DD223616A5 - METHOD FOR PRODUCING TRISUBSTITUTED OXAZOLIDINONE - Google Patents

Abstract

The invention relates to a process for the preparation of trisubstituted oxazolidinones for use as medicaments. The aim of the invention is the provision of new compounds for use as antidepressants. According to the invention, new trisubstituted oxazolidinones of the formula wherein R1 is an aryl or heteroaryl radical, R2 and R3 independently of one another are hydrogen or lower alkyl or together are lower alkylene and alk is lower alkylene whose valencies emanate from adjacent or mutually 1,3-carbon atoms, with with the proviso that in compounds with () -trans arrangement of the hydrogen atoms in the 4- and 5-position of the oxazolidine ring R1 is different from unsubstituted phenyl, when R2 and R3 are hydrogen and alk is 1,3-propylene and their salts.

Description

Berlin, the 2 * .10. 1984 AP C 07 D / 263 648/6 63 996/18

Process for the preparation of trisubstituted Oxazolidinone

Field of application of the invention

The invention relates to a process for preparing trisubstituted Oxazolidinone with valuable pharrnakologischen properties.

The compounds prepared according to the invention are used as medicaments, for example as antidepressants for the treatment of depression.

Characteristic of the known technical solutions

There is no information available on which compounds have been used as antidepressants. There is also no information available about processes for the preparation of oxazolidinones. , ·

Object of the invention . '

The aim of the invention is to provide novel compounds having valuable pharmacological properties suitable for the treatment of depression. ·

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

-Ia-

According to the invention, new trisubstituted oxazolidines

of the formula ^ • - O

^U "^ R 'alk

    , H ; H . .

R _{1 represents} an aryl or heteroaryl radical. R ₂ and R ₃ independently of one another are hydrogen or lower alkyl or together are lower alkylene and are lower alkyls whose valencies emanate from adjacent or mutually 1,3-carbon atoms, with the hassle in that in compounds with (-) - trans arrangement of the hydrogen atoms in the 4- and 5-positions of the ~ oxazolidine ring R different from unsubstituiertera phenyl - is, when Rp and R_ are hydrogen and alk is 1,3-propylene, ie 'Exclusion of the (-J-trans-1-phenyl-S-oxo-perhydro-SH-oxazolo (3i4-a) pyridine, and their salts,

Aryl radicals are, for example, '6-membered monocyclic or at least one 6-membered ring bicyclic aryl radicals, such as phenyl or naphthyl, z. B. 1- or 2-naphthyl »heteroaryl are, for example, monocyclic, ⁷ ^ aIs heteroatom (s) nitrogen, oxygen, sulfur, oxygen and nitrogen or sulfur and nitrogen-containing 5-membered or as heteroatom (e) i or 2 nitrogen atoms having 6 -halogenated hateroaryl radicals, such as furyl ,. z. B, 2-furyl, thienyl, e.g. B "2-thienyl, PyrrolyTr, z. S ^. 1-pyrrolyl, thiazolyl, ζ. B. 2-thiazolyl, oxazolyl, z. B. 2-oxazolyl, pyridyl, ζ «B,. 3- or 4-pyridyl, pyriraidinyl, z, B. 2- or 4-pyrimidinyl, or pyrazinyl, ζ * 3. 2-pyrazinyl.

Suitable substituents of aryl or heteroaryl radicals R are, for example, lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl, where one or more than one, e.g. one, two or three identical or different, of these substituents may be present.

By way of example, "lower" organic radicals and compounds are, for example, those which have 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 tert-butyl, furthermore optionally bound pentyl, hexyl or heptyl. In compounds I in which R and R ₃ are lower alkyl radicals, they are preferably identical or different, but in particular identical, primary lower alkyl radicals, such as methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl.

Lower alkylene is, for example, ethylene or 1,3-propylene, in the case of lower alkylene radicals together represented by: R and'R, the free valencies of which are e.g. of adjacent or each other 1,3-, 1,4-. or 1,5-carbon atoms, or 1,4-butylene, 1,5-pentene, 1,4- (2,2-dimethyl) -butylene or 1,5- (3,3-butylene) Dimethyl) -pentylene and in the case of lower alkylene radicals alk further 1,2- (2-methyl) -propylene, i, 3- (3-methyl) -butylene or 1,3τ (2,2-dimethyl) -propylene.

N'-lower alkoxy is, for example, methoxy, ethoxy, propyloxy, isoprcpoxy, butoxy, isobutyloxy, secondary butoxy or tertiary butoxy, but may also be a pentyloxy, hexyloxy or heptyloxy group. ,

For example, halogen is halogen of the atomic number up to and including 35, such as chlorine, furthermore fluorine or bromine.

The compounds of the formula I have at least 2 asymmetric C atoms (the ring atoms 4 and 5 of the oxazolidine ring). You can therefore

as the cis / trans isomers for mutual orientation .the hydrogen atoms occur at the 4- and 5-positions of the oxazolidine ring, where the trans isomer has threo, the cis isomer has erythro configuration. Accordingly, the novel compounds can occur in the form of two diastereomeric enantiomeric pairs. If, in addition, the variables R and R- are different, or if the substructures represented by R.sup.1,... R.sup.-, -.sup.R and / or alk have at least one further asymmetric center, further stereoisomeric forms are possible. These all correspond to the formula I and. are accordingly also the subject of the invention. However, preferably each of the threo-diastereomers, i. those compounds I in which the hydrogen atoms in the 4-and 5-position of the oxazolidine ring are trans to each other, and optionally derived therefrom Dias'tereomere or Diast'ereomerengemische with at least one further 'center of asymmetry. ,

Salts of compounds of formula I include acid addition salts, especially pharmaceutically acceptable acid addition salts of compounds of formula I wherein R, a basic, ie at least one nitrogen atom-containing heteroaryl .insbesondere with mineral acids or strong organic acids such as hydrohalic acids, sulfonic acids, SuIfaminsäuren ¹ or optionally hydroxylated aliphatic mono- or dicarboxylic acids, z.3. Hydrochlorides, hydrobromides, methanesulfonates, p-toluenesulfonates, N-cyclohexylsulfaminates, fumarates, maleates, maleates or tartrates.

The compounds of formula I 'and their pharmaceutically-acceptable salts have advantageous pharmacological properties. Thus, they effect, for example, on the mouse in the swimming test according to Porsölt et al., 'Arch. Int. Fnarmacodyn. 229 , 327-336 (1977) in the dose range from about 25 ng / kg po a significant increase in motility and at the. Rat in the pin-hole test according to 'Noble and Delini-Scula, Psychopharmacology _4_9_, 17-22 (1976) in the dose range from about 25 to about 50 .mg / kg po a significant increase in the exploration rate. Neurobiocheiaisch 'they draw in the experimental design to Walcmeier, de Herdt and

_Maitre; Chir, Chem. _2 £, 81 (1974) in the dose range from about 100 mg / kg ip. By a marked dopamine and norepinephrine uptake in

Rat brain out, the Dopaminaufnahmeheimriung predominates. The compounds of formula I are also low in toxicity to the LD. in many cases the mouse significantly exceeds 1000 mg / kg p.o.

Accordingly, the novel compounds and their pharmaceutically acceptable salts are useful as antidepressants, particularly with non-amphetamine-like, slightly stimulating activity components.

The invention relates in the first place to the preparation of compounds of the formula I.I, in which R.sup.R is a substituted, optionally lower, lower alkoxy, halogen, cyano and / or trifluorine-I-containing 6-membered monocyclic or at least one 6-membered ring having bicyclic aryl radical or monocyclic heteroaromatic radical containing heteroatom (s) as nitrogen, oxygen, sulfur, oxygen, nitrogen and / or sulfur, and nitrogen-containing 5-membered or hetero-aryl radical having 1 or 2 nitrogen atoms. R2 and R independently represent hydrogen, lower alkyl or together represent lower alkylene and alk lower alkylene whose valencies emanate from adjacent or each other to 1,3-carbon atoms, especially those in which the hydrogen atoms in the 4- and 5-position the oxazolidine ring to each other are trans-continuous, with the proviso that in compounds with (-) - trans-arrangement of

Hydrogen atoms in 4- and 5-position of the oxazolidine ring R ₁ is different from unsubstituted phenyl, · when R ~ and R-. is hydrogen and alk is 1, 3-propylene, ie, excluding the (-) - trans-l-phenyl-3-oxo-perhydro-3H-oxazolo [3,4-ejpyridins, and their salts.

More particularly, the invention relates to the preparation of compounds of formula T wherein R is an unsubstituted or lower alkyl having bis and .with.4-C atoms, such as methyl, lower alkoxy with up to and with 4 C atoms, such as methoxy, halogen of the atomic number to and with 35, such as chlorine, and / or trifluoromethyl substituted .Phenyl, naphthyl, such as 1- or

  .... , - 5 -.,

2-naphthyl, furyl, such as 2-furyl, thienyl, such as 2-thienyl, pyrrolyl, such as 1-pyrrolyl ,. Thiazolyl, such as 2-thiazolyl, oxazolyl, such as '2-0xazolyl', pyridyl such as 3- or 4-pyridyl, pyrimidinyl, such as 2- or 4-pyrimidinyl, or pyrazinyl, such as 2-pyrazinyl radical, and wherein either R _; and R independently of one another are hydrogen or lower alkyl having up to and including 4 C atoms, such as methyl, or together lower alkylene having up to and containing 7 C atoms, the free valencies of which are adjacent to one another or "1,3-, 1,4- or 1" 5-C atoms, such as ethylene, 1,3-propylene, 1,5-pentylene, 1,4-butylene ^, 5- (3,3-dimethyl) -pentylene, and alk lower alkylene with bis and with 7 C atoms whose valencies emanate from adjacent C atoms, such as ethylene or L, 2- (2-methyl) -propylene, or R and R independently of one another are lower alkyl having up to and including 4 C atoms, , such as methyl, or together lower alkylene with up to and with 7 C atoms, the free valences of which come from adjacent or mutually 1,3-, 1,4- or 1,5-C atoms, such as ethylene, 1, 3-propylene, 1,4-butylene, 1,5-pentylene or l, 5- (3,3-dimethyl ·) -pentylene · represent and alk lower alkylene with bis and with 7 C-atoms, whose valences of each other. 1 , 3-stop C atom, such as 1,3-prop ylen, 1,3- (3-methyl) -butylene or l, 3- (2,2-dimethyl) -propylene, and their salts, in particular, their pharmaceutically acceptable salts. _:

In particular, the invention relates to the preparation of compounds of the formula I in which R. unsubstituted or by lower alkyl ^ with .bis' and with 4 C atoms, such as methyl, lower alkoxy with bis and with 4 C atoms, such as meth- OTpj, halogen of the atomic number up to and including 35, such as chlorine, and / or trifluoro-

methyl-substituted phenyl or unsubstituted furyl, eg 2-furyl, thienyl, 3 .3. 2-thienyl ,, or 'pyridyl, eg 3- or 4-yridyl, means, R. and R in each case, preferably identical, lower alkyl radicals with bis. and with "4 C atoms, for example 'methyl, pder together lower alkylene with' bis and with 7 C atoms, the free valences of which come from adjacent or mutually 1,4- or 1,5-carbon atoms, such Ethylene, 1,4-butylene or 1,5-pentylene, and alk ' ^{1 represents} ethylene or 1,3-propylene,' especially those in which the two hydrogen atoms in the 4- and 5-position of the oxazolidine ring 'to each other

trans, and their, in particular pharmaceutically acceptable salts. ,

The invention relates, in the first place, to the preparation of compounds of the formula I in which R, preferably in the 3- and / or 4-position, is phenyl substituted by halogen of the atomic number up to and at 35, such as chlorine, R "and R" represent the same lower alkyl radicals with up to and with 4 C atoms, such as methyl, and alk represents ethylene, especially those in which the two hydrogen atoms in the 4- and 5-position. of the oxazolidine ring to each other trans-constantly, and their salts, inbe, special pharmaceutically acceptable salts.

The invention relates in particular to the preparation of the compounds of the formula I and their salts, in particular pharmaceutically usable salts, which are mentioned in the examples. , <

The compounds of the formula I can be prepared by methods known per se, for example by a) in a compound of the formula

Vl. I H'H

wherein X is a radical convertible to the carboxyl group, or in a salt thereof X is converted to the carbonyl group or

b) a compound of the formula.

0 V * 2 (III),

wherein X represents a nucleofuge leaving group or a salt thereof intramolecularly cyclized or

c) in a compound of the formula

0 Il

^(ΐν) ·

in which alk is a group of the formula -alk-C (R) (R) -, -alk -C (R ₃ ) (R) - 'or -alk = C (R) - which with the nitrogen atom of the Oxazolinringes on the C (R ₂ ) (R -) - or = C (R) group, wherein alk is a Niederalkenylenrest and alk a Niederalkanylyliden- bzw.'Niederalkenylylidenrest, the free valencies of adjacent or mutually .1,3-carbon atoms represents the double bond (s) of the oxazoline ring. and if appropriate the radical alk. and, if desired, an isomer mixture obtainable in accordance with the invention is separated into components or the isomer (s) isolated from such a compound, a compound obtainable according to the process into another compound which converts formula I and or a free compound obtainable according to the method of the invention in a salt or a salt which is ready for use, into the free compound or into another salt. '.

Examples of radicals X which can be converted into the carbonyl group are, for example, functionally modified carbonyl groups of the formula -C '(X ") (X) -, in which X and X independently of one another are esterified hydroxy or etherified with a monohydric alcohol or mercaptan or together with a dihydric alcohol or mercaptan ketalized oxo or thioxo or together optionally substituted imino. Protected hydroxy is, for example, halogen, etherified with a monohydric alcohol or mercaptan, such as hydroxy, for example lower alkoxy or lower alkylthio or optionally substituted, z.3. nitro; and / or halogen-having phenoxy ^or: phenylthio and with a zweiwertigei; Alcohol or mercaptan ketalized oxo beispielsx jeise Niederalk] / lendioxy or Niederaikylendithio

or optionally substituted 1,2-phenylenedioxy or 1,2-phenylenedichio. By X ₉ and X together shown, optionally substituted imino is, for example, imino, lower alkylimino or optionally substituted, such as nitro and / or halogen having, anilo.

Nucleofuge leaving groups X are, for example, reactive esterified hydroxy groups, etherified hydroxy groups, activated amino groups or ammonio groups. Reactive esterified hydroxy is esterified, for example, with a mineral acid and is in particular a halogen atom, such as chlorine. Etherified hydroxy is, for example, lower alkoxy, for example methoxy, ethoxy, isopropyloxy or tertiarybutyloxy, or optionally, in particular by electron-withdrawing substituents, such as nitro and / or halogen, substituted phenoxy, such as phenoxy, p-nitro or 2,4-dinitrophenoxy or 3,5 Di-: chlorophenoxy. Activated amino is, for example, a secondary amino, as part of a heteroaromatic system, such as 1-imidazolyl, 1-pyrazolyl or 1- (3,5-dimethyl) -pyrazolyl. Ammonio is, for example, tri-lower alkyl, for example trimethylammonio, or tertiary ammonio as part of a heteroaromatic system, such as pyridinio.

In unsaturated alk radicals alk for example, vinylene or l, 3-prop-2-enylene and alk, for example, Aethanylyliden or l-prop-l-enyl-3-ylidene.

As salts of intermediates II, III and IV are, for example, their acid addition salts, z.3. Hydrohalides, as salts of intermediates III, and their metal salts in which the proton of the hydroxyl group is replaced by a metal cation, such as corresponding sodium or potassium salts, in

The implementation of the method according to the reactions and the preparation of new starting materials or intermediates is carried out in analogy to the .Reaktions- and formation of known starting materials or '. Intermediates. In this case, even if not expressly mentioned below, .the usual Hilfs'-, such as catalysts, Kondensätions- and Solvolysemittel and / or Lösungsbzw. Diluent, and reaction, such as temperature and pressure conditions, and optionally used protective gases.

The conversion of X into the carbonyl group according to the process variant , a) takes place for example by hydrolysis, preferably under neutral or mildly acidic conditions, for example in the presence of a

(

suitable acidic agent, such as a mineral acid, ζ.B, from chloro or hydrobromic acid, or an organic sulfonic or carboxylic acid, such as an alkane or optionally substituted benzene.

'' / '' '.-'. ' :

sulfonic acid or a lower alkanoic acid, e.g. of p-toluenesulfonic acid

, Or -acetic acid, or by adding the intermediate ΊΊ 'as a salt, e.g. as hydrochlorides or hydrobromide. If necessary, .man works in the presence of further auxiliaries, for example of buffer systems, starting from thioketals II of heavy metal salts or oxidizing agents or starting from N-unsubstituted imines II of nitrous acid. Suitable heavy metal salts are, for example, silver, mercury or copper salts, suitable oxidizing agents are, for example, oxidizing heavy metal compounds, such as copper II, iron III, iron VI, chromium VI, manganese IV and manganese VII Compounds, in particular oxides or chlorides, halogens, such as chlorine or iodine, or halosurfactic acids, z.3. Iodic acid, or its salts. For example, thioketals II can form readily hydrolyzable sulfonium halides with halogens, and N-unsubstituted imines II can react with nitrous acid to give readily hydrolyzable intermediates, at least under the mild conditions mentioned the effect of

Raatien limited to the group X. The stereotaxy of the ring atoms 4 and 5 of the oxazolidine ring and optionally further asymmetric centers is not affected accordingly.

