oxazolidi-non-3-carboxanilide of melting point 175 to 182 ° C. is obtained in 60% yield.

Example 10

100 mmol of 2-amino-1- (3,4-dimethoxyphenyl) ethanol are dissolved in 100 ml of chloroform. After cooling to 0 ° C., a solution of 100 mmol of phosgene in 100 ml of chloro-5 form is slowly added dropwise in such a way that the internal temperature does not rise above 5 ° C. After stirring for 1 hour at 5 to 10 ° C., 200 mmol of pyridine in 100 ml of chloroform are added dropwise and the mixture is stirred for 3 hours. After washing the organic phase with semi-saturated sodium chloride solution, the mixture is evaporated and recrystallized from methanol. 5- (3,4-Dimethoxyphenyl) -2-oxazolidinone of melting point 114 to 117 ° C. is obtained in 75% yield.

Example 11

15 5- (3,4-Dimethoxyphenyl) -2-oxazolidinone

5 mmol of 2-amino-l- (3,4-dimethoxyphenyl) ethanol are dissolved in 5 ml of 2N sodium hydroxide solution. The solution, cooled to 0 ° C., is mixed dropwise with 10 mmol of ethyl chloroformate. After the addition has ended, the mixture is stirred at 0 ° C. for 30 minutes. The crystals formed are suction filtered, washed with water and dried. There are 86% yield of 2- (3,4-dimethoxyphenyl) -2-hydroxyethyl-carbamic acid ethyl ester of melting point 90 to 92 ° C. 3 mmol of 2- (3,4-dimethoxyphenyl) -2-hydroxyethyl-25 carbamic acid ethyl ester are suspended with 4 mmol of sodium methylate in 12 ml of toluene and heated to 110 ° C. bath temperature with exclusion of moisture for 2 hours. Methanol and ethanol distill off. The toluene is then stripped off in vacuo, the residue is taken up in 50 ml of 30 chloroform and distributed against 10 ml of water. After drying, filtering and concentrating the organic phase, the product is recrystallized from methanol. 5- (3,4-Dimethoxyphenyl) -2-oxazolidinone of melting point 114-117 ° C. is obtained in 80% yield.

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Example 12

3-Acetyl-5- (3,4-dimethoxyphenyl) -2-oxazolidinone 8.9 mmol 5- (3,4-dimethoxyphenyl) -2-oxazolidinone are mixed with 10 ml acetic anhydride and 5 ml pyridine for 40 and 5 hours to 100 ° C heated. After concentration, it is recrystallized from ethyl acetate. 3-Acetyl-5- (3,4-di-methoxyphenyl) -2-oxazolidinone is obtained in 73% yield from the melting point 175 to 182 ° C.

45 Example 13

5- (3,4-Dimethoxyphenyl) -5-propyl-2-oxazolidinone 56 mmoles of 3,4-dimethoxybutyrophenone and 61.4 mmoles of trimethylsilyl cyanide with the addition of 20 mg (627 mmoles) of anhydrous zinc iodide are exposed to nitrogen for 4 hours with the exclusion of moisture 90 ° C heated. The reaction mixture is taken up in 15 ml of absolute tetrahydrofuran and added dropwise to a suspension of 60 mmol of lithium aluminum hydride in 35 ml of absolute tetrahydrofuran, the mixture is heated to 60 ° C. for one hour under nitrogen and the excess of lithium aluminum hydride is destroyed by the dropwise addition of ethyl acetate and water. The precipitate is filtered off over silica gel, washed well with ethanol and the mother liquor concentrated. The residue is taken up in ethyl acetate, acidified with 4n 6o hydrochloric acid and extracted. The aqueous phase is adjusted to pH 9 with sodium carbonate, saturated with sodium chloride and extracted with chloroform. The chloroform phase is washed neutral with saturated sodium chloride solution and the solvent is distilled off after drying over 65% sodium sulfate. 5-Amino-4- (3,4-di-methoxyphenyl) -4-pentanol is obtained in 75.5% yield as an oil. An analysis sample as hydrochloride melts at 175 to 176 ° C.

