DE1913534A1 - (A) Cpds. of formula I and their therapeutically active acid addition salts: where n=4 or 5 z=1, 2 or 3 (aryl=Ph, R=R1=H, n=4 when z=3), R=H or lowe - Google Patents

Abstract

(A) Cpds. of formula I and their therapeutically active acid addition salts: where n=4 or 5 z=1, 2 or 3 (aryl=Ph, R=R1=H, n=4 when z=3), R=H or lower alkyl (R=H when R1=lower alkanoyl), R1=H or lower alkanoyl, aryl=Ph, halophenyl(halogen having at no.80), lower alkylphenyl, lower alkoxyphenyl or m-trifluoromethylphenyl (z=2, R=R1=H, n=4 when aryl =m-trifluoromethylphenyl) (B) Cpds. of formula (II) where x=3 or 4, m=1 or 2 Ar=Ph, halophenyl (halogen having at no. 80) lower alkylphenyl or lower alkoxyphenyl (Ar is not = lower alkoxyphenyl when x=4). (C) Cpds. of formulae (III) and (IV) where n=4 or 5, m=1 or 2 Ar=Ph, halophenyl (halogen having at no.80) lower alkylphenyl or lower alkoxyphenyl.

Description

Aralkylpenta- and hexamethyleneimines The invention relates to precise aralkylpenta- and hexamethyleneimines, in particular 1-R-2-aralkyl- (penta- and hexa) methylenimines of the formula in which n is the number 4 or 5, z is an integer from 1 to 3, R is a hydrogen atom or a lower alkyl radical, a, a hydrogen atom or a lower alkanoyl radical and aryl is a phenyl radical or substituted phenyl radical which has one or more substituents from the The group contains halogen, lower alkyl, lower alkoxy and m-trifluomethyl, where a) in cases in which R1 is a lower alkanoyl radical, R is hydrogen, b) in cases in which z is 3, aryl is phenyl and R and R1 both stand for hydrogen and n has the value 4 and c) in cases in which aryl stands for m-trifluoromethylphenyl, s has the value 2, R and R1 both stand for hydrogen n has the value 4.

The therapeutically active, non-toxic acid addition salts of the compounds (A) as well as several new intermediates involved in the synthesis of the compounds (A) also fall within the scope of the invention.

As "lower alkyl" and as "lower alkoxy" are straight-chain or branched saturated hydrocarbons with 1 to 6 carbon atoms in Frags, z. B. methyl, ethyl, propyl, isopropyl, butyl, pentyl, Henxyl and similar alky radicals or the corresponding alkoxy radicals such as methoxy, ethoxy, propoxy, isopropoxy, etc. in question. Preferred as lower are acetyl, propionyl and butyryl. Possible halogens are those with atomic numbers less than 80, ie fluorine, bromine and chlorine.

The compound of formula f), in which z has the value 39 aryl for phenyl stands, n has the value 4 and R and R1 are both hydrogen atoms, is used as 2- (3-phenylpropyl) -2-piperidinemethanol designated. The procedure for the preparation of this compound is given in the examples 56 to 58. The process for the preparation of as 2- [ß- (3-trifluoromethylphenyl) ethyl] -2-piperidinemethanol designated compound of the formula (A), in which aryl is m-trifluoromethylphenyl, z has the value 2, n has the value 4 and R and R1 both represent hydrogen, in Examples 48 to 50 described. It should be noted that according to the examples 57 and 49 produced esters, namely ethyl 2- (3-phenylpropyl) -6-oxopipecolate and Ethyl 2- [ß- (3-trifluoromethylphenyl) ethyl] -6-oxopipecolate, new intermediates and both esters are accordingly also included in the invention.

The remaining compounds falling under the formula (A) can be structurally represented by the following formula: Here n is 1 or 2, n is 4 or 5; R and ben have the meaning already mentioned, and Ar is a Phe radical or substituted phenyl radical which can contain one or more substituents from the group consisting of halogen, lower alkyl and lower alkoxy, although in cases where R1 is a lower alkanoyl radical with R. is a hydrogen atom.

The compounds of formula (I) can be prepared by several methods. For example, the unsubstituted pentamethalenimine-2-methanol derivatives of the formula (I), which are referred to as 2-aralkyl-2-piperidinemethanols and the formula in which n has the value 1 or 2 and Ar is phenyl halophenyl, lower alkyphenyl or lower alkoxyphenyl, can be prepared by the following sequence of synthesis steps: a) Ethyl 2-oxocyclopentene carboxylate is alkylated in Fe of an alkali metal salt with a suitable aralkyl halide of the formula halogen- (CH2) m-Ar in a suitable organic solvent, e.g. B. dimethylformamide and dimethyl sulfoxide, the corresponding ethyl 1-aralkyl-2-oxocyclopentanecarboxylate being obtained.

b) The latter is converted into sin expanded by an iminograph Ring carboxylate, either as ethyl 2-aralkyl-6-oxopentamethyleneimine-2-carboxylate or ethyl 2-aralkyl-6-oxopipecolate is referred to, under the conditions of a Schmidt reaction around, d. H. by treating the ethyl 1-aralkyl-2-oxocyclopentanecarbonate with hydrazoic acid in a suitable organic solvent, e.g. B. Chloroform and Bemzel: in the presence of a strong mineral acid, e.g. B. Ref oleic acid.

c) The iminocarboxylic acid ester obtained from step b) is reduced with a suitable reducing agent, e.g. 3. Lithium aluminum hydride and borax, where the desired piperidinemethanol of the formula (II) is obtained.

The reaction sequence described above is also applicable to the preparation of the N-unsubstituted hexamethyleneimine-2-methanol derivatives of the formula (I) which have the formula have, in which m has the value 1 or 2 and Ar 'is a phenyl radical, a halophenyl radical or a lower alkylphenyl radical. In this case, the alkylation stage (a) begins with ethyl 2-oxocyclohexane carboxylate and an aralkyl halide of the formula halogen- (CH2) m-Ar ', and the ethyl 1-aralkyl-2-oxocyclohexane carboxylate obtained in this way is used in stage (b) converted into ethyl 2-aralkyl-7-oxo-hexamethyleneimine-2-carboxylate, which is then reduced in step (c) to the desired methanol of the formula (III).

Another method can be the above-mentioned ethyl 2-aralkyl-6-oxo-pentamethyleneimine-2-carboxylate produce by the ethyl 1-aralkyl-2-oxocyclopentanecarboxylate obtained in step a) converted into the corresponding ketone oxime by treatment with hydroxylamine and that this obtained ethyl 1-aralkyl-2-oximinocyclopentanecarboxylate under conditions the Beckmann rearrangement, d. H. by vigorously treating the ketone oxime with a acidic reagent, e.g. B. with 85% sulfuric acid and polyphosphoric acid, in the desired Converts pentamethylene imine carboxylate.

It is believed that the above-mentioned ethyl 2-aralkyloxomethyleneimine-2-carboxylate represented by the formula can be represented, new connections are. In this formula, m is the number 1 or 2, x is the number 3 or 4, and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, but in cases where x is 4 ha + r / is not a lower alkoxyphenyl radical. In view of their novelty and their value as intermediates for the syntheses described herein, these previously unknown compounds (IV) constitute a further feature of the invention.

The following scheme, shown for the preparation of compounds of the formula (II), illustrates the above-mentioned syntheses: As an alternative to reaction step (c), the ring carboxylates obtained from step (b) and expanded with an imino group can be converted into the corresponding methanols of the formulas (II) and (III) if the radicals Ar and Ar 'are not a halophenyl radical by the oxo function at the 6- or 7-position of the respective ethyl-2-aralkyl-oxomethyleneimine-2-carboxylate is replaced by sulfur, e.g. B.

by treatment with phosphorus pentasulphide in pyridine solution at temperatures which are generally at or above room temperature, the ethyl-2-aralkyl-6-thio- pentamethyleneimine-2-carboxylate or ethyl 2-aralkyl-7-thiohexamethyleneimine-2-o £ rboxylate desulphurized, e.g. by Treatment with Raney nickel in an organic solvent such as a lower one Alkanol, and then the ethyl 2-aralkyl (penta- or hexa) methylenimine-2-carboxylate obtained in this way reduced in the manner described in step (c) above, the respective Methanol of the formulas (II) and (III) is obtained. As an alternative to the latter The reduction stage can be ethyl 2-aralkyl (penta or hexa) methylenimine-2-carboxylate in the usual way, e.g. B.

by acid hydrolysis of the ester function to the corresponding carboxy function, namely aralkyl (penta- or hexa) methylenimine-2-carboxylic acid, deesterify and the the latter compound with a signed reducing agent, e.g. B.

Borane or lithium aluminum hydride, to the corresponding methanols of formulas (II) and (III).

The above-mentioned reactions are further illustrated in the following scheme, where the preparation of compounds of formula II), in which Ar "is a phenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, is shown as an example: Another process for the preparation of the methanols of the formula (I) starts with the alkali metal salt of an alkyl N-acyl (penta- or hexa) methylenimine-2-carboxylate, z.3. from the lithium salt of methyl or ethyl N-benzoyl (penta- or hexa) methylenimine-2-carboxylate, which is mixed with an aralkyl halide of the formula halogen- (CH2) m-Ar, in which m has the value 1 or 2 and Ar is phenyl, halophenyl, lower alkyphenyl or lower alkoxyphenyl, in a suitable organic reading means, e.g. B. dimethoxymethane (DME) alkylated, giving the corresponding alkyl-N-acyl-2-aralkyl (penta- or hexa) methylenimine-2-carboxylate, which is then hydrolyzed under customary acidic or alkaline conditions.

