CA1097657A - 5-(substituted phenyl)-oxazolidinones and sulphur analogues thereof and also a process for their production - Google Patents
5-(substituted phenyl)-oxazolidinones and sulphur analogues thereof and also a process for their productionInfo
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- CA1097657A CA1097657A CA292,273A CA292273A CA1097657A CA 1097657 A CA1097657 A CA 1097657A CA 292273 A CA292273 A CA 292273A CA 1097657 A CA1097657 A CA 1097657A
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- oxazolidinone
- dimethoxyphenyl
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/16—Sulfur atoms
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides a 5-(substituted phenyl) -oxazolidinone or sulphur analogue thereof of the general formula (I) in which R1 represents a lower alkyl group with up to 6 carbon atoms, or a cycloalkyl or cycloalkylalkyl radical with up to 7 carbon atoms, R2 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, a cycloalkyl or cycloalkylalkyl group with up to 7 carbon atoms, the phenyl group, an aralkyl group with 7 or 8 carbon atoms, an alkenyl or alkynyl group with 2 to 6 carbon atoms or the tetrahydrofuranyl radical, R3 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, an aryl or aralkyl with 6 to 10 carbon atoms which may be ring substituted by lower alkoxy or an acyl group with up to 18 carbon atoms, R4 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, R5 represents hydrogen or a lower alkyl or lower alkoxycarbonyl radical with up to 6 carbon atoms, and each X represents oxygen or sulphur atoms the two X moieties being the same or different, which comprises reacting a 2-amino-1-(3,4-disubstituted phenyl)-ethanol of the general formula (II) in which R1 to R5 have the meanings given above, with a carbonic or thiocarbonic acid derivative of the general formula (III)
The present invention provides a 5-(substituted phenyl) -oxazolidinone or sulphur analogue thereof of the general formula (I) in which R1 represents a lower alkyl group with up to 6 carbon atoms, or a cycloalkyl or cycloalkylalkyl radical with up to 7 carbon atoms, R2 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, a cycloalkyl or cycloalkylalkyl group with up to 7 carbon atoms, the phenyl group, an aralkyl group with 7 or 8 carbon atoms, an alkenyl or alkynyl group with 2 to 6 carbon atoms or the tetrahydrofuranyl radical, R3 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, an aryl or aralkyl with 6 to 10 carbon atoms which may be ring substituted by lower alkoxy or an acyl group with up to 18 carbon atoms, R4 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, R5 represents hydrogen or a lower alkyl or lower alkoxycarbonyl radical with up to 6 carbon atoms, and each X represents oxygen or sulphur atoms the two X moieties being the same or different, which comprises reacting a 2-amino-1-(3,4-disubstituted phenyl)-ethanol of the general formula (II) in which R1 to R5 have the meanings given above, with a carbonic or thiocarbonic acid derivative of the general formula (III)
Description
~Q~
The present invention provides 5- (substitu-ted phenyl)-oxazolidinones and sulphur analogues thereof of the general formula (I) OR2 I
R1 ~ol \/\ R4 R5 (I) .~ I I
~ R3 X
in which Rl represents a lower alkyl group with up to 6 carbon atoms, or a cycloalkyl or cycloalkylalkyl radical with up to 7 carbon atoms, R2 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, a cycloalkyl or cycloalkylalkyl group with up to 7 carbon atoms, the phenyl group, an aralkyl group with 7 or 8 carbon atoms, an alkenyl or alkynyl group with 2 to 6 carbon atoms or the tetrahydrofuranyl radical, R3 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, an aryl or aralkyl with 6 to lO carbon atoms, which may be ring substituted by lower alkoxy or an acyl group with up to 18 carbon atoms, R4 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, R5 represents hydrogen or a lower alkyl or lower alkoxycarbonyl radical with up to 6 carbon atoms, and each X represents oxygen or sulphur atoms the two X moieties being the same or different, which comprises reacting a 2-amino-1-~3,4-disubstituted phenyl~-ethanol of the general formula RlO ~ (II~
Ol~ I~N~3 in which Rl to R5 have the meanings given above, with a carbonic or thiocarbonic acid derivative of the general formula (III) z (S)O-C ~ (III) Y
in which Z and Y each represents chlorine or bxomine or an imidazole radical or represents the group OR, in which R represents an alkyl, aryl or aralkyl radical or the two R's together represent an alkylene radical, and when required an aralkyi ~roup in an ether group i5 split off by reduction with Raney nickel or a free hydroxyl group isalkylated or converted into another radical ; OR2 or the rin~-oxy~en or oxygen of the 2-carbonyl group is exchanged for sulphur by phosphorus pentasulphide or, when R3 represents hydrogen, it t S N-acylated or N-alkylatedO
The compounds oE the general formula (I) have an asymmetrical carbon atom and can therefore exist both as race-mates and also as optical antipodes.
Alkyl radicals containing up to 6 carbon atoms include f~r example, methyl, et~yl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl~ pentyl, 2-methylbutyl, 2,2-dimethylpropyl and hexyl groups. Alk~nyl and alkynyl groups are, ~or example, 1- -propenyl, 2-propenyl, 3-methyl-2-propenyl, vinyl and propargyl groups.
Cycloalkyl and cycloalkylalkyl contain 3 to 7 carbon atoms. There may be mentioned, more especially, cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl groups.
As aryl or aralkyl groups there come into consideration 3 ~ more especially phenyl and ~ groupsO
As acyl radicals there come into consideration radicals of carboxylic acids yielding physiologically tolerable compounds.
, . ~ ,, ~ ,,, ~7~i57 Preferable are those derived from alkanoic acids containing 1 to 18 carbon atoms, and especially 2 -to 8 carbon atoms, such, for example, as monobasic alkanoic acids such, for example, as formic, acetic, propionic, butyric, isobutyric, ~-ethylbutyric, pivalic, valeric, isovaleric, ~-ethylvaleric, trimethylacetic,
The present invention provides 5- (substitu-ted phenyl)-oxazolidinones and sulphur analogues thereof of the general formula (I) OR2 I
R1 ~ol \/\ R4 R5 (I) .~ I I
~ R3 X
in which Rl represents a lower alkyl group with up to 6 carbon atoms, or a cycloalkyl or cycloalkylalkyl radical with up to 7 carbon atoms, R2 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, a cycloalkyl or cycloalkylalkyl group with up to 7 carbon atoms, the phenyl group, an aralkyl group with 7 or 8 carbon atoms, an alkenyl or alkynyl group with 2 to 6 carbon atoms or the tetrahydrofuranyl radical, R3 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, an aryl or aralkyl with 6 to lO carbon atoms, which may be ring substituted by lower alkoxy or an acyl group with up to 18 carbon atoms, R4 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, R5 represents hydrogen or a lower alkyl or lower alkoxycarbonyl radical with up to 6 carbon atoms, and each X represents oxygen or sulphur atoms the two X moieties being the same or different, which comprises reacting a 2-amino-1-~3,4-disubstituted phenyl~-ethanol of the general formula RlO ~ (II~
Ol~ I~N~3 in which Rl to R5 have the meanings given above, with a carbonic or thiocarbonic acid derivative of the general formula (III) z (S)O-C ~ (III) Y
in which Z and Y each represents chlorine or bxomine or an imidazole radical or represents the group OR, in which R represents an alkyl, aryl or aralkyl radical or the two R's together represent an alkylene radical, and when required an aralkyi ~roup in an ether group i5 split off by reduction with Raney nickel or a free hydroxyl group isalkylated or converted into another radical ; OR2 or the rin~-oxy~en or oxygen of the 2-carbonyl group is exchanged for sulphur by phosphorus pentasulphide or, when R3 represents hydrogen, it t S N-acylated or N-alkylatedO
The compounds oE the general formula (I) have an asymmetrical carbon atom and can therefore exist both as race-mates and also as optical antipodes.
Alkyl radicals containing up to 6 carbon atoms include f~r example, methyl, et~yl, propyl, isopropyl, butyl, isobutyl, tertiary-butyl~ pentyl, 2-methylbutyl, 2,2-dimethylpropyl and hexyl groups. Alk~nyl and alkynyl groups are, ~or example, 1- -propenyl, 2-propenyl, 3-methyl-2-propenyl, vinyl and propargyl groups.
Cycloalkyl and cycloalkylalkyl contain 3 to 7 carbon atoms. There may be mentioned, more especially, cyclopropyl, cyclopropylmethyl, cyclopentyl and cyclohexyl groups.
As aryl or aralkyl groups there come into consideration 3 ~ more especially phenyl and ~ groupsO
As acyl radicals there come into consideration radicals of carboxylic acids yielding physiologically tolerable compounds.
, . ~ ,, ~ ,,, ~7~i57 Preferable are those derived from alkanoic acids containing 1 to 18 carbon atoms, and especially 2 -to 8 carbon atoms, such, for example, as monobasic alkanoic acids such, for example, as formic, acetic, propionic, butyric, isobutyric, ~-ethylbutyric, pivalic, valeric, isovaleric, ~-ethylvaleric, trimethylacetic,
2-methyl.butyric, 3-ethylbutyric, caproic, triethylacetic, oenanthic or caprylic acid, or cyclic acids, preferably cyclo-aliphatic acids, such, for example, as cyclopropylideneacetic, cyclobutyl carboxylic, cyclopentyl carboxylic, cyclopentylacetic, ~-cyclopentylpropionic, cyclohexyl carboxylic or cyclohexylacetic acid or also carbocycli.c aryl or aralkyl acids such, for example, as benzoic, 2-, 3- or 4-methylbenzoic acid.
As the chemical character of the acyl group is not critical with regard to the properties of the compounds of -the invention, pro~ided that the acyl group is not toxic, there are also suitable other aliphatic and aromatic unsubstituted or substituted, mono-, di- and poly-basic carboxylic acids, saturated and unsaturated aliphatic, araliphatic and aromatic carboxylic acids containing up to 18 carbon atoms, and preferably up to 8 carbon atoms.
There may be mentioned, for example, the undecyclic, dodecanoic, tetradecanoic, hexadecanoic, octadecanoic, palmitic-, 7~;7 stearlc and ~-cyclohexylpropionic acid, 2,3-, 2,4-, 2,6-, 3,4-and 3,5-dimethylbenzoic, ethylbenzoic, naphthoic, 3-me-thyl-~-naphthoic, ~-phenylpropionic, diphenylacetic and ~-naphthylace-tic acid or carbamic acids such, for example, as carbamic, phenyl-carbamic, n-butylcarbaMic, dimethylcarbamic, diethyl-carbamic and allophanic acid, or heterocyclic acids such, for example, as ~-furylcarboxylic, pyrrole carboxylic, ~-pyrrolidi-nopropionic, N-methylpyrrolidino-2-carboxylic, 6-hydroxy-indolyl-
As the chemical character of the acyl group is not critical with regard to the properties of the compounds of -the invention, pro~ided that the acyl group is not toxic, there are also suitable other aliphatic and aromatic unsubstituted or substituted, mono-, di- and poly-basic carboxylic acids, saturated and unsaturated aliphatic, araliphatic and aromatic carboxylic acids containing up to 18 carbon atoms, and preferably up to 8 carbon atoms.
There may be mentioned, for example, the undecyclic, dodecanoic, tetradecanoic, hexadecanoic, octadecanoic, palmitic-, 7~;7 stearlc and ~-cyclohexylpropionic acid, 2,3-, 2,4-, 2,6-, 3,4-and 3,5-dimethylbenzoic, ethylbenzoic, naphthoic, 3-me-thyl-~-naphthoic, ~-phenylpropionic, diphenylacetic and ~-naphthylace-tic acid or carbamic acids such, for example, as carbamic, phenyl-carbamic, n-butylcarbaMic, dimethylcarbamic, diethyl-carbamic and allophanic acid, or heterocyclic acids such, for example, as ~-furylcarboxylic, pyrrole carboxylic, ~-pyrrolidi-nopropionic, N-methylpyrrolidino-2-carboxylic, 6-hydroxy-indolyl-
3-acetic, N-methylmorpholino-2-carboxylic and pyrrole-2-carboxylic acid. The acyl radicals may be substitute~ one ormore times. As substituents -there rnay be mentioned, for example, the following radicals: hydroxyl, halogen, alkoxy, aralkoxy, acyloxy, sulphonyloxy, amido, sulphato, nitro, mercapto and cyano such, for example, as in the acyl radicals of glycollic, lactic, citric, tartaric, maleic, glycerinic, mannonic, gluconic and salicylic acid, or acyl radicals oE amino acids such, for example, as glycine, aminopropionic, diglycollamino and tri-glycollamino acid, methyl-glycine, and dimethylglycine, diethylglycine. There may also be mentioned the acyl radicals of para-amino-salicylic, para-aminobenzoic, ethylmercaptoace-tic, benzyl-mercaptoacetic, chloracetic, fluoracetic, trichloracetic, trifluoracetic, thiogylcollic, meta-nitrobenzoic, 2,3,4-trimethoxy-benzoic, phenoxyacetic and ~-naphthyloxyacetic acid. There may also be mentioned the alkoxylated and aralkoxylated acyl radicals of formic acid such, for example, as ethoxycarbonyl and benzoxycarbonyl. It is to be understood that the term "acyl"
is used herein to include alkoxycarbonyl, aralkoxycarbonyl and o-ther ester groups. The term also includes carbamoyl groups, for ~ example, a C6H5-NH-CO- yroup.
