AT376659B - METHOD FOR PRODUCING NEW SUBSTITUTED 2-BENZYLPYRROLIDINES - Google Patents

Description

  

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   DE-PS No. 1049380 (Chem. Abstr. 55 [1961] P 4532c) describes a process for the preparation of a-substituted pyrrolidines of the general formula
 EMI1.1
 in which R represents a hydrogen atom, an alkyl, aryl, aralkyl or heterocyclic radical, R 'represents an alkyl, aryl, aralkyl or heterocyclic radical or the cyano group and R2 represents a hydrogen atom or a monovalent organic radical. The compounds obtained by this method are said to be used as drugs, but they do not specify any
 EMI1.2
 
H. Burckhalter [1932] 3971) and R. Lukes (Chem. Listy 27 [1933] 392.409, Chem. Abstr. 29 [1935] 1720). 2-Benzyl-l-methyl-pyrrolidine was obtained in low yield by Fery and van Hove (Bull.



  Soc. chim. Belg. 69 [1960] 63-78; Chem. Abstr. 55 [1961] 4475d) also by rearrangement of 1-thyl-l-benzylpyrrolidinium iodide. In the context of their work on the rearrangement of a-aminoketones during Clemmensen reduction, N.J. Leonard et al (J. Amer.



  Chem. Soc. 75 [1953] 3727-30) the preparation of l-ethyl-2-benzyl-pyrrolidine without specifying a pharmacological effect for it. 2-Benzyl-pyrrolidine showed no activity in relation to the hypertension caused by adrenaline, 2-Benzyl-1-methyl-pyrrolidine only caused a partial reduction in hypertension induced by adrenaline. Thereafter, the latter compounds cannot be used or can only be used to a very limited extent as antihypertensive agents. DE-OS 2548053 (Derwent, Pharmdoc Basic Number 36351X / 20) describes saturated a-substituted benzyl-l-benzhydrylaza heterocycles. in particular, a-substituted benzyl-1-benzhydrylazetidines are described, which are intended to treat obesity.



   The invention now relates to a process for the preparation of new substituted 2-benzylpyrrolidines of the general formula
 EMI1.3
 wherein R1 is a hydrogen atom, a straight-chain or branched aliphatic hydrocarbon radical with l or

   3 to 7 carbon atoms or an alicyclic hydrocarbon radical having 3 to 7 carbon atoms, a cycloalkylalkyl group having 3 to 7 carbon atoms in the cycloalkyl radical and 1 to 4 carbon atoms in the alkyl radical or an aralkyl group having up to 12 carbon atoms in the aryl radical and 1 to 4 carbon atoms in the alkyl radical, R2 represents a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group, an optionally substituted amino group, a nitro group or an optionally substituted phenyl group, R, R4 and R 5 are identical or different and a hydrogen atom, a halogen atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy group, an alkoxy group with 1 to 4 carbon atoms,

   mean an acyloxy group, an optionally substituted amino group, a nitro group or an optionally substituted phenyl group, in the form of their racemates, optical antipodes, the quaternary

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 Alkylpyrrolidinium compounds with 1 to 7 carbon atoms in the alkyl radical or their acid addition salts.



   Straight-chain or branched alkyl radicals having 1 or 3 to 7 carbon atoms are suitable as aliphatic hydrocarbon radicals. Straight-chain alkyl radicals are the methyl, ethyl, propyl, allyl, butyl, pentyl, hexyl or heptyl radical, of which those with 1 to 5, in particular 1 to 3, especially 1 or 2, carbon atoms are preferred. Branched alkyl radicals with 3 to
 EMI2.1
 butyl radical, of which those with 3 to 5, especially with 3 to 4, carbon atoms are preferred. Suitable alicyclic hydrocarbon radicals are cycloalkyl radicals having 3 to 7 carbon atoms, for example the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical, of which those having 5 to 6 carbon atoms are preferred.



   Suitable cycloalkylalkyl groups are those having 1 to 4 carbon atoms in the alkyl radical and 3 to 7 carbon atoms in the cycloalkyl radical, of which those with 1 to 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms in the cycloalkyl radical are preferred. Selected cycloalkylalkyl groups are the cyclopropylmethyl and the cyclobutylmethyl group.



   Suitable aralkyl groups are those with aryl groups which contain up to 12 carbon atoms and alkyl groups which contain 1 to 4 carbon atoms, of which those with 6 carbon atoms in the aryl radical and 1 to 4 carbon atoms in the alkyl radical, especially with 1 carbon atom in the alkyl radical , are preferred. Examples include the benzyl, phenethyl and phenylpropyl group, of which the benzyl group is preferred. The aralkyl groups are also optionally substituted, of which the monosubstituted in the aryl radical are preferred, inter alia by halogen atoms, such as fluorine, chlorine or bromine atoms, alkyl and / or alkoxy groups having 1 to 4 carbon atoms.

   Examples include the p-chlorobenzyl, the m-chlorobenzyl, the p-bromobenzyl, the o-fluorobenzyl, the p-fluorobenzyl, the p-methylbenzyl and the p-methoxybenzyl group. Among the aralkyl groups substituted in the alkyl group, the arylhydroxyalkyl and in particular the aryloxoalkyl groups are preferred, for example the benzoylmethyl, 2-benzoylethyl, 3-benzoylpropyl, preferably the 3- (p-chlorobenzoyl) propyl, in particular those 3- (p-fluorobenzoyl) propyl group.



   Halogen atoms R2, R, R "or R" are fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, bromine, in particular chlorine. Examples of alkyl groups or alkoxy groups R ", R", R "or R 5 which may be mentioned are those having 1 to 4 carbon atoms, of which those with 1 to 3, especially those with 1 carbon atom (s) are preferred. As acyloxy groups among other O-CO-R 'groups in which R 1 has the meaning given above, of which the alkanoyloxy group having 1 to 7, in particular 2 to 5, carbon atoms, especially the acetoxy group, is preferred are.

   In addition to the unsubstituted amino group, substituted amino groups are also suitable as substituents R2, R, R '* or Rs, of which alkyl and dialkylamino groups with 1 to 4, preferably 1 or 2 carbon atoms in the alkyl radical, and acylamino groups with the customary ones are mentioned Use protection of amino groups
 EMI2.2
   In addition to the unsubstituted phenyl group, R "or R are also suitable phenyl groups substituted by halogen atoms, hydroxyl, alkyl and / or alkoxy groups having 1 to 4 carbon atoms, of which the p-substituted phenyl groups, such as the p-chlorophenyl, the p- Fluorophenyl, the p-hydroxyphenyl, the p-methoxyphenyl group are preferred.



   The quaternary alkylpyrrolidinium compounds include the alkylpyrrolidinium
 EMI2.3
 generally has 1 to 7 carbon atoms. Preferred alkylpyrrolidinium compounds are the alkylpyrrolidinium iodides in which the alkyl radical has up to 4 carbon atoms, in particular 1 carbon atom.



   All acid addition salts are suitable as salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts are known to those skilled in the art

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 Process converted into pharmacologically acceptable salts.

   Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydro-
 EMI3.1
 (4-hydroxybenzoyl) salicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4, 4'-diamino-stilbene-2, 2'-disulfonate), embonate (1, l'- Methyl-bis-2-hydroxy -3-naphthoate), metembonate, stearate, tosilate (p-toluenesulfonate), 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate, mesilate (methanesulfo-
 EMI3.2
    (Butylamino) -4-phenoxy-5-sulfamoyl-benzoic acid), oxylacetic acid, etc.



   Preferred substituted 2-benzylpyrrolidines are those of the general formula
 EMI3.3
   wherein R1 * is a hydrogen atom, a straight-chain or branched aliphatic hydrocarbon radical with 1 or 3 to 5 carbon atoms, a cycloalkylalkyl group with 1 to 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms in the cycloalkyl radical or an optionally monosubstituted phenylalkyl group with 1 to 4 carbon atoms in the alkyl radical, R2 * a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an acyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms each Alkyl radical or a nitro group or 3 * 4 * stones optionally substituted in the p-position phenyl group, R,

   R and R independently of one another are a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an acyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms. men each represent an alkyl radical or a nitro group, where at least one of the substituents in the 2- or 6-position of the benzyl group represents a hydrogen atom, or the quaternary (C1-C4) - alkylpyrrolidinium compounds and their acid addition salts.



   Specially selected compounds are those 2-benzylpyrrolidines of the general formula * 2 * 3 * 4 * 5 * mel (I *), in which R-, R-R-R- and R have the meaning given above, where
3 * 4 * 5 * at least one, preferably two of the substituents R, R or R and at least one of the substituents in the 2- or 6-position of the benzyl group denote a hydrogen atom, and also the
 EMI3.4
 
 EMI3.5
 
 EMI3.6
 branched alkyl radical with 3 to 5 carbon atoms, a cycloalkylmethyl radical with 3 to 5 carbon atoms in the cycloalkyl group or optionally in the p-position by halogen, methyl

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 EMI4.1
 group, an amino group or a nitro group, R is a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an amino group or a nitro group,

   where the substituents R2 ** and R are preferably 2-, 3- and / or 4-position, as well as the methylpyrrolidinium compounds and the pharmacologically acceptable acid addition salts.



   Selected substituted 2-benzyl-pyrrolidines of the formula (I **) are those in which R is a hydrogen atom, a methyl group, an isopropyl group, a tert. Butyl group, a cyclo- 2 ** 3 ** propylmethyl group or a benzyl group and R and R have the meaning given above, as well as their pharmacologically acceptable acid addition salts.



   Particularly preferred substituted 2-benzyl-pyrrolidines are those of the formula
 EMI4.2
 
 EMI4.3
 is methyl group and R *** represents a 2-, 3- or 4-membered fluorine, chlorine, hydroxyl, methoxy or amino substituent, and their acid addition salts.
 EMI4.4
    (2-Chlorobenzyl) -1-methyl-pyr - 1-methyl-pyrrolidine, in particular 2- (4-aminobenzyl) -l-methyl-pyrrolidine and 2- (4-chlorobenzyl) - - pyrrolidine, and their pharmacologically acceptable acid addition salts .



   The substituted 2-benzylpyrrolidines of the general formula (I) have a chiral center on the carbon atom marked with (*). The invention therefore includes both the racemates and the enantiomers and their mixtures.



   The substituted 2-benzylpyrrolidines of the general formula (I) and the corresponding alkylpyrrolidinium compounds and the pharmacologically tolerable salts have valuable properties which make them commercially useful. For one thing, the connections, like
 EMI4.5
 ecological properties, in particular effects on the central nervous system (= CNS), on blood pressure and the sensation of pain, on the other hand they can be converted into other substituted 2-benzylpyrrolidines of the general formula (I), thus providing valuable intermediates for the production of pharmacologically active compounds general formula (I) and their alkylpyrrolidinium compounds and their pharmacologically acceptable salts.



   The CNS activity of the new compounds of the formula (I), their alkylpyrrolidinium compounds and the pharmacologically acceptable salts extends to the central stimulation, the increase in vigilance, the promotion of normal and pathologically inhibited drive. In addition, some representatives have a strong analgesic effect or an effect on blood pressure.



   The excellent and broad pharmacological effectiveness of 2-benzyl-pyrrolidine enables their use in both human and veterinary medicine, whereby they can be used to prevent symptoms or to treat symptoms that have already occurred.



   Indications for the human medicine area include lack of drive, vigilance, depression, organic psychosyndrome in cerebral regression processes, lack of performance, blood pressure disorders and states of exhaustion as well as pain, in children the intellectual and psychological development inhibition as well as learning difficulties.



   In the veterinary field, the indications for reduced performance and pain

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 conditions into consideration. For example, higher animals, such as farm animals and pets, can be treated.



   Depending on the type of substitution, the compounds of the general formula (I) have an activity spectrum with different focal points, one of the aforementioned effects,
 EMI5.1
    B.z. B. the analgesic and central stimulating effect, for example in 2- (4-chlorobenzyl) pyrrolidine, 2- (4-chlorobenzyl) -1-methyl-pyrrolidine, 2- (4-chlorobenzyl) -1-isopropyl-pyrrolidine or 2- (4-aminobenzyl) -l-methyl-pyrrolidine, or the central stimulating and blood pressure-influencing effect, for example in the case of 2- 3-hydroxybenzyl) -1-methyl-pyrrolidine, is emphasized. Depending on the desired therapeutic target, one or more of the 2-benzylpyrrolidines of the corresponding action type mentioned are used.



   The new compounds of the general formula (I) can be used as such or, if appropriate, in combination with suitable pharmaceutical carriers for the preparation of medicaments. If the pharmaceutical preparations contain pharmaceutical carriers in addition to the new active ingredients, the active ingredient content of these mixtures is 5 to 95, preferably 25 to 75% by weight of the total mixture.