In a preferred embodiment of process variant a), for example, starting from an acid addition salt, for example the hydrochloride, of an N-unsubstituted.tuierten imine II (X = iminomethylene) and hydrolyzes this with heating to about 40-110 ⁰ C, for example in the boiling heat , in the pH range of about 3.5 to about 9, for example in the presence of a phosphate buffer (pH about 6.5).

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

The intermediates II can be prepared, for example, by reacting a compound of the formula . '

HO ^{HN R}

R.-i

³ (V)

 alk

in the usual way with a compound of formula X -C (X) (X) -Y (VI) reacts, wherein X, X ₀ and X together represent the nitrile group and Y _{1 is} hydroxy or halogen or X and Y independently etherified Hydroxy, ζ.3. Lower alkoxy or optionally substituted phenoxy, and X ₀ and X each with a monohydric alcohol or mercaptan etherified hydroxy or with a

  divalent alcohol or mercaptan means ketalized oxo or X 'and Y ^ reactive esterified hydroxy such as halogen, and X and X together represent thioxo, or X and Y in common

, Oxo and X ₀ and X ₀ each represent etherified with a monohydric mercaptan hydroxy or together with a divalent mercaptan ketalized oxo or X and Y together oxo or thioxo and X and X together represent optionally substituted imino.

Thus, for example, a compound V by reaction with bromine or cyanogen chloride in the presence of an acid-binding agent, such as sodium bicarbonate, N-cyanate and the N-cyano intermediate formed, for example with lower alkanolic hydrochloric acid, to the corresponding imine (II, X «; + X, = imino) cyclize. The conversion takes place under extensive preservation of configuration: From the threo compound V, the corresponding trans compound II is formed and vice versa. Alternatively, the starting material V can be converted into the N-carbamyl derivative with cyanic acid or an alkali metal cyanate under acidic conditions and this can be cyclized with thionyl chloride or phosgene to give imine (II, X " ⁺ Χ-, = imino), in which configuration is reversed. That is, from the threo connection V, the corresponding cis connection II is created. Analogously, a compound V can also be reacted with an organic isothiocyanate, for example a lower alkyl or optionally substituted phenyl isothiocyanate, whereby, with retention of configuration, the corresponding N-substituted .Imin. (II, X "+ X = substituted imino) is also predominantly formed. ; ·.

Intermediates V are preferably prepared by reacting a compound of the formula

H-

Ik

with sodium nitrite and hydrochloric acid _N-nit-dosed or by reaction with 'ethyl formate and then with dimethyl sulfate and cyclohexylamine in the N-Forinamidinderivat transferred and the primary product in tetrahydrofuran at -6O ⁰ C in the presence of lithium N, N-diisopropylamide with an aldehyde of the formula R -CH = O (VIII). According to another method cyclization of a compound of formula ^ '. , , , '

br

(IX),

wherein Y is e.g. Bromine means ammonia or benzylamine by treating with an acid of formula

.HOOC-f - alk

where Yj. Is hydrogen or, preferably, benzyl, or preferably its chloride, in the presence of aluminum trichloride with a compound R -H (XI), reduces each of the primary product of the formula

² '

γ M ._ _R

 alk.

(XII)

the carboxyl group by means of sodium borohydride or sodium diäthylaluminiumdihydrid to Carbinolgruppe and optionally hydrogenates benzyl Y-. In an analogous manner, an acid of the formula

KOOC- <

(XIII)

 alk

or preferably their chloride with the compound XI and implement in the preinoric acid product of the formula

R - · - 1 π 1 0 H

(XIV)

alk

reduce the exocyclic carbonyl to the carbinol and the endocyclic carbonyl to the methylene group with lithium aluminum hydride.

Man. but can also be a carboxylic acid of the formula

C «''

HOOC--

wherein alk. a lower alkenylylidene radical derived from alk ¹ , the free valences of which originate from 1,3-carbon atoms,

¹ '"', for example prop ~ 2-en-l-yl-3-ylidene, mean or preferably their chloride in the presence of aluminum trichloride with the compound XI and react in the reaction product of the formula

h (XVI) ',

by hydrogenation in the presence of Adam-platinum oxide at the same time reduce the Carbony.lgruppe to Carbinolgruppe and the double bonds of the ring to single bonds. . ..; '

The described and further production processes for intermediates V are predominantly stereoselective. For example, both starting materials VII starting process variant as well as in the hydrogenation of starting materials XVI predominantly obtained the erythro-diastereomers. If desired, you can connect. V in a conventional manner, e.g. by treatment with thionyl chloride and then with water or better acetylation with acetic anhydride in M, N-dimethylformamide, reaction with thionyl chloride and treatment with sodium hydroxide, epimerize, i. convert the erythro- to the threo-diastereomer, and desirably split the resulting diastereomer e into the antipodes, for example by forming diastereomeric salts, e.g. using camphorsulfonic acid, separating the diastereomeric salts and releasing the enantiomeric bases therefrom.

The intramolecular cyclization of compound III according to process variant b) is carried out as a spontaneous or in the presence of a suitable condensation agent, if necessary with cooling or heating; -advantage-

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, for example sodium, potassium tertiary, potassium or potassium carbonate, or tertiary organic nitrogen bases, such as Triniederalkylamine, for example trimethyl or triethylamine, or heteroaromatic nitrogen bases ^ eg pyridine, further Halides of oxygen acids of sulfur or phosphorus, for example thionyl chloride, phosphorus tribromide or, phosphorus oxychloride. Thus, the cyclization of compounds III in which X is halogen is generally spontaneous while compounds of the formula III wherein X is etherified hydroxy are basic condensing agents, for example alkali metal alkoxides such as sodium lower alkoxide or starting from compounds III wherein X ₁ is amino, halides and oxygen acid of sulfur, for example thionyl chloride, in the presence of tertiary organic nitrogen bases, for example triethylamine or pyridine, each _{reaktionsbeschleu-:} act nigend.

For the production of. Intermediates III are preferably used compounds of the formula. '

R

HO

HN «-R-

and reacts with a suitable difunctional derivative of carbonic acid. Suitable difunctional derivatives of carbonic acid are, for example, those in which at least one hydroxy group is etherified or converted into reactive esterified hydroxy, ie compounds of the formula X ₁ -C (X ₂ ) (X) -Y ₁ (VI) in which X ₂ and X ₃ together represent oxo and X and Y independently of one another etherified or reactive esterified hydroxy and, for example, has one of the meanings given for such groups X. Suitable carbonic acid derivatives VI are in particular phosgene, haloauric acids

) - 15 -

alkyl esters or di-lower alkyl or optionally substituted diphenyl carbonates. ,. ,

The reaction component VI is advantageously chosen so that the intermediates III can be prepared in situ and further reacted without isolation. '

The formation and cyclization of intermediates III can be carried out stereoselectively. Thus, the formation of the intermediates III is generally carried out under configuration preservation, while the subsequent cyclization can be directed to form end products of the same or inverse configuration. Thus, "by reaction of compounds III with halo-acid lower alkyl ester · (VI, X = lower alkoxy, X ₂ + X = oxo, Y '= halogen, eg chlorine or bromine) under, formation of the corresponding intermediates III. Predominantly Endst.offe same configuration The reaction of compounds V with phosgene (VI ;: X ^ = Y ^ .. = chlorine, X _3. + X ₃ = oxo) in end products I with intermediary formation of intermediates III proceeds with preservation of configuration.

In a particularly preferred embodiment of this process, for example, a starting material V of the desired configuration in toluene or, a similar inert solvent at about 10 to about 35 ⁰ C, 2.B. about 3O ⁰ C with phosgene around. The respective cis-oxazolidinone t .gleicher absolute configuration or, whose Ra'cemat or from each of the enantiomeric threo forms V or their racemate the corresponding trans-oxazotidinone I arises from each of the enantiomeric erythro-forms V or their racemate or its "racemate.

The saturation of the double bond (s) of the oxazoline ring and optionally of the radical alk according to process variant c) is preferably carried out by catalytic hydrogenation, ie treatment with hydrogen in the presence of a hydrogenation catalyst. Suitable hydrogenation catalysts are, for example, palladium, platinum

and nickel catalysts such as platinum oxide, e.g. Adams platinum oxide, palladium, e.g. Palladium carbon ,. or Raney Nickel. If necessary, work is carried out under heating and / or increased pressure.

Intermediates IV "can be prepared, for example, by reacting a corresponding compound of the formula

(XVII)

with a compound of the formula X - C (X) (X) - Y (VI) in which X, X , X and Y have the meanings given for process variant b), preferably under strongly basic conditions, for example in the presence of Sodium hydride, sodium amide or lithium N, N-diisopropylamide.

The aforementioned separation of an isomer mixture obtainable according to the invention or for the isolation of the desired component from such is to be noted in particular:

Diastereomer mixtures, z.3. Mixtures of cis and trans isomers may, by virtue of their different physical properties, be prepared by the usual chemical and physico-chemical separation techniques, e.g. fractionated by crystallization, distillation, chromatography and other phase distribution methods.

Enantiomer mixtures, vie cleavable mixtures of the two and optionally further Enantimeren the same mutual orientation of the hydrogen atoms in the 4- and 5-position of the oxazoiidine ring, know by conventional resolution processes, e.g. Crystallization from an optically active solvent, chromatography on an optically active stationary or mobile phase, or intermediate formation of a diastereomeric auxiliary compound, e.g. of a diastereomeric acid addition

_ ..., - 17 -

salts, with an optically active carboxylic or sulphonic acid, for example with the D or L form of tartaric acid, di-o-toluyltartaric acid, .precurric acid, mandelic acid, quinic acid or a camphorsulfonic acid, separation of the diastereomers and ¹ release of the enantiomeric compound I- be separated. Preferably, one respectively isolates more effective enantiomers, mers. ..

As conversion reactions according to the invention obtainable compounds in other compounds of formula I are in particular introduction, conversion and cleavage reactions at the radical R ^ to mention.

For example, it is possible to introduce the radical R by treatment with chlorine or bromine or N-bromosuccinimide halogen, or to reduce nitro to amino and / or to replace amino by halogeno-cyano, lower alkoxy or trifluoromethyl. ·. '; ·.

The mutual conversion of free compounds and their salts into each other , 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 novel compounds can also be used to purify them and, as mentioned, to enantiomer separation ¹

serve, by converting a compound obtainable according to the method into a salt, this purifies or separates into the diastereomers and from. the salt ^: then releases the free compound. and '' desired? Alls in another salt transferred.

Thus, obtained free compounds can be converted in a conventional manner into acid addition salts, for example by reacting a solution of the free compound in a suitable solvent or

Solvent mixture with one of the abovementioned acids or with a solution thereof, or with a suitable cation exchanger.

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

Acid addition salts obtained can be converted into other acid addition salts in a manner known per se, for example by treating a salt of an organic acid with a suitable metal salt, such as a sodium, 3arium or silver salt, an acid in a suitable solvent in which a forming inorganic salt is insoluble and thus excreted from the reaction mixture.

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

As a result of the close relationship between the new compounds in free form and in the form of their salts, in the preceding and following, among the free compounds or their salts, the corresponding salts or, if appropriate, the corresponding salts and / or. to understand free connections.

The invention also relates to those embodiments of the process starting from a compound obtainable as an intermediate on any reaction step and carrying out the missing process steps or forming a starting material under the reaction conditions or in the form of a derivative thereof, optionally a salt . "

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable. New starting materials and processes for their preparation also form an object of the present invention. '"".

The compounds of formula V and their pharmaceutically acceptable salts referred to ¹ as intermediates have similar pharmacological properties as the compound of formula I and can deraent-

accordingly, also as antidepressants, even though they have a different pharmacological profile, rather based on a dopamine release, use. For example, in the dose range of about 3 to 30 mg / kg po, they stimulate the locomotor activity of the mouse, measured by means of the "electronic motility meter". Likewise, they inhibit in the dose range of about 50 to 100 mg / kg ρ.ο. the noradrenaline uptake in rat brain xin in the experimental set-up of Maitre, Stähelin and Bein, - Pharmacol, 20, 2169-2186 (1971). <

 Accordingly, the invention also relates to a process for the preparation of compounds of the formula

HOHN · ♦ -R

 '·' ... HH "'

wherein R _{1 is} an aryl or heteroaryl radical, R and R_ independently of one another are lower alkyl or together are lower alkylene and alk is lower alkylene, the valencies of which are adjacent or

each of 1,3-carbon atoms, and their salts, and their use as intermediates for the preparation of compounds of formula L ₁ , ' ^! :

In this case, aryl or heteroaryl radicals R, lower-alkyl or lower-alkylene radicals R ₂ and R ₃ , and lower alkylene radicals alk have, for example, the meanings given below under the formula I.

Likewise, salts of compounds of formula V are preferably pharmaceutically acceptable. Acid addition salts, for example with the acids mentioned for salts of compounds of formula I.

The compounds of the formula V likewise have at least 2 asymmetric C atoms and can accordingly be present in at least 4 mutually stereoisomeric forms, in (+) - threo-, (-) - threo-, (+) - erythro-iund ( -) - Erythro form occur. If, in addition, the variables R and R are different or at least one further center of asymmetry is present in the substructures represented by R, R, R and / or alk, further stereoisomeric forms are possible. All of them correspond to the formula V and are accordingly all the subject of the invention. However, preference is given in each case to the threo-diastereomers and diastereomer mixtures derived therefrom with at least one further asymmetric center, both in the form of enantiomeric enantiomers and in the form of individual enantiomers.

The invention relates in the first place to the preparation of compounds of the formula V ', in which R is a bicyclic aryl radical or monocyclic radical having as substituents optionally lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl, 5-membered monocyclic or at least one 6-membered ring in that heteroatom (s) is nitrogen, oxygen, sulfur, oxygen and nitrogen or sulfur, and nitrogen-containing 5-membered or heteroatom (e) 1 or nitrogen-containing 6-membered heteroaryl group, R "and R independently are lower alkyl or together Lower alkylene and alk lower alkylene whose free valencies emanate from adjacent or to each other 1,3-carbon atoms, especially in the form of their threo-diastereomers, and their salts, especially pharmaceutically acceptable salts.

Above all, the invention relates to the preparation of compounds of the formula V in which R is unsubstituted

^: ''' -. - 21 -.

or by lower alkyl having up to and including 4 C atoms, such as methyl, lower alkoxy having up to and including 4 C atoms, such as methoxy, halogen of the atomic number up to and including .35, such as chlorine, and / or

Trifluoromethyl substituted phenyl, / naphthyl, such as 1- or 2-naphthyl ·, furyl, such as 2-furyl, thienyl, such as 2-thienyl, pyrrolyl, such as 1-pyrrolyl, thiazolyl, such as 2- Thiazolyl, oxazolyl, such as 2-oxazolyl, pyridyl, such as 3- or 4-pyridyl, pyrxmidinyl, such as 2- or 4-pyrimidinyl or pyrazinyl, such as 2-pyrazinyl. R and R independently of one another are lower alkyl having up to and including 4 C atoms, such as methyl, or together lower alkylene having up to and including 7 C atoms, the free valencies of which are adjacent or, relative to each other, 1.3, 1.4 - or 1.5-hour

 - * ''

C atoms such as ethylene, l, 37 propylene, 1,4-butylene, 1,5-pantylene and 1,5- (3,3-dimethyl) -pentylene, represent and alk lower alkylane with bis and with 7 C Atoms whose free valencies are derived from contiguous or univalent 1,3-carbon atoms, such as ethylene, 1,3-propylene, 1,2- (2-methyl) -propylene, 1,3- (3-methyl ) -butylene or 1,3-, (2,2-dimethyl) -propylene, especially in the form of the threo-diastereomers and their salts, especially pharmaceutically acceptable salts. \ ; '

More particularly, the invention relates to the preparation of compounds of formula V wherein R is unsubstituted or lower alkyl having up to and including 4 C atoms such as methyl, lower alkoxy having up to and including 4 C atoms such as methoxy, halogen of atomic number to and including 35 , - as chlorine, and / or trifluoro - methyl substituted phenyl or unsubstituted furyl, eg 2-furyl, thienyl ζ. B. ' 2-thienyl, or pyridyl, ζ. 3. 3- or '4- "pyridyl," R "and R are each the same lower alkyl radicals having up to and including 4 C atoms, e.g. Met'hyl, or together lower alkylene with up to and with 7 C atoms, whose, free valencies of adjacent or mutually 1,4- or 1,5-carbon atoms, such as 1,4-butylene or 1, 5-pentylene, and 'alk fyr Aethylen stands, above all in the form of the threo-diastereomers, and their, especially pharmaceutically acceptable salts. ""

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

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

d) from a compound of the formula

, I 2 ON -.- R ₃

R ₁ -; - alk

wherein one of the radicals Y and Y is a leaving group and the

6 7 "

other hydrogen means, or a salt thereof, the cleavable group under, introduction of a hydrogen atom-split off or

e) a compound of the formula

I ⁹

H .H R_

(XIX)

wherein Y is hydroxy and one of Y. and Y. is reactive. 9 10

capable of esterified hydroxy, or Y and Y in common

ο y

are epoxy, wherein the remaining radical Y or Y optionally present in intermediately protected form present and / or substituted by a cleavable radical amino, or a salt thereof cyclized or

f) in, a compound of the formula

.-λ. · .- __ _# ι _alk (XX),

'; ^l Il

in which the nitrogen atom may be intermediately protected, or in a salt thereof reduces the carbonyl to Carbinolgruppe, if necessary, splits off the protecting group and, if desired epimerisiert the according to one of Verfahrensvarianteri d) to f) available compound, an isomer mixture obtainable according to the method in the components or from such a one or the desired isomer (s) is separated off, converts a compound obtainable according to the method into another compound of the formula V and / or a free compound obtainable in accordance with the method in a salt. or a salt obtainable according to the method is converted into the free compound or into another salt. .