~ 30 The compounds of the invention of the general formula ~ (I) are new compounds and have valuable pharmacological properties They exhibit central depressive, antidopaminergic, antinociceptivè
~7~;7 and anticonvulsive actions, and thus have a certain similarity to neurolep-tics such, for example, as chlorpromazine and haloperidol. However, the compounds of the invention differ from the classlcal neuroleptics in having a different kind of influence on receptor-dependent, monoaminergic feedback mechanisms (decrease or extrapyramidal side effects).
Furthermore, the compounds of the invnetion have strong i phosphodiesterase-inhibiting properties and thus influence the metabolism of cyclic nucleotides. As controlled cell growth is decisively regulated by cyclic nucleotides (Pastan et al., 1975) and cyclic nucleotides are par-tially decreased in uncontrolledly proliferating tissue (Ryan and Heidrick, 1974, Voorhees et al., 1974), the compounds are suitable for the treatment of diseases that are hyperproliferative and proceed with uncontrolled cell growth such as psoriasis, polycythaemia vera, neuroblastoma, immunological diseases such as asthma, and bronchial and throm-. boembolic diseases, in which there is a disturbance of the metabolism of cyclic nucleotides (Tateson, J.E.; Trist, D.G., Inhibition of adenosine-3',5'-cyclic monophosphate phosphodie-sterase by potential antiallergic compounds; Life Sci. 18, 153-162, 1976; De Gaetano, G., Pharmacology of platelet aggregation, Pharmacol Res. Commun. 7, 301-309, 1975).
The compounds of the invention may be made up in the form of pharmaceutical preparations for the treatment of the aforesaid diseases. Accordingly, the invention also provides a pharmaceutical preparation which comprises a compound of the general formula (I) in admixture or conjunction with a pharma-ceutically suitable carrier. As carriers there may be used substances known to be sui-table for enteral and parenteral application such, for example, as water, alcohol, gelatine, gum arabic, lactose, starches, magnesium stearate, talcum, vegetable oils and polyalkylene glycol. The preparations may be in solid -- S
form ~s tablets, capsules, dragees, suppositories or in liquid form as solutions, suspensions or emulsions.
The invention also provides a process for the pro-duction of compounds of the general formula (I) when a 2-amino-1-(3,4-disubstituted phenyl) ethanol of the general formula (II) ~ 4 5 in which Rl to R5 have the meanings given above, is reacted with a carboni.c acid derivative or thiocarbonic acid derivative of the general formula (III) ~5~ O=C \ ~III) in which Z and Y each represents chlorine or bromine or an imidazole radical, or represents the group OR (in which R represents alkyl, aryl, aralkyl or together represent alkylene), usually in an inert solvent in the presence of a basic catalyst, and if --desired an aralkyl group in an ether group present is subsequent-: ly split off by reduction with Raney nickel or with a noble metal catalyst or a free hydroxyl group OR2 is alkylated or converted into another radical OR2 or the ring-oxygen and/or oxygen of the 2-carbonyl group is exchanged for sulphur or, when ; 30 R3 represents hydrogen, N-acylation or N-alkylation is carried out.
The ring~closing reaction for compounds of the formula (II) may be carried out with all carbonic acid derivatives of thiocarbonic acid derivatives of the general formula (III).
The R's may be identical or different. R may represent a lower alkyl or aralkyl radical such, for example, as methyl, ethyl and benzyl. The two R's together may also represent an alkylene residue such, for example, as propylene or iso-butylene.
The solvents used are preferably inert towards the reactants. There may be mentioned, for example, ethers such, for example, as diethyl e-ther, glycol dimethyl ether or diethy-lene glycol dimethyl ether, aliphatic and aromatic hydrocarbons such, for example, as hexane, benzene, toluene, xylene and mesitylene, but also alcohols such, for example, as methanol, ethanol, propanol, butanol and also dimethyl sulphoxide, glycol monomethyl ether and diethylene glycol monomethyl ether.
The reaction is preferably carried out at a raised temperature, in the range from above room temperature to the boiling point of the reaction mixture, preferably in the range of from 60 to 200C, and especially lO0 to 160~C.
The ring-closing 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, for example, as sodium methylate and potassium carbonate.
However, there are also suitable organic bases such, for example, as pyridine, triethylamine, alkali metal and alkaline earth metal hydroxides such, for example, as sodium hydroxide, - especially when Z or Y represents halogen. When Z and Y are halogen such, for example, chlorine, the addition of a basic catalyst may be dispensed with. When Z and Y are imidazole radicals it is preferable to work at room temperature, and dimethylformamide, tetrahydrofuran and methylene chloride are suitable as solvents. The subsequent optional reductive split-ting off of an aralkyl group such, for example, as the benzvl ~7~57 .
group, may be carried out with any of the usual rnetal catalysts such, for example, as platinum, palladium, rhodium or nickel, either in the pure form of on carrier materials such, for example, as carbon, calcium carbonate and barium sulphate. As solvents there may be used those that are inert towards the reducing agents under the reaction conclitions. There may be mentioned, for example, organic acids such, for example, as j acetic acid and propionic acid, lower alcohols such, for example, ` as methanol and ehtanol, esters such, for example, as ethyl acetate, aliphatic, cycloaliphatic and aromatic hydrocarbons such, for example, as hexane, cyclohexane and benzene.
The optional subsequent O-alkylation (R2 represents ; hydrogen) may also be carried out by methods in themselves known. The alkylation is preferably carried out with the appropriate R2-halide, -mesylate or -tosylate. As halides there are suitable chlorides, bromides and iodides. For alkylation the hydroxy-compound of the formula (II) is dissolved, for example, in a polar solvent and is heated in the presence of a base with the alkylating agent at temperatures between 30 and 150C. As bases there are suitable, ~or example, sodium hydride, potassium carbonate, alkali metal alcoholates, such as sodium ethylate, potassium butylate and potassium tertiary-butylate.
As solvents there come into consideration dimethylformamide, ; dimethylacetamide, hexamethyl-phosphoric acid triamide, acetoni-trile, dimethyl sulphoxide, tetrahydrofuran, dioxan, ketones - such, for examples, as acetone and methyl isobutyl ketone, and also alcohols such, for example/ as ethanol, butanol and tertiary-butanol.
~he exchange oE the carbonyl-oxygen or the ring-oxygen in compounds of the general formula (I) for sulphur may be -carried out by methods in themselves known such, for example, as according to Scheeren et al. Synthesis 1973, 149.
76~;7 For this purpose there is suitable, for examplc, a polysulphide such, for example, as phosphorus pentasulphide in a solvent or solvent mixture in the presence of a base. The reaction may also be carried out in a suspension. Suitable solvents or suspension media are, for example, acetonitrile, tetrahydrofuran, diethyl ether, glycol dimethyl ether and pyridine. As bases there are suitable, for example, sodium hydrogen carbonate and potassium carbonate. The reaction is complete after about 3 to 24 hours at 30 to 120C.
The subse~uent optional N-acylation or N-alkylation (R3 = H) may also be carried out by methods in themselves known.
hus, the amino-compound is dissolved in a polar solvent and hea-ted at 40 to 150C in the presence of a salt former with, for example, an alkyl halide or aryl halide, or acyl halide or acyl ; anhydride. As polar solvents there may be used, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxan, and also alcohols such, for example, as ethanol and butanol.
Suitable salt formers are, for example, sodium hydride, potassium carbonate, alkali metal alcoholates such, for example, as sodium ethylate and potassium tertiary-butylate. The reaction with an aryl halide, for example, iodobenzene, may also be carried out without a solvent, preferably in the presence of copper powder.
The following Examples illustrate the invention:-~ Example 1 ; 5-(3-Benzyloxy~4-methoxy-phenyl~-2-oxazolidinone.
318.4 mMol of 3-benzyloxy-4-methoxybenzaldehyde are dissolved in 1200 ml of ether. A solution of 558 mMol of potas-~' sium cyanide in 300 ml of water is added at room temperature.
After cooling to 0C., 237 mMol of 2N-sulphuric acid are added dropwise to the well stirred mixture, and the reaction mixture ~ is stirred for 12 hours at room temperature. After separating the aqueous phase, the ether is washed several times with 50 ml ~7~57 of semi-saturated sodium chloride solution and dried well over calcium chloride. After ~iltering off the drying agent and subsequent washing twice with 100 ml of ether the combined organic phases, which contain crude 2-(3-benzyloxy-4-methoxy-phenyl)-2-hydroxy-acetonitrile, are used in the next stage.
In an analogous manner 2-(3,4-dimethoxyphenyl)-2-hydroxyacetonitri]e was prepared from 3,4-dimethoxybenzaldehyde ~ and 2-(3-cyclopentyloxy-4-methoxyphenyl)-2-hydroxyacetonitrile ; was prepared from 3-cyclopentyloxy-4-methoxybenzaldehyde.
1.3 Mol of lithium aluminium hydride are suspended in portions in 1 litre of absolute ether and, while cooling and stirring well, -the ethereal solution of 2-(3-benzyloxy-4-methoxy-phenyl)-2-hydroxyacetonitrile is introduced dropwise in a manner such that only slight refluxing occurs. After stirring at room temperature overnight, there is added dropwise to the mixture, while cooling, firstly 400 ml of ethyl acetate and later 600 ml J of water. The precipitate that forms is then filtered off with suction and the residue is washed -twice with 200 ml of ethanol:
water (1:1) each time. The collecting filtrates are strongly ; 20 concentrated and taken up in 300 ml of semi-concentrated hydro-chloric acid. This solution is extracted twice with 200 ml of a ethyl acetate each time. The ethyl acetate phase is discarded, and the hydrochloric acid solution is cooled and rendered alkaline with potassium hydroxide solution (any precipitatinq aluminium salt being filtered off with suction) and extraction - by agitation three times with 400 ml of ether each time is carried out. The combined p~ganic phases are dried, concentxated after filtration, and xecrystallised from ethyl acetate.
The 2~amino-1 (3-benzyloxy 4-methoxyphenyl)-ethanol, obtained in a yield of 20~, melts at 101 to 102C.
In an analogous manner 2-amino-1-(3,4-dimethoxyphenyl)-ethanol (M.p. 80-81C., benzene) is obtained in a yield of 49%
~7657 from 2-~3,4-dimethoxyphenyl)-2-hydroxy-acetonitrile, and 2-amino-1-(3-cyclopentyloxy 4-methoxyphenyl)-methanol (an oil) is obtained in a yield of 70~ from 2-(3-cyclopentyloxy-4 methoxy-phenyl)-2-hydroxyacetonitrile.
2-Amino-1-(3-benzyloxy-4-methoxyphenyl)-ethanol can be prepared as follows:
50 m Mol of 3-benzyloxy-~-methoxybenzaldehyde and 55 mMol of trimethylalyl cyanide are heated at 90C. with 0.567 mMol of anhydrous zinc iodide for 4 hours under nitrogen and with the exclusion of moisture. The mixture is then taken up in 15 ml of absolute tetrahydrofuran, and this solution is added drop-wise to a suspension of 60 mMol of lithium aluminium hydride in 35 ml of tetrahydrofuran. After heating the mixture for one hour at 60C, working up is carried out as described above.
After recrystallisation from ethyl acetate, 2-amino-1(3-benzy-loxy-~-methoxyphenyl)~ethanol melting at 100-102C, is isolated at a yield of 30%.