2-aralkyl- (penta- or hexa) methylenimine-2-carboxylic acid obtained in this way becomes the desired methanol with borane or lithium aluminum hydride, for example of formula (I) reduced. It is also possible to use these carboxylic acids in the usual way Process with lower alkanols to starve, with the corresponding alkyl esters are obtained, which in turn with a suitable reducing agent, e.g. B.

Lithium aluminum hydride, can be reduced to the corresponding methanols of the formula (I). The reaction sequences described above can be illustrated by the following scheme, which in turn shows the preparation of compounds of the formula (II) as an example: The acids and esters mentioned above, namely the 2-aralkyl- (penta- or hexa) methylenimine-2-carboxylic acids and lower alkyl-2-aralkyl- (p enta- or hexa) methylenimine-2-carboxylates, are new compounds and can. can be represented by the following formulas: In these formulas, n stands for 4 or 5, m for 1 or 2 and Ar stands for a phenyl radical, halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical. Due to their novelty and their value for the syntheses described here, these acids and esters represent another Aspect of the invention.

The N-methyl derivatives of the formula (I) are preferably prepared by reacting the corresponding N-unsubstituted 2-aralkyl-2- (penta- or hexa) methylenimine-methanol with formaldehyde in the presence of a strong mineral acid, preferably hydrochloric acid, the corresponding acid addition salt being a Compound of formula in which a, m and Ar have the meanings already mentioned, is formed. This salt is then treated with a suitable alkali, and the base form obtained is then treated with a suitable reducing agent, e.g.

Lithium aluminum hydride, reduced to the desired 2-aralkyl-N-methyl-2- (penta- or hexa) met1) ylenimine-methanol: In the preferred process for preparing the N-alkyl derivatives of the formula (I) in addition to the N-methyl derivative, the corresponding N-unsubstituted 2-aralkyl-2- (penta- or hexa) methylenimine-methanol is treated with a suitable lower aldehyde under hydrogen pressure in the presence of a catalytic Amount of palladium carbon in a suitable solvent, e.g. B. absolute ethanol treated.

The C-acyl derivatives of the formula (V), in which n, Ar and m have the meanings already mentioned, can be prepared by N-acylation of the corresponding N-unsubstituted 2-aralkyl-2- (penta- or hexa) niethyleniminmethanols with a lower alkanoyl halide, preferably with the chloride, under the conditions of the Schotten-Baumann reaction in the presence of dilute alkali and subsequent reaction with an anhydrous mineral acid, e.g. B. ethereal hydrogen chloride, whereby an acyl migration takes place with the formation of the desired O-acyl derivative CV): The compounds (A) in base form can be converted into therapeutically effective non-toxic acid addition salts by treatment with acids. Suitable acids for this purpose are, for example, inorganic acids such as hydrohalic acids, e.g. B. hydrochloric acid, hydrobromic acid and hydriodic acid, sulfuric acid, nitric acid and phosphoric acid, or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, brittle acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, and p-aminosalicylic acid. Conversely, the salt form can be converted into the free base in the usual way by treatment with a suitable alkali.

Due to the asymmetrical center, which in the invention Compounds CA) is present, they can of course also as separate enantiomorphs Forms are present. These enantiomorphic forms also fall within the scope of the invention.

The compounds of formula (A) in the form of bases or salts have valuable pharmacological properties. They are valuable as a means of treatment of arrhythmia, e recognizable by their ability (Example 46), fibrillation in test animals in doses which are generally only 1 to 20 mg / kg body weight, increases significantly to decrease. The new compounds can be used in therapeutic doses in conventional pharmaceutical Preparations, oral and paranteral, for example in the form of tablets, capsules, Liquids, injection solutions and the like are administered.

It has also been found that the lower alkyl 2-benzylpipecolate are not only new intermediates but are similar to the compounds of formula (A) are effective agents against arrhythmia. For example, if ethyl 2-benzylpipecolate administered as a test compound in the procedure described in Example 46, an effective minimum dose of 5 to 10 eg / kg body weight is determined.

Example 1 Ethyl 2-benzyl-6-oxo-pentamethyleneimine-2-carboxylate Mixture of 100 ml of concentrated sulfuric acid and 200 ml of chloroform is brought to -10 ° C chilled. A Chlorofoor solution (200 ml) of hydrazoic acid is added Prepared using 32-5 g (0.5 mole) sodium azide and stored in an ice bath. Ethyl 1-benzyl-2-oxocyclopentene carboxylate (30.2 g, 0.125 mol) is dissolved in 100 ml of chloroform dissolved and added to the hydrazoic acid solution.

combined chloroform solutions are under vigorous ren within from 1.25 hours to the sulfuric acid mixture give, the reaction temperature is kept below -5 ° C. The evolution of nitrogen is followed by him by one with water. bead filled beaker. After the addition the reaction mixture is stirred for a further 30 minutes in an ice bath. The reaction mixture is then carefully poured onto 700 g of ice, whereupon the layers are separated. The organic layer is diluted with water, sodium hydroxide solution, and water washed. The solution is dried over anhydrous magnesium sulfate and the Solvent removed. The residue is crystallized from ether. Yield 13.35 g (0.051 mol) of ethyl 2-benzyl-6-oxo-pentamethyleneimine-2-carboxylate (also as ethyl 2-benzyl-6-oxopipecolate referred to) as a white solid with a melting point of 88 to 9000, which changes when exposed to slowly turns pink in the air. The light pink substance is in ethyl acetate dissolved and the solution filtered through 30 g of aluminum oxide. The solvent will removed and the residue recrystallized from ether, 10.1 g of the desired Compound can be obtained as an almost white solid with a melting point of 92 to 93.5 ° C.

Elemental analysis: C Calculated for 015H19N03: 68.94 7.33 5.36 Found: 69.21 7.21 5.47 Example 2 2-Benzyl-2-piperidinemethanol Ethyl 2-benzyl-6-oxopipecolate (20 g, 0.08 mol) in 60 ml of freshly distilled tetrahydrofuran is added dropwise to a suspension of 14 g (0.38 mol) of lithium aluminum hydride in 300 ml of tetrahydrofuran given. The reaction mixture is refluxed with stirring overnight.

Water is added dropwise to decompose the excess reducing agent. The inorganic salts are filtered off. The water layer is using several times Ether extracted. The ether solution is dried over anhydrous magnesium sulfate and evaporated under reduced pressure, where 13 g (0.064 mol, 83%) solid 2-ben3yl-2-piperidinemethanol can be obtained. The connection turns off Recrystallized ethyl acetate. Melting point 113-115 ° C.

The corresponding hydrochloride has a melting point of 225 to 227 ° C.

Elemental analysis: a H N Calculated for 013H19N0: 76.05 9.33 6.82 Found: 76.03 9.44 7.09 Example 3 Ethyl 1- (p-fluorobenzyl) -2-oxocyclopentanecarboxylate To a solution containing 114 g (0.70 mol) of the potassium salt of ethyl 2-oxocyclopentanecarboxylate contains in 300 ml of dimethylformamide, 100 g (0.70 mol) of 4-fluorobenzyl chloride given. The reaction mixture is 2 hours at 80 ° C and then 3 hours at room temperature touched. The solvent is evaporated off under reduced pressure and the residue suspended in methylene chloride and washed several times with water. The organic Layer is dried over anhydrous magnesium sulfate and under reduced Pressure evaporated, the residue is distilled at 124 to 129 ° C / 5 mm Hg, whereby 123 g (0.46 mol, 67%) of ethyl 1-Cp-fluorobenzyl) -2-oxocyclopentanecarboxylate were obtained will.

Elemental analysis: CH Calculated for C15H17FO3: 68.16 6.48 Found: 68.25 6.54 Example 4 Ethyl 2- (p-fluorobenzyl) -6-oxo-pentamethyleneimine-2-carboxylate The experiment described in Example 1 is repeated with the difference that an equivalent amount of the product obtained according to Example 3 instead of ethyl 1-benzyl-2-oxocyclopentaacarboxylate is used. As a product, the above-mentioned compound has a melting point of 90 Maintained up to 94 ° C Example 5 2- (p-Fluorobenzyl) -2-piperidinemethanol 21 g (0.075 mol) of ethyl 2- (p-fluorobenzyl) -6-oxo-pentamethyleneimine-2-carboxylate in 150 ml of freshly distilled tetrahydrofuran are added dropwise within 15 minutes added to 300 ml of tetrahydrofuran containing 12.8 g (0.375 mol) of lithium aluminum hydride contains. The reaction mixture is refluxed over seam with stirring. To the Decomposition of the excess reducing agent, 50 ml of water are added dropwise. Inorganic salts are filtered off. The filtrate is extracted with 1N hydrochloric acid. The acid solution is made basic with an oily sodium hydroxide solution and with ether extracted. The organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure, giving 11.34 g (0.052 mol, 6w / o) 2- (p-fluorobenzyl) -2-piperidinemethanol can be obtained. After recrystallization from benzene, the compound has a melting point from 116 to 118 ° C. A hydrochloride is made by adding ethereal hydrogen chloride manufactured.