Cleavable radicals Y or Y are, for example, acyl groups, SiIyI-. · '. σ, 1 ...

groups or optionally substituted a-aralkyl groups, groups Y also a-carbanion-stabilizing groups. When ^p acyl groups are, for example organic carboxylic acids derived acyl groups such as lower alkanoyl or optionally substituted aroyl or .Heteroaroyl, for example of the formula R -C (= 0) -, when silyl groups, for example Triniederalkylsilylgtuppen such as trimethylsilyl, and _as: is optionally substituted substituted a- Aralkyl groups, for example, optionally substituted by lower alkyl, lower alkoxy, halogen and / or nitro substituted a-phenyl, α, α-diphenyl or α, α, α-Triphenylniederalkylgruppen, z.3. Benzyl, furthermore di- or triphenylmethyl, into account, a- carbanion-stabilizing groups' Y are, for example, nitroso- or N-substituted -ininomethyl groups as well as sterically hindered, derived from carbon or thiocarboxylic acids

Acyl groups. Examples of suitable substituents of N-substituted iminomethyl are aliphatic and cycloaliphatic radicals, such as lower alkyl, e.g. Butyl or tertiary butyl, or cycloalkyl of 5 to 8 ring members, e.g. Cyclopentyl or cyclohexyl, into consideration. Acyl groups of the type indicated are, for example, 2,4,6-triisopropyl or 2,4,6-tritertiarybutylbenzoyl groups and tert-butylthio. carbonyl * lgruppen. .Dis cleavable radicals as substituents of the given. if by a-aralkyl protected amino group of compounds of

Formula XIX "are, for example, α-halogenated lower alkanoyl groups, such as trifluoracetyl.

As protecting groups of amino in compounds of formula XIX and as. Protecting groups for the nitrogen atom of / compounds XX include the customary nitrogen protective groups, for example those mentioned as Y or Y, preferably a-aralkyl, such as benzyl.

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

The execution of the process-related reactions and the production of new starting materials or intermediates takes place in j '.' Analogous to the reaction and formation of known starting materials. or intermediates of similar structure. In this case, although not expressly mentioned below, the customary auxiliaries, such as catalysts, condensation and Solvolysemittel and / or solvents, and reaction, such as temperature and pressure conditions, 'and optionally used protective gases.

The cleavage of residues Y ^ or Y according to the process variant ^)

takes place, for example, by solvolysis or reduction. So you can 'acyl groups, except the said trisubstituted benzoyl groups Y, which are reductively removed, and silyl groups and N-substituted iminomethyl and Tertiärbutylthiocarbonylgruppen Y hydro

.Iytic, acyl groups. Y, further alcoholytic and nitroso groups Y further acidolytically split off. a-aralkyl groups and the said trisubstituted benzoyl groups Y ₇ are split off in particular reductively. '

The hydrolysis, alcoholysis or acidolysis is carried out by treatment with water, an alcohol or an acid, if necessary in

: Presence of a Solvolysemittels and / or a solution or

Diluent. Solvolysemittel for the hydrolysis and alcoholysis and for the acidolysis! suitable acids are, for example

      · ·. , , '·.

Mineral acids, e.g. Hydrochloric or hydrobromic acid or sulfuric acid, sulfonic acids, e.g. p-toluenesulfonic acid, optionally '.' halo-genated lower alkanoic acids, for example acetic acid or trifluoroacetic acid, or the like, solvolysis agents for the hydrolysis and alcoholysis as well as basic agents, such as hydroxides, of alkali or alkaline earth metals, for example sodium hydroxide solution or potassium hydroxide.

, lye, for the alcoholysis of acyl Yg furthermore alkoxides, e.g. Sodium. Lysing or diluents are, for example, water-miscible solvents for the hydrolysis, in particular alcohols in excess for the alcoholysis. In a preferred embodiment of this solvolysis process, for example, a compound XVIII in which Y, - is hydrogen and Y - 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 wherein Y, hydrogen, and Y _{7 is} N-substituted iminomethyl is hydrolyzed in the presence of an alkali metal hydroxides, eg, potassium hydroxide, with heating, eg, to about 50-8O ⁰ C in an aqueous solution - _: alkanol, eg in methanol / water or ethanol / water.

, The reductive cleavage of a-aralkyl groups and nitroso Y ,. takes place for example by catalytic hydrogenation, the reductive cleavage of acyl Y, for example by reaction with a di-. leichtmetallhydrid. For the catalytic hydrogenation one treats

for example, the intermediate XVIII in the presence of a platinum, palladium or nickel catalyst, e.g. of platinum oxide, palladium on carbon 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, hydrogenated an intermediate XVl ^ II, wherein Y is hydrogen and Y 1) nitroso and 2) benzyl

6 7

is, 1) in the presence of Raney nickel or 2) at about 40-60 ⁰ C, preferably in methanolic solution at normal or at most slightly elevated pressure, in the presence of palladium-carbon .. The reductive cleavage of acyl Y _c is carried out, for example by Treat with

Sodium borohydride or lithium aluminum hydride.

Intermediates XVIII, wherein Y is hydroxy and Y is an a-aralkyl radical

are prepared, for example, by adding a compound of the formula.

R-CH-CH-alk ⁱ ~ ^Y ₁₀ (XXI),

'" ^R 3,.:'.

wherein Y is, for example, bromine or chlorine, either with benzylamine, the reaction product (XXI; Y, _Q = benzylamino) N-trifluoroacetylated, with N-bromosuccinimide to give a compound of formula

Λ "} ι ^alk _ | - ^Y io. _(XIX) ,

HHR ₃

wherein Y is hydroxy, Y is bromine and Y is N-benzyltrifluoroacetylamino, and this is cyclized, or the compound XXI is epoxidized with hydrogen peroxide and the reaction product (XIX; Y + Y - epoxy, Y = bromine or chlorine) is cyclized with benzylamine.

The starting materials XXI can be prepared, for example, by customary reaction of a compound der'formula

· = Ρ (0 ₆ Η ₅ ) ₃ , (XXII)

with an aldehyde of the formula

0 = · -alk- · - Y '(XXIII)

to be obtained.

Intermediates XVIII, wherein Y is hydroxy and Y is an a-carbanion 6,7.

stabilizing group are obtained, for example, by reacting a compound of the formula

HN -} - R (VII)

H · -alk

substituted in the usual way by a corresponding radical Y, e.g. N-nitrosated or N-formamidated, and the 'reaction product of the formula

^Y 7. 1 "* ^R 3 (XXVIII)

wherein Y _{7 is,} for example, nitroso or N-substituted .Iminomethyl or sterically hindered acyl, metallated in the presence of a metal base and then condensed with an aldehyde of the formula R-CH = O (VIII). Metal bases are, for example, hydrocarbons

Substance compounds, amides, or alkoxides of alkali metals, such as lithium or potassium, for example methyllithium, butyllithium, secondary-butyllithium lithium, tert-butyl lithium, phenyllithium, lithium N, N-diisopropylamide or potassium tertiary butoxide. Thus, for example, the intermediate VII can be N-nitrosated by reaction with an alkyl nitrite or with nitrous acid or an alkali metal nitrite under acidic conditions and the reaction product XXVIII, for example in the presence of lithium N, N-diisopropylamide, preferably in tetrahydrofuran at -60 ⁰ C, or in the presence of potassium tertiary butoxide at about -20 ° to about 0 ⁰ C, also preferably in tetrahydrofuran, with the aldehyde VIII to the reaction. In this case, the erythro-diastereomer V preferably forms. The intermediate VII can also, for example, by reaction with a formic acid ester, such as a Niederalkylformiat, N-formylated the reaction product with a. Methylating agent, for example with dimethyl sulfate, to the corresponding immonium compound of the formula

CH ^ -CH = N - · R_. - ·

³ , 'I 3 (XXIX),

, Ή- · alk. '

wherein A ~ is an anion, for example, the methosulfate ion, converted, this with a primary amine, eg with cyclohexylamine, and subsequent base treatment in the corresponding N-Fpraainidinverbindung XXVIII (Y- eg -CH = NCC ₆ H ₁₁ ) transferred and these, for example in the presence of tert-butyl lithium, preferably at most -2Q ⁰ C, a-metallated. and then reacted with the .Aldehyd VIII. This gives. The corresponding N-formamidine XVIII, which 'if desired, for example by treatment with aqueous methanol, to the corresponding N-Formy! Compound XVIII can be hydrolyzed.

Intermediates XVIII, wherein Y is acyl and Y is hydrogen, are obtained, for example, by reacting a compound of the formula

| -J-R ₃

H- * alk.

obtainable, for example, by N-chlorination of the corresponding saturated compound

f ²

•. Hj-alk. , - :

e.g. with; chloramine T ,. and subsequent elimination of hydrogen chloride, hydrocyanic acid a: reacts, the reaction product of. Formula ',

, , .: - j 'j 3 (XXXII).'. ''. NC · lime. ". -. ''''.' ^H. '',''.:''''.

N-acylated, for example by reaction with the chloride of an acid R ^ COOH (XXXIII), and anschliesserid in a conventional manner, for example in the presence of lithium N, N-diisopropylamide, preferably in tetrahydrofuran, at a maximum of -6O ⁰ C,. - with an aldehyde R-CH = O (VIII). ',

\ .ι ' Ί

The cyclization of compounds XIX according to process variant e) er. if necessary in the presence of a basic condensation agent, such as an alkali or alkaline earth metal hydroxide, for example of sodium or potassium hydroxide, in the presence or absence of a solvent or diluent. preferably in the temperature range

from about 20 to about 80 ^° C. To cyclise compounds XI-X in which Y is hydroxyl, Y is reactive esterified hydroxy and Y is optionally in intermediately protected form and / or is substituted by a cleavable radical, for example trifluoroacetylamino or N-benzyltrifluoroacetylamino, means, advantageously in a water-miscible organic solvent, for example in dioxane, by treatment with aqueous sodium or potassium hydroxide, preferably with heating, for example to about 40 to about 8O ⁰ C. The cyclization of compounds XIX, wherein Y and Y in common are epoxy and Y optionally present in intermediately protected form present amino, for example amino or benzylamino, or Y is hydroxy, Y optionally present in intermediate protected form amino, eg amino or benzylamino, and Y is reactive esterified hydroxy, is generally spontaneous, for example Leave at room temperature. , . ' . ''

Intermediates XIX, wherein Y is hydroxy, Y is bromine and Y _{1 is} N-benzyl-8 9 10

trifluoroacetylamino, are obtained, for example, by reacting a compound of the formula.

²

R ₁ -CH = CH-alk-JY ₁₀ (XXI),

^R 3

wherein Y _ is bromine, initially reacted with benzylamine, the reaction product (XXI; Y = benzylamino) in the presence of potassium carbonate with trifluoroacetic anhydride N-trifluoroacetyl and then reacted in the presence of sulfuric acid with N-bromosuccinimide, preferably in dioxane.

Intermediates XIX, wherein Y "and Y- together are epoxy and Y is optionally present in intermediately protected or substituted by a cleavable group amino, e.g. Amino or benzylamino, or Y is hydroxy, Y reactive

esterified hydroxy and Y, -. optionally in intermediately protected form or substituted by a leaving group, e.g. Amino or Benzylatnino, means körinen

starting from compounds XXI (Y = reactive esterified '..' 'hydroxy) by epoxidation, e.g. by means of hydrogen peroxide, followed by reaction with ammonia or a suitable one in the reaction, e.g. as indicated, protected or: substituted

Amine group resulting derivative and optionally ring opening with an acid Yq-H thereof can be obtained.

% "". ' - . . ' , ^: '

The preparation of the starting materials XXI (Y ₁ = bromine) to be used for this reaction is: under process variant d). wrote. .. '..'

The reduction of the carbonyl group in compounds XX according to variant r ) f) is carried out, for example, by treatment with a light metal or Dileichtmetallhydrid or by katalvtische ', · · · hydrogenation. ...:, ..

. ' ^: Suitable light metal or Dileichtmetailhydride are, for example '- .;''Borohydrides such as borane / Tetrahydrof uranium complex, Alkalimetallbor-.

'J hydrides, such as natrium borohydride, and alkali metal aluminum hydrides, such as

Lithium aluminum hydride or sodium diethylaluminum dihydride. By ^: ".,. .. 'suitable choice of the reducing agent, the reduction can be directed so that together with the reduction of the carbonyl group and the

'Protective group is split off. So you can. An intermediate product

 , / .. · · ·. · '·' '·

XX, worm the nitrogen atom is acylated, directly to the corresponding.

^v Reduce connection V. Further, when using sodium borohydride as a reducing agent, predominantly the one, when using sodium diethylaluminum dihydride, predominantly the other "diastereomer is obtained.

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, for example of Adam-platinum oxide, preferably in the temperature range from about 40 to about 6O ⁰ C, wherein at the same time an a-aralkyl group can be cleaved reductively. .

i

"The intermediates XX are obtained, for example, by reacting a compound of the formula

'' '. ? 2 '· ·. ": '

: · R -.- CH-alk-pY ₁₀ '(XXIV) ,.

wherein Y is reactive esterified hydroxy halogenated in the a-position to the carbonyl group, e.g. by treating with.

Bromine, and the reaction product of the formula

, _R _._ jl _alk _! L _Yio cm

OH R ₃

with ammonia or a suitable one in the reaction _; a, for example, as indicated, protected or substituted amino group resulting derivative thereof cyclized, starting materials XXIV is obtained for example by reacting a lower alkyl ester of an acid.

₁ -Y ₁₁ -CH ₂ -alk-COOH

wherein Y is di-lower alkoxy or lower alkylenedioxymethylene, e.g. Diäthoxy- or Aethylendioxymethylen is, with one mole of an organometallic compound of the formula RM (XXVI) and R -M (XXVII), wherein M is a radical of the formula -Li, -Na or Mg-halogen, and conversion of the hydroxy group formed in reactive esterified hydroxy and ketal cleavage, eg by means of hydrochloric or hydrobromic acid.

  -. '' · '. ·. ..' - 33 -

Intermediates XX can be further prepared by reacting a compound of formula R, -H (XI) in the presence of a Lewis acid, e.g. of aluminum trichloride, with an acid of the formula

^:: Ι ² -'ν

'; ₍ : Y ₅ N - i-R ₃ (X)

, HOOC- · - alk ..- ·

' ^H '' where Y is ₁ . Is hydrogen or a-aralkyl, for example benzyl ,, is, or a reactive acid derivative, for example the chloride, of the same.

;. ; ·: The epimerization proceeds according to the available connections of the> - '. In principle, formula V is carried out by nucleophilic substitution and reintroduction of the hydroxy group, one step under configuration reversal, the other under configuration maintenance. Thus, a compound V with erythro configuration by: reaction with an alkali metal cyanate and hydrochloric acid to the corresponding

, ; _: N-carbamic compound condense with erythro-Konf iguratioü, this with thionyl chloride to the corresponding trans-compound of the formula

'' ^ ^: ' ⁱ ' ^^ .- v \ 'Τ ² ' · "'' ... ' : ''''

  '-....:'; , , '' η η-. '. '. ,

wherein X is iminomethylene, cyclize with threo configuration and " ⁵ V of this by treatment" with an alkali metal hydroxide, for example with

Potassium hydroxide, in an aqueous alkanol, e.g. 50% methanol, hydrolyze to the corresponding threo compound V and vice versa. A variant of this method is that the compound V

first by treating, with. a carboxylic acid, eg Niederalkansäurean-. hydride of the formula R'-C (= O) -Y ". (XXVIIl), wherein R ^{1 is} a hydrocarbon

Substance radical and'-Y represents chlorine or a group -O-C (= O) -R ', especially,. with acetic anhydride acylated, the reaction product with thionyl chloride for. corresponding oxazolidinium chloride of the formula II, in which X is a group of the formula / C-R'Cl ^, and then hydrolyzed, for example with sodium hydroxide, epimerization under Kpnfigurationsumkehr at the exocyclic carbon atom.

The optional separation of a isomer mixture obtainable according to the process or the. Separation of the desired isomer from such and the resolution into the enantiomers is carried out in an analogous manner as indicated for compounds of formula I, but especially by formation of diastereomeric intermediates, which in turn 'have different physical.Eigenschaften, Auf / separation of the same and re-release the compound.V, in the individual enantiomer. For the formation of diastereomeric intermediates are in particular optically active bildende.Säuren with compounds V salts, esters or amides, such as D- or L-tartaric acid, di-o-Toluy! Tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic _acid> ..- .geeignet ''.