17.35 mmol of 5-amino-4- (3,4-dimethoxyphenyl) -4-pen-tanol are dissolved in 10 ml of absolute dimethylformamide and with 18.3 mmol of 98% carbonyldiimidazole in 100 ml of absolute tetrahydrofuran for 4 days at room temperature Exclusion of moisture implemented. After the solvent has been distilled off, the residue is taken up in ethyl acetate, shaken twice with in hydrochloric acid and washed neutral with saturated sodium chloride solution. The oil obtained is purified on a silica gel column (350 g) in a 30: 1 chloroform / methanol system. 5- (3,4-Dimethoxyphenyl) -5-propyl-2-oxazolidinone is obtained as an oil in 81.7% yield.

Example 14

5- (3,4-Dimethoxyphenyl) -5-methyl-2-oxazolidinone Analogously to Example 13, 3,4-dimethoxyacetophenone is converted to 5- (3,4-dimethoxyphenyl) -5-methyl-2-oxazolidinone in 30% overall yield obtained with a melting point of 98 to 101 ° C.

Example 15

10 mmol of 5- (3,4-dimethoxyphenyl) -2-oxazolidinone are dissolved in 20 ml of absolute dimethylformamide and 11 mmol of sodium hydride are added. The mixture is then stirred at 40 ° C for 40 minutes. After cooling, 20 mmol of methyl iodide in 5 ml of dimethylformamide are added dropwise and, after the addition has ended, the mixture is stirred at 50 ° C. for 6 hours. After the dimethylformamide has been stripped off, it is taken up in chloroform, washed first with a little water and then with saturated sodium chloride solution, dried, filtered and concentrated. The residue is chromatographed on 60 g of silica gel using chloroform / methanol (96: 4) as the eluent. After recrystallization from ethanol, 5- (3,4-dimethoxyphenyl) -3-methyl-2-oxazolidi-non of melting point 132 ° to 133 ° C. is obtained in 60% yield.

9 635 578

Example 16

Benzyl 5- (3,4-dimethoxyphenyl) -2-oxazolidinone-3-carboxylate 6.25 mmol 5- (3,4-dimethoxyphenyl) -2-oxazolidinone s are dissolved in 30 ml of dioxane and mixed with 6.25 ml ( 12.50 mM) of a 2 N sodium hydroxide solution. At +4 ° C, the mixture is mixed with 12.5 ml of carbobenzoxychloride and stirred for 4 hours at this temperature.

After adding 50 ml of 2N sodium hydroxide solution, it is washed 3 times

10 extracted with 50 ml of ethyl acetate. The ethyl acetate phase is washed once with 50 ml of 2N sodium hydroxide solution and twice with 50 ml of water each time, dried over Sikkon®, filtered and concentrated. After the carbobenzoxy chloride still present has been stripped off at 100 ° C. and 1 torr, the residue is removed

15 ethyl acetate / petroleum ether recrystallized and gives in 64% yield 5- (3,4-dimethoxyphenyl) -2-oxazolidinone-1-carboxylic acid benzyl ester of melting point 124 to 126 ° C.

Example 17

20 5- (3,4-dimethoxyphenyl) -2-oxazolidinone-3-

carboxylic acid ethyl ester 5 mmol of 5- (3,4-dimethoxyphenyl) oxazolidinone are placed in 20 ml of toluene (abs.) with 10 mmol of triethylamine at 0 ° C. with exclusion of moisture. 10 25 mmol of chloroformic acid ethyl ester are added, the mixture is refluxed for 4 hours and left to stand overnight. The product which has crystallized out is boiled again with suction with 7.6 mmol of triethylamine and 7.6 mmol of chloroformic acid ethyl ester. The crystallized product is sucked off again; the combined filtrates are evaporated. Chromatography of the residue over 80 g of silica gel with cyclohexane-ethyl acetate 1: 1 as the eluent gives, in 43% yield, 5- (3,4-dimethoxyphenyl) -2-oxazolidi-non-1-carboxylic acid ethyl ester of melting point 181 to 35 185 ° C. .

