DK150478B - METHOD OF ANALOGY FOR THE PREPARATION OF N-ARYL-N- (4-PIPERIDYL) -ARYLACETAMIDE DERIVATIVES - Google Patents

Description

in 150478

The present invention relates to an analogous process for the preparation of N-aryl-N- (4-piperidyl) -arylacetamide derivatives of the general formula (I) set forth in the preamble of claim 1, or pharmaceutically acceptable acid addition salts thereof, which is characterized by the process of claim 1. 1's characteristic part. The present compounds are useful as antiarrhythmic agents.

Some N-aryl-N- (4-piperidyl) amide derivatives are known which have analgesic activity. A number of such compounds can be found in the following references: U.S. Patent No. 3,164,600 and C.A., 77, 34349a (1972).

Among other things, the antiarrhythmic compounds prepared by the process of the present invention differ from such known compounds as to the nature of the arylacetamide group attached to the 4-position of the piperidine nucleus.

It is further known from US Patent No. 3,869,436 that certain N-phenyl and N-alkanoylpiperidyl derivatives further substituted with an amide group on the piperidine ring possess one or more of the following properties: antioxotremovine activity, hypotensive activity, anti-inflammatory activity activity or CNS activity. It is not disclosed that such compounds should possess antiarrhythmic activity, and it has been shown in particular that a preferred compound of said patent namely N- (1- [2- (3-indolyl) ethyl] -4-piperidyl) propionanilide is without antiarrhythmic activity.

The novel N-aryl-N- (4-piperidyl) arylacetamide derivatives prepared by the process of the present invention are denoted by the following general formula: sy ·,, - / XN-C-CH 2 -Ar

Ar and the pharmaceutically acceptable acid addition salts thereof, wherein: L represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl or C 3 -C 6 alkenyl,

Ar represents phenyl, mono- or di-substituted phenyl, pyridyl or 2-pyrimidyl, wherein each of the substituents in the mono- or di-substituted phenyl is independently halogen or C 1-6 alkyl,

Ar 1 represents phenyl, mono- or di-substituted phenyl or 2-thienyl, wherein each of the substituents of the mono or di-substituted phenyl is independently halogen, C 1 -C 6 alkyl, hydroxy or C 1 -C 6 alkyloxy, and X represents hydrogen or C 1 -C 6 alkyloxymethyl, and assuming that L is different from C 8 -C 8 cycloalkyl when Ar and Ar 1 are both phenyl or substituted phenyl and X is hydrogen.

When L represents alkyl, it may be straight-chain or branched with from 1 to 10 carbon atoms, such as e.g. methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, butyl, 2-methylbutyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl or decyl. The term "C 1 -C 6 alkyl" used in the preceding and subsequent definitions means straight-chain or branched-chain alkyl groups, such as e.g. methyl, ethyl, 2-methylethyl, propyl, butyl, pentyl or hexyl. The term "C ^-Cg alkenyl" means alkenyl groups such as e.g. 2-propenyl, 2-butenyl, 3-butenyl or 2-pentenyl. The term "Cg-Cg cycloalkyl" means cyclic hydrocarbon groups having from 3 to 6 carbon atoms, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The term "halogen" is common to atomic halogens less than 127, i.e. fluorine, chlorine, bromine and iodine.

The compounds of formula (I) wherein Ar, Ar 1 and X are as previously defined and L is hydrogen, formula (I a) is prepared from a piperidine derivative having the general formula (IV) wherein Ar, Ar 'and X are as previously defined and Z represents C 1 -C 6 alkyloxycarbonyl, by hydrolysis in acidic or basic aqueous medium. The starting compounds (IV) are obtained by acylating the compounds of formula (II) with an arylacetyl halide having the general formula (III), preferably the chloride.

x o Ζ-ΓΛ / + halogen-C-CH 2 -Ar 1 acylation

'-' 'HH

Ar (II) (III) and in hydride

Vc-CH.-Ar ^ L 2 (IV) JT \ ° \ - 'TJ-C-CH.-Ar1 (I-a) I 2

Ar 3 150478

The acylation of (II) with (III) can be carried out by well-known N-acylation methods, e.g. with stirring and heating under reflux of the reactants together in a suitable reaction-inert organic solvent, preferably in the presence of a suitable base. Suitable solvents which may be used include, e.g. aromatic hydrocarbons such as e.g. benzene, methylbenzene or dimethylbenzene, or halogenated hydrocarbons such as trichloromethane. Suitable bases include e.g. alkali metal carbonates or hydrogen carbonates, alkali metal amides such as sodium amide, or organic bases such as e.g. pyridine or N, N-diethylethanamine.

The hydrolysis of compound (IV) can be carried out acidically using a strong mineral acid, e.g. hydrochloric acid, hydrobromic acid or sulfuric acid, and alkaline using alcoholic base, e.g. potassium hydroxide in 2-propanol.

The compounds of formula (I) wherein Ar, Ar 1 and X are as previously defined and L is as previously defined but are different from hydrogen and where L is denoted by L 1, formula (Ib) can be prepared by , by introducing I 1 substituent either into the compound (I a) by N-alkylation.

This N-alkylation is carried out by reacting (Ia) with a compound of formula L1-Y, (V) wherein L · 1 is as defined above and Y is a reactive group, preferably a halogen atom, or a sulfonyl group. such as methanesulfonyl or 4-methylbenzenesulfonyl. This reaction may be carried out in the usual manner, e.g. with stirring and heating under reflux of the reactants together in a suitable reaction-inert organic solvent, e.g. a lower alkanol, e.g. methanol, ethanol, propanol and butanol, an aromatic hydrocarbon, e.g. benzene, methylbenzene or dimethylbenzene, a ketone, e.g. 4-methyl-2-pentanone, an ether, e.g. 1,4-dioxane or 1,1'-oxybisethane, Ν, Ν-dimethylformamide or nitrobenzene. To bind the acid which is released during the reaction, a suitable base may be added, e.g. sodium or potassium carbonate or hydrogen carbonate, or an organic base such as e.g. Ν, Ν-diethylethanamine. A small amount of an alkali metal iodide, e.g. potassium iodide, can be added to increase the rate of reaction, especially when the reactive ester (V) is a chloride or bromide.

When L in compounds (I) (hereinafter referred to as L) means C1-6alkyl, C3-6cycloalkyl or C3_6cycloalkyl-C1-6alkyl, and when at least 2 1 hydrogen atom is attached to the piperidine nitrogen, the introduction of the L group can be equally is well carried out by catalytic hydrogenation of a mixture of an aldehyde or ketone corresponding to the alcohol L -OH and a compound of formula (Ia) in the presence of a suitable catalyst such as e.g. palladium-on-charcoal. To improve the selectivity of hydrogenation, a small amount of a suitable catalyst poison may be added to the mixture, e.g. thiophene.

Yet another method of preparing the compounds of formula (Ib) consists in the N-acylation of an N-aryl-11L-4-piperidinamine having the general formula (VII) with an aryl acetyl halide having the formula (III), as described above for the preparation of (IV) from (II) and (III).

ιΛ-Ν V + (III) _ (I-b)

Y_ / fH

Ar (VII) When Ar 1 in compounds (Ib) means a substituted phenyl group having 1 or 2 hydroxyl groups as substituents alone or together with other substituents, it is suitable to protect these hydroxyl groups in the corresponding starting materials (III) with a suitable protective group, such as lower alkyloxycarbonyl, whereby a corresponding derivative of (Ib) is obtained, from which the protecting group is readily removed by alkaline hydrolysis using e.g. diluted aqueous base.

The present compounds can be converted to the pharmaceutically acceptable acid addition salt form by treatment with a suitable acid, such as e.g. an inorganic acid such as hydrogen halide acid, e.g. hydrochloric or hydrobromic acid, or sulfuric acid, nitric or phosphoric acid, or an organic acid such as e.g. acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, 4-methylbenzenesulfonic acid hydroxybenzoic. Conversely, the salt form can be converted by treatment with alkali to the free base form.

5 150478

The intermediates used as starting materials in the foregoing processes, a number of which are well-known compounds, can be prepared as follows:

The intermediates of the general formula (II) wherein X is hydrogen, (II-a) are conveniently obtained as follows. A 4-piperidinone having the formula (VIII) wherein in the 1-position sits the protective alkyloxycarbonyl group Z is subjected to a condensation reaction with an arylamine (IX), e.g. with stirring and heating under reflux of the reactants under azeotropic water removal in a suitable organic solvent, preferably an aromatic hydrocarbon such as benzene, methylbenzene or dimethylbenzene, in the presence of a suitable acid such as e.g. 4-methylbenzenesulfonic acid, acetic acid, hydrochloric acid or the like. The resulting Schiff base (X) is then reduced with a suitable reducing agent such as e.g. sodium borohydride, or by catalytic hydrogenation using e.g. platinum oxide catalyst to give the corresponding N-aryl-4-piperidinamine (II-a).