Suitable optional conversion reactions in other compounds of the formula V and mutual conversions of bases and salts which can be obtained according to the process into one another are, in particular, the reactions given for compounds of the formula I and their salts.

The compounds of the formula I and V or pharmaceutically acceptable salts thereof are preferably used as active ingredients in pharmaceutical preparations. These are those, for enteral as well as oral or rectal, and parenteral administration to warm-blooded animals containing the pharmacological agent alone or together with a pharmaceutically acceptable carrier. The dosage of the active substance depends on the species of warm-blooded animals, the age and the individual condition, as well as the mode of administration.

Normally, an approximate daily dose of about 10-100 mg, advantageously distributed in several equal sub-doses, is to be estimated for a warm-blooded animal weighing about 75 kg when administered orally.

The novel pharmaceutical preparations contain, for example, from about 10% to about 80%, preferably from about 20% to about 60% of the active ingredient, according to the invention pharmaceutical preparations. enteral or parenteral administration are, for example, those in dosage unit forms, such as dragees, tablets, capsules or suppositories, and also ampoules, which are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolution or lyophilization processes So you can.pharmaceutical preparations for. oral application, by combining the active ingredient with solid carriers, granulating a resulting mixture optionally • ' , and the mixture or granules, if desired or ^ necessary, after addition of suitable excipients, processed into tablets or dragee cores.

   . ''. '' '. '

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate, e.g. Tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes using e.g. of corn, wheat, rice or. Potato starch, gelatin, tragacanth, methylcellulose

, loose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, such as: the above-mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as, sodium alginate. Auxiliaries are, in the first place, lubricants and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, μηα / or poly (ethylene glycol) Enteric coatings, whereby, inter alia, concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide,

solutions in suitable organic solvents or solvent mixtures or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The

Tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different drug doses.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible for stabilizers to be added. , ".

As rectally applicable pharmaceutical preparations are e.g. Supposi- toria into consideration, which consist of a combination of the active ingredient with a suppository base. As suppository base, e.g. natural or synthetic triglycerides, paraffins, polyethyleneglycols or higher alkanols. It is also possible to use gelatin rectal capsules which contain a combination of the active substance with a basic mass; basic materials are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question. , '. ..- '

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or agents such as fatty oils, e.g. Sesame oil, or synthe-. fatty acid esters, e.g. Ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity increasing agents, e.g. Sodium carboxymethyl cellulose, sorbitol and / or dextran and optionally also stabilizers.

The present invention also relates to the use of the compounds of the formulas I and V and the salts of such compounds having salt-forming properties "preferably for the treatment of depression"

embodiment

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in Celsius degrees and pressures in mbar. The ring systems underlying the compounds of the formula I are designated and numbered as follows:

Pyrrolidino (li5-c) pxazolidine piperidino (i, 6-c) oxazolidine

Example 1: erythro ^ and threo-l- (3-chlorophenyl) -5,5-dimethylpyrrplidino (l! S5-c) oxazolidin-3-one

27 * 6 g (Orll5 mol) erythro (3-chlorophenyl) - (5i, 5-dimethylpyrrolidin-2-yl) -methanol are dissolved in 630 ml of a 20% solution of phosgene in toluene and cooled with an ice Water bath at 20-25 ° Innenteraperatur within 40 minutes dropwise with a solution of 58 g (80 ml, 0.57 mol) of triethylarain in 80 ml of toluene. The yellowish reaction mixture, which gradually forms a suspension, is then stirred for 3 days at room temperature. While cooling with an ice-water-8ad then 750 ml of water are added dropwise, the organic phase is separated, 'washed twice with 150 ml of water, dried over sodium sulfate and on the water jet pump to dryness. evaporated. The residue (brownish oil) is dissolved in 50 ml of toluene and filtered through a pad of silica gel. It is eluted with toluene-ethyl acetate-Geraisch (10: 1) and the solvent is evaporated off at the water jet pump. You get

pure erythro-1- (3-chlorophenyl) -5,5-dimethylpyrrolidino [1,5-c] oxazolidin-3-one as a pale yellow oil, which can be crystallized by digestion with hexane at 0 °. Recrystallization from hexanes gives a crystalline product of mp. 84-86 °.

26.4 g (0.11 mol) of threo- (3-chlorophenyl) - (5,5-dimethylppyrolidin-2-yl) -methanol are dissolved in 600 ml of a 20% solution of phosgene in toluene "and with cooling with a solution of 55 g (0.55 mol) of triethylamine in 75 ml of toluene is added dropwise within 40 minutes within an ice-cold bath at 2O-25 ° internal temperature.

mixture, in which a yellowish suspension gradually forms, 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, dried over sodium sulfate and evaporated to dryness on the water jet pump. The remaining, slightly reddish OeI is dissolved in 50 ml of ether and crystallized by addition of-50 ml of hexane first at room temperature, then at 0 °. After filtration and drying of the filter cake at 50 ° in a high vacuum to obtain white crystals of threo-l- (3-chlorophenyl) -5,5-dimethyl-pyrrolidino [l, 5-c] oxazolidin-3-one of Smp-. 83-84 °.

  , , '.' ,

The erythro (3-chlorophenyl) - (5,5-diinethylpyrrolidin-2-yl) -methanol or threo- (3-chlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol which serves as starting material in each case can prepared as follows. become. ; ,

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 to -78 °. At this temperature, 180 ml (0.29 mol) of an about 1.6 molar solution of butyllithium in hexane are added dropwise. By removing the cooling bath, the internal temperature is gradually increased to -10 °. The resulting solution of lithium diisopropylamine is cooled again to -78 °, within 20 minutes

Added dropwise with 32 g (0.25 mol) of l-nitroso-2,2-dimethyl-pyfrolidine and then stirred for a further 10 minutes. Then added dropwise within 15 minutes 35.2 g (0.25 mol) of 3-chlorobenzaldehyde and the mixture is stirred another 3 hours at -75 ^<O. The orange solution is then added dropwise within 20 minutes with a solution of 40 ml (0.7 mol) of glacial acetic acid in 80 ml of tetrahydrofuran. The now pale yellow .Reaktionsmischung is by removing the cooling bath

 '). , , ,

Warmed at room temperature and then poured onto a mixture. Each of 1 liter of saturated sodium chloride solution and methylene chloride. After shaking, the aqueous lower phase is separated off 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 on a water-jet pump. The residue which crystallizes as a result is formed A mixture of 180 ml of toluene and 270 ml of hexane is dissolved and crystallized, and the product is filtered off with suction, dried at 60 ° C. in a high vacuum, and pure erythro-G-chlorophenyl () is obtained (5.5%) dimethyl-1-nitroso-pyrrolidih-2-yl) -methanol in the form of white crystals of mp 143 ° -144 ° C. The filtrate first evaporated in a water-jet, vacuum and then in a high vacuum yields a brownish oily residue, in which the threo- (3-chlorophenyl) - (5,5-dimethyl-l-nitroso-pyrrolidin-2-yl) -methanol is enriched.An analysis-grade sample of the pure threo-diastereomer obtained as OeI can be prepared by filtration through a layer of silica gel with Toluene-ethyl acetate 20: 1 mixture can be obtained as eluent. '.-.

  b> 32.1 g (0.12 mol) of crystalline. erythro (3-chlorophenyl) - (5,5-dimethyl-nitro-2-pyrrolidin-2-yl) -methanol are in a mixture. Of ISO ml of toluene and Dissolved 120 ml of dioxane. Dann.wird 1 hour at room temperature, dry hydrogen chloride gas is introduced. The reaction mixture is then stirred for 12 hours at room temperature, where-itself

, the solution gradually turns deep yellow. The nitrosyl chloride formed is then removed by passing it through two hours of the light-yellow dyeing solution. expelled and the reaction mixture.

β "" θ

cooled to 0 ° with an ice-water bath. The crystallized product is filtered off from the mixture, washed with ether and dried under high vacuum at 50 °. Crystalline erythro-O-chlorophenyD-CSjS-dimethyl is obtained.

, pyrrolidin-2-yl) -methanol hydrochloride of mp. 168-169 °. To release the base, 27.6 g (0.1 mol) of hydrochloride are dissolved in 280 ml of water and dropwise with cooling in an ice-water bath with 26 ml

, semi-concentrated sodium hydroxide solution. The thick white suspension is stirred for 30 minutes, filtered, the filter residue washed with water and then dried under high vacuum at 60 °. The erythro-O-chlorophenyl WSSi-dimethylpyrrolidine-Z-yl-1-methanol is obtained in the form of white crystals, mp 120-121 °. ,

c) The OeI (28.1 g) obtained 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 for 1 hour at.-.- '' room temperature of a stream of dry hydrogen chloride gas. bubbled. The reaction mixture is stirred for 12 hours at room temperature and the nitrosyl chloride formed is driven off by passing nitrogen through for 2 hours. The yellow-brown suspension is then extracted by shaking twice with 100 ml of water each time. The combined aqueous phases are washed twice with 50 ml of methylene chloride and made strongly alkaline with concentrated sodium hydroxide solution. The precipitated product is filtered off, washed with water and dried under high vacuum at 60 °. This gives crude .threo- (3-chlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol. A .analysen-pure sample of the. Base is obtained by recrystallization from isopropanol; Mp. 98-99 °. The crude product is dissolved in 70 ml of methanol and treated with cooling with an ice-water bath with 20 ml of an approximately 4N solution of hydrogen chloride in diethyl ether. After addition of ether crystallizes the weiss.e threo- (3-chlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol hydrochloride, which is filtered off, washed with ether and dried under high vacuum at 60 ° "mp. 209-210 °.

, ·. -.- 41 - '.

Example 2 : erythro- and threo-1- (3,4-dichlorophenyl) -5,5-dimethyl-? ^Yrro -lidino [1, S-cjoxazolidine-S-on

In an analogous manner as described in Example 1, starting from 25 g (0.91 mol) of erythro (3,4-dichlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol, 65 ml of triethylamine and 500 ml 20% Phosgene solution in toluene 'erythro-l- (3,4-dichlorophenyl) -5,5-dimethylpyrrolidino [l, 5-a] oxazolidin-3-one in the form of white crystals of mp. 125 ^ 12O ⁰ (from hexane) as well as from. 6.3 g (0.023 mol) of 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 -l- (3,4-dichloro-phenyl) -5,5-dimethylpyrrolidino [l, 5-c] oxa-2 -olidin-3-one in the form of 'white crystals of mp'. , 108-109 ° '(from diethyl ether / hexane) ^:.

The respectively serving as starting material erythro-; Threo-1- (3,4-dichloro-phenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol may be e.g. for the following reasons:

a) Analogously to the procedure described in Example 1 a), starting from 43.7 g (0.25 mol) of 3,4-dichlorobenzaldehyde and 32.0 g (0.25 mol). 2,2-D-dimethyl-1-nitroso-pyrrolidine, the crystalline erythro- (• 3,4-dichlorophenyl) - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol of the mp. 172- 174 ° and an orange-brown OeI,. in that the ·. . diastereomeric threo-l-C3, - 4-Dichlo.rphenyl> - ⁱ (. 5,5-dimethyl-l-nitrosp- pyrrolidin-2-yl) -methanol is enriched. -.

b) Analogously to the procedure described in Example 1 b), starting from 35.7 g (0.11 mol) of erythro (3,4-dichlorophep.yl) - (5,5-dimethyl -l-nitroso-pyrrolidin-2-yl) -methanol by treatment with hydrogen chloride gas in a toluene-dioxane mixture crystalline erythro-'(3,4-dichlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) i-aiethanolhydrochlorid from _v mp. 275-276 °. The crystalline released from the salt. Base melts at 118-119 °. '"

c) Analogously to the procedure described in Example 1 c) is obtained starting from the obtained according to 2 a) oily residue by

Treatment with hydrogen chloride gas in toluene and subsequent crystallization from methanol / diethyl ether pure threo- (3,4-dichlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol hydrochloride from Snip, 247-249 °. The crystalline base liberated from the salt melts at 76-78 °.

Example 3 : erythro- and threol-1 - (4-chloroph enyl) -5,5-dimethyl-

pyrrolidino [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% solution of phosgene in toluene erythro-l- (4-chlorophenyl) -5,5-dimethyl-pyrrolidino [l, 5-c] oxazolidin-3-one in the form of pale yellowish crystals of mp. 118-119 ° '(from hexane) and starting from 2.5 g (.0, .Ol mol). threo (4-chlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol, 5.3 g of triethylamine and 60 ml of a 20% phosgene solution in toluene, the threo-l- (4-chlorophenyl-SjS DimethylpyrrolidinofljS-cjoxazolidin-S-on in the form of pale yellowish crystals, mp. 101-103 ° (from diethyl ether / hexane).

The starting material erythro or threo (4-chlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol, for example, can be used e.g. be prepared as follows:

a) Analogously to the procedure described in Example la), starting from 35.2 g (0.25 mol) of 4-chlorobenzaldehyde and 32.0 g (0.25 mol) of 2,2-dimethyl-1-nitroso- pyrrolidine crystalline erythro (4-chlorophenyl) - (5,5-dimethy1-1-nitroso-pyrrolidin-2-yl) -methanol, mp. 161-162 ° C and a brownish crystal pulp, in which the diastereomeric threo- 4-chlorophenyl) - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol An analytically pure sample of the isomer-free threo-diastereomer can be prepared by filtration over a layer of silica gel with toluene / ethyl acetate (20: 1 After evaporation of the solvents, the product precipitates in the form of white crystals of melting point 113-115 °.

b) Analogously to the procedure described in Example 1 b). 'Man erythro- (4-chlorophenyl) starting from 26.8 g (0.1 mol) - (5,5-dimethyl-l-nitroso-pyrrolidin-2-yl) -methanol by treatment with hydrogen chloride gas in a toluene / Oioxane mixture crystalline erythro-; C4-chlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol of the mp.

227-228 °. The crystalline base liberated from the salt melts at:;: ': 124-125 °. :,. ;. / .

   ''. "ι

c) Analogous to the procedure described in Example 1 c) ^ obtained starting from 30 g of the obtained under 3 a) crystal pulp, in the ¹ ^ the threo- (4-ehorphenyl) - (5,5-dimethyl-l-nitroso pyrrolidin-2-yl) -

methanol is already enriched 'by treatment with'. Chlorwas.ser- '. Substance gas in toluene: and subsequent crystallization from methanol /. Diethyl ether, the threo- (4-chlorophenyl) - (5, ^l 5-dimethylpyrrolidin-2-yl) -methanol hydrochloride of the mp. 200 - 201 ° .The crystalline base liberated from the salt melts bei.79-80 ° ,

Example 4 : erythro- and

^{Pyro 1-} dino [1,5-c] oxazolidin-3-one . '

In an analogous manner as described in Example 1 is obtained starting. of 4.4 g (0.02 mol) of erythro (3-methylphenyl) - ^{(5,5-dimethylpyrrölidin-> s} i '2-yl) -methanol, 10, -L g of triethylamine. and 110 ml of one. 20% phosgene

/ '.. solution in toluene the erythro-l- (3-methylphenyl) -5,5-dimethyl-pyrrole

  lidino [1,5-C] OXaZOUdIn-S-On in the form of an amorphous white powder

of the mp 50-60 ° and starting from 2.9 g (0.013 mol) of threo- (3-methyl-. '' - ', phenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol, 6, 7 g of triethylamine and 75 ml of a 20% solution of phosgene in toluene. Threo-l- (3-MethylphenyD-S ^ 'S-dimethyl-pyrrblidinof l, 5-c] oxazolidin-3-one in the form of white crystals from Mp 65-67 ° (from H ^ exane).

The starting erythro or threo (3-methylphenyl) - (5,5- "dimethylpyrrolidin-2-yr) -methanol can be prepared, for example, as follows:"

a) Analogous to the procedure described in Example 1 a), starting from 15.0 g (0.125 mol) of 3-toluylaldehyde and 16 g (0.125 mol) of 2,2-dimethyl-l-nitroso-pyrrolidine crystalline erythro - (3 Methylphenyl) - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol hydrochloride, m.p. 136-137 * and a brownish OeI in which the diastereomeric threo (3-methylphenyl) - (5,5-di-ethyl-i-nitroso-pyrrolidin-2-yl) -methanol enriched. , ,

- b) obtained analogously to the procedure described in Example Ib)

starting from 14.9 g (0.06 mol) of erythro (3-methylphenyl) - (5,5 ~ ^ p- dimethyl-l-nitroso-pyrrolidin-2-yl) -methanol by treatment with hydrogen chloride gas in Crystalline erythro- (3-methylphenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol hydrochloride in a toluene / dioxane mixture ^: "" of the mp 200-202 °.

c) obtained analogously to the procedure described in Example 1 c); starting from 14 g of the obtained under 4 a) OeIs, in which the

, Threo- (3-methylphenyl) - (5,5-dimethyl-l-nitroso-pyrrolidin-2-yl ·) -metha-. '..' .. nol 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 from Mp. 230-232 °.