Melting point 205-207 ° C.

Elemental analysis: C Calculated for C13H19ClFN0: 60.11 7.37 5.39 Found: 59.95 7.25 5.45 Example 6 By repeating those described in Examples 3-5 Experiments, but using an equivalent amount of 4-chlorobenzyl chloride in each case and 3,4-dichlorobenzyl chloride as the alkylating agent in place of 4-fluorobenzyl chloride and using ether as a solvent in place of tetrahydrofuran the experiment described in Example 5 are the corresponding end products 2- (p-chlorobenzyl) and 2- (3 ', 4'-dichlorobenzyl) derivatives of 2-piperidinemethanol obtain. The hydrochloride of the former compound melts at 199 to 201 ° C and the hydrochloride of the second compound at 231 to 233 ° C.

Example 7 Ethyl-I - (p-methoxybenzyl) -2-oxo cyclo entancarboxylate To a solution of 162.8 g (0.84 mol) of the potassium salt of ethyl 2-oxocyclopentanecarboxylate 130 g (0.84 mol) of p-NIethoxybenzyl chloride are added to 600 ml of dimethylformamide. The reaction mixture is stirred for 2 hours at 80 ° C. and overnight at room temperature ditched.

The solvent is evaporated and the residue in methylene chloride dissolved and washed several times with water.

The organic layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure.

The residue is distilled at 170 to 1800C / 10 mm Hg, with 149.5 g (0.54 mol, 64%) of ethyl 1- (p-methoxybenzyl) -2-oxocyclopentane are obtained.

Example 8 Ethyl 2- (p-methoxybenzyl) -6-oxopipecolate A mixture of 58 ml of concentrated sulfuric acid and 116 ml of chloroform are cooled to -10 ° C. A chloroform solution (175 ml) of hydrazoic acid is made using from 29.5 g (0.45 moles) of sodium azide.

40 g (0.015 moles) of ethyl 1- (p-methoxybenzyl) -2-oxocyclopene tanecarboxylate are dissolved in 100 ml of chloroform and simultaneously with the hydrogen nitrogen solution added to the sulfuric acid mixture within 30 minutes while stirring vigorously, keeping the temperature between -100 and OOC. The evolution of nitrogen is followed by bubbling it through a beaker filled with water. After the addition is complete, the reaction mixture is allowed to warm to room temperature left. The two liquid pliases are separated. The chloroform phase will discarded and the sulfuric acid solution poured over crushed ice and water and with fresh chloroform extra here. The organic layer is made with water and one 5% sodium hydroxide solution and then washed over anhydrous Dried magnesium sulfate. The solvent is removed. The residue will Crystallized from ether, leaving 4.5 g (0.016 mol) of the above compound can be obtained. After recrystallization from ethyl acetate-hexane, the compound has a melting point of 87 to 88 ° C.

Example 9 2- (p-Methoxybenzyl) -2-piperidinemethanol 4.7 g (0.016 mol) Ethyl 2- (p-methoxybenzyl) -6-oxopipecolate in 50 mol of freshly distilled tetrahydrofuran are added dropwise to 150 ml of freshly distilled tetrahydrofuran within 10 minutes given containing 3.55 g (0.095 mol) of lithium aluminum hydride. The reaction mixture is refluxed overnight with stirring. To decompose the excess 15 ml of water are added dropwise to reducing agent. Inorganic constituents become filtered off.

The aqueous layer is extracted several times with ether.

The combined layers of ether are poured over anhydrous magnesium sulfate dried and evaporated under reduced pressure. The obtained 2- (p-methoxybenzyl) -2-piperidinemethanol is converted to the fumarate, leaving 4.3 g (0.012 mol, 76%) of 2- (p-methoxybenzyl) -2-piperidine methanol fumarate from melting point 172 to 174 ° C can be obtained.

The pure is obtained by recrystallization from methanol and 2-propanol Fumarate obtained from melting point 173 to 175 ° C.

Elemental analysis: C H N Calculated for [C14H21NO2] 3 [C4H4O4] 2: 63.51 7.53 4.38 Found: 63.44 7.60 4.26 Example 10 On that in Examples 7 through 9, but using an equivalent amount of p-ethoxybenz; yl chloride in each case and m-methoxybenzyl chloride as the alkylating agent ' instead of p-methoxybenzyl chloride and using the corresponding acid in the preparation of the acid addition salt, the following end products are obtained: 2- (p-Ethoxybenzyl) -2-piperidine methanol lactate 2- (m-methoxybenzyl) -2-pipèridine methanol hydrochloride.

Example II Ethyl 1- (p-methylbenzyl) -2-oxocyclopentanecarboxylate prepared in the manner described in Example 7 with the difference that as Reactant 32 g (0.18 moles) of the potassium salt of ethyl 2-oxocyclopentanecarboxylate and 25.4 g (0.18 moles) of α-chloro-p-xylene are used.

Example 12 Ethyl 2- (p-methylbenzyl) -6-oxopipecolate is based on the in the manner described in Example 8 but using the following reactants prepared: 42 g (0.16 mol) of ethyl 1- (p-methylbenzyl) -2-oxocyclopentanecarboxylate and 250 ml of hydrazoic acid solution made from 30.5 g (0.47 mol) of sodium azide, 30 ml water and 24 g (0.24 mol) concentrated H2SV4. The yield of product which is a tan powder is about 13 g.

Example 13 2- (p-methylbenzyl) -2-pyridinemethanol is based on the in Example 2 using 11.5 g (0.3 mol) of lithium aluminum hydride and 13 g (0.05 mol) of ethyl 2- (p-methylbenzyl) -6-oxopipecolate. The corresponding Hydrochloril is made in 2-propanol with essential hydrogen chloride. To The white solid hydrochloride has two recrystallizations from methanol-ether Melting point from 190 to 19200.

Elemental analysis: C H N Calculated for C14H21NO.HCl: 65.74 8.67 5.48 Found: 66.00 8.60 5.60 Example 14 Those in Examples 11 Experiments described through 13 are repeated, but using in each case an equivalent amount of p-ethylbenzyl chloride and a-chloro-m-xylene as the alkylating agent instead of α-chloro-p-xylene. The end products are 2- (p-ethylbenzyl) -2-pyridinemethanol and 2- (m-methylbenzyl) -2-pyridinemethanol obtained in the form of the hydrochloride.

Example 15 Ethyl 1-benzyl-2-oxocyclohexanecarboxylate is applied to the prepared in the manner described in Example 7, with 42 g (0.2 mol) of the potassium salt of ethyl 2-oxocyclohexane arboxylate and 25.5 g (0.2 mol) of benzyl chloride as the alkylating agent is assumed. The pure product is distilled at 140 ° C / 0.09 mm Hg.

Example 16 Ethyl 2-benzyl-7-oxo-hexamethyleneimine-2-carboxylate in the manner described in Example 8 from 42 g of CO, 161 mol) of ethyl 1-benzyl-2-oxocyclohexanecarboxylate and 350 ml one of 52 g (0.8 mol) sodium azide, 50 ml water and 40 g (0.4 mol) concentrated sulfuric acid. It is necessary to hold at about LCOOC for about 30 minutes. The raw product, about 27 g of a dark red-amber oil is recrystallized from ether. By triturating with fresh ether, the relatively pure product becomes in shape of a light brown powder with a melting point of 103 to 104.50C.

Example 17 2-Benzyl-2-hexamethyleneimine methanol is based on that in Example 2 using 6.8 g (0.18 mol) of lithium aluminum hydride and 8 g (0.03 mol) of ethyl 2-benzyl-7-oxo-hexamethyleneimine-2-carboxylate in 300 ml of anhydrous Tetrahydrofuran produced. The product will with essential hydrogen chloride treated in ether. The hydrochloride obtained in this way is once made from methanol-ether and recrystallized once from isopropanol ether.

Melting point 139 to 141 ° C.

Elemental analysis: C H N Calculated for C14H21NO.HCl: 65.74 8.67 5.46 Found: 65.10 8.55 5.30 Example 18 Those described in Examples 15-17 Experiments are repeated, but using an equivalent amount of one accordingly substituted benzyl chloride as alkylating agent in place of that in Example 15 used benzyl chloride and the corresponding acid for the preparation of the following acid addition salts mentioned are used. The following end products will be obtained: 2- (p-fluorobenzyl) 2-hexamethyleneimine methanol hydrochloride, 2- (p-isopropylbenzyl) -2-hexamethyleneimine methanol oxalate and 2- (3 ', 4t -dimethylbenzyl) -2-hexamethyleneimine methanol hydrochloride.