   In addition to the new 2-benzylpyrrolidines, the pharmaceutical preparations can also contain one or more pharmacologically active constituents from other drug groups, for example mild stimulants, such as caffeine; Analgesics such as aminophenazone, acetylsalicylic acid, d-propoxyphene; Antidepressants, such as dibenzepin, doxepin, maprotilin, amitriptyline, nortriptyline, melitracen; Tranquilizers, such as benzodiazepines, e.g. B. diazepam, chlodiazepoxide, meprobamate; Cerebral circulation-promoting agents and / or roborants, such as glutamic acid, vitamins or a combination thereof.



   The compounds of the general formula (I) can be converted into pharmacologically active compounds of the general formula (I) by known methods, as is illustrated by the following examples. For example, the acid addition salts are obtained from the free bases by reaction with the corresponding acid or the alkylpyrrolidinium compound by reaction with the corresponding alkyl halides or sulfonates. Ether, d. H. those compounds in which one or more of the substituents R2, R ", R", R is an alkoxy group or
 EMI5.2
 by alkaline hydrolysis, e.g. B. with sodium hydroxide, converted into the free hydroxy compounds.

   The free hydroxy compounds, i.e. H. those in which one or more of the substituents
 EMI5.3
 



   The process according to the invention for the preparation of the new substituted 2-benzylpyrrolidines of the general formula (I) is characterized in that substituted 2-benzylpyrrolidines of the general formula
 EMI5.4
   2'3'4'5 'wherein R, R, R and R are the same or different and a hydrogen atom, a halogen atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy group, an alkoxy group with 1 to 4 carbon atoms, one optionally substituted amino group, a nitrogen group or an optionally substituted phenyl group and

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 EMI6.1
 means in which R 6 has the meaning of R'hat and R 7 is a straight-chain or branched aliphatic hydrocarbon radical with 1 or

   3 to 7 carbon atoms or an aliphatic cyclic hydrocarbon radical with 3 to 7 carbon atoms, a cycloalkylalkyl radical with 3 to 7 carbon atoms in the cycloalkyl radical and 1 to 4 carbon atoms in the alkyl radical or an aralkyl group with up to 12 carbon atoms in the aryl radical and 1 to 4 carbon atoms in the alkyl radical, reduced and, if necessary, for the preparation of a compound of the formula (I) in which R 'is hydrogen, an obtained compound of the formula (I) in which Rl is the benzyl group, N-debenzylated or if necessary for the preparation of a compound in formula (I) in which R 'has a meaning other than hydrogen, a compound of the formula (I) obtained in which R' is hydrogen, N-alkylated (alkyl also including cycloalkyl, aralkyl, cycloalkylalkyl)

   and optionally then converting the product of formula (I) obtained into another product of formula (I) by one or more of the following reaction steps: a) introduction of a nitro group into the phenyl ring by nitration, b) introduction of an amino group into the phenyl ring by reduction a nitro group, c) introduction of a halogen atom into the phenyl ring by nuclear halogenation, d) introduction of a hydroxy group into the phenyl ring by ether cleavage of an alkoxy group, e) introduction of an alkoxy group into the phenyl ring by etherification of a hydroxy group, f) N-quaternization of the pyrrolidine group, g) acylation of a free hydroxyl or amino group in the phenyl ring, h) elimination of an acyl group with liberation of the hydroxyl or amino group in the phenyl ring, i)

   Separation of the racemate obtained into the optical antipodes, j) conversion of an acid addition salt obtained into the free base, k) conversion of a base obtained into its acid addition salts.



   The reduction of the substituted 2-benzylpyrrolidines of the general formulas (IIa) to (IIe) is preferably carried out using hydrogen in organic solvents as are known to the person skilled in the art for hydrogenation reactions, for example ethanol, methanol, cyclohexane, isopropanol, dimethylformamide, in the presence of metal catalysts, e.g.

   B. platinum, platinum on activated carbon, palladium, palladium on activated carbon, Raney nickel, at pressures of about 1 to 500 bar and temperatures around room temperature, for example 0 to 500C. Alternatively, the compounds of the formulas (IIa), (IIc) and (IM) are reduced in the form of their acid addition salts in aqueous

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 - alcoholic solution with sodium borohydride in a manner familiar to the person skilled in the art (cf. "Enamines: Synthesis, Structures and Reactions" edited by A. Gilbert Cook, page 185 ff; Marcel Dekker, New York and London 1969).



   The subsequent functionalization of the benzylpyrrolidines (I) obtained by reduction is carried out depending on the nature of the substituent in the phenyl group ultimately desired. The nitro group is introduced, for example, by nitration with nitric acid, nitric acid / sulfuric acid, potassium nitrate / sulfuric acid, alkyl nitrate at temperatures from −20 to +50 ° C., preferably −20 to +30 ° C. In the end products R2, R "and R then have the meaning of a hydrogen atom and R3 has the meaning of a p-positioned N02 group. Dinitro compounds are formed under more stringent conditions, ie R '* and R have the meaning of a hydrogen atom and R2 and R3 have the meaning of a nitro group .



   The amino group is reduced by reduction of the NO 2 group (s) of a corresponding nitro compound with hydrogen over appropriate catalysts, such as Pt; Pt / C, Pd, Pd / C, Raney-Ni etc. introduced in common solvents such as alcohols, cyclohexane etc. One or two NO 2 groups are then present in the starting compounds, in the end products R '*, R have the meaning of a hydrogen atom and R "and / or R have the meaning of an NH 2 group.



   Halogen atoms, especially chlorine and bromine atoms, are introduced in the usual way by nuclear halogenation. Iron, iron (II 1) chloride or bromide are used as catalysts for the nuclear halogenation. Aluminum chloride or bromide, tin tetrachloride or iodine into consideration, the reaction being carried out without or in inert solvents, if appropriate also in glacial acetic acid without a catalyst, at temperatures between 0 and 20.degree.



   Hydroxy groups are introduced by ether cleavage of the corresponding alkoxy group (s), preferably a methoxy group. The ether cleavage is e.g. B. carried out by boiling with hydroiodic acid or hydrobromic acid or mixtures of hydrogen bromide / glacial acetic acid or by reaction with boron tribromide in inert solvents such as chloroform, dichloromethane, at temperatures from -20 to 20 C.



   The etherification is carried out, for example, by reaction with alkyl halides in the presence of equivalent amounts of alkali metal alcoholate, e.g. B. sodium ethylate.



   The N-debenzylation is carried out by hydrogenolysis in the presence of catalysts, preferably palladium on carbon, in solvents such as methanol, ethanol, benzene, cyclohexane, at 0 to 50 C, preferably room temperature, and a hydrogen pressure of 1 to 300 bar, preferably 1 to 5 bar.



   The N-alkylation and N-quaternization is carried out according to methods known to the person skilled in the art. With a suitable choice of the reaction conditions, the reaction is carried out in such a way that either the N-alkyl derivatives are obtained, alkyl also including the meaning of cycloalkyl, aralkyl and cycloalkylalkyl, or the alkylpyrrolidinium compounds are obtained. If the N-alkylation is to be carried out in such a way that the N-alkyl derivatives are obtained, the N-alkylation is carried out using alkylating agents such as alkyl halides, alkyl sulfonates, e.g. B. tosylates, alkyl sulfates, in inert solvents such as acetone, methyl ethyl ketone, alcohols such as methanol, ethanol, isopropanol, etc. or without solvent, using an auxiliary base such as sodium carbonate, potassium carbonate, triethylamine, at temperatures of about 20 to 1000C carried out.

   If the N-alkylation as N-quaternization, i.e. H. to obtain the alkylpyrrolidinium compounds, the reaction is carried out in solvents such as acetine, methyl ethyl ketone, ethyl acetate, alcohols, with alkylating agents such as alkyl halides, alkyl tosylates, alkyl sulfates at 20 to 100 ° C.



   Any subsequent acylation of free hydroxyl groups or amino groups
 EMI7.1
 ff. or 655 ff.). The acyl groups are released with the release of the hydroxyl groups or amino groups in the usual way by saponification, for. B. by reaction with suitable bases, such as sodium or potassium hydroxide solution.



   Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. B. acetone, water, a low molecular weight aliphatic alcohol (ethanol, isopropanol),

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 which contains the desired acid, or to which the desired acid is then added. The salts are obtained by filtration, precipitation with a non-solvent for the addition salt or by evaporation of the solvent.



   The salts obtained, e.g. B. the hydrochloride, can be converted by neutralization with aqueous sodium or potassium hydroxide in the free base, which is then extracted by solvent with a suitable, water-immiscible solvent such as chloroform, dichloromethane, ether, benzene, toluene, cyclohexane, etc., is won. The free bases can also be obtained by neutralizing an acid addition salt with sodium methylate in methanol and isolating the base by known methods. The salts can also be
 EMI8.1
 optically active acid, such as mandelic acid, tartaric acid, camphorsulfonic acid, dibenzoyl tartaric acid, etc., recrystallizing the resulting salt until the rotation value is constant and releasing the optically active base with alkalis.

   The other enantiomer is obtained analogously from the mother liquors obtained in the crystallization.



   The compounds of the formula to be used as starting compounds
 EMI8.2
 
2'3'4'5 'in which R, R, R and R have the meaning given above are obtained on the basis of or by processes described in the literature. For example, M-chlorobutyronitrile with the corresponding, preferably the chlorine and / or alkoxy substituted benzyl
 EMI8.3
 between 20 and 160 C to the substituted A'-pyrrolines. The compounds of formula (Ha) can also be according to I. Felner et al. (Helv. Chim. Acta 53 [1970] 754) or M.



  Roth et al. (Helv. Chim. Acta 54 [1971] 710) by reacting 2-thiopyrrolidinone (V) with appropriately substituted a-bromo-phenylacetic acid esters (VI) to give the thiolactim ethers (VII), followed by sulfide contraction to give the enamino esters (VIII), Saponification and decarboxylation are obtained, which is represented by the following formula:

   
 EMI8.4
 

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 EMI9.1
 
 EMI9.2
 
 EMI9.3
 
 EMI9.4
 
 EMI9.5
 

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 of R'hat, R ", R", R "and R" are identical or different and are an alkyl radical with 1 to 5 carbon atoms, preferably a methyl group, and R 15 optionally also a cycloalkyl radical with 3 to 6 carbon atoms or an optionally substituted phenyl radical mean, or D and OR 12 together form an alkylidenedioxy group with up to 4, preferably 2 carbon
 EMI10.1
 have the meaning given above, based on the work of N.P. Kostyuchenko et al. (Khim. Geterotsikl. Soedin. 1974, 1212).

   Analogously to the same reference, compounds of the formula (IId) can be obtained from the pyrrolidines (X) and corresponding phenylacetonitriles via benzylidene compounds (IX) in which Q represents a CN group.



   The pyrrolidines (X) are obtained by reacting salts of the formula (XII) with alkali metal alcoholates, such as sodium methoxide, ethanolate, etc. in suitable solvents (based on H. Bredereck et al. Chem. Ber. 97 [1964] 3081; Chem. Ber. 98 [1965] 1078).



   Preferred solvents in the preparation of pyrrolidines (X), in which D is a -0-R "- group, are alcohols of the formula -R 13 -OH, in which R" has the meaning given above; preferred solvents in the preparation of pyrrolidines (X), in which D represents a - NR14 R15 group, are indifferent solvents, such as benzenes and ethers, for. B. diethyl ether.



   The reaction of the pyrrolidines (X) with the acetic acid esters (XI) or the corresponding acetonitriles is generally carried out at temperatures of 20 to 150 ° C., preferably between 40 and 100 ° C., without or preferably with the addition of inert organic solvents, such as aliphatic, for. As petroleum ether, light petrol, ligroin, or cycloaliphatic, z. B. cyclohexane, or aromatic, e.g. As benzene, toluene, xylene, hydrocarbons, carried out.

   The hydrolysis and simultaneous decarboxylation of the esters or the corresponding acetonitriles is carried out by the action of mineral acids, such as hydrochloric acid, hydrobromic acid, etc., preferably concentrated hydrochloric acid, at temperatures between room temperature and 120 ° C., preferably by heating the corresponding solution under reflux until the CO 2 ceases -Development. The enamines (IId) formed from the esters (IX) or the corresponding acetonitriles are relatively unstable compounds and are generally processed immediately, i.e. H. reduced according to the invention to the compounds of formula (I).

   Because of their stability and their easy accessibility and due to the instability of the enamines (IId), the esters (IX) and the corresponding acetonitriles are interesting and valuable intermediates for the preparation of the new 2-benzylpyrrolidines (I).