Example 5 : erythro- and threo-1-phenyl-5,5-dimethyl-pyrrole-idyno- [1,5-c] oxazolidirir-3-one

In an analogous manner as described in Example 1, starting from 5 g (0.024 mol) erythro-phenyl- (5,5-dimethylpyrrolidin-2-yl) -methanol, 17 ml of triethylamine and 133 ml of a 20% solution of phosgene in Toluene the erythro-l-phenyl-S ^ -dimethyl-pyrrolidinotljS-cjoxazol-.idin-3-one in the form of white crystals, mp. 135-137 ° (from hexane) and starting from 1.3 g (0.006 mol) of threo -Phenyl (5,5-di-ethylpyrrolidin-2-yl) -methanol, 4.4 ml of triethylamine and 35 ml of a 20% solution of phosgene in toluene, the threo-1-phenyl-5,5-dimethyl-pyrrolidino [ l, 5-c] oxazolidin-3-one in the form of white crystals, mp. 70-71 °. ('from ether / hexane).

    · ... - 45 - -

The erythro or threo-phenyl- (5,5-dimethylpyrrolidin-2-yl) -methanol used as starting material may be e.g. produced as follows

  become: , '. -.

'a) Analogously to the procedure described in Example 1 a) starting from 13.3 g (0.125 mol) of benzaldehyde and 16.0 g (0.125 Mo. 1) of 2,2-dimethyl-l-nitroso-pyrr. olidin crystalline erythro-phenyl (5,5-dimethyl-l-nitroso-pyrrolidin-2-yl) -ine _i THANOL, mp 119-121 ° as well as a brownish oil in which the diastereomeric thr.eo-phenyl. - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol enriched.

W .. · '. , , , · -. /. . ": b) Analogously to the procedure described in Example 1 b), starting from 15.6 g (0.066 mol) of erythro-phenyl (5,5-dimethyl-nitroso-pyrrolidin-2-yl) -methanol by treatment with hydrochloric acid gas in a toluene / dioxane mixture crystalline erythro-Pheny1-

... (5,5-dimethylpyrrolidin-2-yl.) - Methanol hydrochloride of the mp .. 169 - 170 °. The crystalline base liberated from the salt melts at 105-106. °: ..

'' ..; ':. , c) Analogous to that in Example. 1 c) receives. starting from 11 g of the residue obtained according to 5 a)

Treatment with hydrogen chloride gas in toluene and ahschliessen.de ':. Crystallization from ethanol / diethyl ether pure threo-phenyl (5,5-vV · ' ¹ dimethyipyrrolidin-2-yl) _l- methanol hydrochloride, mp. 222-225 °. The base liberated from the salt is obtained as a yellowish oil.

Example 6 : erythro- and threo-1- (1-naphthyl) -5,5-dimethyl- .

, ' pyrrolidino [l, 5-c] oxazolidin-3-oo

In an analogous manner as described in Example 1, starting from '4 g (0.013 mol) erythro (l-naphthyl) - (5,5-dimethylpyrroli'din-2-yl) -methanol hydrochloride., 11.5 · ml triethylamine and 75 ml of a ^'.:':. 20% phosgene solution in toluene after two crystallization '

The ether-hexane erythro-1- (1-naphthyl) -5,5-dimethyl-pyrrolidino-1 '''''. ₍ ' [1,5-c.] Oxazoiidine) 3-on in the form of pale yellow crystals of mp 138-139 ° and starting from 1.0 g (0.003 mol) of threo- (1-naphthyl) -

(5j5-dimethylpyrrolidin-2-yl) -methanol, 2.8 ml of triethylamine and 18.5 ml of a 20% solution of phosgene in toluene, the threo-l- (1-naphthyl) -5,5-dimethyl-pyrrolidino [ l, 5-c] oxazolidin-3-one in the form of light brown crystals of mp. 132-134 ° (from diethyl ether / hexane).

The starting erythro- or threo (1-naphthyl) - "(5,5-dimethylpyrrolidin-2-yl) -raethanol can be prepared, for example, as follows

become:

a) Analogously to the procedure described in Example Ί a), starting from 19.5 g (0.125 mol) of 1-naphthaldehyde and 16.0 g (0.125 mol) of 2,2-dimethyl-1-nitroso-pyrrolidine, crystalline erythrocyanide is obtained. (1-naphthyl) - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol, mp 159-160 °, and a brownish crystal pulp containing the diastereomeric threo (1-naphthyl) - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol enriched is.

b) Analogously to the procedure described in Example 1 b) starting from ν ₍ οη 9 g (0.031 mol) of erythro (l-naphthyl) - (5,5-dimethyll-nitroso-pyrrolidin-2-yl) -methanol 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-dimethylpyrrolidin-2-yl) -methanol hydrochloride in the form of white crystals of mp. 229- 230 ° The base liberated from the salt melts at 152-154 °. ·· ,. '.

c) Analogously to the procedure described in Example 1 c), starting from 9.2 g of the crystal slurry obtained according to 6 a), in which the threo (1-naphthyl) - (5,5-dimethyl-1-nitroso) pyrrolidin-2-yl) -methanol is enriched, by treatment with hydrogen chloride gas in toluene and subsequent 2-fold crystallization from methanol / diethyl ether pure threo- (1-naphthyl) - (5,5-dimethylpyrrolidin-2-yl) - Methanol hydrochloride of mp. 250 ° (Zers,).

Example 7: Erythro- and threo-1- (3-trifluoromethylphenyl) -5,5-dimethylpyrrolidinyl-1-fluoro-1,5-c] oxazolidin-3-one

The procedure is analogous to that described in Example 1, starting from "3.0 g, (0.0.09 mol) of erythro (3-trifluoromethylphenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol hydrochloride , 6.7 g of triethylamine and 52 ml of a 20% solution of phosgene in toluene, the erythro-l- (3 ~ trifluoromethylphenyl) -5,5-dimethyl-pyrrolidino [l, 5-c] oxazolidin-3-one in white crystals of the mp. 71-72 ° (from diethyl ether / hexane) and starting from 1.9 g (0.006 mol) of threo- (3-trifluoromethylphenyl) -

"^'' (5,5-dimethyl-pyrrolidin-2-yl) methanol, 5.2 ml of triethylamine and 34 ml of a 20% phosgene solution in toluene, the threo-l- (3-tri-.. fluoromethylphenyl) -5,5-dimethy1-pyrrolidino [1,5-c] oxazolidin-3-one in the form of yellowish crystals of mp. 70-71 ° (from diethyl ether / hexane). '.'

The starting erythro or threo (3-trifluoro-methylphenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol may e.g. advertise as follows: ''

a) Analogously to the procedure described in 'Example 1 a) receives ^ ₁ starting from 10.4 g (0.06 mol) of 3-trifluoromethylbenzaldehyde and

7.7 g (0.06 mol) of 2,2-dimethyl-1-nitroso-pyrrolidine after crystallization from toluene erythro (3-trifluoromethylphenyl) - (5,5-dimethyl-1-nitrosopyrrolidin-2-yl) -methanol from the m. 172-174 °, as well as a bräun- ''. , ·. OeI in which the diastereomeric threo- (3-Tr is luormethy! phenyl) - (5,5-dimethyl-l-nLt ^; roso-pyrrolidin-2-yl) methanol enriched.

b) Analogous to the procedure described in Example 1 b), starting from 9.06 g (0.03 mol) erythro (3-trifluoromethylphenyl) - .. (5,5-dimethyl-l-nitroso-pyrrolidine -2-yl) -methanol by treatment with hydrogen chloride gas in a toluene / dioxane mixture and recrystallization of the crude product from methanol / Oiäthyläther erythro {3-trifluoromethylphenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol · Hydrochloride in the form of white crystals of SmD. 205-206 °. The salts released from the salt

sat crystalline base melts at 1O4-1O5 ° C.

c) Analogously to the procedure described in Example 1c), starting from 7.9 g of the oily residue obtained according to 7 a), in which the threo- (3-trifluoromethylphenyl) - (5,5-dimethyl-1-nitroso) is enriched by treatment with hydrogen chloride gas in toluene and subsequent crystallization from methanol / diethyl ether pure threo- (3-trifluoromethylphenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol hydrochloride of mp. 224-227 °. The crystalline base liberated from the salt melts at 65-67 °.

Example 8 : erythro- and threo-1- (3-chlorophenyl) -5,5-dimethyl · - . piperidino ^ !, o-cjoxazolidin-S-on

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

 The starting erythro or threo (3-chlorophenyl) - (6,6-dimethylpiperidin-2-yl) -methanol may e.g. be prepared as follows:

  a) Analogously to the procedure described in Example 1 a) starting from 14.1 g (0.1 mol) of 3-chlorobenzaldehyde and 14.2 g (0.1 mol) of 2,2-dimethyl-l-nitroso- piperidine - see d) - crystalline

, erythro (3-chlorophenyl) - (6,6-dimethyl-1-nitroso-piperidin-2-yl) -methanol of mp 125-127 ° and an orange-brown OeI in which the diastereomeric threo- (3- Chlorophenyl) - (6,6-dimethyl-1-nitroso'-piperidin-2-yl) -methanol. An analytically pure sample

the isomer-free threo-diastereomer can be converted by filtration

tr. *

a. Layer, silica gel with toluoL / ethyl acetate (-20: 1) can be obtained as eluent. After evaporation of the solvent, the product falls in the form of pale yellow crystals of mp. 108-110 °.

b) Analogously to the procedure described in Example 1 b), starting from 14.0 g (0.05 mol) erythro7 (3-chlorophenyl) - (6,6-dimethyl-1-nitroso-piperidin-2-yl ) methanol by treatment with hydrogen chloride gas in a ToluoL / Dioxan mixture crystalline erythro (3-chloro-.phenyl) - (6,6-dimeth.ylpiperidin-r2-yl) -methanol hydrochloride of the mp.

225-227 ° * The crystalline base liberated from the salt melts; 138-139 °. ^: . . '.''.'

c) In analogy to the above under b) described procedure, starting from 3.6 g (0.012 mol) of the pure threo (3-chlorophenyl) - (6,6 ^ din ^ie thyl-l-nitröso-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, mp .240-241 °. The crystalline salt liberated from the salt melts at 155-156 °.

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 treated dropwise at room temperature within 1 hour with 41.4 ml ^y (0.3 Mol) of a 50% aqueous sodium nitrite solution. The reaction mixture is stirred for a further 2 hours at room temperature, then cooled to 0 ° with an ice-water bath and treated dropwise at this temperature with 25 ml of concentrated sodium hydroxide .. Subsequently, the yellow solution is extracted exhaustively with 100 ml of diethyl ether. The combined organic phases are washed with 100 ml of water, dried over sodium sulfate and evaporated at 30 ° bath temperature in a water-jet vacuum. The yellow, oily residue is then distilled in a water-jet vacuum, the 2,2-dimethyl-I-nitrosopiperidine as a yellow liquid from 8Cp = 101-102 ° passes.

Example 9 : erythro- and threo-1- (3,4-dichlorophenyl) -5,5-dimethylpiperidino [1,6-c] oxazolidin-3-one

In an analogous manner as described in Example 1, starting from 9.0 g (0.031 mol) of erythro-O ^ -DichlorphenyO- ^ o-dimethylpiperidin-2-yl) methanol, 15.8 g · triethylamine and 170 ml of a 20th % of phosgene solution in toluene, the erythro-l- (3,4-dichlorophenyl) -5,5-dimethyl-piperid ¹ ino [l, 6-c] oxazolidin-3-one in the form of white crystals, mp. 127 -129 ° (from ether-hexane) and starting from 6.7 g (0.023 mol) of threo- (3,4-dichlorophenyl) - (6,6-dimethyIpiperidin-2-yl) -methanol, 11.7 g of triethylamine and 130 ml of a 20% solution of phosgene in toluene, the threo-1 ^ - (3,4-dichlorophenyl) -5,5-dimethyl-piperidino [1,6-cjoxazolidin-3-one in the form of pale-yellowish crystals of mp 120-121 ° (diethyl ether / hexane). ,

The starting erythro or threo (3,4-dichlorophenyl) - (6,6-dimethylpiperidin-2-yl) -methanol may be e.g. be prepared as follows:

a) Analogously to the procedure described in Example 1 a), starting from 17.6 g (0.1 mol) of 3,4-dichlorobenzaldehyde and 14.2 g (0.1.MoI) of 2,2-dimethyl-l nitroso-piperidine crystalline erythro (3,4-dichlorophenyl) - (6,6-dimethyl-1-nitroso-piperidin-2-yl) -methanol. of mp. 140-141 ° and a yellow-brown crystal pulp, in in which the diastereomeric threo (3,4-dichlorophenyl) - (6,6-dimethy1-1-nitrosopiperidin-2-yl) -methanol is enriched. An analytically pure sample of the isomer-free threo-diastereomer can be obtained by filtration through a layer of silica gel with a toluene / ethyl acetate mixture (10: 1) as eluent. After evaporation of the solvent, the product precipitates in the form of white crystals of mp. 173-174 °. , , , '' '.'

b) Analogously to the procedure described in Example 1 b), starting from 5.5 g (0.017 mol) erythro (3,4-dichlorophenyl) - (6,6-dimethyl-l-nitroso-piperidin-2-yl ) methanol by treatment with hydrogen chloride gas in a toluene / dioxane mixture, the erythro

(3,4-dichlorophenyl) - (6,6-dimethylpiperidin-2-yl) -methanol hydrochloride of Srnp. 288 ° (decomp.). The base liberated from the salt melts at 132-133 °. ' '. , ,

c) In analogy to the reaction described above under b), starting from 3, Og (0.009 mol) threo- (3,4-dichlorophenyl) - (6,6-dimethyl-l-nitroso-piperidin-2-yl) methanol by treatment with hydrogen chloride gas, in a · toluene / Dioxan-Gemis.ch crystalline threo- (3,4-dichlorophenyl) - (6,6-dimethyl-piperidin-2-yl) -methanol hydrochloride of; Mp 257-258 °. The base liberated from the salt melts at 153-154 °,

Example 10 : erythro- and threo-1-o-Dichloro-phenyl-S, 5-dimethyl-.pyrrolidino [l, 5-c] oxazolidin-3-one .

in an analogous manner as described in Example 1 starting from-4 g, (0.003 mol) of erythro (2,6-dichlorophenyr) -5,5-dimethyl-pyrroliditir: 2-yl) -methanol-hydrochloride, 9 ml of triethylamine and 70 ml of a 20% solution of phosgene in toluene erythro-l- (2,6-dichlorophenyl) -5,3-dimethy.l -pyrrolidinofljS-cloxazolidin-S-on in the form of white crystals of mp. 92 ^ 94 ° (from Diäthyläthar / Hexati and starting

"..> ^y

of 2.0 g (0.006 mol) of threo (2,6-di-chlorophenyl) - (5,5-di-ethyl-pyrrole-.idin-2-yl) -methanol hydrochloride, 4.5. ml of triethylamine and 35 ml of a 20% solution: phosgene solution in toluene, 0.5 g (26.3% of theory), threo-1- (2,6-dioichlorophenyl-S, -dimethyl) pyrrolidinone pCl ^ -cjoxazolidin-S-on in the form of white crystals of ether / hexane, mp 143-144 ° (from

Diethyl ether / Hexaft). '.

  ,. '' '-'

The · serving as the starting material threo- or erythro (2,6-dichlorophenyl) ^ ₍₅₎ 5-dimethylpyrrolidin-2-yl) -methanol and its hydrochloride can z: are prepared as follows:

a) Analogously to the beschreibenen in Example la) procedure starting from 21.9 g (0,125.Mol) 2, 6-dichlorobenzaldehyde! : and 16 g (0.125 mol) of 2,2-dimethyl-1-nitroso-pyrrolidine crystalline erythro (2,6-dichlorophenyl) - (5,5-dimethyl-1-nitroso-pyrrolidine)

2-yl) -methanol, mp. 178-180 °, and 18.5 g of a yellowish crystal pulp in which the diastereomeric threo (2,6-dichlorophenyl) - (5,5-dimethyl-l-nitroso-pyrrolidine-2 -yl) -methanol is enriched.

b) Analogously to the procedure described in Example 1 b), starting from 19.0 g (0.063 mol) erythro (2,6-dichlorophenyl) - (5,5-dimethyl-l-nitroso-pyrrolidin-2-yl ) methanol by treatment with hydrogen chloride gas in toluene, crystalline

-?) _He ythro- (2,6-dichlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) - ·.,. · Methanol hydrochloride, mp 243-244 °. The released from the salt; set, crystalline base melts at 112-114 °.

c) Analogously to the procedure described in Example 1 c), starting from 18.5 g of the crystal pulp obtained according to a) in which the diastereomer is enriched, by treatment with hydrogen chloride gas in toluene and subsequent crystallization from ethanol. Diethyl ether Pure threo- (2,6-dichlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) methanol hydrochloride, mp 224-225 ° The crystalline base liberated from the salt melts at 137-138 ° C.

