NO842221L - PROCEDURE FOR THE PREPARATION OF TRISUBSTITUTED OKSAZOLIDINONS - Google Patents

Abstract

Trisubstituted oxazolidinones of the formula ". Wherein R represents an aryl or heteroaryl radical, Rog represents independently hydrogen or lower alkyl or together. the proviso that in compounds with (-) - trans-arrangement of the hydrogen atoms in the 4- and 5-position in the oxazolidine ring, R is different from unsubstituted phenyl, when R 2 and R They are prepared by, for example, intramolecularly cyclizing a compound of the formula, which means a nucleophilic leaving group, or a salt thereof.

Description

The invention relates to a process for the preparation of new trisubstituted oxazolidines with the formula

where means an aryl or heteroaryl residue, and

independently means hydrogen or lower alkyl or together lower alkylene and alk stand for lower alkylene, whose valences originate from neighboring or opposite carbon atoms in the 1,3 position, with the proviso that in compounds with (-)-trans arrangement of the hydrogen atoms in 4- and 5-position in the oxazolidine ring, R^ is different from unsubstituted phenyl when R£ and R^ stand for hydrogen and alk means 1,3-propylene, i.e. excluding (-)-trans-l-phenyl-3- oxo-perhydro-3H-oxazolo[3,4-a]-pyridine, and their salts.

Aryl residues are, for example, 6-membered monocyclic or bicyclic aryl residues, which contain at least one 6-ring,

such as phenyl or naphthyl, e.g. 1- or 2-naphthyl. Heteroaryl radicals are, for example, monocyclic 5-membered heteroaryl radicals which contain as heteroatom(s) nitrogen, oxygen, sulphur, oxygen plus nitrogen or sulfur or nitrogen or 6-membered heteroaryl radicals, which contain as heteroatom(s) 1 or 2 nitrogen atoms, such as furyl, f .ex. 2-furyl, thienyl, e.g. 2-thienyl, pyrrolyl, e.g. 1-pyrrolyl, thiazolyl, e.g. 2-thiazolyl, oxazolyl, e.g. 2-oxazolyl, pyridyl, e.g. 3- or 4-pyridyl, pyrimidinyl, e.g. 2- or 4-pyrimidinyl or pyrazinyl, e.g. 2-pyrazinyl.

As substituents to aryl or heteroaryl radicals R 2 are, for example, lower alkyl, lower alkoxy, halogen, cyano and/or trifluoromethyl, whereby one or more than one, e.g. one, two or three may be the same or different of these substituents present.

"Lower" organic residues and compounds are to be understood above and below, for example, as those which contain up to and including 7, preferably up to and including 4, carbon atoms (C atoms).

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, further in any way bound pentyl, hexyl or heptyl. In compounds I, where and stands for lower alkyl residues, it is preferably the same or different, but especially the same, primary lower alkyl residues, such as methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl.

The lower alkylene is, for example, ethylene or 1,3-propylene,

in the case of when R 2 and R 2 together denote lower alkylene radicals, whose free valences are based on e.g. neighboring or adjacent C atoms in the 1,3-, 1,4- or 1,5-position, further 1,4-butylene, 1,5-pentylene, 1,4-(2,2-dimethyl)- butylene or 1,5-(3,3-dimethyl)-pentylene and in the case of lower alkylene residues alk vider 1,2-(2-methyl)-propylene, 1,3-(3-methyl)-butylene or 1,3- (2,2-dimethyl)-propylene.

Lower oxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy or tertiary butyloxy, but can also be a pentyloxy, hexyloxy or heptyloxy group.

Halogen is, for example, halogen with an atomic number up to and including 35, such as chlorine, further fluorine or bromine.

The compounds of formula I contain at least 2 asymmetric C atoms (ring atoms 4 and 5 in the oxazolidine ring). They can therefore act as cis/trans isomers with respect to the opposite orientation of the hydrogen atoms in the 4- and 5-position in the oxazolidine ring, whereby the trans-isomer has the threo configuration, the cis-isomer has the erythro configuration. The new compounds can therefore appear in the form of two opposite diastereomeric enantiomer pairs. If the further variables R 2 and R 1 are different or the substructures produced by R 2 , R 2 , R 2 and/or alk contain at least one further center of asymmetry, even further stereoisomeric forms are possible. These to-

all correspond to formula I and are therefore also a subject of the present invention. However, the threo-diastereomers are always preferred, i.e. such for-

bonds I, in which the hydrogen atoms in the 4- and 5-position of the oxazolidine ring face each other in the trans position,

and possibly derived diastereomers or diastereomer mixtures with at least one additional center of asymmetry.

Salts of compounds of formula I are, for example, acid addition salts, especially pharmaceutically usable acid addition salts of compounds of formula I, where R

means a basic heteroaryl residue, i.e. a heteroaryl residue containing at least one nitrogen atom, of especially mineral acids or strongly inorganic acids, such as hydrohalic acid, sulphonic acid, sulphamic acids or possibly hydroxylated aliphatic mono- or dicarboxylic acids, e.g. hydrochlorides, hydrobromides, methanesulfonates, p-toluenesulfonates, N-cyclohexylsulfaminates, fumarates, maleates, maleates or tartrates.

in

The compounds of formula I and their pharmaceutically usable salts have advantageous pharmacological properties. Thus, for example, they affect mice in the swimming test according to Porsolt et al., Arch. Int. Pharmacodyn. 22_9 , 327-336 (1977) in the dose range from approx. 25 mg/kg p.o. a clear increase in motility as well as in rats should by perforated plate test according to Noble and Delini-Stula, Psychopharmacology 4_9 , 17-22 (1976) in the dose range from approx. 25 to approx. 50 mg/kg p.o. a clear increase in exploration speed. Neurobiochemically, they excel in the experimental device according to Waldmeier, de Herdt and Maitre, Chir. Chem. 20, 81 (1974) in the dose range from approx. 100 mg/kg i.p. by a clear inhibition of dopamine and norepinephrine uptake in the rat's brain, whereby the inhibition of dopamine uptake predominates. The compounds of formula I are also slightly toxic. The LD^Q value in mice is in many cases clearly above 1000 mg/kg p.o.

in

The new compounds and their pharmaceutically acceptable salts are therefore suitable as antidepressants, especially with non-amphetamine-like, slightly stimulating action components.

The invention primarily relates to the preparation of compounds of formula I, in which R means a 6-membered monocyclic aryl radical with optional lower alkyl, lower alkoxy halogen, cyan and/or trifluoromethyl as substituents or a bicyclic aryl radical containing at least the eh6 member

)ring or a monocyclic 5-membered heteroaryl residue containing as heteroatom(s) nitrogen, oxygen, sulphur, oxygen and nitrogen respectively. sulfur and nitrogen respectively 6-membered heteroaryl radical containing as heteroatom(s)

1 or 2 nitrogen atoms, R2 and R^ independently of each other mean hydrogen, lower alkyl or together lower alkylene and alk means lower alkylene, whose valences originate from neighboring or adjacent C atoms in the 1,3 position, preferably those in which the hydrogen atoms in the 4- and 5-position; in the oxazolidine ring is arranged i

in the trans position to each other, with the proviso that in compounds with (-)-trans arrangement of the hydrogen atoms in the 4- and 5-position in the oxazolidine ring, R^ is different from unsubstituted phenyl, when R2 and R^ stand for hydrogen and alk means 1,3-propylene, i.e. to the exclusion of (-)-trans-1-phenyl-3-oxo-perhydro-3H-oxazolo[3,4-a]pyridine, and their salts.

The invention primarily relates to the preparation of compounds of formula I, where means an unsubstituted or lower alkyl with up to and including 4 C atoms, such as methyl, lower alkoxy with up to and including 4 C atoms, such as methoxy, halogen with atomic number up to and including 35, as chlorine, and/or trifluoromethyl substituted phenyl radical, naphthyl radical, as 1-or 2-naphthyl-, furyl-, as 2-furyl-, thienyl-, as 2-thienyl-, pyrrolyl- as 1-pyrrolyl, thiazolyl-, as 2-thiazolyl-, oxazolyl- as 2-oxazolyl-, pyridyl- as 3-

or 4-pyridyl-, pyrimidinyl- as 2- or 4-pyrimidinyl-, or pyrazinyl- as 2-pyrazinyl residue, and where either R2

and R^ independently of each other means hydrogen or lower alkyl with up to 4 C atoms, such as methyl, or together means lower alkyl with up to 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in 1 ,3- position, 1,4- or 1,5-position, such as ethylene, 1,3-propylene, 1,5-pentylene, 1,4-butylene, 1,5-(3,3-dimethyl)-pentylene .

up to and including 4 C atoms, such as methyl, or together means the lower alkylene with up to and including 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in the 1,3-position, 1,4-position or 1,5-position, such as ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,5-(3,3-dimethyl)-pentylene, and alk means the lower alkylene of up to and including 7 C atoms, whose valences are based on opposite C atoms in the 1,3 position,

such as 1,3-propylene, 1,3-(3-methyl)-butylene or 1,3-(2,2-dimethyl)-propylene, and their salts, especially their pharmaceutically usable salts.

The invention relates in particular to the preparation of compounds of formula I, in which R^ means unsubstituted phenyl or phenyl substituted with lower alkyl with up to and including 4 C atoms, such as methyl, lower alkoxy with up to and including 4 C atoms, such as methoxy, halogen with atomic number to and with 35, as chlorine, and/or trifluoromethyl or unsubstituted furyl, e.g. 2- furyl, thienyl, e.g. 2-thienyl, or pyridyl, e.g. 3- or 4-pyridyl, R 2 and R- each mean, preferably the same, lower alkyl radicals with up to and including 4 C atoms, e.g. methyl, or collectively means lower alkylene with up to 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in the 1,4-position or 1,5-position, such as ethylene, 1,4-butylene or 1,5-pentylene, and alk stands for ethylene or 1,3-propylene, above all those in which the two hydrogen atoms in the 4-

and 5-position in the oxazolidine ring are in the trans-position to each other, and their salts, especially pharmaceutically usable salts.

The invention primarily relates to the preparation of compounds of formula I, where R^means phenyl substituted, preferably in the 3- and/or 4-position, with halogen with atomic number up to and including 35, such as chlorine, R2 and R^mean

same lower alkyl residues with up to and including 4 C atoms, such as methyl, and alk stands for ethylene, especially those in which the two hydrogen atoms in the 4- and 5-position of the oxazolidine ring are in the trans-position to each other, and their salts, especially pharmaceutically acceptable salts.

Namely, the invention relates to the preparation of the compounds of formula I and their salts in the examples mentioned, especially pharmaceutically usable salts.

The compounds of formula I can be prepared according to methods known per se, for example by

a) in a connection with formula

where X means a residue that can be transferred into the carbonyl group, or a salt thereof, transfers X into the carbonyl group, or b) intramolecularly cyclizes a compound with the formula

where X^means a nucleofuge leaving group, or a salt thereof, or

c) in connection with the formula

-halvokr I][-alCk(R1 2b) e(tRy3r )- een llgerur ppale kmIeId :C=C fo(R rme) - len as -aelkr -"Cbu(nRd2e)t R3m)-ed,

the nitrogen atom in the oxazolidine ring above the C(R~)(R.J- or =C{Rj) groups, whereby alk IImeans a lower alkylene residue

III

and alk means a lower alkanylidene - respectively. lower alkenyl ylidene residue, whose free valences proceed from neighboring ones

or adjacent carbon atoms in the 1,3-position, saturates the double bond(s) in the oxazolidine ring and optionally in the remainder alk<1> and, if desired, splits an isomer mixture obtained by the method into the components or isolates from such a mixture the desired isomer(s), converts a compound obtainable by the method ± another compound of formula I and/or a free compound obtained by the method into a salt or transfers a salt obtained by the method into the free compound or in another salt.

Transferable residues X in the carbonyl group are, for example, functionally converted carbonyl groups with the formula - CiX^) ^3)" in which X2 and X^ independently of each other mean esterified or etherified with a monohydric alcohol or mercaptan hydroxy or together with a dihydric alcohol or mercaptan mean ketalized oxo- respectively thiooxo or together optionally substituted imino. Esterified hydroxy is thereby, for example, halogen, with a monohydric alcohol or mercaptan etherified hydroxy, for example lower alkoxy or lower alkylthio or optionally substituted phenoxy or phenylthio substituted with e.g. nitro and/or halogen, and with a dihydric alcohol, respectively mercaptan ketalized oxo, for example lower alkylenedioxy or lower alkylenedithio, or optionally substituted 1,2-r'enylenedithio or 1,2-phenylenedioxy. From X^ and X^ together prepared, optionally substituted imino is for example imino, lower alkylimino or anilo optionally substituted with nitro and/or halogen.

Nucleofuge leaving groups X are, for example, reactive esterified hydroxy groups, etherified hydroxy groups, activated amino groups or ammonio groups. Reactive esterified hydroxy is, for example, esterified with a mineral acid and means in particular a halogen atom, such as chlorine. Etherated hydroxy is, for example, lower alkoxy,

e.g. methoxy, ethoxy, isopropyloxy or tertiary butyloxy,

or optionally, especially by electron-withdrawing substituents, such as nitro and/or halogen, substituted phenoxy, such as phenoxy, p-nitro- or 2,4-dinitrophenoxy or 3,5-dichlorophenoxy. Activated amino is, for example, secondary amino as part of a heteroaromatic system, such as 1-imidazolyl, 1-pyrazolyl or 1-(3,5-dimethyl)-pyrazolyl. Ammonium is, for example, trilower alkyl, e.g. trimethylammonio, or tertiary ammonio as part of a heteroaromatic system,

as pyridinium.

In II

In unsaturated residues alk, alk means, for example, the vinyl

or 1,3-prop-2-enylene and alk<111> for example ethanylylidene or 1-prop-1-enyl-3-ylidene.

Examples of salts of intermediates II, III and IV are their acid addition salts, e.g. hydrohalides, as salts of intermediates III,

further their metal salts, in which the proton of the hydroxy group is replaced by a metal cation, as corresponding to the sodium or potassium salt.

The carrying out of the reactions according to the method as well as the production of new starting materials or intermediate products occur analogously to the reactions and production methods of known starting substances, respectively. intermediate products. In this way, also when not expressly mentioned below, the usual aids are used, such as catalysts, condensation and solvolysis agents and/or dissolution agents, respectively. diluents, and reaction conditions, such as temperature conditions and pressure conditions, as well as any protective gas.

The transfer of X in the carbonyl group according to method variant a) takes place, for example, by hydrolysis, preferably under neutral or mildly acidic conditions, e.g. in the presence of a suitable acidic agent, such as a mineral acid, e.g. hydrochloric or hydrobromic acid, or in the presence of an organic sulphonic or carboxylic acid, such as an alkanoic acid or optionally substituted benzenesulphonic acid or a lower alkanesulphonic acid, e.g. p-toluenesulfonic acid or acetic acid, or using intermediate II as a salt, e.g. as hydrochloride or hydrobromide. If necessary, you work in the presence of additional aids, for example buffer systems, based on thioketals II of heavy metal salts or oxidizing agents, respectively. starting from N-unsubstituted imines II by nitric acid. Suitable heavy metal salts are, for example, silver, mercury or copper salts, suitable oxidizing agents are, for example, oxidising heavy metal compounds, such as copper-II, iron-III, iron-VI, chromium-VI, manganese-IV and manganese-VII compounds, especially oxides or chlorides, halogens, such as chlorine or iodine, or halooxyacids, e.g. iodic acid, or their salts. When hydrolysis is carried out, unstable intermediate steps can be formed. Thus, for example, thioketals II can form with halogens easily hydrolyzable sulfonium halides and N-unsubstituted imines II react with nitric acid to easily hydrolyzable intermediates. At least under the mentioned gentle conditions, the influence of the reagents is limited to the group X. The stereotaxy of the ring atoms 4 and 5 in the oxazolidine ring as well as any further asymmetry centers are therefore not affected.