   The starting compounds (IId) are converted into the benzylidene compounds (IX) and their hydrolysis and decarboxylation according to the following reaction scheme by reacting pyrrolinium salts (XII) with phenylacetic acid derivatives (XIII) in the presence of strong bases
 EMI10.2
   2'3'4'5'7 in which R-, R-, R-R-, R and D have the meaning given above, Q is a -CN group or a -CO-OR "group in which R "has the meaning given above, L i) represents one equivalent of an anion of an organic or inorganic acid, obtained.



   The reaction of the pyrrolinium salts (XII) with the phenylacetic acid derivatives (XIII) is generally carried out without the addition of further solvents in the presence of strong bases, such as solutions of alkali metal alcoholates, for example sodium methoxide, potassium methoxide, potassium propanolate, sodium isopropanolate, potassium butoxide, potassium tert. butanolate, potassium tert. pentanolate, especially sodium ethanolate, at temperatures of 20 to 150 C, preferably 80 to 100 C. If necessary

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 EMI11.1
 
 EMI11.2
 
 EMI11.3
 R represents a nitro group, obtained in the presence of strong bases such as alkali metal alcoholates.

   Suitable alkali metal alcoholates are, for example, sodium methoxide, potassium methoxide, potassium
 EMI11.4
 gases, such as nitrogen, to remove the volatile amine which may be formed.



  The reaction takes place either without the addition of further solvents or with the addition of inert solvents, such as alcohols, for example methanol, ethanol, propanol, isopropanol, butanols, pentanols, such as tertiary nitrogen bases, for. B. pyridine, or hydrocarbons, for example benzene, toluene.



   The starting compounds (IIe) are, for example, described in DE-OS 1470387
 EMI11.5
 from which 2- (p-chlorobenzyl) pyrrole is obtained by reduction. The other substituted benzylpyrroles (IIe) are obtained analogously.

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   The following examples illustrate the invention without restricting it. The abbreviation mp means melting point, Kp means boiling point, decomp. means decomposition. Temperatures are given in C.



   Example 1: 2- (4-chlorobenzyl) -l-methylpyrrolidine a) 28 g of 2- (4-chlorobenzylidene) -I-methylpyrrolidine (obtainable according to c) are in 250 ml
Dissolved methanol and hydrogenated with Raney nickel as a catalyst. The catalyst is filtered off and the filtrate is concentrated. 22.7 g of boiling point 750 at 0.65 Pa are obtained (yield 81% of theory). The base's picrate recrystallized from ethanol melts at 1490.



   The following salts are obtained by reacting the base with the equivalent amount of the corresponding acid:
Hibenzate: colorless oil; Citrate; colorless oil; Fumarate; yellowish oil;
Benzoate: yellowish viscous oil; Maleinate: light yellow oil; Oxalate: pink oil; Embonate: yellow, viscous oil. b) 40 g of 2- [1- (ethoxycarbonyl) -4-chlorobenzylidene] -l-methylpyrrolidine and 150 ml of conc.



   Hydrochloric acid is boiled under reflux until the evolution of carbon dioxide has ended.



   The reaction mixture obtained is made alkaline with 10% sodium hydroxide solution and extracted with five times 70 ml of ether. After drying, the ether extract is concentrated over sodium sulfate and the solid residue [2- (4-chlorobenzylidene) -1-methylpyrrolidine] in 550 ml of ethanol is hydrogenated with Pt / hydrogen. 27.6 g of boiling point 750 at 0.65 Pa are obtained. c) Preproducts a) 9.66 g of p-chlorobenzyl chloride and 1.46 g of magnesium shavings are used in 100 ml
Diethyl ether a Grignard solution. A solution of 8.65 g of 2,2-diethoxy-l-methylpyrrolidine in 50 ml of diethyl ether is added dropwise, with stirring, the reaction mixture remaining at the boil. The mixture is kept boiling for 1 h, 10 ml of saturated are added dropwise
Ammonium chloride solution and collects the ether solution.

   The residue is extracted three times with 100 ml of ether each time, the combined ether solutions are dried over magnesium sulfate and concentrated. After adding 5 ml of methanol, the oily crystallizes
Residue. 2.9 g of 2- (4-chlorobenzylidene) -1-methylpyrrolidine (28% of theory) are obtained,
Mp 63.



   ss) According to the procedure described in Example 6 6 2), 15 g of 2- [1- (cyano) -4-chlorobenzylidene] -1-methylpyrrolidine give 8.8 g of 2- (4-chlorobenzylidene) -1- methylpyrrolidine (77% of theory), decomposable crystals, mp. 60 to 63. y) It is added dropwise with stirring to a solution of 6.76 g of dimethylamine in 45 ml of benzene
22.5 g of 2-methoxy-l-methyl-l-pyrrolinium methyl sulfate and then boiled under reflux for 1 h. The heavy phase is separated off, shaken twice with diethyl ether and freed from solvent residues in vacuo. 19.4 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate (81.4% of theory) are obtained as a red-brown oil.



   6) A solution of 9.6 g of sodium in 200 ml of ethanol is added dropwise to a mixture of 99 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate and 65 g of 4-chlorophenylacetic acid ethyl ester with stirring at 100 bath temperature in a stream of nitrogen .
The alcohol is then removed from the reaction mixture. The mixture is stirred for a further 30 min at 1000, the cooled reaction mixture is mixed with 200 ml of water and extracted with five times 100 ml of ether. The combined ether extracts are concentrated after drying over sodium sulfate and little excess 4-chlorophenylacetic acid.
 EMI12.1
 



     [1- (Ethoxy-EI) 22.7 g of 2,2-diethoxy-1-methylpyrrolidine, 19.8 g of 4-chlorobenzyl cyanide and 90 ml of benzene are boiled with stirring and reflux for 1 h. The volatile constituents are distilled off in vacuo, and the residue is filtered off with a little ether after trituration. Yield 20.8 g (68% of theory) 2- [1- (cyano) -4-chlorobenzylidene] -1-methylpyrrolidine, mp. 71 to 72 (from isopropanol).

  <Desc / Clms Page number 13>

 
 EMI13.1
 in 30 ml of benzene are stirred at 450 for 3 h, the solvent is removed by distillation and the dark brown crystallizing residue is taken up in 10 ml of isopropanol and filtered.

   Yield 2.5 g of 2- [I- (cyano) -4-chlorobenzylidene] -1-methylpyrrolidine as yellowish crystals, mp. 68 to 71. n) To 12.65 g of sodium methylate, suspended in 120 ml of absolute ether, is added dropwise
Stirring at room temperature 50.0 g of 2-dimethylamino-l-methyl-l-pyrroliniummethylsulfate, then boiled under reflux for 1 h, filtered after cooling off the separated product
Remove salt and distill the filtrate in vacuo after removing the ether. You get
9.0 g of 2-dimethylamino-2-methoxy-l-methylpyrrolidine as a very decomposable liquid of bp 45 to 470 at 1466.3 Pa.



  Example 2: 2- (4-chlorobenzyl) -I-isopropylpyrrolidine a) 40.6 g of 2- [l- (ethoxycarbonyl) -4-chlorobenzylidene] -l-isopropylpyrrolidine and 115 ml of conc.



   Hydrochloric acid is refluxed until the evolution of carbon dioxide has ended. It is alkalized with 250 ml of 6N sodium hydroxide solution, extracted with 400 ml of ether, dried over sodium sulfate and concentrated. The residue [2- (4-chlorobenzylidene) -1-isopropylpyrrolidine] is dissolved in 250 ml of ethanol and hydrogenated with platinum / hydrogen. After filtering the catalyst and distilling off the solvent, the product is distilled under high vacuum. Yield 21.8 g (70% of theory) of bp 75 at 0.91 Pa; Picrat: mp 126 to 127 (from ethanol). b) Preproducts a) 89.6 g of l-isopropylpyrrolidinone-2 and 88.9 g of dimethyl sulfate are stirred at 80 for 3 h. The reaction mixture is extracted five times with 50 ml of ether each time and the red oil is dried in a high vacuum.

   167.2 g (94% of theory) of 1-isopropyl-2-methoxy-
 EMI13.2
 
Solution of 43.8 g of dimethylamine dropped in 283 ml of benzene. Then you cook
1, 5 h under reflux, separate the heavy phase and wash it four times with each
50 ml of diethyl ether. After drying under high vacuum, 154 g of 1-isopropyl - 2-dimethylamino-l-pyrrolinium methyl sulfate (91% of theory) are obtained as a reddish oil. y) To a mixture of 32 g of 4-chlorophenylacetate and 59.13 g of 1-isopropyl-2-dimethylamino-1-pyrrolinium methyl sulfate, a solution of 5.1 g of sodium is added dropwise with stirring at 90 to 100 in a stream of nitrogen 100 ml of ethanol. After the addition has ended, the mixture is stirred for a further 30 min, allowed to cool and taken up in water (-100 ml) and ether (-150 ml).

   The organic phase is collected, etherified again, dried, the combined ether extracts and concentrated. Crude yield 45.6 g (92% of theory).



   2- [1- (ethoxycarbonyl) -4-chlorobenzylidene] -1-isopropylpyrrolidine, 5 g are made from ethanol /
Water recrystallized. 4.2 g of mp 70 to 710 are obtained.



  Example 3: 2- (4-chlorobenzyl) pyrrolidine a) 28.5 g of 2- (4-chlorobenzyl) pyrroline-l are hydrogenated in 300 ml of ethanol with Raney nickel / hydrogen. After removal of the solvent and catalyst, the mixture is distilled under high vacuum. 23.0 g (80% of theory) of bp 70 to 72 C at 0.13 Pa are obtained. Mp of the hydrochloride (from methanol / diethyl ether): 190 to 192. b) Preproducts a) A solution of 83 g is added dropwise to a Grignard solution, prepared from 22.3 g of magnesium shavings and 147 g of 4-chlorobenzyl chloride in 250 ml of diethyl ether
4-chlorobutyronitrile in 300 ml ether. The mixture is kept at the boil for 1 h, then the ether is distilled off and 700 ml of xylene are added dropwise at the same time.

   The mixture is boiled under reflux (bath temperature 170), allowed to cool and slowly 150 ml of saturated are added with stirring
Ammonium chloride solution. The magnesium salts are filtered off and washed well with xylene and ether. It is extracted from the combined organic phases

  <Desc / Clms Page number 14>

 basic portions with 15% hydrochloric acid (250 + 150 ml), the aqueous phase washes with 100 ml ether and alkalized with ice-cooling with 6N sodium hydroxide solution: the separated oil is extracted with ether and, after drying, distilled over sodium sulfate. 22.3 g (16% of theory) of 2- (4-chlorobenzyl) pyrroline-l of bp. 109 to 113 at 1.33 Pa are obtained.

   The free base is unstable and is analyzed as perchlorate;
Mp of perchlorate (from ethanol): 196 'to 1980; Mp of the hydrochloride (from methanol / diethyl ether): 176 to 178.



     ss) 80 g of 2- (a-cyano-4-chlorobenzylidene) pyrrolidine and 200 ml of concentrated hydrochloric acid are boiled under reflux for 2.5 hours; after cooling, it is alkalized with 6N sodium hydroxide solution, extracted three times with 200 ml of ether and after drying over
Concentrated sodium sulfate to a yellowish oil, which is distilled in vacuo. Yield 53.0 g (74% of theory) of 2- (4-chlorobenzyl) pyrroline-l, bp. 88 to 89 at 0.52 Pa. y) 106 g of 2-methoxypyrroline-1, 243, 5 g of 4-chlorobenzyl cyanide and 9 ml of triethylamine
Stirred at 1100 for 20 h, after cooling, 200 ml of ether are added and the
Precipitate (80.9 g) 2- (a-cyano-4-chlorobenzylidene) pyrrolidine filtered off.

   From the
After distilling off the solvent and the 4-chlorobenzyl cyanide in a vacuum, a further 42 g of 2- (a-cyano-4-chlorobenzylidene) pyrrolidine are obtained. Total yield 122.9 g (52%), mp 135 to 137.



  Example 4: 2- (3, 4-Dimethoxybenzyl) -l-methylpyrrolidine a) 12.2 g of 2- (3, 4-dimethoxybenzylidene) -l-methylpyrrolidine are dissolved in methanol and reduced with Raney nickel / hydrogen. After filtering off the catalyst and distilling off the methanol, the residue is distilled. 9.6 g (79% of theory) of
Kp. 900 at 0.65 Pa; Picrate (from ethanol) 105 to 106. b) Preproducts a) 21.5 g of phosphorus oxytrichloride are added dropwise to 19.8 g of 1-methylpyrrolidinone-2 in such a way that the temperature does not rise above 40. After 15 min, dropwise drop at 60 16.5 g
N-methylaniline, mixed with 20 ml of 2N hydrochloric acid and 450 ml of ice water.