36 mMol of 2-amino-1-(3-benzyloxy-4-methoxyphenyl)-ethanol are suspended with 50 mMol of sodium methylate and 91.4 mMol of diethyl carbonate in 120 ml of absolute toluene, and the whole is heated for 2 hours at a bath temperature of llO~C. with the exclusion of moisture, methanol and ethanol being distilled off. The toluene is subsequently distilled off finally under an oil pump vacuum. The residue is taken up in 150 ml of chloroform and distrlbution against 100 ml of water is carried out. The aqueous 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 recrystallised from ethyl acetate. There is obtained 5~(3-benzyloxy-4-methoxyphenyl)-2-oxazolidinone melting at 132-133~C.
(91~ yield).
7~;~7 Example 2 In a manner analogous to that in Example 1 there are prepared from the corresponding amino-alcohols the oxazolidinones given in the following Table (R5 = hydrogen).
RlR2 R3 LYleld (.~ Recrystallised Erom -CH3-CH3 -H -H63 114-117 methanol -CH3-CH3 -C~3 -H41 132-134 ethanol ~-CH3 _~ --H45.8 141-143 ethyl acetate/ether -CH3~ -E -El52 111-]12.5 ethyl acetate/ether Example 3 88.3 ~Mol 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 overnight at room temperature. After distilling off the tetrahydrofuran the residue is taken up in 300 ml of ethy1 acetate, the mixture is extracted by agitation twice with lN-hydrochloric acid and is then washed neutral with saturated sodium chloride solution, dried, filtered and concentrated.
By recrystallisation from ethyl acetate 5-(3-benzyl-oxy-4-methoxyphenyl)-2~oxazolidinone melting at 83-91C is obtained in a yield of 66~. ) Example 4 5-(3-Hydroxy-4 methoxyphenyl)-2-oxazolidinone.
40.6 mMol of 5-(3-benzyloxy-4-methoxyphenyl)-2-oxazolidinone are dissolved in 700 ml of ethanol and hydrogen-ated in the presence of 8 gms of Raney nickel (B 113, Fa. Degussa) - Frankfurt) for 2.2 hours at room temperature under a pressure i7 hydrogen of 100 atmospheres. After filtering off the catalyst, evaporation is carried out and the residue is recrystallised from methanol. 6.74 Gms of 5-(3-hydroxy-4-methoxyphenyl)~2-oxazolidinone melting at 157 - 160C. (methanol) are obtained.
Example 5 5-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxazolidinone.
7.2 mMol of 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidi-none are dissolved in 10 ml of absolute dimethylformamide and the solution is stirred with 7.9 mMol of sodium hydride for 1 hour at 50C. After cooling the mixture, 8.6 mMol of cyclo-pentyl bromide are added, and then the whole is stirred for 2 hours at 80~C. When the reaction has terminated the dimethyl-formamide is removed in vacuo at 40C. The residue is taken up in 100 ml of a 2N-solu-tlon of sodium hydroxide and extracted three times with 150 ml chloroform. The combined chloroform phases are washed with water, dried, filtered and concentrated.
The residue is recrystallised from ethyl acetate/ether. 5-(3-Cyclopentyloxy-4 methoxy-phenyl)-2-oxazolidinone melting at 111-112C. is obtained in a yield of 70~.
Example 6 By the method given in Example 5 the compounds (R3=
R~=R5-ll) given in the following Table are prepared from 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone and the halide or tosylate of R2Zl The symbols have the following meanings:
DMF = Dimethylformamide.
Petr. = Petroleum ether.
Chlf. = Chloroform.
Tos. = Tosylate.
NaH = Sodium hydride.
NaOEt = Sodium ethylate.
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_~ o ~r ~r o ~ o o ~ ~o ~ ~ ~ ~ ~r 1~ C~
m . _ ~ _ . __ , , E~l h )I Sl Sl ~ ~1 ` O
m m m m m m ~ H E~
.
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K~ 1 _ O ~ /~
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tq X X ~ ~ ~ `~
_ C3 \ C) ~) C) C~ ` , I
I I i r~ ~ ~ ~ ~ ~ ~ ~ ~ r~
,1 m ~ m :r m x ~ ~ ~ m ~4l l l l l l l l l l _ C
~ 0 ~ O d G)x Z æ z z z; z z ~ ~ ~ ~ ~ ~ ~ \ ~ ~ ~
o o ~ ~ ~ X
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E_ample 7 5-(3,4-Dimethoxyphenyl)-2-oxazolidinthione and 5-(3,4-dimethoxyphenyl-2-thiazolid none.
45 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 65 ml oE absolute dimethyl sulphoxide and at 10C.
there are added in succession 1.3 gms of pulverised potassium hydroxide and 1.4 ml oE carbon disulphide. The reaction mixture is then stirred for 2.5 hours with the exclusion of moisture.
After removing the dimethyl sulphoxide ln vacuo, 100 ml of water are added to the residue ancl extraction three times with 100 ml of chloroform is carried out. The combined chloroform phases are dried over anhydrous magnesium sulphate, filtered and con-centrated. The residue is chromatographed over 125 gms of silica gel with chloroform : methanol (96:4). By recrystallisation of the appropriate fractions from methanol there are obtained in a yield of 9% 5-(3,4-dimethoxyphenyl)-2-oxazolidinthione melting at 177-178C. and also 6% of 5-(3,4-dimethoxyphenyl)-2~thiazolid-inone melting at 167-169C.
Example 8 5-(3,4-Dimethoxyphenyl)-2-thiazolidinone 10 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 6 ml of pyridine and, while cooling at 0C., 11 mMol of carbon disulphide in 10 mMol of -triethylamine are added drop-wise, the temperature rising strongly. The mixture is stirred for one hour at 0C. and -then at the same temperature 10 mMol of benzyl chloride are added dropwise. After stirring overnight at 0C., the mixture is taken up in 40 ml of 3N-sulphuric acid and extracted 3 -times with 50 ml of chloroform each time. The combined chloroform phases are washed in succession with sodium hydro~en carbonate and water, dried, fil-tered and concentrated.
The residue that crystallises spontaneously is recrystallised ~7~7 from benzene and ethyl acetate. [2-(3,4-Dirnethoxyphenyl)-2-hydroxy-ethyl]-dithiocarbamic acid benzyl ester melting at 13~-132~C is obtained in a quantitative yield.
i To 0.67 mMol of ~2-(3,4-dimethoxyphenyl)-2-hydroxy-ethyl]-dithiocarbamic acid benzyl ester in 50 ml of absolute ether are added dropwise a-t +5C. 2.14 mMol of phosphorus tri-bromide. After stirring the mixture for 20 hours at 5C., 10 ml of methanol/water are added dropwise, while cooling, in a manner such that the temperature does not exceed 20C. The reaction mixture is then cautiously stirred into 20 ml of sodium hydrogen carbonate solution. Extraction three times with 50 ml of chloro-form each time is carried out and the combined organic pha~ses 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)-1,3-thiazol-2-ine is obtained in the form of an oil in a yield of 80%.
This oil is dissolved in 20 ml of e-thanol, 20 ml of 6N-hydrochloric acid are added and the whole is boiled for 4 hours under reflux. Afker concentrating, the residue is taken up in 25 ml of ethanol, 19 ml of a lN-solution of sodium hydroxide are added and the mixture is stirred for 3 hours at room temper-ature. The reaction mixture is then neutralised with 2N-hydro-chloric acid, the ethanol is removed and extraction by agitation three times with 100 ml of chloroform each time is carried out.
The chloroform phase is washed with water, dried and concentrated.
The residue is chromatographed over 50 gms of silica gel with the eluant chloroform/mekhanol (96:4). The appropriate fractions are recrystallised from methanol, and 50% of 5-(3,4-dime-thoxy-phenyl)-2--thiazolidinone melting at 167-169C is o~tained.
Example 9 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid.
anilide.
~97~
0.5 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone is heated at 160C in 3 ml of phenyl isocyanate for 3 hours.
After cooling, the reaction mixture is concentrated in vacuo and chromatographed over 50 gms of silica gel with cyclohexane/ethyl acetate (1:1). By recrystallisation of the appropriate fractions from ethyl acetate 5-(3,4-dime-thoxyphenyl)-2- oxazolidinon-3-carboxylic acid anilide meltinc3 at 175-182C. is obtained in a yield of 60%.
~xample 10 5-(3,4-Dimethoxyphenyl)-2-oxazolidinone.
.
100 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 100 ml of chloroform. After cooling to 0C., a solution of 100 mMol of phosgene in 100 ml of chloroform is slowly added dropwise in a manner such that -the internal temper-ature does not exceed 5C. ~fter stirring for one hour at 5-10C., 200 mMol of pyridine in 100 ml of chloroform are added dropwise and stirred for 3 hours. After washing the organic phase with a semi-saturated solution of sodium chloride, evaporation-and recrystallisation from methanol are carried out. 5-(3,4-Dimethoxy-phenyl)-2-oxazolidinone melting at 114-117C. is obtained in a yield of 75%.
Example 11 5-(3,4-Dimethoxyphenyl)-2-oxazolidinone.
5 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 5 ml of a 2N-solution of sodium hydroxide. To the solution, cooled to 0C., are added dropwise 10 mMol of chloro formic acid ethyl ester. When the addition is complete, the - mixture is s-tirred for 30 minutes at 0C. The crystals formed are filtered off with suction~ washed with water and dried.
2-(3,4-Dimethoxyphenyl)-2-hydroxyethyl-carbamic acid ethyl ester melting at 90-92C. is obtained in a yield of 86%.
3 mMol of 2-(3,4-Dimethoxyphenyl)-2-hydroxyethyl-7~S7 carbamic acid ethyl ester are suspended with 4 ~ol of sodium ethylate in 12 ml of toluene, and the whole is heated for 2 hours at a bath temperature of 110C. with -the exclusion of moisture.
Methanol and ethanol distil off. The toluene is then removed _n vacuo, the resiclue is taken up in S0 ml of chloroform, and distribution is carried out ayains-t 10 ml of water. After dryiny, filteriny and concentratiny the oryanic phase recrystallisation from methanol is carried out. 5-(3,4-Dimethoxyphenyl)-2-oxazolidinone meltiny at 114-117C. is obtained in a yield of ~0%-Example 12 3-Acetyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone.
! To 8.9 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are added 10 ml of acetic anhydride and 5 ml of pyridine, and the whole is heated for 5 hours at 100C. After concentratiny, recrystallisation from ethyl acetate is carried out. 3-Ace-tyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone meltiny at 175-182C. is obtained in a yield of 73%.
Example 13 5-(3,4-Dimethoxyphenyl)-S-propyl-2-oxazolidinone.
56 mMol of 3,4-dimethoxybutyrophenone and 6.14 mMol of trimekhylsilyl cyanide with the addition of 200 my (627 mMol) of anhydrous zinc iodide are heated at 90C. or 4 hours under nitroyen and with the exclusion of moisture. The reaction mix-ture is taken up in 15 ml of absolute tetrahydrofuran and added dropwise to a suspension of 60 mMol of lithium aluminium hydride in 35 ml of absolute tetrahydrofuran, the mixture is heated for one hour at 60C under nitroyen and the excess of lithium alumin-ium hydride is decomposed by the dropwise addition of ethyl acetate and water. The precipitate is filtered off with suction over silica yel, washed well with ethanol and the mother liquor is concentrated. The residue is taken up in ethyl acetate, ~ca7~S7 acidified with 4N-hydrochloric acid and extracted ~y ayitation.
The aqueous phase is adjusted to a pH-value of 9 with sodium carbonate~ saturated with sodium chloride and extracted with chloroform. The chloroform phase is washed neutral with a saturated solution of sodium chloride and, after drying over sodium sulphate, the solvent is distilled oEf. 5-Amino-4-(3,4~
dimethoxyphenyl)-4-pentanol is obtained in -the form of an oil in a yield of 75.5%. An analysis test portion in the form of the hydrochloride melts at 175-176C.
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 carbonyl-diimidazole of 98~ strength in 100 ml of absolute tetrahydrofuran for 4 days at room temper-ature with the exclusion of moisture. After distilling off the solvent the residue is taken up in ethyl acetate, extracted by agitation twice with lN-hydrochloric acid and washed neutral with a saturated solution of sodium chloride. The oil so obtained is purified over a column of silica gel (350 gms) in the system chloroform/methanol 30:1. 5-l3,4-Dimethoxyphenyl)-5-propyl-2-oxazolidinone is obtained in the form of an oil in a yield of 81.7%.