In a preferred embodiment of method variant a) one starts, for example, from an acid addition salt, e.g. the hydrochloride, to an N-unsubstituted imine II (X = iminomethylene) and hydrolyzes this while heating to approx. 40-110°C, e.g. at the boiling point temperature, in the pH range from approx. 3.5 to approx. 9, for example in the presence of a phosphate buffer (pH approx. 6.5).

In another preferred embodiment, an N-unsubstituted imine II (X = iminomethylene) is treated in the presence of hydrochloric acid under heating, e.g. at boiling temperature,

with an alkali metal nitrite.

The intermediates II can, for example, be prepared by reacting a compound with the formula

in the usual way with a compound of the formula X^-C(X2)

(X^)-Y^(VI), where X^, X2 and X^ together form the nitrilo group and Y means hydroxy or halogen or X^ and Y independently mean etherified hydroxy, e.g. lower alkoxy.or optionally substituted phenoxy,

and X2 and X^ means with a monohydric alcohol or mercaptan etherified hydroxy or with a dihydric alcohol or mercaptan ketalized oxo or X^ and Y^ means reactive esterified hydroxy, such as halogen, and X2 and X^ together produce thioxo, or X^ and Y^ means together oxo and X2 and X^ means with a monovalent mercaptan etherified hydroxy or together with a divalent mercaptan ketalized oxo or X^ and Y^ together means oxo or thioxo and X2 and X^ together form optionally substituted imino.

Thus, for example, one can N-cyanate a compound V

by reaction with bromine or cyanogen chloride in the presence of an acid-binding agent, e.g. of sodium bicarbonate,

and cyclizing the formed N-cyan intermediate, e.g. with lower alkanol hydrochloric acid, to the corresponding imine (II, X2 + X3 = Imino). The turnover proceeds while the configuration is largely maintained: From the threo compound V, the corresponding trans compound II is formed and vice versa. But you can also transfer the starting material V with cyanic acid or an alkali metal cyanate under acid

conditions in the N-carbamyl derivative and cyclize this with thionyl chloride or phosgene to the imine (II, + X^= imino), whereby configurational mirror reversal occurs, i.e. from the threo-compound V the corresponding cis-compound II is formed. Analogously, a compound V can also be reacted with an organic isothiocyanate, e.g. a lower alkyl or optionally substituted phenyl isothiocyanate, whereby, while maintaining the configuration, is likewise formed predominantly by corresponding N-substituted imines (II, X^+ X^= substituted imino).

Intermediate V is preferably prepared by N-nitrosating a compound of the formula

with sodium nitrite and hydrochloric acid respectively. by reaction with formic acid ethyl ester and then with dimethyl sulfate and cyclohexylamine transfers into N-formamidine derivative and reacts the primary product in tetrahydrofuran at a maximum of -60°C in the presence of lithium-N,N-diisopropylamide with an aldehyde of the formula R^-CH=0 (VIII) . According to another method, one cyclizes a compound with the formula in which Y^q means e.g. bromine, when treated with ammonia or benzylamine or one reacts an acid with the formula where Y^ is hydrogen or preferably benzyl, or preferably its chloride, in the presence of aluminum trichloride with a compound R^-H (XI), each time reducing the carbonyl group in the primary product with the formula by means of sodium borohydride or sodium- diethyl aluminum dihydride to the carbinol group and optionally dehydrogenates benzyl Y,-. In an analogous way, one can react an acid with the formula or preferably its chloride with the compound XI and reduce the exocyclic carbonyl group to a carbinol group and the endocyclic carbonyl group to a methylene group in the primary product with the formula with lithium aluminum hydride. But you can also react a carboxylic acid with the formula where alk<111>means a lower alkenylylidene residue derived from alk, whose free valences start from opposite C atoms in the 1,3 position, e.g. The prop-2-en-1-yl-3-ylidene, or preferably its chloride in the presence of aluminum trichloride, with the compound XI and simultaneously reduces in the reaction product with the formula

by hydration in the presence of Adam-platinum oxide the carbonyl group to the carbinol group and the double bond in the ring to a single bond.

The described and further preparation methods for intermediates V proceed predominantly stereoselectively. Thus, predominantly the erythro-diastereomers are obtained with the process variant starting from starting materials VII and by hydrogenating starting materials XVI. If desired, compounds V can be epimerized in the usual way, i.e. transfer the erythro-diastereomer into the threo-diastereomer, e.g. by treatment with thionyl chloride and then with water or better epimerize by acetylation with acetic anhydride in N,N-dimethylformamide, reaction with thionyl chloride and treatment with caustic soda, and if desired split the formed diastereomers into the antipodes, for example by forming diastereomeric salts, e.g. . by means of camphorsulfonic acid, splitting the diastereomeric salts and releasing the enantiomeric bases thereof.

The intramolecular cyclization of compounds III

according to method variant b) takes place spontaneously or in the presence of a suitable condensing agent, if necessary during cooling or heating, advantageously in an inert solvent. Suitable condensing agents are, for example, basic condensing agents, such as alcoholates, hydroxides or carbonates of alkali or alkaline earth metals, e.g. sodium methanolate, potassium tertiary butanolate, potassium hydroxide or potassium carbonate, or tertiary organic nitrogen bars, such as trilower alkylamines, e.g. trimethyl- or triethylamine, or heteroaromatic nitrogen bases, e.g. pyridine, further halides of oxygen acids to sulfur or phosphorus, e.g. thionyl chloride, phosphorus tribromide or phosphorus oxychloride. Thus, the cyclization of compounds III, where X^ is halogen, generally occurs spontaneously, while starting from compound III, where X^ is etherified hydroxy, basic condensing agents, for example alkali metal alcoholates, such as sodium laveral alkanolate, act to accelerate the reaction.

When starting from compound III, where X^ is amino, halides or oxygen acids of sulfur act, e.g. thionyl chloride, in the presence of tertiary organic nitrogen bases, e.g. triethylamine or pyridine, reaction accelerator.

For the preparation of the intermediate III, one preferably starts from compounds with the formula

and reacts this with a suitable difunctional derivative of the carbonic acid. Suitable difunctional derivatives of the carboxylic acid are, for example, those in which at least one hydroxy group has been transferred in an etherified or in a reactive esterified hydroxy, i.e. compounds with the formula

X-^-C (X2) (X3)-Y^ (VI), where X2 and X3 together stand for oxo and X^ and Y^ independently mean etherified or reactive, esterified hydroxy and has e.g. one for such groups X^indicated meanings. Suitable carboxylic acid derivatives VI are especially phosgene, haloformic acid lower alkyl esters or dilower alkyl resp. optionally substituted diphenyl carbonates.

The reaction components VI are thereby advantageously selected so that the intermediate products III can be produced in situ and further converted without isolation.

The formation and cyclization of the intermediate III can be carried out stereoselectively. Thus, the formation of the intermediate III generally takes place while maintaining configuration, while the subsequent cyclization can occur so that end products are formed with the same or reversed configuration. Thus, by reacting compound III with haloformic acid lower alkyl esters (VI} X1= lower alkoxy, X2+ X3= oxo, Y-j^= halogen, e.g. chlorine or bromine) with the formation of the corresponding intermediates III predominantly end products of the same configuration are obtained. Also in the reaction of compounds V with phosgene (VI; X]_ = Y]_ = chlorine'X2+ X3= oxo t;L1 end product I during intermediate formation of intermediate products III proceeds while maintaining the same configuration.

In a particularly preferred embodiment of this method, for example, a starting material V of the desired configuration is reacted with phosgene in toluene or a similar inert solvent at approx. 10 to approx. 35°C, e.g. about. 30°C. Thereby, each of the enantiomeric erythro-forms V or their racemate the relevant cis-oxazolidinone I of the same absolute configuration, resp. its racemate or of each of the enantiomeric threo-forms V or their racemate the corresponding trans-oxazolidinone I or its race food.

The saturation of the double bond (ei) in the oxazolidine ring and optionally in the residue alk<1> according to process variant c) preferably takes place by catalytic hydrogenation, i.e. treatment with hydrogen in the presence of a hydrogenation catalyst. Suitable hydrogenation catalysts are thereby, for example, palladium, platinum and nickel catalysts, such as platinum oxide, e.g. adams platinum oxide, palladium, e.g. palladium-coal, or Raney-nickel. If necessary, work under heating and/or elevated pressure.

Intermediate IV can, for example, be prepared by reacting a corresponding compound with the formula

with a compound of the formula X^-C(X2)(X^)-Y1 (VI),

where X^, X2, X^ and have the meanings specified for method variant b), preferably under strong basic conditions, e.g. in the presence of sodium hydride, sodium amide or lithium N,N-diisopropylamide.

For the above-mentioned desalting, an isomer mixture has been formed by the invention or for the isolation of the desired component of such the following is particularly noteworthy: Diastereomer mixtures, e.g. mixtures of cis- and trans- isomers, can be separated due to their different physical properties according to the usual, chemical and physico-chemical separation methods, e.g. by fractional crystallization, distillation, chromatography and other phase distribution methods.

Enantiomer mixtures, such as cleavable mixtures of the two and possibly further enantiomers of the same, opposite orientation of the hydrogen atoms in the 4- and 5-position in the oxazolidine ring, can be resolved by usual racemate resolution methods, e.g. by crystallization of an optically active solvent, by chromatography on

an optically active, stationary or mobile phase, or by intermediate formation of a diastereomeric auxiliary compound, e.g. a diastereomeric acid addition salt, of an optically active carboxylic acid or sulphonic acid, e.g. D- or L-form of tartaric acid, di-o-toluenetartaric acid, malic acid, mandelic acid, quinic acid or a camphorsulfonic acid, by separating the diastereomers and liberating the enantiomeric compound I. Preferably, the most active enantiomer is always isolated.

As conversion reactions of compounds that are obtained according to the invention, in other compounds of formula I, special mention should be made of introduction, conversion and cleavage reactions on the residue.

For example, halogen can be introduced into the residue R^ by treatment with chlorine or bromine or N-bromosuccinimide, or reduce nitro to amino and/or replace amino with halogen, cyan, lower alkoxy or trifluoromethyl.

The mutual transfer of free compounds and their salts into each other takes place, for example, by reacting a free compound with an acid, or a salt with a base or a salt of another acid. Salts of the new compounds can also be used for their purification as well as, as discussed, for the resolution of enantiomers, by transferring a compound obtained by the method into a salt, purifying this or splits into the diastereomers and then releases the salt again in the free compound and, if desired, converts into another salt.

Thus, free compounds formed can be transferred in a manner known per se in the acid addition salt, e.g. by reacting the free compound in a solution in a suitable solvent or solvent mixture with one of the above-mentioned acids or with a solution thereof, or with a suitable cation exchanger.

Formed acid addition salts can be converted in a manner known per se into the free compounds, e.g. by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or hydrogen carbonate, or ammonia, or with a suitable anion exchanger.

Formed acid addition salts can be transferred in a manner known per se into other acid addition salts, e.g. by treating a salt of an organic acid with a suitable metal-

salt, such as a sodium, barium or silver salt, by treatment with an acid in a suitable solvent in which a forming inorganic salt is insoluble and thus separated from the reaction mixture.

The new compounds, including their salts, can also be obtained in the form of the hydrates or comprise the solvent used for crystallization.

According to the close relationship between the new connections i

free form and in the form of their salts, in the above and below mentioned free compounds or their salts, where appropriate, the corresponding salts or the free connections.

The invention also relates to such embodiments of the method, in which one starts from a compound obtained at any stage as an intermediate and carries out the missing process steps or forms a starting material under the reaction conditions or uses it in the form of a derivative thereof, possibly a salt.

In the method according to the invention, such starting materials are preferably used which lead to the compounds mentioned above as particularly valuable.

New starting materials and methods for their production likewise form an object of the present invention.

The compounds of formula V mentioned as intermediates

and their pharmaceutically usable salts exhibit similar pharmacological properties to the compounds of formula I

and can therefore also find use as antidepressants, then also with a different profile, closer to a pharmacological profile that is based on a dopamine release. Thus, they stimulate, for example, in the dose range from approx. 3 to 30 mg/kg p.o. the locomotor activity of mice, measured using the "Electronic Motility Meter". Likewise, they inhibit in the dose range from approx. 50 to 100 mg/kg p.o. the noradrenaline uptake in the rat's brain by the experimental device of Maxtre, Stahelin and Bein, Pharmacol. 20, 2169-2186 (1971).

The invention therefore also relates to a method for producing compounds with the formula

in where means an aryl or heteroaryl residue, R2 and R^ independently of each other mean lower alkyl or together lower alkylene and alk stands for lower alkylene, whose valences start from neighboring or adjacent carbon atoms in the 1,3 position, and their salts, as well as their use as intermediates for the preparation of compounds of formula I.

Hereby, aryl or heteroaryl radicals R^, lower alkyl-

respectively lower alkylene radicals R 2 and R 2 as well as lower alkylene radicals alk have, for example, the meanings given above under formula I.

Similarly, salts of compounds of formula V are preferably pharmaceutically usable acid addition salts, for example with the acids mentioned for salts of compounds of formula I.

The compounds of formula V likewise exhibit at least 2 asymmetric C atoms and can therefore exist in at least 4 mutually stereoisomeric forms, in (+)-threo-, (-)-threo-, (+)-erythro- and (-)- erythro-form. If the additional variables R2 and R^ are different or the substructures produced from R-^, R2, R^ and/or alk exhibit at least one additional center of asymmetry, then further stereoisomeric forms are possible. These all correspond to the formula V and are therefore all the subject of the invention. However, preference is always given to the threo-diastereomer and derived diastereomer mixtures with at least one further center of asymmetry,

both in the form of enantiomer mixtures and also in the form of individual enantiomers.

The invention primarily relates to the preparation of compounds of formula V, where R^ denotes a 6-membered monocyclic aryl radical with optional lower alkyl, lower alkoxy, halogen, cyan and/or trifluoromethyl as substituents, or a bicyclic aryl radical containing at least one 6-membered ring or a monocyclic '5-membered heteroaryl radical containing as heteroatom(s) nitrogen, oxygen, sulfur, oxygen plus nitrogen or sulfur plus nitrogen or a 6-membered heteroaryl radical containing as heteroatom(s)

1 or 2 nitrogen atoms, R2 and R^ independently produce lower alkyl or together lower alkylene and alk means lower alkylene, whose free valences originate from neighboring or adjacent C atoms in the 1,3-position primarily in the form of their threo-diastereomers, and their salts, especially pharmaceutically usable salts.