The above reactions are illustrated more clearly in the following schematic arrangement: O + H2H-Ar _Z -N ^ = M-Ar (VIII) (IX) (X)

NaBH.

-i - Ϊ (Il-a)

Intermediates of the general formula (VII) wherein X is hydrogen, (VII-a) are conveniently prepared from (II-a), X being hydrogen, by firstly hydrolysis of Z to give an N-aryl -4-piperidinamine, of formula (XI), followed by introduction of the I I substituent as previously described for the preparation of (Ib) from (Ia).

When L1 in the intermediates (VII-a) means a methyl group, (VII-a-1), they can be obtained directly by reduction of an intermediate (II-a) wherein X is hydrogen, with a suitable reducing agent, such as . lithium aluminum hydride. These turnovers are illustrated in the following schematic layout: 6 150478 _ Η Η

(II-a) hydrolysis χ ΗΜ V introduction ν l1- ^ V

- V-Am ~ Tf ~ Li * \ -AH

Ir I

A Ar (XI) (Vll-a) 'Ci-e ^ i'-o -'- OL CH3-Q ^

Ir Ir (Il-a) (VII-a-1)

The intermediates of the general formulas (II) and (VII), wherein X represents C 1 -C 6 alkoxymethyl, respectively (II-c) and (VII-c), can be prepared as follows: 1-phenylmethyl-4-piperidinone is reacted with a suitable aryl amine and an alkali metal cyanide, e.g. potassium cyanide, in an aqueous organic carboxylic acid system such as acetic acid, or in an aqueous low alkanol in the presence of an equivalent amount of an inorganic acid such as hydrochloric acid, whereby the nitrile function and the amine function take place at the 4-position in the piperidine nucleus.

The nitrile is converted to the corresponding amide by acid hydrolysis.

Advantageously, a concentrated strong aqueous inorganic acid may be used for this purpose, such as hydrochloric acid, phosphoric acid or preferably sulfuric acid. The amide is further hydrolyzed to obtain the corresponding carboxylic acid using well known amide-to-acid hydrolysis methods, e.g. by treatment with a dilute strong acid, e.g. hydrochloric or sulfuric acid, or by alkaline hydrolysis relieves the use of a suitable base, e.g. sodium or potassium hydroxide. The carboxylic acid thus obtained is again converted to a metal salt thereof, preferably the sodium salt, by reaction with base, e.g. with sodium hydroxide. The carboxylic acid does not necessarily need to be isolated or purified, but can be used as a crude mixture for the preparation of the salt, or the salt can be obtained directly by alkaline hydrolysis.

The salt is then converted to the desired ester by reaction with a suitable halo-lower alkane in a suitable solvent, such as e.g. hexamethylphosphorotriamide.

7 150478

Alternatively, the esters may be prepared by converting the acid into an acyl halide in the usual manner by treatment with a suitable halogenating agent, e.g. with sulfinyl chloride, and reacting this acyl halide with a suitable lower alkanol or simply by reacting the acid with a suitable alcohol in the presence of an acid.

The ester is then reduced with a suitable reducing agent such as e.g. sodium dihydro-bi-s- (2-methoxyethoxy) aluminate (Red-Al) in a suitable organic solvent such as e.g. benzene, or with lithium borohydride to give a 4-piperidine methanol. This is then subjected to an O-alkylation reaction with a suitable alkylating agent. The O-alkylation step can be carried out by reacting the piperidine methanol with an appropriate halogen-lower alkane or an appropriate dilavalkyl sulfate in an appropriate organic solvent, such as e.g. benzene, methylbenzene, dimethylbenzene or tetrahydrofuran in the presence of an appropriate quaternary ammonium salt such as Ν, Ν, Ν-triethylbenzene methanaminium chloride to form the corresponding 4-pipe-ridinalkyloxymethyl compound. Elimination of the protective 1-phenylmethyl group herein gives a 4- (C1-C6alkyloxymethyl) -N-aryl-4-piperidinamine. The intermediates (II) and (VII) can be prepared by introducing the (C1-C8) alkyloxycarbonyl group or L1 substituent, respectively, into the compound thus obtained following the methods described herein.

The compounds of general formula (I) and their pharmaceutically acceptable acid addition salts exhibit excellent antiarrhythmic properties and are thus well-suited for the normalization of irregular cardiac rhythms.

The antiarrhythmic effect of the compounds of the invention is evident from the following experiment with dogs.

The test run is performed under neuroleptanalgesia (1 ml per 10 kg body weight of fentanyl (N-phenyl-N- [1- (2-phenyl-ethyl) -4-piperidyl] -propanamide (0.4 mg (ml) and droperidol (20 mg / ml) (1- [1- [4- (4-fluoro-phenyl) -4-oxobutyl] -1,2,3,6-tetrahydro-4-pyridyl] -1,3-dihydro-2H-benzimidazole 2-one)).

About 16 hours after the ligation of the anterior downward branch of the left coronary artery, dogs exhibit a multifocal ventricular arrhythmia.

150478 δ

The test compounds were administered intravenously after a control period of 30 minutes and the following criteria were used: 0: no effect.

+: decrease in the number of premature strokes and increase in the number of normal strokes by at least 30% compared to the control value.

++: decrease in the number of premature strokes and increase in the number of normal strokes by at least 50% compared to the control value.

+++: normalization of cardiac rhythm or decrease in the number of premature beats and increase in the number of normal beats by at least 75% compared to the control value.

The results obtained in this experiment are set forth in the following tables which serve to exemplify the useful antiarrhythmic properties of all the compounds within the scope of formula (I).

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Manufacture of flour products

Example 1

A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 159.5 parts of 4-chlorobenzeneamine, 1520 parts of anhydrous methylbenzene and a few crystals of 4-methylbenzenesulfonic acid is stirred and kept under reflux for 7 hours. (The reaction vessel is equipped with a reflux condenser and water discharger). The methylbenzene is evaporated and the oily residue is distilled in vacuo to give 192 parts of oily ethyl 4- [(4-chlorophenyl) imino] -1-piperidinecarboxylate, boiling point 171 - 176 ° C at 0.4 mm pressure.

Example 2.

By repeating the procedure of Example 1 and using an equivalent amount of a suitable arylamine instead of the 4-chlorobenzeneamine used therein, the following compounds are obtained: 0 1 / "V".

CH3-CH2-O-C-N V = N-Ar

Ar boiling point at specified pressure 2-Cl-CH 160-165 ° C / 0.5-0.6 rom 64 2.6- (CH3) 2-CgH3 142-145 ° C / 0.01 mm 2-Cl, 6 -CH3-C6H3 195-200 ° C / 0.2 mm 16 150478

Ar boiling point at specified pressure 4-F-C „H. 145-147 ° C / 0.01 mm 6 4 3.4- (01) - 0 ° - 190-200 ° C / 0.02-0.03 mm

L · O O

3- C1-C-H. 165-170 ° C / 0.01-0.02 mm 0 4 4- Br-C-H, 180-183 ° C / 0.1 mm 6 4 2.5- (Cl) 2-C6H3 2-pyridinyl

Example 3

A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 parts of 2,6-dichlorobenzamine, 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid is stirred and kept heated under reflux with water discharge. The reaction mixture is evaporated to give 250 parts of ethyl 4 - [(2,6-dichlorophenyl) imino] -1-piperidinecarboxylate as residue.

Example 4-

A mixture of 34 parts of ethyl 4-oxo-1-piperidinecarboxylate, 20 parts of 2-pyrimidinamine, 8 drops of acetic acid and 90 parts of methylbenzene is stirred and heated under reflux for 28 hours with water discharge. The reaction mixture is evaporated to give 50 parts of ethyl 4- (2-pyrimidinylimino) -1-piperidinecarboxylate as residue.

Example p.

To a warm solution of 192 parts of ethyl 4 - [(4-chlorophenyl) imino] -1-piperidinecarboxylate in 560 parts of methanol is added portionwise 23.5 parts of sodium borohydride at 50 ° C and over a period of 1 hour. After complete addition, the mixture is stirred at the same temperature for 2 hours. The methanol is evaporated. The solid residue is heated with 600 parts of water and the product is extracted with benzene. The extract is dried over magnesium sulfate and evaporated.

The oily residue solidifies by treatment with 2,2'-oxybis-propane. The solid is filtered off and dried to give 122 parts of ethyl 4 - [(4-chlorophenyl) amino] -1-piperidinecarboxylate, mp 115-118 ° C.