   To this
Solution is given 21.6 g of sodium perchlorate, colorless crystals precipitating. 38.6 g (95% of theory) of 2-methyl- (phenyl) amino-1-methyl-1-pyrrolinium perchlorate are obtained, which is recrystallized from isopropanol. 96, 5 to 970.



   ss) To a mixture of 5.8 g of 2-methyl- (phenyl) -amino-l-methyl-l-pyrrolinium-l-perchlorate and 4.5 g of ethyl homoveratrate in 15 ml of pyridine, a solution of is added dropwise 0.46 g of sodium in 5 ml of methanol. The mixture is stirred at 60 for 2 h, pyridine and alcohol are distilled off in vacuo and the oily residue is extracted with water and then with petroleum ether. It is placed on a silica gel column and chromatographed with chloroform / methanol 19: 1. The eluate with a Ru-vert 0.76 is concentrated to an oil. Yield 10.5% of theory

   Th. 2- [1- (methoxycarbonyl) -3, 4-dimethoxybenzylidene] - - 1-methylpyrrolidine. y) To a mixture of 5, 8 g of 2-methyl- (phenyl) amino-1-methyl-1-pyrrolinium perchlorate and 4.5 g of ethyl homoveratrate in 20 ml of ethanol is added dropwise
Stir a solution of 0.46 g of sodium in 10 ml of ethanol at room temperature. The mixture is boiled under reflux for 2 h, alcohol and methylaniline are removed under high vacuum and the residue is purified by column chromatography on silica gel. The product with the Rf value
0.72 in eluent chloroform / methanol 19: 1 is collected. Yield 0.9 g (15%
 EMI14.1
 
2- [1- (ethoxycarbonyl) -3, 4-dimethoxybenzylidene] -l-methylpyrrolidine.6) 12.4 g of 2- [1- (methoxycarbonyl) -3, 4-dimethoxybenzylidene] -l-methylpyrrolidine
Boiled for 15 min with 40 ml of concentrated hydrochloric acid.

   After cooling, the mixture is made alkaline with sodium hydroxide solution, the precipitate is filtered off and recrystallized from ethanol / water 2: 1. 3.2 g (32% of theory) of 2- (3,4-dimethoxybenzylidene) - - 1-methylpyrrolidine are obtained, mp. 72. Analogously, 2- (3, 4-dimethoxybenzylidene) -1-methylpyrrolidine is obtained by boiling 2- [l- (ethoxycarbonyl) -3, 4-dimethoxybenzylidene] -1-methylpyrrolidine with concentrated hydrochloric acid.

  <Desc / Clms Page number 15>

 



  Example 5: 2- (4-methoxybenzyl) pyrrolidine a) 15 g of 2- [[1- (tert-butoxycarbonyl) -4-methoxybenzylidene] pyrrolidine are mixed with 80 ml of trifluoroacetic acid while cooling with ice and stirred at room temperature for 2 hours. The acid is distilled off in vacuo, the residue is dissolved in 250 ml of ether and washed with almost saturated cold sodium carbonate solution (150 ml) and saturated sodium chloride solution. After drying over sodium sulfate and distilling off the ether, the residue [2- (4-methoxybenzyl) - - pyrrolin-1] is dissolved in 300 ml of ethanol and reduced with Raney nickel / hydrogen. The
The solution is concentrated to an oil which is distilled in vacuo.

   Yield 7.5 g (76%) of bp 88 to 90 'at 1.04 Pa; Mp of the hydrochloride (from ethanol / ether)
141 to 142. b) precursors a) 18, 4 g of thiopyrrolidinone-2 and 56 g of a-bromo-4-methoxyphenyl-acetic acid tert. butyl esters are boiled in 300 ml of dichloromethane for 3 h. After cooling, the organic phase is washed with 100 ml of 25% aqueous potassium carbonate solution and saturated
Saline solution, dries over sodium sulfate and evaporates to a yellowish oil, which is recrystallized from 500 ml n-hexane with activated carbon. Yield 52.2 g (90% of theory) of 2- (1-tert-butoxycarbonyl-4-methoxybenzyl) mercapto-pyrroline-1, colorless crystals with a melting point of 66 to 670.



   ss) 25 g of 2- (1-tert. butoxycarbonyl-4-methoxybenzyl) mercaptopyrroline-1 and 1.0 g of potassium - - tert. Butylate are stirred in 160 ml of trimethyl phosphate and 24 ml of dimethyl sulfoxide under nitrogen at 1000. After 65 h, the solvents are removed in vacuo, the residue is dissolved in 200 ml of ether and the ether phase is extracted once with 100 ml of water, 1N hydrochloric acid, dilute sodium carbonate solution and saturated
Saline. After drying and concentration, the residue is recrystallized from n-hexane. Yield 13.2 g (59% of theory) of 2- [1- (tert-butoxycarbonyl) -4-methoxy-benzylidene-pyrrolidine, mp. 98 to 100.



  Example 6: 2- (3, 4-dimethoxybenzyl) pyrrolidine a) 13.1 g of 2- (3, 4-dimethoxybenzyl) pyrroline-l are dissolved in 300 ml of ethanol with Raney nickel /
Hydrogen hydrogenates. The catalyst is filtered off, the filtrate is concentrated, the residue is distilled and 3.6 g of bp. 116 are obtained at 0.91 Pa. Further purification is carried out by column chromatography on silica gel. The product with Rc value 0.36 (eluent chloroform / methanol 4: 1, carrier silica gel) is collected.

   Yield 504 mg (5% of theory), mp of the picrate (from ethanol) 180 to 181, of the hydrogen fumarate (from ethanol) 165 to 1660. b) 11.7 g of I-benzyl-2- (3, 4 dimethoxybenzyl) pyrrolidine are hydrogenated in ethanol with 6.5 g palladium / activated carbon (10%) / hydrogen. The product freed from solvent and catalyst is distilled under high vacuum. After cleaning with the picrate, 3.2 g (38.5% of theory) are obtained. c) precursors a) 58.2 g of tert-homoveratric acid. butyl ester and 43.3 g of N-bromosuccinimide are in
1, 3 1 carbon tetrachloride boiled under reflux with a 500 W immersion lamp for 2 h.

   After cooling, the succinimide is filtered off and the filtrate is concentrated, which is dissolved in 250 ml of ether and shaken out with water. The ether solution is freed from the solvent in vacuo. 50 g of a-bromo-3, 4-dimethoxyphenylacetic acid tert remain. Butyl ester (66% of theory) as an undistillable oil.



   ss) 15 g of thiopyrrolidinone-2 and 49 g of a-bromo-3, 4-dimethoxy-phenylacetic acid tert. Butyl esters are boiled under reflux in 200 ml of dichloromethane for 1 h, washed with ice-cold potassium carbonate solution and saturated sodium chloride solution and, after drying over sodium sulfate, concentrated to an undistillable oil. Yield 47.2 g (90% of theory) of 2- (I-tert-butoxycarbonyl-3,4-dimethoxybenzyl) mercaptopyrroline-1. y) 35 g of 2- (I-tert. butoxycarbonyl-3, 4-dimethoxybenzyl) mercaptopyrroline-1 and 1.8 g
 EMI15.1
 

  <Desc / Clms Page number 16>

 tel in a high vacuum, takes up the residue in 300 ml of ether and 100 ml of 1N hydrochloric acid and treats the organic phase with 100 ml of dilute sodium carbonate solution and saturated sodium chloride solution.

   After drying over sodium sulfate and distilling off the ether, 29.5 g (93%) of 2- [[1- (tert-butoxycarbonyl) -3, 4-dimethoxybenzylidene] pyrrolidine are obtained as a light brown, undistillable oil.



    61) 29.3 g of 2- [1- (tert. Butoxycarbonyl) -3, 4-dimethoxybenzylidene] pyrrolidine are in
120 ml of trifluoroacetic acid dissolved with ice cooling and stirred at room temperature for 2 hours. After the acid has been distilled off, the residue is dissolved in 500 ml of ether and extracted with cold saturated sodium carbonate solution and saturated sodium chloride solution.
After drying over sodium sulfate and concentrating, 14.6 g of 1- (3,4-dimethoxy-
 EMI16.1
 Ethanol) 139 to 1410.



  62) 24.4 g of 2- [a- (cyano) -3, 4-dimethoxybenzylidene] pyrrolidine are concentrated with 60 ml.



   Hydrochloric acid boiled under reflux for 15 min; After cooling, it is alkalized with 6N sodium hydroxide solution and the base is extracted with ether. After the solvent has been distilled off, 16.0 g (73% of theory) of [2- (3,4-dimethoxybenzyl) pyrroline-1] remain as a yellowish oil.
 EMI16.2
 
Platinum / hydrogen hydrogenated. Distillation in vacuo gives 2.3 g (77% of theory) of the b.p.



     1730 at 0.91 Pa; Picrate (from ethanol) 153. b) Intermediate products a) 35 g of 1-benzylpyrrolidinone-2 and 25.2 g of dimethyl sulfate are heated at 800 for 8 h.



   The reaction mixture is extracted several times with ether and benzene and the viscous oil is then added dropwise with stirring to a solution of 20 ml of dimethylamine in 80 ml of benzene.
The mixture is boiled under reflux for 1 h, the heavy phase is collected and extracted three times with ether. Yield 35.4 g (55% of theory) of 2-dimethylamino-1-benzyl-1-pyrrolinium-1-methyl sulfate as a viscous oil.



   ss) To 34.5 g of 2-dimethylamino-1-benzyl-1-pyrrolinium methyl sulfate and 19.7 g of ethyl homo-veratrate is added dropwise at 90 in a nitrogen stream with stirring, a solution of 2.6 g of sodium in 50 ml of ethanol. The mixture is kept at this temperature for a further 30 min, the reaction mass is partitioned between water and ether, the ether solution is dried over sodium sulfate and. constricts. Yield 32.2 g (96% of theory) of I-benzyl-2-
 EMI 16.3
 with 75 ml conc. Hydrochloric acid boiled until reflux until the evolution of carbon dioxide had ended. After cooling, it is alkalized with sodium hydroxide solution and the resulting one
Precipitation recrystallized from ethanol. Yield 11.3 g (44% of theory) of 1-benzyl- - 2- (3, 4-dimethoxybenzylidene) pyrrolidine, mp. 105.



  Example 8: 2- (4-aminobenzyl) -1-methylpyrrolidine a) 8.5 g of I-methyl-2- (4-nitrobenzylidene) pyrrolidine are reduced in ethanol with platinum / hydrogen. After removal of the catalyst and solvent, the product is recrystallized from n-hexane. 3.6 g (49% of theory) of mp 59 to 610; Mp of the hydrobromide (from ethanol / ether): 193 to 1960; Mp of the dihydrobromide (from ethanol / diethyl ether): 267 to 2700; Mp of the dihydrochloride (from ethanol / diethyl ether): 2440 (decomp.). b) Preproducts a) 50 g of ethyl 4-nitrophenylacetate and 41.4 g of 2,2-diethoxy-l-methylpyrrolidine are boiled under reflux in 250 ml of benzene for 3 hours.

   After the benzene has been distilled off, the residue is recrystallized from ether / petroleum ether. Yield 52.6 g (77% of theory)
2- [1- (ethoxycarbonyl) -4-nitrobenzylide] -1-methylprrolidine as red crystals, mp.



   82 to 83.



   ss) 11 g of 2- [1- (ethoxycarbonyl) -4-nitrobenzylide] -1-methylprrolidine are concentrated in 100 ml. Boiled hydrochloric acid until the evolution of carbon dioxide has ended. Man alkaline

  <Desc / Clms Page number 17>

 siert with sodium hydroxide solution, the red precipitate (8.7 g) of l-methyl-2- (4-nitro-benzylidene) pyrrolidine is filtered off and a sample is recrystallized from ethanol; M.p. 133 to 134. y) At 130, a solution of 2.35 g of potassium tert is added dropwise to 130 to a mixture of 5.0 g of 2-dimethylamine-1-methyl-1-pyrrolinium methyl sulfate and 2.2 g of 4-nitrotoluene in 15 ml of dimethylformamide. butanolate in 15 ml tert. Butanol and 10 ml of dimethylformamide.



   The mixture is stirred at this temperature for 2 h, allowed to cool, water is added and the mixture is extracted several times with chloroform. The combined chloroform extracts are concentrated; a small excess of 4-nitrotoluene is distilled off under high vacuum and the residue is recrystallized from 10 ml of ethanol. 0.8 g of 1-methyl- (4-nitrobenzylidene) - pyrrolidine is obtained.