The invention primarily relates to the preparation of compounds of the formula V, in which R means an unsubstituted or lower alkyl with up to and including 4 C atoms, such as methyl, lower alkoxy with up to and including 4 C atoms, such as methoxy, halogen with atomic number up to and including 35, as chlorine, and/or trifluoromethyl substituted phenyl, naphthyl residue, as 1-

or 2-naphthyl-, furyl- as 2-furyl-, thienyl-, as 2-thienyl-, pyrrolyl-, as 1-pyrrolyl, thiazolyl-, as 2-thiazolyl-, oxazolyl-, as 2-oxazolyl-, pyridyl- , such as 3- or 4-pyridyl-, pyrimidinyl-, such as 2- or 4-pyrimidinyl- or pyrazinyl-, such as 2-pyrazinyl residue, R2 and R^ independently of each other mean lower alkyl with up to 4 C atoms, such as methyl, or together the lower alkylene with up to and including 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in the 1,3-, 1,4- or 1,5-position, such as ethylene, 1,3-propylene , 1,4-butylene, 1,5-pentylene or 1,5-(3,3-dimethyl)-pentylene, and alk means the lower alkylene with up to and including 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in the 1,3 position such as ethylene, 1 ,3-propylene, 1,2-(2-methyl)-propylene, 1,3-(3-methyl)-butylene or 1,3-(2,2-dimethyl)-propylene, mainly in the form of threo-diastereomers and their salts, especially pharmaceutically acceptable salts.

The invention relates in particular to the preparation of compounds of the formula V, where R^ denotes unsubstituted phenyl or phenyl t substituted with lower alkyl with up to and including 4 C atoms, such as methyl, lower alkoxy with up to and including 4 C atoms, such as methoxy, halogen with atomic number up to and including 35, such as chlorine, and/or trifluoromethyl or unsubstituted phenyl, e.g. 2-furyl, thienyl e.g. 2-thienyl or pyridyl, e.g. 3- or 4-pyrid]R 2 and R 1 each mean equal lower alkyl radicals with up to and including 4 •C atoms, e.g. methyl, or collectively means the lower alkylene with up to 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in the 1,4- or 1,5-position, such as 1,4-butylene or 1,5 -pentylene,

and alk stands for ethylene, primarily in the form of the threo-diastereomers, and their salts, especially pharmaceutically usable salts.

The invention relates to the production of the compounds of formula V and their salts mentioned in the examples.

The compounds of formula V can be prepared according to methods known per se, for example by

d) of a compound with the formula

where one of the residues Y^ and Y^ means a cleavable residue and the

second hydrogen, or a salt thereof, cleaves off the cleavable residue during the introduction of a hydrogen atom, or

e) cyclizes a compound of the formula

or a salt thereof, where Yg is hydroxy and one of the residues Yg and Y-^q means reactive, esterified hydroxy or Yg and Yg together stand for epoxy, whereby the remaining residue Yg or Y^0 optionally means amino present in intermediate protected form and/or amino substituted with a cleavable residue, or f) in a compound with the formula i. in which the hydrogen atom can be intermediately protected,

or a salt thereof, reduces the carbonyl group to the carbinol group, if necessary cleaves off the protecting group and, if desired, epimerizes the obtainable compound according to one of the method variants d) to f), cleaves an isomer mixture obtainable by the method into its components, respectively separates from such a mixture the desired isomer(s) (is) converts a compound obtainable by the method into another compound with formula V and/or transfers a free compound obtainable by the method in a salt or transfers a salt obtainable by the method in the free compound or in another salt.

Cleavable residues Yc b or Y_ / are for example acyl groups, silyl groups or optionally substituted α-aralkyl groups, residues Y_ are likewise α-carbanion stabilizing groups. As acyl groups, for example acyl groups derived from organic carboxylic acids, such as lower alkanoyl or optionally substituted aroyl or heteroaroyl, for example with the formula R^-C(=O)-. As silyl groups, for example trilower alkylsilyl groups, such as trimethylsilyl, and as optionally substituted a-aralkyl groups, for example a-phenyl-, a,a,-diphenyl or a,a,a-triphenyl lower alkyl groups, which are optionally substituted with lower alkyl, lower alkoxy, halogen and/or nitro, e.g. benzyl, further di- or triphenylmethyl. α-carbanion stabilizing groups Y are, for example, nitroso- or N-substituted iminomethyl groups as well as sterically hindered acyl groups derived from carboxylic or thiocarboxylic acids. Aliphatic and cycloaliphatic residues, such as lower alkyl, e.g. butyl or tertiary butyl, or cycloalkyl with 5 to 8 ring members, e.g. cyclopentyl or cyclohexyl. Acyl groups of the type indicated are, for example, 2,4,6-triisopropyl or 2,4,6-tritertiarybutylbenzoyl groups and tertiarybutylthiocarbonyl groups. Cleavable residues as substituents for the optionally α-aralkyl protected amino groups of compounds of formula XIX are, for example, α-halogenated lower alkanoyl groups, such as trifluoroacetyl.

As protecting groups for amino in compounds with

formula XIX as well as as protecting groups for the nitrogen atom of compounds XX the usual nitrogen protecting groups, for example those like Yg or Y^mentioned, preferably α-aralkyl, such as benzyl.

Salts of intermediates XVII, XIX respectively. XX are, for example, their acid addition salts, such as hydrohalides.

The execution of the reactions as well as the production of new starting materials or intermediate products according to the method occur analogously to the reactions and the way of formation of known starting substances or intermediates of similar structure. Hereby, usual aids are always used, such as catalysts, condensation and solvolysis agents and/or solvents, and reaction conditions, such as temperature and pressure conditions, as well as any protective gas, even when this is not expressly mentioned below.

Cleavage of residues Yg and Y^ according to method variant d) takes place, for example, by solvolysis or reduction. Thus acyl groups can be cleaved off hydrolytically, in addition to the mentioned trisubstituted benzoyl groups Y^, which are cleaved reductively, and silyl groups as well as N-substituted iminomethyl and tertiary butylthiocarbonyl groups Y^. Acyl groups Yg of are further cleaved alcoholically and nitroso groups are further cleaved acidolytically. α-aralkyl groups as well as the aforementioned trisubstituted benzoyl groups Y , are particularly reductively cleaved off.

Hydrolysis, alcoholysis or the acidolysis takes place by treatment with water, an alcohol or an acid, if necessary in the presence of a solvolytic agent and/or a dissolving or diluting agent. Solvolytic agents for the hydrolysis and alcoholysis as well as for the acidolysis are suitable acids such as mineral acid, e.g. chlorine or hydrobromic acid or sulfuric acid, sulphonic acids, e.g. p-toluenesulfonic acid, optionally halogenated lower alkanoic acids, e.g. acetic acid or ■ trifluoroacetic acid, or the like. Solvolytic agents for the hydrolysis and alcoholysis are likewise basic agents,

as hydroxides of alkali or alkaline earth metals, e.g. caustic soda or potassium hydroxide, for the alcoholysis of acyl Yg are further alcoholates, e.g. sodium methanolate. Solvents or diluents for the hydrolysis are e.g. solvents miscible with water, for the alcoholysis especially alcohols in excess. In a preferred embodiment of this solvolysis method, for example, a compound XVIII, in which Yg is hydrogen and Y^ is nitroso, is cleaved,

by treatment with hydrogen chloride in benzene or a mixture of toluene and dioxane or with hydrogen bromide in acetic acid.

In another preferred embodiment, a compound XVIII, where Yg is hydrogen and Y^ is N-substituted iminomethyl, is hydrolyzed in the presence of an alkali metal hydroxide, e.g. potassium hydroxide, under heating, e.g. to approx. 50-80°C

in an aqueous lower alkanol, e.g. in methanol/water or ethanol/water. * The reductive cleavage of α-aralkyl groups and of nitroso Y^ occurs, for example, by catalytic hydrogenation, the reductive cleavage of acyl Yg occurs, for example, by reaction with a dilate metal hydride. For catalytic hydrogenation, for example, the intermediate XVIII is treated in the presence of a platinum, palladium or nickel catalyst, e.g. platinum oxide, palladium on charcoal or Raney Nickel, with the stoichiometrically required amount of hydrogen, preferably in an inert solvent, if necessary under pressure and/or heating. In a preferred embodiment, for example, an intermediate XVIII is hydrogenated, where Yg is hydrogen and Y^ is 1) nitroso or 2) benzyl, 1) in the presence of Raney nickel or 2) at approx. 40-60°C, preferably in methanolic solution at normal or very slightly elevated pressure, in the presence of palladium charcoal. The reductive cleavage of acyl Yg takes place, for example, by treatment with sodium borohydride or lithium aluminum hydride. Intermediate products XVIII, where Yg means hydroxy and Y^ means an α-aralkyl residue, are prepared, for example, by reacting a compound with the formula; where Y^q means e.g. bromine or chlorine, either with benzylamine, N-trifluoroacetylates the reaction product (XXI, Y^Q= benzylamino), reacts with N-bromosuccinimide to a compound of the formula ; where Yg is hydroxy, Yg is bromine and Y^Q is N-benzyltrifluoroacetylamino, and cyclizes this, or epoxidizes compound XXI with hydrogen peroxide and cyclizes the reaction product (XIX, YQ+ Yg = epoxy, Y1Q= bromine or chlorine) ;with benzylamine.;The starting materials XXI can, for example, be obtained by ordinary reaction of a compound with the formula; with an aldehyde of the formula Intermediate products XVIII, where Y fi means hydroxy and Y^ means an α-carbanion stabilizing group, are obtained, for example, by substituting a compound of the formula in the usual way with a corresponding residue Y^, e.g. N-nitrosates or N-formamidates, and metalizes in the presence of a metal base the reaction product of the formula; where Y^ is e.g. nitroso or N-substituted iminomethyl or sterically hindered acyl, and then condenses with an aldehyde of the formula R^-CH=O (VIII). Metal bases are, for example, hydrocarbon compounds, amides or alcoholates of alkali metals, such as lithium or potassium, e.g. methyl lithium, butyl lithium, secondary butyl lithium, tertiary butyl lithium,, phenyl lithium, lithium N,N-diisopropylamide or potassium tertiary butanolate. Thus, the intermediate product VII can be N-nitrosated, for example, by reaction with an alkyl nitrite or with nitric acid or an alkali metal nitrite under acidic conditions and bring into circulation the reaction product XXVIII, for example in the presence of lithium-N,N-diisopropylamide, preferably in tetrahydrofuran at a maximum of -60°C, or in the presence of potassium tertiary butanolate at approx. -20°C to approx. 0°C, likewise preferably in tetrahydrofuran, with the aldehyde VIII. Hereby, the erythro-diastereomer V is preferably formed. But the intermediate VII can also be reacted, e.g. by reaction with a formic acid ester, such as a lower alkyl formate, the reaction product is N-formylated with a methylating agent, e.g. with dimethyl sulfate to the corresponding immonium compound of the formula ; where A ø is an anion, e.g. methosulphate ion, this is transferred with a primary amine, e.g. with cyclohexylamine, and subsequent base treatment in the corresponding N-formamide compound XXVIII (Y_, is e.g. -CH^N-c-CgH^) and this is a-metallized, for example in the presence of tertiary butyllithium, preferably at -20°C at most , and is then reacted with the aldehyde VIII. This gives the corresponding N-formamide compound XVIII, which, if desired, can be hydrolysed, e.g. on treatment with aqueous methanol, to the corresponding N-formyl compound XVIII. The intermediate XVIII, where Yg is acyl and Y^ is hydrogen, is obtained, for example, by reacting a compound of formula obtainable, for example, by N-chlorination of the corresponding saturated compound, e.g. with chloramine T, and subsequent chlorine hydrogen decomposition, with hydrocyanic acid, N-acylates the reaction product with the formula; e.g. by reaction with the chloride of an acid R^-COOH (XXXIII), and then reacts in the usual way, for example in the presence of lithium-N,N-diisopropylamide, preferably in tetrahydrofuran at no more than -60°C, with an aldehyde Rj ^-CH^O (VIII) .;The cyclization of compounds XIX according to process variant e) takes place if necessary in the presence of a basic condensation agent, such as an alkali or alkaline earth metal hydroxide, e.g. of sodium or potassium hydroxide, in the presence or absence of a solvent or diluent, preferably in the temperature range from approx. 20 to approx. 80°C. Thus compounds XIX are cyclized, where Yg means hydroxy, Yg means reactive, esterified hydroxy and Y^q optionally means amino in intermediate protected form and/or amino substituted with a cleavable residue, e.g. trifluoroacetylamino or N-benzyltrifluoroacetylamino, advantageously in a water-miscible organic solvent, e.g. in dioxane, by treatment with aqueous sodium or potassium lye, preferably under heating, e.g. at approx. 40 to approx. 80°C. The cyclization of compounds XIX, where Yg and Yg together stand for epoxy and Y^Q is amino optionally in intermediate protected form, e.g. amino or benzylamino, or Yg is hydroxy, Yg is amino, optionally in intermediate protected form, e.g. amino or benzylamino, and Y^Q is reactive, esterified hydroxy generally occurs spontaneously, e.g. when stored at room temperature.

Intermediates XIX, where YQ is hydroxy, YQ is bromine and Yn is N-benzyltrifluoroacetylamino are obtained, for example, by first bringing a compound with the formula

where Y^0 is bromine, with benzylamine, N-trifluoroacetylates the reaction product (XXI, Y^Q= benzylamino) in the presence of potassium carbonate with trifluoroacetic anhydride and then reacts with N-bromosuccinimide in the presence of sulfuric acid, preferably in dioxane.

Intermediates XIX, where Yg and Yg together stand for epoxy and Y^q means amino optionally in intermediate protected form or substituted with a cleavable residue, e.g. amino or benzylamino, resp. Yg means hydroxy, Yg means reactive esterified hydroxy and Y^Q means amino optionally in an intermediately protected form or substituted with a cleavable residue, e.g. amino or benzylamino, can be obtained starting from compounds XXI (Y10= reactive esterified hydroxy) by epoxidation, e.g. by means of hydrogen peroxide, and subsequent reaction with ammonia or a suitable derivative which gives off during the reaction, as indicated a protected, resp. substituted amino group, and possibly ring opening with an acid Yg-H thereof.

The preparation of the starting materials XXI (Y-j_0= bromine) required for this reaction is described under method variant d).

The reduction of the carbonyl group in compounds XX according to method variant f) takes place, for example, by treatment with a light metal or dilite metal hydride or by catalytic hydrogenation.

Suitable light metal or dilate metal hydrides are, for example, borohydrides, such as the borane/tetrahydrofuran complex, alkali metal borohydrides, such as sodium borohydride, and alkali metal aluminum hydrides, such as lithium aluminum hydride or sodium diethylaluminum dihydride. By suitable selection of the reducing agent, the reduction can be controlled so that together with the reduction of the carbonyl group, the protecting group can also be cleaved off. Thus, an intermediate XX, where the nitrogen atom is acylated, can be reduced directly to the corresponding compound V. Furthermore, using sodium borohydride as a reducing agent gives predominantly one diastereomer, using sodium diethylaluminum hydride gives predominantly the other diastereomer.

The catalytic hydrogenation of the carbonyl group takes place, for example, by the action of hydrogen in the presence of a suitable noble metal catalyst, e.g. Adam-platinum oxide, preferably in the temperature range from about 40 to about 60°C, whereby at the same time an α-aralkyl group can also be cleaved off reductively.