Example 6

Following the procedure of Example 5 and using an equivalent amount of an appropriate ethyl 4-arylimino-1-piperidine carboxylate, the following compounds are prepared:

ISLAND

II r ~ \ / H

CH3-CH2-0-C-W Y

Year

Ar melting point / boiling point

2-Cl-CgH 4 m.p. 89-93 ° C

2- Cl, 6-CH3-CgH3 m.p. 99.5 ° C

4-F-CgH4 kp. 140-142 ° C / 0.01 mm

3.4- (Cl) 2-CgH3 m.p. 113.5 ° C

3- Cl-CgH4 m.p. 72 ° C

4- Br-CgH 4 m.p. 116.5 ° C

2.5- (Cl) 2-CgH3 m.p. 107.2-110.3 ° C

2-Pyrimidinyl Example 7.

To a stirred and refluxed mixture of 18 parts of ethyl 4 - [(2,6-dichlorophenyl) imino] -1-piperidine carboxylate in 160 parts of methanol and 160 parts of 2-propanol is added portionwise 30 parts of sodium borohydride. Upon completion, stirring is continued at reflux temperature for 1 hour.

The hot reaction mixture is poured into water and the product is extracted with methylbenzene. The extract is dried and evaporated. The residue is crystallized from a mixture of 160 parts of 2,2'-oxy-bispropane and 160 parts of petroleum ether to give 96 parts of ethyl 4 - [(276-dichlorophenyl) amino] -1-piperidinecarboxylate, m.p. 107.2 - 116.6 ° C.

Example 8.

A mixture of 45 parts of ethyl 4 - [(2,6-dimethylphenyl) imino] -1-piperidinecarboxylate, 0.3 parts of platinum dioxide in 160 parts of methanol is hydrogenated at normal pressure and at a temperature between 24 ° C and 35 ° C. After uptake of the calculated amount of hydrogen, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled to give 30 parts of the oily free base of ethyl 4 - [(2,6-dimethyl-phenyl) amino] -1-piperidine carboxylate, bp 148 - 153 ° C at 0.01 mm pressure. From this distillate, the hydrochloride salt is prepared in the usual manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried to give 28.5 parts of ethyl 4 - [(2,6-dimethylphenyl) amino] -1-piperidinecarboxylate, hydrochloride, mp 195.5 ° C.

A mixture of 10 parts of ethyl 4 - [(2,6-dimethylphenyl) amino] -1-piperidinecarboxylate and 135 parts of hydrobromic acid solution 48% is stirred at a temperature between 80 and 110 ° C until the evolution of gaseous carbon dioxide ceases (about 1 hour ).

The red-colored reaction mixture is evaporated in vacuo. The residue is taken up in 56 parts of methylbenzene and the methylbenzene is evaporated again. Evaporation is then repeated in a mixture of 24 parts of 2-propanone and 40 parts of methylbenzene. The resulting semi-solid residue is triturated in 80 parts of hot 2-propanone and upon cooling the solid product precipitates. This is filtered off, washed with small amounts of absolute ethanol and 2-propanone one after the other, and dried to give 13 parts of N- (2,6-dimethylphenyl) -4-piperidinamine, dihydrobromide, m.p. 300 ° C.

Example 9

To a stirred and cooled (ice bath) mixture of 165 parts of ethyl 4- (2-pyridinylimino) -1-piperidinecarboxylate and 736 parts of methanol is added portionwise 29.5 parts of sodium borohydride (exothermic reaction). Upon completion, stirring is continued for 1 hour and 30 minutes at room temperature. The reaction mixture is evaporated. The residue is slurried in 460 parts of water and the slurry acidified with a concentrated hydrochloric acid solution. The whole is made alkaline with ammonium hydroxide and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is converted to the oxalate salt in 2-propanol and 2,2'-oxybispropane. The salt is filtered off, washed with 2,2'-oxybispropane and dried in vacuo to give 38 parts of ethyl 4- (2-pyridinylamino) -1-piperidinecarboxylate, oxalate.

A mixture of 90 parts of ethyl 4- (2-pyridinylamino) -1-piperidine carboxylate, 90 parts of potassium hydroxide and 720 parts of 2-propanol is stirred and heated under reflux for 2 days. The reaction mixture is evaporated. 1000 parts of water are added to the residue and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane to form 13 parts of N- (4-piperidinyl) -2-pyridinamine.

Example 10.

A mixture of 7 parts of ethyl 4- (2-pyrimidinylamino) -1-piperidinecarboxylate and 120 parts of hydrobromic acid solution is stirred 48% and kept under reflux for 2 hours. The reaction mixture is evaporated and the residue is taken up in water. The whole is made alkaline with a dilute sodium hydroxide solution while cooling in an ice bath. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The solid residue is stirred in 2,2'-oxybispropane. The product is filtered off and converted to the hydrochloride salt in 2-propanol. The salt is filtered off and crystallized from ethanol to give 2 parts of N- (4-piperidinyl) -2-pyrimidinamine, dihydrochloride / hemihydrate, mp 268.5 ° C.

Example 11.

To a stirred solution of 58 parts of ethyl 1- [- (4-chlorophenyl) amino] -1-piperidinecarboxylate in 240 parts of benzene is added dropwise a solution of 46.2 parts of benzene acetyl chloride in 80 parts of benzene at a temperature between 40 and 70 ° C. Upon completion, it is all stirred and kept under reflux for 6 hours and 15 minutes. The reaction mixture is cooled and filtered. The filtrate is washed with water, sodium bicarbonate solution and water one after the other, then dried and evaporated in vacuo. The residue is crystallized from 1,1'-oxybisethane to give 47 parts of ethyl 4- [N- (4-chlorophenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate, m.p. 108 ° C.

Example 12.

Following the procedure of Example 11 and using equivalent amounts of a suitable ethyl 4-aryl amino-1-piperidinecarboxylate and a suitable aryl acetyl chloride, respectively, in place of the ethyl 4 - [(4-chlorophenyl) amino] used therein -piperidinecarboxylate and benzeneacetyl chloride are prepared as follows: - VHo CH - CH - O-CN X || n \ _ / XN-C-CH_-Ar I 2

Ar 21 150478

Ar Ar1 melting point

2,6- (CH 2) 2-thienyl 94.5 ° C

3 Z b 3

4-C1-C6H4 2-thienyl 98.5 C

4-Cl-C ^ .H. 4-C1-C-.H. 127.5 ° C

6 4 6 4

4-Cl-CCH. 4-CH - C ^ H. 112.5 ° C

6 4 3 6 4

2-C1-C.H. CcHc 123.0 C

6 4 6 5 λ

2- Cl, 6-CHO-CtH_ C-H- 114.5 C

3 6 3 6 5 0

4-F-CCII. CcHc 82.0 C

6 4 6 5

3.4- (Cl) 2 "CgH3 CgH5 115.0 C

3- Cl-CgH 4 CgHg 92.0 ° C

4- C1-C4 -H. 4-F-CCH. 109.0 ° C

6 4 6 4 ·

4-Cl-CCH. 3-CH - CJH. 121.5 ° C

6 4 3 6 4

4-Br-C, H. C-H- 114.5 C

6 4 6 5

4-C1-C.H. 3-0CHo-C_H. 121.2 ° C

6 4 3 6 4

4-Cl-CCH. 2-C1-CJH. 139.3 ° C

6 4 6 4

4-Cl-C, H. 3-Cl-CCH. 142.7 ° C

6 4 6 4 '

2-Cl, 6-CH3-CgH3 4-Cl-CgH4 95.6 C

4-Cl-CgH4 2.6- (CH3) 2-CgH3 120.4 ° C

3.4- (Cl) 4-Cl-CcH. 136.9 ° C

2 6 3 6 4

2.5- (Cl) 2-CgH3 4-Cl-CgH4 107.0 C

2.6- (Cl) 2-CgH3 4-Cl-CgH4 140.0 ° C

Example 13

To a stirred solution of 8 parts of ethyl 4 - [(2,6-dimethyl-phenyl) amino] -1-piperidinecarboxylate in 4 parts of pyridine and 80 parts of benzene is added dropwise 7.7 parts of benzene acetyl chloride in 40 parts of benzene. After complete addition, the whole is heated to reflux and stirred at the reflux temperature for 3 hours and 45 minutes. The reaction mixture is cooled and filtered. The benzene phase is washed out with water and then with sodium hydrogen carbonate solution and with water. After evaporation, an oily residue is obtained which solidifies by trituration in 1,1'-oxy-bisethane to give 5 parts of ethyl 4- [N- (2,6-dimethylphenyl) -N- (phenylacetyl) amino] -1- piperidine carboxylate, m.p. 106 ° C.