Example 14 5-(3,4-Dimethoxyphenyl)-5-methyl-2-oxazolidinone.
.
In a manner analogous to that in Example 13 5-(3,4-dimethoxyphenyl)-5-methyl-2 oxazolidinone is obtained from 3,4-dimethoxyacetophenone in a total yield of 30% melting at 98-101C.
Example 15 5-(3,4-Dimethoxyphenyl?-3-methyl-2-oxazolidinone.
10 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are dissolved in 20 ml of absolute dimethyl-formamide and 11 mMol of sodium hydride are added. The mixture is then stirred for 40 minu~es at 40C. After cooling, 20 mMol of methyl iodide in 5 ml . , ' ' , ............ . . .
7~57 of dimethylformamide are added dropwise and, after the addition, the mixture is stirred for 6 hours at 50~C. After removing the dimethylformamide, the mixture is taken up in chloroform, washed first with a little water and then with a saturated soLution of sodium chloride, dried filtered and concentrated.
The reslclue is chromatographed over 60 (Jms of silica c3el with chloroform/me-thanol (96:4) as eluant. After recrystallisation 3 from ethanol, 5-(3,~-dimethoxyphenyl)-3-methyl-2-oxazolidinone melting at 132-133C. is obtained in a yield of 60~.
Example 16 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid benzyl ... . .. . . ~
ester.
6.25 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are dissolved in 30 ml of dioxan and 6.2S ml (12.50 mM) of a 2N-solution of sodium hydroxide are added. At +4C. 12.5 ml of benzoxycarbonyl chloride are added to the mixture, and the whole is stirred for 4 hours at this temperature.
After the addition of 50 ml of a 2N-solution of sodium hydroxide, extraction three times with 50 ml of ethyl acetate each time is carried out. The ethyl acetate phase is washed once with 50 ml of a 2N-solution of sodium hydroxide and twice with 50 ml of water each time, dried over Sikkon ~ , filtered and concentrated. After removing the benzoxycarbonyl chloride still present at 100C. under 1 Torr, the residue is recrysta]lised from ethyl acetate/petroleum ether and 5-(3,4-dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid benzyl ester melting at 124-126C. is obtained in a yield of 64~.
Example 17 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid ethyl ester.
To 5 mMol o~ 5-(3,4-dimethoxyphenyl)-oxazolidinone in 20 ml of toluene (absolu-te) are applied 10 mMol of triethylamine-7~57 at 0C with the exclusion of moisture. To the mixture are added 10 mMol of chloroformic acid ethyl ester, and the mixture is boiled under reflux for 4 hours and allowed to stand overnight.
The product that crystallises out, after being filtered off with suction, is again boiled with 7.6 ~Mol of triethylamine and 7.6 mMol of chloroformic acid ethyl ester. The product tha-t crystallises out is again filtered off with suction. The combined filtrates are evaporated. Chromatography of the residue over 80 gms of silica gel with cyclohexane-ethyl acetate 1:1 as eluant gives 5-(3,4-dimethoxyphenyl)-2-oxazolidinon-1-carboxylic acid ethyl ester melting at 181-185C. in a yield of 43~.
Example 18 In a manner analogous to that in Example 15 the oxazolidinones mentioned in the following Table are prepared from 5-(3,4-dimethoxyphenyl)-2-oxazolidinone:
R4 ~ ¦ Melting Recrystallisation Rl R2 R3 --R5 ~ield ~rom CH3 CH3 iso-proPYl H 47 66-67C. ethyl acetate/
. . petroleum ether CH3 CH3 -CH2-0 H Ç~ i5-760C. ethyl acetate~
. . petroleum ether CH3 CH3 ~CH2-CH2 . H 40 77-78C. ethyl acetate/
~ ~c~ ~
c~
Example 19 5-(3,4-Dimethoxyphenyl)-4-methyl-2-oxazolidinone 3Q 5.5 mMol of 2~amino-1-(3,4-dimethoxyphenyl)-propanol are dissolved in 50 ml of chloroform and stirred with 1.05 gms i7 (6.5 mMol) of carbonyl diimidazole for 2 hours with the exclusion of moisture. After allowing the mixture to stand overnight, it is extracted with 50 ml of distilled water, dried, filtered and concentrated. By chromatography of the residue over 50 gms of silica gel with chloroform/methanol (95:5) as eluant and re-crystallisation from ethyl acetate/petroleum ether, 5-(3,4-dimethoxyphenyl)-4-methyl-2-oxazolidinone melting at 98-99C.
is obtained in a yield of 24~.
The starting material 2-amino-1-(3,4-dirnetho~y)-pro-panol was prepared as follows:
To 100 mMol of 3,4-dimethoxypropiophenone in 160 ml of methylene chloride are added dropwise at room temperature 10 ml of sulphuryl chloride in 80 ml of methylene chloride. The mixture is then further stirred for 3.5 hours at room temper-ature. By removiny the solvent and recrystallisation of the residue from cyclohexane/petroleum ether 2'-chloro-3,4-dimethoxy-propiophenone melting at 56-57C. is obtained in a yield of 89~.
Each 43.86 mMol of 2'-chloro-3,4-climethoxypropiophenone dissolved in 230 ml of acetone is stirred for 7 days with 437 mg of potassium iodide and 87.72 mMol of dibenzylamine with the exclusion of moisture. The mixture is diluted with diethyl ether to 1 litre of solution, filtered and concentrated. The residue is absorbed onto silica gel and the silica gel is stirred first with chloroform and then wi~h ethanol and filtered off with ~ -suction each time. The chloroform phase is chromatographed over 500 yms of silica gel with chloroform as eluant and gives 2'-N,N-dibenzylamino-3,4-dimethoxypropiophenone in the form of an oil in a yield of 49%.
12.39 gms (31.8 mMol) of 2'-N,N dibenzylamino-3,4-dimethoxypropiophenone are dissolved in 75 ml of isopropanol and1.33 gms (35.05 mMol3 of sodium boranate are added. After beiny stirred for one hour at room temperature, the mixture is heated ~76~i~
for 2 hours under reflux. After cooling, the mixture is filtered with suction and the residue is extracted at the boil with ethyl acetate. After filtration,2'-(N,N-dibenzylamino)-1-(3,4-di-methoxyphenyl)-propanol melting at 151-152C. crystallises out of the flltrate in a yield of 59%.
13.2 mMol of the dibenzyl-compound in 50 m:L of ethanol (analytically pure) are hydrogenated with 2.64 gms of palladium/
carbon (10%) for 3 hours at 90C. under an atmosphere of hydro-gen of 10 atmospheres yauye. After filteriny with suction, concentration and recrystallisation from ethanol are carried out.
2-Amino-1-(3,4-dimethoxyphenyl)-propanol meltiny at 131-132C.
is obtained in a yield of 64~.
~xample 20 5-(3,4-Dimethoxyphenyl)-2-_xo-oxazolidirl- _c _ ~ xylic acid ethyl ester.
6 mMol of 2-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-propionic acid ethyl ester are stirred wi-th 12 mMol of carbonyl-diimidazole in 60 ml of chloroform for 4 hours at room temper-ature with the exclusion of moisture. Then the mixture is extracted once with 50 ml of water, dried over silica gel over-night, filtered and concentrated.
The residue is chromatographed over 130 yms of silica gel with chloroform/methanol (90:10) as eluant. Recrystallis-ation from ethyl acetate/ethanol gives 5-(3,4-dimethoxyphenyl)- -2-oxo-oxazolidin-4-carboxylic acid ethyl ester meltiny at 188-189C. in a yield of 34%.
The ~tartiny material 2-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-propionic acid ethyl ester was prepared as follows:
44.37 mMol of 3,4-dimethoxyglycidic acid ethyl ester (prepared according to W. Schne:ider et al., Arch. Pharm. 299, 817 (1966)) are boiled under reFlux wlth 97.61 mMol of dibenzyl-amine in 100 ml of ethanol for 4.5 hours with the exclusion of 7~57 moisture. After being allowed to stand for 3 days at room temperature the mixture is concentrated, and the residue is chromatographed over 400 gms of silica gel with chloroform/
methanol (98:2) as eluant. Chromatoyraphy of the appropriate collected fractions ~ives 2-N,N-dibenzyl-4-(3,4-dimethoxy-phenyl)-3-hydroxypropionic acid ethyl ester in the form of an oil in a yield of 89%.
22.2 mMol of 2-N,N-dibnezylamino-4-(3,4-dimethoxy-phenyl)-3-hydroxypropionic acid ethyl ester are hydrogenated with 4.44 gms of palladium~carbon of 10% strength in 100 ml of undenatured ethanol for 3 hours at 90C. under hydrogen at 10 atmospheres gauge. After filtering off the catlayst with suction, the mixture is concentrated. Recrystallisation from undenatured ethanol gives 2-amino-4-(3,4-dimethoxyphenyl)-3-hydroxypropionic acid ethyl ester melting at 211-212C. (with decomposition in a yield of 80%.
is used herein to include alkoxycarbonyl, aralkoxycarbonyl and o-ther ester groups. The term also includes carbamoyl groups, for ~ example, a C6H5-NH-CO- yroup.
~ 30 The compounds of the invention of the general formula ~ (I) are new compounds and have valuable pharmacological properties They exhibit central depressive, antidopaminergic, antinociceptivè
~7~;7 and anticonvulsive actions, and thus have a certain similarity to neurolep-tics such, for example, as chlorpromazine and haloperidol. However, the compounds of the invention differ from the classlcal neuroleptics in having a different kind of influence on receptor-dependent, monoaminergic feedback mechanisms (decrease or extrapyramidal side effects).
Furthermore, the compounds of the invnetion have strong i phosphodiesterase-inhibiting properties and thus influence the metabolism of cyclic nucleotides. As controlled cell growth is decisively regulated by cyclic nucleotides (Pastan et al., 1975) and cyclic nucleotides are par-tially decreased in uncontrolledly proliferating tissue (Ryan and Heidrick, 1974, Voorhees et al., 1974), the compounds are suitable for the treatment of diseases that are hyperproliferative and proceed with uncontrolled cell growth such as psoriasis, polycythaemia vera, neuroblastoma, immunological diseases such as asthma, and bronchial and throm-. boembolic diseases, in which there is a disturbance of the metabolism of cyclic nucleotides (Tateson, J.E.; Trist, D.G., Inhibition of adenosine-3',5'-cyclic monophosphate phosphodie-sterase by potential antiallergic compounds; Life Sci. 18, 153-162, 1976; De Gaetano, G., Pharmacology of platelet aggregation, Pharmacol Res. Commun. 7, 301-309, 1975).
The compounds of the invention may be made up in the form of pharmaceutical preparations for the treatment of the aforesaid diseases. Accordingly, the invention also provides a pharmaceutical preparation which comprises a compound of the general formula (I) in admixture or conjunction with a pharma-ceutically suitable carrier. As carriers there may be used substances known to be sui-table for enteral and parenteral application such, for example, as water, alcohol, gelatine, gum arabic, lactose, starches, magnesium stearate, talcum, vegetable oils and polyalkylene glycol. The preparations may be in solid -- S
form ~s tablets, capsules, dragees, suppositories or in liquid form as solutions, suspensions or emulsions.
The invention also provides a process for the pro-duction of compounds of the general formula (I) when a 2-amino-1-(3,4-disubstituted phenyl) ethanol of the general formula (II) ~ 4 5 in which Rl to R5 have the meanings given above, is reacted with a carboni.c acid derivative or thiocarbonic acid derivative of the general formula (III) ~5~ O=C \ ~III) in which Z and Y each represents chlorine or bromine or an imidazole radical, or represents the group OR (in which R represents alkyl, aryl, aralkyl or together represent alkylene), usually in an inert solvent in the presence of a basic catalyst, and if --desired an aralkyl group in an ether group present is subsequent-: ly split off by reduction with Raney nickel or with a noble metal catalyst or a free hydroxyl group OR2 is alkylated or converted into another radical OR2 or the ring-oxygen and/or oxygen of the 2-carbonyl group is exchanged for sulphur or, when ; 30 R3 represents hydrogen, N-acylation or N-alkylation is carried out.