Example 18

Analogously to Example 15, the oxazolidinones listed in the following table are prepared from 5- (3,4-dimethoxyphenyl) -2-oxazolidinone:

Ri

R2

R,

Ri - R5

Yield melting point recrystallization from:

ch3

ch3 ch3

ch3 ch3 ch3

i-propyl

-ch2-0 -ch2-çh2

h 47 66-67 ethyl acetate / petroleum ether h 66 75-76 ° C ethyl acetate / petroleum ether h 40 77-78 ° C ethyl acetate / petroleum ether och,

OCH3

Example 19

5- (3,4-Dimethoxyphenyl) -4-methyl-2-oxazolidinone 5.5 mmol 2-amino-1- (3,4-dimethoxyphenyl) propanol are dissolved in 50 ml chloroform and mixed with 1.05 g (6 , 5 mmol) of carbonyldiimidazole was stirred for 2 hours with the exclusion of moisture. After standing overnight, it is extracted against 50 ml of distilled water, dried, filtered and concentrated. After chromatography of the residue over 50 g of silica gel with chloroform / methanol (95: 5) as the eluent and recrystallization from ethyl acetate / petroleum ether, 5- (3,4-dimethoxyphenyl) -4-methyl-2-oxazolidinone is obtained in 24% yield Melting point 98 to 99 ° C.

The starting material 2-amino-l- (3,4-dimethoxy) -pro-panol was prepared as follows:

To 100 mM 3,4-dimethoxypropiophenone in 160 ml of 60 methylene chloride, 10 ml of sulfuryl chloride in 80 ml of methylene chloride are added dropwise at room temperature. The mixture is then stirred at room temperature for 3.5 hours. After stripping off the solvent and recrystallizing the residue from cyclohexane / petroleum ether 65, 2'-chloro-3,4-dimethoxy-propiophenone of melting point 56 to 57 ° C. is obtained in 89% yield.

43.86 mM each of 2'-chloro-3,4-dimethoxypropiophenone dissolved in 230 ml of acetone, with 437 mg of potassium iodide and 87.72

635578

mM dibenzylamine are stirred for 7 days with exclusion of moisture. The mixture is diluted to 11 solution with diethyl ether, filtered and concentrated. The residue is coated on silica gel and the silica gel is first stirred with chloroform and then with ethanol and suctioned off in each case. The chloroform phase is chromatographed over 500 g of silica gel with chloroform as the eluent and gives 2'-N, N-dibenzylamino-3,4-dimethoxypropiophenone as an oil 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 treated with 1.33 g (35.05 mmol) of sodium boranate. After stirring for 1 hour at room temperature, the mixture is heated under reflux for 2 hours. After cooling, the batch is suctioned off and the residue is boiled out with ethyl acetate. After filtering, 2 '- (N, N-dibenzylamino) -1 - (3,4-dimethoxyphenyl) propanol crystallized from the filtrate in a 59% yield from melting point 151 to 152 ° C.

13.2 mmol of the dibenzyl compound are dissolved in 50 ml of ethanol p. a. hydrogenated with 2.64 g palladium / carbon (10%) for 3 hours at 90 ° C under 10 atm hydrogen atmosphere.

After suction, the mixture is concentrated and recrystallized from ethanol. This gives 2-amino-1- (3,4-di-methoxyphenyl) propanol with a melting point of 131 to 132 ° C. in 64% yield.

Example 20

5- (3,4-Dimethoxyphenyl) -2-oxo-oxazolidine-4-carboxylic acid ethyl ester 6 mmol of 2-amino-4- (3,4-dimethoxyphenyl) -3-hydroxy-propionic acid ethyl ester are mixed with 12 mM carbonyldiimidazole in 60 ml chloroform for 4 hours at room temperature

10th

stirred under exclusion of moisture. The mixture is then extracted once against 50 ml of water, dried over silica gel overnight, filtered and concentrated.