Example 19 Ethyl 1-phenethyl-2-oxocyclopentanecarboxylate To one Solution of 17.7 g (0.1 mol) of the potassium salt of ethyl 2-oxocyclopentanecarboxylate 18.5 g (0.1 mol) of phenylethyl bromide are added to 300 ml of dimethylformamide. That The reaction mixture is stirred at 80 ° C. for 2 hours and at room temperature overnight ditched. The solvent is evaporated and the residue in methylene chloride dissolved and washed several times with water. The organic layer becomes over anhydrous Magnesium sulfate dried and evaporated under reduced pressure. Here will be about 10.5 g of an oily product with a boiling point of 115 to 124 ° C / 0.1 mm Hg was obtained0 Example 20 Ethyl 2-phenylethyl-6-oxopipecolate is applied to that described in Example 8 Way from 10.5 g (0.04 mol) ethyl-1-phenyl- ethyl 2-oxocyclopentanecarboxylate and 100 ml one of 16 g (0.25 mol) sodium azide, 16 ml water and 12.5 g (0.125 Mol) of concentrated H2S04 prepared hydrazoic acid solution. After the final removal of the solvent, the product turns out to be oily ll residue obtained without further purification in the case of that described in Example 21 Attempt is used.

Example 21 2-Phenylethyl-2-piperidinemethanol is based on that in Example 2 using 10 g of lithium aluminum hydride and 0.9 g of the ethyl 2-phenylethyl-6-oxopipecolate prepared according to Example 20.

The hydrochloride of 2-phenylethyl-2-piperidinemethanol is made from ethereal Hydrogen chloride produced in ethanol ether. After recrystallization from 1 ethanol-methyl ethyl ketone the pure hydrochloride is a white solid with a melting point of 152.5 to 1550C obtain.

Elemental analysis: C H N Calculated for C14H21NO.HCl: 65.74 8.67 5.48 Found: 65.55 8X75 5s59 Example 22 A. To that described in Examples 19-21 Way, but using an equivalent amount of an appropriately substituted one Phenylethyl bromide as the alkylating agent in place of that used in Example 19 Phenyl äthylbromids and using the appropriate acid for the preparation of the acid addition salt mentioned below become the following end products obtained: 2- (4'-methyl-phenylethyl) -2-piperidinemethanol hydrobromide 2- (4'-fluorophenylethyl) -2-piperidinemethanol oxalate, 2- (4'-methoxyphenylethyl) -2-piperidinemethanol hydrochloride.

B. The experiments described in Examples 19 to 21 are repeated with the difference that an equivalent Amount of ethyl 2-oxocyclohexane carboxylate and an appropriately substituted phenylethyl bromide can be used, the following products in the form of hydrochloride. obtain.

are: 2-phenylethyl-2-hexamathyleniminmethanol, 2- (4'-fluorophenylethyl) -2-hexamathyleniminmethanol, 2- (4'-methyl-phenylethyl) -2-hexamethyleneimine-methanol.

Example 23 A-methyl N -benzoyl pipecolate: 65 g (0.36 mole) methyl pipecolate hydrochloride are dissolved in 400 ml of pyridine. The solution is cooled in an ice bath. Within 63 g (0.45 mol) of benzoyl chloride are added over a period of 30 minutes. The suspension will Stirred for 2 hours at room temperature. The pyridine hydrochloride is filtered off. The filtrate is evaporated under reduced pressure, the residue in a mixture dissolved by ether and water and the ether layer successively with 1N hydrochloric acid, 55% potassium carbonate solution and water. The ether solution becomes over anhydrous Magnesium sulfate dried and the solvent removed under reduced pressure, yielding about 67 g of an amber 018. The oil is determined by chromatography purified on aluminum oxide, methyl N-benzoylpipecolate being obtained.

B. The seven-membered ring ester, thyl-N-benzoyl-2-hexamethyleneimine carboxylate, is made in the manner described in Example 22-A by benzoylating an equivalent Amount of ethyl 2-hexahydro-azepine carboxylate produced (see C.A. 64 9697f (1966)).

Example 24 Methyl N-benzoyl-2-benzylpipecolate: The Oil Solution 3mitteA is made under reduced pressure from 70 ml (about 0.07 mol) of a solution of lithium methyl removed in ether The residue is dissolved in 500 ml of freshly distilled dry dimethoxyethane solved. 17.0 g (0.07 mol) of triphenylmethane are dissolved in 70 ml of dimethoxyethane. The solution will be within of 30 minutes to the lithium methyl solution given. The darkening red solution is stirred for 3 hours at room temperature. Methyl II-benzoylpipecolate is slowly added to the solution until the color is deep red turns into a lighter red-brown, the total amount added is 16.0 g (0.065 Mole). The reaction mixture is stirred for 30 minutes at room temperature. After addition of 8.2 g (0.065 mol) of freshly distilled benzyl chloride is the reaction mixture Stirred for 20 hours at room temperature. The solvent is then reduced under Pressure removed and the residue suspended in ether and washed with water. The ether solution is separated off and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, a darker oily one Obtained residue containing methyl N-benzoyl-2-benzylpipecolate, which without further Purification is used in the experiment described in Example 25.

Example 25 2-Benzylpipecolic acid: that obtained according to Example 24 Crude methyl N-benzoyl-2-benzylpipecolate is suspended in 200 ml of 7N hydrochloric acid. The mixture is refluxed for 20 hours. The dark suspension obtained is cooled and extracted with ether. The aqueous layer is decolorized with charcoal and the solvent removed. The residue is dissolved in 30 ml of water and the Solution slowly neutralized with dilute ammonia solution. The precipitated 2-benzylpipecolic acid is filtered off and washed with acetone.

The yield is 2.1 g of a slightly yellow-brown colored solid of melting point 380 ° C (decomp.).

Example 26 A. The alkylation procedure described in Example 24 and the hydrolysis procedure described in Example 25 are repeated, wherein however, an equivalent amount of p-fluorobenzyl chloride, p-methoxybenzyl chloride, 3.4- Dichlorobenzyl chloride, phenylethyl bromide, p-fluorophenylethyl bromide and p-methylbenzyl chloride in place of that used in Example 24 as the alkylating agent Benzyl chloride is used. The corresponding 2- (p-fluorobenzyl) -, 2- (p-methoxybenzyl) -, 2- (3 ', 4'-dichlorobenzyl) -, <2-phenylethyl-, 2- (p-fluorophenylethyl) - and 2- (p-Lletbylbenzyl) derivatives of pipecolic acid.

B. By repeating those described in Examples 24 and 25 Experiment with the difference that an equivalent amount of ethyl N-benzoyl-2-hexamethyleneimine carboxylate is alkylated with an appropriate aralkyl halide, the following products are obtained: 2-benzyl-2-hexamethyleneimine carboxylic acid, 2- (p-chlorobenzyl) -2-hexamethyleneimine carboxylic acid, 2- (p-Methoxybenzyl) -2-hexamethyleneimine carboxylic acid, 2- (p-fluorophenylethyl) -2-hexamethyleneimine carboxylic acid, 2- (4'-metho-phenylethyl) -2-hexamethyleneimine carboxylic acid 1 2-phenylethyl-2-hexamethyleneimine carboxylic acid.

Example 27 2-Benzyl-2-piperidinemethanol: 2-Benzylpipecolic acid (0.20 g, 0.0009 mol) is suspended in 15 ml of 1 molar borane solution. The suspension will Heated under reflux for 1 hour.

A solution forms during this time. The solution is on a Ice bath cooled and the excess borane decomposed with In hydrochloric acid. make an addition the layers are separated from water and ether. The aqueous layer becomes basic made and extracted with ether. The xtherlösung is over anhydrous magnesium sulfate dried and the solvent removed under reduced pressure, 2-benzyl-2-piperidinemethanol is obtained as a white solid with a melting point of 11 to 1150C. By recrystallization from ethyl acetate the melting point rises to 113 to 1150C.

Example 28 The reduction procedure described in Example 27 is followed repeated with the difference that in each case an equivalent amount of the according to Example 26-A 2-aralkylpipecolic acids obtained and the 2-aralkyl-2-hexamethyleneimine carboxylic acids obtained according to Example 26-B is used in place of 2-benzylpipecolic acid, the corresponding products being used 2-Aralky1-2- (penta- or hexa) methylenimine-methanols are obtained.

Example 29 A. Ethyl 2-benzylpipecolate: 2-Benzylpipecolic acid (1.0 g) is dissolved in 20 ml of ethanolic hydrochloric acid. The solution is refluxed overnight heated and then concentrated under reduced pressure. The ethyl 2-benzylpipecolate hydrochloride formed as the product is crystallized by adding ether. By treating the salt with alkali the corresponding base, ethyl 2-benzylpipecolate, is obtained.

B. By repeating the experiment described in Example 29-A, but using in each case an equivalent amount of the according to Example 26-A and 26-B obtained acids instead of 2-benzylpipecolic acid are the corresponding Alkyl esters, namely ethyl-2-aralkyl-2- (penta- and hexa) methylenimine-carboxylates, received as products.

Example 30 Ethyl-1-benzyl-2-oximino cyclop entancarboxylate ethyl-1 Benzyl 2-oxocyclopentanecarboxylate (12.0 g, 0.049 mol) is dissolved in 25 ml of ethanol and 15 ml of pyridine dissolved. After adding 7.0 g (0.1 mol) of hydroxylamine hydrochloride the resulting solution was refluxed for 2 hours. The solvent is removed and the residue dissolved in a mixture of ether and water. The layers are separated and the organic layer washed with 1N hydrochloric acid and then with water. The solution is dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure, about 12.1 g of a colorless C) oil being obtained will. Through crystallization n-hexane are 9.3 g (0.0355 Mol 73%) ethyl 1-benzyl-2-oximinocyclopentanecarboxylate as a white solid from Melting point 94.5 to 97.5 ° C obtained. Recrystallization from n-hexane increases the melting point at 97 to 98 ° C.