The intermediate products XX are obtained, for example, by halogenating a compound with the formula

where Y1Q means reactive, esterified hydroxy, in the a-position to the carbonyl group, e.g. by treatment with bromine, and cyclizes the reaction product with the formula with ammonia or a suitable derivative which emits during the reaction, e.g. as indicated, a protected or substituted amino group. Starting substances XXIV you get, for example, by reacting a lower alkyl ester of an acid where Y. is dilavereal oxy- or lower alkylenedioxy-methylene, e.g. diethoxy- or ethylenedioxymethylene, with one mole each of an organometallic compound of the formula R2~M (XXVI) and R3~M (XXVII), where M means a residue of the formula -Li, -Na or Mg-halogen, and transfer of the formed hydroxy group in reactive, esterified hydroxy and ketal cleavage, e.g. using hydrochloric or hydrobromic acid. The intermediates XX can further be prepared by reacting a compound with the formula R^-H (XI) in the presence of a Lewis acid, e.g. aluminum trichloride, with an acid of the formula

where Y^ is hydrogen or α-aralkyl, e.g. benzyl, or a reactive acid derivative, e.g. the chloride, of the same.

The epimerization of the method obtainable compound of formula V occurs in principle by nucleophilic substitution and reintroduction of the hydroxy group, whereby one step occurs during configuration inversion, the other during configuration maintenance. Thus one can condense a compound V with erythro configuration by reaction with an alkali metal cyanate and hydrochloric acid to the corresponding N-carbamyl compound with erythro configuration, cyclize this with thionyl chloride to the corresponding trans compound with the formula

where X is iminomethylene, with threo configuration and hydrolyzes this by treatment with an alkali metal hydroxide, e.g. with potassium hydroxide, in an aqueous alkanol, e.g. 50% methanol, to the corresponding threo compound V and vice versa. A variant of this method consists in acylating the compound V first by treatment with a carboxylic acid anhydride, e.g. lower alkanoic anhydride with the formula R'-C(=0)-Y12(XXVIII) where R' means a hydrogen carbon residue and Y^2 means chlorine or a group -0-C(=0)-R', preferably with acetic anhydride, reacts the reaction product with thionyl chloride to the corresponding oxazolidinium chloride of the formula II, where X means a group of the formula C - R'Cl , and then hydrolyzes, e.g. with caustic soda. Here, too, epimerization occurs during configuration inversion on the exocyclic C atom.

The facultative splitting of an isomer mixture obtainable by the method or the separation of the desired isomer of such and the splitting into the enantiomers takes place in an analogous way as indicated for compounds of formula I, but preferably by formation of diastereomeric intermediate bonds, which in turn have different physical properties, splitting these and again releasing the compound V, in the individual enantiomers. For the formation of diastereomeric intermediate compounds, optically active acids which form salts, esters or amides with compounds V, such as D- or L-tartaric acids, di-o-toluylene tartaric acid, malic acids, mandelic acid, camphorsulfonic acid or quinic acid, are particularly suitable.

As facultative conversion reactions of compounds obtainable by the method into other compounds of formula V and mutual conversions of bases and salts obtainable by the method into each other, the reaction methods indicated for compounds of formula I and their salts are particularly taken into account.

The compounds with the formulas I and V respectively pharmaceutically usable salts thereof are preferably used as active substances in pharmaceutical preparations. These are those for enteral as well as oral or rectal, and parenteral administration to warm-blooded beings, which preparations contain the pharmacologically active substances alone or together with a pharmaceutical, usable carrier material. The dosage of the active substances depends on the nature of the warm-blooded being, the age and the individual condition, as well as on the method of application.

Usually, to calculate for an approx. 75 kg heavy warm-blooded being by oral application an approximate daily dose of approx. 10-100 mg, advantageously divided into several equal partial doses.

The new pharmaceutical preparations contain e.g. from approx. 10% to approx. 80%, preferably from approx. 20% to approx. 60% of the active substance. With the invention obtainable pharmaceutical preparations for enteral or parenteral administration is e.g. such in dosage unit form as dragees,

tablets, capsules or suppositories, further ampoules.

These are produced in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilization methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a formed mixture and processing the mixture, respectively. the granulate, if desired or necessary, after the addition of suitable excipients, into tablets or dragee cores.

Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binder,

as starch adhesives using e.g. corn, wheat, rice or potato starch, gelatins, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or,

if desired, explosives, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, Agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily viscosity-regulating agents and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium

or calcium stearate, and/or polyethylene glycol. Dragé cores are provided with suitable, possibly gastric juice-resistant coatings, whereby one uses, among other things, concentrated sugar solutions, which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or , for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragee coatings may have added dyes or pigments, e.g. for identification or for characterization of different active substance doses.

Additional orally usable pharmaceutical preparations are suppositories of gelatins, such as soft, closed capsules of gelatin and a plasticizer, such as glycerin or sorbitol. The capsules may contain active substances in the form of a granulate, e.g. in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate and possibly stabilizers. In soft capsules, the active substance is dissolved or suspended, preferably in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, whereby stabilizers may also be added.

As rectally applicable pharmaceutical preparations come into consideration e.g. suppositories, which consist of a combination of the active ingredient with a suppository base. As a suppository base material, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active ingredient with a base material, such as base materials e.g. in terms of liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are suitable in the first instance, e.g. a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or carriers, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilizers.

The present invention likewise relates to the use of the compounds of formula I and V as well as the salts of such compounds with salt-forming properties, preferably for the treatment of depression.

The following examples illustrate the invention described above, but they should in no way limit its scope. Temperatures are given in degrees Celsius, pressures in mbar. The ring systems underlying the compounds of formula I are designated and numbered as follows:

Pyrrolidino[1,5-c]oxazolidine Piperidino[1,6-c]oxazolide

Example 1

erythro- and threo-1-(3-chlorophenyl)-5,5-dimethyl-pyrrolidino [1,5-c]oxazolidin-3-one

27.6 g (0.115 mol) of erythro-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol are dissolved in 630 ml of a 20% solution of phosgene in toluene and added dropwise while cooling a ice-water bath at 20-25°C internal temperature during 40 minutes with a solution of 58 g (80 ml, 0.57 mol) of triethylamine in 80 ml of toluene. The yellowish reaction mixture, in which little by little a suspension forms, is then stirred for 3 days at room temperature. While cooling with an ice-water bath, 750 ml of water are then added dropwise, the organic phase is separated, washed twice with 150 ml of water each time, dried over sodium sulphate and evaporated to dryness using a water jet pump. The residue (brownish oil) is dissolved in 50 ml of toluene and filtered over

a layer of silica gel. One elutes with toluene-ethyl acetic acid-

ester-bald (10:1) and evaporates the solvent using a water jet pump. Pure erythro-1-(3-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]-oxazolidin-3-one is obtained as a pale gray oil, which can be crystallized at 0°C by trituration with hexane. After recrystallization from hexane, a crystalline product with m.p. 84-86°C.

26.4 g (0.11 mol) of threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol are dissolved in 600 ml of a 20% solution of phosgene in toluene and added dropwise under cooling an ice water bath at 20-25°C. internal temperature during 40 minutes with a solution of 55 g (0.55 mol) of triethylamine in 75 ml of toluene. The reaction mixture, in which a yellowish suspension gradually formed, is then stirred for 3 days at room temperature. While cooling with an ice water bath, 700 ml of water are then added dropwise, the organic phase is separated, washed twice with 150 ml of water each time, dried over sodium sulphate and evaporated to dryness using a water jet pump. The remaining slightly reddish oil is dissolved in 50 ml of ether and crystallizes by adding 50 ml of hexane, first at room temperature then at 0°C. After filtering and drying the extracted material at 50°C in a high vacuum, white crystals of threo-1-(3-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one are obtained with m.p. . 83-84°C.

Each time, erythro-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol or threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol can be prepared as follows: a) 35.4 ml (0.25 mol) of diisopropylamine are dissolved in 350 ml of tetrahydrofuran and cooled under nitrogen with a dry ice-acetone bath at -78°C. At this temperature, 180 ml (0.29 mol) of an approx. 1.6 molar solution of butyllithium in hexane. After removing the cooling bath, the internal temperature is allowed to rise little by little to -10°C. The solution of lithium diisopropylamine thus formed is again cooled to -78°C, added dropwise over 20 minutes with 32 g (0.25 mol) of 1-nitroso-2,2-dimethylpyrrolidine and then stirred for a further 10 minutes. Then, over the course of 15 minutes, add 35.2. g (0.25 mol) of 3-chlorobenzaldehyde and leave to stir for a further 3 hours at -75°C. The orange colored solution is then added dropwise over the course of 20 minutes with a solution of 40 ml (0.7 mol) of glacial acetic acid in 80 ml of tetrahydrofuran. The now pale yellow reaction mixture is heated by removing the cooling bath to room temperature and is then poured onto a mixture of 1 liter of saturated sodium chloride solution and 1 liter of methylene chloride. After shaking, the aqueous lower phase is separated and washed twice with 200 ml of methylene chloride each time. The combined organic phases are washed with 200 ml of water, dried over sodium sulphate and evaporated to dryness using a water jet pump. The immediately crystallized residue is dissolved hot in a mixture of 180 ml of toluene and 270 ml of hexane and allowed to crystallize. One extracts, dries at 60°C in high vacuum and obtains pure erythro-(3-chlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol in the form of white crystals with m.p. 143-144°C. The filtrate evaporated first by water jet vacuum and then in high vacuum gives a brownish, oily residue, in which the threo-(3-chlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched. An analytical sample of the threo-diastereomers obtained as oil can be obtained by filtration over a layer of silica gel with a toluene-acetic ester 20:1 mixture as eluent. b) 32.1 g (0.12 mol) of crystalline erythro-(3-chlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol are dissolved in a mixture of 180 ml of toluene and 120 ml dioxane. Dry chlorine hydrogen gas is then introduced for one hour at room temperature. The reaction mixture is then stirred for 12 hours at room temperature, whereby the solution is gradually colored deep yellow. The formed nitrosyl chloride is expelled: then by passing nitrogen for 2 hours from the solution, which is again colored light yellow, and the reaction mixture is cooled with an ice-water bath to 0°C. The crystallized product is filtered off, washed with ether and dried in a high vacuum at 50°C. Crystalline erythro-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 168-169°C. To release the base, 27.6 g (0.1 mol) of hydrochloride are dissolved in 280 ml of water and added dropwise while cooling in an ice-water bath with 26 ml of semi-concentrated caustic soda. The thick, white suspension is stirred for another 30 minutes, filtered, the filter residue is washed with water and then dried in a high vacuum at 60°C. Erythro-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol is obtained in the form of white crystals, m.p. 12o-121°C. c) The oil (28.1 g) which was recovered as described under a), in which the threo-(3-chlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched, is dissolved in 120 ml of toluene and bubbled through with a stream of dry hydrogen chloride gas for 1 hour at room temperature. The reaction mixture is stirred for 12 hours at room temperature and the nitrosyl chloride formed is expelled by passing nitrogen for 2 hours. The yellow-brown suspension is then shaken twice with 100 ml of water each time.

The combined aqueous phases are washed twice each time

50 ml of methylene chloride and make strongly alkaline with concentrated caustic soda. The precipitated product is filtered off, washed with water and dried in a high vacuum at 60°C. Crude threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)methanol is obtained. An analytical sample of the base is obtained by recrystallization from iso-propanol, m.p. 98-99°C. The crude product is dissolved in 70 ml of methanol and 20 ml of an approx. 4n solution of hydrogen chloride in diethyl ether while cooling with an ice-water bath. After addition of ether, the white threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride crystallizes, which is filtered off, washed with ether and dried in high vacuum at 60°C, m.p. 209-210°C.

Example 2

Erythro- and threo-1-(3,4-dichlorophenyl)-5,5-dimethyl-pyrrolidino [1,5-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 25 g (0.91 mol) erythro-(3,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, 65 ml triethylamine and 500 ml 20% phosgene solution in toluene erythro-1-(3,4-dichlorophenyl)-5,5-dimethylpyrrolidino[1,5-c]oxazolidin-3-one in the form of white crystals with m.p. 125-126°C (from hexane) and starting from 6.3 g (0.023 mol) threo-(3,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, 16.. 3 ml of triethylamine and 120 ml of 20% phosgene solution in toluene, threo-1-(3,4-dichlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one in the form of white crystals with m.p. 108-109° (from diethyl ether/hexane).

Each time, erythrocytes serving as starting material or threo-1-(3,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol can be prepared, e.g. as follows: a) Analogous to the method described in example la) starting from 4, 3.7 g (0.25 mol) of 3,4-dichlorobenzaldehyde and 32.0 g (0.25 mol) of 2,2-dimethyl are obtained -1-nitroso-pyrrolidine the crystalline erythro-(3,4-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol with m.p. 172-174°C as well as an orange-brown oil, in which the diastereomeric threo-1-(3,4-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-'2-yl)-methanol is enriched .<b>)Analogous to the method described in example 1 b), starting from 35.7 g (0.11 mol) erythro-(3,4-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidine) is obtained -2-yl)-methanol by treatment with hydrogen chloride gas in a toluenedioxane mixture crystalline erythro-(3,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 275-276°C. The crystalline base liberated from the salt melts at 118-119°C. c) Analogous to the method described in example 1 c), based on that according to 2 a)

formed oily residue by treatment with chlorine hydrogen gas in toluene and subsequent crystallization from methanol/diethyl ether pure threo-(3,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 247-249 C. The crystalline base liberated from the salt melts at 76-78°C.

Example 3

Erythro- and threo-1-(4-chlorophenyl)-5,5-dimethylpyrrolidino [1,5-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 3.3 g (0.0137 mol) of erythro-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, 6.9 g of triethylamine and 75 ml of a 20% phosgene solution in toluene erythro-1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one in the form of pale yellowish crystals with m.p. 118-119°C (from hexane) and starting from 2.5 g (0.01 mol) threo-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, 5.3 g triethylamine and 60 ml of a 20% phosgene solution in toluene threo-1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one in the form of pale yellow crystals with m.p. 101-103°C

(of diethyl ether/hexane).

Each time, erythrocytes serving as starting material or threo-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol can e.g. is prepared as follows: a) Analogous to the method described in example 1 a), starting from 35.2 g (0.25 mol)

4-chlorobenzaldehyde and 32.0 g (0.25 mol) of 2,2-dimethyl-l-nitroso-pyrrolidine crystalline erythro-(4-chlorophenyl)-(5,5-dimethyl-l-nitroso-pyrrolidin-2-yl) )-methanol with m.p. 161-162°C as well as a brownish crystalline slurry, in which the diastereomeric threo-(4-chlorophenyl)-(5,5-dimethyl-1-nitroso-pyrroli-

din-2-yl)-methanol is enriched. An analytical sample of the isomer-free threo-diastereomers can be obtained by filtration over a layer of silica gel with toluene/acetic ester (20:1) as eluent. After evaporation of the solvent, the product precipitates in the form of white crystals with m.p. 113-115°C. b) Analogous to the method described in example 1 b), starting from 2 6.8 g (0.1 mol) of erythro-(4-chlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) is obtained )-methanol by treatment with chlorine hydrogen gas in a toluene/dioxane mixture crystalline erythro-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol with m.p. 227-228°C. The crystalline base liberated from the salt melts at 124-125°C. c) Analogous to the method described in example 1 c), starting from 30 g of the one under 3 a)

formed crystal mush, in which the threo-(4-chlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol has already been enriched by treatment with hydrogen chloride gas in toluene and subsequent crystallization of methanol/diethyl ether threo The -(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 200-201°C. The crystalline base liberated from the salt melts at 79-80°C.