  Example 9: 2- (4-aminobenzyl) -1-methylpyrrolidine a) 18 g of 2- (4-nitrobenzyl) -1-methylpyrrolidein are hydrogenated in ethanol with 300 mg of platinum dioxide / hydrogen. The catalyst is filtered off, the mixture is concentrated and the residue is recrystallized from n-hexane. Yield 12.7 g (82% of theory). b) 27.9 g of 2-benzyl-l-methylpyrrolidine are concentrated in 130 ml. Dissolved sulfuric acid, then 100 ml of conc. Added dropwise nitric acid. The mixture is stirred for a further 30 min at room temperature, poured into 1 l of ice water and alkalized with cooling with sodium hydroxide solution. It is extracted four times with 150 ml ether each time, the ether phase is dried over sodium sulfate and concentrated to a red oil.

   Yield 33.8 g (96% of theory) of 2- (4-nitrobenzyl) -1-methylpyrrolidine, mp of the hydrogen fumarate (from isopropanol) 145 to 146. c) According to the procedure described in Example 1 b) 10.7 g are obtained from 20 g of 2- [I- (ethoxycarbonyl) benzylidene] -l-methylpyrrolidine via 2-benzylidene-l-methylpyrrolidine
2-Benzyl-l-methylpyrrolidine of bp. 44 to 48 at 0.66 Pa. d) preliminary product
To 84 g of 2-dimethylamino-l-methyl-l-pyrrolinium methyl sulfate and 37.9 g of ethyl phenylacetate are added dropwise with stirring at 90 in a nitrogen stream a solution of 6.8 g
Sodium in 140 ml of ethanol.

   The mixture is stirred at 90 for a further 30 min, the reaction mixture is partitioned between water and ether (300 ml each) and the 2- [l- (ethoxycarbonyl) benzylidene] -1-methylpyrrolidine isolated from the ether phase is distilled, yield 48 g (85% of theory) . Th.) From
Kp. 106 to 1070 at 1, 04 Pa.



  Example 10: 2- (3-Chlorobenzyl) -1-methylpyrrolidine a) According to the procedure described in Example 1b), 62.5 g of 2- [[1- (ethoxycarbonyl) -3-chlorobenzylidene] -1 are obtained -methylpyrrolindine 34 g (72% of theory) 2- (3-chlorobenzyl) - - 1-methylpyrrolidine, bp 81 at 0.91 Pa; Picrate (from ethanol) 186. b) preliminary product
According to the procedure described in Example 9d), 91 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate, 55.1 g of 3-chlorophenylacetic acid ethyl ester and one are obtained
Solution of 8.8 g sodium in 175 ml ethanol 70 g (90% of theory) 2- [1- (ethoxycarbonyl) -3-chlorobenzylidene] -1-methylpyrrolidine of bp. 137 at 0.78 Pa.



  Example 11: 2- (2-chlorobenzyl) -1-methylpyrrolindine a) Following the procedure described in Example 1b), 2- [[l- (ethoxycarbonyl) -2-chlorobenzylidene] -1-methylprrolidine is obtained from 61 g 35.6 g (78% of theory) of 2- (2-chlorobenzyl) - - 1-methylpyrrolidine, bp 81 at 1.04 Pa; Sehmp. of the picrate (from ethanol) 170. b) preliminary product
Following the procedure described in Example 9d), 98.4 g of 2-dimethylamino-l-methyl-l-pyrrolinium methyl sulfate, 56.1 g of 2-chlorophenylacetic acid ethyl ester and a solution of 9.5 g of sodium in 190 are obtained ml of ethanol 73.8 g (93% of theory) of 2- [1- (ethoxycarbonyl) -2-chlorobenzylidene] -1-methylpyrrolidine of bp. 129 at 1.04 Pa.



  Example 12: 2- (4-bromobenzyl) -1-methylpyrrolidine a) 21.5 g of 2- (4-bromobenzylidene) -l-methylpyrrolidine are hydrogenated in 400 ml of ethanol with platinum on activated carbon / hydrogen. The catalyst is filtered off, the mixture is concentrated and the residue is distilled. 18.5 g (85% of theory) of bp 70 at 0.13 Pa are obtained. Mp
Picrates (from ethanol) 140 to 142.

  <Desc / Clms Page number 18>

 b) 2 g of 2-benzyl-l-methylpyrrolidine (obtainable according to Example 9 c)) and 50 mg of iron powder are mixed with 11.4 mmol of bromine at room temperature.

   The mixture is left to stand for 2 hours, made alkaline with 1N sodium hydroxide solution, the base is extracted with ether, distilled and obtained
2- (4-bromobenzyl) -1-methylpyrrolidine as an almost colorless liquid, bp 720 at 0.13 Pa. c) Preproduct a) According to the procedure described in Example 4 d), 59.9 g of 2- [1- (math-
 EMI18.1
 and a solution of 7.2 g of sodium in 145 ml of ethanol 62.4 g (87% of theory) of 2- [1- (ethoxycarbonyl) -4-bromobenzylidene] -1-methylpyrrolidine of bp. 128 at 0 , 78 Pa.



  Example 13: 2- (4-fluorobenzyl) -1-methylpyrrolidine a) According to the procedure described in Example 1 b) (hydrogenation catalyst = platinum)
 EMI18.2
   [1- (ethoxycarbonyl) -4-fluorobenzylidene] -1-methylpyrrolidine 7, 5ethanol) 1680. b) intermediate
According to the procedure described in Example 9d), 4.8 g of 2-dimethylamino-l-methyl-l-pyrrolinium methyl sulfate, 3.3 g of ethyl 4-fluorophenylacetate and a solution of 0.46 g of sodium in 10 are obtained ml of ethanol 1.7 g (36% of theory) of 2- [I- (ethoxycarbonyl) -4-fluorobenzylidene] -1-methylpyrrolidine of melting point 80, purified by column chromatography on silica gel.



  Example 14: 2- (2-methoxybenzyl) -1-methylpyrrolidine a) Following the procedure described in Example 1b), 2- [[l- (ethoxycarbonyl) -2-methoxybenzylidene] -1-methylpyrrolidine is obtained from 55 g 22.3 g (54% of theory) of bp. 73 at
0.65 Pa; Mp of the picrate (from ethanol) 1440. b) intermediate
According to the procedure described in Example 9d), 50 g of 2-methoxyphenylacetic acid ethyl ester, 83.4 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate and a solution of 8.1 g of sodium in 160 ml of ethanol are obtained 63.8 g of 2- [[1- (ethoxycarbonyl) -2-methoxybenzylidene] -1-methylpyrrolidine (71% of theory) of bp. 134 to 137 at 0.65 Pa.



  Example 15: 2- (4-methoxybenzyl) -1-methylpyrrolidine a) Following the procedure described in Example 1b), 2- [1- (ethoxycarbonyl) -4-methylbenzylidene] -1-methylpyrrolidine ( Hydrogenation catalyst = platinum; purification by column chromatography on silica gel) over 2- (4-methoxybenzylidene) -1-methyl-pyrrolidine 7 g (85% of theory) of the title compound, mp of the picrate (from ethanol) 139. b) 0.8 g of 2- [1- (cyano) -4-methoxybenzylidene] -1-methylpyrrolidine are concentrated in 12 ml. Hydrochloric acid boiled at reflux for 15 min. 30 ml of ice water are added, the mixture is made alkaline with 6N sodium hydroxide solution and the base is extracted with ether.

   After the solvent has been distilled off, the oily residue [2- (4-methoxybenzylidene) -1-methylpyrrolidine] (440 mg) is dissolved in ethanol and hydrogenated with platinum / hydrogen. After removal from the catalyst and distilling off the solvent, 320 mg (45% of theory) of a yellowish are obtained
Liquid of bp 79 at 0.65 Pa. c) Preproduct a) According to the procedure described in Example 9 d), 4.8 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate, 3.5 g of 4-methoxyphenylacetic acid ethyl ester and a solution of 0. 46 g sodium in 10 ml ethanol 1 g (20% of theory) 2- [1- (ethoxycarbonyl) -4-methoxybenzylidene] -1-methylpyrrolidine, mp. 81 to 82.



   ss) 30.0 g of 2,2-diethoxy-1-methylpyrrolidine, 25 g of 4-methoxybenzyl cyanide and 150 ml of benzene are boiled under reflux for 4 h. The mixture is concentrated and the residue is distilled twice in vacuo. Yield 30.6 g (79% of theory) of 2- [1- (cyano) -4-methoxybenzylidene] -1-methylpyrrolidine, bp 158 at 0.65 Pa.

  <Desc / Clms Page number 19>

 



  Example 16: I-Methyl-2- (3, 4, 5-trimethoxybenzyl) pyrrolidine a) Following the procedure described in Example 1 b), 30.2 g of 2- [[1- (ethoxy-
 EMI19.1
 
Kp. 118 at 0.78 Pa. (Hydrogenation catalyst: platinum);

   Mp of the picrate (from ethanol) 1250. b) intermediate
According to the procedure described in Example 9d), 51.7 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate, 40.6 g of 3,4,5-trimethoxyphenylacetic acid ethyl ester and a solution of 5 are obtained , 0 g of sodium in 100 ml of ethanol 36.2 g of 2- [[1- (ethoxycarbonyl) -3,4,5-trimethoxybenzylidene] -1-methylpyrrolidine, mp. 115 to 116 (from cyclohexane).



   Example 17: 2- (3-methoxybenzyl) -I-methylpyrrolidine
A solution of 8.1 g of sodium in 160 ml of ethanol is added dropwise to 83.4 g of 2-dimethylamino-1-methyl-l-pyrrolinium methyl sulfate and 48.3 g of ethyl 2-methoxyphenylacetate while stirring at 90 in a stream of nitrogen. The mixture is stirred for a further 30 min at 90, the reaction mixture is partitioned between 300 ml of water and 300 ml of ether, the ether phase is concentrated and the residue [2- (l-ethoxycarbonyl-3-methoxybenzylidene) -1-methylpyrrolidine] is boiled until the end the development of carbon dioxide with conc. Hydrochloric acid.

   After cooling, the mixture is made alkaline with 6N sodium hydroxide solution, extracted with ether, the ether extract is dried over sodium sulfate and concentrated, and the residue [2- (3-methoxybenzylidene) -l-methylpyrrolidine] in methanol is reduced with platinum / hydrogen. The catalyst is filtered, concentrated and distilled. Yield 23.0 g (45% of theory) of bp 880 at 0.65 Pa, mp of the picrate (from ethanol) 1660.



   Example 18: 2- (3-hydroxybenzyl) -l-methylpyrrolidine
10, 5 g of 2- (3-methoxybenzyl) -l-methylpyrrolidine are refluxed in a mixture of 60 ml of acetic acid and 60 ml of 48% hydrobromic acid for 50 hours. It is poured onto ice, neutralized with 6N sodium hydroxide solution to pH 10 and extracted three times with ether. After the combined ether phase has dried, the solvent is distilled off and the residue is distilled in vacuo. Yield 7.95 g (79% of theory) of bp. 128 to 1300 at 0.78 Pa; Mp of fumarate (from isopropanol) 189 to 191.



   Example 19: 2- (4-Hydroxybenzyl) -1-methylpyrrolidine 6.2 g of 2- (4-methoxybenzyl) -1-methylpyrrolidine (prepared according to Example 15) are in a mixture of 30 ml of acetic acid and 30 ml of 48% hydrobromic acid Boiled under reflux for 24 h, a further 20 ml of acetic acid and 20 ml of hydrobromic acid were added and the mixture was boiled for a further 24 h.



  It is poured onto 400 ml of ice water, neutralized to pH 10 with 6N sodium hydroxide solution and extracted four times with 50 ml of ether each time. After drying over sodium sulfate and distilling off the solvent, the residue is recrystallized from 25 ml of ethanol. Yield 65% of theory Th.; M.p. 161 to 162.



   Example 20: 2- (3, 4-Dihydroxybenzyl) -l-methylpyrrolidine
5.0 g of 2- (3,4-dimethoxybenzyl) -1-methylpyrrolidine (prepared according to Example 4) are boiled under reflux in a mixture of 45 ml of acetic acid and 45 ml of 48% hydrobromic acid for 41 h. The main amount of the acid is removed by distillation in vacuo, the residue is taken up in ice water and alkalized with sodium carbonate solution. After extraction of the base with ether for several hours, the residue (4.1 g) obtained after distilling off the solvent is converted into the hydrochloride using methanol / ethereal hydrochloric acid. Yield 3.4 g (67% of theory); Mp



    1880.



   Example 21: 2- (3-methylbenzyl) -1-methylpyrrolidine
A Grignard solution is prepared from 103 g of 3-methylbenzyl chloride and 18 g of magnesium in 400 ml of ether. A solution of 126.9 g of 2,2-diethoxy-l-methylpyrrolidine is added dropwise with stirring and refluxing. The mixture is kept at the boil for 1 h, decomposed dropwise with 130 ml of saturated ammonium chloride solution, the magnesium salts are filtered off and dried over sodium sulfate. The residue freed from ether [31 g of 2- (3-methylbenzlidene) -1-methylpyrrolidine] is hydrogenated with Raney nickel / hydrogen and distilled twice in vacuo. Yield 16.2 g (13% of theory



  Th.), Bp. 560 at 0.13 Pa; Picrate (from ethanol) 135 to 137.