The ring~closing reaction for compounds of the formula (II) may be carried out with all carbonic acid derivatives of thiocarbonic acid derivatives of the general formula (III).
The R's may be identical or different. R may represent a lower alkyl or aralkyl radical such, for example, as methyl, ethyl and benzyl. The two R's together may also represent an alkylene residue such, for example, as propylene or iso-butylene.
The solvents used are preferably inert towards the reactants. There may be mentioned, for example, ethers such, for example, as diethyl e-ther, glycol dimethyl ether or diethy-lene glycol dimethyl ether, aliphatic and aromatic hydrocarbons such, for example, as hexane, benzene, toluene, xylene and mesitylene, but also alcohols such, for example, as methanol, ethanol, propanol, butanol and also dimethyl sulphoxide, glycol monomethyl ether and diethylene glycol monomethyl ether.
The reaction is preferably carried out at a raised temperature, in the range from above room temperature to the boiling point of the reaction mixture, preferably in the range of from 60 to 200C, and especially lO0 to 160~C.
The ring-closing 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, for example, as sodium methylate and potassium carbonate.
However, there are also suitable organic bases such, for example, as pyridine, triethylamine, alkali metal and alkaline earth metal hydroxides such, for example, as sodium hydroxide, - especially when Z or Y represents halogen. When Z and Y are halogen such, for example, chlorine, the addition of a basic catalyst may be dispensed with. When Z and Y are imidazole radicals it is preferable to work at room temperature, and dimethylformamide, tetrahydrofuran and methylene chloride are suitable as solvents. The subsequent optional reductive split-ting off of an aralkyl group such, for example, as the benzvl ~7~57 .
group, may be carried out with any of the usual rnetal catalysts such, for example, as platinum, palladium, rhodium or nickel, either in the pure form of on carrier materials such, for example, as carbon, calcium carbonate and barium sulphate. As solvents there may be used those that are inert towards the reducing agents under the reaction conclitions. There may be mentioned, for example, organic acids such, for example, as j acetic acid and propionic acid, lower alcohols such, for example, ` as methanol and ehtanol, esters such, for example, as ethyl acetate, aliphatic, cycloaliphatic and aromatic hydrocarbons such, for example, as hexane, cyclohexane and benzene.
The optional subsequent O-alkylation (R2 represents ; hydrogen) may also be carried out by methods in themselves known. The alkylation is preferably carried out with the appropriate R2-halide, -mesylate or -tosylate. As halides there are suitable chlorides, bromides and iodides. For alkylation the hydroxy-compound of the formula (II) is dissolved, for example, in a polar solvent and is heated in the presence of a base with the alkylating agent at temperatures between 30 and 150C. As bases there are suitable, ~or example, sodium hydride, potassium carbonate, alkali metal alcoholates, such as sodium ethylate, potassium butylate and potassium tertiary-butylate.
As solvents there come into consideration dimethylformamide, ; dimethylacetamide, hexamethyl-phosphoric acid triamide, acetoni-trile, dimethyl sulphoxide, tetrahydrofuran, dioxan, ketones - such, for examples, as acetone and methyl isobutyl ketone, and also alcohols such, for example/ as ethanol, butanol and tertiary-butanol.
~he exchange oE the carbonyl-oxygen or the ring-oxygen in compounds of the general formula (I) for sulphur may be -carried out by methods in themselves known such, for example, as according to Scheeren et al. Synthesis 1973, 149.
76~;7 For this purpose there is suitable, for examplc, a polysulphide such, for example, as phosphorus pentasulphide in a solvent or solvent mixture in the presence of a base. The reaction may also be carried out in a suspension. Suitable solvents or suspension media are, for example, acetonitrile, tetrahydrofuran, diethyl ether, glycol dimethyl ether and pyridine. As bases there are suitable, for example, sodium hydrogen carbonate and potassium carbonate. The reaction is complete after about 3 to 24 hours at 30 to 120C.
The subse~uent optional N-acylation or N-alkylation (R3 = H) may also be carried out by methods in themselves known.
hus, the amino-compound is dissolved in a polar solvent and hea-ted at 40 to 150C in the presence of a salt former with, for example, an alkyl halide or aryl halide, or acyl halide or acyl ; anhydride. As polar solvents there may be used, for example, dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxan, and also alcohols such, for example, as ethanol and butanol.
Suitable salt formers are, for example, sodium hydride, potassium carbonate, alkali metal alcoholates such, for example, as sodium ethylate and potassium tertiary-butylate. The reaction with an aryl halide, for example, iodobenzene, may also be carried out without a solvent, preferably in the presence of copper powder.
The following Examples illustrate the invention:-~ Example 1 ; 5-(3-Benzyloxy~4-methoxy-phenyl~-2-oxazolidinone.
318.4 mMol of 3-benzyloxy-4-methoxybenzaldehyde are dissolved in 1200 ml of ether. A solution of 558 mMol of potas-~' sium cyanide in 300 ml of water is added at room temperature.
After cooling to 0C., 237 mMol of 2N-sulphuric acid are added dropwise to the well stirred mixture, and the reaction mixture ~ is stirred for 12 hours at room temperature. After separating the aqueous phase, the ether is washed several times with 50 ml ~7~57 of semi-saturated sodium chloride solution and dried well over calcium chloride. After ~iltering off the drying agent and subsequent washing twice with 100 ml of ether the combined organic phases, which contain crude 2-(3-benzyloxy-4-methoxy-phenyl)-2-hydroxy-acetonitrile, are used in the next stage.
In an analogous manner 2-(3,4-dimethoxyphenyl)-2-hydroxyacetonitri]e was prepared from 3,4-dimethoxybenzaldehyde ~ and 2-(3-cyclopentyloxy-4-methoxyphenyl)-2-hydroxyacetonitrile ; was prepared from 3-cyclopentyloxy-4-methoxybenzaldehyde.
1.3 Mol of lithium aluminium hydride are suspended in portions in 1 litre of absolute ether and, while cooling and stirring well, -the ethereal solution of 2-(3-benzyloxy-4-methoxy-phenyl)-2-hydroxyacetonitrile is introduced dropwise in a manner such that only slight refluxing occurs. After stirring at room temperature overnight, there is added dropwise to the mixture, while cooling, firstly 400 ml of ethyl acetate and later 600 ml J of water. The precipitate that forms is then filtered off with suction and the residue is washed -twice with 200 ml of ethanol:
water (1:1) each time. The collecting filtrates are strongly ; 20 concentrated and taken up in 300 ml of semi-concentrated hydro-chloric acid. This solution is extracted twice with 200 ml of a ethyl acetate each time. The ethyl acetate phase is discarded, and the hydrochloric acid solution is cooled and rendered alkaline with potassium hydroxide solution (any precipitatinq aluminium salt being filtered off with suction) and extraction - by agitation three times with 400 ml of ether each time is carried out. The combined p~ganic phases are dried, concentxated after filtration, and xecrystallised from ethyl acetate.
The 2~amino-1 (3-benzyloxy 4-methoxyphenyl)-ethanol, obtained in a yield of 20~, melts at 101 to 102C.
In an analogous manner 2-amino-1-(3,4-dimethoxyphenyl)-ethanol (M.p. 80-81C., benzene) is obtained in a yield of 49%
~7657 from 2-~3,4-dimethoxyphenyl)-2-hydroxy-acetonitrile, and 2-amino-1-(3-cyclopentyloxy 4-methoxyphenyl)-methanol (an oil) is obtained in a yield of 70~ from 2-(3-cyclopentyloxy-4 methoxy-phenyl)-2-hydroxyacetonitrile.
2-Amino-1-(3-benzyloxy-4-methoxyphenyl)-ethanol can be prepared as follows:
50 m Mol of 3-benzyloxy-~-methoxybenzaldehyde and 55 mMol of trimethylalyl cyanide are heated at 90C. with 0.567 mMol of anhydrous zinc iodide for 4 hours under nitrogen and with the exclusion of moisture. The mixture is then taken up in 15 ml of absolute tetrahydrofuran, and this solution is added drop-wise to a suspension of 60 mMol of lithium aluminium hydride in 35 ml of tetrahydrofuran. After heating the mixture for one hour at 60C, working up is carried out as described above.
After recrystallisation from ethyl acetate, 2-amino-1(3-benzy-loxy-~-methoxyphenyl)~ethanol melting at 100-102C, is isolated at a yield of 30%.
36 mMol of 2-amino-1-(3-benzyloxy-4-methoxyphenyl)-ethanol are suspended with 50 mMol of sodium methylate and 91.4 mMol of diethyl carbonate in 120 ml of absolute toluene, and the whole is heated for 2 hours at a bath temperature of llO~C. with the exclusion of moisture, methanol and ethanol being distilled off. The toluene is subsequently distilled off finally under an oil pump vacuum. The residue is taken up in 150 ml of chloroform and distrlbution against 100 ml of water is carried out. The aqueous 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 recrystallised from ethyl acetate. There is obtained 5~(3-benzyloxy-4-methoxyphenyl)-2-oxazolidinone melting at 132-133~C.
(91~ yield).
7~;~7 Example 2 In a manner analogous to that in Example 1 there are prepared from the corresponding amino-alcohols the oxazolidinones given in the following Table (R5 = hydrogen).
RlR2 R3 LYleld (.~ Recrystallised Erom -CH3-CH3 -H -H63 114-117 methanol -CH3-CH3 -C~3 -H41 132-134 ethanol ~-CH3 _~ --H45.8 141-143 ethyl acetate/ether -CH3~ -E -El52 111-]12.5 ethyl acetate/ether Example 3 88.3 ~Mol 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 overnight at room temperature. After distilling off the tetrahydrofuran the residue is taken up in 300 ml of ethy1 acetate, the mixture is extracted by agitation twice with lN-hydrochloric acid and is then washed neutral with saturated sodium chloride solution, dried, filtered and concentrated.
By recrystallisation from ethyl acetate 5-(3-benzyl-oxy-4-methoxyphenyl)-2~oxazolidinone melting at 83-91C is obtained in a yield of 66~. ) Example 4 5-(3-Hydroxy-4 methoxyphenyl)-2-oxazolidinone.
40.6 mMol of 5-(3-benzyloxy-4-methoxyphenyl)-2-oxazolidinone are dissolved in 700 ml of ethanol and hydrogen-ated in the presence of 8 gms of Raney nickel (B 113, Fa. Degussa) - Frankfurt) for 2.2 hours at room temperature under a pressure i7 hydrogen of 100 atmospheres. After filtering off the catalyst, evaporation is carried out and the residue is recrystallised from methanol. 6.74 Gms of 5-(3-hydroxy-4-methoxyphenyl)~2-oxazolidinone melting at 157 - 160C. (methanol) are obtained.
Example 5 5-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxazolidinone.
7.2 mMol of 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidi-none are dissolved in 10 ml of absolute dimethylformamide and the solution is stirred with 7.9 mMol of sodium hydride for 1 hour at 50C. After cooling the mixture, 8.6 mMol of cyclo-pentyl bromide are added, and then the whole is stirred for 2 hours at 80~C. When the reaction has terminated the dimethyl-formamide is removed in vacuo at 40C. The residue is taken up in 100 ml of a 2N-solu-tlon of sodium hydroxide and extracted three times with 150 ml chloroform. The combined chloroform phases are washed with water, dried, filtered and concentrated.
The residue is recrystallised from ethyl acetate/ether. 5-(3-Cyclopentyloxy-4 methoxy-phenyl)-2-oxazolidinone melting at 111-112C. is obtained in a yield of 70~.
Example 6 By the method given in Example 5 the compounds (R3=
R~=R5-ll) given in the following Table are prepared from 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone and the halide or tosylate of R2Zl The symbols have the following meanings:
DMF = Dimethylformamide.
Petr. = Petroleum ether.
Chlf. = Chloroform.
Tos. = Tosylate.
NaH = Sodium hydride.
NaOEt = Sodium ethylate.
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E_ample 7 5-(3,4-Dimethoxyphenyl)-2-oxazolidinthione and 5-(3,4-dimethoxyphenyl-2-thiazolid none.
45 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 65 ml oE absolute dimethyl sulphoxide and at 10C.
there are added in succession 1.3 gms of pulverised potassium hydroxide and 1.4 ml oE carbon disulphide. The reaction mixture is then stirred for 2.5 hours with the exclusion of moisture.