Example 4

Erythro- and threo-1-(3-methylphenyl)-5,5-dimethylpyrrolidino [1,5-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 4.4 g (0.02 mol) of erythro-(3-methylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, 10.1 g of triethylamine and 110 ml of a 20% phosgene solution in toluene erythro-1-(3-methylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one in the form of an amorphous white powder with m.p. 50-60°C and starting from 2.9 g (0.013 mol) threo-(3-methylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, 6.7 g triethylamino and 75 ml of a 20% -ig phosgene solution in toluene threo-1-(3-methylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one in the form of white crystals with m.p. 65-67°C (from hexane).

The erythro serving as starting material or threo-(3-methylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol can e.g. is prepared as follows: a ) Analogous to the method described in example 1 a), starting from 15.0 g (0.125 mol) 3-toluylaldehyde and 16 g (0.125 mol) 2,2-dimethyl-1-nitroso-pyrrolidine-2 -yl)-methanol hydrochloride with m.p. 136-137°C

as well as a brownish oil, in which the diastereomeric threo-(3-methylphenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched.

b) Analogous to the method described in example 1 b), starting from 14.9 g (0.06 mol) erythro-(3-methylphenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -

methanol by treatment with chlorine hydrogen gas in a toluene/dioxane mixture crystalline erythro-(3-methylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 200-202°C.

c) Analogous to the method described in example 1 c), starting from 14 g of the one under 4 a)

obtained oil, in which threo-(3-methylphenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched, by treatment with hydrogen chloride gas in toluene and subsequent crystallization from isopropanol/diethyl ether pure threo-(3-methylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 230-232°C.

Example 5

Erythro- and threo-l-phenyl-5,5-dimethyl-pyrrolidino-[1,5-cI oxazolidin-3-one

In an analogous manner to that described in example 1, the starting material is 5 g (0.024 mol) of erythro-phenyl-(5,5-dimethylpyrrolidin-2-yl)-methanol, 17 ml of triethylamine and 133 ml of a 20% phosgene- solution in toluene erythro-l-phenyl-5,5-dimethyl-pyrrolidino [1,5-c]oxazolidin-3-one in the form of white crystals with m.p. 135-137°C (from hexane) and starting from 1.3 g (0.0006 mol) threo-phenyl-(5,5-dimethylpyrrolidin-2-yl)-methanol,

4.4 ml of triethylamine and 35 ml of a 20% phosgene solution in toluene threo-l-phenyl-5,5-dimethyl-pyrrolidino-[1,5-c]-oxazolidin-3-one in the form of white crystals with m.p. 70-71°C (from ether/hexane).

The .as starting material used erythro- or threo-phenyl-(5,5-dimethylpyrrolidin-2-yl)-methanol can e.g. is prepared as follows: a) Analogous to the method described in example 1 a), starting from 13.3 g (0.125 mol) benzaldehyde and 16.0 g (0.125 mol) 2,2-dimethyl-1-nitroso-pyrrolidine crystalline erythro-phenyl-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol with m.p. 119-121°C as well as a brownish oil, in which the diastereomeric threo-phenyl-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched. b) Analogous to the method described in example 1 b), starting from 15.6 g (0.066 mol)

erythro-phenyl-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol by treatment with chlorine hydrogen gas in a toluene/dioxane mixture crystalline erythro-phenyl-(5,5-dimethylpyrrolidin-2- yl)-methanol hydrochloride with m.p. 169-170°C. The crystalline base liberated from the salt melts at 105-106°C.

c) Analogous to the method described in example 1 c), starting from 11 g of the according to 5 a)

obtained residue by treatment with chlorine hydrogen gas in toluene and subsequent crystallization from ethanol/diethyl ether pure threo-phenyl-(5,5-dimethylpyrrolidin-2-yl)-methanol-

hydrochloride with m.p. 222-225°C. The base liberated from the salt is obtained as a yellowish oil.

Example 6

Erythro- and threo-1-(1-naphthyl)-5,5-dimethylpyrrolidino[1,5-c] oxazolidin-3-one

In an analogous manner as described in example 1, starting from 4 g (0.013 mol) erythro-(1-naphthyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride, 11.5 ml triethylamine and 75 ml of a 20% phosgene solution in toluene after two crystallizations of ether-hexane erythro-1-(1-naphthyl)-5,5-dimethyl-pyrrolidino-[1,5-c]oxazolidin-3-one in form of pale yellowish crystals with m.p. 138-139°C, and starting from 1.0 g (0.003 mol) threo-(1-naphthyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, 2.8 ml of triethylamine and 18.5 ml of a 20% phosgene solution in toluene threo-1-(1-naphthyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one in the form of light brown crystals with m.p. 132-134°C (from diethyl ether/hexane).

The erythro serving as starting material or threo-(1-naphthyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol can, for example, be prepared as follows: a) analogously to the method described in example 1 a), starting from 19.5 g ( 0.125 mol) 1-naphthaldehyde and 16.0 g (0.125 mol) 2,2-dimethyl-1-nitrolo-pyrrolidine crystalline erythro-(1-naphthyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) )-methanol with m.p. 159-160°C, as well as a brownish crystalline slurry, in which the diastereomeric threo-(1-naphthyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched. b) analogously to the method described in example 1 b), starting from 9 g (0.031 mol) erythro-(1-naphthyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is obtained by treatment with hydrogen chloride gas in toluene and recrystallization of the crude product from a methanol/diethyl ether mixture erythro-(1-naphthyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol hydrochloride in the form of white crystals with m.p. . 229-230°C. The base liberated from the salt melts at 152-154°C.

c) Analogous to the method described in example 1 c), starting from 9.2 g of that according to 6 a)

obtained crystal slurry, in which the threo-(1-naphthyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched,

by treatment with chlorine hydrogen gas in toluene and subsequent 2-fold crystallization from methanol/diethyl ether pure threo-(1-naphthyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol hydrochloride with m.p. 250°C (decomposition).

Example 7

Erythro- and threo-1-(3-trifluoromethylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 3.0 g (0.009 mol) erythro-(3-trifluoromethylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride, 6.7 g of triethylamine and 52 ml of a 20% phosgene solution in toluene erythro-1-(3-trifluoromethylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c] oxazolidin-3-one in the form of white crystals with m.p. 71-72°C (from diethyl ether/hexane) and starting from 1.9 g

(0.006 mol) threo-(3-trifluoromethylphenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol, 5.2 ml of triethylamine and 34 ml of a 20% solution of phosgene in toluene threo-1 -(3-trifluoromethylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one in the form of yellowish crystals with m.p. 70-71°C (from diethyl ether/hexane).

The erythro serving as starting material or threo-(3-trifluoromethylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol can e.g. is prepared as follows: a) Analogous to the method described in example 1 a), starting from 10.4 g (0.06 mol) 3-trifluoromethylbenzaldehyde and 7.7 g (0.06 mol) 2,2-dimethyl -1-nitroso-pyrrolidine after crystallization from toluene erythro-(3-trifluoromethylphenyl)-(5,5-dimethyl-1-nitrosopyrrolidin-2-yl)-methanol with m.p. 172-174°, as well as a brownish oil, in which the diastereomeric threo-(3-trifluoromethylphenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched.

"' Analogous to the method described in example 1 b), starting from 9.06 g (0.03 mol) erythro-(3-trifluoromethylphenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol by treatment with hydrogen chloride gas in a toluene/dioxane mixture and recrystallization of the crude product from methanol/diethyl ether erythro-(3-trifluoromethylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride in the form of white crystals with mp 205-206° C. The crystalline base liberated from the salt melts at 104-105° C.

c) Analogous to the method described in example 1 c), starting from 7.9 g of that according to 7 a)

oily residue obtained, in which the threo-(3-trifluoro-methylphenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched, by treatment with hydrogen chloride gas in toluene and subsequent crystallization of methanol/diethyl ether pure threo-(3-trifluoromethylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 224-227°C. The crystalline base liberated from the salt melts at 65-67°C.

Example 8

Erythro- and threo-1-(3-chlorophenyl)-5,5-dimethylpiperidino[1,6-c] oxazolidin-3-one -

In an analogous manner as described in example 1, starting from 5.8 g (0.023 mol) erythro-(3-chlorophenyl)-(6,6-dimethyl-piperidin-2-yl)-methanol, 11.6 g of triethylamine and 125 ml of a 20% phosgene solution in toluene erythro-1-(3-chlorophenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one in the form of white crystals with m.p. 69-70°C (of ether/hexane) and starting from 1.0 g (0.004 mol) threo-(3-chlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol, 2.9 ml of triethylamine and 25 ml of a 20% phosgene solution in toluene threo-1-(3-chlorophenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one in the form of white crystals with m.p. 69-71° (from hexane).

The erythro serving as starting material or threo-(3-chlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol can e.g. is prepared as follows: a) Analogously to the method described in example 1 a), starting from 14.1 g (0.1 mol) 3-chlorobenzaldehyde and 14.2 g (0.1 mol) 2,2-dimethyl- 1-nitroso-piperidine - see under d) - crystalline erythro-(3-chlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl)-methanol with m.p. 125-127°C as well as an orange-brown oil, in which the diastereomeric threo-(3-chlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl)-methanol is enriched. An analytical sample of the isomer-free threo-diastereomers can be obtained by filtration over a layer of silica gel with toluene/ethyl acetate (20:1) as eluent. After evaporation of the solvent, the product precipitates in the form of pale yellow crystals with m.p. 108-110°C. b) Analogous to the method described in example 1 b, starting from 14.0 g (0.05 mol) erythro-(3-chlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl)- methanol by treatment with hydrogen chloride gas in a toluene/dioxane mixture crystalline erythro-(3-chlorophenyl)-(6,6-dimethyl-piperidin-2-yl)-methanol hydrochloride with m.p. 225-227°C.

The crystalline base liberated from the salt melts at 138-139°C.

c) Analogous to the method described above under b), starting from 3.6 g (0.012 mol) of the

pure threo-(3-chlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl) methanol by treatment with hydrogen chloride gas in a toluene/dioxane mixture crystalline threo-(3-chlorophenyl)-( 6,6-dimethylpiperidin-2-yl)-methanol hydrochloride with m.p. 240-241°C. The crystalline base liberated from the salt melts at 155-156°C. d) 19.4 g (0.1 mol) of 2,2-dimethylpiperidine hydrobromide are dissolved in a mixture of 30 ml of water and 15 ml of glacial acetic acid and added dropwise with 41.4 ml (0.3 mol) of a 50% ig aqueous sodium nitrite solution at room temperature within an hour. The reaction mixture is stirred for a further 2 hours at room temperature, then cooled in an ice-water bath to 0°C and at this temperature 25 ml of concentrated caustic soda is added dropwise. The yellow solution is then exhaustively extracted repeatedly with 100 ml of diethyl ether each time. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate and evaporated at 30°C bath temperature with a water jet vacuum. The yellow, oily residue is then distilled in a water jet vacuum, whereby 2,2-dimethyl-1-nitroso-piperidine is distilled as a yellow liquid with Kp13= 101-102°C.

Example 9

Erythro- and threo-1-(3,4-dichlorophenyl)-5,5-dimethylpiperidino-[1,6-c]oxazolidin-3-one

In an analogous manner to that described in example 1, starting from 9.0 g (0.031 mol) erythro-(3,4-dichlorophenyl)-(6,6-dimethyl-piperidin-2-yl)-methanol, 15, 8 g of triethylamine and 170 ml of a 20% phosgene solution in toluene erythro-1-(3,4-dichloro-phenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one in the form of white crystals with m.p. 127-129°C (from ether-hexane) and starting from 6.7 g (0.023 mol) threo-(3,4-dichlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol, 11.7 g triethylamine and 130 ml of a 20% phosgene solution in toluenethreo-1-(3,4-dichlorophenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one

in the form of pale yellowish crystals with m.p. 120-121°C

(of diethyl ether/hexane).

The erythro serving as starting material or threo-(3,4-dichlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol, can e.g. is prepared as follows: a) Analogous to the method described in example 1 a), starting from 17.6 g (0.1 mol) 3,4-dichlorobenzaldehyde and 14.2 g (0.1 mol) 2,2-dimethyl -1-nitroso-piperidine crystalline erythro-(3,4-dichlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl)-methanol with m.p. 140-141°C as well as a yellow-brown crystalline slurry, in which the diastereomeric threo-(3,4-dichlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl)-methanol is enriched. An analytical sample of the isomer-free threo-diastereomers can be obtained by filtration over a layer of silica gel with a toluene/acetic ester mixture (10:1) as eluent. After evaporation of the solvent, the product is obtained in the form of white crystals with m.p. 173-174°C. b) Analogous to the method described in example 1 b), starting from 5.5 g (0.017 mol) erythro-(3,4-dichlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl) -methanol by treatment with chlorine hydrogen gas in a toluene/dioxane mixture the erythro-(3,4-dichlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol hydrochloride with m.p. 288°C (decomposition).

The base liberated from the salt melts at 132-133°C.

c) Analogous to the reaction described above under b), starting from 3.0 g (0.009 mol) threo-(3,4-dichlorophenyl)-(6,6-dimethyl-1-nitroso-piperidin-2-yl)- methanol by treatment with hydrogen chloride gas in a toluene/dioxane mixture crystalline threo-(3,4-dichlorophenyl)-(6,6-dimethyl-piperidin-2-yl)-methanol hydrochloride with m.p. 257-258°. The base liberated from the salt melts at 153-154°C.

Example 10

Erythro- and threo-1-(2,6-dichlorophenyl)-5,5-dimethylpyrrolidino [1,5-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 4 g (0.003 mol) erythro-(2,6-dichlorophenyl)-5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride, 9 ml of triethylamine and 70 ml of a 20% phosgene solution in toluene erythro-1-(2,6-dichlorophenyl)-5,5-dimethylpyrrolidino[1,5-c]oxazolidin-3-one in the form of white crystals with m.p. 92-94°C (of diethyl ether/hexane) and starting from 2.0 g (0.006 mol) threo-(2,6-dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol hydrochloride, 4.5 ml of triethylamine and 35 ml of a 20% phosgene solution in toluene, 0.5 g (26.3% of theory), threo-1-(2,6-dichlorophenyl)-5,5- dimethyl-pyrrolidino [1,5-c]oxazolidin-3-one as white crystals from ether/hexane, m.p. 14 3-144°C (of diethyl ether/hexane).

The erythro serving as starting material or threo-(2,6-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol or its hydrochloride can e.g. is prepared as follows: a) Analogous to the method described in example la) starting from 21.9 g (0.125 mol) 2,6-dichlorobenzaldehyde and 16 g (0.125 mol) 2,2-dimethyl-1-nitroso-pyrrolidine crystalline erythro-(2,6-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol, m.p. 178-180°C, as well as 18.5 g of a yellowish crystalline slurry, in which the diastereomeric threo-(2,6-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched. b) Analogous to the method described in example 1 b), starting from 19.0 g (0.063 mol) erythro-(2,6-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol by treatment with hydrogen chloride gas in toluene, crystalline erythro-(2,6-dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol hydrochloride, m.p. 243-244°C. The one of the salt

liberated, crystalline base melts at 112-114oc.

c) Analogous to the method described in example 1 c) one obtains starting from 18.5 g of the crystal slurry obtained according to a) above, in which the diastereomer is enriched, by treatment with chlorine hydrogen gas in toluene and

subsequent crystallization from ethanol/diethyl ether pure threo-(2,6-dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl) methanol hydrochloride, m.p. 224-225°C. The crystalline base liberated from the salt melts at 137-138°C.