22 150478

Example 14;

To a stirred solution of 15 parts of ethyl 4 - [(4-chlorophenyl) amino] -1-piperidinecarboxylate, 5.4 parts of Ν, Ν-diethylethanamine and 160 parts of benzene is added dropwise 11.07 parts of 4-methoxy-benzeneacetyl acid. chloride at a temperature between 32 and 40 ° C. After complete addition, the whole is stirred and kept under reflux for 3 hours. The reaction mixture is cooled and filtered. The filtrate is washed with water, sodium bicarbonate solution and water one after the other, dried, filtered and evaporated in vacuo.

The oily residue is crystallized from a mixture of 56 parts of 1,1'-oxybisethane and 40 parts of hexane. The crude solid product is filtered off and recrystallized from a mixture of benzene and 1,1'-oxybisethane to give 3 parts of ethyl 4- 4- N- (4-chlorophenyl) -N - [(4-methoxyphenyl) acetyl] amino | -1-piperidinecarboxylate, mp 137 ° C.

Example 15

To a stirred and refluxed mixture of 48 parts of 1- (1-methylethyl) -4-piperidinone, 1 part of 4-methylbenzenesulfonic acid and 540 parts of methylbenzene, a solution of 30 parts of benzenamine in 90 parts of methylbenzene is added dropwise. Upon completion, it is all stirred and kept under reflux for 3 hours with water discharge. The reaction mixture is evaporated to give 72 parts of N- [1- (1-methylethyl) -4-piperidinylidene] -benzenamine as a residue.

To a stirred and heated (30-40 ° C) solution of 72 parts of N- [1- (1-methylethyl) -4-piperidinylidene] benzenamine in 480 parts of methanol is added portionwise 20 parts of sodium borohydride. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in water. The solution is extracted with 4-methyl-2-pentanone. The extract is washed with water and acidified with a dilute hydrochloric acid solution. The aqueous acid phase is made alkaline with a dilute sodium hydroxide solution until pH = 9 and the product is extracted with 4-methyl-2-pentanone. The extract is washed with water, dried, filtered and evaporated. The residue is distilled (bp 135-140 ° C at 0.2 mm pressure) and the distillate is crystallized from petroleum ether to give 21 parts of 1- (1-methylethyl) -N-phenyl-4-piperidinamine, mp 69.3 ° C.

Example 16.

A mixture of 19 parts of 1- (phenylmethyl) -4-piperidinone, 11.8 parts of 3-pyridinamine, 120 parts of methylbenzene and a small volume of 4-methylbenzenesulfonic acid is stirred and kept under reflux for 5 hours. (The reaction vessel is equipped with reflux condenser and water discharge). After separating the calculated amount of water, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2'-oxybispropane and again evaporated to give 27 parts of N- [1- (phenylmethyl) -4-piperidinylidene] -3-pyridinamine as a tan oil.

To a stirred solution of 27 parts of N- [1- (phenylmethyl) -4-piperidinylidene] -3-pyridinamine in 40 parts of ethanol is added portionwise 3.8 parts of sodium borohydride. After completion of the addition, the whole is heated to 50 ° C. The solvent is evaporated. The oily residue is dissolved in 150 parts hydrochloric acid 1N and filtered. The filtrate is made alkaline with ammonium hydroxide and extracted with methylbenzene. The organic layer is dried over magnesium sulfate, filtered and evaporated. The solid residue is washed with 2,2'-oxybispropane and dried to give 14 parts of N- [1- (phenylmethyl) -4-piperidinyl] -3-pyridinamine, mp 131-133 ° C, beige, amorphous powder.

A mixture of 20 parts of N- [1- (phenylmethyl) -4-piperidinyl] -3-pyridinamine, 160 parts of methanol, 30 parts of water and 12 parts of a concentrated hydrochloric acid solution is hydrogenated at normal pressure and at a temperature between 22 and 39 ° C in the presence of 7 parts palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. Dissolve the oily residue in water. The solution is made alkaline with ammonium hydroxide, saturated with solid potassium carbonate and then extracted with methylbenzene. The extract is dried over potassium carbonate and evaporated. The solid residue is recrystallized from a mixture of 40 parts of benzene and 32 parts of 1,1-oxybisethane to give 3 parts of N- (4-piperidinyl) -3-pyridinamine, m.p. 127 - 129 ° C.

A mixture of 52 parts of 2-bromopropane, 19 parts of N- (4-piperidinyl) -3-pyridinamine, 33.3 parts of sodium carbonate, 3 parts of potassium iodide and 720 parts of 4-methyl-2-pentanone is stirred and kept under reflux for 24 hours. hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The residue is purified by column chromatography over silica gel using methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybis-propane to give 1.5 parts of N- [1- (1-methylethyl) -4-piperidinyl] -3-pyridinamine, mp 100.7 ° C.

Example 17

Following the procedure of Example 16 (last section), and using equivalent amounts of a suitable bromide and a suitable 4- (arylamino) -4-X-piperidine, respectively, as starting materials and in carrying out the reaction in the solvent mentioned, the following compounds are obtained. free base form or after treatment with hydrochloric acid in hydrochloric salt form: 150478 25 ^ ooo • ri asc! 6. «M * J3 $ J2 SS § g .2 5 .2 5 6 _ja __- ϋ υ η °

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Example 18

To a stirred mixture of 15 parts of N- (4-chlorophenyl) -4-piperidinamine, 12 parts of N, N-diethylethanamine in 130 parts of benzene is added dropwise a solution of 10.3 parts of 3-bromo-1-propene in 70 parts of benzene. . After the addition is complete, the whole is first stirred for 20 hours and 30 minutes at room temperature and further for 40 minutes at reflux temperature. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in 1,1'-oxybisethane and treated with activated charcoal. This is filtered off and the 1,1'-oxybisethane is again evaporated to give 2.9 parts of N- (4-chlorophenyl) -1- (2-propenyl) -4-piperidinamine, m.p. 90 ° C.

Example 19

To a hot (about 40 ° C) and stirred mixture of 5 parts of N- (2,6-dimethylphenyl) -4-piperidinamine, 5 parts of sodium carbonate, a few crystals of potassium iodide in 120 parts of benzene, dropwise a solution of 5.1 parts 1-iodopropane in 80 parts of benzene. After the addition is complete, stirring is continued for 40 hours at reflux temperature. The reaction mixture is cooled and 50 parts of water are added. The organic layer is separated and evaporated in vacuo. The oily residue is distilled to give 10.2 parts of N- (2,6-dimethylphenyl) -1-propyl-4-piperidinamine, boiling point 135 ° C at 0.2 mm pressure.

Example 20

To 0.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol are added 2 parts of cydopentanone, 5.5 parts of N- (4-piperidinyl) -2-pyrimidinamine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in 4-methyl-2-pentanone and a small amount of trichloromethane.

The whole is washed twice with dilute sodium hydroxide solution, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried to give 2.3 parts of N- (1-cyclopentyl-4-piperidinyl) -2-pyrimidine-amine, m.p. 118 ° C.

Example 21 -

To 0.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol are added 4 parts of 2-propanone, 4.5 parts of N- (4-piperidinyl) -2-pyrimidinamine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts palladium-on-charcoal catalyst 10%. After taking up the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in trichloromethane. The solution is washed with a dilute sodium hydroxide solution and water successively, dried, filtered and evaporated to give 3 parts of N- [1- (1-methylethyl) -4-piperidinyl] -2-pyrimidinamine as residue.

Example 22

To a stirred and refluxed slurry of 2 parts of lithium aluminum hydride in 120 parts of 1,1'-oxybisethane is added dropwise a solution of 13 parts of ethyl 4- [N- (2,6-dimethyl-phenyl) amino] -1-piperidinecarboxylate in 40 parts of 1,11-oxybisethane. After the addition is complete, stirring and heating under reflux are continued for 20 hours. The reaction mixture is cooled to 5 ° C and 7 parts of water are added. The resulting precipitate is filtered off, washed on the filter with 1,1'-oxybisethane and the filtrate is evaporated. The oily residue is distilled to give 5.8 parts of N- (2,6-dimethylphenyl) -1-methyl-4-piperidinamine, boiling point 90 -93 ° C at 0.003 mm pressure. Upon standing, the distillate solidifies to form solid N- (2,6-dimethylphenyl) -1-methyl-4-piperidinamine, m.p. 45 ° C.