Elemental analysis: CH Calculated for C15H19NO3: 68.94 7.33 5.36 Found: 68.75 7.27 5.23 Example 71 Ethyl 2-benzyl-6-oxopipecolate: 130 g of polyphosphoric acid are heated to 11000. 10 grams (0.0385 moles) of ethyl 1-benzyl 2-oximinocyclopentane carboxylate are ground to a fine powder and added to the acid while stirring vigorously The temperature of the reaction mixture rises to 150 ° C. during the addition. These The temperature is maintained for 10 minutes. The hot mixture is slowly over Poured 500 ml of ice water and extracted with ether. The ether extracts are over Dried magnesium sulfate. The solvent is evaporated off under reduced pressure. The obtained oil of light amber color is crystallized from ether, whereby about 2.8 g of ethyl 2-benzyl-6-oxopipecolate as a white solid with a melting point of 91.5 to 92.5 ° C can be obtained. The increases by recrystallization from ethyl acetate-hexane Melting point at 92.5 to 93.5 ° C.

Example 32 By repeating those described in Examples 30 and 31 Experiments, however, in each case an equivalent amount of a corresponding ethyl 1-aralkyl-2-oxopentanecarboxylate used in place of the corresponding 1-benzyl derivative used in Example 23 the following products are obtained: ethyl 2- (p-fluorobenzyl) -6-oxopipecolate Ethyl 2- (p-methoxybenzyl) -6-oxopipecolate. Ethyl 2- (p-methylbenzyl) -6-oxopipecolate.

Example 33 Ethyl 2-benzylpipecolate: ethyl 2-benzyl-6-thiopipecolate is prepared as follows: 13 g (0.05 Uol) ethyl 2-benzyl-6-oxopipecolate and 13 g (0.06 mol) of phosphorus pentasulfide are suspended in 100 ml of pyridine. The reaction mixture is refluxed for 20 minutes. It is poured onto ice water and treated with potassium hydroxide made basic (pH 9).

The basic solution is extracted several times with ether Layer is washed with water and dried over anhydrous magnesium sulfate evaporated under reduced pressure, leaving about 5.5 g of ethyl 2-benzyl-6-thiopipecolate is obtained as brown oil. This oil is dissolved in 200 ml of absolute ethanol. 60 g of Raney nickel, which has been washed with ethanol, are added to this solution is. The mixture is stirred at room temperature for 1 hour and under reflux for 30 minutes heated. The catalyst is filtered off and the solvent is reduced under reduced pressure Pressure evaporated. The residue is gel in ether and with ethereal hydrochloric acid treated wherein 38 g (0.012 mol, 24%) of ethyl 2-benzylpipecolate hydrochloride of melting point 206 to 207 ° C can be obtained.

Elemental Analysis: C H N Calculated for C15H20CINO2: 68.83 7.74 4.89 Found: 62.92 7.87 4.86 Example 34 2-Benzylpipecolic acid: 3.8 g of ethyl 2-benzylpipecolate are dissolved in 100 ml of 9N HCl. The solution is refluxed overnight. The solvent is evaporated and the residue is dissolved in water. The solution is neutralized with dilute sodium hydroxide solution and the product obtained 2-Benzylpipecolic acid was filtered off.

Melting point 380 ° C (decomp.), White crystals.

By repeating the in; the examples 33 and 34 described Try, However, using an equivalent amount of the 2- (p-l-ethylbenzyl) and 2- (p-ethoxybenzyl) derivatives of 6-oxopipecolate as starting material are 2- (p-methylbenzyl) -pipecolic acid and 2- (p-Methoxybenzyl) -pipecolsaure obtained as products.

Example 36 2-Benzyl-2-piperidinemethanol: 1 g of ethyl 2-benzylpipecolate is dissolved in 20 ml of 1,2-dimethoxyethane. After adding 0.5 g of lithium aluminum hydride the reaction mixture is refluxed overnight. The excess hydride is decomposed by the slow addition of water. Inorganic salts are filtered off. The aqueous layer is extracted several times with ether. The ethereal solution is over dried anhydrous magnesium sulfate and evaporated under reduced pressure, whereby 2-benzyl-2-piperidinemethanol is obtained as the product.

Example 37 The reduction procedure described in Example 36 is followed repeated, but in each case an equivalent amount of the according to Example 29-B obtained ester is used as the starting material to be reduced. If the If the 2-benzyl component contains a chlorine substituent, water is used instead of 1,2-dimethoxyethane used as a solvent. The corresponding 2-aralkyl-2- (penta and hexa) methylenimine methanol.

Example 38 8a-Benzyl-3H-oxazalo [3,4a] piperidine: a suspension of 9 g (0> 044 mol) of 2-benzyl-2-piperidinemethanol in 50 ml of water is added adjusted to pH 5 to 6 by concentrated hydrochloric acid. After adding 125 ml aqueous 3 'o, o'igem formaldehyde to the resulting solution, the mixture is 2 hours heated on the steam bath. After cooling, the mixture is brought to pH 3 with hydrochloric acid set to 4 and washed with ether. The aqueous layer is cooled and with made basic with a 50% sodium hydroxide solution. The educated gummy product is extracted with ether.

The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, giving 8a-benzyl-3H-oxazalo [3,4a] piperidine as oily product is obtained which, without further purification, in Example 35 described experiment is used.

Example 39 2-Benzyl-N-methyl-2-piperidinemethanol: To a suspension of lithium aluminum hydride (2.7 g, 0.07 mol) in 250 ml of anhydrous ether is added dropwise with stirring, a solution of 7.5 g (0.035 mol) of 8α-benzyl-3H-oxazalo [3,4α] piperidine within 15 minutes given in 50 ml of anhydrous ether. The mixture is left for 2.5 hours at room temperature stirred and left to stand overnight. Then 12 ml of water are slowly added dropwise added with stirring. After adding anhydrous magnesium sulfate, the suspension filtered. Concentration under reduced pressure gives 7.8 crude 2-benzyl-N-methyl-2-piperidinemethanol received as Ö1. The hydrochloride is dissolved in anhydrous ether with essential hydrochloric acid manufactured. Trituration with acetone leaves about 6.2 g of the crude hydrochloride obtained from melting point 165 to 167 ° C. By recrystallization from methanol and Acetone is the pure hydrochloride from melting point 166 to 168 ° C white solid obtain.

Elemental analysis: C H N Calculated for C14H22NOCl: 65.74 8.67 5.48 Found: 65.68 8.59 5.54 Example 40 By repeating the steps in Examples 38 and 39 experiments described, but using one equivalent each time Amount of the corresponding N-unsubstituted 2-aralkyl- (penta- or hexa) methylenimine-methanol As a starting material, there will be the following end products obtain: 2- (p-Fluorobenzyl) -N-methyl-2-piperidinemethanol 2- (p-Methoxybenzyl) -N-methyl-2-piperidinemethanol 2-phenylethyl-N-methyl-2-piperidinemethanol, 2-benzyl-N-methyl-2-hexamethyleneimine-methanol 2- (p-Fluorobenzyl) -N-methyl-hexamethyleneimine-methanol 2-phenylethyl-N-methyl -hexamethylene iminme thano 1 2- (p-Isopropylbenzyl) -N-methyl-hexamethyleneimine-methanol.

Example 41 2-Benzyl-1-n-butyl-2-piperidinemethanol: A solution of 7.0 g (0.034 mol) of 2-benzyl-2-piperidinemethanol and 2.8 g (0.039 mol) of n-butyraldehyde in 200 ml of absolute ethanol is under a hydrogen pressure of 2.8 kg / cm2 at 5000 shaken for 24 hours with 0.5 g of 10% palladium carbon as a catalyst. That The mixture is cooled and the catalyst is filtered off. The filtrate is reduced under Pressure concentrated to an oily residue, which was dissolved in 250 ml of ether. and twice is extracted with 100 ml of 1O5'ciger hydrochloric acid. The combined acid solutions are washed with ether. The aqueous layer is made with 50% sodium hydroxide solution made basic. The gummy product obtained is washed twice with 200 ml of ether each time extracted, dried over anhydrous magnesium sulfate and reduced under reduced Pressure restricted. The oily product, 2-benzyl-1-butyl-2-piperidinemethanol, is through dry column chromatography on liesel gel and isolated as the hydrochloride from the melting point 174 to 17700 identified (from ethyl acetate).