Example 11 : Erythro- and threo (3-chlorophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol

3.5 g of crude (3-chlorophenyl) - [1- (cyclohexyliminomethyl) -5,5-dimethyl-pyrrolidin-2-yl] -methanol are dissolved in 50 ml of methanol, treated with 50 ml of 2N sodium hydroxide solution and 4 hours heated to reflux '. It is evaporated to dryness, taken up in ether, washed with saturated brine, dried over sodium sulphate and evaporated again to dryness. A mixture of erythro- and threo - (. 3-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol obtained by fractional

Crystallization from isopropanol and chromatography on silica gel in the erythro-form from the mp. 120.5 ° and the threo form, mp. 96 ° can be separated. ₍

The (3-chlorophenyl) used as starting material - [l- (cyclohexyl · iminomethyl) -5,5-dimethyl-pyrrolidin-2-yl] -methanol can following mass. getting produced:

a) 9.9 g of 2,2-dimethylpyrrolidine are dissolved in 25 ml of methanol, treated with 7.4 g of ethyl formate and heated to reflux for 3 hours. Concentrate, - in half, add 100 ml of toluene, separating

& ''. , '

'; the toluene phase, washed twice with water and then with saturated brine and evaporated to dryness under reduced pressure. This gives 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 sulphate and heated under nitrogen for 3 hours to 70 °. Allow to cool, take up in 100 ml of ether, washed twice with n-sodium. - Hydrogen carbonate and then with saturated saline solution and evaporated to 'dryness'. This gives crude 1-methoxymethylene - ^^ - dimethyl- · ..- .. pyrrolidinium methosulfate, which is further processed immediately. .

'Vc) The product obtained according to b) is reacted with 20 g of cyclohexylamine; stirred and stirred for 15 'hours at room temperature. Man. Takes methylene

Chloride, washed with 10% potassium hydroxide solution, dried over: sodium sulfate and evaporated to dryness. This gives 15 g of 1-Gyclöhexyliminomethyl-2,2-dimethyl-pyrrolidine, which is processed immediately.

d) The product obtained according to c) is in 50 ml tetrahydrofuran ge. cooled, cooled under argon to -78 °, treated with 6.5 g Tertiärbutyllithium, heated for one hour at -25 ° and again cooled to -78 °. Then with vigorous stirring at -78 ° 10.5 g of 3-chlorobenzaldehyde

ο * _Λ OO _ O

- 54 -

dropwise. The mixture is stirred for 15 minutes at -70 ° and then allowed to slowly warm to room temperature, 10 ml of methanol added, neutralized with dilute acetic acid and evaporated under reduced pressure to dryness .. Get crude (3-chlorophenyl) - [! - (cyclohexyliminomethyl) -5,5-dimethyl-pyrrolidin-2-yl] -methanol, which can be used without further purification. . ·.

ι '·

In an analogous manner, it is also possible to prepare the compounds of the formula V according to Examples 2-10.

Example 12 : erythro- and threo (3-chlorophenyl) - (5,5-dimethyl-pyrrole -''-idin-2-yl) -methanol

5 g of crude (3-chlorophenyl) - (l-benzyl-5,5-dimethyl) -methanol are dissolved in. 50 ml of methanol, treated with 0.8 g of palladium (5%) and under an excess pressure of 0.5 bar at 50 ° until the end of the '. Hydrogenation hydrogenated (about 40 minutes). It is filtered from the catalyst and evaporated to dryness. A mixture of erythro- and threo- (3-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol, - the 'by fractional crystallization of first. Ether / hexane and then from isopropanol in the erythro form of mp 120 ° and the threo form of mp 97 ° can be separated. ,

The starting material (3-chlorophenyl) - (1-benzyl-5,5-dimethyl) -methanol may be e.g. as follows:

a) 2.5 g of sodium hydride (50 ml of a 5% suspension in mineral oil, deoiled with hexane) are suspended under nitrogen in.einem mixture of 100 ml of tetrahydrofuran and 100 ml Dime thy ls.ulf oxide and stirring at 5 ^a dropwise with a solution of 46.7 g of 3-chlorobenzyl. triphenylphosphonium bromide and 13.0 g of 4-oxobutyric acid ethyl ester in 150 ml of tetrahydrofuran. The mixture is stirred for 30 hours at room temperature, evaporated to dryness under reduced pressure,

takes up in 1000 ml of ether, shaking with 5 g of activated charcoal and 50 g of anhydrous sodium sulfate; filtered and evaporated to dryness. -Man receives crude S-O-ChlorphenyD-pent-A-en-carboxylic acid ethyl ester 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 methylmagnesium bromide (prepared from 5 g of magnesium turnings and 30 g of methyl bromide) in 100 ml of tetrahydrofuran. The mixture is stirred for 1 hour at room temperature and 4 hours at 60 °, evaporated to dryness, taken up in 500 ml of toluene,>' ^! shake with charcoal and anhydrous sodium sulfate, filter

~ and d, vaporizes to dryness under reduced pressure. This gives crude 6- (3-chlorophenyl) -2-methyl-hex-5-enol, which is processed immediately "... - · '/,

, c) The crude product obtained according to b) is dissolved in 150 ml of toluene, on

'Cooled 5 °, with 1Ό0'ml 20% hydrochloric acid and .2.5 g of tetrabutylammonium _n , .- "chloride added and vigorously stirred for 1 hour at 5-10 ° and 2 hours at room temperature, the organic phase is separated, with 5 g of activated carbon and 10 g of anhydrous magnesium sulfate ausge-;

shakes and filtered. A toluene solution of 2-chloro-6- (3-chlorophenyl) -2-methyl-hex-5-ene is obtained.

d). To 15 g of benzylamine are added to the toluene solution obtained according to c), stirred for 1 hour at room temperature, then heated slowly to boiling, allowed to boil for 2 hours at reflux and then evaporated to dryness, finally under reduced pressure on.

A viscous oil, which is taken up in 100 ml of ether, is obtained.

Hydrogen chloride gas is introduced 'until no precipitation occurs, sucks and dried in air. This gives N- [6- (3-chlorophenyl) -2-

  ,. methyl-hex-5r-enyl) -benzylammoniumchloride, which can be used without further purification.

ο c. ο ο ο

e) The crude product obtained according to d) is dissolved in 100 ml of methylene chloride, treated with 50 ml of trifluoroacetic anhydride and 10 g of sodium carbonate and stirred for 2 hours at room temperature. It is washed twice with 25 ml of a 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. Mari receives 20.5 g of crude N- [6- (3-chlorophenyl) -2-methyl-hex-5-enyl) -N-benzyl-trifluoroacetamide.

f) The crude product obtained according to e) is dissolved in 75 ml of dioxane, mixed at 10 ° to 15 ° and with 10 ml of sulfuric acid (density = 1.83). Then, a solution of 8.2 g of N-bromosuccinimide in 50 ml of dioxane is added dropwise with stirring at 10 °. The mixture is stirred for 30 minutes at 10 ° to 15 ° and 15 hours at room temperature, washed with water and saturated brine and dried over sodium sulfate. A solution of N- [5-bromo-6- (3-chlorophenyl) -6-hydroxy-2-methyl-hexyl] -N-benzyltrifluoroacetamide in dioxane is obtained. ,

g) The product solution obtained according to f) is admixed with 80 ml of n-sodium hydroxide solution and heated to reflux for 1 hour with stirring. It is concentrated strongly, taken up in ether, washed with water and saturated saline solution, dried over sodium sulfate and evaporated to dryness. This gives crude O-chlorophenyO-Cl-benzyl-SjS-dimethyl-methanol, which can be used without further purification.

In an analogous manner, it is also possible to prepare the compounds of the formula V according to Examples 2-10.

Example 13: threo-1- (4-chlorophenyl) -5,5-dimethyl-pyrrolidino

[l, 5-c] oxazolidin-3-one 6 g of threo-1- (4-chlorophenyl) -3-iinino-5,5-dimethyl-pyrrolidino [1,5-c] oxazolidine are dissolved in 150 ml of water and 50 ml of phosphate buffer · (P = 6.5)

suspended and heated to reflux with stirring for 22 hours. It is allowed to cool, acidified to pH 4 with dilute hydrochloric acid and extracted twice with 100 ml of ethyl acetate each time. The extracts are combined, washed with saturated brine, dried over sodium sulphate and evaporated to dryness under reduced pressure.

evaporated. The crystalline residue is recrystallized from ethyl acetate / hexane. The threo-1- (4-chlorophenyl) -5,5-dimethylpyrrolidino [l, 5-c] oxazolidin-3-one, m.p. 100-102 °, is obtained. , ... '. ·.

The starting material may e.g. be prepared by one of the following methods:.

a) 23.3 g of threo- (4-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol are dissolved in 1ÖO _: ml of ethanol and dropwise with stirring with a solution of 6.5 g of cyanogen chloride in 25 ml of ethanol added. The mixture is heated briefly to reflux, the solvent is distilled off and the residue is recrystallized twice from isopropanol. You get

oxazolidine, which can be used without further purification.

b) 23.3 g of erythro (4-chloro-phenyl) - (5,5-dimethyl-pyrrolidin-2-yl) - methanol are dissolved in Ϊ50 ml of n-hydrochloric acid, with 8.1 g of potassium cyanate 'added and' 12 Stirred hours at room temperature. It is concentrated until the beginning of the crystallization, cooled to 5 °, filtered off with suction and left. air dry. The erythro (4-chlorophenyl) - (1-car- 'bamyl-5,5-dimethyl-pyrrolidin-2-yl) -methanol is obtained. This is dissolved in 200 ml of tetrahydrofuran and added dropwise with stirring 12.0 g of thionyl chloride. The mixture is heated briefly to reflux, evaporated under reduced pressure.

      ν * ·

"N 5-dimethyl-pyrrolidino [l, 5-c] oxazolidin reduced pressure to a dryness, and crystallized from ethanol to. ¹ ^, is obtained threo-l- (4-chlorophenyl) -3-1HiInO-S ,,, which after identification of the IR spectrum is identical to the product obtained according to a). '

Analogously, the compounds of formulas I and V can also be prepared according to Examples 1, 2 and 4-10. , ^:

Example 14: 1- (4-Chlorophenyl) -5,5-dimethylpyrrolidino [l, 5-c] oxazolidine-3-ση, mixture of diastereomers . .

1.5 g of erythro (4-chlorophenyl) - '(1-carbamyl-5,5-dimethyl-pyrrölidin-2-yl) methanol are dissolved in 25 ml of pyridine, treated with 1 g .Thionylchlorid and heated to boiling for 4 hours , It is evaporated under reduced pressure

Dry to dryness, dissolve in ether, wash twice with water and '. then with saturated brine, dried over sodium sulfate, evaporated to dryness and recrystallized several times from hexane / ether to. A mixture of erythro- and threo-1- (4-chlorophenyl) -5,5-dimethylpyrrolidino [l, 5-c] oxazolidin-3-one, mp 82-87 ° ..

The starting material may be e.g. following are manufactured:

3.0 g of erythro (4-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol are suspended in 25 ml of n-hydrochloric acid, admixed with 1.5 g of potassium cyanate and stirred at room temperature for 12 hours , You narrow to the. Beginning crystallization, cooled to 5 °, filtered off and crystallized from ethanol / water to. Erythro (4-chlorophenyl) -Q-carbamoyl-5,5-dimethyl-pyrrolidin-2-yl) -methanol, which can be used without further purification, is obtained. '.

In an analogous manner, it is also possible to prepare the compounds of the formula I according to Examples 1, 2 and 4-10.

Example 15: Erythro- and threo-1- (3-chlorophenyl) -5,5-dimethylpyrrolidino [l, 5-c] oxazolidin-3-one

30.5 g of erythro (3-chlorophenyl) - (l-ethoxycarbonyl-5,5-dimethyl-pyrrolidin-2-yl) -methanol dissolved in 100 ml of ethanol are mixed with 0.2 g of sodium and heated to reflux for 4 hours , It is evaporated to dryness and recrystallized several times from hexane. The erythro-1 - (3-chlorophenyl) -5,5-dimethyl-pyrrolidino [1,5-c] oxazplidin-3-one, mp. 83-84 °.

, 30.5 g of erythro-O-chlorophenyl O-Cl-ethoxycarbonyl-S.S-dimethylpyrrolidin-2-yl) -methanol are dissolved in 100 ml of ether, treated dropwise with 11.5 g of thionyl chloride and heated for 6 hours zur.Rückfluss. It is evaporated to dryness, taken up in ether, washed with water. and with saturated brine, dried over sodium sulfate, evaporated again to dryness and crystallized from hexane to. The threo-1- (3-chlorophenyl) -5,5-dimethyl-pyrrolidino [l, 5-c] oxazolidin-3-one, mp. 81 °. ,

»Ο« * " ^β

   '. '.' - 59 -

The starting material may e.g. be prepared as follows:

, . 47.6 g of erythro - (3-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) ^-methanol: are dissolved in 1000 ml of benzene, treated with 20 g anhydrous potassium carbonate, cooled to + 5 ° and vigorous stirring added dropwise with 21.8 g of ethyl chloroformate. The mixture is stirred for 1 hour, 5 ° to 10 ° and 1 hour at room temperature, filtered off and evaporated to dryness. Erythro (3-chlorophenyl) - (1-ethoxycarbonyl-5,5-dimethylpyrrolidin-2-yl) -methanol is obtained which can be used without further purification.

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

Example 16 '.':. Mixture of erythro- and threo- (3-chlorophenyl) - (6,6-di- • methyl-piperidin-2-yl) -methanol

26.3 g of 1- (3-chlorobenzoyl) -6,6-diniethylpiperidine-2-carboniliril are dissolved in. Dissolved 50 ml of tetrahydrofuran and added to a cooled to -78 ° C solution of 12 g of lithium-N , ^? N-diisopropylamide züge- in .150 -ml ^{tetrahydrofuran:} drips .. Man. Stir for 15 minutes at -78 °, add 15 g of 3-chlorobenzaldehyde dissolved in a little tetrahydrofuran and allow to gradually warm to room temperature. The mixture is stirred for 1 hour add 5 g of sodium borohydride added in 50 ml of methanol is stirred, treated with 25 ml of acetone, heated for 2 hours under reflux, evaporated to dryness and crystallized from isopropanol to further 6 hours \. Man. receives a mixture of erythro and threo (3-chlorophenyl) - (6,6-dimethyl-piperidin-2-yl) -nethanol '", mp. 126-131 °.

<''. ^: '. . '".

, The 1- (3-chlorobenzoyl) -6,6-dimethylpiperidine-2-carbonitrile used as a starting material may be e.g. by reaction of 6,6-dimethyl- ··. , piperidine-2-carbonitrile, obtainable in a manner analogous to that described in Example 18a), with S-chlorobenzoyl chloride / potassium carbonate in methylene chloride.

In an analogous manner, it is also possible to prepare the compounds of the formula V according to Examples 1-7, 9 and 10. , '·. <

Example 17 : Isomerization of erythro- to threo (3-chlorophenyl) - (StS-dimethyl-pyrrolidine-Z-y-D-ethanol

5 g of erythro (3-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol are dissolved in 50 ml of chloroform, cooled to 0 ° and treated dropwise with 10 ml of thionyl chloride. The mixture is stirred for 1 hour at room temperature, poured onto 200 g of ice, allowed to stir for 30 minutes at room temperature and 2 hours under reflux, cooled again to 0 °, with sodium hydroxide solution to pH = 11 and extracted four times with 50 ml of chloroform. The extracts are combined, washed with water, dried over sodium sulfate and evaporated to dryness. It is taken up in ethyl acetate, 10 ml of 5N hydrochloric acid added, allowed to stir for 15 minutes at 0 ° and filtered off with suction. The threo- (3-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol hydrochloride of mp. 209-210 °.

This can be converted by shaking with 100 ml of methylene chloride and 10 ml of 2N sodium hydroxide solution and separating and evaporating the Methylenchlorxdphase in the free base of mp. 68 °.

In an analogous manner, it is also possible to isomerize the threo isomer to the erythro isomer and the erythro (threo) forms of the compounds of the formula V according to Examples 2-10 to the threo (erythro) isomers.

Example IS: erythro (4-chlorophenyl) - (5, 5

methanol ·

12.5 g of '' - ('4-chlorobenzoyl) -5,5-dimethyl-pyrrolidine dissolved in 50 ml of tetrahydrofuran are added dropwise to a suspension of 1.6 g of lithium aluminum hydride in 250 ml of tetrahydrofuran. The mixture is refluxed for 2 hours, cooled in an ice bath, 5 ml of water are added dropwise, the mixture is stirred for 30 minutes, evaporated to dryness under reduced pressure, taken up in benzene, washed twice with water and then with saturated brine, dried Sodium sulfate, evaporated again under reduced pressure and crystallized from benzene / Dloxan to. The erythro (4-chlorophenyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol of mp. 123-124 °.

"The starting material can e.g. be prepared as follows:

a) 20.8 g, l-Cyclohexyliminomethyl-2,2-dimethyl-pyrrolidine (see Example lic) - are dissolved in 100 ml of tetrahydrofuran, under argon, cooled to -78 °, treated with 6.4 g Tertiärbutyllithium and 30 Minutes at, '- 75. stirred to -70 °. The resulting solution is transferred to a dropping funnel cooled to -78 ° and slowly added to a vigorously stirred, ¹ to -75 ° cooled solution of 6.2 g of cyanogen chloride in 50 ml.