The residue is chromatographed on 130 g of silica gel using chloroform / methanol (90:10) as the eluent. The recrystallization from ethyl acetate / ethanol yields 5- (3,4-dimethoxyphenyl) -2-oxooxazo-lidin-4-carboxylic acid ethyl ester of melting point 188 to 189 ° C. in 34% yield.

io The starting material 2-amino-4- (3,4-dimethoxy-phenyl) -3-hydroxy-propionic acid ethyl ester was prepared as follows:

44.37 mmol of 3,4-dimethoxyglycidic acid ethyl ester (produced according to W. Schneider et al., Arch. Pharm. 299, 817 ls (1966)) are mixed with 97.61 mM dibenzylamine in 100 ml of ethanol for 4.5 hours with exclusion of moisture on Reflux cooked. After standing for 3 days at room temperature, the mixture is concentrated and the residue is chromatographed over 400 g of silica gel with chloroform / methanol (98: 2) as 20 eluents. Chromatography of the correspondingly combined fractions again gives 2-N, N-dibenzyl-4- (3,4-dimethoxyphenyl) -3-hydroxy-propionic acid ethyl ester as an oil in 89% yield.

22.2 mmol of 2-N, N-dibenzylamino-4- (3,4-dimethoxy-25 phenyl) -3-hydroxypropionic acid ethyl ester are mixed with 4.44 g of palladium / carbon 10% in 100 ml of undenatured ethanol at 90 ° for 3 hours C hydrogenated under 10 atm hydrogen pressure. After the catalyst has been suctioned off, the mixture is concentrated. Recrystallization from undenatured ethanol in 80% yield yields 2-amino-4- (3,4-dimethoxyphenyl) -3-hydroxypropionic acid ethyl ester of melting point 211 to 212 ° C. (decomposition).

Claims (32)