Example 11

Erythro- and threo-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol

Dissolve 3.5 g of crude (3-chlorophenyl)-[1-(cyclohexyliminomethyl)-5,5-dimethylpyrrolidin-2-yl]-methanol in 50 ml of methanol, add 50 ml of 2n-sodium hydroxide solution and boil for 4 hours at reflux. Evaporate to dryness, take up in ether, wash with saturated sodium chloride solution, dry over sodium sulfate and evaporate again to dryness. A mixture of erythro- and threo-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol is obtained, which can be separated by fractional crystallization from iso-propanol and chromatography on silica gel in the erythro form with m.p. 120.5°C and in the threo form with m.p. 9 6°C.

The (3-chlorophenyl)-[1-(cyclohexyl-iminomethyl)-5,5-dimethyl-pyrrolidin-2-yl]-methanol used as starting material can be prepared as follows: a) 9.9 g of 2,2-dimethylpyrrolidine is dissolved in 25 ml of methanol, 7.4 g of formic acid ethyl ester are added and heated

3 hours in the case of reflux. Evaporate to half, add 100 ml of toluene, separate the toluene phase, wash twice with water and then with saturated sodium chloride solution and evaporate under reduced pressure to dryness. You get crude 1-formyl-2,2-dimethyl-pyrrolidine, which can be used without

further purification.

b) The crude product obtained according to a) is stirred with 9.4 g of dimethyl sulfate and heated under nitrogen for 3 hours at

70°C. Allow to cool, take up in 100 ml of ether, wash twice with n-sodium bicarbonate and then with saturated sodium chloride solution and evaporate to dryness. Crude l-methoxymethylene-2,2-dimethyl-pyrrolidinium methosulphate is obtained, which is immediately further processed. c) The product obtained according to b) is stirred with 20 g of cyclohexylamine and stirred for 15 hours at room temperature.

Take up in methylene chloride, wash with 10% potassium hydroxide solution, dry over sodium sulphate and evaporate to dryness. 15 g of 1-cyclohexyl-iminomethyl-2,2-dimethylpyrrolidine is obtained, which is immediately further processed.

d) The product obtained according to c) is dissolved in 50 ml tetrahydrofuran, cooled to -78°C under argon, added

6.5 g of tertiary butyllithium, heated for one hour to -25°C

and cooled again to -78°C. 10.5 g of 3-chlorobenzaldehyde are then added dropwise with vigorous stirring at -78°C. The mixture is stirred for 15 minutes at -70°C and then slowly allowed to warm to room temperature, 10 ml of methanol is added, neutralized with dilute acetic acid and evaporated under reduced pressure to dryness. Crude (3-chlorophenyl)-[1-(cyclohexyliminomethyl)-5,5-dimethyl-pyrrolidin-2-yl]-methanol is obtained, which can be used without further purification.

In an analogous way, the compounds of formula V can also be prepared according to examples 2-10.

Example 12

Erythro- and threo-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol Dissolve 5 g of crude (3-chlorophenyl)-(1-benzyl-5,5-dimethyl)-methanol in 50 ml of methanol, 0.8 g of palladium charcoal (5% strength) is added and hydrogenated at an excess pressure of 0.5 bar at 50°C until complete hydrogen uptake (approx. 40 minutes). It is filtered off from the catalyst and evaporated to dryness. A mixture of erythro- and threo-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol is obtained, which can be split up by fractional crystallization first from ethyl hexane and then from isopropanol in erythro- the form with m.p. 120°C and the threo form with m.p. 97°C.

The (3-chlorophenyl)-(1-benzyl-5,5-dimethyl)methanol used as starting material can e.g. is prepared as follows: a) 2.5 g of sodium hydride (50 ml of a 5% suspension in mineral oil, deoiled with hexane) is suspended in a mixture of 100 ml of tetrahydrofuran and 100 ml of dimethylsulfoxide under nitrogen and added with stirring at 5°C dropwise with a solution of 46.7 g of 3-chlorobenzyltriphenylphosphonium bromide and 13.0 g of 4-oxobutyric acid ethyl ester in 150 ml of tetrahydrofuran. It is allowed to stir for 30 hours at room temperature, evaporated at reduced pressure to dryness, absorbed in

1000 ml of ether, shake with 5 g of activated carbon and 50 g of anhydrous sodium sulfate, filter and evaporate to dryness. Crude 5-(3-chlorophenyl)-pent-4-ene-carboxylic acid ethyl ester is obtained in the form of yellowish crystals.

b) The crude product obtained according to a) is dissolved in 100 ml of tetrahydrofuran and added dropwise to a solution

of methyl magnesium bromide (prepared from 5 g of magnesium shavings and 30 g of methyl bromide) in 100 ml of tetrahydrofuran. Leave to stir for 1 hour at room temperature and 4 hours at room temperature

60°C, evaporate to dryness, take up in 500 ml of toluene, shake with activated carbon and anhydrous sodium sulfate, filter and evaporate under reduced pressure to dryness. You get crude 6-(3-chlorophenyl)-2-methyl-hex-5-enol, which is immediately further processed.

c) The crude product obtained according to b) is dissolved in

150 ml of toluene, cool to 5°C, add 100 ml of 20% hydrochloric acid and 2.5 g of tetrabutylammonium chloride and stir vigorously for 1 hour at 5-10°C and 2 hours at room temperature. The organic phase is separated, shaken with 5 g of activated carbon and 10 g of anhydrous magnesium sulfate and filtered. 2-Chloro-6-(3-chlorophenyl)-2-methyl-hex-5-ene is obtained in a solution of toluene.

d) To the production solution obtained according to c) in toluene, 15 g of benzylamine is added, allowed to stir

1 hour at room temperature, then heat slowly to the boiling point temperature, allow to boil for 2 hours at reflux and then evaporate, finally under reduced pressure, to dryness. A viscous oil is obtained, which is taken up in 100 ml of ether. Chlorine hydrogen gas is introduced until no more sediment is formed, suction and drying in contact with the air atmosphere. N-[6-(3-chlorophenyl)-2-methyl-hex-5-enyl)-benzylammonium chloride is obtained, which can be used without further purification. e) The crude product obtained according to d) is dissolved in 100 ml of methylene chloride, 50 ml of trifluoroacetic anhydride and 10 g of sodium carbonate are added and stirred for 2 hours at room temperature. It is washed twice with each time 25 ml of a 10% aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated to dryness. 20.5 g of crude N-[6-(3-chlorophenyl)-2-methyl-hex-5-enyl]-N-benzyl-trifluoroacetamide are obtained. f) The crude product obtained according to e) is dissolved in 75 ml of dioxane and 10 ml of sulfuric acid is added at 10 to 15°C

(density = 1.83). A solution of 8.2 g of N-bromosuccinimide in 50 ml of dioxane is then added while stirring at 10°C. It is left to stir for 30 minutes at 10 to 15°C and 15 hours at room temperature, washed with water and saturated sodium chloride solution and dried over sodium sulfate. A solution of N-[5-bromo-6-(3-chlorophenyl)-6-hydroxy-2-methyl-

hexyl]-N-benzyltrifluoroacetamide in dioxane.

g) The product solution obtained according to f) is added to 80 ml of n-sodium lye and heated for 1 hour while stirring

to reflux temperature. Evaporate vigorously, take up in ether, wash with water and saturated sodium chloride solution, dry over sodium sulfate and evaporate to dryness. You get raw

(3-chlorophenyl)-(1-benzyl-5,5-dimethyl)-methanol, which can be used without further purification.

In an analogous manner, the compounds of formula V according to examples 2-10 can also be prepared.

Example 13

Threo-1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino-[1,5-c]oxazolidin-3-one 6 g threo-1-(4-chlorophenyl)-3-imino-5,5- dimethyl-pyrrolidino-1,5-c]-oxazolidine is suspended in 150 ml of water and 50 ml of phosphate buffer (P = 6.5) and heated for 22 hours with stirring at reflux temperature. Allow to cool, acidify with dilute hydrochloric acid to PR = 4 and shake twice with 100 ml of vinegar each time. The extracts are combined,

washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure to dryness.

The crystalline residue is recrystallized from ethyl acetate/hexane. Threo-1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino [1,5-c]oxazolidin-3-one is obtained, m.p. 100 - 102°C.

The starting material can be produced e.g. according to one of the following methods: a) 23.3 g of threo-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol are dissolved in 100 ml of ethanol and added dropwise while stirring with a solution of 6, 5 g of cyanogen chloride in 25 ml of ethanol. It is heated briefly at reflux temperature, the solvent is distilled off and the residue is crystallized twice from isopropanol. Threo-1-(4-chlorophenyl)-3-imino-5,5-dimethyl-pyrrolidino [1,5-c]-oxazolidine is obtained, which can be used without further purification. b) 23.3 g of erythro-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol are dissolved in 150 ml of n-hydrochloric acid,

8.1 g of potassium cyanate are added and stirred for 12 hours at room temperature. Evaporate until crystallization begins, cool to 5°C, exhaust and allow to dry in contact with air. Erythro-(4-chlorophenyl)-(1-carbamyl-5,5-dimethyl-pyrrolidin-2-yl)-methanol is obtained. This is dissolved in 200 ml of tetrahydrofuran and 12.0 g of thionyl chloride is added dropwise while stirring. It is heated briefly at reflux temperature, evaporated under reduced pressure to dryness and recrystallized from ethanol. Threo-1-(4-chlorophenyl)-3-imino-5,5-dimethyl-pyrrolidino-[1,5-c]oxazolidine is obtained, which according to the IR spectrum is identical to the product obtained according to a).

In an analogous way, the compounds with the formulas I and V according to examples 1, 2 and 4-10 can also be prepared.

Example 14

1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, mixture of diastereomers

Dissolve 1.5 g of erythro-(4-chlorophenyl)-(1-carbamyl-5,5-dimethyl-pyrrolidin-2-yl)-methanol in 25 ml of pyridine, add 1 g

in thionyl chloride and boiled for 4 hours. Evaporate under reduced pressure to dryness, dissolve in ether, wash twice with water and then with saturated sodium chloride solution, dry over sodium sulfate, evaporate to dryness and recrystallize several times from hexane/ether. You get a mixture of

erythro- and threo-1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c] oxazolidin-3-one with m.p. 82-87°C.

The starting material can e.g. produced as follows:

3.0 g of erythro-(4-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol are suspended in 25 ml of n-hydrochloric acid, 1.5 g of potassium cyanate are added and stirred for 12 hours at room temperature.

Evaporate to initial crystallization, cool to

5°C, suction and recrystallize from ethanol/water. Erythro-(4-chlorophenyl)-(1-carbamyl-5,5-dimethyl-pyrrolidin-2-yl)-methanol is obtained, which can be used without further purification.

In an analogous way, the compounds of formula I according to examples 1, 2 and 4-10 can also be prepared.

Example 15

erythro- and threo-1-(3-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]-oxazolidin-3-one

30.5 g of erythro-(3-chlorophenyl)-(1-ethoxycarbonyl-5,5-dimethylpyrrolidin-2-yl)-methanol are dissolved in 100 ml of ethanol and 0.2 g of sodium is added and heated for 4 hours at reflux.

Evaporate to dryness and recrystallize several times

of hexane. Erythro-1-(3-chlorophenyl)-5,5-dimethyl-pyrrolidino [1,5-c]oxazolidin-3-one is obtained with m.p. 83-84°C.

Dissolve 30.5 g of erythro-(3-chlorophenyl)-(1-ethoxycarbonyl-5,5-dimethylpyrrolidin-2-yl)-methanol in 100 ml of ether, add dropwise 11.5 g of thionyl chloride and heat at reflux for 6 hours. Evaporate to dryness, take up in ether,

wash with water as well as with saturated sodium chloride<p>solution, dry over sodium sulfate, re-evaporate to dryness and recrystallize from hexane. Threo-1-(3-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one is obtained with m.p. 81°C.

The starting material can e.g. produced as follows:

Dissolve 47.6 g of erythro-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol in 1000 ml of benzene, add 20 g of anhydrous potassium carbonate, cool to +5°C and add dropwise with vigorous stirring 21 .8 g ethyl chloroformate. It is allowed to stir for 1 hour at 5 to 10°C and 1 hour at room temperature, filtered off and evaporated to dryness. Erythro-(3-chlorophenyl)-(1-ethoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl)-methanol is obtained, which can be used without further purification.

In an analogous manner, the compounds of formula I according to examples 2-10 can also be prepared.

Example 16

Mixture of erythro- and threo-(3-chlorophenyl)-(6,6-dimethyl-piperidin-2-yl)-methanol

26.3 g of 1-(3-chlorobenzoyl)-6,6-dimethyl-piperidine-2-carbonitrile are dissolved in 50 ml of tetrahydrofuran and added dropwise to a solution cooled at -78°C of 12 g of lithium-N,N- diisopropylamide in 150 ml of tetrahydrofuran. The mixture is left to stir for 15 minutes at -78°C, 15 g of 3-chlorobenzaldehyde, dissolved in a little tetrahydrofuran, is added and allowed to warm up to room temperature little by little. The mixture is allowed to stir for 1 hour, 5 g of sodium borohydride in 50 ml of methanol are added, allowed to stir for a further 6 hours, 25 ml of acetone are added, heated for 2 hours at reflux, evaporated to dryness and recrystallized from isopropanol. You get a mixture of erythro-

and threo-(3-chlorophenyl)-(6,6-dimethyl-piperidin-2-yl)-methanol with m.p. 126-131°C.

The 1-(3-chlorobenzoyl)-6,6-dimethylpiperidine-2-carbonitrile used as starting material can be prepared, e.g. by reacting 6,6-dimethylpiperidine-2-carbonitrile, obtainable in an analogous manner as described in example 18a), with 3-chloro-benzoyl chloride/potassium carbonate in methylene chloride.

In an analogous way, the compounds of formula V according to examples 1-7, 9 and 10 can also be prepared.

Example 17

Isomerization of erythro- to threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol

5 g of erythro-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol are dissolved in 50 ml of chloroform, cooled to 0°C and added dropwise with 10 ml of thionyl chloride. Leave to stir for 1 hour at room temperature, rather on 200 g of ice, leave to stir for 30 minutes. at room temperature and 2 hours at reflux temperature, cools again to 0°C, adjusts with caustic soda to pH = 11 and shakes 4 times with each time 50 ml of chloroform. The extracts are combined, washed with water, dried over sodium

sulfate and evaporated to dryness. Take up in vinegar, add 10 ml of 5n-hydrochloric acid, leave to stir for 15 minutes at 0°C and remove with suction. The threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride is obtained with m.p. 209-210°C.

This can be transferred into the free base with m.p. 68°C at

shaking with 100 ml of methylene chloride and 10 ml of 2n sodium hydroxide solution and separation and evaporation of the methylene chloride phase.

In an analogous manner, one can also isomerize the threo isomer to the erythro isomer as well as the erythro-(threo) forms of the compounds of formula V according to examples 2-10 to the threo-(erythro) isomers.