Elementary Analysis: C, H, N Calculated for C17H27NO.HCl: 68.55 9.47 4.70 Found: 68.45 9.40 4.69 EXAMPLE 42 In the manner described in Example 41; However, under Ver; use of an equivalent amount of the corresponding aldehyde and of the corresponding N-unsubstituted 2-aralkyl-2- piperidinemethanol, the following N-alkylmethanols of the formula (I) are obtained: 2-benzyl-1-propyl-2-piperidinemethanol 2-phenylethyl-1-n-butyl-2-piperidinemethanol 2- (p-methoxybenzyl) -1-n-butyl-2-piperidinemethanol 2- (p-fluorobenzyl) -1-ethyl-2-piperidinemethanol 2- (p-methylbenzyl) -1 -n-propUrl-2-piperidinemethallol 2-Benzyl-1-n-butyl-2-hexamethyleneimine-methanol 2- (p-fluorobenzyl) -1-ethyl-2-hexamethyleneimine-methanol 2-Phenylethyl-1-ethyl-2-hexamethyleneimine-methanol Example 43 2-Benzyl-2-piperidinemethyl acetate hydrochloride To a solution of 5.6 g (0.026 mol) of 2-benzyl-2-piperidinemethanol in 40 ml of methylene chloride 1.6 g (0.02 mol) of sodium hydroxide are added to 20 ml of water. The mixture will stirred and cooled in an ice bath., while a solution of 2.4 g (0.03 mol) of acetyl chloride, is added dropwise in 10 ml of methylene chloride within 5 minutes. The mixture 1.5 Stirred at 0 to 1000 hours. The layers are separated and the organic Phase dried over anhydrous magnesium sulfate. By concentrating under reduced About 8.8 g of the oily N-acetyl intermediate compound are obtained under pressure. The oil is dissolved in 150 ml of anhydrous ether, whereupon essential hydrochloric acid is added drop by drop (50 ml) is added under tubes. The suspension is stirred for 2 hours and filtered. The crude hydrochloride is recrystallized twice from methanol-ether, with about 6.3 g of pure 2-benzyl-2-piperidinemethyl acetate as a white solid with a melting point 222 to 224 ° can be obtained.

Elemental analysis: N Calculated for C15H21NO2.HCl: 4.94% Found: 4.79% Example 44 Be described in Example 43 O-acylation is repeated, but with one equivalent amount of a corresponding lower alkanoyl chloride as acylating agent and an equivalent amount of a corresponding 2-aralkyl-2- (penta- or hexa) methylene imine methanol can be used and the following products are obtained in the form of the hydrochloride are: 2-benzyl-2-piperidinemethylpropionate 2-phenylethyl-2-piperidinemethyl acetate 2- (p-fluorobenzyl) -2-piperidine methyl acetate 2- (p-methoxybenzyl) -2-piperidine methyl butyrate 2-Benzyl-2-hexamethyleneimine-methyl acetate, 2 (p-methylphenyl-ethyl) -2-hexane-ethylene-imine-methyl acetate 2- (p-fluorobenzyl) -2-hexamethyleneimine methyl acetate.

Example 45 Separation of 2-benzyl-2-piperidinemethanol Dissolve 13.17 g (0.064 mol) of 2-benzyl-2-piperidinemethanol and 9.75 g (0.064 mol) of d-mandelic acid in 250 ml of acetone and lets the salt so formed crystallize. After cooling down the product is filtered off to about 5 to 15 ° C., about 9.8 g of a white Solid received. Recrystallization three times from acetone gives aan about 5.8 g of the (+) - salt of melting point 161 to 162.5 ° C, αD = + 42.8 °.

The (+) - mandelate is dissolved in water, basic with sodium hydroxide made and extracted with methylene chloride.

The solution is dried over anhydrous magnesium chloride and you removed the solvent under reduced pressure, whereby (+) - 2-benzyl-2-piperidinethanol as a white solid. By recrystallization from ethyl acetate-n-hexane 2.5 g of white needles with a melting point of 115.5 to 117 ° C. are obtained. αD = + 8.23 °.

The original mother liquor from the crystallization of the (+) - salt is evaporated. The residue is in water dissolved, with sodium hydroxide basified and extracted with methylene chloride. The solution becomes over anhydrous Magnesium sulfate dried and the solvent removed under reduced pressure. The residue is dissolved in 200 ml of acetone. 5.55 g (0.0365 moles) of l-iandelic acid added, and after dissolution, the salt is allowed to crystallize (yield 9.74 G). Four recrystallization from acetone gives about 4.5 g of the (-) - salt obtained from melting point 161.5 to 163.5 ° C. OD = -43.10 °. The (-) - mandelate is on treated in the manner described above with a base, the (-) - 2-benzyl-2-piperidinemeth-anol as a white solid. By recrystallization from ethyl acetate-n-hexane about 1.73 g of white needles with a melting point of 115 to 116 ° C. are obtained. αB = -8.51 °.

Example 46 This example illustrates the effect of the compounds of formula (A) as an anti-arrhythmic agent.

The right antechamber of an anesthetized dog becomes through right-sided Thoracotomy and retraction of the pericardium exposed. Atrial fibrillation, definitely with a standard limb lead of the electrocardiograph is triggered by two drops of a 10% acetylcholine solution are placed on the atrium and the atrium is smeared with a blunt spatula. The flicker time is recorded.

Two control periods of flicker are produced 15 minute apart. The compound to be tested is administered intravenously 10 seconds after the next induction of fibrillation. The connection is said to be effective if it shortens the flicker period by at least 50%. The table below lists the effective indestdoses for several compounds of the formula (A). This is not intended to restrict the invention, but rather these compounds are to be regarded as examples of the valuable properties of all compounds of the formula (I) falling within the scope of the invention, including the pharmaceutically acceptable acid addition salts.

n z R R1 Aryl Effective Minimum dose, mg / kg 4 1. H H Phenyl 1-2.5 * 4 1 H K p-Cl-phenyl 10 4 1 H H p-F-phenyl 10-20 4 1 H H 3,4-di-Cl-phenyl 10 4 1 H H p -MeO-phenyl 10 4 2 H H m -Cf3-phenyl 10 4 1 H H p-Me-phenyl 5.10 5 1 H E phenyl 5-10 4 2 H H phenyl 2.5-5 4 1 Me H phenyl <5 4 1 Bu H phenyl 1-2.5 4 1 H acetyl Phenyl 2.5-5 4 3 H H Phenyl 2.5 4 2 H Acetyl Phenyl 10 * Die (*) - and. (-)To shape this compound had similar activity. Example 47 2-Phenylethyl-2-piperidinemethanolacetate hydrochloride 2-Phenylethyl-2-piperidinemethanol (8.1 g, 0.037 mol) is dissolved in 200 ml of dichloromethane solved. 75 ml of 1N sodium hydroxide solution are added to the solution. This to 0 ° C cooled mixture are within 15 minutes 3.14 g (0.04 mol) of acetyl chloride added in 35 ml of dichloromethane. The received Mixture becomes 2 Stirred at 0 ° G for hours. The phases are separated. The organic phase is with Washed water, dried over sodium sulfate and concentrated under reduced pressure, about 8.5 g of a yellowish oily residue are obtained, which in 250 ml of ether dissolved and treated with essential hydrochloric acid until complete precipitation will. The precipitate is stirred in a mixture of ether and hydrochloric acid for 5 hours. Through treatment with decolorizing charcoal and two recrystallizations from methanol-ether the desired Product obtained as a light yellow solid with a melting point of 182.5 to 184,500.

Example 48 Ethyl 1- (3-trifluomethylphenylethyl) -2-oxocyclopentanecarboxylate: 118 g (0.62 klol) ß- (3-trifluoromethylphenyl) ethanol are dissolved in 120 ml benzene. 136 g (0.5 mol) of phosphorus tribromide are added dropwise to the solution. The temperature is rising slowly to about 58 ° C, but begins to drop after about a third is added is. The reaction mixture is heated to 65 ° C and the addition continued while the temperature is slowly increased to 75 ° C. The addition requires about 1 hour. The reaction mixture is then heated to 80 to 85 ° C. for 1 hour. Ample Gas evolution is detected. The mixture is left to cool and then added to 1 l of ice water and extracted with benzene. The benzene phase is with water, dilute sodium bicarbonate solution and water washed neutral over sodium sulfate dried and evaporated to a colorless oil, which by the nuclear magnetic Resonance spectrum is identified as ß- (3-trifluoromethylphenyl) ethyl bromide.

The potassium salt of ethyl 2-oxocyclopentanecarboxylate (84 g, 0.43 mol) is dissolved in 750 ml of sulfoxide. The solution becomes 76 g within 30 minutes (0.3 mol) ß- (3-trifluoromethylphenyl) ethyl bromide added. The yellow solution obtained; is stirred overnight and then. poured into 2.5 l of ice water.

The mixture is extracted with n-IIexane and the organic layer washed with water, dried over magnesium sulfate and evaporated, leaving about 65 g of an oily residue are obtained. The aqueous layer is made with chloroform extracted and the chloroform solution washed with water, dried over magnesium sulfate and evaporated to give about 28 g of a yellow oil. The two oily Residues are combined and distilled.

The ethyl 1- (3-trifluoromethylphenylethyl) -2-oxocyclopentanecarboxylate obtained as the product boils at 125 to 175 ° C / 0.075-0.25 mm Hg.

Example 49 Ethyl 2- [β- (3-trifluoromethylphenyl) ethyl] -6-oxopipecolate is prepared in the manner described for ethyl 2- (phenylethyl) -6-oxopipecolate, whereby of 45 g (0.137 mol) of ethyl 1 - (3-trifluoromethylphenylethyl) -2-oxocyclopentanecarboxylate and 400 ml of hydrazoic acid solution is started, consisting of 42 g (0.64 Uol) NaN3, 42 ml of water and 32 g (0.32 mol) of concentrated sulfuric acid in chloroform has been made. The yield of crude lactam is about 35 g. It has In the form of a yellow oil that crystallizes. By two recrystallizations from ether In a cooling bath of dry matter and acetone, the desired pure lactam turns white Solid obtained from melting point 97 to 990C.