Dropped tetrahydrofuran. The mixture is stirred for 30 minutes at -78 °, then gradually heated to 20 °. Add 50 ml of water and 10 ml of methanol

£: /. stir for 4 hours at 2O ° -3O °, evaporated to dryness,

takes up in ether, dried over sodium sulfate and evaporated again. This gives the 5, S-dimethyl-pyrrolidine - ^ - carbonitrile, which. can be used without further purification.

b) The crude product obtained according to a) and 10 g of 4-chlorobenzene are dissolved in 150 ml of nitrobenzene, treated portionwise with 30 g of aluminum trichloride and stirred for 2 hours at 80 ° C. The mixture is allowed to cool and poured into a mixture 500 g of ice and 500 ml of 5N hydrochloric acid and leaves

'. : Stir vigorously for 12 hours. The precipitate formed is sucked off,

  · '' "'' '' .. ♦"

dried in air and recrystallized from ethyl acetate. One gets

  "Holds crude 2- (4-chlorobenzoyl) -5,5-dimethy! -Pyrrolidine, which without

J , 'further purification is used.

Example 19 : Isomerization of erythro- to-threo- (3-chloro- phenyl) -; (5,5-dimethylpyrrolidin-2-yl) -methanol

To a solution of 3.6 g (0.015 mol) of erythro (3-chlorophenyl), - (5,5-dimethylpyrrolidin-2-yl) -methanol in 20 ml of dimethylformamide are added at 0-5 ° 1, 53 g (0.015 mol) of acetic anhydride were added dropwise. The solution is subsequently stirred at room temperature for 1 hour, 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 a saturated

aqueous sodium bicarbonate solution washed over magnesium. dried sulfate and evaporated to dryness in 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 at 5-10 ° inside, from 5 minutes to a solution of 2.6 g of thionyl chloride 'in 10 ml

Methylene chloride added dropwise. The solution is then stirred at room temperature overnight, then evaporated in a water-jet vacuum. This gives crude threo-1- (3-chlorophenyl) -3-methyl-5,5-dimethynyl

 '..-' '. ''

Pyrrolidinotljf-cjöxazoliniumchlorid as thick, soon crystallizing OeI. The hygroscopic crystals can be recrystallized from diethyl ether, mp 114-117 °. ,

2.1 g (0.007 mol) of the crystalline oxazolinium chloride are refluxed in 10 ml of ethanol and 3.5 ml of concentrated sodium hydroxide solution for 1 hour. Subsequently, the mixture is poured onto 60 ml of ice water and extracted three times with 20 ml of ethylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated to dryness on a water-jet vacuum. The residue thus obtained is taken up in 5 ml of methanol and treated with 2 ml of a hydrogen chloride solution (4N in diethyl ether). After addition of a little diethyl ether, the precipitated crystals are filtered off with suction and dried. This gives threo- (3-chlorophenyl) ^ - (5, 5-dimethyl-.pyrrolidin-2-yl) -methanol hydrochloride of mp. 208-209 °.

Example 20 : erythro-1- (3-cyanophenyl) -5,5-dimethyl-pyrrolidinof1,5-c] oxazolidin-3-one

In an analogous manner as described in Example 1, starting from 2.2 g (0.008 mol) of. Erythro- (3-cyanophenyl) - (5, 5-dimethyl-pyrrolidin-2-yl) -methanol hydrochloride in 50th Suspended toluene, 24 ml of a 12.5% aqueous potassium hydroxide solution and 13.1 ml of a 20% solution of phosgene in toluene by working up after 1 hour crystalline

erythro-1- (3-cyanophenyl) -5,5-dimethyl-1-pyrrolidino [1,5-c] oxazolidin-3-one, m.p. 113-115 ° C. ^:

The starting material can e.g. be prepared as follows:

a) Analogous to the procedure described in Example la), starting from 16.4 g (0.125 mol) of 3-cyanobenzaldehyde and 16 g C0.12 mmol) 2, 2-dimethyl-1-nitroso-pyrrolidine, crystalline erythro (3-cyanophenyl) - (5,5-dimethy ll-nitroso-pyrrolidin-2-y I) - · methanol, ¹ m.p. 133-134 °..

'. ^N b) Analogously to the procedure described in Example 1 b), starting from 12.0 g (0.046 mol) of erythro (3-cyanophenyl) - (5,5-di-

  methyl, 1-nitroso-pyrrolidin-2-yl) -methanol by treatment with hydrogen chloride gas in a toluene-dioxane mixture, crystalline erythro (3-gyanophenyl) - (5,5-dimethyl-pyrrolidine -2-yl) -methano 1-hydro chloride, mp 203-205 ° ... The crystalline liberated from the salt

', · Base melts at .111-113 ° .-'. ,

Example 21 : erythro- and

In an analogous manner as described in Example 1 is obtained starting

\ '. '''· .: , ''''

\ Of 4.1 g (0.015 mol) of erythro (2,4-dichlorophenyl) - (5, '5-dime thyl- ⁱ · pyrrolidin-2-yl) -methanol dissolved in 50 ml of toluene, 39 ml.einer 25% aqueous potassium hydroxide solution and 24.5 ml of a 20% solution of phosgene, in toluene by working up after 1 hour crystalline verythro-l- (2,4-dichlorophenyl) -5,5-dimethyl-pyrrolidino [1, 5 -c] oxa-zolidin-3-one, mp 153-155 ° and starting from 3.9 g (0.012 mol). Threo- (2,4-dichlorophenyl) - (5, 5-dimethyl-pyrrolidin-2-yl) -methanol in 50 ml of 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-l- (2,4-dichlorophenyl) -5,5-dimethy1-pyrrolidino [1 "5-c] -oxazolidin-3-one in the form of a pale yellow resin.

The starting erythro or threo (2,4-dichloro-1-phenyl) (5,5-dimethyl-pyrrolidin-2-yl) -methanol can be prepared, for example, as follows:

a) Analogously to the procedure described in Example 1 a), starting from 52.5 g (0.3 mol) of 2,4-dichlorobenzaldehyde and 38.4 g (0.3 mol) of 2,2-dimethyl-1-one nitroso-pyrrolidine, the crystalline one

ι. , , '

erythro (2,4-dichlorophenyl) - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol, mp 156-158 ", and 41.0 g of a yellowish oil in which the diastereomer threo- (2,4-dichlorophenyl) - (5,5-dimethyl-l-nitrosopyrrolidin-2-yl) -methanol enriched.

b) Analogously to the procedure described in Example Ib), starting from 49.9 g (0.164 mol) of erytromo (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 of mp .249-251 °. The crystalline base liberated from the salt melts at 113-115 °.

c) Analogously to the procedure described in Example Ic): starting from 41.0 g of the oil obtained under a), in which the threo- (2,4-dichlorophenyl) - (5,5-dimethyl-l-nitroso -pyrrolidin-2-yl) -methanol is already enriched, by treatment with hydrogen chloride gas in toluene and then twice crystallization from dichloroethane / diethyl ether pure threo- (2,4-dichlorophenyl) - (5,5-dimethyl-pyrrolidine 2-yl) -methanol hydrochloride of mp 221-222 °. The base liberated from the salt melts at 50-51 °.

Example 22 ; erythro and threo-1- (4-pyridyl) -5,5-dimethyl-pyrrole idino [1,5-c] oxazolidin-3-one

In an analogous manner as described in Example 1, starting from 5.0 g (0.018 mol) of erythro (4-pyridyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol dihydrochloride in 70 ml of toluene suspended , 77 ml of one

  ; ' '· ·.' -65 -. ,

12% aqueous potassium hydroxide solution and 28 ml of 20% Phos-. solution in '.Toluol by working up after 1 hour crystalline erythro-l- (4-pyridyl) -5,5-dimethyl-pyrrolidino [l, 5-c] oxazolidin-3-one, mp. 96-98 °, which can be prepared by treatment with an excess of a hydrogen chloride solution (4N in diethyl ether), a crystalline hydrochloride of mp. 175 ° (Z.), And 'starting from 2.7 g' (0.013 mol) of 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% solution of phosgene in toluene by work-up One hour pure threo-1- (4-pyridyl) -5,5-dimethylpyrrolidino [1,5-c] oxazolidin-3-one in the form of white crystals, mp. 120-121 °. By treatment with an excess of an approximately 4N solution of _: hydrogen chloride in diethyl ether, a kri.s- 'talliries hydrochloride can be prepared, mp. 205 ° (Z.). ,

The starting material erythro or threo (4-pyridyl) - (5,5-dimethyl-pyrrolidin-2-yl) -methanol may be e.g. following: · be prepared:

a) Analogously to the procedure described in Example la), starting from 10.7 g (0.1 mol) of pyridine-4-aldehyde and 12.8 g (0.1 mol) of 2,2-dimethyl-1-nitroso -pyrrolidine, 12.8 g of crystalline erythro (4-pyridyl) - (5,5-dimethyl-1-nitroso-pyrrolidin-2-yl) -methanol, mp 181-183 °, and 10.5 g of a reddish oils in which the diastereomeric threo (4-pyridyl) - (5,5-dimethyl-l-nitrosopyr'rolidin-2-yl) methanol is enriched. ,

b) Analogously to the procedure described in Example 1 b), starting from 12.8 g. (0.054 mol) erythro (4-pyridyl) - (5, 5-dimethyl)

, l-nitroso-pyrroridin-2-yl) -methanol by treatment with hydrogen chloride gas in a toluene / dioxane mixture crystalline -erythro- (4-pyridyl) - (5,5-dimeyl-pyrrolidin-2-yl) - methanol dihydrochloride, mp 225-227 °. The crystalline released from the salt. Base melts at 122-124 °. ' , ... '... ·

  - 66 -

c) Analogously to the procedure described in Example lc) starting from 10.5 g of the oil obtained under a) obtained in the. threo- (4-pyridyl) - (5,5-dimethyl-l-nitroso-pyrrolidin-2-yl) -methanol enriched, by treatment with hydrogen chloride gas in toluene and subsequent 2-fold crystallization from methanol / ether pure threo - (4-pyridyl) - (5 ', 5-dimethyl-pyrrolidin-2-yl) methanol hydrochloride, mp 178-179 ° ^s.. The base liberated from the salt melts. at 122-124 ° ..

Example 23 : -erythro- and threo-1-chloro-chloro-O-S-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) - (p.yrrolidin-2-yl) - "methanol, 7.6 g of triethylamine and 8.5 ml of a 20% phosgene solution in toluene crystalline .erythro-l- (4-chlorophenyl) -pyrrolidino [l, 5-c] -. Oxazolidin-3-one, mp 114-115 °, and starting from 2,7 g (0.011 mol) of threo- (4-chlorophenyl) - (pyrrolidin-2-yl) -methanol-hydro-chloro, suspended in 50 ml of toluene ^ 35 ml of a 12.5% aqueous potassium hydroxide solution and 19 ml a 20% solution of phosgene in toluene by working-up after 1 hour, threo-1- (4-chlorophenyl) -pyrrolidino [l, 5-c] oxazolidin-3-one, mp 82-84 °.

Example 24 ; erythro-l-phenyl-ρyrroll · · dino [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-henyl- (pyrrolidin-2-yl) -methanol, 10.1 g of triethylamine and 110 ml of a 20% phosgene Solution in toluene crystalline erythro-1-phenyl-pyrrolidino [1,5-c] oxazolidin-3-one, mp 67-69 °, and starting from 5.0 g (0.028 mol) of threo-phenyl ( pyrrolidin-2-yl) -methanol, 14.1 g of triethylamine and 154 ml of a 20% solution of phosgene in toluene, crystalline threo-1-phenyl-pyrrolidino [!, S-cJoxazolidin-S-one, m.p. 67 °.

Example 25 : erythro- and tareo-1- (3, 4-di-chlorophenyl) -5,5-tetramethylene-piperidinof l, 6-c.] Oxazol-idin-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-tetramethylenepiperidin-2-yl) -methanol dissolved in 70 ml of toluene, 15.6 ml of a 12.5% aqueous potassium hydroxide solution and 9.8 ml of a 20%

- ι ... ' , .'-, - ..

Phosgene solution in toluene by working-up after 1 hour, crystalline erythro-1- (3,4-dichloro-phenyl) -5,5-tetramethylene-piperidino [1,6-c] oxazolidin-3-one, m.p. 152- 153 °, and starting from 1.4 g (0.0045 mol) of 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% .n Phosgene solution in toluene, by working up after 1 hour, crystalline threo-l- (3,4-dichlorophenyl) -5 , S-tetramethylene-piperidinoCljö-cjoxazblidin-S-one, m.p. 101-103 ° .. ''. "...."

The starting material erythro or threo (3,4-dichlorophenyl) - (6,6-tetramethyl-1-piperidin-2-yl) -methanol can be e.g. as follows:, '.

a) From 72.4 g (0.4 mol) of l-bromo-4-ethoxybutane, 33.7 g (0.4 mol) of cyclopentanone and 10 g of magnesium in 150 ml of diethyl ether is obtained 1- (4-AethoxybutyO-cyclopentanol, b.p. _n = 73-75 °

b) From 32.8 g (0.176 mol) of 1- (4-ethoxybutyl) cyclopentanone, 12 g of potassium cyanide in 23 ml of glacial acetic acid and 44 g of concentrated sulfuric acid in 23 ml of glacial acetic acid are obtained after alkaline work-up. Ethoxybutyl) cyclopentylamine, bp, - = 130-132 °.

c) From 16 g (0.086 mol) of 1- (4-ethoxybutyl) -cyclopentylamine and 90 ml of 48% aqueous hydrogen bromide gives 1- (4-bromobutyl) cyclopentylamine hydrobromide, mp. 205-206 °.

d) From 24.2 g (0.08 mol) of l - ^ - BrombutyD-cyclopentylamine hydrobromide

in 300 ml of water and 80 ml of η-sodium hydroxide solution gives 6-azaspiro [4,5] decane,

Bp = 67-69 °. The corresponding hydrobromide melts at 161-163 °. io

e) In analogy to the procedure 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. q _Q , = 174-177 °. .

f) Analogously to the procedure described in Example la), starting from 10.9 g (0.065 mol) of 6-nitroso-6-azaspiro [4,5 j.decan

and 11.4 g (0.065 g) of 3,4-dichlorobenzaldehyde crystalline erythro (3,4-dichlorophenyl) - (6,6-tetramethylene-1-nitroso-piperidin-2-yl) -methanol, Mp 148-149 ° and a yellowish crystal pulp in which the diastereomeric threo (3,4-dichlorophenyl) - (6,6-tetramethylene-initroso-piperidin-2-yl) -methanol enriched an analytically pure sample of isomer-free Threo-diastereomers can be obtained by filtration through a layer of silica gel with a toluene / ethyl acetate (10: 1) mixture as eluent After evaporation of the solvents, the product is whiter in form

,: Crystals of the order of 151-152 °.

g) Analogously to the procedure described in Example Ib) is obtained from 10.3 g (0.03 mol) of erythro (3,4-dichlorophenyl) - (6,6-tetramethylene-l-nitroso-piperidin-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, mp 281-282 °. The released from the salt,

, .. Base melts at 116-118 ° .. ',

H). Analogously to the reaction described above under g), starting from 3.3 g (0.009 mol) of 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-tetraroethylene-piperidin-2-yl) '- methanol hydrochloride,' m.p. 261-262 ^ °. The salt liberated from the salt melts at 172-173 °.

Example 26: In a manner analogous to that described in Examples 1-25, it is also possible to prepare the following compounds:

thfeo (3-cyahophenyl) - (5,5-dimethylpyrrolidin-2-yl) -methanol, threo (3-cyanophenyl) -5, S-dimethylpyrrolidine q Clj S-c-joxazolidine-S-one, erythro- and threo -l- (3-chlorophenyl) -5,5-diethyl-piperidino [l, 6-c] pxazolidin-3-one,

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

erythro- as well as threp-1- (3-chlorophenyl) -5,5-tetra-methylene-piperidino- [l, 6-c] oxazolidin-3-one and '..' '.. erythro- and threo-l- (3-chlorophenyl) -5,5-pentamethylene-piperidino [!, O-c] oxazolidine-S-on. ·. ','. '

Example 27 : Tablets containing 25 mg of active ingredient; ζ ..3. Threo- (3,4-dichlorophenyl) -5, S-dimethyl-piperidinoflj-coxazolidine-S-on can be prepared as follows:

Besfandteile (for 1000 tablets),

Active ingredient. , 25.0 g .- '' '' · ...

Lactose 100.7 g. · ".

Wheat starch; , 7.5 g '·.

Folyleneethylene glycol 6000 · 5.0 g ·

Talc, .. 5.0 g '. , , ''

Magnesium tear at -1.8 .g

deionized water .q.s. '' ''

Preparation: All solid ingredients are first driven through a sieve of 0.6 mm mesh size. Then the active ingredient, lactose, talc, magnesium cearate and half of the starch are mixed. The. Another half of the starch is suspended in 40 ml of water, and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water, and the mixture is granulated, if necessary, with the addition of water. The granules are dried overnight at 35 °, - driven through a sieve with 1.2 mm mesh size and pressed to both sides concave tablets of about 6 mm in diameter,

Example 28 Tablets containing 10 mg of active ingredient, for example threo-1- (3,4-dichlorophenyl) -5,5-dimechylpLp'eridino [1,6-c] oxazolidin-3-one, can be prepared as follows:

Ingredients (for 1000 tablets)

Active ingredient 10.0 g.