Example 18

Erythro-(4-chlorophenyl)-(5,5-dimethyl- pyrrolidin-2-yl)- methanol

12.5 g of 2-(4-chlorobenzoyl)-5,5-dimethyl-pyrrolidine, dissolved in 50 ml of tetrahydrofuran, is added dropwise to a suspension of 1.6 g of lithium aluminum hydride in 250 ml of tetrahydrofuran. Boil for 2 hours at reflux, cool in the ice bath, carefully add 5 ml of water, leave to stir for 30 minutes, evaporate under reduced pressure to dryness, take up in benzene, wash twice with water and then with saturated sodium chloride solution, dry over sodium sulfate, evaporate again

under reduced pressure and recrystallizes from benzene/dioxane. Erythro-(4-chlorophenyl-(5,5-dimethyl-pyrrolidin-2-yl)-methanol with a melting point of 123-124°C is obtained.

The starting material can e.g. produced as follows:

a) Dissolve 20.8 g of 1-cyclohexyliminomethyl-2,2-dimethylpyrrolidine (compare example 11 c) in 100 ml

tetrahydrofuran, cool to -78°C under argon, add 6.4 g of tertiary butyllithium and stir for 30 minutes at -75°C

to -70°C. The obtained solution is transferred in a wood

-78°C cooled dropping funnel and slowly added dropwise to a vigorously stirred, at -75°C cooled solution of 6.2 g cyanogen chloride in 50 ml tetrahydrofuran. The mixture is left to stir for 30 minutes at -78°C, heated little by little to 20°C, 50 ml of water and 10 ml of methanol are added, left to stir for 4 hours at 20-30°C, evaporated to dryness, taken up in ether, dried over sodium sulfate and reevaporate. 5,5-dimethyl-pyrrolidine-2-carbonitrile is obtained, which can be used without further purification.

b) Dissolve the crude product obtained according to a) and 10 g of 4-chlorobenzene in 150 ml of nitrobenzene, add

30 g of aluminum trichloride in portions and stir for 2 hours at 80°C. Allow to cool, rather in a mixture of 500 g of ice and 500 ml of 5n-hydrochloric acid and leave to stir vigorously for 12 hours.

The formed precipitate is filtered off, dried in air and recrystallized from vinegar. Crude 2-(4-chlorobenzoyl)-5,5-dimethyl-pyrrolidine is obtained, which is used without further purification.

Example 19

Isomerization of erythro- to threo-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol

To a solution of 3.6 g (0.015 mol) erythro-(3-chlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol in 20 ml of dimethylformamide is added dropwise at 0-5°C 1.53 g (0.015 mole) of acetic anhydride. The solution is then stirred for 1 hour at room temperature, then poured into 100 ml of water and extracted twice with 40 ml of diethyl ether each time. The combined organic phases are washed with 30 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness in a water jet vacuum. Erythro-(3-chlorophenyl)-(5,5-dimethyl-1-acetylpyrrolidin-2-yl)methanol is obtained as a colorless oil.

This is dissolved in 15 ml of methylene chloride and added dropwise at 5-10°C over 5 minutes to a solution of 2.6 g of thionyl chloride in 10 ml of methylene chloride. The solution is then stirred at room temperature overnight, then evaporated in a water jet vacuum. Crude threo-1-(3-chlorophenyl)-3-methyl-5,5-dimethylpyrrolidino[1,5-c]oxazolinium chloride is obtained as a thick, soon crystallizing oil. The hygroscopic crystals can be recrystallized from diethyl ether, m.p. 114-117°C.

2.1 g (0.007 mol) of the crystalline oxazolinium chloride is heated in 10 ml of ethanol and 3.5 ml of concentrated caustic soda for 1 hour at reflux. The mixture is then poured on

60 ml of ice-water and extracted three times with 20 ml each time

in ethylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated to dryness under a water jet vacuum. The residue thus obtained is taken up in 5 ml of methanol and 2 ml of hydrogen chloride solution (4n in diethyl ether) is added. After adding a little diethyl ether, the precipitated crystals are filtered off with suction and dried. Threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride with m.p. 208-209°C.

Example 20

Erythro-1-(3-cyanophenyl)-5,5-dimethyl-pyrrolisino[1,5-c]-oxazolidin-3-one

In an analogous manner to that described in example 1, starting from 2.2 g (0.008 mol) of erythro-(3-cyanophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride suspended in 50 ml of toluene, 24 ml of a 12.5% aqueous potassium hydroxide solution and 13.1 ml of a 20% phosgene solution in toluene by working up after 1 hour crystalline erythro-1-(3-cyanophenyl)-5,5-dimethyl -pyrrolidino[1,5-c] oxazolidin-3-one, m.p. 113-115°C.

The starting material can e.g. produced as follows:

a) Analogous to the method described in example 1 a), starting from 16.4 g (0.125 mol) of 3-cyanobenzaldehyde and 16 g (0.125 mol) of 2,2-dimethyl-1-nitroso-pyrrolidine, crystalline erythro-(3 -cyanophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol, m.p. 133-134°. b) Analogously to the method described in example lb), starting from 12.0 g (0.046 mol) erythro-(3-cyanophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is obtained by treatment with hydrogen chloride gas in a toluene/dioxane mixture, crystalline erythro-(3-cyanophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol hydrochloride, m.p. 203-205°C. The crystalline base liberated from the salt melts at 111-113°C.

Example 21

Erythro- and threo-1-(2,4-dichlorophenyl)-5,5-dimethylpyrrolidino-[1,5-c]oxazolidin-3-one

In an analogous manner to that described in example 1, starting from 4.1 g (0.015 mol) of erythro-(2,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, dissolved in 50 ml of toluene, 39 ml of a 25% aqueous potassium hydroxide solution and 24.5 ml of a 20% phosgene solution in toluene by working up after 1 hour crystalline erythro-1-(2,4-dichlorophenyl)-5,5-dimethyl- pyrrolidino [1,5-c]oxazolidin-3-one, m.p. 153-155°C and starting from 3.9 g (0.012 mol) threo-(2,4-dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol in 50 ml toluene, 38.5 ml of a 12.5% potassium hydroxide solution and 20.6 ml of a 20% phosgene solution in toluene by working up after 1 hour threo-1-(2,4-dichlorophenyl)-5,5-dimethyl -pyrrolidino-[1,5-c]-oxazolidin-3-one in the form of a pale yellow resin.

The erythrocyte serving as starting material, or threo-(2,4-dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol can e.g. is prepared as follows: a) Analogous to the method described in example 1 a), starting from 52.5 g (0.3 mol) 2,4-dichlorobenzaldehyde and 38.4 g (0.3 mol) 2,2-dimethyl -1-nitroso-pyrrolidine, the crystalline erythro-(2,4-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol, m.p. 156-158°C, as well as 41.0 g of a yellowish oil in which the diastereomeric threo-(2,4-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched. b) Analogous to the method described in example lb), starting from 49.9 g (0.164 mol) erythro-(2,4-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)- methanol by treatment with hydrogen chloride gas in a toluene/dioxane mixture, crystalline erythro-(2,4-dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol hydrochloride with m.p. 249-251°C. The crystalline base liberated from the salt melts at 113-115°C. c) Analogous to the method described in example 1 c), starting from 41.0 g of that under a)

obtained oil, in which the threo-(2,4-dichlorophenyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is already enriched, by treatment with hydrogen chloride gas in toluene and subsequently two times crystallization of dichloromethane/diethyl ether pure threo-(2,4-dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol hydrochloride with m.p. 221-222°C. The off

the salt liberated base melts at 50-51°C.

Example 22

Erythro- and threo-1-(4-pyridyl)-5,5-dimethyl-pyrrolidino[1,5-c]-oxazolidin-3-one

The analogous method as described in example 1 is obtained starting from 5.0 g (0.018 mol) erythro-(4-pyridyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol dihydrochloride suspended in 70 ml toluene, 77 ml of a 12% aqueous potassium hydroxide solution and 28 ml of a 20% phosgene solution in toluene by working up after 1 hour crystalline erythro-1-(4-pyridyl)-5,5- dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, m.p. 96-98°, whereby a crystalline hydrochloride with mp. 175°C (decomposition),

and starting from 2.7 g (0.013 mol) threo-(4-pyridyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol in 50 ml of toluene, 41 ml of a 12.5% aqueous potassium hydroxide solution and 22 ml of a 20% phosgene solution in toluene by working up after one hour pure threo-1-(4-pyridyl)-5,5-dimethylpyrrolidino-[1,5-c]oxazolidine-3- on in the form of white crystals,

m.p. 120-121°C. When treating with an excess of approx.

4n solution of hydrogen chloride in diethyl ether a crystalline hydrochloride can be prepared, m.p. 205°C (decomposition).

The erythro serving as starting material or threo-(4-pyridyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol can e.g. is prepared in the following way: a) Analogous to the method described in example 1 a), starting from 10.7 g (0.1 mol) pyridine-4-aldehyde and 12.8 g (0.1 mol) 2,2 -dimethyl-1-nitroso-pyrrolidine, 12.8 g of crystalline erythro-(4-pyridyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol, m.p. 181-183°C, as well as 10.5 g of a reddish oil, in which the diastereomeric threo-(4-pyridyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched. b) Analogous to the method described in example 1 b), starting from 12.8 g (0.054 mol) erythro-(4-pyridyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is obtained on treatment with hydrogen chloride gas in a toluene/dioxane mixture crystalline erythro-(4-pyridyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol dihydrochloride, m.p. 225-227°C.

The crystalline base liberated from the salt melts at 122-124°C.

c) Analogous to the method described in example 1 c, starting from 10.5 g of that under a)

oil obtained, in which the threo-(4-pyridyl)-(5,5-dimethyl-1-nitroso-pyrrolidin-2-yl)-methanol is enriched, by treatment with chlorine hydrogen gas in toluene and subsequent 2-fold crystallization of methanol/ ether pure threo-(4-pyridyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol hydrochloride, m.p. 178-179°C. The base liberated from the salt melts at 122-124°C.

Example 23

Erythro- and threo-1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino [1,5-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 3.2 g (0.015 mol) of erythro-(4-chlorophenyl)-(pyrrolidin-2-yl)-methanol, 7.6 g of triethylamine and 85 ml of a 20% -ig phosgene solution in toluene crystalline erythro-1-(4-chlorophenyl)-pyrrolidino[1,5-c]-oxazolidin-3-one, m.p. 114-115°C, and starting from 2.7 g (0.011 mol) threo-(4-chlorophenyl)-(pyrrolidin-2-yl)-methanol hydrochloride, suspended in 50 ml of toluene, 35 ml of a 12.5 % aqueous potassium hydroxide solution and 19 ml of a 20% phosgene solution in toluene by working up after 1 hour, threo-1-(4-chlorophenyl)-pyrrolidino[1,5-c]oxazolidin-3-one , m.p. 82-84°C.

Example 24

Erythro-1-phenyl-pyrrolidino[1,5-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 3.5 g (0.02 mol) of erythro-phenyl-(pyrrolidin-2-.yl)-methanol, 10.1 g of triethylamine and 110 ml of a 20% -ig phosgene solution in toluene crystalline erythro-1-phenyl-pyrrolidino[1,5-c]oxazolidin-3-one, m.p. 67-69°C, and starting from 5.0 g (0.028 mol) threo-phenyl-(pyrrolidin-2-yl)-methanol, 14.1 g triethylamine and 154 ml of a 20% phosgene solution in toluene , crystalline threo-l-phenyl-pyrrolidino[1,5-c]oxazolidin-3-one,

m.p. 66-67°C.

Example 25

Erythro- and threo-1-(3,4-dichlorophenyl)-5,5-tetramethylene-piperidino [1,6-c]oxazolidin-3-one

In an analogous manner as described in example 1, starting from 1.9 g (0.006 mol) of erythro-(3,4-dichlorophenyl)-(6,6-tetra-methylenepiperidin-2-yl)-methanol in 70 ml of toluene, 15.6 ml of a 12.5% aqueous potassium hydroxide solution and '9.8 ml

of a 20% phosgene solution in toluene on working up or 1 hour, crystalline erythro-1-(3,4-dichlorophenyl)-5,5-tetramethylene-piperidino[1,6-c]oxazolidin-3-one, m.p. 152-153°C, and starting from 1.4 g (0.0045 mol) threo-(3,4-dichlorophenyl)-(6,6-tetramethylene-piperidin-2-yl)-methanol dissolved in 60 ml of toluene, 11.8 ml of a 12.5% aqueous potassium hydroxide solution and 7.4 ml of a 20% phosgene solution in toluene, after working up after 1 hour, crystalline threo-1-(3,4-dichlorophenyl )-5,5-tetramethylene-piperidino [1,6-c]oxazolidin-3-one, m.p. 101-103C.

The erythro serving as starting material or threo-(3,4-dichlorophenyl)-(6,6-tetramethylene-piperidin-2-yl)-methanol

. can e.g. produced in the following way:

a) Of 72.4 g (0.4 mol) of 1-bromo-4-ethoxybutane,

33.7 g (0.4 mol) of cyclopentanone and 10 g of magnesium in 150 ml of diethyl ether gives 1-(4-ethoxybutyl)-cyclopentanol, boiling point Q = 7 3-75°C.

b) From 32.8 g (0.176 mol) 1-(4-ethoxybutyl)-cyclopentanol, 12 g potassium cyanide in 23 ml glacial acetic acid and 44 g concentrated

sulfuric acid in 23 ml of glacial acetic acid, after alkaline work-up 1-(4-ethoxybutyl)-cyclophenylamine is obtained, bp.16=130-132°C.

°) From 16 g (0.086 mol) 1-(4-ethoxybutyl)-cyclopentylamine and 90 ml of 48% aqueous hydrogen bromide, 1-(4-bromobutyl)-cyclopentylamine hydrobromide is obtained, m.p. 205-206°C.

d) From 24.2 g (0.08 mol) 1-(4-bromobutyl)-cyclopentylamine hydrobromide in 300 ml of water and 80 ml of n-sodium hydroxide solution, you get

6-azaspiro[4,5]decane, bp.lnoo= 67-69°C. The corresponding hydrobromide melts at 161-163 C.

e) Analogous to the method described in example 8 d), starting from 15.6 g (0.071 mol) of 6-azaspiro[4,5]decane, dissolved in 30 ml of water and 15 ml of glacial acetic acid, by treatment with 29.4 ml of a 50% aqueous sodium nitrite solution 6-nitroso-6-azaspiro[4,5]decane as a yellow liquid, b.p. nn, = 174-177 C. f) Analogous to the method described in example 1 a), starting from 10.9 g (0.065 mol) 6-nitroso-6-aza-spiro[4,5]decane and 11.4 g (0.065 mol) 3,4-dichlorobenzaldehyde crystalline erythro-(3,4-dichlorophenyl)-(6,6-tetramethylene-1-nitroso-piperidin-2-yl)-methanol, m.p. 148-149°C, as well as a yellowish crystalline slurry, in which the diastereomeric threo-(3,4-dichlorophenyl)-(6,6-tetramethylene-1-nitroso-piperidin-2-yl)-methanol is enriched. An analytical sample of the isomer-free threo-diastereomers can be obtained by filtration over a layer of silica gel with a toluene/acetic acid ethyl ester mixture (10:1) as eluent. After evaporation of the solvent, the product precipitates in the form of white crystals with a melting point of 151-152°C. g) Analogous to the method described in example 1 b), 10.3 g (0.03 mol) of erythro-(3,4-dichlorophenyl)-(6,6-tetra-methylene-1-nitroso-piperidine- 2-yl)-methanol by treatment with hydrogen chloride gas in a toluene/dioxane mixture crystalline 'erythro-(3,4-dichlorophenyl)-(6,6-tetramethylene-piperidin-2-yl)-methanol hydrochloride, sm<p .>281-282°C. The base liberated from the salt melts at 116-118°C. h) Analogous to the reaction described above under g), starting from 3.3 g (0.009 mol) threo-(3,4-dichlorophenyl)-(6,6-tetramethylene-1-nitroso-piperidin-2-yl)- methanol by treatment with hydrogen chloride gas in toluene, 3.2 g of crystalline threo-(3,4-dichlorophenyl)-(6,6-tetramethylene-piperidin-2-yl)-methanol hydrochloride, m.p. 261-262°C. The desalted base melts at 172-173°C.