Example 50 2- [ß- (3-Trifluoromethylphenyl) ethyl] -2-piperdine methanol: A solution of 11 g (0.032 mol) of ethyl 2- (3-trifluoromethylphenyl) ethyl] -6-oxopipecolate in 150 ml of ether is added dropwise with stirring to a suspension of 10 g of lithium aluminum hydride given in 200 ml of ether. The mixture is refluxed overnight. After cooling down 50 ml of water are added in an ice bath in such a way that the temperature does not reach 300.degree exceeds. Then another hour stirred at room temperature. The inorganic salts are filtered off. The cake is poured several times with water washed.

The filtrates are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-g - (3-trifluoromethylphenyl) ethyl7-2-piperidinemethanol as a crude product in the form of an oil. The hydrochloride is produced in ether by adding a solution of ethereal hydrochloric acid. The pure hydrochloride, which melts at 146 to 15600, is obtained by recrystallization from methanol-ether. The free base is dissolved in aqueous sodium hydroxide at a p- \ lert 10 regenerated and extracted twice with 50 ml of methylene chloride each time. The combined extracts are washed with saturated brine.

The methylene chloride phase is dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, with the free Base is obtained as an oil which crystallizes from 50 ml of hexane. By recrystallization more hexane becomes the desired pure free base with a melting point of 65 bis 72 ° C obtained.

Elemental analysis: C H N Calculated for C15H20F3NO: 62.70 7.02 Found: 62.44 6.80 4.96% Example 51 Ethyl 1- (p-fluorophenylethyl) -2-oxocyclopentanecarboxylate 39 g (0.28 mol) of ß- (4-fluorophenyl) -ethanol are dissolved in 50 ml-benzene and heated to 50C chilled. Then 57 g (0.21 mol) of phosphorus tribromide are slowly added, whereby the temperature is kept between 50 and 1000. The reaction mixture is 1 hour stirred and then refluxed for 1 hour. The mixture is then cooled and poured into ice water and extracted with benzene. The benzene extract is diluted with Sodium bicarbonate solution and water, dried over magnesium sulfate and washed evaporated to give 46 g of a yellow oil, which by the nuclear magnetic Resonance spectrum as ß- (4-fluorophenyl) ethyl bromide identified will.

48.5 g (0.25 mol) of the potassium salt of ethyl 2-oxocyclopentanecarboxylate are dissolved in 500 ml of dimethyl sulfoxide.

46 g (0.23 mol) of ß- (4-fluorophenyl) ethyl bromide are added to the solution given for 30 minutes. The mixture was stirred overnight and then poured into 1 l of ice water poured and extracted with n-hexane. The extract is washed well with water, dried over magnesium sulfate and evaporated to a light pink liquid which is then distilled. Here, about 31 g of the desired compound are colorless Obtained oil with a boiling point of 145 to 165 ° C / 0.02 to 0.03 mm Hg.

Example 52 Ethyl 2- (4-fluorophenylethyl) -6-oxopipecolate A hydrazoic acid solution is made from 40 g (0.6 mol) of sodium azide, 25 g of sulfuric acid and 40 g of water in 100 ml Chloroform produced. This solution is dried over magnesium sulfate with a Solution of 25 g (0.09 mol) of ethyl 1- (p-fluorophenylethyl) -2-oxocyclopentanecarboxylate mixed in 100 ml of chloroform. The combined solutions are cooled to £ 0 and within 30 minutes with rapid stirring to one held at 150 to -10 ° C Mixture of 100 ml of sulfuric acid and 200 ml of chloroform added. The previously colorless one Mixture changes from light yellow to green-yellow. The mixture is cooled to -20 ° C and stirred for a further 10 minutes. The phases are separated. The color is exclusive contained in the acid layer, added to 1 1 of ice water, stirred for 15 minutes and extracted with ether. The extract is diluted with sodium hydroxide and Washed water neutral, dried over magnesium sulfate and evaporated, whereby a gummy white solid is obtained which crystallizes from hexane and chloroform will, with the desired compound as a glistening white solid of melting point 98.5 to 100 ° C is obtained.

Example 53 2- [β- (4-fluorophenyl) ethyl] -2-piperidinemethanol hydrochloride is prepared in the manner described in Example 50 using 10.2 g (0.035 Mol) ethyl 2- (4-fluophenylethyl) -6-oxopipecolate and 10 g lithium aluminum hydride made in 350 ml of ether. ï) The hydrochloride is after recrystallization from methanol-ether a white solid melting point 179 to 181 ° C.

Example 54 8a-Phenylethyl-3H-oxazalo [3.4a] piperidine 8 g (0.036 mol) 2-Phenylethyl-2-piperidinemethanol are suspended in 50 ml of water. The pH is adjusted to 4 with lion-centered hydrochloric acid. Become a pale yellow solution 200 ml of 37% formaldehyde solution are given. The received.

tene solution is heated on the steam bath for 3.5 hours. The solution is cooled and washed three times with 300 ml of ether, made basic and three times extracted with 300 ml of ether.

The combined extracts are washed neutral with water and dried over sodium sulfate. The ether is evaporated, with about 7.5 g of the desired compound can be obtained as a pale yellow oil without further purification in the experiment described in Example 55 is used.

Example 55 1-Methyl-2-phenylethyl-2-piperidinemethanol To a suspension of S g (0.21 mol) of lithium aluminum hydride in 400 ml of ether is within 15 Minutes while stirring a solution of 7.5 g (0.052 mol) of 8a-phenylethyl-3H-oxazalo [3,4a] piperidine given in 100 ml of ether. This suspension is stirred overnight, - whereupon the excess Hydride by carefully adding 32 ml of water and anhydrous sodium sulfate gets destroyed. The suspension is filtered and the colorless filtrate is evaporated, with about 7 g of 1-methyl-2-phenylethyl-2-piperidinemethanol as colorless Oil can be obtained. The hydrochloride is made by adding ethereal hydrochloric acid prepared to an ether solution of the base. The hydrochloride is made once from methanol-ether and recrystallized a second time from isopropyl alcohol. Melting point 172 to 182 ° C.

Example 56 Ethyl 1- (3-phenylpropyl) -2-oxocyclopentanecarboxylate one Solution of 29? 1 g (0.15 mol) of the potassium salt of ethyl 2-oxocyclopentanecarboxylate in 300 ml of dimethyl sulfoxide are 31.7 g (0.16 mol) of 3-phenylpropyl bromide within one hour added dropwise with stirring. The mixture is stirred at room temperature overnight and then added to 1 l of ice water and extracted with hexane. The extract is over dried anhydrous magnesium sulfate and concentrated under reduced pressure, about 36 g of the desired compound from boiling point 158 to 1600C / 0.7 mm Hg.

Example 57 Ethyl 2- (3-phenylpropyl) -6-oxopipecolate A chloroform solution of hydrazoic acid is converted into sodium azide in the usual way from 32.5 g (0.5 mol) Track made. 34.25 g (0.125 mol) of ethyl-1 - (3-phenylpropyl) are added to this solution -2 ~ oxocyclopentanecarboxylate given in 100 ml of chloroform0 The mixture is within one hour with rapid stirring to a mixture of 200 ml of chloroform and 100 ml of concentrated sulfuric acid given at -20 ° C. When the addition is done, it will Let the mixture warm to -1-0 ° C. The phases are separated. The sulfuric acid phase is washed once with benzene, added to 600 g of ice and stirred for 1 hour. That Product is extracted with benzene and washed with dilute sodium hydroxide. The benzene solution is dried over anhydrous magnesium sulfate and reduced under reduced pressure Evaporated pressure to give about 16.5% of a pale yellow oil will. Ethyl 2- (3-phenylpropyl) -6-oxopipecolate is crystallized from ether at -780C. Melting point 62-64 ° C.

Example 58 2- (3-Phenylpropyl) -2-piperidinemethanol 9 C (0.031 ol) Ethyl 2- (3-phenylpropyl) -6-oxopipecolate are dissolved in 150 ml of dimethoxyethane. The solution becomes a suspension of 4.5 within 15 minutes while stirring g (0.12 mol) of lithium aluminum hydride in 150 ml of dimethoxyethane. The mixture is refluxed for 4.5 hours, cooled to 100 ° C. and slowly with 18 ml of water offset. The resulting viscous mixture is stirred until it is completely white, and filtered. The clear colorless filtrate is evaporated to a colorless oil, which solidifies on standing, leaving about 6.5 g of a white solid, melting point 78 to 820C can be obtained.

This solid is crystallized from ether at room temperature, by dissolving it in an excess of ether and then evaporating the ether until there is about 8 ml of solvent per gram of material. That crystallized in this way Product, 2- (3-phenylpropyl) -2-piperidinemethanol, melts at 89 to 90,500-.