After removing the dimethyl sulphoxide ln vacuo, 100 ml of water are added to the residue ancl extraction three times with 100 ml of chloroform is carried out. The combined chloroform phases are dried over anhydrous magnesium sulphate, filtered and con-centrated. The residue is chromatographed over 125 gms of silica gel with chloroform : methanol (96:4). By recrystallisation of the appropriate fractions from methanol there are obtained in a yield of 9% 5-(3,4-dimethoxyphenyl)-2-oxazolidinthione melting at 177-178C. and also 6% of 5-(3,4-dimethoxyphenyl)-2~thiazolid-inone melting at 167-169C.
Example 8 5-(3,4-Dimethoxyphenyl)-2-thiazolidinone 10 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 6 ml of pyridine and, while cooling at 0C., 11 mMol of carbon disulphide in 10 mMol of -triethylamine are added drop-wise, the temperature rising strongly. The mixture is stirred for one hour at 0C. and -then at the same temperature 10 mMol of benzyl chloride are added dropwise. After stirring overnight at 0C., the mixture is taken up in 40 ml of 3N-sulphuric acid and extracted 3 -times with 50 ml of chloroform each time. The combined chloroform phases are washed in succession with sodium hydro~en carbonate and water, dried, fil-tered and concentrated.
The residue that crystallises spontaneously is recrystallised ~7~7 from benzene and ethyl acetate. [2-(3,4-Dirnethoxyphenyl)-2-hydroxy-ethyl]-dithiocarbamic acid benzyl ester melting at 13~-132~C is obtained in a quantitative yield.
i To 0.67 mMol of ~2-(3,4-dimethoxyphenyl)-2-hydroxy-ethyl]-dithiocarbamic acid benzyl ester in 50 ml of absolute ether are added dropwise a-t +5C. 2.14 mMol of phosphorus tri-bromide. After stirring the mixture for 20 hours at 5C., 10 ml of methanol/water are added dropwise, while cooling, in a manner such that the temperature does not exceed 20C. The reaction mixture is then cautiously stirred into 20 ml of sodium hydrogen carbonate solution. Extraction three times with 50 ml of chloro-form each time is carried out and the combined organic pha~ses 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)-1,3-thiazol-2-ine is obtained in the form of an oil in a yield of 80%.
This oil is dissolved in 20 ml of e-thanol, 20 ml of 6N-hydrochloric acid are added and the whole is boiled for 4 hours under reflux. Afker concentrating, the residue is taken up in 25 ml of ethanol, 19 ml of a lN-solution of sodium hydroxide are added and the mixture is stirred for 3 hours at room temper-ature. The reaction mixture is then neutralised with 2N-hydro-chloric acid, the ethanol is removed and extraction by agitation three times with 100 ml of chloroform each time is carried out.
The chloroform phase is washed with water, dried and concentrated.
The residue is chromatographed over 50 gms of silica gel with the eluant chloroform/mekhanol (96:4). The appropriate fractions are recrystallised from methanol, and 50% of 5-(3,4-dime-thoxy-phenyl)-2--thiazolidinone melting at 167-169C is o~tained.
Example 9 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid.
anilide.
~97~
0.5 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone is heated at 160C in 3 ml of phenyl isocyanate for 3 hours.
After cooling, the reaction mixture is concentrated in vacuo and chromatographed over 50 gms of silica gel with cyclohexane/ethyl acetate (1:1). By recrystallisation of the appropriate fractions from ethyl acetate 5-(3,4-dime-thoxyphenyl)-2- oxazolidinon-3-carboxylic acid anilide meltinc3 at 175-182C. is obtained in a yield of 60%.
~xample 10 5-(3,4-Dimethoxyphenyl)-2-oxazolidinone.
.
100 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 100 ml of chloroform. After cooling to 0C., a solution of 100 mMol of phosgene in 100 ml of chloroform is slowly added dropwise in a manner such that -the internal temper-ature does not exceed 5C. ~fter stirring for one hour at 5-10C., 200 mMol of pyridine in 100 ml of chloroform are added dropwise and stirred for 3 hours. After washing the organic phase with a semi-saturated solution of sodium chloride, evaporation-and recrystallisation from methanol are carried out. 5-(3,4-Dimethoxy-phenyl)-2-oxazolidinone melting at 114-117C. is obtained in a yield of 75%.
Example 11 5-(3,4-Dimethoxyphenyl)-2-oxazolidinone.
5 mMol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol are dissolved in 5 ml of a 2N-solution of sodium hydroxide. To the solution, cooled to 0C., are added dropwise 10 mMol of chloro formic acid ethyl ester. When the addition is complete, the - mixture is s-tirred for 30 minutes at 0C. The crystals formed are filtered off with suction~ washed with water and dried.
2-(3,4-Dimethoxyphenyl)-2-hydroxyethyl-carbamic acid ethyl ester melting at 90-92C. is obtained in a yield of 86%.
3 mMol of 2-(3,4-Dimethoxyphenyl)-2-hydroxyethyl-7~S7 carbamic acid ethyl ester are suspended with 4 ~ol of sodium ethylate in 12 ml of toluene, and the whole is heated for 2 hours at a bath temperature of 110C. with -the exclusion of moisture.
Methanol and ethanol distil off. The toluene is then removed _n vacuo, the resiclue is taken up in S0 ml of chloroform, and distribution is carried out ayains-t 10 ml of water. After dryiny, filteriny and concentratiny the oryanic phase recrystallisation from methanol is carried out. 5-(3,4-Dimethoxyphenyl)-2-oxazolidinone meltiny at 114-117C. is obtained in a yield of ~0%-Example 12 3-Acetyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone.
! To 8.9 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are added 10 ml of acetic anhydride and 5 ml of pyridine, and the whole is heated for 5 hours at 100C. After concentratiny, recrystallisation from ethyl acetate is carried out. 3-Ace-tyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone meltiny at 175-182C. is obtained in a yield of 73%.
Example 13 5-(3,4-Dimethoxyphenyl)-S-propyl-2-oxazolidinone.
56 mMol of 3,4-dimethoxybutyrophenone and 6.14 mMol of trimekhylsilyl cyanide with the addition of 200 my (627 mMol) of anhydrous zinc iodide are heated at 90C. or 4 hours under nitroyen and with the exclusion of moisture. The reaction mix-ture is taken up in 15 ml of absolute tetrahydrofuran and added dropwise to a suspension of 60 mMol of lithium aluminium hydride in 35 ml of absolute tetrahydrofuran, the mixture is heated for one hour at 60C under nitroyen and the excess of lithium alumin-ium hydride is decomposed by the dropwise addition of ethyl acetate and water. The precipitate is filtered off with suction over silica yel, washed well with ethanol and the mother liquor is concentrated. The residue is taken up in ethyl acetate, ~ca7~S7 acidified with 4N-hydrochloric acid and extracted ~y ayitation.
The aqueous phase is adjusted to a pH-value of 9 with sodium carbonate~ saturated with sodium chloride and extracted with chloroform. The chloroform phase is washed neutral with a saturated solution of sodium chloride and, after drying over sodium sulphate, the solvent is distilled oEf. 5-Amino-4-(3,4~
dimethoxyphenyl)-4-pentanol is obtained in -the form of an oil in a yield of 75.5%. An analysis test portion in the form of the hydrochloride melts at 175-176C.
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 carbonyl-diimidazole of 98~ strength in 100 ml of absolute tetrahydrofuran for 4 days at room temper-ature with the exclusion of moisture. After distilling off the solvent the residue is taken up in ethyl acetate, extracted by agitation twice with lN-hydrochloric acid and washed neutral with a saturated solution of sodium chloride. The oil so obtained is purified over a column of silica gel (350 gms) in the system chloroform/methanol 30:1. 5-l3,4-Dimethoxyphenyl)-5-propyl-2-oxazolidinone is obtained in the form of an oil in a yield of 81.7%.
Example 14 5-(3,4-Dimethoxyphenyl)-5-methyl-2-oxazolidinone.
.
In a manner analogous to that in Example 13 5-(3,4-dimethoxyphenyl)-5-methyl-2 oxazolidinone is obtained from 3,4-dimethoxyacetophenone in a total yield of 30% melting at 98-101C.
Example 15 5-(3,4-Dimethoxyphenyl?-3-methyl-2-oxazolidinone.
10 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are dissolved in 20 ml of absolute dimethyl-formamide and 11 mMol of sodium hydride are added. The mixture is then stirred for 40 minu~es at 40C. After cooling, 20 mMol of methyl iodide in 5 ml . , ' ' , ............ . . .
7~57 of dimethylformamide are added dropwise and, after the addition, the mixture is stirred for 6 hours at 50~C. After removing the dimethylformamide, the mixture is taken up in chloroform, washed first with a little water and then with a saturated soLution of sodium chloride, dried filtered and concentrated.
The reslclue is chromatographed over 60 (Jms of silica c3el with chloroform/me-thanol (96:4) as eluant. After recrystallisation 3 from ethanol, 5-(3,~-dimethoxyphenyl)-3-methyl-2-oxazolidinone melting at 132-133C. is obtained in a yield of 60~.
Example 16 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid benzyl ... . .. . . ~
ester.
6.25 mMol of 5-(3,4-dimethoxyphenyl)-2-oxazolidinone are dissolved in 30 ml of dioxan and 6.2S ml (12.50 mM) of a 2N-solution of sodium hydroxide are added. At +4C. 12.5 ml of benzoxycarbonyl chloride are added to the mixture, and the whole is stirred for 4 hours at this temperature.
After the addition of 50 ml of a 2N-solution of sodium hydroxide, extraction three times with 50 ml of ethyl acetate each time is carried out. The ethyl acetate phase is washed once with 50 ml of a 2N-solution of sodium hydroxide and twice with 50 ml of water each time, dried over Sikkon ~ , filtered and concentrated. After removing the benzoxycarbonyl chloride still present at 100C. under 1 Torr, the residue is recrysta]lised from ethyl acetate/petroleum ether and 5-(3,4-dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid benzyl ester melting at 124-126C. is obtained in a yield of 64~.
Example 17 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid ethyl ester.
To 5 mMol o~ 5-(3,4-dimethoxyphenyl)-oxazolidinone in 20 ml of toluene (absolu-te) are applied 10 mMol of triethylamine-7~57 at 0C with the exclusion of moisture. To the mixture are added 10 mMol of chloroformic acid ethyl ester, and the mixture is boiled under reflux for 4 hours and allowed to stand overnight.
The product that crystallises out, after being filtered off with suction, is again boiled with 7.6 ~Mol of triethylamine and 7.6 mMol of chloroformic acid ethyl ester. The product tha-t crystallises out is again filtered off with suction. The combined filtrates are evaporated. Chromatography of the residue over 80 gms of silica gel with cyclohexane-ethyl acetate 1:1 as eluant gives 5-(3,4-dimethoxyphenyl)-2-oxazolidinon-1-carboxylic acid ethyl ester melting at 181-185C. in a yield of 43~.
Example 18 In a manner analogous to that in Example 15 the oxazolidinones mentioned in the following Table are prepared from 5-(3,4-dimethoxyphenyl)-2-oxazolidinone:
R4 ~ ¦ Melting Recrystallisation Rl R2 R3 --R5 ~ield ~rom CH3 CH3 iso-proPYl H 47 66-67C. ethyl acetate/
. . petroleum ether CH3 CH3 -CH2-0 H Ç~ i5-760C. ethyl acetate~
. . petroleum ether CH3 CH3 ~CH2-CH2 . H 40 77-78C. ethyl acetate/
~ ~c~ ~
c~
Example 19 5-(3,4-Dimethoxyphenyl)-4-methyl-2-oxazolidinone 3Q 5.5 mMol of 2~amino-1-(3,4-dimethoxyphenyl)-propanol are dissolved in 50 ml of chloroform and stirred with 1.05 gms i7 (6.5 mMol) of carbonyl diimidazole for 2 hours with the exclusion of moisture. After allowing the mixture to stand overnight, it is extracted with 50 ml of distilled water, dried, filtered and concentrated. By chromatography of the residue over 50 gms of silica gel with chloroform/methanol (95:5) as eluant and re-crystallisation from ethyl acetate/petroleum ether, 5-(3,4-dimethoxyphenyl)-4-methyl-2-oxazolidinone melting at 98-99C.
is obtained in a yield of 24~.