Example 23

A mixture of 50 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxamide and 600 parts of concentrated hydrochloric acid solution is kept refluxed for 16 hours. After cooling, the reaction mixture is concentrated under reduced pressure to a volume of 400 parts and a precipitate is formed. This is filtered off, washed with water and 2-propanone and dried to give 43 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid, dihydrochloride, mp 261-263 ° C (dec).

A mixture of 19 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylic acid, dihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol is stirred and kept under reflux for 16 hours. The solvent is decanted off. The residue is dissolved in water. The aqueous solution is made alkaline with ammonium hydroxide and extracted with a mixture of methylbenzene and 2,2'-oxybispropane. The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The oily residue is dissolved in 200 parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introduced into the solution. The precipitated hydrochloride is filtered off, washed with 2-propanol, filtered again and dried to give 11.5 parts of ethyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate, dihydrochloride, mp 212 - 214.4 ° C .

To a stirred and refluxed solution of 101.4 parts of ethyl 4- (phenylamino) -1- (phenylmethyl) -4-piperidinecarboxylate in 640 parts of dry benzene is added dropwise a solution of 172 parts of sodium dihydro-bis (2- methoxyethoxy) aluminate, 70% in benzene, in 160 parts of dry benzene. After the addition is complete, stirring is continued for 2 hours and 30 minutes at 80 ° C. The reaction mixture is cooled, poured into ice water, made alkaline with sodium hydroxide solution and the product extracted with benzene. The extract is washed twice with water, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 2-propanol and 1,1'-oxy-bisethane. The salt is filtered off, boiled in 2-propanol and after cooling the product is filtered off. It is again boiled in acetonitrile, and the salt is filtered off again after cooling. The free base is released in a conventional manner. After extraction with 1,1'-oxy-bisethane, the base is washed with water, dried and evaporated to give 56.6 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidine-methanol as oily residue.

To a solution of 32 parts of 4- (phenylamino) -1- (phenylmethyl) -4-piperidine methanol in 90 parts of benzene is added 0.2 parts of Ν, Ν, Ν-triethylbenzene methanaminium chloride and 150 parts of sodium hydroxide solution 60%. After vigorous stirring, 10.9 parts of dimethyl sulfate are added dropwise at a temperature below 30 ° C.

29 150478

After the addition is complete, stirring is continued at room temperature, first for 2 hours and 30 minutes and after the addition of another portion of 2.6 parts of dimethyl sulfate for an additional 1 hour and 30 minutes. The reaction mixture is cooled in ice water and 200 parts of water are added. The organic phase is separated and the aqueous phase is extracted with benzene. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and 3% methanol saturated with ammonia as eluent. The pure fractions are collected and the eluent is evaporated to give 24.8 parts of 4- (methoxymethyl) -N-phenyl-1- (phenylmethyl) -4-piperidinamine as residue.

A mixture of 10 parts of 4- (methoxymethyl) -N-phenyl-1- (phenylmethyl) -4-piperidinamine and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated.

The oily residue is dissolved in water, cooled and made alkaline with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated.

The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume), saturated with gaseous ammonia, as eluent. The pure fractions are combined and the eluent is evaporated to give 4.5 parts of 4- (methoxymethyl) -N-phenyl-4-piperidinamine as an oily residue.

A mixture of 10 parts of 2-bromopropane, 9 parts of 4- (methoxymethyl) -N-phenyl-4-piperidinamine, 4.9 parts of N, N-diethylethane-amine and 72 parts of Ν, Ν-dimethylacetamide is stirred and kept under reflux. for 10 hours and 25 minutes. After cooling, the resulting N, N-diethylethanamine, hydrobromide is filtered off and the filtrate is diluted with water. The product is extracted with methylbenzene. The extract is thoroughly washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated to give 5.7 parts (42.6%) of 4- (methoxymethyl) -1- (1-methylethyl) -N-phenyl-4-piperidinamine as oily residue.

3047478

Manufacture of end products.

Example 2 4

A mixture of 20 parts of ethyl 4- [N- (2-chlorophenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate and 300 parts of hydrobromic acid solution 48% is stirred and kept under reflux for 1 hour and 10 minutes. The hydrobromic acid solution 48% is removed in vacuo and to the residue are added water and sodium hydroxide solution successively. The free base is extracted with trichloromethane. The extract is dried and evaporated. The solid residue is washed with 1,1'-oxybisethane and dried to give 10.6 parts of N- (2-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, mp 135.5 ° C.

Example 25

Following the procedure of Example 24 and using an equivalent amount of an appropriate ethyl 4- [N-aryl-N- (arylacetyl) amino] -1-piperidinecarboxylate in place of the ethyl 4- [N- (2-Chlorophenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate gives the following compounds: Ο'ϊ, '- NC-CH₂-Ar I 2

Ar 31 150478

Ar Ar + melting point

2- Cl, 6-CH3-C6H3 CgH5 157 ° C

4 ° F-C6H4 C6H5 96.5 ° C

3.4- (Ci) 2 ”cgH3 C6H5 81 ° C

3- C1-C6H4 CgH5 110.5 ° C

4- C1-C6H4 4-P-CgH4 109 ° C

4-Cl-C, H. 3-CH, -C, H. 104.5 ° C

4-Br-CgH4 C6H53 121.5 ° C

4-C1-C6H4 2-C1-C6H4 72.9 ° C

4-Cl-CgH4 3-Cl-CgH4 64 ° C

2-Cl, 6-CH3-CgH3 4-Cl-CgH4 120.7 ° C

4-Cl-CgH4 2.6- (CH3) 2-CgH3 147.3 ° C

3.4- (Cl) 2-CgH3 4-Cl-CgH4 98.7 ° C

2.5- (Cl) 2-CgH3 4-Cl-CgH4 125.6 ° C

2.6- (Cl) 2-CgH3 4-Cl-CgH4 126.3 ° C

Example 26

A mixture of 5 parts of ethyl 4- [N- (2,6-dimethylphenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate in 60 parts of hydrogen bromic acid solution is heated 48% until the evolution of carbon dioxide ceases. Heating is continued for 15 minutes at a temperature between 80 and 120 ° C. The reaction mixture is evaporated. The solid residue is washed with methylbenzene and 2-propanone one after the other and dried to give 4.1 parts of N- (2,6-dimethylphenyl) -N- (4-piperidinyl) benzeneacetamide, hydrobromide, mp 251.5 ° C.

Example 2 7

A mixture of 10 parts of ethyl 4- [N- (4-chlorophenyl) -N- (phenylacetyl) amino] -1-piperidinecarboxylate and 125 parts of glacial acetic acid, previously saturated with gaseous hydrogen bromide, is heated under stirring for 9 hours. and 45 minutes at 62 ° C. The reaction mixture is cooled and the glacial acetic acid is evaporated in vacuo. The semi-solid residue is taken up in 150 parts of water, then made alkaline with a concentrated sodium hydroxide solution and the product is extracted with trichloromethane. The extract is dried over sodium sulfate and evaporated.

The oily residue is triturated in 56 parts of 1,1'-oxybisethane and the solid crude free base is filtered off. This is converted into hydro

A

The chloride salt in the usual manner in 1,1'-oxybisethane and 2-propanone to give 4 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzene-acetamide, hydrochloride, m.p. 206.5 ° C.

Example 2 8

Following the procedure of Example 27 and using an equivalent amount of an appropriate ethyl 4- [N-aryl-N- (arylacetyl) amino] -1-piperidinecarboxylate as starting material, the following compounds are prepared: N- (2.6 -dimethylphenyl) -N- (4-piperidinyl) -2-thiophenacetamide, mp 128 ° C; N- (4-chlorophenyl) -N- (4-piperidinyl) -2-thiophenacetamide, hydrochloride, m.p. 201.5 ° C * 4-chloro-N- (4-chlorophenyl) -N- (4-piperidinyl) -4 -benzene-acetamide, hydrochloride, m.p. 222 ° C and N- (4-chlorophenyl) -4-methyl-N (4-piperidinyl) benzeneacetamide;

Example 2 9

To a hot (40 ° C) solution of 12 parts of potassium hydroxide in 240 parts of 2-propanol is added at once 21 parts of ethyl 4- [N- (4-chlorophenyl) -N - [(4-methoxyphenyl) acetyl] amino] -1-piperidinecarboxy lat, and the whole is stirred and kept under reflux for 21 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in water and the aqueous solution acidified with dilute hydrochloric acid solution. The acid solution is washed out with 1,1'-oxybisethane, made alkaline with sodium hydroxide and the free base extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is dissolved in 1,1'-oxybisethane and after crystallization 10 parts of N- (4-chlorophenyl) -4-methoxy-N- (4-piperidinyl) bee are obtained. acetamide, m.p. 129.5 ° C.