Example 26

In an analogous way as described in examples 1-25, the following compounds can also be prepared:

in

threo-(3-cyanophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol, threo-(3-cyanophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3- on

erythro- and threo-1-(3-chlorophenyl)-5,5-diethyl-piperidino-[1,6-c]oxazolidin-3-one,

erythro- and threo-1-(3-chlorophenyl)-5,5-di-n-pentyl-piperidino-[1, 6-c]oxazolidin-3-one,

erythro- and threo-1-(3-chlorophenyl)-5,5-tetramethylene-piperidino-[1,6-c]oxazolidin-3-one and

erythro- and threo-1-(3-chlorophenyl)-5,5-pentamethylene-piperidino-[1,6-c]oxazolidin-3-one.

Example 27

Tablets containing 25 mg of active substance, e.g. threo-

i (3,4-dichlorophenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one, can be prepared as follows:

Ingredients (for 1000 tablets)

Manufacturing:

All solid ingredients are first passed through a sieve with a mesh size of 0.6 mm. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water and a boiling solution of polyethylene glycol in 100 ml of water is added to this suspension and the mixture, if necessary by adding water, is granulated. The granulate is dried overnight at 34°C, driven through a sieve with a mesh size of 1.2 mm and pressed to make it concave on both sides

tablets with approx. 6 mm diameter.

Example 28

Tablets containing 10 mg of active substance, e.g. threo-1-(3,4-dichlorophenyl)-5,5-dimethylpiperidino[1,6-c]oxazolidin-3-one can be prepared as follows:

Ingredients (for 1000 tablets)

Manufacturing

All solid ingredients are first passed through a sieve with a mesh size of 0.6 mm. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water and the mixture, if necessary with the addition of water, is granulated. The granulate is dried overnight at 35°C, driven through a sieve with a mesh size of 1.2 mm and pressed into concave tablets with approx. 6 mm diameter.

Example 2 9

Tablets containing 75 mg of active substance, e.g. threo-1-(3,4-dichlorophenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one, can be prepared as follows:

Ingredients (for 1000 tablets)

Manufacturing

All solid ingredients are first run through one

, sieve with 0.6 mm mesh size. The active substance, lactose, talc, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water and the mixture, if necessary with the addition of water, is granulated. The granulate is dried overnight at 35°C, passed through a sieve with a mesh size of 1.2 mm and pressed on both sides

concave tablets with approx. 6 mm diameter.

Example 30 In an analogous way as described in examples 27-29, pharmaceutical preparations containing another compound of formula I or a compound of formula V or a salt thereof, each time according to examples 1-26 or threo-1-phenyl-piperidino[1,6-c]oxazolidin-3-one or a salt thereof.

Claims (12)

1. Process for the preparation of trisubstituted oxazolidinones with the formula where R^ means an aryl or heteroaryl residue, R2 and R^ independently of each other mean hydrogen or lower alkyl or together lower alkylene and alk stands for lower alkylene, whose valences originate from neighboring or adjacent carbon atoms in the 1,3-position, with the caveat that in compounds with (-)-trans arrangement of the hydrogen atoms in the 4- and 5-position of the oxazolidine ring, R^ is different from unsubstituted phenyl, when R2 and R^ stand for hydrogen and alk means 1,3-propylene, and their salts , characterized by that mana) in a connection with the formula where X means a residue transferable in the carbonyl group, or in a salt thereof, X transfers in the carbonyl group, orb) intramolecularly cyclizes a compound with the formula where X^ means a nucleofuge leaving group, or a salt thereof, or c) in connection with the formula where alk <1> means a group with the formula -alk-C(R2 )(R^ )-, -alki:C-C(R2) (R3)- or -alkIi:E=C (R2) - which is bound to the nitrogen atom in the oxazolidine ring above C(R~ )(R.,)- or II =C(R~) the group, whereby alk means a lower alkenylene residue III and alk means a lower alkanylidene - respectively. lower alkenyl-ylidene residue, whose free valences originate from neighboring or adjacent carbon atoms in the 1,3-position, saturates the double bond(s) in the oxazolidine ring and possibly the remainder of alk" <1> " and, if desired, splits an isomer mixture obtainable by the method into the components respectively isolates from such a mixture the desired isomer(s), converts a compound obtained by the method into another compound of formula I and/or transfers a free compound obtainable by the method into a salt or a salt obtainable by the method in the free compound or in another salt. 2. Method according to claim 1, characterized in that a compound of formula I is prepared, where means an unsubstituted or lower alkyl with up to and including 4 C atoms, lower alkoxy with up to and including 4 C atoms, halogen with atomic number up to and including 35 and/or trifluoromethyl substituted phenyl-, naphthyl-, furyl-, thienyl-. pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl or pyrazinyl residue, and wherein either R2 and R^ independently of one another are hydrogen or lower alkyl with up to and including 4 C atoms or together lower alkyl with up to and including 7 C atoms , whose free valences originate from neighboring or adjacent C atoms in the 1,3-, 1,4-, or 1,5-position, and alk means the lower alkylene with up to and including 4 C atoms, whose valences originate from neighboring C-atoms, or R2 and R^ independently of each other mean lower alkyl with up to and including 4 C-atoms or together lower alkylene with up to and including 7 C-atoms, whose free valences originate from neighboring or adjacent C-atoms in 1, 3-, 1,4- or 1,5-position and alk means the lower alkylene with up to and including 7 C atoms, whose valences are based on adjacent C atoms in the 1,3-position, or a salt thereof. 3. Method according to claim 1, characterized in that a compound of the formula I is prepared, where R^ means unsubstituted phenyl or phenyl substituted with lower alkyl, with up to and including 4 C atoms, lower alkoxy with up to and including 4 C atoms, halogen with atomic number up to and including 35 and/or trifluoromethyl, or unsubstituted furyl, thienyl or pyridyl, R2 and R^ each mean lower alkyl radicals with up to and including 4 C atoms or together lower alkylene with up to and including 7 C atoms, the free valences of which are omitted from neighboring or adjacent C atoms, in the 1,4- or 1,5-position and alk stands for ethylene or 1,3-propylene, or a salt thereof. 4. Method according to claim 1, characterized in that a compound of formula I is prepared, where means phenyl substituted with halogen of atomic number up to and including 35, R 2 and R 3 form the same lower alkyl radicals with up to and including 4 C atoms and alk stands for ethylene, or a salt thereof. 5. Method according to claims 1-4, characterized in that the threo-diastereomer is produced, where the hydrogen atoms in the 4- and 5-position in the oxazolidine ring are facing each other trans, or a salt thereof. 6. Method according to claim 1, characterized in that erythro-1-(3-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, threo-1-(3-chlorophenyl) is produced )-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, erythro-1-(3,4-dichlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin- 3-one, threo-1-(3,4-dichlorophenyl)-5,5-dimethylpyrrolidino[1,5-c]oxazolidin-3-one, erythro-1-(4-chlorophenyl)-5,5-dimethyl- pyrrolidino[1,5-c]oxazolidin-3-one, threo-1-(4-chlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, erythro-1-(3 -methylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, threo-1-(3-methylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin- 3-one, erythro-l-phenyl-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, threo-l-phenyl-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidine -3-one, erythro-1-(1-naphthyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, threo-1-(1-naphthyl)-5,5-dimethyl -pyrrolidino[1,5-c]oxazolidin-3-one, erythro-1-(3-trifluoromethylphenyl)-5,5-dimethyl-pyrrolidino[1,5-c]-oxazolidin-3-one, threo-1-(3-trifluoromethylphenyl)-5,5-dimethylpyrrolidino[1,5 -c]oxazolidin-3-one, erythro-1-(3-chlorophenyl)-5,5-dimethyl-piperidino [1,-6-c]oxazolidin-3-one, threo-1-(3-chlorophenyl)- 5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one, erythro-1-(3,4-dichlorophenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3 -one, threon-1-(3,4-dichlorophenyl)-5,5-dimethyl-piperidino[1,6-c]oxazolidin-3-one, erythro-1-(2,6-dichlorophenyl)-5,5 -dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, threo-1-(2,6-dichlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, erythro-1-(3-cyanophenyl)-5,5-dimethylpyrrolidino[1,5-c]oxazolidin-3-one, threo-1-(3-cyanophenyl)-5,5-dimethylpyrrolidino[1,5- c]oxazolidin-3-one, erythro-1-(2,4-dichlorophenyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, threo-1-(2,4-dichlorophenyl) )-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3-one, erythro-1-(4-pyridyl)-5,5-dimethyl-pyrrolidino[1,5-c]oxazolidin-3- on, threo-1-(4-pyridyl)-5,5-dimethyl-pyrrolidine o[1,5-c]oxazolidin-3-one, erythro-1-(3-chlorophenyl)-5,5-diethyl-piperidino[1,6-c]oxazolidin-3-one, threo-1-(3-chlorophenyl)-5,5-diethyl-piperidino[1, 6-c]oxazolidin-3-one, erythro-1-(3-chlorophenyl)-5,5-di-n-pentyl-piperidino[1,6-c]oxazolidin-3-one, threo-1-(3 -chlorophenyl)-5,5-di-n-pentyl-piperidino[1,6-c]oxazolidin-3-one, erythro-1-(3-chlorophenyl)-5,5-tetramethylene-piperidino[1,6-c]oxazolidin-3-one, threo-1-(3-chlorophenyl)-5,5-tetramethylenepiperidino[1,6- c]oxazolidin-3-one, erythro-1-(3-chlorophenyl)-5,5-pentamethylene-piperidino[1,6-c]oxazolidin-3-one, threo-1-(3-chlorophenyl)-5, 5-pentamethylene-piperidino[1,6-c]oxazolidin-3-one, erythro-1-phenyl-pyrrolidino[1,5-c]oxazolidin-3-one, erythro-1-(3,4-dichlorophenyl)- 5,5-tetramethylene-piperidino-[1,6-c]oxazolidin-3-one or threo-1-(3,4-dichlorophenyl)-5,5-tetramethylene-piperidino[1,6-c]oxazolidin- 3-Mon or a salt thereof. 7. Method according to one of claims 1-6, characterized in that the (+)-threo enantiomer of a compound of formula I with threo configuration or a salt thereof is prepared. 8. Process according to one of claims 1-6, characterized in that (-)-threo enantiomers of a compound of formula I with threo configuration are produced. 9. Process for the preparation of compounds of formula where means an aryl or heteroaryl residue, R2 and R^ independently of each other mean lower alkyl or together lower alkylene, and alk stands for lower alkylene, the valences of which originate from neighboring or adjacent carbon atoms in the 1,3-position, and their salts, characterized by that mana) of a compound with the formula where one of the residues Yg and Y^ means a cleavable residue and the other hydrogen, or a salt thereof, cleaves the cleavable residue with the introduction of a hydrogen atom, orb) cyclizes a compound of the formula where Yg is hydroxy and one of the residues Yg and Y^Q means reactive, esterified hydroxy, or Yg and Yg together stand for epoxy, whereby the remaining residue Yg or Y^ q means amino optionally in intermediate protected form and/or amino substituted with a cleavable residue, or a salt thereof, or c) in connection with the formula in which the nitrogen atom can be intermediately protected, or a salt thereof, reduces the carbonyl group to the carbinol group, if necessary cleaves off the protecting group and, if desired, epimerizes the compound obtainable according to one of the methods a) to c), - cleaves an isomer mixture obtainable by the method into the components or separates from such a mixture the desired isomer(s), converts a compound obtainable by the method into another compound of formula V, and/or transfers a free compound obtainable by the method in a salt or a salt obtainable by the process in the free compound or in another salt. 10. Process according to claim 9, characterized in that a compound of formula V is prepared, where means an unsubstituted or with lower alkyl with up to and including 4 C atoms, lower alkoxy with up to and including 4 C atoms, halogen with atomic number up to and including 35 and/or trifluoromethyl substituted phenyl, naphthyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl or pyrazinyl residue, R 2 and R 3 independently mean lower alkyl with up to 4 C- atoms or together the lower alkylene with up to and including 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in the 1,3-, 1,4- or 1,5-position, and alk means the lower alkylene with up to and with 7 C atoms, whose free valence comes from neighboring or adjacent C atoms in the 1,3 position, or a salt thereof. 11. Method according to claim 9, characterized in that a compound of formula V is prepared, where R^ means unsubstituted phenyl or phenyl substituted with lower alkyl with up to 4 C atoms, lower alkoxy with up to 4 C atoms, halogen with atomic number up to and including 35 and/or trifluoromethyl or unsubstituted furyl, thienyl or pyridyl, R 2 and R^ means each together lower alkyl radicals with up to and including 4 C atoms or together with lower alkylene with up to and including 7 C atoms, whose free valences originate from neighboring or adjacent C atoms in the 1,4- or 1,5-position , and alk stands for ethylene, or a salt thereof. 12. Process according to claim 9, characterized in that erythro-(3-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, threo-(3-chlorophenyl)-(5,5-dimethylpyrrolidine- 2-yl)-methanol, erythro-(3,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, threo-(3,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2- yl)-methanol, erythro-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, threo-(4-chlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro -(3-methylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, threo-(3-methylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro-phenyl-(5, 5-dimethylpyrrolidin-2-yl)-methanol, threo-phenyl-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro-(1-naphthyl)-(5,5-dimethyl-pyrrolidin-2-yl) -methanol, threo-(1-naphthyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro-(3-trifluoromethylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, threo-( 3-trifluoromethylphenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro-(3-chlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol, threo-(3-chlorophenyl)-( 6,6-dimethylpiperidin-2-yl)-methane ol, erythro-(3,4-dichlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol, threo-(3,4-dichlorophenyl)-(6,6-dimethylpiperidin-2-yl)-methanol, erythro-(3-cyanophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, threo-(3-cyanophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro-(2,4 -dichlorophenyl)-(5,5-dimethyl-pyrrolidin-2-yl)-methanol, threo-(2,4-dichlorophenyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro-(4-pyridyl )-(5,5-dimethylpyrrolidin-2-yl)-methanol, threo-(4-pyridyl)-(5,5-dimethylpyrrolidin-2-yl)-methanol, erythro-(3,4-dichlorophenyl)-(6 ,6-tetramethylenepiperidin-2-yl)-methanol or threo-(3,4-dichlorophenyl)-(6,6-tetramethylenepiperidin-2-yl)-methanol or a salt thereof.