635 578 PATENT CLAIMS 1. Process for the preparation of new 5- (subst. Phenyl) oxyzolidinones and their sulfur analogs of the general formula I X. wherein R-! lower alkyl or cycloalkyl, R2 is hydrogen, optionally substituted lower alkyl, cycloalkyl, aryl, aralkyl, alkenyl, heterocyclic radicals having a heteroatom, this heteroatom being oxygen or nitrogen, alkynyl and cycloalkylalkyl, R3 is hydrogen, lower alkyl, alkenyl, alkynyl, aryl, aralkyl or acyl, R4 is hydrogen or lower alkyl and Rs is lower alkyl, lower alkoxycarbonyl and hydrogen and Xj and X2 independently of one another are oxygen or sulfur, characterized in that 2-amino-1- (3,4-disubst. Phenyl) ethanols of the general Formula II OR wherein Rj_5 have the meaning given above, with a carbonic acid or thiocarbonic acid derivative of the general formula III X = C (III), XY wherein X for oxygen or sulfur, X 'and Y are OR, chlorine, bromine or imidazole, with R being alkyl, aryl, aralkyl and together as alkylene, or if X is sulfur, X' and Y can also together be sulfur, in an inert solvent in the heat in the presence of a basic catalyst. 2. The method according to claim 1, characterized in that an araliphatic ether group present is cleaved reductively with Raney nickel or with a noble metal catalyst. 3. The method according to claim 1, characterized in that one alkylates a free hydroxy group. 4. The method according to claim 1, characterized in that one exchanges the ring oxygen and / or the oxygen of the 2-carbonyl group for sulfur. 5. The method according to claim 1, characterized in that, if R3 is hydrogen, N-acylated. 6. The method according to claim 1, characterized in that, if R3 is hydrogen, N-alkylated. 7. The method according to any one of claims 1 to 6, characterized in that 5- (3-benzyloxy-4-methoxy-phenyl) -2-oxazilidinone is prepared. 8. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) -2-ox-azolidinone is prepared. 9. The method according to any one of claims 1 to 6, characterized in that 3-methyl-5- (3,4-dimethoxyphenyl) -2-oxazolidinone is prepared. 10. The method according to any one of claims 1 to 6, characterized in that 5- (3-methoxy-4-cyclopentyl-oxyphenyl) -2-oxazolidinone is prepared. 11. The method according to any one of claims 1 to 6, characterized in that 5- (3-cyclopentyloxy-4-methoxyphenyl) -2-oxazolidinone is prepared. 12. The method according to any one of claims 1 to 6, characterized in that (3-propyloxy-4-methoxy-phenyl) -2-oxazolidinone is prepared. 13. The method according to any one of claims 1 to 6, characterized in that 5- (3-isobutyloxy-4-methoxyphenyl) -2-oxazolidinone is prepared. 14. The method according to any one of claims 1 to 6, characterized in that 5- (3-cyclobutyloxy-4-methoxyphenyl) -2-oxazolidinone is prepared. 15. The method according to any one of claims 1 to 6, characterized in that 5- (3-n-butoxy-4-methoxy-phenyl) -2-oxazolidinone is prepared. 16. The method according to any one of claims 1 to 6, characterized in that 5- (3-allyloxy-4-methoxy-phenyl) -2-oxazolidinone is prepared. 17. The method according to any one of claims 1 to 6, characterized in that 5- (3-propargyloxy-4-methoxyphenyl) -2-oxazolidinone is prepared. 18. The method according to any one of claims 1 to 6, characterized in that 5- (3-methylallyloxy-4-methoxyphenyl) -2-oxazolidinone is prepared. 19. The method according to any one of claims 1 to 6, characterized in that 5- (3-phenyloxy-4-methoxy-phenyl) -2-oxazolidinone is prepared. 20. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) -2-oxazolidinthione is prepared. 21. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) -2-thiazolidinone is prepared. 22. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) -5-methyl-2-oxazolidinone is prepared. 23. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) -5-propyl-2-oxazolidinone is prepared. 24. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) - 2-oxazolidinone-3-carboxylic acid benzyl ester. 25. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) - 3-isopropyl-2-oxazolidinone. 26. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) -3-benzyl-2-oxazolidinone is prepared. 2nd 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 3rd 635 578 27. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) - 3- (3,4-Dimethoxyphenylethyl) -2-oxazolidinone. 28. The method according to any one of claims 1 to 6, characterized in that 5- (3,4-dimethoxyphenyl) - 4-methyl-2-oxazolidinone produces. 29. Process for the preparation of new 5- (subst. Phenyl) oxazolidinones and their sulfur analogs of the general formula I, X \ / N-R, * Y 5 X. wherein R] lower alkyl or cycloalkyl, R2 is lower alkyl, cycloalkyl, aryl, aralkyl, alkenyl or a heterocyclic radical with a hetero atom, this hetero atom being oxygen or nitrogen, R3 is hydrogen, R4 is hydrogen or lower alkyl, R5 is hydrogen or lower alkyl, Xj sulfur and X2 is oxygen, characterized in that a compound of the formula II, in which R, _5 have the meaning given above, is first reacted with carbon disulfide in the presence of an organic base with cooling and then with further cooling with benzyl chloride to give a compound of the formula OR, R 1 C » N OH wherein R1; R2, R4 and Rs have the meaning given above, then this compound in an inert solvent with cooling with phosphorus tribromide to a 2-benzylthio-1,3-thiazole-2 in the formula R 1 s-resp. implemented and the compound thus obtained hydrolyzed in the heat. 30. Process for the preparation of new 5- (subst. Phenyl) oxazolidinones of the general formula I, OR : 1 ° wherein Rj lower alkyl or cycloalkyl, R2 lower alkyl, cycloalkyl, aryl, aralkyl, alkenyl or a heterocyclic radical with a hetero atom, this hetero atom being oxygen or nitrogen, R3 hydrogen, R4 is hydrogen or lower alkyl, R5 is hydrogen or lower alkyl, X! and X2 are oxygen, characterized in that a compound of the formula II, in which R, _5 have the meaning given above, is dissolved in an organic base and with ethyl chloroformate with cooling to give an ethyl carbamic acid of the formula OR, R 1 OH NH-COOEt wherein R1; R2, R4 and R5 have the meaning given above, reacted and then treated this compound with an alkali metal alcohol in an inert solvent under heat. 5 10th 15 20th 25th 30th 35 40 45 50 55 60 635 578