Example 30

To a stirred and hot (40 ° C) solution of 12 parts of potassium hydroxide in 200 parts of 2-propanol is added at once 21 parts of ethyl 4- [N- (4-chlorophenyl) -N- [(3-methoxyphenyl) acetyl] amino β-1-piperidinecarboxylate, and it is all stirred and kept under reflux for 17 hours. The reaction mixture is cooled, filtered and evaporated. The semi-solid residue is acidified with a dilute hydrochloric acid solution, washed with 1,1'-oxybisethane and the aqueous acid phase made alkaline with sodium hydroxide solution. The free base is extracted with trichloromethane. The extract is dried and evaporated. The residue is crystallized from a mixture of 1,1'-oxybisethane and hexane to give 7.8 parts of N- (4-chlorophenyl) -3-methoxy-N- (4-piperidinyl) benzeneacetamide, mp 85.7 ° C.

Example 31

To a stirred slurry of 5 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of butanol, 4 parts of 2-bromopropane are added dropwise at room temperature. After the addition is complete, it is all stirred and kept under reflux for 20 hours. Then another portion of 4 parts of 2-bromopropane is added and stirring and heating under reflux for a further 19 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. From the oily free base, the hydrochloride salt is prepared in the usual manner in 1,11-oxybisethane and 2-propanoh.

The precipitated solid salt is filtered off and crystallized from a mixture of 2-propanone and 2-propanol to form 2 parts of N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, hydrochloride, mp 263 ° C.

Example 32

Following the procedure of Example 31 and using equivalent amounts of a suitable bromide and a suitable N-aryl-N- (4-piperidinyl) arylacetamide, respectively, as starting materials, the following compounds are prepared in hydrochloride salt form: 34 150473. - j. υ υ υ υυυυυ υ j

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Example 33

To a stirred and hot (40 ° C) mixture of 4.75 parts of (N- (4-fluorophenyl) -N- (4-piperidyl) benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide and 200 parts of n-butanol are added. , 1 part 2-bromopropane, and the whole is stirred and kept under reflux for 24 hours, then another portion of 4.1 parts of 2-bromopropane is added and stirring is continued at reflux temperature for an additional 30 hours. , the filtrate is evaporated. The oily residue solidifies by trituration of 11,11-oxybisethane. The solid product is filtered off and crystallized from 1,1,1-oxybisethane to give 1.5 parts of N- (4-fluorophenyl) - N- (2-propyl-4-piperidyl) benzeneacetamide, mp 108.5 ° C.

Example 34

Following the procedure of Example 33 and using equivalent amounts of a suitable bromide and a suitable N-aryl-N- (4-piperidinyl) arylacetamide, respectively, as starting materials, the following compounds are obtained:

Ar L Ar Ar1 melting point

(CH3) 2-CH-4-Cl-C6H4 4-Cl-CgH4 106.5 ° C

> 37 150478 L Ar Ar1 snip.

(CH3) 2-CH-4-Br-C6H4 97 ° C

(CH3) 2-CH-4-C1-C6H4 2-C1-C6H4 143.2eC

(CH3) 2-CH-4-C1-C6H4 3-OCH3-C6H4 96.4eC

(CH3) 2-CH-4-C1-C6H4 3-C1-C6H4 6l, 6 ° C

(CH3) 2-CH-2-Cl, e-CH3-C6H3 4-Cl-C6H4 94.2eC

(CH3) 2-CH-4-Cl-C6H4 2.6- (CH3) 2-C6H3 126.6 ° C

(CH3) 2-CH-2,5- (Cl) 2-C6H3 4-Cl-C6H4 102.5 ° C

(CH3) 2-CH- 2.6- (Cl) 2-C6H3 4-Cl-C6H4 129, leC

(CH3) 2-CH-2-Cl-C6H4 C6Hg 87.5 ° C

Example 35 h

To a stirred and refluxed mixture of 5 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium bicarbonate and 200 parts of benzene are added portionwise 6/7 parts (bromomethyl) cyclopropane, and stirring and heating. refluxing is continued for 23 hours. The reaction mixture is cooled and filtered. The filtrate is evaporated. The semi-solid residue is dissolved in a mixture of benzene and 1,1'-oxybisethane. The precipitated impurities are filtered off and the filtrate is evaporated again. From the oily free base, the hydrochloride salt is prepared in the usual manner to form "after crystallization of the crude salt from a mixture of trichloromethane and 1,1'-oxybisethane" of 1.5 parts of N- (4-chlorophenyl) -N- [1- (cyclopropylmethyl) -4-piperidinyl] benzeneacetamide, hydrochloride, mp 224 ° C.

Example 36

To a stirred solution of 5 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, 3.8 parts of Ν, Ν-diethylethanamine in 200 parts of benzene is added portionwise 5 parts of 3-bromo-1-propene. After the addition is complete, the whole is heated for 21 hours at a temperature between 50 - 60 ° C. The reaction mixture is cooled and filtered. The filtrate is washed with water, sodium bicarbonate solution and water one after the other, dried over potassium carbonate and evaporated. The oily residue is converted to the hydrochloride salt in 1,1'-oxybisethane and 2-propanone to give 4 parts of N- (4-chlorophenyl) -N- [1- (2-propenyl) -4-piperidinyl] benzeneacetamide, hydro chloride, mp 225.5 ° C.

Example 37> Following the procedure of Example 36 and using an equivalent amount of a suitable N-aryl-N- (4-piperidinyl) -arylacetamide in place of the N- (4-chlorophenyl) -N- (4- piperidinyl) benzeneacetamide, the following compounds are prepared: N- (2,6-dimethylphenyl) -N- [1- (2-propenyl) -4-piperidinyl] -2-thiophenacetamide, hydrochloride, mp 203.5 ° C and N- ( 2,6-dimethylphenyl) -N- [1- (2-propenyl) -4-piperidinyl] benzeneacetamide, hydrochloride, mp 214 ° C.

Example 38

To a hot slurry of 5 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of n-butanol, 4 parts of 2-chloro-2-methylpropane are added temperature of 30 - 40 ° C. It is all stirred and kept under reflux for 140 hours, adding 35 parts of 2-chloro-2-methylpropane in portions as follows: After a reflux time of 15 hours, 4 parts of 2-chloro-2-methylpropane are added, after 8 hours, 10 parts, after 16 hours 11 parts and finally after 47 hours 10 parts. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in a mixture of methylbenzene, dimethoxyethane and 1,1'-oxybisethane. The solution is filtered off from some impurities and the filtrate is evaporated again. From the oily residue, the hydrochloride salt in 1,11-oxybisethane is prepared in the usual manner to form, after recrystallization of the crude solid salt from 2-propanone, 0.9 parts of N- (4-chlorophenyl) -N- [1- (1,1-dimethylethyl) -4-piperidinyl] benzeneacetamide, hydrochloride, m.p. 221 ° C.

Example 39

A mixture of 4 parts of iodoethane, 5 parts of N- (2,6-dimethyl-phenyl) -N- (4-piperidinyl) benzeneacetamide, 5 parts of sodium carbonate, a few crystals of potassium iodide in 200 parts of benzene is stirred and kept under reflux for 23 hours. hours. The reaction mixture is filtered hot and the filtrate is evaporated in vacuo. The solid residue is crystallized from 1,1'-oxybisethane to give 2 parts of N- (2,6-dimethylphenyl) -N- (1-ethyl-4-piperidinyl) benzene acetamide, m.p. 86.4 ° C.

Example 40

Following the procedure of Example 39 and using an equivalent amount of an appropriate N-aryl-N- (4-piperidinyl) -arylacetamide in place of the N- (2,6-dimethylphenyl) -N- (4-piperidinyl) used therein ) benzeneacetamide, the following compounds are prepared: 2-chloro-N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) -benzeneacetamide, hydrochloride, mp 234.6 ° C N- (4-chlorophenyl) -N - (1-ethyl-4-piperidinyl) -3-methyl-benzeneacetamide, m.p. 78.5 ° C; N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) -4-methyl-benzeneacetamide, m.p. 50 ° C and N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) -4-fluoro-benzeneacetamide, m.p. 62.3 ° C.

Example 4 1

To a stirred and refluxed mixture of 5 parts of 4-chloro-N- (4-chlorophenyl) -N- (4-piperidinyl) benzene acetamide, 5 parts of sodium carbonate, 0.4 parts of potassium iodide and 200 parts of butanol is added 4, 7 parts of 1-iodopropane and it is all stirred and refluxed for 22 hours. Then a second portion of 4, b parts of 1-iodopropane is added and stirring and heating at reflux is continued for 27 hours and 30 minutes. The reaction mixture is cooled, filtered and the filtrate is evaporated. The semi-solid residue is dissolved in methylbenzene. The solution is filtered from some impurities and the filtrate is evaporated again. The residue is crystallized from 1,1'-oxybisethane at -10 ° C to give 0.9 parts of 4-chloro-N- (4-chlorophenyl) -N- (1-propyl-4-piperidinyl) benzeneacetamide, m.p. 118.6 ° C.