  <Desc / Clms Page number 20>

 



   Example 22: 2- (4-chlorobenzyl) pyrrolidine
20 g of 2- (4-chlorobenzoyl) pyrrole, 15 g of hydrazine hydrate, 28 g of potassium hydroxide and 100 ml of ethylene glycol are heated to 1500 for 2 hours. The mixture is allowed to cool, diluted to twice the volume with water, hydrochloric acid to about PH 3 is added, extracted with ether, the organic phase is freed from the solvent, and the remaining oil [2- (4-chlorobenzyl) pyrrole] is dissolved in 25 ml of ethanol and this solution is added at the boiling point to a mixture of 150 ml of 20% hydrochloric acid and zinc amalgan (made from 100 g zinc, 10 g mercury chloride and 150 ml 0.5 N hydrochloric acid).

   A further 200 ml of 20% hydrochloric acid and 50 g of amalgam are then added, the mixture is boiled for a further 4 h, allowed to cool, filtered, extracted with ethyl acetate (five times 200 ml), the organic solution is concentrated, 6 N sodium hydroxide solution is added until the Zinc salts and extracted with ether. The ether solution is concentrated, the remaining oil is dissolved in 200 ml of alcohol and hydrogenated at the Pt / C contact. The catalyst is filtered off, concentrated, distilled in vacuo and 2- (4-chlorobenzyl) - pyrrolidine (bp. 76 to 79 at 0.65 Pa) is obtained, the hydrochloride of which melts at 190 to 1920.



   Example 23: 2- (4-methoxybenzyl) pyrrolidine 3.3 g of 2- (p-methoxybenzyl) pyrroline-3 are hydrogenated in 100 ml of ethanol at the Pt / C contact.



  The solution freed from the catalyst is concentrated and the oily residue is treated with ethanol / ethereal hydrochloric acid. 2- (4-Methoxybenzyl) pyrrolidine hydrochloride of mp.



  140 to 142 (ethanol / ether).



   Example 24: I-methyl-2- (3, 4, 5-trihydroxybenzyl) pyrrolidine
3, 6 g of I-methyl-2- (3, 4, 5-trimethoxybenzyl) pyrrolidine (prepared according to Example 16), 30 ml of 48% hydrobromic acid and 30 ml of acetic acid are boiled under reflux for 9 h, a further 10 ml of hydrobromic acid and 10 ml of acetic acid were added and the mixture was boiled for a further 3 h. The mixture is then evaporated to dryness and the residue is recrystallized twice from methanol / ether. Yield 2.56 g (61%) of pale pink crystals, mp of the hydrobromide 168 to 171.
 EMI20.1
 Carbonate, 3.4 g of allyl bromide and 50 ml of ethyl methyl ketone are boiled under reflux for 1 h, the solvent is evaporated off, the residue is taken up in 50 ml of water and extracted three times with 30 ml of ether each time.

   The combined ether phases are dried over sodium sulfate, the solvent is distilled off and the residue is distilled in vacuo. Yield 5.12 g (85%), b.p. 84 to 870 at 0.65 Pa; Picrate (from ethanol) 115 to 117.



   Example 26: 2- (4-chlorobenzyl) -I-hexylpyrrolidine
5 g of 2- (4-chlorobenzyl) pyrrolidine (prepared according to Example 3), 3.53 g of anhydrous potassium carbonate, 4.6 g of 1-bromohexane and 50 ml of ethyl methyl ketone are boiled under reflux for 18 h.



  The mixture is worked up as in Example 25 and 5.8 g (81%) of a colorless liquid of bp is obtained.



  110 to 1120 at 0.65 Pa.



   Example 27: 2- (3, 4-diacetoxybenzyl) -1-methylpyrrolidine
3.25 g of 2- (3,4-dihydroxybenzyl) -l-methylpyrrolidine (prepared according to Example 20) are left to stand for 1 hour in 30 ml of acetic anhydride / pyridine. It is concentrated in vacuo and, after distillation of the residue, 3.5 g (76%) of a yellowish oil (bp. 135 to 1400 at 0.65 Pa) is obtained, which solidifies on standing to a crystalline mass of mp. 44 to 450.



   Example 28: 2- (4-chlorobenzyl) -l, l-dimethylpyrrolidinium iodide
3.72 g of methyl iodide are added dropwise to 5.5 g of 2- (4-chlorobenzyl) -1-methylpyrrolidine in 40 ml of acetone while stirring. The crystalline precipitate is filtered off and recrystallized twice from methanol / ether. Yield 6.9 g (72%), mp. 184 to 1860.



   Example 29: 2- (2,4-dichlorobenzyl) -1-methylpyrrolidine a) Following the procedure described in Example 1b), 2- [1- (ethoxycarbonyl) -2, 4-dichlorobenzylidene is obtained from 18.5 g ] -1-methylpyrrolidine over 2- (2, 4-dichlorobenzylidene) -l-methylpyrrolidine 10.4 g (72%) of a colorless liquid, bp 91 at 0.65 Pa, mp.

   of the picrate (from ethanol) 174 to 1760. b) intermediate
According to the procedure described in Example 1 6), 47.7 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate and 23 g of 2, 4-dichlorophenylacetic acid ethyl ester are obtained

  <Desc / Clms Page number 21>

 19 g (61%) 2- [l- (ethoxycarbonyl) -2, 4-dichlorobenzylidene] -1-methylpyrrolidine as a reddish-colored oil, bp. 130 at 0.13 Pa.
 EMI21.1
 dissolved, are mixed with a solution of 27 g of dibenzoyl-L-tartaric acid in 200 ml of acetone.

   The mixture is left to stand at room temperature for 6 h and at 0 'for 4 days, the crystals (8.5 g) are filtered off, the filtrate is concentrated a little, left to stand at 0' for a further 12 h, and the precipitated crystals are collected (4.53 g) , recrystallized the collected crystals from 100 ml of acetone and obtained 9.9 g of dibenzoyl tartrate, mp. 117 to 1200. a] s = -64 (25 mg / ml in methanol). 9.4 g of this salt are shaken with ether / sodium hydroxide solution until completely dissolved; the ether phase is dried, the solvent is evaporated off and the residue is distilled. 2.73 g of base of bp are obtained.



    70 at 0.65 Pa; [a] ss = +78.9 (25 mg / ml in methanol). From the combined filtrates of the crystal
 EMI21.2
 
158, = 12.5.



   Example 31: 2- (4-Acethylaminobenzyl) -1-methylpyrrolidine
A solution of 0.78 g of acetyl chloride in 5 ml of benzene is added dropwise to a solution of 1.9 g of 2- (4-aminobenzyl) -1-methylpyrrolidine (prepared according to Example 8) and 1 g of triethylamine in 10 ml of benzene. After 1 h, concentrate, take up water and ether, collect the organic phase and concentrate to a yellowish oil.
 EMI21.3
 480 mg pivaloyl chloride in 5 ml abs. Pyridine stirred for 2, 5 h at 1000, poured into 50 ml of ice water, mixed with 20 ml of saturated sodium carbonate solution and extracted with ether. The ether extract is dried over sodium sulfate, the solvent is distilled off and the residue is distilled under high vacuum. 320 mg (58% of theory) of colorless liquid with a bp of 95 to 100 at 0.26 Pa.



   Example 33: 2- (4-aminobenxyl) -1-methylpyrrolyen a) Following the procedure described in Example 15 b), 3.3 g of 2- [[l- (cyano) -4-aminobenzylidene] -1 are obtained -methylpyrrolidine over 2- (4-aminobenzylidene) -1-methylpyrrolidine
2.2 g of the title compound of mp 59 to 60. b) Precursors a) 10 g of 2- [1- (cyano) -4-nitrobenzylidene] -1methylpyrrolidine are dissolved in ethanol and reduced with platinum / hydrogen. After hydrogen uptake has ended,
The catalyst is filtered off, the solvent is distilled off and the residue is recrystallized from 50 ml of ethanol. 5.5 g of 2- [1- (cyano) -4-aminobenzylidene] -1-methylpyrrolidine are obtained as light brown crystals of mp 116 to 118.



   ss) 29.9 g of 2,2-diethoxy-1-methylpyrrolidine and 28 g of 3-nitrophenylacetonitrile in 80 ml
Benzene is stirred for 1 h at room temperature, the solvent is distilled off in vacuo and the crystalline residue is recrystallized from ethanol / ether. After this
Concentration of the mother liquor gives 29.5 g (70% of theory) of 2- [I- (cyano) -4-nitrobenzylidene] -1-methylpyrrolidine as dark brown, shiny crystals with a melting point of 67.



   Example 34: 2- (4-chlorobenzyl) pyrrolidine
20 g of 2- [1- (cyano) -4-chlorobenzylidene] pyrrolidine and 50 ml of conc. Hydrochloric acid are boiled under reflux for 2.5 hours, adjusted to pH 5 to 6 after cooling with 6N sodium hydroxide solution, 50 ml of methanol are added and within 20 minutes to the solution 1, 72 containing 2- (4-chlorobenzyl) pyrroline-1 g of sodium borohydride added. The pH value is kept constant by occasional dropping of hydrochloric acid. The mixture is stirred for 30 min, alkalized with sodium hydroxide solution, extracted with methylene chloride, the organic phase is dried over sodium sulfate, concentrated and the residue is distilled in vacuo. Yield 11.12 g (63% of theory) of bp 800 at 0.65 Pa; Mp of the hydrochloride (from methanol / ether) 189 to 1920.



   Example 35: (-) - 2- (4-Chorbenzyl) pyrrolidine
19.57 g of 2- (4-chlorobenzyl) pyrrolidine, dissolved in 200 ml of acetone, is mixed with a solution of 37.6 g of dibenzoyl-L-tartaric acid in 250 ml of acetone. The mixture is left to stand for 12 h and the crystals (25.8 g) are filtered off. [= -84.7 (25 mg / ml in methanol). It is crystallized from 75 ml

  <Desc / Clms Page number 22>

 Methanol / 100 ml acetone and receives 15.43 g of mp 178 to 1790. [a] sg = -880 (25 mg / ml) in methanol). 14.85 g of this salt are stirred with sodium hydroxide solution / ether until two clear phases have formed. The ether phase is collected, dried over sodium sulfate and concentrated to a colorless oil (5.0 g), which is converted into the hydrochloride by treatment with methanol / ethereal hydrochloric acid.

   Yield 4.83 g of mp 216-218. [a]; = -31.4 (25 mg / ml in methanol).



   The right-turning enantiomer of hydrochloride is isolated from the filtrate of the crystalline dibenzoyl tartrate with an optical purity of 0.79. [A] s g = +24.8 (25 mg / ml in methanol).



   Example 36: 2- (2, 4-diaminobenzyl) -1-methylpyrrolidine a) 3.0 g of 2- (2, 4-dinitrobenzylidene) -1-methylpyrrolidine are hydrogenated in 50 ml of ethanol with platinum / hydrogen. The catalyst is filtered off and the mixture is concentrated to a yellowish, viscous oil which decomposes under the action of air and light. b) preliminary product
7, 0 g 2, 4-dinitrotoluene and 9, 65 g 2, 2-diethoxy-l-methyl-pyrrolidine in 50 ml
Benzene stirred at 400 for 5 h. The mixture is allowed to cool, the precipitate is filtered off and washed with a little benzene and hexane. Yield 3.5 g of 2- (2,4-dinitrobenzylidene) -1-methyl-pyrrolidine as black-violet crystals of mp. 188 to 190.



   Example 37: 2 - (4-Chlorobenzyl) -1-methylpyrrolidine
99 g of 1-methylpyrrolidinone-2 and 126 g of dimethyl sulfate are stirred at 800 for 3 h. The mixture is allowed to cool and, while cooling with ice, a solution of 150 ml of dimethylamine in 150 ml of benzene is added dropwise over the course of 30 minutes. The mixture is then boiled under reflux for 3 h, 121 g of 4-chlorobenzyl cyanide are added and a solution of 23 g of sodium in 500 ml of ethanol is added dropwise to this mixture at 900 for 3 h. The mixture is then boiled under reflux for a further 1 1/2 hours, most of the solvent is distilled off, and 400 ml of water are added to the residue and the mixture is extracted with dichloromethane. The organic phase containing 2- [l- (cyano) -4-chlorobenzylidene] -1-methylpyrrolidine is concentrated and concentrated with 250 ml.