The starting material 2-amino-1-(3,4-dirnetho~y)-pro-panol was prepared as follows:
To 100 mMol of 3,4-dimethoxypropiophenone in 160 ml of methylene chloride are added dropwise at room temperature 10 ml of sulphuryl chloride in 80 ml of methylene chloride. The mixture is then further stirred for 3.5 hours at room temper-ature. By removiny the solvent and recrystallisation of the residue from cyclohexane/petroleum ether 2'-chloro-3,4-dimethoxy-propiophenone melting at 56-57C. is obtained in a yield of 89~.
Each 43.86 mMol of 2'-chloro-3,4-climethoxypropiophenone dissolved in 230 ml of acetone is stirred for 7 days with 437 mg of potassium iodide and 87.72 mMol of dibenzylamine with the exclusion of moisture. The mixture is diluted with diethyl ether to 1 litre of solution, filtered and concentrated. The residue is absorbed onto silica gel and the silica gel is stirred first with chloroform and then wi~h ethanol and filtered off with ~ -suction each time. The chloroform phase is chromatographed over 500 yms of silica gel with chloroform as eluant and gives 2'-N,N-dibenzylamino-3,4-dimethoxypropiophenone in the form of an oil in a yield of 49%.
12.39 gms (31.8 mMol) of 2'-N,N dibenzylamino-3,4-dimethoxypropiophenone are dissolved in 75 ml of isopropanol and1.33 gms (35.05 mMol3 of sodium boranate are added. After beiny stirred for one hour at room temperature, the mixture is heated ~76~i~
for 2 hours under reflux. After cooling, the mixture is filtered with suction and the residue is extracted at the boil with ethyl acetate. After filtration,2'-(N,N-dibenzylamino)-1-(3,4-di-methoxyphenyl)-propanol melting at 151-152C. crystallises out of the flltrate in a yield of 59%.
13.2 mMol of the dibenzyl-compound in 50 m:L of ethanol (analytically pure) are hydrogenated with 2.64 gms of palladium/
carbon (10%) for 3 hours at 90C. under an atmosphere of hydro-gen of 10 atmospheres yauye. After filteriny with suction, concentration and recrystallisation from ethanol are carried out.
2-Amino-1-(3,4-dimethoxyphenyl)-propanol meltiny at 131-132C.
is obtained in a yield of 64~.
~xample 20 5-(3,4-Dimethoxyphenyl)-2-_xo-oxazolidirl- _c _ ~ xylic acid ethyl ester.
6 mMol of 2-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-propionic acid ethyl ester are stirred wi-th 12 mMol of carbonyl-diimidazole in 60 ml of chloroform for 4 hours at room temper-ature with the exclusion of moisture. Then the mixture is extracted once with 50 ml of water, dried over silica gel over-night, filtered and concentrated.
The residue is chromatographed over 130 yms of silica gel with chloroform/methanol (90:10) as eluant. Recrystallis-ation from ethyl acetate/ethanol gives 5-(3,4-dimethoxyphenyl)- -2-oxo-oxazolidin-4-carboxylic acid ethyl ester meltiny at 188-189C. in a yield of 34%.
The ~tartiny material 2-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-propionic acid ethyl ester was prepared as follows:
44.37 mMol of 3,4-dimethoxyglycidic acid ethyl ester (prepared according to W. Schne:ider et al., Arch. Pharm. 299, 817 (1966)) are boiled under reFlux wlth 97.61 mMol of dibenzyl-amine in 100 ml of ethanol for 4.5 hours with the exclusion of 7~57 moisture. After being allowed to stand for 3 days at room temperature the mixture is concentrated, and the residue is chromatographed over 400 gms of silica gel with chloroform/
methanol (98:2) as eluant. Chromatoyraphy of the appropriate collected fractions ~ives 2-N,N-dibenzyl-4-(3,4-dimethoxy-phenyl)-3-hydroxypropionic acid ethyl ester in the form of an oil in a yield of 89%.
22.2 mMol of 2-N,N-dibnezylamino-4-(3,4-dimethoxy-phenyl)-3-hydroxypropionic acid ethyl ester are hydrogenated with 4.44 gms of palladium~carbon of 10% strength in 100 ml of undenatured ethanol for 3 hours at 90C. under hydrogen at 10 atmospheres gauge. After filtering off the catlayst with suction, the mixture is concentrated. Recrystallisation from undenatured ethanol gives 2-amino-4-(3,4-dimethoxyphenyl)-3-hydroxypropionic acid ethyl ester melting at 211-212C. (with decomposition in a yield of 80%.
Claims (68)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a 5-(substituted phenyl)-oxazolidinone or a sulphur analogue thereof of the general formula (I) (I) in which R1 represents a lower alkyl group with up to 6 carbon atoms, or a cycloalkyl or cycloalkylalkyl radical with up to 7 carbon atoms, R2 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, a cycloalkyl or cycloalkylalkyl group with up to 7 carbon atoms, the phenyl group, an aralkyl group with 7 or 8 carbon atoms, an alkenyl or alkynyl group with 2 to 6 carbon atoms or the tetrahydrofuranyl radical, R3 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, an aryl or aralkyl with 6 to 10 carbon atoms, which may be ring substituted by lower alkoxy or an acyl group with up to 18 carbon atoms, R4 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, R5 represents hydrogen or a lower alkyl or lower alkoxycarbonyl radical with up to 6 carbon atoms, and each X
represents oxygen or sulphur atoms, the two X moieties being the same or different, which comprises reacting a 2-amino-1-(3,4-disubstituted phenyl)-ethanol of the general formula (II) in which R1 to R5 have the meanings given above, with a carbonic or thiocarbonic acid derivative of the general formula (III) (III) in which Z and Y each represents chlorine or bromine or an imidazole radical or represents the group OR, in which R represents an alkyl, aryl or aralkyl radical or the two R's together represent an alkylene radical, and when required an aralkyl group in an ether group is split off by reduction with Raney nickel or a free hydroxyl group isalkylated or converted into another radical OR2 or the ring-oxygen or oxygen of the 2-carbonyl group is exchanged for sulphur by phosphorus pentasulphide or, when R3 represents hydrogen, it is N-acylated or N-alkylated.
represents oxygen or sulphur atoms, the two X moieties being the same or different, which comprises reacting a 2-amino-1-(3,4-disubstituted phenyl)-ethanol of the general formula (II) in which R1 to R5 have the meanings given above, with a carbonic or thiocarbonic acid derivative of the general formula (III) (III) in which Z and Y each represents chlorine or bromine or an imidazole radical or represents the group OR, in which R represents an alkyl, aryl or aralkyl radical or the two R's together represent an alkylene radical, and when required an aralkyl group in an ether group is split off by reduction with Raney nickel or a free hydroxyl group isalkylated or converted into another radical OR2 or the ring-oxygen or oxygen of the 2-carbonyl group is exchanged for sulphur by phosphorus pentasulphide or, when R3 represents hydrogen, it is N-acylated or N-alkylated.
2. A process as claimed in claim 1 in which the reaction is effected in an inert solvent in the presence of a basic catalyst.
3. A process as claimed in claim 2 in which the reaction is effected at a temperature of 60 to 200°C in a solvent selected from ethers, hydrocarbons alcohols, dimethyl sulphoxide, glycol monomethyl ether and diethylene glycol amino methyl ether in the presence of a basic catalyst, selected from alkali metal and alkylene earth metal carbon atoms, alcoholide or hydroxides or oxzamine base.
4. A 5-(substituted phenyl)-oxazolidinone or sulphur analogue thereof of the general formula (I) (I) in which R1 represents a lower alkyl group with up to 6 carbon atoms, or a cycloalkyl or cycloalkylalkyl radical with up to 7 carbon atoms, R2 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, a cycloalkyl or cycloalkylalkyl group with up to 7 carbon atoms, the phenyl group, an aralkyl group with 7 or 8 carbon atoms, an alkenyl or alkynyl group with 2 to 6 carbon atoms or the tetrahydrofuranyl radical, R3 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, an aryl or aralkyl with 6 to 10 carbon atoms, which may be ring substituted by lower alkoxy, or an acyl group with up to 18 carbon atoms, R4 represents hydrogen or a lower alkyl group with up to 6 carbon atoms, R5 represents hydrogen or a lower alkyl or lower alkoxycarbonyl radical with up to 6 carbon atoms, and each X represents oxygen or sulphur atoms, the two X moieties being the same or different, whenever prepared or produced by the process as claimed in claim 1, 2 or 3, or an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 in which in the reactants R1 is methyl or cyclopentyl, R2 is benzyl, methyl cyclopentyl, hydrogen, n-propyl, isobutyl, cyclobutyl, n-butyl, allyl, propargyl, methallyl, phenyl or 3-tetrahydrofuranoyl,R3 is hydrogen, methyl, acetyl, benzyl or 3,4-dimethoxy phenylethyl, R4 is hydrogen, methyl, n-propyl, or isopropyl and R5 is hydrogen or methyl.
6. A compound of formula I given in claim 1 wherein X is as in claim 1 and R1, R2, R3, R4 and R5 are as in claim 5, whenever prepared or produced by the process as claimed in claim 5, or an obvious chemical equivalent thereof.
7. A process as claimed in claim 1 which comprises heating 2-amino-1-(3-benzyloxy-4-methoxyphenyl)-ethanol with sodium methylate and diethyl carbonate in toluene under anhydrous conditions.
8. A process as claimed in claim 1 which comprises reacting 2-amino-1-(3-benzyloxy-4-methoxy-phenyl)-ethanol under anhydrous conditions in absolute tetrahydrofuran with carbonyl diimidazole.
9. 5-(3-Benzyloxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 7 or 8 or an obvious chemical equivalent thereof.
10. A process as claimed in claim 8, in which the 5-(3-benzyloxy-4-methoxyphenyl)-2-oxazolidinone so obtained is hydrogenated in ethanol in the presence of Raney nickel at room temperature under hydrogen pressure.
11. 5-(3-Hydroxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 10 or an obvious chemical equivalent thereof.
12. A process as claimed in claim 7, which comprises heating 2-amino-1-(3,4,-dimethoxyphenyl)-ethanol with sodium methylate and diethyl carbonate in toluene under anhydrous conditions.
13. A process as claimed in claim 10, in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained in absolute dimethyl formamide is heated with sodium hydride at elevated temperature with methyl iodide.
14. A process as claimed in claim 1 which comprises heating 2-amino-1-(3,4-dimethoxyphenyl)--ethanol in chloroform with cooling and subsequently adding pyridine thereto.
15. A process as claimed in claim 1 which comprises treating 2-amino-1-(3,4-dimethoxyphenyl)-ethanol in sodium hydroxide with cooling with chIoroformic acid ethyl ester and heating the 2-(3,4-dimethoxyphenyl)-2-hydroxyethyl-carbamic acid ethyl ester so obtained in toluene under anhydrous conditions with sodium ethylate.
16. 5-(3,4-Dimethoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 12, 13 or 14, or an obvious chemical equivalent thereof.
17. A process as claimed in claim 7, which comprises heating 2-methyl-amino-1-(3,4-dimethoxyphenyl)-ethanol with sodium methylate, and diethyl carbonate in toluene under anhydrous conditions.
18. A process as claimed in claim 12 in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone so obtained is treated in absolute dimethyl formamide with sodium hydride and then methyl iodide.
19. 3-Methyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 17 or 18 or an obvious chemical equivalent thereof.
20. A process as claimed in claim 7, which comprises heating 2-amino-1-(3-methoxy-4-cyclopentyloxyphenyl)-ethanol with sodium methylate and diethyl carbonate in toluene under anhydrous conditions.
21. 5-(3-Methoxy-4-cyclopentyloxyphenyl)-2-oxazolidin-one whenever prepared or produced by the process as claimed in claim 20 or an obvious chemical equivalent thereof.
22. A process as claimed in claim 7, which comprises heating 2-amino-1-(3-cyclopentyoxy-4-methoxyphenyl)-ethanol with sodium methylate and diethyl carbonate in toluene under anhydrous conditions.
23. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then cyclopentylbromide.
24. 5-(3-Cyclophenyloxy-4-methoxyphenyl)-2-oxazolidin-one whenever prepared or produced by the process as claimed in claim 22 or 23 or an obvious chemical equivalent thereof.
25. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then n-propyl bromide.
26. 5-(3-Propyloxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 25 or an obvious chemical equivalent.
27. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then isobutyl bromide.
28. 5-(3-Isobutyloxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 27 or an obvious chemical equivalent thereof.
29. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then cyclobutyl bromide.
30. 5-(3-Cyclobutyloxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 29 or an obvious chemical equivalent thereof.
31. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then n-butyl bromide.
32. 5-(3-n-Butoxy-4-methoxyphenyl)-2-oxazolidinone whenPver prepared or produced by the process as claimed in claim 31 or an obvious chemical equivalent thereof.
33. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is kreated with sodium hydride in absolute dimethyl formamide and then allyl bromide.
34. 5-(3-Allyloxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 33 or an obvious chemical equivalent thereof.
35. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then propargyl bromide.
36. 5-(3-Propargyloxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 35 or an obvious chemical equivalent thereof.
37. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then methylallyl chloride.
38. 5-(3-Methylallyloxy-4-methoxyphenyl)-2-oxazolidin-one whenever prepared or produced by the process as claimed in claim 37 or an obvious chemical equivalent thereof.
39. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium ethylate in ethanol and then either iodo or chlorobenzene.
40. 5-(3-Phenyloxy-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 39 or an obvious chemical equivalent thereof.
41. A process as claimed in claim 10 in which the 5-(3-hydroxy-4-methoxyphenyl)-2-oxazolidinone so obtained is treated with sodium hydride in absolute dimethyl formamide and then 3-tetrahydrofuranyl-tosylate.
42. 5-(3-(3-Tetrahydrofuranyloxy)-4-methoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 41 or an obvious chemical equivalent thereof.
43. A process as claimed in claim 1 which comprises treating under anhydrous conditions 2-amino-1-(3,4-dimethoxy-phenyl)-ethanol in absolute dimethyl sulphoxide with potassium hydroxide and carbon disulphide, removing the dimethyl sulphoxide in vacuo, adding water to the residue, extracting with chloro-form, drying the chloroform phases over anhydrous magnesium sul-phate and filtering, concentrating and chromatographing the product obtained.
44. 5-(3,4-Dimethoxyphenyl)-2-oxazolidinthione whenever prepared or produced by the process as claimed in claim 43 or an obvious chemical equivalent thereof.
45. A process as claimed in claim 1 which comprises treating 2-amino-1-(3,4-dimethoxyphenyl)-ethanol with cooling in pyridine with carbon disulphide and triethylamine, treating the product obtained with benzyl chloride, treating the benzyl ester obtained with phosphorus tribromide in absolute ether, then a methanol/water mixture and finally sodium hydrogen carbonate solution, dissolving the thaizol-2-one so obtained in ethaolic hydrochloric acid, boiling the solution under reflux and treating the product obtained in ethanol with sodium hydroxide.
46. 5-(3,4-Dimethoxyphenyl)-2-thiazolidinone whenever prepared or produced by the process as claimed in claim 43 or 45 or an obvious chemical equivalent thereof.
47. A process as claimed in claim 10 in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone so obtained is treated with phenyl isocyanate.
48. 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid anilide whenever prepared or produced by the process as claimed in claim 47 or an obvious chemical equivalent thereof.
49. A process as claimed in claim 10 in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone so obtained is treated with acetic anhydride in pyridine.
50. 3-Acetyl-5-(3,4-dimethoxyphenyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 49 or an obvious chemical equivalent thereof.
51. A process as claimed in claim 1 which comprises treating 4-amino-3-(3,4-dimethoxyphenyl)-3-butenol in absolute dimethyl formamide under anhydrous conditions with carbonyl diimidazole in absolute tetrahydrofuran.
52. 5-(3,4-Dimethoxyphenyl)-5-propyl-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 51 or an obvious chemical equivalent thereof.
53. A process as claimed in claim 1 which comprises treating 5-amino-4-(3,4-dimethoxyphenyl)-4-pentanol in absolute dimethyl formamide under anhydrous conditions with carbonyl diimidazole in absolute tetrahydrofuran.
54. 5-(3,4-Dimethoxyphenyl)-5-methyl-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 53 or an obvious chemical equivalent thereof.
55. A process as claimed in claim 10 in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone is treated in dioxan with sodium hyclroxide and benzoxy carbonyl chloride.
56. 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carbox-ylic acid benzyl ester whenever prepared or produced by the process as claimed in claim 55 or an obvious chemical equivalent thereof.
57. A process as claimed in claim 10 in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone obtained is refluxed under anhydrous conditions in absolute toluene and in the presence of triethylamine with chloroformic acid ethyl ester.
58. 5-(3,4-Dimethoxyphenyl)-2-oxazolidinon-3-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 57 or an obvious chemical equivalent thereof.
59. A process as claimed in claim 12 in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone so obtained is treated in absolute dimethyl formamide with sodium hydride and then isopropyl iodide.
60. 5-(3,4-Dimethoxyphenyl)-3-isopropyl-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 59 or an obvious chemical equivalent thereof.
61. A process as claimed in claim 12 in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone so obtained is treated in absolute dimethyl formamide with sodium hydride and then benzyl iodide.
62. 5-(3,4-Dimethoxyphenyl)-3-benzyl-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 61 or an obvious chemical equivalent thereof.
63. A process as claimed in claim 12, in which the 5-(3,4-dimethoxyphenyl)-2-oxazolidinone so obtained is treated in absolute dimethyl formamide with sodium hydride and then 3,4-dimethoxyphenyl ethyl iodide.
64. 5-(3,4-Dimethoxyphenyl)-3-(3,4-dimethoxyphenyl-ethyl)-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 63 or an obvious chemical equivalent thereof.
65. A process as claimed in claim 1 which comprises treating 2-amino-1-(3,4-dimethoxyphenyl)-propanol in chloroform under anhydrous condtions with carbonyl diimidazole.
66. 5-(3,4-Dimethoxyphenyl)-4-methyl-2-oxazolidinone whenever prepared or produced by the process as claimed in claim 65 or an obvious chemical equivalent thereof.
67. A process as claimed in claim 1 which comprises treating 2-amino-4-(3,4-dimethoxyphenyl)-3-hydroxy-propionic acid ethyl ester in chloroform under anhydrous conditions with carbonyl diimidazole.
68. 5-(3,4-Dimethoxyphenyl)-2-oxo-oxazolidin-4-carboxylic acid ethyl ester whenever prepared or produced by the process as claimed in claim 67 or an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2655369.5 | 1976-12-03 | ||
| DE19762655369 DE2655369A1 (en) | 1976-12-03 | 1976-12-03 | 5- (SUBST. PHENYL) -OXAZOLIDINONE AND THEIR SULFUR ANALOGS AND PROCESS FOR THEIR PRODUCTION |
| DE19772745320 DE2745320A1 (en) | 1977-10-05 | 1977-10-05 | 5-Alkoxyphenyl-oxazolidine-2-one and sulphur analogues - useful as neuroleptics and phospho-di:esterase inhibitors |
| DEP2745320.9 | 1977-10-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1097657A true CA1097657A (en) | 1981-03-17 |
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|---|---|---|---|
| CA292,273A Expired CA1097657A (en) | 1976-12-03 | 1977-12-02 | 5-(substituted phenyl)-oxazolidinones and sulphur analogues thereof and also a process for their production |
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| JP (1) | JPS5382777A (en) |
| AT (1) | AT357529B (en) |
| AU (1) | AU519994B2 (en) |
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| DK (1) | DK149850C (en) |
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| SE (1) | SE441446B (en) |
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| DE2701215C2 (en) * | 1977-01-13 | 1982-10-14 | Bayer Ag, 5090 Leverkusen | Process for the preparation of thiazoline-2-thiones |
| US4348393A (en) * | 1978-06-09 | 1982-09-07 | Delalande S.A. | N-Aryl oxazolidinones, oxazolidinethiones, pyrrolidinones, pyrrolidines and thiazolidinones |
| DE3438839A1 (en) * | 1984-10-19 | 1986-04-24 | Schering AG, 1000 Berlin und 4709 Bergkamen | PHARMACEUTICAL PREPARATIONS |
| WO1987006576A1 (en) * | 1986-04-29 | 1987-11-05 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
| US5459145A (en) * | 1988-01-19 | 1995-10-17 | Pfizer Inc. | Calcium independent camp phosphodiesterase inhibitor antidepressant |
| JPH01135098U (en) * | 1988-03-11 | 1989-09-14 | ||
| WO1991007177A1 (en) * | 1989-11-13 | 1991-05-30 | Pfizer Inc. | Pyrimidone derivatives and analogs in the treatment of asthma or certain skin disorders |
| US5461056A (en) * | 1992-05-08 | 1995-10-24 | Pfizer Inc. | Pyrimidone derivatives and analogs in the treatment of asthma or certain skin disorders |
| GB9212673D0 (en) * | 1992-06-15 | 1992-07-29 | Celltech Ltd | Chemical compounds |
| GB9222253D0 (en) * | 1992-10-23 | 1992-12-09 | Celltech Ltd | Chemical compounds |
| GB9226830D0 (en) * | 1992-12-23 | 1993-02-17 | Celltech Ltd | Chemical compounds |
| US5622977A (en) * | 1992-12-23 | 1997-04-22 | Celltech Therapeutics Limited | Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same |
| GB9304919D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| GB9304920D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| DE69433594T2 (en) * | 1993-12-22 | 2004-08-05 | Celltech R&D Ltd., Slough | TRISUBSTITUTED PHENYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF AS PHOSPHODIESTERASE (TYPE IV) INHIBITORS |
| GB9326173D0 (en) * | 1993-12-22 | 1994-02-23 | Celltech Ltd | Chemical compounds and process |
| US6245774B1 (en) | 1994-06-21 | 2001-06-12 | Celltech Therapeutics Limited | Tri-substituted phenyl or pyridine derivatives |
| US5786354A (en) * | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
| GB9412571D0 (en) * | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| GB9412573D0 (en) * | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
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| GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
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| GB9625184D0 (en) * | 1996-12-04 | 1997-01-22 | Celltech Therapeutics Ltd | Chemical compounds |
| WO1998028281A1 (en) | 1996-12-23 | 1998-07-02 | Celltech Therapeutics Limited | Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors |
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- 1977-12-01 LU LU78616A patent/LU78616A1/xx unknown
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- 1977-12-02 IL IL53520A patent/IL53520A/en unknown
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- 1977-12-02 CH CH1477977A patent/CH635578A5/en not_active IP Right Cessation
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- 1977-12-02 GB GB50350/77A patent/GB1588639A/en not_active Expired
- 1977-12-02 JP JP14492277A patent/JPS5382777A/en active Granted
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- 1977-12-02 GR GR54913A patent/GR64964B/en unknown
- 1977-12-05 AT AT868677A patent/AT357529B/en not_active IP Right Cessation
- 1977-12-05 CS CS778086A patent/CS199694B2/en unknown
- 1977-12-05 FR FR7736525A patent/FR2372814A1/en active Granted
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| AU3117577A (en) | 1979-06-07 |
| GB1588639A (en) | 1981-04-29 |
| DK149850C (en) | 1987-04-27 |
| LU78616A1 (en) | 1978-04-20 |
| DK536677A (en) | 1978-06-04 |
| IT1089341B (en) | 1985-06-18 |
| FR2372814A1 (en) | 1978-06-30 |
| HU175676B (en) | 1980-09-28 |
| ATA868677A (en) | 1979-12-15 |
| AT357529B (en) | 1980-07-10 |
| NL7713153A (en) | 1978-06-06 |
| SE7713635L (en) | 1978-06-04 |
| SU888821A3 (en) | 1981-12-07 |
| IL53520A0 (en) | 1978-03-10 |
| IE46435B1 (en) | 1983-06-15 |
| CH635578A5 (en) | 1983-04-15 |
| JPS5382777A (en) | 1978-07-21 |
| CS199694B2 (en) | 1980-07-31 |
| FR2372814B1 (en) | 1980-10-10 |
| IL53520A (en) | 1981-07-31 |
| DD133667A5 (en) | 1979-01-17 |
| DK149850B (en) | 1986-10-13 |
| GR64964B (en) | 1980-06-10 |
| AU519994B2 (en) | 1982-01-07 |
| IE772446L (en) | 1978-06-03 |
| JPS6154792B2 (en) | 1986-11-25 |
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