Example 42

To a stirred solution of 4 parts of N- (4-chlorophenyl) -N- (4-piperidinyl) benzeneacetamide and 3 parts of Ν, Ν-diethylethanamine in 200 parts of benzene is added portionwise 4 parts of 1-iodopropane and the whole is stirred and heated under reflux for 47 hours. Then a second portion of 4 parts of 1-iodopropane is added and stirring and heating under reflux for a further 20 hours and 20 minutes. The reaction mixture is cooled and filtered. The filtrate is washed with water, dried and evaporated in vacuo. From the oily free base, the hydrochloride salt in 1,1'-oxybisethane is prepared in the usual manner. The precipitated solid salt is filtered off and dried to give 3.5 parts of N- (4-chlorophenyl) -N- (1-propyl-4-piperidinyl) benzeneacetamide, hydrochloride, mp 233.5 ° C.

Example 43

Following the procedure of Example 42 and using an equivalent amount of a suitable iodine alkane and a suitable N-aryl-N- (4-piperidinyl) arylacetamide, respectively, in place of the 1-iodopropane and N- (4-chlorophenyl) used therein, respectively. N- (4-piperidinyl) -benzeneacetamide is obtained from the following compounds: N- (2,6-dimethylphenyl) -N- (1-ethyl-4-piperidinyl) -2-thiophene-acetamide, hydrochloride, m.p. 258 ° C (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) -2-thiophenacetamide, hydrochloride, mp 220.5 ° C; N- (4-chlorophenyl) -N- (1-ethyl-4-piperidinyl) benzeneacetamide, hydrochloricyl, mp 215 ° C 4-chloro-N- (4-chlorophenyl) -N- (1-ethyl-4) piperidinyl) benzene-acetamide hydrochloride; mp 224 ° C and N- (4-chlorophenyl) -N- (1-propyl-4-piperidinyl) -2-thiophene acetamide, mp 241 ° C.

Example 44

A mixture of 4.5 parts of N- (1-cyclopentyl-4-piperidinyl) -2-pyrimidinamine, 3.4 parts of 3-methylbenzeneacetyl chloride, 2 parts of sodium carbonate and 180 parts of dimethylbenzene is stirred and heated under reflux for 17 hours. An additional 9 parts of 3-methylbenzeneacetyl chloride are added dropwise. After the addition is complete, stirring is continued for 67 hours at reflux temperature. The reaction mixture is cooled, water is added and the layers are separated.

The organic phase is extracted with a dilute hydrochloric acid solution. The combined aqueous phases are washed with benzene and made alkaline with a dilute sodium hydroxide solution while cooling in an ice bath. The product is extracted twice with trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is converted to the oxalate salt in 2-propanol. The salt is filtered off and crystallized twice, first from ethanol and then from methanol to give 1 part N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (2-pyrimidinyl) benzeneacetamide, ethanedioate, m.p. 204 -1 ° C.

Example 45

Following the procedure of Example 44 and using equivalent amounts of a suitable N-aryl-4-piperidinamine and a suitable arylacetyl chloride, respectively, as starting materials, the following compounds are obtained in base form or after treatment with the appropriate acid in acid addition salt form: 42 150478 ~ cx1 λ— / NC-CH, -Arx

Ar L Ar Ar1 base or salt form m.p.

V 3-pyridinyl CgH, - (E) -2-butenedioate 219.6 ° C

3-pyridinyl 3-CH 2 -Cgir (E) -2-butenedioate 250.3 ° C y. 2-pyridinyl 3-Cl-CgH 4 (COOH) 2 205.9 ° C

Γ-2-pyridinyl 3-CH 3 -C 3 H 4 base 107.8 ° C

2 - 2-Pyridinyl 4-C1-C6 H3 base 119.2 ° C

Q-2-pyridinyl 2-thienyl base 129.4 ° C

2-pyridinyl CgHg base 108.8 ° C

2-pyrimidinyl C 9 H 5 (COOH) 223.5 ° C

(CH3) 2-CH-3-pyridinyl CgH5 base 129.4 ° C

(CH3) 2-CH-3-pyridinyl 3-C1-C6 H3 base 117.7 ° C

(CH3) 2-CH-3-pyridinyl 4-C1-C6 H6 base 146.6 ° C

(CH3) 2-CH-3-pyridinyl 2-thienyl base 126, 7 ° C

(CH3) 2-CH-3-pyridinyl 3-CH3-C6H4 base 10 ° β (:

(CH 3) 2-CH-2-pyridinyl 3-C 1 -C 8 base 102.6 ° C

(CH3) 2-CH-2-pyridinyl CgH5 base 72.1 ° C

(CH3) 2-CH-2-pyridinyl 4-C1-C6H4 base 83.3 ° C

(CH3) 2 ~ CH-2-pyridinyl 3-CH3-C6H4 (COOH) 2 190.6 ° C

(CH 3) 2-CH-2-pyridinyl 2-thienyl (COOH) 2 196.1 ° C

(CH 3) 2-CH-2-pyrimidinyl 4-C 1 -C 3 H 4 (COOH) 2 195.7 ° C

Example 46

43

To a stirred mixture of 4.4 parts of 1- (1-methylethyl) -N-phenyl-4-piperidinamine, 5.3 parts of sodium carbonate and 180 parts of benzene is added dropwise 5 parts of benzeneacetyl chloride. After the addition is complete, stirring is continued overnight under reflux. The reaction mixture is cooled, washed with water, sodium hydrogen carbonate solution and again with water successively, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. The resulting salt is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane to give 2.5 parts of N- [1- (1-methylethyl) -4-piperidinyl] -N-phenylbenzeneacetamide, hydrochloride, m.p. 184.4 ° C.

Example 47.

Following the procedure of Example 46 and using equivalent amounts of a suitable N-aryl-4-piperidine amine and a suitable arylacetyl chloride as starting materials, respectively, the following compounds are obtained in base form or after treatment with the appropriate acid in acid addition salt form: in 2

Ar T of Av1 base or L Ar Ar salt form m.p.

(CH3) 2-CH-CgH5 3-CH3-CgH4 HCl 173.6 ° C

(CH3) 2-CH-CgH5 3-Cl-CgH4 HCl 204.8 ° C

(CH3) 2-CH-CgHg 2-thienyl (E) -2-butenedioab168 # λ ° c

CH3 2.6- (CH3) 2-CgH3 CgHg base 95.5 ° C

CH-4-Cl-CcH. CcH base 115 ° C

C2H5 4-Cl-CgH4 3-OCH3-CgH4 base 90.7 ° C

nC3H7 2.6- (CH3) 2-CgH3 2-thienyl (COH) 2 153 ° C

44 150478 ————— ι * x base or {L _Ar__Ax sgltform__smp 'j

nC3H? 2.6- (CH3) 2-c6H3 c6h5 (COOH) 216 ° C J

CH2 = CH-CH2 4-Cl-C6H4 2-thienyl HCl ZZtf5 ° C

o '2-thienyl base j 119eC I

| ^ 3-Pyridinyl 4-Cl-C ^ H ^ base 149.9 * 0

Q. 3-Pyridinyl 3-Cl-C ^H ^₂HCl, 1 / 2H₂O 236V6 * C

3-pyridinyl 2-thienyl base 159.8 ° G

Example 48 «

A slurry of 1.25 parts of sodium amide in 56 parts of benzene is stirred under a nitrogen atmosphere and heated to a temperature of 40 ° C. Then a solution of 6 parts of N- (4-chlorophenyl) -1- (1-methylethyl) -4-piperidinamine in 56 parts of benzene is added dropwise. After the addition is complete, the whole is stirred and kept under reflux for 16 hours and 45 minutes. The mixture is cooled to 25 ° C and a mixture of 7.8 parts of 3,4-dichlorobenzene acetyl chloride in 88 parts of benzene is added. After stirring and heating at reflux for a further 2 hours, the reaction mixture is cooled and 80 parts of water are added. Make it all acidic with a dilute hydrochloric acid solution. The aqueous acid phase is made alkaline with sodium hydroxide solution and the free base is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is dissolved in a mixture of 80 parts of 1,1'-oxybisethane and 120 parts of hexane. The solution is cooled overnight at -10 ° C, filtered from some impurities and the filtrate is evaporated again. The residue is dissolved in 120 parts of 1,1'-oxybisethane, treated with activated charcoal, filtered and evaporated. This residue is crystallized from hexane at -10 ° C to give 2.2 parts of 3,4-dichloro-N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, m.p. 101.7 ° C.