Claims (43)

Claims 1. Process for the preparation of aralkylmethyleneiminene of the formula in which n is 4 or 5, z is an integer from 1 to 3, R fl; -r is hydrogen or a lower alkyl radical, R1 is a hydrogen atom or a lower alkanoyl radical and aryl is a phenyl radical, a halophenyl radical, a lower one Alkylphenyl radical, a lower alkoxyphenyl radical or an m-trifluoromethylphenyl radical, where the halogen function is a halogen with an atomic number of less than 80, but a) in cases in which R1 is a lower alkanoyl radical, R is hydrogen, b) in cases in which z has the value 3, aryl stands for phenyl, IL and R1 are both hydrogen atoms and dn has the value 4, and c) in cases in which aryl stands for m-trifluomethylphenyl, z has the value 2, R and R1 are both hydrogen atoms and n has the value 4., and the therapeutically active acid addition salts of these aralkylmethyleneimines, characterized in that I. a compound of the formula in which m has the lEert 1 or 2, x de-n has the value 3 or 4 and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, but Ar in cases where x has the value 4, no is lower alkoxyphenyl to a compound of the formula in which R and R1 are both hydrogen atoms, reduced or II, a compound of the formula wherein m and Ar are as defined above, to a compound of the formula in which R and R1 are both hydrogen atoms, reduced or III is a compound; the formula reduced to the corresponding 6-deoxy-2-methanol or IV. a compound of the formula reduced to the corresponding 6-deoxy-2-methylanol and optionally the compound I, in which R- and R1 are hydrogen, with formaldehyde in the presence of a strong mineral acid, the product is reacted with an alkali and then the base thus obtained with a suitable one Redulftant for compound I, in which R is a methyl radical and R1 is a hydrogen-reduced atom, and optionally the compound 1, in which R and R1 are both hydrogen atoms, with a corresponding lower aldehyde under hydrogen pressure in the presence of a catalyst in a suitable solvent to give a compound I in which R1 is a hydrogen atom and R is a lower alkyl radical with the exception of methyl is, reacts and optionally the compound I, in which R and R1 are both hydrogen atoms, acylated under the conditions of the Schotten-Baumann reaction with a lower alkanoyl halide in the presence of dilute alkali and subsequent treatment with an anhydrous mineral acid, thereby acyl migration from Nitrogen atom causes the oxygen atom and the compound I is obtained, in which R is a hydrogen atom and R1 is a lower alkanoyl radical, and optionally prepares therapeutically effective acid addition salts of the compounds (A). 2. Process for the preparation of ethyl-2-aralkyl-oxomethyleneimine-2-carboxylates of the formula in which x is 3 or 4 and m is 1 or 2 and Ar is a phenyl radical, an ifalogenophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, the IIalogen function being a halogen with an atomic number of less than 80, but Ar in Cases in which x has the value 4 is not a lower alkoxyphenyl radical, characterized in that compounds of the formula reacts with hydrazoic acid in a suitable solvent in the presence of a strong mineral acid or reacts the compound with hydroxylamine and reacts the 2-oximino compound obtained under the conditions of the Beckmann rearrangement. 3. Process for the preparation of 2-aralkyl-methylenimine-2-carboxylic acids of the formula in which n has the value 4 or 5 and m has the value 1 or 2 and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, the halogen function being a halogen with an atomic number of less than 80, marked thereby that the corresponding lower alkyl ester of 2-carboxylic acid is saponified by acid hydrolysis. 4. Process for the preparation of lower alkyl-2-aralkyl-methylenimine-2-carboxylates of the formula in which the value 4 or 5 and m has the value 1 or 2 and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, the halogen function being a halogen of an atomic number of less than 80, characterized in that one the corresponding acid reacts with a lower alkanol. .5. Process for the preparation of 2-benzyl-2-piperidinemethanol, thereby characterized in that ethyl 2-benzyl-6-oxopip ecolate with lithium aluminum hydride reduced. 6. Process for the preparation of 2- (p-fluorobenzyl) -2-piperidinemethanol, characterized in that the corresponding ethyl 6-oxopipecolate with lithium aluminum hydride reduced. 7. Process for the preparation of 2- (p-methoxybenzyl) -2-piperidinemethanol, characterized in that the corresponding 6-oxopipecolate with lithium aluminum hydride reduced. 8. Process for the preparation of 2- (p-methylbenzyl) -2-piperidinemethanol, characterized in that the corresponding ethyl 6-oxopipecolate with lithium aluminum hydride reduced. 9. Process for the preparation of 2-benzyl-2-hexamethyleneimine methanol, characterized in that one xthyl-2-benzyl-7-oxo-hexamethyleneimine-2-carboxylate reduced with lithium aluminum hydride. 10. Process for the preparation of 2-phenylethyl-2-piperidinemethanol, characterized in that the corresponding ethyl 6-oxopipecolate with lithium aluminum hydride reduced. 11. Process for the preparation of 2-benzyl-N-methyl-2-piperidinemethanol, characterized in that 8a-benzyl-3H-oxazalo [3,4α] -piperidine with lithium aluminum hydride reduced. 12. A process for the preparation of 2-benzyl-1-n; -butyl-2-piperidinemethanol, characterized in that 2-benzyl-2-piperidinemethanol is used with n-butyric acid under hydrogen pressure in the presence of palladium carbon as a catalyst. 13. Process for the preparation of 2-benzyl-2-piperidinemethyl acetate hydrochloride, characterized in that 2-benzyl-2-piperidinemethanol with acetyl chloride in Reacts the presence of dilute sodium hydrochloride and the product with anhydrous Treated hydrogen chloride. 14. Aralkylmethyleneimines of the formula in which n is 4 or 5, z is an integer from 1 to 3, R is a hydrogen atom or a lower alkyl radical, R1 is a hydrogen atom or a lower alkyl radical and aryl is a phenyl radical, an ealogenphenyl radical, a lower alkylphenyl radical, a lower alkoxyphenyl radical or a m-? rifluoromethylphenyl radical, where the IIalogenfunktion is a halogen with an atomic number of less than 8Q, but where a) R stands for hydrogen when R1 is a lower alkanoyl radical, b) aryl stands for phenyl and R and are both hydrogen atoms and n den Has the value 4 if s has the value 3 and c) z has the value 2, R. and R1 are both hydrogen atoms and n. Has the value 4 if aryl stands for m-trifluoromethylphenyl and the therapeutically active acid addition salts of these aralkylmethyleneimines . 15. 2-aralkyl-2-piperidinemethanols of the formula in which m has the meaning of 1 or 2 and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, and the therapeutically active acid addition salts of these compounds, the halogen function being a halogen with an atomic number of less than 80. 16. 2-aralkyl-hexamethyleneimine-2-methanols of the formula in which m has the value 1 or 2 and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, and the therapeutically active acid addition salts of these compounds, the halogen function being a halogen with an atomic number of less than 80. 17. 2-Benzyl-2-piperidinemethanol. 18. 2- (p-Fluorobenzyl) -2-piperidinemethanol. 19. 2- (p-Methoxy-benzyl) -2-piperidinemethanol. 20. 2- (p-Methoxybenzyl) -2-pyridinemethanol. 21. 2-Benzyl-2-hexamethyleneimine methanol. 22. 2-Phenylethyl-2-piperidinemethanol. 23. 2-Benzyl-N-methyl-2-piperidinemethanol. 24. 2-Benzyl-1-n-butyl-2-piperidinemethanol. 25. 2-Benzyl-2-piperidine methyl acetate hydrochloride. 26. Ethyl-2-aralkyl-oxomethyleneimine-2-carboxylate of Forms 1 in which x is 3 or 4 and m is 1 or 2 and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, the halogen function being a halogen with an atomic number of less than 80 and cases in which x has the value 4, hr is not a lower alkoxyphenyl radical 0 27. Ethyl 2-benzyl-6-oxo-pentamethyleneimine-2-carboxylate. 28. Ethyl 2- (p-fluorobenzyl) -6-oxo-pentamethyleneimine-2-carboxylate. 29. Ethyl 2- (p-methoxybenzyl) -6-oxopipecolate. 30. Ethyl 2- (p-methylbenzyl) -6-oxopipecolate. 31. Ethyl 2-benzyl-7-oxo-henxamethyleneimine-2-carboxylate. 32. Ethyl 2-phenylethyl-6-oxopipecolate. 33 .. 2-aralkyl-methylenimine-2-carboxylic acids of the formula in which n is 4 or 5 and m is 1 or 2 and Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, the halogen function being a halogen with an atomic number of less than 80. 34. 2-Benzylpipecolic acid. 35. Lower alkyl-2-aralkyl-methylenimine-2-carboxylates of the formula in which n is 4 or 5 and m is 1 or 2 and -Ar is a phenyl radical, a halophenyl radical, a lower alkylphenyl radical or a lower alkoxyphenyl radical, the halogen function being a halogen of an order of less than 80. 36. Lower alkyl 2-benzyl pipecolate. 37. Ethyl 2-benzylpipecolate. 38. 2- (3-phenylpropyl) -2-piperidinemethanol. 39. Ethyl 2- (3-phenylpropyl) -6-oxopipecolate. 40. 2- [β- (3-Trifluomethylphenyl) ethyl] -2-piperidinemethanol. 41. Ethyl 2- [ß- (3-trifluomethylphenyl) ethyl] -6-oxopipecolate. 42. Use of compounds of the formula (A) as agents against arrhythmia. 43. Medicines for combating arrhythmia, characterized by a content of a compound of the formula (A) as an active ingredient.