   Hydrochloric acid is boiled under reflux until the evolution of carbon dioxide has ended. It is alkalized with 6N sodium hydroxide solution, extracted with dichloromethane, the organic phase is concentrated to a light brown oil [2- (4-chlorobenzylidene) -l-methylpyrrolidine], which is dissolved in 250 ml of ethanol and hydrogenated with platinum / carbon / hydrogen becomes. The catalyst is filtered off, the mixture is concentrated and the residue is distilled under high vacuum. 85 g of the title compound of bp are obtained.



  73 to 78 at 0.65 Pa.



   Examples of use
Example 1: batch for 100 1 (ampoules)
2.5 kg of 2- (4-chlorobenzyl) -1-methylpyrrolidine are dissolved in about 80 liters of double-distilled water with addition of the equivalent amount of hydrochloric acid, then 4.0 kg of mannitol are added. The solution is on a PH of 7, 0:! : 0, 5 set and made up to 100 liters with water (Aqua bidest). The solution is sterilized via a filter and filled into 2 ml ampoules under aseptic conditions.



   Example 2: Approach for tablets
5.0 kg of glutamic acid are mixed with 5.0 kg of milk sugar and finely ground. This mixture is mixed with 10.0 kg of 2- (4-chlorobenzyl) pyrrolidine hydrochloride and 30 kg of corn starch, 32 kg of milk sugar, 1.5 kg of Aerosil and 2.0 kg of sodium lauryl sulfate and sieved. This mixture is moistened with a solution of 2.5 kg of gelatin and 0.5 kg of glycerol in 35 l of water and pressed through a sieve with a mesh size of 1.25 mm. After drying, the granules are mixed well with 8 kg of corn starch, 2.5 kg of talc and 1.0 kg of magnesium stearate and compressed into 200 mg tablets.



   Example 3: Approach for tablets
30 kg of 2- (4-aminobenzyl) -1-methylpyrrolidine dihydrochloride, 8.5 kg of cellulose (Rehocel 25 kg of milk sugar and 22.2 kg of corn starch are mixed with 3.0 kg of polyvinylpyrrolidone (Kollidon RR 25) (in 15 1 Water is dissolved) and the granules are then pre-dried in a drying cabinet at 500 and then passed through a sieve The granules are dried to a relative humidity of 45 to 50% and after the addition of 8.5 kg of carboxymethyl cellulose

  <Desc / Clms Page number 23>

 (Primojel), 2.5 kg talc and 0.3 kg magnesium stearate and careful mixing into tablets of 100 mg weight.



   Example 4: Approach for tablets
25 kg of 2- (3-hydroxybenzyl) -1-methylpyrrolidine fumarate, 8.5 kg of cellulose (Rehocel), 30 kg of milk sugar and 22.2 kg of corn starch are mixed with 3 kg of polyvinylpyrrolidone (Kollidon R 25) (in 15 1 Water dissolved) moistened and granulated. It is then pre-dried in a drying cabinet at 500 and then passed through a sieve. The granules are dried to a relative humidity of 45 to 50% and, after the addition of 8.5 kg of carboxymethyl cellulose (Primojel), 2.5 kg of talc and 0.3 kg of magnesium stearate and careful mixing, are compressed into tablets of 100 mg in weight.



   Pharmacological examinations
The pharmacological properties of the compounds obtainable according to the invention can be clearly demonstrated in albino mice and rats, e.g. B. central stimulation, reserpine antagonism, analgesic effect, anticataleptic effect and hypotensive effect.



   In the subsequent tablets, the examined compounds are identified by a serial number, which is assigned as follows:
 EMI23.1
 
 <tb>
 <tb> running <SEP> no. <SEP> name <SEP> the <SEP> connection
 <tb> 1 <SEP> 2- <SEP> (3-methoxybenzyl) <SEP> -1-methylpyrrolidine <SEP>
 <tb> 2 <SEP> 2- <SEP> (4-chlorobenzyl) -1-methylpyrrolidine
 <tb> 3 <SEP> 2- <SEP> (4-aminobenzyl) -1-methylpyrrolidine
 <tb> 4 <SEP> 2 <SEP> (2-methoxybenzyl) -1-methylpyrrolidine
 <tb> 5 <SEP> 2- <SEP> (4-chlorobenzyl) <SEP> -1-isopropyl-pyrrolidine <SEP>
 <tb> 6 <SEP> 2- <SEP> (4-chlorobenzyl) pyrrolidine
 <tb> 7 <SEP> 2- <SEP> (3-hydroxybenzyl) -1-methylpyrrolidine
 <tb> 8 <SEP> 2- <SEP> (4-fluorobenzyl) -1-methylpyrrolidine
 <tb> 9 <SEP> 2- <SEP> (4-bromobenzyl) -1-methylpyrrolidine
 <tb> 10 <SEP> 2- <SEP> (4-chlorobenzyl) -1-cyclopropylmethylpyrrolidine
 <tb> 11 <SEP> 2- <SEP> (4-methoxybenzyl)

    <SEP> -pyrrolidine <SEP>
 <tb> 12 <SEP> 2- <SEP> (4-hydroxybenyl) -1-methylpyrrolidine
 <tb> 13 <SEP> 1-methyl-2- <SEP> (4-nitrobenzyl) pyrrolidine
 <tb> 14 <SEP> 2- <SEP> (3, <SEP> 4-dimethoxybenzyl) -1-methylpyrrolidine
 <tb> 15 <SEP> 2- <SEP> (2, <SEP> 4-dichlorobenzyl) <SEP> -1-methylpyrrolidine <SEP>
 <tb> 16 <SEP> 1-methyl-2- (3-methylbenzyl) pyrrolidine
 <tb> 17 <SEP> 2- <SEP> 3-chlorobenzyl <SEP>) <SEP> -1-methyl <SEP> pyrrolidine <SEP>
 <tb> 18 <SEP> 2- <SEP> (4-methoxybenzyl) -1-methylprrolidine
 <tb> 19 <SEP> 2- (3,4-dihydroxybenzyl) -1-methylrrolidine
 <tb> 20 <SEP> l-allyl-2- <SEP> (4-chlorobenzyl) pyrrolidine <SEP>
 <tb> 21 <SEP> 1-methyl-2- <SEP> (3, <SEP> 4, <SEP> 5-trimethoxybenzyl) pyrrolidine
 <tb> 22 <SEP> 2- <SEP> (4-chlorobenzyl) <SEP> -l-hexyl-pyrrolidine <SEP>
 <tb> 23 <SEP> 2- <SEP> (2-chlorobenzyl) -1-methylpyrrolidine
 <tb> 24 <SEP> l-methyl-2- <SEP> (3, <SEP> 4,

    <SEP> 5-trihydroxybenzyl) pyrrolidine <SEP>
 <tb>
 

  <Desc / Clms Page number 24>

 
Compounds obtainable according to the invention are characterized by the central stimulation, which is expressed in an increase in vigilance and excitability, in rare cases also in a slight motor activity promotion. The results of the behavioral studies are shown in Table I.



   Table I
 EMI24.1
 
 <tb>
 <tb> vigilance <SEP> and <SEP> increase in excitability <SEP> from <SEP> additional <SEP> increased activity <SEP> from
 <tb> Current <SEP> no. <SEP> mg / kg <SEP> p. <SEP> o. <SEP> intensity <SEP> running <SEP> no. <SEP> mg / kg <SEP> p. <SEP> o. <SEP> intensity
 <tb> 1 <SEP> 5 <SEP> ++ <SEP> 5 <SEP> 25 <SEP> + <SEP>
 <tb> 2 <SEP> 5 <SEP> ++ <SEP> 10 <SEP> 100 <SEP> +
 <tb> 3 <SEP> 5 <SEP> ++ <SEP> 22 <SEP> 100 <SEP> +
 <tb> 4 <SEP> 5 <SEP> ++ <SEP> 9 <SEP> 200 <SEP> +
 <tb> 5 <SEP> 5 <SEP> ++
 <tb> 6 <SEP> 10 <SEP> + <SEP> (+)
 <tb> 7 <SEP> 25 <SEP> +
 <tb> 8 <SEP> 5 <SEP> + <SEP> (+)
 <tb> 9 <SEP> 25 <SEP> +
 <tb> 10 <SEP> 25 <SEP> +
 <tb> 11 <SEP> 25 <SEP> +
 <tb> 12 <SEP> 25 <SEP> +
 <tb> 13 <SEP> 50 <SEP> +
 <tb> 14 <SEP> 50 <SEP> +
 <tb> 15 <SEP> 50 <SEP> +
 <tb> 16 <SEP> 50 <SEP> (+) <SEP>
 <tb> 17 <SEP> 50 <SEP> (+) <SEP>
 <tb> 18 <SEP> 50 <SEP> (+)

    <SEP>
 <tb> 19 <SEP> 100 <SEP> (+) <SEP>
 <tb> 20 <SEP> 50 <SEP> (+) <SEP>
 <tb> 21 <SEP> 50 <SEP> (+) <SEP>
 <tb> 22 <SEP> 30 <SEP> (+) <SEP>
 <tb> 23 <SEP> 5 <SEP> (+) <SEP> * <SEP>
 <tb>
   Intensity scale: ++ greatly increased + (+) very significantly increased + significantly increased (+) slightly increased * reduction from 50 mg / kg p. O.



   Some of the compounds obtainable according to the invention have a particularly strong reserpine antagonistic effect. This antagonism can be demonstrated with prophylactic and therapeutic administration. Table II shows the ED 50 values after tests on the albino mouse.

  <Desc / Clms Page number 25>

 



   Table II a) Prophylactic administration to the mouse
 EMI25.1
 
 <tb>
 <tb> running <SEP> no. <SEP> cancellation <SEP> the <SEP> Ptosis <SEP> funding <SEP> des <SEP> drive
 <tb> (mg / kg <SEP> p. <SEP> o.) <SEP> (mg / kg <SEP> p. <SEP> o.) <SEP>
 <tb> 3 <SEP> 10 <SEP> 12
 <tb> 6 <SEP> 28 <SEP> 10
 <tb> 1 <SEP> 25 <SEP> 25
 <tb> 19 <SEP> 50 <SEP> 50
 <tb> 16 <SEP> 75 <SEP> 50
 <tb> 7 <SEP> 80 <SEP> 55
 <tb> 15 <SEP>> <SEP> 100 <SEP> 50
 <tb> 5 <SEP> (100) <SEP> 65
 <tb> 10 <SEP> (100) <SEP> 70
 <tb> 9 <SEP> 150 <SEP> 0
 <tb>
 b) Therapeutic administration on the mouse
 EMI25.2
 
 <tb>
 <tb> running <SEP> no. <SEP> cancellation <SEP> the <SEP> Ptosis <SEP> funding <SEP> des <SEP> drive
 <tb> (mg / kg <SEP> p. <SEP> o.) <SEP> (mg / kg <SEP> p.

    <SEP> o.)
 <tb> 3 <SEP> 18 <SEP> 37
 <tb> 7 <SEP> 25 <SEP> 30
 <tb> 1 <SEP> 50 <SEP> 75
 <tb> 5 <SEP> 75 <SEP> 75
 <tb> 16 <SEP> 25 <SEP> (100)
 <tb> 11 <SEP> 90 <SEP> 90
 <tb> 4 <SEP> 80 <SEP> 100
 <tb> 17 <SEP> (75) <SEP> 75
 <tb> 13 <SEP> (100) <SEP> 60
 <tb> 10 <SEP> (100) <SEP> 85
 <tb>
 
For compounds obtainable according to the invention, analgesic effects can be demonstrated in various analgesia models on the albino mouse. Table III shows the ED 50 values calculated from the dose response curves.

  <Desc / Clms Page number 26>

 



  Table III a) Hot plate test
 EMI26.1
 
 <tb>
 <tb> running <SEP> no. <SEP> (mg / kg <SEP> p. <SEP> c.) <SEP>
 <tb> 4 <SEP> 2, <SEP> 0 <SEP>
 <tb> 6 <SEP> 2, <SEP> 5 <SEP>
 <tb> 22 <SEP> 3, <SEP> 5 <SEP>
 <tb> 18 <SEP> 5
 <tb> 2 <SEP> 5
 <tb> 17 <SEP> 20
 <tb> 13 <SEP> 25
 <tb> 11 <SEP> 25
 <tb> 14 <SEP> 35
 <tb> 3 <SEP> 50
 <tb> 19 <SEP> 50
 <tb> 23 <SEP> 50
 <tb> 21 <SEP> 50
 <tb>
 b) Focal beam test
 EMI26.2
 
 <tb>
 <tb> running <SEP> no. <SEP> (mg / kg <SEP> p. <SEP> o.)
 <tb> 5 <SEP> 25
 <tb> 3 <SEP> 50
 <tb> 9 <SEP> 50
 <tb> 19 <SEP> 50
 <tb> 22 <SEP> 70
 <tb> 11 <SEP> 80
 <tb>
 c) Writhing test (acetic acid)
 EMI26.3
 
 <tb>
 <tb> running <SEP> no. <SEP> (mg / kg <SEP> p.