Example 49

Following the procedure of Example 48 and using equivalent amounts of a suitable N-aryl-4-piperidine amine and a suitable arylacetyl chloride, respectively, as starting materials, the following compounds are obtained in base form or after treatment with the appropriate acid in acid addition salt form: N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, m.p. 118.1 ° C; 4-Chloro-N- (2,6-dimethylphenyl) -N- [1- (1-methylethyl) -4-piperidinyl] -benzeneacetamide, hydrochloride, m.p. 268.2 ° C and N- (4-chlorophenyl) -4 - (1-methylethyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, m.p. 104.9 ° C.

Example 50

5 parts of 4-chloro-N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide are dissolved in a mixture of 60 parts of 1,1'-oxybisethane and 16 parts of 2-propanone. The resulting solution is acidified with an excess of 2-propanol, which is previously saturated with gaseous hydrogen chloride. The precipitated salt is filtered off and dried to give 7.5 parts of 4-chloro-N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, hydrochloride, mp 266.6 ° C.

Example 51

From 6 parts of N- [1- (1-methylethyl) -4-piperidinyl] -N-phenyl-2-thiophenacetamide, (E) -2-butenedioate, the free base is released in a conventional manner with a dilute sodium hydroxide solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted to the ethanedioate in 2-propanol. The salt is filtered off and dried to give 3.2 parts of N- [1- (1-methylethyl) -4-piperidinyl] -N-phenyl-2-thio-phenacetamide, ethanedioate, mp 167.4 ° C.

Example 52 46

From an aqueous solution of 2.8 parts of N- (2,6-dimethylphenyl) -N- (1-propyl-4-piperidinyl) -2-thiophenacetamide, dihydrochloride is released from the free base by alkalization with sodium hydrogen carbonate solution. The free base is extracted with 1,1'-oxybis-ethane. The extract is dried and evaporated. The oily residue is dissolved in 56 parts of hexane and after cooling to -10 ° C the solid free base is precipitated. It is filtered off and dried to give 1.6 parts of N- (2,6-dimethylphenyl) -N- (1-propyl-4-piperidinyl) -2-thiophenacetamide, mp 62.5 ° C.

Example 53

From 3.9 parts of N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (3-pyridiny 1) benzeneacetamide, (E) -2-butenedioate, the free base is conventionally released with a dilute sodium hydroxide solution.

After extraction with 2,2'-oxybispropane, the extract is washed with water, dried, filtered and evaporated. The residue is converted to the ethanedioate in ethanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane to give 3 parts of N- (1-cyclopentyl-4-piperidinyl) -3-methyl-N- (3-pyridinyl) benzeneacetamide, ethanedioate, m.p. 192.6 ° C.

Example 54

To a stirred mixture of 5.5 parts of 4- (methoxymethyl) -1- (1-methylethyl) -N-phenyl-4-piperidinamine in 56 parts of benzene is added dropwise a solution of 13.8 parts of benzeneacetyl chloride in 45 parts of benzene at 26 - 32 ° C. After the addition is complete, stirring is first continued for 1 hour at 26 - 32 ° C and then for an additional 3.60 hours at 38 - 55 ° C. After cooling, the precipitated product is filtered off and converted to the hydrochloride salt in a mixture of 2-propanol and 2-propanone (5: 1 by volume). The salt is filtered off and dissolved in absolute ethanol. After standing for 72 hours at room temperature, the precipitated product is filtered off, washed with a small amount of 2-propanone and dried to give 1.05 parts of N- [4- (methoxymethyl) -1- (1-methylethyl) -4-piperidinyl] -N-phenylbenzeneacetamide, hydrochloride, mp 249.1 ° C.

Example 55 47

To a stirred mixture of 7.5 parts of N- (4-chlorophenyl) -1- (1-methylethyl) -4-piperidinamine and 80 parts of 4-methyl-2-pentanone is added dropwise to 9 parts [4- (2-chloro-phenyl)]. 2-oxoethyl) phenyl] ethyl carbonate. After the addition is complete, the whole is heated to reflux and stirring is continued for 1 hour at reflux temperature. After cooling, the precipitated product is filtered off and stirred for 30 minutes in a mixture of alkaline water and trichloromethane. The teams are separated. The organic phase is dried, filtered and evaporated. The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 5.5 parts of 4- [2- [(4-chlorophenyl) - [1- (1-methylethyl) -4-piperidinyl] amino] -2-oxoethyl] phenyl] ethyl carbonate as oily residue.

A mixture of 5.5 parts of 4- [2- [(4-chlorophenyl) [1- (1-methylethyl) -4-piperidinyl] amino] -2-oxoethyl] phenyl] ethyl carbonate and 50 parts of sodium hydroxide solution 10% is stirred for 90 minutes at 45 ° C. The reaction mixture is cooled to room temperature and acidified with acetic acid to pH 5.5 - 6. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) as eluent. The pure fractions are collected and the eluent is evaporated.

The oily residue is converted to the hydrochloride salt in 4-methyl-2-pentanone. The salt is filtered off and dried in vacuo for 12 hours at 60 ° C to give 1.9 parts of N- (4-chlorophenyl) -4-hydroxy-N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, mono hydrochloride, mp 242.9 ° C.

48 150478

Example 56

A mixture of 8 parts of 2-propanone and 9.9 parts of N- (4-chlorophenyl) N- (4-piperidinyl) benzeneacetamide, hydrochloride in 160 parts of methanol is hydrogenated at normal pressure and room temperature with 2 parts of palladium on top. charcoal catalyst 10%.

After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is collected in a mixture of 2-propanone and 1,1'-oxybispropane and precipitated as the hydrochloride salt. The product is filtered off and dried to yield 6.3 parts of N- (4-chlorophenyl) -N- [1- (1-methylethyl) -4-piperidinyl] benzeneacetamide, hydrochloride, m.p. 262.3 ° C.

Claims (2)

4 9 150478 An analogous process for the preparation of N-aryl-N- (4-piperidinyl) arylacetamide derivatives of the general formula - NC-CH.-ArX ir or pharmaceutically acceptable acid addition salts thereof, wherein: L represents hydrogen, (C q) alkyl, (C 3 -C 8) cycloalkyl, (C 3 -C 8) cycloalkyl (C 1 -C 8) alkyl or (C 1 -C 6) alkenyl, Ar represents phenyl, mono- or di-substituted phenyl, pyridyl or 2- pyrimidyl wherein each of the substituents of the mono- or di-substituted phenyl is independently halogen or (C 1 -C 6) alkyl, Ar "- represents phenyl, mono- or di-substituted phenyl or 2-thienyl, wherein any of the substituents of the mono- or di-substituted phenyl independently of one another denotes halo, (C 1 -C 6) alkyl, hydroxy or (c 1 -C 6) cycloxy / X represents hydrogen or (C 1 -C 6) alkyloxymethyl, and below it provided that L is different from (Cg-Cg) cycloalkyl when Ar and Ar "*" are both phenyl or substituted phenyl and X is hydrogen, FEATURED by a) hydrolyzing a compound of the general formula C-Cglalkyl-O-C-N V O (IV) '-' N-C-CHO-Arl I 2 Ar wherein Ar, Ar 1 and X have the meaning given above, in an acidic or basic aqueous medium to prepare a compound of formula 150478 Of *. '-' NC-CH_-ArX I 2 Ar wherein Ar, Ar1 and X have the meanings set forth above, which compound (Ia) is then, if desired, reacted with a compound of formula I / hf, having the same meaning as L but is different from hydrogen and Y represents a reactive group, preferably a halogen atom, the reaction being carried out in a reaction inert organic solvent, preferably in the presence of a base, to prepare a compound having the formula 1ΛΛ / ο V-YVc-CH. -Ar1 II- °> I 2 Ar. 1 in which L, Ar, Ar and X have the meanings set forth above, or b) for the preparation of a compound of the general formula aTY? Wherein: Ar, Ar and X have the meanings given above and L is (C 1 -C 10) alkyl, (-C 8) cycloalkyl or (C 1 -C 6) ) cycloalkyl (C 1 -C 18 gelkyl), and the carbon attached to the piperidine nitrogen carries at least 1 hydrogen atom, catalytically hydrogenates a mixture of an aldehyde or ketone corresponding to the alcohol and a compound of formula (Ia), in the presence of a suitable catalyst, or