Lactose 100.7 g

Wheat starch ''; , 7.5 g.

Polyethylene glycol 5000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g.

demineralized water q.s ..- '.'

Preparation: All solid ingredients are first driven through a sieve of 0.6 Hsu mesh size. Then the active ingredient, the lactose, the talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed on both sides concave tablets of about 6 mm in diameter.

, , ; , Example 29 ; tablet: tea containing 75 mg of active ingredient, for example, threo-l- (3,4-dihydroquinone) -5,5-dimettiyl-piperidino [l, 6-c] oxazoli.din-3-one be prepared as follows: '. ,

' Ingredients (for 1000 tablets) - -.

Active ingredient. 75.0 g. ·

Lactose, .100.7 g

  Wheat starch 7.5 g

Polyethylene glycol 6000 5.0 g

: Talc '5.0 g

j /. Magnesium stearate 1.8 g. ,

demineralised water q.s. -

Preparation : All solid ingredients are first through a

Sieve "of 0.6 mm mesh size.Then the active ingredient, the .. '.. Lactose, the talc, the Magnesiuastearat and half' of the starch.

mixed. The other half of the starch is suspended in 40 ml of water. diert and this suspension to a boiling solution of Polyäthylanglykols in 100 ml of water, added and the mixture, if necessary, with the addition of water, granulated. The granules are dried at 35 ° overnight, forced through a sieve of 1.2 mm mesh size. '·; : ' and on both sides concave tablets of about 6 mm in diameter. squeezes ... , '·. "

, Example 30 In a manner analogous to that described in Examples 27-29, pharmaceutical preparations containing another compound may also be used.

j, of the formula I or a compound of the formula V or a salt thereof, in each case according to the examples 1-26 or threo-1-phenylpiperidino [l, 6-c] oxazolidin-3-one or a salt thereof , , '·

Claims (22)

- 72 Inventions claim , ¹ , ·, "' 50. Method according to one of the items 1-10, 12, 14, 16, 18, 20, 22'i 24, 26, 28, 30, 32, 34, 36, 38, 40, 42 and 44, characterized by preparing the (+) - threo enantiomer or a salt thereof. 51. The method of any one of ^I-10: 12, 14, 16, 18, 20, 1. Process for the preparation of trisubstituted oxazolidinones of the formula ο ' wherein R _{1 is} an aryl or heteroaryl, R ₂ and R independently of one another hydrogen or lower alkyl or together NiederalkyFdarstellenstellen and alk is lower alkylene, whose valencies emanating from adjacent or each l _f 3 -content carbon atoms, with the proviso that in compounds with (-) - trans arrangement of the hydrogen atoms in the 4- and 5-position of the oxazolidine ring R ₁ . is different from unsubstituted phenyl; when R ₂ and R _{3 are} hydrogen and alk is 1,3-propylene, and their salts, characterized in that a) in a compound of the formula R Ί ι 1 H H r ^R 3 wherein X represents a radical convertible to the carbonyl group, or converted into a salt thereof X in the carbonyl group or b) a compound of the formula I 2 (III) HO "J- ^R
! HH wherein X _{1 represents} a nucleofugic leaving group, or a salt thereof intramolecularly cyclized or c) in a compound of the formula (IV). where alk is a group of the formula: -alk-C (R _o ) (R 1,) -, -alk \ TTT o. C (R ₂ ) (R ₃ ) - or -alk = C (R ₂ ) - which with the nitrogen atom of the Oxazolinringes on the C (R ₀ ) (R,) - or "> '." , ·. , 'TT - ') -'', = G (R ₀ ) group, where alk is a lower 2. The method according to item 1, characterized in that starting from an acid addition salt of an N-unsubstituted Irains II (X = iminomethylene) and this with heating to about 40-110 ⁰ C in the pH range of about 3.5 to about 9 hydroliysiert. , 3. Method ¹ according to item 1, characterized in that. a starting material V the desired configuration in toluene or similar inert solvent beö, about 10 to about 35 ⁰ C _1, z. 8. about 20 to about 30 ⁰ C ,. reacted with phosgene. 4. The method according to any one of items 1-3, characterized by proceeding from an obtainable at any stage of the process as an intermediate compound and performs the missing process steps or forms a starting material under the reaction conditions or in the form of a derivative thereof, optionally a salt used , ''^; -4 · ·. '.''TTT''' Alkenylenrest and alk a Niederalkanylyliden- or Niederalkenylylidenrest whose free valencies emanating from adjacent or each other to 1,3-carbon atoms, represents »the Doppeibindüng (s) of oxazoline ring and optionally the radical alk saturated and, if desired, a VerfahrensgeOiäß available isomer mixture into the components or isolated from such a one or more desired isomers (s), converts a compound obtainable according to the process into another compound of the formula I and / or a free compound obtainable by the process in a salt or a salt obtainable in the process into the free compound or transferred to another salt, 5. The method according to any one of the items 1-4, characterized by reacting a compound of formula I, wherein R _{1 is} a substituent optionally lower alkyl, lower alkoxy, halogen, cyano and / or trifluoromethyl having 6-membered monocyclic or at least one having bicyclic aryl radical or heterocyclic ring-containing bicyclic aryl radical or heteroatom (s) nitrogen, oxygen, sulfur, oxygen and nitrogen or sulfur and nitrogen-containing 5-membered or heteroatom (e) roder 2 nitrogen atoms having 6-membered heteroaryl, R ₂ and R, independently of one another represent hydrogen, lower alkyl or together are lower alkylene and alk denotes lower alkylene whose valencies emanate from adjacent or mutually C 1 -C atoms, with the proviso that in compounds with (-) - trans arrangement the hydrogen atoms , in the 4- and 5- ^ position of the oxazolidine ring R ₁ is other than unsubstituted phenyl, when R ₂ and R ^ is hydrogen and alk is 1,3-propylene, or a salt thereof, 6. The method according to any one of the items 1-4, characterized by reacting a compound of formula I, wherein R _{1 is} an unsubstituted or lower alkyl with up to 4 carbon atoms * lower alkoxy with bis and with 4 C-atoms, halogen the atomic neat to and with 35 and / or trifluoroethyl substituted phenyl, naphthyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl or pyrazinyl, R ₂ and R independently hydrogen or Lower alkyl with bis and with 4 - 75 - '. C atoms or together lower alkylene with up to and with 7 carbon atoms, whose free valences emanate from adjacent or mutually 1,3-, 1,4- or 1,5-carbon atoms, and alk lower alkylene with bis and with 7 C atoms whose valencies emanate from adjacent C atoms, means, or produces a salt thereof. 7. A process according to any one of items 1-4, characterized by reacting a compound of formula I wherein R _{1 is} an unsubstituted or lower alkyl having up to and including 4 C atoms, lower alkoxy having up to and including 4 C atoms, Halogen of the atomic number to and with 35 and / or trifluoromethyl substituted phenyl, naphthyl, furyl, thienyl, pyrrolyl, thiazolyl ,; Oxazolyl, pyridyl, pyriridinyl or pyrazinyl, R and R independently of one another are lower alkyl having up to and with 4 C atoms or together lower alkylene having up to and with 7 C atoms, the free, valencies of adjacent or to each other 1.3 -, 1,4- or 1,5-C atoms, represent and alk lower alkylene with up to and with 7 carbon atoms, whose valences emanate from each other to 1,3-carbon atoms, means, or a S. Alz produces it. 8. A process as claimed in one of the items ₁ to 4, characterized in that a compound of the formula I in which R _{1 is} unsubstituted or substituted by lower alkyl having up to and including 4 C atoms, lower alkoxy having up to and including 4 C Atoms, halogen of the atomic number to and substituted with 35 and / or trifluoromethyl phenyl or unsubstituted Furyi, thienyl or pyridyl, R ₂ and R _{3 are} each lower alkyl radicals having up to and with 4 C atoms or together lower alkylene with up to and with 7 C atoms , whose free valencies emanate from adjacent or mutually 1,4- or 1,5-carbon atoms, and alk is ethylene or 1,3-propylene, or produces a salt thereof. 9. The method according to any one of the items 1-4, characterized by reacting a compound of formula I, wherein R ₁ by halogen of the atomic Nn to 35 and substituted phenyl, R and R _{3 are the} same lower alkyl radicals with up to and with 4 C. -Ats and Alk represents ethylene, or a salt thereof produces. 10. The method according to any one of items 1-9, characterized in that one produces the threo-diastereomers, wherein the Wasserstoffatorae in A and 5-position of the oxazolidine ring to each other trans-constantly, or a salt thereof, 11. The method according to any of items 1-4, characterized in that one prepares the erythro-l- (3-chlorophenyl) -5,5-dimethylpyrrolidino (l, 5-c) -oxazolidin-3-one or a salt thereof , , 12. The method according to any of items 1-4, characterized in that one produces the threo-l- (3-chlorophenyl) -5,5-dimethylpyrrolidino (1, 5-c) -oxazolidin-3-one or a salt thereof , 13. The method according to any of items 1-4, characterized in that the erythro-l -; (3,4-dichlorophenyl) -5, 5-dimethyl-pyrrolidino- (l, 5-c) oxazolidin-3-one or a salt thereof. 14. The method according to any one of items 1-4, characterized in that the threo-l- (3,4-dichlorophenyl) -5,5-dimethyl-pyrrolidino- (l, 5-c) oxazolidin-3-one or to make a salt of it. 15. A method according to any one of items 1-4, characterized in that the erythro-l- (4-chlorophenyl) -5,5-dimethylpyrrolidino (l, 5-c) -oxazolidin-3-one or a salt thereof prepared ,   - 77 - 16 * Process according to one of the items 1-4, characterized in that the threo-l- (4-chlorophenyl) -5,5-dimethylpyrrolidino (l, 5-c) -oxazolidin-3-one or a salt thereof ' , manufactures. 17. The method according to any one of the items 1-4, characterized in that the erythro-l- (3-methylphenyl) -5 ^! ', 5-dimethyl-pyrrolidino (l, 5-c) -oxazolidin-3-one or a salt of it manufactures. - i   ·. ' , 18. The method according to any one of items 1-4, characterized in that the threo-l- (3-methyl ^ Lphenyr) -5,5-dim8thylpyrrolidino (l, 5-c) -oxazolidin-3-one or a salt from that , _ 'Manufactures'. , · ·. , '·' ' 19. Method according to any one of items 1-4, characterized 'by "- - that one prepares the erythro-l-phenyl-5,5-dimethyl-pyrrolidino (l, 5-c) oxazolidin-3-one or a salt thereof. 20. The method according to any one of items 1-4, characterized da-,.,. in that the threo-1-phenyl-5,5-dimethyl-pyrroli- dino (l ^ 5-c) -oi <azolidin-3-one or a salt thereof -'- ·. , '-right. _. ' '' ... '' -; 21. The method according to any one of items 1-4, characterized in that: the erythro-l- (l-naphthyl) -5,5-dimethylpyrrolidino (l, 5-c) -oxazolidin-3-one or a salt thereof manufactures. 22. A process according to any one of items 1-4, characterized by preparing the threo-1- (1-naphthyl) -5,5-dimethylpyrrolidino (1,5-c) oxazolidin-3-one or a salt thereof , .,. 23. The method according to any of items 1-4, characterized in that the erythro-l- (3-trifluoromethylphenyl) - '5,5-dimethyl-pyrrolidino (l, 5-c) oxazolidin-3-one or a salt of it manufactures. 24. The method according to any one of the items 1-4, characterized in that the threo-l- (3-trifluoromethylphenyl-5,5-dimethyl-pyrrolidino- (l, 5-c) oxazolidin-3-one or a salt thereof manufactures. Process according to any one of items 1-4, characterized in that the erythro-1- (3-chlorophenyl) -5,5-dimethylpiperidino (1,6-c) oxazolidin-3-one or a salt thereof manufactures. i>. 26. A process according to any one of items 1-4, characterized in that the threo-1- (3-chlorophenyl) -5,5-dimethylpiperidino (1,6-c) oxazolidin-3-one or a salt thereof
manufactures. , 27. The method according to any one of items 1-4, characterized in that the erythro-l- (3,4-dichlorophenyl) -5,5-dimethy.l-piperidino- (l, 6-c) oxazolidin-3 on or a salt thereof. 28. The method according to any one of the items 1-4 characterized in that the threo-l- (3,4-dichlorophenyl) -5,5-diraethyl-piperidino- (l, 6-c) oxazolidin-3-one or to make a salt of it. . 29. A method according to any one of items 1-4, characterized in that the erythro-l- (2,6-dichlorophenyl) -5,5-dimethyl-pyrrolidino- (l, 5-c) oxazolidin-3-one or a salt thereof. 30. The method according to any one of items 1-4, characterized in that the threo-i- (2,6-dichlorophenyl) -5,5-dimethyl-pyrrolidino- (l ', 5-c) qxazolidin-3-one or a salt thereof. , 31. The method according to any one of items 1-4, characterized in that the erythro-l- (3-cyanophenyl) -5,5-diaethylpyrrolidino- (l, 5-c) oxazolidin-3-one or a salt thereof
manufactures. '/'; '> A process according to any one of items 1-4, characterized by preparing the threo-1- (3-cyanophenyl) -5,5-dimethylpyrrolidino (i, 5-c) oxazolidin-3-one or a salt thereof , Method according to one of the items 1-4, characterized in that the erythro-1,1-dichlorophenyl J-SiS-dimethyl-pyrrolidino-1- (5-c) oxazolidin-3-one or a salt thereof is prepared 34. The method according to any one of items 1-4, characterized in that the threo-l- (2,4-dichlorophenyl) -5,5-dimethyl-pyrrolidino- (l, 5-c) oxazolidin-3-one or to make a salt of it. , ' 35. The method according to any one of items 1-4, characterized in that the erythro-l- {4-pyridyl) -5 =, 5-dimethylpyrrolidino (1, 5-c) -oxazolidl-3-one or a salt of it manufactures. · 36. The method according to any one of items 1.-4, characterized in that the threo-l- (4-pyridyl) -5,5-din3ethylpyrrolidino (l, 5-c) -oxazolidin-3-one or a salt thereof manufactures. '. . 37. The method according to any one of items 1-4, characterized in that the erythro-l- (3-chlorophenyl) -5,5-diethylpiperidino- (l, 6-c) oxazolidin-3-one 'or a salt thereof manufactures. 38. Method according to one of the items 1-4,. characterized by reacting the threo-1- (3-chlorophenyl) -5,5-diethylpiperidino (1 _f 6-c) oxazolidin-3-one or a salt thereof :. manufactures. , 39. The method according to any of items 1-4, characterized in that the erythro-l- (3-chlorophenyl) -5,5-di-npentyl-piperidino- (l, 6-c) oxazolidin-3-one or to make a salt of it. 40. The method according to any one of the items 1-4, characterized in that the threo-l- {3-chlorophenyl) -5,5-di-npentyl-piperidino- (l, 6-c) oxazolidin-3-one or a salt.
of which · 41. The method according to any one of items 1-4, characterized in that the erythro-l- (3-chlorophenyl) -5,5-tetramethylene-piperidino- (l, 6-c) oxazolidin-3-one or a salt of it manufactures. 42. The method according to any of items 1-4, characterized in that the threo-l- (3-chlorophenyl) -5,5-tetraflvethylen-piperidino- (l, 6-c) oxazolidin-3-one or a salt of it manufactures. 43. The method according to any one of items 1-4, characterized in that the erythro-l- (3-chlorophenyl) -5,5-pentaraethylen-piperidinö- (l, 6-c) oxazolidin-3-one or a salt of it manufactures. 44. The method according to one of the items 1-4, characterized in that the threo-l- (3-chlorophenyl) -5,5-pentamethylene-piperidino (l, 6-c) oxazolidin-3-one or a salt of it manufactures. 45. The method according to any of items 1-4, characterized in that the erythro-l-phenylpyrrolidino (1, 5-c) oxazolidin-6-one or a salt thereof prepared. . 46. The method according to any one of items 1-4, characterized in that the erythro-l- (3,4-dichlorophenyl) -5,5, -tetramethylene-piperidino (l, 6-c) oxazolidin-3-one or to make a salt of it. 47. The method according to any of items 1-4, characterized in that the threo-l- (3,4-dichlorophenyl) -5,5, -tetramethylene-piperidino (l, 6-c) oxazolidin-3-one or to make a salt of it. ο, - ο ο β "ο '~"" I ^ ο- "- 81 - 48. A process according to any one of the preceding claims characterized in that the (+) - threo-1- (3,4-dichlorophenyl) -5,5-tetramethylene-piperidino (1,6-c) oxazolidine-3 on or a salt thereof · 49 ". Process according to one of the items 1-4, characterized in that the (-) - threo-1- (3,4-dichlorophenyl) -5> 5V. tetramethylene-piperidino- (1,6-c) oxazolidin-3-one or no salt thereof. 22, 24, 26, 28, 30, 32/34, 36, 38, 40, 42 and 44, characterized by preparing the (-) - three enantiomer or a salt thereof.