    <SEP> o.) <SEP>
 <tb> 6 <SEP> 35
 <tb> 18 <SEP> 45
 <tb> 3 <SEP> 50
 <tb> 4 <SEP> 60
 <tb>
 
Compounds obtainable according to the invention have prophylactic effects against the development of a catalepsy caused by haloperidol. Table IV shows the ED 50 values after tests on the albino mouse. 1
Table IV
 EMI26.4
 
 <tb>
 <tb> running <SEP> no. <SEP> (mg / kg <SEP> p. <SEP> o.) <SEP>
 <tb> 6 <SEP> 7
 <tb> 2 <SEP> 24
 <tb> 21 <SEP> 25
 <tb> 5 <SEP> 25 <SEP> - <SEP> 50 <SEP>
 <tb> 20 <SEP> 65
 <tb> 3 <SEP> 80
 <tb>
 
Compounds obtainable according to the invention cause a reduction in blood pressure in the anesthetized, normotonic albino rat.

   Table V shows the maximum reduction in blood pressure (in kPa) in the range of the first 5 min and 60 min after application at a dose of 50 I1 mol / kg i. v. reproduced.

  <Desc / Clms Page number 27>

 Table V
 EMI27.1
 
 <tb>
 <tb> lf. <SEP> no. <SEP> lowering blood pressure <SEP> (kPa)
 <tb> Max. <SEP> (5th <SEP> min) <SEP> 60 <SEP> min <SEP> p .. <SEP> a.
 <tb>



  19th <SEP> 4, <SEP> 66 <SEP> 3, <SEP> 72 ** <SEP>
 <tb> 23 <SEP> 6, <SEP> 78 <SEP> 5.19
 <tb> 7 <SEP> 5, <SEP> 32 <SEP> 4, <SEP> 26 <SEP>
 <tb> 4 <SEP> 5, <SEP> 32 <SEP> 5, <SEP> 05 <SEP>
 <tb> 3 <SEP> 5, <SEP> 05 <SEP> 2, <SEP> 53 <SEP>
 <tb> 6 <SEP> 4, <SEP> 79 <SEP> 2, <SEP> 39 <SEP>
 <tb> 16 <SEP> 3, <SEP> 72 <SEP> 1, <SEP> 33 <SEP>
 <tb> 2 <SEP> 3, <SEP> 59 <SEP> 1, <SEP> 20 <SEP>
 <tb> 1 <SEP> 3, <SEP> 46 <SEP> 1, <SEP> 20 <SEP>
 <tb> 24 <SEP> 3, <SEP> 01 <SEP> 2, <SEP> 93 <SEP>
 <tb> 5 <SEP> 1, <SEP> 20 <SEP> 1, <SEP> 60 <SEP>
 <tb>
 ** with application of 10 I1 mol / kg The pharmacological properties were determined using the following methods: 1. Behavior
 EMI27.2
 fig type II held. There was a comparative assessment compared to untreated
Controls.

   Vigilance and increased motor activity are assessed from the behavior of the undisturbed mice; The increased excitability is assessed on the basis of the reaction to external stimuli, such as sounds and touch, in comparison to the reaction of the control animals.



  2. Reserpine antagonism
Subcutaneous application of 2 mg / kg reserpine triggers ptosis in the albino mice over a period of several hours, and the normal movement activity of the animals (drive) is considerably inhibited. The intensity of both symptoms is assessed using a point system: 0-1-2-3, which reflects the degree of effect (none up to full ptosis or none until complete inhibition of drive). These experiments can be carried out with prophylactic as well as therapeutic application of the test substances. The tested substances antagonize the symptoms depending on the dose. The EDso of the antagonistic effect is evaluated in comparison to the daily control. Literature: Reserpine drive inhibition (Sulser, Bickel, Brodie, 1961
Med.

   Exp. 5, 454); Reserpine ptosis (Domenjoz and Theobald [1959], Arch. Int. Pharmacodyn. 120/450).



  3. Analgesia a) Hot plate test: Female albino mice are placed on a 50 C hot plate and the reaction time is stopped until the paws are licked. Normal values are in the range of
7 to 8 s. The tested substances cause delayed reactions to the heat stimulus, i. H. decreased sensitivity to heat pain. The dose that extended the reaction time by 50% was determined. Literature: Eddy, N. B. and Leimbach, D.



   (1953) J. Pharmacol. Exp. Ther. 107.385. b) Focal beam test: female albino mice are placed with a focused heat beam, a thermal pain at the base of the tail and the time until the tail is pulled away is stopped. Usually it is in the range of 4 to 5 s. The audited

  <Desc / Clms Page number 28>

 ten substances cause a delayed reaction to the heat pain, i. H. a reduced heat pain reaction. The dose that extended the reaction time by 50% was determined. Literature: D'Amour, F.E. and Smith DL (1941) J. Pharmacol. Exp. Ther.



   72.74. c) Writhing test (acetic acid writhing): intraperitoneal injection of 0.2 ml / 20 mg
Mouse of a 0.75% gene acetic acid solution induces a typical syndrome occurring over the body with dorsiflexion, called "writhing", in albino mice. This in
 EMI28.1
 moved to the daily check, reduced by 50%. Literature: Koster, Anderson, de Beer (1959) Fed. Proc. 18.42.



   4. Haloperidol antagonism
Subcutaneous application of haloperidol (7.5 mmg / kg) triggers catalapsia in albino mice. The cateptic attitude of the animals is checked by placing the animals on a wire bracket bridge for 30 s. The tested substances prevent the occurrence of catalepsy after haloperidol application in a dose-dependent manner. The dose was determined which inhibits the occurrence of catalepsy in 50% of the animals. Literator: L. Julou, M.-C.



   Bardone, R. Ducrot, B. Laffargue et G. Loiseau in Neuro-Psycho-Pharmacology, Ed. H.



   Brill et al., Exerpta Medica Foundation Internat. Congress Series No. 129, 293-303 (1967).



   5. Blood pressure determinations
The substances are administered to normotonic albino rats (Sprague Dawley; male) anesthetized with chloralose (80 mg / kg i.p.) i. v. applied. Blood pressure is measured in the
A. carotis dexter using a Statham pressure transducer, measuring the heart rate using the EKA - pulse rate meter. The body temperature is kept constant at 37, 50, 2 C.



   Warming with an incandescent lamp, which is controlled by a rectal temperature sensor.



   The registration takes place continuously over 1 h p. a. The maximum of the
Effect within the first 5 min and the effect after 60 min.

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

  PATENT CLAIMS: 1. Process for the preparation of new substituted 2-benzylpyrrolidines of the general formula  EMI28.2  wherein R 1 is a hydrogen atom, a straight-chain or branched aliphatic hydrocarbon radical with 1 or 3 to 7 carbon atoms or an alicyclic hydrocarbon radical with 3 to 7 carbon atoms, a cycloalkylalkyl group with 3 to 7 carbon atoms in the cycloalkyl radical and 1 to 4 carbon atoms in the alkyl radical or an aralkyl group up to 12 carbon atoms in the aryl radical and 1 to 4 carbon atoms in the alkyl radical, R2 denotes a halogen atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy group, an alkoxy group with 1 to 4 carbon atoms, an acyloxy group, an optionally substituted amino group,  represents a nitro group or an optionally substituted phenyl group, R \ R "and R5 are identical or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group,  <Desc / Clms Page number 29>  an optionally substituted amino group, a nitro group or an optionally substituted phenyl group, in the form of their racemates, optical antipodes, the quaternary alkylpyrrolidinium compounds having 1 to 7 carbon atoms in the alkyl radical or their acid addition salts, characterized in that substituted 2-benzylpyrrolidines of the general formula  EMI29.1    EMI29.2  atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy group,  an alkoxy group having 1 to 4 carbon atoms, an optionally substituted amino group, a nitro group  EMI29.3    EMI29.4  means in which R 6 has the meaning of R 1 and R 7 is a straight-chain or branched aliphatic hydrocarbon radical with 1 or  3 to 7 carbon atoms or an alicyclic hydrocarbon radical having 3 to 7 carbon atoms, a cycloalkylalkyl radical having 3 to 7 carbon atoms in the cycloalkyl radical and 1 to 4 carbon atoms in the alkyl radical or an aralkyl group having up to 12 carbon atoms in the aryl radical and 1 to 4 carbon atoms in the alkyl radical and N-debenzylated, if necessary for the preparation of a compound of the formula (I) in which R1 is hydrogen, an obtained compound of the formula (I) in which R1 is the benzyl group or if necessary for the preparation of a compound of formula (I) in which R1 has a meaning other than hydrogen, a compound of the formula (I) obtained in which R1 is hydrogen, N-alkylated (alkyl also meaning cycloalkyl, aralkyl,  Cycloalkylalkyl includes) and optionally then the product of the formula (I) obtained is converted into another product of the formula (I) by one or more of the following reaction steps: a) introduction of a nitro group into the phenyl ring by nitration, b) introduction of an amino group into the Phenyl ring by reduction of a nitro group, c) introduction of a halogen atom into the phenyl ring by nuclear halogenation,  <Desc / Clms Page number 30>  d) introduction of a hydroxyl group into the phenyl ring by ether cleavage of an alkoxy group, e) introduction of an alkoxy group into the phenyl ring by etherification of a hydroxyl group, f) N-quaternization of the pyrrolidine group, g) acylation of a free hydroxyl or amino group in the phenyl ring, h) cleavage of an acyl group with liberation of the hydroxy or amino group in the Phenyl ring, i)  Separation of the racemate obtained into the optical antipodes, j) conversion of an acid addition salt obtained into the free base, k) conversion of a base obtained into its acid addition salts.  2. The method according to claim 1, characterized in that one uses an unsaturated 2-benzylpyrrolidine of the general formula (IIa) or (IId).  3. The method according to claim 2, characterized in that one carries out the reduction with hydrogen in the presence of metal catalysts.  4. The method according to any one of claims 1 to 3 for the preparation of new substituted 2-benzylpyrrolidines of the general formula  EMI30.1    wherein R1 * is a hydrogen atom, a straight-chain or branched aliphatic hydrocarbon radical with 1 or 3 to 5 carbon atoms, a cycloalkylalkyl group with 1 to 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms in the cycloalkyl radical, or an optionally monosubstituted phenylalkyl group with 1 to 4 Carbon atoms in the alkyl radical, R is a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an acyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms per alkyl radical or a nitro group ,  a 3 * 4 * 5 * optionally substituted in the p-position, R, R and R is a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an acyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group having 1 to 2 carbon atoms per alkyl radical or a nitro group, where at least one of the substituents in the 2- or 6-position of the benzyl group represents a hydrogen atom, the quaternary (C 1 -C.) -Alkylpyrrolidinium compounds and their acid addition salts, characterized in that an appropriately substituted 2-benzylpyrrolidine of the formula (II)  reduced and if necessary then the product obtained by one or more of the reaction steps listed in claim 1 converted into another product of formula (I *).  5. The method according to any one of claims 1 to 3 for the preparation of new substituted 2-benzylpyrrolidines of the general formula  EMI30.2    <Desc / Clms Page number 31>  wherein R is a hydrogen atom, a straight-chain alkyl radical with 1 to 3 carbon atoms, a branched alkyl radical with 3 to 5 carbon atoms, a cycloalkylmethyl radical with 3 to 5 carbon atoms in the cycloalkyl group or a benzyl radical optionally substituted in the p-position by halogen, methyl or methoxy, R2 ** is a halogen atom, a hydroxyl group, a methoxy group, an amino group or a nitro group, R is a hydrogen atom, a halogen atom, a hydroxyl group, a methoxy group, an amino group or a nitro group, where  EMI31.1  nium compounds or their pharmacologically acceptable acid addition salts, characterized in that  that an appropriately substituted 2-benzylpyrrolidine of the formula (II) is reduced and, if necessary, the product obtained is subsequently converted into another product of the formula (I **) by one or more of the reaction steps mentioned in claim 1.  6. The method according to any one of claims 1 to 3 for the preparation of new substituted 2-benzylpyrrolidines of the general formula  EMI31.2    EMI31.3  mean methyl group and R represents a 2-, preferably 3- or 4-position fluorine, chlorine, hydroxyl, methoxy or amino substituent, and their pharmacologically acceptable acid addition salts, characterized in that an appropriately substituted 2-benzylpyrrolidine of the formula ( II) reduced and, if necessary, the product obtained subsequently converted into another product of the formula (l ***) by one or more of the reaction steps mentioned in claim 1.